Clinical trial NCT05067439
Conditions: Healthy Participants
Keywords: abrocitinib drug-drug interaction omeprazole caffeine efavirenz
Sponsor: Pfizer
Start date: 2021-10-21; Completion date: 2022-02-26
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1, open-label, multiple dose, single fixed-sequence, 2-period study to evaluate the effect of abrocitinib on the pharmacokinetics (PK) of caffeine, efavirenz and omeprazole in healthy adult participants. A total of approximately 13 healthy male and/or female participants will be enrolled in the study to obtain at least 12 evaluable participants who complete the study. Participants who withdraw from the study or are considered non-evaluable may be replaced at the discretion of the sponsor. Participants will be screened within 28 days of the first dose of study intervention. Participants will have a phone contact 3 days prior to Day 1 dosing (Day -3) in Period 1 as a reminder to abstain from caffeine-containing products. Participants will be admitted to the clinical research unit (CRU) at least 24 hours prior to Day 1 dosing (Day 1) in Period 1. Participants will remain in the CRU for a total of 15 days and 14 nights. Participants will have a telephone contact between 28-35 calendar days after the last administration of the investigational product.

Detailed description:

Arms: arm 1: In Period 1, all the participants will receive single doses of the probe drugs, including caffeine 100 mg, efavirenz 50 mg and omeprazole 10 mg, together on Day 1. arm 2: In Period 2, participants will receive abrocitinib 200 mg once daily (QD) on Day 1-10, single dose of omeprazole on Day 2 and single dose of probe drugs together on Day 8.
Interventions: intervention 1: Abrocitinib intervention 2: Omeprazole intervention 3: Caffeine intervention 4: Efavirenz
Intervention descriptions: intervention 1: 200 mg once daily (QD) intervention 2: single doses of 10 mg intervention 3: single dose of 100 mg intervention 4: single doses of 50 mg

Protocol documents:
Prot_000.pdf: 
PF-04965842
Protocol B7451092
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PFIZER CONFIDENTIAL
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A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE, 2-PERIOD STUDY TO 
ESTIMATE THE EFFECT OF MULTIPLE DOSE ABROCITINIB ON THE 
PHARMACOKINETICS OF SINGLE DOSES OF CAFFEINE, EFAVIRENZ, AND
OMEPRAZOLE IN HEALTHY PARTICIPANTS
Study Intervention Number:
PF-04965842
Study Intervention Name:
Abrocitinib
US IND Number:
123554
EudraCT Number:
N/A
ClinicalTrials.gov ID:
N/A
Protocol Number:
B7451092
Phase:
1
Brief Title: A Phase 1 Study to Estimate the Effect of Multiple Dose Abrocitinib on the 
PK of Caffeine, Efavirenz, and Omeprazole in Healthy 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.
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Document History
Document
Version Date
Original protocol
28 July 2021
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema (Not Applicable)..........................................................................................9
1.3. Schedule of Activities .............................................................................................10
2. INTRODUCTION ...............................................................................................................14
2.1. Study Rationale .......................................................................................................14
2.2. Background .............................................................................................................14
2.2.1. Nonclinical Pharmacology..........................................................................14
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................14
2.2.3. Nonclinical Safety ......................................................................................15
2.2.4. Clinical Overview.......................................................................................16
2.2.4.1. Summary of Safety Data from Completed Studies ...................16
2.2.4.2. Summary of Abrocitinib Pharmacokinetics, Metabolism 
and In Vitro Enzymology..................................................................18
2.3. Benefit/Risk Assessment.........................................................................................19
3. OBJECTIVES AND ENDPOINTS.....................................................................................20
4. STUDY DESIGN.................................................................................................................20
4.1. Overall Design.........................................................................................................20
4.2. Scientific Rationale for Study Design.....................................................................21
4.2.1. Diversity of Study Population ....................................................................22
4.2.2. Choice of Contraception/Barrier Requirements .........................................22
4.3. Justification for Dose ..............................................................................................22
4.4. End of Study Definition ..........................................................................................23
5. STUDY POPULATION......................................................................................................23
5.1. Inclusion Criteria.....................................................................................................23
5.2. Exclusion Criteria....................................................................................................24
5.3. Lifestyle Considerations..........................................................................................28
5.3.1. Meals and Dietary Restrictions...................................................................28
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................29
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5.3.3. Activity .......................................................................................................29
5.3.4. Contraception..............................................................................................29
5.4. Screen Failures ........................................................................................................30
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................30
6.1. Study Intervention(s) Administered........................................................................30
6.1.1. Administration............................................................................................30
6.2. Preparation, Handling, Storage, and Accountability...............................................31
6.2.1. Preparation and Dispensing........................................................................32
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................32
6.3.1. Allocation to Study Intervention ................................................................32
6.4. Study Intervention Compliance...............................................................................32
6.5. Dose Modification...................................................................................................32
6.6. Continued Access to Study Intervention After the End of the Study......................32
6.7. Treatment of Overdose............................................................................................33
6.8. Concomitant Therapy..............................................................................................33
6.8.1. Rescue Medicine.........................................................................................34
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................34
7.1. Discontinuation of Study Intervention ....................................................................34
7.2. Participant Discontinuation/Withdrawal From the Study.......................................34
7.2.1. Withdrawal of Consent...............................................................................35
7.3. Lost to Follow up ....................................................................................................35
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................36
8.1. Efficacy Assessments..............................................................................................37
8.2. Safety Assessments .................................................................................................37
8.2.1. Physical Examinations................................................................................37
8.2.2. Vital Signs ..................................................................................................38
8.2.2.1. Temperature ..............................................................................38
8.2.3. Electrocardiograms.....................................................................................38
8.2.4. Clinical Safety Laboratory Assessments ....................................................39
8.2.5. COVID-19 specific assessments.................................................................40
8.2.6. Pregnancy Testing ......................................................................................40
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8.2.7. Suicidal Ideation and Behavior Risk Monitoring.......................................40
8.3. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................41
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......42
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................42
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................42
8.3.2. Method of Detecting AEs and SAEs ..........................................................43
8.3.3. Follow-Up of AEs and SAEs......................................................................43
8.3.4. Regulatory Reporting Requirements for SAEs...........................................43
8.3.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................43
8.3.5.1. Exposure During Pregnancy......................................................44
8.3.5.2. Exposure During Breastfeeding ................................................45
8.3.5.3. Occupational Exposure .............................................................46
8.3.6. Cardiovascular and Death Events (not applicable).....................................46
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs (not applicable) ...................................................46
8.3.8. Adverse Events of Special Interest (not applicable)...................................46
8.3.8.1. Lack of Efficacy (not applicable)..............................................46
8.3.9. Medical Device Deficiencies (not applicable)............................................46
8.3.10. Medication Errors.....................................................................................46
8.4. Pharmacokinetics ....................................................................................................47
8.7. Immunogenicity Assessments.................................................................................49
8.8. Health Economics ...................................................................................................49
9. STATISTICAL CONSIDERATIONS ................................................................................49
9.1. Statistical Hypotheses .............................................................................................49
9.2. Analysis Sets ...........................................................................................................49
9.3. Statistical Analyses .................................................................................................49
9.3.1. Pharmacokinetic Analysis ..........................................................................50
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9.3.1.1. Analysis Population...................................................................50
9.3.1.2. Derivation of Pharmacokinetic Parameters...............................50
9.3.2. Other Safety Analyses ................................................................................51
9.4. Interim Analyses .....................................................................................................52
9.5. Sample Size Determination.....................................................................................52
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................53
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............53
10.1.1. Regulatory and Ethical Considerations ....................................................53
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................53
10.1.2. Financial Disclosure .................................................................................54
10.1.3. Informed Consent Process ........................................................................54
10.1.4. Data Protection .........................................................................................55
10.1.5. Committees Structure ...............................................................................55
10.1.5.1. Data Monitoring Committee ...................................................55
10.1.6. Dissemination of Clinical Study Data ......................................................55
10.1.7. Data Quality Assurance ............................................................................57
10.1.8. Source Documents....................................................................................58
10.1.9. Study and Site Start and Closure ..............................................................58
10.1.10. Publication Policy...................................................................................59
10.1.11. Sponsor’s Qualified Medical Personnel .................................................60
10.2. Appendix 2: Clinical Laboratory Tests .................................................................61
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................63
10.3.1. Definition of AE .......................................................................................63
10.3.2. Definition of an SAE ................................................................................64
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................65
10.3.4. Reporting of SAEs....................................................................................69
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................70
10.4.1. Male Participant Reproductive Inclusion Criteria....................................70
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10.4.2. Female Participant Reproductive Inclusion Criteria.................................70
10.4.3. Woman of Childbearing Potential ............................................................70
10.4.4. Contraception Methods.............................................................................71
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-Up Assessments .......74
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................76
10.8. Appendix 8: Abbreviations ...................................................................................78
11. REFERENCES ..................................................................................................................82
LIST OF TABLES
Table 1.
Pharmacokinetics Sampling Schema........................................................13
Table 2.
Treatment Flow Diagram..........................................................................21
Table 3.
Plasma Pharmacokinetic Parameter Definitions.......................................50
Table 4.
Width of 90% CIs for Different Estimated Effects of 
Test/Reference Ratio ................................................................................52
Table 5.
Protocol-Required Safety Laboratory Assessments .................................61
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Brief Title: A Phase 1 Study to Estimate the Effect of Multiple Dose Abrocitinib on the PK 
of Caffeine, Efavirenz, and Omeprazole in Healthy Adult Participants
Rationale
The purpose of the study is to evaluate the effect of abrocitinib on the in vivo PK of sensitive 
CYP1A2, 2B6 and 2C19 substrates, caffeine, efavirenz, and omeprazole, respectively.
Objectives and Endpoints
Objectives
Endpoints
Primary: 
Primary: 
•
To estimate effect of multiple dose abrocitinib on 
the PK of single, oral doses of caffeine, efavirenz
and omeprazole in healthy participants.
•
AUCinf (if applicable, otherwise AUClast) of caffeine, 
efavirenz and omeprazole. 
Secondary: 
Secondary: 
•
To evaluate the safety and tolerability of abrocitinib 
when co administered with single doses of caffeine,
efavirenz and omeprazole.
•
Vital signs, laboratory tests and AEs.
 
