Conditions: COVID-19
Keywords: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Coronavirus disease 2019 (COVID-19) Paxlovid Nirmatrelvir Immunocompromised
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 158
Healthy volunteers: no

Brief summary:
The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called Nirmatrelvir/Ritonavir) for the possible treatment of COVID-19.

Patients with COVID-19 who have more difficulty in fighting against infections have a higher chance of severe illness. Such patients may benefit from longer treatment durations compared to the standard treatment regimen.

The study is seeking participants who:

* Have a confirmed COVID-19 infection
* Are Immunocompromised
* Experience onset of signs/symptoms attributable to the current COVID-19 infection within 5 days prior to screening and ≥1 signs/symptoms attributable to COVID-19 present on the day of randomization.

In addition, this study will also evaluate the efficacy and safety of a second treatment course of nirmatrelvir/ritonavir in people who experience that their COVID-19 is flaring up within 14 days of having taken a 5-day treatment course of nirmatrelvir/ritonavir.

For this group, the study is seeking participants who:

* Have a confirmed COVID-19 infection
* Experience a worsening of signs/symptoms after completing an initial 5-day course of nirmatrelvir/ritonavir
* The worsening of COVID-19 symptoms must occur within 14 days after completion of the initial 5-day course of nirmatrelvir/ritonavir
* Are Immunocompromised
* Experience onset of signs/symptoms attributable to the current COVID-19 infection within 48 hours prior to screening and ≥1 signs/symptoms attributable to COVID-19 present on the day of randomization.

All participants will be taking the study medicine for either 5, 10, or 15 days. The study medication will be taken by mouth 2 times a day. Participants will take part in this study for about 24 weeks. The first dose of study medication is taken at the study site and the rest at home. Selected participants will need to visit the study site at least 10 times during the study.

Detailed description:

Arms:
arm 1: Nirmatrelvir (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 5 days followed by placebo for nirmatrelvir (2 tablets) plus placebo for ritonavir (1 capsule) every 12 hours for 10 days arm 2: Nirmatrelvir (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 10 days followed by placebo for nirmatrelvir (2 tablets) plus placebo for ritonavir (1 capsule) every 12 hours for 5 days arm 3: Nirmatrelvir (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 15 days.

Interventions: intervention 1: Nirmatrelvir intervention 2: Ritonavir intervention 3: Placebo for nirmatrelvir intervention 4: Placebo for ritonavir
Intervention descriptions: intervention 1: Participants will receive 2 tablets of nirmatrelvir every 12 hours intervention 2: Participants will receive 1 capsule of ritonavir every 12 hours intervention 3: Participants will receive 2 tablets of placebo for nirmatrelvir every 12 hours. A placebo does not have any medicine in it but looks just like the medicine being studied. intervention 4: Participants will receive 1 capsule of placebo for ritonavir every 12 hours. A placebo does not have any medicine in it but looks just like the medicine being studied.

Protocol document:
Prot_000.pdf: 
Nirmatrelvir/ritonavir 
Protocol C4671034 
Final Protocol Amendment 01, 13 September 2022 
PFIZER CONFIDENTIAL 
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022) 
Page 1 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except 
as otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) 
or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 
 
 
Title Page 
AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2, RANDOMIZED, 
DOUBLE-BLIND, 3-ARM STUDY TO INVESTIGATE 
NIRMATRELVIR/RITONAVIR IN NONHOSPITALIZED PARTICIPANTS AT 
LEAST 12 YEARS OF AGE WITH SYMPTOMATIC COVID-19 WHO ARE 
IMMUNOCOMPROMISED 
 
 
Study Intervention Number: 
PF-07321332 
Study Intervention Name: 
nirmatrelvir 
US IND Number: 
153517 
EudraCT/CTIS Number: 
2022-001362-35 
ClinicalTrials.gov ID: 
NCT05438602 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C4671034 
Phase: 
2 
Brief Title: 
A Study to Learn About the Study Medicines Called Nirmatrelvir/Ritonavir in People at 
Least 12 Years of Age With COVID-19 Who Are Immunocompromised 
 


Nirmatrelvir/ritonavir 
Protocol C4671034 
Final Protocol Amendment 01, 13 September 2022 
PFIZER CONFIDENTIAL 
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022) 
Page 2 
 
 
Document History 
 
Document 
Version Date 
Amendment 1 
13 September 2022 
Original protocol 
27 May 2022 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s). 


Nirmatrelvir/ritonavir 
Protocol C4671034 
Final Protocol Amendment 01, 13 September 2022 
PFIZER CONFIDENTIAL 
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022) 
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Protocol Amendment Summary of Changes Table 
Amendment 1 (13 September 2022): 
Overall Rationale for the Amendment: This protocol was amended based on regulatory feedback to update the primary analysis and 
include an additional population of nonhospitalized symptomatic participants who are immunocompromised with a rebound in 
COVID-19. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
1.1 Synopsis 
3.0 Objectives, 
Endpoints, and 
Estimands 
9.1.1.1 Primary 
Estimand/Copri 
mary Estimands 
Revised estimand to include patients who received non-study antiviral or 
monoclonal antibody therapy as not achieving the primary endpoint. 
To address regulatory feedback 
recommending a more 
conservative approach and 
considering patients who received 
non-study antiviral or monoclonal 
antibody therapy as a failure in the 
primary analysis. 
substantial 
1.1 Synopsis 
3.0 Objectives, 
Endpoints, and 
Estimands 
9.1.1.1 Primary 
Estimand/Copri 
mary Estimands 
For the primary endpoint, changed the beginning of the sustained period 
from “the end of active treatment” to “Day 15”. 
To address regulatory feedback 
recommending a standard follow- 
up period duration for all 
treatment groups for the primary 
endpoint. 
substantial 
9.3.2.1 
Definitions of 
Endpoint(s) 
9.3.2.2 Main 
Analytical 
Approach 
9.5 Sample Size 
Determination 


Nirmatrelvir/ritonavir 
Protocol C4671034 
Final Protocol Amendment 01, 13 September 2022 
PFIZER CONFIDENTIAL 
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022) 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
9.3.2.1 
Definition of 
Endpoint(s) 
Revised sustained definition for the primary endpoint NP swab SARS- 
CoV-2 RNA level from “not ≥2.5 log10 copies/mL” to “not ≥2.0 log10 
copies/mL” at any study visit (through Day 44) following the first study 
visit where the participant’s NP swab SARS-CoV-2 RNA <LLOQ. 
To address regulatory feedback 
recommending modification to the 
definition of sustained. 
substantial 
9.3.2.3 
Supplementary 
Analysis/Analy 
ses 
Revised supplementary analysis for the primary endpoint to exclude data 
after the date of nonstudy antiviral or monoclonal antibody start for 
participants who received non-study antiviral or monoclonal antibody 
therapy. 
To address regulatory feedback by 
designating this as a supplemental 
analysis instead of primary 
analysis. 
substantial 
1.1 Synopsis 
2.1 Study 
Rationale 
4.1 Overall 
Design 
4.2 Scientific 
Rationale for 
Study Design 
Added an additional population of participants to the study who are 
immunocompromised with COVID-19 rebound within 14 days following 
completion of an initial 5-day nirmatrelvir/ritonavir treatment course. 
To address regulatory feedback by 
adding this population to the 
study. 
substantial 
1.1 Synopsis 
5.1 Inclusion 
Criteria 
10.9.5 Inclusion 
Criteria for 
Additional 
Population 
With COVID- 
19 Rebound 
Added Inclusion Criterion #5 that allows participants who are 
immunocompromised and have COVID-19 rebound to enroll in the study; 
and added Section 10.9.5 that further describes inclusion criteria for the 
additional population with COVID-19 rebound. 
To address regulatory feedback 
pertaining to the importance of 
studying rebound as a separate 
group of immunocompromised 
patients previously treated with a 
5-day course of PAXLOVID. 
substantial 
1.1 Synopsis 
5.1 Inclusion 
Criteria 
Revised Inclusion Criterion #2 to specify participants with COVID-19 
rebound must have confirmed SARS-CoV-2 infection as specified in 
Appendix 9, Section 10.9.2 for the main study population or Appendix 9, 
Section 10.9.5 for the additional population with rebound. 
To address regulatory feedback 
pertaining to the importance of 
studying rebound as a separate 
group of immunocompromised 
substantial 


Nirmatrelvir/ritonavir 
Protocol C4671034 
Final Protocol Amendment 01, 13 September 2022 
PFIZER CONFIDENTIAL 
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022) 
Page 5 
 
 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
10.9.2 Confirm 
SARS-CoV-2 
Infection 
Details for the 
Main Study 
Population 
10.9.5 Inclusion 
Criteria for 
Additional 
Population 
With COVID- 
19 Rebound 
patients previously treated with a 
5-day course of PAXLOVID and 
establishing specific inclusion 
criteria for this group. 
Synopsis 1.1 
4.1 Overall 
Design 
6.3 Assignment 
to Study 
Intervention 
Added that enrollment of participants considered immunocompromised 
based solely on receiving corticosteroids or TNF blockers in the additional 
population with rebound will not be capped or stratified. 
To clarify enrollment of 
participants in the additional 
population with rebound. 
substantial 
6.9 Prior and 
Concomitant 
Therapy 
10.9.7 
Prior/Concomit 
ant Therapy 
Added prior therapy of a 5-day nirmatrelvir/ritonavir course for 
participants in the additional population with rebound is required and not 
prohibited. 
To be consistent with eligibility 
criteria. 
substantial 
8.5 
Pharmacokineti 
cs 
Clarified that 1 mL of blood is needed for measurement of nirmatrelvir and 
ritonavir. 
To clarify total blood volume so 
that extra blood is not needlessly 
drawn. 
substantial 
10.8 Prohibited 
Concomitant 
Medications 
That May 
Result in DDI 
Text describing Tables 4 and 5 was revised to clarify DDI table content. 
Tables were updated with information from the Fact Sheet for Healthcare 
Providers: Emergency Use Authorization for Paxlovid (August 2022). 
Updates to the list of 
precautionary and prohibited 
medications. 
substantial 


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Protocol C4671034 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
Cover page and 
1.1 Synopsis 
Added NCT number. 
To incorporate changes from the 
12 July 2022 PACL. 
nonsubstantial 
1.1 Synopsis 
Revised the definition of enrolled to include those who complete informed 
consent/assent and screening. 
To clarify that potential 
participants who are screened for 
the purpose of determining 
eligibility for the study, but do not 
participate in the study, are not 
considered enrolled. To 
incorporate changes from the 12 
July 2022 PACL. 
nonsubstantial 
1.1 Synopsis 
4.1 Overall 
Design 
Added text for the timing of enrollment for the additional population with 
rebound. 
To clarify enrollment of the 
population with rebound in 
relation to the main study 
population. 
nonsubstantial 
Synopsis 1.1 
4.1 Overall 
Design 
Removed autoimmune disorder treatment for sole reason why enrolled 
participants receive corticosteroids or TNF blockers, which are capped at 
approximately 25%. 
To clarify that participants on 
corticosteroids or TNF blockers, 
who are capped at ~25%, is not 
restricted to only participants 
treated for autoimmune disorders. 
nonsubstantial 
1.1 Synopsis 
5.2 Exclusion 
Criteria 
6.1 Study 
Intervention(s) 
Administered 
6.1.1 
Administration 
6.6 Dose 
Modification 
7.1 
Discontinuation 
Updated units for eGFR as mL/min/1.73m2 and units for CrCl as mL/min. 
in these sections. 
Updated for consistency. 
nonsubstantial 


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Protocol C4671034 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
of Study 
Intervention 
1.1 Synopsis 
9.1.1.1 Primary 
Estimand/Copri 
mary Estimands 
9.3.2.1 
Definition of 
Endpoint(s) 
9.3.2.2 Main 
Analytical 
Approach 
Clarified data will be analyzed separately for the main study population 
and the additional population with rebound. 
To clarify data analysis. 
nonsubstantial 
1.1 Synopsis 
4.1 Overall 
Design 
9.5 Sample Size 
Determination 
Added that sample size of participants with COVID-19 rebound would be 
up to 50, and accordingly specified that total sample size of study is up to 
200 participants. 
To specify maximum sample size 
of the additional population with 
rebound and maximum total 
sample size of study. 
nonsubstantial 
1.3 Schedule of 
Activities 
Added note for vital status check that secondary contacts may be used. 
To be consistent with revisions to Inclusion Criterion #2, updated the note 
for a positive SARS-CoV-2 test obtained within 5 days for the main study 
population or 24 hours for the population with rebound prior to 
randomization. 
Updated the note for the rapid antigen testing to clarify that postbaseline 
tests will be performed by an HCP. 
Added cross-reference to Section 8.1.4 for telehealth activities and 
removed ‘telemedicine’ from Serious and nonserious AE monitoring notes 
since telehealth and telemedicine are synonymous. 
Updated for consistency with 
Section 8.1.1.3. 
To be consistent with Inclusion 
Criterion #2 and to clarify that 
postbaseline rapid antigen testing 
should be performed by an HCP 
as opposed to self-testing. 
Updated for consistency with 
Section 8.1.4. 
nonsubstantial 


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 Final Protocol Amendment 01, 13 September 2022 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial01· 
-
Nonsubstantial 
1.3 Schedule of 
Activities 
 
2.2 Background 
Added infonnation on rebound in COVID-19. 
To provide clinical relevance on 
the addition of the population with 
rebound to this study. 
nonsubstantial 
4.1 Overall 
 Defined timing of analyses, described primaiy and follow-up analyses, and 
To clarify data analysis. 
Design 
stated that the additional population with rebound will be analyzed 
9.0 Statistical 
separately from the main study population. 
Considerations 
9.5 Sample Size 
Detennination 
nonsubstantial 
5.3.2 Other 
Included exception for participants who have an oncology disease. 
To avoid excluding pa1ticipants 
Restrictions 
 
 who are immunocomproinised 
with an oncology disease who are 
often participating in oncology 
clinical trials from the study 
population. To incorporate 
changes from the 12 July 2022 
PACL. 
nonsubstantial 
6.1.1 
Updated timing of dose adininistration. 
To align with dosing 
Administration 
administration in other C467 
protocols. 
nonsubstantial 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
6.3 Assignment 
to Study 
Intervention 
Added stratification text for participants in the main study population who 
are considered immunocompromised solely based on corticosteroids or 
TNF blocker use. 
Updated for consistency. 
nonsubstantial 
6.9 Prior and 
Concomitant 
Therapy 
Described ritonavir is an inhibitor of CYP3A4 and provided guidance 
accordingly. 
To provide clinical guidance for 
participants who take concomitant 
medications metabolized by 
CYP3A4. 
nonsubstantial 
8.1.1.1 Medical 
History 
Added that risk factors for the participant developing severe COVID-19 
illness will be recorded. 
To clarify medical history. 
nonsubstantial 
8.1.1.3 
Secondary 
Contacts 
Added that secondary contacts may be used to determine if a participant is 
lost to follow-up or vital status check. 
To clarify utility of collecting 
secondary contact information. 
nonsubstantial 
8.4.1 Time 
Period and 
Frequency for 
Collecting AE 
and SAE 
Information 
8.4.1.1 
Reporting 
SAEs to Pfizer 
Safety 
8.4.5.1 
Exposure 
During 
Pregnancy 
8.4.5.2 
Exposure 
During 
Breastfeeding 
Updated CT SAE Report Form and the EDP Supplemental Form to PSSA 
and added minor edits for clarification. 
To align with Pfizer’s new 
platform for submission of SAEs 
to the Drug Safety Unit. 
nonsubstantial 


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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial01· 
Nonsubstantial 
8.4.5.3 
 
Occupational 
Exposure 
8.4.10 
Medication 
En-ors 
10.3.3 
Recording/Rep 
011ing and 
Follow-Up of 
AEs and/or 
SAEsDuring 
the Active 
Collection 
Period 
10.3.4 
Repo1ting of 
SAEs 
- 
 
9.2 Analysis 
Sets 
Clarified that analysis sets will be applied for the main study population 
and the population with rebound. 
To clarify analysis sets defined in 
the protocol will be applied to 
both populations. 
nonsubstantial 
10.2 Appendix 
Separated urea and creatinine. 
To clarify they are 2 separate 
nonsubstantial 
2: Clinical 
laboratory assessments. To 
Laborato1y 
incorporate changes from the 12 
Assessments 
July 2022 PACL. 
10.4.2. Female 
Paitici ant 
Separated the pai·agraphs for WOCBP and WONCBP. 
For clai·ification 
nonsubstantial 


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Protocol C4671034 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Substantial or 
Nonsubstantial 
Reproductive 
Inclusion 
Criteria 
Section 10.9.4 
Immunocompro 
mised Criteria 
Details 
Clarified length of time for corticosteroid use prior to study entry. 
To clarify corticosteroid use 
requirements. 
nonsubstantial 
Throughout the 
protocol 
General editorial changes. 
To correct grammatical errors, to 
maintain consistency, and/or to 
increase clarity. 
nonsubstantial 


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Protocol C4671034 
Final Protocol Amendment 01, 13 September 2022 
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TABLE OF CONTENTS 
LIST OF TABLES ................................................................................................................... 18 
1. PROTOCOL SUMMARY ................................................................................................... 19 
1.1. Synopsis ................................................................................................................... 19 
1.2. Schema..................................................................................................................... 26 
1.3. Schedule of Activities .............................................................................................. 27 
2. INTRODUCTION ................................................................................................................ 36 
2.1. Study Rationale ........................................................................................................ 36 
2.2. Background .............................................................................................................. 36 
2.2.1. Clinical Overview ....................................................................................... 38 
2.3. Benefit/Risk Assessment ......................................................................................... 38 
2.3.1. Risk Assessment ......................................................................................... 39 
2.3.2. Benefit Assessment ..................................................................................... 41 
2.3.3. Overall Benefit/Risk Conclusion ................................................................ 41 
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ............................................................ 41 
4. STUDY DESIGN ................................................................................................................. 43 
4.1. Overall Design ......................................................................................................... 43 
4.2. Scientific Rationale for Study Design ..................................................................... 44 
4.2.1. Diversity of Study Population ..................................................................... 45 
4.2.2. Choice of Contraception/Barrier Requirements .......................................... 45 
4.2.3. Collection of Retained Research Samples ................................................... 45 
4.2.4. Inclusion of Pediatric Participants............................................................... 45 
4.3. Justification for Dose ............................................................................................... 46 
4.4. End of Study Definition ........................................................................................... 47 
5. STUDY POPULATION ...................................................................................................... 47 
5.1. Inclusion Criteria ..................................................................................................... 47 
5.2. Exclusion Criteria .................................................................................................... 48 
5.3. Lifestyle Considerations .......................................................................................... 49 
5.3.1. Contraception .............................................................................................. 49 
5.3.2. Other Restrictions ........................................................................................ 50 
5.4. Screen Failures ......................................................................................................... 50 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .................................. 50 


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6.1. Study Intervention(s) Administered .........................................................................50 
6.1.1. Administration .............................................................................................53 
6.2. Preparation, Handling, Storage, and Accountability ...............................................54 
6.2.1. Preparation and Dispensing .........................................................................55 
6.3. Assignment to Study Intervention ...........................................................................55 
6.4. Blinding ...................................................................................................................56 
6.4.1. Blinding of Participants ...............................................................................56 
6.4.2. Blinding of Site Personnel ...........................................................................56 
6.4.3. Blinding of the Sponsor ..............................................................................56 
6.4.4. Breaking the Blind ......................................................................................56 
6.5. Study Intervention Compliance ...............................................................................57 
6.6. Dose Modification ...................................................................................................58 
6.7. Continued Access to Study Intervention After the End of the Study ......................58 
6.8. Treatment of Overdose ............................................................................................58 
6.9. Prior and Concomitant Therapy ...............................................................................59 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................60 
7.1. Discontinuation of Study Intervention .....................................................................60 
7.2. Participant Discontinuation/Withdrawal From the Study .......................................61 
7.2.1. Withdrawal of Consent ...............................................................................62 
7.3. Lost to Follow-Up ...................................................................................................62 
8. STUDY ASSESSMENTS AND PROCEDURES ...............................................................62 
8.1. Administrative and Baseline Procedures .................................................................62 
8.1.1. Baseline Procedures ....................................................................................63 
8.1.1.1. Medical History .........................................................................63 
8.1.1.2. Study Kit ....................................................................................63 
8.1.1.3. Secondary Contacts ...................................................................64 
8.1.2. Home Health Visits .....................................................................................64 
8.1.3. Mobile Visits ...............................................................................................64 
8.1.4. Telehealth Visits ..........................................................................................65 
8.2. Efficacy Assessments ..............................................................................................66 
8.2.1. Participant Diary .........................................................................................66 


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8.2.2. COVID-19-Related Hospitalizations and Medical Details ......................... 66 
8.2.3. Oxygen Support Details .............................................................................. 66 
8.2.4. PRO Assessments ....................................................................................... 66 
8.2.4.1. Global Impression Questions ..................................................... 66 
8.2.4.2. SF-36 v2® Health Survey (Acute Form) .................................... 67 
8.2.4.3. WPAI ......................................................................................... 67 
8.2.4.4. EQ-5D-5L Scale ........................................................................ 67 
8.2.5. COVID-19 Signs and Symptoms ................................................................ 68 
8.3. Safety Assessments .................................................................................................. 68 
8.3.1. Targeted Physical Examinations ................................................................. 68 
8.3.2. Vital Signs ................................................................................................... 68 
8.3.2.1. Blood Pressure and Pulse Rate .................................................. 69 
8.3.2.2. Temperature and Respiratory Rate ............................................ 69 
8.3.2.3. Oxygen Saturation Level ........................................................... 69 
8.3.2.4. At-Home Devices for Vital Signs .............................................. 69 
8.3.3. Point-of-Care Serum Creatinine Assessments ............................................ 69 
8.3.4. Clinical Safety Laboratory Assessments ..................................................... 69 
8.3.4.1. Alternative Facilities for Clinical Safety Laboratory 
Assessment ......................................................................................... 70 
8.3.5. Pregnancy Testing ....................................................................................... 70 
8.3.5.1. At-Home Pregnancy Testing...................................................... 70 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................. 70 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information ....... 71 
8.4.1.1. Reporting SAEs to Pfizer Safety ............................................... 72 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 72 
8.4.2. Method of Detecting AEs and SAEs ........................................................... 72 
8.4.3. Follow-Up of AEs and SAEs ...................................................................... 72 
8.4.4. Regulatory Reporting Requirements for SAEs ........................................... 73 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ...................................................... 73 
8.4.5.1. Exposure During Pregnancy ...................................................... 73 
8.4.5.2. Exposure During Breastfeeding ................................................. 75 
8.4.5.3. Occupational Exposure .............................................................. 75 


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CCI 
8.4.6. Cardiovascular and Death Events ................................................................ 75 
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 76 
8.4.8. Adverse Events of Special Interest ............................................................. 76 
8.4.8.1. Lack of Efficacy ........................................................................ 76 
8.4.9. Medical Device Deficiencies ...................................................................... 76 
8.4.10. Medication Errors ...................................................................................... 76 
8.5. Pharmacokinetics ..................................................................................................... 77 
8.6. Genetics ................................................................................................................... 78 
8.6.1. Specified Genetics ....................................................................................... 78 
8.6.2. Retained Research Samples for Genetics .................................................... 78 
8.7. Biomarkers ............................................................................................................... 79 
 
 
 
 
 
 
8.7.6. Specified Metabolomic Research ................................................................80 
8.7.7. Retained Research Samples for Biomarkers ............................................... 80 
8.8. Immunogenicity Assessments ................................................................................. 81 
8.9. Health Economics .................................................................................................... 81 
9. STATISTICAL CONSIDERATIONS ................................................................................. 81 
9.1. Statistical Hypotheses .............................................................................................. 81 
9.1.1. Estimands .................................................................................................... 81 
9.1.1.1. Primary Estimand/Coprimary Estimands .................................. 81 
9.1.1.2. Secondary Estimands ................................................................. 81 
9.1.2. Multiplicity Adjustment .............................................................................. 82 
9.2. Analysis Sets ............................................................................................................ 82 
9.3. Statistical Analyses .................................................................................................. 82 
9.3.1. General Considerations ............................................................................... 82 
9.3.2. Primary Endpoint(s)/Estimand(s) Analysis ................................................ 83 


Nirmatrelvir/ritonavir 
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9.3.2.1. Definition of Endpoint(s) ...........................................................83 
9.3.2.2. Main Analytical Approach .........................................................83 
9.3.2.3. Supplementary Analysis/Analyses .............................................83 
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis ............................................83 
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis .................................................84 
9.3.5. Safety Analyses ...........................................................................................84 
9.3.6. Other Analyses ............................................................................................85 
9.4. Interim Analyses ......................................................................................................85 
9.5. Sample Size Determination .....................................................................................85 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...........................................................................................................87 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ................87 
10.1.1. Regulatory and Ethical Considerations .....................................................87 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP .........................................................................87 
10.1.2. Financial Disclosure ..................................................................................88 
10.1.3. Informed Consent/Assent Process ............................................................88 
10.1.3.1. Informed Consent Process .......................................................88 
10.1.3.2. Informed Assent Process .........................................................89 
10.1.4. Data Protection ..........................................................................................90 
10.1.5. Committees Structure ................................................................................91 
10.1.5.1. Data Monitoring Committee ....................................................91 
10.1.6. Dissemination of Clinical Study Data .......................................................91 
10.1.7. Data Quality Assurance .............................................................................92 
10.1.8. Source Documents ....................................................................................93 
10.1.9. Study and Site Start and Closure ...............................................................94 
10.1.10. Publication Policy ...................................................................................95 
10.1.11. Sponsor’s Medically Qualified Individual ..............................................95 
10.2. Appendix 2: Clinical Laboratory Tests .................................................................97 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ......................................................................99 
10.3.1. Definition of AE ........................................................................................99 
10.3.2. Definition of an SAE ...............................................................................100 


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10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period ..........................................................................101 
10.3.4. Reporting of SAEs ..................................................................................104 
10.4. Appendix 4: Contraceptive and Barrier Guidance ...............................................106 
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................106 
10.4.2. Female Participant Reproductive Inclusion Criteria ...............................106 
10.4.3. Woman of Childbearing Potential ...........................................................106 
10.4.4. Contraception Methods ...........................................................................107 
10.5. Appendix 5: Genetics ..........................................................................................109 
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
and Study Intervention Rechallenge Guidelines ......................................................110 
10.7. Appendix 7: Age-Specific Kidney Function Calculation Recommendations ......112 
10.7.1. Adults (18 Years and Above)—2021 CKD-EPI Equations ....................112 
10.7.1.1. Adolescents (12 Years to <18 Years)—Cockcroft-Gault 
Formula ............................................................................................112 
10.7.2. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities .................................................................................................112 
10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI ......113 
10.9. Appendix 9: Eligibility Criteria ...........................................................................125 
10.9.1. Age and Sex ............................................................................................125 
10.9.2. Confirmed SARS-CoV-2 Infection Details for the Main Study 
Population.......................................................................................................125 
10.9.3. Signs and Symptoms Attributable to COVID-19....................................125 
10.9.4. Immunocompromised Criteria Details ....................................................125 
10.9.5. Inclusion Criteria for Additional Population With COVID-19 
Rebound .........................................................................................................126 
10.9.6. Oxygen Saturation Criterion Details .......................................................127 
10.9.7. Prior/Concomitant Therapy .....................................................................127 
10.10. Appendix 10: Participant-Reported COVID-19-Related Signs and 
Symptoms ................................................................................................................128 
10.11. Appendix 11: Abbreviations ..............................................................................129 
11. REFERENCES .................................................................................................................133 


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LIST OF TABLES 
Table 1. 
Study Schedule of Assessment..................................................................27 
Table 2. 
Width of 95% CI for the Proportion of Participants with Sustained 
NP Swab SARS-CoV-2 RNA <LLOQ .....................................................86 
Table 3. 
Protocol-Required Safety Laboratory Assessments ..................................97 
Table 4. 
Drugs That are Contraindicated With Nirmatrelvir/Ritonavir ................113 
Table 5. 
Established and Other Potentially Significant Drug Interactions............116 


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: 
An Interventional Efficacy And Safety, Phase 2, Randomized, Double-Blind, 3-Arm Study 
To Investigate Nirmatrelvir/Ritonavir in Nonhospitalized Participants at Least 12 Years Of 
Age With Symptomatic COVID-19 Who Are Immunocompromised 
Brief Title: 
A Study to Learn About the Study Medicine Called Nirmatrelvir/Ritonavir in People at Least 
12 Years of Age With COVID-19 Who Are Immunocompromised 
Regulatory Agency Identification Number(s): 
 
US IND Number: 
153517 
EudraCT/CTIS Number: 
2022-001362-35 
ClinicalTrials.gov ID: 
NCT05438602 
Pediatric Investigational Plan Number: 
NA 
Protocol Number: 
C4671034 
Phase: 
2 
 
 
Rationale: 
Patients with COVID-19 who are immunocompromised are at increased risk of progressing 
to severe illness due to prolonged infection, limited contribution by the immune system in 
clearing the infection, and increased potential for viral resistance. Emergence of variants that 
are resistant to available treatment also puts the wider population at risk. Patients who are 
immunocompromised may benefit from extended treatment durations. The purpose of the 
study is to evaluate the efficacy and safety of nirmatrelvir/ritonavir (5, 10, and 15-day dosing 
durations) for the treatment of COVID-19 in nonhospitalized symptomatic participants 
≥12 years of age and weigh ≥40 kg who are immunocompromised (main study population). 
In addition, this study will also evaluate the efficacy and safety of a second treatment course 
of nirmatrelvir/ritonavir (5-, 10-, or 15-days) in an additional population of nonhospitalized 
symptomatic participants who are immunocompromised with a rebound in COVID-19 within 
14 days following completion of an initial 5-day treatment course of nirmatrelvir/ritonavir 
(population with rebound). 


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Objectives, Endpoints, and Estimands: 
 
Objectives 
Endpoints 
Estimands 
Primary: 
Primary: 
Primary: 
• To describe the effect of 
nirmatrelvir/ritonavir on viral RNA 
levels in NP swabs over time for the 
treatment of COVID-19 in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
• Proportion of participants with 
sustained NP swab SARS-CoV-2 
RNA <LLOQ (defined as <2.0 log10 
copies/mL) from Day 15 through 
Day 44. 
• The proportion of participants with 
sustained NP swab SARS-CoV-2 
RNA <LLOQ (defined as <2.0 
log10 copies/mL) from Day 15 
through Day 44 in nonhospitalized, 
symptomatic patients ≥12 years of 
age with COVID-19 who are 
immunocompromised. This will be 
estimated without regard to study 
treatment discontinuation and 
considering participants receiving 
non-study antiviral or monoclonal 
antibody therapy post-baseline for 
the treatment of COVID-19 as not 
achieving sustained NP swab 
SARS-CoV-2 RNA <LLOQ. 
Secondary: 
Secondary: 
Secondary: 
• To describe the effect of 
nirmatrelvir/ritonavir treatment 
duration on the rate of sustained 
virologic clearance in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
• Time to first NP swab SARS-CoV-2 
RNA<LLOQ (<2.0 log10 copies/mL) 
for participants with NP swab 
SARS-CoV-2 RNA ≥LLOQ at 
baseline. 
• Time to sustained NP swab 
SARS-CoV-2 RNA <LLOQ 
(<2.0 log10 copies/mL) through 
Day 44 for participants with NP 
swab SARS-CoV-2 RNA ≥LLOQ at 
baseline. 
• Not applicable. 
• To describe the effect of 
nirmatrelvir/ritonavir on viral 
clearance for the treatment of 
COVID-19 in nonhospitalized 
symptomatic participants ≥12 years 
of age with COVID-19 who are 
immunocompromised. 
• Proportion of participants with 
SARS-CoV-2 RNA <LLOQ in 
plasma over time. 
• Proportion of participants with 
SARS-CoV-2 RNA level in NP 
swabs <2.0 log10 copies/mL at each 
study visit through Day 44. 
• Change from baseline in 
SARS-CoV-2 RNA level in NP 
swabs and in plasma over time. 
• Rebound in SARS-CoV-2 RNA 
level in NP swabs at follow up (ie, 
any study visit after end of treatment 
through Day 44) that is defined as a 
half (0.5) log10 copies/mL increase 
or greater in SARS-CoV-2 RNA 
level relative to end of treatment 
SARS-CoV-2 RNA level based on 
treatment regimen, with a follow-up 
viral RNA level ≥2.5 log10 
copies/mL. 
• Not applicable. 
• To describe the safety and 
tolerability of nirmatrelvir/ritonavir 
• Incidence of TEAEs. 
• Not applicable. 


