Clinical trial NCT05554237
Conditions: Healthy
Sponsor: Pfizer
Start date: 2022-10-07; Completion date: 2023-06-23
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this clinical trial is to learn about the pharmacokinetics, safety and tolerability of various single- and multiple-doses of CTB+AVP in healthy adult participants. CTB+AVP is a study medicine that is being developed to treat people with complicated urinary tract infections.

This study is seeking healthy adult male and female participants, 18-60 years of age, with a body weight \> 50 kg and a BMI of 17.5 to 30.5 kg/m2.

Participants in Part-1 of the study will receive increasing single doses of CTB and/or AVP. Participants in Part-2 will receive increasing multiple doses of CTB+AVP three times a day for 7 days. The study team will monitor how each participant is doing with the study treatments via close monitoring in an in-patient setting. Experiences of people receiving CTB+AVP will be compared to those of people who do not. This will help determine if CTB+AVP is safe and well-tolerated at each dose of the study medicine.

Participants will take part in this study for a maximum of 12 weeks for Part-1 (up to 4 weeks for screening, up to 3 weeks of taking study medicine and up to 5 weeks for safety follow-up visit) and for a maximum of 10 weeks for Part-2 (up to 4 weeks for screening, up to 1 week of taking study medicine and up to 5 weeks for safety follow-up visit). During the duration of the study, blood samples for study medicine levels, and various measures for monitoring safety such as blood samples for clinical laboratory measurements, electrocardiograms and vital sign measurements will be taken.

Detailed description:
This is a 2-part study in healthy male and female adult participants.

Part-1 is to evaluate safety, tolerability and pharmacokinetics (PK) of 3 planned and 2 optional doses in 8 participants, in a 5-period sequential single dose design.

Part-2 is to evaluate safety, tolerability and PK of 1 planned and 2 optional cohorts in 8 participants each, in a multiple dose sequential design, with 7 days of repeated every 8 hours (q8h) dosing in each cohort. In addition, 2 optional cohorts in 6 participants each of Japanese descent and Chinese descent will also receive multiple doses of CTB+AVP repeated every 8 hours (q8h) for 7 days.

Arms: arm 1: Part-1: Dose 1, Dose 2, Dose 4, Dose 5 Part-2: Cohort 2-5 arm 2: Part-1: Dose 1-5 Part-2: Cohort 2-4 arm 3: Part-1: Dose 3, Dose 5
Interventions: intervention 1: Placebo intervention 2: PF-07612577 intervention 3: PF-06264006
Intervention descriptions: intervention 1: Placebo intervention 2: PF-07612577 intervention 3: PF-06264006

Protocol documents:
Prot_000.pdf: 
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 1
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED, SINGLE AND MULTIPLE-DOSE STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF 
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP]) IN HEALTHY ADULT 
PARTICIPANTS
Study Intervention Number:
PF-07612577
Study Intervention Name:
PF-06264006 (CTB) & PF-07338233 
(AVP)
US IND Number:
NA
EudraCT Number:
2021-005428-39
ClinicalTrials.gov ID:  
NA
Pediatric Investigational Plan Number:
NA
Protocol Number:
C4691001
Phase:
1
Brief Title: A Phase 1 Single and Multiple-Dose Study of PF-07612577 
(PF-06264006 [CTB] + PF 07338233 [AVP]) in Healthy Adult Participants
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.


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 2
Document History
Document
Version Date
Amendment 1
06 September 2022
Original protocol
18 July 2022
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any global protocol administrative 
change letter(s).
Protocol Amendment Summary of Changes Table
Amendment 1 (06 September 2022)
Overall Rationale for the Amendment: Changes to original protocol, based on regulatory 
feedback received from Belgian Health Authority.
Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 4.3. 
Justification 
for Dose and
Section 1.2.
Schema
Lowered starting dose 
regimen in Cohort 2 to
400 mg CTB + 
900/1350 mg AVP. 
Recent PK/PD modeling 
and simulation suggest 
that 400 mg CTB and 
1350 mg AVP TID doses 
are likely to achieve the 
PK/PD target. Therefore, 
reduced starting dose for 
CTB in DR1, consistent 
with Belgian Health 
Authority feedback.
Substantial
Section 6.6.1. 
Dose 
Escalation and 
Stopping Rules
Added stopping criteria for 
CTB:
CTB Cmax >100 μg/mL 
(estimated CTB Cmax at 
NOAEL in the 1-month rat 
toxicology study).
Stopping criteria for CTB 
Cmax added, based on 
Belgian Health Authority 
feedback. 
Substantial


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 3
Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 1.1. 
Synopsis,
Section 4.1. 
Overall 
Design, and 
Section 9.5.
Sample Size 
Determination
Added optional Cohort 4 
(planned to enroll 
8 participants who are to 
receive DR3). Updated the 
Cohort number of optional 
Japanese and Chinese 
Cohorts to Cohort 5 and 6, 
respectively. 
Increased total number of 
participants from 36 to 44. 
Additional optional 
cohort in PART-2 to 
allow for evaluation up 
to 1200 mg CTB if 
needed. 
Substantial 
Section 1.3. 
Schedule of 
Activities,
Table 2
Added assessments on 
Day 3 PART-2:
•
12-lead ECG 
(triplicate)
•
Vital signs (BP and 
pulse rate)
•
Safety laboratory 
assessments
•
urinalysis
Additional safety 
assessments added at 
Day 3 after steady state 
achieved to monitor for 
adverse events, 
laboratory values, vitals 
and ECG assessment.
Substantial
Section 1.3.
Schedule of 
Activities,
Table 1
Removed ECG assessment 
at Day -1 in PART-1.
Day 1 time 0 ECG 
assessment will serve as 
baseline assessment.
Substantial
Section 1.3.
Schedule of 
Activities,
Tables 1 and 2, 
and 
Section 10.22. 
Appendix 2: 
Clinical 
Laboratory 
Tests,
Table 13. 
Cystatin C: removed note 
that it is performed on 
Day -1 only or at 
Screening.
Local practice updated to 
perform Cystatin C with 
all safety labs. 
Substantial
Section 10.22. 
Appendix 2: 
Clinical 
Laboratory 
Tests,
Table 13.
Removed eCrCl 
Kidney function 
assessment is already 
monitored with eGFR 
(CKD-EPI) and cystatin.
Substantial


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 4
Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 4.1. 
Overall Design
Added statement:
“Except D1 in PART-1 
and DR1 in” PART-2 of 
the study, the dose levels, 
frequency of 
administration, and/or 
meal condition may be 
changed based on 
emerging PK, safety, and 
tolerability data.
Clarification that Dose 1 
and DR1 have fixed 
doses, all other doses can 
change after review of 
new data from prior 
doses/dose regimens.
Substantial
Section 4.1. 
Overall Design
Added statement:
If the AVP dose 
mg 
with 
 mg CTB needs 
to be evaluated, then the 
CTB
 mg 
 
will not be evaluated in 
Clarification that 
Period 5 can be either 
1200 mg CTB + 
1800 AVP or 1600 mg 
CTB alone.
Substantial
Section 1.2.
Schema
Updated Figure 1. 
C4691001 Study Design 
and footnotes.
Updated study design to 
match proposed changes 
in DR1 (lowered starting 
CTB dose) and addition 
of optional Cohort 4 for 
evaluation of DR3, if 
needed.
Substantial
Section 8.1 
Administrative 
and Baseline 
Procedures
Updated blood sampling 
volume to 291 ml in 
PART-2.
Additional blood volume 
needed due to safety lab 
assessment added on 
Day 3 in PART-2.
Substantial
Section 1.3. 
Schedule of 
Activities, 
Table 1
The time point of 14 hours 
post dose was updated to 
be included in Day 1 
instead of Day 2.
To correct a formatting 
error.
Nonsubstantial
CCI
CCI
CCI
CCI
CCI


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 5
Section # and 
Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 1.3.
Schedule of 
Activities,
Tables 1 and 2
COVID-19 Questionnaire: 
clarified in notes that 
assessment to be done as 
per local practice.
Removed “at least 48 
hours before Day 1 or.”
Allowed for flexibility 
when assessment is done 
as it will depend on local 
practice. 
Nonsubstantial
Section 1.3.
Schedule of 
Activities,
Tables 1 and 2
Clarified that PE is to be 
done at Screening or 
Day -1 in Period 1 only in 
PART-1 and at Screening 
or Day -1 in PART-2.
Clarification.
Nonsubstantial
Section 1.3.
Schedule of 
Activities,
Table 1
Clarified that Pregnancy 
test (β -hCG) WOCBP
only is to be conducted at 
Day -1 Period 1 and Day 2 
last period.
Clarification.
Nonsubstantial
Section 1.3.
Schedule of 
Activities,
Table 1 and 2
COVID 19 testing: to be 
done as per local practice.
Updated to state testing 
will be performed as per 
local practice to allow for 
flexibility
Nonsubstantial
Section 1.1.
Synopsis and 
Section 5.2.
Exclusion 
Criteria
Exclusion criteria: 
removed 2 examples of 
COVID-19 risks.
Given widespread 
prevalence of COVID-19 
geographical location, 
either residence or site of 
travel as risk factors, 
were removed. 
Nonsubstantial
Section 11. 
References
Updated reference #28:
Original text: 
Investigator’s Brochure, 
PF-07612577. 26 Oct 
2021.
Updated text:
Investigator’s Brochure, 
PF-07612577. Version 2.0. 
July 2022.
Provided updated 
reference since the 
IB V2.0 was updated 
22-Jul-2022 following 
protocol approval. 
Nonsubstantial


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 6
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................12
LIST OF FIGURES .................................................................................................................12
1. PROTOCOL SUMMARY...................................................................................................13
1.1. Synopsis ..................................................................................................................13
1.2. Schema ....................................................................................................................22
1.3. Schedule of Activities .............................................................................................23
2. INTRODUCTION ...............................................................................................................37
2.1. Study Rationale .......................................................................................................37
2.2. Background .............................................................................................................37
2.2.1. Nonclinical Pharmacology..........................................................................37
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................39
2.2.2.1. AVP and AVI............................................................................39
2.2.2.2. CTB ...........................................................................................40
2.2.3. Nonclinical Safety ......................................................................................41
2.2.4. Biopharmaceutics .......................................................................................42
2.2.5. Clinical Overview.......................................................................................42
2.2.5.1. AVP...........................................................................................42
2.2.5.2. AVI............................................................................................43
2.2.5.3. CTB ...........................................................................................43
2.3. Benefit/Risk Assessment.........................................................................................44
2.3.1. Risk Assessment.........................................................................................45
2.3.2. Benefit Assessment.....................................................................................47
2.3.3. Overall Benefit/Risk Conclusion................................................................47
3. OBJECTIVES AND ENDPOINTS.....................................................................................47
4. STUDY DESIGN.................................................................................................................49
4.1. Overall Design.........................................................................................................49
4.2. Scientific Rationale for Study Design.....................................................................52
4.2.1. Choice of Contraception/Barrier Requirements .........................................53
4.2.2. Collection of Retained Research Samples..................................................53
4.3. Justification for Dose ..............................................................................................53
4.4. End of Study Definition ..........................................................................................57


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 7
5. STUDY POPULATION......................................................................................................57
5.1. Inclusion Criteria.....................................................................................................58
5.2. Exclusion Criteria....................................................................................................58
5.3. Lifestyle Considerations..........................................................................................60
5.3.1. Contraception..............................................................................................60
5.3.2. Meals and Dietary Restrictions...................................................................61
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................62
5.3.4. Activity .......................................................................................................62
5.4. Screen Failures ........................................................................................................62
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................62
6.1. Study Intervention(s) Administered........................................................................63
6.1.1. Administration............................................................................................64
6.1.2. Medical Devices .........................................................................................65
6.2. Preparation, Handling, Storage, and Accountability...............................................65
6.2.1. Preparation and Dispensing........................................................................66
6.3. Assignment to Study Intervention...........................................................................66
6.4. Blinding...................................................................................................................66
6.4.1. Blinding of Participants..............................................................................66
6.4.2. Blinding of Site Personnel..........................................................................67
6.4.3. Blinding of the Sponsor..............................................................................67
6.4.4. Breaking the Blind......................................................................................67
6.5. Study Intervention Compliance...............................................................................68
6.6. Dose Modification...................................................................................................68
6.6.1. Dose Escalation and Stopping Rules..........................................................68
6.7. Continued Access to Study Intervention After the End of the Study......................70
6.8. Treatment of Overdose............................................................................................70
6.9. Prior and Concomitant Therapy ..............................................................................70
6.9.1. Rescue Medicine.........................................................................................71
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................71
7.1. Discontinuation of Study Intervention ....................................................................71
7.1.1. Liver Injury.................................................................................................71


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 8
7.1.2. ECG Changes..............................................................................................71
7.1.3. Potential Cases of Acute Kidney Injury .....................................................72
7.1.4. Pregnancy ...................................................................................................72
7.1.5. COVID-19 ..................................................................................................72
7.1.6. Temporary Discontinuation........................................................................73
7.2. Participant Discontinuation/Withdrawal From the Study.......................................73
7.2.1. Withdrawal of Consent...............................................................................73
7.3. Lost to Follow-up....................................................................................................74
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................74
8.1. Administrative and Baseline Procedures.................................................................74
8.1.1. Baseline Procedures....................................................................................75
8.1.2. Telehealth Visits.........................................................................................76
8.2. Efficacy Assessments..............................................................................................76
8.3. Safety Assessments .................................................................................................76
8.3.1. Physical Examinations................................................................................76
8.3.2. Vital Signs ..................................................................................................77
8.3.2.1. Blood Pressure and Pulse Rate..................................................77
8.3.2.2. Temperature ..............................................................................77
8.3.3. Electrocardiograms.....................................................................................77
8.3.4. Clinical Safety Laboratory Assessments ....................................................78
8.3.5. COVID-19 Specific Assessments...............................................................79
8.3.6. Pregnancy Testing ......................................................................................79
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................79
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......80
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................80
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................81
8.4.2. Method of Detecting AEs and SAEs ..........................................................81
8.4.3. Follow-Up of AEs and SAEs......................................................................81
8.4.4. Regulatory Reporting Requirements for SAEs...........................................81
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................82
8.4.5.1. Exposure During Pregnancy......................................................82




PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 10
9.3.2. Primary Endpoint(s) Analysis.....................................................................90
9.3.3. Secondary Endpoint(s) Analysis.................................................................91
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis ................................................91
9.3.4.1. PK Analysis...............................................................................91
9.3.4.2. Statistical Methods for PK Data................................................93
9.3.5. Safety Analyses ..........................................................................................94
9.3.5.1. Electrocardiogram Analyses......................................................95
9.3.6. Other Analyses............................................................................................95
9.3.6.1. Pharmacogenomic/Biomarker Assessment...............................95
9.4. Interim Analyses .....................................................................................................95
9.5. Sample Size Determination.....................................................................................96
9.5.1. PART-1: Single Dose .................................................................................96
9.5.2. PART-2: Multiple Dose..............................................................................96
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................97
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............97
10.1.1. Regulatory and Ethical Considerations ....................................................97
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................97
10.1.2. Financial Disclosure .................................................................................98
10.1.3. Informed Consent Process ........................................................................98
10.1.4. Data Protection .........................................................................................99
10.1.5. Committees Structure ...............................................................................99
10.1.5.1. Data Monitoring Committee ...................................................99
10.1.6. Dissemination of Clinical Study Data ......................................................99
10.1.7. Data Quality Assurance ..........................................................................100
10.1.8. Source Documents..................................................................................102
10.1.9. Study and Site Start and Closure ............................................................102
10.1.10. Publication Policy.................................................................................103
10.1.11. Sponsor’s Medically Qualified Individual............................................104
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................105
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ...................................................................107


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 11
10.3.1. Definition of AE .....................................................................................107
10.3.2. Definition of an SAE ..............................................................................108
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period..........................................................................109
10.3.4. Reporting of SAEs..................................................................................113
10.4. Appendix 4: Contraceptive and Barrier Guidance ..............................................114
10.4.1. Male Participant Reproductive Inclusion Criteria..................................114
10.4.2. Female Participant Reproductive Inclusion Criteria...............................114
10.4.3. Woman of Childbearing Potential ..........................................................115
10.4.4. Contraception Methods...........................................................................116
10.5. Appendix 5: Genetics..........................................................................................118
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments 
Potential Cases of Drug-Induced Liver Injury ........................................................119
10.7. Appendix 7: Kidney Safety: Monitoring Guidelines ..........................................121
10.7.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury............................................................................121
10.7.2. Age-Specific Kidney Function Calculation Recommendations.............121
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations.........................................................................................121
10.7.3. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities.................................................................................................121
10.8. Appendix 8: ECG Findings of Potential Clinical Concern .................................122
10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI.....124
10.10. Appendix 10: Abbreviations .............................................................................125
11. REFERENCES ................................................................................................................130


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 12
LIST OF TABLES
Table 1.
Study Schedule of Assessment - PART-1: Single Dose...........................23
Table 2.
Study Schedule of Assessment - PART-2: Multiple Dose (Including 
Optional Japanese and Chinese Cohorts) .................................................30
Table 3.
Study Schedule of Assessment - PART-2: PK Days (Day 1 [fed], 
Day 6 [fed], Day 7 [fasted]) in Multiple Dose Cohorts............................35
Table 4.
Antibacterial Activity of CTB and CTB-AVI Against Gram-
Negative Bacterial Isolates From JMI Laboratories.................................38
Table 5.
Antibacterial Activity of CTB and CTB-AVI 
Against Enterobacterales From IHMA.....................................................39
Table 6.
Provisional Dosing Scheme in PART-1 ...................................................50
Table 7.
Provisional Dosing Scheme in PART-2* .................................................51
Table 8.
Predicted Human Exposure and Safety Margins of CTB Relative to 
Exposure Limits at Planned Dose Levels in PART-1 ..............................56
Table 9.
Predicted Human Exposure and Safety Margins of AVI Relative to 
Exposure Limits at Planned Dose Levels in PART-1 ..............................56
Table 10.
Predicted Human Exposure and Safety Margins of CTB Relative to 
Exposure Limits at Planned Dose Levels in PART-2 ..............................57
Table 11.
Plasma cis-CTB, AVP, AVI, and HPA PK Parameters for PART-1: 
Single Doses .............................................................................................92
Table 12.
Plasma and Urine cis-CTB, trans-CTB, AVP, AVI and HPA PK 
Parameters for PART-2: Multiple Doses..................................................93
Table 13.
ProtocolRequired Safety Laboratory Assessments.................................105
LIST OF FIGURES
Figure 1.
C4691001 Study Design...........................................................................22
Figure 2.
Proposed Mechanism of Conversion of AVP to AVI and HPA...............39


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (01 April 2022)
Page 13
1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: A Phase 1, Randomized, Double-Blind, Sponsor-Open, Placebo-Controlled, 
Single and Multiple-Dose Study to Evaluate the Safety, Tolerability and Pharmacokinetics of 
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP]) in Healthy Adult Participants
Brief Title: A Phase 1 Single and Multiple-Dose Study of PF-07612577 
(PF-06264006 [CTB] + PF-07338233 [AVP]) in Healthy Adult Participants
Regulatory Agency Identification Number(s):
US IND Number:
NA
EudraCT Number:
2021-005428-39
ClinicalTrials.gov ID:  
NA
Pediatric Investigational Plan Number:
NA
Protocol Number:
C4691001
Phase:
1
Rationale:The current study is a Phase 1 study of PF-07612577 (PF-06264006 [CTB] +
PF-07338233 [AVP]) in approximately 44 healthy adult participants. It is a 2-PART study 
combining PART-1: Single dose PK, safety and tolerability of various CTB doses alone or 
when coadministered with AVP, and PART-2: Multiple dose PK, safety and tolerability of 
CTB + AVP coadministered, including optional Japanese and Chinese cohorts.
Objectives and Endpoints:
PART-1: Single Dose
Objectives
Endpoints
Primary:
Primary:
To assess the plasma PK profile of CTB following a 
single dose of CTB alone or in combination with 
AVP.
Plasma PK parameters of cis-CTB: 

Cmax, Tmax, AUClast, Cmax(dn), AUClast(dn).

