Final Full Clinical Study Report
Protocol C4671002

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Study Title: An Interventional Efficacy and Safety, Phase 2/3, Double-Blind, 2‑Arm Study
to Investigate Orally Administered PF‑07321332/Ritonavir Compared With Placebo in
Nonhospitalized Symptomatic Adult Participants With COVID-19 Who are at Low Risk ofProgressing to Severe Illness
Study Number: C4671002
Regulatory Agency or Public Disclosure Identifier Number:
EudraCT Number: 2021-002857-28
NCT ID: NCT05011513
Study Phase: 2/3
Name of Study Intervention: PF-07321332 (nirmatrelvir)
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date: Final CSR (Last Participant Last Visit) Version 1.0;
09 March 2023
Number of Study Center(s) and Investigator(s):A list of study centers and investigators involved in this study is provided inAppendix 16.1.4.1.
Publications: None
Study Period:
Study initiation date (First Participant First Visit): 25 August 2021
Last Participant Last Visit: 25 July 2022
This study was terminated early.
Rationale:
The purpose of this Phase 2/3 double-blind, 2-arm, interventional study was to evaluate theefficacy, safety, and tolerability of nirmatrelvir/ritonavir for the treatment of nonhospitalized,
symptomatic, adult participants with coronavirus disease 2019 (COVID-19) who are at low
risk of progression to severe illness.

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Final Full Clinical Study Report
Protocol C4671002

CLINICAL STUDY REPORT SYNOPSIS
Objectives, Endpoints, and Statistical Methods:
Table S1. Study Objectives, Endpoints, and Estimands
Type
Primary
Efficacy

Secondary
SafetyEfficacy

Objectives

Endpoints

Estimands

To compare the efficacy ofnirmatrelvir/ritonavir toplacebo for the treatment ofsymptomatic COVID-19 innonhospitalized adultparticipants with COVID-19
who are at low risk ofprogression to severe disease.

 Time (days) to sustained
alleviation of all targeted
COVID-19 signs/symptoms
through Day 28.

The difference in mediantime (days) to sustained
alleviation of all targeted
COVID-19 signs andsymptoms through Day 28
betweennirmatrelvir/ritonavir andplacebo in nonhospitalized
adult patients with
COVID-19 who are at low
risk of progression to severe
disease at baseline and weretreated ≤5 days after
COVID-19 symptom onset.
This was estimatedirrespective of adherence torandomized treatment.

To describe the safety andtolerability ofnirmatrelvir/ritonavir relative toplacebo in the treatment of
nonhospitalized symptomatic
adult participants with
COVID-19 who are at low riskof progression to severe
disease.
To compare
nirmatrelvir/ritonavir versus
placebo for COVID-19 related
hospitalization and all-cause
mortality in nonhospitalized
adult participants with
COVID-19 who are at low riskof progression to severe
disease.

 Incidence of treatmentemergent adverse events(TEAEs).
 Incidence of serious adverse
events (SAEs) and adverse
events (AEs) leading todiscontinuations.

Not Applicable.

 Proportion of participants
with COVID-19 related
hospitalization or deathfrom any cause through Day
28.

 Proportion of participants
with death (all cause)through Week 24.

PFIZER CONFIDENTIAL
Page 2 The difference inproportion of patients
experiencing
COVID-19 related
hospitalization ordeath from any causethrough Day 28 innonhospitalized adultpatients with
COVID-19 who are at
low risk of progression
to severe disease andwere treated ≤5 days
after COVID-19
symptom onset. Thiswas estimated without
regard to adherence torandomized treatment.
 Not Applicable.

Final Full Clinical Study Report
Protocol C4671002

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives, Endpoints, and Estimands
Type
Efficacy

Objectives
To compare
nirmatrelvir/ritonavir versus
placebo for COVID-19 related
medical visits innonhospitalized adultparticipants with COVID-19
who are at low risk ofprogression to severe disease

Endpoints
 Number of COVID-19
related medical visits
through Day 28.

 Number of days in hospitaland intensive care unit
(ICU) stay in participants
with COVID-19-related
hospitalization throughDay 28.