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Objectives 
Endpoints 
Estimands 
for the treatment of COVID-19 in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
• Incidence of SAEs and AEs leading 
to discontinuations. 
• To describe the effect of 
nirmatrelvir/ritonavir on 
hospitalization and all-cause 
mortality in nonhospitalized 
symptomatic participants ≥12 years 
of age with COVID-19 who are 
immunocompromised. 
• Proportion of participants with 
COVID-19-related hospitalization 
>24 hours, or death from any cause 
through Day 28. 
• Proportion of participants with death 
(all cause) through Week 24. 
• Not applicable. 
• To describe COVID-19 related 
healthcare resource utilization in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised and treated 
with nirmatrelvir/ritonavir. 
• Proportion of participants with 
COVID-19-related hospitalization of 
any duration. 
• Proportion of participants with 
COVID-19-related ICU admission 
of any duration. 
• Proportion of participants requiring 
invasive mechanical ventilation or 
ECMO. 
• Number of days in hospital and ICU 
stay in participants with 
COVID-19-related hospitalization. 
• Number of COVID-19-related 
medical visits through Day 44 and 
through Week 24. 
• Not applicable. 
• To evaluate nirmatrelvir/ritonavir 
for the duration and severity of 
signs and symptoms in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
• Duration of each targeted 
COVID-19 signs/symptoms. 
• Proportion of participants with 
severe signs/symptoms attributed to 
COVID-19 through Day 44. 
• Not applicable. 
• To determine the PK of 
nirmatrelvir/ritonavir in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
• Nirmatrelvir and ritonavir PK in 
plasma and whole blood (if feasible). 
• Not applicable. 
 
Overall Design: 
This Phase 2, randomized, double-blind study will evaluate the efficacy and safety of 
nirmatrelvir/ritonavir (5-, 10-, and 15-day dosing durations) for the treatment of COVID-19 
in approximately 150 nonhospitalized symptomatic participants aged at least 12 years and 
weigh ≥40 kg who are immunocompromised (main study population). In addition, this study 
will also evaluate the efficacy and safety of a second treatment course of 
nirmatrelvir/ritonavir (5-, 10-, or 15-days) in an additional population of nonhospitalized 
symptomatic participants who are immunocompromised with a rebound in COVID-19 within 


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14 days following completion of an initial 5-day treatment course of nirmatrelvir/ritonavir 
(population with rebound). 
Participants in the additional population with rebound will be recruited during the enrollment 
phase for the main study population. Enrollment of the population with rebound will stop 
after the main study population is fully enrolled or after 50 participants in the population with 
rebound have been enrolled, whichever occurs sooner. 
Participants will be screened on the same day as randomization or 1 calendar day before 
randomization. The total study duration is up to 24 weeks, including study intervention 
administration through Day 15 or Day 16, safety assessments through Day 44, efficacy 
assessments through Week 24, and long-term follow-up at Weeks 12 and 24. 
An independent E-DMC will review unblinded data to ensure the safety of participants on an 
ongoing basis throughout the duration of the study. 
Number of Participants: 
Up to approximately 200 participants will be enrolled in this study. 
The study will randomize approximately 150 participants in a 1:1:1 randomization ratio, 
resulting in approximately 50 participants in each treatment arm (main study population). 
Randomization of the main study population will be stratified by those who are considered 
immunocompromised solely based on corticosteroids or TNF blocker use (yes/no). 
Enrollment of participants in the main study population considered immunocompromised 
based solely on receiving corticosteroids or TNF blockers will be capped at 
approximately 25%. 
In addition, the study will also randomize an additional population of up to 
50 nonhospitalized symptomatic participants (in a 1:1:1 randomization ratio) who are 
immunocompromised with a rebound in COVID-19 within 14 days following completion of 
an initial 5-day treatment course of nirmatrelvir/ritonavir (population with rebound). 
Randomization for the population with rebound will not be stratified by those who are 
considered immunocompromised solely based on corticosteroids or TNF blocker use. 
Enrollment of participants considered immunocompromised based solely on receiving 
corticosteroids or TNF blockers in the additional population with rebound will not be capped. 
Note: "Enrolled" means a participant's, or their legally authorized representative’s, agreement 
to participate in a clinical study following completion of the informed consent/assent process 
and screening. A participant will be considered enrolled if the informed consent/assent is not 
withdrawn prior to participating in any study activity after screening. Potential participants 
who are screened for the purpose of determining eligibility for the study, but do not 
participate in the study, are not considered enrolled. 


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Study Population: 
Key inclusion and exclusion criteria are listed below: 
Inclusion Criteria 
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study: 
1. Participants aged 12 years or older and weighing ≥40 kg at screening. 
• Refer to protocol for reproductive criteria for female participants. 
2. Confirmed SARS-CoV-2 infection as determined by RT-PCR or other acceptable test 
method in any specimen collected. 
3. ≥1 sign/symptom attributable to COVID-19 present on the day of randomization. 
4. Immunocompromised. 
In addition, the following inclusion criteria only apply to the additional population with 
rebound: 
5. Presenting with documented, symptomatic, COVID-19 rebound within 14 days 
following completion of an initial 5-day treatment course with nirmatrelvir/ritonavir. 
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded: 
1. Current need for hospitalization or anticipated need for hospitalization within 24h 
after randomization in the clinical opinion of the site investigator. 
2. Known medical history of active liver disease (other than nonalcoholic hepatic 
steatosis), including chronic or active hepatitis B or C infection, primary biliary 
cirrhosis, Child-Pugh Class C, or acute liver failure. 
3. History of hypersensitivity or other contraindication to any of the components of the 
study interventions, as determined by the investigator. 
4. Suspected or confirmed concurrent active systemic infection other than COVID-19 
that may interfere with the evaluation of response to the study intervention. 
5. Any comorbidity requiring hospitalization and/or surgery within 7 days prior to study 
entry, or that is considered life threatening within 30 days prior to study entry, as 
determined by the investigator. 


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6. Receiving dialysis or have known age-specific eGFR <30 mL/min/1.73 m2 or 
eCrCl <30 mL/min at screening as measured by a serum creatinine point of care 
device. 
7. Oxygen saturation of <92% on room air obtained at rest within 24h prior to 
randomization. 
8. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study. 
9. Current use of any prohibited concomitant medication(s). 
10. Current or previous administration with an investigational product (drug or vaccine) 
within 30 days (or as determined by the local requirement) or 5 half-lives preceding 
the first dose of study intervention used in this study (whichever is longer). 
Authorized or products with conditional approval are not considered investigational. 
11. Prior participation in this trial. 
12. Females who are pregnant up to <14 weeks gestation. Pregnancy ≥14 weeks is not 
exclusionary. 
13. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
Study Arms and Duration: 
Eligible participants for this study will be randomly assigned (1:1:1) to receive nirmatrelvir 
plus ritonavir orally q12h as specified in the table below. 


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Study Intervention(s) 
Intervention Name 
Nirmatrelvir 
Placebo for 
nirmatrelvir 
Ritonavir 
Placebo for 
ritonavir 
Arm Name 
(group of participants 
receiving a specific 
treatment or no 
treatment) 
nirmatrelvir/ritonavir 
placebo 
nirmatrelvir/ritonavir 
placebo 
Unit Dose Strength(s) 
150 mg 
0 mg 
100 mg 
0 mg 
Route of Administration 
Oral 
Oral 
Oral 
Oral 
Use 
Experimental 
Placebo 
Experimental 
Placebo 
IMP or NIMP/AxMP 
IMP 
IMP 
IMP 
IMP 
 
 
Study Arm(s) 
Arm Title 
Nirmatrelvir/ 
ritonavir 5-day 
Nirmatrelvir/ 
ritonavir 10-day 
Nirmatrelvir/ritonavir 15-day 
Arm Type 
Experimental, placebo 
Experimental, placebo 
Experimental 
Arm Description 
Participants will receive 
Participants will receive 
Participants will receive 
nirmatrelvir/ 
nirmatrelvir/ 
nirmatrelvir/ 
ritonavir 300 mg/100 mg (or 
ritonavir 300 mg/100 mg (or 
ritonavir 300 mg/100 mg (or 
150 mg/100 mg for 
150 mg/100 mg for 
150 mg/100 mg for 
participants with eGFR ≥30 
participants with eGFR ≥30 to 
participants with eGFR ≥30 
to <60 mL/min/1.73 m2 or 
<60 mL/min/1.73 m2 or eCrCl 
to <60 mL/min/1.73 m2 or 
eCrCl ≥30 to <60 mL/min) 
≥30 to <60 mL/min) q12h 
eCrCl ≥30 to <60 mL/min) 
q12h from Day 1 through 
from Day 1 through Day 10 
q12h from Day 1 through 
Day 5 followed by placebo 
followed by placebo for 
Day 15. 
for nirmatrelvir/placebo for 
nirmatrelvir/placebo for 
ritonavir q12h for Day 6 
ritonavir q12h for Day 11 
through Day 15. 
through Day 15. 
 
Statistical Methods: 
No formal hypothesis testing will be performed for this study. 
The primary estimand, reported separately for the main study population and the population 
with rebound, is the proportion of participants with sustained NP swab SARS-CoV-2 RNA 
<LLOQ (defined as <2.0 log10 copies/mL) from Day 15 through Day 44 in nonhospitalized 
symptomatic patients ≥12 years of age with COVID-19 who are immunocompromised. This 
will be estimated without regard to study treatment discontinuation and considering 
participants receiving non-study antiviral or monoclonal antibody therapy post-baseline for 
the treatment of COVID-19 as not achieving sustained NP swab SARS-CoV-2 RNA 
<LLOQ. 


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The efficacy and safety data will be analyzed and summarized separately for the main study 
population and the additional population with rebound. 
No formal interim analysis will be conducted for this study. 
Ethical Considerations: 
Previous studies have demonstrated efficacy, safety, and tolerability of nirmatrelvir/ritonavir 
in adults at increased risk of progressing to severe COVID-19 illness, which included 
participants who were immunocompromised. The FDA has granted EUA for 
nirmatrelvir/ritonavir for the treatment of mild-to-moderate COVID-19 in adults and 
pediatric patients (12 years of age and older) with positive results of direct SARS-CoV-2 
testing, and who are at high risk for progression to severe COVID-19, including 
hospitalization or death. Because people who are immunocompromised are less likely to 
mount a robust immune response if infected, they may benefit from an extended duration of 
nirmatrelvir/ritonavir. The most common adverse events described with nirmatrelvir/ritonavir 
treatment are allergic reactions, change in taste, diarrhea, headache, and vomiting. Taking 
into account the measures to minimize risk to study participants, the potential risks identified 
in association with nirmatrelvir/ritonavir are justified by the anticipated benefits that may be 
afforded to participants who are immunocompromised. Additional potential benefit to 
individual pregnant study participants treated with nirmatrelvir/ritonavir may include 
reduction in risks associated with severe COVID-19 to pregnancy and pregnancy outcome, 
such as serious morbidity from obstetric complications, preeclampsia, gestational diabetes, 
preterm birth, low birth weight, and stillbirth. 
Participants will be expected to commit time and may experience some discomfort while 
undergoing study assessments. In addition, participants must avoid use of a non-study 
antiviral or monoclonal antibody therapy for the treatment of COVID-19 within 15 days after 
randomization, except for participants who progress to severe or critical COVID-19. Female 
participants of childbearing potential must agree to use appropriate contraception methods. 
1.2. Schema 
 


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1.3. Schedule of Activities 
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed infonnation on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the paiiicipant. 
 
Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this table 
may be found in Se.ction 10.11. 
Sc1·eening Baseline 
(Day 1) 
Day5 Day 
10 
Day 
15 
Day 
21 
Day 
28 
Day 
35 
Day 
44 
LTF/U 
ET 
Notes 
Week 
12 
Week 
24 
(pliol' •  Day relative to start of study intervention (Day 1). 
to Day. Baseline (Day 1) visit is a mandatory site visit. 
44) • Assessments indicated in brackets [X] are only to be 
conducted if indicated as described in the "Notes". 
Visit Window 
Day-1 to 
Dayl 
0 days 1 day 1±1 da)
±2 
days 
±2 
days 
±2 
days 
±3 
days 
±3 
days 
±7 
days 
±7 
days 
±5 
days • Screening procedures may be done from Day -1 to 
Day 1, and may be completed on the same calendar 
day as Baseline/Day 1 procedures. If screening and 
baseline visits are conducted on the same calendar 
day, assessments and procedures that are listed to 
occur at both visits only need to be completed once. 
Study Visit Location 
s 
s 
s 
s 
SIP 
SIP 
SIP SIP SIP SIP SIP 
SIP • All study visits are expected to be in-person visits. Site
staff should, in discussion with participants, detennine
the most appropriate location to conduct study visits. 
Visits should take place at the investigational site (S). 
If this is not feasible, then alternate venues may 
include the participant's location (P). Refer to 
Section 8.1.2 and Section 8.1.3. 
• If an in-person visit is held at a location other than the 
investigational site, the HCP perfonning the visit 
should perform all assessments. If the HCP is unable 
to collect all required information for the study visit 
(eg, AEs, concomitant medications, contraception), the 
site should contact the participant via a follow-up 
telephone call to collect the additional infonnation 
possible. Refer to Section 8.1.4. 
ELIGIBILITY 
Infonued consent (and assent 
if applicable) 
X 
• Infonued consent/assent should be obtained prior to 
undergoing anv studv-soecific orocedm·es. 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this table 
may be found in Se.ction 10.11. 
Sc1·eening Baseline 
(Day 1) 
Day5 Day 
10 
Day 
15 
Day 
21 
Day 
28 
Day 
35 
Day 
44 
LTF/U 
ET 
Notes 
Week 
12 
Week 
24 
(pliol' •  Day relative to start of study intervention (Day 1). 
to Day.  Baseline (Day 1) visit is a mandatory site visit. 
44) • Assessments indicated in brackets fXl are only to be 
conducted if indicated as described in the "Notes". 
Visit Window 
Day-1 to 
Dayl 
0 days lf:1 day lf:1 da)
±2 
days 
±2 
days 
±2 
days 
±3 
days 
±3 
days 
±1 
days 
±7 
days 
±5 
days • Screening procedures may be done from Day -1 to 
Day 1, and may be completed on the same calendar 
day as Baseline/Day 1 procedures. If screening and 
baseline visits are conducted on the same calendar 
day, assessments and procedures that are listed to 
occur at both visits only need to be completed once. 
• See Se-ction 10.1.3 for additional information. 
Verify inclusion/exclusion 
criteria 
X 
• See Se-ction 5.1 and Section 5.2. 
Demographics and medical 
historv 
X 
• See Se-ction 8.1.1.1. 
Physical Examination and 
Vital Shms 
Targeted physical 
examination 
X 
X 
•  Physical examinations to be completed before 
administration of study intervention. 
• See Se-ction 8.3.1. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X • See Se-ction 8.3.2 and Section 8.1.4. 
Weight, height 
X 
• Height may be self-repo,ted for paiticipants ::::18 years 
of age. 
• See Se-ction 8.3.1. 
Vital status check 
X 
X 
X • Seconda,y contacts may be used for a vital status 
check. 
Laboratory Assessments 
• See Section 8.3.4 for additional information. 
• See Appendix 2 for a list of Clinical Laboratory tests to 
be done. 
• For laboratory collection volumes, see the laboratory 
manual. 
Hematology 
X 
X 
X 
X 
[X] 
[X] 
[X] 
[X] 
[X] • Baseline laborato,y assessments should be collected 
prior to first dose of study intervention. 
• If deemed necessary to confirm eligibility, laborato,y 
assessments at screening may be pe1fo1med at the 
local laborato1y at the investigator's discretion. 
Blood chemistry 
X 
X 
X 
X 
[X] 
[X] 
[X] 
[X] 
[X] 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this table 
may be found in Se.ction 10.11. 
Sc1·eening Baseline 
(Day 1) 
Day5 Day 
10 
Day 
15 
Day 
21 
Day 
28 
Day 
35 
Day 
44 
LTF/U 
ET 
Notes 
Week 
12 
Week 
24 
(pliol' •  Day relative to start of study intervention (Day 1). 
to Day. Baseline (Day 1) visit is a mandatory site visit. 
44) • Assessments indicated in brackets fXl are only to be 
conducted if indicated as described in the "Notes". 
Visit Window 
Day-1 to 
Dayl 
0 days lf:1 day lf:1 da)
±2 
days 
±2 
days 
±2 
days 
±3 
days 
±3 
days 
±1 
days 
±7 
days 
±5 
days • Screening procedures may be done from Day -1 to 
Day 1, and may be completed on the same calendar 
day as Baseline/Day 1 procedures. If screening and 
baseline visits are conducted on the same calendar 
day, assessments and procedures that are listed to 
occur at both visits only need to be completed once. 
Thyroid function 
X 
X 
X 
X 
X • Abnonual laborato1y values related to AEs should be 
followed until resolution. 
SARS-CoV-2 Seroloev 
X 
X 
X 
X 
X 
X 
X 
X 
Point-of-care semm creatinine
assessment 
X 
[X) 
[X) 
[X) 
•  Screening visit: A semm creatinine point-of-care 
device assessment for detenuining estimation of 
kidney function (eGFR for adults 18 years and older, 
and CrCl for adolescents 12 years to <18 years) is 
required for eligibility. See Section 10.7.1 for age 
specific kidney function calculations. 
• Baseline visit assessment expected only if screening 
and baseline visits are held on different days. 
• Day 5 and/or Day 10 assessment to be pe,formed at 
discretion of the investigator. 
• See Se.ction 8.3.3. 
Pregnancy test 
X 
X 
X • A negative urine or semm beta human chorionic 
gonadotropin (P-hCG) pregnancy test must be 
confinued at screening for only WOCBP who are not 
pregnant at screening. Pregnancy tests will also be 
done whenever 1 menstmal cycle is missed during the 
active treatment period (or when potential pregnancy 
is otherwise suspected) and at Day 44 or ET visit. 
• See Se.ction 8.3.5 and Section 8.1.4. 
FSH 
X 
•  FSH is to be pe,fonued to confinu postmenopausal 
status in female pa,ticipants <60 years of age at 
screening who are not using hormonal contraception 
or ho,monal replacement therapy. Female participants 
aged 50 to 60 vears with no menses for 12 months do 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this table 
may be fonnd in Se.ction 10.11. 
Sc1·eening Baseline 
(Day 1) 
Day 5 Day 
10 
Day 
15 
Day 
21 
Day 
28 
Day 
35 Da 
44 y ---------------- ET 
Week Week (pliol' 
12 
24 
to Day 
Notes 
Day relative to start of study intervention (Day 1). 
Baseline (Day 1) visit is a mandatory site visit. 
Assessments indicated in brackets fXl are only to be 
conducted if indicated as described in the "Notes". 
44) 
Visit Window 
Day -1 to 
Dayl 
O days 
±2 
days 
±2 
days 
±2 
days 
±3 
days 
±3 
days 
±7 
days 
±7 
±5 
days  days 
Screening procedures may be done from Day -1 to 
Day 1, and may be completed on the same calendar 
day as Baseline/Day 1 procedures. If screening and 
baseline visits are conducted on the same calendar 
day, assessments and procedures that are listed to 
occur at both visits on! need to be com leted once. 
not need FSH testing to be performed to confinn 
postmenopausal status. 
•  When FSH testing is required to confinn 
postmenopausal status, a participant may be enrolled 
in the study prior to the test result being available as 
long as the FSH test result confinns postmenopausal 
status prior to dosing. A female whose menopausal 
status is in doubt will be required to use a highly 
effective method of contraception during the study 
(Section 10.4.4). 
• See Se-ction 10.4.2 and Section 10.2. 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this table 
may be fonnd in Se.ction 10.11. 
Sc1·eening Baseline 
(Day 1) 
Day 5 Day 
10 
Day 
15 
Day 
21 
Day 
28 
Day 
35 
Day 
44 - ----------------------- i ET 
Week Week (pliol' 
12 
24 
to Day
Notes 
Day relative to start of study intervention (Day 1). 
Baseline (Day 1) visit is a mandatory site visit. 
Assessments indicated in brackets fXl are only to be 
conducted if indicated as described in the "Notes". 
44) 
Visit Window 
Day -1 to 
Dayl 
O days 
±2 
days 
±2 
days 
±2 
days 
±3 
days 
±3 
days 
±1 
days 
±7 
±5 
days  days 
Screening procedures may be done from Day -1 to 
Day 1, and may be completed on the same calendar 
day as Baseline/Day 1 procedures. If screening and 
baseline visits are conducted on the same calendar 
day, assessments and procedures that are listed to 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK sampling (ninuatrelvir 
and ritonavir) 
X 
X 
X 
X 
[X] •  At baseline/Day 1, the time of sample collection is 
l-2h after dose administration. 
•  On Day 5, Day 10, and Day 15, one venous blood 
sample for PK will be collected on each day at any 
time dtuing the visit. 
PK sample will be collected at ET visit only if the ET 
visit occtu·s within 2 days (48h) of the last dose of 
study intervention. 
• See Se.ction 8.5. 
tud Intervention 
Rando 
atio 
S . Secfon 6.3. 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this table 
may be found in Se.ction 10.11. 
Sc1·eening Baseline 
(Day 1) 
Day5 
Day 
10 
Day 
15 
Day 
21 
Day 
28 
Day 
35 
Day 
44 
LTF/U 
ET 
Notes 
Week 
12 
Week 
24 
(pliol'•  Day relative to start of study intervention (Day 1). 
to Day. Baseline (Day 1) visit is a mandatory site visit. 
44) • Assessments indicated in brackets fXl are only to be 
conducted if indicated as described in the "Notes". 
Visit Window 
Day-1 to
Dayl 
0 days bl:1 day bl:1 da) 
±2 
days 
±2 
days 
±2 
days 
±3 
days 
±3 
days 
±1 
days 
±7 
days 
±5 
days • Screening procedures may be done from Day -1 to 
Day 1, and may be completed on the same calendar 
day as Baseline/Day 1 procedures. If screening and 
baseline visits are conducted on the same calendar 
day, assessments and procedures that are listed to 
occur at both visits onlv need to be completed once. 
Study intervention 
dispensation 
X 
X 
X 
• Study intervention will be dispensed on Day 1, Day 5, 
and Day 10 (see Section 6.1.1). 
• Should eGFR or eCrCl (based on the point-of-care 
creatinine) on Day 5 or Day 10 wan-ant a dose 
modification, replacement study intervention will be 
dispensed on Day 5 or Day 10. See Se-ction 10.7.1 for 
age specific kidney function calculations. 
• See Se-ction 6.6. 
Study intervention 
administration 
Day 1 through Day 15 
• Baseline assessments should be pe1fo1med before 
administration of the first study intervention, except 
for PK sampling. 
• The first dose of study intervention will be 
administered to all pa1ticipants on Day 1 during the in 
person visit. All subsequent doses of study 
intervention (ie, 29) will be self-administered (or 
administered to the pa1ticipant by a legal guardian or 
caregiver). If only 1 dose of study intervention is 
administered on Day 1, study intervention 
administration should end on Day 16. 
• See Se-ction 6.1.1. 
Study Intel'Vention 
Accountability 
Retrieval of unused study 
intervention and empty study 
intervention containers 
X 
X 
X 
X •  If the Day 15 visit is conducted prior to last dose of 
study intervention, empty study intervention 
containers and unused study intervention should be 
retumed at the Day 21 visit. 
• See Se-ction 6.5. 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this table 
may be found in Se.ction 10.11. 
Sc1·eening Baseline 
(Day 1) 
Day5 
Day 
10 
Day 
15 
Day 
21 
Day 
28 
Day 
35 
Day 
44 
LTF/U 
ET 
Notes 
Week 
12 
Week 
24 
(pliol'•  Day relative to start of study intervention (Day 1). 
to Day. Baseline (Day 1) visit is a mandatory site visit. 
44) • Assessments indicated in brackets fXl are only to be 
conducted if indicated as described in the "Notes". 
Visit Window 
Day-1 to
Dayl 
0 days bl:1 day bl:1 da) 
±2 
days 
±2 
days 
±2 
days 
±3 
days 
±3 
days 
±1 
days 
±7 
days 
±5 
days • Screening procedures may be done from Day -1 to 
Day 1, and may be completed on the same calendar 
day as Baseline/Day 1 procedures. If screening and 
baseline visits are conducted on the same calendar 
day, assessments and procedures that are listed to 
occur at both visits onlv need to be completed once. 
Study intervention 
accountability 
X 
X 
X 
X 
[if 
!needed
l 
• Study intervention accountabilityis only pe1fo1med at 
the Day 21 visit if the participant administered 
treatment after the Day 15 visit was conducted. 
Patient Repo11ed Outcomes 
6nly adult participants (c::18 years of age) will be asked to 
omplete PRO assessments. 
• See Section 8.2.4. 
Collection of global 
impression questions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X • Participants will answer 3 global impression questions. 
• See Se.ction 8.2.4.1. 
SF-36 
X 
X 
X 
X 
X 
X 
• See Se.ction 8.2.4.2. 
WPAI 
X 
X 
X 
X 
• See Se-ction 8.2.4.3. 
EQ-5D-5L 
X 
X 
X 
X 
X 
X 
• See Se-ction 8.2.4.4. 
lstudy Pl'ocedul'es & 
IA sessments 
Provide participants with 
studv emere:encv contact card 
X 
• See Section 10.1.11. 
Collect/update seconda,y 
contacts 
X 
X 
X 
X 
X 
X 
X 
X 
• See Se-ction 8.1.1.3. 
Record oxygen suppo,t details 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X • See Se-ction 8.2.3. 
Study kit dispensed and 
participant instmcted on its 
use 
X 
• See Se-ction 8.1.1.2. 
Pa,ticipant-completed study 
intervention log 
Daily on Day 1 through Day 15 
• Study intervention logshould be completed daily on 
Days 1 through Day 16 if only 1 dose was 
administered on Day 1. 
• See Se-ction 8.2.1. 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this table 
may be found in Se.ction 10.11. 
Sc1·eening Baseline 
(Day 1) 
Day5 
Day 
10 
Day 
15 
Day 
21 
Day 
28 
Day 
35 
Day 
44 
LTF/U 
ET 
Notes 
Week 
12 
Week 
24 
(pliol'•  Day relative to start of study intervention (Day 1). 
to Day. Baseline (Day 1) visit is a mandatory site visit. 
44) • Assessments indicated in brackets fXl are only to be 
conducted if indicated as described in the "Notes". 
Visit Window 
Day-1 to
Dayl 
0 days bl:1 day bl:1 da)
±2 
days 
±2 
days 
±2 
days 
±3 
days 
±3 
days 
±1 
days 
±7 
days 
±5 
days • Screening procedures may be done from Day -1 to 
Day 1, and may be completed on the same calendar 
day as Baseline/Day 1 procedures. If screening and 
baseline visits are conducted on the same calendar 
day, assessments and procedures that are listed to 
occur at both visits onlv need to be completed once. 
Staff review of study 
intervention loQ, 
Daily on Day 1 through Day 15
• See Se-ction 6.5. 
Record COVID-19-related 
medical visits 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X • COVID-19-related medical visits a participant has 
attended since the last assessment will be collected. 
• See Se-ction 8.2.2. 
Contraception check 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X • See Section 5.3.1, Section 8.1.4, and Annendix 4. 
Prior/concomitant medications
X 
X 
X 
X 
X 
X 
X 
X 
X 
X • All prescription and over-the-counter medications 
including vaccines taken by the pa1ticipant within 
30 days before study entty (considered prior 
tt-eattuent) will be recorded. 
• COVID 19-related vaccinations and monoclonal 
antibody or antiviral treattuent for the tt-eattuent of 
COVID-19 at any time prior to the planned first dose 
will also be collected. 
•  Concomitant therapies will be collected thrnugh the 
Day 44 visit or at ET visit. 
• See Se-ction 6.9 and Section 8.1.4. 
Adjunctive therapeutic 
procedm·es 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X • Will be collected through the Day 44 visit or at ET 
visit. 
COVID-19 signs and 
svmotoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X • See Se-ction 8.2.5 and Appendix 10. 
Serious and nonserious AE 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X • AEs should be assessed by means of a telehealth visit 
if not feasible via an in-person visit. 
• See Se-ction 8.1.4. 
• Previously identified AEs (either by interview, 
physical exam, or other assessment) should be 
monitored to the extent oossible if telehealth is used. 


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Table 1. 
Study Schedule of Assessment 
 
Visit Identifiel' 
Abbreviations used in this table 
may be found in Se.ction 10.11. 
Sc1·eening Baseline 
(Day 1) 
Day5 Day 
10 
Day 
15 
Day 
21 
Day 
28 
Day 
35 
Day 
44 
LTF/U 
ET 
Notes 
Week 
12 
Week 
24 
(pliol'•  Day relative to start of study intervention (Day 1). 
to Day. Baseline (Day 1) visit is a mandatory site visit. 
44) • Assessments indicated in brackets fXl are only to be 
conducted if indicated as described in the "Notes". 
Visit Window 
Day-1 to 
Dayl 
0 days bl:1 day bl:1 da) 
±2 
days 
±2 
days 
±2 
days 
±3 
days 
±3 
days 
±1 
days 
±7 
days 
±5 
days • Screening procedures may be done from Day -1 to 
Day 1, and may be completed on the same calendar 
day as Baseline/Day 1 procedures. If screening and 
baseline visits are conducted on the same calendar 
day, assessments and procedures that are listed to 
occur at both visits onlv need to be completed once. 
•  After the defined active collection period for safety 
events, long-tenu follow-up visits are also conducted 
at Weeks 12 and 24. Any new SAE occtming dllling 
this long-term follow-up period and detenuined to be 
related to study intervention must be repo1ted to Pfizer 
Safety immediately upon awareness and under no 
cu·cU111Stance should this exceed 24 holll·s. 
• See Se-ction 8.4.3 for follow-up AE and SAE 
assessments. 


