Final Full Clinical Study Report
Protocol C4671005

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 Increased Risk
of Progressing to Severe Illness
Study Number: C4671005
Regulatory Agency or Public Disclosure Identifier Number:
EudraCT Number: 2021-002895-38
ClinicalTrials.gov ID: NCT04960202
Study Phase: 2/3

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Name of Study Intervention: PF-07321332 (nirmatrelvir)
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date:
Final CSR (Amendment to 06 June 2022), 08 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:Hammond J, Leister-Tebbe H, Gardner A, et al. Oral nirmatrelvir for high-risk,
nonhospitalized adults with COVID-19. N Engl J Med. 2022;386(15):1397-1408.
Study Period:
Study Initiation Date (First Participant First Visit): 16 July 2021
Primary Completion Date: 09 December 2021
Study Completion (Last Participant Last Visit) Date: 26 April 2022
This study was neither discontinued nor interrupted.

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Final Full Clinical Study Report
Protocol C4671005

CLINICAL STUDY REPORT SYNOPSIS
Rationale:
The purpose of this Phase 2/3 double-blind, 2-arm, interventional study was to evaluate theefficacy and safety of PF-07321332 (also referred to as nirmatrelvir)/ritonavir for thetreatment of nonhospitalized, symptomatic adult participants with coronavirus disease 2019
(COVID-19) who are at increased risk of progressing to severe illness.
Objectives, Endpoints, and Statistical Methods:
Table S1. Study Objectives, Endpoints, and Estimands

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Primary
Efficacy

Secondary:
SafetyEfficacy

Efficacy

Objectives

Endpoints

Estimands

To compare the efficacy ofnirmatrelvir/ritonavir toplacebo for the treatment of
COVID-19 innonhospitalized symptomatic
adult participants with
COVID-19 who are atincreased risk of progression
to severe disease.

Proportion of participants
with COVID-19 related
hospitalization or death fromany cause through Day 28.

The difference in proportions ofpatients experiencing
COVID-19-related hospitalization
or death from any cause throughDay 28 innonhospitalized adult patients withsymptomatic COVID-19 who are atincreased risk of progression tosevere disease, who did not receive
COVID-19 therapeutic monoclonal
antibody (mAb) treatment and weretreated ≤3 days after COVID-19
symptom onset. This will be
estimated without regard toadherence to randomized treatment.

To describe the safety andtolerability ofnirmatrelvir/ritonavir relative
to placebo in the treatment of
nonhospitalized symptomatic
adult participants with
COVID-19 who are atincreased risk of progression
to severe disease.
To compare the efficacy ofnirmatrelvir/ritonavir toplacebo for the treatment of
COVID-19 innonhospitalized symptomatic
adult participants with
COVID-19 who are atincreased risk of 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 ofparticipants with
COVID-19-related
hospitalization or deathfrom any cause throughDay 28.

The difference in proportions ofpatients experiencing
COVID-19-related hospitalization
or death from any cause throughDay 28 in nonhospitalized adultpatients with symptomatic
COVID-19 who are at increased
risk of progression to severe
disease and who did not receive
COVID-19 therapeutic mAbtreatment. This will be estimatedwithout regard to adherence torandomized treatment.

To compare
nirmatrelvir/ritonavir toplacebo for the duration andseverity of signs andsymptoms in nonhospitalized Time (days) to sustained
alleviation of all targeted
signs/symptoms throughDay 28.

The absolute difference in mediantime to sustained alleviation or
resolution of symptoms for allnonhospitalized adult patients with
COVID-19 who are at increased

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Table S1. Study Objectives, Endpoints, and Estimands

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Type

Efficacy

Pharmacokinetics

Efficacy

Efficacy

Objectives
symptomatic adultparticipants with COVID-19
who are at increased risk ofprogression to severe
disease.

