INSTITUTE FOR CLINICAL AND ECONOMIC REVIEW Special Assessment of Outpatient Treatments for COVID-19 Final Evidence Report and Meeting Summary May 10, 2022 Prepared for Ewa MIDWEST m= CEPAC MSS) COMPARATIVE EFFECTIVENESS PUBLIC ADVISORY COUNCIL Olnstitute for Clinical and Economic Review, 2022 AUTHORS: Kai Yeung, PharmD, PhD Assistant Investigator Kaiser Permanente Washington Health Research Institute Melanie D. Whittington, PhD, MS Director of Health Economics Institute for Clinical and Economic Review Molly Beinfeld, MPH Senior Research Lead, Evidence Synthesis Institute for Clinical and Economic Review Rasheed Mohammed, PharmD, MPH Health Technology Assessment Fellow Institute for Clinical and Economic Review Abigail Wright, PhD, MSc Senior Research Lead, Evidence Synthesis Institute for Clinical and Economic Review Emily Nhan Research Assistant Institute for Clinical and Economic Review Noemi Fluetsch, MSc, MPH Research Assistant, Health Economics and Outcomes Research Institute for Clinical and Economic Review Marina Richardson, MSc Health Economist Institute for Clinical and Economic Review Steven D. Pearson, MD, MSc President Institute for Clinical and Economic Review DATE OF PUBLICATION: May 10, 2022 How to cite this document: Yeung K, Whittington MD, Beinfeld M, Mohammed R, Wright A, Nhan E, Fluetsch N, Richardson M, Pearson SD. Special Assessment of Outpatient Treatments for COVID-19; Final Evidence Report and Meeting Summary. Institute for Clinical and Economic Review, May 10, 2022. https://icer.org/assessment/covid- 19-2022/. Kai Yeung served as the lead author for the report. Molly Beinfeld led the systematic review and authorship of the comparative clinical effectiveness section of this report in collaboration with Rasheed Mohammed, Abigail Wright, and Emily Nhan. Melanie Whittington developed the cost-effectiveness model and authored the corresponding sections of the report with assistance from Noemi Fluetsch and Marina Richardson. Steven D. Pearson provided methodologic guidance on the clinical and economic evaluations. We would also like to thank Laura Cianciolo and Monica Frederick for their contributions to this report. ©lnstitute for Clinical and Economic Review, 2022 Page i Special Assessment of Outpatient Treatments for COVID-19 About ICER The Institute for Clinical and Economic Review (ICER) is an independent non-profit research organization that evaluates medical evidence and convenes public deliberative bodies to help stakeholders interpret and apply evidence to improve patient outcomes and control costs. Through all its work, ICER seeks to help create a future in which collaborative efforts to move evidence into action provide the foundation for a more effective, efficient, and just health care system. More information about ICER is available at https://icer.org/. The funding for this report comes from government grants and non-profit foundations, with the largest single funder being the Arnold Ventures. No funding for this work comes from health insurers, pharmacy benefit managers, or life science companies. ICER receives approximately 29% of its overall revenue from these health industry organizations to run a separate Policy Summit program, with funding approximately equally split between insurers/PBMs and life science companies. Life science companies relevant to this review who participate in this program include GlaxoSmithKline, Merck, Pfizer, and Regeneron. For a complete list of funders and for more information on ICER's support, please visit https://icer.org/who-we-are/independent-funding/. For drug topics, in addition to receiving recommendations from the public, ICER scans publicly available information and also benefits from a collaboration with IPD Analytics, an independent organization that performs analyses of the emerging drug pipeline for a diverse group of industry stakeholders, including payers, pharmaceutical manufacturers, providers, and wholesalers. IPD provides a tailored report on the drug pipeline on a courtesy basis to ICER but does not prioritize topics for specific ICER assessments. About Midwest CEPAC The Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC) - a core program of ICER - provides a public venue in which the evidence on the effectiveness and value of health care services can be discussed with the input of all stakeholders. Midwest CEPAC seeks to help patients, clinicians, insurers, and policymakers interpret and use evidence to improve the quality and value of health care. The Midwest CEPAC is an independent committee of medical evidence experts from across the Midwest, with a mix of practicing clinicians, methodologists, and leaders in patient engagement and advocacy. All Council members meet strict conflict of interest guidelines and are convened to discuss the evidence summarized in ICER reports and vote on the comparative clinical effectiveness and value of medical interventions. More information about Midwest CEPAC is available at https://icer.org/who-we-are/people/independent-appraisal- committees/midwest-comparative-effectiveness-public-advisory-council-m-cepac/. The findings contained within this report are current as of the date of publication. Readers should be aware that new evidence may emerge following the publication of this report that could potentially influence the results. ICER may revisit its analyses in a formal update to this report in the future. The economic models used in ICER reports are intended to compare the clinical outcomes, expected costs, and cost effectiveness of different care pathways for broad groups of patients. Model results therefore represent average findings across patients and should not be presumed to represent the clinical or cost outcomes for any specific patient. In addition, data inputs to ICER models often come from clinical trials; patients in these trials may differ in real-world practice settings. ©lnstitute for Clinical and Economic Review, 2022 Page ii Special Assessment of Outpatient Treatments for COVID-19 In the development of this report, ICER's researchers consulted with several clinical experts, patients, manufacturers, and other stakeholders. The following experts provided input that helped quide the ICER team as we shaped our scope and report. It is possible that expert reviewers may not have had the opportunity to review all portions of this report. None of these individuals is responsible for the final contents of this report, nor should it be assumed that they support any part of it. The report should be viewed as attributable solely to the ICER team and its affiliated researchers. For a complete list of stakeholders from whom we requested input, please visit: https://icer.org/wp-content/uploads/2021/08/ICER_COVID-19-Stakeholder-List_082621.pdf. Expert Reviewers Andrew D. Badley, MD Professor of Infectious Diseases Professor and Chair, Department of Molecular Medicine Chair, SARS-CoV-2 COVID-19 Task Force Mayo Clinic Dr. Badley is supported by grants from the National Institute of Allergy and Infectious Diseases, Amfar, and Mayo Clinic. Dr. Badley is a paid consultant for Abbvie, Gilead, Freedom Tunnel, Pinetree Therapeutics, Primmune, lmmunome, MarPam, Rion, Symbiosis, and Flambeau Diagnostics, is a paid member of the Data and Safety Monitoring Board for Corvus Pharmaceuticals, Equilium, CSL Behring, and Excision Biotherapeutics, has received fees for speaking from Reach MD, Peer Voice, and Medscape, owns equity for scientific advisory work in Zentalis Rion, and Nference, and is Founder and President of Splissen therapeutics. Rajesh Gandhi, MD Professor of Medicine, Harvard Medical School Director, HIV Clinical Services and Education Massachusetts General Hospital Co-Director and Principal Investigator, Harvard University Center for AIDS Research Dr. Gandhi previously served on a scientific advisory board for a Merck HIV medication. Shivanjali Shankaran, MD Assistant Professor Director, General Inpatient Infectious Diseases Associate Director, Adult Antimicrobial Stewardship Program Division of Infectious Diseases Rush University Medical Center Dr. Shankaran served as the principal investigator for "A Phase II Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir in Participants With Moderate COVID-19 Compared to Standard of Care Treatment" and "Study to Evaluate the Safety and Antiviral Activity of Remdesivir in Participants With Severe Coronavirus Disease (COVID-19)." ©lnstitute for Clinical and Economic Review, 2022 Page iii Special Assessment of Outpatient Treatments for COVID-19 Table of Contents Executive SUIMMALY............::::cccceeeeeeeeneceneeeceeeeeeeneensceneaeaeeeeeenecesacoaseesenesesnessaceaeseseeeeasnenensneaesesenenetae ES1 BaCkQrounG ......cscsssseseecssecesccsesssseneesseetseesensnceesascesseeusesnpenssassecasenesseaeeaneceseasecenscagnaseeetsessesspecnenaces ES1 REPOrt AIM .......... cee escessesssscsssessesssnssesessseneneneeeseessseeeeeeeeeeeeeeeeeeeeeeeaeeeaeeeeeeeaeeeeeeeeeeaaeeaaeeaseeeeeneenagan ES1 Mechanisms of Action and FDA Regulatory StatuS..............:csscccccesssrseessssceseeessseeeeesssseseneesseeeeess ES2 Comparative Clinical Effectiveness..............:ccssscccsscecsssecensecceesseeresneessaeeeseaesseeeesaeeceaaeseneeneneeees ES2 Cost Effectiveness ..........cccccscsssseeseeeseeseceeseaeeeseeescenesasecaeeeaeessceseaesecaeasaaseeeeeaeesssesesasenseseeneaaaeane ES4 1. Background ...........cccccsccsecccsssesseeeesscseecessesececsseesensessnsseesesseesessesensseeaesusesenssucessseaesnesesesueeseseesseneeeessas 1 REPOrt AIM 00... seee teen teen nee e eae 2 2. Patient Caregiver Perspectives .........ccccccccceecseecsnccenecsnessecsnecenecenecsacsaacsnccssecsussasonsconsconsassaneneneaennenoees 4 3. Comparative Clinical Effectiveness ............:::cccccssssccccsssseccessssneceessnseecesssnteecessauceeecssnaeeecesseeeeeaseanaeees 6 3.1. Methods Overview ..........eesessessecesseeseeeseeeeseeesseseneesneessceesseessneseenecseeesseseseeecenesensseeeeseeeoeseeaes 6 Scope Of REVIOW .........:ccccssscseessssssceeesseceeenssseeseecessaesensssersenuecsuaesesesaeneeessecuseeeessaneeeesssceseseesseeeeeeseas 6 EVIG@NCe BaSe..........ecceccceecnesseeeeeceneceneceseseeesaeesaessecseensesaeeessesaceasoesesseecnsecaeeeeaeeeeeseesasesesseeseeeeteanee 6 3.2. RESUITS .......cscscscsesesesresssessscsuseessseessceevseesserceseesseuseseescsescoreveeesesusessusentsesersesuseseusesesensesoessseneses 10 Clinical Benefits and Harims..............ccccssseeseeeseeeseeeesnseseneesneesnsseneseeeecsneesaeesseeseensesceesaeeesseessneseaees 10 Subgroup Analyses and Heterogeneity. ..........cccccscccscessssssecnecscecsencessansensestecsnenessscscenserseessecsssazee 13 Uncertainty and Controversies.......ccccssscssecssssssecsvssscsscvsssescesssssnesecssssusesssessuseesesssenesssssrassusessses 13 3.3. SUMMaALy ANd COMMENL..........ccsssscrerrscccecessessssenestectecssesausueuensececeseesasenneessecetessesauscnnserecereees 18 Midwest CEPAC Vote .........sccssccssecsssceesseeesseesseecseasesseesseesseacseasecesecssecsuseserseeesseceseceseceesseeasenensaes 21 4. Long-Term Cost Effectiveness ..........:ceecseesseseeesseceseneeesseeeeeaeeeensaseneneeesnaceeeceesesanseesnecenseaeessaeeeenneeess 22 4.1. Methods Overview ..0........cccceccesecceeesesneceneenseeeeeeteceeeeeeuaaeesensaeaaeesneceaeesassaaenesesneaeentenseeeetenenaaes 22 4.2. Key Model Assumptions and INPuts .........ccccseesssessecnseceececessnscneeeeeennsecessnsceeneesectsecsesneensieecesees 25 4.3. RESUITS 00... cccceceeseesesesscesersenesecenecsnecsusneaesecenseeeseseasseassecasedanenecassdasseasscasesseessedsseseseaseessecseteeens 28 Base-Case ReSUItS.........cccccsseesecessecerecetsseeesseesseesseesseneeeeecseeeuessenseesecoeseanessecsssceseaeteeeesseessnensaes 28 Sensitivity Analyses. .............:ccescsceeeeseeneneeneeceeesecnceeeeseneneceensausaesneaaacensescaeseeensaceaeaseneaeneeenaneaeass 28 Threshold Analyses. ..............::cccccsecceeeesenceeenenseeeeeessaneeeeneaaeensessaeeaeessaeeaeeeessaeeasaneneaeeesenseeeensnaneaes 30 Scenario ANalySes............ssccccccessescecesseneseceeseseeeeseneesecessesensessneseesessrsensssansseeeesusesenssseeseesessneneess 30 Model Validation...........ccccssecssscssecenecesssenesseesseesseessenseeeecaeeesnessaneesaeeconseaaessaesseceeeaeseaesesseesseesaes 33 Uncertainty and ControverSies...........csssccccccsssssecesssessecesssneeenessaesessssceseesaeseeeeessscesenensseseneassneess 33 'Institute for Clinical and Economic Review,2022-i(iti'é Ct!]!|!~*~*~C~#OéR gO Special Assessment of Outpatient Treatments for COVID-19 4.4 Summary and COMMENA............s:ccccccsssscsecsssscceeessaeesecssssnsesuessanseeessaaeseessesaeseecesseeeeesssseseeeasseees 35 5. Contextual Considerations and Potential Other Benefits ............:seccesseesssssecserssseessetevseessereeseenes 36 Midwest CEPAC Votes ..........sssccessessceesseeeceeeceecsateesseesenecensesessesnsesueessneeseeseeeeesaeesaeeeneessenseenensaes 38 6. Health-Benefit Price Benchmarks ............:ssecssscseeeseessnesseesseeseeneecseesseessecerseeseeeesseesseesseeseseseeneeeeeees 39 Midwest CEPAC Votes ........sscssscsssssseceessessnssesecssersssesssesensscesssossessensscsncseseseesnscensessesssnseeesanensees 40 7. Potential BUdget IMpPact...........sssscsscccecsseesssssersrestecssesssscnensteesacessesnseneneeeecscessessueeneeeseetteeeessnseneneess 41 B. Policy RECOMMENAALIONS ...........seccscecccessessssnscereetcessenessneuareeesseseeusseagnaseeensessessseansestceatecessnseuseetes 42 Federal GOVeErniMe nt .........ceccseccseeceeecereseeesneesseesseeeesseeeneesonecseeeeaeseoeecsnecenessacssecseeaeeeneeseecesseessaes 42 Guideline Developers .............cs:ccccceesecceeeesseceeeesenaneeetensneceeeeaaaseesesaneeesasaaaesesensaesaeesensaneneennaneneess 44 Manufacturer.......cccsscccceccessesscessecesseesesneesseesseeseeassusccssscseseseeseenseosseceeseceesseesseesecessecesesensseeseees 45 Payers And Manufacturers .........ccssssssccsscccecessessssstenssecceeessusesueneneecesasesssseuseassecenesessansenenarseeesenss 45 RESCArCHESS .......secseccseeceeeceessnecsecesseessceneseeesseessesencesseesesueeeseecsuesseeseaceeeaeseaeessecssscessceseseeseeessnesaes 46 REFEFENCES .0.....ceeccessecesseeeesceeccaeeeensneecnceeeeaaeesnenenenaeesenaaessnaeenenaeeensueeasnaeeeeauaeeqaoeseenaeeseaaaetsaneeennaaeeaes 48 Supplemental Materials A. Background: Supplemental Information ............ccccccccsssceesssceesseecesseeensaneeeenaeeeenesenneceeecaeeeesseenenaeess Al A1. Definitions .......... ce eeeccesscesesceesseeesneecesseesesaceeseneeceseeecnaeeeeaaeeseeasassaeeseaeaeseaasenseaeaeeaaeseeeeeeenaeeees Al Intervention Definitions ..........eeeceecesseesesseeseesseeeeseeeeseeesaessaeseaaeeeaeeeseeenaeeeseeaoeseeaeeaeseaaeneaansaes Al Outcome Measure Definitions ......... ee scescesscesseeeseeeeceeecneecsneeseesseeeesoeseanessnessecseecetecenenseesenesaess Al A2. Potential Cost-Saving Measures in COVID-19.............cccscsscccssssssceesssseceecesseeseseessneeessssenseeesssaees A2 B. Patient Perspectives: Supplemental Information .............:cccssccssscceessecesseccesseeeesaceesenecensseeeesaeenseaes Bi B1. Methods. ......... se eeeecesceesceessessseeeseeecscecsseeeseeesusesansceneeescerscesesnecseesesceesceseseeseesssssessneseseessasessnesenss B1 C. Clinical Guidelines «2.0.0.0... essesseesseeeeesceeeceesseeceeeseseeeeseeeseeecsescseesssseeseeesenseneesessesceesneeesneseeesseneesaneees C1 IDSA Guidelines as of April 20, 2022..............sc:sccccssssecesessseeeeessaesecnsssneeneeesaeeeeesssacseesseseseeessanes c1 National Institutes of Health COVID-19 Treatment Guidelines as of April 20, 2022 ............0000 C2 D. Comparative Clinical Effectiveness: Supplemental Information.............:cssscsccssseccesessssssceereneesenes D1 D1. Detailed Methods ...........esesseeseccseeceessseesseeseeessnssessesenencsnsesnsseeesesneeesescnesseeseeceesaueeneessenersnessaes D1 PICOTS .....eseseeceessnessccsseceesceeesseesseesseessaceesseceneeeseeesessenseaseeesseecoessscesecesesenesensscessacsseaseseessaeseenensas D1 Data Sources and S@arches........ccsccsscscseesseesssrecsecseseecseesssessseeseseseseessseseserscsnseseesseeseceesseseseeseets DS StuAY S@lOCtION ........csessccccccesesessensceccettectsesessanensuestecensenssseeaeeecteetsesnssenenstcesssesssanseusestecensenseuaseees D8 'Institute for Clinical and Economic Review,2022,-(isti'é'é U*;*;*;CC#C#éR ON Special Assessment of Outpatient Treatments for COVID-19 Data Extraction and Quality ASSeESSMENIL............cccs:cccccssssssecesssescecesssneeeecesanesecessenseesaesanseeesssness D9 Assessment of Level of Certainty in EVid@Nnce...........cccssssssscscsercescsessnssncessceceeecsesensecereneccesseness D1i0 ASSESSMENT Of Bia ..........cesesesseeseeecseteseeeeseeecceecenereneseceeesneesaeeeseeseonsesnsesaeeeseesoeeseneseateesseessneeses D10 Data Synthesis and Statistical Analyses ............::csccsccssscsssesceseceseeessesesasceensessenenseaesencesseensnaseeas D1i0 D2. 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Detailed Methods........cccsscesscesscsseceesssecseeesseasseaseseeessecseccseaseesecesecsesaneasseessecaseceseeessecseseaneaes El Target Population............ccc2cccccsssssecccssssesesssserseesessneseeessseesensassneeeeacseseseeesssnseesasecseeeessusesenseseness E2 Treatment Strategies... eeesescsscccneeeeeeeeeeeeeneeeeeeeeeeeseseseeaeaeeeeeeeseasesseaaoeeseseeesaesenenseoeesenenenseas E3 E2. Model Inputs and ASSUMPTIONS ...............::ccesssccceeeeseeeeetensaeeeeeseneeeensenceneeeaneaeeeeaeeneaseneeseaeeeeeeeas E4 Model IMputs ..............c:scccsssseeceessseeeeecssusrseseesseseseessuneeenssuceseesessunesecseeesecessseeeseeseeesenssseceseesesaeeess E5 E3. ROSUICS ........cccesseesseessneeseceneseeeseeeeeesneessseeseeseaeeecanesseeeseesesoaecaseseeesseeseeceneaesssesesseeseeessacsesseeseneens E16 Description of evLY Gained Calculations .............cc::2:cccccssssseccesseececesssneeeeesseesecessensensssseseeessaes E16 Base-Case ReSUItS........:cccceseesseeseeseeseceeessaeeseseaeeneseeensaaaaseesenseceaseaseaseoesecsueessseaesneeasesseeenseansenes E17 E4. Sensitivity ANalyses ...........:s:sccccceccssssssssscceseceecesssenssscceseseeceususssssceeusecercescesseaceeseecenstssssssssensees E17 ES. Scenario Analyses ..........:.cccccssssccecsssscceesessescessssensenesesseeseeussensensecsauesenssuaesessnsseseeeesssaeseseassneseess E23 E6. Model Validation «2.2... cceseesscesssesseceeeseseseeesneeseeesssesesneecaeecenessaeseceeeeaeeeseessaeseeeneaeteanesseeeteaenes E24 Prior ECONOMIC MOCels ........:csecsescsesteesseecseecescccsessesseesueessescseesenseseesessscserseesseseessetsersessersseeeees E24 F. PUBlIC COMMENTS. ........ceeeseeceesseesseeeeseeseeecsneeeseeeseetecessensssaeeesueessnsseneeseeeesneesaeesseeseensesceeeeesseeesenensees F1 G. Conflict of Interest DisClOSUIeS ...........ccsesseeeeceeseeeeaeesseesseeseeneecseeeseeesseeseeeseseeessensseseseeeeeeeeerseeneeens G1 'Institute for Clinical and Economic Review,2022,-i(isti'é ;U;*;*;C;CC#CéR OE Special Assessment of Outpatient Treatments for COVID-19 List of Acronyms and Abbreviations Used in this Report AHRQ Agency for Healthcare Research and Quality BMI Body mass index CDC Centers for Disease Control and Prevention Cl Confidence interval EUA Emergency Use Authorization evLY Equal-value life year FDA Food and Drug Administration HIV Human immunodeficiency virus HR Hazard ratio ICER Institute for Clinical and Economic Review ICU Intensive care unit IDSA Infectious Diseases Society of America IV Intravenous kg Kilogram mg Milligram mL Milliliter N Total number n Number NIH National Institutes of Health PCR Polymerase chain reaction PICOTS Population, Intervention, Comparators, Outcomes, Timing, Settings QALY Quality-adjusted life year RCT Randomized controlled trial RNA Ribonucleic acid RR Risk ratio SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 SpO02 Oxygen saturation SSRI Selective serotonin reuptake inhibitor US United States WAC Wholesale acquisition cost WHO World Health Organization @Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page vii Executive Summary Background COVID-19 is an infectious respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of April 2022, there have been over 80 million confirmed COVID-19 cases and 980,000 COVID-19 deaths in the United States (US).1 The severity of the disease is classified into four levels. Most symptomatic COVID-19 patients have mild or moderate disease and do not require hospitalization. Patients who develop severe or critical disease require hospitalization with respiratory support. Many factors can increase the risk for developing severe or critical COVID-19. Some of the most common risk factors are older age, obesity, cardiovascular disease, and chronic obstructive pulmonary disease. This Evidence Report is considered an Institute for Clinical and Economic Review (ICER) Special Assessment because the epidemiological landscape and evidence base for potential treatments for COVID-19 are both rapidly evolving and will continue to change throughout and beyond the course of this review. This constantly shifting landscape is a dominant contextual reality. However, due to the unprecedented immediacy and scale of COVID-19, and the near-term policy decisions that will be made across multiple treatment options, ICER believes that an independent review of existing evidence on comparative clinical effectiveness and value of these treatment options will be helpful to all stakeholders. Report Aim In this Evidence Report, ICER is presenting a full evaluation of clinical and economic outcomes of three treatments for mild-to-moderate COVID-19 among outpatients at high risk of progression to severe disease: molnupiravir, Paxlovid™, and fluvoxamine. The scope of the review had additionally included two monoclonal antibody treatments, REGEN-COV and sotrovimab. However, neither treatment currently has emergency use authorization (EUA) from the Food and Drug Administration (FDA) for use in any US region due to substantially reduced activity against the Omicron variant and Omicron BA.2 subvariant, respectively.2? Around the time of posting of the draft Evidence Report, the FDA granted EUAs for remdesivir and bebtelovimab for our population of interest. Further, peginterferon lambda is seeking EUA based upon recent positive trial results.*, While these treatments emerged too late for us to consider in the Evidence Report, we note that the interactive economic model will be available on ICER Analytics. Decisionmakers can input clinical and economic data on other emerging treatments to generate cost-effectiveness results and suggested health-benefit price benchmarks. ©lnstitute for Clinical and Economic Review, 2022 Page ES1 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Mechanisms of Action and FDA Regulatory Status Molnupiravir is an oral ribonucleoside analog that causes viral genome replication errors. Nirmatrelvir/ritonavir (Paxlovid) is a combination oral drug that inhibits SARS-CoV-2-3CL protease, an enzyme necessary to produce other functional SARS-CoV-2 proteins. Fluvoxamine is an oral selective serotonin reuptake inhibitor (SSRI) with FDA approval for the treatment of obsessive- compulsive disorder. One hypothesized mechanism of action for fluvoxamine in the treatment of COVID-19 is through modulation of the body's inflammatory response. Molnupiravir and Paxlovid currently have EUAs from the FDA. Fluvoxamine is available on the US market while university- based researchers are pursuing an EUA specifically for the treatment of COVID-19. Comparative Clinical Effectiveness Studies of all three therapies were conducted in overlapping timeframes but with potentially important differences in location (US vs. overseas), and in the spectrum and relative prevalence of SARS-CoV-2 variants within the population. None of the clinical trials were performed at a time when the Omicron variant was present. Within this context, trial results demonstrated that, if given within a limited number of days following initial symptoms of COVID-19, all three drugs of interest were superior to placebo in reducing hospitalization related to the acute infection. Molnupiravir and Paxlovid significantly reduced the relative risk of hospitalization or death from any cause compared to placebo by 30% and 88%, respectively. Fluvoxamine reduced the relative risk of COVID-19-associated acute care (i.e., retention in a COVID-19 emergency setting or transfer to tertiary hospital due to COVID-19) by 32% over placebo. A per-protocol analysis of fluvoxamine limited to individuals who did not stop treatment (i.e., had greater than 80% adherence) suggested substantially greater efficacy (66% relative risk reduction) in reducing acute care use. Molnupiravir and Paxlovid were well tolerated and had low discontinuation rates in their Phase III clinical trials.) However, each drug has some notable risks. With molnupiravir there were important safety considerations given laboratory evidence suggesting it may be mutagenic, teratogenic, and toxic to growing bone and cartilage. Based on a short five-day course of therapy, the FDA considers molnupiravir to have low risk for mutagenicity, but the EUA label limits usage to individuals 18 years and older who are not pregnant or breastfeeding and who are without alternative COVID-19 treatment options.> The FDA also recommends that men of reproductive potential who are sexually active with individuals of childbearing potential should abstain from sex or use a reliable method of contraception for the duration of treatment and for at least three months after the last dose of molnupiravir. Molnupiravir is only authorized for individuals for whom alternative COVID-19 treatment options approved or authorized by the FDA are not accessible or clinically appropriate. Paxlovid is a combination therapy containing ritonavir. Ritonavir has many known drug-drug interactions that pose a safety risk. These include interactions with certain anticoagulants, ©lnstitute for Clinical and Economic Review, 2022 Page ES2 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents antiplatelets, antiarrhythmics, anticonvulsants, and immunosuppressants.