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2. INTRODUCTION 
Nirmatrelvir, a potent and selective SARS-CoV-2 3CL orally administered protease inhibitor, 
is being investigated in participants with COVID-19 who are immunocompromised. 
2.1. Study Rationale 
Patients with COVID-19 who are immunocompromised are at increased risk of progressing 
to severe illness due to prolonged infection, limited contribution by the immune system in 
clearing the infection, and increased potential for viral resistance.1,2 A limited number of 
participants who were immunocompromised participated in Study C4671005 (EPIC-HR, 
NCT04960202). Such patients may benefit from extended treatment durations. The purpose 
of the study is to evaluate the efficacy and safety of nirmatrelvir/ritonavir (5-day, 10-day, and 
15-day dosing durations) for the treatment of COVID-19 in nonhospitalized, symptomatic 
participants ≥12 years of age and weighing at least 40 kg who are immunocompromised 
(main study population). 
In addition, this study will also evaluate the efficacy and safety of a second treatment course 
of nirmatrelvir/ritonavir (5-, 10-, or 15-days) in an additional population of nonhospitalized 
symptomatic participants who are immunocompromised with a rebound in COVID-19 within 
14 days following completion of an initial 5--day treatment course of nirmatrelvir/ritonavir 
(population with rebound). 
2.2. Background 
COVID-19, caused by the SARS-CoV-2 coronavirus, was declared a global pandemic by the 
WHO on 11 March 2020,3 and continues to be a serious global threat to public health and to 
health care systems. As of 07 March 2022, COVID-19 has infected at least 446 million 
people, and has led to at least 6 million deaths worldwide.4 
In order to prevent SARS-CoV-2 infection, several COVID-19 vaccines have been approved 
or authorized for emergency use by Health Authorities and are being administered globally.5 
Duration and sufficiency of vaccine protection may be inadequate in patients who are 
immunocompromised.2,6 Even with the administration of a booster dose, 
immunocompromised patients may be less likely to develop strong immune protection from 
vaccines. 
Currently authorized/approved vaccines may not be as effective against potential outbreaks 
from new coronavirus variants.7 Emergence of the omicron variant in late 2021 provides an 
example of the potential impact emerging variants of SARS-CoV-2 may have on vaccine 
efficacy. More specifically, gene mutations in the omicron variant appear to result in vaccine 
efficacy against symptomatic disease that is significantly lower than against the Delta 
variant.7 The omicron variants account for almost all SARS-CoV-2 infections in the US as of 
mid-January 2022.8 
A limited number of antiviral agents and monoclonal antibody-based regimens have been 
approved or have received EUA by the FDA for the treatment of nonhospitalized high-risk 
patients with symptomatic COVID-19.9 In December 2021, four anti-SARS-CoV-2 


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monoclonal antibody products have received EUA for the treatment of nonhospitalized 
patients with mild-to-moderate COVID-19. However, distribution of these agents have been 
paused as Omicron variants of concern (BA.1 and BA.2) have reduced in vitro susceptibility 
to these agents and these antibody regimens are not expected to provide clinical benefit.9 
An additional preventive treatment, tixagevimab co-packaged with cilgavimab, has received 
EUA for pre-exposure prophylaxis in patients with moderate to severe immune 
compromise.10 
In December 2021, the FDA granted EUA for a 5 day course of treatment for 2 separate oral 
antiviral agents, nirmatrelvir/ritonavir11 and molnupiravir12, for the treatment of COVID-19 
in adult and pediatric patients 12 years of age and older who weigh at least 40 kg, with mild 
to moderate COVID-19 who are at high risk for progressing to severe illness. Molnupiravir is 
not recommended during pregnancy, as findings from animal reproduction studies showed 
that molnupiravir may cause fetal harm when administered to pregnant individuals. In 
January 2022, remdesivir received approval for this same population.13 This treatment is 
administered by IV infusion over 3 days for nonhospitalized patients with mild to moderate 
COVID-19 who are at high risk for progressing to severe illness. 
Case reports in the literature describe individuals in the general population who have 
experienced symptomatic relapses of SARS-CoV-2 infection following completion of a 
5-day course of nirmatrelvir/ritonavir.14-16 The time course of symptom rebound suggests that 
symptom recurrence is likely not related to re-exposure and that it does not reflect a potential 
re-infection event. A retrospective review of 483 high-risk patients treated with 
nirmatrelvir/ritonavir reported 4 (0.8%) of patients experienced rebound of symptoms. 
Median time to rebound was reported as 9 days.17 Rapid recurrence in symptoms along with 
a positive RT-PCR or rapid antigen test following the completion of a 5-day course of 
nirmatrelvir/ritonavir may indicate these patients require additional therapy to achieve 
sustained viral clearance. 
Certain comorbidities and characteristics such as an immunocompromised status and older 
age increase an individual’s risk for developing severe COVID-19.18,19 COVID-19 may pose 
a unique threat to patients who are immunocompromised because COVID-19 vaccines are 
less effective in preventing infection.2,6 In addition, immunocompromised patients may be at 
risk for prolonged infection. Prolonged viral shedding in immunocompromised patients with 
influenza infection is well-documented and is associated with an increased frequency of 
treatment-resistant virus variants.20,21 Prolonged viral shedding in immunocompromised 
patients with SARS-CoV-2 infection has also been observed and has been associated with the 
emergence of treatment-resistant and novel virus variants.22,23 
Given the risk for prolonged viral infection in patients who are immunocompromised, this 
patient population may benefit from longer duration therapy. 
In this study of participants with symptomatic COVID-19 who are immunocompromised 
(including an additional population of symptomatic participants with rebound in COVID-19), 
nirmatrelvir/ritonavir will be administered for 5, 10, or 15 days. 


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2.2.1. Clinical Overview 
The safety and efficacy of a 5-day treatment with nirmatrelvir/ritonavir in adults was 
demonstrated in Study C4671005 (EPIC-HR, NCT094960202), which enrolled 
nonhospitalized symptomatic adults, including participants who were immunocompromised, 
with laboratory-confirmed diagnosis of SARS-CoV-2 infection with at least 1 risk factor for 
progression to severe disease and with a COVID-19 symptom onset of ≤5 days. In the 
analysis of the primary endpoint from all participants enrolled in Study C4671005, an 89% 
reduction in COVID-19-related hospitalization or death from any cause compared with 
placebo in participants treated within 3 days of symptom onset was observed. 0.72% of 
participants who received nirmatrelvir/ritonavir were hospitalized through Day 28 following 
randomization (5 of 697 hospitalized with no deaths), compared to 6.45% of participants who 
received placebo and were hospitalized or died (44 of 682 hospitalized with 9 subsequent 
deaths) (p<0.001). In a secondary endpoint, nirmatrelvir/ritonavir reduced the risk of 
hospitalization or death for any cause by 88% compared with placebo in participants treated 
within 5 days of symptom onset; 0.77% of patients who received nirmatrelvir/ritonavir were 
hospitalized through Day 28 following randomization (8 of 1039 hospitalized with no deaths) 
compared with 6.31% of patients who received placebo (66 of 1046 hospitalized with 
12 subsequent deaths) (p<0.001). Treatment with nirmatrelvir/ritonavir was safe and well 
tolerated.24 
On 22 December 2021, the US FDA granted EUA to nirmatrelvir/ritonavir for the treatment 
of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age or older 
weighing ≥40 kg) who are at risk for progression to severe disease.11 
Refer to the IB25 for more details on studies, including clinical efficacy, safety, and PK 
results for completed and ongoing studies. 
2.3. Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of nirmatrelvir/ritonavir may be found in the IB, which is the SRSD for this 
study. 


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2.3.1. Risk Assessment 
 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s): Nirmatrelvir 
Emesis 
In Study C4671005, vomiting occurred at a greater 
frequency in the nirmatrelvir/ritonavir group than in 
the placebo group. 
AEs will be monitored, and participants may 
receive antiemetics if needed. 
Hypertension 
Transient increases in systolic, diastolic, and mean 
blood pressure were observed in the preclinical 
studies. In Study C4671005 (adults at high risk for 
severe disease), a small imbalance in hypertension 
AEs (1% vs <1%) was reported. 
Vital signs and all AEs will be monitored in the 
study. 
Refer to Section 8.4. 
Reduced maternal and fetal weight 
In rabbit embryo-fetal development toxicity studies, 
nirmatrelvir-related lower maternal body weight 
change and food consumption were observed at 
1000 mg/kg/day but were not considered adverse 
based on low magnitude of difference from control 
and lack of impact on absolute body weights. 
Nirmatrelvir -related, adverse, lower fetal weight 
(0.91x control) was observed at 1000 mg/kg/day. 
Lower dose of 300 mg q12h is used in this study. 
Study Intervention(s): Ritonavir 
Gastrointestinal disturbances (including 
diarrhea, nausea, vomiting and abdominal pain) 
Frequently reported adverse reaction in HIV-positive 
patients who are HIV-positive at 600 mg BID. 
Lower dose of 100 mg twice daily is used in this 
study. There will be close observation of AEs. In 
addition to ongoing review of AEs by the sponsor, 
an E-DMC will review safety data as described in 
Section 10.1.5.1. 
Taking study intervention with food may improve 
tolerability. 
Neurological disturbances (eg, paresthesia, 
including oral paresthesia, dysgeusia and 
dizziness) 
Frequently reported adverse reaction in patients who 
are HIV-positive at 600 mg BID. 
Lower dose used in this study. There will be close 
observation of AEs. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
In addition to ongoing review of AEs by the 
sponsor, an E-DMC will review safety data as 
described in Section 10.1.5.1. 
Rash (most commonly reported as erythematous 
and maculopapular, followed by pruritic) 
Frequently reported adverse reaction in patients who 
are HIV-positive at 600 mg BID. 
Lower dose used in this study. There will be close 
observation of AEs and monitoring through 
targeted physical exams. If needed therapeutic 
interventions per SoC may be provided. 
Fatigue/Asthenia 
Frequently reported adverse reaction in patients who 
are HIV-positive at 600 mg BID. 
Lower dose used in this study. There will be close 
observation of AEs. 


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2.3.2. Benefit Assessment 
Nirmatrelvir/ritonavir has been shown to have SARS-CoV-2 antiviral activity in vitro. 
Efficacy, safety, and tolerability of nirmatrelvir/ritonavir was demonstrated in adults at 
increased risk of progressing to severe COVID-19 illness, which includes participants who 
are immunocompromised. The EMA has granted conditional approval for 
nirmatrelvir/ritonavir for the treatment COVID-19 in adults who do not require supplemental 
oxygen and who are at increased risk for progressing to severe COVID-19.26 The FDA has 
granted EUA for nirmatrelvir/ritonavir11 for the treatment of mild to moderate COVID-19 in 
adults and pediatric patients (12 years of age and older and weighing ≥40 kg) with positive 
results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe 
COVID-19, including hospitalization or death. Because people who are 
immunocompromised are less likely to mount a robust immune response if infected, potential 
benefits from an extended duration of nirmatrelvir/ritonavir therapy may include a shorter 
time to reduction in viral RNA levels, clinical recovery, prevention of hospitalization, and a 
lower probability of progressing to more severe illness or death. 
2.3.3. Overall Benefit/Risk Conclusion 
Considering the current COVID-19 global pandemic, the high burden of both mortality and 
morbidity, the potential for future epidemic outbreaks, the lack of readily available outpatient 
treatment options, and the measures taken to minimize risk to study participants, the potential 
risks identified in association with nirmatrelvir/ritonavir are justified by the anticipated 
benefits that may be afforded to participants who are immunocompromised. 
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
 
Objectives 
Endpoints 
Estimands 
Primary: 
Primary: 
Primary: 
• To describe the effect of 
nirmatrelvir/ritonavir on viral RNA 
levels in NP swabs over time for the 
treatment of COVID-19 in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
• Proportion of participants with 
sustained NP swab SARS-CoV-2 
RNA <LLOQ (defined as <2.0 log10 
copies/mL) from Day 15 through 
Day 44. 
• The proportion of participants with 
sustained NP swab SARS-CoV-2 
RNA <LLOQ (defined as <2.0 
log10 copies/mL) from Day 15 
through Day 44 in nonhospitalized, 
symptomatic patients ≥12 years of 
age with COVID-19 who are 
immunocompromised. This will be 
estimated without regard to study 
treatment discontinuation and 
considering participants receiving 
non-study antiviral or monoclonal 
antibody therapy post-baseline for 
the treatment of COVID-19 as not 
achieving sustained NP swab 
SARS-CoV-2 RNA <LLOQ. 
Secondary: 
Secondary: 
Secondary: 
• To describe the effect of 
nirmatrelvir/ritonavir treatment 
duration on the rate of sustained 
virologic clearance in 
• Time to first NP swab SARS-CoV-2 
RNA<LLOQ (<2.0 log10 copies/mL) 
for participants with NP swab 
• Not applicable. 


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Objectives 
Endpoints 
Estimands 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
SARS-CoV-2 RNA ≥LLOQ at 
baseline. 
• Time to sustained NP swab 
SARS-CoV-2 RNA <LLOQ 
(<2.0 log10 copies/mL) through 
Day 44 for participants with NP 
swab SARS-CoV-2 RNA ≥LLOQ at 
baseline. 
• To describe the effect of 
nirmatrelvir/ritonavir on viral 
clearance for the treatment of 
COVID-19 in nonhospitalized 
symptomatic participants ≥12 years 
of age with COVID-19 who are 
immunocompromised. 
• Proportion of participants with 
SARS-CoV-2 RNA <LLOQ in 
plasma over time. 
• Proportion of participants with 
SARS-CoV-2 RNA level in NP 
swabs <2.0 log10 copies/mL at each 
study visit through Day 44. 
• Change from baseline in 
SARS-CoV-2 RNA level in NP 
swabs and in plasma over time. 
• Rebound in SARS-CoV-2 RNA 
level in NP swabs at follow up (ie, 
any study visit after end of treatment 
through Day 44) that is defined as a 
half (0.5) log10 copies/mL increase 
or greater in SARS-CoV-2 RNA 
level relative to end of treatment 
SARS-CoV-2 RNA level based on 
treatment regimen, with a follow-up 
viral RNA level ≥2.5 log10 
copies/mL. 
• Not applicable. 
• To describe the safety and 
tolerability of nirmatrelvir/ritonavir 
for the treatment of COVID-19 in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
• Incidence of TEAEs. 
• Incidence of SAEs and AEs leading 
to discontinuations. 
• Not applicable. 
• To describe the effect of 
nirmatrelvir/ritonavir on 
hospitalization and all-cause 
mortality in nonhospitalized 
symptomatic participants ≥12 years 
of age with COVID-19 who are 
immunocompromised. 
• Proportion of participants with 
COVID-19-related hospitalization 
>24 hours, or death from any cause 
through Day 28. 
• Proportion of participants with death 
(all cause) through Week 24. 
• Not applicable. 
• To describe COVID-19 related 
healthcare resource utilization in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised and treated 
with nirmatrelvir/ritonavir. 
• Proportion of participants with 
COVID-19-related hospitalization of 
any duration. 
• Proportion of participants with 
COVID-19-related ICU admission 
of any duration. 
• Proportion of participants requiring 
invasive mechanical ventilation or 
ECMO. 
• Number of days in hospital and ICU 
stay in participants with 
COVID-19-related hospitalization. 
• Not applicable. 


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Objectives 
Endpoints 
Estimands 
• Number of COVID-19-related 
medical visits through Day 44 and 
through Week 24. 
• To evaluate nirmatrelvir/ritonavir 
for the duration and severity of 
signs and symptoms in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
• Duration of each targeted 
COVID-19 signs/symptoms. 
• Proportion of participants with 
severe signs/symptoms attributed to 
COVID-19 through Day 44. 
• Not applicable. 
• To determine the PK of 
nirmatrelvir/ritonavir in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised. 
• Nirmatrelvir and ritonavir PK in 
plasma and whole blood (if feasible). 
• Not applicable. 
 
4. STUDY DESIGN 
4.1. Overall Design 
This Phase 2, randomized, double-blind, study will evaluate the efficacy and safety of 
nirmatrelvir/ritonavir (5-, 10-, and 15-day dosing durations) for the treatment of COVID-19 
in approximately 150 nonhospitalized symptomatic participants aged at least 12 years and 
weigh ≥40 kg who are immunocompromised (main study population). In addition, this study 
will also evaluate the efficacy and safety of a second treatment course of 
nirmatrelvir/ritonavir (5-, 10-, or 15-days) in an additional population of nonhospitalized 
symptomatic participants who are immunocompromised with a rebound in COVID-19 within 
14 days following completion of an initial 5-day treatment course of nirmatrelvir/ritonavir 
(population with rebound). 
Participants in the additional population with rebound will be recruited during the enrollment 
phase for the main study population. Enrollment of the population with rebound will stop 
after the main study population is fully enrolled or after 50 participants in the population with 
rebound have been enrolled, whichever occurs sooner. 
Eligible participants (main study population and additional population with rebound) for this 
study will be randomly assigned (1:1:1) to receive: 
• nirmatrelvir plus ritonavir orally q12h for 5 days followed by placebo for nirmatrelvir 
plus ritonavir q12h for 10 days; or 
• nirmatrelvir plus ritonavir orally q12h for 10 days followed by placebo for nirmatrelvir 
plus ritonavir q12h for 5 days; or 
• nirmatrelvir plus ritonavir orally q12h for 15 days. 


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Participants will be screened on the same day as randomization or 1 calendar day before 
randomization. For the main study population, enrollment of participants considered 
immunocompromised based solely on receiving corticosteroids or TNF blockers will be 
capped at approximately 25%. Enrollment of participants considered immunocompromised 
based solely on receiving corticosteroids or TNF blockers in the additional population with 
rebound will not be capped. 
For the main study population, randomization will be stratified by those who are considered 
immunocompromised solely based on corticosteroids or TNF blocker use (yes/no) 
(Section 10.9.4, Point #4). Randomization for the population with rebound will not be 
stratified by those who are considered immunocompromised solely based on corticosteroids 
or TNF blocker use. 
The total study duration is up to 24 weeks, including study intervention administration 
through Day 15 or Day 16, safety assessments through Day 44, efficacy assessments through 
Week 24, and long-term follow-up at Weeks 12 and 24. 
Analyses will be conducted after the main study population is fully enrolled and have 
completed the Day 44 visit regardless of the number of randomized participants in the 
population with rebound. There will be 2 analysis time points for reporting the results of this 
study. The primary analysis will be performed after all participants in the main study 
population have completed the Day 44 visit. The follow-up analysis will be performed after 
all participants in the main study population have completed the Week 24 visit. In addition, 
both analyses (primary and follow-up) will include separate results for the main study 
population and the additional population with rebound. 
An independent E-DMC will review unblinded data to ensure the safety of participants on an 
ongoing basis throughout the duration of the study (Section 10.1.5.1). 
4.2. Scientific Rationale for Study Design 
Patients with COVID-19 who are immunocompromised are at increased risk of progressing 
to severe illness due to prolonged infection, limited contribution by the immune system in 
clearing the infection, and increased potential for viral resistance.1,2 Emergence of variants 
that are resistant to available treatment also puts the wider population at risk. Patients who 
are immunocompromised may benefit from extended treatment durations. The purpose of the 
study is to evaluate the efficacy and safety of nirmatrelvir/ritonavir (5, 10, and 15-day dosing 
durations) for the treatment of COVID-19 in nonhospitalized symptomatic participants 
≥12 years of age and weigh ≥40 kg who are immunocompromised (main study population). 
In addition, this study will also evaluate the efficacy and safety of a second treatment course 
of nirmatrelvir/ritonavir (5-, 10-, or 15-days) in an additional population of nonhospitalized 
symptomatic participants who are immunocompromised with a rebound in COVID-19 within 
14 days following completion of an initial 5-day treatment course of nirmatrelvir/ritonavir 
(population with rebound). 


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4.2.1. Diversity of Study Population 
This is a global study and the US diversity strategy will include sites with the potential to 
support the recruitment of diverse populations. In the US, medical institutions with varying 
characteristics, such as urban and suburban institutions, will be included. The strategy to help 
ensure diversity includes: 
• Providing investigators with recruitment materials for both potential participants and 
other HCPs; 
• Creating individual site recruitment plans in collaboration with sites and providing 
supplemental diverse recruitment tools; 
• Developing recruitment and retention materials using imagery along with culturally 
and linguistically appropriate language to resonate with underrepresented 
populations; 
• Translating all patient-facing materials into US Spanish; 
• Educating site staff on the importance of including diverse participants; 
• Monitoring diverse enrollment, in real time; 
• Implementing additional strategies to mitigate trending below goals. 
4.2.2. Choice of Contraception/Barrier Requirements 
Human reproductive safety data are limited for nirmatrelvir/ritonavir, but there is no 
suspicion of human teratogenicity based on the intended pharmacology of the 
compound. Therefore, the use of a highly effective method of contraception is required for 
female participants who are not pregnant at entry (see Appendix 4). 
4.2.3. Collection of Retained Research Samples 
Retained Research Samples will be collected and stored for further analyses which may, for 
example, provide greater understanding of the study intervention. 
4.2.4. Inclusion of Pediatric Participants 
Individuals of all ages are susceptible to SARS-CoV-2 infection. While younger patients 
appear to be less affected than the adult population and typically present with milder 
symptoms, children are at risk for MIS-C. Certain subsets of the pediatric population may 
present with severe disease, requiring hospitalization and intensive care. Risk factors for 
severe disease include neonatal age group and pre-existing medical conditions including 
children who are immunocompromised. There is an urgent need for safe and effective 
therapeutic interventions for individuals of all age groups that can reduce viral transmission, 
improve time to clinical recovery and prevent the progression of infection to more severe 
disease, hospitalization, and death in the current COVID-19 epidemic, as well as for potential 
future coronavirus epidemics. 


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This study includes participants of 12 years of age and older and weighing ≥40 kg, which is 
consistent with the Fact Sheet for nirmatrelvir/ritonavir where FDA has granted EUA for the 
treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age 
and older and weighing ≥40 kg).11 
4.3. Justification for Dose 
On 22 December 2021, the US FDA granted EUA to nirmatrelvir/ritonavir for the treatment 
of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age or older 
weighing at least 40 kg) who are at risk for progression to severe disease, including patients 
who are immunocompromised. The recommended dose is 300 mg nirmatrelvir co- 
administered with 100 mg ritonavir q12h for 5 days. This dose was well tolerated in EPIC- 
HR and reduced the rate of hospitalization or death by 89% compared with placebo in 
symptomatic adult participants with COVID-19 who were at increased risk of progression to 
severe disease. 
Based on pharmacokinetic modelling and simulation, the authorized dosing regimen is 
expected to result in comparable plasma exposures of nirmatrelvir and ritonavir in 
participants 12 years of age and older and weighing ≥40 kg as observed in adults. 
In this study, in addition to the authorized 5-day treatment regimen of nirmatrelvir/ritonavir 
(300/100 mg q12h), 10-day and 15-day treatment durations will be studied. Patients who are 
immunocompromised may have higher viral RNA levels and prolonged viral shedding, 
which has been associated with more severe COVID-19 and the development of resistant 
viral variants. Consequently, these patients may benefit from longer anti-viral treatment 
durations to prevent an increase in viral RNA levels once treatment is completed. A 
quantitative systems pharmacology model of SARS-CoV-2 infection has been developed to 
describe SARS-CoV-2 viral RNA dynamics and was used to simulate the effects of different 
nirmatrelvir/ritonavir treatment durations in immunocompromised patients.27 In order to 
assess the ability of longer treatment durations to mitigate the risk of viral rebound, this 
model was used to predict that a nirmatrelvir/ritonavir dosing duration of 10 days will result 
in a viral RNA reduction similar to the viral RNA reduction that is observed in the 
nonimmunocompromised patients treated for 5 days. An additional reduction in viral RNA is 
predicted with a 15-day treatment regimen. 
Results from a first-in-human study in healthy participants showed a clinically acceptable 
safety profile up to the highest dose and exposure evaluated (500 mg of nirmatrelvir plus 
100 mg of ritonavir twice daily for 10 days).28 The safety and effectiveness of 
nirmatrelvir/ritonavir have not been established in pediatrics. 
Results from the renal impairment study showed that the adjusted geometric mean (90% CI) 
test/reference ratios comparing moderate renal impairment (test) to normal renal function 
(reference) for nirmatrelvir AUCinf and Cmax was 187.40% (148.52%, 236.46) and 138.12% 
(113.18%, 168.55%), respectively.29 Due to the increase in exposures of nirmatrelvir in those 
with moderate renal impairment, and verified by modeling and simulation, the 
nirmatrelvir/ritonavir dose in patients with moderate renal impairment was reduced to 
150 mg/100 mg. 


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4.4. End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit, or as shown in the SoA. 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age and Sex: 
1. Participants aged 12 years or older and weighing ≥40 kg at screening (Appendix 9, 
Section 10.9.1). 
• Refer to Appendix 4 for reproductive criteria for female (Section 10.4.2) 
participants. 
Disease Characteristics: 
2. Confirmed SARS-CoV-2 infection as determined by RT-PCR or other acceptable test 
method in any specimen collected as specified in Appendix 9, Section 10.9.2 for the 
main study population or Appendix 9, Section 10.9.5 for the additional population 
with rebound. 
3. ≥1 sign/symptom attributable to COVID-19 present on the day of randomization 
(Appendix 9, Section 10.9.3). 
4. Immunocompromised (Appendix 9, Section 10.9.4). 


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In addition, the following inclusion criteria only apply to the additional population with 
rebound: 
5. Presenting with documented, symptomatic COVID-19 rebound within 14 days 
following completion of an initial 5-day treatment course with nirmatrelvir/ritonavir 
as specified in Appendix 9, Section 10.9.5. 
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions: 
1. Current need for hospitalization or anticipated need for hospitalization within 24h 
after randomization in the clinical opinion of the site investigator. 
2. Known medical history of active liver disease (other than nonalcoholic hepatic 
steatosis), including chronic or active hepatitis B or C infection, primary biliary 
cirrhosis, Child-Pugh Class C, or acute liver failure. 
3. History of hypersensitivity or other contraindication to any of the components of the 
study interventions, as determined by the investigator. 
4. Suspected or confirmed concurrent active systemic infection other than COVID-19 
that may interfere with the evaluation of response to the study intervention. 
5. Any comorbidity requiring hospitalization and/or surgery within 7 days prior to study 
entry, or that is considered life threatening within 30 days prior to study entry, as 
determined by the investigator. 
6. Receiving dialysis or have known age-specific eGFR <30 mL/min/1.73 m2 or 
eCrCl <30 mL/min at screening as measured by a serum creatinine point of care 
device (Appendix 7, Section 10.7). 
7. Oxygen saturation of <92% on room air obtained at rest within 24h prior to 
randomization. (See Appendix 9, Section 10.9.6). 
8. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study. 
Prior/Concomitant Therapy: 
9. Current use of any prohibited concomitant medication(s) (see Section 6.9, 
Section 10.9.7, and Appendix 8). 


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Prior/Concurrent Clinical Study Experience: 
10. Current or previous administration with an investigational product (drug or vaccine) 
within 30 days (or as determined by the local requirement) or 5 half-lives preceding 
the first dose of study intervention used in this study (whichever is longer). 
Authorized or products with conditional approval are not considered investigational. 
11. Prior participation in this trial. 
Other Exclusion Criteria: 
12. Females who are pregnant up to <14 weeks gestation. Pregnancy ≥14 weeks is not 
exclusionary. 
13. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members. 
5.3. Lifestyle Considerations 
5.3.1. Contraception 
All female participants who are not pregnant at study entry, and who in the opinion of the 
investigator, are biologically capable of having children must agree to use a highly effective 
method of contraception consistently and correctly for at least 28 days after the last study 
intervention. 
Note: If the childbearing potential changes after start of the study (eg, a premenarchal female 
participant experiences menarche) or the risk of pregnancy changes (eg, a female participant 
who was not heterosexually active becomes active), the participant must discuss this with the 
investigator, who should determine if a female participant must begin a highly effective 
method of contraception. If reproductive status is questionable, additional evaluation should 
be considered. 
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4, 
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. At time points indicated in the SoA, the investigator or designee will inform the 
participant of the need to use highly effective contraception consistently and correctly and 
document the conversation and the participant’s affirmation in the participant’s chart. 
Participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception, considering that their risk for pregnancy may have changed since 
the last visit. 
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 


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alternate protocol-specified method, including if the participant will no longer use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner. 
5.3.2. Other Restrictions 
Participants may not participate in another interventional clinical study with an 
investigational compound, including those for COVID-19 therapeutics, through the long- 
term follow-up period. Participants who are in long-term follow-up in oncology or malignant 
hematology trials but who have not received investigational product within the timeline 
specified (see Section 5.2, Exclusion Criterion #10 for timeline) are eligible for enrollment 
provided they meet the other eligibility criteria defined in Section 5. 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study interventions are all prespecified investigational and noninvestigational medicinal 
products/auxiliary medicinal products, medical devices, and other interventions (eg, surgical 
and behavioral) intended to be administered to the study participants during the study 
conduct. 
 
For the purposes of this protocol, study intervention refers to nirmatrelvir 150 mg tablets and 
matching placebo and ritonavir 100 mg capsules and matching placebo. 
6.1. Study Intervention(s) Administered 
Study intervention will be self-administered by the participant OR administered to the 
participant by a legal guardian or caregiver. 
A legal guardian or caregiver may administer study medication. Study personnel should 
review dose administration requirements with the participant, as appropriate, and with the 
delegated caregiver(s) (may include school nurse) before administration and throughout the 
study as necessary. 