To compare
nirmatrelvir/ritonavir toplacebo for all-cause
mortality in nonhospitalized
symptomatic adultparticipants with COVID-19
who are at increased risk ofprogression to severe
disease.
To determine thepharmacokinetics (PK) of
nirmatrelvir in
nonhospitalized symptomatic
adult participants with
COVID-19 who are atincreased risk of progression
to severe disease.
To describe the viral load innasal samples over time innonhospitalized symptomatic
adult participants with
COVID-19 who are atincreased risk of progression
to severe disease.
To compare
PF-07321332/ritonavir toplacebo for COVID-19related medical visits innonhospitalized symptomatic
adult participants with
COVID-19 who are at

Endpoints
 Proportion ofparticipants with severe
signs/symptoms
attributed to COVID-19
through Day 28.
 Time (days) to sustained
resolution of all targeted
signs/symptoms throughDay 28.
 Duration of eachtargeted COVID-19
sign/symptom.
 Progression to aworsening status in 1 ormore self-reported
COVID-19 associatedsymptoms throughDay 28.
 Proportion ofparticipants with aresting peripheral
oxygen saturation ≥95%
at Days 1 and 5.
Proportion of participants
with death (all cause)through Week 24.

Estimandsrisk of progression to severe
disease. This will be estimatedirrespective of adherence torandomized treatment.

PF-07321332 PK in plasma
and whole blood (iffeasible).

Not applicable.

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

Not applicable.

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

Not applicable.

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Not applicable.

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Protocol C4671005

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

Objectives
increased risk of progression
to severe disease.
To compare
nirmatrelvir/ritonavir toplacebo for
COVID-19-related
hospitalizations in
nonhospitalized symptomatic
adult participants with
COVID-19 who are atincreased risk of progression
to severe disease.

Endpoints

Estimands

Number of days in hospitaland ICU stay in participants
with COVID-19 related
hospitalization.

Table S2. Summary of Efficacy Analyses
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Endpoint

Analysis Type

Population

Analysis Model

Proportion of participants with
COVID-19 related
hospitalization or death fromany cause through Day 28.
Proportion of participants with
COVID-19 related
hospitalization or death fromany cause through Day 28.
Time to sustained alleviation of
all targeted signs/symptoms
through Day 28.
Time to sustained resolution of
all targeted signs/symptoms
through Day 28.
Proportion of participants withsevere signs/symptoms
attributed to COVID-19 throughDay 28.
Duration of each targeted
COVID-19 sign/symptom.

Primary Efficacy
analysismITT

Kaplan-Meier method

Key secondary analysis

mITT1

Kaplan-Meier method

Secondary analysis

mITT
mITT1
mITT2
mITT
mITT1
mITT2
mITT
mITT1
mITT2

Cox proportional hazard
model

Descriptive statistics

Progression to a worsening
status in 1 or more self-reported
COVID-19-associatedsymptoms through Day 28.
Proportion of participants with aresting peripheral oxygen
saturation ≥95% at Days 1
and 5.

Secondary analysis

mITT
mITT1
mITT2
mITT
mITT1
mITT2
mITT
mITT1
mITT2

Breslow-Day test for
Homogeneity of theOdds Ratios

Secondary analysis

Secondary analysis

Secondary analysis

Secondary analysis

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model
Logistic regression

Logistic regression

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CLINICAL STUDY REPORT SYNOPSIS
Table S2. Summary of Efficacy Analyses

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Endpoint

Analysis Type

Proportion of participants withdeath (all cause) through Week
24.
Viral titers measured via
RT-PCR in nasal swabs overtime.
Number of COVID-19 related
medical visits through Day 28.

Secondary analysis

Number of days in hospital andICU stay in participants with
COVID-19 related
hospitalization.

Secondary analysis

Secondary analysis

Secondary analysis

Population
mITT
mITT1
mITT2
mITT
mITT1
mITT2
mITT
mITT1
mITT2
mITT
mITT1
mITT2

Analysis Model
Logistic regression or
Fisher Exact test (ifappropriate)
MMRM analysis

Descriptive statistics(based on negative
Binomial Distribution)
Descriptive statistics

mITT: All participants randomly assigned to study intervention, who took at least 1 dose of study intervention, who atbaseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment and were treated ≤3 daysof COVID-19 onset.
mITT1: All participants randomly assigned to study intervention, who took at least 1 dose of study intervention, and
who at baseline did not receive nor were expected to receive COVID-19 therapeutic mAb treatment.
mITT2: All participants randomly assigned to study intervention, who took at least 1 dose of study intervention.