 
 
 
 
Overall Design
Brief Summary
This is a Phase 1, open-label, multiple dose, single fixed-sequence, 2-period study to evaluate
the effect of abrocitinib on the PK of caffeine, efavirenz and omeprazole in healthy adult 
participants. A total of approximately 13 healthy male and/or female participants will be 
enrolled in the study to obtain at least 12 evaluable participants who complete the study.
Participants who withdraw from the study or are considered non-evaluable may be replaced 
at the discretion of the sponsor.
Participants will be screened within 28 days of the first dose of study intervention. 
Participants will have a phone contact 3 days prior to Day 1 dosing (Day -3) in Period 1 as a 
reminder to abstain from caffeine-containing products. Participants will be admitted to the 
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CRU at least 24 hrs prior to Day 1 dosing (Day -1) in Period 1. Participants will remain in the 
CRU for a total of 15 days and 14 nights.
Participants will have a telephone contact between 28-35 calendar days after the last 
administration of the investigational product.
Number of Participants
A total of approximately 13 healthy male and/or female participants will be enrolled in the 
study to obtain at least 12 evaluable participants who complete the study.
Note: “Enrolled” means a participant’s, or his or her legally authorized representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process and screening. 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.
Intervention Groups and Duration
In Period 1, all the participants will receive single doses of the probe drugs, including 
caffeine 100 mg, efavirenz 50 mg and omeprazole 10 mg, together on Day 1. After 3 days of 
PK sampling in Period 1, Period 2 will immediately follow with no washout. The Day 1 of 
Period 2 begins on the fourth day following the start of Period 1. In Period 2, participants 
will receive abrocitinib 200 mg QD on Day 1-10. Participants will receive single doses of the 
probe drugs (caffeine 100 mg, efavirenz 50 mg and omeprazole 10 mg together) again on 
Day 8, and omeprazole 10 mg alone on Day 2, within approximately 5 minutes after 
administration of abrocitinib 200 mg on the morning of the respective day. 
The total planned duration of participation, from the Screening visit to the last Follow-up 
phone call, is approximately up to 11 weeks.
Data Monitoring Committee or Other Independent Oversight Committee: No
Statistical Methods
Natural log‑transformed parameters (AUCinf, AUClast
) will be analyzed using a 
mixed effect model with treatment as a fixed effect and subject 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% CI for the ratios. 
1.2. Schema (Not Applicable)
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Identifiera
Screening
Period 1 
Period 2
Follow-Up 
Phone Call 
Early 
Termination/
Discontinuation
Days Relative to Day 1
Day -28 to Day -4
Day -3
Day -1o
Day 1
Day 2-3
Day 1
Day 2
Day 3-7
Day 8
Day 9-10
Day 11
28-35 Daysb
Informed consent
X
Phone contact reminderp
X
CRU confinement
X
→
→
→
→
→
→
→
X
Inclusion/exclusion criteria
X
X
Medical, drug, tobacco and 
alcohol history 
X
X
Physical exam (including 
height and weight)c
X
Safety laboratory
X
X
X
X
Demography
X
Pregnancy test (WOCBP only)
X
X
X
X
Contraception check 
X
X
X
X
X
FSH
X
Urine drug testing
X
X
TB screeningd
X
Single 12-Lead ECGe
X
X
X
X
BP, pulse rate and 
temperaturee
X
X
X
X
HIV, HBsAg, HCVAb and 
HBcAbf
X
COVID-19 questionnaireg
X
X
COVID-19 testingh
X
X
COVID-19 check temperaturei
X
X
X
X
X
X
X
X
X
X
X
C-SSRS
X
X
X
X
X
X
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Visit Identifiera
Screening
Period 1 
Period 2
Follow-Up 
Phone Call 
Early 
Termination/
Discontinuation
Days Relative to Day 1
Day -28 to Day -4
Day -3
Day -1o
Day 1
Day 2-3
Day 1
Day 2
Day 3-7
Day 8
Day 9-10
Day 11
28-35 Daysb
Abrocitinib QD
administrationj
X
X
X
X
X
Caffeine, efavirenz, and 
omeprazole administrationk
X
X
Omeprazole administration
onlyl
X
PK blood samplingm
X
X
X
X
X
X
X
 
Serious and nonserious AE 
monitoring
X
→
→
→
→
→
→
→
→
X
X
X
Prior/concomitant treatment 
assessment
X
→
→
→
→
→
→
→
→
X
X
X
CRU discharge 
X
Abbreviations used in this table may be found in Appendix 8.
a.
Visit Identifier: Day relative to start of study intervention (Day 1).
b.
28‑35 Days: Participants will have a telephone contact between 28-35 calendar days after the last administration of the investigational product.
c.
Physical exam (including height and weight): Complete physical exam could be done at screening or admission Period 1. Brief physical exam to be done only in case of a finding at 
previous exam or new/open AE if applicable, at the discretion of the investigator.
d.
TB screening: TB screening will utilize IGRA. Details of eligibility are described in Appendix 2.
e.
Single 12‑Lead ECG, BP, pulse rate and temperature: ECG and vital signs will be collected at screening, before dosing on Day 1 of period 1, and on Day 11 of period 2.
f.
HIV, HBsAg, HCVAb and HBcAb: All participants will undergo screening for Hepatitis B and Hepatitis C for eligibility. Please refer to Appendix 2 for testing algorithm, reflex testing, 
and full eligibility criteria.
g.
COVID-19 questionnaire: Check exposure to positive subject, residence or travel in area of high incidence and COVID-19 related signs and symptoms. To be done at each visit.
h.
COVID-19 testing: The testing for COVID-19 pathogen by PCR will be performed at each visit. For participants admitted for residence, 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.
i.
COVID-19 check temperature: To be done at least daily during residence.
j.
Abrocitinib QD administration: The dosing of abrocitinib will be administered at approximately 08:00 ± 2 hours.
k.
Caffeine, efavirenz, and omeprazole administration: Participants will be dosed with caffeine, efavirenz, and omeprazole following an overnight fast of at least 10 hours at 
approximately 08:00 ± 2 hours. On the day of co administration abrocitinib, abrocitinib will be administered first. After swallowing the abrocitinib dose, caffeine, efavirenz, and 
omeprazole should be administered within approximately 5 minutes.
l.
Omeprazole administration only: Participants will be dosed with omeprazole following an overnight fast of at least 10 hours, within approximately 5 minutes after the abrocitinib 
administration.
m.
PK blood sampling: Refer to Table 1 for detailed PK blood sampling schedules.
 
