Clinical trial NCT03732807
Conditions: Alopecia Areata
Keywords: Alopecia Alopecia totalis Alopecia universalis Patchy hair loss Diffuse hair loss Hair loss Hair disease PF-06651600 Ritlecitinib
Sponsor: Pfizer
Start date: 2018-12-03; Completion date: 2021-06-24
Enrollment: 718 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a global Phase 2b/3 study to evaluate the safety and effectiveness of an investigational study drug (called PF-06651600) in adults and adolescents (12 years and older) who have 50% or greater scalp hair loss. The study is placebo-controlled, meaning that some patients entering the study will not receive active study drug but will receive tablets with no active ingredients (a placebo). This is a dose-ranging study, investigating 5 different dosing regimens. It will be double-blinded, meaning that the sponsor, the study doctors, the staff, and the patients will not know whether a patient is on active study drug (or the dose) or placebo.

Detailed description:

Arms: arm 1: Induction dose given once daily (QD) for 4 weeks followed by maintenance dose #1 given QD for 44 weeks arm 2: Induction dose given QD for 4 weeks followed by maintenance dose #2 given QD for 44 weeks arm 3: Maintenance dose #1 given QD for 48 weeks arm 4: Maintenance dose #2 given QD for 48 weeks arm 5: Maintenance dose #3 given QD for 48 weeks arm 6: Placebo given QD for 24 weeks followed by induction dose given QD for 4 weeks then maintenance dose #1 given QD for 20 weeks arm 7: Placebo given QD for 24 weeks followed by maintenance dose #1 given QD for 24 weeks
Interventions: intervention 1: PF-06651600 Induction Dose intervention 2: PF-06651600 Maintenance Dose #1 intervention 3: PF-06651600 Maintenance Dose #2 intervention 4: PF-06651600 Maintenance Dose #3 intervention 5: Placebo
Intervention descriptions: intervention 1: Oral tablets taken once daily (QD) intervention 2: Oral tablets taken QD intervention 3: Oral tablets taken QD intervention 4: Oral tablets taken QD intervention 5: Oral tablets taken QD

Protocol documents:
Prot_000.pdf: 
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A PHASE 2B/3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
DOSE-RANGING STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF
PF-06651600 IN ADULT AND ADOLESCENT ALOPECIA AREATA 
(AA) SUBJECTS WITH 50% OR GREATER SCALP HAIR LOSS
Investigational Product Number:
PF-06651600 
Investigational Product Name:
Janus Kinase 3 inhibitor
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2018-001714-14
Protocol Number:
B7981015
Phase:
2b/3
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.
CCI


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Document History
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Amendment 
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13 April 
2021

In the Protocol Summary – Objectives and Endpoints, in Section 2, 
Objectives and Endpoints, and in Section 9, Data Analysis/Statistical 
Methods, language was added to clarify the known regional requirements 
for the analysis of primary and secondary endpoints.
         Rationale: Differences in regulatory feedback from various regions have 
necessitated distinctive reporting requirements for the primary and 
secondary endpoints.  These differences were already described in the 
protocol; this language provides more clarity.  

Throughout the protocol, a key secondary objective for the study was 
added with the key secondary endpoint of “Response based on an absolute 
SALT Score ≤10 at Week 24”. This key secondary endpoint will be 
analyzed utilizing an appropriate testing procedure to control overall Type I 
error. This change applies to the overall study; therefore, it does not 
change the primary and key secondary objectives and endpoints for the 
European Medicines Agency (EMA), which are different than those for the 
overall study and remain the same as the one from previous version of the 
protocol. a key secondary objective for the study was added with the key 
secondary endpoint of “To evaluate the efficacy of PF-06651600 compared 
to placebo in adult and adolescent alopecia areata (AA) subjects with 50% 
or greater scalp hair loss on regrowth of lost hair (as measured by an 
absolute Severity of Alopecia Tool (SALT) Score ≤10) at Week 24”.  A 
secondary endpoint of “Response based on an absolute SALT Score ≤10 at 
Week 24” was also added and will be analyzed as a key secondary endpoint 
utilizing an appropriate testing procedure to control overall Type I error.  
This does not change the primary and key secondary objectives and 
endpoints for the European Medicines Agency (EMA), which remain the 
same. 
         Rationale: Previous versions of the protocol indicated that when SALT 
≤20 response at Week 24 is utilized as the primary endpoint, SALT ≤10 
will be analyzed controlling for Type I error. This change formalizes that 
analysis in the form of a key secondary endpoint.

Throughout the protocol, the secondary endpoint of “Response based on a 
SALT score of ≤10 at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48” was 
updated to clarify that this refers to “an absolute SALT score” for 
consistency with other SALT endpoints.
         Rationale: This change has been made to correct a typographic error.  

In the Protocol Summary – Objectives and Endpoints and in Section 2, 
Objectives and Endpoints, clarification was added regarding the key 
secondary endpoint of “PGI-C response defined as a score of “moderately 
improved” or “greatly improved” at Week 24” for the EMA and competent 
authorities in the Voluntary Harmonisation Procedure (VHP) countries. 
         Rationale: This key secondary objective for the EMA and competent 
authorities in the VHP countries was already described in the protocol; 
addition of this language in the tables describing the study objectives and 
endpoints in the Protocol Summary – Objectives and Endpoints and in 
Section 2, Objectives and Endpoints (rather than just in the footnotes) 
provides more clarity.


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
In the protocol summary, the secondary endpoint for the Patient’s Global 
Impression of change (PGI-C) response was updated from “PGI-C response 
defined as a score of “moderately improved” or “greatly improved” at 
Weeks 4, 8, 12, 18, 24, 34, 40, and 48” to “PGI-C response defined as a 
PGI-C score of “moderately improved” or “greatly improved” at Weeks 4, 
8, 12, 18, 24, 34, 40, and 48”.
         Rationale: This change has been made to ensure consistency with the 
wording of this endpoint in Section 2.  

In the Protocol Summary – Statistical Methods and in Section 9.7, Interim 
Analysis, language was added to provide clarification on the objective of 
the interim analysis and that the results will have no impact on the study 
conduct, analysis, or reporting.
         Rationale: This change has been made at the request of the United States 
Food and Drug Administration (FDA) to clarify the objectives of the 
interim analysis.

In the Protocol Summary – Statistical Methods and in Section 9.1, Sample 
Size Determination,  the sample size section was updated to incorporate the 
power of the study based on the key secondary endpoint of SALT ≤ 10 at 
Week 24, and using the α levels of 0.01 (for EMA) and 0.00125 (for 
FDA/Japan Pharmaceuticals and Medical Devices Agency [PMDA]).
         Rationale: This change has been made to align with the reorganization of 
the endpoints for the study.

In the Protocol Summary – Statistical Methods and in Section 9.1, Sample 
Size Determination, a reference was added for the abstract presenting the 
Concert CTP-543 Phase 2b Study Week 24 data which was used to 
estimate the treatment difference and placebo response rate for the Patient’s 
Global Impression of Change (PGI-C).  
        Rationale: This change has been made to correct an error of omission.

In the Protocol Summary – Statistical Methods and in Section 9.2, Efficacy 
Analysis, the definition of the Full Analysis Set (FAS) was updated.
         Rationale: This change has been made at the request of the FDA to 
include all subjects, regardless of whether they received study 
medication, in the FAS.

In the Protocol Summary – Statistical Methods and in Section 9.2.1, 
Testing Procedure for Multiple Comparisons, this language was revised.  
The Protocol Summary reflects the testing procedure overall for the study 
and Section 9.2.1 and new Sections 9.2.1.1, 9.2.1.2, and 9.2.1.3 detail the 
testing procedures used for the overall study, for the FDA/PMDA, and for 
the EMA.  
         Rationale: This change has been made to align with the reorganization of 
the endpoints for the study.  