Methodology:
This Phase 2/3, randomized, double-blind, placebo-controlled study in nonhospitalized,
symptomatic adult participants with COVID-19 at increased risk of progressing to severe
illness determined the efficacy, safety, and tolerability of nirmatrelvir/ritonavir comparedwith placebo. Eligible participants with a confirmed diagnosis of SARS-CoV-2 infection
were randomized (1:1) to receive nirmatrelvir/ritonavir or placebo orally q12h for 5 days
(10 doses total). Randomization was stratified by geographic region and whether participants
had received/were expected to receive COVID-19 therapeutic mAb treatment (yes/no) basedon the site investigator’s assessment at the time of randomization. The total study duration is
up to 24 weeks.
An interim CSR was prepared separately to present the results of a planned interim analysis
that was conducted after approximately 45% of participants in the mITT analysis set
completed the Day 28 assessments and included participants randomized through29 September 2021 (data cutoff 26 October 2021).The previous final CSR, dated 05 January2022, included data up to the primary completion date (PCD) of 09 December 2021 (datacutoff 11 December 2021) and was generated to present the results of the primary analysis of
all enrolled participants who completed the Day 34 visit. This final CSR includes all data asof last participant last visit (LPLV).

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Number of Participants (planned and analyzed):
Approximately 3000 participants were to be randomly assigned to study intervention. A totalof 2246 participants were randomized to study intervention. The number of participants
analyzed per analysis population was: Full Analysis Set (FAS: all participants randomly
assigned to study intervention regardless of whether or not study intervention was
administered), 2246; Safety Analysis Set (all participants who received at least 1 dose of
study intervention), 2224; mITT, 1379; mITT1, 2085; and mITT2, 2224; Per-protocol set,1319.
Based on the exclusion of 2 sites from the reanalyses, 2113 participants were randomized to
study intervention. The number of participants analyzed per analysis population was: Full
Analysis Set (FAS: all participants randomly assigned to study intervention regardless ofwhether or not study intervention was administered), 2113; Safety Analysis Set (allparticipants who received at least 1 dose of study intervention), 2091; mITT, 1318; mITT1,
1966; and mITT2, 2091; Per-protocol set, 1262.

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Diagnosis and Main Criteria for Inclusion and Exclusion:
Nonhospitalized, symptomatic adult participants with COVID-19, who were at increased riskof progressing to severe illness were enrolled in this study.
Study Interventions, Dose, Mode of Administration, and Batch Number(s):Participants were randomly assigned to 1 of 2 treatment groups in the study:

Nirmatrelvir 300 mg (ie, 2 tablets of 150 mg, or 3 tablets of 100 mg for participants inthe sentinel cohort]) and ritonavir 100 mg (ie, 1 capsule of 100 mg) every 12 hours(q12h) by mouth (PO) for 5 days.

Placebo for nirmatrelvir (2 tablets [3 tablets for the sentinel cohort]) and placebo forritonavir (1 capsule) q12h PO for 5 days.

Participants in either treatment group were permitted to receive standard of care therapy solong as it was not prohibited.

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Table S3. Investigational Product Description, Vendor Lot Number, Pfizer Lot
Number, Strength/Potency and Dosage Form
Investigational Product
Description

Vendor Lot
No.

Pfizer Lot
No.