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Visit Identifiera
Screening
Period 1 
Period 2
Follow-Up 
Phone Call 
Early 
Termination/
Discontinuation
Days Relative to Day 1
Day -28 to Day -4
Day -3
Day -1o
Day 1
Day 2-3
Day 1
Day 2
Day 3-7
Day 8
Day 9-10
Day 11
28-35 Daysb
o.
Day ‑1: Participants will be admitted to the CRU at least 24 hrs prior to Day 1 dosing (Day -1) in Period 1.
p.
Phone contact reminder: Participants will have a phone contact 3 days prior to Day 1 dosing (Day -3) in Period 1 as a reminder to abstain from caffeine-containing products. Please refer 
to Section 5.3.2 for the list of caffeine-containing products.
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Table 1.
Pharmacokinetics Sampling Schema
Study Period
1
2
2
2
Study Day
1
2
3
1
2
8
9
10
11
Hours Before/After Dose
0
0.5
1
2
3
4
5
6
8
12
16
24
48
72
0
1
3
6
8
0
0.5
1
2
3
4
5
6
8
12
16
24
48
72
Caffeine, efavirenz, and 
omeprazole administration
X
X
PK blood sampling for 
caffeine, efavirenz, and 
omeprazoleb
Xa
X
X X X
X X
X
X
X
X
X
X
Xa
Xa
X
X X
X
X X
X X
X
X
X
X
X
Abrocitinib QD 
administrationc
X
X
X
X
X
Omeprazole administration
X
PK blood sampling for 
omeprazole only
Xa
X
X
X
X
a.
PK sample will be collected before the abrocitinib dose.
b.
For 48 and 72 hour samples, only efavirenz will be analyzed.
c.
Note that abrocitinib is administered QD and this table only depicts administration on days with pharmacokinetic samples.
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2. INTRODUCTION
Abrocitinib (also referred to as PF-04965842) is an orally bioavailable potent JAK1 inhibitor 
with good selectivity over the broader kinome being developed for the treatment of AD.1
2.1. Study Rationale 
The purpose of the study is to evaluate the effect of abrocitinib on the in vivo PK of sensitive 
CYP1A2, 2B6 and 2C19 substrates, caffeine, efavirenz, and omeprazole, respectively. 
2.2. Background 
2.2.1. Nonclinical Pharmacology
Abrocitinib inhibits cytokines implicated in AD pathogenesis. For example, in vitro, 
abrocitinib inhibits IL-4 and IL-13 signaling in B cells, monocytes and keratinocytes, IL-4 
signaling in T cells and IL-31 signaling in THP-1 cells. Abrocitinib also inhibits IL-22 in 
keratinocytes and IFN-α, IFN-γ, IL-6 and other JAK1 dependent cytokines in PBMCs and 
human whole blood. The primary human metabolites of abrocitinib (M1 and M2) showed a 
profile of cytokine inhibition, via JAK1-dependent pathways, similar to the parent compound 
abrocitinib, while M4 was pharmacologically inactive. In AIA rats, abrocitinib exhibited a 
significant and maximal inhibition of disease for this model as well as significant inhibition 
of cytokine dependent STAT phosphorylation in ex vivo stimulated whole blood. Significant 
abrocitinib inhibition (>50%) of binding or enzyme activity of MAO-A and KDR kinase 
(VEGFR2) was observed, with IC50 values that were respectively 4.8× and 1.0× the unbound 
human Cmax at a clinical dose of 200 mg QD. 
In vitro safety pharmacology studies were conducted to assess potential hERG (GLP) and 
Nav1.5 (non-GLP) inhibition and the IC50 was 76× and 240×, respectively, at the unbound 
human Cmax. These ion channel in vitro assessments satisfy ICH S7A/B guidelines. In the 
broad ligand profile screen, less than 50% inhibition of calcium channel binding was 
observed. Overall, the nonclinical in vitro data for abrocitinib (and M1, M2, and M4) 
contribute to the weight of evidence for no significant effects at clinically relevant 
concentrations on the primary cardiac ion channels (eg, hERG, Nav1.5, or Cav1.2) generally 
considered to be most important for risk assessment of QT prolongation.
In vivo safety pharmacology studies were conducted to assess potential effects on the 
nervous, cardiovascular, and pulmonary systems. Abrocitinib produced lower locomotor 
activity (horizontal and vertical movements) and body temperature in rats and increases in 
HR and diastolic BP in cynomolgus monkeys. No other effects on parameters in the FOB 
were observed or on the telemetry-based activity measure in the rat or cynomolgus monkey 
cardiovascular safety pharmacology studies were observed. No primary QT signals, 
including no QTc prolongation, were observed in the cardiovascular safety pharmacology 
study in cynomolgus monkeys.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Plasma profiling from the [14C]abrocitinib human mass balance study indicated unchanged 
abrocitinib as the most prevalent circulating species (26%), with 3 major and more polar 
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mono-hydroxylated metabolites identified. M1, M2, and M4 are not unique to humans, and 
were shown to have sufficient exposures at NOAEL doses in rats (rat/human AUC24
ratios ≥1) relative to the projected highest therapeutic human dose of 200 mg daily.
In vitro and in vivo metabolite profiling suggested that the primary clearance mechanism for 
abrocitinib was CYP-mediated oxidation, with CYP2C19 the primary contributor at 
approximately 50%. CYP metabolism played a minor role (<25%) in the clearance of 
metabolites M1, M2 and M4. Renal excretion of parent drug was limited in the mouse, rat 
and humans, while urinary excretion was the major route of elimination for M1, M2, and M4. 
Abrocitinib, M1, M2, and M4 were not significant competitive inhibitors of CYP enzymes, 
but showed varying weak TDI activities versus CYP3A, CYP2C19 and CYP2D6. 
Abrocitinib exhibited a weak potential to induce CYP1A2, CYP3A4 and CYP2B6. M1, M2, 
and M4 did not induce CYP3A4 enzyme activity or mRNA. M1 and M2 showed a weak 
potential to induce CYP1A2 and CYP2B6. Clinical results with midazolam as a victim 
indicated no significant risk of interaction through inhibition or induction of CYP3A after 
abrocitinib administration.
Abrocitinib, M1, M2, and M4 were not significant inhibitors of the major UGT enzymes or
SULT enzymes. Clinical results with ethinyl estradiol as a victim indicated no significant risk 
of UGT or SULT inhibition by abrocitinib and its metabolites. 
Abrocitinib was not a substrate for OATP1B1 or OATP1B3, nor inhibited these transporters. 
Abrocitinib did not inhibit OAT1, OCT2, or bile salt export pump, but inhibited OAT3, P-gp, 
BCRP, OCT1, MATE1, and MATE2K. M1, M2, and M4 did not inhibit P-gp, OCT2, and 
OAT1. M2 and M4 did not inhibit OATP1B1 and OATP1B3.  M1, M2, and M4 inhibited 
BCRP, MATE1, MATE2K, and OAT3. Clinical results showed abrocitinib co-administration 
increased dabigatran exposure <2 fold, indicative of the inhibition of dabigatran etexilate 
efflux by P-gp, and showed no significant effect on the exposure of rosuvastatin (BCRP, 
OAT3 probe substrate) or metformin (OCT2, MATE1/2K, OCT1 probe substrate).
Overall risk as a victim of a transporter interaction from M1, M2, and M4 is considered low. 
M1, M2 and M4 were substrates of OAT3, but not MATE1, MATE2K, OAT1 or OCT2. 
Clinical results with probenecid (an OAT3 inhibitor) coadministration significantly increased 
exposure of M1, M2, and M4, but had no effect on abrocitinib exposure.
2.2.3. Nonclinical Safety
Abrocitinib was assessed in a series of nonclinical toxicity studies.  In repeat-dose toxicity 
studies, abrocitinib was administered chronically to rats and cynomolgus monkeys in studies 
up to 6 and 9 months in duration, respectively. In these toxicity studies, abrocitinib-related 
findings were generally consistent with the expected immunomodulatory pharmacology of 
abrocitinib, no unique or unanticipated immunotoxicities were noted after abrocitinib 
administration, and most abrocitinib-related effects had reversed by the end of a 12-week 
recovery phase. 
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Target organs identified included the immune and hematolymphopoietic systems, bone, liver, 
kidney, and skin. In addition, effects on HR, diastolic BP, locomotor activity, and body 
temperature were observed in the safety pharmacology studies. Administration of abrocitinib
was also associated with emesis in cynomolgus monkeys and an increase in small 
cytoplasmic vacuolation of brown adipose tissue in rats. No evidence of proliferative or 
neoplastic lesions was noted in the chronic toxicity studies. 
Abrocitinib is not mutagenic or clastogenic based on the results of a series of in vitro and in 
vivo tests for gene mutations and chromosomal aberrations. 
Abrocitinib did not affect the male reproductive system, including fertility or 
spermatogenesis, but did result in reversible decreased female fertility. Effects on female 
fertility (decreased fertility index, corpora lutea, implantation sites) and increased post-
implantation loss were observed in rats at 70 mg/kg/day and 30 mg/kg/day with 
exposures 29× and ≥11, respectively, the unbound human AUC at the clinical dose of 
200 mg QD and were fully reversible following a 1-month recovery. 
Abrocitinib did not cause malformations in rats or rabbits. 
Additionally, data from animal studies revealed that abrocitinib is not genotoxic, and does 
not have an impact on male fertility, and no histopathological changes were noted in the 
testes and epididymides with abrocitinib administration for up to 6 and 9 months at doses up 
to 70 and 75 mg/kg/day in rats and cynomolgus monkeys, respectively, and corresponding 
exposures were 26× and 10× the unbound AUC at the human clinical dose of 200 mg. 
Furthermore, in vivo data show that abrocitinib does not have phototoxicity potential.
2.2.4. Clinical Overview
2.2.4.1. Summary of Safety Data from Completed Studies
Based on the clinical experience with abrocitinib and its mechanism of action, the potential 
risks of treatment with JAK inhibitors include: (1) viral reactivation; (2) serious infection and 
opportunistic infections; (3) malignancy and lymphoproliferative disorders; (4) decreased 
lymphocyte counts; (5) decreased neutrophil counts; (6) decreased platelets; (7) alterations in 
the lipid profile; and (8) venous thromboembolism (deep venous thrombosis/pulmonary 
embolism).
In the completed Phase 1 and 2 studies in healthy participants, participants with psoriasis and 
participants with AD, abrocitinib was generally safe and well tolerated.
In the completed Phase 1 studies in healthy participants receiving single doses of abrocitinib 
up to 800 mg and multiple doses up to 200 mg BID or 400 mg QD, the most commonly 
reported AEs were diarrhea, nausea, vomiting, headache, acne, and dizziness. Following 
single or multiple dose of abrocitinib, most reported TEAEs were mild or moderate in 
severity. In study B7451001, during the single ascending dose phase, 1 participant in the 
placebo group had maximum QTcF interval of 450 <480 msec, and 1 participant in the 
abrocitinib 800 mg treatment group had maximum QTcF interval increase from baseline of 
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30 to <60 msec. In the multiple ascending dose phase, 3 participants (1 each in the placebo, 
abrocitinib 30 mg QD, and 100 mg QD treatment groups) had maximum QTcF interval of 
450 <480 msec, and 2 participants in the abrocitinib 200 mg BID treatment group had 
maximum QTcF interval increase from baseline of 30 to <60 msec. 
In the completed Phase 2 study in participants with moderate to severe psoriasis (B7451005), 
the most frequently reported AEs across the abrocitinib treatment groups (200 mg BID, 
200 mg QD, and 400 mg QD) were nausea, followed by headache. Other commonly reported 
AEs include neutropenia and neutrophil counts decreased, thrombocytopenia and platelet 
count decreased. One of the participants in the 200 mg QD group with an AE categorized as 
infections and infestations was reported as having VIIth nerve paralysis (Bell’s palsy) and 
later developed herpes zoster (shingles). The incidence of normal and abnormal ECG 
recordings was similar across all treatment groups at each time point. None of the abnormal 
ECG recordings were determined to be clinically significant by the investigator.
In the completed 12-week Phase 2b study (B7451006) in participants with AD, AEs and 
SAEs were numerically higher in participants receiving abrocitinib (10, 30, 100, and 200 mg 
QD) compared to placebo, but did not appear to increase with dose. The most common AEs 
were in the infections and infestations, skin and subcutaneous tissue disorders and 
gastrointestinal disorders SOC, and the majority of the AEs were mild. The most commonly 
reported TEAEs across all the treatment groups were dermatitis atopic (38 events), and viral 
upper respiratory tract infection (33 events). The most frequently reported treatment related 
TEAE was nausea. There were 2 cases of nonserious herpes zoster, one in the 10 mg group 
(not treatment-related), and one in the 30 mg group (treatment-related). There were 
2 participants (doses of ≥100 mg QD) with treatment related SAEs reported, the SAEs were 
eczema herpeticum and pneumonia. One participant randomized to the abrocitinib 10 mg 
group reported an SAE of malignant melanoma. Dose dependent mean platelet count 
decreases from baseline were observed with a nadir at Week 4. At Week 4 the mean platelet 
count and the 90% CI were within the normal reference range for both the 100 mg dose and 
200 mg dose. In these treatment groups, the mean platelet count increased towards baseline 
after Week 4. There were no clinically significant findings in vital signs or physical 
examinations. Most of the ECG results were normal. The incidence of normal and abnormal 
ECG recordings was similar between abrocitinib and placebo groups at each time point.
In the completed 12-week Phase 3 study (B7451012) in adult and adolescent participants 
aged 12 years and older with moderate to severe AD, the most frequent all-causality TEAEs 
that occurred in ≥5% of participants of any treatment group (100 mg QD and 200 mg QD) 
were nausea, nasopharyngitis, upper respiratory tract infection, headache, and dermatitis 
atopic. Nausea was the most frequently reported treatment-related TEAE with ≥5% higher 
incidence in the abrocitinib treatment groups compared with the placebo group. Majority of 
TEAEs reported were mild to moderate in severity.
Similarly, safety data from the completed 12-week Phase 3 study (B7451013) in adult and 
adolescent participants aged 12 years and older with moderate to severe AD, have reported 
similar TEAEs to the ones observed in study B7451012. The safety data reported in this 
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study showed that the most frequent all-causality TEAEs that occurred in ≥5% of participants 
of any treatment group (100 mg QD and 200 mg QD) were nausea, nasopharyngitis, upper 
respiratory tract infection, headache, and dermatitis atopic. Nausea was the most frequently
reported treatment-related TEAE with ≥5% higher incidence in the abrocitinib 200 mg 
treatment group compared with the placebo group. Majority of TEAEs reported were mild to 
moderate in severity.
2.2.4.2. Summary of Abrocitinib Pharmacokinetics, Metabolism and In Vitro 
Enzymology
2.2.4.2.1. Single and Multiple Dose Pharmacokinetics
Abrocitinib was absorbed rapidly following single oral solution/suspension doses of 3 mg to 
200 mg with median time to Tmax observed less than 1 hour (ranging from 0.55 to 
0.77 hours), and more slowly at the higher doses with median Tmax of 1.5 and 4.0 hours for 
the 400 mg and 800 mg doses, respectively (Study B7451001). Following attainment of Cmax, 
the disposition of abrocitinib generally showed a monophasic decline at the lower doses of 3 
to 30 mg (mean apparent t½ of 1.9 to 2.5 hours) while a biphasic decline was observed at 
doses of 100 to 800 mg with a mean t½ of 3.6 to 4.9 hours. Plasma abrocitinib Cmax appeared 
to increase proportionally across the entire dose range from 3 mg to 800 mg, while increases 
in AUCinf were greater than proportional at doses of 400 and 800 mg. For the 2-fold doses 
increase between 200 to 400 mg and between 400 to 800 mg, the mean AUCinf values in 
Western participants in this study appeared to increase approximately 3.5- and 2.7-fold, 
respectively.
On Day 10 of multiple-dose administration, abrocitinib was absorbed rapidly with median 
Tmax of about 1 hour or less (ranging from 0.50-1.05 hours) across the entire range of doses, 
from a total daily dose of 30 mg (30 mg QD) up to 400 mg (200 mg BID or 400 mg QD). 
Following attainment of Cmax, the disposition of abrocitinib was consistent with that observed 
following single dose administration, showing a biphasic decline following all but the lowest 
dose and a mean t½ of about 2.8 to 5.0 hours. Plasma Cmax and AUCtau both appeared to show 
a trend towards greater than proportional increases at doses higher than 200 mg given once
daily. Geometric mean values for the observed Rac, that compares AUCtau for multiple dose 
administration to AUCtau for single dose administration, ranged from 1.3 to 1.5 for QD 
dosing and 1.3 to 2.3 for BID dosing. Similar ratios for Cmax comparison (Rac, Cmax) ranged 
from 1.1 to 1.3 for QD dosing and from 1.3 to 2.8 for BID dosing. These results showed that 
drug concentration accumulation after repeated oral QD or BID administration is less than 
about 1.5- and 2.3-fold, respectively; at doses up to 200 mg QD, the accumulation was 
minimal and generally consistent with the prediction from t½. 
At a single 800 mg dose, the geometric mean Cmax was similar in Western and Japanese 
participants. However, geometric mean AUCinf was 26% higher in Western participants than 
that observed in Japanese participants. Geometric mean Cmax and AUCtau following multiple
dose administration of 200 mg BID was 17% and 56% higher, respectively, in the Western 
participants than in Japanese participants. 
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The urinary recovery of abrocitinib was low, with <4% of the dose recovered unchanged in 
urine across all doses and regimens in all cohorts in Study B7451001. 
The BA of a solid dose formulation of abrocitinib relative to a suspension formulation was 
evaluated in an open-label, single dose, 3 way crossover study in 12 healthy participants 
under fasting and fed conditions (Study B7451004). Following single oral 400 mg doses 
under fasted conditions, Cmax was reached rapidly for the oral suspension (median Tmax
0.52 hours) and more slowly for the tablet formulation (4×100 mg, median Tmax 2.0 hours). 
When the tablet was administered under fed conditions, Tmax was further delayed with a 
median value of 4.0 hours. Mean t½ was 4.9 hours for the oral suspension fasted, 5.3 hours 
for the tablet fasted, and 3.2 hours for the tablet under fed conditions. Relative BA of 
4×100 mg abrocitinib tablets compared to 400 mg oral suspension under fasted condition was 
96.54% and the 90% CI for the ratio (tablet/suspension) of adjusted geometric mean AUCinf
values was (90.31%, 103.21%), within the 80% to 125% interval demonstrating equivalence 
of total exposure. The ratio (90% CI) for Cmax was 79.48% (62.88%, 100.46%). 
Administration of 4×100 mg abrocitinib tablets with food did not change AUCinf and 
appeared to result in slightly lower Cmax with reduced variability compared to fasted 
conditions. The ratio (90% CI) of adjusted geometric means for fed/fasted administration was 
100.70% (94.42%, 107.40%) for AUCinf and 95.56% (76.22%, 119.82%) for Cmax. The 
magnitude of decrease in Cmax (<5%) was not considered to be clinically important. 
Therefore, abrocitinib can be administered with or without food. There were no clinically 
significant changes in ECG findings during the study.
2.2.4.2.2. Population Pharmacokinetics
PK analyses in male and female AD patients and healthy volunteers indicated that systemic 
exposure (AUC) of abrocitinib in the extremes of body weight (52 kg to 111 kg) was similar 
(within 20%) to that of a 70 kg individual. The enzymatic activity of CYP enzymes is 
reduced in patients with atopic dermatitis due to chronic inflammation. Patients with 
inflammatory disease had approximately 30% higher steady-state abrocitinib exposures 
compared to healthy volunteers. The observed metabolite/parent ratios of each of the 
metabolites in AD patients are similar to those observed in healthy subjects. Adolescent 
patients, including those with lower body weight (down to 25 kg), have similar exposures of 
abrocitinib compared to adults. There are no clinically relevant differences in exposure for 
abrocitinib or active moiety in adolescents ≥25 kg compared with adult AD patients. Based 
on population PK analyses, atopic dermatitis, age, sex, body weight, and race did not have a 
clinically meaningful effect on exposures of abrocitinib and active moiety.
2.3. Benefit/Risk Assessment
Abrocitinib is not expected to provide any clinical benefit to healthy participants. This study 
is designed primarily to generate PK, safety, and tolerability data for further clinical 
development of abrocitinib. Caffeine, efavirenz, and omeprazole are used as probes of 
CYP1A2/2B6/2C19, respectively, which PK may be affected by abrocitinib. A study that 
shows lack of DDI when these substrates are co-administered with abrocitinib improves 
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confidence in the co-administration of abrocitinib with a wide variety of commonly used 
drugs.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of abrocitinib may be found in the IB, which is the SRSD for this study.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
•
To estimate effect of multiple dose abrocitinib on 
the PK of single, oral doses of caffeine, efavirenz
and omeprazole in healthy participants.
•
AUCinf (if applicable, otherwise AUClast) and of 
caffeine, efavirenz and omeprazole. 
Secondary:
Secondary: 
•
To evaluate the safety and tolerability of abrocitinib 
when co administered with single doses of caffeine,
efavirenz and omeprazole.
•
Vital signs, laboratory tests and AEs.
 