® These interactions may be more common among certain patients who are at particularly high risk for severe COVID-19 disease (e.g., immunosuppressed patients).' Paxlovid is not recommend for patients with severe renal or hepatic impairment. As an SSRI, fluvoxamine also carries an FDA drug class warning for increased risk of suicidal thinking for children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders. The risk of adverse events in the fluvoxamine arm was similar to the risk in the placebo arm of the Phase II| TOGETHER trial as well as to the risks in intervention arms in the Phase Ill trials for the other drugs of interest. However, there was a sizeable percentage of individuals who stopped treatment due to tolerability in both the fluvoxamine and placebo arms of the TOGETHER trial (11.3% and 8.4%, respectively). Table ES1. Number and Percentage of Hospitalizations or Deaths in Key Phase III Trials®**3 Hospitalization or Death from Any Intervention (Trial) Cause, n/N (%) Death, n/N (%) Intervention Placebo Intervention Placebo Molnupiravir (MOVe-OUT) | 48/709 (6.8) 68/699 (9.7) 1/709 (0.1) 9/699 (1.3) Paxlovid (EPIC-HR) 8/1,039 (0.8) 66/1,046 (6.3) 0/1,039 (0) 12/1,046 (1.1) Fluvoxamine (TOGETHER) 79/741 (11)* 119/756 (16)* 17/741 (2.3) 25/756 (3.3) n: number, N: total number *Observed in a COVID-19 emergency setting (for more than six hours) or hospitalized. While further evidence on all three treatments of interest continues to be gathered and analyzed, the COVID-19 landscape has been evolving so rapidly that currently available data cannot be expected to have evaluated the safety and effectiveness of these drugs in the real-world US population as of the date of this report. Important uncertainties that must be considered include: 1) the rapid evolution of SARS-CoV-2 leading to variants with treatment resistance and with different morbidity and mortality impacts; 2) the enrollment of predominantly unvaccinated patients who were generally healthier and lower risk than those in the general population; and 3) the uncertain generalizability of data related to hospitalization rates and other health care resource utilization from studies conducted prior to the advent of the Omicron variant and based predominately or exclusively in countries outside of the US. Such issues are compounded by the early phase of evidence generation in which only one Phase Ill trial has been conducted for each drug in the population of interest at this time. Substantial differences in patient populations across the Phase Ill trials preclude us from making direct comparisons or formal quantitative indirect comparisons of safety and effectiveness across the drugs of interest. For example, the molnupiravir trial enrolled substantially larger proportions of individuals with obesity compared to the fluvoxamine and Paxlovid trials. Further, as noted, large variability in the countries of recruitment and the timing of trial enrollment periods reduce study comparability. The Phase III trials also defined outcomes differently. In particular, data from @Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page ES3 Return to Table of Contents the fluvoxamine TOGETHER trial appears to be the least comparable to others since this trial used a distinct composite primary outcome of retention in a COVID-19 emergency setting for more than six hours or transfer to a hospital. Keeping this context of substantial uncertainty in mind, ICER Evidence Ratings shown in Table ES2 should be viewed with corresponding caution, particularly when making inferences between the comparative effectiveness of the different agents. Table ES2. Evidence Ratings Treatment Comparator Evidence Rating Molnupiravir* Usual care C+ Paxlovid Usual care B+ Fluvoxamine Usual care C+ *Note: Population excludes individuals who are pregnant or who have childbearing potential. Cost Effectiveness To estimate the cost effectiveness of each outpatient treatment, we used estimates of relative treatment effectiveness from each intervention's pivotal trial and applied those estimates to a common "usual care" comparator synthesized by pooling across the usual care arms of each pivotal trial. This approach was considered optimal given how disparate the results were in the usual care arms across the pivotal trials, reflective of the differences in the background patient population, timing of study in relation to COVID-19 variants, and differences in health care practices across the different countries in which the trials were conducted. Base-case results were calculated from the health care sector perspective over a lifetime time horizon. We acknowledge the societal perspective may have particular relevance when the government is paying for the treatments outside of usual health care cost budgets. Therefore, we present results from a modified societal perspective as a scenario analysis. All treatments had base-case estimates lower than $100,000 per quality-adjusted life year (QALY) gained and equal-value life year (evLY) gained from both perspectives at their current price set by government negotiation or the generic marketplace. Results were particularly sensitive to assumptions regarding the relative effectiveness of the intervention and the background rate of hospitalization within the common usual care comparator arm. Table ES3 reports the health-benefit price benchmarks for each treatment from the base-case health care sector perspective and the scenario modified societal perspective. The current treatment course price listed is based on government negotiation or the generic marketplace; the pricing and value considerations for these treatments will shortly transition to the private market. ©lnstitute for Clinical and Economic Review, 2022 Page ES4 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Table ES3. Health-Benefit Price Benchmarks for Outpatient Treatments for COVID-19 Perspective: Health Care Sector Treatment Course Treatment Course Treatment Course Treatment . . . Treatment* Course Price Price at Price at Price at $50,000/QALY $100,000/QALY $150,000/QALY Molnupiravir $707 $560 $1,200 $1,900 Paxlovid $529 $1,660 53,600 55,600 Fluvoxamine $12 $600 $1,300 $2,000 Treatment Course Treatment Course Treatment Course Treatment . . . Treatment* Course Price Price at Price at Price at $50,000/evLYG $100,000/evLYG $150,000/evLYG Molnupiravir $707 $590 $1,300 $2,000 Paxlovid $529 $1,750 $3,800 $5,800 Fluvoxamine $12 $630 $1,400 $2,100 Perspective: Modified Societal Treatment Course Treatment Course Treatment Course x Treatment . . . Treatment Course Price Price at Price at Price at $50,000/QALY $100,000/QALY $150,000/QALY Molnupiravir $707 $830 $2,200 $3,600 Paxlovid $529 $2,400 $6,500 $10,600 Fluvoxamine $12 $880 $2,400 53,800 Treatment Course Treatment Course Treatment Course Treatment . . . Treatment* Course Price Price at Price at Price at $50,000/evLYG $100,000/evLYG $150,000/evLYG Molnupiravir $707 $890 $2,300 $3,800 Paxlovid $529 $2,600 $6,900 $11,100 Fluvoxamine $12 $950 $2,500 $4,000 evLYG: equal value of life years gained, QALY: quality-adjusted life year *We advise against comparing between interventions given the systematic differences in the trial populations and design. These treatments also have important potential benefits that may not be fully captured or evaluated in the economic model, including the potential for preventing further spread of SARS- CoV-2. We modeled quantitatively the potential impact on improving hospital intensive care unit (ICU) capacity but, in addition, effective outpatient treatments may help address the disparate burden of the pandemic in disadvantaged communities and help provide psychological reassurance, allowing for broader opening of schools and workplaces. There are also important relative disadvantages of each drug when considered against other options. These disadvantages are described in Section 5. In conclusion, assessment of the evidence on outpatient treatments for COVID-19 must be viewed as highly sensitive to the evolving landscape of COVID-19 variants and vaccination status in the US. The available data come from single pivotal trials, all conducted in settings not reflective of the health care patterns and the background risk of progression to severe disease occurring in the current Omicron wave of infections in the US. With these limitations in mind, current evidence does suggest that the drugs of interest reduce hospitalizations among patients with mild-to- @Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page ESS Return to Table of Contents moderate COVID-19 who are at high risk of progression to severe disease. Numbers of deaths in the pivotal trials are too small to draw firm conclusions. There are no short-term data suggesting serious concerns for side effects of these drugs when limited to the populations for which they are indicated. And at their current negotiated price (molnupiravir and Paxlovid) or their generic market price (fluvoxamine), these drugs appear-at this time-to have prices reasonably aligned with patient benefits. To the degree that hospitalization from mild-moderate COVID-19 is reduced with the Omicron (or future) variant, and to the degree these treatments are used in lower-risk populations, including patients with full vaccination, their cost effectiveness would be reduced. Appraisal committee votes on questions of comparative effectiveness and value, along with key policy recommendations regarding pricing, access, and future research are included in the main report. Several key themes are highlighted below. e Federal policymakers should view the advance market commitment strategy followed with outpatient COVID-19 treatments as a success that should be built upon. This approach substantially reduced manufacturer risk and resulted in multiple drugs becoming available in a relatively short time at prices that were aligned with clinical benefit. The framework for drug price negotiation between the government and drug makers during a pandemic should be made more transparent so that the public is aware of the parameters that the federal government considers in pricing negotiations. e The FDA needs to establish a clear and effective pathway for supporting evaluation of repurposed drugs. This may include proactive outreach to study investigators to invite applications and providing technical assistance during application development as well as consider internal FDA application initiation and development in cases where there is not a clear external sponsor. e The federal government should work with states and other policymakers to adopt policy changes needed to improve the effectiveness of its "test-to-treat" program. Test-to-treat sites are greatly needed to more immediately link diagnosis with treatment. Further, test- to-treat sites, which offer the convenience of co-located services, may differentially benefit individuals with low incomes since these individuals may have lower means to make multiple visits to access testing and treatment. Given the need for rapid and broad distribution of treatment during pandemic, the federal government should consider working with states and professional stakeholders to broaden the functional scope of practitioners who can prescribe COVID-19 treatments. It may be possible to use telemedicine or other means to accomplish this goal, but allowing pharmacists to prescribe under certain circumstances should also be considered. ©lnstitute for Clinical and Economic Review, 2022 Page ES6 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents e When COVID-19 drug pricing and payment moves from federal contracts into private markets, manufacturers and payers should work together to explore innovative approaches for coverage and pricing that minimize the use of restrictive coverage access as a means of cost control. Manufacturers should price treatments so they are affordable to private insurance systems and patients. Given the need to treat COVID-19 rapidly upon symptom onset, payers should ensure that any prior authorization process leads to immediate coverage for an available and appropriate treatment and does not risk having patients not fill their prescriptions. e Future research is needed to understand the epidemiology of long COVID and the impact of different prevention and treatment strategies on this condition as well as to define and measure the effects of treatments on a more inclusive set of patient-centered and societal outcomes. ©lnstitute for Clinical and Economic Review, 2022 Page ES7 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents 1. Background COVID-19 is an infectious respiratory disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As of March 2022, there have been over 80 million confirmed COVID- 19 cases and 966,000 COVID-19 deaths in the United States (US).1 The direct medical costs of health care utilization from COVID-19, while substantial (>$100 billion'* over the expected course of the pandemic), are overshadowed by the costs of reduced economic output due to the pandemic (>$7 trillion). Further, COVID-19 has uneven clinical and economic impacts as older individuals, those living with comorbidities, and Black and Hispanic populations are at higher risk of infection, hospitalization, and mortality,?® while younger individuals, women, and Hispanic populations are at higher risk of job loss as a result of the pandemic.'" COVID-19 is typically diagnosed using nucleic acid and antigen tests taken from the nose or throat.*81° The severity of disease is changing as the proportion of individuals who are vaccinated increases and the prevalence of different SARS-CoV-2 variants changes. Symptoms of COVID-19 typically appear two to 14 days after infection and include fever, dry cough, fatigue, joint/muscle pains, nasal congestion, loss of smell/taste, sore throat, headache, diarrhea, nausea/vomiting, shortness of breath, cyanosis, persistent chest pain, loss of appetite, or confusion. Prior to the Omicron variant becoming the predominant strain, roughly 30% of unvaccinated individuals infected with COVID-19 were asymptomatic."° Among those who were symptomatic, 80% developed mild-to-moderate disease while the other 20% progressed to require oxygen and/or mechanical ventilation.2+22 The severity of symptomatic infections can be classified into four levels,2?* as illustrated below. 1. Mild disease: Individuals have symptoms but do not have shortness of breath or abnormal chest imaging. 2. Moderate disease: Individuals show evidence of lower respiratory tract disease but have oxygen saturation (SpO2) 294%. 3. Severe disease: Individuals have pneumonia and one of the following: SpO2 <94%, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen <300, require more than 30 breaths per minute, or have >50% lung infiltrates. 4. Critical disease: Individuals have respiratory failure, septic shock, and/or multiple organ dysfunction. The rise of more infectious variants and the failure to reach population vaccination goals highlight the need for outpatient treatment options for mild-moderate disease. Oral options will be particularly helpful in improving access to treatment across diverse communities in the US. Multiple outpatient treatments for COVID-19 are in varying stages of development, and evaluation of the rapidly evolving evidence of the comparative clinical effectiveness and potential cost ©lnstitute for Clinical and Economic Review, 2022 Page 1 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents effectiveness at different pricing levels for highly anticipated emerging outpatient treatments will be important to guide policy decision-making. Report Aim Due to the unprecedented immediacy and scale of COVID-19, ICER recognizes the need for a timely review to inform policy even though definitive evidence on all treatments and outcomes of interest is not available at the time of review. The treatments for this report were chosen based on the timing of expected availability of clinical evidence, expected Food and Drug Administration (FDA) approval, and clinical expert input on which treatments would be likely to have the greatest relevance for patients and clinicians. Using these criteria, we selected to evaluate the health and economic outcomes of molnupiravir, nirmatrelvir/ritonavir (Paxlovid™), and fluvoxamine for the treatment of mild-to-moderate COVID-19 among patients at high risk of progression to severe disease. Our scoping document" had included two additional drugs, casirivimab/imdevimab (REGEN-COV) and sotrovimab. However, these two treatments are not authorized by the FDA for use in any US region due to their markedly lower activity against the Omicron variant and Omicron BA.2 subvariant, respectively. Therefore, this report will focus on the other drugs of interest." A discussion of the clinical evidence on REGEN-COV and sotrovimab is available in Section D2 of the Supplement. Description of Interventions Molnupiravir is a ribonucleoside analog that inhibits SARS-CoV-2 viral replication by being incorporated into viral ribonucleic acid (RNA), resulting in an accumulation of errors in the viral genome. Molnupiravir is administered orally at a dose of 800 mg every 12 hours for five days. Nirmatrelvir/ritonavir (Paxlovid) is a combination treatment. Nirmatrelvir is a protease inhibitor that blocks the activity of the SARS-CoV-2-3CL protease, an enzyme necessary to produce other functional SARS-CoV-2 proteins. Ritonavir is used in this combination to slow the metabolism of nirmatrelvir, thereby increasing nirmatrelvir concentrations in the body. Paxlovid is administered orally at a dose of 300 mg of nirmatrelvir and 100 mg of ritonavir every 12 hours for five days. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) and a o-1 receptor agonist.26 While fluvoxamine's exact mechanism of action for the treatment of COVID-19 is unknown, one theory is that by binding to the o-1 receptor, fluvoxamine modulates cytokine production and dampens the body's excessive inflammatory response to COVID-19.?" Fluvoxamine is administered orally at a dose of 100 mg twice daily for 10 days. ©lnstitute for Clinical and Economic Review, 2022 Page 2 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Molnupiravir and Paxlovid are available under EUA from the FDA. Fluvoxamine is already available as a generic medication with FDA approval for the treatment of obsessive compulsive disorder, but an EUA is being pursued by a university-based group for its use in COVID-19.78 Table 1.1. Interventions of Interest receptor agonist : Mechanism of Route of Dosage and . Intervention Action Delivery Administration EUA Population Individuals >18 years old, with mild-to- moderate COVID-19 who are at high ____ | promotes RNA 800 mg every 12 risk for progression to severe COVID- Molnupiravir replication error Oral hours for 5 days 19; not recommended for pregnant individuals; only for individuals without alternative COVID-19 treatment options 300 mg of Individuals 212 years old, weighing >40 . Protease nirmatrelvir and 100 | kg with mild-to-moderate COVID-19 Paxlovid pate Oral . . we . inhibitor mg of ritonavir, every | who are at high risk for progression to 12 hours for 5 days severe COVID-19 EVA is being reviewed; but in the Unknown, 100 mg twice daily pivotal trial,? individuals were 218 Fluvoxamine | potentially 0-1 Oral years old, with mild-to-moderate for 10 days COVID-19, at high risk for progression to severe COVID-19 EUA: Emergency Use Authorization, IV: intravenous, kg: kilogram, mg: milligram, RNA: ribonucleic acid Other Potential Treatments suggested health-benefit price benchmarks. Note Regarding Emerging COVID-19 Treatments Reflecting the rapidly developing evidence base for COVID-19 treatments, around the time of posting of the draft Evidence Report, the FDA granted EUAs for remdesivir and bebtelovimab for our population of interest. And on March 17, 2022, trial results were reported via press release of peginterferon lambda suggesting clinically significant results in reducing hospitalization or emergency room visits among a vaccinated population with mild-moderate COVID-19. The manufacturer of peginterferon lambda announced imminent plans to submit the data to the FDA for consideration of an EUA. While these treatments emerged too late for us to consider in the Evidence Report, we note that the interactive economic model is available on ICER Analytics. Decisionmakers can input clinical and economic data on these and any other available treatments to generate drug-specific cost-effectiveness results and @Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 3 Return to Table of Contents 2. Patient Caregiver Perspectives We spoke with three patients, a physician-scientist who maintains a COVID-19 patient registry to track longitudinal quality-of-life trends, and the Chief Executive Officer of Solve ME, a non-profit organization whose goal is to promote research on chronic fatigue and long-term COVID-19. We supplemented our understanding with a published systematic review that documented the diversity of symptoms associated with COVID-19.7° Patients mentioned the importance of comorbid respiratory conditions (e.g., chronic obstructive pulmonary disease, asthma, and being an ex-smoker) that exacerbated their experience of COVID- 19 symptoms. For instance, one patient described her difficulty in being transported to the hospital with their existing supplemental oxygen support that she uses for her chronic obstructive pulmonary disease. A patient with asthma mentioned that COVID-19 greatly exacerbated her shortness of breath causing her to feel like she was "unable to breathe" and "about to faint" while carrying out activities of daily living. Caregivers were heavily involved with supporting activities of daily living after patients were discharged from the hospital. Caregivers supported activities such as preparing meals, bathing, and providing care for other household members who were previously cared for by the patient with COVID-19. A complicating factor for caregivers of COVID-19 patients was that they themselves may have been infected at the same time as the patient, which would greatly limit their own capacity to provide care. If the caregiver were not infected, they would need to exercise particular caution to reduce the risk of infection. Adding to this, households with members not eligible to be vaccinated or with members who were at higher risk from COVID-19 faced greater care impact and disruptions to daily life due to greater need for isolation. Patients endorsed averting death as being the most important outcome. Patients also endorsed the restoration of their ability to carry out activities of daily living as being very important. A systematic review of quality of life and symptoms associated with COVID-19 documented a large number of symptoms, with fever, muscle pain, cough, shortness of breath, and diarrhea being the most common.?? Additionally, the study noted that symptoms may persist for months after infection, with respiratory symptoms, fatigue, and reduced mental health being some of the most common longer-term symptoms. In terms of their experience with treatment, a patient reported appreciating the near immediate restoration of their ability to taste and to smell. At the time that the interviews were conducted, only monoclonal antibodies were available. However, patients expressed a preference for oral agents, and intramuscular and subcutaneous injections over IV infusions. Patients ultimately expressed willingness to use whichever treatment was most effective, regardless of mode of administration. ©lnstitute for Clinical and Economic Review, 2022 Page 4 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Patients with employer-sponsored health insurance (in contrast to patients dually eligible for Medicare and Medicaid) mentioned the substantial financial burden of COVID-19 hospitalization. Whereas COVID-19 testing and vaccines are covered without out-of-pocket costs, there is no federal requirement that plans fully cover the costs of COVID-19 treatment. Earlier in the pandemic, many individual health plans waived cost-sharing for treatment either voluntarily or due to state requirement.*° However, the majority of the voluntary cost-sharing waivers have now expired. Research supports the potentially large financial burden of COVID-19 hospitalizations. Even early in the pandemic, when cost-sharing waivers were likely more common, out-of-pocket costs for hospitalizations for COVID-19 for privately insured and Medicare beneficiaries were $788 and $277.31 Among those who did not have hospital facility cost-sharing waived in that study, out- of-pocket costs for hospitalizations for COVID-19 for privately insured and Medicare beneficiaries were $3,840 and $1,536, respectively. Stakeholders also discussed the need for easy access to rapid diagnostic tests so that patients could be treated early. Currently, treatment is constrained in part by lack of availability of rapid testing, leading to a potential undercounting of COVID-19 cases. Inequities in diagnostic access could amplify inequities in treatment. Further, with constrained diagnostic capacity, patients need to rely on self-assessment of symptoms. Indeed, several patients indicated that difficulty breathing was a key reason for initially seeking treatment. ©lnstitute for Clinical and Economic Review, 2022 Page 5 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents 3. Comparative Clinical Effectiveness 3.1. Methods Overview Details on our systematic literature review methodology may be found in Section D1 of the Supplement. Scope of Review In January 2022, the FDA revised the EUA for REGEN-COV to exclude its use all US geographic regions due to the emergence of the Omicron variant, which is not susceptible to REGEN-COV. Similarly in April 2022, with the emergence of the Omicron variant sub-lineage BA.2, the FDA similarly revised the EUA for sotrovimab. The BA.2 Omicron subvariant is currently the dominant variant in all US regions.32 This review focuses on assessing the evidence of the clinical effectiveness of molnupiravir, Paxlovid, and fluvoxamine for non-hospitalized patients with mild-to- moderate COVID-19. The full scope of the review is in Section D1 of the Supplement. A discussion of the clinical effectiveness of REGEN-COV is available in Section D2 of the Supplement and a discussion of sotrovimab is available in Section D2 of the Supplement. Evidence Base Key information about the pivotal trials for each agent, including information on study size, duration, patient characteristics, and outcome measures is shown in Table 3.1. Molnupiravir We identified a Phase lla and a Phase II/IIl randomized, double-blind, placebo-controlled trial of molnupiravir as well as a Phase Ill, open-label RCT in India of a generic formulation of molnupiravir supported by a generic drug licensee. The Phase Ila study evaluated the effect of molnupiravir on viral load, safety, and tolerability.23 The pivotal trial for molnupiravir, MOVe-OUT, included a Phase Il portion and a Phase III portion. The Phase II portion served as a dose-finding study and was followed by the Phase III portion of the study, which evaluated the 800 mg dose of molnupiravir (the authorized dose in the EUA).3* In this review, we focus on the Phase III portion of the trial and refer to this Phase III portion as "MOVe-OUT." We obtained results from this Phase III portion from an interim data analysis and a final data analysis from an FDA Advisory Committee Meeting and from a peer-reviewed publication.**?2> Information on the Phase Ila trial is included in Section D2 and Tables D5, D10, D15, and D22 of the Supplement. In addition to the MOVe-OUT trial, we identified a Phase III, open-label RCT conducted in India evaluating the safety and efficacy of a generic formulation of molnupiravir for COVID-19. Data for ©lnstitute for Clinical and Economic Review, 2022 Page 6 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents this study was acquired from a conference presentation.*© The inclusion criteria were not fully defined in the conference presentation but appear to be different from our population of interest. This study included individuals who had mild (as opposed to mild-to-moderate) COVID-19 symptoms and who were not required to have a risk factor for progression to severe COVID-19. In addition, individuals in this trial had substantially lower levels of comorbidities and were younger than participants in the MOVe-OUT trial. Due to these differences, we describe the results of this trial in Section D2 of the Supplement. MOVe-OUT MOVe-OUT was a randomized, double-blind, placebo-controlled Phase III trial of molnupiravir. Patient enrollment took place globally with 46% of the participants from Latin America, 33% from Europe, 12% from Africa, and 3% from Asia.'