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Study Intervention(s) 
Intervention 
Name 
Nirmatrelvir 
Placebo for 
nirmatrelvir 
Ritonavir 
Placebo for ritonavir 
Arm Name 
(group of 
participants 
receiving a 
specific 
treatment or 
no 
treatment) 
nirmatrelvir/ritonavir 
placebo 
nirmatrelvir/ritonavir 
placebo 
Type 
drug 
placebo 
drug 
placebo 
Dose 
Formulation 
tablet 
tablet 
capsule 
capsule 
Unit Dose 
Strength(s) 
150 mg 
0 mg 
100 mg 
0 mg 
Dosage 
Level(s) 
300 mg q12h for 
5 days, 10 days, or 
15 days 
150 mg q12h for 
5 days, 10 days, or 
15 days (for 
participants with 
eGFR ≥30 to <60 
mL/min/1.73 m2 or 
eCrCl ≥30 to 
<60 mL/min at 
screening) 
0 mg q12h for 
5 days or 10 days 
100 mg q12h for 
5 days, 10 days, or 
15 days 
0 mg q12h for 5 days 
or 10 days 
Route of 
Administrati 
on 
Oral 
Oral 
Oral 
Oral 
Use 
Experimental 
Placebo 
Experimental 
Placebo 
IMP or 
NIMP/AxM 
P 
IMP 
IMP 
IMP 
IMP 
Sourcing 
Provided centrally by 
the sponsor. 
Refer to the IPM. 
Provided 
centrally by the 
sponsor. 
Refer to the IPM. 
Provided centrally by 
the sponsor. 
Refer to the IPM. 
Provided centrally by 
the sponsor. 
Refer to the IPM. 
Packaging 
and Labeling 
Study intervention 
will be provided in 
blister wallets. Each 
Study 
intervention will 
be provided in 
Study intervention 
will be provided in 
HDPE bottles. Each 
Study intervention 
will be provided in 
HDPE bottles. Each 


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Study Intervention(s) 
wallet will be labeled 
as required per 
country requirement. 
Products will be 
provided with 
blinded labels. 
blister wallets. 
Each wallet will 
be labeled as 
required per 
country 
requirement. 
Products will be 
provided with 
blinded labels. 
bottle will be labeled 
as required per 
country requirement. 
Products will be 
provided with 
blinded labels. 
bottle will be labeled 
as required per 
country requirement. 
Products will be 
provided with blinded 
labels. 
Current/For 
mer Name(s) 
or Alias(es) 
PF-07321332 
NA 
ritonavir 
NA 
 
 
Study Arm(s) 
Arm Title 
Nirmatrelvir/ritonavir 5-day 
Nirmatrelvir/ritonavir 10-day 
Nirmatrelvir/ritonavir 
15-day 
Arm Type 
Experimental, placebo 
Experimental, placebo 
Experimental 
Arm 
Participants will receive 
Participants will receive 
Participants will 
Description 
nirmatrelvir/ritonavir 
nirmatrelvir/ritonavir 
receive 
300 mg/100 mg (or 150 
300 mg/100 mg (or 150 mg/100 
nirmatrelvir/ritonavir 
mg/100 mg for participants 
mg for participants with eGFR 
300 mg/100 mg (or 
with eGFR ≥30 to <60 
≥30 to <60 mL/min/1.73 m2 or 
150 mg/100 mg for 
mL/min/1.73 m2 or eCrCl ≥30 
eCrCl ≥30 to <60 mL/min) 
participants with 
to <60 mL/min) q12h from 
q12h from Day 1 through Day 
eGFR ≥30 to <60 
Day 1 through Day 5 followed 
10 followed by placebo for 
mL/min/1.73 m2 or 
by placebo for 
nirmatrelvir/placebo for 
eCrCl ≥30 to 
nirmatrelvir/placebo for 
ritonavir q12h for Day 11 
<60 mL/min) q12h 
ritonavir q12h for Day 6 
through Day 15. 
from Day 1 through 
through Day 15. 
Day 15. 
Associated 
Intervention 
Labels 
Nirmatrelvir/ritonavir (5-day) 
Nirmatrelvir/ritonavir (10-day) 
Nirmatrelvir/ritonavir 
(15-day) 


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Nirmatrelvir/ritonavir may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for the 
nirmatrelvir/ritonavir. Pfizer does not permit the shipment of nirmatrelvir/ritonavir by mail. 
The tracking record of shipments, including temperature monitoring data, and the chain of 
custody of nirmatrelvir/ritonavir must be kept in the participant’s source documents/medical 
records. 
6.1.1. Administration 
The first dose of study intervention will be administered at the site. 
Nirmatrelvir 150 mg tablets or placebo for nirmatrelvir will be administered with ritonavir 
100 mg or placebo for ritonavir capsules for 15 days. Participants will be dispensed 1 blister 
wallet card of nirmatrelvir 150 mg tablets and 1 bottle of ritonavir capsules at the Day 1 site 
visit. Participants will be dispensed 1 blister wallet card of nirmatrelvir 150 mg or placebo 
for nirmatrelvir tablets and 1 bottle of ritonavir capsules or placebo for ritonavir at the 
subsequent Day 5 and Day 10 visits. Participants will be instructed to take: 
• 2 tablets of nirmatrelvir 150 mg or placebo for nirmatrelvir q12h; 
• 1 capsule of ritonavir 100 mg or placebo for ritonavir q12h. 
o Participants with moderate renal impairment (eGFR ≥30 to <60 mL/min/1.73 
m2 or eCrCl ≥30 to <60 mL/min at screening) will receive either 1 tablet of 
nirmatrelvir 150 mg and placebo for nirmatrelvir or 2 tablets of placebo for 
nirmatrelvir (Section 6.6). The dose for ritonavir remains unchanged (ie, 
participants will receive 1 capsule of ritonavir 100 mg or placebo for ritonavir 
q12h). 
Participants should take the first dose of study intervention on Day 1, during the in-person 
visit; that is, participants should take 2 tablets of nirmatrelvir 150 mg and 1 capsule of 
ritonavir 100 mg at the same time and no more than 15 minutes apart. The study intervention 
should be taken every 12 hours (±4 hours), but no more than twice in a calendar day. Timing 
of the second dose of nirmatrelvir/ritonavir may be adjusted slightly to allow participants to 
select a convenient 12-hour dosing schedule as long as the second dose is taken at least 
4 hours but no later than 16 hours after the first dose. Once the dosing schedule is adjusted, 
subsequent doses should be taken every 12 hours (±4 hours). 
If a dose is delayed, it should be taken as soon as possible, but no later than 4 hours before 
the next scheduled dose, and then resume the normal dosing schedule. If the participant 
misses a dose by more than 8 hours, the participant should not take the missed dose and 
instead take the next dose at the regularly scheduled time. The participant should not double 
the dose to make up for a missed dose. Dosing should be stopped at the end of the treatment 
period (30 doses total). Any remaining tablets and/or capsules at the Day 5, Day 10, and 
Day 15 visits should be returned. 


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Participants will swallow the study intervention whole and will not manipulate or chew the 
study intervention prior to swallowing. Participants may take the study intervention with or 
without food. Taking study intervention with food may improve tolerability. Refer to the 
IPM for additional dosing and administration instructions. 
6.2. Preparation, Handling, Storage, and Accountability 
The excipients used in the nirmatrelvir tablets/ritonavir capsules are safe for administration to 
pediatric participants. 
Study intervention will be self-administered by the pediatric participant or administered to 
the pediatric participant by the parent/caregiver. 
1. The investigator or designee must confirm that appropriate conditions (eg, 
temperature) have been maintained during transit for all study interventions received 
and any discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff. At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented upon 
return to business. 
4. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with actions taken. The site should actively 
pursue options for returning the study intervention to labeled storage conditions, as 
soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not used until Pfizer provides permission to use the study 
intervention. Specific details regarding the excursion definition and information to 
report for each excursion will be provided to the site in the IPM. 
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. Site staff will instruct participants on the proper storage 
requirements for take-home study intervention. 
6. Study interventions should be stored in their original containers. 
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, 
reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records), such as the IPAL or sponsor-approved equivalent. All study 
interventions will be accounted for using a study intervention accountability 


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form/record. All nirmatrelvir/ritonavir that is taken home by the participant, both used 
and unused, must be returned to the investigator by the participant. Returned study 
intervention must not be redispensed to the participants. 
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IPM. All destruction must be adequately 
documented. If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer. 
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM. 
6.2.1. Preparation and Dispensing 
A qualified staff member will dispense the nirmatrelvir/ritonavir using unique container 
numbers via an IRT system in the bottles and blister cards provided, in quantities appropriate 
according to the SoA. A second staff member will verify the dispensing. The 
participant/caregiver should be instructed to maintain the product in the bottle and blister 
cards, as provided throughout the course of dosing and return the bottle and blister cards, as 
appropriate to the site at the next study visit. 
The study intervention will be administered in a blinded fashion to the participants. 
6.3. Assignment to Study Intervention 
Allocation of participants to treatment groups will proceed through the use of an IRT system. 
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s ID and password, the protocol number, 
and the participant number. The site personnel will then be provided with a randomization 
number corresponding to the assigned treatment group, and DU or container number(s) when 
study intervention is being supplied via the IRT system. The IRT system will provide a 
confirmation report containing the participant number, randomization number, and DU or 
container number assigned. The confirmation report must be stored in the site’s files. 
For the main study population, randomization will be stratified by participants who are 
considered immunocompromised solely based on corticosteroids or TNF blocker use 
(yes/no). Enrollment of participants who are considered immunocompromised solely based 
on corticosteroids or TNF blocker use will be capped at approximately 25% for the main 
study population. 
Randomization for the population with rebound will not be stratified by those who are 
considered immunocompromised solely based on corticosteroids or TNF blocker use. 
Enrollment of participants considered immunocompromised based solely on receiving 
corticosteroids or TNF blockers in the additional population with rebound will not be capped. 
Study intervention will be dispensed at the study visits summarized in the SoA. 


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The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system. 
Returned study intervention must not be redispensed to the study participants. 
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system. 
6.4. Blinding 
This is a double-blind study. 
6.4.1. Blinding of Participants 
Participants and their caregivers will be blinded to their assigned study intervention. 
6.4.2. Blinding of Site Personnel 
Investigators and other site staff will be blinded to participants’ assigned study intervention. 
 
Participants will be assigned to receive study intervention according to the assigned treatment 
group from the randomization scheme. Investigators will remain blinded to each participant’s 
assigned study intervention throughout the course of the study. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately. 
6.4.3. Blinding of the Sponsor 
Sponsor staff will be blinded to participants’ assigned study intervention. 
Sponsor staff who are not directly involved with the conduct of this study will prepare 
analyses and documentation containing unblinded data while the study is ongoing to support 
interactions with the E-DMC. 
The study will be unblinded after all participants complete the Day 44 visit (or ET prior to 
Day 44 visit) and analyses through Day 44, including the primary efficacy endpoint analyses, 
will be conducted. 
Details of the unblinded sponsor staff supporting the E-DMC and the timing of unblinding 
will be outlined in the Unblinding Plan. 
6.4.4. Breaking the Blind 
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the study medical monitor prior to 
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of the participant. If a participant’s treatment assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and CRF. 
The study specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system. 
6.5. Study Intervention Compliance 
Participants will use a participant-completed electronic dosing diary to record the date and 
time of their study intervention dosing, and will be educated at the time of first dose. 
Site personnel will review the participant-completed electronic dosing diary daily during the 
study intervention period, preferably after the participant has self-administered the morning 
dose of nirmatrelvir/ritonavir. If any noncompliance with dosing is suspected, site personnel 
will promptly contact the participant by phone, to remind them of the relevant study 
procedures and/or entering the information in the electronic diary as applicable. 
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose of study 
intervention administered in the clinic will be recorded by the participant in the ediary. The 
dose of study intervention and study participant identification will be confirmed at the time 
of dosing by a member of the study site staff other than the person administering the study 
intervention. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by delegated study 
personnel upon return of study intervention through counting returned tablets/capsules and 
direct questioning, if applicable during the site visits and documented in the source 
documents. 
A record of the number of nirmatrelvir tablets/ritonavir capsules dispensed to and taken by 
each participant must be maintained and reconciled with study intervention and compliance 
records. 
The following noncompliance cases will be considered medication errors (see 
Section 8.4.10). 
• Participants interrupting study intervention for 2 consecutive doses; 
• Participants taking either nirmatrelvir or ritonavir alone for 2 consecutive doses; 
• Participants who have an overall study intervention compliance <80% or >115%. 
In addition to the above listed-medication errors, any deviation from protocol-specified 
dosing (eg, missed single dose or partial dose) should be recorded as a protocol deviation and 


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the investigator or designee is to counsel the participant/guardian and ensure steps are taken 
to improve compliance. 
6.6. Dose Modification 
The dose may need to be modified on Day 5 or Day 10, based on the eGFR or eCrCl result 
from the point-of-care device: 
• Participants with a Day 5 or Day 10 eGFR <60 mL/min/1.73 m2 or eCrCl 
<60 mL/min will receive a wallet consisting of 1 tablet of nirmatrelvir 150 mg and 
placebo for nirmatrelvir or 2 tablets of placebo for nirmatrelvir. The dose of ritonavir 
remains unchanged. 
• Participants with a Day 5 or Day 10 eGFR >60 mL/min/1.73 m2 or eCrCl 
>60 mL/min, will receive a wallet consisting of 2 tablets of nirmatrelvir 150 mg or 
2 tablets of placebo for nirmatrelvir. The dose of ritonavir remains unchanged. 
6.7. Continued Access to Study Intervention After the End of the Study 
No study intervention will be provided to participants at the end of their study participation. 
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician. 
6.8. Treatment of Overdose 
Study sites should warn parents/caregivers to store the study intervention out of reach of 
children and to provide close supervision when intervention will be self-administered by the 
child. 
For this study, any dose of nirmatrelvir/placebo greater than 900 mg (or any dose greater than 
450 mg for participants on the reduced nirmatrelvir/placebo regimen) or ritonavir/placebo 
greater than 300 mg within a 24-hour time period will be considered an overdose. 
There is no specific treatment for an overdose. 
In the event of an overdose, the investigator should: 
1. Contact the study medical monitor within 24 hours. 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF. 
4. Overdose is reportable to Pfizer Safety only when associated with an SAE. 


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5. Obtain a blood sample for PK analysis within 1 days from the date of the last dose of 
study intervention if requested by the study medical monitor (determined on a 
case-by-case basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant. 
6.9. Prior and Concomitant Therapy 
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4). 
Prior Therapy 
Use of an antiviral or monoclonal antibody therapy for the treatment of COVID-19 within 
30 days prior to screening is prohibited, except for participants in the additional population 
with rebound, who must have completed a recent (ie, within 14 days) initial 5-day course of 
nirmatrelvir/ritonavir (see Section 10.9.5). 
Permitted During the Study 
Participants may receive concomitant medications, including SoC therapy for COVID-19, in 
addition to study intervention, unless listed as prohibited medication (see Appendix 8) or as 
defined in Section 5.2. However, use of antiviral therapy, including monoclonal antibody 
therapy, is prohibited through the entire treatment period, except for participants who 
progress to severe or critical COVID-19.30 
 
SoC therapy is defined as any therapy that is approved and used as indicated by the local 
regulatory authorities (including approvals for emergency use, compassionate use, or through 
similar regulatory guidance), or any therapy as recommended by a relevant national (or a 
reputable international) scientific body (eg, WHO, ECDC, CDC, NIH). 
 
Sites should consult with the sponsor if a new SoC option becomes available after study 
initiation. Investigator should ensure that any recommended SoC therapy is not a strong 
inducer of CYP3A4 or highly dependent on CYP3A4 for clearance. 
Ritonavir is an inhibitor of CYP3A4 and may increase plasma concentrations of drugs that 
are primarily metabolized by CYP3A4. Participants will receive ritonavir for at least 5 days 
and up to 15 days but as treatment is blinded, some concomitant medications (Appendix 8, 
Table 5) may require monitoring of drug levels, consideration of temporary withdrawal of the 
concomitant medication, or dose adjustment throughout the study treatment period and 
following completion of the blinded treatment duration period. 


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Prohibited During the Study 
Use of a non-study antiviral or monoclonal antibody therapy for the treatment of COVID-19 
within 15 days after randomization is prohibited, except for participants who progress to 
severe or critical COVID-19.30 
Nirmatrelvir and ritonavir are both primarily metabolized by cytochrome P450 (CYP) 3A4. 
In addition, ritonavir is a strong inhibitor of CYP3A4. Therefore, concomitant use of 
medications that are strong inducers of CYP3A4 and which are contraindicated in 
combination with nirmatrelvir/ritonavir (see Appendix 8) are prohibited during study 
treatment. 
Additionally, coadministration of nirmatrelvir/ritonavir with other medications that are not 
contraindicated but are highly dependent on CYP3A4 for clearance may require dose 
adjustment or additional monitoring. Investigators should reference Appendix 8 for a 
nonexhaustive list of these medications and consult the Pfizer medical monitor for guidance 
on coadministration with nirmatrelvir/ritonavir. 
Medications or substances that are strong inducers of CYP3A4 and that are contraindicated 
in combination with nirmatrelvir/ritonavir must be discontinued for an appropriate washout 
period prior to the first dose of nirmatrelvir/ritonavir and are prohibited for the duration of 
the study treatment period and for 4 days after the last dose of nirmatrelvir/ritonavir 
(Appendix 8). The appropriate washout period for CYP3A4 inducers should be determined 
based on the prescribing information for the concomitant medication and in consultation with 
the medical monitor. 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following: 
• AE of Grade 3 severity or greater and considered by the investigator to be related to 
study intervention; 
• SAE considered by the investigator to be related to study intervention; 
• Requirement for prohibited concomitant medication; 
• Participants who become pregnant during the course of the study; 
• Study terminated by sponsor; 
• Withdrawal by participant or legally authorized representative 


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• If post-screening eGFR <30 mL/min/1.73 m2 or eCrCl is <30 mL/min the participant 
will be instructed to discontinue any remaining study intervention doses as soon as 
study staff become aware of the eGFR results. 
In the event that a participant is hospitalized, study intervention may continue to be 
administered, as feasible, and based on medical judgment of the investigator. 
Note that discontinuation of study intervention does not represent withdrawal from the study. 
If study intervention is permanently discontinued, the participant should remain in the study 
to be evaluated for all subsequent scheduled assessments. See the SoA for data to be 
collected at the time of discontinuation of study intervention and follow-up for any further 
evaluations that need to be completed. 
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, posttreatment study follow-up, 
and/or future collection of additional information. 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from the study include the following: 
• Refused further study procedures; 
• Lost to follow-up; 
• Study terminated by sponsor; 
• Withdrawal of consent/assent by parent/legal guardian or by a child who has provided 
assent during any phase of the study. 
At the time of discontinuing from the study (if before Day 44), if possible, an early 
discontinuation visit should be conducted. See the SoA for assessments to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
If a participant withdraws from the study at any time, they may request destruction of any 
remaining samples taken and not tested, and the investigator must document any such 
requests in the site study records and notify the sponsor accordingly. 
If the participant withdraws from the study at any time and also withdraws consent (see 
Section 7.2.1) for disclosure of future information, no further evaluations will be performed 


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and no additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent/assent for any further 
contact with them or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to be available for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible. Counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether the participant wishes to and/or should 
continue in the study; 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record; 
• Should the participant continue to be unreachable, the participant will be considered 
to have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES 
8.1. Administrative and Baseline Procedures 
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 


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Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner. 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
The total blood sampling volume for individual adult participants in this study is 
approximately 260 mL. The total blood sampling volume for individual pediatric participants 
is approximately 195 mL. The actual collection times of blood sampling may change. 
Additional blood samples may be taken for safety assessments at times specified by Pfizer, 
provided the total volume taken during the study does not exceed 550 mL during any period 
of 56 consecutive days. For pediatric participants, every effort will be made to ensure that 
blood volume collections do not exceed 1% of the total blood volume at any single time and 
3% of the total blood volume during any period of 4 weeks. 
8.1.1. Baseline Procedures 
8.1.1.1. Medical History 
Medical history in addition to COVID-19 disease history and demographics will be collected 
at screening. Smoking status will be collected. Complete medication history of all 
prescription or nonprescription drugs (including vaccinations), and dietary and herbal 
supplements taken within 30 days prior to the planned first dose will be collected. 
COVID-19-related vaccinations and monoclonal antibody treatment for the treatment of 
COVID-19 at any time prior to the planned first dose will also be collected. 
Risk factors for the participant developing severe COVID-19 illness will be recorded. 
8.1.1.2. Study Kit 
The study kit includes the pulse oximeter that is to be used based on the instruction and 
medical judgement of the site investigator as well as dosing instructions. 


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8.1.1.3. Secondary Contacts 
On Day 1 and at times specified in the SoA, the investigator will collect contact information 
for at least 2 individuals who can be contacted if the participant cannot be reached after 
multiple attempts (repeat/update as needed). Secondary contacts may be used to determine if 
a participant is lost to follow-up or for a vital status check. 
8.1.2. Home Health Visits 
A home health visit may be utilized to facilitate scheduled visits. Home health visits include 
a healthcare provider conducting an in-person study visit at the participant’s location, rather 
than an in-person study visit at the site. The following may be performed during a home 
health visit (see the SoA): 
• Review and record study intervention(s), including compliance and missed doses. 
• Review and record any AEs and SAEs since the last contact. Refer to Section 8.4. 
• Review and record any new concomitant medications or changes in concomitant 
medications since the last contact. 
• Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Appendix 4. 
• Collect clinical laboratory, PK, and biomarker samples. 
• Collect NP swab samples. 
• Collect vital signs. 
• Confirm the participant has completed the PRO assessments. 
• If the HCP is unable to collect AEs, concomitant medications or contraception use, 
the site should contact the participant via a follow-up telephone call to collect the 
additional information. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 
8.1.3. Mobile Visits 
In the event that an in-person visit is not feasible at the site, the following may be performed 
by a licensed healthcare professional at an alternate site approved by the investigator (see the 
SoA): 
• Review and record study intervention(s), including compliance and missed doses. 


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• Review and record any AEs and SAEs since the last contact. Refer to Section 8.4. 
• Review and record any new concomitant medications or changes in concomitant 
medications since the last contact. 
• Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Appendix 4. 
• Collect clinical laboratory, PK, and biomarker samples. 
• Collect NP swab samples. 
• Collect vital signs. 
• Confirm the participant has completed the PRO assessments. 
• If the HCP is unable to collect AEs, concomitant medications or contraception use, 
the site should contact the participant via a follow-up telephone call to collect the 
additional information. 
8.1.4. Telehealth Visits 
Telehealth visits are not intended to replace in-person visits; however, may be used to assess 
participant safety and collect data points if an in-person visit is unable to be performed. 
Telehealth includes the exchange of healthcare information and services via 
telecommunication technologies (eg, audio, video, videoconferencing software) remotely, 
allowing the participant and the investigator to communicate on aspects of clinical care, 
including medical advice, reminders, education, and safety monitoring. The following 
assessments must be performed during a telehealth visit (see the SoA): 
• Review and record any AEs and SAEs since the last contact. Refer to Section 8.4. 
• Review and record any new concomitant medications or changes in concomitant 
medications since the last contact. 
• Review and record contraceptive method and results of pregnancy testing. Confirm 
that the participant is adhering to the contraception method(s) required in the 
protocol. Refer to Appendix 4. 
• Collect vital signs (pulse and O2 saturation using pulse oximeter device at home; 
temperature if available). 
Study participants must be reminded to promptly notify site staff about any change in their 
health status. 


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8.2. Efficacy Assessments 
8.2.1. Participant Diary 
Participants will be provided an electronic handheld device or will use their own device to 
record study intervention administration (as well as reason for changed or missed dose), signs 
and symptoms of COVID-19, and PRO assessments in the study diary. 
Participants will receive daily reminders to complete entries on their own as specified in the 
SoA. The diary should be completed at approximately the same time every day. Staff will 
review the participant’s study diary online as specified in the SoA. 
The diary allows recording of these assessments only within a fixed time window (next 
calendar day), thus providing an accurate representation of the participant’s experience at 
that time. The participant is able to make revisions to incorrect entries before pressing the 
save or submit button. In the event that a participant becomes aware of an error in data after 
the entry is saved, a change to the diary data may only be made by the investigator 
submitting a data clarification form. Data reported in the participant diary will be transferred 
electronically to a third-party vendor, where they will be available for review by investigators 
and the sponsor or delegate at all times via an internet-based portal. 
8.2.2. COVID-19-Related Hospitalizations and Medical Details 
Details of participants’ COVID-19-related medical visits (ie, hospitalization of any duration, 
urgent care, emergency room ≤24h) will be collected during study visits, including level of 
care (ICU status) and dates of utilization, including admission and discharge, as applicable. 
Hospitalization >24 hours is defined as >24h of acute care in a hospital or similar acute care 
facility, including Emergency Rooms or temporary facilities instituted to address medical 
needs of those with severe COVID-19. This includes specialized acute medical care unit 
within an assisted living facility or nursing home. This does not include hospitalization for 
the purposes of public health and/or clinical trial execution. 
8.2.3. Oxygen Support Details 
Type of oxygen support (eg, oxygen supplementation received, mechanical ventilation or 
ECMO received in hospital) will be collected. 
8.2.4. PRO Assessments 
Only adult study participants ≥18 years of age at the time of screening will be asked to 
complete PRO assessments. PRO assessments will be recorded in the study ediary. 
8.2.4.1. Global Impression Questions 
Three questions will be included in the ePRO to assess patient-reported global impression 
items: a) return to usual health; b) return to usual activities; and c) overall COVID-19-related 
symptoms.31 


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8.2.4.2. SF-36 v2® Health Survey (Acute Form) 
SF-36 v2® Health Survey (the acute form) is a 36-item questionnaire that measures 
functional health and well-being from a patient’s perspective over 1-week recall period. It is 
a generic questionnaire and can be used across age (adults), disease, and treatment groups. 
The questionnaire consists of 8 health domain scales: physical functioning (10 items), 
role-physical (4 items), bodily pain (2 items), general health (5 items), vitality (4 items), 
social functioning (2 items), role-emotional (3 items), mental health (5 items), reported 
health transition (1 item) and 2, physical and mental component summary scores. Each health 
domain scale raw score is transformed to 0-100 scale which can then be converted to 
norm-based T-scores (Mean=50, SD=10). SF-36 v2® Health Survey will be completed as 
specified in the SoA. 
8.2.4.3. WPAI 
COVID-19 impacts manual and office-based work, and results in missed work due to illness 
or quarantine and loss of productivity.32 The WPAI-GH is being implemented for COVID-19 
(ie, WPAI-COVID-19) in order to evaluate change from baseline in work burdens. The 
WPAI-GH has demonstrated validity, reliability and sufficient predictive value to measure 
the impact of disease on absenteeism, presenteeism, and overall productivity in a manner that 
can also be monetized. 33 
The WPAI-COVID-19 consists of 6 questions that refer to the following assessments for 
work productivity: 1 = currently employed, 2 = hours missed due to health problems, 3 = 
hours missed other reasons, 4 = hours actually worked, 5 = degree health affected 
productivity while working (using a 0 to 10 VAS), and 6 = degree health affected 
productivity in regular unpaid activities. The recall period for questions 2 through 6 is 7 days. 
Four main outcomes will be generated from the WPAI-COVID-19 and reported as: 
1) percent work time missed due to COVID-19 for those who are currently employed, 
2) percent impairment while working due to COVID-19 for those who are currently 
employed and actually worked in the past 7 days, 3) percent overall work impairment due to 
COVID-19 for those who are currently employed, and 4) percent activity impairment due to 
COVID-19 for all respondents.33 The WPAI-COVID-19 will be completed during site visits, 
as specified in the SoA. 
8.2.4.4. EQ-5D-5L Scale 
The EQ-5D is a validated, standardized, generic instrument that is a preference-based health 
related quality of life questionnaire in cost effectiveness and HTA.34-36 Recently, a version 
was developed called EQ-5D-5L with 5 response levels on each dimension compared to the 
3 response levels in the EQ-5D-3L.34-40 
Measurement properties of the EQ-5D-5L demonstrated to be a valid version of the 3 level 
questionnaire that improved measurements by adding discriminatory power, reducing the 
ceiling, and establishing convergent and known groups validity.34,36,38,39 Both the EuroQol 
EQ-5D-3L and EQ-5D-5L versions are well established instruments used to measure health 
states and utilities in various diseases areas and assess mobility, self care, usual activities, 


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pain/discomfort, anxiety/depression and health status using a VAS37,41 The EQ-5D-5L should 
be completed as described in the SoA. 
8.2.5. COVID-19 Signs and Symptoms 
On Day 1, participants will complete the COVID-19 signs and symptoms (Appendix 10) in 
the study diary, before receiving study intervention. COVID-19-related symptoms will be 
evaluated in accordance with FDA guidelines. Participants will record a rating of their 
symptom severity over the past 24 hours based on a 4-point scale in which 0 is reported if no 
symptoms were present; 1 if mild; 2 if moderate; and 3 if severe. 
 
Vomiting and diarrhea will each be rated on a 4-point frequency scale where 0 is reported for 
no occurrence, 1 for 1 to 2 times, 2 for 3 to 4 times, and 3 for 5 or greater. 
 
Sense of smell and sense of taste will each be rated on a 3-point Likert scale where 0 is 
reported if the sense of smell/taste was the same as usual, 1 if the sense of smell/taste was 
less than usual, and 2 for no sense of smell/taste. 
8.3. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues. 
8.3.1. Targeted Physical Examinations 
Physical examinations to be completed before administration of study intervention. 
A targeted physical examination will include, at a minimum, cardiopulmonary assessments. 
Investigators should pay special attention to any previously identified or new AE/targeted 
condition that the participant has experienced. Height and weight will also be measured and 
recorded at screening, though height may be self-reported for participants ≥18 years of age. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3. 
8.3.2. Vital Signs 
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3. 


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Temperature, pulse rate, respiratory rate, oxygen saturation level, and blood pressure will be 
assessed as specified in the SoA. 
8.3.2.1. Blood Pressure and Pulse Rate 
BP and PR measurements will be assessed with the participant, preferably in the supine or 
seated position with their feet on the floor when possible with a completely automated 
device.42 It is recommended that the same position should be used for a participant 
throughout the study duration. Manual techniques will be used only if an automated device is 
not available. 
8.3.2.2. Temperature and Respiratory Rate 
Temperature, and respiratory rate, will be assessed. 
8.3.2.3. Oxygen Saturation Level 
Oxygen saturation level will be assessed as part of the vital signs assessment. 
8.3.2.4. At-Home Devices for Vital Signs 
Each participant will also be supplied with a pulse oximeter to be used based on the 
instruction and medical judgment of the site investigator. 
8.3.3. Point-of-Care Serum Creatinine Assessments 
A serum creatinine point-of-care device will be used to assess kidney function as described in 
the SoA and Appendix 2. 
8.3.4. Clinical Safety Laboratory Assessments 
Laboratory safety parameters will be graded according to the DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events43, version 2.1. See Appendix 2 for the list of 
clinical safety laboratory tests to be performed and the SoA for the timing and frequency. All 
protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the SoA. Unscheduled clinical laboratory 
measurements may be obtained at any time during the study to assess any perceived safety 
issues. 
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 
All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or study medical monitor. 


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If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
DILI. 
See Appendix 7 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities. 
8.3.4.1. Alternative Facilities for Clinical Safety Laboratory Assessment 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/ 
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the participant’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF. 
8.3.5. Pregnancy Testing 
A serum or urine pregnancy test is required at screening. Following screening, pregnancy 
tests may be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. 
Pregnancy tests will be performed in WOCBP at the times listed in the SoA. Pregnancy tests 
will also be done whenever 1 menstrual cycle is missed during the active treatment period (or 
when potential pregnancy is otherwise suspected) and at Day 44 or ET visit. Pregnancy tests 
may also be repeated if requested by IRBs/ECs or if required by local regulations. If a urine 
test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded if the serum pregnancy result is 
positive. 
For female pediatric participant who becomes pregnant, this information will be shared with 
the study participant’s parent/guardian if the participant’s age is within specific range based 
on local/country regulations. 
8.3.5.1. At-Home Pregnancy Testing 
A home urine pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be used by 
the participant to perform the test at home, if compliant with local regulatory requirements. 
The pregnancy test outcome should be documented in the participant’s source 
documents/medical records and relevant data recorded on the CRF. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol. 
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting 
The definitions of an AE and an SAE can be found in Appendix 3. 
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally 


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authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant/parent/legal 
guardian/legally authorized representative will be questioned about the occurrence of AEs in 
a nonleading manner. 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention, through and including a minimum of 28 calendar days, except as indicated 
below, after the last administration of the study intervention. 
Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator. 
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment. 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the PSSA. 
After the defined active collection period for safety events, long-term follow-up visits are 
also conducted at Weeks 12 and 24. Any new SAE occurring during this long-term follow-up 
period and determined to be related to study intervention must be reported to Pfizer Safety 
immediately upon awareness and under no circumstance should this exceed 24 hours. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 


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including a death, at any time after a participant has completed the study, and they consider 
the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to Pfizer using the PSSA. 
8.4.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety using PSSA immediately upon awareness and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of its being 
available. 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4. 
8.4.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. Follow-Up of AEs and SAEs 
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 


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and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is provided in Appendix 3. 
8.4.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure. 
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. 
8.4.5.1. Exposure During Pregnancy 
An EDP occurs if: 
• A female participant is found to be newly pregnant while receiving or after 
discontinuing study intervention. 
• A male participant who is receiving or has discontinued study intervention 
inseminates a female partner. 
• A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP: 


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• A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion. 
• A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then inseminates his female partner prior to or around 
the time of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
• If EDP occurs in a participant or participant’s partner, the investigator must report 
this information to Pfizer Safety using the EDP Supplemental form within PSSA, 
regardless of whether an SAE has occurred. Details of the pregnancy will be collected 
after the start of study intervention and until a minimum of 28 calendar days after the 
last administration of study intervention. 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using PSSA. Since the exposure information does not 
pertain to the participant enrolled in the study, the information is not recorded on a 
CRF; however, a copy of the completed case report from PSSA is maintained in the 
investigator site file. 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up using PSSA. In the case of a live birth, the structural integrity of the neonate can 
be assessed at the time of birth. In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless preprocedure test findings are 
conclusive for a congenital anomaly and the findings are reported). 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
• Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE; 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 


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SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
8.4.5.2. Exposure During Breastfeeding 
An EDB occurs if: 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
• A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by 
ingestion. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the PSSA. When EDB occurs in the setting of environmental exposure, the exposure 
information does not pertain to the participant enrolled in the study, so the information is not 
recorded on a CRF. However, a copy of the completed SAE Case Report from PSSA is 
maintained in the investigator site file. 
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB. 
8.4.5.3. Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the investigator’s awareness using the PSSA, regardless of whether there is an 
associated SAE. Since the information about the occupational exposure does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed SAE Case Report from PSSA must be maintained in the investigator site 
file. 
8.4.6. Cardiovascular and Death Events 
Not applicable. 