Strength/
Potency

DosageForm

PF-07321332 100 mg Tablet (10mm Round)PF-07321332 150 mg Tablet(Croscarmellose Sodium)PF-07321332 150 mg Tablet(Croscarmellose Sodium)PF-07321332 150 mg Tablet(Croscarmellose Sodium)
Placebo for PF-07321332 Tablet(10 mm Round)
Placebo for PF-07321332 Tablet(Pink Oval)
Placebo for Ritonavir 100 mg
Size AAA Swedish Orange
CapsulePlacebo for Ritonavir 100 mg
Size AAA Swedish Orange
CapsulePlacebo for Ritonavir 100 mg
Size AAA Swedish Orange
CapsuleRitonavir 100 mg Size AAA
Swedish Orange Capsule
Ritonavir 100 mg Size AAA
Swedish Orange Capsule
Ritonavir 100 mg Size AAA
Swedish Orange Capsule

PA2103562OTH

21-DP-00508

100 mgTABLET

FG913121-DP-00654

150 mgTABLET

N/A

21-DP-00625

150 mgTABLET

N/A

21-DP-00651

150 mgTABLET

PA2103560OTH

21-DP-00507

0 mg

TABLET

N/A

21-DP-00601

0 mg

TABLET

74132.1

21-DP-00588

0 mg

CAPSULE

74132.3

21-DP-00682

0 mg

CAPSULE

N/A

21-DP-00560

0 mg

CAPSULE

74132.2

21-DP-00591

100 mgCAPSULE

74132.4

21-DP-00681

100 mgCAPSULE

N/A

21-DP-00561

100 mgCAPSULE

Duration of Study Intervention:
The planned treatment duration was 5 days (10 doses total).
Summary of Results:
Demographic and Other Baseline Characteristics:
Demographic and baseline characteristics for the FAS were similar between thenirmatrelvir/ritonavir and placebo groups.
The proportion of male and female participants was balanced and the majority wereWhite (70.8%). Approximately 41% of the participants in each treatment group wereHispanic or Latino. The median (range) age was 45.00 (18.0, 88.0) years and
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263 (12.4%) participants were 65 years of age or greater at the time of randomization.
The mean (SD) body mass index (BMI) was 29.05 (5.56) kg/m2.
All participants had a laboratory confirmed severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) diagnosis, with most (94.9%) participants having aqualifying SARS-CoV-2 positive test collected within 3 days of first dose of study
intervention. Nearly 67% of participants received their first dose of study intervention
within 3 days of symptom onset. Most (94.0%) participants did not receive or were
not planning to receive mAbs for the disease under study at the time ofrandomization.



Across treatment groups, 48.9% of participants were SARS-CoV-2 serologicalnegative at baseline. All but 1 participant had at least 1 risk factor for severe
COVID-19 with over half having 2 or more prespecified risk factors. Most (80.1%)
participants had a baseline BMI ≥25 kg/m2. Other common comorbidities included
cigarette smoker (39.1%), hypertension (31.8%), and diabetes mellitus (10.8%). In
total, 61.9% participants had a baseline viral load ≥4 log10 copies/mL and 26.9% ofparticipants had a baseline viral load ≥7 log10 copies/mL.

Exposure:
The mean duration (SD) of treatment (5.03 [0.81] days) was similar across treatment groups.
Overall, approximately 94% of participants received study intervention over the duration ofat least 5 calendar days.
Efficacy Results:
Primary Endpoint Results
Based on the sequential design and prespecified interim analysis specifications, the primary
analysis result was statistically significant (p<0.0001) and the primary objective of the study
was met and confirmed in the final analysis. Treatment with nirmatrelvir/ritonavir
significantly reduced the proportion of participants with COVID-19-related hospitalization ordeath from any cause through Day 28 in nonhospitalized symptomatic adult participants with
COVID-19 who were at increased risk of progression to severe illness at baseline.
The observed event rate of COVID-19-related hospitalization or death from any causewith COVID-19 symptom onset ≤3 days from first dosing and no mAb treatment was
44 of 647 (6.801%) participants in the placebo group and 5 of 671 (0.745%)
participants who were treated with nirmatrelvir/ritonavir.

After accounting for premature study discontinuation (ie, to include participants
discontinued from study before Day 28 without having experienced a primary
endpoint event) by using the follow-up time in the Kaplan-Meier calculation, theestimated event rate of COVID-19-related hospitalization or death from any cause
over the 28-day period among those treated with placebo was 6.888%. Among those
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CLINICAL STUDY REPORT SYNOPSIS
treated with nirmatrelvir/ritonavir, the event rate was 0.752%, a 6.137% absolute
reduction, indicating a statistically significant improvement (p<0.0001).


