STATISTICAL ANALYSIS PART 1 REPORT
Platform Adaptive trial of NOvel antiviRals for eArly treatMent of covid-19 In theCommunity
Reference Number / Short title: PANORAMICMOLNUPIRAVIR

Ethics Ref: 21/SC/0393
IRAS Project ID: 1004274
EudraCT Number: 2021-005748-31
Based on protocol version 5.0 9th May 2022
Version 1.0

Date: 22nd September 2023

Report prepared and analysis carried out by

Dr Victoria Harris, Department of Primary
Care Health Sciences, University of Oxford

Report reviewed by

Dr Milensu Shanyinde, Department ofPrimary Care Health Sciences, University of
OxfordStatistical Analysis Part 1 Report

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2 CONTENTS
LIST OF TABLES ................................................................................................................. 4
LIST OF FIGURES ............................................................................................................... 51

BACKGROUND ............................................................................................................ 6

2

INTRODUCTION .......................................................................................................... 6
2.1

3

SOFTWARE EMPLOYED ........................................................................................................ 8

METHODS .................................................................................................................. 9
3.1 TRIAL OVERVIEW ............................................................................................................... 9
3.2 STUDY DESIGN ................................................................................................................... 9
3.3 ADAPTIVE DESIGN ............................................................................................................ 10
3.4 OBJECTIVES .................................................................................................................... 10
3.5 TARGET POPULATION ........................................................................................................ 12
3.5.1 Inclusion Criteria .................................................................................................. 13
3.5.2 Exclusion criteria .................................................................................................. 14
3.5.3 A Risk factors ........................................................................................................ 14
3.5.4 Concomitant use of other COVID-19 medications ............................................... 17
3.6 INTERVENTIONS ............................................................................................................... 18
3.7 OUTCOMES .................................................................................................................... 18
3.7.1 Primary outcome .................................................................................................. 18
3.7.2 Secondary outcomes ............................................................................................ 18
3.7.2.1
3.7.2.2
3.7.2.3
3.7.2.4
3.7.2.5
3.7.2.6
3.7.2.7
3.7.2.8

TIME TO RECOVERY ................................................................................................................................... 18
PATIENT REPORTED ILLNESS SEVERITY ..................................................................................................... 18
DURATION OF SEVERE SYMPTOMS AND SYMPTOM RECURRENCE .......................................................... 19
CONTACTS WITH HEALTH SERVICES BETWEEN RANDOMISATION AND DAY 28 OF FOLLOW-UP (FU). .... 19
NEW INFECTIONS IN THE HOUSEHOLD ..................................................................................................... 19
SAFETY OF ANTIVIRAL AGENTS ................................................................................................................. 19
LONGER TERM EFFECTS: SYMPTOMS AND WELL-BEING AT 3 AND 6 MONTHS ........................................ 19
HEALTHCARE MEASURES (EQ-5D-5L) ........................................................................................................ 20

3.8 SAMPLE SIZE ................................................................................................................... 20
3.9 RANDOMISATION AND BLINDING IN THE ANALYSIS STAGE ......................................................... 20
3.10
DEFINITION OF POPULATION FOR ANALYSIS ........................................................................ 21
3.10.1.1
3.10.1.2

4

Primary analysis population.................................................................................................................. 21
Secondary analysis population ............................................................................................................. 22

RESULTS ................................................................................................................... 23

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4.1 RECRUITMENT ................................................................................................................. 23
4.2 BASELINE CHARACTERISTICS OF PARTICIPANTS ........................................................................ 25
4.3 NUMBER ANALYSED .......................................................................................................... 34
4.4 PRIMARY ANALYSES.......................................................................................................... 34
4.4.1 Primary outcome .................................................................................................. 34
4.4.2 Secondary outcomes ............................................................................................ 35
4.5 SUBGROUP ANALYSES ....................................................................................................... 40
4.6 VIROLOGY SUB-STUDY ANALYSIS .......................................................................................... 42

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LIST OF TABLES
Table 1 The ministry of health, labour and welfare defined risk factors for severe COVID-19................................................................................................................................................. 14
Table 2 The modified definition of risk factors for severe COVID-19 ..................................... 15
Table 3 The diagnostic criteria for each risk factor in the PANORAMIC study ....................... 16
Table 4 The definition of other COVID-19 medications.......................................................... 17
Table 5 Baseline characteristic by randomised group for the concurrent and eligible
population ............................................................................................................................... 25
Table 6 Baseline characteristic of the subgroup population by randomised group .............. 29
Table 7 Prevalence of risk factors for severe COVID-19 (modified definition) among eligible
participants ............................................................................................................................. 33
Table 8 Primary outcome ........................................................................................................ 34
Table 9 Secondary outcomes .................................................................................................. 37
Table 10 Summary of Virology sub-study ............................................................................... 42
Table 11 Virology substudy ..................................................................................................... 43

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LIST OF FIGURES
Figure 1 Flow diagram of trial participants for the subgroup population ............................. 24
Figure 2 Kaplan-Meier curve and model estimates for time to recovery .............................. 39
Figure 3 Forest plot of Subgroup analysis of primary outcome ............................................. 40
Figure 4 Forest plot of Subgroup analysis of Time to recovery .............................................. 41

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1 BACKGROUNDThe Center for Outcomes Research and Economic Evaluation for Health (C2H) is currently
conducting a cost-effectiveness evaluation of Molnupiravir as a part of the Japanese healthtechnology assessment (HTA) process. The data from the PANORAMIC study(Butler CC, et al. Lancet.
2023:28;401:281-293) could potentially be the source to assess the additional benefit of Molnupiravir
in the Japanese setting. However, there are several differences between the study design of
the PANORAMIC and the indication for Molnupiravir in Japan. For example, Molnupiravir isapproved in Japan for the treatment of COVID-19 in adults with risk factors for severe COVID19 whereas the PANORAMIC study included adults without these risk factors. Additionally,
differences in the definition of standard of care also exist. In Japan, concomitant use of
Molnupiravir with other COVID-19 medications (e.g., remdesivir) is not recommended. Given
these differences, the purpose of this report is to present the results of sub-group analysis of
the PANORAMIC study in line with the indication and clinical practice of Molnupiravir in Japan.
The results are presented excluding both A) participants without risk factors; and B)
participants using other COVID-19 medications at the prescription of Molnupiravir .
DISCLAIMER: Publication of the results presented in this report requires approval inwriting to the Chief Investigators.

2 INTRODUCTION
This document details the analysis for the subgroup reporting results for the comparison of
Molnupiravir with usual care from the PANORAMIC trial. The results reported in these papers
follow the strategy set out in the statistical analysis plan. Subsequent analyses of a more
exploratory nature will not be bound by this strategy, though they are expected to follow thebroad principles laid down here.
The analysis strategy will be available on request when the principal papers are submitted for
publication in a journal. Suggestions for subsequent analyses by journal editors or referees,
will be considered carefully, and carried out as far as possible in line with the principles of thisanalysis strategy; if reported, the source of the suggestion will be acknowledged.
This report is based on the statistical analysis plan { Subgroup analysis of PANORAMIC study
in Japan_Plan1.docx}. Any deviations from the statistical analysis plan will be described andjustified in this report of the trial.

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Trial/Study statistician(s):Dr Victoria Harris
Lead Trial Statisticians Professor Ly-Mee Yu and Dr Ben SavilleCo-chief Investigator:
Professor Chris Butler, Professor Paul Little, and Professor Richard Hobbs
Senior Trial Manager: Lucy Cureton
Senior Data Manager: Meena Patil

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2.1 SOFTWARE EMPLOYED
Analysis was carried out using STATA v18

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3

METHODS

3.1 TRIAL OVERVIEW
Despite high uptake of vaccination against COVID-19, the disease remains prevalent in the UK
and in many countries around the world, with many patients continuing to require hospital
admission. COVID-19 causes considerable suffering, including loss of ability to perform
activities of daily living, loss of educational and work opportunities, and inability to perform
caring duties, with far reaching personal and societal consequences. Many go on toexperience persisting and/or relapsing symptoms. People with underlying health conditions,unvaccinated people, and those in whom the vaccine is not effective are at increased risk ofmore severe disease. 1 1 New ‘vaccine escaping’ variants may yet emerge, and the impact ofearly antiviral treatment on long COVID syndromes is as yet unknown. Early treatment withantiviral agents may prevent progression to the later phase of COVID-19. Therefore, there isan urgent need to identify treatments for COVID-19 for use in the community early on in theillness that speeds recovery and prevents the need for hospital admission.
Antiviral agents may reduce viral shedding, and use of antiviral agents may lead to theemergence of resistance to novel antiviral agents, but the impact of novel antiviral agents on
shedding and resistance is not yet known.