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8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
8.4.8. Adverse Events of Special Interest 
Not applicable. 
8.4.8.1. Lack of Efficacy 
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer 
Safety only if associated with an SAE. 
8.4.9. Medical Device Deficiencies 
Not applicable. 
8.4.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
Medication errors are recorded and reported as follows: 
 
Recorded on the 
Medication Error Page 
of the CRF 
Recorded on the 
Adverse Event Page 
of the CRF 
Reported Using the PSSA 
to Pfizer Safety Within 24 
Hours of Awareness 
All (regardless of whether 
associated with an AE) 
Any AE or SAE associated 
with the medication error 
Only if associated with an 
SAE 


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Medication errors include: 
• Medication errors involving participant exposure to the study intervention; 
• Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the study participant. 
• The administration of expired study intervention; 
• The administration of an incorrect study intervention; 
• The administration of an incorrect dosage; 
• The administration of study intervention that has undergone temperature 
excursion from the specified storage range, unless it is determined by the sponsor 
that the study intervention under question is acceptable for use. 
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF. 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
Medication errors should be reported to Pfizer Safety within 24 hours using PSSA only when 
associated with an SAE. 
8.5. Pharmacokinetics 
A blood sample of approximately 1 mL, to provide approximately 0.5 mL plasma, will be 
collected for measuring plasma concentrations of nirmatrelvir and ritonavir (if feasible) as 
specified in the SoA. 
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded. 
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
the baseline sample obtained <30 min later than the 1-2 hour post-dose timepoint will not be 
captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF. This protocol deviation does not apply to samples that are 
specified to be collected “at any time”. 


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PK samples may be collected at any time during the visit on Days 5, 10, and 15. PK samples 
collected within the allowed visit window schedule will not be captured as a protocol 
deviation. 
Samples collected for analyses of ninnatrelvir and ritonavir concentrntions may also be used 
to evaluate safety or efficacy aspects related to concerns arising during or after the study, for 
metabolite identification and/or evaluation of the bioanal ical method or for research 
related to the stud intervention s and COVID-19 
 
 
 
If a participant cannot attend in-clinic visits, PK samples may be collected via home health or 
mobile visit. The time of PK samples being taken will be recorded. 
Genetic analyses will not be perfo1med on these plasma samples unless consent for this was 
included in the infonned consent. Paiiicipant confidentiality will be maintained. 
Samples collected for measurement of plasma concentrations of study intervention will be 
analyzed using a validated analytical method in compliance with applicable SOPs. Potential 
metabolites may be analyzed with either validated or explorato1y methods. 
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage, or shipping 
conditions), including any actions taken, must be documented, and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a detennination as to whether sample 
integrity has been compromised. 
Dmg concenti·ation info1mation that would unblind the study will not be repo1ied to 
investigator sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then ai·chived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be infonned of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD. 
8.6. Genetics 
8.6.1. Specified Genetics 
Specified genetic analyses are not evaluated in this study. 
8.6.2. Retained Research Samples for Genetics 
Retained Reseai·ch Samples will be collected from adult paiiicipants only; these samples will 
not be collected from participants who ai·e under the age of 18 at the time of enrollment. 


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A 4-mL blood sample optimized for DNA isolation Prep D1 will be collected according to 
the SoA, as local regulations and IRBs/ECs allow. 
Retained Research Samples may be used for research related to the study intervention(s) and 
COVID-19. Genes and other analytes (eg, proteins, RNA, nondmg metabolites) may be 
studied using the retained samples. 
See Appendix 5 for info1mation regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laborato1y manual. 
8.7. Biomarkers 
Collection of samples for biomarker research is also part of this study. 
The following samples for biomarker research are required and will be collected in this study 
as specified in the SoA: 
 
I 
 
I  
 
I 
 
Residuals of all samples may be stored for future research. Storage and shipping instructions 
will be in accordance with the laborato1y manual. 
 
Residuals of all samples may be stored for future research. Storage and shipping instructions 
will be in accordance with the laborato1y manual. 


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Details on processes for collection and shipment of these samples can be found in the 
laborato1y manual and suppo1iing documents. 
8.7.6. Specified Metabolomic Research 
Specified metabolomic research is not included in this study. 
8.7.7. Retained Research Samples for Biomarkers 
These Retained Research Samples will be collected in this study: 
• 
 
I 
 
I 
 
Retained Research Samples will be collected as local regulations and IRB/ECs allow 
according to the SoA. Retained Research Samples will be collected from adult paiiicipants 
only; these samples will not be collected from paiiicipants who ai·e under the age of 18 at the 
time of enrollment. 
Retained Reseai·ch Samples may be used for reseai·ch related to the study intervention(s) and 
COVID-19. Genes and other analytes (eg, proteins, RNA, nondmg metabolites) may be 
studied using the retained samples. 
See Appendix 5 for infonnation regarding genetic reseai·ch. Details on processes for 
collection and shipment of these samples can be found in the laborato1y manual. 


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8.8. Immunogenicity Assessments 
Immunogenicity assessments are not included in this study. 
8.9. Health Economics 
Health economics/medical resource utilization and health economics parameters will be 
evaluated for this study (Section 8.2.2 and Section 8.2.4). 
9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment. 
The efficacy and safety data will be analyzed and summarized separately for the main study 
population and the additional population with rebound. Further details on the analyses 
planned for the additional population with rebound will be included in the SAP. 
There will be 2 analysis time points for reporting the results of this study. The primary 
analysis will be performed after all participants in the main study population have completed 
the Day 44 visit. The follow-up analysis will be performed after all participants in the main 
study population have completed the Week 24 visit. In addition, both analyses (primary and 
follow-up) will include separate results for the main study population and the additional 
population with rebound. 
9.1. Statistical Hypotheses 
No formal hypothesis testing will be performed for this study. 
9.1.1. Estimands 
9.1.1.1. Primary Estimand/Coprimary Estimands 
The primary estimand, reported separately for the main study population and the population 
with rebound, is the proportion of participants with sustained NP swab SARS-CoV-2 RNA 
<LLOQ (defined as <2.0 log10 copies/mL) from Day 15 through Day 44 in nonhospitalized, 
symptomatic patients ≥12 years of age with COVID-19 who are immunocompromised. This 
will be estimated without regard to study treatment discontinuation and considering 
participants receiving non-study antiviral or monoclonal antibody therapy post-baseline for 
the treatment of COVID-19 as not achieving sustained NP swab SARS-CoV-2 RNA 
<LLOQ. 
9.1.1.2. Secondary Estimands 
Not Applicable. 


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9.1.2. Multiplicity Adjustment 
There will be no adjustment for multiplicity. 
9.2. Analysis Sets 
For purposes of analysis, the following analysis sets are defined and will be applied for the 
main study population and the population with rebound: 
 
Participant Analysis Set 
Description 
Full analysis set 
All participants randomly assigned to study 
intervention. 
Evaluable analysis set/Safety 
Analysis Set 
All participants randomly assigned to study 
intervention and who take at least 1 dose of study 
intervention. 
 
The evaluable analysis set will be the primary analysis set for evaluating the primary 
estimand. 
9.3. Statistical Analyses 
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. 
9.3.1. General Considerations 
Descriptive statistics for all endpoints will be provided by treatment arm. 
The number of participants screened, completing the study drug administration, and 
completing the study will be summarized. The reason for all discontinuations will be 
summarized. 
Baseline demographic and other characteristics will be tabulated for the FAS. 
For continuous endpoints, descriptive statistics for change from baseline will be provided. 
For binary endpoints, the proportion of participants with the event will be summarized. 
For categorical endpoints, the proportion of participants for each category will be 
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9.3.2. Primary Endpoint(s)/Estimand(s) Analysis 
9.3.2.1. Definition of Endpoint(s) 
The primary endpoint, summarized separately for the main study population and the 
population with rebound, is the proportion of participants with sustained NP swab 
SARS-CoV-2 RNA <LLOQ (defined as <2.0 log10 copies/mL) from Day 15 through Day 44. 
Sustained is defined as NP swab SARS-CoV-2 RNA level not ≥2.0 log10 copies/mL at any 
study visit (through Day 44) following the first study visit where the participant's NP swab 
SARS-CoV-2 RNA <LLOQ. 
9.3.2.2. Main Analytical Approach 
The primary descriptive analysis will summarize, separately for the main study population 
and the population with rebound, the number and proportion of participants with sustained 
NP swab SARS-CoV-2 RNA <LLOQ (defined as <2.0 log10 copies/mL) from Day 15 
through Day 44 for each treatment arm in the Evaluable Analysis Set and FAS. Participants 
receiving non-study antiviral or monoclonal antibody therapy post-baseline for the treatment 
of COVID-19 will be considered as not achieving sustained NP swab SARS-CoV-2 RNA 
<LLOQ in the primary analysis. In addition, 95% CIs for the proportion of participants with 
sustained NP swab SARS-CoV-2 RNA <LLOQ from Day 15 through Day 44 for each 
treatment arm will be calculated. The difference in proportions for the primary endpoint and 
associated 95% CI will be calculated for each pairwise comparison of the treatment arms. 
9.3.2.3. Supplementary Analysis/Analyses 
Supplemental analyses will be performed for the primary efficacy endpoint: 
1. An analysis of the primary endpoint will be conducted excluding data after the date of 
non-study antiviral or monoclonal antibody start for participants receiving non-study 
antiviral or monoclonal antibody therapy post-baseline for the treatment of 
COVID-19. 
2. An analysis of the primary endpoint will be conducted to include all NP swab 
SARS-CoV-2 RNA data regardless of whether participants received non-study 
antiviral or mAb treatment post-baseline for the treatment of COVID-19. 
9.3.3. Secondary Endpoint(s)/Estimand(s) Analysis 
Details on the definitions and analyses of secondary endpoints will be described in the SAP. 
Secondary endpoints include: 
• Time to first NP swab SARS-CoV-2 RNA<LLOQ (<2.0 log10 copies/mL) for 
participants with NP swab SARS-CoV-2 RNA ≥LLOQ at baseline. 
• Time to sustained NP swab SARS-CoV-2 RNA <LLOQ (<2.0 log10 copies/mL) 
through Day 44 for participants with NP swab SARS-CoV-2 RNA ≥LLOQ at 
baseline. 


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• Proportion of participants with SARS-CoV-2 RNA <LLOQ in plasma over time. 
• Proportion of participants with SARS-CoV-2 RNA level in NP swabs <2.0 log10 
copies/mL at each study visit through Day 44. 
• Change from baseline in SARS-CoV-2 RNA level in NP swabs and in plasma over 
time. 
• Rebound in SARS-CoV-2 RNA level in NP swabs at follow up (ie, any study visit 
after end of treatment through Day 44) that is defined as a half (0.5) log10 copies/mL 
increase or greater in SARS-CoV-2 RNA level relative to end of treatment SARS- 
CoV-2 RNA level based on treatment regimen, with a follow-up viral RNA level ≥2.5 
log10 copies/mL. 
• Incidence of TEAEs. 
• Incidence of SAEs and AEs leading to discontinuations. 
• Proportion of participants with COVID-19-related hospitalization >24 hours, or death 
from any cause through Day 28. 
• Proportion of participants with death (all cause) through Week 24. 
• Proportion of participants with COVID-19-related hospitalization of any duration. 
• Proportion of participants with COVID-19-related ICU admission of any duration. 
• Proportion of participants requiring invasive mechanical ventilation or ECMO. 
• Number of days in hospital and ICU stay in participants with COVID-19-related 
hospitalization. 
• Number of COVID-19-related medical visits through Day 44 and through Week 24. 
• Duration of each targeted COVID-19 signs/symptoms. 
• Proportion of participants with severe signs/symptoms attributed to COVID-19 
through Day 44. 
• Nirmatrelvir and ritonavir PK in plasma and whole blood (if feasible). 
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis 
• Not applicable. 
9.3.5. Safety Analyses 
All safety analyses will be performed on the safety analysis set. 


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9.3.6. Other Analyses 
Pharmacogenomic and/or biomarker data from samples collected as described in the SoA, as 
well as Retained Research Samples may be retained for future analyses; the results of such 
analyses are not planned to be included in the CSR. 
Rates of detection of cell culture infectious virus over time will be characterized during the 
trial and will be reported in a separate report outside of the CSR. 
PRO data (SF-36, WPAI, EQ-5D-5L, and global impression questions) will be collected 
during the trial and are not planned to be included in the CSR. 
Results from population PK analyses will be reported in a separate report outside of the CSR. 
9.4. Interim Analyses 
No formal interim analysis will be conducted for this study. 
9.5. Sample Size Determination 
Up to approximately 200 participants will be enrolled in this study. 
The study will randomize approximately 150 participants in a 1:1:1 randomization ratio, 
resulting in approximately 50 participants in each treatment arm (main study population). In 
addition, the study will also enroll up to 50 additional nonhospitalized symptomatic 
participants (in a 1:1:1 randomization ratio) who are immunocompromised with a rebound in 
COVID-19 within 14 days following completion of an initial 5-day treatment course of 
nirmatrelvir/ritonavir (population with rebound). 
Analyses will be conducted after the main study population is fully enrolled and have 
completed the Day 44 visit regardless of the number of randomized participants in the 
population with rebound. There will be 2 analysis time points for reporting the results of this 
study. The primary analysis will be performed after all participants in the main study 
population have completed the Day 44 visit. The follow-up analysis will be performed after 
all participants in the main study population have completed the Week 24 visit. In addition, 
both analyses (primary and follow-up) will include separate results for the main study 
population and the additional population with rebound. 
As no formal hypothesis testing will be performed for this study, no power calculation was 
carried out to assess the number of participants required for each treatment arm. For the main 
study population, the goal of the primary analysis is to estimate the treatment effect for each 
duration of nirmatrelvir/ritonavir. The smaller numbers of participants in these groups will be 
reflected in the precision of the estimate of the primary endpoint. Table 2 displays which 
effect sizes would be excluded based on the expected width of the confidence interval around 
the estimate of the proportion of participants with sustained NP swab SARS-CoV-2 RNA 
<LLOQ (defined as <2.0 log10 copies/mL) from Day 15 through Day 44 with a sample size 
of 50. 


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When the proportion of participants with sustained NP swab SARS-CoV-2 RNA <LLOQ 
from Day 15 through Day 44 ranges from 0.1 to 0.5, Table 2 displays the precision (width of 
the confidence interval) for the respective proportion to be estimated with a sample size of 
50. That is, the width of the 95% CI does not exceed 14%. 
 
Table 2. 
Width of 95% CI for the Proportion of Participants with Sustained NP 
Swab SARS-CoV-2 RNA <LLOQ 
 
Nirmatrelvir/Ritonavir (n=50) 
Proportion of Participants With Sustained Viral 
RNA level <LLOQ 
Width of CI 
0.1 
0.083 
0.2 
0.111 
0.3 
0.127 
0.4 
0.136 
0.5 
0.139 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines; 
• Applicable ICH GCP guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the investigator, and reviewed and approved by the IRB/EC before the study is initiated. 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC; 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures; 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 
536/2014 for clinical studies, European Medical Device Regulation 2017/745 for 
clinical device research, and all other applicable local regulations; 
• Reporting cases of suspected child abuse and/or neglect according to local medical 
association (eg, AAP) or health department guidelines. 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 


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information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of. 
10.1.2. Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
10.1.3. Informed Consent/Assent Process 
10.1.3.1. Informed Consent Process 
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or their legally authorized representative 
and answer all questions regarding the study. The participant or their legally authorized 
representative should be given sufficient time and opportunity to ask questions and to decide 
whether or not to participate in the trial. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative (if allowed by local regulations) will be required to sign a statement 
of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and the IRB/EC or 
study center. 
The investigator must ensure that each participant or their legally authorized representative is 
fully informed about the nature and objectives of the study, the sharing of data related to the 
study, and possible risks associated with participation, including the risks associated with the 
processing of the participant’s personal data. 
The participant or their legally authorized representative must be informed that their personal 
study-related data will be used by the sponsor in accordance with local data protection law. 
The level of disclosure must also be explained to the participant or their legally authorized 
representative. 
The participant or their legally authorized representative must be informed that their medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities. 


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The investigator further must ensure that each study participant or their legally authorized 
representative is fully informed about their right to access and correct their personal data and 
to withdraw consent for the processing of their personal data. 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD. 
Participants or their legally authorized representative must be reconsented to the most current 
version of the IRB/EC-approved ICD(s) during their participation in the study as required per 
local regulations. 
A copy of the ICD(s) must be provided to the participant or their legally authorized 
representative (if allowed by local regulations). 
10.1.3.2. Informed Assent Process 
The investigator or their representative will explain the nature of the study to the 
participant and their parent(s)/legal guardian and answer all questions regarding the 
study. The participant and their parent(s)/legal guardian should be given sufficient time and 
opportunity to ask questions and to decide whether or not to participate in the trial. 
When consent is obtained from a participant’s parent(s)/legal guardian, the participant’s 
assent (affirmative agreement) must be subsequently obtained when the participant has the 
capacity to provide assent, as determined by the IRB/EC. If the investigator determines that a 
participant’s decisional capacity is so limited they cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
participant’s assent may be waived with source documentation of the reason assent was not 
obtained. If the study participant does not provide their own assent, the source documents 
must record why the participant did not provide assent (for example, the child is not of 
assenting age per local regulations or policies), how the investigator determined that the 
person signing the consent was the participant’s parent(s)/legal guardian, the consent signer’s 
relationship to the study participant, and that the participant’s assent was obtained or 
waived. If assent is obtained verbally, it must be documented in the source documents. 
If study participants are minors who reach the age of majority or if a child reaches the age of 
assent (per local IRB/EC requirements) during the study, as recognized under local law, the 
child or adolescent must then provide the appropriate assent or consent to document their 
willingness to continue in the study. For an adolescent who reaches the age of consent, 
parental consent would no longer be valid. If the enrollment of emancipated minors is 
permitted by the IRB/EC and local law, the participant must provide documentation of legal 
status to give consent without the permission of a legally authorized representative. 
Participants and their parent(s)/legal guardian must be informed that their participation is 
voluntary. The Participant’s parent(s)/legal guardian will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, HIPAA requirements, where applicable, and the IRB/EC or study center. 


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The investigator must ensure that each study participant’s parent(s)/legal guardian and the 
study participant as applicable are fully informed about the nature and objectives of the 
study, the sharing of data related to the study, and possible risks associated with 
participation, including the risks associated with the processing of the participant’s personal 
data. 
The participant’s parent(s)/legal guardian must be informed that the participant’s personal 
study-related data will be used by the sponsor in accordance with local data protection 
law. The level of disclosure must also be explained to the participant’s parent(s)/legal 
guardian. 
The participant’s parent(s)/legal guardian must be informed that the participant’s medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities. 
The investigator further must ensure that each study participant’s parent(s)/legal guardian is 
fully informed about their right to access and correct their child’s personal data and to 
withdraw consent for the processing of their child’s personal data, keeping in mind the 
privacy rights that may restrict access of older adolescents’ medical records by their 
parent(s)/legal guardian in certain regions. 
The source documentation must include a statement that written informed consent and as 
applicable, assent, was obtained before the participant was enrolled in the study and the date 
the written consent/assent was obtained. The authorized person obtaining the informed 
consent must also sign the ICD. 
Parent(s)/legal guardian and the participant must be reconsented to the most current version 
of the ICD(s)/assent during their participation in the study. 
A copy of the ICD(s) and assent, if written, must be provided to the parent(s)/legal 
guardian and the participant. 
10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
Participants’ personal data will be stored at the study site in encrypted electronic form and 
will be password protected to ensure that only authorized study staff have access. The study 
site will implement appropriate technical and organizational measures to ensure that the 
personal data can be recovered in the event of disaster. In the event of a potential personal 
data breach, the study site will be responsible for determining whether a personal data breach 
has in fact occurred and, if so, providing breach notifications as required by law. 
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 


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participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws. 
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems. 
10.1.5. Committees Structure 
10.1.5.1. Data Monitoring Committee 
This study will use an E-DMC. The E-DMC is independent of the study team and includes 
only external members. The E-DMC charter describes the role of the E-DMC in more detail. 
The E-DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter. The recommendations made by the E-DMC will be forwarded 
to the appropriate authorized Pfizer personnel for review and final decision. Pfizer will 
communicate such decisions, which may include summaries of aggregate analyses of safety 
data to regulatory authorities and investigators, as appropriate. 
10.1.6. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 


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EudraCT/CTIS 
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements. 
www.pfizer.com 
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized. 
Documents within marketing applications 
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized. 
Data sharing 
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
24 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized. 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 
10.1.7. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document. 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties. 
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR. 


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The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained. 
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems. 
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 
10.1.8. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 


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Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor. 
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements. 
10.1.9. Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed. 
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants. 
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or the ICH GCP 
guidelines; 
• Inadequate recruitment of participants by the investigator; 
• Discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 


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requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
10.1.10. Publication Policy 
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study. 
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section. 
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication. 
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication. 
10.1.11. Sponsor’s Medically Qualified Individual 
The contact information for the sponsor’s MQI for the study is documented in the study 
contact list located in the supporting study documentation/study portal or other electronic 
system. 


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To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from non-study healthcare professionals, participants are provided 
with an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol 
and study intervention identifiers, (b) participant’s study identification number, (c) site 
emergency phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center 
number. 
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their investigator and site staff, and between the investigator and 
sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the investigator or site staff related to the care of a 
participant. The Pfizer Call Center number is to be used when the investigator and site staff 
are unavailable. The Pfizer Call Center number is not for use by the participant directly; if a 
participant calls that number directly, they will be directed back to the investigator site. 


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10.2. Appendix 2: Clinical Laboratory Tests 
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues. 
If deemed necessary to confirm eligibility, additional laboratory assessments at screening 
may be performed at the local laboratory at the investigator’s discretion. 
 
Table 3. 
Protocol-Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Other 
Reflex Testing: 
Hemoglobin 
Hematocrit 
RBC count 
Platelet count 
WBC count 
Total neutrophils 
(Abs) 
Eosinophils (Abs) 
Monocytes (Abs) 
Basophils (Abs) 
Lymphocytes 
(Abs) 
Urea 
Creatinine 
eGFR or CrCla, 
Sodium 
Potassium 
AST, ALT 
Total bilirubin 
Alkaline phosphatase 
Albumin 
Total protein 
Glucose (random) 
Calcium 
Chloride 
Total CO2 (bicarbonate) 
At screening only: 
FSHb 
As per Schedule of 
Activities: 
Pregnancy test 
(β-hCG)c 
Thyroid function 
TSH 
T4 (free) 
Viral Serology 
SARS-CoV-2 
For suspected DILI: 
AST/ALT 
Total bilirubin, direct and 
indirect bilirubin 
Total bile acids, GGT 
Total protein, albumin 
CK 
PT, INR 
Acetaminophen/paracetamol 
or 
protein adduct levels 
Hepatitis serology 
Renal Function for 
Eligibility and 
Determination of Dosing: 
eGFR or eCrCl will be 
assessed from creatinine value 
that will be obtained from a 
point-of-care device provided 
by the sponsor at screening 
(and also at baseline if 
screening and baseline visits 
are held on different days). An 
additional assessment may be 
performed on Day 5 or Day 10 
at the investigator’s discretion 
a. 
eGFR will be calculated using the method developed by the CKD-EPI for participants 18 years or older 
or eCrCl using the Cockcroft-Gault formula for participants 12 years to <18 years 
b. FSH testing is performed locally when needed to confirm postmenopausal status at screening. 
c. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC. Serum or urine β-hCG for female participants of childbearing potential. 


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The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting 
10.3.1. Definition of AE 
 
AE Definition 
• 
 An AE is any untoward medical occunence in a patient or clinical study 
paiiicipant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention. 
• 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abno1mal laborato1y finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• 
 Any abno1mal laborato1y test results (hematology, clinical chemistiy, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abno1mal laborato1y test 
results that meet any of the conditions below must be recorded as an AE: 
• 
Is associated with accompanying symptoms. 
• 
Requires additional diagnostic testing or medicaVsurgical intervention. 
• 
 Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
conc01nitant drng ti·eatment, or other therapy. 
• 
Exacerbation of a chronic or inte1mittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition. 
• 
New condition detected or diagnosed after study intervention adtninisti·ation, even 
though it may have been present before the staii of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected dtug-dtug interaction. 
• 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be repo1ied as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidaVself-haiming intent. Such overdoses should be repo1ied regardless of 
sequelae. 


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Events Meeting the AE Definition 
• 
Any clinically significant abno1mal laborato1y findings or other abno1mal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the paiticipant's condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
paiticipant's condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
 Situations in which an untowai·d medical occunence did not occur (social and/or 
convenience admission to a hospital). 
• 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the stait of the study that do not worsen. 
10.3.2. Definition of an SAE 
 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below: 
a. Results in death 
b. Is life-threatening 
The te1m "life-threatening" in the definition of "serious" refers to an event in which the 
paiticipant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the paiticipant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency wai·d for observation 
and/or treatment that would not have been appropriate in the physician's office or 
outpatient setting. Complications that occur during hospitalization ai·e AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether "hospitalization" occuned or was necessaiy, the 
AE should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 


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d. Results in persistent or significant disability/incapacity 
• The te1m disability means a substantial disrnption of a person's ability to conduct 
nonnal life functions. 
•  This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diaiThea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent eve1yday life functions but do not constitute a substantial disrnption. 
e. Is a congenital anomaly/birth defect 
f. Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or nonpathogenic 
The event may be suspected from clinical symptoms or laborato1y findings indicating 
an infection in a pa1ticipant exposed to a Pfizer product. The tenns "suspected 
transmission" and "transmission" are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by phaimacovigilance 
personnel. Such cases ai·e also considered for repo1ting as product defects, if 
appropriate. 
g. Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE repo1ting is appropriate in other situations, such as significant 
medical events that may jeopardize the paiticipant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of diug 
dependency or diug abuse. 
 
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
 
AE and SAE Recording/Reporting 
The table below summarizes the requirements for recording AEs on the CRF and for 
repo1ting SAEs using PSSA to Pfizer Safety throughout the active collection period. These 
requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious AEs; and (3) 
exposure to the study intervention under study during pregnancy or breastfeeding, and 
occupational exposure. 


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It should be noted that the PSSA for reporting of SAE information is not the same as the 
AE page of the CRF. When the same data are collected, the forms must be completed in a 
consistent manner. AEs should be recorded using concise medical terminology and the 
same AE term should be used on both the CRF and the PSSA for reporting of SAE 
information. 
* 
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using the PSSA; if the EDP is associated with an SAE, then the SAE is reported to Pfizer Safety 
using PSSA. 
** EDB is reported to Pfizer Safety using the PSSA, which would also include details of any SAE that 
might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the PSSA. 
• When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
• The investigator will then record all relevant AE or SAE information in the CRF. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of PSSA/AE or SAE CRF 
page. 
• There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
Safety Event 
Recorded on the CRF 
Reported Using PSSA to 
Pfizer Safety Within 24 
Hours of Awareness 
SAE 
All 
All 
Nonserious AE 
All 
None 
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs or SAEs associated 
with EDP or EDB 
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF 
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)* 
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)** 
Environmental or 
occupational exposure to 
the product under study to 
a nonparticipant (not 
involving EDP or EDB) 
None. Exposure to a study 
nonparticipant is not 
collected on the CRF 
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported*** 


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exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
•  The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical info1mation. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories, which are based on the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events43, version 
2.1 (July2017): 
GRADE 
Clinical Description of Severity 
1 
MILD adverse event 
2 
MODERATE adverse event 
3 
SEVERE adverse event 
4 
POTENTIALLY LIFE-THREATENING event 
5 
DEATH RELATED TO adverse event 
An event is defined as "serious" when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occunence of each AE or SAE. The investigator will use clinical 
judgment to dete1mine the relationship. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be rnled out. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• 
The investigator will also consult the IB and/or product info1mation, for marketed 
products, in their assessment. 
• 
For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have provided an assessment of causality. 
• 
There may be situations in which an SAE has occmTed and the investigator has 
minimal info1mation to include in the initial repo1i to the sponsor. However, it is 


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very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor. 
• 
The investigator may change their opinion of causality in light of follow-up 
info1mation and send an SAE follow-up repo1t with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when dete1mining regulato1y 
repo1ting requirements. 
• 
 If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as "related to study intervention" for repo1ting 
pmposes, as defined by the sponsor. In addition, if the investigator detennines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and repo1t such an 
assessment in the dedicated section of PSSA and in accordance with the SAE 
repo1ting requirements. 
 
 
Follow-Up of AEs and SAEs 
• 
 The investigator is obligated to perfonn or aiTange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laborato1y tests or investigations, 
histopathological exaininations, or consultation with other healthcai·e providers. 
• 
If a paiticipant dies during pa1ticipation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmo1tem findings, including histopathology. 
• 
New or updated infonnation will be recorded in the originally submitted 
documents. 
• 
The investigator will subinit any updated SAE data to the sponsor within 24 hours 
of receipt of the info1mation. 
10.3.4. Reporting of SAEs 
 
SAE Reporting to Pfizer Safety via an Electronic DCT 
• 
The primaiy mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT (eSAE or PSSA). 


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• 
If the electronic system is unavailable, then the site will use the paper fonn (see 
next section) to repo1i the event within 24 hours. 
• 
The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper f01m (as applicable) as soon as the data become available. 
• 
 After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entiy of new data or changes to existing data. 
• 
If a site receives a repo1i of a new SAE from a study paiiicipant or receives updated 
data on a previously repo1ied SAE after the electi·onic DCT has been taken off-line, 
then the site can report this infonnation on a paper SAE fonn (see next section) or 
to Pfizer Safety by telephone. 
 
 
SAE Reporting to Pfizer Safety via the CT SAE Report Form 
• 
Facsimile ti-ansmission of the CT SAE Repo1i Fo1m is the prefened method to 
ti·ansrnit this infonnation to Pfizer Safety. 
• 
 In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transpo1i Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Repo1i Fo1m sent by overnight mail or courier service. 
• 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Repo1i Fo1m pages within the designated repo1iing 
time frames. 


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10.4. Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100 fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies. 
10.4.2. Female Participant Reproductive Inclusion Criteria 
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 
• A female participant is eligible to participate if at least 1 of the following conditions 
applies: 
• Is not a WOCBP (see definition in Section 10.4.3). 
• OR 
• Is a WOCBP who is pregnant (at least 14 weeks gestation). 
• OR 
• Is a WOCBP who is not pregnant at screening and agrees to use a highly effective 
contraceptive method (failure rate of <1% per year) during the intervention period 
and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate any reproductive safety risk of the 
study intervention(s). If a highly effective, user-dependent method is chosen, she 
agrees to concurrently use an effective barrier method of contraception. The 
investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 


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Women in the following categories are not considered WOCBP: 
1. Premenarchal. 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to a medical cause other than the above (eg, 
mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
3. Postmenopausal female: 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition: 
• A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 50 years of age and not using hormonal 
contraception or HRT. 
• A female on HRT and whose menopausal status is in doubt will be required to use 
one of the highly effective nonestrogen hormonal contraception methods if she 
wishes to continue her HRT during the study. Otherwise, she must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
The following contraceptive methods are appropriate for this study: 
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
2. Intrauterine device. 