If data permit, AUCinf, AUCinf(dn), t½, Vz/F, and 
CL/F.
To assess the plasma PK profile of AVP following 
administration with single doses of CTB in 
combination with AVP.
Plasma PK parameters of AVP, AVI and HPA:

Cmax, Tmax, AUClast, Cmax(dn), AUClast(dn).

If data permit, AUCinf, AUCinf(dn), t½, Vz/F, and 
CL/F.


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
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Objectives
Endpoints
To assess the safety and tolerability following a 
single dose of CTB alone or in combination with 
AVP.

Frequency, severity, and causal relationship of 
TEAEs and withdrawals due to TEAEs.

Frequency and magnitude of abnormal 
laboratory findings.

Changes from baseline in vital sign 
measurements and 12-lead ECG parameters.
PART-2: Multiple Dose (including optional Japanese and Chinese Cohorts)
Objectives
Endpoints
Primary:
Primary:
To assess the plasma PK profile of cis-CTB and trans-
CTBa following multiple doses of CTB in combination 
with AVP.
Plasma PK parameters of cis-CTB and trans-CTBa on 
Day 1 (fed, single dose), Day 6 (fed, steady state) and 
Day 7 (fasted, steady state): 

Cmax, Tmax, AUCtau, Cmax(dn), AUCtau(dn).

If data permit, t½, Vz/F, and CL/F.
To assess the plasma PK profile of AVP following 
multiple doses of CTB in combination with AVP. 
Plasma PK parameters of AVP, AVI and HPA on Day 1 
(fed, single dose), Day 6 (fed, steady state) and Day 7 
(fasted, steady state): 

Cmax, Tmax, AUCtau, Cmax(dn), AUCtau(dn)

If data permit, t½, Vz/F, and CL/F.
To assess the safety and tolerability following multiple 
doses of CTB in combination with AVP.

Frequency, severity, and causal relationship of 
TEAEs and withdrawals due to TEAEs.

Frequency and magnitude of abnormal laboratory 
findings.

Changes from baseline in vital sign measurements 
and 12-lead ECG parameters.
Secondary:
Secondary:
To assess the urinary PKb profile of cis-CTB, trans-CTBa, 
AVP, AVI and HPA on Day 6 following multiple doses of 
CTB in combination with AVP.
cis-CTB, trans-CTBa, AVP, AVI and HPA urinary PK 
parameters (if data permit): 

Aetau and Aetau%, CLr.
To assess PK profile of CTB and AVP when administered 
in combination in Japanese and Chinese participants.
Plasma PK parameters of cis-CTB, AVP, AVI and HPA on 
Day 1 (fed, single dose), Day 6 (fed, steady state) and 
Day 7 (fasted, steady state) in Japanese and Chinese 
cohorts: 

Cmax, Tmax, AUCtau, Cmax(dn), AUCtau(dn).

If data permit, t½, Vz/F, and CL/F.
a.
trans-CTB will be measured only on Day 1, Day 6, and Day 7 in Cohort 2 PART-2.
b.
cis-CTB, trans-CTB, AVP, AVI and HPA in urine will be measured on Day 6 only in Cohort 2, PART-2.


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Overall Design:
This study will consist of PART-1: Single dose and PART-2: Multiple dose, including
optional Japanese and Chinese cohorts. PART-1 and PART-2 are randomized, double-blind 
(participant and investigator blinded and sponsor open) cohorts. 
PART-1: Single Dose
PART-1 will include 1 cohort and up to 5 periods with approximately 8 participants in total. 
This part will have a randomized, double-blind (sponsor-open), 5-period, sequential single 
dose design. Periods 4 and 5 are optional and may be used to further explore PK at additional 
doses, based on emerging PK data. In each period, approximately 6 participants will receive 
a single oral dose of CTB or CTB and AVP combined, and approximately 2 participants will 
receive the matching placebo under fed state. Each participant may receive either a single 
dose of CTB, CTB and AVP combined, or matching placebo during each period. In each 
period, participants on active treatment will receive D1, D2, D3, D4 (optional), or D5 
(optional) dose levels, respectively. There will be a washout interval of a minimum of 3 days 
between doses for a given participant. Participants will be required to stay at the CRU for the 
duration of the washout interval. 
PART-2: Multiple Dose
PART-2 will include up to 5 cohorts, ie, Cohort 2, and up to 4 optional cohorts including
optional Cohort 5 (Japanese Cohort) and optional Cohort 6 (Chinese Cohort) with 
approximately 8 participants each in Cohorts 2, 3 and 4, and six participants each in Cohorts 
5 and 6, and up to approximately 36 participants planned in total. This part will have a 
randomized, double-blind (sponsor-open), sequential multiple-dose design. In Cohorts 2,3
and 4, approximately 6 participants will receive 1 of the dose regimens of CTB and AVP 
combined, and approximately 2 participants will receive the matching placebo orally under 
fed state (except Day 7 which will be administered fasted). In Cohorts 5 and 6, 
approximately 5 participants will receive 1 of the dose regimens of CTB and AVP combined
and approximately 1 participant will receive the matching placebo orally under fed state 
(except Day 7 which will be administered fasted.) From Day 1 to Day 7, CTB and AVP 
combined or the matching placebo will be administered q8h (ie, TID), with the dose regimen 
of DR1 (for Cohort 2), DR2 (for optional Cohort 3), DR3 (for optional cohort 4) and either 
DR1, DR2 or DR3 (for Cohort 5, optional Japanese Cohort and Cohort 6, optional Chinese 
Cohort).
Number of Participants:
Up to 44 participants (8 in PART-1 and 36 in PART-2) will be randomly assigned to study 
intervention. 
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 process and
randomization to study intervention. A participant will be considered enrolled if the informed 
consent is not withdrawn prior to participating in any study activity after screening. Potential 


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Protocol C4691001
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participants who are screened for the purpose of determining eligibility for the study, but do 
not participate in the study, are not considered enrolled, unless otherwise specified by the 
protocol.
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:
Age and Sex:
1. Participants 18 to 60 years of age (or the minimum age of consent in accordance with 
local regulations), inclusive, at screening.
•
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, PE, laboratory tests, vital signs and standard 
12-lead ECGs.
Other Inclusion Criteria:
3. For optional Japanese cohort only: Japanese participants who have 4 Japanese 
biologic grandparents who were born in Japan. 
4. For the optional Chinese cohort only: Chinese participants who were born in 
mainland China, and both parents are of Chinese descent. 
5. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
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2.
Known allergy to the cephalosporin group of antibiotics.
3. History of HIV infection, hepatitis B or hepatitis C; positive testing for HIV, HBsAg, 
or HCVAb. Hepatitis B vaccination is allowed.
4. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality [or other conditions or 
situations related to COVID-19 pandemic (eg, Contact with positive case)] that may 
increase the risk of study participation or, in the investigator’s judgment, make the 
participant inappropriate for the study.
Prior/Concomitant Therapy:
5. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention (Refer to Section 6.9 for additional details).
6. Current use of any prohibited concomitant medication(s) or those unwilling/unable to 
use a permitted concomitant medication(s). Hormonal contraceptives that meet the 
requirements of this study are allowed to be used in participants who are WOCBP. 
(Refer to Section 6.9 for additional details).
Prior/Concurrent Clinical Study Experience:
7. Previous administration with an investigational drug 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). 
Diagnostic Assessments:
8. A positive urine drug test.
9. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.
10. Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities that
may affect participant safety or interpretation of study results (eg, baseline QTcF 
interval >450 msec, complete LBBB, signs of an acute or indeterminate-age 
myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, 
second- or third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). 
If the baseline uncorrected QT interval is >450 msec, this interval should be rate
corrected using the Fridericia method and the resulting QTcF should be used for 
decision making and reporting. If QTcF exceeds 450 msec, or QRS exceeds 
120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or 
QRS values should be used to determine the participant’s eligibility.


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Computer-interpreted ECGs should be overread by a physician experienced in 
reading ECGs before excluding a participant.
11. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
•
AST or ALT level ≥1.25 × ULN;
•
Total bilirubin level ≥1.5 灤ULN; participants with a history of Gilbert's 
syndrome may have direct bilirubin measured and would be eligible for this 
study provided the direct bilirubin level is ≤ULN;
•
eGFR <90 mL/min (estimated using the CKD-EPI equation).  
Other Exclusions Criteria:
12. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces (240 mL) beer, 
1 ounce (30 mL) of 40% spirit or 3 ounces (90 mL) of wine).
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
14. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
15. Participants who are unwilling and/or unable to comply with all scheduled visits, 
treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
16. 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:
Duration of Participant Involvement in the Study: 
The total planned duration of participation, from Screening visit to the Follow-up phone call,
is approximately 12 weeks for participants in PART-1 (up to 4 weeks for screening, up to 
3 weeks of dosing and up to 5 weeks for safety follow-up visit), and 10 weeks for 


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
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participants in PART-2 (up to 4 weeks for screening, up to 1 week of dosing and up to 
5 weeks for safety follow-up visit).
Study Intervention(s)
Intervention Name
CTB
AVP
PF-06264006
Placebo
PF-07338233
Placebo
Arm Name
(group of 
participants 
receiving a specific 
treatment or no 
treatment)
PF-06264006 
Double-Blind 
Treatment
Placebo 
Double-Blind 
Treatment
PF-07338233
Double-Blind 
Treatment
Placebo 
Double-Blind 
Treatment
Unit Dose 
Strength(s)
400 mg 
0 mg
225 mg 
0 mg
Route of 
Administration
Oral
Oral
Oral 
Oral 
Use
Experimental
Placebo 
Experimental
Placebo
IMP or 
NIMP/AxMP
IMP 
IMP 
IMP 
IMP
Study Arms – PART-1
Arm Title
CTB or CTB + AVP
Placebo
Arm Type
Experimental
Placebo 
Arm Description
Participants may receive a single dose of 400 mg 
CTB + 900 mg AVP, or 800 mg CTB + 1350 mg 
AVP, or 1200 mg CTB + 1350 mg AVPa, or 800 mg 
CTB alone, or 1600 mg CTB alone, or 1200 mg CTB 
+ 1800 mg AVP on Day 1 in up to 5 periods.  
Participants will receive a single dose of 
placebo on Day 1 in up to 5 periods.
a. 1350 mg AVP may be replaced with 900 mg AVP.
Study Arms – PART-2
Arm Title
CTB + AVPa
Placebo
Arm Type
Experimental
Placebo
Arm Description
Participants may receive 400 mg CTB + 1350 mg AVP
(DR1), or 400 mg/800 mg CTB + 1350 mg AVPa TID
(DR2) or 800/1200 mg CTB + 1350 mg AVPa TID (DR3)
for 7 days.
Participants will receive placebo TID 
for 7 Days.
a. 1350 mg AVP may be replaced with 900 mg AVP.


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In PART-1 and PART-2, treatment sequences and the dosing regimen may be adjusted
during the study based on emerging safety, tolerability, and PK data. The provisional dosing 
regimens for Parts 1 and 2 are provided in Table 6 and Table 7, respectively. Except D1 in 
PART-1, all other dose levels and/or meal condition may be changed based on emerging PK, 
safety, and tolerability data. Dose escalation of CTB (and AVP, when applicable) to higher 
doses will be based on all available (a minimum of 24 hours post-dose) safety data in a 
minimum of 5 participants (4 active and 1 placebo) at the previous dose levels of CTB and/or 
AVP. AVP dose for PART-1 may be 900 mg, 1350 mg, or 1800 mg (in Period 5 only) as 
long as PK exposures for AVI in the next higher cohort are not projected to be higher than 
PK stopping limit (AVI AUC ≤354 μg.hr/ml- NOAEL in the 14-day pivotal repeat-dose 
toxicology study in rats). In PART-2, at least 6 days of safety data in a minimum of 
5 participants (4 active and 1 placebo) from Cohort 2 will be reviewed prior to proceeding to 
optional Cohorts 3, 4, 5 and/or 6.  
PART-1: Single Dose
PART-1 includes 1 cohort and up to 5 periods (Period 4 and 5 are optional). In each period, 
approximately 6 participants will receive a single oral dose of CTB or CTB and AVP 
combined, and approximately 2 participants will receive the matching placebo, all under fed 
conditions. Each participant may receive either a single dose of CTB, CTB and AVP 
combined, or matching placebo during each period. In each period, participants on active 
treatment will receive D1, D2, D3, D4 (optional), or D5 (optional) dose levels, respectively 
(Section 4.3). The washout period between doses is planned to be a minimum of 3 days.
PART-2: Multiple Dose
PART-2 is planned with up to 5 cohorts (Cohorts 3, 4,5 and 6 are optional). In Cohorts 2, 3
and 4, approximately 6 participants will receive 1 of the dose regimens of CTB and AVP 
combined and approximately 2 participants will receive the matching placebo orally under 
fed state (except Day 7 which will be administered fasted). In Cohorts 5 and 6,
approximately 5 participants will receive 1 of the dose regimens of CTB and AVP combined, 
and approximately 1 participant will receive the matching placebo orally under fed state 
(except Day 7 which will be administered fasted). From Day 1 to Day 7, CTB and AVP 
combined or the matching placebo will be administered q8h (ie, TID), with the dose regimen 
of DR1 (for Cohort 2), DR2 (for optional Cohort 3), DR3 (for optional Cohort 4), and either 
DR1, DR2 or DR3 (for Cohort 5, optional Japanese Cohort and Cohort 6, optional Chinese 
Cohort) (Section 4.3). 
Statistical Methods:
There are no formal statistical hypotheses for this study. 
PART-1: Single Dose
A sample size of approximately 8 participants (6 active, 2 placebo) for this single-cohort,
cross-over study has been chosen based on the need to minimize first exposure of healthy 


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
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participants to CTB + AVP and the requirement to provide adequate safety and tolerability
information and PK information at each dose level.
PART-2: Multiple Dose
A sample size of approximately 36 participants (8 participants each in Cohorts 2, 3 and 4: six
on CTB + AVP, 2 on matching placebo and 6 participants each in Cohorts 5 and 6: five on 
CTB + AVP, 1 on matching placebo) for this 5-cohort (1 cohort and 4 optional cohorts) 
multiple dose study has been selected to provide adequate PK, safety and tolerability
information. This sample size has been judged sufficient to obtain a preliminary evaluation of 
safety, tolerability, and PK data in these populations.
All safety analyses will be performed on the safety analysis set, which is defined as all 
participants randomly assigned to study intervention and who take at least 1 dose of study 
intervention. Participants will be analyzed according to the product they actually received. 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Plasma concentrations will be listed and summarized descriptively by PK sampling time and
treatment. The plasma PK parameters will be summarized descriptively by dose. No formal 
inferential statistics will be applied to the PK data apart from the comparisons of CTB PK 
parameters when CTB is administered in combination with AVP or alone in PART-1, and 
food effect on CTB and AVP in PART-2.
Ethical Considerations:
This study will be conducted in healthy participants who are not expected to receive any 
clinical benefit from participation in the study. Potential risks from CTB + AVP include 
nausea and vomiting, hypersensitivity, pseudomembranous colitis and convulsions/seizures.   
The trial-specific risks and burdens for participants includes the requirement to be confined 
during study intervention in the CRU, the potential increased risk of acquiring SARS-CoV-2 
infection by undergoing procedures at a study facility, they may experience discomforts 
undergoing study assessments (eg, blood samples, ECGs), and the need to be compliant with 
lifestyle and dietary restrictions.


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1.2. Schema
Figure 1.
C4691001 Study Design
PART-1: Dose 1 = 400 mg CTB + 900 mg AVP; Dose 2 = 800 mg CTB + 1350 mg AVP;
Dose 3 = 800 mg CTB alone; Dose 4 = 1200 mg CTB + 1350 mg AVP*; Dose 5 = 1600 mg CTB
alone or 1200 mg CTB + 1800 mg AVP.
PART-2: DR1 = 400 mg CTB + 1350 mg AVP* q8h for 7 days; DR2 = 400 mg/800 mg CTB + 
1350 mg AVP* q8h for 7 days; DR3 = 800 mg/1200 mg CTB + 1350 AVP q8h for 7 days.
* 1350 mg AVP may be replaced with 900 mg AVP, based on safety, tolerability and PK data.
Note that except Dose 1 in PART-1, all other dose levels and/or meal condition may be changed based on 
emerging PK, safety, and tolerability data.






