 
 
 
 
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, open-label, multiple dose, single fixed-sequence, 2-period study to evaluate
the effect of abrocitinib on the PK of caffeine, efavirenz and omeprazole in healthy adult 
participants. A total of approximately 13 healthy male and/or female participants will be 
enrolled in the study to obtain at least 12 evaluable participants who complete the study. 
Participants who withdraw from the study or are considered non-evaluable may be replaced 
at the discretion of the sponsor.
Participants will be screened within 28 days of the first dose of study intervention. 
Participants will have a phone contact 3 days prior to Day 1 dosing (Day -3) in Period 1 as a 
reminder to abstain from caffeine-containing products. Participants will be admitted to the 
CRU at least 24 hrs prior to Day 1 dosing (Day -1) in Period 1. Participants will remain in the 
CRU for a total of 15 days and 14 nights.
In Period 1, all the participants will receive single doses of probe drugs, including caffeine 
100 mg, efavirenz 50 mg and omeprazole 10 mg, together on Day 1. The Day 1 of Period 2 
begins on the fourth day following the start of Period 1.The predose and up to 24 hours post 
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dose PK samples will be analyzed for caffeine, efavirenz, and omeprazole; while the 48 and 
72 hours post dose PK samples will be analyzed for efavirenz PK only. After 3 days of PK 
sampling in Period 1, Period 2 will immediately follow with no washout. 
In Period 2, participants will receive abrocitinib 200 mg QD on Day 1-10. On Period 2 
Day 2, participants will receive single dose of omeprazole 10 mg alone within approximately
5 minutes after administration of a 200 mg dose of abrocitinib in the morning. PK samples 
for omeprazole concentration measurement will only be collected from predose and up to 
8 hours post dose. Participants will receive single doses of the probe drugs (caffeine 100 mg, 
efavirenz 50 mg and omeprazole 10 mg together) again on Day 8, and omeprazole 10 mg 
alone on Day 2, within approximately 5 minutes after administration of abrocitinib 200 mg 
on the morning of the respective day. The predose and up to 24 hours post dose PK samples 
will be analyzed for caffeine, efavirenz, and omeprazole; while the 48 and 72 hours post dose 
PK samples will be analyzed for efavirenz PK only.
Participants will have a telephone contact between 28-35 calendar days after the last 
administration of the investigational product.
The total planned duration of participation, from the Screening visit to the last Follow-up 
phone call, is approximately up to 11 weeks.
Table 2.
Treatment Flow Diagram
Treatment
Period 1
Period 2
Day 1
Day 2-3
Day 1
Day 2
Day 3-7
Day 8
Day 9-11
Abrocitinib 200 mg QD
X
X
X
X
X
Caffeine 100 mg SD
X
X
Efavirenz 50 mg SD
X
X
Omeprazole 10 mg SD
X
X
X
4.2. Scientific Rationale for Study Design
Inhibition and induction of the CYP1A2/2B6/2C19 enzymes by abrocitinib were assessed in 
HLM and human hepatocytes. Abrocitinib was a weak TDI of CYP2C19 and a weak inducer 
of CYP1A2/2B6/2C19 enzymes. The purpose of the study is to evaluate the effect of 
abrocitinib on the in vivo PKs of sensitive CYP1A2, 2B6 and 2C19 substrates, caffeine, 
efavirenz, and omeprazole. The probe drugs used in this study, caffeine, efavirenz, and 
omeprazole are a subset of the Basel cocktail, which has been validated for simultaneous 
phenotyping of CYP isoforms2, and can be used without additional validation.
Multiple dose administration of the investigational drug for a minimum of 7 days is generally 
recommended to evaluate its induction effect on enzyme activity, as inducers can take several 
days to exert their effects. While the onset of inhibition effect on CYP enzymes by potential 
inhibitors is relatively quick. Therefore, caffeine, efavirenz, and omeprazole will be given on 
Day 8 during the 10 days of abrocitinib QD dosing to assess the potential induction effect of 
abrocitinib on CYP1A2/2B6, and net effect of TDI and induction on CYP2C19. Omeprazole 
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will be given on Day 2 to assess the TDI effect of abrocitinib on CYP2C19, with only sparse 
PK samples to be taken for future exploration using PBPK modeling approach.
Efavirenz has a long t½ ranging from 52-76 hours. PK samples collected up to 72 hr may not 
support t½ and AUCinf calculation, therefore, partial AUC0-72 hr (AUClast) may be used as the 
primary endpoint for efavirenz. At a single dose of 50 mg, efavirenz is not expected to induce 
or inhibit (competitively or mechanism based) any metabolizing system2.
PK samples collected up to 24 hr is sufficient to capture the full PK profiles of caffeine and 
omeprazole considering their relatively short half-lives of approximately 5 hr and 1-4 hr, 
respectively. 
 
 
4.2.1. Diversity of Study Population
Reasonable attempts will be made to enroll participants with balanced distribution of gender 
and race to ensure the study population is representative of the patient population that will 
use abrocitinib in clinical practice.
4.2.2. Choice of Contraception/Barrier Requirements
Human reproductive safety data are not available for abrocitinib, but there is no suspicion of 
human teratogenicity based on the intended pharmacology of the compound. Therefore, the 
use of a highly effective method of contraception is required (see Appendix 4).
 