In the Protocol Summary – Statistical Methods and in Section 9.2.2, 
Analysis of the Primary and Key Secondary Endpoints, this language was 
revised.  The statistical methods for the analysis of the primary endpoint for 
the EMA were revised. Section 9.2.2, Analysis of the Primary and Key 
Secondary Endpoints was re-organized by adding new Sections 9.2.2.1 and 
9.2.2.2 to detail the analyses used for the overall study, for the 
FDA/PMDA, and for the EMA. In addition, description of the per-protocol 
analysis was moved to a separate section (Section 9.2.2.3).  


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         Rationale: This change has been made to incorporate advice received 
from a European national agency regarding the approach for how 
missing data due to COVID-19 should be handled in the analysis of the 
primary endpoint.

In the Protocol Summary – Statistical Methods and in Section 9.2.2.1, For 
the Overall Study, the FDA/PMDA (Analysis of the Primary Endpoint), the 
procedure for handling of missing data was updated to exclude subjects 
from the primary analysis who are missing the SALT assessment at Week 
24 due to coronavirus disease 19 (COVID-19) related reasons.  Subjects 
with SALT assessments missing at Week 24 for other reasons will be 
counted as non-responders.  In addition, a supportive analysis has been 
added which will count all subjects with missing Week 24 SALT 
assessments, regardless of the reason, as non-responders. 
         Rationale: This change has been made to mitigate the impact of missed 
SALT assessments at Week 24 due to COVID-19.  

In the Protocol Summary – Statistical Methods and in Section 9.2.3, 
Analysis of Secondary Endpoints, the procedure for handling of missing 
data for binary endpoints was updated to exclude subjects from the analysis 
of secondary endpoints for any visit for which the assessment is missing 
due to COVID-19 related reasons.  Subjects with assessments missing for 
other reasons will be counted as non-responders. 
         Rationale: This change has been made to mitigate the impact of missed 
assessments due to COVID-19 and is consistent with the handling of 
missing data for the primary endpoint.  

In Section 1.4, Clinical Experience, references were added to reference the 
clinical study reports or the clinical protocols for the following Pfizer 
studies: B7931005, B7981005, B7981006, B7981007, B7981019, and 
B7981032. 
         Rationale: This change has been made to correct an error of omission.

In Sections 4.2, Exclusion Criteria and 5.8.2, Prohibited Medications and 
Treatments, the prohibition of medications that prolong the time from the 
beginning of the QRS complex to the end of the T wave (QT interval) was 
removed.  
         Rationale: Pfizer has performed an analysis of nonclinical and clinical 
data, which indicate that there is no evidence of any clinically relevant 
QT interval prolongation due to PF-06651600 and therefore the risk for 
PF-06651600 to cause QT prolongation in humans is low. Prohibition of 
these medications is no longer required.

In Sections 5.8.3, Vaccinations, language was added to provide 
clarification on the use of COVID-19 vaccines.
         Rationale: This change was necessary due to the wide-spread use of 
COVID-19 vaccines globally in the setting of the COVID-19 pandemic.

In Section 9.2.2 Analysis of the Primary and Key Secondary Endpoints, the 
details of the “tipping point analysis” were removed.
         Rationale: The details of these analysis will be included in the Statistical 
Analysis Plan.   

In Section 9.2.2.3 Per-Protocol Analysis (Analysis of the Primary and Key 
Secondary Endpoints), language was added detailing the protocol 
deviations which will be evaluated for each subject prior to unblinding to 


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determine if a subject will be excluded from the Per Protocol Analysis Set 
(PPAS).
         Rationale: Feedback from the FDA requested that the criteria used to 
define the per protocol analysis population be included in the protocol.   

Section 9.2.3, Analysis of Secondary Endpoints, was revised to clarify how 
secondary endpoints that are not α-controlled will be analyzed. In addition, 
Information from former Section 9.2.2.1, Analysis of the Primary Endpoint 
to Assess the Secondary Objective, was moved to new Section 9.2.3.1 and 
retitled Analysis of Exposure-Response.
         Rationale: These changes were made to align with the reorganization of 
the endpoints for the study.

Section 9.2.5 Subgroup Analysis was added to check for consistency of key 
efficacy results from across subgroups which will also support the 
International Council for Harmonisation (ICH) E17 (General Principles for 
Planning and Design of Multi-Regional Clinical Trials) registration 
approach, as applicable.
         Rationale: The descriptive subgroup analyses will support the evaluation 
of consistency of treatment effect across subsets.   

Added Section 9.4, Pharmacokinetic/Pharmacodynamic Early Unblinding, 
to provide details regarding early unblinding of the PK/PD data that is 
planned when ≥90% of subjects have reached 24 weeks post-randomization 
(or discontinued prior to the Week 24 visit). Access to the unblinded data 
will be limited to the list of PK/PD analysts and programmers that will be 
appropriately documented on the early unblinding for PK/PD form.
Rationale: Early unblinding of the PK/PD data will enable PK and 
concentration/response model building for study readout.

In Appendix 1, Abbreviations, news abbreviations were added for “body 
mass index” or “BMI”; “Japan Pharmaceuticals and Medical Devices 
Agency” or “PMDA”; “United States Food and Drug Administration” or 
“FDA”; and “generalized linear mixed model” or “GLMM”.
         Rationale: This change was made for clarification.

Removed Appendices 5 through 17 (Severity of Alopecia Tool [SALT], 
Columbia Suicide Severity Rating Scale [C-SSRS], AAPPO [Alopecia 
Areata Patient Priority Outcomes], Patient’s Global Impression of Change 
[PGI-C], Patient Satisfaction with Hair Growth [P-Sat], Hospital Anxiety 
and Depression Scale [HADS], EuroQol 5 Dimensions [EQ-5D-5L], 
EuroQol 5 Dimensions – Youth [EQ-5D-Y], Patient Health Questionnaire 
– 8 Items [PHQ-8], 36-Item Short Form Health Survey Version 2 Acute 
[SF-36v2 Acute], Alopecia Areata Resource Utilization [AARU], Work 
Productivity and Activity Impairment: Alopecia Areata [WPAI:AA], and 
Clinician Global Impression – Alopecia Areata [CGI-AA]) as well as 
cross-references to the deleted appendices. Remaining appendices were 
renumbered as needed due to the deletions. 
         Rationale: Updated per current practice not to include copyrighted 
instruments in protocol appendices. 

In Appendix 6.3, Alternative Facilities for Safety Assessments, Table 8 was 
updated from “Windows for Remote Visits and Laboratory Sample 
Collections if Required Due to COVID-19 Disruptions” to “Windows for 


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Remote Visits and Laboratory Sample Collections if Required Due to 
Disruptions from Public Emergencies”.
         Rationale: This change was made for clarification.

Throughout the document, references to the European Union (EU) 
(including VHP countries) were updated to European Medicines Agency 
(EMA) and competent authorities in the VHP countries, as applicable.
         Rationale: This change was made for clarification.

Throughout the document, references to table numbers were updated to 
reflect the addition of Tables 4, 5, 6, and 7 and figure numbers were 
updated to reflect the reorganization of the figures in Section 9.2.1.
         Rationale: This change was made for correctness of numbering of in-text 
tables and figures.

Global corrections to typographical errors, abbreviations, and definitions 
were made.
Amendment 
4
20 October 
2020

Throughout the protocol, it has been specifically clarified that for the 
European Union (EU) (including the Voluntary Harmonisation Procedure 
[VHP] countries), the primary objective and primary endpoint will utilize 
an absolute Severity of Alopecia Tool (SALT) Score of ≤10 and not ≤20 at 
Week 24.
         Rationale: While this was previously included in the protocol (to use 
either SALT ≤10 or ≤20 for the primary objective and endpoint based on 
regulatory feedback), these changes have been made to align with a 
regulatory agency request to specify that SALT ≤10 will be used in the 
EU.