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Estimands
 The difference in theestimated rate of thenumber of COVID-19related medical visits
through Day 28 innonhospitalized adultpatients with COVID19 who are at low riskof progression tosevere disease andwere treated ≤5 days
after COVID-19
symptom onset. This
will be estimatedwithout regard toadherence torandomized treatment.
 The difference in theestimated rate ofnumber of days in
hospital and ICU stayin patients with
COVID-19-related
hospitalization throughDay 28 innonhospitalized adultpatients with
COVID-19 who are at
low risk of progression
to severe disease andwere treated ≤5 days
after COVID-19
symptom onset. This
will be estimatedwithout regard toadherence torandomized treatment.

Final Full Clinical Study Report
Protocol C4671002

CLINICAL STUDY REPORT SYNOPSIS
Table S1. Study Objectives, Endpoints, and Estimands
Type
Efficacy

Objectives
To compare
nirmatrelvir/ritonavir toplacebo for the duration andseverity of signs and symptoms
in nonhospitalized symptomatic
adult participants with
COVID-19 who are at low riskof progression to severe
disease.

PK

To determine thepharmacokinetics (PK) of
nirmatrelvir in nonhospitalized
adult participants with
COVID-19 who are at low riskof progression to severe
disease.
To describe the viral load innasal samples over time innonhospitalized adultparticipants with COVID-19
who are at low risk ofprogression to severe disease.

Efficacy

Endpoints
 Proportion of participants
with severe signs/symptoms
attributed to COVID-19
through Day 28.
 Time (days) to sustained
resolution of all targeted
COVID-19 signs/symptom
through Day 28.
 Duration of each targeted
COVID-19 sign/symptom.
 Progression to a worsening
status in 1 or more
self-reported
COVID-19-associatedsymptoms through Day 28.
 Proportion of participants
with a resting peripheral
oxygen saturation ≥95% atDays 1 and 5.
Nirmatrelvir PK in plasma andwhole blood (if feasible).

Estimands
Not Applicable.

Viral titers measured via reverse
transcription polymerase chain
reaction (RT-PCR) in nasal swabs
over time.

Not Applicable.

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Not Applicable.

Final Full Clinical Study Report
Protocol C4671002

CLINICAL STUDY REPORT SYNOPSIS
Table S2. Summary of Efficacy Analyses (Modified Intention-to-Treat 1[mITT1])
Endpoint

Analysis TypeTime (days) to sustained alleviation of all targeted
COVID-19 signs/symptoms through Day 28.
Proportion of participants with COVID-19-related
hospitalization or death from any cause through Day 28.
Proportion of participants with death (all cause) throughWeek 24.
Number of COVID-19-related medical visits throughDay 28.
Number of days in hospital and ICU stay in participants
with COVID-19-related hospitalization through Day 28.
Proportion of participants with severe signs/symptoms
attributed to COVID-19 through Day 28.aTime (days) to sustained resolution of all targeted
COVID-19 signs/symptom through Day 28.
Duration of each targeted COVID-19 sign/symptom.

Primary
Efficacy
Analysis
Key secondary
analysisSecondaryanalysisSecondaryanalysisSecondaryanalysisSecondary
Efficacy
AnalysisSecondaryanalysisSecondaryanalysisSecondaryanalysisAnalysis Model
Kaplan-Meier & Log rank test
Kaplan-Meier method
Logistic Regression
Descriptive statistics (based on
negative Binomial Model)
Descriptive statistics
Logistic regression model
Kaplan-Meier & Log rank test
Kaplan-Meier estimate, Descriptive
statistics (median, quartiles)
Logistic regression model

Progression to a worsening status in 1 or more
self-reported COVID-19-associated symptoms throughDay 28.b
Proportion of participants with a resting peripheral
SecondaryBreslow-Day test for Homogeneity
oxygen saturation ≥95% at Days 1 and 5.
analysisof the Odds Ratios
Viral titers measured via RT-PCR in nasal swabs overSecondaryMixed model for repeated measures
time.
analysisanalysisa. Definition for severity of signs and symptoms included case report form (CRF) data (hospitalization due to
COVID-19 and death of any cause) that was considered as having severe signs and symptoms.
b. Definition for worsening of signs and symptoms was expanded to include hospitalization due to COVID-19 anddeath of any cause based on CRF data. Participants with hospitalization due to COVID-19 and death of any cause
were considered as having worsening of signs and symptoms.