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2. INTRODUCTION
PF-07612577 is a combination of ceftibuten (CTB) and PF-07338233 (avibactam prodrug 
[AVP]), referred to in this protocol as CTB + AVP, that is currently being developed for the 
treatment of cUTI, including pyelonephritis. CTB is a third-generation FDA-approved oral 
cephalosporin. PF-07338233 is an orally bioavailable prodrug which breaks down rapidly to 
avibactam (PF-06416494, referred to as AVI), a well-established IV β-lactamase inhibitor 
with activity against a broad spectrum of β-lactamases.
2.1. Study Rationale 
The current study is a Phase 1 study of CTB + AVP in approximately 44 healthy adult 
participants. It is a 2-part study combining PART-1: Single dose PK, safety and tolerability 
of various CTB doses alone or when coadministered with AVP, and PART-2: multiple dose 
PK, safety and tolerability of CTB + AVP coadministered, including optional Japanese and 
Chinese cohorts.
2.2. Background 
ESBL-producing Enterobacterales cause serious infections affecting approximately 
200,000 patients and causing 9,100 deaths per year in the US.1 These pathogens are flagged 
as a ‘Critical’ priority by the WHO2 and a ‘Serious Threat’ by the CDC.3 Resistance to 
antibiotics is increasing, with a 50% increase observed in US hospital cases between 2012 
and 2017.1 Oral treatment for ESBL infection is limited and most patients require OPAT or 
hospital admission solely to receive IV therapy. UTI is the most common infection caused by 
ESBL-producing Enterobacterales.
AVP is an orally bioavailable prodrug which breaks down rapidly to AVI in vivo. AVI is a 
well-established IV β-lactamase inhibitor with activity against a broad spectrum of 
β-lactamases including ESBLs and serine carbapenemases. CTB is a third-generation FDA-
approved oral cephalosporin whose clinical utility against Enterobacterales has been eroded 
by the spread of ESBLs. The combination of CTB with AVP is expected to provide an 
effective and well-tolerated oral treatment option for ESBL-producing Enterobacterales 
infections. The current SOC for treating ESBL-producing Enterobacterales are limited as far 
as oral options for discharge and community setting care are concerned. Oral antibiotic 
options for Enterobacterales infections are associated with high and increasing resistance 
rates, with many patients having no oral option, requiring OPAT or hospital admission solely 
to receive IV therapy. By offering patients with MDR cUTIs a carbapenem-sparing oral 
antibiotic option, CTB + AVP has the potential to be a breakthrough versus SOC, supporting 
early hospital discharge or allowing patients to avoid hospitalization or OPAT IV. 
2.2.1. Nonclinical Pharmacology
AVP is an oral prodrug of the BLI, AVI. AVI combined with CAZ (CAZ-AVI; AVYCAZ®) 
is an approved BL/BLI, whereby AVI restores the microbiological activity of CAZ against 
class A, class C, and some class D β-lactamases. The microbiological profile of CTB-AVI 
has been demonstrated in reports from 2 independent organizations (JMI laboratories and 
IHMA) that specialize in susceptibility testing and surveillance. As highlighted in the reports, 


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CTB-AVI demonstrates potent activity against many of the key Gram-negative pathogens of 
interest. This includes Enterobacterales with ESBL, KPC and OXA-48. The inhibitor is 
known not to inhibit metallo-β-lactamases; therefore, isolates that possess one of these 
enzymes would be expected to be resistant.
In report 17-SLA-01 (from JMI Laboratories)4, a total of 253 clinical isolates from the 2015-
2016 SENTRY Antimicrobial Surveillance Program organism collection were tested. 
Randomly selected isolates (212 Enterobacterales [158 molecularly characterized]; 
30 Pseudomonas aeruginosa; 11 Acinetobacter baumannii). Broth microdilution 
susceptibility testing with CTB-AVI (inhibitor at fixed concentration of 4 mg/L). The MIC90 
of CTB-AVI was ≤1 mg/L for all Enterobacterale isolates and selected subsets of different 
key resistant pathogens (Table 4). As expected, no antibacterial activity of CTB-AVI against 
NDM containing isolates was observed. The MIC90 of CTB-AVI against non-
Enterobacterales Gram-negative isolates (ie, P. aeruginosa and A. baumannii) was 
>32 mg/L.
Table 4.
Antibacterial Activity of CTB and CTB-AVI Against Gram-Negative 
Bacterial Isolates From JMI Laboratories
MIC (mg/L)
Organism (N)a
agent
range
MIC50
MIC90
Enterobacterales (54)
Ceftibuten
≤0.03 - >32
0.25
32
Ceftibuten-avibactam
≤0.03 - 16
≤0.03
0.25
Enterobacterales ESBL (50)
Ceftibuten
≤0.03 - >32
4
32
Ceftibuten-avibactam
≤0.03 – 0.12
≤0.03
0.06
Enterobacterales ESBL + OXA-48 (16)
Ceftibuten
4 - >32
16
32
Ceftibuten-avibactam
≤0.03 – 0.25
0.06
0.25
Enterobacterales ESBL + KPC (13)
Ceftibuten
2 - >32
16
32
Ceftibuten-avibactam
≤0.03 – 0.25
0.06
0.12
Enterobacterales pAmpC (28)
Ceftibuten
8 - >32
>32
>32
Ceftibuten-avibactam
≤0.03 – 1
0.12
1
Enterobacterales NDM-1 (2)
Ceftibuten
>32
>32
NA
Ceftibuten-avibactam
>32
>32
NA
P. aeruginosa (30)
Ceftibuten
8 - >32
>32
>32
Ceftibuten-avibactam
1 - >32
>32
>32
A. baumannii (11)
Ceftibuten
8 - >32
32
>32
Ceftibuten-avibactam
2 - >32
32
>32
a. Not all subsets are being displayed in the table.
Source: Report 17-SLA-014
In report 3471 (from IHMA)5, a total of 314 randomly selected Enterobacterales
(201 wildtype, 28 ESBL, 23 KPC, 22 OXA, 20 cAmpC and 20 pAmpC) were tested from 
years 2015-2017 (Table 5). The MIC90 of CTB-AVI was ≤0.5 mg/L for all Enterobacterales
isolates and subset of different key resistant pathogens except cAmpC and pAmpC 
containing isolates. The MIC90 of CTB-AVI was 8 mg/L for cAmpC and pAmpC containing 
isolates. 






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CTB is cleared predominantly by renal excretion of unchanged drug in preclinical species 
and in humans.17,19 CTB drug product is primarily the cis-isomer. Following administration 
of CTB to rats and dogs, cis-ceftibuten is the primary circulating and urinary component, 
while trans-ceftibuten was also detected, comprising 4% to 25% of the urinary radioactivity. 
This is similar to what was observed in a radiolabeled human ADME study, wherein the 
major radiolabeled species in plasma and urine was cis-ceftibuten, while trans-ceftibuten 
comprised approximately 11% of the dose. Two additional minor metabolites (<2% of dose) 
were observed in human ADME study, but were not identified.17,19
The potential interaction of CTB with CYP enzymes has not been reported. However, given 
the lack of CYP metabolism of CTB and the lack of CYP interactions with cephalosporins in 
general, it is considered unlikely that CTB would interact with CYPs. A clinical DDI study 
was conducted as part of the Cedax development program. Orally administered CTB did not 
affect the PK of theophylline, a CYP1A2 probe substrate.19
Based on in vitro studies, CTB is a substrate for the renal transporters OAT1 and OAT3, and 
is also a weak inhibitor of these transporters (IC50 values of 247 to 563 μM).20 Even though 
both AVI and CTB are substrates and weak inhibitors of OAT1 and OAT3, a PK interaction 
between the 2 compounds is unlikely based on the weak inhibition (high IC50 values) and the 
lack of interaction observed between AVI and coadministered aztreonam (OAT1/OAT3 
substrate and weak inhibitor) or ceftaroline (OAT1/OAT3 weak inhibitor).21,22
2.2.3. Nonclinical Safety
In repeat dose toxicity studies, systemic toxicity was not observed for AVP, AVI, and CTB at 
relatively high doses after repeat dose administration, with the exception of gastrointestinal 
effects which were generally not considered adverse. The only adverse effect noted with 
CTB (fatal enteritis) was not a direct effect of CTB, but rather was secondary to disruption of 
the intestinal flora, was not reproduced in repeat studies, and only manifested after prolonged 
dosing (≥2 months). Systemic exposures for AVI and CTB in toxicity studies support the 
proposed clinical exposures. 
AVP, AVI, and CTB were evaluated in genetic toxicity studies. AVP was positive in an in 
vitro micronucleus assay in TK6 cells. This result was not considered relevant following 
negative results in a liver and stomach Comet assay and a Big Blue mutation assay. Both 
AVI and CTB were nongenotoxic. AVI has no phototoxicity potential based on a negative 
result in the in vitro 3T3 Neutral Red Uptake assay.
Developmental and reproductive toxicity studies have been conducted with AVI by IV 
administration, as well as with an HPA-related compound that releases the major AVP 
metabolite, HPA, and no risks were identified for fertility, embryo-fetal development, or 
postnatal development except at higher exposures in rabbits. Developmental and 
reproductive toxicity studies were conducted with CTB and there were no risks identified for 
fertility, embryo-fetal development, or postnatal development.




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2.2.5.2. AVI
The PK of IV-administered AVI has been investigated in 12 clinical pharmacology studies in 
the CAZ-AVI program after administration of AVI alone or CAZ-AVI by IV infusion in 
healthy participants and patients with different degrees of renal impairment. The studies in 
healthy participants included young participants, male and female participants, participants 
≥65 years of age, and Japanese and Chinese participants. In addition, AVI PK data is also 
available from 5 Phase 1 clinical pharmacology studies in the ceftaroline-AVI development 
program.
The exposure of AVI was dose proportional at doses tested 
mg to 
mg), with no 
evidence of time-dependent kinetics following multiple dosing. The terminal elimination t½
of AVI was approximately 2 hours across studies, and there was no or little accumulation of 
AVI following repeated IV 
doses. AVI is approximately 100% eliminated through renal 
excretion, with the majority of AVI excreted as unchanged drug. Exposure of AVI increases 
with increasing renal impairment such that dose adjustments are required based on renal 
function. AVI is hemodialyzable. Based on the high degree of CLr and the minimal 
metabolism of AVI, no dose adjustment is needed in patients with impaired hepatic function. 
No dose adjustment is needed based on age, gender, race, or BMI. There are no drug 
interactions with CAZ, ATM, ceftaroline, and metronidazole.
No SAEs have been reported in the patients treated with AVI alone in Phase 1 studies 
(including the CAZ-AVI program and the ATM-AVI Phase 1 study). Only 1 discontinuation 
due to an AE was reported for a subject in an AVI-only treatment group (due to an 
asymptomatic AE of hyperamylasemia [which was demonstrated to be of salivary amylase]). 
AEs were generally mild to moderate and reported from a wide range of SOCs. Of note, 
several subjects had elevations in transaminase levels. In a Phase 1 study in healthy Japanese 
participants, elevations in liver transaminases in a single subject who received AVI alone was 
reported as an “other significant AE”.
A thorough QT study of supratherapeutic doses of AVI, with negative results, has been 
completed for CAZ-AVI and ceftaroline-AVI.
2.2.5.3. CTB
CTB (CEDAX) is a third-generation oral cephalosporin, approved in the US in 1995 at a 
dose of 400 mg QD. Although approved dose for CTB is 400 mg QD, there is some literature 
data regarding safe and well-tolerated use of higher doses up to 300 mg TID or 400 mg 
TID.26,27
CTB is rapidly absorbed after oral administration with a short terminal elimination t½ of 
2.5 hours. With repeated QD dosing for 7 days, CTB accumulation in plasma is about 20% at 
steady state. The average apparent Vz/F of CTB is 0.21 L/kg (± 1 SD = 0.03 L/kg). CTB is 
39% bound to plasma proteins. The protein binding is independent of plasma CTB 
concentration.
CTB is excreted in the urine; 95% of the administered radioactivity was recovered either in 
urine or feces. Approximately 56% of the administered dose of CTB was recovered from 
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Protocol C4691001
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urine and 39% from the feces within 24 hours. Since renal excretion is a significant pathway 
of elimination, patients with renal dysfunction and patients undergoing hemodialysis require 
dosage adjustment. Food delays the time of CTB Cmax by 1.75 hours, decreases the Cmax by 
18%, although AUC is unchanged.
Although CTB systemic exposures in plasma were 40% higher at steady state in elderly 
participants as compared to young adults, the significance of this finding for clinical use in 
elderly patients is not clear since renal function was not evaluated in these participants. CTB 
dosage adjustment in elderly patients may be necessary. CTB plasma t½ increased and CL/F 
decreased proportionately with increasing degree of renal dysfunction, requiring dose 
adjustment for varying degrees of renal impairment. CTB is hemodialyzable. There are no 
drug interactions with theophylline and liquid antacid. Although a slight interaction was 
noted (23% increase in Cmax and 16% increase in AUC) with ranitidine, it is unlikely to be of 
any clinical relevance. The safety and efficacy of CTB are described in the USPI. ADRs 
attributed to CTB in this label are considered ADRs for CTB + AVP.
Additional information on the PK, safety, and tolerability of AVP, AVI, and CTB can be 
found in the IB.28
2.3. Benefit/Risk Assessment
CTB + AVP is not expected to provide any clinical benefit to healthy participants. This study 
is designed primarily to generate safety, tolerability, and PK data to support further clinical 
development.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of CTB + AVP may be found in the IB, which is the SRSD for this study.
Study C4691001 is the first time that CTB and AVP will be administered together in humans.
For healthy participants participating in this single and multipledose study, no clinical benefit 
is expected. The purpose of the study is to provide the basis for further clinical development 
of CTB + AVP as a potential new, pharmacological agent for the treatment of participants 
with cUTI. As of 18 July 2022, the known specific human risks are summarized in the IB. 
The clinical impact of these potential risks will be minimized through the proposed cautious 
dose-escalation process wherein higher doses of CTB + AVP will be administered only after 
lower doses have been found to be well tolerated with an acceptable safety profile. In 
addition, this study includes standard, intensive, inpatient monitoring of the participants 
following administration of single and multiple oral doses of the study intervention.


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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) : AVP
Potential risks associated with CTB + AVP include 
the following: nausea and vomiting.  
This potential risk is based on the fact that nausea 
and vomiting are reported at an incidence of 4% 
and 1%, respectively in the CTB USPI. In 
addition, AEs of nausea and vomiting were 
reported by 1 patient in the FIH study of AVP. 
This information is described in the SRSD for 
CTB + AVP.
AEs will be monitored and participants will be 
managed as clinically indicated.
Study Intervention(s) : CTB
Hypersensitivity is a potential risk of CTB.
The risk of hypersensitivity is described in the 
USPI for CTB and the SRSD for CTB + AVP.
Eligibility criteria have been selected to ensure 
that only appropriate participants are included in 
the study (see Section 5.2 Exclusion criteria).
Pseudomembranous colitis is a potential risk of 
CTB.
The risk of pseudomembranous colitis is described 
in the USPI for CTB and the SRSD for CTB +
AVP.
Participants over 60 years of age and with 
significant medical history will be excluded from 
the study (see Section 5.1 Inclusion Criteria,
Criterion 1 and Section 5.2 Exclusion criteria, 
Criterion 1). AEs will be monitored and 
participants will be managed as clinically indicated 
and per guidance in the SRSD.
Convulsions/seizures is a potential risk of CTB.
The risk of convulsions/seizures is related to the 
cephalosporin class and is described in the USPI 
for CTB and the SRSD for CTB + AVP. 
Participants with renal impairment and significant 
medical history will be excluded from the study 
(see Section 5.2 Exclusion criteria, Criterion 1). 
AEs will be monitored and participants will be 
managed as clinically indicated and per guidance 
in the SRSD.


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Other 
The COVID-19 pandemic may pose risks to study 
participation. 
Participants may have increased risk of SARS-
CoV-2 infection by undergoing a study procedure 
at a study facility.
Inclusion of COVID-19 specific assessments 
according to the SoA.


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2.3.2. Benefit Assessment
For healthy participants in this study, no clinical benefit is expected. 
2.3.3. Overall Benefit/Risk Conclusion
CTB + AVP is not expected to provide any clinical benefit to healthy participants in this 
study. Taking into account the measures to minimize risk to study participants, the potential 
risks identified in association with the administration of CTB + AVP are clinically 
acceptable.
3. OBJECTIVES AND ENDPOINTS
PART-1: Single Dose
Objectives
Endpoints
Primary:
Primary:
To assess the plasma PK profile of CTB following a 
single dose of CTB alone or in combination with 
AVP.
Plasma PK parameters of cis-CTB: 

Cmax, Tmax, AUClast, Cmax(dn), AUClast(dn).

If data permit, AUCinf, AUCinf(dn), t½, Vz/F, and 
CL/F.
To assess the plasma PK profile of AVP following 
administration of single doses of AVP in 
combination with CTB.
Plasma PK parameters of AVP, AVI and HPA: 

Cmax, Tmax, AUClast, Cmax(dn), AUClast(dn).

If data permit, AUCinf, AUCinf(dn), t½, Vz/F, and 
CL/F.
To assess the safety and tolerability following a 
single dose of CTB alone or in combination with 
AVP.

Frequency, severity, and causal relationship of 
TEAEs and withdrawals due to TEAEs.

Frequency and magnitude of abnormal 
laboratory findings.

Changes from baseline in vital sign 
measurements and 12-lead ECG parameters.
PART-2: Multiple Dose (including optional Japanese and Chinese Cohorts)
Objectives
Endpoints
Primary漣
Primary漣
To assess the plasma PK profile of cis-CTB and 
trans-CTBa following multiple doses of CTB in 
combination with AVP.
Plasma PK parameters of cis-CTB and trans-CTBa on 
Day 1 (fed, single dose), Day 6 (fed, steady state) 
and Day 7 (fasted, steady state): 

Cmax, Tmax, AUCtau, Cmax(dn), AUCtau(dn).

If data permit, t½, Vz/F, and CL/F.


PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
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Objectives
Endpoints
To assess the plasma PK profile of AVP following 
multiple doses of CTB in combination with AVP. 
Plasma PK parameters of AVP, AVI and HPA on 
Day 1 (fed, single dose), Day 6 (fed, steady state) 
and Day 7 (fasted, steady state): 

Cmax, Tmax, AUCtau, Cmax(dn), AUCtau(dn)

If data permit, t½, Vz/F, and CL/F.
To assess the safety and tolerability following 
multiple doses of CTB in combination with AVP.

Frequency, severity, and causal relationship of 
TEAEs and withdrawals due to TEAEs.

Frequency and magnitude of abnormal 
laboratory findings.

Changes from baseline in vital sign 
measurements and 12-lead ECG parameters.
Secondary漣
Secondary漣
To assess the urinary PKb profile of cis-CTB, 
trans-CTBa, AVP, AVI and HPA on Day 6 following 
multiple doses of CTB in combination with AVP.
cis-CTB, trans-CTBa, AVP, AVI and HPA urinary 
PK parameters (if data permit): 

Aetau and Aetau%, CLr.
To assess PK profile of CTB and AVP when 
administered in combination in Japanese and 
Chinese participants.
Plasma PK parameters of cis-CTB, AVP, AVI and 
HPA on Day 1 (fed, single dose), Day 6 (fed, steady 
state) and Day 7 (fasted, steady state) in Japanese 
and Chinese cohorts: 

Cmax, Tmax, AUCtau, Cmax(dn), AUCtau(dn).