Based on the Continuous Mapping Theorem, nirmatrelvir/ritonavir showed an 89.1%
relative reduction in primary events compared to placebo.

Primary endpoint events were mostly COVID-19-related hospitalizations that did not
result in death.

Through Day 28, there were 9 deaths in the placebo group and none in thenirmatrelvir/ritonavir group.

First Key Secondary Efficacy Endpoint Results

090177e19cd55c5a\Approved\Approved On: 09-Mar-2023 02:34 (GMT)The observed event rate of COVID-19-related hospitalization or death from any causethrough Day 28 in the mITT1 analysis set who received treatment within 5 days of symptom
onset and no mAb treatment was 64 of 989 (6.471%) participants in the placebo group, and 9of 977 (0.921%) participants in the nirmatrelvir/ritonavir group.
Because the primary endpoint was statistically significant, the first key secondary efficacy
endpoint was tested at an overall level of 5% as prespecified in the protocol and SAP.
Treatment with nirmatrelvir/ritonavir reduced COVID-19-related hospitalization or death in
the mITT1 population from 6.571% to 0.933% compared to placebo, showing a
5.638% (95% CI: -7.308% to -3.967%; p<0.0001) absolute reduction or an 85.8% relative
reduction in primary endpoint events.
Through Day 28, there were 12 deaths in the placebo group and 0 deaths in thenirmatrelvir/ritonavir group.
Secondary Efficacy Endpoints Results
Secondary efficacy endpoint results are summarized below for the mITT analysis set who
received treatment within 3 days of symptom onset and no mAb treatment. Results for the
mITT1 analysis set, who received treatment within 5 days of symptom onset and no mAbtreatment, were consistent with the mITT analysis set for all endpoints except where noted
below.


Because statistical significance was achieved in the analyses of both the primary endpoint
and the first key secondary efficacy endpoint, the time to sustained alleviation in all
targeted signs/symptoms through Day 28 was analyzed with an alpha level of 5% in thesequential testing procedure as specified in the protocol and SAP. Treatment withnirmatrelvir/ritonavir significantly reduced the median time to sustained alleviation of all
targeted signs and symptoms through Day 28 (15 days for placebo and 12 days fornirmatrelvir/ritonavir). The hazard ratio for treatment with nirmatrelvir/ritonavir versus
placebo was 1.294 days (95% CI: 1.136, 1.476, p=0.0001).
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Because statistical significance was achieved in the analyses of the primary endpoint andthe first and second key secondary efficacy endpoints, the time to sustained resolution in
all targeted signs/symptoms through Day 28 was analyzed with an overall alpha level of
5% in a Hochberg procedure, together with the COVID-19-related medical visits throughDay 28, and the proportion of participants with a resting peripheral oxygen saturation≥95% at Days 1 and 5 as specified in the SAP. Treatment with nirmatrelvir/ritonavir
reduced the median time to sustained resolution of all targeted signs and symptoms
through Day 28 (18 days for placebo; 16 days for nirmatrelvir/ritonavir). The hazard ratio
for treatment with nirmatrelvir/ritonavir versus placebo was 1.219 days (95% CI: 1.061,
1.401; p=0.0053).



Because statistical significance was achieved in the analyses of the primary endpoint andthe first and second key secondary efficacy endpoints, the proportion of participants witha resting peripheral oxygen saturation ≥95% at Days 1 and 5 was analyzed with an
overall alpha level of 5% in a Hochberg procedure, together with the time to sustained
resolution in all targeted signs/symptoms through Day 28 and the COVID-19-related
medical visits through Day 28 as specified in the SAP. Participants who had a resting
peripheral oxygen saturation ≥95% at baseline (Day 1) were more likely to maintainthose levels at Day 5 than those with a resting peripheral oxygen saturation <95% atbaseline (OR 8.948 for placebo; OR 19.400 for nirmatrelvir/ritonavir), but the treatment
difference was not significant (p=0.1997).