Throughout the protocol, it has been specifically clarified that for the EU 
(including VHP countries), the evaluation of the effect of PF-06651600 on 
patient centered outcomes (as measured by Patient’s Global Impression of 
Change [PGI-C] response at Week 24) is a key secondary objective.  The 
PGI-C response at Week 24 will be analyzed as a key secondary endpoint 
utilizing an appropriate testing procedure to control overall Type I error. 
         Rationale: While it was previously included in the protocol that the 
PGI-C response will be analyzed as a key secondary endpoint utilizing 
an appropriate testing procedure to control overall Type I error in a 
separate analysis where required, these changes have been made to 
specify that in the EU PGI-C response will be analyzed as a key 
secondary endpoint.

Throughout the protocol, footnotes d and e in the Objectives and Endpoints 
tables were updated to clarify which secondary endpoints will be controlled 
for Type I error based on which SALT parameter at Week 24 (ie, ≤20 or 
≤10) is utilized as the primary endpoint.
         Rationale: While this was previously included in the protocol, the 
footnotes have been revised for clarity. 

Throughout the protocol, footnote g in the Objectives and Endpoints tables 
was updated to clarify that for the EU (including VHP countries), the 
endpoints utilizing the HADS will be analyzed as secondary endpoints.
         Rationale: While this was previously included in the protocol, the 
footnotes have been revised to specify that in the EU the HADS will be 
analyzed as secondary endpoints.


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Amendment 
3
14 July 
2020
Throughout the protocol, the primary objective and the primary endpoint 
were changed from absolute severity of alopecia tool (SALT) score of 
“≤10” to “≤20”.  It has also been noted that “Response based on an 
absolute SALT Score ≤10 at Week 24” will be analyzed as the primary 
endpoint in a separate analysis where required.
         Rationale: These changes have been made to align with newly published 
literature (Wyrwich et al, 2020) and new feedback from clinical experts 
in alopecia areata that SALT ≤20 best distinguishes treatment success 
from lack of success, from the perspective of both clinicians and 
patients. These changes have been made after consultation with a 
regulatory agency.
Throughout the protocol, the secondary endpoint to characterize the 
exposure response was changed from absolute SALT score of “≤10” to 
“≤20”.  It has also been noted that where regulatory agencies require SALT 
≤10 to be utilized for the primary endpoint, exposure response will also be 
analyzed utilizing SALT ≤10 in a separate analysis.
         Rationale: These changes have been made to align with changes to the 
primary endpoint.

Throughout the protocol, secondary endpoints were updated to include: 

SALT score ≤10 at all timepoints (except at Week 24 if SALT ≤10 is 
the primary endpoint);

SALT score ≤20 at all timepoints (except at Week 24 if SALT ≤20 is 
the primary endpoint);

Change from baseline in SALT scores at all timepoints.
Language was also added to indicate that if requested by specific 
regulatory agencies, SALT score ≤20 at Weeks 4, 8, 12, and 18 and SALT 
score ≤10 at Week 24 will be analyzed as secondary endpoints with Type 
I error control.  
         Rationale: These changes have been made to align with changes to the 
primary endpoint. 

Throughout the protocol, the secondary endpoint for 90% improvement in 
SALT score from baseline was removed. 
         Rationale: This change has been made to reduce redundancy between 
90% improvement in SALT and SALT ≤10.

Throughout the protocol, a secondary endpoint was added to evaluate the 
Patient’s Global Impression of Change (PGI-C) response defined as PGI-C 
score of “moderately improved” or “greatly improved” at Weeks 4, 8, 12, 
18, 24, 34, 40 and 48.  In addition, an exploratory endpoint was added to 
evaluate the improvement on the PGI-C at Weeks 4, 8, 12, 18, 24, 34, 40, 
and 48.  It was also noted that at the request of regulatory agencies, the 
PGI-C response at Week 24 will be analyzed as a key secondary endpoint 
utilizing an appropriate testing procedure to control overall Type I error in 
a separate analysis where required.
         Rationale: These changes have been made to align with regulatory 
agency feedback to include a patient-reported outcome measurement as a 
key secondary endpoint and to report on multiple aspects of this patient 
reported outcome.


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
Throughout the protocol, language was added to indicate that the study 
may be unblinded once ≥90% of subjects have reached 24 weeks post-
randomization (or discontinued prior to the Week 24 visit).  This includes 
the addition of Section 9.6, Interim Analysis.
         Rationale: These changes are consistent with the study design (placebo-
controlled through Week 24 after which all subjects will receive active 
investigational product); this data will be used for internal decision-
making by the sponsor.

Throughout the protocol, “dose response” was updated to “exposure 
response”.
         Rationale: These changes are made to ensure consistency throughout the 
document.

In the Protocol Summary – Objectives and Endpoints and in Section 2, 
Study Objectives and Endpoints, the following secondary endpoints were 
changed to exploratory endpoints:

50% improvement from baseline in SALT score at all timepoints.

Absolute SALT score at all timepoints.

Change from baseline in Hospital Anxiety and Depression Scale 
(HADS) at Weeks 4, 8, 12, 24, and 48.

Change from baseline in 36-Item Short Form Health Survey version 2 
Acute (SF36v2 Acute) at Weeks 4, 8, 12, 24, and 48.
Language was also added to indicate that if required by specific regulatory 
agencies, HADS endpoints will be analyzed as secondary endpoints.
         Rationale: These changes were made to align with regulatory feedback 
to reduce the number of secondary endpoints.

In the Protocol Summary – Objectives and Endpoints and in Section 2, 
Study Objectives and Endpoints, reference to the specific domain scores 
were removed from secondary endpoint evaluating a change from baseline 
in the Alopecia Areata Patient Priority Outcomes (AAPPO).  The scales are 
now described in section 7.8.1.
         Rationale: These changes have been made because the validation and 
scoring for this patient reported outcome has now been completed and 
this reflects the correct domain scales.
In the Protocol Summary – Objectives and Endpoints and in Section 2, 
Study Objectives and Endpoints, the exploratory endpoint (previously 
secondary endpoint) evaluating a change from baseline in the Hospital 
Anxiety and Depression Scale (HADS) was split into two separate 
endpoints to clarify that the depression and anxiety subscales will be 
analyzed separately.  In addition, two new exploratory endpoints were 
added to assess an improvement in HADS subscale scores for anxiety and 
depression, respectively in subjects with baseline scores indicative of 
anxiety or depression.
         Rationale: These changes have been made to align with feedback from 
the developer’s scoring manual and clinical experts in alopecia areata to 
analyze depression and anxiety separately and to measure a change in 
individual subscales.

In the Protocol Summary – Objectives and Endpoints and in Section 2, 
Study Objectives and Endpoints, the exploratory endpoint for Patient 


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Satisfaction with Hair Growth (P-Sat) was revised from a continuous score 
to a categorical assessment to accurately indicate a subject’s categorical 
improvement at the item level.
         Rationale: These changes have been made because the scaling and 
scoring for this patient reported outcome is still in the process of being 
established.   

In the Protocol Summary – Objectives and Endpoints and in Section 2, 
Study Objectives and Endpoints, footnotes d and e were revised to state 
that the Sponsor may also analyze SALT ≤10 and/or SALT ≤20 at other 
timepoints controlling for Type 1 error at the request of regulatory 
agencies.
         Rationale: The changes have been made to reflect that the decision on 
additional analysis of SALT ≤10 or SALT ≤20 will be made following 
consultation with regulatory agencies.

In the Protocol Summary – Study Design, and in Section 3, Study Design, 
language was added to describe the stratification of subjects during the 
randomization process. 
         Rationale: This change has been made to align with regulatory feedback.  
No changes to the randomization process itself have been implemented.  
This change was previously communicated to sites in the protocol 
administrative change letter dated 26 June 2019.