3.2 STUDY DESIGNPANORAMIC is an open label, prospective, individually randomised, platform, adaptive,
controlled clinical trial in community care. Trial arms will include:
Intervention arms: Novel antiviral agents (or combinations) targeting SARS-CoV-2, initially
specified by The UK Antivirals National Taskforce (ATF) and with capacity for sequential
introduction of each treatment regimen into the trial plus Usual Care. This report presents
the primary and secondary analysis for the Molnupiravir arm.
Comparator arm: Usual Care, defined as the currently recommended treatment delivered byresponsible clinicians. Usual Care was not mandated by the trial, as recommended treatments
may change and be tailored to individual characteristics, and self-care will vary. Use of overthe counter medication as well as key medications such as inhaled steroids and monoclonal
antibodies was captured. In this report only usual care participants randomised concurrently
and eligible to Molnupiravir were included.

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3.3 ADAPTIVE DESIGN
The trial design allows for interim analysis and early stopping due to futility or efficacy andthe addition or removal of interventions. The number and timing of interim analyses depends
on the rate of recruitment. Full details of the design and decision criteria are given in the
Adaptive Design Report. Due to rapid recruitment no interim analyses were carried out on
the Molnupiravir arm. Paxlovid was added as an additional arm on 21st April 2022.

3.4 OBJECTIVES
Main Trial: The primary aim is to determine the effectiveness of selected antiviral agents inpreventing hospitalisation and/or death in higher-risk patients with a confirmed positive PCRor LFT SARS-CoV-2 test result (see Inclusion/Exclusion Criteria, below).

Main Study

Objectives

Endpoint Measures

Timepoint (s)Primary

To determine whether
antiviral treatment in thecommunity safely reduces
non-elective
hospitalisations/ deaths inhigher risk,

All cause, non-elective Within 28 days of
hospitalisation and/or randomisation
death, within 28 days
Patient report, Studyof randomisation
Partner report,
HES/ONS/medical
record data linkage

symptomatic patients withconfirmed COVID-19
SecondaryTo
explorewhether
antiviral treatment affects
1) Time to recovery 1-3) Participant(defined as the firstreports symptoms
instancethatadaily for 28 days
participant report ofand at 3 and 6
feeling recovered frommonths.
the illness)

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symptom scores.
Telephone call ortext on days 7, 14
and 28 if data is not
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2) Participant reported
illness
severity,
reported by daily
rating of how wellparticipant
feels,
enabling identificationof sustained recovery.

Also, at 3 and 6
months.

3) Duration of severe
symptoms
andsymptom recurrence,
including time toalleviationofsymptoms, time toinitial reduction ofseverity of symptoms,
time to sustained
recovery, time tosustained alleviationof symptoms, numberof days of severe
symptoms
andworseningof
symptoms

4) Contacts withhealth services

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the4) Contacts withhealth services
reported bypatients and/or
captured by reportsof patients’ medical
records

4) GP notes review if
available throughOxford RCGP RSC
network; otherwise,other sources ofroutinely collected
data after 28 days.
Medical notes

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review for up to 10
years.
5) New infections
householdin 5) Reports of new
infections in thehousehold fromdaily diary6) To investigate the 6) Evaluation ofsafety of antiviraloverall safety ofagentsdrugs by themonitoring ofadverse events (AEsas defined in the
ISAs)7) Longer term effects, 7) Well-being,
including proportion
symptoms andwith long covid, longheath care
covid
symptoms,
utilisation
health care use andwellness8) Cost effectiveness8) Resource use andcost data and EQ5D-5L5) Daily online
symptom scores ortelephone call or text
on days 7, 14 and 28

6) For the duration of
the antiviral course
and a defined period
after the antiviralfinishes (see ISAs)

7) Patient contact atthree and six
months, electronic
medical record
search for up to one
year8) Baseline and Day 28

3.5 TARGET POPULATION
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The trial includes participants who test positive for SARS-CoV-2 infection and with ongoing
symptoms consistent with COVID-19, not hospitalised, and who are aged 50 years and over,or 18-49 years and considered clinically vulnerable (see Inclusion Criteria below).
3.5.1 INCLUSION C RITERIAParticipant is able and willing to provide informed consent, or their legal
representative is willing to provide informed consent
Symptoms attributable to COVID-19 started within the past 5 days and ongoing
A positive PCR or LFT SARS-CoV-2 test* Aged ≥50 years OR aged 18-49 years with oneof the following known underlying chronic health condition considered to make themclinically vulnerable:o chronic respiratory disease (including chronic obstructive pulmonary disease(COPD), cystic fibrosis and asthma requiring at least daily use of preventative
and/or reliever medication)o chronic heart or vascular diseaseo chronic kidney diseaseo chronic liver diseaseo chronic neurological disease (including dementia, stroke, epilepsy)
o severe and profound learning disabilityo Down’s syndromeo Diabetes mellitus (Type I or Type II)o immunosuppression: primary (e.g., inherited immune disorders resulting fromgenetic mutations, usually present at birth and diagnosed in childhood) or
secondary due to disease or treatment (e.g., sickle cell, HIV, cancer,
chemotherapy)
o solid organ, bone marrow and stem cell transplant recipientso morbid obesity (BMI >35)
o severe mental illness
o care home resident
o judged by recruiting clinician or research nurse (registered medical
practitioner or trained study nurse) to be clinically vulnerable* Any positive PCR test taken between two days before symptom onset and randomisation
qualifies. A positive lateral flow test in a symptomatic person qualifies for randomisation andwill be subject to pre-specified secondary analysis by type of diagnostic test.
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3.5.2 EXCLUSION CRITERIAPatient currently admitted to hospital (inpatient)Previous randomisation in the PANORAMIC trial
Currently participating in a clinical trial of a therapeutic agent for acute COVID-19
Additional exclusions specific to each intervention arm, if any, as listed in theIntervention Specific Appendices (ISA’s) of currently open trial arms

3.5.3 A RISK FACTORS
Risk factors for severe COVID-19 by the Ministry of Health, Labour and Welfare (MHLW) in
Japan may not be available in the PANORAMIC study. Therefore, we propose the following 2
options to extract the data according to risk or modified risk factors that could be applicableto the Japanese setting.
1. Risk factors for severe COVID-19 defined by the Ministry of Health, Labour and Welfare(MHLW) is shown in Table 1.
TABLE 1 THE MINISTRY OF HEALTH, LABOUR AND WELFARE DEFINED RISK FACTORS FOR SEVERE COVID-19

Older adults aged ≥ 65 years

Hypertension

History of smoking

Malignant tumor

Dyslipidemia

Immunodeficiency after solidorgan transplantation

Chronic respiratory disease(i.e., COPD)

Cardiovascular disease

Use of immunomodulatory
agent orimmunosuppressant

Chronic renal disease

Cerebrovascular disease

HIV infection(particularly CD4 < 200/μL)

Diabetes

Obesity (BMI ≥ 30 kg/m )2

Clinical Management of Patients with COVID-19 in Japan version 9.0 (In Japanese)(https://www.mhlw.go.jp/content/000936655.pdf)
The diagnostic criteria for each risk factor have not been clearly indicated.

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2. The modified definition of risk factors for severe COVID-19 is shown in Table 2. By

reviewing the article of the PANORAMIC study, we believe that we could define themodified risk factors as follows:
TABLE 2 THE MODIFIED DEFINITION OF RISK FACTORS FOR SEVERE COVID-19

Older adults aged ≥ 65 years

Hypertension

Current smoker(high blood pressure)
Cancer or chemotherapy

Chronic heart or vasculardiseaseSolid organ, bone marrowand stem cell transplant
recipients

Chronic respiratory disease

StrokeImmunosuppression

Chronic kidney disease

Obesity (BMI ≥ 30 kg/m )a2

HIV infection

Diabetes2

a: Obesity was originally defined as BMI ≥ 35 kg/m in the PANORAMIC study.