4.3. Justification for Dose
Two hundred mg QD oral doses of abrocitinib will be used in this study as it is the highest 
dose evaluated in the Phase 3 AD program. Both Cmax and AUC values of abrocitinib 
increase in proportion to increases in dose following single administrations of up to 400 mg 
of abrocitinib. Oral doses of abrocitinib as high as 800 mg (single dose), 400 mg QD and 
200 mg BID (up to 10 days) have been found to be safe and well-tolerated. Based on the 
safety data of abrocitinib and prior clinical experience described above, the 200 mg QD for 
10 days is expected to pose little risk to healthy adult participants.
Single oral doses of 100 mg caffeine, 50 mg efavirenz, and 10 mg omeprazole will be used in 
this study as consistent with the validated Basel cocktail. The probe drugs are expected to be
generally safe and well tolerated by healthy participants and have no mutual interactions2. 
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4.4. End of Study Definition
The end of the study is defined as the date of last scheduled procedure shown in the SoA for 
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 Follow-up phone call.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants must be Ŏ18 years of age at the time of signing the ICD.
•
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Male and female participants who are healthy as determined by medical evaluation 
including a detailed medical history, complete physical examination, laboratory tests, 
and cardiovascular tests.
3. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
Weight:.
4. BMI of 17.5 to 32 kg/m2; and a total body weight >50 kg (110 lb).
Informed Consent:
5. 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.
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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. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
3. Participants with moderate to severe GERD symptoms (ie, heartburn and/or 
regurgitation) during the last 6 months.
4. History of HIV infection, hepatitis B, or hepatitis C; positive testing for HIV, HBsAg, 
or HCVAb. Hepatitis B vaccination is allowed.
5. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
6. Evidence or history of clinically significant dermatological condition (eg, AD or 
psoriasis) or visible rash present during physical examination.
7. History of TB (active or latent) or inadequately treated TB infection. Positive 
QuantiFERON® – TB Gold test. 
8. Any history of chronic infections, any history of recurrent infections, any history of 
latent infections, or any acute infection within 2 weeks of baseline (Day -1). 
9. History of disseminated herpes zoster, or disseminated herpes simplex, or recurrent 
localized dermatomal herpes zoster. 
10. Have any malignancies or have a history of malignancies with the exception of 
adequately treated or excised nonmetastatic basal cell or squamous cell cancer of the 
skin, or cervical carcinoma in situ. 
11. History of hypersensitivity, intolerance, or allergic reaction associated to prior 
exposure to caffeine, omeprazole, efavirenz, and abrocitinib or any of their
excipients.
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12. Any psychiatric condition including recent or active suicidal ideation or behavior that 
meets any of the following criteria:
•
Suicidal ideation associated with actual intent and a method or plan in the past 
year: “Yes” answers on items 4 or 5 of the C-SSRS (Section 8.2.7).
•
For participants who had previous history of suicidal behaviors in the past >1 year 
to 10 years: “Yes” answer (for events that occurred in the past 10 years) to any of 
the suicidal behavior items of the C-SSRS or any lifetime history of serious or 
recurrent suicidal behavior, a risk assessment must be performed, and 
documented, by a qualified MHP to assess whether it is safe for the participant to 
participate in the trial.
•
The presence of any current major psychiatric disorder that is not explicitly 
permitted in the inclusion/exclusion criteria.
NOTE: For any participant who has significant depression or any suicidal behavior, 
the participant will not be randomized and should be referred for appropriate 
evaluation and treatment. 
13. Participants, who according to the product label for efavirenz, would be at increased 
risk if dosed with efavirenz (ie, including but not limited to patients with severe 
hepatic impairment [Child Pugh Class C]).
14. Participants, who according to the product label for efavirenz, with a history of 
seizures.
Prior/Concomitant Therapy:
15. 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 6.8 for additional details).
16. Systemic therapy with any of the medications that are moderate or strong CYP1A2, 
CYP2B6, or CYP2C19 inhibitors within 28 days or 5 half-lives (whichever is longer) 
or moderate or strong CYP1A2, CYP2B6, or CYP2C19 inducers within 28 days or 
5 half-lives (whichever is longer) prior to the first dose.
17. Herbal supplement, hormonal contraceptives and HRT must be discontinued at least 
28 days prior to the first dose of investigational product; Depo-Provera® must be 
discontinued at least 6 months prior to dosing of investigational product.
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18. Participants who are vaccinated with vaccines that have live components (or live 
attenuated vaccines) within the 6 weeks prior to the first dose of abrocitinib or who
are expected to be vaccinated during treatment or during the 6 weeks following 
discontinuation of abrocitinib.
NOTE regarding COVID vaccines with authorization or approval for 
emergency use:
There is no requirement for washout of COVID vaccines prior to the first dose of 
abrocitinib if the vaccine is not live attenuated (eg, mRNA, utilizing a viral vector, 
inactivated virus). 
There is no protocol-specified requirement for the interruption of abrocitinib dosing 
prior to or after vaccination if the COVID vaccine is not live attenuated.
Prior/Concurrent Clinical Study Experience:
19. 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:
20. A positive urine drug test.
21. 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.
22. 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.
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23. 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 ≥1.5× ULN;
•
TBili 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 ≤1.5× ULN.
•
eGFR <60 mL/min/1.73 m2 (see Appendix 2 for CKD-EPI formula).
•
In the opinion of the investigator or Pfizer (or designee), have any clinically 
significant laboratory abnormality that could affect interpretation of study data or 
the participant's participation in the study.
24. Participants with abnormal complete blood count test results (eg, hemoglobin, 
platelets, WBCs- including lymphocytes, neutrophils) as assessed by the study
specific laboratory, and confirmed by a single repeat test, if deemed necessary.
Other Exclusions:
25. 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).
26. Pregnant female participants; breastfeeding female participants; female participants of 
childbearing potential who are unwilling or unable to use 1 highly effective method 
of contraception as outlined in this protocol (see Appendix 4, Section 10.4) for the 
duration of the study and for at least 28 days after the last dose of study intervention.
27. Participants who routinely consumed more than five 8-ounce cups of coffee (or 
caffeine equivalent) or greater than 6 servings (1 serving is approximately equivalent 
to 125 mg of caffeine) of tea, Cola or other caffeinated beverage per day.
28. Consumption of chocolate and chocolate-containing products (eg, hot chocolate, ice 
cream, cookies, etc) within 48 hours prior to the first dose and during the study.
29. Smokers and/or participants who used nicotine based products within 3 months prior 
to the first dose of the investigational product.
30. Consumption of charcoal-broiled beef within 7 days prior to the first dose as it is 
known to induce CYP1A2 enzyme.
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31. Consumption of cruciferous vegetables (eg, cauliflower, broccoli, Brussel sprouts, 
and cabbage) within 7 days prior to the first dose as cruciferous vegetables are known 
to increase CYP1A2 activity. 
32. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
33. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
34. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.
5.3. Lifestyle Considerations
The following guidelines are provided:
5.3.1. Meals and Dietary Restrictions
•
Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample.
•
Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. 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.
•
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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5.3.2. Caffeine, Alcohol, and Tobacco
•
Participants will abstain from caffeine-containing products for 48 hours prior to the 
start of dosing until collection of the final PK sample of each study period. 
o
Caffeine–containing products including but not limited to coffee, tea, Cola or 
other caffeinated beverage (eg, energy drinks), chocolate and chocolate-
containing products (eg, hot chocolate, ice cream, cookies, etc), guarana.
•
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 
3 months prior to the start of study intervention in Period 1 and continue abstaining 
from tobacco- or nicotine-containing products until collection of the final PK sample 
of Period 2.
5.3.3. 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.
5.3.4. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant from the permitted list of contraception methods (see Appendix 4 Section 10.4.4)
and will confirm that the participant has been instructed in its consistent and correct use. At 
time points indicated in the SoA, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart (participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception)
considering that their risk for pregnancy may have changed since the last visit. In addition, 
the investigator or designee will instruct the participant to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the participant
or partner.
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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 if prior reason for not meeting the eligibility criteria has been resolved. 
Rescreening may only occur with Sponsor approval.
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to the investigational products, 
including abrocitinib, caffeine, efavirenz and omeprazole.
6.1. Study Intervention(s) Administered
For this study, the investigational products are abrocitinib (PF-04965842, 200 mg provided 
as one 200 mg tablet), caffeine (100 mg provided as one 100 mg tablet), efavirenz (50 mg 
provided as one 50 mg tablet) and omeprazole (10 mg provided as one 10 mg tablet).
Abrocitinib 200 mg tablet will be supplied to the CRU in bulk along with individual dosing 
containers for unit dosing.
Caffeine 100 mg tablet, efavirenz 50 mg tablet, and omeprazole 10 mg tablet will be supplied 
locally by the CRU (Upon confirmation that the external CRU will provide comparator 
agents).
6.1.1. Administration
Period 1: On Day 1, following an overnight fast of at least 10 hours, participants will receive 
study interventions (100 mg caffeine, 50 mg efavirenz, and 10 mg omeprazole
simultaneously) at approximately 08:00 hours (plus or minus 2 hours). Investigator site 
personnel will administer study intervention with ambient temperature water to a total 
volume of approximately 240 mL. Participants will swallow the study intervention whole, 
and will not manipulate or chew the study intervention prior to swallowing.
Period 2: From Day 1 to Day 10, 200 mg abrocitinib will be administered at approximately 
08:00 hours (plus or minus 2 hours). On the morning of Day 2, omeprazole will be 
administered within approximately 5 min after the abrocitinib dose, following an overnight 
fast of at least 10 hours. On the morning of Day 8, caffeine, efavirenz, and omeprazole will 
be administered simultaneously within approximately 5 min after the abrocitinib dose, 
following an overnight fast of at least 10 hours. Investigator site personnel will administer 
study intervention with ambient temperature water to a total volume of approximately 
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240 mL. Participants may receive additional ambient temperature water up to 100 mL, if 
needed.
Participants will swallow the study intervention whole, and will not manipulate or chew the 
study intervention prior to swallowing.
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.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm appropriate temperature conditions 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 or administer study intervention. 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 for 
all site storage locations upon return to business.
3. Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, 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 definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. The investigator, institution, or the head of the medical institution (where applicable) 
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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7. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. 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 ID of a product complaint, notify the sponsor within 1 business day of discovery as 
described in the IP manual.
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.
Abrocitinib (200 mg provided as one 200 mg tablet), caffeine (100 mg provided as one 
100 mg tablet), efavirenz (50 mg provided as one 50 mg tablet) and omeprazole (10 mg 
provided as one 10 mg tablet) will be prepared in the CRU by 2 operators, 1 of whom is a 
pharmacist. Prepared doses will be provided in unit dose containers and labeled in 
accordance with Pfizer regulations and the investigator site’s labeling requirements.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
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. 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.
6.5. Dose Modification
Dose modification is not allowed in this study.
6.6. Continued Access to Study Intervention After the End of the Study
No intervention will be provided to study participants at the end of their study participation.
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6.7. Treatment of Overdose
For this study, any dose of abrocitinib greater than 800 mg within a 24-hour time period (±12
hours) will be considered an overdose.
Any dose of caffeine greater than 1600 mg within a 24-hour time period (±12 hours) will be 
considered an overdose3.
Any dose of efavirenz greater than 600 mg within a 24-hour time period (±12 hours) will be 
considered an overdose4.
Any dose of omeprazole greater than 2400 mg within a 24-hour time period (±12 hours) will 
be considered an overdose4.
There is no specific treatment for an overdose for abrocitinib. For caffeine, efavirenz or 
omeprazole, investigators should consider the treatment of overdose as per Scientific Opinion 
on the Safety of Caffeine3, or USPIs for efavirenz or omeprazole4.
In the event of an overdose, the investigator should:
1. Contact the medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at 
least 5 half-lives or 28 calendar days after the overdose of the study intervention
(whichever is longer).
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 4 days from the date of the last dose of 
study intervention if requested by the 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 medical monitor based on the clinical evaluation of the participant.
6.8. 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.
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Systemic therapy with any of the medications that are moderate or strong CYP1A2, 
CYP2B6, or CYP2C19 inhibitors within 28 days or 5 half-lives (whichever is longer) or 
moderate or strong CYP1A2, CYP2B6, or CYP2C19 inducers within 28 days or 5 half-lives 
(whichever is longer), are prohibited prior to the first dose of caffeine.
Females using hormonal contraceptives or taking HRT may be eligible to participate in this 
study if they are willing to discontinue therapy at least 28 days prior to the first dose of study 
treatment and remain off hormonal therapy for the duration of the study. Depo Provera® must 
be discontinued at least 6 months prior to the first dose of study treatment. Note that another 
approved method of contraception must then be used (Section 10.4.3).
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.
6.8.1. Rescue Medicine
There is no rescue therapy to reverse the AEs observed with abrocitinib, caffeine, efavirenz 
or omeprazole; 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.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following:
•
Refused further study procedures;
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•
Lost to follow-up;
•
Death;
•
Study terminated by sponsor;
•
At the discretion of the investigator for behavioral, compliance or administrative 
reasons.
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. 
If a participant withdraws from the study, he/she 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 should be performed and no 
additional data should 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 him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study intervention or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
7.3. Lost to Follow up 
A participant will be considered lost to follow-up if he or she 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 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 
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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, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND 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.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
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.
 
 
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 may make it unfeasible to perform 
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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 he or she has 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.
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 
260 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days.
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. Efficacy Assessments
Not applicable.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. 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.
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 
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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 8.3.1 to 8.3.3.
8.2.2. Vital Signs
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.
8.2.2.1. Temperature
Temperature will be measured orally. No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement.
8.2.3. 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, QT, and QTc intervals 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 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. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements (Period 1 Day 1, pre-dose). Additional ECG 
monitoring will occur if a) a postdose QTcF interval is increased by ≥60 msec from the 
baseline and is >450 msec; or b) an Abs QT value is ≥500 msec for any scheduled ECG. If 
either of these conditions occurs, then 2 additional ECGs will be collected approximately 2 to 
4 minutes apart to confirm the original measurement. If the QTc values from these repeated 
ECGs remain above the threshold value, then a single ECG must be repeated at least hourly 
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until QTc values from 2 successive ECGs fall below the threshold value that triggered the 
repeat measurement.
If a) a postdose QTcF interval remains ≥60 msec from the baseline and is >450 msec; or 
b) an Abs QT value is ≥500 msec for any scheduled ECG for greater than 4 hours (or sooner,
at the discretion of the investigator); or c) QTcF intervals get progressively longer, the 
participant should undergo continuous ECG monitoring. A cardiologist should be consulted 
if QTcF intervals 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 7.
8.2.4. 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 relevant changes occurring during the study in the AE section of the CRF. 
Clinically significant abnormal laboratory findings are those which 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 significantly abnormal during 
participation in the study or within 28 calendar days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or 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 
drug-induced liver injury.
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. 
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8.2.5. COVID-19 specific assessments
Participants will be tested for SARS-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 
(i.e. upon completion of 4×24 hours in house), or if they develop COVID-19 like symptoms. 
Additional testing may be required by local regulations or by the PI.
8.2.6. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but 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 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.
8.2.7. Suicidal Ideation and Behavior Risk Monitoring
The C-SSRS is an interview based rating scale to systematically assess suicidal ideation and 
suicidal behavior. Versions are available for “lifetime” and “since last evaluation”. The 
“lifetime” evaluation is done at screening, and the “since last evaluation” is done at all other 
time points.
The C-SSRS should be collected at times specified in the SoA section of this protocol by an 
appropriately trained CRU staff member. The C-SSRS can also be administered at any time 
in the study at the discretion of the investigator based on any reasonable concern. 
At each suicidality assessments as per SoA, participants felt to have significant suicidal 
ideation with actual plan and intent or suicidal behavior, must be evaluated by a 
clinician/MHP skilled in the evaluation of suicidality in the participants by virtue of training 
or experience (eg, psychiatrist, licensed clinical psychologist) who will determine if it is safe 
for the participant to participate/continue in the trial. Specific criteria that indicate a need for 
such an assessment are:
•
Suicide ideation associated with actual intent and/or plan in the past year (a “YES” 
answer to C SSRS questions 4 “some intent to act without specific plan” or 
5 “specific plan and intent”);
•
Previous history of suicide behaviors in the past 10 years (a “YES” answer to any of 
the suicidal behavior items of the C-SSRS with the behavior occurring in the past 
10 years);
•
In the investigators judgment a risk assessment or exclusion is warranted.
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A written copy of the risk assessment should be included in the participant’s clinical record 
(source documentation).
Other possible suicidality AEs or other clinical observations may, based on the judgment of 
the investigator, also trigger a risk assessment and require a narrative.
Suicidality AEs or other clinical observations may, based on the judgment of the investigator 
and clinician/MHP, also trigger a risk assessment and a narrative using information from the 
C-SSRS, and available information, prior to screening and baseline information, and the 
clinician/MHP assessment. When there is a positive response to any question on the C-SSRS, 
the investigator should determine whether an AE has occurred.
At the screening visit, a risk assessment will be done by qualified staff at the CRU to 
determine whether it is safe for the participant to be enrolled or to continue to participate in 
the trial. 
Participants who respond “YES” to items 4, 5 or to any behavioral question of the C-SSRS at 
any time after the baseline visit will be assessed by clinician/MHP to determine whether it is 
safe for the participant to continue in the trial.
Participants who respond “YES” to items 4, 5 or to any behavioral question of the C SSRS 
on more than one occasion during a trial must have their suicidality managed appropriately 
by the PI together with clinician/MHP (or the PI alone if the PI is a qualified MHP. 
Depending on the specifics of the participant as assessed by the PI and/or clinician/MHP, 
participant may be discontinued from the trial.
8.3. 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 
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 8.3.1, 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.
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8.3.1. 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 the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days after the last administration of the study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the
investigator.
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 he/she 
considers 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.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 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 it being available.
8.3.1.2. 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 8.3.1, 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.
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8.3.2. 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.
8.3.3. 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 given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. 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 
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exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An EDP occurs if: 
•
A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.
•
A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to 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 inhalation or skin contact.
•
A male family member or healthcare provider who has been exposed to the study 
intervention by inhalation or skin contact then exposes his female partner prior to 
or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
•
If EDP occurs in a participant or 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 28 days 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 
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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;
•
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 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.3.5.2. Exposure During Breastfeeding
An EDB occurs if:
•
A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.
•
A female 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 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.
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An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accord with authorized use. However, 
if the infant experiences an SAE associated with such a drug, the SAE is reported together
with the EDB.
8.3.5.3. 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.
8.3.6. Cardiovascular and Death Events (not applicable)
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs (not applicable)
8.3.8. Adverse Events of Special Interest (not applicable)
8.3.8.1. Lack of Efficacy (not applicable)
8.3.9. Medical Device Deficiencies (not applicable)
8.3.10. 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.
Exposures to the study intervention under study may occur in CT settings, such as 
medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report Form to Pfizer 
Safety Within 24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
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.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
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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.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Pharmacokinetics 
If an indwelling catheter is used, approximately 3× the device dead volume of blood will be 
discarded prior to PK blood collection at each sample collection time point.
Blood samples of approximately 6 mL, to provide a minimum of 2.4 mL plasma, will be 
collected for measurement of plasma omeprazole, caffeine, and efavirenz concentrations as 
specified in the SoA. Instructions for the collection, processing, handling, and storage 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 collected for analyses of omeprazole, caffeine, and efavirenz plasma concentration 
may also be used to evaluate safety or efficacy aspects related to concerns arising during or 
after the study, for metabolites 5-hydroxy omeprazole, paraxanthine, and 8-hydroxy 
efavirenz concentrations, metabolite identification and/or evaluation of the bioanalytical 
method, 
 