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3. Intrauterine hormone-releasing system. 
4. Bilateral tubal occlusion. 
5. Vasectomized partner: 
• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• Oral + barrier* 
• Intravaginal + barrier* 
• Transdermal + barrier* 
7. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• Oral + barrier* 
• Injectable + barrier* 
Sexual Abstinence 
8. Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following: 
• Male or female condom, with or without spermicide; 
• Cervical cap, diaphragm, or sponge with spermicide; 
• A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods). 
Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents 
are co-administered, a barrier method or other nonhormonal method of contraception must 


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also be used if the participant is using estradiol-containing contraceptives during the 15 days 
of treatment and until 1 menstrual cycle after stopping study intervention. 
10.5. Appendix 5: Genetics 
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRBs/ECs allow, a blood sample will be collected for DNA analysis. 
• The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation. 
• The samples may be analyzed as part of a multistudy assessment of genetic factors 
involved in the response to nirmatrelvir/ritonavir or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves. 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision making without being included in a 
study report. 
• The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• The samples will be retained as indicated: 
• Retained samples will be stored indefinitely or for another period as per local 
requirements. 
• Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, 
any remaining material will be destroyed. Data already generated from the samples 
will be retained to protect the integrity of existing analyses. 
• Samples for genetic research will be labeled with a code. The key between the code 
and the participant’s personally identifying information (eg, name, address) will be 
held securely at the study site. 


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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments and 
Study Intervention Rechallenge Guidelines 
Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are “adaptors” or are “susceptible.” 
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations (>2 × 
ULN) by several days or weeks. The increase in T bili typically occurs while AST/ALT is/are 
still elevated above 3 × ULN (ie, AST/ALT and T bili values will be elevated within the same 
laboratory sample). In rare instances, by the time T bili elevations are detected, AST/ALT 
values might have decreased. This occurrence is still regarded as a potential DILI. Therefore, 
abnormal elevations in either AST OR ALT in addition to T bili that meet the criteria outlined 
below are considered potential DILI (assessed per Hy’s law criteria) cases and should always 
be considered important medical events, even before all other possible causes of liver injury 
have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values: 
• Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value 
≥2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available. 
• For participants with baseline AST OR ALT OR T bili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is 
smaller). 
• Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller). 


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Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, liver imaging (eg, biliary tract), and collection of serum 
samples for acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
T bili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 


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10.7. Appendix 7: Age-Specific Kidney Function Calculation Recommendations 
10.7.1. Adults (18 Years and Above)—2021 CKD-EPI Equations 
 
2021 CKD- 
EPI 
Scr 
Only 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤ 0.7 
N/A 
eGFR = 143 × (Scr/0.7)-0.241 × (0.9938)Age 
Female 
if > 0.7 
N/A 
eGFR = 143 × (Scr/0.7)-1.200 × (0.9938)Age 
Male 
if ≤ 0.9 
N/A 
eGFR = 142 × (Scr/0.9)-0.302 × (0.9938)Age 
Male 
if > 0.9 
N/A 
eGFR = 142 × (Scr/0.9)-1.200 × (0.9938)Age 
2021 CKD- 
EPI 
Scr- 
Scys 
Combined 
Scr 
(mg/dL) 
Scys 
(mg/L) 
Recommended eGFR Equation 
Female 
if ≤ 0.7 
if ≤ 0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if ≤ 0.7 
if > 0.8 
eGFR = 130 × (Scr/0.7)-0.219 × (Scys/0.8)-0.778 × (0.9961)Age 
Female 
if > 0.7 
if ≤ 0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Female 
if > 0.7 
if > 0.8 
eGFR = 130 × (Scr/0.7)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if ≤ 0.9 
if ≤ 0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if ≤ 0.9 
if > 0.8 
eGFR = 135 × (Scr/0.9)-0.144 × (Scys/0.8)-0.778 × (0.9961)Age 
Male 
if > 0.9 
if ≤ 0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.323 × (0.9961)Age 
Male 
if > 0.9 
if > 0.8 
eGFR = 135 × (Scr/0.9)-0.544 × (Scys/0.8)-0.778 × (0.9961)Age 
Inker LA et al. N Engl J Med. 2021;385:1737-49.44 
 
 
10.7.1.1. Adolescents (12 Years to <18 Years)—Cockcroft-Gault Formula 
CrCl (mL/min) 
Males: Cr/Cl = [(140 – age) × body weight (in kg)] / [Scr (in mg/dL) × 72] 
Females: Cr/Cl = 0.85 × [(140 – age) × body weight (in kg)] / [Scr (in mg/dL) × 72] 
10.7.2. Adverse Event Grading for Kidney Safety Laboratory Abnormalities 
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO 
criteria. 


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10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI 
Nirmatrelvir and ritonavir are both primarily metabolized by CYP3A4. Therefore, 
concomitant use of any medications or substances that are strong inducers of CYP3A4 and 
that are contraindicated in combination with nirmatrelvir/ritonavir are prohibited without the 
appropriate washout prior to the first dose of study intervention. 
A nonexhaustive list of prohibited and precautionary medications is provided below 
(Table 4 and Table 5). If a medication is not listed as contraindicated, it should not 
automatically be assumed it is safe to coadminister. Appropriately qualified site staff will 
review all concomitant medications to determine if they are prohibited. The Pfizer study team 
is to be notified of any prohibited medications taken during the study. After consulting with 
the sponsor, the investigator will make a judgment on the ongoing participation of any 
participant with prohibited medication use during the study. 
This list of drugs prohibited for potential DDI concerns with the study intervention may be 
revised during the course of the study with written notification from sponsor, to include or 
exclude specific drugs or drug categories for various reasons (eg, emerging DDI results for 
the IMP, availability of new information in literature on the DDI potential of other drugs). 
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI. 
Table 4 and Table 5 list clinically significant drug interactions, with Table 4 listing the drugs 
contraindicated for use with nirmatrelvir/ritonavir. The drugs listed in Table 4 and Table 5 
are a guide and not considered a comprehensive list of all possible drugs that may interact 
with nirmatrelvir/ritonavir. The healthcare provider should consult appropriate references 
such as the prescribing information for the interacting drug for comprehensive information 
on dosing or monitoring with concomitant use of a strong CYP3A inhibitor such as ritonavir. 
 
Table 4.  Drugs That are Contraindicated With Nirmatrelvir/Ritonavir 
 
Drug Class 
Drugs Within 
Class 
Effect on Concentration 
Clinical Comments 
Alpha 1-adrenoreceptor 
antagonist 
alfuzosin 
↑ alfuzosin 
Co-administration 
contraindicated due to 
potential hypotension. 
Antianginal 
ranolazine 
↑ ranolazine 
Co-administration 
contraindicated due to 
potential for serious and/or 
life-threatening reactions. 
Antiarrhythmics 
amiodarone, 
dronedarone, 
flecainide, 
propafenone, 
quinidine 
↑ antiarrhythmic 
Co-administration 
contraindicated due to 
potential for cardiac 
arrhythmias. 
Anticancer drugs 
apalutamide 
↓ nirmatrelvir/ritonavir 
Co-administration 
contraindicated due to 
potential loss of virologic 


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Drug Class 
Drugs Within 
Class 
Effect on Concentration 
Clinical Comments 
response and possible 
resistance. 
Anticonvulsants 
carbamazepine, 
phenobarbital, 
primidone, 
phenytoin 
↓ nirmatrelvir/ritonavir 
Co-administration 
contraindicated due to 
potential loss of virologic 
response and possible 
resistance. 
Anti-gout 
colchicine 
↑ colchicine 
Co-administration 
contraindicated due to 
potential for serious and/or 
life-threatening reactions in 
patients with renal and/or 
hepatic impairment. 
Antimycobacterial 
rifampin 
↓ nirmatrelvir/ritonavir 
Co-administration 
contraindicated due to 
potential loss of virologic 
response and possible 
resistance. Alternate 
antimycobacterial drugs 
such as rifabutin should be 
considered. 
Antipsychotics 
lurasidone, 
pimozide 
↑ lurasidone 
↑ pimozide 
Co-administration 
contraindicated due to 
serious and/or 
life-threatening reactions 
such as cardiac 
arrhythmias. 
Benign prostatic 
hyperplasia agents 
silodosin 
↑ silodosin 
Co-administration 
contraindicated due to 
potential for postural 
hypotension. 
Cardiovascular agents 
eplerenone 
ivabradine 
↑ eplerenone 
↑ ivabradine 
Co-administration with 
eplerenone is 
contraindicated due to 
potential for hyperkalemia. 
Co-administration with 
ivabradine is 
contraindicated due to 
potential for 
bradycardia or conduction 
disturbances. 
Cystic fibrosis 
transmembrane 
conductance regulator 
potentiators 
lumacaftor/ivacaftor 
↓ nirmatrelvir/ritonavir 
Co-administration 
contraindicated due to 
potential loss of virologic 
response and possible 
resistance. 
Ergot derivatives 
dihydroergotamine, 
ergotamine, 
methylergonovine 
↑ dihydroergotamine 
↑ ergotamine 
↑ methylergonovine 
Co-administration 
contraindicated due to 
potential for acute ergot 


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Drug Class 
Drugs Within 
Class 
Effect on Concentration 
Clinical Comments 
toxicity characterized by 
vasospasm and ischemia of 
the extremities and other 
tissues including the central 
nervous system. 
Herbal products 
St. John’s Wort 
(hypericum 
perforatum) 
↓ nirmatrelvir/ritonavir 
Co-administration 
contraindicated due to 
potential loss of virologic 
response and possible 
resistance. 
HMG-CoA reductase 
inhibitors 
lovastatin, 
simvastatin 
↑ lovastatin 
↑ simvastatin 
Co-administration 
contraindicated due to 
potential for myopathy 
including rhabdomyolysis. 
Discontinue use of 
lovastatin and 
simvastatin at least 12 
hours prior to initiation of 
nirmatrelvir/ritonavir, 
during 
nirmatrelvir/ritonavir 
treatment duration, and for 
5 days after completing 
nirmatrelvir/ritonavir. 
Immunosuppressants 
voclosporin 
↑ voclosporin 
Co-administration 
contraindicated 
due to potential for acute 
and/or 
chronic nephrotoxicity. 
Microsomal triglyceride 
transfer protein inhibitor 
lomitapide 
↑ lomitapide 
Co-administration 
contraindicated due to 
potential for hepatotoxicity 
and gastrointestinal adverse 
reactions. 
Migraine medications 
eletriptan 
ubrogepant 
↑ eletriptan 
↑ ubrogepant 
Co-administration of 
eletriptan within at least 72 
hours of 
nirmatrelvir/ritonavir is 
contraindicated due to 
potential for serious 
adverse reactions including 
cardiovascular and 
cerebrovascular events. 
Co-administration of 
ubrogepant with 
nirmatrelvir/ritonavir is 
contraindicated due to 


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Drug Class 
Drugs Within 
Class 
Effect on Concentration 
Clinical Comments 
potential for serious 
adverse 
reactions. 
Mineralocorticoid 
receptor antagonists 
finerenone 
↑ finerenone 
Co-administration 
contraindicated due to 
potential for serious 
adverse reactions including 
hyperkalemia, hypotension, 
and hyponatremia. 
Opioid antagonists 
naloxegol 
↑ naloxegol 
Co-administration 
contraindicated due to the 
potential for opioid 
withdrawal symptoms 
Pulmonary hypertension 
agent (PDE5 inhibitor) 
sildenafil 
(Revatio®) when 
used for pulmonary 
arterial 
hypertension 
↑ sildenafil 
Co-administration 
contraindicated due to the 
potential for sildenafil 
associated adverse events, 
including visual 
abnormalities hypotension, 
prolonged erection, and 
syncope. 
Sedative/hypnotics 
triazolam, 
oral midazolam 
↑ triazolam 
↑ midazolam 
Co-administration 
contraindicated due to 
potential for extreme 
sedation and respiratory 
depression. 
Serotonin receptor 1A 
agonist/serotonin 
receptor 2A antagonist 
flibanserin 
↑ flibanserin 
Co-administration 
contraindicated due to 
potential for hypotension, 
syncope, and CNS 
depression. 
Vasopressin receptor 
antagonists 
tolvaptan 
↑ tolvaptan 
Co-administration 
contraindicated due to 
potential for dehydration, 
hypovolemia and 
hyperkalemia. 
 
 
Table 5. 
Established and Other Potentially Significant Drug Interactions 
 
Drug Class 
Drugs within Class 
Effect on 
Concentration 
Clinical Comments 
Alpha 1- 
adrenoreceptor 
antagonist 
tamsulosin 
↑ tamsulosin 
Avoid concomitant use with 
nirmatrelvir/ritonavir. 


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Drug Class 
Drugs within Class 
Effect on 
Concentration 
Clinical Comments 
Antiarrhythmics 
lidocaine (systemic), 
disopyramide 
↑ antiarrhythmic 
Caution is warranted and 
therapeutic concentration 
monitoring is recommended for 
antiarrhythmics if available. 
Anticancer drugs 
abemaciclib, 
ceritinib, 
dasatinib, 
encorafenib, 
ibrutinib, 
ivosidenib, 
neratinib, 
nilotinib, 
venetoclax, 
vinblastine, 
vincristine 
↑ anticancer drug 
Avoid co-administration of 
encorafenib or ivosidenib due 
to potential risk of serious 
adverse events such as QT 
interval prolongation. Avoid 
use of neratinib, venetoclax or 
ibrutinib. 
Co-administration of 
vincristine and vinblastine may 
lead to significant hematologic 
or gastrointestinal side effects. 
For further information, refer 
to individual product label for 
anticancer drug. 
Anticoagulants 
warfarin 
rivaroxaban 
dabigatran 
apixaban 
↑↓ warfarin 
↑ rivaroxaban 
↑ dabigatran 
↑ apixaban 
Closely monitor INR if 
co-administration with 
warfarin is necessary. 
Increased bleeding risk with 
rivaroxaban. Avoid 
concomitant use. 
Increased bleeding risk with 
dabigatran. Depending on 
dabigatran indication and renal 
function, reduce dose of 
dabigatran or avoid 
concomitant use. Refer to the 
dabigatran product label for 
further information. 
Combined P-gp and strong 
CYP3A4 inhibitors increase 
blood levels of apixaban and 
increase the risk of bleeding. 
Dosing recommendations for 
co-administration of apixaban 
with nirmatrelvir/ritonavir 
depend on the apixaban dose. 
Refer to the apixaban product 
label for more information. 


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Drug Class 
Drugs within Class 
Effect on 
Concentration 
Clinical Comments 
Anticonvulsants 
clonazepam 
↑ anticonvulsant 
A dose decrease may be 
needed for clonazepam when 
co-administered with 
nirmatrelvir/ritonavir and 
clinical monitoring is 
recommended. 
Antidepressants 
bupropion 
trazodone 
↓ bupropion and 
active metabolite 
hydroxy-bupropion 
↑ trazodone 
Monitor for an adequate 
clinical response to bupropion. 
Adverse reactions of nausea, 
dizziness, hypotension, and 
syncope have been observed 
following co-administration of 
trazodone and ritonavir. A 
lower dose of trazodone should 
be considered. Refer to 
trazadone product label for 
further information. 
Antifungals 
voriconazole, 
ketoconazole, 
isavuconazonium sulfate, 
itraconazole 
↓ voriconazole 
↑ ketoconazole 
↑ isavuconazonium 
sulfate 
↑ itraconazole 
↑ 
nirmatrelvir/ritonavir 
Avoid concomitant use of 
voriconazole. 
Refer to ketoconazole, 
isavuconazonium sulfate, and 
itraconazole product labels for 
further information. 
Anti-HIV protease 
inhibitors 
atazanavir, 
darunavir, 
tipranavir 
↑ protease inhibitor 
For further information, refer 
to the respective protease 
inhibitors’ prescribing 
information. 
Patients on ritonavir- or 
cobicistat-containing HIV 
regimens should continue their 
treatment as indicated. Monitor 
for increased 
nirmatrelvir/ritonavir or 
protease inhibitor adverse 
events. 
Anti-HIV 
efavirenz, 
maraviroc, 
nevirapine, 
zidovudine, 
bictegravir/ 
emtricitabine/ 
tenofovir 
↑ efavirenz 
↑ maraviroc 
↑ nevirapine 
↓ zidovudine 
↑ bictegravir 
↔ emtricitabine 
↑ tenofovir 
For further information, refer 
to the respective anti-HIV 
drugs prescribing information. 


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Drug Class 
Drugs within Class 
Effect on 
Concentration 
Clinical Comments 
Anti-infective 
clarithromycin, 
erythromycin 
↑ clarithromycin 
↑ erythromycin 
Refer to the respective 
prescribing information for 
anti-infective dose adjustment. 
Antimycobacterial 
bedaquiline 
rifabutin 
rifapentine 
↑ bedaquiline 
↑ rifabutin 
↓ 
nirmatrelvir/ritonavir 
Refer to the bedaquiline 
product label for further 
information. 
Refer to rifabutin product label 
for further information on 
rifabutin dose reduction. 
Avoid concomitant use with 
nirmatrelvir/ritonavir. 
Antipsychotics 
quetiapine 
clozapine 
↑ quetiapine 
↑ clozapine 
If co-administration is 
necessary, reduce quetiapine 
dose and monitor for 
quetiapine-associated adverse 
reactions. Refer to the 
quetiapine prescribing 
information for 
recommendations. 
If co-administration is 
necessary, consider reducing 
the clozapine dose and monitor 
for adverse reactions. 
Calcium channel 
blockers 
amlodipine, 
diltiazem, 
felodipine, 
nicardipine, 
nifedipine 
↑ calcium channel 
blocker 
Caution is warranted and 
clinical monitoring of patients 
is recommended. A dose 
decrease may be needed for 
these drugs when 
co-administered with 
nirmatrelvir/ritonavir. 
If co-administered, refer to 
individual product label for 
calcium channel blocker for 
further information. 
Cardiac glycosides 
digoxin 
↑ digoxin 
Caution should be exercised 
when co-administering 
nirmatrelvir/ritonavir with 
digoxin, with appropriate 
monitoring of serum digoxin 
levels. 
Refer to the digoxin product 
label for further information. 


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Drug Class 
Drugs within Class 
Effect on 
Concentration 
Clinical Comments 
Cardiovascular 
agents 
aliskiren, 
ticagrelor, 
vorapaxar 
clopidogrel 
cilostazol 
↑ aliskiren 
↑ ticagrelor 
↑ vorapaxar 
↓ clopidogrel active 
metabolite 
↑ cilostazol 
Avoid concomitant use with 
nirmatrelvir/ritonavir. 
Dosage adjustment of 
cilostazol is recommended. 
Refer to the cilostazol product 
label for more information. 
Corticosteroids 
primarily 
metabolized by 
CYP3A 
betamethasone, 
budesonide, 
ciclesonide, 
dexamethasone, 
fluticasone, 
methylprednisolone, 
mometasone, 
triamcinolone 
↑ corticosteroid 
Co-administration with 
corticosteroids ( all routes of 
administration) of which 
exposures are significantly 
increased by strong CYP3A 
inhibitors can increase the risk 
for Cushing’s syndrome and 
adrenal suppression. However, 
the risk of Cushing’s syndrome 
and adrenal suppression 
associated with short-term use 
of a strong CYP3A inhibitor is 
low. 
Alternative corticosteroids 
including beclomethasone, 
prednisone, and prednisolone 
should be considered. 
Cystic fibrosis 
transmembrane 
conductance 
regulator 
potentiators 
ivacaftor 
elexacaftor/tezacaftor/ 
ivacaftor 
tezacaftor/ivacaftor 
↑ ivacaftor 
↑ 
elexacaftor/tezacafto 
r/ivacaftor 
↑ tezacaftor/ivacaftor 
Reduce dosage when co- 
administered with 
nirmatrelvir/ritonavir. 
Refer to individual product 
labels for further information. 
Dipeptidyl 
peptidase 4 
inhibitors 
saxagliptin 
↑saxagliptin 
Dosage adjustment of 
saxagliptin is recommended. 
Refer to the saxagliptin product 
label for more information. 
Endothelin 
receptor 
antagonists 
bosentan 
↑ bosentan 
Discontinue use of bosentan at 
least 36 hours prior to initiation 
of nirmatrelvir/ritonavir. 
Refer to the bosentan product 
label for further information. 


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Drug Class 
Drugs within Class 
Effect on 
Concentration 
Clinical Comments 
Hepatitis C direct 
acting antivirals 
elbasvir/grazoprevir, 
glecaprevir/pibrentasvir 
ombitasvir/paritaprevir/ritona 
vir and dasabuvir 
sofosbuvir/velpatasvir/voxila 
previr 
↑ antiviral 
Increased grazoprevir 
concentrations can result in 
ALT elevations. 
Avoid concomitant use of 
glecaprevir/pibrentasvir with 
nirmatrelvir/ritonavir. 
Refer to the 
ombitasvir/paritaprevir/ritonavi 
r and dasabuvir label for 
further information. 
Refer to the 
sofosbuvir/velpatasvir/voxilapr 
evir product label for further 
information. 
Patients on ritonavir-containing 
HCV regimens should continue 
their treatment as indicated. 
Monitor for increased 
nirmatrelvir/ritonavir or HCV 
drug adverse events with 
concomitant use. 
HMG-CoA 
reductase 
inhibitors 
atorvastatin, 
rosuvastatin 
↑ atorvastatin 
↑ rosuvastatin 
Consider temporary 
discontinuation of atorvastatin 
and rosuvastatin during 
treatment with 
nirmatrelvir/ritonavir. 
Atorvastatin and rosuvastatin 
do not need to be held prior to 
or after completing 
nirmatrelvir/ritonavir. 
Hormonal 
contraceptive 
ethinyl estradiol 
↓ ethinyl estradiol 
An additional, non-hormonal 
method of contraception should 
be considered during 
nirmatrelvir/ritonavir treatment 
and until one menstrual cycle 
after stopping 
nirmatrelvir/ritonavir. 
Immunosuppressa 
nts 
cyclosporine, 
tacrolimus 
↑ cyclosporine 
↑ tacrolimus 
Avoid use of 
nirmatrelvir/ritonavir when 
close monitoring of 
immunosuppressant 
concentrations is not feasible. 
If co-administered, dose 


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Drug Class 
Drugs within Class 
Effect on 
Concentration 
Clinical Comments 
everolimus, 
sirolimus 
↑ everolimus 
↑ sirolimus 
adjustment of the 
immunosuppressant and 
monitoring for 
immunosuppressant 
concentrations and 
immunosuppressant-associated 
adverse reactions is 
recommended. Refer to the 
individual immunosuppressant 
product label for further 
information and obtain expert 
consultation from the patient’s 
immunosuppressive therapy 
specialist. 
Avoid concomitant use of 
everolinus and sirolimus and 
nirmatrelvir/ritonavir. 
Janus kinase 
(JAK) inhibitors 
tofacitinib 
upadacitinib 
↑ tofacitinib 
↑ upadacitinib 
Dosage adjustment of 
tofacitinib is recommended. 
Refer to the tofacitinib product 
label for more information. 
Dosage recommendations for 
co-administration of 
upadacitinib with 
nirmatrelvir/ritonavir depends 
on the upadacitinib indication. 
Refer to the upadacitinib 
product label for more 
information. 
Long-acting 
beta-adrenoceptor 
agonist 
salmeterol 
↑ salmeterol 
Avoid concomitant use with 
nirmatrelvir/ritonavir. The 
combination may result in 
increased risk of cardiovascular 
adverse events associated with 
salmeterol, including QT 
prolongation, palpitations, and 
sinus tachycardia. 
Migraine 
medications 
rimegepant 
↑ rimegepant 
Avoid concomitant use with 
nirmatrelvir/ritonavir. 
Muscarinic 
receptor 
antagonists 
darifenacin 
↑ darifenacin 
The darifenacin daily dose 
should not exceed 7.5 mg when 
co-administered with 
nirmatrelvir/ritonavir. Refer to 
the darifenacin product label 
for more information. 


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Drug Class 
Drugs within Class 
Effect on 
Concentration 
Clinical Comments 
Narcotic 
analgesics 
fentanyl, 
hydrocodone, 
oxycodone, 
meperidine 
methadone 
↑ fentanyl 
↑ hydrocodone 
↑ oxycodone 
↑ meperidine 
↓ methadone 
Careful monitoring of 
therapeutic and adverse effects 
(including potentially fatal 
respiratory depression) is 
recommended when fentanyl, 
hydrocodone, oxycodone, or 
meperidine is concomitantly 
administered with 
nirmatrelvir/ritonavir. If 
concomitant use with 
nirmatrelvir/ritonavir is 
necessary, consider a dosage 
reduction of the narcotic 
analgesic and monitor patients 
closely at frequent intervals. 
Refer to the individual product 
label for more information. 
Monitor methadone-maintained 
patients closely for evidence of 
withdrawal effects and adjust 
the methadone dose 
accordingly. 
Neuropsychiatric 
agents 
Suvorexant 
aripiprazole, 
brexpiprazole, 
cariprazine, 
iloperidone, 
lumateperone, 
pimavanserin 
↑ suvorexant 
↑ aripiprazole, 
↑ brexpiprazole, 
↑ cariprazine, 
↑ iloperidone, 
↑ lumateperone, 
↑ pimavanserin 
Avoid concomitant use of 
suvorexant with 
nirmatrelvir/ritonavir. 
Dosage adjustment of 
aripiprazole, brexpiprazole, 
cariprazine, iloperidone, 
lumateperone, and 
pimavanserin is recommended. 
Refer to individual product 
label for more information. 
Pulmonary 
hypertension 
agents (PDE5 
inhibitors) 
Pulmonary 
hypertension 
agents (sGC 
stimulators) 
tadalafil (Adcirca®) 
riociguat 
↑ tadalafil 
↑ riociguat 
Avoid concomitant use with 
nirmatrelvir/ritonavir. 
Dosage adjustment is 
recommended for riociguat. 
Refer to the riociguat product 
label for more information. 


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Drug Class 
Drugs within Class 
Effect on 
Concentration 
Clinical Comments 
Erectile 
dysfunction agents 
(PDE5 inhibitors) 
avanafil 
↑ avanafil, 
Do not use 
nirmatrelvir/ritonavir with 
avanafil because a safe and 
effective avanafil dosage 
regimen has not been 
established. 
sildenafil, 
tadalafil, 
vardenafil 
↑ sildenafil, 
↑ tadalafil, 
↑ vardenafil 
Dosage adjustment is 
recommended for use of 
sildenafil, tadalafil, or 
vardenafil with 
nirmatrelvir/ritonavir. Refer to 
individual product labels for 
more information. 
Sedative/hypnotics 
buspirone, 
clorazepate, 
diazepam, 
estazolam, 
flurazepam, 
zolpidem 
↑sedative/hypnotic 
A dose decrease may be 
needed for these drugs when 
co-administered with 
nirmatrelvir/ritonavir and 
monitoring adverse events 
midazolam (administered 
parenterally) 
↑ midazolam 
Co-administration of 
midazolam (parenteral) should 
be done in a setting which 
ensures close clinical 
monitoring and appropriate 
medical management in case of 
respiratory depression and/or 
prolonged sedation. Dosage 
reduction for midazolam 
should be considered, 
especially if more than a single 
dose of midazolam is 
administered. 
Refer to the midazolam 
product label for further 
information. 


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10.9. Appendix 9: Eligibility Criteria 
10.9.1. Age and Sex 
Inclusion Criterion #1: Participants aged 12 years or older and weighing ≥40 kg at screening: 
• Participants 12 years of age or older at the time of signing the informed consent. 
Adolescent participants below the age of 18 years (or country-specific age of 
majority) will only be enrolled if approved by the country regulatory/health authority. 
If these approvals have not been granted, only participants 18 years of age (or 
country-specific age of majority) or older at the time of signing of informed consent 
may be enrolled. 
• Refer to Appendix 4 for reproductive criteria for female (Section 10.4.2) participants. 
10.9.2. Confirmed SARS-CoV-2 Infection Details for the Main Study Population 
Inclusion Criterion #2: Confirmed SARS-CoV-2 infection as determined by RT-PCR or 
other acceptable test method in any specimen collected within 5 days prior to randomization 
for the main study population. 
Note: RT-PCR is the preferred method; however, with evolving approaches to confirmation 
of SARS-CoV-2 infection, other molecular or antigen tests that detect viral RNA or protein 
are allowed. The test result must be available to confirm eligibility. Participants may be 
enrolled based on positive results of a rapid SARS-CoV-2 antigen test performed at 
screening. 
10.9.3. Signs and Symptoms Attributable to COVID-19 
Inclusion Criterion #3: ≥1 sign/symptom attributable to COVID-19 present on the day of 
randomization (Appendix 10). 
10.9.4. Immunocompromised Criteria Details 
Inclusion Criterion #4: Immunocompromised with ≥1 of the following: 
1. Solid organ (eg, liver, heart, lung or kidney) transplant recipient who is receiving 
immunosuppressive therapy; 
2. Receipt of CAR-T-cell therapy or HCT either within 2 years of transplantation or 
who are receiving immunosuppressive therapy; 
3. Moderate or severe primary immunodeficiency (eg, DiGeorge syndrome, 
Wiskott-Aldrich syndrome); 
4. Use of at least 1 of the following immune-weakening medications: 
a. Recent treatment with corticosteroids equivalent to prednisone ≥20 mg daily 
for at least 14 consecutive days, all of which must have been within the last 
30 days prior to study entry OR are currently receiving ≥20 mg daily that must 
have been administered for at least 14 consecutive days at the time of study 
entry. 


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b. Active treatment causing significant immunosuppression, including alkylating 
agents, antimetabolites, transplant-related immunosuppressive drugs, cancer 
chemotherapeutic agents, TNF blockers, or other highly immunosuppressive 
drugs such as biologics (eg, ustekinumab, anti-CD20). 
5. Active immunosuppressive treatment for solid tumor or hematological malignancy 
(including leukemia, lymphoma, and myeloma). 
6. HIV infection with CD4 cell count <200 mm3 from known medical history within the 
past 6 months of screening. 
10.9.5. Inclusion Criteria for Additional Population With COVID-19 Rebound 
Inclusion Criterion #2: Confirmed SARS-CoV-2 infection as determined by RT-PCR or 
rapid antigen testing in any specimen collected within 24h prior to randomization and 
collected within 14 days after the completion of the initial 5-day treatment course of 
nirmatrelvir/ritonavir. 
Note: RT-PCR is the preferred method; however, with evolving approaches to confirmation 
of SARS-CoV-2 infection, other molecular or antigen tests that detect viral RNA or protein 
are allowed. The test result must be available to confirm eligibility. Participants may be 
enrolled based on positive results of a rapid SARS-CoV-2 antigen test performed at 
screening. 
Inclusion Criterion #5: Presenting with documented, symptomatic, COVID-19 rebound 
within 14 days following completion of an initial 5-day treatment course with 
nirmatrelvir/ritonavir, defined as: 
1. Participants must have written documentation, such as electronic health record, 
medical record, or prescription receipt of treatment with nirmatrelvir/ritonavir (verbal 
assertion of treatment is not acceptable) with patient-reported 100% compliance (ie, 
completed a 5-day course of nirmatrelvir/ritonavir). They must have symptom 
alleviation or resolution in COVID-19 signs/symptoms followed by a worsening 
(rebound) of signs/symptoms after completing an initial 5-day course of 
nirmatrelvir/ritonavir based on the judgement of both the participant and investigator. 
2. The onset of rebound in COVID-19 symptoms must occur within 14 days after the 
completion of the initial 5-day course of nirmatrelvir/ritonavir. 
3. Onset of signs/symptoms attributable to rebound COVID-19 within 48 hours prior to 
randomization and ≥1 sign/symptom to COVID-19 present on the day of 
randomization. 