? Patients were included in this trial if they were unvaccinated, at high risk for progression to severe COVID-19, and had a laboratory-confirmed diagnosis of COVID-19 as well as symptom onset within five days of randomization. Obesity was the most common qualifying risk factor for progression of disease (74%).12 A total of 1,433 patients were enrolled, short of the 1,500-enrollment goal, after a decision was made to stop recruiting patients based on positive interim results. Participants were randomized to 800 mg of molnupiravir or placebo twice daily for five days. The median age of participants in the full-population analysis of the MOVe-OUT trial at baseline was 43 years, and 51% were female.2 Most of the participants in the trial were White (57%), 5% were Black, and 50% of the participants identified as Hispanic or Latino.1* The primary outcome assessed in MOVe-OUT was the percentage of patients who were hospitalized and/or died from the time of randomization through day 29 and incidence of adverse events. The secondary outcome for the study is a patient-reported outcome of improvement or progression of COVID-19 signs and symptoms through day 29, which was reported by measuring the severity of disease at different timepoints using the World Health Organization (WHO) 11-point scale.? Paxlovid Evidence to inform our review of Paxlovid in non-hospitalized patients came from one Phase II/III randomized clinical trial, EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients).7? An additional Phase II/III trial, EPIC-SR (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients) is described in Section D2 and Tables D5, D12, and D19 of the Supplement. The EPIC-HR trial was a multi-center Phase III trial that randomized 2,246 patients to 400 mg oral tablets of Paxlovid or placebo twice daily for five days (Table 3.1).23 Non-hospitalized adults were eligible to participate if they had a positive SARS-CoV-2 test with symptom onset no more than five days prior to randomization and had at least one risk factor for high risk of progression to severe ©lnstitute for Clinical and Economic Review, 2022 Page 7 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents disease. Patients were excluded if they had been admitted to a hospital or had received any treatments for COVID-19 prior to randomization, had received a vaccination for SARS-CoV-2, had a known human immunodeficiency virus (HIV) infection with a viral load greater than 400 copies/mL or taking certain medications for HIV treatment, or were pregnant, breastfeeding, or could become pregnant. The mean age of the participants in the EPIC-HR trial at baseline was 46 years, and 49% were female. The majority (72%) of participants were White and a small minority (5%) were Black. The most common risk factor for severe COVID-19 was obesity (33%) (Table 3.1).4% The primary outcome of EPIC-HR was COVID-19-related hospitalization or death for any cause through day 28. Secondary outcomes included adverse events, COVID-19 symptom severity and time to resolution, pharmacokinetics, viral load, and hospital and intensive care unit (ICU) length of stay. Fluvoxamine Our review of fluvoxamine was informed primarily by one randomized placebo-controlled Phase III trial conducted at 11 sites in Brazil (TOGETHER). Two additional small US-based trials of fluvoxamine, STOP-COVID and STOP-COVID 2 and one open-label cohort study, were also identified and are reviewed in Section D2 and Tables D5, D8, D13, D17, D20, D23, D28, D34, and D40 of the Supplement. The TOGETHER trial was an adaptive platform-based trial focused on evaluating repurposed drugs (i.e., drugs already marketed for other indications) with anti-inflammatory properties for mild COVID-19 symptoms.?" In the TOGETHER trial, 1,497 patients were randomized to receive 100 mg fluvoxamine or placebo twice daily for 10 days (Table 3.1).° Patients 18 years and older were eligible to participate if they presented to a participating outpatient care site with symptoms consistent with COVID-19 that began within seven days, had a positive rapid antigen test for SARS- CoV-2, and had at least one risk factor for high risk of progression to severe disease. Patients were excluded if they had been hospitalized previously for COVID-19, had been vaccinated for SARS-CoV- 2, had any other concomitant infections, were currently using SSRIs, or had uncontrolled psychiatric disorders or suicidal ideation consistent with the FDA black box warning for fluvoxamine.?® The mean age of the participants in the TOGETHER trial at baseline was 50 years, and 58% were female. The vast majority (96%) of participants were mixed race. The most common risk factor for severe COVID-19 was age 250 years (44%) (Table 3.1). The primary outcome of the trial was a composite endpoint of COVID-19-related admission to an emergency setting (defined as observation for more than six hours) or referral to tertiary hospital due to COVID-19 progression within 28 days. Retention in a hospital-like setting was described as an adequate proxy for conventional hospitalization given that the wave of COVID-19 infection in Brazil during the study period (June 2020 to August 2021) exceeded conventional hospital capacity. At that time, Brazil implemented hospital-like services in emergency settings that provided care including oxygen support and mechanical ventilation.? 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Hospitalization or Death from Change in Viral Load from Intervention P Any Cause, n/N (%) Mortality, n/N (%) Baseline, log10 Copies/mL (Trial) y vase, (95% Cl) Intervention Placebo Intervention Placebo Intervention | Placebo Molnupiravir Difference from placebo: (MOVe-OUT) 48/709 (6.8) | 68/699 (9.7) 1/709 (0.1) 9/699 (1.3) 0.33 (-0.5, -0.16)+ Paxlovid Difference from placebo: (EPIC-HR) 8/1,039 (0.8) | 66/1,046 (6.3) | 0/1,039(0) | 12/1,046 (1.1) 0.70 (-0.86, -0.53)t Fluvoxamine * « (TOGETHER) 79/741 (11) 119/756 (16) 17/741 (2.3) | 25/756 (3.3) NR NR Cl: confidence interval, mL: milliliter, n: number, N: total number, NR: not reported *Observed in a COVID-19 emergency setting (for more than six hours) or hospitalized. tReported on day five. Molnupiravir In the full-population analysis of the MOVe-OUT trial (N=1,433), 48/709 (6.8%) of participants in the molnupiravir group and 68/699 (9.7%) of participants in the placebo group had been hospitalized or were dead by day 29 following randomization, a 30% (no 95% Cl reported) relative risk reduction in favor of molnupiravir (Table 3.2).12 One death occurred in the treatment arm and nine deaths occurred in the placebo arm; the patient who died in the treatment arm had metastatic cancer and died due to multiorgan failure from COVID-19. No formal statistical testing was performed for this relatively rare outcome of death, other than as part of the composite outcome with hospitalization described above. At the time of the interim analysis (N=775), the primary outcome was more favorable; 28/385 (7.3%) of participants in the molnupiravir group and 53/377 (14.1%) of participants in the placebo group were hospitalized or dead by day 29 following randomization, a relative risk reduction of 48%.2 This represents a decrease in the reported efficacy for the primary endpoint from the interim analysis to the full population analysis of 18 percentage points in relative risk reduction. Similarly, the absolute risk difference dropped from 6.8% (95% CI: -11.3 to -2.4) in the interim analysis to 3% (95% Cl: -5.9 to -0.1) in the full population analysis (Table 3.1).22 Diarrhea, nausea, and dizziness were the most common adverse reactions in the MOVe-OUT trial. The incidence of adverse events was higher in the placebo group due to the higher incidence of COVID-19 complications. A total of 216 patients (30.4%) in the molnupiravir arm had one or more Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 10 Return to Table of Contents adverse events compared to 231 patients (33%) in the placebo arm. Participants in the treatment arm were also less likely to discontinue their treatment regimen due to an adverse event, an outcome that occurred in 10 patients (1.4%) in the treatment arm and in 20 patients (2.9%) in the placebo arm (Table 3.3).2 Molnupiravir is also suspected to cause embryo-fetal toxicity and bone and cartilage toxicity based on data from animal models.' It is not recommended for use during pregnancy and is not authorized for use for patients under 18 years of age.? While molnupiravir's mechanism of action (causing viral mutagenesis) raised concerns with mutagenicity in initial in-vitro assays,*? subsequent in-vivo animals assays and the short course of therapy has caused the FDA to classify molnupiravir as "low risk" for genotoxicity. Paxlovid The primary endpoint of the EPIC-HR trial was hospitalization or death calculated in the modified intention-to-treat analysis population, which was defined as the participants randomized within three days of symptom onset who did not receive previous monoclonal antibody treatment. To align with our reporting of the molnupiravir Phase III trial, we present the outcome of hospitalization or death among participants randomized within five days of symptom onset (n=2,085). In this population, the proportion of patients with a COVID-19-related hospitalization or death through day 28 was 8/1,039 (0.8%) in the Paxlovid group and 66/1,046 (6.3%) in the placebo group, an 88% relative risk reduction (no Cl provided) and an absolute reduction of 5.62% (95% Cl: - 7.21, -4.03, Kaplan-Meier estimated) (Table 3.2). In the EPIC-HR trial, adverse events were more common in the placebo group. Adverse events that occurred more frequently in the Paxlovid group than the placebo group included distorted sense of smell (6%), diarrhea (3%), hypertension (1%}, and muscle pain (1%). Discontinuation due to adverse events occurred in 2% of participants in the Paxlovid group and 4% in the placebo group." Fluvoxamine In the TOGETHER trial, 79/741 (11%) of participants in the fluvoxamine group (intention-to-treat analysis) were observed in a COVID-19 emergency setting (for more than six hours) or transferred to a hospital compared to 119/756 (16%) of participants in the placebo group (relative risk reduction 32%, 95% Cl: 12% to 48%) (Table 3.2). The observed difference in the primary endpoint between fluvoxamine and placebo was driven largely by the proportion of patients observed in an emergency setting (1% in the fluvoxamine vs. 5% in the placebo group, p=0.0001), while rates of hospitalization (all cause or COVID-19-related) did not differ between groups. There were also no statistically significant differences in viral clearance, time to hospitalization, hospital length of stay, death, or mechanical ventilation between the two groups. ©lnstitute for Clinical and Economic Review, 2022 Page 11 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Adherence to both fluvoxamine and placebo treatment regimens (defined as adhering more than 80% of the time) was relatively low in the TOGETHER trial. See the Uncertainty and Controversies Specific to Fluvoxamine section for further discussion of potential reasons for non-adherence in this trial. Among patients taking fluvoxamine, 548/741 (74%) were adherent, compared to 619/758 (82%) for patients taking placebo. In the per-protocol population, the relative risk reduction of the primary endpoint was more favorable (relative risk reduction 66%, 95% Cl: 46% to 79%) than in the intention-to-treat population. Furthermore, in the per-protocol analysis, there was one death (<1%) in the fluvoxamine group and 12 deaths (2%) in the placebo group (p=0.022). The exclusion of the relatively large number of non-adherent individuals can introduce bias in the per-protocol analysis. Therefore, we suggest that the intention-to-treat analysis be given greater consideration than the per-protocol analysis for informing clinical and policy decision-making. In a recent systematic review with meta-analysis, the researchers judged that the primary composite outcome in the TOGETHER trial (observation in a COVID-19 emergency setting for more than six hours or hospitalization) was not comparable to the hospitalization outcome in the STOP- COVID 1 or STOP-COVID 2 trials and, instead, researchers pooled data on emergency room visits or hospitalizations lasting >24 hours across the three trials." In this pooled estimate, 88/1,093 (8.1%) in the fluvoxamine group had an emergency department visit or hospitalization lasting >24 hours compared to 121/1,103 (11%) in the control group (RR: 0.75; 95% Cl: 0.58 to 0.97). As noted earlier, in the TOGETHER trial, 84 (26%) participants in the fluvoxamine group and 64 (18%) participants in the placebo group discontinued due to treatment intolerability.2 However, the risk for having any adverse event or a serious adverse event in the fluvoxamine arm is similar to the risk in the placebo arm of the TOGETHER trial as well as to the intervention arms in the Phase III trials for the other drugs of interest (Table 3.3). Table 3.3. Key Adverse Events®?1%12.13 Serious Adverse Events, n/N Discontinuation Due to Intervention Any Adverse Event, n/N (%) (%) Adverse Event, n/N (%) (Trial) Intervention Placebo Intervention Placebo Intervention Placebo Molnupiravir (MOVe-OuT) 216/710 (30) 231/701 (33) 49/710 (7) 67/701 (10) | 10/710(1) | 20/701 (3) (ePleuR) 255/1,109 (23)* | 266/1,115 (24)* | 18/1,109 (2) | 74/1,115(7) | 23/1,109 (2) | 47/1,115 (4) Fluvoxamine + + (TOGETHER) 169/741 (23) 188/756 (25) 59/741 (8) 70/756 (9) 84/741 (26) | 64/756 (18)+ n: number, N: total number *Treatment-emergent adverse event. tSummed treatment-emergent adverse events of various severities. Discontinuation due to side effects. ©Institute for Clinical and Economic Review, 2022 Page 12 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Subgroup Analyses and Heterogeneity In the pivotal trials of the agents in this review, treatment effects across most subgroups were generally indistinguishable from the average treatment effect. In patients with diabetes in the MOVe-OUT trial (full analysis set) of molnupiravir, patients treated with molnupiravir had slightly greater risk of being hospitalized or dying compared to the placebo arm (15.9% vs. 14.5%).?° In the EPIC-HR trial of Paxlovid, lower risk patients (such as those 65 years of age or younger or with SARS- CoV-2 seropositive status) had lower absolute risk reduction relative to placebo compared with higher risk patients.7% We sought subpopulation data from manufacturers on the effectiveness of the interventions in subgroups of interest such as race, vaccination status, variant of concern, time since randomization, serum antibody status, and individual risk factors for progression to severe disease. Data was either not available or insufficient to assess differential effectiveness in these populations. In particular, we highlight the low representation of Black patients in the Phase Ill trials for molnupiravir and Paxlovid. This is problematic because Black populations are at higher risk of infection, hospitalization, and mortality due to COVID-19.*¢ Uncertainty and Controversies While the clinical trials of all three agents demonstrate statistically significant benefits of treatment, there remains substantial uncertainty regarding the comparative effectiveness of each drug in the current US landscape. Some of this uncertainty comes from the preliminary nature of the evidence base, which rests upon a single Phase Ill RCT for each drug, without an additional confirmatory trial. Further, in attempts to compare these drugs to each other, we note that there are some differences in the composite outcome measures used, and differences in the spectrum of risk factors for progression to severe COVID-19 among different trial populations. But perhaps the most notable source of uncertainty is the difficulty in interpreting the generalizability of results of studies conducted in ex-US settings during periods with different prevalent COVID-19 variants. This is not to criticize the design of the clinical trials of these drugs, nor should anyone expect studies done during a fast-moving pandemic to be able to provide high certainty in all areas. Clinical and policy decisions will need to be made given the best evidence available, yet it will be equally important for decisionmakers to be aware of the limitations of the evidence and the key remaining questions that future studies should address. We expand on these issues below. ©lnstitute for Clinical and Economic Review, 2022 Page 13 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Early Status of the Evidence Base The evidence base for all three drugs remains at an early stage of maturity. Each drug's evidence is based on a single Phase III RCT among the population of interest. This lack of data makes it difficult to fully evaluate these drugs. Illustrating the evolution of our understanding of treatment efficacy, in the molnupiravir Phase III trial, the interim analysis reported a relative risk reduction of 48% in all-cause hospitalization or death while the full analysis reported a relative risk reduction of 30% (Table 3.2).72 However, as we note in Section 3.1 and in Section D2 of the Supplement, there is an additional open-label Phase III RCT conducted in India evaluating a generic formulation of molnupiravir for the treatment of COVID-19 not in the population of interest and with different outcome measures. The results of that study support the efficacy of molnupiravir over standard of care. Lack of Comparability Across Trials for the Drugs of Interest Substantial differences in patient populations across the Phase Ill trials preclude us from making direct comparisons across these trials. Molnupiravir trials enrolled substantially larger proportions of individuals with obesity compared to the fluvoxamine and Paxlovid trials. Clinical experts have advised that the current broad definition of "high-risk" outpatients contains groups that are at much higher risk, such as older individuals, than others, such as individuals with hypertension only. Further, as will be emphasized below, the large variability in the countries of recruitment and the timing of trial enrollment reduces study comparability. Another factor in the uncertainty across trials is that they defined outcomes differently. The trials of molnupiravir and Paxlovid have very similar composite outcomes, but experienced clinical trial experts know that even identical composite outcomes in different trials are prone to differences in clinical record-keeping and other factors that can create unknown biases. In this review, the most obvious difference lies in the composite outcome measure for fluvoxamine compared to the other agents. The fluvoxamine TOGETHER trial appears to be the least comparable in this regard. The primary outcome in the fluvoxamine TOGETHER trial was retention in a COVID-19 emergency setting for more than six hours or transferred to a hospital. In contrast, the primary outcome for the Phase III trials for molnupiravir and Paxlovid was hospitalization or death. The authors of the TOGETHER trial, which was performed in Brazil, point out that the way they defined their composite outcome was driven by the limits on hospital capacity in that country during peak COVID-19 waves.° These limits meant that very ill patients were required to be held for long periods of time in emergency department settings rather than be admitted to hospital. This broader definition was described therefore as an adequate proxy for conventional hospitalization, but the comparability of these outcomes remains unclear. Further, while molnupiravir and Paxlovid reduced hospitalizations or death, fluvoxamine did not have a statistically significant effect on hospitalizations alone or death alone as secondary outcomes. ©lnstitute for Clinical and Economic Review, 2022 Page 14 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Generalizability of Results The SARS-CoV-2 virus is rapidly evolving, with different variants appearing and gaining dominance in different parts of the world at different points in time. None of the Phase Ill trials reported inclusion of patients infected with the Omicron variant. Only the Phase III trial for molnupiravir (MOVe-OUT) reported inclusion of patients infected with the Delta variant. This rapid evolution reduces the certainty with which we can apply results from trials conducted even as recently as one year ago to the current population of patients who will become infected with COVID-19 in the US now and in the future. As a result of these shifts, the relative effectiveness of treatments may vary. As an extreme example, as noted earlier, while REGEN-COV demonstrated high efficacy in its Phase Ill RCT and was the dominant outpatient treatment used for many months," when the Omicron variant emerged, laboratory data indicated that REGEN-COV had limited activity against it, and its EUA was revised to limit its use.324° Similarly, when Omicron variant sub-lineage BA.2 emerged, laboratory data indicated that sotrovimab had limited activity against it, and its EUA was also revised. The clinical consequences of COVID-19 infection appear to be changing as well, with the Omicron variant leading to less severe disease compared to prior variants.'" All else being equal, less severe disease will reduce the clinical and economic value of treatment, whereas If a more lethal variant were to emerge and become dominant, the relative effectiveness of outpatient treatments might lead to significantly greater absolute benefit across the population. In addition to rapid evolution of SARS-CoV-2 affecting the generalizability of prior study findings, the population being treated in the studies we reviewed also differs from the full population of patients likely to be treated today. First, key trials for the drugs of interest either explicitly excluded individuals vaccinated against SARS-CoV-2 or were conducted at a time when few to no individuals were vaccinated. Compared to trial results among unvaccinated groups with comorbid risk factors, clinical experts have advised that it is likely that vaccinated groups with comorbid risk factors would have lower risks of serious infection progressing to a requirement for hospitalization, thereby reducing to some extent the relative and absolute benefit of treatment. Second, individuals enrolled in the Phase III trials may be healthier than treated individuals in the real world. We identified 10 real-world studies of populations treated with the drugs of interest or REGEN-COV.*#*° See Section D2 and Tables D23-D27, D29-D33, and D35-D40 of the Supplement for more details regarding these studies. When comparing the characteristics of the trial populations to the real-world study populations, we find that the trial populations were younger than those reported in real-world study populations, with median ages ranging between 43 and 53 in the Phase Ill trials (Table 3.1), and 51 and 65 in the real-world studies we identified. Similarly, the trial populations were less likely to have chronic obstructive pulmonary disease, diabetes, chronic kidney disease, or liver disease than the treated populations in the real-world studies. These factors may be associated with the highest risks for severe COVID-19 disease.©°*? Perhaps reflecting the lower- risk population in the clinical trials, the rates of hospitalization for the untreated COVID-19 ©lnstitute for Clinical and Economic Review, 2022 Page 15 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents population (i.e., placebo arm) in the Phase III trials-with the exception of fluvoxamine-were lower than in most of the control arms in these real-world studies (Table 3.2). Lastly, study participants in the molnupiravir and fluvoxamine trials were primarily or exclusively outside of the US. This reduces the generalizability of results to the US population since countries may vary in prevalent SARS-CoV-2 variants, health care practices and infrastructure, and risk factors for developing COVID-19. Recent information from the Centers for Disease Control and Prevention (CDC) suggests that in the current Omicron wave, the risk for hospitalization among known-infected individuals has been dropping well below the rates seen in the usual care arms of each of these agents.*"7 Even among the trials of the agents themselves, there exist important differences in the background rate of hospitalization and death in the usual care arms. For example, the primary outcome rates for the usual care arm in the TOGETHER trial of fluvoxamine were substantially higher (16%) than in the Phase Ill trials for molnupiravir and Paxlovid (6.3 to 9.7%). Uncertainty and Controversies Specific to Molnupiravir The dramatic change in efficacy between the interim and final data from the Phase Ill trial is very unusual and raises substantial questions about how to interpret the results. Without a clear explanation for the potential cause of this shift, we have focused on the final data findings as the best estimate of the effectiveness of molnupiravir, but the uncertainty around that estimate is high. Also adding to the uncertainty about the risk-benefit balance with molnupiravir are concerns that use of this drug could lead to new, viable viral variants. A briefing document prepared by FDA staff for the Antimicrobial Drugs Advisory Committee Meeting to judge molnupiravir's efficacy and safety contained additional data on the potential for molnupiravir to cause mutations that result in reduced viral susceptibility to host antibodies or other COVID-19 antiviral or antibody treatments. In the Phase III MOVe-OUT trial, among the 12% of patients with full genome sequence data, there was a Statistically significant increase in the viral mutation rate after the five day course of therapy, as compared to placebo. The briefing document also reported on findings from the Phase | and II studies suggesting that molnupiravir could cause mutations in the SARS-CoV-2 spike protein, a key determinant of host antibody and targeted monoclonal activity. However, there is no clear evidence that emergence of spike protein amino acid changes in MOVe-OUT was associated with a rebound in viral RNA shedding, or prolonged detection of infectious virus beyond treatment day three. Clinicians and policymakers will need to balance the concrete needs of an individual patient for treatment against the theoretical concerns that such treatment has for entire populations. Further, since the EUA of molnupiravir, there have been reports of three cases of hypersensitivity reactions, including anaphylaxis. ©lnstitute for Clinical and Economic Review, 2022 Page 16 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Uncertainty and Controversies Specific to Paxlovid A key source of uncertainty with Paxlovid is the early status of the evidence base. At the time of this Evidence Report, the efficacy and safety of Paxlovid is principally supported by one study, the Phase III EPIC-HR trial.2? This limits our ability to fully evaluate the quality of the study, understand the generalizability of the results, and assess potential subgroup effects. Another potential, albeit theoretical, concern is that viral resistance to Paxlovid, a protease inhibitor, is possible as HIV has developed resistance to certain protease inhibitors. Uncertainty and Controversies Specific to Fluvoxamine Aside from the issues that reduce comparability, it is possible that fluvoxamine may not help contain the population-level spread of COVID-19 as much as other treatment options. In contrast to the other drugs of interest, fluvoxamine treatment did not reduce patient viral load, so it is possible that treated patients could spread the disease for a longer time. This hypothesis was not tested in any of the trials. An additional source of uncertainty specific to fluvoxamine is the large number of study participants who did not adhere to treatment in both the fluvoxamine (26%) and usual care (18%) arms. As noted earlier, there was a much higher relative risk reduction in the primary outcome in the per- protocol analysis (66%) as compared to the intention-to-treat analysis (32%). While the reasons for this lack of adherence are unknown, it is possible that the longer duration of treatment (10 days compared to five days for Paxlovid and molnupiravir) combined with many individuals' symptoms resolving before day 10,°' contributes to lower reported adherence. Fluvoxamine is generally well- tolerated and similar numbers of participants stopped fluvoxamine (n=84) and placebo (n=64) owing to issues of tolerability. None of the Phase Ill trials for the other drugs of interest reported on adherence, so clinicians and policymakers will need to weigh the degree to which the per- protocol results for fluvoxamine should be considered in decision-making. ©lnstitute for Clinical and Economic Review, 2022 Page 17 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents 3.3. Summary and Comment An explanation of the ICER Evidence Rating Matrix (Figure 3.1) is provided here. Figure 3.1. ICER Evidence Rating Matrix Comparative Clinical Effectiveness High y Certainty v ° vu 3 > ly uv <= bo & > Moderate in . <& Certainty g o © o vu > v ~ Low Certainty Negative Comparable Small Substantial Net Benefit Net Benefit Net Benefit Net Benefit Comparative Net Health Benefit A= "Superior" - High certainty of a substantial (moderate-large) net health benefit B = "Incremental" - High certainty of a small net health benefit C = "Comparable"- High certainty of a comparable net health benefit D= "Negative"- High certainty of an inferior net health benefit B+= "Incremental or Better" - Moderate certainty of a small or substantial net health benefit, with high certainty of at least a small net health benefit C+ = "Comparable or Incremental" - Moderate certainty of a comparable or small net health benefit, with high certainty of at least a comparable net health benefit C- = "Comparable or Inferior" - Moderate certainty that the net health benefit is either comparable or inferior with high certainty of at best a comparable net health benefit C++ = "Comparable or Better" - Moderate certainty of a comparable, small, or substantial net health benefit, with high certainty of at least a comparable net health benefit P/l = "Promising but Inconclusive" - Moderate certainty of a small or substantial net health benefit, small (but nonzero) likelihood of a negative net health benefit 1 = "Insufficient" - Any situation in which the level of certainty in the evidence is low ©lnstitute for Clinical and Economic Review, 2022 Page 18 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Molnupiravir Molnupiravir significantly reduced the risk of hospitalization or death from any cause (relative risk reduction of 30%; no 95% Cl reported)./2 Determining the clinical relevance of this relatively small absolute benefit is further complicated by the likelihood of lower baseline risks for progression to serious illness with the Omicron variant, and by lower hospitalization rates in general in the US compared to overseas health systems. Theoretical concerns about an increased risk of evolution of new viral variants and potential side effects due to the mechanism of action also cloud the precision with which the overall net health benefit can be determined. We believe that when molnupiravir use is restricted to the FDA label (e.g., individuals 18 years and older, who are not pregnant or breastfeeding, and who are without alternative COVID-19 treatment options and limited to a course of therapy of five days), much of this risk can be mitigated, but it does not seem unreasonable to assume that these risks may, on a population basis, negate the relatively small clinical benefits. For these reasons, we have assigned an ICER Evidence Rating for the overall net health benefits of molnupiravir of "Comparable or Incremental" (C+). Paxlovid Paxlovid significantly reduced the risk of hospitalization or death from any cause (relative risk reduction of 88%; no 95% Cl reported). The treatment was generally well-tolerated and had low discontinuation rates. There are a large number of known drug interactions with ritonavir that present a safety risk (due to its mechanism of action of inhibiting the cytochrome P450, family III, subfamily A [CYP3A] enzyme).