Throughout the Protocol Summary – Statistical Methods, and throughout 
subsections of Section 9, Data Analysis/Statistical Methods, the description 
of the primary endpoint, the assumptions for sample size calculations, and 
the testing procedures for multiple comparisons were all updated to reflect 
the changes in the primary endpoint as well as elevation of the PGI-C as a 
key secondary endpoint where required.  
         Rationale: These changes have been made to align with changes in the 
primary endpoint and key secondary endpoint. 

In the Schedule of Activities, reference to Appendix 19, Alternative 
Measures During Public Emergencies, was added.
         Rationale: This change has been made to clarify alternative measures to 
accommodate study procedures during public emergencies, including the 
coronavirus disease 2019 (COVID-19) pandemic.  This change was 
previously communicated to sites in the protocol administrative change 
letter dated 05 June 2020.

In Schedule of Activities (footnote #k) and in Section 7.5.5, Audiological 
Evaluation, language was added to indicate that all procedures for 
audiological evaluation must be performed according to the Audiometry 
Study Guide. 
         Rationale: These changes have been made for clarification.

In Section 1.3, Nonclinical and Phase 1 Efficacy and Safety Data and 
Section 1.6, Dose Rationale, updated information was provided on non-
clinical studies and the no observed adverse effect level (NOAEL).
         Rationale: These changes have been made to provide updated 
information to sites.

In Section 1.3, Nonclinical and Phase 1 Efficacy and Safety Data, a 
statement was added to indicate that if new information is available on 
drug-drug-interactions (DDI) demonstrating that prohibition of a 


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concomitant medication is no longer required, this information will be 
communicated to sites via an administrative letter.
         Rationale: This change has been made to clarify the process for updating 
prohibited medications based on emerging results from PF-06651600 
DDI studies.

In Section 1.4, Clinical Experience, and Section 1.4.1, Phase 2a Study in 
Alopecia, information was updated to include new ongoing studies with 
PF-06651600. In addition, a statement was added to indicate that the final 
results of the Phase 2a study in subjects with alopecia areata (B7931005) 
are now available in the Investigator’s Brochure.
         Rationale: This change has been made to provide updated information 
now available in the January 2020 Investigator’s Brochure.

In Section 1.4.2, Phase 2a Study in Rheumatoid Arthritis, information was 
updated to include the dose of PF-06651600 utilized in the protocol.
         Rationale: This change has been made to align with information 
available in the January 2020 Investigator’s Brochure.

In Section 4.2, Exclusion Criteria #6.c, language was updated to correct "a" 
to "the".
         Rationale: This change has been made to correct a typographic error.

Throughout the protocol, several updates were made to the list of 
prohibited medications:

Everolimus and ibrutinib were included in the list of examples of 
prohibited immunosuppressants.

All cytochrome P450 isoenzyme 3A (CYP3A) inhibitors and several 
sensitive and moderate CYP3A substrates were removed from the 
prohibited medications list.

A separate list was also added to clarify CYP3A inducers and substrates 
which are now permitted.

Guidance was provided on which medications that prolong QT interval 
are prohibited.
         Rationale: The changes to the list of prohibited CYP3A inhibitors and 
substrates were made to align with results from recent DDI studies.  
Other changes noted here have been made for clarification.

In Section 4.2, Exclusion Criteria #14 and Section 7.5.9, Varicella-Zoster 
Virus Immunoglobulin G Antibody (VZV IgG Ab) Testing, language was 
updated to reflect that subjects with documentation of vaccination (2 doses) 
can be enrolled even if VZV IgG Ab testing is negative.
         Rationale: This change has been made to ensure consistency with the
Centers for Disease Control varicella vaccine recommendations, which 
state that commercial assays are not sensitive enough to always detect 
antibodies after vaccination.  Documented receipt of 2 doses of varicella 
vaccine supersedes results of subsequent serologic testing.         
(https://www.cdc.gov/vaccines/vpd/varicella/hcp/recommendations.html, 
accessed 27Jan2020).

In Section 4.3.1, Contraception, bilateral tubal ligation was added to the list 
of highly effective contraceptive methods.
         Rationale: This change has been made for clarification; “bilateral tubal 
occlusion” already listed in this section was intended to encompass the 


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procedures for both bilateral tubal occlusion and bilateral tubal ligation 
since both prevent ova from moving through the fallopian tubes, thereby 
preventing contact with sperm.  This change was previously 
communicated to sites in the protocol administrative change letter dated 
06 November 2019.

In Section 6.1, Screening, Visit 1, clarifications were made to information 
collected on history of alcohol consumption and of previous drug 
treatments for alopecia areata (AA).
         Rationale: These changes have been made for clarification.  These 
changes were previously communicated to sites in the protocol 
administrative change letter dated 11 October 2019.  

In Section 7, Assessments, reference to Appendix 19, Alternative Measures 
During Public Emergencies, was added.
         Rationale: This change has been made to clarify alternative measures to 
accommodate study procedures during public emergencies, including the 
COVID-19 pandemic.  This change was previously communicated to 
sites in the protocol administrative change letter dated 05 June 2020.

In Section 7.5.1, Vital Signs, language was updated to allow the use of 
temporal artery temperature measurements.
         Rationale: This change has been made to reflect current clinical practice 
for temperature measurement.

In Section 7.5.6.2.2, Potential Drug-Related Rash and Unexplained Rash, 
the title was updated to include “Potential” drug-related rashes and 
“Unexplained Rash”.
         Rationale: This update was made for clarification. 

In Section 7.5.12, Events for Adjudication/Review Committee Submission, 
language was added to indicate that additional types of events, not already 
listed in the protocol, may be adjudicated.
         Rationale: This change was made to allow for addition types of events to 
be requested for review and adjudication. 

In Section 7.8.1, Alopecia Areata Patient Priority Outcomes (AAPPO), 
language was updated to correct “psychological” to “emotional” to more 
accurately reflect the concepts being measured by the AAPPO.  In addition,
language was relocated from Section 9.2.4, Analysis of Other Endpoints, to 
this section providing information on the anchor-based methodology to be 
used for interpretation of the AAPPO. 
         Rationale: This change has been made for clarification.

In Section 7.8.4, Hospital Anxiety and Depression Scale (HADS), language 
was updated to correct the description of the subscales for the HADS.  
         Rationale: This change has been to limit any observer bias at sites.

In Section 7.11.1, Samples for Interferon Gamma-Induced Protein – 10 (IP-
10) Analysis, a statement was added to indicate that IP-10 samples will not 
be collected if the exportation of these samples from the country of origin 
is prohibited by local regulations or institutional review board (IRB)/ethics 
committee (EC) decision. 
         Rationale: This change was made to align with a decision from one 
country’s local Good Clinical Practices (GCP) office to prohibit the 
exportation of IP-10 samples from within the country of origin to the 


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central laboratory for analysis.  This change was previously 
communicated to sites in the protocol administrative change letter dated 
18 July 2019.

Throughout the subsections of Section 9, Data Analysis/Statistical 
Methods, language was added to describe the testing method for controlling 
the Type I error for SALT ≤10 with a primary endpoint of SALT ≤20.  
         Rationale: These changes have been made to align with changes in the 
primary endpoint and key secondary endpoint. 

Section 9.1.1, Efficacy Analysis changed to Section 9.2 and subsequent 
sections within Section 9 were appropriately renumbered. 
         Rationale: Change made to align with protocol template section 
numbering requirements.

In Section 9.2.1, Testing Procedure for Multiple Comparisons, the 
following statement was removed “If the observed p-values after 
accounting for the test procedure is ≤0.00125, it will be concluded that PF-
06651600 demonstrates ‘clear and compelling’ evidence of effectiveness in 
treating moderate to severe AA patients as measured by the primary 
endpoint.”
         Rationale: There is no single p-value that will be accepted in all 
regions. While additional statistical thresholds may be considered 
during regulatory reviews, it is not appropriate to include in the protocol. 