Table S3. Analysis Sets
Population

Description

Full analysis
set (FAS)
Safetyanalysis set(SAS)
Modified
intention-totreat (mITT)

All participants randomly assigned to study intervention regardless of whether or not study
intervention was administered.
All participants who received at least 1 dose of study intervention. Participants were analyzed
according to the intervention they actually received. A randomized but not treated participant was
excluded from the safety analyses.
All participants randomly assigned to study intervention who took at least 1 dose of study
intervention and with at least 1 postbaseline visit through Day 28 who were treated ≤3 days after
COVID-19 symptom onset. Participants were analyzed according to the study intervention to which
they were randomized.
All participants randomly assigned to study intervention, who took at least 1 dose of study
intervention. Participants were analyzed according to the study intervention they were randomized.
All participants in the mITT1 set without important protocol deviations considered to impact theinterpretation of the primary efficacy endpoint. Protocol deviations were reviewed to generate the listof participants with significant deviations to be excluded from the PP analysis set. The PP exclusion
criteria were finalized prior to breaking the blind.

mITT1
Per protocol(PP)

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Protocol C4671002

CLINICAL STUDY REPORT SYNOPSIS
Methodology:
This Phase 2/3, randomized, double-blind, placebo-controlled study in nonhospitalized
symptomatic adult participants with COVID-19 who are at low risk of progressing to severe
illness evaluated the efficacy, safety, and tolerability of nirmatrelvir/ritonavir compared withplacebo. Eligible participants with a confirmed diagnosis of severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection were randomized (1:1) to receive
nirmatrelvir/ritonavir or placebo orally every 12 hours (q12h) for 5 days (10 doses total).
Randomization was stratified by geographic region, by vaccination status, and by COVID-19
symptom onset (≤3 days vs >3 to 5 days).
Due to a very low rate of hospitalization or death observed in the standard-risk patient
population, the decision was made to cease enrollment and terminate the study as of
15 June 2022. An interim clinical study report (CSR) presented the results of participants
enrolled through Protocol Amendment 4 who completed the Day 34 assessments (data cutoff
19 December 2021).
This final (last participant last visit [LPLV]) CSR presents all data as of LPLV.
Number of Participants (planned and analyzed):
Approximately 1980 participants were to be randomly assigned to study intervention. Basedon the 4 site exclusions: 1288 participants were assigned to treatment. The number ofparticipants analyzed per analysis population was: FAS, 1296; SAS, 1288; mITT1, 1288;
mITT, 929; and PP analysis set, 1218.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Nonhospitalized, symptomatic adult participants with COVID-19 who were at low risk ofprogression to severe illness were enrolled in this study.
Participants ≥18 years of age (or the minimum country specific age of consent if >18) at thetime of the Screening Visit with a confirmed SARS-CoV-2 infection as determined by
RT-PCR in any specimen collected within 5 days prior to randomization and initial onset ofsigns/symptoms attributable to COVID-19 within 5 days prior to the day of randomization
and at least 1 of the specified signs/symptoms attributable to COVID-19 present on the dayof randomization were enrolled in this study.
Eligibility criteria for vaccination status changed based on regulatory feedback and eligibility
to receive PaxlovidTM.
Prior to Protocol Amendment 5 (21 January 2022), participants with underlying
medical conditions associated with an increased risk of developing severe illness
from COVID-19 and who were fully vaccinated and met the other eligibility criteria
were eligible to participate in the study.

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CLINICAL STUDY REPORT SYNOPSIS

Participants without underlying medical conditions associated with an increased riskof developing severe illness from COVID-19 and were either not vaccinated (before
Protocol Amendment 5) or were vaccinated more than 12 months before screening(for participants enrolled under Protocol Amendment 5 [21 January 2022]) and met
the other eligibility criteria were permitted to participate in the study.

Study Interventions, Dose, Mode of Administration, and Batch Number(s):Participants were randomly assigned to 1 of 2 treatment groups in the study:

Two tablets of nirmatrelvir 150 mg and 1 capsule of ritonavir 100 mg every 12 hours(q12h) orally (PO) for 5 days.