® Further, it is not recommend for patients with severe renal or hepatic impairment. There was only one Phase III RCT to support Paxlovid's efficacy and safety. For these reasons, we believe the evidence is adequate to demonstrate at least incremental net health benefit compared to usual care, but the true magnitude of that benefit cannot be determined given the current status of the evidence and the rapidly evolving COVID-19 landscape. We have assigned an ICER Evidence Rating for the comparative clinical effectiveness of Paxlovid of "incremental or Beiter" (B+). Fluvoxamine Fluvoxamine significantly reduced the risk of COVID-19-related emergency observation (more than six hours) or tertiary hospital stay (RR of 32%; 95% Cl, 12% to 48%) in the TOGETHER trial.° However, there is uncertainty regarding fluvoxamine's efficacy in the US given the relatively wide confidence intervals, differences in health care management and outcomes in Brazil versus the US, the lack of effect on hospitalizations alone, and the potential implications of a smaller US-based trial that was stopped early due to slowing recruitment and lack of efficacy. Further, the relatively long duration of treatment (10 days in the largest trial) may lead to lower real-world adherence and effectiveness. There was a lower percentage of serious adverse events in the intervention arm compared to the placebo arm but there was a sizeable percentage of individuals who stopped ©lnstitute for Clinical and Economic Review, 2022 Page 19 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents treatment due to tolerability in both arms (11.3% and 8.4%, respectively). As an SSRI, fluvoxamine also carries an FDA drug class warning for increased risk of suicidal thinking for children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders.*® For these reasons, we do not feel we can have high certainty in the overall net health benefits of fluvoxamine and have assigned an ICER Evidence Rating of "Comparable or Incremental" (C+). Table 3.4. Evidence Ratings Treatment Comparator Evidence Rating Molnupiravir* Usual care C+ Paxlovid Usual care B+ Fluvoxamine Usual care C+ *Population excludes individuals who are pregnant or who have childbearing potential. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 20 Return to Table of Contents Midwest CEPAC Votes Table 3.5. Votes on Comparative Clinical Effectiveness Question Yes No Given the currently available evidence, is the evidence adequate to demonstrate that the net 3 11 health benefit of molnupiravir is superior to that provided by symptomatic care alone? Given the currently available evidence, is the evidence adequate to demonstrate that the net 13 0 health benefit of Paxlovid is superior to that provided by symptomatic care alone? Given the currently available evidence, is the evidence adequate to demonstrate that the net 7 6 health benefit of fluvoxamine is superior to that provided by symptomatic care alone? A majority of the panel voted that the evidence is inadequate to demonstrate that molnupiravir is superior to symptomatic care alone. Panelists cited the uncertainty around potential harms as well as the dramatic change in efficacy between the interim and final data from the Phase III trial. The panel voted unanimously that the evidence is adequate to determine that Paxlovid is superior to symptomatic care alone. Panel members emphasized the strength of the evidence, and in particular, the relative risk reduction of 88% demonstrated in the Phase Ill trial. Further, Paxlovid was well-tolerated and had low discontinuation rates. The panel was split on whether the evidence was sufficient to demonstrate that fluvoxamine is superior to symptomatic care alone. Panelists who voted "Yes" cited the treatment's ability to reduce the risk of emergency observation and hospital stay, while those who voted "No" expressed uncertainty around adherence, wide confidence intervals, differences in health care management and outcomes in Brazil versus the US, and the lack of clarity around the exact mechanism of action. ©lnstitute for Clinical and Economic Review, 2022 Page 21 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents 4. Long-Term Cost Effectiveness 4.1. Methods Overview The primary aim of this analysis was to estimate the cost effectiveness of REGEN-COV, sotrovimab, molnupiravir, Paxlovid, and fluvoxamine for the treatment of COVID-19. At the time of posting of this Final Evidence Report and Meeting Summary, REGEN-COV and sotrovimab were judged by US authorities to not be effective against the dominant Omicron COVID-19 variant and are no longer authorized within the US. Therefore, economic analyses for REGEN-COV and sotrovimab are not included in this report, but we have included those findings based on pre-Omicron data in Supplement E. We continue to use evidence from the usual care arm of the REGEN-COV and sotrovimab pivotal trials to inform the comparator arm of our economic model due to the large percentage of US patients within each of these trials. We developed a decision analytic model for this evaluation, informed by ICER's inpatient model for COVID-19,% key clinical trials, and other prior relevant economic models."""2 Additional components were added to the model structure to account for the outpatient setting of these interventions of interest. The base-case analysis utilized a lifetime time horizon, with future costs and outcomes discounted at 3% per year, and a health care sector perspective. Productivity changes and the potential for other indirect costs and effects were considered using a modified societal perspective as a scenario analysis. The model focused on an intention-to-treat analysis, with a hypothetical cohort of patients with mild-to-moderate COVID-19 being treated in an outpatient setting entering the model. The target population mirrored that in the pivotal trials and consisted of individuals with mild-to-moderate COVID-19 who also had clinical characteristics denoting a high risk of progression to severe disease or hospitalization. The outcomes in the usual care arm of the model were derived as a weighted average (based on US sample size) across the control arms of the pivotal trials. Given that these trials occurred prior to the emergence of the Omicron variant, it is likely these probabilities of hospitalization, respiratory support, and death may be high in comparison to the current landscape in the US. This approach would overvalue the cost effectiveness of these outpatient interventions. Another difference between the data in the trials and the likely real-world cost effectiveness of treatment is related to the vaccination status of patients in the pivotal trials. The key clinical trials enrolled primarily unvaccinated individuals with COVID-19. For our base case, we chose to model a population including both unvaccinated and vaccinated individuals to reflect what we believe will be the true real-world population of patients treated in the US once these treatments are widely available. The model was developed in Microsoft Excel, Version 2111. A cohort of patients transitioned between health states during cycles of one month over a lifetime time horizon, modeling patients ©lnstitute for Clinical and Economic Review, 2022 Page 22 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents from treatment initiation until death. The model consisted of an acute phase decision tree followed by a lifetime Markov model. The acute phase decision tree represented the COVID-19 infected period and tracked the highest setting of care received (e.g., outpatient management; emergency department visit; or inpatient hospitalization, with stratifications for level of respiratory support received). The acute phase decision tree had a duration of one month in alignment with the typical follow-up period from the pivotal trials. The lifetime Markov model consisted of health states for alive and dead. Individuals in the alive health state who did not experience any long-term sequelae of COVID-19 had costs and consequences characteristic of the general population throughout the Markov model. Individuals who experienced long-term sequelae of COVID-19 had additional utility decrements, costs, and mortality as suggested by the evidence. Patients remained in the model until they died. All patients transitioned to death due to all-cause or COVID-19-specific mortality. The model structure is presented below in Figure 4.1. Figure 4.1. Model Structure COVID-19 Infected Period Post-COVID-19 Infected Period ) \ Outpatient . ; Management Alone Individuals with Mild-to-Moderate COVID-19 anda High Risk of Progression to Severe Disease or Hospitalization Emergency a Department Visit M Inpatient Hospitalization* = to Markov Model *Model included stratifications based on level of respiratory support received. tThe alive health state tracked long-term sequelae and its associated costs and consequences, as data suggested. Cost effectiveness was estimated using incremental cost-effectiveness ratios, with incremental analyses comparing each intervention to usual care. Health outcomes and costs were dependent on the highest setting of care received, respiratory support received if hospitalized, time spent in each health state, clinical events, adverse events, and direct medical costs. Model outcomes included costs, life years, quality-adjusted life years (QALYs), equal-value life years (evLYs), and inpatient hospitalizations. ©lnstitute for Clinical and Economic Review, 2022 Page 23 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents The evidence for the comparator was based on a pooling of the usual care arms from each pivotal trial. Pooling was based on a weighted average across the trials, where the weight assigned was based on the US sample size (i.e., trial overall sample size multiplied by the percent of trial participants from the US). If a model input from the usual care arm of an individual trial was not available, that trial was excluded from the pooling of comparator evidence for that input. If the input was missing from more than 50% of the weighted comparator, literature was used to estimate the model input for those trials that did not report the input. More detail on how missing data were accounted for in the pooling of comparator evidence is explained within the Model Inputs section of Supplement E. In response to public comments and new evidence since the posting of previous versions of this Evidence Report, we have made the following key changes: 1) incorporated new evidence around the percent of infections occurring among those vaccinated; 2) updated the approach for how excess deaths averted are calculated in the modified societal perspective; and 3) added a scenario analysis without future unrelated health care costs. ©lnstitute for Clinical and Economic Review, 2022 Page 24 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents 4.2. Key Model Assumptions and Inputs Our model includes several key assumptions stated in Table 4.1. Additional assumptions may be found in Supplement E. Table 4.1. Key Model Assumptions Assumption Rationale The comparator arm was consistent across all interventions studied. The evidence for the comparator was based on a pooling of the usual care arms from each pivotal trial. Pooling was based ona weighted average across the trials, where the weight assigned was based on the US sample size (i.e., trial overall sample size multiplied by the percent of trial participants from the US). Pooling across the usual care arms from each pivotal trial provided a more generalizable finding to the outcomes experienced by patients receiving usual care by accounting for different time periods within the pandemic, patient populations, and variants. The relative treatment effects reported in each trial were applied to the outcomes from the pooled usual care evidence. The relative effectiveness seen in the trial population was generalizable to the comparator arm in the model that was constructed based on pooling evidence across the usual care arms in the pivotal trials. If a trial did not report a specific treatment effect, or the reported treatment effect was not statistically significant, a treatment effect of 1.0 was assumed. The systematic differences in the trial populations should not affect the relative effectiveness of any of the drugs relative to usual care. We did not compare the cost effectiveness between the interventions given the systematic differences in the trial populations and design. The baseline characteristics of the cohort modeled was consistent across all intervention arms and the comparator arm. The baseline characteristics of the cohort modeled was based on a pooling of the baseline characteristics from each pivotal trial. Pooling was based on a weighted average across the trials, where the weight assigned was based on the US sample size (i.e., trial overall sample size multiplied by the percent of trial participants from the US). The US population eligible for each treatment is expected to be similar based on clinical expert consultation. Pooling across each pivotal trial was likely to provide a more generalizable finding to the population of individuals with mild-to-moderate COVID-19 and a high risk of progression to severe disease or hospitalization. Adjustments were made to the risk of hospitalization and death observed in the usual care arms in the pivotal trials to account for the effectiveness of the vaccine in reducing hospitalization and death for the percent of infected patients that were vaccinated. The trials were either conducted prior to an available vaccine or predominately included unvaccinated individuals. Given that a vaccine is now available, more than 70% of US adults have received at least one dose"? and the vaccine is effective at reducing hospitalization and death even for breakthrough cases,"" the evidence from the trials was weighted by the effectiveness of the vaccine for those individuals who were infected but also vaccinated. Clinical experts advised that these treatments, once widely available, are unlikely to be reserved solely for unvaccinated patients, and, in fact, would likely be widely prescribed for patients who are not at high risk of progression, leading to lower absolute risks of hospitalization and death than those seen in the clinical trials. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 25 Return to Table of Contents Assumption Rationale Deaths in patients who only received outpatient management or an emergency department visit are not common." Further, evidence suggested an increased probability of death with higher levels of respiratory support required during the hospitalization."© Therefore, we modeled deaths averted indirectly based on hospitalizations averted and higher levels of respiratory support within a hospitalization averted. Trial estimates of the Patients were hospitalized prior to dying from COVID- 19. Any deaths averted between the intervention and the comparator arm resulted from reductions in the severity of the hospitalization associated with the treatment. mortality in the intervention arm were not used given the small numbers and clinical rationale that the deaths averted should result from a treatment's effect on averting hospitalizations or reducing the severity of hospitalizations. The model accounted for the long-term sequelae of Recommendations in the US report the occurrence COVID-19 for those who were discharged alive and features characteristic of the long-term sequelae following a hospitalization that required mechanical possible after a COVID-19 infection." Continued ventilation. These long-term sequelae consisted of an | patient engagement is needed to further inform the additional disutility, cost, and mortality risk. long-term sequelae of COVID-19. Key model inputs are described in Table 4.2. The population characteristics used in the model equated to a baseline age of 49 years, and 52% of the population was female. Recent data (from January 2022) suggest that approximately 29% of COVID-19 cases occurring today are among individuals who are fully vaccinated with at least the primary series, and thus our model included a population that was weighted 29% vaccinated versus 71% unvaccinated."? Using this current mix of vaccinated/unvaccinated, the model finds that among patients receiving usual care without an active treatment, 1.5% require an emergency department visit, 3.6% are hospitalized, and the remaining are managed with an outpatient visit alone. In the model, each intervention could reduce the probability of receiving an emergency department visit or being hospitalized, with the relative risk associated with each intervention reported in Table 4.2. For the three interventions included within this review, the pivotal trials did not suggest a treatment effect of the intervention on reducing emergency department visits, potentially because the effect was not statistically significant, the effect was not reported, or emergency department visits were assumed to be included as an outpatient visit. An intervention could also reduce the severity of the respiratory support received, with the relative risk associated with each treatment also reported in Table 4.2. For the three interventions included within this review, the evidence did not suggest a treatment effect of the intervention on reducing the respiratory support required, either because the effect was not reported or the effect was not statistically significant. If evidence becomes available that suggests the three treatments (molnupiravir, Paxlovid, fluvoxamine) reduce the respiratory support required among those hospitalized, the cost effectiveness of these treatments would become more favorable. Among those hospitalized in the comparator arm of the model, the respiratory support received equated to ©lnstitute for Clinical and Economic Review, 2022 Page 26 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents 26% requiring no oxygen support, 35% requiring low-flow oxygen, 29% requiring high-flow oxygen or non-invasive ventilation, and 10% requiring mechanical ventilation. The probability of death among the comparator arm of the model, after pooling across trials and adjusting for the vaccinated population, equated to 0.44%. A treatment could only reduce mortality by way of preventing a hospitalization and/or reducing the severity of the hospitalization. Using recommendations from recent COVID-19 research, our model included post-acute costs and consequences for patients who were discharged alive after being mechanically ventilated. Our model included an increased probability of death for five years (hazard ratio of 1.33), a decrease in quality of life for five years (-0.13 in the first year and -0.04 in years two to five), and an increase in health care costs for one year ($7,859 in the first year) for patients discharged from the hospital alive after being mechanically ventilated." Table 4.2. Key Model Inputs 20212 Parameter Molnupiravir Paxlovid Fluvoxamine Relative Risk of an ED Visit 1.0 1.0 1.0 Relative Risk of a Hospitalization 0.70 0.12 0.68* Relative Risk of Respiratory Support 1.0 10 10 Required Cost of a Treatment Course $707 $529 $12 Primary Source Jayk Bernal et al., FDA EUA label® TOGETHER? ED: emergency department, EUA: Emergency Use Authorization, FDA: Food and Drug Administration *Using the outcome of retention in a COVID-19 emergency setting or transfer to a tertiary hospital, which was suggested by clinical experts as a reasonable proxy for hospitalization in the US. Detail on all inputs used in the model, along with their respective reference, can be found in Supplement E. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 27 Return to Table of Contents 4.3. Results Base-Case Results The total discounted costs, hospitalizations, QALYs, life years, and evLYs over the lifetime time horizon are detailed in Table 4.3. Each outpatient intervention resulted in additional costs, but also resulted in fewer inpatient hospitalizations, resulting in more QALYs, life years, and evLYs. Table 4.3. Results for the Base Case, Health Care Sector Perspective Treatment* Treatment Cost Total Cost Inpatient QALYs Life Years evLYs Hospitalizations Molnupiravir $707 $298,500 | 2.49% 15.9380 | 19.4739 15.9386 Paxlovid $529 $298,500 | 0.43% 15.9637 | 19.5046 15.9654 Fluvoxamine $12 $297,800 | 2.42% 15.9389 | 19.4750 15.9395 Usual Care - $297,700 | 3.56% 15.9247 | 19.4580 15.9247 evLY: equal-value life year, QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Table 4.4 presents the incremental cost-effectiveness ratios from the base-case analysis, which includes estimates for the incremental cost per QALY gained, incremental cost per life year gained, incremental cost per evLY gained, and incremental cost per inpatient hospitalization averted. If evidence becomes available that suggests molnupiravir, Paxlovid, and fluvoxamine reduce the respiratory support required among those hospitalized, the cost effectiveness of these treatments would become more favorable. Table 4.4. Incremental Cost-Effectiveness Ratios for the Base Case, Health Care Sector Perspective Cost per Cost per QALY Cost per Life Cost per evLY Inpatient Treatment* Comparator Gained Year Gained Gained Hospitalization Averted Molnupiravir Usual care $61,000 $51,000 $58,000 $76,000 Paxlovid Usual care $21,000 $18,000 $20,000 $26,000 Fluvoxamine Usual care $8,000 $7,000 $8,000 $10,000 evLY: equal-value life year, QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Sensitivity Analyses To demonstrate the effects of uncertainty on both costs and health outcomes, we varied input parameters using available measures of parameter uncertainty (i.e., standard errors where available or reasonable ranges) to evaluate changes in findings. Supplement Figures E1-E3 present the results from the one-way sensitivity analysis for each intervention as compared to usual care. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 28 Return to Table of Contents Notably, the most influential inputs on the cost effectiveness included the relative risk of hospitalization for each intervention and the probability of hospitalization among usual care. Supplement Tables E15-E17 present the inputs and results for each input that appeared in the tornado diagrams. One-way sensitivity analyses were conducted to vary one input at a time across a plausible range. The results for molnupiravir ranged from further improvement in cost effectiveness to incremental cost-effectiveness ratios that far exceeded common thresholds when the relative risk of hospitalization was near 1.0. Cost-effectiveness estimates for Paxlovid all remained below $100,000 per QALY/evLY gained and ranged as low as to be nearly cost-saving. Paxlovid would become cost-saving at a probability of hospitalization greater than 7% for usual care. Cost- effectiveness estimates in sensitivity analyses for fluvoxamine all remained well below common cost-effectiveness thresholds and included results that the drug would be cost-saving at a probability of hospitalization greater than 5% for usual care. A probabilistic sensitivity analysis was conducted to vary all inputs with noted uncertainty simultaneously. Tables 4.5 and 4.6 present the percent of the 1,000 iterations that were beneath thresholds of $50,000, $100,000, $150,000, and $200,000 per QALY gained and evLY gained. The majority of the iterations were beneath thresholds of $100,000 per QALY gained or per evLY gained. Additional results from the probabilistic sensitivity analyses can be found in Supplement Tables E18- E19 and Supplement Figures E4-E6. Table 4.5. Probabilistic Sensitivity Analysis Incremental Cost per QALY Gained Results Cost Effective at Cost Effective at Cost Effective at Cost Effective at Treatment* $50,000 per $100,000 per $150,000 per $200,000 per QALY Gained QALY Gained QALY Gained QALY Gained Molnupiravir 31% 69% 84% 89% Paxlovid 97% 100% 100% 100% Fluvoxamine 100% 100% 100% 100% QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Table 4.6. Probabilistic Sensitivity Analysis Incremental Cost per evLY Gained Results Cost Effective at Cost Effective at Cost Effective at Cost Effective at Treatment* $50,000 per evLY | $100,000 per evLY | $150,000 per evLY | $200,000 per evLY Gained Gained Gained Gained Molnupiravir 33% 71% 85% 90% Paxlovid 98% 100% 100% 100% Fluvoxamine 100% 100% 100% 100% evLY: equal-value life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 29 Return to Table of Contents Threshold Analyses Threshold analyses were conducted to identify at what treatment course price each intervention would meet certain cost-effectiveness thresholds. Tables 4.7 and 4.8 present the findings from these threshold analyses using outcomes of both the QALY and evLY, respectively. Table 4.7. QALY-Based Threshold Analysis Results, Health Care Sector Perspective Treatment Treatment Treatment Treatment Current Course Price Course Price Course Price Course Price Treatment* Treatment to Achieve to Achieve to Achieve to Achieve Course Price $50,000 per $100,000 per | $150,000 per | $200,000 per QALY QALY QALY QALY Molnupiravir $707 $560 $1,200 51,900 $2,600 Paxlovid $529 $1,660 $3,600 $5,600 $7,500 Fluvoxamine $12 $600 $1,300 $2,000 $2,700 QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Table 4.8. evLY-Based Threshold Analysis Results, Health Care Sector Perspective Treatment Treatment Treatment Treatment Treatment Course Price Course Price Course Price Course Price Treatment* Course Price to Achieve to Achieve to Achieve to Achieve $50,000 per $100,000 per $150,000 per $200,000 per evLY evLY evLY evLY Molnupiravir $707 $590 $1,300 52,000 $2,700 Paxlovid $529 $1,750 $3,800 55,800 $7,800 Fluvoxamine $12 $630 $1,400 $2,100 $2,900 evLY: equal-value life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Scenario Analyses We conducted numerous scenario analyses to assess the robustness of the results across different economic perspectives and different assumptions about critical features of the evolving epidemiology of COVID-19 and corresponding health care utilization. Scenario Analysis 1: Modified Societal Perspective In the modified societal perspective, we included societal costs and outcomes associated with productivity gains/losses and ICU capacity. Supplement E provides information on the methods and inputs used to generate estimates from the modified societal perspective. Table 4.9 reports the model outcomes from the modified societal perspective. Tables 4.10 and 4.11 report the threshold prices from the modified societal perspective using outcomes of both the QALY and evLyY, Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 30 Return to Table of Contents respectively. The threshold prices were higher in the societal perspective as compared to the health care sector perspective for treatments. Although we do not present the societal perspective as a co-base-case, we acknowledge it may have particular relevance when the government is paying for the treatments outside of usual health care cost budgets. The pricing and value considerations for these treatments will transition shortly to the private market. Table 4.9. Model Outcomes, Modified Societal Perspective Treatment* ia Total Costt ICU Admissions QALYst | Life Yearst evLYst Molnupiravir $707 $301,400 | 0.97% 15.9524 19.4916 15.9537 Paxlovid $529 $302,300 | 0.17% 16.0059 19.5566 16.0097 Fluvoxamine $12 $300,800 | 0.95% 15.9543 19.4939 15.9556 Usual Care -- $300,200 | 1.39% 15.9247 19.4580 15.9247 evLY: equal-value life year, ICU: intensive care unit, QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. tIncludes costs/outcomes for the treated patient and any excess death averted as a societal benefit. Table 4.10. QALY-Based Threshold Analysis Results, Societal Perspective Treatment Treatment Treatment Treatment Treatment Course Price Course Price Course Price Course Price Treatment* Course Price to Achieve to Achieve to Achieve to Achieve $50,000 per $100,000 per | $150,000 per | $200,000 per QALY QALY QALY QALY Molnupiravir $707 $830 $2,200 $3,600 $5,000 Paxlovid $529 $2,400 $6,500 510,600 $14,600 Fluvoxamine $12 $880 $2,400 $3,800 $5,300 QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Table 4.11. evLY-Based Threshold Analysis Results, Societal Perspective Treatment Treatment Treatment Treatment Treatment Course Price Course Price Course Price Course Price Treatment* Course Price to Achieve to Achieve to Achieve to Achieve $50,000 per $100,000 per | $150,000 per | $200,000 per evLY evLY evLY evLY Molnupiravir $707 $890 $2,300 $3,800 $5,200 Paxlovid $529 $2,600 $6,900 $11,100 $15,400 Fluvoxamine $12 $950 $2,500 $4,000 $5,600 evLY: equal-value life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 31 Return to Table of Contents Scenario Analysis 2: Unvaccinated Population Only In this scenario analysis, we restricted the population to unvaccinated individuals and therefore did not make any adjustments to the usual care arms from the pivotal trials used in the pooled comparator arm of our model. Table 4.12 reports the incremental cost-effectiveness ratios for this subpopulation. Cost-effectiveness estimates for this subpopulation were slightly more favorable than the base-case estimates that included vaccinated individuals. Table 4.12. Incremental Cost-Effectiveness Ratios for Unvaccinated Only Subpopulation Cost per Cost per QALY Cost per Life Cost per evLY Inpatient Treatment* Comparator Gained Year Gained Gained Hospitalization Averted Molnupiravir Usual care $48,000 $41,000 $46,000 $51,000 Paxlovid Usual care $15,000 $12,000 $14,000 $15,000 Fluvoxamine Usual care $4,000 $3,000 $3,800 $4,000 evLY: equal-value life year, QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Scenario Analysis 3: Lower Probability of Hospitalization In this scenario analysis, we reduced the probability of hospitalization among usual care by half of what was used in the base case. Recent research has suggested that the Omicron variant of COVID- 19 may be associated with a reduced risk of severe clinical endpoints (e.g., hospitalization) by approximately half.*" Thus, in this scenario analysis, we assumed a probability of hospitalization among usual care of approximately 2%. Table 4.13 reports the incremental cost-effectiveness ratios for this subpopulation. Not surprisingly, cost-effectiveness estimates for this scenario were less favorable than our base-case estimates that assumed a higher probability of hospitalization, but all incremental results remained lower than $100,000 per additional QALY/evLY. Table 4.13. Incremental Cost-Effectiveness Ratios for Lower Risk Subpopulation Cost per Cost per QALY Cost per Life Cost per evLY Inpatient Treatment* Comparator Gained Year Gained Gained Hospitalization Averted Molnupiravir Usual care $74,000 $61,000 $71,000 $181,000 Paxlovid Usual care $34,000 $27,000 $32,000 $82,000 Fluvoxamine Usual care $21,000 $17,000 $20,000 $50,000 evLY: equal-value life year, QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 32 Return to Table of Contents Scenario Analysis 4: Exclusion of Future Unrelated Health Care Costs In this scenario analysis, we excluded future unrelated health care costs despite best practices recommending their inclusion."" Table 4.14 reports the incremental cost-effectiveness ratios for this scenario. Not surprisingly, cost-effectiveness estimates for this scenario are more favorable than our base-case estimates because this scenario includes the future life years gained but excludes the future costs associated with those life years gained. Table 4.14, Incremental Cost-Effectiveness Ratios Excluding Future Unrelated Health Care Costs Cost per Cost per QALY Cost per Life Cost per evLY Inpatient Treatment* Comparator Gained Year Gained Gained Hospitalization Averted Molnupiravir Usual care $30,000 $25,000 $29,000 $37,000 Paxlovid Usual care Cost-saving Cost-saving Cost-saving Cost-saving Fluvoxamine Usual care Cost-saving Cost-saving Cost-saving Cost-saving evLY: equal-value life year, QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Model Validation We used several approaches to validate the model. First, we provided the preliminary model structure, methods, and assumptions to manufacturers. Based on feedback from these groups, we refined data inputs used in the model. Second, we varied model input parameters to evaluate face validity of changes in results. We performed model verification for model calculations using internal reviewers. As part of ICER's efforts in acknowledging model transparency, we also shared the model with relevant manufacturers for external verification around the time of publishing the draft Evidence Report. Finally, we compared results to other cost-effectiveness models in this therapy area. The outputs from the model were validated against the trial/study data of the interventions. Uncertainty and Controversies The COVID-19 pandemic continues to evolve as new variants emerge, vaccination uptake slowly increases, and the role of booster vaccinations becomes a major issue. Linked to these factors, the rate of new infections changes across seasons of the year and region of the country. The management of more serious disease also evolves, resulting in ever-changing approaches to the "usual care" of patients in emergency room and hospital settings. And all these evolving factors also affect overall hospital capacity in different regions of the country as well as broader considerations of policies such as management of infections in school and business settings. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 33 Return to Table of Contents As these factors evolve, the impact and the cost effectiveness of new therapies for outpatient treatment change. To capture this uncertainty and variability, we have conducted numerous sensitivity and scenario analyses. Key analyses are described above and further details on these analyses and others can be found in Supplement E. Our base-case analysis used a common pooled comparator for each intervention. If we had chosen to compare each intervention to its own usual care arm in its pivotal trial, we would have provided very context-specific results. Pooling across the usual care arms of these pivotal trials allowed us to be more generalizable to the eligible population and representative of various secular trends observed. Given the wide differences in usual care outcomes across the trials, we believe the pooled comparator approach we used will be less likely to provide results that could be misinterpreted. Another reason for our selection of a pooled comparator approach was driven by input from clinical experts. Experts advised us that, with the exception of the pregnancy limitations on molnupiravir and drug-drug interaction concerns with Paxlovid, clinicians will view these drugs as possible choices for the same population of patients. We therefore pooled the demographic characteristics (e.g., age and sex) across the pivotal trials to unify the population characteristics in the economic model. Given that we pooled the demographic characteristics, it was imperative that we also pool the outcomes (hospitalization, death) given the documented relationship between age and these outcomes. Our current approach to estimate the hospitalization risk, a key driver of model findings, was based on what was observed in the pooling of the pivotal trials. However, we understand the pandemic rapidly evolves and the hospitalization risk may change based on which variant(s) exist and which are dominant. Our justification for a pooled approach notwithstanding, any pooling of data introduces its own degree of uncertainty due to systematic differences among the trials (e.g., definition of hospitalization, symptom days to start treatment, etc.) that could influence the relative effectiveness estimate for each intervention. All stakeholders should be aware that due to all of the factors that make this report a Special Assessment, we advise heightened caution in making inferences of intervention versus intervention cost effectiveness and suggest that stakeholders make use of ICER Analytics to update analyses with new data on relative clinical effectiveness and health care utilization as they become available. Our model captures the long-term sequelae of COVID-19 through an increased mortality, increased cost, and decreased quality of life for individuals that are discharged alive after being mechanically ventilated. This approach follows recently published recommendations, but we understand that uncertainty and variability in these long-term sequelae exist, and the evidence is continuing to evolve, especially as it relates to the prevalence, duration, associated consequences, and the influence of an outpatient COVID-19 treatment on these sequelae. Ongoing engagement with patients will be important to further inform the long-term sequelae associated with COVID-19. ©lnstitute for Clinical and Economic Review, 2022 Page 34 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Our modified societal perspective has important limitations and assumptions to consider when interpreting the estimates. In the modified societal perspective, we included productivity gains/losses for the patient treated during the time of the COVID-19 infection and the indirect costs and benefits to society associated with alleviating ICU capacity. We heard from stakeholders that these outpatient COVID-19 treatments could play an important role in reducing ICU capacity, and reducing health system overload is undoubtedly a good outcome for society. Capturing these system-level capacity constraints is challenging, but we attempted to do so. In our approach, we extrapolated evidence around system-level capacity outcomes to an indirect societal benefit at the per-treated patient level to quantify this in the model. We had to make numerous methodological assumptions. First, we calculated the excess deaths by calculating the slope from the non-COVID-19 ICU occupancy to the total ICU occupancy (COVID-19 and non-COVID-19 ICU stays). Second, we assumed that the excess deaths averted at the national-occupancy level could be divided evenly among each ICU admission to estimate a per-treated patient effect. Our model did not include the potential productivity benefits associated with preventing premature mortality nor did it include the potential societal costs that may result if fewer people receive vaccinations with the availability of these treatments. Because the incremental cost-effectiveness ratios did not cross the $100,000 or $150,000 threshold between the two perspectives, the modified societal perspective was not presented as a co-base-case. 4.4 Summary and Comment Our analyses suggest that each outpatient intervention produces improved clinical outcomes. At their current prices, each intervention is estimated to meet standard cost-effectiveness levels in the US health care system, even under a scenario with a lower hospitalization risk that may reflect the current Omicron wave. The cost-effectiveness findings are primarily driven by a treatment's ability to reduce hospitalization and the baseline probability of hospitalization. ©lnstitute for Clinical and Economic Review, 2022 Page 35 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents 5. Contextual Considerations and Potential Other Benefits Our reviews seek to provide information on potential other benefits offered by the intervention(s) to the individual patient, caregivers, the delivery system, other patients, or the public that were not captured in clinical trials and may not be fully captured within the cost-effectiveness model. These elements are listed in the table below and on the following page, with related information gathered from patients and other stakeholders. Table 5.1. Contextual Considerations Contextual Consideration Relevant Information Acuity of need for treatment of individual patients based on short-term risk of death or progression to permanent disability The acuity of need for treatment is low given the relatively low rates of hospitalization and death from COVID-19 in the population of interest. Magnitude of the lifetime impact on individual patients of the condition being treated The magnitude of lifetime impact is expected to be low. While a certain proportion of patients experience long-term symptoms, the large majority of patients no longer experience symptoms by 12 weeks, ®7,78 ©lnstitute for Clinical and Economic Review, 2022 Page 36 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Table 5.2. Potential Other Benefits or Disadvantages Potential Other Benefit or Disadvantage Relevant Information Patients' ability to achieve major life goals related to education, work, or family life COVID-19 has a low impact on patients' ability to achieve life goals. While the acute phase of infection limits activities of daily living, this phase is short. Caregivers' quality of life and/or ability to achieve major life goals related to education, work, or family life COVID-19 has low impact on caregivers' quality of life and ability to achieve life goals, given the limited duration of acute illness. Patients' ability to manage and sustain treatment given the complexity of regimen All treatments are short term and not expected to impose a substantial burden for administration. Some patients may prefer oral treatments over injectable treatments. Society's goal of reducing health inequities COVID-19 has had a higher prevalence and greater severity within communities of color in the US. Non-White COVID-19 patients and patients living in rural areas appear to be less likely to receive neutralizing antibody treatment for COVID-19."9* If the oral drugs of interest (molnupiravir, Paxlovid, and fluvoxamine) are fairly distributed, these drugs would have some role in addressing the ongoing disparities in care and outcomes in disadvantaged communities since neutralizing antibody treatments require administration by a health care professional typically in an infusion facility or hospital. Preventing spread of COVID-19 By reducing viral loads, molnupiravir, and Paxlovid could theoretically reduce the likelihood of treated individuals spreading SARS-CoV-2. However, this may be counteracted by symptom improvements among treated individuals that result in more social interactions than in untreated individuals. Improving hospital capacity Surges in hospitalizations for COVID-19 strain available capacity of local health systems to appropriately care for COVID-19 patients as well as patients with other conditions who require hospitalization.®23 The drugs of interest have a potential other benefit of alleviating hospital capacity by reducing hospitalization rates among the treated. We have sought to capture this quantitatively in the societal perspective analysis, but further consideration may be warranted. Providing support for policies to manage the pandemic with fewer restriction on schools and businesses Effective outpatient treatments for mild-moderate COVID-19 may help provide psychological reassurance allowing for broader opening of schools and workplaces. Drug-Specific Potential Benefits/Disadvantages Molnupiravir Molnupiravir cannot be used in people who are attempting to conceive or who are pregnant. Paxlovid Paxlovid is a combination therapy containing ritonavir. Ritonavir has a large number of known drug-drug interactions that pose a safety risk. These include interactions with certain anticoagulants, antiplatelets, antiarrhythmics, anticonvulsants, and immunosuppressants.® These interactions are especially important among patients who are at particularly high risk for severe COVID-19 disease (e.g., immunosuppressed patients)." Fluvoxamine Fluvoxamine affects a different phase in COVID-19 pathophysiology and therefore it may be possible to combine its use with other agents. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 37 Return to Table of Contents Midwest CEPAC Votes Table 5.3. Votes on Contextual Considerations and Potential Other Benefits patients of the condition being treated : . Very Low Low Average High Very High Contextual Consideration priority Priority Priority priority priority Acuity of need for treatment of individual patients based on short-term risk of death or 0 2 2 progression to permanent disability Magnitude of the lifetime impact on individual 0 4 0 A majority of the panel voted that treatments for COVID-19 should be given high priority relative to other diseases. Although rates of COVID-19 have decreased, many panelists felt that effective treatments would offer additional protection for vulnerable populations, including individuals with comorbidities and those of older age. Further, though theoretical, effective treatments for COVID- 19 may help address long COVID. Potential Other Benefits and Disadvantages Effective outpatient treatments for mild-moderate COVID-19 may help reduce population spread of COVID-19. Effective outpatient treatments for mild-moderate COVID-19 may reduce the number of hospitalized patients enough to increase capacity to treat non-COVID-19-related conditions. pandemic in disadvantaged communities. Effective outpatient treatments for mild-moderate COVID-19 will help address the disparate burden of the Effective outpatient treatments for mild-moderate COVID-19 may help provide psychological reassurance allowing for broader opening of schools and workplaces. Molnupiravir cannot be used in people who are attempting to conceive or who are pregnant. Paxlovid has many drug-drug interactions that may limit the number of patients who can use it. its use with other agents. Fluvoxamine affects a different phase in COVID-19 pathophysiology and therefore it may be possible to combine The above table includes potential benefits or disadvantages specific to the review of outpatient treatments for COVID-19. No vote was taken on these elements. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 38 Return to Table of Contents 6. Health-Benefit Price Benchmarks The health-benefit price benchmark is defined as the price range that would achieve incremental cost-effectiveness ratios between $100,000 and $150,000 per QALY gained or per evLY gained. health-benefit price benchmarks for the cost of a treatment course for each outpatient treatment are presented in Table 6.1. Table 6.1. Health-Benefit Price Benchmarks for Outpatient Treatments for COVID-19 Treatment Course Treatment Course Treatment* Treatment Price at Price at Discount to Reach Course Price $100,000/QALY $150,000/QALY Threshold Prices Threshold Threshold Molnupiravir $707 $1,200 $1,900 | No discount needed Paxlovid $529 $3,600 $5,600 | No discount needed Fluvoxamine $12 $1,300 $2,000 | No discount needed Treatment Course Treatment Course Treatment* Treatment Price at Price at Discount to Reach Course Price $100,000/evLY $150,000/evLY Threshold Prices Gained Threshold Gained Threshold Molnupiravir $707 $1,300 $2,000 | No discount needed Paxlovid $529 $3,800 $5,800 | No discount needed Fluvoxamine $12 $1,400 $2,100 | No discount needed evLY: equal value of life years, QALY: quality-adjusted life year *We advise against comparing the cost effectiveness between interventions given the systematic differences in the trial populations and design. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 39 Return to Table of Contents Midwest CEPAC Votes Table 6.2. Votes on Long-Term Value for Money at Current Prices Question Low Intermediate High Given the available evidence on comparative effectiveness, incremental cost effectiveness, and potential other benefits or disadvantages, what is the long-term value for money of treatment at current pricing with molnupiravir versus usual symptomatic care? Given the available evidence on comparative effectiveness, incremental cost effectiveness, and potential other benefits or disadvantages, what is the long-term value for money of treatment at current pricing with Paxlovid versus usual symptomatic care? Given the available evidence on comparative effectiveness, incremental cost effectiveness, and potential other benefits or disadvantages, what is the long-term value for money of treatment at current pricing with fluvoxamine versus usual symptomatic care? A majority of the panel voted that molnupiravir represents a "low" value for money at current pricing. Although molnupiravir's incremental cost-effectiveness ratio is below traditional thresholds, panelists reiterated the substantial uncertainty around the data (as described in Section 3). On Paxlovid, eight out of 13 panelists voted "high," in line with the treatment's favorable incremental cost-effectiveness ratio ($21,000 per QALY gained) and the strength and magnitude of the clinical evidence. Lastly, and similar to the vote on clinical evidence, the panel was somewhat split on fluvoxamine, with seven panelists voting "intermediate" and five voting "high." Although fluvoxamine had the lowest cost per QALY gained at $8,000, there still exists considerable uncertainty around the evidence. Olnstitute for Clinical and Economic Review, 2022 Special Assessment of Outpatient Treatments for COVID-19 Page 40 Return to Table of Contents 7. Potential Budget Impact A potential budget impact analysis was not conducted for this Special Assessment. Due to the narrow margins of cost and survival benefit, a potential budget impact analysis was not considered policy relevant. ©lnstitute for Clinical and Economic Review, 2022 Page 41 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents 8. Policy Recommendations Following its deliberation on the evidence, the Midwest CEPAC engaged in a moderated discussion with a policy roundtable about how best to apply the evidence on the use of outpatient treatments for COVID-19. The policy roundtable members included one patient advocate, two clinical experts, two payer representatives, and three representatives from the drug companies. The discussion reflected multiple perspectives and opinions, and therefore, none of the statements below should be taken as a consensus view held by all participants. Federal Government Federal policymakers should view the advance market commitment strategy followed with outpatient COVID-19 treatments as a success that should be built upon. The federal government's advance market commitment mechanism was effective in reducing the financial uncertainty that could deter manufacturers from bringing a drug to market. These financial risks are due to uncertainty regarding the expected market size and duration because of difficulty in predicting to FDA indication, uptake by providers, and evolving variants with different treatment susceptibility and virulence. The federal government's advance market commitment approach substantially reduced manufacturer risk and resulted in multiple drugs becoming available in a relatively short time at prices that were aligned with clinical benefit. The framework for drug price negotiation between the government and drug makers during a pandemic should be made more transparent so that the public is aware of the parameters that the federal government considers in pricing negotiations. There is a lack of clarity regarding the parameters that the federal government uses to negotiate drug prices and the justification for the amount of treatment purchased for different therapies. Such frameworks for pricing and volume should be determined prior to the pandemic. The federal government should continue to include pricing protection clauses in future pricing negotiations in order to be good stewards of tax-funded budgets. The contract terms between the federal government and Pfizer for Paxlovid were made public through a FOIA request.®* The contract terms included a buyback clause in which Pfizer would buy back the US government's Paxlovid supply if its EUA were withdrawn. The contract also contained a most-favored nation clause, which guarantees that if one of six other high-income countries gets a lower price, the US would automatically get the same lower price. Such provisions provide assurance that tax-funded budgets are being used to purchase treatments that are aligned with clinical benefit. ©lnstitute for Clinical and Economic Review, 2022 Page 42 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents The FDA needs to establish a clear and effective pathway for supporting evaluation of repurposed drugs. Since manufacturers do not have a direct financial incentive to pursue FDA authorization to repurpose off-patent drugs for the treatment of COVID-19, the FDA needs to establish a proactive pathway to identify potential drugs where the data suggests that a review is warranted. For instance, this may include proactive outreach to study investigators to invite applications and providing technical assistance during application development as well as internal application initiation and development by the FDA. The federal government needs to work with stakeholders to develop more robust data infrastructure and standardized treatment allocation approaches to achieve more efficient and equitable distribution of treatment supplies during a pandemic. A recent study of Medicare beneficiaries reported that from November 2020 to August 2021 only 7.2% of outpatients with a new COVID-19 diagnosis received monoclonal antibody treatment.