If data permit, t½, Vz/F, and CL/F.
Tertiary/Exploratory漣
Tertiary/Exploratory漣
To explore the effect of food on PK of cis-CTB, 
trans-CTB, AVP, AVI and HPA.
In PART-2, comparison of plasma PK parameters of 
cis-CTB, trans-CTB, AVP, AVI and HPA on Day 6 
(fed) versus Day 7 (fasted).
To explore the potential drug-drug interaction when
CTB and AVP are co-administered.
In PART-1, comparison of plasma PK parameters of 
cis-CTB and trans-CTB after administration of 
Dose 2 (800 mg CTB + 1350 mg AVP) versus after 
Dose 3 (800 mg CTB alone).
To determine the potential effect of CTB on cardiac 
repolarization, if data permit.
In PART-1, if supratherapeutic concentrations are 
achieved, C-QT modeling will be conducted to 
assess potential effect of CTB on QTc prolongation.
a.
trans-CTB will be measured only in Cohort 2 PART-2.
b.
cis-CTB, trans-CTB, AVP, AVI and HPA in urine will be measured on Day 6 only in Cohort 2, 
PART-2.
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Protocol C4691001
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4. STUDY DESIGN
4.1. Overall Design
The current study is a Phase 1 study of CTB + AVP in healthy adult participants. It is a 
2-part study combining PART-1: Single dose PK, safety and tolerability of various CTB 
doses when administered alone or with AVP, and PART-2: Multiple dose PK, safety and 
tolerability of CTB + AVP, including optional Japanese and Chinese cohorts. PART-1 and 
PART-2 are randomized, double-blind (participant and investigator blinded and sponsor 
open) cohorts.
In both parts, participants will be screened within 28 days of their first dose of investigational 
product. Participants will be admitted to the CRU on Day -1 or earlier and may be discharged 
at investigator discretion following completion of assessments per SoA. If a participant has 
any clinically significant, study related abnormalities at the conclusion of a scheduled 
inpatient portion of the study, the Pfizer medical monitor (or designated representative) 
should be notified and the participant may be asked to remain in the CRU until such 
abnormalities are deemed not clinically significant, or it is safe for outpatient follow-up. 
Participants who discontinue for non-safety related reasons prior to completion of the study 
may be replaced, at the discretion of the PI and sponsor. The replacement participant(s) may 
or may not be required to complete all periods of the cohort in which they are participating at 
the discretion of the PI and sponsor.
In PART-1 and PART-2, treatment sequences, actual doses, dose increments, and dosing 
regimen may be adjusted, and intermediate or alternative dose levels may be substituted 
during the study based on emerging safety, tolerability, and PK data.
PART-1: Single Dose
PART-1 will include 1 cohort (Cohort 1) with approximately 8 participants planned in total.
This part will have a randomized, double-blind (sponsor-open), 5-period, sequential single 
dose design. Approximately 6 participants will receive either a single dose of CTB or CTB +
AVP combined, and approximately 2 participants will receive the matching placebo under 
fed state. PART-1 will have a cross-over design with up to 5 periods, as Period 4 and 5 are 
optional. Periods 4 and 5 may be used to further explore PK at additional doses, based on 
emerging PK data. When on active treatment, participants will receive D1, D2, D3, D4 
(optional), and D5 (optional) for each period, respectively, as specified in Table 6. 
Participants will be dosed in a fed state, as specified in Sections 5.3.2 and 6.1. Provisional 
dosing scheme in PART-1 is provided in Table 6. Except D1 in PART-1, all other dose levels 
and/or meal condition may be changed based on emerging PK, safety, and tolerability data. 
Dose escalation of CTB (and AVP, when applicable) to higher doses will be based on all 
available (a minimum of 24 hours post-dose) safety data in a minimum of 5 participants 
(4 active and 1 placebo) at the previous dose levels of CTB and/or AVP. AVP dose for 
Period 4 onwards may be
mg based on PK and tolerability 
data. In addition, AVP dose for Period 5
mg if it appears from 
Period 2 and Period 4 that AVI AUC is less than target (
 μg.hr/mL). 
If the AVP dose 
mg with
mg CTB needs to be evaluated, then the CTB 
mg 
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dose oral administration of CTB + AVP in PART-2. These cohorts will have all evaluations 
as specified in SoA for PART-2 cohorts and the dose level in this cohort will be equal or 
lower than the highest dose level evaluated in healthy Western participants. Frequency of 
administration will be based on safety, tolerability and PK data from Western participants. 
Urine samples will be collected up to 8 hours post dose on Day 6 in Cohort 2 as specified in 
the SoA. 
Table 7.
Provisional Dosing Scheme in PART-2*
Cohort #
DR#
Dosing Regimen 
Cohort 2
DR1
400 mg CTB + 1350 mg AVP or Placebo
Cohort 3
DR2
400 or 800 CTB + 1350 mg AVP or Placebo
Cohort 4
DR3
800 mg or 1200 mg CTB + 1350 mg AVP or Placebo 
Cohort 5
DR1,DR2 or DR3
400, 800 or 1200 mg CTB + 1350 mg AVP or Placebo
Cohort 6
DR1,DR2 or DR3
400, 800 or 1200 mg CTB + 1350 mg AVP or Placebo
* 1350 mg AVP may be replaced with 900 mg AVP, depending on safety, tolerability and/or PK 
considerations
Except D1 (Dose 1) in PART-1 and DR1 (Dose Regimen 1) in PART-2 of the study, the dose 
levels, frequency of administration, and/or meal condition may be changed based on 
emerging PK, safety, and tolerability data. During PART-1 and PART-2, the dose increments 
and planned doses may be adjusted, as the study progresses dependent upon emerging PK, 
safety, and tolerability data. Other intermediate doses or lower doses may be administered 
instead of the planned doses, or changes in dosing frequency or titration schemes may be 
proposed for PART-2 cohorts if safety/tolerability or PK issues become apparent, if evidence 
of nonlinear PK dictates the need to escalate more slowly, or if subsequent doses are 
predicted to result in exposures that exceed the target limits. Any potential altered dose 
scheme will be equal to or less than a 3.3-fold increase in exposure from the previous highest 
dose if a higher dose is warranted to achieve exposure. The projected average exposure of the 
altered dose scheme will not exceed the exposure limit specified in Section 4.3.
In all cohorts (all parts of the study), participants can be released after completing activities 
specified in SoA. A telephone follow-up contact will occur between 28 to 35 days after the 
day of last administration of study intervention. At the discretion of the investigator, 
telephone follow-up contact may be substituted with an on-site visit in case of additional 
follow-up of open AEs or clinically significant laboratory findings. 
The total planned duration of participation, from Screening visit to the Follow-up phone call, 
may be approximately 12 weeks for PART-1 (up to 4 weeks for screening, up to 3 weeks of 
dosing and up to 5 weeks for safety follow-up visit), and 10 weeks for PART-2 (up to 
4 weeks for screening, up to 1 week of dosing and up to 5 weeks for safety follow-up visit).






PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Protocol C4691001
Final Protocol Amendment 1, 06 September 2022
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Results from in vivo studies (studies in progress):
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Table 8.
Predicted Human Exposure and Safety Margins of CTB Relative to 
Exposure Limits at Planned Dose Levels in PART-1
Dose Levels
Dose (mg)
Estimated Human 
CTB AUCinf
AUCinf safety margind
D1
400 CTB + 900 AVP
60
17 × (rat) and 23 × (dog)
D2
800 CTB + 1350 AVP
120c
9 × (rat) and 11 × (dog)
D3
800 CTB
120c
9 × (rat) and 11 × (dog)
D4b
1200 CTB + 1350 AVPa
180c
6 × (rat) and 8 × (dog)
D5b
1600 CTB alone
240c
4 × (rat) and 6 × (dog)
a.
AVP 1350 mg may be replaced with AVP 900 mg.
b.
D4 and D5 are optional.
c.
Assumes dose-proportional increase in human AUC at higher doses.
d.
Safety margin calculations based on estimated human AUCinf of 55-60 μg.hr/mL after single dose of 400 mg CTB; 
rat AUC of 1046 μg.hr/mL at NOAEL in the 1-month toxicology study; and dog AUC of 1379 μg.hr/mL at NOAEL 
in 1-month and 3-month toxicology studies.
Table 9.
Predicted Human Exposure and Safety Margins of AVI Relative to 
Exposure Limits at Planned Dose Levels in PART-1
Toxicology 
Study
Dose 
(mg/kg/day)
Cmax
(μg/mL)
AUC24,ss
(μg.hr/mL)
Exposure
margin for 
900 mg 
AVP dosea
Exposure
margin for 
1350 mg 
AVP doseb
Exposure
margin for 
1800 mg 
AVP dosec
5-day repeat dose 
in rats
2000
61.9
753
7.2
5.7
3.6
14-day pivotal 
repeat-dose study 
in rats
1000 
(NOAEL)
32.7
354
3.4
2.7
1.7
14-day pivotal 
repeat-dose study 
in dogs
1000 
(NOAEL)
265
1370
13.2
10.3
6.6
a.
All exposure margins were based on the human AVI AUC (104 μg•h/mL) at the projected human dose of 900 mg 
TID AVP. 
b.
All exposure margins were based on the human AVI AUC (133 μg•h/mL) at the projected human dose of 1350 mg 
TID AVP.
c.
All exposure margins were based on the human AVI AUC (208 μg•h/mL) ) at the projected human dose of 1800 mg 
TID AVP, assuming dose-proportional increase in AVI exposures from 900 mg to 1800 mg. 
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Table 10.
Predicted Human Exposure and Safety Margins of CTB Relative to 
Exposure Limits at Planned Dose Levels in PART-2 
Dose 
Regimens
Dose (mg) and 
Frequency
AUC24,ss
safety marginb
Cmax safety marginc
DR1
400 mg CTB + 
1350a mg AVP TID
6 × (rat) and 8 × (dog): 400 mg CTB 
dose
6.4 x (rat): 400 mg CTB dose
DR2
400 mg or 800 mg 
CTB + 1350a mg 
AVP TID
6 × (rat) and 8 × (dog): 400 mg CTB 
dose
3 × (rat) and 4 × (dog): 800 mg CTB 
dose
6.4 x (rat): 400 mg CTB dose
3.2 x (rat): 800 mg CTB dose
DR3
800 mg or 1200 mg 
CTB + 1350a mg 
AVP TID
3 × (rat) and 4 × (dog): 800 mg CTB 
dose 
2 × (rat) and 2.6 × (dog): 1200 mg 
CTB dose
3.2 x (rat): 800 mg CTB dose
2.1 x (rat): 1200 mg CTB 
dose
a.
AVP 1350 mg may be replaced with AVP 900 mg.
b.
Based on estimated human AUC (540 μg.hr/mL) at the maximum human dose of 1200 mg TID CTB; assuming 
proporitional increase from lower doses.
c.
Based on estimated human Cmax (15.7 μg/mL at 400 mg CTB dose, 31.4 μg/mL at 800 mg CTB dose, 47.1 μg/mL at 
1200 mg CTB dose) and estimated Cmax of 100 μg/mL in 1-month rat toxicology study
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 he/she has completed all periods of 
the study, including the last visit.
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. Use of 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, and 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.


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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 18 to 60 years of age (or the minimum age of consent in accordance with 
local regulations), inclusive, at screening.
•
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
2. Male and female participants who are overtly healthy as determined by medical 
evaluation including medical history, PE, laboratory tests, vital signs and standard 
12-lead ECGs.
Other Inclusion Criteria:
3. For optional Japanese cohort only: Japanese participants who have 4 Japanese 
biologic grandparents who were born in Japan. 
4. For the optional Chinese cohort only: Chinese participants who were born in 
mainland China, and both parents are of Chinese descent. 
5. BMI of 17.5 to 30.5 kg/m2; and a total body weight >50 kg (110 lb). 
6. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Known allergy to the cephalosporin group of antibiotics.
3. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, 
or HCVAb. Hepatitis B vaccination is allowed.
4. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality [or other conditions or 
situations related to COVID-19 pandemic (eg, Contact with positive case)] that may 


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increase the risk of study participation or, in the investigator’s judgment, make the 
participant inappropriate for the study.
Prior/Concomitant Therapy:
5. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention (Refer to Section 6.9 for additional details).
6. Current use of any prohibited concomitant medication(s) or those unwilling/unable to 
use a permitted concomitant medication(s). Hormonal contraceptives that meet the 
requirements of this study are allowed to be used in participants who are WOCBP. 
(Refer to Section 6.9 for additional details).
Prior/Concurrent Clinical Study Experience:
7. Previous administration with an investigational product 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). 
Diagnostic Assessments:
8. A positive urine drug test.
9. Screening supine BP ≥140 mm Hg (systolic) or ≥90 mm Hg (diastolic), following at 
least 5 minutes of supine rest. If BP is ≥140 mm Hg (systolic) or ≥90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the participant’s eligibility.
10. Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities that
may affect participant safety or interpretation of study results (eg, baseline QTcF 
interval >450 msec, complete LBBB, signs of an acute or indeterminate-age 
myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, 
second- or third-degree AV block, or serious bradyarrhythmias or tachyarrhythmias). 
If the baseline uncorrected QT interval is >450 msec, this interval should be rate-
corrected using the Fridericia method and the resulting QTcF should be used for 
decision making and reporting. If QTcF exceeds 450 msec, or QRS exceeds 
120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or 
QRS values should be used to determine the participant’s eligibility.
Computer-interpreted ECGs should be overread by a physician experienced in 
reading ECGs before excluding a participant.
11. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 
•
AST or ALT level ≥1.25 × ULN;


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•
Total bilirubin level ≥1.5 × ULN; participants with a history of Gilbert’s 
syndrome may have direct bilirubin measured and would be eligible for this 
study provided the direct bilirubin level is ≤ULN;
•
eGFR <90 mL/min (estimated using the CKD-EPI equation).
Other Exclusions Criteria:
12. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general rule, 
alcohol intake should not exceed 14 units per week (1 unit = 8 ounces [240 mL] beer, 
1 ounce [30 mL] of 40% spirit or 3 ounces [90 mL] of wine).
13. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing. 
14. History of sensitivity to heparin or heparin-induced thrombocytopenia. 
15. Participants who are unwilling and/or unable to comply with all scheduled visits, 
treatment plan, laboratory tests, lifestyle considerations, and other study procedures
16. 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
The following guidelines are provided:
5.3.1. Contraception 
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 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 
alternate protocol-specified method, including if the participant will no longer use abstinence 


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as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Meals and Dietary Restrictions
•
When fasted PK is being evaluated (Day 7 of every cohort in PART-2), participants 
will receive study intervention at approximately 0800 hours (± 2 hours) following an 
overnight fast of at least 10 hours. 
•
When safety labs are being evaluated in PART-1 or -2, participants must fast (except 
water) for at least 4 hours prior to blood draw.
•
When fed PK is being evaluated (Day 1 for each Period in PART-1) and on 
Days 1 - 6 in PART-2, participants will receive study intervention at approximately 
0800 hours (± 2 hours) under fed conditions. Participants should begin breakfast 
approximately 30 minutes prior to dose administration which should be consumed 
within 20 minutes. Dose will be administered approximately 30 minutes after starting 
the breakfast.
•
Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing, except water 
consumed during breakfast on the days under fed conditions. Noncaffeinated drinks 
(except grapefruit or grapefruit-related citrus fruit juices - see below) may be 
consumed with meals and the evening snack.  
•
Lunch will be provided approximately 4 hours after dosing.
•
Dinner will be provided approximately 9 to 10 hours after dosing.
•
An evening snack may be permitted.
•
For dosing conducted under fed conditions, after an overnight fast of 10 hours, 
participants will start a high-fat/high-calorie breakfast approximately 30 minutes prior 
to administration of the investigational product. The breakfast will be consumed over 
approximately 20 minutes with investigational product administered within 
approximately 10 minutes after completion of the meal. Participants will be 
encouraged to eat the full meal. If participants are unable to complete the entire meal, 
the approximate portion of the meal consumed will be documented. No food will be 
allowed for at least 2 hours post-dose.
•
Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample.  
•
While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.


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5.3.3. Caffeine, Alcohol, and Tobacco
•
Participants will abstain from caffeine-containing products for 24 hours prior to the 
start of dosing until collection of the final PK sample of each study period.  
•
Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.
•
Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.4. Activity
•
Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted;
•
In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except when required for BP, pulse rate, and 
ECG measurements), eating, and drinking beverages other than water during the first 
4 hours after dosing. In PART-2 participants may lie down following the second and 
third dose of the day on Days 1 through 6. 
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. Screen failure data are collected and remain as 
source and are not reported on the CRF.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions includes all prespecified investigational 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 all of the following:
•
PF-06264006, CTB
•
Placebo for CTB
•
PF-07338233, AVP
•
Placebo for AVP


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6.1. Study Intervention(s) Administered
Study Interventions
Intervention Name
CTB
AVP
PF-06264006
Placebo
PF-07338233
Placebo
ARM Name
(group of patients 
receiving a specific 
treatment)
PF-06264006 
Double-Blind 
Treatment
Placebo Double-
Blind Treatment
PF-07338233 
Double-Blind 
Treatment
Placebo Double-
Blind Treatment
Type
Drug
Placebo
Drug
Placebo
Dose Formulation
Capsule
Capsule
Capsule
Capsule
Unit Dose
Strength(s)
400 mg
0 mg
225 mg
0 mg
Dosage Level(s)
400 mg
0 mg
225 mg
0 mg
Route of 
Administration
Oral
Oral
Oral
Oral
Use
Experimental
Placebo
Experimental
Placebo
IMP or NIMP/AxMP
IMP
IMP
IMP
IMP
Sourcing
Provided centrally 
by the sponsor
Provided centrally 
by the sponsor
Provided centrally 
by the sponsor
Provided centrally 
by the sponsor
Packaging and 
Labeling
Capsules will be 
provided in blister 
packs. CRU staff 
will prepare 
individual doses 
for administration. 
Individual dose 
containers will be 
labeled by site 
staff per country 
requirement
Capsules will be 
provided in blister 
packs. CRU staff 
will prepare 
individual doses 
for administration. 
Individual dose 
containers will be 
labeled by site 
staff per country 
requirement
Capsules will be 
provided in bulk. 
CRU staff will 
prepare individual 
doses for 
administration. 
Individual dose 
containers will be 
labeled by site 
staff per country 
requirement
Capsules will be 
provided in bulk. 
CRU staff will 
prepare individual 
doses for 
administration. 
Individual dose 
containers will be 
labeled by site staff 
per country 
requirement
Current/Former 
Name(s) or Alias(es)
NA
NA
NA
NA


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Study Arms – PART-1
Arm Title
CTB or CTB + AVP
Placebo
Arm Type
Experimental
Placebo 
Arm Description
Participants may receive a single dose of 400 mg 
CTB + 900 mg AVP, or 800 mg CTB + 1350 mg 
AVP, or 800 mg CTB alone, or 1200 mg CTB + 
1350 mga AVP, or 1600 mg CTB alone, or 1200 mg 
CTB + 1800 mg AVP on Day 1 in up to 5 periods.
Participants will receive a single dose of 
Placebo on Day 1 in up to 5 periods.
a. 1350 mg AVP may be replaced with 900 mg AVP.
Study Arms – PART-2
Arm Title
CTB + AVPa
Placebo
Arm Type
Experimental
Placebo
Arm Description
Participants may receive 400 mg CTB + 1350 mg AVP
(DR1), or 400 mg/800 mg CTB + 1350 mg AVPa TID
(DR2) or 800 mg/1200 mg CTB + 1350 mg AVPa TID
(DR3) for 7 days.
Participants will receive placebo TID 
for 7 Days.
a. 1350 mg AVP dose may be replaced with 900 mg AVP.
PF-07338233 (AVP) and placebo for AVP will be provided by Pfizer as bulk capsules to the 
CRU. PF-06264006 (CTB) and matching placebo for CTB will be provided as blistered
capsules to the CRU.
Study intervention and placebo will be presented to the participants in individual dosing 
containers that were supplied by Pfizer.
AVP will be supplied as 225 mg/capsule. Matching placebo capsules will also be provided.
CTB 400 mg capsules along with matching placebo will be supplied as packaged blisters and 
labeled according to local regulatory requirements. The blisters will be provided to the site 
for dispensing by the pharmacy. 
6.1.1. Administration
When fasted PK is being evaluated (Day 7 of every cohort in PART-2), participants will 
receive study intervention at approximately 0800 hours (±2 hours) following an overnight 
fast of at least 10 hours. On all other days throughout the study, participants will receive 
study intervention under fed conditions. Investigator site personnel will administer study 
intervention during each period with ambient temperature water to a total volume of 
approximately 240 mL. Additional water (100 mL) may be given to participants, as needed, 
to help ingestion of study interventions. Participants will swallow the study intervention
whole, and will not manipulate or chew the study intervention prior to swallowing. When 
applicable, CTB and AVP will be dosed simultaneously (within no more than 7 minutes of 
each other), starting with CTB.


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In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for BP, pulse rate, and ECG 
measurements), eating, and drinking beverages other than water during the first 4 hours after 
dosing. In PART-2 participants may lie down following the second and third dose of the day 
on Days 1 through 6.
6.1.2. Medical Devices 
Not applicable
6.2. Preparation, Handling, Storage, and Accountability
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 the 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 PCRU local/site 
procedures.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
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 
form/record.


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8. Further guidance and information for the final disposition of unused study 
interventions are provided in the PCRU’s local/site procedures. 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.
6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
Details of dose preparation will be given in a separate EDR. Prepared doses will be provided 
in unit dose containers and labeled in accordance with Pfizer regulations and the investigator 
site’s labeling requirements.
Study interventions and placebo will be prepared by qualified unblinded site personnel 
according to the IP manual. Blinded study intervention will be administered in a blinded 
fashion to the participant. 
CTB capsules and AVP capsules will be prepared at the CRU in the individual dosing 
containers by 2 operators, 1 of whom is an appropriately qualified and experienced member 
of the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist). The capsules will be provided in unit dose containers 
and labeled in accordance with Pfizer regulations and the clinical site’s labeling 
requirements. 
6.3. Assignment to Study Intervention
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
6.4. Blinding
This is a double-blind (sponsor-unblinded) study. 
6.4.1. Blinding of Participants
Participants will be blinded to their assigned study intervention. The investigator has the sole 
responsibility for determining if unblinding of a participant’s study intervention assignment 


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is warranted. Participant safety must always be the first consideration in making such a 
determination. The investigator should make every effort to contact the medical monitor 
prior to unblinding a participant’s study intervention assignment, unless this could delay 
further management of the participant.
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 order to maintain this blind, an otherwise uninvolved third party will be responsible for 
administration of the study intervention. This includes ensuring that there are no differences 
in time or effort taken to administer the study intervention and no blinded site staff are able 
to view the administration.
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
A limited number of sponsor staff will be unblinded to participants’ assigned study 
intervention in order to permit real time interpretation of the safety and PK data during dose 
escalation meetings and/or to support clinical development.. 
6.4.4. Breaking the Blind
The method for breaking the blind in this study will be manual. A sealed envelope that 
contains the study intervention assignment(s) for each participant will be provided to the 
investigator. The sealed envelope will be retained by the investigator (or representative) in a 
secured area. 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 unblinding a participant’s treatment assignment 
unless this could delay further management of the participant. If a participant’s treatment 
assignment is unblinded, the sponsor must be notified within 24 hours after breaking the 
blind. When the blinding code is broken, the reason must be fully documented and entered on 
the CRF.
Once the study is complete, all envelopes (sealed and opened) must be inventoried and 
retained until authorization for destruction has been provided.