Two tablets of placebo for nirmatrelvir and 1 capsule of placebo for ritonavir q12h
PO for 5 days

Participants in either treatment group were permitted to receive standard of care (SoC)
therapy so long as it was not prohibited.
Table S4. Investigational Product Description, Vendor Lot Number, Pfizer Lot
Number, Strength/Potency, and Dosage Form
Investigational Product
Description

VendorLot
Number

Pfizer Lot
NumberStrength/
Potency

Dosage Form

PF-07321332 150 mg Tablet(Croscarmellose Sodium)PF-07321332 150 mg Tablet(Croscarmellose Sodium)
Placebo for PF-07321332 Tablet(Pink Oval)
Placebo for PF-07321332 Tablet(Pink Oval)
Placebo for Ritonavir 100 mg Size
AAA Swedish Orange Capsule
Placebo for Ritonavir 100 mg Size
AAA Swedish Orange Capsule
Placebo for Ritonavir 100 mg Size
AAA Swedish Orange Capsule
Ritonavir 100 mg Size AAA
Swedish Orange Capsule
Ritonavir 100 mg Size AAA
Swedish Orange Capsule
Ritonavir 100 mg Size AAA
Swedish Orange Capsule

FG994621-DP-00680

150 mgTABLET

Not
applicableNot
applicableNot
applicable74132.1

21-DP-00651

150 mgTABLET

21-DP-00601

0 mg

TABLET

21-DP-00720

0 mg

TABLET

21-DP-00588

0 mg

CAPSULE

74132.3

21-DP-00682

0 mg

CAPSULE

74132.7

21-DP-00726

0 mg

CAPSULE

74132.13

21-DP-00825

100 mgCAPSULE

74132.2

21-DP-00591

100 mgCAPSULE

74132.4

21-DP-00681

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Final Full Clinical Study Report
Protocol C4671002

CLINICAL STUDY REPORT SYNOPSIS
Duration of Study Intervention:
The planned treatment duration was 5 days (10 doses total).
Summary of Results:
Demographic and Other Baseline Characteristics:
Demographic characteristics for the mITT1 analysis set were similar between thenirmatrelvir/ritonavir and placebo groups.
Over half of participants were female and the majority were White. Approximately
41% of participants were Hispanic or Latino.

The median age was 41.00 (18.00, 87.00) years and nearly 90% of participants were
under 60 years of age at the time of randomization. The mean (standard deviation[SD]) body mass index (BMI) was 26.26 (5.15) kg/m2, and approximately 49% ofparticipants had a BMI ≥25 kg/m2 at the time of screening.

Baseline characteristics were balanced between both treatment groups.
Exposure:
The mean duration of treatment was similar across treatment groups. Overall, mostparticipants received study intervention for at least 5 calendar days. Participants receiving
only 1 dose of treatment on Day 1 were expected to receive the last dose on Day 6 if thetreatment was completed.
Efficacy Results:
Primary Efficacy Endpoint Results
The primary analysis result was not statistically significant and the primary objective of thestudy was not met. Treatment with nirmatrelvir/ritonavir reduced the median time tosustained alleviation of all targeted signs and symptoms through Day 28 by 1 day in the
mITT1 analysis set who received treatment within 5 days of symptom onset, but thedifference was not statistically significant (p=0.6027) as assessed by the log rank test (ie, nocovariate adjustment).
Secondary Efficacy Endpoint Results
All further analyses used nominal p-values for reporting.
The observed event rate of COVID-19-related hospitalization or death from any causethrough Day 28 in the mITT1 analysis set was 10 of 634 (1.577%) participants in theplacebo group, and 5 of 654 (0.765%) in the nirmatrelvir/ritonavir group. Afteraccounting for premature study discontinuation (ie, to include participants discontinued
from the study before Day 28 without having experienced an event) by using the
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Protocol C4671002

CLINICAL STUDY REPORT SYNOPSIS
follow-up time in the Kaplan-Meier calculation, treatment with nirmatrelvir/ritonavir
showed a -0.813% (95% confidence interval [CI]: -1.999 to 0.374; p=0.1796) absolute
reduction (51.215% relative risk reduction), reducing the event rate from 1.587% to0.774%. Through Day 28, there was 1 death in the placebo group and 0 deaths in thenirmatrelvir/ritonavir group.
o In the post hoc subgroup analysis by risk status at baseline, the risk reduction was
more apparent in the subgroup of participants who were considered as high risk(ie, vaccinated with at least 1 risk factor) than in participants who were considered
as standard risk (ie, participants who did not have risk factors and were either
vaccinated or not vaccinated).
In the mITT1 analysis set, there was 1 death in the placebo group (Day 6) and none in thenirmatrelvir/ritonavir group through Week 24.