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TABLE 3 THE DIAGNOSTIC CRITERIA FOR EACH RISK FACTOR IN THE PANORAMIC STUDY

Risk factor

Diagnostic criteria or definition

Older adults aged ≥ 65 years

Aged ≥ 65 years

Cancer or chemotherapy

Free text field mentions “cancer”. Only current cancers
included.

Chronic respiratory disease

Self-reported long term lung disease (including chronic
obstructive pulmonary disease (COPD), cystic fibrosis or
asthma requiring at least daily use of inhalers)

Chronic kidney disease

Self-reported long term kidney disease

Diabetes

Self-reported diabetes

Hypertension (high blood pressure)Self-reported high blood pressure

Chronic heart or vascular disease

Self-reported long term heart or vascular disease

StrokeSelf-reported long term neurological disease (including
dementia, stroke, epilepsy) or free text mentions stroke22

Obesity (BMI ≥ 30 kg/m )BMI ≥ 35 kg/m

Current smoker

Current smoker

Solid organ, bone marrow and stem Self-report have had a transplant (e.g. kidney, liver, heart,cell transplant recipientslung, bone marrow or stem cells)

Immunosuppression

Self-reported weakened immune system due to a condition
you were born with or due to disease or treatment (e.g. sickle
cell, HIV, cancer, chemotherapy)

HIV infection

Collected under immunosuppression.

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3.5.4 CONCOMITANT USE OF OTHER COVID-19 MEDICATIONSIn Japan, concomitant use of Molnupiravir with other COVID-19 medications (e.g., remdesivir)
is not recommended. We would like to exclude adults taking the following medications at theprescription of Molnupiravir (Table 4) from the dataset. On the other hand, we consider that
adults using the following medications after the completion of treatment with Molnupiravir
should not be excluded from the analysis because they are most likely to have progressed tosevere COVID-19 (e.g., adults prescribed the following medications 10 days after aprescription for Molnupiravir , adults who stopped treatment with Molnupiravir within 5 days
and subsequently received the following medications).

TABLE 4 THE DEFINITION OF OTHER COVID-19 MEDICATIONS

Remdesivir

Tixagevimab/cilgavimab

Any other neutralizing
antibody for COVID-19

Nirmatrelvir/ritonavir

Tocilizumab

Any otherimmunosuppressive
medications for COVID-19

Ensitrelvir

Baricitinib

Favipiravir

Casirivimab/imdevimab

Dexamethasone

Ivermectin

Sotrovimab

Any other antiviral
medications for COVID-19

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3.6 INTERVENTIONS
Based on version 5.0 of the Protocol, the main randomisation was between the following
treatment arms (although not all treatments were available at all times and not all
participants were eligible for all treatments). However, the trial design accommodates
interventions being added and dropped as appropriate.
Usual care
Molnupiravir (recruitment between 8th December 2021 and 27th April 2022)
PAXLOVID (recruitment started 21st April 2022)

3.7 OUTCOMES
3.7.1 PRIMARY OUTCOME
The primary outcome is all-cause, non-elective hospitalisation and/or death within 28 days of
randomisation.
3.7.2 SECONDARY OUTCOMES
Secondary outcomes include time to self-reported recovery defined as the first instance thata participant reports feeling fully recovered from the illness; duration of symptoms; symptom
recurrence; daily rating of feeling well reported by participants; healthcare service use;
participant reported household infection rate; safety outcomes and cost-effectivenessoutcomes; symptoms and well-being at three and six months (with determination of
proportion with Long Covid) from randomisation.
3.7.2.1 TIME TO RECOVERYTime to recovery from COVID-19 infection within 28 days from randomisation, where
recovery is defined as the first instance that a participant reports feeling recovered.
3.7.2.2 PATIENT REPORTED ILLNESS SEVERITY

Participants are asked to rate how well they are feeling overall each day on a scale of 1-10 (1being the worst and 10 being the best). This is captured on the patients’ daily diaries andthe Call CRF.

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3.7.2.3 DURATION OF SEVERE SYMPTOMS AND SYMPTOM RECURRENCE

Participants are asked to rate their symptoms of fever, cough, shortness of breath, fatigue(tiredness), muscle ache, nausea / vomiting, diarrhoea, loss of smell and/or taste, headache,dizziness, abdominal pain and generally feeling unwell on a four point scale from 0=no
problem, 1=mild problem, 2=moderate problem and 3=major problem.
This is captured on patients’ daily diaries and Call CRF.
The outcomes to be analysed include time to alleviation of symptoms, time to initial
reduction in severe symptoms, time to sustained recovery, time to sustained alleviation ofsymptoms, number of days of severe symptoms, number reporting severe symptoms atdays 7, 14 and 28, symptom recurrence and worsening of symptoms.
3.7.2.4 CONTACTS WITH HEALTH SERVICES BETWEEN RANDOMISATION AND DAY 28 OF
FOLLOW-UP (FU).

This is captured on patients’ daily diaries and telephone call CRFs.
3.7.2.5 NEW INFECTIONS IN THE HOUSEHOLD

Number of new infections within the household are captured within the participant daily
diaries and call CRF.
3.7.2.6 SAFETY OF ANTIVIRAL AGENTS

Common side effects, according to the SmPC, include dizziness, headache, diarrhoea, andnausea. These symptoms, potential medication side-effects and Serious Adverse Events(SAE) were collected from participant daily diaries, calls to participants/Study Partners, faceto-face visits with Hub clinicians, medical records, notes reviews, NHS Digital data extracts
and RCGP data downloads.
Pregnancy was recorded as an AE of Special Interest and was monitored from the start oftreatment for the 28-day trial duration.
3.7.2.7 LONGER TERM EFFECTS: SYMPTOMS AND WELL-BEING AT 3 AND 6 MONTHS

The primary analysis is based on data collected through 28 days from randomisation;
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long term outcomes of participants. This report covers outcomes for the first 28 days followup. The long term follow-up analysis will be covered in a future report.
3.7.2.8 HEALTHCARE MEASURES (EQ-5D-5L)

The EQ-5D-5L is a questionnaire consisting of 5 items (crosswalk) and a scale from 0 to 100(VAS) defining overall health. These were captured in participant’s daily diaries and call CRF.
Cost effectiveness outcomes will be reported in a separate health economic analysis report
and the analysis of this outcome will be described in a separate health economic analysis plan.

3.8 SAMPLE SIZE
The sample size calculation as stated in the protocol:
An estimated maximum of approximately 5300 participants per arm will be required toprovide approximately 90% power for detecting a 33% relative reduction in thehospitalisation/death in an experimental arm relative to Usual Care, based on the assumptionof an underlying 3% combined hospitalisation/death rate in the Usual Care arm, and anintervention lowering the hospitalisation/death rate to 2%. We expect fewer participants will
be needed to detect the same relative reduction if the event rate is larger than 3% in the
Usual Care arm, or if there is a greater reduction in the relative risk of hospitalisation/death
for a given intervention. However, should the event rate be lower than expected, then thetarget sample size will be increased to reflect this.
We recruited 25783 for the comparison of Molnupiravir with Usual Care.

3.9 RANDOMISATION AND BLINDING IN THE ANALYSIS STAGE
Participants were randomised using a secure, fully validated and compliant web-based
randomisation system. Once deemed eligible, the medically qualified clinician or researchnurse from the central clinical team or Hub (as documented on the delegation log)
randomised the participant. Participants were randomised to one study arm using equal
allocation ratios corresponding to the number of arms they were eligible for that wererecruiting in the trial at that time. This started as 1:1 Molnupiravir :Usual Care, and once
Paxlovid was introduced on 21st April 2022 changed to 1:1:1 Molnupiravir :Usual
Care:Paxlovid. Patients had to be eligible for at least two arms (Usual Care and at least one
novel antiviral intervention). Stratification was by age ( < 50/ ≥ 50 years) and vaccination
status (see 2.2.3).
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The randomisation database automatically alerted the relevant IMP distributor and theparticipant, trial team and legal representative if applicable were notified electronically of thetreatment allocation. If the participant did not have an email address, they were notified by
telephone.