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Blood specimens will be obtained from all participants for PK analysis to maintain the study 
blind at the investigator site. Only the investigator site staff and blinded study monitor, if 
assigned, will be blinded to study treatment. Other Pfizer personnel will be unblinded to 
participant treatments in order to permit real-time interpretation of the safety and PK data; 
and provide information necessary to potentially alter the dose-escalation sequence. The 
blinded study monitor, if assigned, will remain blinded to treatment until all monitoring for 
the study has been completed. Specimens from participants randomized to placebo will not 
be routinely analyzed. To minimize the potential for bias, treatment randomization 
information will be kept confidential by Pfizer unblinded personnel and will not be released 
to the blinded investigator or blinded investigator site personnel until the study database has 
been locked or the investigator requests unblinding for safety reasons.
6.5. Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff.
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 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
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. Study site personnel will examine each participant’s mouth to ensure that 
the study intervention was ingested.
6.6. Dose Modification
Progression to the next dose in PART-1 will occur if the last dose was well tolerated and 
after satisfactory review of the available safety data. Each dose escalation will be based on 
review of the safety data up to a minimum of 24 hours postdose, in at least 4 actively treated 
participants and at least 1 placebo-treated participant dosed in the previous dose level.
AVP dose in PART-1 may be 900 mg, 1350 mg, or 1800 mg (in Period 5 only) as long as 
average PK exposures for AVI are not projected to be higher than PK stopping limit (AVI 
AUC ≤354 ug hr /mL: NOAEL in the 14 day pivotal repeat dose toxicology study in rats). 
Progression to the next higher optional dose regimen (DR2) in PART-2 may occur if the first
DR1 was well tolerated and after satisfactory review of the available safety data. Dose 
escalation will be based on review of the safety data up to a minimum of 6 days, in at least 
4 actively treated participants and at least 1 placebo-treated participant dosed in the previous 
dose level. If the DR1 dose is not well-tolerated, the dose in DR2 can be modified to be a 
lower dose than DR1 to allow for dose de-escalation.
6.6.1. Dose Escalation and Stopping Rules
Dose escalation stopping rules will be used to determine whether the maximal tolerated dose 
has been attained. Dose escalation may be stopped if it is determined that the limits of safety 
and/or tolerability have been reached. This decision will be made after a discussion takes 
place between the sponsor study team and the investigator. The sponsor study team may not 


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overrule the investigator’s decision to stop dose escalation. If dose escalation is stopped 
because of any of these criteria, additional cohorts may receive the same or lower doses of 
the study intervention.
The dose escalation will be terminated based on the following criteria:
•
If 50% or more of the participants receiving active drug at a given dose level (but not 
participants receiving placebo) develop similar clinically significant laboratory, ECG, 
or vital sign abnormalities, in the same organ class, indicating dose-limiting 
intolerance.
•
Severe nonserious AEs, considered as, at least, possibly related to study intervention
administration, in 2 participants at a given dose level (but not participants receiving 
placebo), independent of within or not within the same system organ class, indicating 
dose-limiting intolerance.
•
Dosing will be paused for any SAE that occurs in a participant receiving active 
treatment until causality is fully assessed by the PI and sponsor. Dosing may resume 
if the SAE is determined to be not drug-related by the PI and sponsor. If the SAE is 
determined to be either drug-related or unknown, either dosing will cease or the SAE 
will be evaluated by the sponsor’s protocol review committee (or similar review 
group), which is independent of the study team and investigators. If the protocol 
review committee determines that dosing may resume, a plan that mitigates risks to 
participants with the resumption of dosing will be implemented. Such a plan could 
include a revision of inclusion/exclusion criteria, repeating or reducing the dose, or 
adding appropriate safety monitoring.
•
It is determined that the limit of safety and/or tolerability has been reached. This 
decision will be made following discussions between the study team and the 
investigator.
•
Other findings that, at the discretion of the study team and investigator, indicate that 
dose escalation should be halted.
•
If, at any dose level, the average human exposure (AUC0-24hr) reaches or exceeds the 
PK stopping limits: CTB AUCinf ≥1046 μg.hr/mL (NOAEL in the 1-month rat 
toxicology study), AVI AUC0-24hr ≥354 μg.hr/mL (NOAEL in the 14-day pivotal 
repeat-dose rat toxicology study), or the average Cmax reaches or exceeds the Cmax PK 
stopping limits: CTB Cmax >100 μg/mL (estimated CTB Cmax at NOAEL in the 
1-month rat toxicology study), or AVI Cmax ≥32.7 μg/mL (AVI Cmax at NOAEL in the 
14-day pivotal repeat-dose rat toxicology study).
•
If, based on the observed data, the group mean Cmax or AUC (based on total plasma 
concentration) of the next planned dose is projected to exceed the escalation limits, 
that dose will not be explored. Modified doses may be explored if they are not 
expected to exceed PK stopping criteria.


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Progression to the next dose will occur if the last dose was well tolerated and after 
satisfactory review of the available safety and PK data.
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
For this study, any dose of CTB greater than
mg or of AVP greater than 
 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/treating physician 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 visit.
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.
5. Obtain a blood sample for PK analysis within 1 day 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
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses 
of ≤1 g/day.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).
CCI
CCI


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All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments (see Appendix 9).
6.9.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with CTB or AVP; standard medical 
supportive care must be provided to manage the AEs. 
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 requiring discontinuation in investigator’s view;
•
Pregnancy;
•
Positive COVID-19 test.
If study intervention is permanently discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention.
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.
7.1.1. Liver Injury       
A participant who meets the criteria as described in Appendix 6 will be withdrawn from 
study intervention. 
7.1.2. ECG Changes
A participant who meets either bulleted criteria based on the average of triplicate ECG 
readings will be withdrawn from the study intervention. 
•
QTcF >500 ms.
•
Change from baseline: QTcF >60 ms and QTcF >450 ms.


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If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
7.1.3. Potential Cases of Acute Kidney Injury
Abnormal values in Scr concurrent with presence or absence of increase in BUN that meet 
the criteria below, in the absence of other causes of kidney injury, are considered potential 
cases of acute kidney injury and should be considered important medical events. 
An increase of ≥0.3 mg/dL (or ≥26.5 μmol/L) in Scr level relative to the participant’s own 
baseline measurement should trigger another assessment of Scr as soon as practically 
feasible, preferably within 48 hours from awareness.
If the second assessment (after the first observations of ≥0.3 mg/dL [or ≥26.5 μmol/L] in Scr
relative to the participant’s own baseline measurement) is ≥0.4 mg/dL (or ≥35.4 μmol/L), the 
participant should be discontinued from the study and adequate, immediate, supportive 
measures taken to correct apparent acute kidney injury.
Participants should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the second assessment confirming abnormal 
Scr result. This evaluation should include laboratory tests, detailed history, and physical 
assessment. In addition to repeating Scr, laboratory tests should include serum BUN, serum 
creatine kinase, and serum electrolytes (including at a minimum potassium, sodium, 
phosphate/phosphorus, and calcium), in addition to urinary dipstick, urine microscopic 
examination, and urinary indices. All cases confirmed on repeat testing as meeting the 
laboratory criteria for acute kidney injury, with no other cause(s) of laboratory abnormalities 
identified, should be considered potential cases of drug-induced kidney injury irrespective of 
availability of all the results of the investigations performed to determine etiology of the 
abnormal Scr. If ≥2 healthy participants in a given period/treatment arm are noted to have 
2 consecutive Scr results of ≥0.3 mg/dL (or ≥26.5 μmol/L), an assessment of whether the 
finding may be considered an adverse drug reaction should be undertaken.
7.1.4. Pregnancy
Pregnancy tests are conducted at each visit and dosing of study intervention will occur only
in the presence of a negative pregnancy test. If a participant is confirmed to be pregnant (see
Section 8.3.6) during any visit, further dosing with study intervention (if in PART-2) will be
discontinued immediately and permanently.
Section 8.4.5.1 describes the follow-up activities if a participant meets the EDP criteria.
7.1.5. COVID-19
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. If the participant is diagnosed 


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with COVID-19 during confinement in the CRU, further dosing with study intervention will 
be discontinued. It is recommended that the investigator discuss temporary or permanent 
discontinuation of study intervention with the study medical monitor.
7.1.6. Temporary Discontinuation
Not applicable.
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;
•
Death;
•
Study terminated by sponsor;
•
Pregnancy.
At the time of discontinuing from the study, 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.
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, 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 and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed 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 for any further contact 
with them or persons previously authorized by the participant to provide this information. 


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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 return to the clinic for/attend 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.
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 
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Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may be used without repeat collection, as appropriate.
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.
Safety assessments and laboratory results that have been collected for the purposes of this 
study and could unblind the study will not be reported to investigative sites or other blinded 
personnel until the study has been unblinded.
If an IV catheter is utilized for blood sample collections, ECGs and vital sign assessments 
(pulse rate and BP) should be collected prior to the insertion of the catheter.
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 participants in this study is approximately 
519 mL in PART-1 and 291 mL in PART-2. 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.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Concomitant Therapy sections of the protocol.
8.1.1. Baseline Procedures
Baseline procedures include the collection of medical history, concomitant medication use, 
demography, physical exam, vital signs, contraception check, COVID-19 assessment 
(questionnaire and testing), 12-lead ECG completion, eGFR (CKD-EPI), and blood and urine 
sample collection. 


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The blood sample includes the following laboratory studies: pregnancy test and FSH for 
women, and safety labs and screening for HIV, HBV (HBsAg, HBsAb, and HBcAb) and 
HCV (HCVAb) infections for all participants.  
The urine sample includes urine drug testing and urinalysis. 
8.1.2. Telehealth Visits
Telehealth visits may be used to assess participant safety and collect data points. 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 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. 
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
8.2. Efficacy Assessments
No efficacy assessment is planned in this study.
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. Physical Examinations
A complete physical examination will include, at a minimum, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant-reported symptoms.


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Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
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
8.3.2.1. Blood Pressure and Pulse Rate
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
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.
8.3.2.2. Temperature
Temperature will be measured orally. No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement.
8.3.3. Electrocardiograms
Standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 


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standard limb lead placement. All scheduled ECGs should be performed after the participant
has rested quietly for at least 5 minutes in a supine position. 
Triplicate 12-lead ECGs will be obtained approximately 2 to 4 minutes apart; the average of 
the triplicate ECG measurements collected at 3 time points prior to dose administration on 
Day 1 will serve as each participant’s baseline QTcF value.
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements. Additional ECG monitoring will occur if a) the mean 
value from the triplicate measurements for any postdose QTcF interval is increased by 
≥60 ms from the baseline and is >450 ms; or b) an absolute QT value is ≥500 ms for any 
scheduled ECG. If either of these conditions occurs, then a single ECG measurement must be 
repeated at least hourly until QTcF values from 2 successive ECGs fall below the threshold 
value that triggered the repeat measurement.
If a) a postdose QTcF interval remains ≥60 ms from the baseline and is >450 ms; or b) an 
absolute QT value is ≥500 ms for any scheduled ECG for greater than 4 hours (or sooner, at 
the discretion of the investigator); or c) QTcF value get progressively longer, the participant
should undergo continuous ECG monitoring. A cardiologist should be consulted if QTcF
values do not return to less than the criteria listed above after 8 hours of monitoring (or 
sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
ECG values of potential clinical concern are listed in Appendix 8.
8.3.4. Clinical Safety Laboratory Assessments
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 
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be repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or study medical monitor.
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.
Participants may undergo random urine drug testing at the discretion of the investigator.
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.3.5. COVID-19 Specific Assessments
Participants will be tested for COVID-19 infection by PCR prior to being admitted to the 
clinic for confinement and a subsequent COVID-19 test will be performed after 4 days (ie,
upon completion of 4 × 24 hours in house), or if they develop COVID-19-like symptoms. 
Site will review COVID-19 related signs and symptoms using a COVID questionnaire that 
will be done at screening and at least 48 hours before Day -1 or as per local procedures.
Additional testing may be required by local regulations or by the PI.
8.3.6. Pregnancy Testing
A serum 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. Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and a second negative 
pregnancy test result will be required at the baseline visit prior to the participant’s receiving 
the study intervention. 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 the end of the study. Pregnancy tests may also be repeated if requested by 
IRBs/ECs or if required by local regulations. 
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 
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 


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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 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 CT SAE Report Form.
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, 
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 CT SAE Report Form.
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 on the CT SAE Report Form 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.


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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 
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.


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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 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:  
•
A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation, or skin 
contact.
•
A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact 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 


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should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
•
If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 24 hours 
after the last dose.
•
If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. 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 CT SAE Report Form 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 to the initial EDP Supplemental Form. 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 
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 


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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, inhalation, or skin contact.  
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 CT SAE Report Form. 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 CT SAE Report 
Form 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 CT SAE Report Form 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 CT SAE Report Form must be maintained in the 
investigator site file.
8.4.6. Cardiovascular and Death Events
Not applicable
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


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8.4.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
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, 
or through the wrong route.
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 on the CT SAE 
Report Form 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
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.
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 on a CT SAE Report 
Form only when associated with an SAE.
8.5. Pharmacokinetics 
8.5.1. Pharmacokinetic Analysis in Plasma (AVP, AVI, HPA, cis-, and trans-CTB) 
One blood sample of approximately 3 mL K2EDTA, to provide approximately 1.2 mL 
plasma, will be collected for measurement of plasma concentrations of AVP, AVI, and HPA




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sponsor and site study files, but will not constitute a protocol amendment. The IRB/EC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
8.5.2. Pharmacokinetic Analysis in Urine (AVP, AVI, HPA, cis-CTB, and trans-CTB)
Urine samples will only be collected in Cohort 2 of PART-2 on Day 6 for measurement of 
AVP, AVI, HPA, cis-CTB and trans-CTB at time points specified in the SoA. Two blank 
urine samples (approximately 5 mL each) for PK (one for AVP, AVI, and HPA; and the 
other one for CTB) will be collected within 24 hours prior to dosing on Day 1. For urinary 
PK, urine samples (0-8 h) will be collected and saved in one container for the duration of the 
collection interval. Participants will have a forced void into the collection container at the 
end of the collection interval. After all urine collections are mixed during each interval, 
2 urine aliquots, each approximately 5 mL, one for AVP, AVI, and HPA, and the other for 
CTB will be stored frozen in appropriately labeled tubes for PK analyses. Instructions for the 
use of tubes, additives, collection, processing, aliquoting, handling, storage, and shipment 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 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) 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. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing 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 window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
Samples 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 bioanalytical 
method, or for other internal exploratory purposes. These data will not be reported in the 
CSR.
Samples will be analyzed using a validated analytical method/s in compliance with 
applicable SOPs.
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 determination as to whether sample 
integrity has been compromised.




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8.7.4. Retained Research Samples for Biomarkers
These Retained Research Samples will be collected in this study:
•
10mL whole blood Prep B2.
Retained Research Samples will be collected as local regulations and IRB/ECs allow
according to the SoA.  
Retained Research Samples may be used for research related to the study intervention(s). 
Genes and other analytes (eg, proteins,
 nondrug metabolites) may be studied using the 
retained samples. 
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment of these samples can be found in the laboratory manual and 
supporting documentation. 
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 are not 
evaluated in this study.
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.
9.1. Statistical Hypotheses
There are no statistical hypotheses for this study. No formal inferential statistics will be 
applied to the PK data apart from the comparisons of CTB PK parameters when CTB is 
administered in combination with AVP or alone in PART-1 and food effect on CTB and 
AVP in PART-2, as detailed in Section 9.3 below.
CCI


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9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled 
"Enrolled" means a participant's, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and
randomization to study intervention. A participant will be 
considered enrolled if the informed consent 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, unless otherwise 
specified by the protocol.
Full Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.
Safety Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the product they actually 
received.
PK Concentration Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value is reported for the given part of 
the study.
PK Parameter Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest are reported for the 
given part of the study.
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, secondary, and 
tertiary/exploratory endpoints.
9.3.1. General Considerations
The data from each part of the study will be analyzed and reported separately in a single CSR 
issued at the end of this study. 
9.3.2. Primary Endpoint(s) Analysis
The primary endpoints in PART-1 and -2 are related to safety/tolerability with analyses as 
described in Section 9.3.5. 


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In addition, primary endpoints in PART-1, and -2 also include the plasma PK endpoints 
whose analyses are described in Sections 9.3.4.1 and 9.3.4.2.
Evaluation of a drug interaction when CTB and AVP are co-administered versus CTB 
administered alone will be conducted in PART-1. 
9.3.3. Secondary Endpoint(s) Analysis
The secondary endpoints in PART-2 include urinary PK endpoints whose analyses are 
described in Sections 9.3.4.1 and 9.3.4.2. Secondary endpoint in PART-2 includes plasma 
PK endpoints for Japanese and Chinese participants whose analyses are described in 
Sections 9.3.4.1 and 9.3.4.2. 
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis
Tertiary endpoint in PART-2 also includes effect of food on plasma PK of cis-CTB, trans-
CTB, AVP, AVI and HPA. Tertiary endpoint in Cohort 2 PART-2 includes metabolite 
scouting using plasma and urine samples, if data permit. Tertiary endpoints such as 
metabolite scouting in PART-2 and C-QT modeling may not be reported in the CSR and may 
be reported separately.  
9.3.4.1. PK Analysis
9.3.4.1.1. Derivation of PK Parameters
Plasma PK parameters for cis-CTB, trans-CTB, AVP, AVI and HPA will be derived (if data 
permit) from the concentration-time data using standard noncompartmental methods 
following a single oral dose (Table 11) and multiple oral doses (Table 12). Urine cis-CTB, 
trans-CTB, AVP, AVI and HPA PK parameters are described in Table 12. Actual PK 
sampling times will be used in the derivation of PK parameters. In the case that actual PK 
sampling times are not available, nominal PK sampling time will be used in the derivation of 
PK parameters.


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Table 11.
Plasma cis-CTB, AVP, AVI, and HPA PK Parameters for PART-1: 
Single Doses
Parameter
Definition
Method of Determination
AUClast
Area under the concentration-time curve 
from time zero to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
AUCinfa
Area under the concentration-time curve 
from time zero extrapolated to infinite 
time
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point from the log-linear 
regression analysis
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time 
of first occurrence
t½a
Terminal half-life
Loge(2)/kel, 
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the log-linear 
concentration-time curve. Only 
those data points judged to describe 
the terminal log-linear decline are 
used in the regression.
CL/Fa
Apparent clearance
Dose/AUCinf
Vz/Fa
Apparent volume of distribution
Dose/(AUCinf × kel)
AUClast(dn)
Dose normalized AUClast
AUClast/Dose
AUCinf(dn)a
Dose normalized AUCinf
AUCinf/Dose
Cmax(dn)
Dose normalized Cmax
Cmax/Dose
dn=dose normalized to a 1 mg dose.
a.
If data permit.