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10.9.6. Oxygen Saturation Criterion Details 
Exclusion Criterion #7: Oxygen saturation of <92% on room air obtained at rest within 
24 hours prior to randomization. 
Note: for a potential participant who regularly receives chronic supplementary oxygen for an 
underlying lung condition, oxygen saturation should be measured while on their standard 
home oxygen supplementation. 
10.9.7. Prior/Concomitant Therapy 
Exclusion Criterion #9: Current use of any prohibited concomitant medication(s). 
1. Current use of any medications that are highly dependent on CYP3A4 for clearance 
and which are contraindicated in combination with nirmatrelvir/ritonavir (see 
Appendix 8). Participants taking lovastatin and simvastatin may enroll, provided that 
they have discontinued use at least 12h prior to initiation of nirmatrelvir/ritonavir and 
refrain from use during treatment and for 5 days after the last dose of study 
intervention. Coadministration of nirmatrelvir/ritonavir with other medications that 
are not contraindicated but are highly dependent on CYP3A4 for clearance may 
require dose adjustment or additional monitoring (See Appendix 8 in protocol). 
2. Use of any medications or substances that are strong inducers of CYP3A4 and that 
are contraindicated in combination with nirmatrelvir/ritonavir without the appropriate 
washout prior to the first dose of nirmatrelvir/ritonavir (see Appendix 8 in protocol). 
The appropriate washout period for CYP3A4 inducers should be determined based on 
the prescribing information for the concomitant medication and in consultation with 
the medical monitor. 
3. Use of an antiviral or monoclonal antibody therapy for the treatment of COVID-19 
within 30 days prior to screening, except for participants in the additional population 
with rebound, who must have completed a recent (ie, within 14 days) initial 5-day 
course of nirmatrelvir/ritonavir (see Section 10.9.5). 
4. Current or expected use of a non-study antiviral or monoclonal antibody therapy for 
the treatment of COVID-19 within 15 days after randomization. 


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10.10. Appendix 10: Participant-Reported COVID-19-Related Signs and Symptoms 
 
 
Sign and Symptom Collection4 
Entry Criterion #3 
Targeted (used for study 
entry) 
Signs and Symptom 
Collection 
Cough 
X 
X 
Shortness of breath or difficulty breathing 
X 
X 
Fever (documented temperature >38˚C [100.4˚F]) 
or subjective fever (eg, feeling feverish) 
X 
Feeling feverish 
X 
Chills or shivering 
X 
X 
Fatigue (low energy or tiredness) 
X 
X 
Muscle or body aches 
X 
X 
Diarrhea (loose or watery stools) 
X 
X 
Nausea (feeling like you wanted to throw up) 
X 
X 
Vomiting (throw up) 
X 
X 
Headache 
X 
X 
Sore throat 
X 
X 
Stuffy or runny nose 
X 
X 
Loss of smell 
X 
X 
Loss of taste 
X 
X 


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10.11. Appendix 11: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
AAP 
American Academy of Pediatrics 
Abs 
absolute 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AxMP 
auxiliary medicinal product 
β-hCG 
β-human chorionic gonadotropin 
BID 
twice a day 
BP 
blood pressure 
CAR-T 
chimeric antigen receptor T-cell 
CDC 
United States Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
CKD-EPI 
chronic kidney disease epidemiology 
CO2 
carbon dioxide (bicarbonate) 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CrCl 
creatinine clearance 
CRF 
case report form 
CRO 
contract research organization 
CSR 
Clinical Study Report 
CT 
computed tomography/clinical trial 
CTIS 
Clinical Trial Information System 
CYP 
cytochrome P450 
DAIDS 
Division of AIDS 
DCT 
data collection tool 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
EC 
ethics committee 
ECC 
emergency contact card 
ECDC 
European Centre for Disease Prevention and Control 
ECG 
electrocardiogram or electrocardiography 
ECMO 
extracorporeal membrane oxygenation 
eCrCl 
estimated creatinine clearance 
eCRF 
electronic case report form 
EDB 
exposure during breastfeeding 
E-DMC 
External Data Monitoring Committee 


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Abbreviation 
Term 
EDP 
exposure during pregnancy 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EQ-5D-3L 
Euroquol Quality of Life 5 Dimension 3-Level Scale 
EPIC-HR 
Evaluation of Protease Inhibition for COVID-19 in High-Risk 
Patients 
ePRO 
electronic patient-reported outcome 
EQ-5D-5L 
Euroquol Quality of Life 5 
eSAE 
electronic serious adverse event 
ET 
early termination 
EU 
European Union 
EUA 
Emergency Use Authorization 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database) 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
F/U 
follow-up 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
H 
home 
HCP 
healthcare professional 
HCT 
hematopoietic cell transplantation 
HCV 
hepatitis C virus 
HDPE 
high density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HMG-CoA 
3-hydroxy-3-methylglutaryl co-enzyme A 
HRT 
hormone replacement therapy 
HTA 
health technology assessment 
IB 
Investigator’s Brochure 
ICD 
informed consent document 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICU 
intensive care unit 
ID 
identification 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IPAL 
Investigational Product Accountability Log 
IPM 
investigational product manual 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 


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Abbreviation 
Term 
JAK 
Janus Kinase 
KDIGO 
Kidney Disease: Improving Global Outcomes 
LFT 
liver function test 
LLOQ 
lower limit of quantitation 
LT 
long-term 
mAb 
monoclonal antibody 
MIS-C 
multisystem inflammatory syndrome in children 
MQI 
medically qualified individual 
n 
number 
NA 
not applicable 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIMP 
noninvestigational medicinal product 
NOAEL 
no observed adverse effect level 
NP 
nasopharyngeal 
P 
participant’s location 
PACL 
protocol administrative change letter 
PDE5 
phosphodiesterase-5 
P-gp 
p-glycoprotein 
PK 
pharmacokinetic(s) 
POC 
point-of-care 
PR 
pulse rate 
PRO 
patient-reported outcome 
PSSA 
Pfizer’s Serious Adverse Event Submission Assistant 
PT 
prothrombin time 
q12h 
every 12 hours 
QTL 
quality tolerance limit 
RBC 
red blood cell 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcription polymerase chain reaction 
S 
investigational site 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
Scr 
serum creatinine 
Scys 
serum cystatin C 
SF-36 
Short Form-36 
sGC 
soluble guanylate cyclase 
SoA 
schedule of activities 
SoC 
standard of care 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
SUSAR 
suspected unexpected serious adverse reaction 


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Abbreviation 
Term 
T4 
thyroxine 
T bili 
total bilirubin 
TEAE 
treatment-emergent adverse event(s) 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analog scale 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
woman/women of childbearing potential 
WONCBP 
woman/women not of childbearing potential 
WPAI 
Work Productivity and Activity Impairment 
WPAI-GH 
Work Productivity and Activity Impairment – General Health 


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11. REFERENCES 
1. 
Abbasi J. Researchers Tie Severe Immunosuppression to Chronic COVID-19 and 
Virus Variants. JAMA. 2021;325(20):2033-35. 
2. 
Corey L, Beyrer C, Cohen MS, et al. SARS-CoV-2 Variants in Patients with 
Immunosuppression. N Engl J Med. 2021;385(6):562-66. 
3. 
World Health Organization. (2022). WHO Situation Report - 51 Coronavirus disease 
2019 (COVID-19). 11 March 2020. Available from: 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports. 
Accessed on: 26 May 2022. 
4. 
US Food and Drug Administration. Assessing COVID-19-Related Symptoms in 
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US Food and Drug Administration. COVID-19 Vaccines. Available from: 
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2019-covid-19/covid-19-vaccines. Accessed on: 29 Jun 2021. 
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Parker EPK, Desai S, Marti M, et al. Response to additional COVID-19 vaccine 
doses in people who are immunocompromised: a rapid review. Lancet Glob Health. 
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UK Health Security Agency. SARS-CoV-2 variants of concern and variants under 
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nt_data/file/1042367/technical_briefing-31-10-december-2021.pdf. Accessed on: 02 
March 2022. 
8. 
Centers for Disease Control and Prevention. COVID Data Tracker. Variant 
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National Institutes of Health. Characteristics of SARS-CoV-2 Antibody-Based 
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10. 
Infectious Disease Society of America. FDA EUA for COVID-19 pre-exposure 
prophylaxis with long-acting monoclonals is a key proof of concept. 2021. Available 
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exposure-prophylaxis-with-long-acting-monoclonals-is-a-key-proof-of-concept/. 
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US Food and Drug Administration. Fact sheet for healthcare providers emergency use 
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inhibitor clinical candidate for the treatment of COVID-19. Science. 
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Assess the Pharmacokinetics, Safety and Tolerability of PF-07321332 Boosted With 
Ritonavir in Adult Participants With Renal Impairment and in Healthy Participants 
With Normal Renal Function. Clinical Study Report. 19 November 2021. 
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CDC. COVID-19. May 2020. Available from: 
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31. 
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US Bureau of Labor Statistics. (2021). Effects of COVID-19 Pandemic on 
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costs-statistics.htm. Accessed on: 26 May 2022. 
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Ramos-Goni JM, Pinto-Prades JL, Oppe M, et al. Valuation and Modeling of EQ-5D- 
5L Health States Using a Hybrid Approach. Med Care. 2017;55(7):e51-e58. 
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and responsiveness. Eur J Health Econ. 2015;16(9):927-39. 
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Janssen MF, Pickard AS, Golicki D, et al. Measurement properties of the EQ-5D-5L 
compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual 
Life Res. 2013;22(7):1717-27. 
39. 
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the 
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Agborsangaya CB, Lahtinen M, Cooke T, et al. Comparing the EQ-5D 3L and 5L: 
measurement properties and association with chronic conditions and multimorbidity 
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EuroQol G. EuroQol--a new facility for the measurement of health-related quality of 
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U.S. Department of Health and Human Services NIoH, National Heart, Lung, and 
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U.S. Department of Health and Human Services NIoH, National Institute of Allergy 
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SAP_001.pdf: 
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Protocol C4671034
AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2, RANDOMIZED, 
DOUBLE-BLIND, 3-ARM STUDY TO INVESTIGATE 
NIRMATRELVIR/RITONAVIR IN NONHOSPITALIZED PARTICIPANTS AT 
LEAST 12 YEARS OF AGE WITH SYMPTOMATIC COVID-19 WHO ARE 
IMMUNOCOMPROMISED
Statistical Analysis Plan 
(SAP)
Version:
1.0
Date:
28 Apr 2023  
Version:
2.0
Date:
03-AUG-2023


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................7
2.1. Modifications to the Analysis Plan Described in the Protocol..................................7
2.2. Study Objectives, Endpoints, and Estimands............................................................8
2.2.1. Primary Estimand(s).....................................................................................9
2.2.2. Secondary Estimand(s)...............................................................................10
2.3. Study Design ...........................................................................................................10
2.4. Sample Size Determination.....................................................................................11
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................12
3.1. Primary Endpoint(s) ................................................................................................12
3.2. Secondary Endpoint(s) ............................................................................................12
3.3. Other Endpoint(s)....................................................................................................13
3.4. Baseline Variables...................................................................................................13
3.5. Safety Endpoints .....................................................................................................14
3.5.1. Adverse Events...........................................................................................14
3.5.2. Laboratory Data..........................................................................................14
3.5.3. Vital Signs ..................................................................................................15
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................15
5.1. Hypotheses and Decision Rules ..............................................................................15
5.2. General Methods .....................................................................................................15
5.2.1. Analyses for Binary Endpoints...................................................................16
5.2.2. Analyses for Continuous Endpoints ...........................................................16
5.2.3. Analyses for Time-to-Event Endpoints ......................................................16
5.3. Methods to Manage Missing Data ..........................................................................16
6. ANALYSES AND SUMMARIES ......................................................................................16
6.1. Primary Endpoint(s) ................................................................................................16


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6.1.1. Main Analysis.............................................................................................16
6.1.2. Sensitivity/Supplementary Analyses ..........................................................17
6.2. Secondary Endpoint(s) ............................................................................................17
6.2.1. Time to first NP swab SARS-CoV-2 RNA<LLOQ (<2.0 log10
copies/mL) for participants with NP swab SARS-CoV-2 RNA ≥LLOQ 
at baseline.........................................................................................................17
6.2.1.1. Main Analysis ...........................................................................17
6.2.2. Time to sustained NP swab SARS-CoV-2 RNA <LLOQ (<2.0 log10
copies/mL) through Day 44 for participants with NP swab SARS-CoV-2 
RNA ≥LLOQ at baseline ...............................................................................18
6.2.3. Proportion of participants with SARS-CoV-2 RNA <LLOQ in 
plasma over time..............................................................................................19
6.2.4. Proportion of participants with SARS-CoV-2 RNA level in NP 
swabs <2.0 log10 copies/mL at each study visit...............................................19
6.2.5. Change from baseline in SARSCoV-2 RNA level in NP swabs and 
in plasma over time..........................................................................................19
6.2.6. Rebound in SARS-CoV-2 RNA level in NP swabs ...................................19
6.2.7. Incidence of TEAEs....................................................................................20
6.2.8. Incidence of SAEs and AEs leading to discontinuations............................20
6.2.9. Proportion of participants with COVID-19-related hospitalization 
>24 hours, or death from any cause through Day 28.......................................20
6.2.10. Proportion of participants with death (all cause) through Week 24 .........20
6.2.11. Proportion of participants with COVID-19-related hospitalization 
of any duration.................................................................................................20
6.2.12. Proportion of participants with COVID-19-related ICU admission 
of any duration.................................................................................................21
6.2.13. Proportion of participants requiring invasive mechanical ventilation 
or ECMO..........................................................................................................21
6.2.14. Number of days in hospital and ICU stay in participants with 
COVID-19-related hospitalization...................................................................21
6.2.15. Number of COVID-19-related medical visits through Day 44 and 
through Week 24..............................................................................................21
6.2.16. Duration of each targeted COVID-19 signs/symptoms............................21
6.2.17. Proportion of participants with severe signs/symptoms attributed to 
COVID-19 through Day 44 .............................................................................22
6.2.18. Nirmatrelvir and ritonavir PK in plasma and whole blood.......................22


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6.2.19. Other Endpoint(s) .....................................................................................22
6.3. Subset Analyses.......................................................................................................23
6.4. Baseline and Other Summaries and Analyses.........................................................23
6.4.1. Baseline Summaries....................................................................................23
6.4.2. Study Conduct and Participant Disposition................................................24
6.4.3. Study Treatment Exposure .........................................................................24
6.4.4. Concomitant Medications and Nondrug Treatments..................................24
6.5. Safety Summaries and Analyses .............................................................................24
6.5.1. Adverse Events...........................................................................................24
6.5.2. Laboratory Data..........................................................................................25
6.5.3. Vital Signs ..................................................................................................25
6.5.4. Electrocardiograms.....................................................................................25
7. INTERIM ANALYSES.......................................................................................................25
7.1. Interim Analyses and Summaries............................................................................25
7.2. Data Monitoring Committee ...................................................................................25
8. APPENDICES .....................................................................................................................26


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LIST OF TABLES
Table 1.
Summary of Changes..................................................................................6
Table 2.
Width of 95% CI for the Proportion of Participants with Sustained 
NP Swab SARS-CoV-2 RNA <LLOQ.....................................................12
LIST OF FIGURES
Figure 1.
C4671034 Study Design...........................................................................11
APPENDICES
Appendix 1 - Summary of Efficacy Analyses was modified to provide clarification on 
statistical method. .......................................................................................7
Appendix 1. Summary of Efficacy Analyses...........................................................................26
Appendix 2. Data Derivation Details.......................................................................................30
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................30
Appendix 3. List of Abbreviations...........................................................................................31


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
28 Apr 2023
Original 
N/A
SAP Original Version
2
30 Jun 2023
Original
To add 
subgroup 
analysis of 
primary 
endpoint by 
symptoms 
onset and 
provide 
clarification in 
section 6 of the 
SAP

Section 4: Exclude site 1001 from 
all efficacy analysis.

Section 4 was amended to delete the 
paragraph about multiple enrollers 
as it is not applicable.

Section 6.1.1 was modified to add 
statistical methodology for primary 
endpoint. 

Section 6.1.2: added sensitivity
analysis of primary endpoint 
excluding all participants from site
1030.

Section 6.2.16 modified to add 
censoring method and definition 
signs and symptoms 
alleviation/resolution for duration of 
signs and symptoms endpoint.

Section 6.3 modified to add 
subgroup analysis of primary 
endpoint as follows: Duration since 
first symptom (<= 5 days, > 5 days
<=30, >30)

Section 6.3 was modified to remove 
the subgroup analysis of primary 
endpoint by baseline serology
(positive, negative) as it is not 
applicable in this study.


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Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
Appendix 1 - Summary of Efficacy 
Analyses was modified to provide 
clarification on statistical method.
2. INTRODUCTION
Patients with COVID-19 who are immunocompromised are at increased risk of progressing 
to severe illness due to prolonged infection, limited contribution by the immune system in 
clearing the infection, and increased potential for viral resistance. Emergence of variants that 
are resistant to available treatment also puts the wider population at risk. Patients who are 
immunocompromised may benefit from extended treatment durations. The purpose of the 
study is to evaluate the efficacy and safety of nirmatrelvir/ritonavir 5, 10, and 15-day dosing 
durations for the treatment of COVID-19 in nonhospitalized symptomatic participants 
≥12 years of age and weigh ≥40 kg who are immunocompromised (main study population).
In addition, this study will also evaluate the efficacy and safety of a second treatment course 
of nirmatrelvir/ritonavir (5-, 10-, or 15-days) in an additional population of nonhospitalized 
symptomatic participants who are immunocompromised with a rebound in COVID-19 within 
14 days following completion of an initial 5-day treatment course of nirmatrelvir/ritonavir 
(population with rebound). 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C4671034.  
2.1. Modifications to the Analysis Plan Described in the Protocol
Not Applicable.


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2.2. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
To describe the effect of 
nirmatrelvir/ritonavir on viral RNA 
levels in NP swabs over time for the 
treatment of COVID-19 in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised.
Proportion of participants with 
sustained NP swab SARS-CoV-2 
RNA <LLOQ (defined as <2.0 log10
copies/mL) from Day 15 through 
Day 44.
The proportion of participants with 
sustained NP swab SARS-CoV-2 
RNA <LLOQ (defined as <2.0 log10
copies/mL) from Day 15 through 
Day 44 in nonhospitalized, 
symptomatic patients ≥12 years of 
age with COVID-19 who are 
immunocompromised. This will be 
estimated without regard to study 
treatment discontinuation and 
considering participants receiving 
non-study antiviral or monoclonal 
antibody therapy post-baseline for 
the treatment of COVID-19 as not 
achieving sustained NP swab 
SARS-CoV-2 RNA <LLOQ.
Secondary: 
Secondary:
Secondary: 
To describe the effect of 
nirmatrelvir/ritonavir treatment 
duration on the rate of sustained 
virologic clearance in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised.
Time to first NP swab SARS-CoV-2 
RNA<LLOQ (<2.0 log10 copies/mL) 
for participants with NP swab 
SARS-CoV-2 RNA ≥LLOQ at 
baseline.
Time to sustained NP swab 
SARS-CoV-2 RNA <LLOQ 
(<2.0 log10 copies/mL) through 
Day 44 for participants with NP 
swab SARS-CoV-2 RNA ≥LLOQ at 
baseline.
Not applicable.
To describe the effect of 
nirmatrelvir/ritonavir on viral 
clearance for the treatment of 
COVID-19 in nonhospitalized 
symptomatic participants ≥12 years 
of age with COVID-19 who are 
immunocompromised.
Proportion of participants with 
SARS-CoV-2 RNA <LLOQ in 
plasma over time.
Proportion of participants with 
SARS-CoV-2 RNA level in NP 
swabs <2.0 log10 copies/mL at each 
study visit through Day 44.
Change from baseline in 
SARS-CoV-2 RNA level in NP 
swabs and in plasma over time.
Rebound in SARS-CoV-2 RNA 
level in NP swabs at follow up (ie, 
any study visit after end of treatment 
through Day 44) that is defined as a 
half (0.5) log10 copies/mL increase 
or greater in SARS-CoV-2 RNA 
level relative to end of treatment 
SARS-CoV-2 RNA level based on 
treatment regimen, with a follow-up 
viral RNA level ≥2.5 log10
copies/mL.
Not applicable.
To describe the safety and 
tolerability of nirmatrelvir/ritonavir 
for the treatment of COVID-19 in 
Incidence of TEAEs.
Incidence of SAEs and AEs leading 
to discontinuations.
Not applicable.


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Objectives
Endpoints
Estimands
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised.
To describe the effect of 
nirmatrelvir/ritonavir on 
hospitalization and all-cause 
mortality in nonhospitalized 
symptomatic participants ≥12 years 
of age with COVID-19 who are 
immunocompromised.
Proportion of participants with 
COVID-19-related hospitalization 
>24 hours, or death from any cause 
through Day 28.
Proportion of participants with death 
(all cause) through Week 24.
Not applicable.
To describe COVID-19 related 
healthcare resource utilization in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised and treated 
with nirmatrelvir/ritonavir.
Proportion of participants with 
COVID-19-related hospitalization of 
any duration.
Proportion of participants with 
COVID-19-related ICU admission 
of any duration.
Proportion of participants requiring 
invasive mechanical ventilation or 
ECMO.
Number of days in hospital and ICU 
stay in participants with 
COVID-19-related hospitalization.
Number of COVID-19-related 
medical visits through Day 44 and 
through Week 24.
Not applicable.
To evaluate nirmatrelvir/ritonavir 
for the duration and severity of 
signs and symptoms in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised.
Duration of each targeted COVID-
19 signs/symptoms. 
Proportion of participants with 
severe signs/symptoms attributed to 
COVID-19 through Day 44.
Not applicable.
To determine the PK of 
nirmatrelvir/ritonavir in 
nonhospitalized symptomatic 
participants ≥12 years of age with 
COVID-19 who are 
immunocompromised.
Nirmatrelvir and ritonavir PK in 
plasma and whole blood (if feasible).
Not applicable.
2.2.1. Primary Estimand(s)
The primary estimand, reported separately for the main study population and the population 
with rebound, is the proportion of participants with sustained NP swab SARS-CoV-2 RNA 
<LLOQ (defined as <2.0 log10 copies/mL) from Day 15 through Day 44 in nonhospitalized 
symptomatic patients ≥12 years of age with COVID-19 who are immunocompromised. This 
will be estimated without regard to study treatment discontinuation and considering
participants receiving non-study antiviral or monoclonal antibody therapy post-baseline for 
the treatment of COVID-19 as not achieving sustained NP swab SARS-CoV-2 RNA 
<LLOQ.


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2.2.2. Secondary Estimand(s)
Not Applicable.
2.3. Study Design
This Phase 2, randomized, double-blind, study will evaluate the efficacy and safety of 
nirmatrelvir/ritonavir (5-, 10-, and 15-day dosing durations) for the treatment of COVID-19 
in approximately 150 nonhospitalized symptomatic participants aged at least 12 years and 
weigh ≥40 kg who are immunocompromised (main study population). In addition, this study 
will also evaluate the efficacy and safety of a second treatment course of 
nirmatrelvir/ritonavir (5-, 10-, or 15-days) in an additional population of nonhospitalized 
symptomatic participants who are immunocompromised with a rebound in COVID-19 within 
14 days following completion of an initial 5-day treatment course of nirmatrelvir/ritonavir 
(population with rebound).
Participants in the additional population with rebound will be recruited during the enrollment 
phase for the main study population. Enrollment of the population with rebound will stop 
after the main study population is fully enrolled or after 50 participants in the population with 
rebound have been enrolled, whichever occurs sooner.
Eligible participants (main study population and additional population with rebound) for this 
study will be randomly assigned (1:1:1) to receive:

nirmatrelvir plus ritonavir orally q12h for 5 days followed by placebo for nirmatrelvir 
plus ritonavir q12h for 10 days; or

nirmatrelvir plus ritonavir orally q12h for 10 days followed by placebo for nirmatrelvir 
plus ritonavir q12h for 5 days; or 

nirmatrelvir plus ritonavir orally q12h for 15 days.
Participants will be screened on the same day as randomization or 1 calendar day before 
randomization. For the main study population, enrollment of participants considered 
immunocompromised based solely on receiving corticosteroids or TNF blockers will be 
capped at approximately 25%. Enrollment of participants considered immunocompromised 
based solely on receiving corticosteroids or TNF blockers in the additional population with 
rebound will not be capped.
For the main study population, randomization will be stratified by those who are considered 
immunocompromised solely based on corticosteroids or TNF blocker use (yes/no; see 
Protocol Section 10.9.4 Point #4). Randomization for the population with rebound will not be 
stratified by those who are considered immunocompromised solely based on corticosteroids 
or TNF blocker use.
The total study duration is up to 24 weeks, including study intervention administration 
through Day 15 or Day 16, safety assessments through Day 44, efficacy assessments through 
Week 24, and long-term follow-up at Weeks 12 and 24. 


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Figure 1.
C4671034 Study Design
Analyses will be conducted after the main study population is fully enrolled and have 
completed the Day 44 visit regardless of the number of randomized participants in the 
population with rebound. There will be 2 analysis time points for reporting the results of this 
study. The primary analysis will be performed after all participants in the main study 
population have completed the Day 44 visit. The follow-up analysis will be performed after 
all participants in the main study population have completed the Week 24 visit. In addition, 
both analyses (primary and follow-up) will include separate results for the main study 
population and the additional population with rebound.
An independent E-DMC will review unblinded data to ensure the safety of participants on an 
ongoing basis throughout the duration of the study.
2.4. Sample Size Determination
Up to approximately 200 participants will be enrolled in this study.
The study will randomize approximately 150 participants in a 1:1:1 randomization ratio, 
resulting in approximately 50 participants in each treatment arm (main study population). In 
addition, the study will also enroll up to 50 additional nonhospitalized symptomatic 
participants (in a 1:1:1 randomization ratio) who are immunocompromised with a rebound in 
COVID-19 within 14 days following completion of an initial 5-day treatment course of
nirmatrelvir/ritonavir (population with rebound).
Analyses will be conducted after the main study population is fully enrolled and have 
completed the Day 44 visit regardless of the number of randomized participants in the 
population with rebound. There will be 2 analysis time points for reporting the results of this 
study. The primary analysis will be performed after all participants in the main study 
population have completed the Day 44 visit. The follow-up analysis will be performed after 
all participants in the main study population have completed the Week 24 visit. In addition, 
both analyses (primary and follow-up) will include separate results for the main study 
population and the additional population with rebound.
As no formal hypothesis testing will be performed for this study, no power calculation was 
carried out to assess the number of participants required for each treatment arm. For the main 
study population, the goal of the primary analysis is to estimate the treatment effect for each 
duration of nirmatrelvir/ritonavir. The smaller numbers of participants in these groups will be 
reflected in the precision of the estimate of the primary endpoint. Table 2 displays which 
effect sizes would be excluded based on the expected width of the confidence interval around 


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the estimate of the proportion of participants with sustained NP swab SARS-CoV-2 RNA 
<LLOQ (defined as <2.0 log10 copies/mL) from Day 15 through Day 44 with a sample size 
of 50.  
When the proportion of participants with sustained NP swab SARS-CoV-2 RNA <LLOQ 
from Day 15 through Day 44 ranges from 0.1 to 0.5, Table 2 displays the precision (width of 
the confidence interval) for the respective proportion to be estimated with a sample size of 
50. That is, the width of the 95% CI does not exceed 14%.
Table 2.
Width of 95% CI for the Proportion of Participants with Sustained NP 
Swab SARS-CoV-2 RNA <LLOQ 
Nirmatrelvir/Ritonavir (n=50)
Proportion of Participants With Sustained Viral 
RNA level <LLOQ
Width of CI
0.1
0.083
0.2
0.111
0.3
0.127
0.4
0.136
0.5
0.139
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
The primary endpoint, summarized separately for the main study population and the 
population with rebound, is the proportion of participants with sustained NP swab SARS-
CoV-2 RNA <LLOQ (defined as <2.0 log10 copies/mL) from Day 15 through Day 44.
Sustained is defined as NP swab SARS-CoV-2 RNA level not ≥2.0 log10 copies/mL at any 
study visit (through Day 44) following the first study visit where the participant's NP swab 
SARS-CoV-2 RNA <LLOQ.
3.2. Secondary Endpoint(s)
Secondary endpoints include:

Time to first NP swab SARS-CoV-2 RNA<LLOQ (<2.0 log10 copies/mL) for 
participants with NP swab SARS-CoV-2 RNA ≥LLOQ at baseline.

Time to sustained NP swab SARS-CoV-2 RNA <LLOQ (<2.0 log10 copies/mL) 
through Day 44 for participants with NP swab SARS-CoV-2 RNA ≥LLOQ at 
baseline.

Proportion of participants with SARS-CoV-2 RNA <LLOQ in plasma over time.


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
Proportion of participants with SARS-CoV-2 RNA level in NP swabs <2.0 log10
copies/mL at each study visit through Day 44.

Change from baseline in SARS-CoV-2 RNA level in NP swabs and in plasma over 
time.

Rebound in SARS-CoV-2 RNA level in NP swabs at follow up (ie, any study visit 
after end of treatment through Day 44) that is defined as a half (0.5) log10 copies/mL 
increase or greater in SARS-CoV-2 RNA level relative to end of treatment SARS-
CoV-2 RNA level based on treatment regimen, with a follow-up viral RNA level ≥2.5 
log10 copies/mL.

Incidence of TEAEs.

Incidence of SAEs and AEs leading to discontinuations.

Proportion of participants with COVID-19-related hospitalization >24 hours, or death 
from any cause through Day 28.

Proportion of participants with death (all cause) through Week 24.

Proportion of participants with COVID-19-related hospitalization of any duration.

Proportion of participants with COVID-19-related ICU admission of any duration.

Proportion of participants requiring invasive mechanical ventilation or ECMO.

Number of days in hospital and ICU stay in participants with COVID-19-related 
hospitalization.

Number of COVID-19-related medical visits through Day 44 and through Week 24.

Duration of each targeted COVID-19 signs/symptoms.

Proportion of participants with severe signs/symptoms attributed to COVID-19 
through Day 44.

Nirmatrelvir and ritonavir PK in plasma and whole blood (if feasible).
3.3. Other Endpoint(s)
Not applicable for this study.
3.4. Baseline Variables
For viral load data from NP swabs, the baseline window is set up according to study days of 
Day -2 to Day 1. Only results for samples collected within up to 1 hour post start of dosing 
will be treated as baseline data. This implies that if there is any issue with the Baseline (Day 


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1) measurement (eg, missing, undetectable, taken >1 hour post dose), then the screening 
measurement, if available, will be utilized as the baseline value.  If the screening 
measurement is not available and the Day 1 measurement is undetectable and taken ≤1 hour 
post dose, then the baseline will be considered undetectable.  If the screening measurement is 
not available and the Day 1 measurement is missing or taken >1 hour post dose, then the 
baseline will be considered missing.
For viral load data from plasma samples, the baseline window will be Day -2 to Day 1, but 
only results for samples collected within up to 1 hour post start of dosing will be treated as 
baseline.
For laboratory assessments, COVID-19 signs and symptoms, and vital signs, the baseline 
window will be Day -2 to Day 1, without any consideration to the time factor. 
The following baseline variables will be used in efficacy analysis summarization. See below 
a list of derived baseline variables: 

eGFR/eCrCl (POC value) categories: Normal (≥90), Mild Impairment (≥60 to <90), 
Moderate Impairment (≥30 to <60), and Severe Impairment (<30).

Participants considered immunocompromised based solely on receiving 
corticosteroids or TNF blockers (yes/no)
3.5. Safety Endpoints
The safety endpoints of this study are: 

Incidence of TEAEs. 