In Section 9.2.2, Analysis of the Primary Endpoint, language was added to 
indicate the key criteria used to define a per-protocol analysis that will be 
performed for the primary endpoint. 
         Rationale: These changes have been made to align with regulatory 
feedback.

In Section 9.2.4, Analysis of Other Endpoints, language was revised to 
reflect that other endpoints will not be analyzed using the same procedure 
as the primary endpoint; instead they will be analyzed using descriptive 
statistics.  In addition, the language describing the anchor-based 
methodology to be used for interpretation of the AAPPO was revised and 
relocated to Section 7.8.1, Alopecia Areata Patient Priority Outcomes 
(AAPPO).
         Rationale: This change was made for clarification.

Section 9.7, Data Monitoring Committee, was renumbered (previously 
Section 9.6) to allow for inclusion of new section 9.6, Interim Analysis. 
         Rationale: These changes have been made for administrative purposes.

In Section 15.1, Communication of Results by Pfizer, language was revised 
to align with updated Pfizer template language on public disclosure of 
clinical trial results.  
         Rationale: This change has been made to align with updated Pfizer 
protocol template language.

In Section 16, References (#59), and in Appendix 2, Hepatitis B Testing 
Algorithm and Full Eligibility Criteria, a correction has been made to the 
reference for Hepatitis B virus global prevalence.
         Rationale: These changes have been made to correct typographic errors.

In Section 16, References, a new reference #87 was added to support the 
clarification that the analysis of the HADS depression and anxiety 


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subscales should be performed separately to align with feedback from the 
developer’s scoring manual.
         Rationale: This change has been made to support the updates in the 
analysis of the HADS scores.

In Section 16, References, a new reference #88 was added to support the 
addition of exploratory endpoints that evaluate proportion of subjects who 
achieve ‘normal’ anxiety and depression subscale among subjects with 
abnormal scores at baseline.
         Rationale: This change has been made to support the changes in the 
analysis of the HADS scores.

In Section 16, References, a new reference #89 was added to provide a 
reference for SALT ≤20 as a clinically meaningful treatment effect.
         Rationale: This change has been made to support the change to the 
primary endpoint.

In Appendix 1, Abbreviations, new abbreviations were added for:
“Brainstem auditory evoked potentials” or “BAEP”;
“Coronavirus disease 2019” or “COVID-19”;
“Contract research organization” or “CRO”;
“Clinical study report” or “CSR”;
“Cytochrome P450 isoenzyme 3A” or “CYP3A”;
“European Medicines Agency” or “EMA”;
“Per Protocol Analysis Set” or “PPAS”;
“50% improvement in SALT score from baseline” or “SALT50”;
“75% improvement in SALT score from baseline” or “SALT75”;
“Severe acute respiratory syndrome coronavirus 2” or “SARS-CoV2”;
“Torsades de pointes” or “TdP”.  
         Rationale: These changes have been made for clarification. 

Appendix 3.1, Monitoring, and Appendix 3.2, Discontinuation, all 
references to “creatinine kinase” were updated to “creatine kinase”.” to 
correct a typographic error.  
         Rationale: These changes have been made to correct a typographical 
error.

In Appendix 3.1, Monitoring, and Appendix 3.2, Discontinuation, language 
was added to provide clarification regarding the timelines for re-testing of 
laboratory values.
         Rationale: These changes have been made for clarification.

Appendix 3.2, Discontinuation, updated discontinuation criterion for ECG 
findings to clarify that an “increase” from baseline in QTcF of >60 
milliseconds requires discontinuation.  A decrease of this amount does not 
require discontinuation.  
         Rationale: These changes have been made for clarification.

Appendix 19, Alternative Measures During Public Emergencies, was 
added.
         Rationale: This change has been made to clarify alternative measures to 
accommodate study procedures during the public emergencies, including 


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the COVID-19 pandemic.  This change was previously communicated to 
sites in the protocol administrative change letter dated 05 June 2020.
Amendment 
2
30 May 
2019

Voluntary Harmonisation Procedure (VHP) was added to the list of 
abbreviations.  The VHP countries participating in this study are Czech 
Republic, Germany, Hungary, Poland, and Spain. 

In the Schedule of Activities, “Contraception check for WOCBP” was 
updated to “Contraception check, as applicable”.  
       Rationale: This change was made to align with a request from the VHP 
to require male subjects in VHP countries in the EU to use a barrier 
method of contraception during heterosexual intercourse.

In the Schedule of Activities, footnote p was updated to indicate that at 
sites in VHP countries in the European Union (EU) female subjects of 
childbearing potential will be instructed to perform a urine pregnancy test 
at home between the Week 40 and 48 visits (at approximately Week 44). 
        Rationale: This change was made to align with a request from the VHP 
to include more frequent pregnancy testing for females of childbearing 
potential in VHP countries in the EU.

In the Schedule of Activities, footnote dd was updated to indicate that 
pregnancy tests should be performed “according to the Schedule of 
Activities” instead of “at every visit”.
         Rationale: This change was made to ensure consistency with the 
Schedule of Activities. 

In Section 1.7, Summary of Benefit/Risk Assessment, the phrase “Men in 
the study are not required to use birth control because” was deleted.
         Rationale: This change was made to align with a request from the VHP 
to require male subjects in VHP countries in the EU to use a barrier 
method of contraception during heterosexual intercourse.

In Section 4, Subject Eligibility Criteria, a statement was added to explain 
that there are certain eligibility requirements specific to the VHP countries 
in the EU and to include the list of participating VHP countries.
         Rationale: This change was made for clarification of VHP-specific 
requirements for eligibility. 

In Section 4.1, Inclusion Criteria, criterion #3 was updated to “Male or 
female subjects age 12 years and older, inclusive, at time of informed 
consent/assent.  Adolescent subjects below the age of 18 years will only be 
enrolled into this study if permitted by the sponsor, local competent 
authority, and institutional review board (IRB)/ethics committee (EC).  
Otherwise, only subjects 18 years or older (or age specified by applicable 
reviewer) will be enrolled in those countries, regions, or sites.  Within VHP 
countries in the EU, subjects must be aged 18 through 74 years at the time 
of informed consent.”
         Rationale: This change was made to align with a request from the VHP 
to exclude subjects age 75 years and older in VHP countries in the EU.

In Section 4.1, Inclusion Criteria, criterion #4 was updated to include male 
reproductive safety requirements.  Specifically, it indicates that in VHP 
countries in the EU male subjects should use a male condom during sexual 
intercourse with females of childbearing potential and should refrain from 
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intervention.  Language was also added to clarify that there are no such 
requirements outside of VHP countries in the EU.
         Rationale: This change was made to align with a request from the VHP 
to require male subjects in VHP countries in the EU to use a barrier 
method of contraception during heterosexual intercourse and to refrain 
from donating sperm during the relevant period.  

In Section 4.1, Inclusion Criteria, criterion #4.b, bullet 3 (Postmenopausal 
female) was updated to “A postmenopausal state is defined as no menses 
for 12 months without an alternative medical cause.  In addition, a high 
follicle stimulating hormone (FSH) level in the postmenopausal range must 
also be used to confirm a postmenopausal state in women under 60 years 
old and not using hormonal contraception or hormone replacement therapy 
(HRT).  Females on HRT and whose menopausal status is in doubt will be 
required to use one of the nonestrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.”  The requirement for 
follicle stimulating hormone (FSH) testing has not changed.
         Rationale: This change was made to align with a request from the VHP 
to update the definition of “postmenopausal state”.