Including participants with and without hospitalizations, the nirmatrelvir/ritonavir groupreported fewer days in the hospital than in the placebo group (0.088 days per participant
versus 0.844 days per participant on average). No participants in thenirmatrelvir/ritonavir group reported any ICU visits. The placebo group spent
0.179 days/participant on average in the ICU. No participant in the nirmatrelvir/ritonavirgroup received mechanical ventilation.

Over the study period from Day 1 through Day 28, the proportion of participants withsevere signs and symptoms was numerically lower in the nirmatrelvir/ritonavir groupcompared to the placebo group (18.168% vs 20.775%, p=0.3473). Although these overall
proportions were not significantly different, further examination by study period revealed
that nirmatrelvir/ritonavir significantly reduced sign and symptom severity throughDay 28 (Day 7 to Day 28: severe signs and symptoms in 7.207% participants innirmatrelvir group vs 11.318% in placebo group [p=0.0287]).

Median time to sustained alleviation and sustained resolution of each targeted COVID-19
sign and symptom was achieved 1 to 2 days earlier and 1 to 3 days earlier, respectively,
with nirmatrelvir/ritonavir treatment compared with placebo except for diarrhea andvomiting, which was the same for both groups. The number of participants achieving
sustained alleviation and resolution of each targeted COVID-19 sign and symptom washigher in the nirmatrelvir/ritonavir group compared with placebo, except for vomiting,
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which was the same for both groups. Results for the mITT1 analysis set and the mITT2
analysis set were generally consistent with the mITT analysis set.
Participants in both treatment groups had a similar likelihood of progression to aworsening status (ie, increasing severity for any targeted symptom) through Day 28 (ORversus placebo 1.088 [95% CI: 0.836, 1.416; p=0.5293]).

On-treatment reduction in viral load was significantly (p<0.0001) larger in thenirmatrelvir/ritonavir group than in the placebo group.

090177e19cd55c5a\Approved\Approved On: 09-Mar-2023 02:34 (GMT)o Baseline (Day 1) log10 (viral load) was 5.942 log10 copies/mL in the placebogroup and 6.029 log10 copies/mL in the nirmatrelvir/ritonavir group. At Day 5,
after accounting for treatment, geographic region, baseline SARS-CoV-2 serology
status and baseline viral load, the adjusted mean (SE) reduction in log10 (viralload) was -2.405 (0.083) log10 copies/mL in the placebo group, and -3.311 (0.083)
log10 copies/mL in the nirmatrelvir/ritonavir group, reflecting an additional
average reduction (95% CI) of -0.905 (-1.102 to -0.709, p<0.0001) log10
copies/mL.


Because statistical significance was achieved in the analyses of the primary endpoint andthe first and second key secondary efficacy endpoints, the COVID-19-related medical
visits through Day 28 was analyzed with an overall alpha level of 5% in a Hochberg
procedure, together with the time to sustained resolution in all targeted signs/symptoms
through Day 28 and the proportion of participants with a resting peripheral oxygen
saturation ≥95% at Days 1 and 5 as specified in the SAP. Compared with thenirmatrelvir/ritonavir group, there were approximately 5 times as many participants in theplacebo group who had COVID-19 related medical visits (52 vs 10 participants,
respectively). The total number of visits was approximately 4 times as high in the placebogroup (81 vs 22). After adjusting for geographic region, baseline SARS-CoV-2 serology
status and baseline viral load, the COVID-19 related medical visits occurred lessfrequently in the nirmatrelvir/ritonavir group at approximately 27.0% of the rate in theplacebo group (p=0.0002).

In the mITT analysis set, there were 11 deaths in the placebo group and none in thenirmatrelvir/ritonavir group through Week 24: Of these, 9 deaths occurred throughDay 28 and the other 2 deaths occurred during the long-term follow-up period (Day 67
and Day 96). In both the mITT1 and mITT2 analysis sets, there were 15 deaths in theplacebo group and none in the nirmatrelvir/ritonavir group through Week 24.