Compared with the nirmatrelvir/ritonavir group (15 participants), more participants in theplacebo group (25 participants) had COVID-19-related medical visits and reported more
visits (nirmatrelvir/ritonavir: 24 visits; placebo: 36 visits). After adjusting for geographic
region, symptom onset duration, baseline SARS-CoV-2 serology status, vaccination
status, and baseline viral load, the COVID-19-related medical visits occurred lessfrequently in the nirmatrelvir/ritonavir group at 50.2% of the rate in the placebo group,
but the difference was not significant (p=0.0971).

Including participants with and without hospitalizations, the nirmatrelvir/ritonavir groupreported fewer days in the hospital than in the placebo group: mean (SD) 0.049 (0.591)
days for nirmatrelvir/ritonavir and 0.181 (1.787) days for placebo. Similar results wereobserved for non-ICU visit. No participants in the nirmatrelvir/ritonavir group reported
any ICU visits. For the 3 participants in the placebo group with an ICU visit, the durationof hospitalization ranged from 10 days to 21 days.

Over the study period from Day 1 through Day 28, the proportion of participants withsevere signs and symptoms was lower in the nirmatrelvir/ritonavir group (19.136%)
compared with the placebo group (21.643%) (p=0.1622). Similar findings were observed
at baseline (Day 1) and during treatment (Days 2 to 6), but the difference was not
significant (p=0.2494 and p=0.0783, respectively). However, after treatment and during
the follow-up period (Day 7 to Day 28), the proportion of participants with severe signs
and symptoms was lower in the nirmatrelvir/ritonavir group compared with placebo(p=0.0280).

Treatment with nirmatrelvir/ritonavir reduced the median time to sustained resolution of
all targeted COVID-19-related signs and symptoms through Day 28 by 1 day comparedwith placebo (15 days vs 16 days, respectively), but the mean difference was not
significant (15.598 days vs 16.285 days, respectively; p=0.4298).

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Protocol C4671002

CLINICAL STUDY REPORT SYNOPSISReductions in the median time to sustained alleviation and sustained resolution of eachtargeted COVID-19 sign and symptom were observed with nirmatrelvir/ritonavir
treatment compared with placebo by 2 days for stuffy or runny nose and 1 day forshortness of breath or difficulty breathing; cough; feeling hot or feverish; and sore throat(sustained alleviation) and by 2 days for headache and sore throat and by 1 day formuscle or body aches; shortness of breath or difficulty breathing; chills or shivering;
cough; feeling hot or feverish; and stuffy or runny nose (sustained resolution).

Participants in the nirmatrelvir/ritonavir group were less likely to progress to a worsening
status (ie, increased severity for any targeted symptom) through Day 28 compared withthe placebo group, but the treatment difference was not significant (odds ratio versus
placebo 0.802, p=0.1086).

Among participants with resting peripheral oxygen saturation ≥95% at baseline (Day 1),
twice as many participants in the placebo group than in the nirmatrelvir group had an
oxygen saturation <95% (12 vs 6 participants, respectively). Participants who had aresting peripheral oxygen saturation ≥95% at baseline (Day 1) were more likely tomaintain those levels at Day 5 than those with a resting peripheral oxygen saturation<95% at baseline, but the treatment difference was not significant (p=0.3262).

On-treatment reduction in viral load (ie, change from baseline in viral load ribonucleic
acid [RNA] concentration) was significantly (p<0.0001) larger in thenirmatrelvir/ritonavir treatment group than in the placebo group.
o Mean baseline (Day 1) (SD) log10 viral load was 6.045 (1.862) log10 copies/mL in
the placebo group and 6.214 (1.794) log10 copies/mL in the nirmatrelvir/ritonavirgroup. After accounting for treatment, geographic region, baseline SARS-CoV-2
serology status, symptom onset duration, vaccination status, and baseline viralload, the change from baseline to Day 5 adjusted mean (standard error [SE])reduction in log10 viral load was -2.551 (0.088) log10 copies/mL in the placebogroup and -3.419 (0.084) log10 copies/mL in the nirmatrelvir/ritonavir group,reflecting an additional average reduction (95% CI) of -0.868 (-1.073 to -0.663),
p<0.0001) log10 copies/mLo Among participants with detectable viral load at baseline (545 fornirmatrelvir/ritonavir; 517 for placebo), overall reductions in viral load over time(ie, change from baseline in viral RNA concentration through Day 14) occurred
more rapidly in the nirmatrelvir/ritonavir group than in the placebo group with thedifference between both groups most apparent at Day 5: Least squares meandifference (SE) log10 copies/mL: -0.736 (0.120) at Day 3; -0.834 (0.106) at Day 5;-0.231 (0.100) at Day 10; and -0.215 (0.077) at Day 14.