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Table 12.
Plasma and Urine cis-CTB, trans-CTB, AVP, AVI and HPA PK 
Parameters for PART-2: Multiple Doses
Parameter
Day(s)
Definition
Method of Determination
Plasma
AUCtau
1, 6, 7
Area under the plasma concentration-
time profile from time zero to time tau 
(τ), the dosing interval, where τ = 8 for 
TID dosing 
Linear/Log trapezoidal method
Cmax
1, 6, 7
Maximum plasma concentration during 
the dosing interval
Observed directly from data
Tmax
1, 6, 7
Time for Cmax
Observed directly from data as time of 
first occurrence
Cmin
6, 7
Minimum observed concentration 
during the dosing interval
Observed directly from data
PTR
6, 7
Peak-to-trough ratio
Cmax/Cmin
Rac
1, 6
Observed accumulation ratio for AUCtau
Day 6 AUCtau/Day 1 AUCtau
Rac,Cmax
1, 6, 
Observed accumulation ratio for Cmax
Day 6 Cmax/Day 1 Cmax
CL/Fa
1, 6, 7
Apparent clearance
Dose/AUCtau
t½a
7
Terminal half-life
Loge(2)/kel, 
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the log-linear 
concentration-time curve. Only those 
data points judged to describe the 
terminal log-linear decline are used in 
the regression
Vz/Fa
1,6,7
Apparent volume of distribution
Dose/(AUCtau × kel)
AUCtau(dn)
1, 6, 7
Dose normalized AUCtau
AUCtau/Dose
Cmax(dn)
1, 6, 7
Dose normalized Cmax
Cmax/Dose
Urine
Aetau
6
Amount excreted in urine as unchanged 
drug over the dosing interval τ
Sum of (urine volume × urine 
concentration) for each collection over 
the dosing interval 
Aetau%
6
Percent of dose excreted in urine as 
unchanged drug over the dosing interval 
τ
100 × Aetau/Dose
CLr
6
Renal clearance
Aetau /AUCtau
dn=dose normalized to a 1 mg dose.
a.
If data permit.
9.3.4.2. Statistical Methods for PK Data
For all parts of the study, plasma concentrations will be listed and summarized descriptively 
by PK sampling time and treatment. Individual participant and median profiles of the 
concentration-time data will be plotted by treatment. For summary statistics and median plots 
by sampling time, the nominal PK sampling time will be used; for individual participant plots 


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by time, the actual PK sampling time will be used for plasma samples. Median profiles will 
be presented on both linear-linear and log-linear scales.
The plasma PK parameters listed in Table 11 and Table 12 will be summarized descriptively 
by dose.
For PART-1, dose normalized (to 1 mg) AUCinf or AUClast and Cmax of cis-CTB will be 
plotted against dose (using a logarithmic scale) and will include individual participant values 
as well as the geometric means for each dose. These plots may be used to help understand the 
relationship between the PK parameters and dose for CTB. 
For PART-1, drug interaction evaluation for the treatments “800 mg CTB + 900/1350 mg 
AVP” (Test) versus “800 mg CTB alone” (Reference) and for PART-2, food effect 
evaluation for fed PK on Day 6 (Test) versus fasted PK on Day 7 (Reference) will be done. 
For those participants receiving both treatments (Test, Reference), natural log transformed 
cis-CTB, trans-CTB and AVI AUClast, Cmax, and AUCinf (if data permit) will be analyzed using 
a mixed effect model with treatment included as a fixed effect and participant as a random 
effect. Estimates of the adjusted mean differences (Test-Reference) and corresponding 90% 
CIs will be obtained from the model. The adjusted mean differences and 90% CIs for the 
differences will be exponentiated to provide estimates of the ratio of adjusted geometric 
means (Test/Reference) and 90% CIs for the ratios.
For PART-2, urine amounts of CTB and AVI will be listed and summarized descriptively, if 
data permit. In PART-2 plasma PK parameters for Japanese and Chinese participants will be 
compared to Western participants. 
Additional specifications about the tables, listings, and figures will be outlined in the SAP.
9.3.5. Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants. Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and PE and neurological examination information, as applicable, collected 
during the course of the study will be considered source data and will not be required to be 
reported, unless otherwise noted. However, any untoward findings identified on physical 
and/or neurological examinations conducted during the active collection period will be 
captured as AEs, if those findings meet the definition of an AE. Data collected at screening 
that are used for inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs,
will be considered source data, and will not be required to be reported, unless otherwise 
noted. Demographic data collected at screening will be reported.


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9.3.5.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters HR, QTcF, PR interval, and QRS complex 
will be summarized by treatment and time. The frequency of uncorrected QT values above 
500 ms will be tabulated.
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment: 
Safety QTcF Assessment
Degree of Prolongation
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value
>450-480
>480 - 500
>500
Increase from baseline
NA
30 - 60
>60
If more than 1 ECG is collected at a nominal time after dose administration (for example, 
triplicate ECGs), the mean of the replicate measurements will be used to represent a single 
observation at that time point. If any of the 3 individual ECG tracings has a QTcF value 
>500 msec, but the mean of the triplicates is not >500 msec, the data from the participant’s 
individual tracing will be described in a safety section of the CSR in order to place the 
>500-msec value in appropriate clinical context. However, values from individual tracings 
within triplicate measurements that are >500 msec will not be included in the categorical 
analysis unless the average from the triplicate measurements is also >500 msec. Changes 
from baseline will be defined as the change between the postdose QTcF value and the 
average of the time-matched baseline triplicate values on Day -1, or the average of the 
predose triplicate values on Day 1.
In addition, an attempt will be made to explore and characterize the relationship between 
plasma concentration and QT interval length using a PK/PD modeling approach. If a PK/PD 
relationship is found, the impact of participant factors (covariates) on the relationship will be 
examined.
9.3.6. Other Analyses 
9.3.6.1. Pharmacogenomic/Biomarker Assessment
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR.
9.4. Interim Analyses
No interim analysis will be conducted for this study. As this is a sponsor-open study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose-escalation decisions, facilitating PK/PD 
modeling, and/or supporting clinical development. 


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9.5. Sample Size Determination
There are no statistical hypotheses for this study.
9.5.1. PART-1: Single Dose
A sample size of approximately 8 participants (6 active, 2 placebo) for this single-cohort, 
cross-over study has been chosen based on the need to minimize first exposure of healthy 
participants to CTB + AVP; since these agents have never been co-administered in humans 
and to address the requirement to provide adequate safety and tolerability information and 
PK information at each dose level.
9.5.2. PART-2: Multiple Dose
A sample size of up to 36 participants (8 participants each in Cohorts 2, Cohort 3 and 
Cohort 4): six on CTB + AVP, 2 on matching placebo and 6 participants each in Cohorts 5
and Cohort 6: five on CTB + AVP, 1 on matching placebo) for this 5-cohort (1 cohort and 
4 optional cohorts) study has been selected to provide adequate PK, safety, and tolerability
information. 
This sample size has been judged sufficient to obtain a preliminary evaluation of safety, 
tolerability, and PK data in these populations.


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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.
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 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.  


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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 Process
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant and answer all questions regarding the 
study. The participant 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 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 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 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.
The participant 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.
The investigator further must ensure that each study participant 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 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.


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A copy of the ICD(s) must be provided to the participant.
Participants who are rescreened are required to sign a new ICD.
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 and/or paper 
form and will be password protected or secured in a locked room 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 
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
Not Applicable
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC.
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.


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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.
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 


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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 and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
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.


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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.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
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 if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.


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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 
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.


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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 CTMS.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy 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.
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. 


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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.
Table 13.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
T bili
Alkaline phosphatase
Uric acid
Albumin
Total protein
Cystatin C and eGFR (CKD-
EPI)
Additionally for suspected 
Hy’s law cases:
CK
Direct and indirect bilirubin
GGT
PT/INR
Total bile acids
Local Dipstick:
Urobilinogen
Urine bilirubin
pHe
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopy and 
culturea
COVID-19 testing (per
PCRU procedures)
Scr
Urine drug screeningc
Pregnancy test (β-hCG)d
At screening only:
•
FSHb
•
HBsAg
•
HBsAb
•
HBcAb
•
HCVAb
•
HIV
Only if UTI is suspected and urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase or both.
For confirmation of postmenopausal status only.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, and 
amphetamines (others are site and study specific).
Serum/urine testing is required for pregnancy testing of female participants of childbearing potential.
Can be performed on dipstick or pH-meter device.
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.
Laboratory results that could unblind the study and have been collected for the purpose of the 
study will not be reported to investigator sites or other blinded personnel until the study has 
been unblinded.










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It should be noted that the CT SAE Report Form 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 CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form 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/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 
non-participant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated AE or SAE): any pregnancy information is reported to 
Pfizer Safety using the CT SAE Report Form and EDP Supplemental Form; if the EDP is 
associated with an SAE, then the SAE is reported to Pfizer Safety using the CT SAE Report 
Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, 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 CT SAE Report Form. 
•
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.








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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements 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 reproductive safety risk of the study 
intervention(s): 
•
Refrain from donating sperm.
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR
•
Must agree to use contraception/barrier as detailed below:
•
Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception, as a condom 
may break or leak, when having sexual intercourse with a WOCBP who is not 
currently pregnant.
•
In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 10.4.4).
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 she is not pregnant or breastfeeding 
and at least 1 of the following conditions applies:
•
Is not a WOCBP (see definition in Section 10.4.3).
•
OR
•
Is a WOCBP 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 


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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.
Women in the following categories are not considered WOCBP:
1. 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.
2. 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 60 years old 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 


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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.
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*


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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).


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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 PF-07612577 (PF-06264006 [CTB] + PF-07338233
[AVP]) 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 
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).
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. 


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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: Kidney Safety: Monitoring Guidelines
10.7.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline serum 
creatinine (Scr measurement to estimate glomerular filtration rate [Scr-based eGFR] or 
creatinine clearance [eCrCl]). Baseline and postbaseline serum Scys makes it feasible to 
distinguish AKI from other causes of Scr increase. If Scr increase is confirmed after baseline, 
then reflex measurement of Scys is indicated to estimate the combined Scr-Scys eGFR 
calculation (for adults only).
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.7.2. Age-Specific Kidney Function Calculation Recommendations
10.7.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations29
2021 CKD-
EPI            
Scr Only
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ō 0.7
NA
eGFR = 143 × (Scr/0.7)-0.241  ×  (0.9938)Age
Female
if > 0.7
NA
eGFR = 143 × (Scr/0.7)-1.200  ×  (0.9938)Age
Male
if ō 0.9
NA
eGFR = 142 × (Scr/0.9)-0.302  ×  (0.9938)Age
Male
if > 0.9
NA
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 ō 0.7
if ō 0.8
eGFR = 130 × (Scr/0.7)-0.219  灤(Scys/0.8)-0.323  灤(0.9961)Age
Female
if ō 0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.219  灤(Scys/0.8)-0.778  灤(0.9961)Age
Female
if > 0.7
if ō 0.8
eGFR = 130 × (Scr/0.7)-0.544  灤(Scys/0.8)-0.323  灤(0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Scr/0.7)-0.544  灤(Scys/0.8)-0.778  灤(0.9961)Age
Male
if ō 0.9
if ō 0.8
eGFR = 135 × (Scr/0.9)-0.144  灤(Scys/0.8)-0.323  灤(0.9961)Age
Male
if ō 0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.144  灤(Scys/0.8)-0.778  灤(0.9961)Age
Male
if > 0.9
if ō 0.8
eGFR = 135 × (Scr/0.9)-0.544  灤  (Scys/0.8)-0.323  灤(0.9961)Age
Male
if > 0.9
if > 0.8
eGFR = 135 × (Scr/0.9)-0.544  灤  (Scys/0.8)-0.778  灤(0.9961)Age
10.7.3. 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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10.9. Appendix 9: Prohibited Concomitant Medications That May Result in DDI  
There are no known prohibited concomitant medications for PF-07612577 (PF-06264006 
[CTB] + PF-07338233 [AVP]) at the time of the IB update (Version 2.0).
Possible drugs prohibited for potential DDI concerns with the IMP 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).  
Site staff should consult with the sponsor or designee with any questions regarding potential 
DDI.
Investigators should consult the product label for any other medication used during the study 
for information regarding medication that is prohibited for concomitant use. 


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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
A. baumanni
Acinetobacter baumannii
Abs
absolute
ADL
activity/activities of daily living
ADME
absorption, distribution, metabolism, and excretion
ADR
adverse drug reaction
AE
adverse event
Aetau
amount excreted in urine as unchanged drug over the dosing 
interval τ/tau
Aetau%
percent of dose excreted in urine as unchanged drug over the 
dosing interval τ/tau
AKI
acute kidney injury
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATM
aztreonam
AUC
area under the curve
AUC24,ss
area under the plasma concentration-time profile from time zero to 
the time 24 hours at steady state
AUCinf
area under the plasma concentration-time curve from time 0
extrapolated to infinite time
AUCinf(dn)
dose normalized AUCinf
AUClast
area under the plasma concentration time curve from time 0 to the 
time of the last quantifiable concentration
AUClast(dn)
dose normalized AUClast
AUCtau
area under the plasma concentration-time profile from time zero to 
time tau (τ), the dosing interval
AUCtau(dn)
dose normalized AUCtau
AV
atrioventricular
AVI
avibactam
AVP
avibactam prodrug
AxMP
auxiliary medicinal product
BBS
Biospecimen Banking System
β-hCG
β-human chorionic gonadotropin
BL
β-lactam antibiotic
BLI
β-lactamase inhibitor
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
C8h
plasma concentration 8 hours after dosing
cAmpC
cytosolic type C ampicillinase


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Abbreviation
Term
CAZ
ceftazidime
CDC
Centers for Disease Control and Prevention
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology
Clast
the last quantifiable concentration
CLr
renal clearance
CL/F
apparent clearance
Cmax
maximum observed concentration
Cmax(dn)
dose normalized Cmax
Cmin
minimum plasma concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
C-QT
concentration-QT
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
CT
clinical trial
CTB
ceftibuten
CTIS
Clinical Trial Information System
CTMS
clinical trial management system
cUTI
complicated urinary tract infection
CYP
cytochrome P450
D#
Dose#
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DR#
Dose Regimen#
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
eGFR
estimated glomerular filtration rate
eSAE
electronic serious adverse event
CCI


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Abbreviation
Term
ESBL
extended spectrum β-lactamase
ET
early termination
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
fAUC
area under the unbound concentration–time curve
FaSSIF
fasted state simulated intestinal fluid
FDA
US Food and Drug Administration
FeSSIF
fed state simulated intestinal fluid
FIH
first in human
FSH
follicle-stimulating hormone
fT
fraction of time of dosing interval above a threshold concentration
F/U
follow-up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HBV
hepatitis B virus
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HPA
hydroxypivalic acid
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IHMA
International Health Management Associates
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IP
investigational product
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IV
Intravenous(ly)
K2EDTA
dipotassium ethylenediaminetetraacetic acid
kel
rate constant for terminal phase
KPC
Klebsiella pneumoniae carbapenemase
KDIGO
Kidney Disease Improving Global Outcomes
LBBB
left bundle branch block


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Abbreviation
Term
LFT
liver function test
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
medical device regulation
MIC
minimum inhibitory concentration
MIC50
minimum inhibitory concentration required to inhibit the growth 
of 50% of organisms
MIC90
minimum inhibitory concentration required to inhibit the growth 
of 90% of organisms
MQI
medically qualified individual
NA
not applicable
NDM
New Delhi metallo-β-lactamase
NHP
non-human primates
NIMP
noninvestigational medicinal product
NOAEL
no-observed-adverse-effect level
OAT
organic anion transporter
OPAT
outpatient parenteral antimicrobial therapy
OXA
oxacillinase
P. aeruginosa
Pseudomonas aeruginosa
pAmpC
plasmidic type C ampicillinase
PCR
polymerase chain reaction
PCRU
Pfizer Clinical Research Unit
PD
pharmacodynamic(s)
PE
physical examination
PI
principal investigator
PK
pharmacokinetic(s)
pKa
the negative base-10 logarithm of the acid dissociation constant
PO
oral(ly)
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
PTR
peak to trough ratio
PVC
premature ventricular contraction/complex
q8h
once every 8 hours
QD
once daily
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
Rac
observed accumulation ratio for AUCtau
Rac,Cmax
observed accumulation ratio for Cmax
RBC
red blood cell
SAD
single ascending dose
CCI


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Abbreviation
Term
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
Scr
serum creatinine
Scys
serum cystatin C
SD
standard deviation
SoA
schedule of activities
SOC
standard of care; System Organ Class
SOP
standard operating procedure
SRSD
Single Reference Safety Document
SUSAR
suspected unexpected serious adverse reaction
t½
terminal half-life
T bili
total bilirubin
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
TID
three times daily
TK6
thymidine kinase 6
Tmax
time for Cmax
ULN
upper limit of normal
US
United States
USPI
United States Prescribing Information
UTI
urinary tract infection
Vz/F
apparent volume of distribution
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
WT
wild type


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11. REFERENCES
1
Centers for Disease Control and Prevention. Extended-spectrum beta-lactamase (ESBL) 
producing Enterobacteriaceae. Available from: 
https://www.cdc.gov/drugresistance/pdf/threats-report/esbl-508.pdf. Accessed: 01 May 
2021.
2
World Health Organization. Global priority list of antibiotic-resistant bacteria to guide 
research, discovery, and development of new antibiotics. Available from: 
https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-
ET_NM_WHO.pdf. Published 27 Feb 2017. Accessed: 01 May 2021.
3
Centers for Disease Control and Prevention. Antibiotic resistance threats in the United 
States, 2019. Atlanta, GA: US Department of Health and Human Services, CDC; 2019. 
Available from: https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-
report-508.pdf. Accessed: 01 May 2021.
4
JMI Labs Final report (17-SLA-01). Activity of regemonam alone and in combination
with E-lactamase inhibitors tested against gram-negative clinical isolates. 18 Jan 2018.
5
IHMA Report (IHMA 3471). MIC Testing of 314 Enterbacteriaceae including 
molecularly characterized isolates. 18 Sep 2018.
6
Gordon EM, Duncton MAJ, Gallop MA. Orally absorbed derivatives of the E-lactamase 
inhibitor avibactam. Design of novel prodrugs of sulfate containing drugs. J Med Chem. 
2018;61:10340-4. 
7
Arixa study number 17003 (Eurofins Study AB79163). A pharmacokinetic (PK) study 
in male Sprague-Dawley (SD) rats following intravenous (IV) and oral (PO) 
administrations of Avibactam at 2mg/kg and two prodrugs (AV-006 and AV-007) at 
10mg/kg, respectively. 14 Jun 2017. 
8
Arixa study number 17005 (Eurofins Study AB81456). Single dose pharmacokinetics 
and oral bioavailability of avibactam and six prodrugs of Avibactam (AV-006, AV-019, 
AV-020, AV-021, AV-022 and AV-023) in rats following oral or intravenous 
administration. 2017. 
9
Arixa study number 18002 (CRL study number 01068001). Avibactam, AV-006, AV-
016, AV-017 and AV-029: Pharmacokinetic evaluation of intravenous and oral 
intubation administration in male cynomolgus monkeys. 2018.
                                                