Safety Results:The proportion of participants with all-causality treatment-emergent adverse events(TEAEs) that started on or prior to the Day 34 visit was comparable between thenirmatrelvir/ritonavir (22.0%) and placebo (24.3%) groups.
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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 TEAEs (Grade 4) was
lower in the nirmatrelvir/ritonavir group (4.0%) compared with the placebo group (8.5%).

Of the most frequently reported TEAEs in the nirmatrelvir/ritonavir group (≥1%),
Dysgeusia (4.6%), Diarrhoea (3.0%), and Vomiting (1.2%) were reported at a higher
frequency than in the placebo group (0.1%, 1.5%, and 0.9%, respectively). These AEs
were nonserious and mostly mild (Grade 1) to moderate (Grade 2) in severity. In thenirmatrelvir/ritonavir group, Dysgeusia, Diarrhoea, and Vomiting led to few
discontinuations from study intervention: 2 participants, 1 participant, and 4 participants,
respectively.

The overall incidence of participants with all-causality treatment-emergent serious
adverse events (SAEs) that started on or prior to the Day 34 visit was lower in thenirmatrelvir/ritonavir treatment group (1.7%) compared with placebo (6.7%). The mostfrequently reported SAEs in the nirmatrelvir/ritonavir group (≥2 participants) were
COVID-19 pneumonia and COVID-19 and were reported more frequently in the placebogroup than in the nirmatrelvir/ritonavir group. COVID-19 pneumonia and COVID-19
were considered related to the disease under study; none of these SAEs were consideredby the investigator to be related to study intervention.

Fewer participants in the nirmatrelvir/ritonavir group compared to the placebo group
discontinued study intervention due to an AE (2.0% and 4.3%, respectively) or
discontinued the study due to an AE (0% and 1.2% [all due to death], respectively).
All-causality TEAEs that led to discontinuation of study intervention in more than
1 participant in either treatment group were COVID-19 pneumonia, Nausea, Creatinine
renal clearance decreased, Vomiting, COVID-19, Glomerular filtration rate decreased,
Pneumonia, Pneumonitis, White blood cell count decreased, and Dysgeusia.

No participants in the nirmatrelvir/ritonavir group experienced an AE resulting in death(Grade 5) through Day 34, compared to 13 (1.2%) in the placebo group, all of whichwere related to the disease under study. Two deaths in the placebo group occurred during
the long-term follow-up period, of which one was related to the disease under study.



The incidence of participants with all-causality hemodynamic, inflammatory, andthyroid-related TEAEs was generally comparable between treatment groups. Fibrin D
dimer increased occurred at a greater frequency in the placebo group than in thenirmatrelvir/ritonavir group (22 [2.1%] participants for nirmatrelvir/ritonavir versus
30 [2.8%] participants for placebo).

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

No potential Hy’s Law cases were identified in either treatment group through Day 34.

No clinically meaningful findings in vital sign measurements were observed in this study,
and the assessments and observations were comparable across treatment groups. Few(≤5%) participants in either treatment group had clinically significant ECG findings.

Pharmacokinetic Results:
Geometric mean (coefficient of variation [CV%]) concentrations, representative of maximum
observed concentration (Cmax) on Day 1 (30 to 90 minutes postdose) and Day 5 (preferably
up to 2 hours postdose) were 1510 (97%) ng/mL and 2426 (93%) ng/mL, respectively.
Conclusions:

090177e19cd55c5a\Approved\Approved On: 09-Mar-2023 02:34 (GMT)

Based on the sequential design and prespecified interim analysis specifications, theprimary analysis result was statistically significant (p<0.0001) and the primary objectiveof the study was met and confirmed in the final analysis. Treatment withnirmatrelvir/ritonavir was efficacious in reducing the incidence of COVID-19-related
hospitalization or death from any cause in nonhospitalized symptomatic adult participants
with COVID-19 who were at increased risk of progression to severe disease.
In participants who were treated within 3 days of symptom onset and no mAbtreatment, nirmatrelvir/ritonavir significantly reduced the proportion ofparticipants with COVID-19-related hospitalization or death from any causethrough Day 28 by 89.1% (0.752% vs 6.888%, p<0.0001) compared to placebo innonhospitalized symptomatic adult participants who were at increased risk ofprogression to severe illness at baseline.