®° A large proportion of these patients are likely eligible for treatment since older age and many chronic conditions common among the elderly are risk factors for severe COVID-19. The study also found that some of the highest risk patients were the least likely to receive treatment and that there was also substantial variation in the percent of patients treated across states with Rhode Island (21%) and Washington state (1%) having the highest and lowest percentages, respectively. Greater investment in data infrastructure is needed to prioritize the communities where treatments are most needed. Often, these are communities in which there are many people of color or other communities in which access to care is inadequate. The federal government also needs to develop a standardized approach to allocating treatments to states and for states to collaborate with private distributors systems in a manner that ensures equitable and efficient distribution. Without appropriate data infrastructure and standardized approaches to distribution of supplies from the federal government to states and private entities, the distribution of new treatments for COVID-19 will continue to be ad hoc and likely to exacerbate inequities. The federal government should work with states and other policymakers to adopt policy changes needed to improve the effectiveness of its "test-to-treat" program. As of April 2022, there is a paucity of sites nationwide that provide point-of-care testing and treatment in a single visit.2°> While limited in number, CVS Health's "MinuteClinics" are an emerging example of how such a test and treat strategy can be implemented. These clinics have co-located services for testing, prescribing, and pharmacy supply where patients may access all three services in a single visit. Test-to-treat sites like these are greatly needed to more immediately link diagnosis with treatment. ©lnstitute for Clinical and Economic Review, 2022 Page 43 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents One barrier to implementing test-to-treat is the FDA's restrictions on who may prescribe COVID-19 outpatient treatments.®°*" Given the need for rapid and broad distribution of treatment during a pandemic, the federal government should consider working with states and professional stakeholders to broaden the functional scope of practitioners who can prescribe COVID-19 treatments. It may be possible to use telemedicine or other means to accomplish this goal, but allowing pharmacists to prescribe under certain circumstances should also be considered. Beyond prescribing, strategies should also be developed to increase the options for testing and for delivering medications to patients, including mobile units, kiosks, and even drones. This kind of infrastructure should be considered a long-term strategic priority for the federal government as it assesses preparedness for future pandemics. The federal government needs to ensure that test-to-treat sites are equitably located. COVID-19 has had a higher prevalence and greater severity within communities of color in the US. Non-White COVID-19 patients and patients living in rural areas appear to be less likely to receive neutralizing antibody treatment for COVID-19."?*! Further, test-to-treat sites, which offer the convenience of co-located services, may differentially benefit individuals with low incomes since these individuals may have lower means to make multiple visits to access testing and treatment. Therefore, the location of test-to-treat sites should address such access disparities. Guideline Developers Guideline developers (including clinical societies®® and the National Institutes of Health®?) should adopt certain best practices in guideline development. These include: e Involving patients from diverse communities in guideline development to make sure that patient preferences are reflected in guidelines. e Defining the target audience of their guideline, whether it is individual primary care providers or specialists, health system leaders, payers, or policymakers. e Tailoring guidelines to the target audience such that the guidelines can serve as useful decision aids rather than just data summaries. e To the extent possible, different guideline development groups should coordinate and communicate so that recommendations are consistent across groups. ©lnstitute for Clinical and Economic Review, 2022 Page 44 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Manufacturers Manufacturers should anticipate from the earliest possible stage how they will share COVID-19 treatment intellectual property with low-income countries and, if possible, provide technical assistance with scaling of the manufacturing process. Given the large global health burden of COVID-19, and the inability to contain spread of SARS-CoV2 across borders, it is imperative that we manage the pandemic from a global perspective. Manufacturers should consider development of additional treatment options for immunocompromised patients. There are seven million immunocompromised adults in the US. These individuals have among the highest risks for severe COVID-19.% Further, immunocompromised patients may remain infectious for a longer period of time than non-immunocompromised patients. Yet for immunocompromised patients, vaccines have lower efficacy in preventing severe COVID-19. Further, some patients on immunosuppressants may not be able to use Paxlovid due to drug interactions.* Molnupiravir may have relatively lower efficacy and has not specifically been tested in this population. Therefore, manufacturers should consider developing treatment options to address this unmet need. Payers and Manufacturers When COVID-19 drug pricing and payment moves from federal contracts into private markets, manufacturers and payers should work together to explore innovative approaches for coverage and pricing that minimize the use of restrictive coverage access as a means of cost control. Recommendations for Manufacturers e Manufacturers should price treatments so they are affordable to private insurance systems and patients. Aligning the price with the relative benefit to patients, as measured in cost- effectiveness analysis, is a good starting point, but other factors should be weighed as well. The scale and immediacy of the need for treatments can create an affordability challenge even with value-based pricing. Similarly, lower pricing or some form of installment payment over a longer time period may be warranted when there has been federal investment in the early science or later development of a drug. e For uninsured and underinsured patients, manufacturers should collaborate with governmental policymakers to ensure that patients have access to treatments independent of their ability to pay out of pocket. e Manufacturers should consider collaborating with private payers on innovative reimbursement approaches. For example, these approaches may include subscription-based models in which manufacturers provide as much supply of drugs as needed for a flat ©lnstitute for Clinical and Economic Review, 2022 Page 45 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents recurring fee.*2 Alternately, manufacturers and payers should consider volume-based purchasing models similar to current federal contracts where a pre-specified volume of drugs are supplied at an agreed upon price. Recommendations for Payers e Given the need to treat COVID-19 rapidly upon symptom onset, payers should ensure that any prior authorization process leads to immediate coverage for an available and appropriate treatment and does not risk having patients not fill their prescriptions. e The treatments available currently through EVA are so different in their effectiveness and their risk and side effect profiles that any form of step therapy would not be clinically appropriate. In the future, if there are multiple therapeutically equivalent oral outpatient treatment options for COVID-19, payers may consider formulary negotiation approaches that include the possibility of step therapy as long as those coverage policies follow criteria established to protect patients. Researchers Future research is needed to understand the epidemiology of long COVID and the impact of different prevention and treatment strategies on this condition. Current estimates of the number of Americans with long COVID are imprecise, but may be as high as eight to 23 million.2? Common symptoms include fatigue, shortness of breath, and cognitive dysfunction typically one to three months after initial infection.°"°° Given the potentially large population and non-specific symptoms, more research is needed to understand the incidence, prevalence, risk factors, and symptoms of long COVID as well as ways to prevent and treat this condition. Among the treatments of interest in our review, we identified only one study that evaluated the impact of treatment on long COVID,® although we identified other treatments in earlier stages of development focusing specifically on treatment of individuals with long COVID.272° We recommend that the clinical research community work with patients in the design and conduct studies of long COVID and that the federal government fund these studies. Future research is needed to define and measure the effects of treatments on a more inclusive set of patient-centered and societal outcomes. The key trials in our review primarily measured efficacy in clinical terms including viral load, hospitalization, and death. In these trials, there was a lack of inclusion of patient-reported outcomes and a lack of uniformity in those outcomes when they were reported. The key trial for Paxlovid did not measure patient-reported outcomes.**! The key fluvoxamine trial? measured the patient-reported outcomes measurement information (PROMIS) Global Health Scale while the key molnupiravir trial'? measured specific patient-reported COVID-19 symptoms. Researchers should work to define patient-important outcomes and clinical trialists should apply them uniformly across ©lnstitute for Clinical and Economic Review, 2022 Page 46 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents trials. For instance, patient-important outcomes in COVID-19 could include time to recovery and restoration of activities of daily living. Further, the impacts of improving ICU capacity, caregiver burden, and broader impacts on the opening of education and businesses are important societal outcomes that require better measurement. ©lnstitute for Clinical and Economic Review, 2022 Page 47 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents References 1. 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Cook DJ, Mulrow CD, Haynes RB. Systematic reviews: synthesis of best evidence for clinical decisions. Ann Intern Med. 1997;126(5):376-380. Higgins J, Thomas, J, Chandler, J, Cumpston, M, Li, T, Page, MJ, Welch, VA. Cochrane Handbook for Systematic Reviews of Interventions version 6.1 (updated September 2020). Published 2020. Accessed, Moher D, Liberati A, Tetzlaff J, Altman DG, The PG. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLOS Medicine. 2009;6(7):e1000097. ©lnstitute for Clinical and Economic Review, 2022 Page 53 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents 116. Ollendorf DA, Pearson SD. An integrated evidence rating to frame comparative effectiveness assessments for decision makers. Medical care. 2010;48(6 Suppl):S145-152. 117. Ollendorf D, Pearson, SD. ICER Evidence Rating Matrix: A User's Guide. . Published 2020. Updated January 31, 2020. Accessed. 118. Mlcochova P, Kemp SA, Dhar MS, et al. 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Fluvoxamine for Early Treatment of COVID-19: The STOP COVID Clinical Trials. August 20, 2021, 2021. ©lnstitute for Clinical and Economic Review, 2022 Page 54 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Supplemental Materials ©lnstitute for Clinical and Economic Review, 2022 Page 55 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents A. Background: Supplemental Information A1. Definitions Intervention Definitions Casirivimab/imdevimab (REGEN-COV) is a cocktail of two recombinant human monoclonal antibodies administered as a onetime IV infusion or subcutaneous injection of 600 mg of each antibody. It works by binding to the receptor-binding domain of the SARS-CoV-2 spike protein, inhibiting either attachment or fusion to human cells. At the time of this report, REGEN-COV not authorized in any US region. Sotrovimab is a recombinant human monoclonal antibody administered as a onetime 500 mg IV infusion. It works by binding to the receptor-binding domain of the SARS-CoV-2 spike protein, inhibiting either attachment or fusion to human cells. At the time of this report, sotrovimab is not authorized in any US region. Outcome Measure Definitions COVID-19 progression: Progression of signs and symptoms of COVID-19 (i.e., cough, body ache, and fever) that gives insight into the course of disease and resources required during the illness.1° WHO 11-Point Clinical Progression Scale: An ordinal scale used to represent clinical progression of COVID-19 from mild, moderate, and severe stages, with a score of 0 being assigned to people who are uninfected and have no detectable viral RNA and a score of 10 being assigned to people who die.1° Viral clearance: Period when a patient is determined to have a negative nasopharyngeal or PCR test (two negative tests may be required to be confirmed as being negative).*% InFLUenza Patient-Reported Outcome (FLU-PRO): A standardized measure of symptom severity for influenza patient-reported outcomes that requires a patient to record symptoms twice daily for 14 days to assess the presence, severity, and duration of symptoms across six body systems. SARS-CoV-2 antigen test: A diagnostic test that can generate results in approximately 15 minutes at the point-of-care. These tests tend to have high diagnostic specificity but lower sensitivity than molecular diagnostic tests. Molecular diagnostic tests: A category of laboratory-based nucleic acid amplification tests that include reverse-transcription PCR tests. Molecular diagnostic tests are considered the gold standard for diagnostic COVID-19 testing and are also used for quantifying COVID-19 viral load. ©lnstitute for Clinical and Economic Review, 2022 Page Al Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Oxygen saturation: Defined as the percentage of hemoglobin in the blood that is bound to oxygen as oxyhemoglobin relative to total hemoglobin in the blood. This is typically measured using a rapid, noninvasive pulse oximeter. Hospitalization with oxygen saturation below 94% is considered severe disease.?% Variant of concern: Defined by the CDC as a variant "for which there is evidence of an increase in transmissibility, more severe disease, significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures."?°" COVID-19 viral load: Measures SARS-CoV-2 concentration after nucleic acid amplification. Viral load is typically used as secondary or surrogate measures for more clinically relevant measures such as hospitalization or death. A2. Potential Cost-Saving Measures in COVID-19 ICER includes in its reports information on wasteful or lower-value services in the same clinical area that could be reduced or eliminated to create headroom in health care budgets for higher-value innovative services (for more information, see |CER's Value Assessment Framework). These services are ones that would not be directly affected by therapies for COVID-19 (e.g., hospitalizations), as these services will be captured in the economic model. Rather, we sought services used in the current management of COVID-19 beyond the potential offsets that arise from a new intervention. During stakeholder engagement and public comment periods, ICER encouraged all stakeholders to suggest services (including treatments and mechanisms of care) currently used for patients with COVID-19 that could be reduced, eliminated, or made more efficient. No suggestions were received. ©lnstitute for Clinical and Economic Review, 2022 Page A2 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents B. Patient Perspectives: Supplemental Information B1. Methods We spoke with three COVID-19 patients, a physician-scientist who maintains a COVID-19 patient registry to track longitudinal quality of life trends, and the Chief Executive Officer of Solve ME, a non-profit organization whose goal is to promote research on chronic fatigue and long-term COVID- 19. We supplemented our understanding with a published systematic review that documented the diversity of symptoms associated with COVID-19.7° The three patients were identified through Savvy Cooperative, patient-owned public benefit cooperative focused on connecting health care researchers to patients. We spoke to these stakeholders individually for 30 to 45 minutes. The conversations were informed by a semi-structured interview guide, which focused the conversation on several themes: 1. What is it like to live with this condition? What is the experience of caregivers? 2. What is the diversity of experience with the condition; what are the differences of those who have a mild versus a serious case? How does racial and socioeconomic status factor in the diversity of the patient journey? 3. What outcomes matter most to patients? Are there some clinical outcome measures in the clinical trials that are more relevant to what patients care about most? What outcomes are missing entirely from the "evidence" base? 4. What are the most important "potential other benefits" and "contextual considerations" that payers and other policymakers should be aware of in judgments of value? 5. What is the experience with insurance access and affordability for treatments for this condition? After each of these conversations, patient comments were transcribed, collated, organized, and summarized. We drew upon themes that emerged from our conversations and summaries for the Patient and Caregiver Perspectives section of the report. ©lnstitute for Clinical and Economic Review, 2022 Page B1 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents C. Clinical Guidelines Treatment guidelines for COVID-19 are rapidly changing, in part reflecting the changing treatment evidence and prevalence of different variants. We highly recommend that readers refer to current guidelines from the Infectious Diseases Society of America (IDSA). We briefly summarize this guideline-current as of March 2022-below. IDSA Guidelines as of April 20, 2022 For non-hospitalized outpatients with mild-to-moderate disease who are at high risk of progression to severe disease (defined in Table C1), the IDSA recommends treatment with Paxlovid or remdesivir.? For this same population, the IDSA recommends molnupiravir for patients who have no other treatment options, citing concerns with low certainty regarding efficacy, the small effect size, potential viral mutagenesis as well as safety among persons of reproductive age. The IDSA currently recommends fluvoxamine only in the context of a clinical trial, citing the need for more precise estimates of efficacy and the need for greater generalizability of the results, as a key fluvoxamine trial was performed with patients having extended stays in mobile hospitals as part of the primary endpoint.' Similarly, the IDSA recommends bebtelovimab only in the context of a clinical trial, citing the need for more precise estimates of efficacy.®* Table C1. Factors or Conditions that Place Individuals at High Risk for Progression to Severe COVID-19 Disease4?199-111 Age 265 years Cancer Cerebrovascular disease Chronic kidney disease Chronic lung diseases Chronic liver diseases Cystic fibrosis Dementia Diabetes mellitus, types 1 and 2 Certain disabilities, including limitations with self-care or activities of daily living Heart conditions Human immunodeficiency virus Mood disorders, including depression Primary Immunodeficiencies Pregnancy and recent pregnancy Physical inactivity Schizophrenia spectrum disorders Smoking, current and former Solid organ or hematopoietic cell transplantation Tuberculosis Use of corticosteroids or other immunosuppressive medications ©lnstitute for Clinical and Economic Review, 2022 Page C1 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents National Institutes of Health COVID-19 Treatment Guidelines as of April 20, 2022 For non-hospitalized outpatients with mild-to-moderate disease who are at high risk of progression to severe disease (Table C1), the National Institutes of Health recommends the following treatments in order of preference: Paxlovid (recommendation rating Alla: strong recommendation based on other randomized trials or subgroup analyses of randomized trials) and remdesivir (recommendation rating Blla: moderate recommendation based on other randomized trials or subgroup analyses of randomized trials).142,_ Molnupiravir (recommendation rating Clla: optional recommendation based on other randomized trials or subgroup analyses of randomized trials) and bebtelovimab (CIll: expert opinion) are recommended only when none of the above options can be used. The National Institutes of Health panel's judgment is that there is insufficient evidence to recommend either for or against the use of fluvoxamine for this population. ©lnstitute for Clinical and Economic Review, 2022 Page C2 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents D. Comparative Clinical Effectiveness: Supplemental Information D1. Detailed Methods PICOTS Population The population of focus for the review is adults and adolescents ages 12 and older with mild-to- moderate COVID-19 (confirmed with a positive SARS-CoV-2 PCR or antigen test) and a high risk of progression to severe disease. interventions The list of interventions evaluated includes: e Molnupiravir e Paxlovid (PF-07321332/ritonavir) e Fluvoxamine Comparators We compared each treatment to outpatient "usual care" involving only symptomatic treatments, as found in the clinical trials of each product. Data permitting, we also included real-world evidence as appropriate. Differences in patient populations and the natural history of care and outcomes for patients with COVID-19 have been evolving rapidly, making formal quantitative indirect comparisons challenging. Outcomes The outcomes of interest are described in the list below. ® Patient-important outcomes © Time to symptom resolution o Return to work or usual activities o Symptom severity o Progression to severe or critical illness ©lnstitute for Clinical and Economic Review, 2022 Page D1 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents o Degree of respiratory support =" Conventional oxygen therapy =" High-flow nasal cannula =" Non-invasive positive pressure ventilation =" Mechanical ventilation o Medically attended visit o Hospitalization = Length of stay = Readmission ICU admission Long COVID Death Adverse events including: = Side effects =" Anaphylaxis Oo 0 90 0 e Other outcomes o Viral load SARS-CoV-2 clearance Oxygen saturation Antiviral resistance Inflammatory markers Adverse events including: =" Treatment-emergent adverse events and serious adverse events 000 0 0 Timing Evidence on intervention effectiveness and harms were derived from studies of any duration. Settings The primary focus was on care settings in the US, but relevant clinical outcomes data from international settings were included. 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Wall 8as) JUBWSSasse JaA] BWODINO Aue 'ajqeyieAe JI 'pue Apnjs ude JO SeIq JO SII UO BVe Udssol (ZT waz! aas) } [aaa] 7 [qejleae 41 'pue Apnys ydea Jo selq Jo s1 yep} d| 61 ulyain seig 40 STH *suO!}EUD 9Y} apiAoid pue (polsad dn-moyj|o4 'SOdId 'azIs Apnys "3*3) payoesjxa asam eyep YdIYM JO} Soijsayoeseyo Juasaid 'Apnjs ydea 104 "WeJIZeIP MO] 2 YUM Ajjeap! 'ade1s Yoed je SUOISN]IXS JOJ SUOSed1 YIM 'MaIAS 3} Ul PapN|oul Pue 'AjI|!GISI|/a 10} passasse 'PausaJIs SaIpNys JO SuaquuNU BAIN SLINS3IY SW} 3SI|[}994D ST soiysjiazoesey Apnis LT uonsajas Apnis Data Sources and Searches Procedures for the systematic literature review assessing the evidence on outpatient treatments for mild-to-moderate COVID-19 followed established best research methods.*!*"4 We conducted the review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.*> The PRISMA guidelines include a checklist of 27 items, which are described further in Table D1. We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials for relevant studies. Each search was limited to English-language studies of human subjects and excluded articles indexed as guidelines, letters, editorials, narrative reviews, case reports, or news items. We included abstracts from conference proceedings identified from the systematic literature search. All search strategies were generated utilizing the Population, Intervention, Comparator, and Study Design elements described above. The proposed search strategies included a combination of indexing terms (MeSH terms in MEDLINE and EMTREE terms in EMBASE) as well as free-text terms. To supplement the database searches, we performed manual checks of the reference lists of included trials and systematic reviews and invited key stakeholders to share references germane to the scope of this project. We also supplemented our review of published studies with data from conference proceedings, regulatory documents, information submitted by manufacturers, and other grey literature when the evidence met ICER standards (for more information, see https://icer.org/policy-on-inclusion-of-grey-literature-in-evidence-reviews/). ©lnstitute for Clinical and Economic Review, 2022 Page DS Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Table D2. Search Strategy of Medline 1996 to Present with Daily Update and Cochrane Central Register of Controlled Trials 1 exp COVID-19/ or exp SARS-COV-2/ (COVID* or coronovir* or coronavir* or SARS* or 2019-nCoV or "2019 nCoV" or 2019nCoV or nCov 2019 or 2 "Severe Acute Respiratory Syndrome Coronavirus 2" or HCoV* or ((corona* or corono*) adj1 (virus* or viral* or virinae*))).ti,ab 3 lor2 4 exp "Antibodies, monoclonal"/ 5 ({antibod* or mAb or nAb*) adj2 (therap* or treatment)).ti,ab or ("monoclonal antibody").ti,ab 6 4or5 ("casirivimab and imdevimab" or casirivimab-imdevimab or "casirivimab plus imdevimab" or (casirivimab 7 ADJ3 imdevimab) or casirivimab or imdevimab or (regn10933 adj3 regn10987) or regn10933 or regn10987 or regn-10933 or regn-10987 or regen10933 or regen10987 or regen-10933 or regen-10987 or regen- COV* or "regen COV2" or regn-COV* or "regn COV2" or ronapreve).ti,ab 8 (sotrovimab or "vir 7831" or vir-7831 or "gsk 4182136" or gsk-4182136 or xevudy).ti,ab 9 (molnupiravir or "mk 4482" or mk-4482 or "eidd 2801" or eidd-2801 or lagevrio).ti,ab 10 (paxlovid or pf-07321332 or "pf 07321332" or nirmatrelvir or ((pf-07321332 or nirmatrelvir) adj3 (ritonavir or "a 84538" or "a-84538" or "abt 538" or abt538 or "abt-538" or norvir or RTV))).ti,ab 11 | exp Fluvoxamine/ ("ratio fluvoxamine" or "fluvoxamine maleate" or luvox or floxyfral or fevarin or dumirox or faverin or 12 desiflu or du-23000 or "du 23000" or "luvox cr").ti,ab 13 | 110r12 14 | Gor7or8or9ori10or 13 15 | 3and14 (addresses or autobiography or bibliography or biography or comment or congresses or consensus development conference or duplicate publication or editorial or guideline or in vitro or interview or lecture or legal cases or legislation or letter or news or newspaper article or patient education handout or periodical index or personal narratives or portraits or practice guideline or review or video audio media).pt 17 | 15 not 16 18 | animals.mp. not (humans and animals).sh. 19 | 17 not 18 20 | Limit 19 to English language 21 | remove duplicates from 20 *Search last updated on February 11, 2022. tSearch strategy updated to incorporate new search terms on February 11, 2022. 