3.10 DEFINITION OF POPULATION FOR ANALYSISThe analysis population will include participants as defined by the protocol eligibility criteria
and having at least one of the vulnerabilities as listed in Table 3.
As per ICH E9 guidance the following participants will be excluded from the analysis
population;(a) Participants randomised but subsequently found to be not eligible for randomization(b) Participants previously randomised to an arm in the PANORAMIC trial (subsequent
randomisations will be excluded)
In addition, the following participants will be excluded;(c) Participants who withdraw consent for data linkage and notes review and for whom no
outcome data has been collected.
(d) Participants taking medications listed in Table 4

3.10.1.1 P RIMARY ANALYSIS POPULATION

The primary analysis population is defined as participants who were randomised to
Molnupiravir or usual care and were eligible for randomisation to Molnupiravir , during thesame time frame when Molnupiravir was actively randomising (i.e. Concurrent Randomisedand Eligible Analysis Population). That is, participants who were eligible for Molnupiravir
and randomised to either Molnupiravir or usual care between 8th December 2021 and 27th
April 2022.
This includes participants for whom data are available with participants analysed according
to the groups they were randomly allocated to, regardless of deviation from protocol.

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3.10.1.2 S ECONDARY ANALYSIS POPULATION

Analysis of the secondary outcomes for a given intervention will be based on the same
population as the primary analysis.

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4 RESULTS
4.1 RECRUITMENT
Randomisation to the Molnupiravir arm was stopped on 27th April 2022. Participants
randomised to the Molnupiravir arm and Usual Care between 8th December 2021 and 27th
April 2022 (inclusive) are included in this report (see SAP for more details). During this time
111,383 participants were screened, 44,073 of whom were not eligible on screening and afurther 41,517 were excluded after GP eligibility check (see CONSORT in appendix forreasons). 25,793 in total were randomised, of which 25,783 were randomised between
Molnupiravir and Usual Care and were eligible for randomisation to Molnupiravir. 504
participants were randomised to other arms or randomised to Usual Care and not eligible for
Molnupiravir. 75 participants were excluded from the analysis population as they were foundto be ineligible after randomisation, leaving 25,708 participants in the analysis population.
Figure 2 shows the flow of participants for the subgroup analysis as presented in this report.
9520 participants were excluded as they did not have any risk factors for severe COVID-19
and a further 54 were excluded due to taking other medications. This leaves 16,134 in thesubgroup analysis population.

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FIGURE 1 FLOW DIAGRAM OF TRIAL PARTICIPANTS FOR THE SUBGROUP POPULATIONPANORAMIC study participants (n=25,708)(12,774 Molnupiravir plus usual care group + 12,934 usual care group)↓↓→

Excluded
Adults without any risk factors for severe COVID-19(n= 9520)a

Adults with risk factors for severe
COVID-19(n=16188 )↓→Excluded
Adults using other COVID-19 medications (n=54)b
Remdesivir (n=0)
Nirmatrelvir/ritonavir (n=5)
Ensitrelvir (n=0)
Casirivimab/imdevimab (n=0)
Sotrovimab (n=0)
Tixagevimab/cilgavimab (n=0)
Tocilizumab (n=0)
Baricitinib (n=0)
Dexamethasone (n=1)
Any other antiviral medications for COVID-19 (n=2)
Any other neutralizing antibody for COVID-19 (n=46)
Any other immunosuppressive medications for COVID19 (n=0)
Favipiravir (n=0)
Ivermectin (n=0)↓

Eligible participants(n=16134)

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4.2 BASELINE CHARACTERISTICS OF PARTICIPANTS
Baseline characteristics by randomised group and overall are given in Table 5 for the
concurrent and eligible population.
TABLE 5 BASELINE CHARACTERISTIC BY RANDOMISED GROUP FOR THE CONCURRENT AND ELIGIBLE POPULATION

Age, mean(SD) [min,max]

Molnupiravir
plus usual care
(N=12821)
56.7 (12.5)[18.0 to 99.0]

Usual Care

Overall(N=12962)
56.5 (12.7)[18.0 to 98.0](N=25783)
56.6 (12.6)[18.0 to 99.0]

7451 (58.1%)
5367 (41.9%)
3 (0.0%)2.0 (2.0 to 2.0)7650 (59.0%)5308 (41.0%)
4 (0.0%)N/A

15101 (58.6%)
10675 (41.4%)
7 (0.0%)2.0 (2.0 to 2.0)

5.0 (4.0 to 6.0)

N/A

5.0 (4.0 to 6.0)

12088 (94.3%)
366 (2.9%)203 (1.6%)
78 (0.6%)
86 (0.7%)

12182 (94.0%)
434 (3.3%)
189 (1.5%)77 (0.6%)80 (0.6%)24270 (94.1%)
800 (3.1%)
392 (1.5%)
155 (0.6%)
166 (0.6%)

259 (2.0%)539 (4.2%)
1117 (8.7%)

272 (2.1%)
577 (4.5%)1114 (8.6%)

531 (2.1%)1116 (4.3%)
2231 (8.7%)

1496 (11.7%)

1464 (11.3%)

2960 (11.5%)6541 (51.0%)746 (5.8%)6591 (50.8%)768 (5.9%)

13132 (50.9%)1514 (5.9%)997 (7.8%)1063 (8.2%)

2060 (8.0%)1126 (8.8%)1113 (8.6%)

2239 (8.7%)

2491 (19.4%)
2679 (20.9%)2524 (19.7%)
2784 (21.7%)

2558 (19.7%)
2636 (20.3%)
2660 (20.5%)2767 (21.3%)

5049 (19.6%)5315 (20.6%)5184 (20.1%)
5551 (21.5%)

Sex, n(%)
FemaleMale
OtherDays from randomisation to reporting receipt of
medication*, median(IQR)
Days from start of symptoms to taking
medication*, median(IQR)
Data unavailable, n(%)
Ethnicity category, n(%)
White
Asian
Mixed Race
Black
Other
NHS priority category, n(%)
Aged ≥80
Aged ≥75 and <80
Aged ≥70 and <75 OR Aged ≥18 and <70 andclinically extremely vulnerable
Aged ≥65 and <70 and not clinically extremely
vulnerable
Aged ≥18 and <65 in an at risk group
Aged ≥60 and <65 and not clinically extremely
vulnerable or in an at risk group
Aged ≥55 and <60 and not clinically extremely
vulnerable or in an at risk group
Aged ≥50 and <55 and not clinically extremely
vulnerable or in an at risk group
Predicted risk quintile, n(%)
1 (lowest risk)
2
3
4
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5 (highest risk)
Confirmed PCR positive, n(%)
IMD quintile, n(%)(Most deprived) 1
2
3
4(Least deprived) 5
Data unavailable, n(%)
Took at least 4 doses IMP, n(%)
Received vaccination, n(%)
Number of COVID-19 vaccine doses, n(%)
1
2
34Data unavailable, n(%)
Current smoker, n(%)
Baseline Symptoms
Shortness of breath, n(%)
No problem
Minor problem
Moderate problem
Major problem
Fatigue, n(%)
No problem
Minor problem
Moderate problem
Major problem
Muscle ache, n(%)
No problem
Minor problem
Moderate problem
Major problem
Vomiting, n(%)
No problem
Minor problem
Moderate problem
Major problem
Diarrhoea, n(%)
No problem
Minor problem
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Molnupiravir
plus usual care
(N=12821)
2343 (18.3%)
5965 (46.5%)

Usual Care

Overall(N=12962)
2341 (18.1%)
5902 (45.5%)(N=25783)
4684 (18.2%)
11867 (46.0%)1234 (9.6%)
1913 (14.9%)2569 (20.0%)3216 (25.1%)
3839 (29.9%)50 (0.4%)
11892 (92.8%)
12678 (98.9%)1182 (9.1%)
1956 (15.1%)
2592 (20.0%)3213 (24.8%)
3960 (30.6%)
59 (0.5%)
N/A
12830 (99.0%)2416 (9.4%)
3869 (15.0%)5161 (20.0%)6429 (24.9%)
7799 (30.2%)
109 (0.4%)
11892 (46.1%)
25508 (98.9%)87 (0.7%)519 (4.0%)11836 (92.3%)
236 (1.8%)
143 (1.1%)
795 (6.2%)

88 (0.7%)458 (3.5%)
12044 (92.9%)240 (1.9%)
132 (1.0%)805 (6.2%)