Genetic analyses will not be performed on these plasma samples. Participant confidentiality 
will be maintained.
PK samples will be analyzed using a validated analytical method in compliance with 
applicable SOPs. Potential metabolites may be analyzed with either validated 
 
methods.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
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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. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.8. 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 a 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
No formal inferential statistics will be applied to the data.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Enrolled/Randomly assigned to 
study intervention
“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 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. A 
participant will be considered enrolled if the informed consent is not withdrawn 
prior to participating in any study activity after screening.
PK Concentration
The PK concentration population is defined as all enrolled participants who 
received at least 1 dose of investigational product and in whom at least 1 plasma 
concentration value is reported.
PK Parameter
The PK parameter analysis population is defined as all participants who received 
at least 1 dose of investigational product and have at least 1 of the PK parameters 
of interest in at least 1 treatment period.
Safety Analysis Set
All participants randomly assigned to investigational product and who take at least 
1 dose of investigational product. Participants will be analyzed according to the 
product they actually received.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
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9.3.1. Pharmacokinetic Analysis
9.3.1.1. Analysis Population
The PK concentration population is defined as all participants randomized and treated who 
have at least 1 concentration in at least 1 treatment period.
The PK parameter analysis population is defined as all participants randomized and treated 
who have at least 1 of the PK parameters of primary interest in at least 1 treatment period.
 
 
 
9.3.1.2. Derivation of Pharmacokinetic Parameters
PK parameters will be derived from the plasma concentration time profiles as shown in 
Table 3.
Table 3.
Plasma Pharmacokinetic Parameter Definitions
Parameter
Definition
Method of Determination
AUClast
area under the concentration-time curve from 
time 0 to time of the last measureable
concentration
Linear/Log trapezoidal rule
AUCinf
area under the concentration-time curve from 
time 0 to infinity
AUClast + (Clast∗/kel), where Clast∗is the 
predicted plasma concentration at the last 
quantifiable time point estimated from the 
loglinear regression analysis, and kel is the 
terminal phase rate constant calculated by a 
linear regression through at least 3 data points 
in the terminal phase of the loglinear 
concentration time curve
 
 
 
 
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Natural log‑transformed parameters (AUCinf, AUClast
) will be analyzed using a 
mixed effect model with treatment as a fixed effect and subject 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% CI for the ratios. The Test and Reference treatments to estimate 
the treatment difference for each of the study objectives are as follows:
•
Objective 1: caffeine 100 mg (Period 1, Day 1) will be the Reference treatment; 
abrocitinib 200 mg + caffeine 100 mg (Period 2, Day 8) will be the Test treatment. 
•
Objective 2: efavirenz 50 mg (Period 1, Day 1) will be the Reference treatment; 
abrocitinib 200 mg + efavirenz 50 mg (Period 2, Day 8) will be the Test treatment. 
•
Objective 3: omeprazole 10 mg (Period 1, Day 1) will be the Reference treatment; 
abrocitinib 200 mg + omeprazole 10 mg (Period 2, Day 8) will be the Test treatment. 
Residuals from the model will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals but these will not be included in the CSR. If there are major deviations from 
normality or outliers, then the effect of these on the conclusions will be investigated through 
alternative transformations and/or analyses excluding outliers. Justification for any 
alternative to the planned analysis will be given in the report of the study.
9.3.2. Other 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 physical examination 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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9.4. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label study,
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, and/or supporting clinical development. 
9.5. Sample Size Determination
A sample size of 12 participants will provide 90% CIs for the difference between treatments 
of ±0.1099, ±0.2029 and ±0.2114 on the natural log scale for AUCinf in the assessment of 
caffeine, efavirenz, and omeprazole, respectively, with 80% coverage probability. The width 
of 90% CIs for different estimated effects is presented in Table 4.
Table 4.
Width of 90% CIs for Different Estimated Effects of Test/Reference Ratio
Reference
Estimated Effect 
(100×Test/Reference) (%)
AUCinf
90% CI (%)
CI Width
(%)
Caffeine
80
(71.67, 89.29)
17.62
90
(80.63, 100.46)
19.83
100
(89.59, 111.62)
22.03
110
(98.55, 122.78)
24.23
120
(107.51, 133.94)
26.44
Efavirenz
80
(65.31, 98.00)
32.69
90
(73.47, 110.25)
36.78
100
(81.63, 122.50)
40.87
110
(89.80, 134.75)
44.95
120
(97.96, 147.00)
49.04
Omeprazole
80
(64.76, 98.83)
34.08
90
(72.85, 111.19)
38.34
100
(80.95, 123.54)
42.59
110
(89.04, 135.89)
46.85
120
(97.13, 148.25)
51.13
These estimates are based on the assumption that within-participant standard deviations are
0.13, 0.24 and 0.25 for lnAUCinf of caffeine, efavirenz, and omeprazole, respectively, as 
obtained from previous Pfizer studies in healthy participants.
Participants who fail to complete the study may be replaced at the discretion of the sponsor.
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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 (if applicable), European MDR 2017/745 for clinical 
device research (if applicable), 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 his/her 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 study 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 his/her 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 his/her 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 his or 
her right to access and correct his or her personal data and to withdraw consent for the 
processing of his or her 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.
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Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.
A copy of the ICD(s) must be provided to the participant 
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic 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 his or her 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.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use a 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, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
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www.clinicaltrials.gov
Pfizer posts CT 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
Pfizer posts CT results on EudraCT for Pfizer-sponsored interventional studies in accordance 
with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are
posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the EU Policy 0070, the proactive publication of clinical data to the 
EMA website. Clinical data, under Phase 1 of this policy, includes clinical overviews, 
clinical summaries, CSRs, and appendices containing the protocol and protocol amendments, 
sample CRFs, and statistical methods. Clinical data, under Phase 2 of this policy, includes the 
publishing of individual participant data. Policy 0070 applies to new marketing authorization 
applications submitted via the centralized procedure since 01 January 2015 and applications 
for line extensions and for new indications submitted via the centralized procedure since 
01 July 2015.
Data sharing
Pfizer provides researchers secure access to patient-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. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted.
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.
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10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic 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 
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provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the clinical 
monitoring plan, 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.
Study monitors will perform ongoing source data verification 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. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
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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
The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or 1 year after the end of the study 
(or study termination), whichever comes first. 
The investigator agrees to refer to the primary publication in any subsequent publications,
such as secondary manuscripts, and submits all manuscripts or abstracts to the sponsor 
30 days before submission. This allows the sponsor 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- or Pfizer-intervention 
related information necessary for the appropriate scientific presentation or understanding of 
the study results.
For all publications relating to the study, the investigator will comply with recognized ethical 
standards concerning publications and authorship, including those established by the 
International Committee of Medical Journal Editors.
The sponsor will comply with the requirements for publication of the overall study results 
covering all investigator sites. In accordance with standard editorial and ethical practice, the 
sponsor will support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
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If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.11. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor’s appropriately qualified medical personnel for the 
study is documented in the study contact list located in the STOD.
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, 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 ID number, (c) site emergency phone number active 24 hours/day, 
7 days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site.
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10.2. Appendix 2: Clinical Laboratory Tests
The safety laboratory tests listed in Table 5 will be performed at times defined in the SoA 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 concerns. 
The eGFR will be calculated using the following equation developed by the CKD-EPI which 
utilizes SCr:
CKD-EPI
If female and SCr is ≤0.7 mg/dL:
GFR (mL/min/1.73 m2) = 144 × (SCr/0.7) – 0.329 × 0.993age (× 1.159, if Black).
If female and SCr is >0.7 mg/dL:
GFR (mL/min/1.73 m2) = 144 × (SCr/0.7) – 1.209 × 0.993age (× 1.159, if Black).
If male and SCr is ≤0.9 mg/dL:
GFR (mL/min/1.73 m2) = 141 × (SCr /0.9) – 0.411 × 0.993age (× 1.159, if Black).
If male and SCr is >0.9 mg/dL:
GFR (mL/min/1.73 m2) = 141 × (SCr /0.9) – 1.209 × 0.993age (× 1.159, if Black).
Table 5.
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/urea and creatinine
Cystatin C 
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
TBili
Alkaline phosphatase
Uric acid
Albumin
Total protein
eGFR based on the 
CKD-EPI equation
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
•
COVID-19 testing
•
Urine drug screeningb
•
Pregnancy testc
At screening only:
•
FSHd
•
HBsAg
•
HBcAb
•
HBsAbe
•
HCVAb
•
HIV
•
QuantiFERON®-TB Gold 
Testf
Additional Tests (Needed 
for Hy’s Law)
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Table 5.
Protocol-Required Safety Laboratory Assessments
Hematology 
Chemistry
Urinalysis
Other
AST, ALT (repeat)
TBili (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
CK
GGT
PT/INR
Total bile acids
Acetaminophen drug and/or 
protein adduct levels
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, and 
amphetamines (others are site specific).
c.
Pregnancy test for female participants of childbearing potential.
d.
For confirmation of postmenopausal status only (only females who are amenorrheic for at least 12 consecutive 
months).
e.
HBsAb tested as reflex test only in participants who are HBsAg negative, but are HBcAb positive.
f.
Complete at screening. Previous testing for QuantiFERON®-TB Gold Test will be accepted if completed within 12 
weeks prior to baseline. Otherwise should be completed at screening and results available prior to Day 1.
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.
Any remaining serum from samples collected for clinical safety laboratory measurements at 
baseline and at all times after dose administration may be retained and stored for the duration 
of the study.
 