16 ©lnstitute for Clinical and Economic Review, 2022 Page D6 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Table D3. Search Strategy of EMBASE SEARCH #1 = (| 'coronavirus disease 2019'/exp OR 'coronavirus disease 2019' (COVID* OR coronavir* OR coronovir* OR SARS* OR HCoV* OR 'nCov 2019' OR '2019-nCoV infection' OR #2 | '2019 nCoV' OR 2019nCoV OR 'severe acute respiratory syndrome 2' OR ((corona* or corono*) NEAR/1 (virus* or viral* or virinae*))):ti,ab #3 #1 OR #2 #4 | 'monoclonal antibody therapy'/exp OR 'monoclonal antibody therapy' #5 | ('monoclonal antibody' OR ((antibod* or mAb* or nAb*) NEAR/2 (therap* or treatment*))):ti,ab #6 | #4ORH#5 #7 neutralizing:ti,ab #8 =| #6 NOT #7 #9 =| 'casirivimab plus imdevimab'/exp OR casirivimab/exp OR imdevimab/exp ('casirivimab-imdevimab' OR 'casirivimab/imdevimab' OR 'casirivimab and imdevimab' OR 'imdevimab and casirivimab' OR regn10933 OR regn10987 OR 'regn-10933' OR 'regn-10987' OR regen10933 OR regen10987 OR 'regen-10933' OR 'regen-10987' OR 'regen-COV*"' OR 'regn-COV*' OR 'regn COV2' OR ronapreve):ti,ab OR (casirivimab NEAR/3 imdevimab):ti,ab #11 | #9 OR #10 #12 | sotrovimab/exp #13 | ('vir-7831' OR 'vir 7831' OR xevudy):ti,ab #14 | #12 OR #13 #15 | molnupiravir/exp #16 | ('mk-4482' OR 'mk 4482' OR 'eidd-2801' OR 'eidd 2801' OR lagevrio):ti,ab #17 | #15 OR #16 (paxlovid OR 'pf-07321332' OR 'pf 07321332' OR nirmatrelvir OR (('pf-07321332' OR nirmatrelvir) NEAR/3 #18 | (Ritonavir OR 'abt 538' OR abt538 OR 'abt-538' OR 'a-84538' OR 'abt 84538' OR 'abt-84538' OR norvir OR RTV))):ti,ab #19 | fluvoxamine/exp #20 | (luvox OR fluoxamine OR 'fluvoxamine maleate' OR 'du 23000' OR 'fluroxamine'):ti,ab #21 | #19 OR #20 #22 | #8 OR #11 OR #14 OR #17 OR #18 OR #21 #23 | #3 AND #22 ('case report'/de OR 'practice guideline'/de OR 'questionnaire'/de OR 'chapter'/it OR 'conference review'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it OR 'review'/it OR 'short survey'/it) #25 | #23 NOT #24 #26 | ('animal'/exp OR 'nonhuman'/exp OR 'animal experiment'/exp) NOT 'human'/exp #27 | #25 NOT #26 #28 | #27 AND [english]/lim *Search last updated on February 11, 2022. tSearch strategy updated to incorporate new search terms on February 11, 2022. #10 #24 ©lnstitute for Clinical and Economic Review, 2022 Page D7 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Figure D1. PRISMA Flowchart Showing Results of Literature Search for COVID-19 Treatments 2,697 references identified through literature search 30 references identified through other sources Y 2,394 references after duplicate removal 2,394 references screened 2,269 citations excluded 80 citations excluded 31 population 20 intervention 25 study design 4 duplicate data 125 references assessed for eligibility in full text total references 12 RCTs, 1 non-RCT, 16 RWEs and 3 SLRs Study Selection We performed screening at both the abstract and full-text level. A single investigator screened all abstracts identified through electronic searches according to the inclusion and exclusion criteria described earlier. We did not exclude any study at abstract-level screening due to insufficient information. For example, an abstract that did not report an outcome of interest would be accepted for further review in full text. We retrieved the citations that were accepted during abstract-level screening for full text appraisal. One investigator reviewed full papers and provided justification for exclusion of each excluded study. ©lnstitute for Clinical and Economic Review, 2022 Page D8 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents We also included FDA documents related to products approved under EUA. These included the manufacturer's submission to the agency, internal FDA review documents, and the transcript of Advisory Committee deliberations and discussions, if relevant. All literature that did not undergo a formal peer review process is described separately. Data Extraction and Quality Assessment We used criteria published by the US Preventive Services Task Force (USPSTF) to assess the quality of RCTs and comparative cohort studies, using the categories "good," "fair," or "poor." Guidance for quality ratings using these criteria is presented below, as is a description of any modifications we made to these ratings specific to the purposes of this review. Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study; reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; all important outcomes are considered; and appropriate attention is paid to confounders in analysis. In addition, intention-to-treat analysis is used for RCTs. Fair: Studies were graded "fair" if any or all of the following problems occur, without the fatal flaws noted in the "poor" category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred with follow-up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are addressed. Intention-to-treat analysis is done for RCTs. Poor: Studies were graded "poor" if any of the following fatal flaws exists: Groups assembled initially are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied equally among groups (including not masking outcome assessment); and key confounders are given little or no attention. For RCTs, intention-to- treat analysis is lacking. Note that case series are not considered under this rating system - because of the lack of comparator, these are generally considered to be of poor quality. ©lnstitute for Clinical and Economic Review, 2022 Page D9 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Assessment of Level of Certainty in Evidence We used the ICER Evidence Rating Matrix to evaluate the level of certainty in the available evidence of a net health benefit among each of the interventions of focus.17®1!" The main report summarizes the ratings and rationale for molnupiravir, Paxlovid, and fluvoxamine. Assessment of Bias As part of our quality assessment, we evaluated the evidence base for the presence of potential publication bias. Given the emerging nature of the evidence base for these newer treatments, we performed an assessment of publication bias for REGEN-COV, sotrovimab, molnupiravir, Paxlovid, and fluvoxamine using the ClinicalTrials.gov website. We scanned the site to identify studies completed more than two years ago that would have met our inclusion criteria and for which no findings have been published and did not find any evidence of publication bias. We provided qualitative analysis of the objectives and methods of these studies to ascertain whether there may be a biased representation of study results in the published literature. The primary concern is the lack of peer-reviewed, published data for the molnupiravir and Paxlovid trials. Data Synthesis and Statistical Analyses The studies and their results were summarized in evidence tables and synthesized qualitatively in the body of the review. Analyses were descriptive only as differences in entry criteria, patient populations, outcome assessments, and other factors precluded formal quantitative direct or indirect assessments of sotrovimab, molnupiravir, Paxlovid, and fluvoxamine versus usual care. D2. Additional Clinical Evidence Evidence Base REGEN-COV The discussion of the evidence of REGEN-COV in this section summarizes studies conducted early in the pandemic, prior to the Delta and Omicron variants and should be interpreted with caution. Evidence informing our review of REGEN-COV in outpatients with mild-to-moderate COVID-19 was derived from one multi-center RCT with three phases. Our systematic literature review also identified several real-world studies of REGEN-COV, which are summarized below. Weinreich 2021 was a multi-center Phase III trial that randomized 2,519 patients to 1200 or 2400 mg IV REGEN-COV or placebo." Non-hospitalized adults were eligible to participate if they had tested positive no more than 72 hours prior with symptom onset no more than seven days prior to randomization. On November 12, 2020, the trial was amended to include only patients with at least ©lnstitute for Clinical and Economic Review, 2022 Page D10 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents one risk factor for severe COVID-19. Patients were excluded if they had been admitted to a hospital prior to randomization due to COVID-19, had received any other treatments for COVID-19, or were pregnant, breastfeeding, or could become pregnant. Participants received REGEN-COV or placebo intravenously and completed a symptom questionnaire daily and regular virologic testing for 29 days. The primary outcome was COVID-19-related hospitalization or death for any cause through day 29. Secondary outcomes included COVID-19-related hospitalization or death from day four through 29, time to COVID-19 symptom resolution, and adverse events. The mean age of the trial participants at baseline was 48 years, and 52% were female. The majority (84%) of participants were White and a minority (5%) were Black. The most common risk factor for severe COVID-19 was obesity (57%) (Evidence Table D6). Benefits and Harms In the Phase III trial of REGEN-COV, COVID-19-related hospitalization or death from any cause by day 29 occurred in 7/736 (1.0%) of participants in the REGEN-COV 1200 mg arm and in 24/748 (3.2%) of participants in the concurrent placebo group, a 70.4% risk reduction (95% Cl: 31.6 to 87.1; p=0.002). There was one death (from any cause) in both groups. Among those hospitalized, median length of stay was 4.0 days (IQR: 3 to 6 days) in the REGEN-COV 1200 mg group and 5.5 days (IQR: 4 to 10.5 days) in the placebo group. Three (0.4%) patients in the REGEN-COV 1200 mg arm were admitted to the ICU and one (0.1%) required mechanical ventilation, while seven (0.9%) in the placebo group were admitted to the ICU and two (0.3%) required mechanical ventilation. Median time to symptom resolution was 10 days in the REGEN-COV 1200 mg group and 14 days in the placebo group (p<0.001) (Evidence Table D11). Adverse events were more common in the placebo group (safety population, N=1,843) and the majority were COVID-19-related. In the placebo group, 74 (4.0%) participants experienced serious adverse events compared to nine (1.1%) in the REGEN-COV 1200 mg group. No patients in the REGEN-COV 1200 mg group withdrew or discontinued treatment, however, one (0.1%) participant had an infusion-related reaction (Evidence Table D18). Real-World Studies of REGEN-COV We identified 10 real-world evidence studies of REGEN-COV in our population of interest (non- hospitalized patients with mild-moderate COVID-19 symptoms); nine of these studies were based in the US."*5° Eight out of 10 studies were retrospective clinical data extraction studies. All studies included a group of patients who either received REGEN-COV or who were not treated acting as the control group (Evidence Table D23). Of note, the Delta variant was first reported in March 2021 and became the most prominent variant in the US in June 2021.118179 Six studies completed data collection by April 2021, thus patients in these studies likely contracted earlier variants COVID-19, but four studies included patients with COVID-19 from June to October 2021, all of whom had contracted the Delta variant.5*>®575° In the review of the real-world evidence, we focused on three ©lnstitute for Clinical and Economic Review, 2022 Page D11 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents commonly reported outcomes: hospitalization, emergency department visits, and death, at day 14- 16 or day 28-30. 14-16 Day Outcomes Three studies examined clinical outcomes at day 14-16 in individuals who received REGEN-COV compared to a control group of patients who did not receive this agent.*®*° Razonable et al. (2021) was a retrospective study of 1,392 adults (696 who received REGEN-COV and 696 matched controls) from Mayo Clinic sites in five states in the US."° All patients had confirmed COVID-19 using PCR tests with symptomatic disease and symptom onset within no more than 10 days, and had at least one medical risk factor; around 50% of patients were >65 years of age, had obesity, or had hypertension (Evidence Table D24). The primary endpoint was hospitalizations at 14, 21, and 28 days, and ICU admission and death at 14, 21, and 28 days were secondary endpoints. By day 14, 9/679 (1.3%) of the patients who received REGEN-COV had been hospitalized for any cause, compared to 22/679 (3.3%) of the control group, representing an absolute 2.0% risk difference (95% Cl: 0.5%, 3.7%) in favor of REGEN-COV. There was one death (0.15%) in the group of patients who received REGEN-COV, as a result of issues secondary to COVID- 19, and three deaths (0.44%) in the control group, representing a non-significant absolute risk difference of 0.29% (95% Cl: -0.3%, 0.9%). By day 28, a total of 11/668 (1.6%) of the patients who received REGEN-COV had been hospitalized for any cause, compared to 32/671 (4.8%) of the control group, representing an absolute 3.2% risk difference (95% Cl: 1.4%, 5.1%) in favor of REGEN- COV. At day 28, mortality remained at 1/668 (0.15%) in those who received REGEN-COV, and there was a total of four deaths (0.59%) in the control group, representing a non-significant absolute risk difference of 0.33% (95% Cl: -0.2%, 1.1%) (Evidence Table D30). Safety data were only reported for treated patients, with seven patients (1%) reporting adverse events that were all Grade 1 (Evidence Table D38). Webb et al. (2021) was a retrospective study of 6,130 patients (115 received REGEN-COV, 479 received bamlanivimab [not reviewed here], and 5,536 were untreated contemporaneous controls) in the Intermountain Healthcare system in Utah and Southeastern Idaho in the US.** Similar to Razonable et al. (2021), all patients were over 18 years of age and had confirmed COVID-19 with symptomatic disease and symptom onset within no more than seven days before infusion.*? However, patients in this trial were required to meet specific criteria for high risk constituting a risk score of 27.5. For example, a score of two points was assigned to individuals who identified as either non-White race or Hispanic/Latinx ethnicity, had diabetes mellitus, were severely immunocompromised, or had obesity (BMI >30), and a score of one point was given if patients had hypertension, coronary artery disease, chronic liver disease, amongst others. As a result, the patients in this study had more comorbidities compared to other real-world studies, such as reported in Razonable et al. (2021). The median number of total comorbidities was four (IQR: 3 to 5); the most common comorbidities were hypertension (79-89%), obesity (54-62%), and diabetes ©lnstitute for Clinical and Economic Review, 2022 Page D12 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents (48-64%) (Evidence Table D24). The primary outcome was a composite of emergency department visits or hospitalizations at day 14. Secondary endpoints were mortality and adverse events at day 14. In this review, only data from patients treated with REGEN-COV or untreated were included. At day 14, 1/115 (0.9%) patient who received REGEN-COV had been hospitalized, compared to 538/5,536 (9.7%) of the control group. In the REGEN-COV group, 9/115 (7.8%) patients visited the emergency room, compared to 944/5,536 (17.1%) in the control group. Thus, 10/115 (8.7%) patients receiving REGEN-COV met the composite endpoint of hospitalization/emergency department visit in this study, compared to 1,482/5,536 (26.8) in the control group. The statistical significance of these differences was not reported. There were no deaths in those patients who received REGEN-COV, compared to 57/5,536 deaths (1.0%) in the control group (Evidence Table D30). Safety data were only reported for those who received REGEN-COV, and one patient reported an infusion-related reaction (Evidence Table D38). Kakinoki et al. (2022)°* was a retrospective clinical data extraction study that obtained data from patients aged 20 years or older with COVID-19, and with at least one risk factor for progression to severe disease in Asahikawa City Hospital and non-medical facilities in Japan between June and September 2021. Patients received REGEN-COV (N=55) or were placed under watchful observation (N=53), acting as the control group. The primary outcome was the need for additional treatment (such as oxygen support, steroid administration, or antiviral medication) and the secondary outcome was the duration of fever and adverse events in the REGEN-COV group only. Patients had a median age of 51 years (REGEN-COV group) and 52 years (watchful observation group). All other demographics were reported for the full sample, instead of by group, and reported the most common comorbidities were hypertension/cardiovascular disease (20.5%) and diabetes (21.3%) (Evidence Table D27). The study reported that 13/55 (23.6%) in the REGEN-COV group needed further medical interventions but no further deterioration was reported beyond day five. For those in the watchful observation group, 22/53 (41.5%) were transferred to the hospital by day 16. They did not conduct statistical analyses on the comparison of the rate of hospitalization between the groups (Evidence Table D33). For those who received REGEN-COV, three patients reported adverse events related to infusion reaction or skin eruption (Evidence Table D40). 28-30 Day Outcomes Eight real-world evidence studies examined clinical outcomes at days 28, 29, or 30.4957" Day 28 outcomes from Razonable et al. (2021) are described above. Polk et al. (2021) was a retrospective study of 324 patients (125 received REGEN-COV, 199 were untreated controls) in a single health system in the US.>° All patients had confirmed COVID-19 and were assessed and infused within 10 days of symptom onset. Nearly half (43% in the REGEN-COV group vs. 53% in the control group) of the patients had more than one comorbidity; hypertension was the most common comorbidity (45% in REGEN-COV group and 58% of the control group) (Evidence Table D25). The study focused on several outcomes at day 30: COVID-19-related ©lnstitute for Clinical and Economic Review, 2022 Page D13 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents hospitalizations, COVID-19-related emergency department visits, ICU admission, mechanical ventilation, death, and adverse events. At day 30, 1/125 (2%) patient who received REGEN-COV had a COVID-19 related hospitalization, compared to 25/199 (12%) of the untreated control group, and 1/125 (1%) patient who received REGEN-COV had a COVID-19-related emergency department visit, compared to 18/199 (9%) of the untreated control group. At day 30, there were no deaths in the group of patients who received REGEN-COV and 4/199 (2%) deaths in the group of untreated controls. All four deaths were deemed to be related to COVID-19 (Evidence Table D31). No safety data were reported specifically for patients receiving REGEN-COV. Note that this was a poster presented at IDWeek Conference 2021 and has not been peer-reviewed. Piccicacco et al. (2021) was a retrospective single-center study of 48 patients who received REGEN- COV and 200 control patients who were randomly selected from the high-risk COVID-19 patients but did not receive REGEN-COV and either declined or were not offered REGEN-COV during the candidacy window.*?>* Patients were 12 years of age and older (only one patient in the control group was under the age of 18), had mild-to-moderate COVID-19 symptoms for 10 days or fewer before infusion, and were considered high risk for progression to severe COVID-19 (Evidence Table D25). The primary outcome was a composite of COVID-19-related hospitalization and emergency department visits at day 29 and secondary outcomes were incidence of hospitalization, emergency department visits, death, and serious adverse events at day 29. At day 29, 5/48 (10.4%) patients were reported to have had a COVID-19-related emergency department visit or hospitalization, compared to 81/200 (40.5%) in the control group. When examining the individual components of the composite score, all five of the cases in the patients who received REGEN-COV were related to emergency department visits and 26/200 (13%) patients in the control group visited the emergency department for COVID-19-related issues. Thus, no patients who received REGEN-COV were hospitalized for COVID-19 compared to 60/200 (30%) patients in the control group. There were also no deaths in the group of patients who received REGEN-COV, compared to 7/200 deaths (3.5%) in the control group (Evidence Table D31). One serious adverse event was reported for the patients who received REGEN-COV (Evidence Table D339). Chilimuri et al. (2021) was a single-center retrospective study aimed to provide an inner-city experience of the implementation of infusion therapy in the BronxCare Health System in the South Bronx, New York.°° The study included patients who received monoclonal antibody therapy, including REGEN-COV (N=22), or who were untreated as they declined therapy (N=11). The sample was more racially diverse than the earlier studies, with 50% of patients who received REGEN-COV identified as Hispanic/Latinx and 27.2% identified as Black/African American (Evidence Table D25). Demographics for the untreated control group were not reported. The primary outcome was hospitalization or death by day 30. At day 30, 1/22 (4.5%) patients who received REGEN-COV had been hospitalized due to COVID-19, compared to 6/11 (54.5%) in the control group. There were no deaths among the patients who received REGEN-COV and there were 2/11 (18.1%) deaths in the control group (Evidence Table D31). No safety data were reported. ©lnstitute for Clinical and Economic Review, 2022 Page D14 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents A pre-print published by McCreary et al. (2021) describes a prospective quality improvement project that utilized electronic health record data from a 40-hospital health system in Pennsylvania in the US. The study aimed to evaluate the real-world effectiveness of REGEN-COV, administered subcutaneously, in preventing all-cause hospitalization and death at 28 days in patients with the Delta variant of COVID-19, as compared to an untreated control group." The study also aimed to evaluate the effectiveness of REGEN-COV as administered by IV injection compared to subcutaneous injection. All patients were 12 years of age or older, had a positive COVID-19 test, had not been hospitalized due to COVID-19, and were at risk for progression to severe disease. Patients were younger than earlier real-world studies (mean age of 54 years) and the most common comorbidities were hypertension (46%) and asthma (31%), percentages sufficiently lower than the other real-world studies reviewed (Evidence Table D26). The primary outcome of the study was hospitalization or death at day 28, and secondary outcomes were the rate of hospitalization, death, emergency department admission and hospitalization, and adverse events at day 28. To examine the real-world effectiveness of REGEN-COV given subcutaneously, the study obtained data from 652 patients who were treated with REGEN-COV via subcutaneous injection and 1,304 propensity-score matched nontreated control patients. The symptom status of the nontreated patients was unknown, such that patients in this group may have been asymptomatic. At day 28, 22/652 (3.4%) patients who received REGEN-COV had been hospitalized, compared to 85/1,304 (6.5%) in the control group. This difference was statistically significant (p=0.005) providing support for the use of subcutaneous infusion of REGEN-COV. There was one death (0.2%) in the group of patients who received REGEN-COV as compared to 29 deaths (2.2%) in the untreated control group (p=0.009). No initial safety data were available. To examine whether the subcutaneous injection was clinically similar to IV, data was obtained from 969 patients treated with REGEN-COV via subcutaneous injection and 1,216 treated via IV. Around half of the patients in this analysis reported having been given a COVID-19 vaccine, with a higher rate of vaccination in those treated subcutaneously (55.5%) compared to those treated intravenously (44.1%), and such vaccination status was adjusted for within the analysis. At day 28, 27/969 (2.8%) patients who received REGEN-COV subcutaneously had been hospitalized, compared to 20/1,216 (1.6%) of those treated intravenously (p=0.05). There was one reported death (0.1%) in the group of patients treated subcutaneously as compared to three deaths (0.2%) in the intravenously-treated group, which was not statistically significant (Evidence Tables D32 and D36). Initial safety data reported two serious adverse events in those who were treated intravenously, and none reported in those treated subcutaneously (Evidence Table D339). A pre-print published by Huang et al. (2021) used the same electronic medical record data as McCreary et al. (2021) to evaluate the real-world effectiveness of REGEN-COV on patients with the Delta variant of COVID-19, compared to a matched control group.