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10
Arixa study number 18003 (CRL study number 01068002). Avibactam, AV-006, AV-
016, AV-017 and AV-029: Pharmacokinetic evaluation of intravenous and oral 
intubation administration in male beagle dogs. 2018.
11
Arixa study number 19004 (Quintara study number 20190314-A016-01). Binding of 
AV-006 and hyroxypyvalic acid in human plasma. 2019. 
12
Arixa study number 19010 (Quintara study number 2019021502). Investigation of in vitro 
metabolites of AV-006 formed in rat, dog and human hepatocytes incubations. 2019.
13
Arixa study number 19006 (Quintara study number 20190220-A016-01 (plasma) 20190308-
A016-01 (blood)). Assessment of AV-006 stability in human blood and plasma. 2019.
14
Arixa study number 19009 (Quintara study number 20190219-A016-01). Assessment of 
AV-006 stability in human liver S9. 2019. 
16
AstraZeneca Study Report D4910C00001: A Phase I, randomized, double-blind, 3-part 
study in healthy young and elderly subjects to assess the safety and tolerability, and 
investigate the pharmacokinetics of aztreonam and avibactam given alone and in 
combination (ATM-AVI). 23 Oct 2015.
17
US Food and Drug Administration, Center for Drug Evaluation and Research. Cedax 
Summary Basis of Approval (Dec 20 1995). Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/050685Orig1s000rev.pdf. 
Accessed: 01 May 2021.
18
Nakashimizu H, Kimura Y, Otsubo R, et al. Pharmacokinetics of 7432-S, a new oral 
cephalosporin, in experimental animals. Chemotherapy. 1989;37(Suppl 1):756-73.  
19
Barr WH, Lin CC, Radwanski E, et al. The pharmacokinetics of ceftibuten in humans. 
Diagn Microbiol Infect Dis. 1991;14:93-100.
20
Ueo H, Motohashi H, Katsura T, et al. Human organic anion transporter hOAT3 is a 
potent transporter of cephalosporin antibiotics, in comparison with hOAT1. Biochem 
Pharmacol. 2005;70:1104-13.
21
Study Pfizer-85-11Nov2019. In vitro interaction studies of ceftaroline and ceftaroline 
fosamil with human BCRP and MDR1 efflux (ABC) transporters, and with human 
CCI


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MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 and OCT2 uptake 
transporters. December 2020. 
22
Riccobene TA, Su SF, Rank D. Single- and multiple-dose study to determine the safety, 
tolerability, and pharmacokinetics of ceftaroline fosamil in combination with avibactam 
in healthy subjects. Antimicrob Agents Chemother. 2013;57(3):1496-504.
23
Sugawara M, Iseki K, Miyazaki K, et al. Transport characteristics of ceftibuten, 
cefixime and cephalexin across human jejunal brush-border membrane. Journal of 
Pharmacy and Pharmacology. 1991;43(12):882-4.
24
Nakashima, M., Uematsu, T., Takiguchi, Y., et al. Phase I Clinical Studies of 7432-S: 
Effect of 7432-S on Platelet Aggregation and Blood Coagulation. The Journal of 
Clinical Pharmacology. 1988;28: 253-258. 
25
Arixa Pharmaceuticals Clinical Study Report AV-006-01. A placebo controlled, double 
blind, single ascending dose study of AV-006 in healthy subjects. 05 Mar 2020. 
26
Kudo K, Kabe J. Clinical Study of 7432-S in Respiratory Infectious Diseases. 1989;
37(Supple 1): 241-5. 
27
Kishi M, Yamada d, Nasu Y, et al. 7432-S in Complicated Urinary Tract Infections.
Chemotherapy. 1989; 37(Supple 1):478-88. 
28
Investigator’s Brochure, PF-07612577. Version 2.0. July 2022.
29
Inker LA, Eneanya ND, Coresh J, et al. New creatinine- and cystatin C–based equations 
to estimate GFR without race. N Engl J Med. 2021;385:1737-49.

SAP_001.pdf: 
Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol C4691001
A PHASE 1, RANDOMIZED, DOUBLE-BLIND, SPONSOR-OPEN, 
PLACEBO-CONTROLLED, SINGLE AND MULTIPLE-DOSE STUDY TO 
EVALUATE THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF 
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP]) IN HEALTHY ADULT 
PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
1.0  
Date:
21 Oct 2022  


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Modifications to the Analysis Plan Described in the Protocol..................................4
2.2. Study Objectives, Endpoints, and Estimands............................................................4
PART-2: Multiple Dose (including optional Japanese and Chinese Cohorts) .......6
2.3. Study Design .............................................................................................................7
2.3.1. Overall Design..............................................................................................7
2.3.2. Number of Participants.................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoint(s) ..................................................................................................9
3.2. Secondary Endpoint(s) ..............................................................................................9
3.3. Other Endpoints.........................................................................................................9
3.4. Baseline Variables...................................................................................................11
3.5. Safety Endpoints .....................................................................................................11
3.5.1. Adverse Events and Serious Adverse Events.............................................12
3.5.2. Laboratory Data..........................................................................................12
3.5.3. Vital Signs ..................................................................................................12
3.5.4. Electrocardiogram (ECG)...........................................................................13
3.6. Other Endpoint(s)....................................................................................................14
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................14
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................14
5.1. Hypotheses and Decision Rules ..............................................................................14
5.2. General Methods .....................................................................................................15
5.2.1. Analyses for Continuous Endpoints ...........................................................15
5.2.2. Analyses for Categorical Endpoints ...........................................................15
5.3. Methods to Manage Missing Data ..........................................................................15
5.3.1. Safety Data: ................................................................................................15


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5.3.2. Pharmacokinetic (PK) Data:.......................................................................15
6. ANALYSES AND SUMMARIES ......................................................................................16
6.1. Primary Endpoint(s) ................................................................................................16
6.1.1. PK Data.......................................................................................................16
6.2. Secondary Endpoint(s) ............................................................................................17
6.2.1. PK Data.......................................................................................................17
6.3. Exploratory Endpoints.............................................................................................19
6.4. Baseline and Other Summaries and Analyses.........................................................20
6.4.1. Study Conduct and Participant Disposition................................................20
6.4.2. Demographic Data......................................................................................20
6.4.3. Concomitant Medications and Nondrug Treatments..................................20
6.5. Safety Summaries and Analyses .............................................................................20
6.5.1. Adverse Events...........................................................................................20
6.5.2. Laboratory Data..........................................................................................21
6.5.3. Vital Signs ..................................................................................................21
6.5.4. Electrocardiograms.....................................................................................21
7. INTERIM ANALYSES.......................................................................................................22
APPENDICES .........................................................................................................................23
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................4
LIST OF FIGURES
Figure 1.
C4691001 Study Design.............................................................................8
APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern .....23


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
PFIZER CONFIDENTIAL
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) is for study C4691001 and is based on Protocol 
Amendment 1 dated 06-Sep-2022.
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
Version 1.0
21 Oct 2022
Protocol 
Amendment 1
06 Sep 2022
N/A
(This is the 1st
version of SAP)
N/A
2. INTRODUCTION
This study is a Phase 1 study of PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP]) 
in approximately 44 healthy adult participants. It is a 2-PART study combining PART-1: 
Single dose PK, safety and tolerability of various CTB doses alone or when coadministered 
with AVP, and PART-2: Multiple dose PK, safety and tolerability of CTB + AVP 
coadministered, including optional Japanese and Chinese cohorts.
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C4691001. 
2.1. Modifications to the Analysis Plan Described in the Protocol
N/A
2.2. Study Objectives, Endpoints, and Estimands
The below tables list the study objectives with relative endpoints for PART-1 and PART-2
which are copied directly from the protocol. There are no estimands for this study.


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
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PART-1: Single Dose
Type
Objective
Endpoint
Primary
Primary
PK
To assess the plasma PK profile of CTB 
following a single dose of CTB alone or 
in combination with AVP.
Plasma PK parameters of cis-CTB: 

Cmax, Tmax, AUClast, Cmax(dn), AUClast(dn).

If data permit, AUCinf, AUCinf(dn), t½, 
Vz/F, and CL/F.
PK
To assess the plasma PK profile of AVP 
following administration with single 
doses of CTB in combination with AVP.
Plasma PK parameters of AVP, AVI and 
HPA:

Cmax, Tmax, AUClast, Cmax(dn), AUClast(dn).

If data permit, AUCinf, AUCinf(dn), t½, 
Vz/F, and CL/F.
Safety /
Tolerability
To assess the safety and tolerability 
following a single dose of CTB alone or 
in combination with AVP.

Frequency, severity, and causal 
relationship of TEAEs and withdrawals 
due to TEAEs.

Frequency and magnitude of abnormal 
laboratory findings.

Changes from baseline in vital sign 
measurements and 12-lead ECG 
parameters.


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
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PART-2: Multiple Dose (including optional Japanese and Chinese Cohorts)
Note: In addition to PART-2, the below table (directly extracted from Protocol Amendment 
1) also includes some tertiary/exploratory objectives for PART-1.
Type
Objective
Endpoint
Primary
Primary
PK
To assess the plasma PK profile of cis-CTB 
and trans-CTBa following multiple doses of 
CTB in combination with AVP.
Plasma PK parameters of cis-CTB and trans-CTBa 
on Day 1 (fed, single dose), Day 6 (fed, steady 
state) and Day 7 (fasted, steady state): 

Cmax, Tmax, AUCtau, Cmax(dn), AUCtau(dn).

If data permit, t½, Vz/F, and CL/F.
PK
To assess the plasma PK profile of AVP 
following multiple doses of CTB in 
combination with AVP. 
Plasma PK parameters of AVP, AVI and HPA on 
Day 1 (fed, single dose), Day 6 (fed, steady state) 
and Day 7 (fasted, steady state): 

Cmax, Tmax, AUCtau, Cmax(dn), AUCtau(dn)

If data permit, t½, Vz/F, and CL/F.
Safety /
Tolerability
To assess the safety and tolerability following 
multiple doses of CTB in combination with 
AVP.

Frequency, severity, and causal relationship 
of TEAEs and withdrawals due to TEAEs.

Frequency and magnitude of abnormal 
laboratory findings.

Changes from baseline in vital sign 
measurements and 12-lead ECG parameters.
Secondary
Secondary
PK
To assess the urinary PKb profile of cis-CTB, 
trans-CTBa, AVP, AVI and HPA on Day 6 
following multiple doses of CTB in 
combination with AVP.
cis-CTB, trans-CTBa, AVP, AVI and HPA urinary 
PK parameters (if data permit): 

Aetau and Aetau%, CLr.
PK
To assess PK profile of CTB and AVP when 
administered in combination in Japanese and 
Chinese participants.
Plasma PK parameters of cis-CTB, AVP, AVI and 
HPA on Day 1 (fed, single dose), Day 6 (fed, steady 
state) and Day 7 (fasted, steady state) in Japanese 
and Chinese cohorts: 

Cmax, Tmax, AUCtau, Cmax(dn), AUCtau(dn).

If data permit, t½, Vz/F, and CL/F.
Tertiary/ Exploratory
Tertiary/ Exploratory
PK
PK
To explore the effect of food on PK of 
cis-CTB, trans-CTB, AVP, AVI and 
HPA.
In PART-2, comparison of plasma PK 
parameters of cis-CTB, trans-CTB, AVP, AVI 
and HPA on Day 6 (fed) versus Day 7 
(fasted).
PK
To explore the potential drug-drug 
interaction when CTB and AVP are co-
administered.
In PART-1, comparison of plasma PK 
parameters of cis-CTB and trans-CTB after 
administration of Dose 2 (800 mg CTB + 
1350 mg AVP) versus after Dose 3 (800 mg 
CTB alone).
Safety / 
Tolerability
To determine the potential effect of CTB 
on cardiac repolarization, if data permit.
In PART-1, if supratherapeutic concentrations 
are achieved, C-QT modeling will be 
CCI


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
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conducted to assess potential effect of CTB on 
QTc prolongation.
a.
trans-CTB will be measured only in Cohort 2 PART-2.
b.
cis-CTB, trans-CTB, AVP, AVI and HPA in urine will be measured on Day 6 only in Cohort 2, PART-2.
2.3. Study Design
2.3.1. Overall Design
This study will consist of PART-1: Single dose and PART-2: Multiple dose, including 
optional Japanese and Chinese cohorts. PART-1 and PART-2 are randomized, double-blind 
(participant and investigator blinded and sponsor open) cohorts. 
In PART-1 and PART-2, treatment sequences and the dosing regimen may be adjusted during 
the study based on emerging safety, tolerability, and PK data. The provisional dosing 
regimens for Parts 1 and 2 are provided in Table 6 and Table 7 of the Protocol Amendment 
(06 Sep 2022), respectively. Except D1 in PART-1, all other dose levels and/or meal 
condition may be changed based on emerging PK, safety, and tolerability data. Dose 
escalation of CTB (and AVP, when applicable) to higher doses will be based on all available 
(a minimum of 24 hours post-dose) safety data in a minimum of 5 participants (4 active and 1 
placebo) at the previous dose levels of CTB and/or AVP. AVP dose for PART-1 may be 900 
mg, 1350 mg, or 1800 mg (in Period 5 only) as long as PK exposures for AVI in the next 
higher cohort are not projected to be higher than PK stopping limit (AVI AUC ≤ 354 
μg.hr/ml- NOAEL in the 14-day pivotal repeat-dose toxicology study in rats). In PART-2, at 
least 6 days of safety data in a minimum of 5 participants (4 active and 1 placebo) from 
Cohort 2 will be reviewed prior to proceeding to optional Cohorts 3, 4, 5 and/or 6.  
PART-1: Single Dose
PART-1 will include 1 cohort and up to 5 periods with approximately 8 participants in total. 
This part will have a randomized, double-blind (sponsor-open), 5-period, sequential single 
dose design. Periods 4 and 5 are optional and may be used to further explore PK at 
additional doses, based on emerging PK data. In each period, approximately 6 participants 
will receive a single oral dose of CTB or CTB and AVP combined, and approximately 
2 participants will receive the matching placebo under fed state. Each participant may 
receive either a single dose of CTB, CTB and AVP combined, or matching placebo during 
each period. In each period, participants on active treatment will receive D1, D2, D3, D4 
(optional), or D5 (optional) dose levels, respectively. There will be a washout interval of a 
minimum of 3 days between doses for a given participant. Participants will be required to 
stay at the CRU for the duration of the washout interval. 
PART-2: Multiple Dose 
PART-2 will include up to 5 cohorts, ie, Cohort 2, and up to 4 optional cohorts including 
optional Cohort 5 (Japanese Cohort) and optional Cohort 6 (Chinese Cohort) with 
CCI


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
PFIZER CONFIDENTIAL
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approximately 8 participants each in Cohorts 2, 3 and 4, and six participants each in 
Cohorts 5 and 6, and up to approximately 36 participants planned in total. This part will 
have a randomized, double-blind (sponsor-open), sequential multiple-dose design. In 
Cohorts 2,3 and 4, approximately 6 participants will receive 1 of the dose regimens of CTB 
and AVP combined, and approximately 2 participants will receive the matching placebo 
orally under fed state (except Day 7 which will be administered fasted). In Cohorts 5 and 6, 
approximately 5 participants will receive 1 of the dose regimens of CTB and AVP combined
and approximately 1 participant will receive the matching placebo orally under fed state 
(except Day 7 which will be administered fasted.) From Day 1 to Day 7, CTB and AVP 
combined or the matching placebo will be administered q8h (ie, TID), with the dose regimen 
of DR1 (for Cohort 2), DR2 (for optional Cohort 3), DR3 (for optional cohort 4) and either 
DR1, DR2 or DR3 (for Cohort 5, optional Japanese Cohort and Cohort 6, optional Chinese 
Cohort).
Figure 1 shows the study schema indicating the two parts and the details on dosage.
Figure 1.
C4691001 Study Design
PART-1: Dose 1 = 400 mg CTB + 900 mg AVP; Dose 2 = 800 mg CTB + 1350 mg AVP; 
Dose 3 = 800 mg CTB alone; Dose 4 = 1200 mg CTB + 1350 mg AVP*; Dose 5 = 1600 mg CTB 
alone or 1200 mg CTB + 1800 mg AVP.
PART-2: DR1 = 400 mg CTB + 1350 mg AVP* q8h for 7 days; DR2 = 400 mg/800 mg CTB + 
1350 mg AVP* q8h for 7 days; DR3 = 800 mg/1200 mg CTB + 1350 AVP q8h for 7 days.
* 1350 mg AVP may be replaced with 900 mg AVP, based on safety, tolerability and PK data.
Note that except Dose 1 in PART-1, all other dose levels and/or meal condition may be changed based on 
emerging PK, safety, and tolerability data.


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
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2.3.2. Number of Participants
Up to 44 participants (8 in PART-1 and 36 in PART-2) will be randomly assigned to study 
intervention. 
In PART-1, a sample size of approximately 8 participants (6 active, 2 placebo) for this 
single-cohort, cross-over study has been chosen based on the need to minimize first exposure 
of healthy participants to CTB + AVP and the requirement to provide adequate safety and 
tolerability information and PK information at each dose level.
In PART-2, approximately 36 participants (8 participants each in Cohorts 2, 3 and 4: six on 
CTB + AVP, 2 on matching placebo and 6 participants each in Cohorts 5 and 6: five on CTB 
+ AVP, 1 on matching placebo) for this 5-cohort (1 cohort and 4 optional cohorts) multiple 
dose study has been selected to provide adequate PK, safety and tolerability information. 
This sample size has been judged sufficient to obtain a preliminary evaluation of safety, 
tolerability, and PK data in these populations.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
Section 2.2 lists the study objectives and endpoints for PART-1 and PART-2. The primary 
endpoints of PART-1 and PART-2 are related to safety/tolerability and plasma PK endpoints.
These are described futher in Section 3.5.
The definition and additional details of the PK parameters for PART-1 and PART-2 are 
provided in Table 2 and 3, respectively.
3.2. Secondary Endpoint(s)
The secondary endpoints are only for PART-2 and they include urinary PK endpoints as well 
as the plasma PK endpoints for Japanese and Chinese participants.
3.3. Other Endpoints
Tertiary/exploratory objective/endpoint includes effect of food on plasma PK of cis-CTB, 
trans-CTB, AVP, AVI and HPA. Tertiary endpoint in Cohort 2 PART-2 includes 
 
Tertiary endpoints such as 
in PART-2 and C-QT modeling may not be reported in the CSR and may 
be reported separately. In PART-1, to explore the potential drug-drug interaction when CTB 
and AVP are co-administered, tertiary endpoint also includes comparison of plasma PK 
parameters of cis-CTB and trans-CTB after administration of Dose 2 versus after Dose 3.
The PK parameters for cis-CTB, trans-CTB, AVP, AVI and HPA will be derived (if data 
permit) from the concentration-time data using standard noncompartmental methods 
following a single oral dose (Table 2) and multiple oral doses (Table 3). Urine cis-CTB, 
trans-CTB, AVP, AVI and HPA PK parameters are described in Table 3. Actual PK sampling 
times will be used in the derivation of PK parameters. In the case that actual PK sampling 
CCI
CCI


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
PFIZER CONFIDENTIAL
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times are not available, nominal PK sampling time will be used in the derivation of PK 
parameters.
Table 2.
Plasma cis-CTB, AVP, AVI, and HPA PK Parameters for PART-1: Single 
Doses
Parameter
Analysis Scale
PF-07612577 (or PF-06264006*)
AUClast
Ln
D, A
AUCinfa
Ln
D, A
Cmax
Ln
D, A
Tmax
R
D
t½a
Ln
D
CL/Fa
Ln
D
Vz/Fa
Ln
D
AUClast(dn)
Ln
D
AUCinf(dn)a
Ln
D
Cmax(dn)
Ln
D
* Note that Dose 3 in PART-1 is PF-06264006 (CTB) only
D=display with descriptive statstics,
R=raw (untransformed),
Ln=natural-log transformed
A=analyzed
dn=dose normalized to a 1 mg dose.
a.
If data permit