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CLINICAL STUDY REPORT SYNOPSIS
Safety Results:The proportion of participants with all-causality TEAEs that started on or prior to the
Day 34 visit was comparable between the nirmatrelvir/ritonavir (25.8%) and placebo(24.1%) groups.



Most of the all-causality TEAEs experienced by participants in both treatment groups
were mild (Grade 1) to moderate (Grade 2) in severity. The proportion of participants
with all-causality severe (Grade 3) or potentially life threatening (Grade 4) TEAEs wascomparable between the nirmatrelvir/ritonavir (3.7%) and placebo (3.9%) groups.

Of the most frequently reported all-causality TEAEs (≥1%), the following were reported
at a higher frequency (≥3 participant difference) in the nirmatrelvir/ritonavir groupcompared with the placebo group: Dysgeusia (6.7% vs 0.5%%, respectively), Diarrhoea(4.0% vs 3.0%, respectively), Dyspepsia (1.2% vs 0.3%, respectively), Nausea (3.1% vs
2.7%, respectively), Alanine aminotransferase (ALT) increased (2.1% vs 1.3%,
respectively), and Aspartate aminotransferase (AST) increased (1.4% vs 0.6%,
respectively).
In the nirmatrelvir/ritonavir group, these TEAEs were nonserious and mostly mild
(Grade 1) or moderate (Grade 2) in severity.

Of these TEAEs, discontinuation of nirmatrelvir/ritonavir occurred in 3 participantsfor Dysgeusia, 2 participants each for Diarrhoea and Dyspepsia, and 1 participant for
Nausea.



The proportion of participants with all-causality treatment-emergent SAEs was low andcomparable between the nirmatrelvir/ritonavir (1.2%) and placebo (1.9%) groups. The
most frequently reported all-causality SAEs (≥2 participants) in the nirmatrelvir/ritonavir
and placebo groups were COVID-19 pneumonia (0.5% and 1.3%, respectively) and
Pneumonia (0.2% and 0.3%, respectively). No SAEs were considered treatment-relatedby the investigator.



Hemodynamic and inflammatory adverse events of special interest (AESIs) reported at agreater frequency (≥2 participant difference) in the nirmatrelvir/ritonavir group comparedwith the placebo group were: Syncope (3 [0.5%] vs 0 participants, respectively),
Hypotension (2 [0.3%] vs 0 participants, respectively), and Prothrombin time prolonged(3 [0.5%] vs 1 [0.2%] participants, respectively). No thyroid-related AESIs were reported
at a greater frequency (≥2 participant difference) in the nirmatrelvir/ritonavir groupcompared with the placebo group. AESIs reported at a greater frequency (≥2 participant
difference) in the placebo group compared with the nirmatrelvir/ritonavir group were:
Tachycardia (3 [0.5%] vs 1 [0.2%] participants, respectively), Activated partial
thromboplastin time prolonged (12 [1.9%] vs 7 [1.1%] participants, respectively), andBlood thyroid stimulating hormone increased (7 [1.1%] vs 3 [0.5%] participants,
respectively).
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CLINICAL STUDY REPORT SYNOPSIS

In the nirmatrelvir/ritonavir group, 16 (2.4%) participants discontinued study intervention
due to at least 1 AE and continued the study compared with 5 (0.8%) participants in theplacebo group. Of the 21 participants who discontinued study intervention in both groups,
13 participants had at least 1 TEAE that was considered by the investigator to be related
to study intervention.

No participants in the nirmatrelvir/ritonavir group experienced an AE resulting in death(Grade 5), compared to 1 participant in the placebo group who experienced an SAE of
COVID-19 pneumonia that resulted in death.

No clinically meaningful differences were observed between the nirmatrelvir/ritonavir
and placebo groups with respect to hematology and clinical chemistry laboratory test
results.

One participant in the nirmatrelvir/ritonavir group met laboratory criteria as a potential
Hy’s Law case at baseline; however, this was not a case of drug-induced liver injury
because the liver laboratory abnormalities occurred prior to exposure of study
intervention. The participant completed study intervention and no longer met the protocol
definition of potential Hy’s law by Day 7; liver laboratory values improved over timewith ALT and AST returning to normal levels by Day 37.