In participants who were treated within 5 days of symptom onset and no mAbtreatment, nirmatrelvir/ritonavir also significantly reduced the proportion ofparticipants with COVID-19-related hospitalization or death from any causethrough Day 28 by 85.8% (0.933% vs 6.571%, p<0.0001) compared to placebo.

Sensitivity and supplemental analyses of the primary endpoint were consistent
with the primary analysis.

Treatment with nirmatrelvir/ritonavir significantly reduced the duration and severity of
COVID-19 signs and symptoms compared with placebo.
Treatment with nirmatrelvir/ritonavir significantly shortened the median time tosustained alleviation of all targeted COVID-related signs and symptoms from15 days to 12 days, and shortened the median time to sustained resolution of these
symptoms from 18 days to 16 days.

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Final Full Clinical Study Report
Protocol C4671005

090177e19cd55c5a\Approved\Approved On: 09-Mar-2023 02:34 (GMT)

CLINICAL STUDY REPORT SYNOPSISThe nirmatrelvir/ritonavir group had significantly more participants with severe
symptoms before treatment, but had significantly less participants with severe
symptoms after treatment.



A numerical nonsignificant trend in reducing the frequency of postbaseline resting
peripheral oxygen <95% was observed in the nirmatrelvir/ritonavir groupcompared with placebo.



COVID-19-related medical visits were significantly less frequent in thenirmatrelvir/ritonavir group occurring at approximately 27.0 % of the rate in the placebogroup. The nirmatrelvir/ritonavir group on average spent 0.088 days/participant (noparticipants reported any ICU stays) in the hospital, compared with the 0.844
days/participant (0.179 days/participant in ICU) in the placebo group. No participants inthe nirmatrelvir/ritonavir group required mechanical ventilation.



The mean predose concentration (Ctrough) (ie, trough or minimum observed concentration[Cmin]) of nirmatrelvir on Day 5 were consistent with the predicted profile via apreliminary population PK model and were confirmed by exposures (Ctrough) previously
associated with nirmatrelvir/ritonavir 300 mg/100 mg.



The antiviral effect of nirmatrelvir/ritonavir was demonstrated by significant reduction of
SARS-CoV-2 viral load compared with placebo, a 0.905 log10 copies/mL reduction
among participants treated within 3 days of COVID-19 onset and no mAb treatment(mITT), or a 0.777 log10 copies/mL reduction among participants treated within 5 days ofsymptom onset and no mAb treatment (mITT1).

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

The overall incidence of all-causality TEAEs was comparable for both treatmentgroups. Most all-causality TEAEs in both treatment groups were mild (Grade 1)
to moderate (Grade 2) in severity. Fewer participants in the nirmatrelvir/ritonavirgroup reported severe events (Grade 3) or potentially life-threatening events(Grade 4) compared with the placebo group.

Fewer all-causality treatment-emergent SAEs were reported in thenirmatrelvir/ritonavir group compared with placebo.



There were 15 deaths in the placebo group (12 in the 28-day period, 1 in thesafety follow-up period, and 2 in the long-term follow-up period) and none in thenirmatrelvir/ritonavir group.

Discontinuation of study intervention or of the study due to an AE was lower in
the nirmatrelvir/ritonavir group compared with placebo.

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090177e19cd55c5a\Approved\Approved On: 09-Mar-2023 02:34 (GMT)

CLINICAL STUDY REPORT SYNOPSIS

The incidence of participants with hemodynamic, inflammatory, and thyroidrelated TEAEs was generally comparable between treatment groups. Fibrin D
dimer increased was the only TEAE that occurred at a greater frequency(≥5 participant difference) in the placebo group compared with thenirmatrelvir/ritonavir group.

Nirmatrelvir/ritonavir was not associated with clinically meaningful changes inlaboratory values or vital signs. Nirmatrelvir/ritonavir was not associated with any
clinically significant ECG findings.

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