 
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition
•
An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or 
not considered related to the study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (eg, ECG, radiological scans, vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator. Any 
abnormal laboratory test results that meet any of the conditions below must be 
recorded as an AE:
•
Is associated with accompanying symptoms;
•
Requires additional diagnostic testing or medical/surgical intervention;
•
Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.
•
Exacerbation of a chronic or intermittent preexisting condition, including either 
an increase in frequency and/or intensity of the condition.
•
New condition detected or diagnosed after study intervention administration,
even though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected DDI.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
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suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition
•
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
•
The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event that hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
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Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, 
pathogenic or non-pathogenic, is considered serious. 
The event may be suspected from clinical symptoms or laboratory findings 
indicating an infection in a participant exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These 
cases are considered unexpected and handled as serious expedited cases by 
pharmacovigilance personnel. Such cases are also considered for reporting as 
product defects, if appropriate.
g. Other situations:
•
Medical or scientific judgment should be exercised by the investigator in 
deciding whether SAE reporting is appropriate in other situations, such as 
significant medical events that may jeopardize the participant or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious.
•
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; 
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(2) nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
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 breastfeeding
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 non-participant (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 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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•
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.
•
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
•
Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
•
Moderate: Minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. Instrumental ADL refers to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc.
•
Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self care ADL. Self care ADL refers to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.
•
A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out.
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•
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.
•
The investigator will also consult the IB and/or product information, for 
marketed products, in his/her assessment.
•
For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the 
sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.
•
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
•
If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for 
reporting purposes, as defined by the sponsor. In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator 
must record this causal relationship in the source documents and CRF, and report 
such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
Follow-Up of AEs and SAEs
•
The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations, as medically indicated or as 
requested by the sponsor, to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
healthcare providers.
•
If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.
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•
New or updated information will be recorded in the originally submitted 
documents.
•
The investigator will submit any updated SAE data to the sponsor within 
24 hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool
•
The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT.
•
If the electronic system is unavailable, then the site will use the paper SAE DCT
(see next section) to report the event within 24 hours.
•
The site will enter the SAE data into the electronic system as soon as the data
become available.
•
After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic DCT has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via CT SAE Report Form
•
Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.
•
In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated 
reporting time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance
10.4.1. Male Participant Reproductive Inclusion Criteria
No contraception methods are required for male participants in this study, as the calculated 
safety margin is ≥100-fold between the estimated maternal exposure due to seminal transfer 
and the NOAEL for serious manifestations of developmental toxicity in nonclinical studies.
According to the efavirenz or omeprazole USPIs, there is no requirement for male 
contraceptive use during treatment
10.4.2. Female Participant Reproductive Inclusion Criteria
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 definitions below in Section 10.4.3);
or
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), as described below, 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 method that is user dependent is chosen, a second effective method of 
contraception, as described below, must also be used. 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;
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•
Documented bilateral salpingectomy;
•
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate 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. 
•
For Women using HRT, FSH should be measured after an appropriate 
washout of HRT (at least 14 days after the last dose of HRT). HRT must be 
discontinued at least 28 days before first dose of investigational product 
during the study.
•
Females whose menopausal status is in doubt will be required to use one of 
the allowed non-hormonal highly effective contraception methods.
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 CTs.
Highly Effective Methods That Are User Dependent 
1. Non-hormonal IUD.
2. Bilateral tubal occlusion (eg, bilateral tubal ligation).
3. Vasectomized partner.
•
A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and 
the absence of sperm has been confirmed. If not, an additional highly effective 
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method of contraception should be used. The spermatogenesis cycle is 
approximately 90 days.
4. Sexual abstinence.
•
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.
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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 TBili elevations 
(>2× ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3× ULN (ie, AST/ALT and TBili values will be elevated within the 
same laboratory sample). In rare instances, by the time TBili 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 TBili 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 TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3× ULN and a TBili 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 TBili 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 TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1× ULN or if the value reaches >3× ULN 
(whichever is smaller).
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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili 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 
TBili 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: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs
•
Marked sinus bradycardia (rate <40 bpm) lasting minutes.
•
New PR interval prolongation >280 msec.
•
New prolongation of QTcF to >480 msec (Abs) or by ≥60 msec from baseline.
•
New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.
•
New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration.
•
Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs
•
QTcF prolongation >500 msec.
•
New ST-T changes suggestive of myocardial ischemia.
•
New-onset LBBB (QRS >120 msec).
•
New-onset right bundle branch block (QRS >120 msec).
•
Symptomatic bradycardia. 
•
Asystole:
•
In awake, symptom-free participants in sinus rhythm, with documented 
periods of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an 
escape rhythm that is below the AV node. 
•
In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer. 
•
Atrial flutter or fibrillation, with rapid ventricular response rate:
rapid = rate >120 bpm.
•
Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).
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•
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR
<40 bpm), accelerated idioventricular rhythm (HR >40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm (such as 
torsades de pointes)).
•
Type II second-degree (Mobitz II) AV block.
•
Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs
•
Change in pattern suggestive of new myocardial infarction. 
•
Sustained ventricular tachyarrhythmias (>30 seconds’ duration).
•
Second- or third-degree AV block requiring pacemaker placement.
•
Asystolic pauses requiring pacemaker placement.
•
Atrial flutter or fibrillation with rapid ventricular response requiring 
cardioversion.
•
Ventricular fibrillation/flutter.
•
At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.
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10.8. Appendix 8: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
Abs
absolute
AD
atopic dermatitis
ADL
activities of daily living
AE
adverse event
AIA
adjuvant-induced arthritis
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-72
area under the concentration-time curve from time 0 to 72 hours.
AUC24
area under the concentration-time curve from time 0 to 24 hours 
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to time of the 
last measureable concentration
AUCtau
area under the concentration-time curve at steady state over the 
dosing interval τ
AV
atrioventricular
BA
bioavailability
BCRP
breast cancer resistance protein
BID
twice a day
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
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 Collaboration
CL/F
apparent clearance of drug from eg, plasma
Clast
last quantifiable concentration
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSR
Clinical Study Report
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Abbreviation
Term
C-SSRS
the Columbia Suicide Severity Rating Scale
CT
clinical trial
CYP
cytochrome P450 
DCT
data collection tool
DDI
drug-drug interaction 
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
eGFR 
estimated glomerular filtration rate 
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FOB
functional observational battery
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IC50
50% inhibitive concentration
ICD
informed consent document
ICH
International Council for Harmonisation
ID
identity
IFN-α
interferon-alpha
IFN-γ
interferon-gamma
IL
interleukin
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Abbreviation
Term
IND
Investigational New Drug 
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
Institutional Review Board
IUD
Intrauterine device
IV
intravenous
JAK
Janus Kinase
KDR
kinase insert domain receptor
kel
elimination rate constant
LBBB
left bundle branch block
LFT
liver function test
MAO-A
Monoamine oxidase A
MATE
multidrug and toxin extrusion protein
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
medical device regulation
MHP
mental health professional
mRNA
messenger ribonucleic acid
msec
millisecond
N/A
not applicable
NOAEL
no observed adverse effect level
OAT
organic anion transporter
OATP
organic anion transporting polypeptide
OCT
organic cation transporter
PBMC
Peripheral blood mononuclear cell
PCR
polymerase chain reaction
P-gp
p-glycoprotein
PGx 
pharmacogenomic(s)
pH
negative logarithm of hydrogen ion concentration
PI
primary investigator
PK
pharmacokinetic(s)
PT
prothrombin time
PVC
premature ventricular contraction/complex
QD
once daily
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
Rac
accumulation ratio based on AUC (observed)
RBC
red blood cell
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Abbreviation
Term
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS
severe acute respiratory syndrome
SCr
serum creatinine
SoA
schedule of activities
SOC
System Organ Class
SOP
standard operating procedure
SRSD
single reference safety document
STAT
signal transducer and activator of transcription
STOD
Study Team on Demand
SULT
sulfotransferase
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal phase half-life
TB
tuberculosis
TBili
total bilirubin
TDI
time-dependent inhibition
TEAE
treatment-emergent adverse event
THC
tetrahydrocannabinol
Tmax
time to reach Cmax
UGT
uridine 5’-diphospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
VEGFR2
vascular endothelial growth factor receptor 2
Vz/F
apparent volume of distribution for extravascular dosing
WBC
white blood cell
WOCBP
woman/women of childbearing potential
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11. REFERENCES
1.
Investigator’s Brochure, Abrocitinib (PF-04965842). May 2021
2.
Donzelli M, Derungs A, Serratore MG, et al. The basel cocktail for simultaneous 
phenotyping of human cytochrome P450 isoforms in plasma, saliva and dried blood 
spots. Clin Pharmacokinet 2014;53(3):271-82.
3.
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Scientific Opinion on 
the safety of caffeine. EFSA Journal 2015;13(5):4102.
4.
United Surgical Partners International. USPI website. Available from:
https://www.uspi.com. Accessed: 24 June 2021.
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Protocol B7451092 (PF-04965842) Statistical Analysis Plan
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PFIZER CONFIDENTIAL
Protocol B7451092
A PHASE 1, OPEN-LABEL, FIXED-SEQUENCE, 2-PERIOD STUDY TO ESTIMATE 
THE EFFECT OF MULTIPLE DOSE ABROCITINIB ON THE
PHARMACOKINETICS OF SINGLE DOSES OF CAFFEINE, EFAVIRENZ, AND
OMEPRAZOLE IN HEALTHY PARTICIPANTS
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
(FSP Statistician –
 