In Section 4.2, Exclusion Criteria, criterion #8.i, a reference was added for 
the website www.CredibleMeds.org.  Subsequent references were 
renumbered as appropriate.
         Rationale: This change was made to correct an omission of the 
reference.
In Section 4.3.1, Contraception, language was added to indicate that in 
VHP countries in the EU male subjects should use a male condom during 
sexual intercourse with a female of childbearing potential and should 
refrain from donating sperm during the study for 90 days after the last dose 
of study intervention.  Language was also added to clarify that there are no 
such requirements outside of VHP countries in the EU. 
         Rationale: This change was made to align with a request from the VHP 
to require male subjects in VHP countries in the EU to use a barrier 
method of contraception during heterosexual intercourse and to refrain 
from donating sperm during the relevant period.

In Section 6, Study Procedures, paragraph 3 was added to indicate that at 
sites in VHP countries in the EU female subjects of childbearing potential 
will be instructed to perform a urine pregnancy test at home between the 
Week 40 and 48 visits (at approximately Week 44).
         Rationale: This change was made to align with a request from the VHP 
to include more frequent pregnancy testing for females of childbearing 
potential in VHP countries in the EU.

In Section 6.2.11, Visit 12, Day 281/ Week 40 (±7 days), bullet 6 was 
updated to indicate that at sites in VHP countries in the EU female subjects 
of childbearing potential will be instructed to perform a urine pregnancy 
test at home between the Week 40 and 48 visits (at approximately Week 
44).


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         Rationale: This change was made to align with a request from the VHP 
to include more frequent pregnancy testing for females of childbearing 
potential in VHP countries in the EU.

In Section 7.1, Check for Initiation of Menarche (for Premenarchal 
Females Only), the language was updated to indicate that pregnancy tests 
should be performed “according to the Schedule of Activities” instead of 
“at every visit”.
         Rationale: This change was made to ensure consistency with the 
Schedule of Activities.  

In Section 7.2, Pregnancy Testing, the third paragraph was added to 
indicate that at sites in VHP countries in the EU female subjects of 
childbearing potential will be instructed to perform a urine pregnancy test 
at home between the Week 40 and 48 visits (at approximately Week 44).
        Rationale: This change was made to align with a request from the VHP 
to include more frequent pregnancy testing for females of childbearing 
potential in VHP countries in the EU.

In Section 7.5.8.1, Purified Protein Derivative (PPD) Test, a typographic 
error in paragraph 2 was corrected to reflect that the test should be 
performed and interpreted as “negative” (not “positive”) according to local 
standards.
         Rationale: This clarification was made to correct a typographic error and 
was previously communicated to active sites in the protocol 
administrative change letter dated 18-Apr-2019.

In Section 9, Data Analysis/Statistical Methods was updated to include 
more specific information on the timing of the finalization of the statistical 
analysis plan (SAP). 
        Rationale: This change was made to align with a request from the VHP 
to provide information on when the SAP would be finalized.
In Appendix 3, Guidelines for Subject Safety Monitoring and Discontinuation, 
a typographic error in the monitoring criteria for hemoglobin was 
corrected to reflect that a decrease greater than or equal to 2.0 g/dL (not 
just a decrease of 2.0 g/dL) requires additional monitoring activities.
         Rationale: This clarification was made to correct a typographic error and 
was previously communicated to active sites in the protocol 
administrative change letter dated 18-Apr-2019.

In Appendix 5, Severity of Alopecia Tool (SALT), typographic errors were 
corrected in the calculations shown for the first example. 
        Rationale: This clarification was made to correct a typographic error. 
Amendment 
1
28 
February 
2019

Throughout the protocol, text has been updated to clarify Japan-specific 
requirements for Hepatitis B testing, which have been added to Appendix 
18.1 under country-specific requirements, specifically, in the Schedule of 
Activities (footnotes r and s), Exclusion Criterion #20, Section 6.1 
(screening visit), Section 7.5.7 (footnotes d and e for Table 3), 
Section 7.5.11, and Appendix 2.  
         Rationale: This clarification was made to align with local regulations in 
Japan which require that Hepatitis B surface antibody testing be included 
in the initial screening for Hepatitis B testing and not in reflex testing.

Throughout the protocol, the text has been updated to change “audiogram” 
to “audiological evaluation” and to provide additional details on the 


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required evaluations, specifically in the Schedule of Activities (footnote k) 
and Section 7.5.5, Audiogram.  
         Rationale: This clarification was made to provide a high level summary 
of the tests required for audiological evaluation detailed in the 
Audiometry Study Guide.

Throughout the protocol, “CYP3A4” was updated to “CYP3A” in all 
references to excluded/prohibited medications.  In addition, Exclusion 
Criteria for use of CYP3A4 inducers were updated to reflect a washout 
period of 4 weeks (or 28 days).  
         Rationale: These clarifications were made as the language in the body of 
the protocol was previously inconsistent with Appendix 4. There are no 
changes to the medications that are excluded/prohibited.

Exploratory Endpoints for Patient’s Global Impression of Change (PGI-C) 
and Patient Satisfaction with Hair Growth (P-Sat) have been updated from 
“Change from baseline in” to “Absolute score of”.  
         Rationale: This clarification was made as the questionnaires themselves 
report on a change from baseline.

Throughout the protocol, an assessment was added to address a new 
exploratory endpoint.  The Clinician Global Impression – Alopecia Areata 
(CGI-AA) was added to the Protocol Summary, Schedule of Activities, 
Section 2, Study Objectives and Endpoints, Section 6, Study Procedures, 
Section 7.6.5, Clinician Global Impression – Alopecia Areata (CGI-AA), 
Section 7.12, Rater Qualifications, and Appendix 17, Clinician Global 
Impression – Alopecia Areata (CGI-AA).  
         Rationale: The addition of this clinician reported outcome assessment 
will provide an additional anchor for validation of the Severity of 
Alopecia Tool (SALT) and will provide information on concordance or 
discordance between patient and clinician perspectives.

Throughout the protocol, the assessment of both the Patient’s Global 
Impression of Change (PGI-C) and the Patient’s Impression of Satisfaction 
(P-Sat) were removed from the Day 1 visit.  
         Rationale: These questionnaires themselves report on a change from 
baseline; therefore, there is no need to capture a baseline assessment.

Throughout the protocol, the method of body temperature evaluation was 
updated to include “axillary”.  
        Rationale: This clarification was made to correct an error of omission.

In Section 1.4.1, Phase 2a Study in Alopecia, information was updated to 
reflect changes in the Phase 2a study design, changing the single-blind 
extension phase into an open-label extension phase.

In Section 1.7, Summary of Benefit/Risk Assessment, information on 
fertility was updated.  
         Rationale: This change was made in response to new data available in 
the Investigator’s Brochure.

In Section 4.1, Inclusion Criterion #3 was updated to “Male or female 
subjects age 12 years and older, inclusive, at time of informed 
consent/assent. Adolescent subjects below the age of 18 years will only be 
enrolled into this study if permitted by the sponsor, local competent 
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(EC). Otherwise, only subjects 18 years or older (or age specified by 
applicable reviewer) will be enrolled in those countries, regions, or sites.”  
         Rationale: This clarification was made to indicate that IRBs/ECs could 
render a decision on the inclusion of adolescents at a site level (in 
addition to local competent authorities and the Sponsor).

In Section 4.1, Inclusion Criterion #6 was updated from “must” to 
“should”.  
         Rationale: This change is to accommodate the use of some ad hoc 
medications (eg, those medications used for headache, menstrual 
cramps, etc).

In Section 4.2, Exclusion Criterion #8 sub-bullet d was updated to “5α-
Reductase inhibitors (5-ARIs) (eg, finasteride, dutasteride)”.  In addition, 
“oral minoxidil” and “spironolactone if used specifically for alopecia 
areata” were also added to examples of systemic treatments that could 
affect AA.  These changes were also reflected in Section 5.8.2, Prohibited 
Medications and Treatments.  
         Rationale: These clarifications were made to provide more specific 
examples of prohibited systemic treatments.