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
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Table 3.
Plasma and Urine cis-CTB, trans-CTB, AVP, AVI and HPA PK 
Parameters for PART-2: Multiple Doses
Plasma
Parameter
Analysis Scale
PF-07612577
AUCtau
Ln
D, A
Cmax
Ln
D, A
Tmax
R
D
Cmin
R
D
PTR
Ln
D
Rac
Ln
D
Rac,Cmax
Ln
D
CL/Fa
Ln
D
t½a
R
D
Vz/Fa
Ln
D
AUCtau(dn)
Ln
D
Cmax(dn)
Ln
D
Urine
Parameter
Analysis Scale
PF-07612577
Aetau
R
D
Aetau%
R
D
CLr
R
D
D=display with descriptive statstics,
R=raw (untransformed),
Ln=natural-log transformed
A=analyzed
dn=dose normalized to a 1 mg dose.
a= If data permit
3.4. Baseline Variables
Baseline variables are those collected prior to dosing on Day 1 or before Day 1. 
Baseline for laboratory data, vital signs and ECG are defined in sections 3.5.2, 3.5.3 and 
3.5.4 respectively.
3.5. Safety Endpoints
Safety endpoints include:

Adverse events (AEs) and serious adverse events (SAEs),

Vital signs,

Electrocardiograms (ECG),


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
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
Laboratory data,
3.5.1. Adverse Events and Serious Adverse Events
Active collection period of AEs and SAEs 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.
An adverse event is considered a Treatment-Emergent Adverse Event (TEAE) if the event 
started during the effective duration of treatment. All events that start on or after the first 
dosing day and time/start time, if collected, but before the end of the study will be flagged as 
TEAEs. The algorithm will not consider any events that started prior to the first dose date.
A 3-tier approach for summarizing AEs will not be used due to the low number of 
participants planned to be recruited. 
3.5.2. Laboratory Data
Safety laboratory tests will be performed as described in the protocol.
For PART-1, baseline will be the last pre-dose measurement prior to dosing in each study 
period. For PART-2, baseline will be the last pre-dose measurement prior to dosing on Day
1.
Clinically significant abnormal laboratory test findings will be 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 24 hours 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.
3.5.3. Vital Signs
Supine BP and pulse will be measured with the participant’s arm supported at the level of the 
heart, and recorded to the nearest mm Hg after approximately 5 minutes of rest.
For PART-1, baseline will be the last pre-dose measurment prior to dosing on Day 1 in each 
study period. For PART-2, baseline will be the last pre-dose measurement prior to dosing on 
Day 1.
The following vital signs endpoints will be determined:
•
Change from baseline for all measurements taken post-dose
•
The maximum increase from baseline over all measurements taken post-dose 


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
Statistical Analysis Plan
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•
The maximum decrease from baseline over all measurements taken post-dose 
The maximum increase from baseline will be calculated by first subtracting the baseline 
value from each post-dose measurement to give the change from baseline. The maximum of 
these values over the respective period will then be selected, except in the case where a 
participant does not show an increase. In such an instance, the minimum decrease should be 
taken. 
Similarly, the maximum decrease from baseline will be determined by selecting the 
minimum value of the changes from baseline.  In cases where a participant does not show a 
decrease, the minimum increase should be taken.
3.5.4. Electrocardiogram (ECG)
ECG values of potential clinical concern are listed in Appendic 8 of the protocol. Standard 
12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be collected at time 
detailed in the SoA given in the protocol to automatically calculates the HR and measures 
PR interval, QT interval, QTcF, and QRS complex. They should be performed after the 
participant has rested quietly for at least 5 minutes in a supine position.
For PART-1, all ECGs are collected in triplicate, except at screening. Baseline will be 
defined as the average of the triplicate measurements prior to dose administration on Day 1
in each study period.
For PART-2, baseline will be defined as the average of the triplicate ECG measurements 
collected at 3 time points prior to dose administration on Day 1 where triplicate 12-lead 
ECGs will be obtained approximately 2 to 4 minutes apart.
The following ECG endpoints will be determined:
•
Change from baseline in QT interval, heart rate, QTcF interval, PR interval, and QRS 
complex.
•
The maximum absolute value (post-dose) will be calculated for QTcF, PR and QRS.
•
The maximum increase from baseline over all measurements taken post-dose will be 
calculated for QTcF. 
The maximum increase from baseline will be calculated by first subtracting the baseline value 
from each triplicate-average post-dose measurement to give the change from baseline. The 
maximum of these values over the respective period will then be selected, except in the case 
where a participant does not show an increase. In such an instance, the minimum decrease 
should be taken.


Protocol C4691001
PF-07612577 (PF-06264006 [CTB] + PF-07338233 [AVP])
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3.6. Other Endpoint(s)
Pharmacogenomic or biomarker data from Retained Research Samples may be collected 
during or after the trial and retained for future analyses; the results of such analyses are not 
planned to be included in the CSR.
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:
Participant Analysis Set
Description
Enrolled 
"Enrolled" means a participant's, or their legally authorized 
representative’s, agreement to participate in a clinical study 
following completion of the informed consent process and
randomization to study intervention. A participant will be 
considered enrolled if the informed consent 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, unless otherwise 
specified by the protocol.
Full Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention.
Safety Analysis Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the product they actually 
received.
PK Concentration Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 concentration value is reported for the given part of 
the study.
PK Parameter Set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention and in whom at 
least 1 of the PK parameters of interest are reported for the 
given part of the study.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
There are no statistical hypotheses or decision rules.


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5.2. General Methods
In general, the data from each part of the study will be analysed and accordingly report in a 
single CSR which will be issued at the end of the study. Where appropriate, graphical 
representatios will be used to summarize some of the measurments by treatment and visits.
5.2.1. Analyses for Continuous Endpoints
Continuous variables will be presented using summary statistics: number of observations, 
arithmetic mean, standard deviation, cv%, median, minimum and maximum values.
Log transformed continuous variables will be presented using summary statistics: number of 
observations, arithmetic mean, median, cv%, standard deviation, minimum, maximum, 
geometric mean and geometric cv%.
5.2.2. Analyses for Categorical Endpoints
Categorical variables will be presented using summary statistics: number of observations and 
percentages.
5.3. Methods to Manage Missing Data
5.3.1. Safety Data:
The sponsor data standard rules for imputation will be applied for the analysis of the safety 
endpoints.
5.3.2. Pharmacokinetic (PK) Data:
To handle the missing PK data the following methods will be implied:
PK Parameters:
If a PK parameter cannot be measured, the parameter will be coded as “Not Calculated”. This 
values will be set to missing when the summary tables are to be calculated. If a subject 
discontinues the trial, the “Not Calculated” values won’t be generated after the day of 
discontinuation.
If the PK parameter has a known biased estimated because of any unexpected event before 
the complete absorbtion, a footnote in the summary tables will be created to mention that. 
The statistical analysis and the summary tables won’t include these values.
Concentrations Below the Limit of Quantification:
Concentrations below the limit of quantification (BLQ) for all data presentations (except 
listings) will be set to 0. For listings, BLQ will be reported as “< Lower Limit Quantifcation 
(LLQ)”.
Anamalous, Deviations and Missing Concentration:


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If one of the folowings happens then the statistics will be calculated having set 
concentrations to missing in summary tables and plots of median profiles:
1. A deviation in sampling time is concerning or a concentration has been flagged 
anomalousely by pharmacokineticists.
2. A concentration has been collected as “Not Done” or “No Sample”.
6. ANALYSES AND SUMMARIES
This section describes the analyses planned for endpoints that are either primary for PART-1 
and PART-2, or secondary and tertiary/exploratory for PART-2. 
Separate tables will be produced for PART-1: Single Dose and PART-2: Multiple dose, 
unless otherwise specified. In PART-2, Japanese and Chinese will be separate groups.
6.1. Primary Endpoint(s)
This section describes the analyses planned for the primary endpoints which include the
pharmacokinetics of PF-06264006 (CTB) and PF-07338233 (AVP) in PART-1 and PART-2.
6.1.1. PK Data
•
Response based on plasma concentrations in PART-1 and PART-2. 
•
Population: PK Parameter Set
•
Statistical methods:
o
Plasma concentrations: Will be listed and summarized descriptively by
nominal PK sampling time and treatment.
o
Individual participant and median profiles of the concentration-time: Will be
plotted by treatment by the use of actual PK sampling time.
o
Median profiles: Will be presented on both linear-linear and log-linear scales.
o
PK parameters listed in Tables 11 and 12 of the protocol: Will be summarized 
descriptively by dose.
o
PART-1 dose normalized: Will be plotted against dose (using a logarithmic 
scale) and will include individual participant values as well as the geometric 
means for each dose.
Missing values will be handled as described in Section 5.3. Each PK parameter will be 
presented by time and treatment and have the following set of summary statistics:


Protocol C4691001
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Parameter
Parameters
Summary Statistics
Primary (Plasma PK)
Cmax, AUClast, Cmax(dn), AUClast(dn).
If data permit, AUCinf, AUCinf(dn), 
Vz/F, and CL/F.
N, Mean (arithmetic), Median, Standrad 
Deviation (SD), Minimum, Maximum, 
Percentage of Coefficient of Variation, 
Geometric Mean, Geometric Coefficient 
of Variation.
Primary (Plasma PK)
Tmax
N, Median, Minimum, Maximum
Primary (Plasma PK)
If data permit, t½
N, Mean (arithmetic), Median, 
Percentage of Coefficient of Variation, 
Minimum, Maximum
6.2. Secondary Endpoint(s)
This section describes the analyses planned for the secondary endpoints which include the 
PK of PF-06264006 (CTB) and PF-07338233 (AVP) in PART-2.
6.2.1. PK Data 
•
Response based on urinary concentrations in PART-2. 
•
Population: PK Parameter Set
•
Statistical methods:
o
PART-2, urine amounts of CTB and AVI: Will be listed and summarized 
descriptively.
o
PART-2 plasma PK parameters for Japanese and Chinese participants: Will 
be compared to Western participants.
Missing values will be handeled as described in Section 5.3. Each PK parameter will be 
presented by time and treatment and have the following set of summary statistics:


Protocol C4691001
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Parameter
Parameters
Summary Statistics
Secondary (Urinary)
Aetau and Aetau%, CLr
N, Mean (arithmetic), Median, Standrad 
Deviation (SD), Minimum, Maximum, 
Percentage of Coefficient of Variation, 
Geometric Mean, Geometric Coefficient 
of Variation.
Secondary (Japanese 
and Chinese 
Participants)
Cmax, AUCtau, Cmax(dn), AUCtau(dn).
If data permit, Vz/F, and CL/F.
N, Mean (arithmetic), Median, Standrad 
Deviation (SD), Minimum, Maximum, 
Percentage of Coefficient of Variation, 
Geometric Mean, Geometric Coefficient 
of Variation.
Secondary (Japanese 
and Chinese 
Participants)
Tmax
N, Median, Minimum, Maximum
Secondary (Japanese 
and Chinese 
Participants)
If data permit, t½
N, Mean (arithmetic), Median, 
Percentage of Coefficient of Variation, 
Minimum, Maximum
To assess the relationship between the PK parameters and dose, dose normalized Cmax, 
AUClast, and AUCinf  (PART-1) and Cmax and AUCτ (PART-2) of each of the individual 
analytes- cis-CTB, trans-CTB, AVI will be plotted against dose (using a logarithmic scale), 
and will include individual participant values and the geometric means for each dose. 
Geometric means will have a different symbol than the individual values. In PART-2, the 
data from the Japanese and Chinese subjects will be identified by different symbols/colours. 
The values will be dose normalized (to a 1 mg dose) by dividing the individual values and 
raw geometric means by dose. A footnote will be added to the plots to indicate that geometric 
means are presented. All dose normalized parameters will be listed along with other 
individual PK parameters.
Supporting data from the estimation of t½ will be listed by treatment and dose where 
applicable: terminal phase rate constant (kel); goodness of fit statistic from the log-linear 
regression (r2); the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, 
and number of time points used in the estimation of kel. These data may be included in the 
CSR.
Presentations for each of the individual analytes- cis-CTB, trans-CTB, AVP, AVI and HPA 
concentrations will be presented using participants in the PK Concentration Set and will 
include:
•
a listing of all concentrations sorted by participant ID, dose, matrix and nominal time 
post-dose.  The concentration listing will also include the actual times. Deviations from 
the nominal time will be given in a separate listing.
•
a summary of concentrations by dose and nominal time post-dose, where the set of 
statistics will include n, mean, median, standard deviation, coefficient of variation (cv), 
minimum, maximum and the number of concentrations above the lower limit of 
quantification.


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•
individual concentration-time plots by dose (on both linear and semi-log scales) against 
actual time post-dose (there will be separate spaghetti plots for each dose per scale).
•
individual concentration-time plots by participant (on both linear and semi-log scales) 
against actual time post-dose (there will be separate spaghetti plots for each dose per 
scale).
•
median concentration-time plots (on both linear and semi-log scales) against nominal 
time post-dose by dose (all doses on the same plot per scale, based on the summary of 
concentrations by dose and time post-dose).
•
mean concentration-time plots (on both linear and semi-log scales) against nominal time 
post-dose by dose (all doses on the same plot per scale, based on the summary of 
concentrations by dose and time post-dose).
The scale used for the x-axis (time) of these plots will be decided on review of the data, and 
will depend on how long PF-07612577 concentration is quantifiable in the matrix.
For summary statistics, median and mean plots by sampling time, the nominal PK sampling 
time will be used. For individual participant plots by time, the actual PK sampling time will be 
used.
For PART-2, urine amounts of PF-07612577 will be listed and summarized descriptively, if 
data permit.
6.3. Exploratory Endpoints
This section describes the analyses planned for the exploratory endpoints in PART-2.
•
Response based on plasma concentrations in PART-1 and PART-2. 
•
Population: PK Parameter Set
•
Statistical methods:
o
PART-1, drug interaction defined as treatments “800 mg CTB + 900/1350 mg 
AVP” (Test) versus “800 mg CTB alone” (Reference): For those participants 
receiving both treatments (Test, Reference), natural log transformed AUCinf, 
AUClast, and Cmax for cis-CTB and trans-CTB will be analyzed using a mixed 
effect model with treatment included as a fixed effect and participant as a 
random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% CIs will be obtained from the model. The adjusted 
mean differences and 90% CIs for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) 
and 90% CIs for the ratios.


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o
PART-2, food effect evaluation defined as fed PK on Day 6 (Test) versus 
fasted PK on Day 7 (Reference): For those participants with PK measured in 
both the fed and fasted states (Test, Reference), natural log transformed Cmax 
and AUCtau for cis-CTB, trans-CTB, AVP and AVI will be analyzed using a 
mixed effect model with treatment (i.e. fed-state) included as a fixed effect and 
participant as a random effect. Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% CIs will be obtained from the model. 
The adjusted mean differences and 90% CIs for the differences will be 
exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CIs for the ratios.
6.4. Baseline and Other Summaries and Analyses
Medical history and PE and neurological examination information, as applicable, collected 
during the course of the study will be considered source data and will not be required to be 
reported, unless otherwise noted. However, any untoward findings identified on physical 
and/or neurological examinations conducted during the active collection period will be 
captured as AEs, if those findings meet the definition of an AE. Data collected at screening 
that are used for inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs, 
will be considered source data, and will not be required to be reported, unless otherwise 
noted. Demographic data collected at screening will be reported.
6.4.1. Study Conduct and Participant Disposition
Participant evaluation groups will show participant disposition by treatment. Frequency 
counts and percentages will be supplied for participant discontinuation(s) by treatment. Data 
will be reported in accordance with the sponsor reporting standards.
6.4.2. Demographic Data
Demographic data will be summarised for PART-1, by cohort for PART-2, and overall (if 
applicable) in accordance with the sponsor reporting standards. 
6.4.3. Concomitant Medications and Nondrug Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be reported according to 
current sponsor reporting standards.
6.5. Safety Summaries and Analyses
•
Response based on safety/tolerability in PART-1 and PART-2. 
•
Population: Safety Analysis Set
6.5.1. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards.


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6.5.2. Laboratory Data
Lab data will be summarized and listed by treatment in accordance with the sponsor 
reporting standards. Baseline is defined in Section 3.5.2.
6.5.3. Vital Signs
Absolute values and changes from baseline in supine sysolic and diastolic blood pressure, 
pulse rate, temperature and respiratory rate will be summarized by treatment and time post-
dose, according to sponsor reporting standards. Tables will be paged by parameter. Baseline 
is defined in Section 3.5.3.
Mean changes from baseline for supine systolic and diastolic blood pressure, pulse rate, 
temperature and respiratory rate will be plotted against time post-dose. Each part will have its 
own output with 1 line for each treatment. Placebo will be pooled in the plots for PART-2, 
although the Japanese/Chinese placebo may be plotted separately. Corresponding individual 
plots of changes from baseline will also be produced for each treatment.
Maximum decrease from baseline for supine systolic and diastolic blood pressures and 
respiratory rate and maximum increase from baseline for supine pulse rate and temperature 
will be summarized by treatment, according to sponsor reporting standards.
Minimum and/or maximum absolute values and changes from baseline for supine vital signs 
will also be summarized descriptively by treatment using categories as defined in 
Appendix 1. Numbers and percentages of participants meeting the categorical criteria will be 
provided. All planned and unplanned post-dose time points will be counted in these 
categorical summaries.  
6.5.4. Electrocardiograms
Changes from baseline for the ECG parameters HR, QTcF, PR interval, and QRS complex 
will be summarized by treatment and time. The frequency of uncorrected QT values above 
500 ms will be tabulated. The number (%) of participants with maximum postdose QTcF 
values and maximum increases from baseline in the categories (See Appendix 1) will be 
tabulated by treatment. If more than 1 ECG is collected at a nominal time after dose 
administration (for example, triplicate ECGs), the mean of the replicate measurements will 
be used to represent a single observation at that time point. If any of the 3 individual ECG 
tracings has a QTcF value >500 msec, but the mean of the triplicates is not >500 msec, the 
data from the participant’s individual tracing will be described in a safety section of the CSR 
in order to place the >500-msec value in appropriate clinical context. However, values from 
individual tracings within triplicate measurements that are >500 msec will not be included in 
the categorical analysis unless the average from the triplicate measurements is also 
>500 msec. Changes from baseline will be defined as the change between the postdose QTcF 
value and the average of the time-matched baseline triplicate values on Day -1, or the 
average of the predose triplicate values on Day 1. 
C-QT modeling/analysis may be conducted if data permit, and will be reported in a separate 
report.


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7. INTERIM ANALYSES
No interim analysis will be conducted for this study. As this is a sponsor-open study, the 
sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose-escalation decisions, facilitating PK/PD 
modeling, and/or supporting clinical development. 


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APPENDICES
Appendix 1. Categorical Classes for ECG and Vital Signs of Potential Clinical Concern
Categories for QTcF
Mild (msec)
Moderate (msec)
Severe (msec)
Absolute value of
QTcF (msec)
>450 and ≤480
>480 and ≤500
>500
Increase from baseline
in QTcF (msec)
>30 and ≤60
>60
Categories for PR and QRS
PR (ms)
max. ≥300
PR (ms) increase 
from baseline
Baseline >200 
and max. 
≥25% increase
Baseline ≤200 and 
max. ≥50% 
increase
QRS (ms)
max. ≥140
QRS (ms) 
increase from 
baseline
≥50% increase
Categories for Vital Signs 
Systolic BP (mm Hg)
min. <90
Systolic BP (mm Hg) 
change from baseline
max. decrease ≥30
max. increase ≥30
Diastolic BP (mm Hg)
min. <50
Diastolic BP (mm Hg) 
change from baseline
max. decrease ≥20
max. increase ≥20
Supine pulse rate (bpm)
min. <40
max. >120