)
Date:
27-Sep-2021
PPD
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Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1.0
September 27, 2021
Not Applicable
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD
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TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................6
2. INTRODUCTION .................................................................................................................6
2.1. Study Design .............................................................................................................6
2.2. Study Objectives .......................................................................................................7
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................7
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................7
5.1.1. Concentration Analysis Set...........................................................................7
5.1.2. Parameter Analysis Set.................................................................................7
5.2. Pharmacodynamic Analysis Set................................................................................8
5.3. Safety Analysis Set....................................................................................................8
5.4. Other Analysis Sets ...................................................................................................8
5.5. Treatment Misallocations..........................................................................................8
5.6. Protocol Deviations...................................................................................................8
5.6.1. Deviations Assessed Prior to Randomization...............................................8
5.6.2. Deviations Assessed Post-Randomization....................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................9
6.1. Efficacy Endpoint(s) .................................................................................................9
6.2. Safety Endpoints .......................................................................................................9
6.2.1. Adverse Events.............................................................................................9
6.2.2. Laboratory Safety Tests................................................................................9
6.2.3. Vital Signs Data............................................................................................9
6.2.4. ECG Results................................................................................................10
6.2.5. Other Safety Data .......................................................................................10
6.3. Other Endpoints.......................................................................................................10
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6.3.1. PK Endpoints..............................................................................................10
6.3.2. PD Endpoints..............................................................................................10
6.4. Covariates................................................................................................................10
7. HANDLING OF MISSING VALUES ................................................................................11
7.1. Concentrations Below the Limit of Quantification.................................................11
7.2. Deviations, Missing Concentrations and Anomalous Values .................................11
7.3. Pharmacokinetic Parameters ...................................................................................11
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................11
8.1. Statistical Methods ..................................................................................................11
8.2. Statistical Analyses .................................................................................................12
8.3. Safety Analysis........................................................................................................13
8.3.1. Treatment and Disposition of Participants .................................................13
8.3.2. Demographic and Clinical Examination Data............................................14
8.3.3. Discontinuation(s).......................................................................................14
8.3.4. Adverse Events...........................................................................................14
8.3.5. Laboratory Data..........................................................................................14
8.3.6. Vital Signs Data..........................................................................................14
8.3.7. ECG Data....................................................................................................14
8.3.8. Other Safety Data .......................................................................................14
8.3.9. Concomitant Treatments.............................................................................14
8.3.10. Screening and Other Special Purpose Data ..............................................14
9. REFERENCES ....................................................................................................................15
10. APPENDICES ...................................................................................................................16
LIST OF TABLES
Table 1.
Treatment Flow Diagram............................................................................6
Table 2.
Noncompartmental PK Parameters...........................................................10
Table 3.
PK Parameters to be Summarized Descriptively by Treatment ...............12
LIST OF FIGURES
None
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APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................16
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
Abrocitinib (also referred to as PF-04965842) is an orally bioavailable potent JAK1 
inhibitor with good selectivity over the broader kinome being developed for the treatment of 
AD.
The purpose of the study is to evaluate the effect of abrocitinib on the in vivo PK of sensitive
CYP1A2, 2B6 and 2C19 substrates, caffeine, efavirenz, and omeprazole, respectively.
2.1. Study Design
This is a Phase 1, open-label, multiple dose, single fixed-sequence, 2-period study to 
evaluate the effect of abrocitinib on the PK of caffeine, efavirenz and omeprazole in healthy 
adult participants. A total of approximately 13 healthy male and/or female participants will 
be enrolled in the study to obtain at least 12 evaluable participants who complete the study.
Participants who withdraw from the study or are considered non-evaluable may be replaced
at the discretion of the sponsor.
In Period 1, all the participants will receive single doses of probe drugs, including caffeine 
100 mg, efavirenz 50 mg and omeprazole 10 mg, together on Day 1. The Day 1 of Period 2 
begins on the fourth day following the start of Period 1. After 3 days of PK sampling in 
Period 1, Period 2 will immediately follow with no washout.
In Period 2, participants will receive abrocitinib 200 mg QD on Days 1-10. On Period 2
Day 2, participants will receive single dose of omeprazole 10 mg alone within approximately
5 minutes after administration of a 200 mg dose of abrocitinib in the morning. Participants 
will receive single doses of the probe drugs (caffeine 100 mg, efavirenz 50 mg and 
omeprazole 10 mg together) again on Day 8.
Table 1.
Treatment Flow Diagram
Treatment
Period 1
Period 2
Day 1
Days 2-3
Day 1
Day 2
Days 3-7
Day 8
Days 9-11
Abrocitinib 200 mg QD
X
X
X
X
X
Caffeine 100 mg SD
X
X
Efavirenz 50 mg SD
X
X
Omeprazole 10 mg SD
X
X
X
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2.2. Study Objectives
•
Primary Objective:
•
To estimate effect of multiple dose abrocitinib on the PK of single, oral doses of 
caffeine, efavirenz and omeprazole in healthy participants.
•
Secondary Objective:
•
To evaluate the safety and tolerability of abrocitinib when co administered with 
single doses of caffeine, efavirenz and omeprazole.
 
 
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis is planned.  Final analysis will follow the official database release.  As 
this will be an open-label study, there is no formal unblinding of the randomization code.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
There are no statistical hypotheses.
4.2. Statistical Decision Rules
There are no statistical decision rules.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The PK concentration population is defined as all enrolled participants who received at least 
1 dose of investigational product and in whom at least 1 plasma concentration value is 
reported.
5.1.2. Parameter Analysis Set
The PK parameter analysis population is defined as all participants who received at least 
1 dose of investigational product and have at least 1 of the PK parameters of interest in at 
least 1 treatment period.
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5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All participants who take at least 1 dose of investigational product. Participants will be 
analyzed according to the product they actually received.
5.4. Other Analysis Sets
None.
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
participants who are enrolled but not treated.
If a participant takes a treatment that is not consistent with the treatment they are randomized 
to, for example takes a treatment out of sequence or takes the same treatment twice, then they 
will be reported under the treatment that they actually receive for all safety and PK analyses, 
where applicable.
5.6. Protocol Deviations
Participants who experience events that may affect their PK profile (eg lack of compliance 
with dosing) may be excluded from the PK analysis.  At the discretion of the 
pharmacokineticist a concentration value may also be excluded if the deviation in sampling 
time is of sufficient concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess participants against the inclusion and exclusion 
criteria as set out in Sections 5.1 and 5.2 of the protocol.
5.6.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
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6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Follow-up) will be counted as 
treatment emergent and attributed to the previous treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):
•
adverse events,
•
laboratory data.
6.2.1. Adverse Events
Any events occurring following start of treatment or increasing in severity will be counted as 
treatment emergent.
Events that occur in a non-treatment period (for example, Follow-up) will be counted as 
treatment emergent and attributed to the previous treatment taken.
6.2.2. Laboratory Safety Tests
Safety laboratory tests will be performed as described in the protocol.
To determine if there are any clinically significant laboratory abnormalities, the 
haematological, clinical chemistry (serum) and urinalysis safety tests will be assessed against 
the criteria specified in the sponsor reporting standards.  The assessment will take into 
account whether each participant’s baseline test result is within or outside the laboratory 
reference range for the particular laboratory parameter.
Baseline is defined as the last predose measurement taken.
6.2.3. Vital Signs Data
BP, pulse rate and temperature measurements will be taken at times detailed in the Schedule 
of Activities given in the protocol.
Baseline is the last planned predose recording in each study period.
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6.2.4. ECG Results
QT interval, QTcF, PR, RR, QRS and heart rate will be recorded at each assessment time 
indicated in the Schedule of Activities given in the protocol.
If not supplied, QTcF will be derived using Fridericia’s heart rate correction formula:
QTcF = QT / (RR)1/3
where RR = 60/HR (if not provided)
Baseline is the last planned predose recording in each study period.
6.2.5. Other Safety Data
Additional safety data will be collected as described in the protocol and will be listed if 
collected in the sponsor’s database.
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood samples for PK analysis of caffeine, efavirenz and omeprazole will be taken according 
to the Schedule of Activities given in the protocol.
The following PK parameters will be calculated for caffeine, efavirenz and omeprazole (if 
possible) from the concentration-time data using standard noncompartmental methods:
Table 2.
Noncompartmental PK Parameters
PK Parameter
Analysis Scale
Caffeine, Efavirenz and Omeprazole
AUCinf*
ln
A, D
AUClast
ln
A, D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, 
 *=if data permits.
6.3.2. PD Endpoints
None.
6.4. Covariates
None.
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7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. Concentrations Below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification.)
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample).
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter 
will be coded as NC (ie not calculated). (Note that NC values will not be generated beyond 
the day that a participant discontinues.)
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular treatment with ≥3 evaluable measurements.  For statistical 
analyses (ie analysis of variance), PK parameters coded as NC will also be set to missing; 
and analyses will not be performed for a particular parameter if more than 50% of the data 
are NC.
If an individual participant has a known biased estimate of a PK parameter (due for example 
to an unexpected event such as vomiting before all the compound is adequately absorbed in 
the body), this will be footnoted in summary tables and will not be included in the calculation 
of summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
The interactive effect on PK parameters will be determined by constructing 90% confidence 
intervals around the estimated difference between the treatments using a mixed effects model 
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based on natural log transformed data.  The mixed effects model will be implemented using 
SAS Proc Mixed, with REML estimation method and Kenward-Roger degrees of freedom 
algorithm.
8.2. Statistical Analyses
Natural log‑transformed parameters (AUCinf, AUClast
) will be analyzed using a
mixed effect model with treatment as a fixed effect and subject 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% CI for the ratios. The Test and Reference treatments to estimate
the treatment difference for each of the study objectives are as follows:
•
Objective 1: caffeine 100 mg (Period 1, Day 1) will be the Reference treatment;
abrocitinib 200 mg + caffeine 100 mg (Period 2, Day 8) will be the Test treatment.
•
Objective 2: efavirenz 50 mg (Period 1, Day 1) will be the Reference treatment;
abrocitinib 200 mg + efavirenz 50 mg (Period 2, Day 8) will be the Test treatment.
•
Objective 3: omeprazole 10 mg (Period 1, Day 1) will be the Reference treatment;
abrocitinib 200 mg + omeprazole 10 mg (Period 2, Day 8) will be the Test treatment.
Residuals from the model will be examined for normality and the presence of outliers via
visual inspection of plots of residuals vs predicted values and normal probability plots of
residuals but these will not be included in the CSR. If there are major deviations from
normality or outliers, then the effect of these on the conclusions will be investigated through
alternative transformations and/or analyses excluding outliers. Justification for any
alternative to the planned analysis will be given in the report of the study.
Table 3.
PK Parameters to be Summarized Descriptively by Treatment
Parameter
Summary Statistics
AUCinf, 
AUClast, 
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
 
 
 
Box and whisker plots for individual participant parameters (AUCinf, AUClast
) will 
be presented by treatment and overlaid with geometric means.
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Supporting data from the estimation of 
 AUCinf will be listed by analyte and treatment: 
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.  This data may be included in the clinical study 
report.
Presentations for caffeine, efavirenz and omeprazole concentrations will include:
•
A listing of all concentrations sorted by participant ID, period and nominal time 
postdose.  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 treatment and nominal time postdose, 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.
•
Median concentrations time plots (on both linear and semi-log scales) against 
nominal time postdose by treatment (all treatments on the same plot per scale, based 
on the summary of concentrations by treatment and time postdose).
•
Mean concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by treatment (all treatments on the same plot per scale, based on the 
summary of concentrations by treatment and time postdose).
•
Individual concentration time plots by treatment (on both linear and semi-log scales) 
against actual time postdose (there will be separate spaghetti plots for each treatment 
per scale).
•
Individual concentration time plots by participant (on both linear and semi-log scales) 
against actual time postdose [there will be separate plots for each participant
(containing all treatments) per scale].
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.
8.3. Safety Analysis
A set of summary tables will be produced to evaluate any potential risk associated with the 
safety and toleration of administering abrocitinib when co administered with single doses of 
caffeine, efavirenz and omeprazole.
8.3.1. Treatment and Disposition of Participants
Participant evaluation groups will show end of study participant disposition and will show 
which participants were analyzed for pharmacokinetics, as well as for safety (adverse events 
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and laboratory data).  Frequency counts will be supplied for participant discontinuation(s) by 
treatment.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A breakdown of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Participants’ in accordance 
with the sponsor reporting standards.
8.3.3. Discontinuation(s)
Participant discontinuations, temporary discontinuations or dose reductions due to adverse 
events will be detailed and summarized by treatment.
Data will be reported in accordance with the sponsor reporting standards.
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
treatment.
8.3.5. Laboratory Data
Laboratory data will be listed in accordance with the sponsor reporting standards.
8.3.6. Vital Signs Data
Vital Signs data will be databased and available upon request.
8.3.7. ECG Data
ECG data will be databased and available upon request.
8.3.8. Other Safety Data
None.
8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.10. Screening and Other Special Purpose Data
If these data is brought in-house, then it will be listed.
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9. REFERENCES
None.
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10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
An example of the PROC MIXED code is provided below:
proc mixed data=tab.pk;
by analyte;
class trt participant;
model l&var= trt/ ddfm=KR;
random participant /participant=participant;
lsmeans trt;
estimate 'Combined single agents alone vs Coadministration with abrocitinib ' trt -1 1
/cl alpha=0.1;
ods 'Estimates' out=est&var;
ods 'lsmeans' out=ls&var;
ods 'covparms' out=cov&var;
ods 'tests3' out=tst&var;
run;
/* Letter assignments for treatments (trt) within the estimate statement above are as follows;
A = Combined single agents alone (caffeine, efavirenz, omeprazole (Reference));
B = Coadministration (caffeine, efavirenz, omeprazole with abrocitinib (Test));
*/;
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