In Section 4.2, Exclusion Criterion #8 sub-bullet f was updated to include 
“topical irritants (eg, anthralin) and liquid nitrogen cryotherapy”.  These 
changes were also reflected in Section 5.8.2, Prohibited Medications and 
Treatments.  
         Rationale: These clarifications were made to provide more specific 
examples of prohibited topical treatments.

In Section 4.2, Exclusion Criterion #14 was updated to clarify the 
eligibility requirements for adolescents regarding varicella exposure.  This 
clarification was also reflected in the Schedule of Activities, Section 6.1, 
Screening, Visit 1, Section 7.5.7, Clinical Laboratory Tests, and Section 
7.5.9, Varicella-Zoster Virus Immunoglobulin G Antibody (VZV IgG Ab) 
Testing.  
         Rationale: This clarification was made to provide specific information 
on the number of required doses of varicella vaccination and to avoid 
any confusion as to how the eligibility criteria related to vaccination 
records and varicella-zoster virus immunoglobulin G antibody results 
should be applied.

In Section 4.2, Exclusion Criterion #21 after sub-bullet c was updated to 
add the following sentence: “A subject who is currently being treated for 
active TB infection must be excluded from the study.”  
         Rationale: This clarification was made to provide specific guidance on 
subjects with active TB infection.  Active infection was already excluded 
under criterion #16; however, this language was added to #21 as well for 
clarity.

In Section 4.2, Exclusion Criterion #24 sub-bullet c was updated to 
“Platelet count <150 × 109/L or <150,000/mm3”.  
         Rationale: This change was made to correct a typographic error.  This 
change was previously communicated to active sites in the protocol 
administrative letter dated 16-Nov-2018. 


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
In Section 4.3.1, Contraception, the allowable methods of contraception 
were updated to include the use of combination hormonal contraceptives in 
combination with a barrier method. 
         Rationale: This change has been made based on the results of the 
drug-drug-interaction study B7981018.  Further information is available 
in the current version of the Investigator’s Brochure (IB).

In Section 5.8.1, Permitted Concomitant Medications, the dose of 
acetaminophen was updated from “1.5 g/day” to “3 g/day”.  
        Rationale: This change was made to better align with the dosing 
instructions for acetaminophen. 

In Section 5.8.4, Surgery, the following text was added for clarity: 
“Subjects who do have elective surgery should temporarily discontinue 
study intervention for 1 week prior to the surgical procedure and remain off 
study intervention after the surgical procedure until sutures/staples are 
removed.  If absorbing sutures or chemical closure methods are utilized, 
study intervention can be resumed when the operative site is sufficiently 
healed, and risk of infection is minimal.”
        Rationale: This change was made to provide sites with specific 
instructions on how to manage dosing of investigational product in the 
event that a subject requires surgery during the study. 

In Section 6.1, Screening, Visit 1, clarified that audiological evaluation can 
be performed within 8 weeks of Day 1. 
        Rationale: This is a clarification to ensure consistency with language in 
the Schedule of Activities and in Section 7.5.5, Audiological Evaluation.

In Section 6.3.2, Early Termination (ET) Visit, and Schedule of Activities, 
the IP-10 assessment has been deleted at the ET visit.  
        Rationale: IP-10 sampling has been removed from the ET visit due to the 
intended collection of these samples only up to Week 24, as well as due 
to expected differences in timing of the prior dose of study drug relative 
to IP-10 sampling under early termination circumstances which could 
reduce their value in pharmacodynamic analyses.

In Section 7.5.6.2.2, Drug Related Rash, the following text was added “In 
addition, the subject will be asked to rate the severity of pruritus within the 
last 24 hours on a scale from 0 (No itching) to 10 (Worst possible itching)”.
        Rationale: The text was added for clarification of requirements for 
assessment of drug-related rash which were detailed in other supporting 
documentation.

In Section 7.5.6.2.2, Drug Related Rash, the text has clarified tests 
performed and that results are forwarded to the Sponsor.  
        Rationale: This change was made to correct a typographic error and/or 
omission. 

In Section 7.6.1, Severity of Alopecia Tool (SALT), the text has been 
clarified.  
        Rationale: This language was reworded for clarity. 

In Section 7.5.7, Table 3, Varicella-zoster virus immunoglobulin G 
antibody (VZV IgG Ab) testing was added to the table.  
        Rationale: This change as made to correct a typographic error.


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
In Appendix 3.2, Discontinuation, text on how to handle subjects with a 
clinically meaningful decline in hearing has been updated.  
        Rationale: The clarification was made to align with instructions included 
in the Audiometry Study Guide. 

In Appendix 4, Prohibited Concomitant Medications, text has been updated 
to indicate that amiodarone and mitotane can be used in an emergency 
situation, but the subject must then be discontinued from the study.  
        Rationale: This clarification was made to provide specific information on 
how to handle emergency situations requiring these two medications.

In Appendix 12, EuroQoL 5 Dimensions-Youth (EQ5D Y), the second 
page of the questionnaire has been added.  
        Rationale: This change was made to correct a typographic error. 

Global corrections to typographical errors, abbreviations, and definitions 
were made.
Original 
protocol
17 
September 
2018
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................27
LIST OF FIGURES .................................................................................................................27
APPENDICES .........................................................................................................................28
PROTOCOL SUMMARY.......................................................................................................29
SCHEDULE OF ACTIVITIES................................................................................................38
1. INTRODUCTION ...............................................................................................................45
1.1. Mechanism of Action/Indication.............................................................................45
1.2. Background and Rationale ......................................................................................45
1.2.1. Background on Alopecia Areata.................................................................45
1.2.2. Drug Development Rationale .....................................................................47
1.3. Nonclinical and Phase 1 Efficacy and Safety Data.................................................47
1.4. Clinical Experience .................................................................................................48
1.4.1. Phase 2a Study in Alopecia ........................................................................48
1.4.2. Phase 2a Study in Rheumatoid Arthritis.....................................................49
1.4.3. Clinical Pharmacokinetics and Metabolism ...............................................49
1.5. Study Rationale .......................................................................................................50
1.6. Dose Rationale ........................................................................................................51
1.7. Summary of Benefit/Risk Assessment....................................................................52
1.8. Additional Information............................................................................................53
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................54
3. STUDY DESIGN.................................................................................................................57
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................59
4.1. Inclusion Criteria.....................................................................................................59
4.2. Exclusion Criteria....................................................................................................62
4.3. Lifestyle Requirements ...........................................................................................68
4.3.1. Contraception..............................................................................................68
4.3.2. Cosmetic Treatments/Applications.............................................................69
4.4. Sponsor’s Qualified Medical Personnel..................................................................70
5. STUDY TREATMENTS.....................................................................................................70
5.1. Allocation to Treatment ..........................................................................................71
5.2. Breaking the Blind ..................................................................................................71