Incidence of SAEs and AEs leading to discontinuations. 
Clinical Data Interchange Standards Consortium (CDISC) and Pfizer Standards (CaPS) will 
be used for the analysis of standard safety data.
3.5.1. Adverse Events
An adverse event (AE) is any untoward medical occurrence in a study participant 
administered a product or medical device; the event need not necessarily have a causal 
relationship with the treatment or usage. An adverse event is considered a Treatment-
Emergent Adverse Event (TEAE) if the event started on or after the study medication start 
date. Since time of AE is not collected, AEs that begin on day 1, even if prior to study 
treatment start, will be considered TEAE.
3.5.2. Laboratory Data
Laboratory data includes hematology, chemistry, and other safety tests. To determine if there 
are any clinically significant laboratory abnormalities, the hematological and clinical 
biochemistry and other safety tests will be assessed against the criteria specified in the Pfizer 


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reporting standards. This assessment will take into account whether each participant’s 
baseline test results are within or outside the laboratory reference range for a particular 
laboratory parameter.
3.5.3. Vital Signs
Vital sign measurements, including temperature, pulse rate, respiratory rate, oxygen 
saturation level, and blood pressure.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
For purposes of analysis, the following analysis sets are defined (excluding participants from 
Site 1001 from all efficacy analyses):
Participant Analysis Set
Description
Full analysis set (FAS)
All participants randomly assigned to study intervention.
Evaluable analysis set/Safety 
Analysis Set (SAS)
All participants randomly assigned to study intervention 
and who take at least 1 dose of study intervention. 
The evaluable analysis set will be the primary analysis set for evaluating the primary 
estimand.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
No formal hypothesis testing will be performed for this study. 
5.2. General Methods
All data will be presented by treatment group. Descriptive statistics will be provided for all 
endpoints. 
The number of participants screened, randomized to the double-blind treatment phase, 
completing the study drug administration, and completing the study will be summarized from 
the FAS. The reason for all discontinuations will be summarized by treatment group. 
Baseline demographic and other characteristics will be tabulated for the FAS and 
summarized by treatment group. Quantitative variables will be described by standard 
descriptive statistics (mean, standard deviation, median and range), and qualitative variables 
will be summarized by frequency tables with number and proportion in each category (with 
the corresponding sample sizes).


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5.2.1. Analyses for Binary Endpoints
For binary endpoints (eg, proportion of participants with SARS-CoV-2 RNA <LLOQ in 
plasma over time, proportion of participants with COVID-19-related hospitalization >24 
hours, or death from any cause through Day 28, etc), proportion of participants with the event 
will be summarized for each group.
5.2.2. Analyses for Continuous Endpoints
For continuous endpoints, (eg, change from baseline in SARS-CoV-2 RNA level in NP 
swabs and in plasma over time), results and/or changes from baseline over time, as applicable 
will be summarized with descriptive statistics (mean, SD, etc).
5.2.3. Analyses for Time-to-Event Endpoints
For time-to-event endpoints (eg, time to first NP swab SARS-CoV-2 RNA<LLOQ [<2.0 
log10 copies/mL] for participants with NP swab SARS-CoV-2 RNA ≥LLOQ at baseline), 
Kaplan-Meier analysis where tabular summaries of the Kaplan-Meier curves providing the
median and quartiles, will be provided for each treatment group. In addition, the Kaplan-
Meier curves will be presented graphically.
5.3. Methods to Manage Missing Data
For SARS-CoV-2 RNA data, samples producing a result of <LLOQ or undetectable will not 
be considered missing, but rather will be imputed using values of 1.7 [log10(50)] or 0.0 log10
copies/mL, respectively. Missing SARS-CoV-2 RNA data will not be imputed.
As all analyses are descriptive, missing endpoint data will result in a summary where the N 
for that endpoint (and time point) is smaller than the total N of the corresponding analysis 
set. No imputation of the missing data will be performed. 
For safety data, missing and partial dates will be programmatically handled according to 
Pfizer standards.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
The primary endpoint, summarized separately for the main study population and the 
population with rebound, is the proportion of participants with sustained NP swab SARS-
CoV-2 RNA <LLOQ (defined as <2.0 log10 copies/mL) from Day 15 through Day 44.
Sustained is defined as NP swab SARS-CoV-2 RNA level not ≥2.0 log10 copies/mL at any 
study visit (through Day 44) following the first study visit where the participant's NP swab 
SARS-CoV-2 RNA <LLOQ.
6.1.1. Main Analysis  
The primary descriptive analysis will summarize, separately for the main study population 
and the population with rebound, the number and proportion of participants with sustained 
NP swab SARS-CoV-2 RNA <LLOQ (defined as <2.0 log10 copies/mL) from Day 15
through Day 44 for each treatment arm in the Evaluable Analysis Set and FAS. Participants 


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receiving non-study antiviral or monoclonal antibody therapy post-baseline (between 
randomization and Day 44 visit) for the treatment of COVID-19 will be considered as not 
achieving sustained NP swab SARS-CoV-2 RNA <LLOQ in the primary analysis.
As viral load measurements from NP swabs are taken on Days 15, 21, 28, 35, and 44 during 
the time interval from Day 15 to Day 44, all of the measurements that are non-missing must 
be <LLOQ (including undetectable), and the Day 15, Day 44, and no more than one of the 
Day 21, 28, and 35 measurements can be missing in order for the event to be considered 
sustained.  
In addition, 95% CIs for the proportion of participants with sustained NP swab SARS-CoV-2 
RNA <LLOQ from Day 15 through Day 44 for each treatment arm will be calculated using 
binomial distribution normal approximation. The difference in proportions for the primary 
endpoint and associated 95% CI will be calculated for each pairwise comparison of the 
treatment arms.
6.1.2. Sensitivity/Supplementary Analyses
Supplemental analyses will be performed for the primary efficacy endpoint:
1. An analysis of the primary endpoint will be conducted excluding data after the date of 
non-study antiviral or monoclonal antibody start for participants that received non-
study antiviral or monoclonal antibody therapy post-baseline (between randomization 
and Day 44) for the treatment of COVID-19.
2. An analysis of the primary endpoint will be conducted to include all NP swab SARS-
CoV-2 RNA data regardless of whether participants received non-study antiviral or 
mAb treatment post-baseline (between randomization and Day 44) for the treatment 
of COVID-19.
3. An analysis of the primary endpoint will be conducted where participants with 
baseline SARS-CoV-2 RNA level <LLOQ will be excluded.
4. An analysis of the primary endpoint will be conducted where participants who do not 
meet the protocol-defined immunocompromised criteria will be excluded.
5. An analysis of the primary endpoint will be conducted excluding participants from
site 1030.
6.2. Secondary Endpoint(s)
6.2.1. Time to first NP swab SARS-CoV-2 RNA<LLOQ (<2.0 log10 copies/mL) for 
participants with NP swab SARS-CoV-2 RNA ≥LLOQ at baseline
6.2.1.1. Main Analysis
Time (days) to first NP swab SARS-CoV-2 RNA<LLOQ (<2.0 log10 copies/mL) will be 
evaluated for participants with NP swab SARS-CoV-2 RNA ≥LLOQ at baseline. The first 
day of NP swab SARS-CoV-2 RNA<LLOQ will be considered the First Event Date. Time 


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(days) to first NP swab SARS-CoV-2 RNA<LLOQ will be calculated as (First Event Date) –
(First Dose Date) +1. 
There are limitations to the timing of the first event date as NP viral RNA is generally only 
captured at in-person scheduled visits during the study. 
The Day 44 visit day is the last possible day the NP swab SARS-CoV-2 RNA<LLOQ can be 
achieved.
For a participant that either completes the Day 44 visit of the study or discontinues from the 
study before the Day 44 visit without NP swab SARS-CoV-2 RNA<LLOQ (censored), 
censoring date will be at the last date on which NP swab SARS-CoV-2 RNA is assessed, and 
time will be calculated as (Censoring Date) – (First Dose Date) +1 or the Day 44 visit
whichever occurs first.
Time to NP swab SARS-CoV-2 RNA<LLOQ will be summarized graphically using Kaplan-
Meier plots for each of the treatment groups in main study population.
6.2.2. Time to sustained NP swab SARS-CoV-2 RNA <LLOQ (<2.0 log10 copies/mL) 
through Day 44 for participants with NP swab SARS-CoV-2 RNA ≥LLOQ at baseline
Time (days) to sustained NP swab SARS-CoV-2 RNA<LLOQ (<2.0 log10 copies/mL) will be 
evaluated. Sustained is defined as NP swab SARS-CoV-2 RNA level not ≥2.0 log10
copies/mL at any study visit (through Day 44) following the first study visit where the 
participant's NP swab SARS-CoV-2 RNA <LLOQ. 
Let t represent the number of days between 5 and 35 inclusive for which there is a protocol-
specified measurement of SARS-CoV-2 RNA level on Day t. 
Then a sustained event will correspond to the first possible value of t to satisfy the following 
criteria:
a) The Day 44 SARS-CoV-2 RNA level is <LLOQ 
b) The Day t SARS-CoV-2 RNA level is <LLOQ 
c) All available (non-missing) protocol-specified SARS-CoV-2 RNA measurements 
between Day t and Day 44 are <LLOQ 
d) No more than one of the protocol-specified SARS-CoV-2 RNA measurements 
between Day t and Day 44 are missing.
There are limitations to the timing of the first event date as NP viral RNA is generally only 
captured at in-person scheduled visits during the study. 
The Day 35 visit is the last possible day the sustained NP swab SARS-CoV-2 RNA<LLOQ 
can be achieved.


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The time to the sustained event is defined as:

For a participant with sustained event at Day t, the First Event Date is the date of the 
Day t measurement, and time to event will be calculated as (First Event Date) – (First 
Dose Date) +1.

For a participant for which no possible value of t ≤ the 35 visit satisfies the criteria for 
a sustained event (censored), censoring date will be the date of the last available 
protocol-specified SARS-CoV-2 RNA measurement other than Day 44, and time will 
be calculated as (Censoring Date) – (First Dose Date) +1.
Time to sustained NP swab SARS-CoV-2 RNA<LLOQ will be summarized graphically 
using Kaplan-Meier plots for each of the treatment groups in main study population.
6.2.3. Proportion of participants with SARS-CoV-2 RNA <LLOQ in plasma over time.

The proportion of participants with SARS-CoV-2 RNA <LLOQ as measured in 
plasma will be summarized at each study visit through week 24 for each treatment arm. In 
addition, 95% CIs for the proportion of participants with SARS-CoV-2 RNA <LLOQ in 
plasma at each study visit will be calculated for each treatment arm.
6.2.4. Proportion of participants with SARS-CoV-2 RNA level in NP swabs <2.0 log10
copies/mL at each study visit 
The proportion of participants with SARS-CoV-2 RNA < 2.0 log10 copies/mL as measured 
by NP swab will be summarized at each study visit through Week 24 for each treatment arm. 
In addition, 95% CIs for the proportion of participants with SARS-CoV-2 RNA <2.0 log10
copies/mL as measured by NP swabs at each study visit will be calculated for each treatment 
arm.
6.2.5. Change from baseline in SARSCoV-2 RNA level in NP swabs and in plasma over 
time.
Descriptive statistics by treatment group for the change from baseline to each study visit 
(Day 5, 10, 15, 21, 28, 35, 44) will be provided. Participants are excluded from the analysis 
for reasons of Not Detected, Zero or Missing baseline and/or post-baseline viral load results. 
6.2.6. Rebound in SARS-CoV-2 RNA level in NP swabs 
Rebound in SARS-CoV-2 RNA level in NP swabs at follow up (ie, any study visit after end 
of active treatment through Day 44) that is defined as a half (0.5) log10 copies/mL increase or 
greater in SARS-CoV-2 RNA level relative to end of active treatment SARS-CoV-2 RNA 
level based on treatment regimen, with a follow-up viral RNA level ≥2.5 log10 copies/mL.
In addition, two alternative definitions of rebound will also be evaluated: 

Rebound that is defined as: SARS-CoV-2 RNA level in NP swabs at follow up 
(ie, any study visit after end of active treatment through Day 44) that is defined as 
a half (0.5) log10 copies/mL increase or greater in SARS-CoV-2 RNA level 


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relative to end of active treatment SARS-CoV-2 RNA level based on treatment 
regimen, with a follow-up viral RNA level ≥3.0 log10 copies/mL. 

Rebound that is defined as: SARS-CoV-2 RNA level in NP swabs at follow up 
(ie, any study visit after end of active treatment through Day 28) that is defined as 
a half (0.5) log10 copies/mL increase or greater in SARS-CoV-2 RNA level 
relative to end of active treatment SARS-CoV-2 RNA level based on treatment 
regimen, with a follow-up viral RNA level ≥3.0 log10 copies/mL. 
The rebound analyses will be restricted to those participants with non-missing end of active 
treatment SARS-CoV-2 RNA measurement and at least one non-missing measurement 
among the study visits after end of treatment through the Day 44 visit (or through the Day 28 
visit for the second alternative definition of rebound analysis).
6.2.7. Incidence of TEAEs

The incidence of TEAEs will be summarized by treatment group, by SOC and PT 
using the Safety Analysis Set.
6.2.8. Incidence of SAEs and AEs leading to discontinuations
The incidence of SAEs and AEs leading to discontinuation will be summarized by treatment 
group using the safety analysis set.
6.2.9. Proportion of participants with COVID-19-related hospitalization >24 hours, or 
death from any cause through Day 28
The proportion of participants with COVID-19-related hospitalization >24 hours, or death 
from any cause through Day 28 will be summarized. The cumulative proportion of 
participants hospitalized for the treatment of COVID-19 or death during the first 28 days of 
the study will be estimated for each treatment group using the Kaplan-Meier method to take 
account of losses to follow-up and summarized graphically for each treatment group.
For participants without an event who complete the Day 28 assessment, they will be censored 
at Day 28. For participants without an event who discontinue or are lost to follow-up before 
the Day 28 assessment, they will be censored at the last known date in the study.
6.2.10. Proportion of participants with death (all cause) through Week 24
The proportion of participants who died from any cause through Week 24 will be analyzed 
using the method specified in Section 6.2.9 and summarized for each treatment group. KM 
plots for each treatment group will also be provided.  Participants without an event will be 
censored at the last known date in the study.
6.2.11. Proportion of participants with COVID-19-related hospitalization of any 
duration
The proportion of participants with COVID-19-related hospitalization of any duration will be 
analyzed using the method specified in Section 6.2.9 and summarized by treatment arm


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through day 44 and through week 24. Participants without an event (at Day 44/Week 24) will 
be censored at that time or at the last known date in the study, whichever is later.
6.2.12. Proportion of participants with COVID-19-related ICU admission of any 
duration
The proportion of participants with COVID-19-related ICU admission of any duration will be 
analyzed using the method specified in Section 6.2.9 and summarized by treatment arm
through day 44 and through week 24. Participants without an event (at Day 44/Week 24) will 
be censored at that time or at the last known date in the study, whichever is later.
6.2.13. Proportion of participants requiring invasive mechanical ventilation or ECMO
The proportion of participants requiring invasive mechanical ventilation or ECMO will be 
analyzed using the method specified in Section 6.2.9 and summarized by treatment arm
through day 44 and through week 24. Participants without an event (at Day 44/Week 24) will 
be censored at that time or at the last known date in the study, whichever is later.
6.2.14. Number of days in hospital and ICU stay in participants with COVID-19-related 
hospitalization
The number of days of hospital stay and number of days of ICU stay in participants with 
COVID-19-related hospitalization will be summarized through Day 44 and through Week 24
by treatment group using descriptive statistics (ie, mean, median, range).
6.2.15. Number of COVID-19-related medical visits through Day 44 and through Week 
24
The number of COVID-19-related medical visits through Day 44 and through Week 24 will 
be summarized by treatment group using descriptive statistics (ie, mean, median, range).
6.2.16. Duration of each targeted COVID-19 signs/symptoms
Duration of each targeted COVID -19 signs/symptoms is defined as (First Date when the 
symptom alleviated/resolved) – (First Dose Date) +1 for each participant with baseline 
severity of mild, moderate, or severe.
For a participant that either completes the Day 44 visit of the study or discontinues from the 
study before the Day 44 visit without alleviation/resolution of signs/symptoms (censored), 
censoring date will be at the date of discontinuation from the study or day 44 whichever
comes first, and time will be calculated as (Censoring Date) – (First Dose Date) +1. 
Symptoms Alleviation through day 44 of each targeted COVID-19 sign/symptom is defined 
as the first time when each targeted symptom scored as moderate or severe at study entry are 
scored as mild or absent AND a targeted symptom scored mild or absent at study entry are 
scored as absent.
Symptoms Resolution through day 44 of each targeted COVID-19 sign/symptom is defined 
as the first time when each targeted symptom scored as mild, moderate or severe at study
entry are scored as absent. 


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For symptoms with no reported severity in baseline, the symptom will have to be absent in 
order to be counted as alleviated/resolved (missing severity at baseline will be treated as 
mild).
For duration of each targeted COVID19 sign/symptom, a Kaplan-Meier analysis providing 
the event rate, median and quartiles will be provided for each treatment arm.
6.2.17. Proportion of participants with severe signs/symptoms attributed to COVID-19 
through Day 44
Participants will record a daily severity rating of their symptom severity over the past 24 
hours based on a 4-point scale in which 0 is reported if no symptoms were present; 1 if mild; 
2 if moderate; and 3 if severe. 
Vomiting and diarrhea will each be rated on a 4-point frequency scale where 0 is reported for 
no occurrence, 1 for 1 to 2 times, 2 for 3 to 4 times, and 3 for 5 or greater. Sense of smell and 
sense of taste will each be rated on a 3-point Likert scale where 0 is reported if the sense of 
smell/taste was the same as usual, 1 if the sense of smell/taste was less than usual, and 2 for 
no sense of smell/taste.
The proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 through Day 44 will be summarized by treatment group. A participant with 
severe score for any targeted symptoms post-baseline will be counted as severe. Additionally, 
the proportion of participants reporting the presence of each targeted sign and symptom that 
is mild, moderate, or severe categories over time will also be presented. 
In addition, to understand the severity of signs/symptoms attributed to COVID-19, the 
following analysis will be performed:
1. Proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 at DAY 1 (baseline). 
2. Proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 Day 2 to end of active study treatment (during treatment; treatment arm 
dependent). 
3. Proportion of participants with any severe targeted signs/symptoms attributed to 
COVID-19 from end of active treatment to Day 44 (post treatment). 
6.2.18. Nirmatrelvir and ritonavir PK in plasma and whole blood
Nirmatrelvir and ritonavir PK in plasma and whole blood (if feasible) will be performed and 
summarized by the PK/PD group.
6.2.19. Other Endpoint(s)
Not applicable for this study.


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6.3. Subset Analyses
Subgroup analysis will be performed for the main study population as numbers permit and 
results will be summarized only. Subgroup analyses of the primary endpoint will include: 

age group (<65, ≥65 and <18; ≥18);

Sex (Male, Female);

Race (White, Black or African American, Asian, Other);

Ethnicity (Hispanic/Latino, Not Hispanic/Latino);

BMI category (<25, 25-29, ≥30);

Immunocompromised Category (stratification factor*): Participants considered 
immunocompromised based solely on receiving corticosteroids or TNF blockers (yes/no)

Baseline viral load defined as: < 104 copies/mL vs ≥104 copies/mL

Baseline viral load defined as: < 107 copies/mL vs ≥107 copies/mL);

Duration since first symptom (<= 5 days, > 5 days <= 30, >30)

Vaccination status (unvaccinated or received last vaccination more than 6 months prior to 
randomization vs received last vaccination within 6 months prior to randomization)

*: Participants will be analyzed according to the category as determined by the CRF 
data and not according to the category selected at randomization (when different).

Subgroup analysis is not planned for the population with rebound, but may be 
performed if numbers permit.
6.4. Baseline and Other Summaries and Analyses
6.4.1. Baseline Summaries
The demographic characteristics will be summarized by treatment group within the FAS. 
This will include age, sex, race, ethnicity, baseline height, baseline weight, BMI, 
eGFR/eCrCl, renal function category, and region. Renal function will be based on the 
baseline eGFR/eCrCl (mL/min/1.73 m2) using the following categories: Normal (≥90), Mild 
Impairment (≥60 to <90), Moderate Impairment (≥30 to <60), and Severe Impairment (<30). 
All baseline disease characteristics, including COVID-19 disease (e.g., vaccination status, 
baseline serology, baseline viral load) and immunocompromised disease characteristics, will 
be summarized by treatment group within the FAS.


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6.4.2. Study Conduct and Participant Disposition
Participant evaluation groups will be presented for all enrolled participants, and participant 
disposition will be summarized within the FAS population. The number of participants, 
treated, completing, and discontinuing by study phase, as well as the number of participants 
in each analysis set will be summarized by treatment group. For participants who did not 
complete the study, the reasons for withdrawal from the study will be presented. 
6.4.3. Study Treatment Exposure
Duration of treatment will be summarized within the SAS population. The duration of 
treatment will be calculated as follows: 
Duration of treatment = Date of last dose of study drug - date of first dose of study drug +1.
Compliance over the whole treatment period will be calculated as follows: 
Compliance = _____Actual Number of Doses Received __ * 100                                                 
Planned Number of Doses 
A subject is considered compliant if between 80% and 120% of the planned number of doses 
is received. Medication compliance will be summarized by treatment group. The compliance 
will be summarized in the following categories: < 80%, ≥80%.
6.4.4. Concomitant Medications and Nondrug Treatments
The frequency of prior and concomitant medications will be summarized by treatment based 
on the WHO-drug coding dictionary within SAS population in accordance with Clinical Data 
Interchange Standards Consortium (CDISC) and Pfizer Standards (CaPS).
Concomitant medications of special interest will include anti-viral and mAb therapies (eg., 
remdesivir, dexamethasone, baricitinib, and tocilizumab). Prior medications of special 
interest will include molnupiravir, Evusheld, monoclonal antibodies, convalescent plasma, 
steroid treatment, and immunosuppressant medications (ie., medications that qualify the 
participant for the study).
6.5. Safety Summaries and Analyses
Standard summary tables and listings will be generated in accordance with Clinical Data 
Interchange Standards Consortium (CDISC) and Pfizer Standards (CaPS) for safety reporting 
for the following parameters: adverse events, lab parameters, vital signs, discontinuations 
from study, discontinuations from treatment, and treatment duration.
6.5.1. Adverse Events
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 


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generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. 
All adverse events will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be summarized by treatment group within SAS population. 
6.5.2. Laboratory Data
Laboratory values and the corresponding changes from baseline will be summarized with 
descriptive statistics by treatment group over time in the SAS.
Laboratory shift tables from baseline utilizing central lab data will be presented for the 
following laboratory parameters at baseline: Liver function tests (ALT/AST), estimated 
glomerular filtration rate and Creatinine Clearance (derived using eGFR CKD EPI or 
Cockcroft-Gault Equation respectively), TSH, T4 (free), platelets, albumin, and total protein, 
and WBC. 
All laboratory data will be reported in accordance with Clinical Data Interchange Standards 
Consortium (CDISC) and Pfizer Standards (CaPS) for safety reporting.
6.5.3. Vital Signs
The measurement taken immediately prior to start of study drug will be used as the baseline 
for calculating changes in vital signs. All vital sign data will be descriptively summarized by 
treatment group within SAS population and reported in accordance with the Pfizer Data 
Standards for safety reporting.
6.5.4. Electrocardiograms
Not Applicable.
7. INTERIM ANALYSES
7.1. Interim Analyses and Summaries
There is no interim analysis planned for this study.
7.2. Data Monitoring Committee
This study will use an E-DMC. The E-DMC is independent of the study team and includes
only external members. The E-DMC charter describes the role of the DMC in more detail.
The E-DMC will be responsible for ongoing monitoring of the safety of participants in the
study according to the charter. The recommendations made by the E-DMC will be forwarded
to the appropriate authorized Pfizer personnel for review and final decision. Pfizer will
communicate such decisions, which may include summaries of aggregate analyses of safety
data to regulatory authorities or investigators, as appropriate.


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8. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis 
Model
Proportion with 
sustained SARS-
CoV-2 RNA < 
LLOQ from Day 15 
to Day 44 (NP)
Primary
Evaluable, 
FAS
Intercurrent event: non-study anti-
viral or mAb therapy – participant 
considered failure
No imputation of missing data
Descriptive 
(n, %), 95% 
CI for 
proportion and 
the difference 
in proportion 
using 
binomial 
distribution 
normal 
approximation
.
Proportion with 
sustained SARS-
CoV-2 RNA < 
LLOQ from Day 15 
to Day 44 (NP)
Supplementary
Evaluable
Intercurrent event: non-study anti-
viral or mAb therapy – data 
excluded/considered missing
No imputation of missing data
Descriptive 
(n, %), 95% 
CI for 
proportion and 
the difference 
in proportion 
using 
binomial 
distribution 
normal 
approximation
Proportion with 
sustained SARS-
CoV-2 RNA < 
LLOQ from Day 15 
to Day 44 (NP)
Supplementary
Evaluable
Intercurrent event: non-study anti-
viral or mAb therapy – data 
included as is
No imputation of missing data
Descriptive 
(n, %),95% CI 
for proportion 
and the
difference in 
proportion 
using 
binomial 
distribution 
normal 
approximation
Proportion with 
sustained SARS-
CoV-2 RNA < 
LLOQ from Day 15 
to Day 44 (NP)
Supplementary
Evaluable
Participants with baseline SARS-
CoV-2 RNA level <LLOQ will be 
excluded
Intercurrent event: non-study anti-
viral or mAb therapy – participant 
considered failure
Descriptive 
(n, %), 95% 
CI for 
proportion and 
the difference 
in proportion 
using 
binomial 
distribution 


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis 
Model
No imputation of missing data
normal 
approximation
Proportion with 
sustained SARS-
CoV-2 RNA < 
LLOQ from Day 15 
to Day 44 (NP)
Supplementary
Evaluable
Participants who do not meet the 
protocol-defined 
immunocompromised criteria will 
be excluded.
Intercurrent event: non-study anti-
viral or mAb therapy – participant 
considered failure
No imputation of missing data
Descriptive 
(n, %), 95% 
CI for 
proportion and 
the difference 
in proportion 
using 
binomial 
distribution 
normal 
approximation
Time to first SARS-
CoV-2 RNA < 
LLOQ (NP)
Secondary
Evaluable 
with BL ≥
LLOQ
No imputation for missing data
KM curves
Time to sustained 
SARS-CoV-2 RNA 
< LLOQ (NP)
Secondary
Evaluable 
with BL ≥
LLOQ
No imputation for missing data
KM curves
Proportion with 
SARS-CoV-2 RNA 
<LLOQ over time 
(plasma)
Secondary
Evaluable
Missing at timepoint imputed as 
not <LLOQ
Descriptive 
(n, %)
Proportion with 
SARS-CoV-2 RNA 
<LLOQ over time 
(NP)
Secondary
Evaluable
Missing at timepoint imputed as 
not <LLOQ
Descriptive 
(n, %)
Change from 
baseline in SARS-
CoV-2 RNA level 
over time (NP & 
plasma)
Secondary
Evaluable
<LLOQ imputed as 1.7, post-BL 
undetectable imputed as 0.0, no 
imputation for missing data
Descriptive 
summary
Rebound in SARS-
CoV-2 RNA up to 
Day 44 (NP) defined 
as a half log10
copies/mL increase 
or greater relative to 
EOT (active) with 
follow-up viral RNA 
level ≥2.5 log10
copies/mL
Secondary
Evaluable 
with EOT 
(active) and 
1 post-EOT 
not missing
No imputation for missing data
Descriptive 
(n, %)


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis 
Model
Rebound in SARS-
CoV-2 RNA up to 
Day 44 (NP) defined 
as a half log10
copies/mL increase 
or greater relative to 
EOT (active) with 
follow-up viral RNA 
level ≥3.0 log10
copies/mL
Secondary
Evaluable 
with EOT 
(active) and 
1 post-EOT 
not missing
No imputation for missing data
Descriptive 
(n, %)
Rebound in SARS-
CoV-2 RNA up to 
Day 28 (NP) defined 
as a half log10
copies/mL increase 
or greater relative to 
EOT (active) with 
follow-up viral RNA 
level ≥3.0 log10
copies/mL
Secondary
Evaluable 
with EOT 
(active) and 
1 post-EOT 
not missing
No imputation for missing data
Descriptive 
(n, %)
Proportion with 
COVID-19-related 
hospitalization >24 
hours, or death 
through Day 28
Secondary
Evaluable
Max censor time at Day 28
KM method
Proportion with 
death (all cause) 
through Week 24
Secondary
FAS
Max censor time at Week 24
KM method
Proportion with 
COVID-19-related 
hospitalization
Secondary
Evaluable
Max censor time at Day 44
KM method
Proportion with 
COVID-19-related 
ICU admission 
Secondary
Evaluable
Max censor time at Day 44
KM method
Proportion requiring 
IMV or ECMO
Secondary
Evaluable
Max censor time at Day 44
KM method
Number of days in 
hospital and ICU 
stay 
Secondary
Evaluable, 
participants 
with 
COVID-
19-related 
hospitalizat
ion
In the absence of a specific record 
of a COVID-19-related 
hospitalization, participants will 
be considered to be out of 
hospital
Descriptive 
summary


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Endpoint
Analysis Type
Population
Data Inclusion and Rules for 
Handling Intercurrent Events 
and Missing Data 
Analysis 
Model
Number of COVID-
19-related medical 
visits through Day 
44 and through 
Week 24
Secondary
Evaluable
In the absence of a specific record 
of a COVID-19-related medical 
visit, participants will be 
considered to not have a COVID-
19-related medical visit.
Descriptive 
summary
Duration of each 
targeted COVID-19 
signs/symptoms
Secondary 
Evaluable
No imputation for missing data
KM method
Proportion with 
severe 
signs/symptoms 
attributed to 
COVID-19 
Secondary 
Evaluable
No imputation for missing data
Descriptive 
(n, %)


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Appendix 2. Data Derivation Details
Appendix 2.1. Definition and Use of Visit Windows in Reporting
The following table defines the visit windows and labels to be used for reporting:
Visit Label
Target Day
Definition [Day window]
Baseline 
1
Day -2 to Day 1 
Day 5 
5
Day 2 to Day 7 
Day 10 
10
Day 8 to Day 12 
Day 15 
15
Day 13 to Day 18 
Day 21 
21
Day 19 to Day 24 
Day 28 
28
Day 25 to Day 31 
Day 35 
35
Day 32 to Day 39 
Day 44 
44
Day 40 to Day 49
Week 12
84
Day 77 to Day 91 
Week 24
168
Day 161 to Day 175
If multiple observations fall into the same window, choose the one closest to the visit and if 
equidistance, then choose the latter of the two. .


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Appendix 3. List of Abbreviations
Abbreviation
Term
AE
adverse event
ANCOVA
analysis of covariance
BL
Baseline
BMI
body mass index
CaPS
CDISC aligned Pfizer Standards
CDISC
Clinical Data Interchange Standard Consortium
CI
confidence interval
COVID-19
coronavirus disease 2019
CRF
case report form
CSR
clinical study report
DMC
data monitoring committee
ECMO
extracorporeal membrane oxygenation
E-DMC
external data monitoring committee 
eGFR
estimated glomerular filtration rate
FAS
full analysis set
ICU
intensive care unit
IMV
invasive mechanical ventilation
IRC
internal review committee
KM
Kaplan-Meier
LLOQ
lower limit of quantitation
LS
least-squares
LSM
least-squares mean
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-effects model with repeated measures
MNAR
missing not at random
N/A
not applicable
NP
nasopharyngeal
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PT
preferred term
RAT
rapid antigen test
RNA
ribonucleic acid
RR
relative risk
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SAS
safety analysis set
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure


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Abbreviation
Term
TEAE
treatment emergent adverse event
ULN
upper limit of normal
US
United States
WHO 
World Health Organization
WHODD
World Health Organization Drug Dictionary