175 (0.7%)977 (3.8%)23880 (92.6%)476 (1.8%)275 (1.1%)
1600 (6.2%)

6111 (47.7%)4514 (35.2%)
1936 (15.1%)
260 (2.0%)6125 (47.3%)
4684 (36.1%)
1896 (14.6%)
257 (2.0%)12236 (47.5%)
9198 (35.7%)
3832 (14.9%)517 (2.0%)1251 (9.8%)
4721 (36.8%)5083 (39.6%)
1766 (13.8%)

1216 (9.4%)
4853 (37.4%)5127 (39.6%)
1766 (13.6%)

2467 (9.6%)
9574 (37.1%)
10210 (39.6%)3532 (13.7%)

3479 (27.1%)
4504 (35.1%)
3763 (29.4%)
1075 (8.4%)3425 (26.4%)
4791 (37.0%)3684 (28.4%)
1062 (8.2%)

6904 (26.8%)
9295 (36.1%)
7447 (28.9%)2137 (8.3%)

10440 (81.4%)
1847 (14.4%)478 (3.7%)
56 (0.4%)

10503 (81.0%)
1913 (14.8%)477 (3.7%)
69 (0.5%)

20943 (81.2%)
3760 (14.6%)955 (3.7%)
125 (0.5%)10600 (82.7%)
1649 (12.9%)

10732 (82.8%)
1681 (13.0%)

21332 (82.7%)3330 (12.9%)

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Usual Care

Overall

Moderate problem
Major problem

Molnupiravir
plus usual care
(N=12821)
471 (3.7%)
101 (0.8%)(N=12962)
457 (3.5%)
92 (0.7%)(N=25783)
928 (3.6%)
193 (0.7%)

No problem
Minor problem
Moderate problem
Major problem

9066 (70.7%)2484 (19.4%)
825 (6.4%)
446 (3.5%)9402 (72.5%)
2368 (18.3%)
800 (6.2%)
392 (3.0%)

18468 (71.6%)4852 (18.8%)
1625 (6.3%)
838 (3.3%)

No problem
Minor problem
Moderate problem
Major problem

2702 (21.1%)
5194 (40.5%)3783 (29.5%)
1142 (8.9%)2820 (21.8%)5215 (40.2%)3838 (29.6%)
1089 (8.4%)5522 (21.4%)
10409 (40.4%)7621 (29.6%)2231 (8.7%)

No problem
Minor problem
Moderate problem
Major problem

8446 (65.9%)3087 (24.1%)
1096 (8.5%)
192 (1.5%)

8382 (64.7%)
3295 (25.4%)
1087 (8.4%)
198 (1.5%)

16828 (65.3%)
6382 (24.8%)
2183 (8.5%)
390 (1.5%)

No problem
Minor problem
Moderate problem
Major problem

10391 (81.0%)
1834 (14.3%)
524 (4.1%)
72 (0.6%)

10440 (80.5%)
1920 (14.8%)
542 (4.2%)
60 (0.5%)

20831 (80.8%)3754 (14.6%)
1066 (4.1%)
132 (0.5%)

No problem
Minor problem
Moderate problem
Major problem

525 (4.1%)
5028 (39.2%)
5789 (45.2%)
1479 (11.5%)535 (4.1%)
5145 (39.7%)
5838 (45.0%)1444 (11.1%)

1060 (4.1%)
10173 (39.5%)
11627 (45.1%)
2923 (11.3%)

No problem
Minor problem
Moderate problem
Major problem

5670 (44.2%)
4813 (37.5%)2107 (16.4%)
231 (1.8%)5765 (44.5%)4955 (38.2%)
2042 (15.8%)200 (1.5%)

11435 (44.4%)9768 (37.9%)4149 (16.1%)
431 (1.7%)1410 (11.0%)6153 (48.0%)4502 (35.1%)
756 (5.9%)
5.1 (1.7) [0.0 to
10.0]1343 (10.4%)6384 (49.3%)
4509 (34.8%)
726 (5.6%)
5.2 (1.7) [0.0 to
10.0]2753 (10.7%)12537 (48.6%)
9011 (34.9%)1482 (5.7%)
5.1 (1.7) [0.0 to
10.0]1660 (12.9%)
6113 (47.7%)

1660 (12.8%)6019 (46.4%)

3320 (12.9%)
12132 (47.1%)

Loss of smell or taste, n(%)

Headache, n(%)

Dizziness, n(%)

Abdominal pain, n(%)

Generally unwell, n(%)

Fever, n(%)

Cough, n(%)
No problem
Minor problem
Moderate problem
Major problem
Wellness score, mean(SD) [min,max]People in household, n(%)
01
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2
3
4
Taking inhaled corticosteroids, n(%)
Taking inhaled corticosteroids for COVID, n(%)
Monoclonal antibodies for COVID, n(%)
Comorbidities
Lung disease
Heart disease
Kidney disease
Liver disease
Neurological disease
Learning disability
Down's syndrome'
Diabetes
Weakened immune system
Transplant recipient
Obesity
Mental illness
Hypertension
Other vulnerability

Molnupiravir
plus usual care
(N=12821)
2129 (16.6%)
1765 (13.8%)808 (6.3%)
2990 (23.3%)
183 (1.4%)
26 (0.2%)

Usual Care

Overall(N=12962)
2176 (16.8%)
1979 (15.3%)
772 (6.0%)3152 (24.3%)
158 (1.2%)
19 (0.1%)(N=25783)
4305 (16.7%)
3744 (14.5%)
1580 (6.1%)
6142 (23.8%)341 (1.3%)
45 (0.2%)

3014 (23.5%)1000 (7.8%)
227 (1.8%)
159 (1.2%)
430 (3.4%)
36 (0.3%)
24 (0.2%)
1483 (11.6%)1125 (8.8%)
57 (0.4%)
1968 (15.3%)
198 (1.5%)2880 (22.5%)2295 (17.9%)

3171 (24.5%)
957 (7.4%)
253 (2.0%)
144 (1.1%)
438 (3.4%)
27 (0.2%)30 (0.2%)
1512 (11.7%)
1070 (8.3%)
71 (0.5%)
1944 (15.0%)
220 (1.7%)2902 (22.4%)
2341 (18.1%)

6185 (24.0%)
1957 (7.6%)
480 (1.9%)
303 (1.2%)
868 (3.4%)
63 (0.2%)
54 (0.2%)2995 (11.6%)
2195 (8.5%)
128 (0.5%)3912 (15.2%)
418 (1.6%)
5782 (22.4%)4636 (18.0%)*Median and interquartile range presented for non-normally distributed variables.

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TABLE 6 BASELINE CHARACTERISTIC OF THE SUBGROUP POPULATION BY RANDOMISED GROUP

Age, mean(SD) [min,max]

Molnupiravir
plus usual care
(N=8088)
59.2 (13.4)[18.0 to 99.0]

Usual Care

Overall(N=8046)59.2 (13.6)[18.0 to 98.0](N=16134)59.2 (13.5)[18.0 to 99.0]4452 (55.0%)3634 (44.9%)
2 (0.0%)2.0 (2.0 to 2.0)4450 (55.3%)
3595 (44.7%)
1 (0.0%)N/A

8902 (55.2%)
7229 (44.8%)
3 (0.0%)2.0 (2.0 to 2.0)

4.0 (3.0 to 5.0)

N/A

4.0 (3.0 to 5.0)

Sex, n(%)
FemaleMale
OtherDays from randomisation to reporting receipt of
medication*, median(IQR)
Days from start of symptoms to taking medication*,
median(IQR)
Data unavailable, n(%)
Ethnicity category, n(%)
White
Asian
Mixed Race
Black
Other
NHS priority category, n(%)
Aged ≥80
Aged ≥75 and <80
Aged ≥70 and <75 OR Aged ≥18 and <70 andclinically extremely vulnerable
Aged ≥65 and <70 and not clinically extremely
vulnerable
Aged ≥18 and <65 in an at risk group
Aged ≥60 and <65 and not clinically extremely
vulnerable or in an at risk group
Aged ≥55 and <60 and not clinically extremely
vulnerable or in an at risk group
Aged ≥50 and <55 and not clinically extremely
vulnerable or in an at risk group
Predicted risk quintile, n(%)
1 (lowest risk)
23
4
5 (highest risk)
Confirmed PCR positive, n(%)
IMD quintile, n(%)(Most deprived) 1
2
3
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233 (2.9%)
117 (1.4%)
53 (0.7%)
57 (0.7%)7573 (94.1%)
269 (3.3%)
105 (1.3%)
53 (0.7%)
46 (0.6%)