No clinically meaningful findings in vital sign measurements were observed in this study.
The incidence of participants with diastolic blood pressure >90 mmHg or systolic bloodpressure >140 mmHg was comparable between the nirmatrelvir/ritonavir (9.1% and9.6%, respectively) and placebo (11.6% and 11.0%, respectively) groups.

Pharmacokinetic Results:
Geometric mean (coefficient of variation % [CV%]) nirmatrelvir concentrations,representative of maximum observed concentration (Cmax) on Day 1 (30 to 90 minutes
postdose) and predose concentration (Ctrough) on Day 5 (preferably up to 2 hours predose)were 1521 (74%) ng/mL and 2566 (71%) ng/mL, respectively.
Conclusions:

The primary analysis result was not statistically significant and the primary objective of
the study was not met. Treatment with nirmatrelvir/ritonavir reduced the median time tosustained alleviation of all targeted signs and symptoms through Day 28, but thedifference was not statistically significant.

Treatment with nirmatrelvir/ritonavir reduced the proportion of participants with
COVID-19-related hospitalization or death from any cause through Day 28 comparedwith placebo; the event rate was reduced from 1.587% to 0.774% with a -0.813%
absolute reduction or a 51.215% relative reduction. There was 1 death in the placebogroup and none in the nirmatrelvir/ritonavir group.
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CLINICAL STUDY REPORT SYNOPSISCOVID-19-related medical visits were less frequent in the nirmatrelvir/ritonavir groupthan in the placebo group, but the difference was not statistically significant. The
nirmatrelvir/ritonavir group reported fewer days in the hospital compared with theplacebo group. No participants in the nirmatrelvir/ritonavir group reported any ICU visitscompared with the 3 participants in the placebo group.

Treatment with nirmatrelvir/ritonavir showed consistent improvements in
COVID-19-related signs and symptoms compared with placebo, although not all meandifferences were statistically significant.

Participants in the nirmatrelvir/ritonavir group were less likely to progress to a worsening
status (ie, increasing severity for any targeted symptom) through Day 28 compared withthe placebo group, but the treatment difference was not statistically significant.

Participants who had a resting peripheral oxygen saturation ≥95% at baseline (Day 1)
were more likely to maintain those levels at Day 5 than those with a resting peripheral
oxygen saturation <95% at baseline, but the treatment difference was not statisticallysignificant.



The antiviral effect of nirmatrelvir/ritonavir was demonstrated by a significant reductionof SARS-CoV-2 viral load compared with placebo at Day 5.

The geometric mean trough concentration of nirmatrelvir on Day 5 was consistent withthe predicted concentrations via a population PK model and were similar to exposures(Ctrough) associated with the administration of nirmatrelvir/ritonavir 300 mg/100 mg.

Treatment with nirmatrelvir/ritonavir was safe and well tolerated.


The incidence of all-causality TEAEs was comparable for both treatment groups.
Most all-causality TEAEs in both treatment groups were mild (Grade 1) to moderate(Grade 2) in severity. The proportion of participants with all-causality severe(Grade 3) or potentially life-threatening (Grade 4) TEAEs was comparable between
treatment groups.

The proportion of participants with all-causality treatment-emergent SAEs was low
and comparable between treatment groups.

No participants in the nirmatrelvir/ritonavir group discontinued the study due to an
all-causality AE compared with 1 participant in the placebo group. In total, 16 (2.4%)
participants in the nirmatrelvir/ritonavir group discontinued study intervention due toat least 1 AE and continued the study compared with 5 (0.8%) participants in theplacebo group.



The incidence of participants with hemodynamic, inflammatory, or thyroid-related
AESIs was comparable between treatment groups, except for Syncope, Hypotension,
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Final Full Clinical Study Report
Protocol C4671002

CLINICAL STUDY REPORT SYNOPSIS
and Prothrombin time prolonged which occurred at a greater frequency in thenirmatrelvir/ritonavir group; and Tachycardia, Activated partial thromboplastin time
prolonged, and Blood thyroid stimulating hormone increased which occurred at agreater frequency in the placebo group.
Treatment with nirmatrelvir/ritonavir was not associated with clinically meaningfulchanges in laboratory values or vital signs.


One participant in the nirmatrelvir/ritonavir group met laboratory criteria as apotential Hy’s law case at baseline, which was not a drug-induced liver injury
since the laboratory abnormalities occurred prior to exposure of study
intervention; liver laboratory values improved over time with ALT and AST
returning to normal levels by Day 37.

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