*© The study also examined the effectiveness of sotrovimab compared to a matched control group, which is described below. The study only reported combined demographic information for patients who received REGEN-COV and sotrovimab. Patients had a mean age of 54 years and a lower proportion of patients had medical ©lnstitute for Clinical and Economic Review, 2022 Page D15 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents comorbidities than the earlier reviewed studies, with obesity (59%) and hypertension (30%) as the most common comorbidities (Evidence Table D26). The study obtained data from 712 patients who received REGEN-COV and 2,046 propensity-matched nontreated control patients. The primary outcome was hospitalization or death at 28 days and secondary outcomes were the rate of hospitalization, ICU admission, mechanical ventilation, and mortality at day 28. At day 28, 19/712 (2.7%) patients who received REGEN-COV had been hospitalized, compared to 134/2,046 (6.6%) in the control group, representing a risk ratio of 0.41 (95% Cl: 0.25 to 0.65) (p<0.001), in favor of REGEN-COV. There was one death (0.1%) in the group of patients who received REGEN-COV as compared to 60 deaths (2.9%) in the untreated control group, representing a risk ratio of 0.05 (95% Cl: 0.01 to 0.34) group (p=0.003), in favor of REGEN-COV (Evidence Table D32 and D36). No safety data were available. Bierle et al. (2021)°" was a retrospective clinical data extraction study that obtained data from patients with COVID-19 during the Delta surge (July 2021) within Mayo Clinic sites in the Midwestern US. Patients were either treated with REGEN-COV (N=112) or were eligible for treatment but did not receive it (N=291). The primary outcome was the rate of hospitalization at day 28. Demographics were reported for the total sample only. Patients had a mean age of 46.5 years, 47% were male, and common comorbidities included obesity (39.8%), hypertension (24.3%), and cardiovascular disease (11.6%) (Evidence Table D27). The study reported significantly lower hospitalization rates for those who had received REGEN-COV (2.6%) compared to those who did not receive it (16.6%), OR: 0.14, 95% Cl: 0.04 to 0.45, p=0.001 (Evidence Table 33). The study also reported the lowest rate of hospitalization for those who were vaccinated and had received REGEN- COV (1.8%) and the highest rate of hospitalization for those who were both vaccinated (15.1%) and unvaccinated (13.7%) but did not receive REGEN-COV, suggesting that during the Delta surge prior vaccination may not be as protective for high-risk patients in preventing hospitalization (Evidence Table D37). However, these particular results were only reported descriptively and included individuals who had COVID-19 but were ineligible to receive REGEN-COV. Safety data reported that 2/112 (1.8%) of patients who received REGEN-COV reported hypoxia, compared to 47/518 (9.1%) in the control group (Evidence Table D40). Wei et al. (2022)°° was a large retrospective cohort study that analyzed data from patients with a confirmed COVID-19 diagnosis in the past 10 days in two claims databases in the US: Optum® Clinformatics® Data Mart (CDM) and IQVIA Pharmetrics Plus (PMTX+) from December 2020 to March 2021. Patients received REGEN-COV (CDM N=1,116, PMTX+ N=3,280) or did not receive this agent and were matched by demographics to those who did (CDM N=5,291, PMTX+ N=16,284). Across the two databases, the median age across the groups of 56.5 years, with 0.5% of patients in CDM and 0.55% in PMTX+ under the age of 18. The most common comorbidities were hypertension or cardiovascular disease (CDM: 54% and PMTXt+: 57.8%) and diabetes (CDM: 30.2% and PMTX+: 32.4%). The groups and databases were matched, with only vaccination status reported as higher in the CDM database (7.2%) compared to the PMTX+ database (2.6%) (Evidence ©lnstitute for Clinical and Economic Review, 2022 Page D16 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Table D27). The primary outcome for data in CDM database was a composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalization, and the primary outcome for PMTX+ was 30-day COVID-19-related hospitalization. In the CDM database, those who received REGEN-COV were less likely to be hospitalized due to COVID-19 (23/1,116, 2.1%) and there were no reports of mortality in this group, compared to 276/5,291 (5.3%) in the untreated group were hospitalized due to COVID-19 or had died during this time. There were 27/5,291 deaths (0.5%) reported in the control group in the CDM database, which was significantly higher than in the REGEN-COV group (survival probability analysis, p=0.015, 95% Cl: 0.26, 0.60). In the PMTX+ database, those who received REGEN-COV were less likely to be hospitalized due to COVID-19 (59/3,280, 1.9%), compared to a matched untreated group (752/16,284, 4.8%), 95% Cl: 0.30, 0.51 (Evidence Table D33). Furthermore, earlier treatment of REGEN-COV (one day) was associated with fewer reports of all-cause death or COVID-19-related hospitalizations in the CDM database (1.2%) compared to later treatment (25 days) (4.6%), p=0.027, and a similar pattern was reported of fewer reports of COVID-19-related hospitalizations in the PMTX+ database (one day: 1.3% vs. 25 days: 3.28%), p=0.025 (Evidence Table D37). Finally, Osugi et al. (2022)!7° was a retrospective cohort study of patients with COVID-19 diagnosed in a medical center in Toyota, Japan. Patients either received REGEN-COV (N=30) or did not receive REGEN-COV (N=74). The primary outcome was hospitalization due to COVID-19, and the secondary outcome was mortality due to COVID-19. Patients had a mean age of 47.8 years with those who received REGEN-COV as significantly older (mean age: 54.4 years) than those in the control group (mean age: 45.1 years), 56% were male, and the most common comorbidities were cardiovascular disease (18.1%), chronic lung disease (18.8%), and diabetes (13.1%); lower than other real-world evidence studies (Evidence Table D29). Those who received REGEN-COV had a significantly higher BMI than those who did not receive REGEN-COV. There was a median follow-up of 12 days (IQR: 10-16). There were 19 hospital admissions for COVID-19 across both groups and admissions tended to be lower for those who received REGEN-COV than those who did not (HR: 0.76), but this was not significant (p=0.65). This lack of difference may be the result of the demographic differences across the two groups, but the interpretation is limited as the study did not report the number of patients admitted to the hospital in each group (Evidence Table D35). There were no reports of mortality in either group. No safety data were reported. The real-world evidence studies provide support for the association between the use of REGEN-COV and lower rates of both all-cause and COVID-19-related hospitalization, emergency visits, and death for patients with mild-to-moderate COVID-19 symptoms. IV infusion of REGEN-COV appeared to be more effective than subcutaneous injection in preventing hospitalizations, but not deaths, although more research is needed. In general, patients in the real-world studies were older than those in the RCTs. The higher overall mortality and hospitalization rates in the real-world evidence studies, as compared to the RCTs, may be explained by this age difference. Additionally, due to the nature of real-world studies that utilize retrospective clinical data, there were several uncontrolled factors ©lnstitute for Clinical and Economic Review, 2022 Page D17 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents that may have led to this increased rate of hospitalization/death, such as non-random group assignment, lack of blinding, and potential loss of longitudinal data (e.g., if a patient sought care outside of the particular health system) that should be considered when interpreting the studies. Finally, adverse events may be underreported in real-world studies and safety data should be reviewed with caution. Sotrovimab The discussion of the evidence of sotrovimab in this section summarizes studies conducted at different timepoints in the pandemic and should be interpreted with caution. We identified two RCTs that met our inclusion criteria for sotrovimab. COMET-ICE is a Phase III trial that randomized 1,057 patients to 500 mg IV single infusion administration of sotrovimab or placebo. Evidence for COMET-ICE was acquired from a conference poster and the most recent peer-reviewed publication of the trial.2424_ We also examined a non-peer-reviewed pre-print of a real-world study that assessed the effectiveness of sotrovimab in non-hospitalized patients diagnosed with mild-to- moderate severity of COVID-19 (Delta variant) compared to a propensity-matched cohort.** This observational real-world study included patients from an integrated health system of 40 hospitals located in Pennsylvania.*° We included this study in our review as it may be more generalizable than the pivotal trials. COMET-TAIL is a non-inferiority trial that randomized 983 patients to 500 mg intramuscular or 500 mg IV single infusion of sotrovimab.'2"?23 At the time of this review, data for COMET-TAIL only exists in the form of a press release and data submission; as such, this section will mainly focus on the data for the IV administration of sotrovimab from the COMET-ICE trial. COMET-ICE COMET-ICE was a Phase III randomized, placebo-controlled multi-center trial with 57 clinical sites: 45 in the US, six in Brazil, three in Spain, two in Canada, and one in Peru.® Patients included in the study were unvaccinated adults with a high risk of progression to severe COVID-19 that had COVID- 19 symptom onset as well as a PCR or antigen test within five days of randomization.? Obesity was the most common qualifying risk factor in the COMET-ICE trial population (63%),)71 which is consistent with some of the other trials in our review. A total of 1,057 adult participants were randomly assigned to either of the two treatment arms with 528 participants receiving sotrovimab and 527 participants receiving placebo. The median age of participants in COMET-ICE at baseline was 53 years, and 54% were female. Most participants were White (87%) and 8% were Black; 65% of participants identified as Hispanic or Latino (Evidence Table D6).® The primary efficacy outcome of COMET-ICE was the proportion of patients with COVID-19 progression that resulted in hospitalization for more than 24 hours or death through day 29.® The main secondary outcome of the trial was a composite of emergency department visit, ©lnstitute for Clinical and Economic Review, 2022 Page D18 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents hospitalization of any duration, or death due to any cause by day 29 (Evidence Table D5). The trial was stopped early due to positive results. COMET-TAIL COMET-TAIL is a Phase III randomized, open-label, multi-center, non-inferiority trial designed to evaluate the efficacy, safety, and tolerability of the intramuscular administration of sotrovimab.*22 The trial included adults and adolescents (12 years and up) with (n=376) participants receiving the 500 mg dose of intramuscular sotrovimab and (n=378) participants receiving the 500 mg dose of IV sotrovimab.'%* For the primary endpoint, a 3.5% non-inferiority margin for the upper-bound of the 95% confidence interval was established for the trial in conjunction with input from the FDA (Evidence Table D5).122123 Benefits and Harms In COMET-ICE, 6/528 (1%) of participants who received sotrovimab and 30/529 (6%) of participants who received placebo progressed to hospitalization or death by day 29, a 79% (95% Cl: 50% to 91%) relative risk reduction in favor of sotrovimab (Evidence Table D11).® Mortality by day 29 did not differ significantly between the two groups.® No deaths occurred in the treatment arm while two deaths were reported in the placebo arm; of the two deaths that occurred in the placebo arm, one patient died without being hospitalized.* Sotrovimab was associated with a 66% reduction in the composite outcome of emergency department visit, hospitalization, or death. Among patients hospitalized, none of the participants in the sotrovimab group required high-flow oxygen or mechanical ventilation while 10 patients in the placebo group required high-flow oxygen and four patients were placed on mechanical ventilation (Evidence Table D11). The secondary endpoint in COMET-ICE, change in total symptom score, was evaluated using the FLU-PRO assessment tool. When compared to the placebo arm, participants that received IV administration of sotrovimab reported a higher mean reduction of -1.07 (95% Cl: -1.38 to -0.75, p<0.001) in their FLU-PRO score, which is consistent with the primary outcome (Evidence Table D17). The clinical importance of this tool in patients with COVID-19 is unknown.' Overall, in the safety population, the incidence of any adverse or infusion-related reaction was similar in the treatment and placebo group. Adverse events occurred in 11/523 (2%) of participants in the sotrovimab arm and in 32/526 (6%) of participants in the placebo arm (Evidence Table D18). The most notable disease-specific adverse event was COVID-19 pneumonia, which occurred in 5/523 (<1%) of patients in the sotrovimab arm and in 22/526 (4%) of patients in the placebo arm.® In COMET-TAIL, 2.7% of patients in the intramuscular administration arm of sotrovimab progressed to hospitalization (greater than 24 hours) or death compared to 1.3% of patients in the IV administration arm.122723 The 500 mg intramuscular administration of sotrovimab was determined ©lnstitute for Clinical and Economic Review, 2022 Page D19 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents to be equivalent (non-inferior) to the 500 mg IV administration based on an adjusted difference of 1.07% (95% Cl: -1.25% to 3.39%), which is below the pre-specified 3.5% non-inferiority margin.122723 The risk of hospitalization or death in the IV arm was consistent with the risk in the IV arm in COMET-ICE (Evidence Table D11). Of note, the evidence from COMET-TAIL only exists in the form of a press release and data submission. Real-World Studies of Sotrovimab Huang 2021 was a real world study that corroborates the evidence in COMET-ICE and supports the effectiveness of sotrovimab against the Delta variant.** This study compares outcomes of a cohort of 311 patients who received 500 mg IV single infusion of sotrovimab to 2,046 propensity-matched patients who did not receive active treatment (Evidence Table D23). Participants enrolled in this study had mild-to-moderate COVID-19 (Delta variant) and were enrolled between July 14, 2021 and September 29, 2021. A comparative analysis of sotrovimab with another monoclonal antibody was also performed in this real-world study but is not the focus of our review (Evidence Table D26). The primary outcome for the real-world study was hospitalization or death by day 28. Sixteen out of 311 (5.1%) patients who received sotrovimab experienced the primary outcome compared to 174/2,046 (8.5%) patients in the nontreated arm by day 28 (RR: 0.60, 95% Cl: 0.37 to 1.00, p=0.05). This difference in the primary outcome was mostly driven by higher mortality in the nontreated arm (60/2,046 [2.9%] compared to 0 deaths in the treatment arm).°© In the sotrovimab arm, 16 out of 311 (5.1%) patients were hospitalized and 134/2,046 (6.6%) of patients were hospitalized in the nontreated group (RR: 0.79, 95% Cl: 0.47 to 1.30, p=0.35) (Evidence Table D32).°° Aggarwal et al. (2022) was an observational cohort study of outpatient adults with COVID-19. Health record data from the largest health system in Colorado was used for propensity matching of patients who did not receive monoclonal antibody treatment (n=1,563), to patients who received outpatient treatment with sotrovimab (n=522), in a 3:1 ratio. Health data used in this trial included participants infected with COVID-19 from October 1, 2021 to December 11, 2021, which coincides with when the Delta variant was the dominant strain (Evidence Table D23). Most patients in the study were female: 56.7% of patients treated with sotrovimab and 56.1% of patients not treated with a monoclonal antibody. Approximately 81% of participants identified as non-Hispanic White, 7.5% as Hispanic and 8% as non-Hispanic Black. The most common comorbidities in patients treated with sotrovimab include hypertension (30.7%), obesity (25.5%), pulmonary disease (25.1%), cardiovascular disease (16.5%), and diabetes (11.9%) (Evidence Table D29). The primary outcome in the study was all-cause hospitalization within 28 days of a positive COVID-19 test. The secondary outcome included all-cause mortality by day 28 and emergency department visit by day 28. Assessment of disease severity based on ICU admission and invasive mechanical ventilation, or death were calculated as percentages. A total of 11 patients (2.1%) and 89 patients (5.7%) reached the primary outcome of all-cause hospitalization in the treated and un-treated arms, respectively (OR: 0.37, 95% Cl: 0.19 to 0.66) (Evidence Table D35). By day 28, none of the patients who received ©lnstitute for Clinical and Economic Review, 2022 Page D20 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents sotrovimab had died, compared to 15 patients (1%) in untreated arm. However, there was a higher percentage of patients (8.4%) who received sotrovimab and had a visit to the emergency department, compared to 7.6% of patients not treated with a monoclonal antibody. Furthermore, hospital length of stay and disease severity was assessed by the maximum level of respiratory support in-patient as part of the secondary outcome. The average length of stay for hospitalized patients who received sotrovimab was 5.3 days compared to 9.4 days in patients not treated with a monoclonal antibody. Out of the hospitalized population, two patients (18.2%) treated with sotrovimab were admitted to the ICU compared to 19 patients (21.3%) who were not treated with a monoclonal antibody. None of the patients who received sotrovimab died or required invasive mechanical ventilation while in contrast, 19 patients (21.3%) reached this outcome. No safety data were reported.?25 Zaqout et al. (2022) is a matched case-control study that includes patients from a national database in Qatar who were diagnosed with COVID-19 between October 20, 2021 and February 28, 2022. Cases of COVID-19 occurring after December 19, 2021 were classified as occurring when Omicron was the dominant variant, during which 70% of cases were due to the BA.2 Omicron subvariant. All other cases were classified as occurring during the Delta variant dominant phase. Cases and controls were matched ina 1:2 ratio; resulting in 345 participants in the treatment arm who received sotrovimab and 583 in the untreated arm (Evidence Table D23). Participants were matched and adjusted for COVID-19 vaccination status, prior infection status, sex, age group, nationality, comorbidity count, and the phase of the pandemic that infection occurred. Overall, participants were eligible to be in the study if they had a confirmatory diagnosis of COVID-19 via PCR or antigen test and fit the eligibility criteria to receive sotrovimab. Patients were excluded if they showed signs or symptoms of severe COVID-19 within seven days of diagnosis. The baseline characteristic across the matched cases and controls were similar. Patients who received sotrovimab had a median age of 39 years, majority were female (64.1%), 94.8% had no prior history of infection, 33.6% were unvaccinated, while a majority 191 (55.4%) participants had received two doses of a vaccine and 38 (11%) had received three doses (Evidence Table D29). The primary outcome of the study was progression to severe, critical, or fatal COVID-19, which was assessed by adjusted odd ratios of progressing to more severe stages of COVID-19. Taking sotrovimab was not shown to reduce the risk of advancing to a more severe form of COVID-19 (OR: 2.67, 95% Cl: 0.17 to 11,91) (Evidence Table D35). This result was consistent in a subgroup of patients that included participants who were immunocompromised, pregnant, unvaccinated, and 75 years of age or older (OR: 0.65, 95% Cl: 0.17 to 2.48). No specific mortality or safety data were reported.?26 Molnupiravir In the Evidence Report, evidence for molnupiravir focused on the primary outcomes from the full population analysis and interim analysis of the Phase III portion of the MOVe-OUT trial. We also identified one open-label trial of molnupiravir conducted in India, which is described below.2° One of ©lnstitute for Clinical and Economic Review, 2022 Page D21 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents the secondary endpoint outcome measures in MOVe-OUT is the change in the WHO 11-point scale. The WHO 11-point scale measures the progression of COVID-19 through the mild, moderate, and severe stages with a higher numerical value being assigned to more severe patients. As measured by this outcome, patients in the molnupiravir group were less likely to have clinical progression of the disease by days three, five, 10, and 15. This secondary outcome of clinical progression was only statistically significant at day 10 and day 15, with the maximum difference occurring at day 10 (OR 1.58, 95% Cl: 1.14 to 2.20).72 The Phase Ila portion of the MOVe-OUT trial functioned primarily as a dose-finding trial and evaluated three doses of molnupiravir (200 mg, 400 mg, and 800 mg) compared to placebo. Outcomes were reported primarily in participants in the 800 mg dose that was carried forward into the Phase III portion of the MOVe-OUT trial (Evidence Table D5).3? The primary endpoint of this study was time to clearance of viral RNA in nasopharyngeal swabs confirmed by PCR detection. Median time to viral clearance was 14 days in the 800 mg molnupiravir group compared to 15 days in the placebo group (p=0.013) (Evidence Table D15). This primary outcome was not statistically significant when compared to placebo in the 200 mg and 400 mg molnupiravir treatment arms.*? The secondary endpoint of the study was the percentage of participants in each treatment arm that had infectious virus isolations via nasopharyngeal swabs from baseline through days three and five. By the third day of treatment, infectious virus was isolated from 1/53 (1.9%) participants in the 800 mg molnupiravir group and in 9/54 participants in the placebo group (p=0.016). This outcome was consistent with the results on day five, in which 0/53 (0%) participants in the 800 mg molnupiravir group had infectious virus isolated compared to 6/54 (16.7%) participants in the placebo group (p=0.027) (Evidence Table D15). The median time to symptom resolution was not statistically significant across all treatment arms and placebo." Kumarasemyet 2022 Conference material by Kumarasemyet et al. (2022) presented results of a Phase Ill, open-label RCT that studied the safety and efficacy of a generic formulation of molnupiravir in outpatients with mild COVID-19 symptoms in India (Evidence Table D5). Sixty-four percent of trial participants were male and average age was approximately 35 years. Obesity was the most common risk factor for severe disease (Evidence Table D7). Nineteen out of 608 (3.1%) of patients in the molnupiravir arm had obesity, compared to 17/610 (2.8%) of patients in the standard-of-care arm. To be included in the trial, patients had to have mild COVID-19 infection confirmed by PCR, no breathlessness, and an uncomplicated upper respiratory tract infection diagnosis. Patients in the intervention arm (n=608) received 800 mg of molnupiravir twice a day for five days (plus standard of care), while patients in the comparison arm (n=610) received standard of care alone. The primary outcome of the trial was the rate of hospitalization up to day 14. Secondary outcomes were the proportion of patients with ©lnstitute for Clinical and Economic Review, 2022 Page D22 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents a 2-point improvement on the WHO-11-point scale and rate of negativity from PCR nasopharyngeal swabs. Results of these secondary endpoints were documented on days five, 10, and 14.76 Nine patients (1.5%) who received molnupiravir were hospitalized by day 14, compared to 26 patients (4.3%) who received standard of care alone (p<0.01) (Evidence Table D12). Patients who received molnupiravir had clinical improvement rates of 80.8%, 95.6%, and 97.4%, while patients on standard of care alone had clinical improvement rates of 32.1%, 74.3%, and 94.1% by days five, 10 and 14, respectively (p<0.0001). Patients who received molnupiravir had SARS-CoV-2 negativity rates of 77.1%, 91.3%, and 93.9%, while patients on standard of care alone had negativity rates of 29.3%, 70.2%, and 89.0% by days five, 10, and 14 (p<0.001). No serious adverse events were reported in either group. Mild or self-limiting adverse events occurred in 4.8% of the patients in the molnupiravir arm compared to 2.6% of patients in the standard-of-care alone arm (Evidence Table D19). The median time to clinical improvement was six days in the group that received molnupiravir and 10 days in the group that received standard of care alone.*° Paxlovid The Evidence Report discusses the primary source of data to inform our comparison of Paxlovid to usual care: the EPIC-HR trial, a Phase II/III randomized trial in non-hospitalized patients with mild- to-moderate COVID-19 at high risk of disease progression. In December 2021, the manufacturer released top-line, interim data from the EPIC-SR trial, a Phase II/II| randomized trial of Paxlovid in non-hospitalized patients with mild-to-moderate COVID-19 at standard risk for disease progression (including those who were vaccinated with at least one risk factor for progression).?2" EPIC-SR The primary outcome of the EPIC-SR trial was a self-reported sustained alleviation of all COVID-19 symptoms for four consecutive days. Secondary outcomes included a composite outcome of hospitalization and no death, viral load, and adverse events. In the interim analysis including 45% of the trial's planned enrollment, the primary endpoint for Paxlovid compared to placebo was not met and not reported.'?" However, in a follow-on analysis including 80% of enrolled patients the secondary outcome of hospitalization and no death was 70% lower in the Paxlovid group compared to the placebo group, with 3/428 hospitalized (0.7%) in the Paxlovid group and 10/329 (2.4%) in the placebo group (p=0.051) (Evidence Table D12). Treatment-emergent adverse events were similar across treatment groups (22% in the Paxlovid group and 21% in placebo), as were serious adverse events (1.4% in the Paxlovid group and 1.9% in placebo). Discontinuation rates due to adverse events were 2.1% in the Paxlovid group and 1.2% in placebo (Evidence Table D19). Based on the totality of the data available at the time of the interim results, the Data Monitoring Committee recommended that the trial continue.!2" ©lnstitute for Clinical and Economic Review, 2022 Page D23 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents Fluvoxamine The report discusses the primary source of data to inform our comparison of fluvoxamine to usual care, the TOGETHER trial. In addition to the TOGETHER trial, our systematic review identified two additional trials of fluvoxamine, STOP-COVID 1 and STOP-COVID 2 and one real-world study. STOP-COVID 1 STOP-COVID 1 was a double-blind, single-site US-based trial that randomized 181 non-hospitalized adults with mild-to-moderate COVID-19 and symptom onset within seven days to 100 mg of fluvoxamine or placebo three times daily for 15 days.!78 The trial was conducted early in the pandemic (April 2020 to August 2020). The primary outcome was clinical deterioration within 15 days of randomization (defined as shortness of breath or hospitalization for shortness of breath or pneumonia or oxygen saturation <92% or need for supplemental oxygen). Secondary outcomes included symptom severity, hospitalization, or emergency department visit (self-reported), and adverse events (Evidence Table D5). Of the 181 patients who were randomized, 152 were included in the study analysis. Mean age of the participants was 46 years at baseline, 25% were Black, and the majority were female (70-74%). The most frequent risk factors for severe disease were obesity (54-58%), hypertension (19-21%), asthma (13-21%), and diabetes (11%) (Evidence Table D8). In the STOP-COVID 1 trial, 0/80 participants in the fluvoxamine arm and 6/72 (8.3%) in the placebo arm met both criteria for clinical deterioration, the primary outcome (absolute difference 8.7, 95% Cl: 1.8 to 16.4, p=0.009).728 Symptom severity, as measured on a 7-point scale (lower is better) was 0.22 points lower in the fluvoxamine group (95% Cl: -0.41 to -0.04, p=0.02). There was no difference in hospitalization or emergency department visits (self-reported) between the two groups (Evidence Table D13). Serious adverse events were reported by one (1.3%) patient in the fluvoxamine group and five (6.9%) in the placebo group (Evidence Table D20). STOP-COVID 2 STOP-COVID 2 was a double-blind, multi-center US and Canada-based trial that randomized 547 non-hospitalized adults with mild-to-moderate COVID-19 and at least one risk factor for severe disease and symptom onset within seven days to 100 mg of fluvoxamine or placebo twice daily for 15 days. Enrollment occurred between December 2020 and May 2021. Like STOP-COVID 1, the primary outcome was clinical deterioration within 15 days of randomization. Secondary outcomes included hospitalization and adverse events (Evidence Table D5). Mean age of the participants was 48 years at baseline and 62% were female; approximately 8% were Black and 13% were Hispanic/Latino. Like STOP-COVID 1, the most frequent risk factors for severe disease were obesity (42-45%), hypertension (20-23%), asthma (12-15%), and diabetes (9-10%) (Evidence Table D8). The STOP-COVID 2 trial was stopped early due to low power for the primary outcome. In the interim analysis, 13/272 (4.8%) participants in the fluvoxamine arm and 15/275 (5.5%) in the ©lnstitute for Clinical and Economic Review, 2022 Page D24 Special Assessment of Outpatient Treatments for COVID-19 Return to Table of Contents placebo arm met both criteria for clinical deterioration, the primary outcome (absolute difference 0.0058, 95% Cl: -0.034 to 0.045, p=0.758).® In the fluvoxamine arm, nine (3.3%) participants had a COVID-19-related hospitalization compared to 10 (3.6%) in the placebo arm (Evidence Table D13). Adverse events were not reported. Real-World Study of Fluvoxamine Seftel and Boulware (2021)?2° was an open-label cohort study in an occupational setting in California that enrolled 152 outpatients with positive rapid test for COVID-19 and allowed individuals to choose fluvoxamine or no treatment. Approximately half of the patients were asymptomatic. Patients were evaluated at days seven and 14. Outcomes included hospitalization, ICU stay with mechanical ventilation, and symptoms. Mean age of the participants was 43-44 years at baseline and 41-59% were female; approximately 1% were Black and the majority were Latino (71-94%). A minority (25-38%) had one chronic comorbidity such as diabetes (8-17%) and hypertension (17-35%) (Evidence Table D23). Demographics were generally similar between the fluvoxamine and no therapy groups, except for race/ethnicity. Latino participants were more likely to opt for fluvoxamine (Evidence Table D28). No patients in the fluvoxamine group (0/65) and 6/48 (12.5%) in the no treatment group were hospitalized. Of the six patients who were hospitalized, two required an ICU stay with mechanical ventilation and one died. At day 14, all patients in the fluvoxamine group had COVID-19 symptom resolution, compared to 40% in the no treatment group (p<0.001) (Evidence Table D34). 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