15201 (94.2%)
502 (3.1%)
222 (1.4%)
106 (0.7%)103 (0.6%)

256 (3.2%)
537 (6.6%)1115 (13.8%)271 (3.4%)
573 (7.1%)
1108 (13.8%)

527 (3.3%)1110 (6.9%)
2223 (13.8%)1488 (18.4%)

1463 (18.2%)

2951 (18.3%)4545 (56.2%)
37 (0.5%)4474 (55.6%)
35 (0.4%)

9019 (55.9%)
72 (0.4%)

43 (0.5%)56 (0.7%)

99 (0.6%)

67 (0.8%)66 (0.8%)

133 (0.8%)623 (7.7%)
1698 (21.0%)
1861 (23.0%)2084 (25.8%)
1822 (22.5%)3680 (45.5%)633 (7.9%)
1660 (20.6%)
1898 (23.6%)2063 (25.6%)
1792 (22.3%)
3585 (44.6%)

1256 (7.8%)3358 (20.8%)3759 (23.3%)
4147 (25.7%)3614 (22.4%)
7265 (45.0%)835 (10.3%)1250 (15.5%)
1659 (20.5%)808 (10.0%)1265 (15.7%)
1629 (20.2%)1643 (10.2%)2515 (15.6%)
3288 (20.4%)

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4(Least deprived) 5
Data unavailable, n(%)
Took at least 4 doses IMP, n(%)
Received vaccination, n(%)
Number of COVID-19 vaccine doses, n(%)
1
2
34Data unavailable, n(%)
Current smoker, n(%)
Baseline Symptoms
Shortness of breath, n(%)
No problem
Minor problem
Moderate problem
Major problem
Fatigue, n(%)
No problem
Minor problem
Moderate problem
Major problem
Muscle ache, n(%)
No problem
Minor problem
Moderate problem
Major problem
Vomiting, n(%)
No problem
Minor problem
Moderate problem
Major problem
Diarrhoea, n(%)
No problem
Minor problem
Moderate problem
Major problem
Loss of smell or taste, n(%)
No problem
Minor problem
Moderate problem
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Molnupiravir
plus usual care
(N=8088)
2011 (24.9%)2305 (28.5%)
28 (0.3%)
7495 (92.7%)
7994 (98.8%)

Usual Care

Overall(N=8046)
1967 (24.4%)
2340 (29.1%)
37 (0.5%)
7974 (99.1%)(N=16134)
3978 (24.7%)4645 (28.8%)65 (0.4%)
7495 (46.5%)
15968 (99.0%)

54 (0.7%)
290 (3.6%)7440 (92.0%)
210 (2.6%)
94 (1.2%)
787 (9.7%)

48 (0.6%)
249 (3.1%)
7464 (92.8%)
213 (2.6%)
72 (0.9%)799 (9.9%)102 (0.6%)539 (3.3%)
14904 (92.4%)423 (2.6%)
166 (1.0%)
1586 (9.8%)

3871 (47.9%)2834 (35.0%)1221 (15.1%)
162 (2.0%)3786 (47.1%)
2891 (35.9%)1198 (14.9%)
171 (2.1%)

7657 (47.5%)5725 (35.5%)2419 (15.0%)333 (2.1%)

803 (9.9%)2960 (36.6%)
3187 (39.4%)
1138 (14.1%)

788 (9.8%)2952 (36.7%)
3186 (39.6%)1120 (13.9%)

1591 (9.9%)5912 (36.6%)6373 (39.5%)2258 (14.0%)2264 (28.0%)2734 (33.8%)
2371 (29.3%)
719 (8.9%)2155 (26.8%)2934 (36.5%)
2290 (28.5%)
667 (8.3%)

4419 (27.4%)5668 (35.1%)
4661 (28.9%)1386 (8.6%)6603 (81.6%)
1151 (14.2%)
298 (3.7%)
36 (0.4%)6564 (81.6%)
1140 (14.2%)
288 (3.6%)
54 (0.7%)

13167 (81.6%)
2291 (14.2%)
586 (3.6%)
90 (0.6%)

6599 (81.6%)
1073 (13.3%)
331 (4.1%)
85 (1.1%)

6593 (81.9%)1094 (13.6%)
296 (3.7%)
63 (0.8%)

13192 (81.8%)2167 (13.4%)
627 (3.9%)
148 (0.9%)5660 (70.0%)
1589 (19.6%)
541 (6.7%)

5802 (72.1%)
1473 (18.3%)
512 (6.4%)

11462 (71.0%)3062 (19.0%)1053 (6.5%)

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Molnupiravir
plus usual care
(N=8088)298 (3.7%)

Usual Care

Overall(N=8046)259 (3.2%)(N=16134)
557 (3.5%)

No problem
Minor problem
Moderate problem
Major problem

1753 (21.7%)
3293 (40.7%)2316 (28.6%)
726 (9.0%)

1837 (22.8%)3205 (39.8%)2337 (29.0%)
667 (8.3%)

3590 (22.3%)
6498 (40.3%)4653 (28.8%)1393 (8.6%)

No problem
Minor problem
Moderate problem
Major problem

5306 (65.6%)
1946 (24.1%)
701 (8.7%)
135 (1.7%)5174 (64.3%)2034 (25.3%)
699 (8.7%)
139 (1.7%)10480 (65.0%)3980 (24.7%)
1400 (8.7%)
274 (1.7%)

No problem
Minor problem
Moderate problem
Major problem

6541 (80.9%)1143 (14.1%)
359 (4.4%)
45 (0.6%)

6466 (80.4%)
1191 (14.8%)351 (4.4%)
38 (0.5%)

13007 (80.6%)2334 (14.5%)710 (4.4%)
83 (0.5%)

No problem
Minor problem
Moderate problem
Major problem

347 (4.3%)
3162 (39.1%)
3637 (45.0%)
942 (11.6%)345 (4.3%)
3212 (39.9%)3591 (44.6%)
898 (11.2%)

692 (4.3%)
6374 (39.5%)
7228 (44.8%)
1840 (11.4%)

No problem
Minor problem
Moderate problem
Major problem

3563 (44.1%)
3019 (37.3%)
1375 (17.0%)
131 (1.6%)3583 (44.5%)3021 (37.5%)1315 (16.3%)
127 (1.6%)7146 (44.3%)
6040 (37.4%)
2690 (16.7%)
258 (1.6%)

837 (10.3%)
3811 (47.1%)
2910 (36.0%)
530 (6.6%)
5.2 (1.7) [0.0 to
10.0]802 (10.0%)3805 (47.3%)
2968 (36.9%)
471 (5.9%)
5.2 (1.7) [0.0 to
10.0]1639 (10.2%)7616 (47.2%)
5878 (36.4%)
1001 (6.2%)
5.2 (1.7) [0.0 to
10.0]1106 (13.7%)
4167 (51.5%)
1211 (15.0%)
938 (11.6%)
446 (5.5%)
220 (2.7%)
1607 (19.9%)93 (1.1%)

1127 (14.0%)4104 (51.0%)1197 (14.9%)
998 (12.4%)
412 (5.1%)
208 (2.6%)
1696 (21.1%)
84 (1.0%)2233 (13.8%)8271 (51.3%)2408 (14.9%)
1936 (12.0%)858 (5.3%)
428 (2.7%)3303 (20.5%)
177 (1.1%)

Major problem
Headache, n(%)

Dizziness, n(%)

Abdominal pain, n(%)

Generally unwell, n(%)

Fever, n(%)

Cough, n(%)
No problem
Minor problem
Moderate problem
Major problem
Wellness score, mean (SD) [min,max]People in household, n(%)
0
1
2
3
4
5
Taking inhaled corticosteroids, n(%)
Taking inhaled corticosteroids for COVID, n(%)
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Monoclonal antibodies for COVID, n(%)
Comorbidities
Lung disease
Heart disease
Kidney disease
Liver disease
Neurological disease
Learning disability
Down's syndrome'
Diabetes
Weakened immune system
Transplant recipient
Obesity
Mental illness
Hypertension
Other vulnerability

Molnupiravir
plus usual care
(N=8088)
0 (0.0%)Usual Care

Overall(N=8046)
0 (0.0%)(N=16134)
0 (0.0%)1620 (20.0%)993 (12.3%)
222 (2.7%)
131 (1.6%)295 (3.6%)
32 (0.4%)
24 (0.3%)
1473 (18.2%)1110 (13.7%)
55 (0.7%)
1957 (24.2%)
143 (1.8%)2854 (35.3%)
1683 (20.8%)1718 (21.4%)
952 (11.8%)
253 (3.1%)
119 (1.5%)281 (3.5%)
26 (0.3%)
26 (0.3%)
1507 (18.7%)1055 (13.1%)
69 (0.9%)
1932 (24.0%)
159 (2.0%)2895 (36.0%)
1615 (20.1%)3338 (20.7%)
1945 (12.1%)
475 (2.9%)250 (1.5%)
576 (3.6%)
58 (0.4%)
50 (0.3%)2980 (18.5%)2165 (13.4%)
124 (0.8%)3889 (24.1%)
302 (1.9%)5749 (35.6%)
3298 (20.4%)*Median and interquartile range presented for non-normally distributed variables.

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TABLE 7 PREVALENCE OF RISK FACTORS FOR SEVERE COVID-19 (MODIFIED DEFINITION) AMONG ELIGIBLE PARTICIPANTS

Risk factors
Older adults aged ≥ 65 years
Cancer or chemotherapy
Chronic respiratory disease
Chronic kidney disease
Diabetes
Hypertension (high blood pressure)
Chronic heart or vascular disease
StrokeObesity (BMI ≥ 35 kg/m2)
Current smoker
Solid organ, bone marrow and stem celltransplant recipients
Immunosuppression and HIV infection

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Molnupiravir
plus usual care(n=8088)

Usual care

3396 (42.0%)
10 (0.1%)
1620 (20.0%)222 (2.7%)
1473 (18.2%)
2854 (35.3%)
993 (12.3%)
16 (0.2%)
1957 (24.2%)
787 (9.7%)
55 (0.7%)3415 (42.4%)
14 (0.2%)
1718 (21.4%)
253 (3.1%)
1507 (18.7%)2895 (36.0%)
952 (11.8%)
24 (0.3%)
1932 (24.0%)
799 (9.9%)69 (0.9%)1110 (13.7%)1055 (13.1%)(n=8046)

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4.3 NUMBER ANALYSED
Of the 16134 participants included in the subgroup analysis 15703 (97.3%) had data collectedon hospitalisation/death and so could be included in the primary analysis. 15324 (95.0%)
completed any diaries or calls and so could be included in the secondary analysis.

4.4 PRIMARY ANALYSES
4.4.1 PRIMARY OUTCOME
The primary outcome is defined as all cause unplanned hospitalisation or death fromrandomisation to 28 days follow-up. Data is derived from participant daily diaries, phone calls,
and routine electronic data. If a primary endpoint is reported from any data source then thisoutcome is counted as “yes”. If the participant has completed 28 days follow-up and is not
hospitalised or is lost to follow-up but has been checked against routine electronic data andno hospitalisation or death is found then this outcome is coded “no”. An odds ratio<1 suggests
fewer hospitalisations/deaths in the Molnupiravir arm. The results show probability ofsuperiority just below 0.5, indicating equivalence of Molnupiravir with Usual Care.
TABLE 8 PRIMARY OUTCOME

Molnupiravir
plus usual care
(N=8088)
81/7933 (1.0%)

Hospitalization ordeath
Deaths3/7933
Hospitalizations
79/7933 (1.0%)*OR < 1 favours Molnupiravir

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Usual care
(N=8046)

Estimated treatment
effect (95% BCI)

78/7770 (1.0%)

1.022 (0.738 to 1.382)

Probabilityofsuperiority
0.47785/777076/7770 (1.0%)

Not estimable
1.023 (0.737 to 1.385)

0.4762

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4.4.2 SECONDARY OUTCOMES
Definition of outcomes:
1. Time to recovery: time to first reporting of feeling recovered in diary or call. A hazard ratio>1 suggests faster recovery in the Molnupiravirarm
2. Time to sustained recovery: time to reporting recovery in diary or call followed by no subsequent relapse. A hazard ratio>1 favours
Molnupiravir.
3. Early sustained recovery: reported recovered within the first 14 days with no subsequent relapse. An odds ratio >1 favours Molnupiravir.
4. Alleviation of symptoms: Time to first rating of symptoms as mild/none. If all symptoms are rated mild/none at baseline then theparticipant is censored at day 0. A hazard ratio>1 favours Molnupiravir.
5. Sustained alleviation of symptoms: Time to rating of symptoms as mild/none followed by no subsequent relapse. If all symptoms are
rated mild/none at baseline then the participant is censored at day 0. A hazard ratio>1 favours Molnupiravir.
6. Reduction of symptoms: Time to reduction of all symptoms by at least one grade. A hazard ratio>1 favours Molnupiravir.
7. Rating of how well participant feels (1 worst, 10 best): Participant rating of wellness at each day. Estimates represent the meandifferences and a values >0 favours Molnupiravir.
8. Household infections: Participant reported another member of their household becoming unwell with COVID-19. Participants who live
alone at baseline are excluded. An odds ratio <1 favours Molnupiravir (fewer household infections). For number of infections a rate ratio<1 favours Molnupiravir.
The following assumptions have been made in the following analysis:
1. For time to event outcomes participants are censored at the last point of contact or 28 days, whichever is sooner. For time to sustained
recovery if a participant reported feeling recovered and is subsequently lost to follow-up it is assumed they remained recovered (lastStatistical Analysis Part 1 Report

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2.
3.
4.
5.

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observation carried forward). A similar principle is used for time to sustained alleviation of symptoms. Therefore the only missing data
for time to event outcomes is participants who completed no diary data
For early sustained recovery if a participant is lost to follow-up, such that it is not possible to establish if they remained recovered, thenthis outcome is treated as missing.
For time to alleviation and time to reduction of symptoms if a symptom is missing but the participant reported feeling recovered, thatsymptom is assumed to be rated “none”.
For household infections if a participant has incomplete diaries but has not stated that they have an infection within the household thisoutcome is assumed to be zero. Participants who live alone at baseline are excluded from the analysis.
Analysis of daily symptom scores uses a frequentist mixed model, due to the computational difficultly running the Bayesian model with
the number of parameters.

Results in Table 9 have showed that the estimated median (95% BCI) TTR from the Bayesian model were 10.022 (9.775 to 10.274) days and13.940 (13.447 to 14.445) days, respectively, which suggested that Molnupiravir has a nearly 4 days benefit in TTR compared with Usual Care.
There was a significant benefit in early sustained recovery by 9.5%, i.e. recovered within the first 14 days and remained well until day 28 fromrandomisation, in Molnupiravir group (32.8%) compared to Usual Care (23.3%) (OR = 1.6; 95% BCI (1.52 to 1.77)).

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TABLE 9 SECONDARY OUTCOMES

Molnupiravir plus
usual care (N=8088)

Usual care

Estimated treatment
effect (95% BCI)

Estimated benefit (95%
BCI)

Probability ofsuperiority

First reported recovery

6177/7850 (78.7%)

5195/7474 (69.5%)

Days to first reported recovery

10.022 (9.775 to 10.274)

13.940 (13.447 to 14.445)

1.353 (1.301 to 1.403) *-3.920 (-4.453 to -3.384) †>0.99

Early sustained recovery

2360/7188 (32.8%)

1547/6649 (23.3%)

1.638 (1.517 to 1.768) **Sustained recovery

5401/7850 (68.8%)4512/7474 (60.4%)

Days to sustained recovery

19.746 (19.275 to 20.232)

23.272 (22.882 to 23.611)

Alleviation of all symptoms

5674/6132 (92.5%)5136/5816 (88.3%)

Days to alleviations of all symptoms

3.694 (3.589 to 3.802)

4.388 (4.252 to 4.535)

Sustained alleviation of all symptoms

5125/6132 (83.6%)

4609/5816 (79.2%)

Days to sustained alleviation of all
symptoms

9.374 (8.974 to 9.799)

11.038 (10.585 to 11.525)

Initial reduction of symptom severity

6821/7835 (87.1%)

6010/7464 (80.5%)

Days to initial reduction of symptom
severity

7.349 (7.167 to 7.534)

Day 7(N=8046)>0.99

1.237 (1.189 to 1.288) *-3.524 (-4.093 to -2.926) †>0.99

1.188 (1.143 to 1.234) *-0.695 (-0.856 to -0.535) †>0.99

1.134 (1.090 to 1.178) *-1.669 (-2.221 to -1.111) †>0.99

9.162 (8.929 to 9.404)

1.278 (1.234 to 1.322) *-1.812 (-2.086 to -1.537) †>0.99

7.3 (1.8) [7471]

6.8 (1.8) [6927]

0.5 (0.5 to 0.6) ¶P<0.001 ll

Day 147.8 (1.7) [7276]

7.6 (1.7) [6605]

0.3 (0.2 to 0.3) ¶P<0.001 ll

Day 218.1 (1.7) [6782]

7.9 (1.7) [5927]

0.1 (0.1 to 0.2) ¶P<0.001 ll

Day 288.4 (1.6) [6746]

8.2 (1.6) [6062]

0.1 (0.1 to 0.2) ¶P<0.001 ll

2542/ (31.4%)

2469/ (30.7%)

0.961 (0.896 to 1.025) **0.8873404/7849 (5.1%)

510/7470 (6.8%)

0.738 (0.645 to 0.841) **>0.99

Participant rating of wellness

New infections in household
Contact with health and social careservices
NHS 111
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Molnupiravir plus
usual care (N=8088)

Usual care
(N=8046)

Estimated treatment
effect (95% BCI)

Estimated benefit (95%
BCI)

Probability ofsuperiority

General practitioner

1673/7848 (21.3%)

1885/7470 (25.2%)

0.797 (0.738 to 0.860) **>0.99

Ambulance service (nothospitalised)

225/7845 (2.9%)

203/7460 (2.7%)

1.060 (0.868 to 1.281) **0.2966

Community nurse

193/7849 (2.5%)

216/7468 (2.9%)0.854 (0.696 to 1.035) **0.9466

Physiotherapist

98/7849 (1.2%)

57/7468 (0.8%)

1.659 (1.184 to 2.270) **0.0020Counsellor

53/7849 (0.7%)66/7468 (0.9%)

0.762 (0.520 to 1.071) **0.9419Social worker

18/7849 (0.2%)

24/7468 (0.3%)

0.736 (0.384 to 1.281) **0.8785Home carer

74/7848 (0.9%)73/7466 (1.0%)

0.973 (0.695 to 1.328) **0.5979

Occupational therapist

167/7848 (2.1%)

146/7468 (2.0%)

1.100 (0.870 to 1.366) **0.2201

Hospital emergency department

445/7849 (5.7%)

401/7468 (5.4%)

1.056 (0.916 to 1.213) **0.2334Outpatient respiratory clinic

152/7849 (1.9%)

173/7467 (2.3%)

0.835 (0.665 to 1.038) **0.9492

Hospital at home for COVID-19

253/7849 (3.2%)

298/7468 (4.0%)

0.803 (0.673 to 0.947) **0.9960

Other services

429/7849 (5.5%)

469/7467 (6.3%)

0.862 (0.751 to 0.985) **0.9849*Estimated HR derived from a piecewise exponential model adjusted for age, comorbidity and vaccination status. HR > 1 favours Molnupiravir.

†Model based estimated benefit median time to event > 0 favours Molnupiravir.
ll Frequentist model estimates display p-value rather than a probability.
¶Linear mixed effect model adjusted for age, comorbidity and vaccination status. Participant fitted as a random effect. Estimated mean difference > 0 favours Molnupiravir.
**Bayesian logistic regression, adjusted for, age, comorbidity and vaccination status

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The following plot shows the actual data for time to recovery (solid lines) and the modelbased estimates (dashed lines). The model-based estimates are derived from the piecewise
exponential where all the standardised covariates are set to zero (corresponding to thesample average).
FIGURE 2 KAPLAN-MEIER CURVE AND MODEL ESTIMATES FOR TIME TO RECOVERY

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4.5 SUBGROUP ANALYSES
Frequentist model estimates are presented for the moderation analysis of the primary
outcome. An odds ratio<1 favours Molnupiravir. P-values indicate the test for the interaction
and statistically significant p-value suggests a differential effect size between subgroups.
FIGURE 3 FOREST PLOT OF SUBGROUP ANALYSIS OF PRIMARY OUTCOME

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Frequentist model estimates are presented for the moderation analysis of time to recovery.
A hazard ratio>1 favours Molnupiravir. P-values indicate the test for the interaction and astatistically significant p-value suggests a differential effect size between subgroups.
FIGURE 4 FOREST PLOT OF SUBGROUP ANALYSIS OF TIME TO RECOVERY

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4.6 VIROLOGY SUB-STUDY ANALYSISTABLE 10 SUMMARY OF VIROLOGY SUB-STUDY

Molnupiravir
plus usual care

Usual Care

Total

Number of participants, nIntensive samples cohortLess intensive samples cohort
At least 7 samples received from
intensive samples cohort, n/N (%)
At least 2 samples received fromless intensive sample cohort, n/N(%)
Female, n/N (%)
Intensive samples cohortLess intensive samples cohort

23
126
23/23 (100%)30
149
29/30 (96.7%)53
275
52/53 (98.1%)

126/126 (100%)

149/149 (100%)275/275(100%)

11/23 (47.8%)
67/126 (53.2%)

16/30 (53.3%)
87/129 (58.4%)

Overall

78/149 (52.3%)

103/159(57.5%)

27/53 (50.9%)
154/255(56.0%)
181/308(55.2%)

61.0 (8.7)
61.3 (11.0)
61.2 (10.7)

63.6 (9.5)
62.0 (11.4)
62.3 (11.1)

62.5 (9.1)
61.7 (11.2)
61.8 (10.9)

Age, mean (SD)Intensive samples cohortLess intensive samples cohort
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TABLE 11 VIROLOGY SUBSTUDY

Intensive samples
Undetectable viral load, n/N(%)
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7*
Viral load, mean(sd)
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
All samples
Undetectable viral load, n/N(%)
Day 5
Day 14
Viral load, mean(sd)Day 5
Day 14

Molnupiravir
plus usual care

Usual care

Estimated treatment
effect (95% CI)

P value

0/23
0/23
1/22 (0.5%)
3/20 (15%)
3/20 (15 %)3/20 (15 %)

0/29
0/29
0/30
0/29
1/29 (0.3%)
1/29 (0.3%)

5.508 (0.501 to 60.549) †6.041 (0.306 to 119.352) †0.16300.23747.318 (1.173)
6.794 (1.457)
6.196 (1.408)
5.409 (1.541)
4.590 (1.574)
4.276 (1.477)
3.959 (1.245)

7.346 (1.266)
7.077 (1.144)
6.435 (1.148)
6.000 (1.182)
5.781 (1.133)
5.412 (1.340)
4.930 (1.413)-0.342 (-0.908 to 0.225) ‡-0.270 (-0.831 to 0.292) ‡-0.606 (-1.164 to -0.048) ‡-1.221 (-1.782 to -0.660) ‡-1.151 (-1.709 to -0.593) ‡-0.986 (-1.543 to -0.428) ‡0.23680.34640.0333<0.0001
0.00010.0005

11/144 (7.6%)
55/123 (44.7%)

5/167 (3.0%)
78/152 (51.3%)

3.684 (0.920 to 14.763)**0.664 (0.307 to 1.435)**

0.06550.29724.473 (1.567)
2.940 (1.357)

5.576 (1.300)
2.526 (1.145)-1.133 (-1.548 to -0.718) ‡0.318 (-0.008 to 0.644) ‡<0.0001
0.0556* Primary outcome† Firth logistic regression adjusting for sex, age, and baseline log10(viral load). Adjusted OR > 1 favours Molnupiravir‡Mixed effect model adjusting for sex, age, and baseline log10(viral load); adjusted difference < 0 favours Molnupiravir** Mixed effects logistic regression adjusting for sex, age, and baseline log 10(viral load). Adjusted OR > 1 favours
Molnupiravir

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~~~ END OF REPORT ~~~Statistical Analysis Part 1 Report

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