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5.3. Subject Compliance.................................................................................................71
5.4. Investigational Product Supplies.............................................................................72
5.4.1. Dosage Form(s) and Packaging..................................................................72
5.4.2. Preparation and Dispensing........................................................................73
5.5. Administration.........................................................................................................73
5.6. Investigational Product Storage ..............................................................................74
5.7. Investigational Product Accountability...................................................................75
5.7.1. Destruction of Investigational Product Supplies ........................................75
5.8. Concomitant Medications/Treatment(s)..................................................................75
5.8.1. Permitted Concomitant Medications ..........................................................75
5.8.2. Prohibited Medications and Treatments .....................................................76
5.8.3. Vaccinations ...............................................................................................78
5.8.4. Surgery........................................................................................................78
6. STUDY PROCEDURES .....................................................................................................78
6.1. Screening, Visit 1 ....................................................................................................79
6.2. Study Period ............................................................................................................81
6.2.1. Visit 2, Day 1 (Randomization)..................................................................81
6.2.2. Visit 3, Day 15/Week 2 (±3 days) ..............................................................83
6.2.3. Visit 4, Day 29/Week 4 (±3 days) ..............................................................84
6.2.4. Visit 5, Day 57/Week 8 (±7 days) ..............................................................85
6.2.5. Visit 6, Day 85/Week 12 (±7 days) ............................................................85
6.2.6. Visit 7, Day 127/Week 18 (±7 days) ..........................................................86
6.2.7. Visit 8, Day 169/Week 24 (±7 days) ..........................................................87
6.2.8. Visit 9, Day 183/Week 26 (±3 days) ..........................................................88
6.2.9. Visit 10, Day 197/Week 28 (±3 days) ........................................................89
6.2.10. Visit 11, Day 239/Week 34 (±7 days) ......................................................90
6.2.11. Visit 12, Day 281/Week 40 (±7 days) ......................................................91
6.2.12. Visit 13, Day 337/Week 48/End of Treatment (±7 days).........................92
6.3. Follow-up Period.....................................................................................................93
6.3.1. Visit 14, End of Study/Follow-up...............................................................93
6.3.2. Early Termination Visit..............................................................................93
6.4. Subject Withdrawal/Early Termination ..................................................................94


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7. ASSESSMENTS..................................................................................................................96
7.1. Check for Initiation of Menarche (for Premenarchal Females Only) .....................96
7.2. Pregnancy Testing...................................................................................................96
7.3. Banked Biospecimens .............................................................................................97
7.4. Additional Research ................................................................................................98
7.5. Safety Assessments .................................................................................................98
7.5.1. Vital Signs ..................................................................................................99
7.5.2. Medical History, Physical Exam, Height, and Weight...............................99
7.5.3. Chest Radiography....................................................................................100
7.5.4. Electrocardiogram (ECG).........................................................................100
7.5.5. Audiological Evaluation...........................................................................101
7.5.6. Special Safety Assessment .......................................................................101
7.5.6.1. Suspected Opportunistic Infections.........................................101
7.5.6.2. Dermatological Events ............................................................101
7.5.7. Clinical Laboratory Tests .........................................................................102
7.5.8. Tuberculosis Testing.................................................................................104
7.5.8.1. Purified Protein Derivative (PPD) Test...................................105
7.5.9. Varicella-Zoster Virus Immunoglobulin G Antibody (VZV IgG Ab) 
Testing............................................................................................................105
7.5.10. Baseline Viral Screen .............................................................................105
7.5.11. Hepatitis B DNA (HBVDNA) Testing...................................................105
7.5.12. Events for Adjudication/Review Committee Submission......................105
7.6. Clinical Assessments.............................................................................................106
7.6.1. Severity of Alopecia Tool (SALT)...........................................................106
7.6.2. Eyelash Assessment (ELA) ......................................................................106
7.6.3. Eyebrow Assessment (EBA) ....................................................................107
7.6.4. Assessment of Fingernails Affected by Alopecia Areata.........................108
7.6.5. Clinician Global Impression – Alopecia Areata (CGI-AA) .....................108
7.7. Assessment of Suicidal Ideation and Behavior.....................................................108
7.7.1. Columbia Suicide Severity Rating Scale (C-SSRS).................................108
7.8. Patient Reported Outcome (PRO).........................................................................109
7.8.1. Alopecia Areata Patient Priority Outcomes (AAPPO).............................109


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7.8.2. Patient’s Global Impression of Change (PGI-C)......................................109
7.8.3. Patient Satisfaction with Hair Growth (P-Sat)..........................................109
7.8.4. Hospital Anxiety and Depression Scale (HADS).....................................109
7.8.5. EuroQoL 5 Dimensions (EQ-5D-5L) and EuroQoL 5 Dimensions—
Youth (EQ-5D-Y)..........................................................................................110
7.8.6. Patient Health Questionnaire – 8 Items (PHQ-8) .....................................110
7.8.7. 36-Item Short Form Health Survey Version 2 Acute (SF36v2 Acute) ....110
7.8.8. Alopecia Areata Resource Utilization (AARU) .......................................110
7.8.9. Work Productivity and Activity Impairment: Alopecia Areata 
(WPAI: AA)...................................................................................................110
7.9. Photography of Alopecia Areata...........................................................................111
7.10. Pharmacokinetics ................................................................................................111
7.10.1. Plasma for Analysis of PF-06651600.....................................................111
7.10.2. Shipment of Pharmacokinetic Samples ..................................................112
7.11. Pharmacodynamics Markers ...............................................................................112
7.11.1. Samples for Interferon Gamma-Induced Protein – 10 (IP-10) 
Analysis..........................................................................................................112
7.11.2. Samples for fluorescence-activated cell sorting (FACS) analysis (T 
cell, B cell, and NK cell subsets)...................................................................113
7.11.3. Samples for Immunoglobulins (IgA, IgG, IgM) Analysis......................113
7.11.4. Shipment of Pharmacodynamic Samples ...............................................113
7.12. Rater Qualifications.............................................................................................113
8. ADVERSE EVENT REPORTING....................................................................................113
8.1. Requirements.........................................................................................................113
8.1.1. Additional Details on Recording Adverse Events on the CRF.................115
8.1.2. Eliciting Adverse Event Information........................................................115
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Subject Withdrawal/Early Termination section) ...........................................115
8.1.4. Time Period for Collecting AE/SAE Information....................................115
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................115
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............116
8.1.5. Causality Assessment ...............................................................................116
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................116


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8.2. Definitions.............................................................................................................116
8.2.1. Adverse Events.........................................................................................116
8.2.2. Abnormal Test Findings ...........................................................................117
8.2.3. Serious Adverse Events ............................................................................118
8.2.4. Hospitalization..........................................................................................118
8.3. Severity Assessment..............................................................................................119
8.4. Special Situations ..................................................................................................120
8.4.1. Protocol-Specified Serious Adverse Events.............................................120
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................120
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................121
8.4.3.1. Exposure During Pregnancy....................................................122
8.4.3.2. Exposure during Breastfeeding ...............................................123
8.4.3.3. Occupational Exposure ...........................................................123
8.4.4. Medication Errors .....................................................................................123
8.4.5. Safety Adjudication Committees..............................................................124
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................125
9.1. Sample Size Determination...................................................................................127
9.2. Efficacy Analysis ..................................................................................................128
9.2.1. Testing Procedure for Multiple Comparisons...........................................128
9.2.1.1. Overall Study (Testing Procedure for Multiple 
Comparisons Incorporating the SALT ≤10 as a Key Secondary 
Endpoint).........................................................................................128
9.2.1.2. For the FDA/PMDA (Testing Procedure for Multiple 
Comparisons With no Key Secondary Endpoints)..........................131
9.2.1.3. For the EMA and Competent Authorities in the VHP 
Countries (Testing Procedure for Multiple Comparisons 
Incorporating the PGI-C Response as a Key Secondary 
Endpoint).........................................................................................133
9.2.2. Analysis of the Primary and Key Secondary Endpoints...........................135
9.2.2.1. For the Overall Study and the FDA/PMDA (Analysis of 
the Primary and Key Secondary Endpoints) ...................................135
9.2.2.2. For the EMA and Competent Authorities in the VHP 
Countries (Analysis of the Primary and Key Secondary 
Endpoints)........................................................................................136


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9.2.2.3. Per-Protocol Analysis (Analysis of the Primary and Key 
Secondary Endpoints)......................................................................137
9.2.3. Analysis of Secondary Endpoints.............................................................138
9.2.3.1. Analysis of Exposure-Response..............................................138
9.2.4. Analysis of Other Endpoints.....................................................................138
9.2.5. Subgroup Analyses...................................................................................138
9.3. Pharmacokinetic Analysis during the Treatment Period.......................................139
9.4. Pharmacokinetic/Pharmacodynamic Early Unblinding ........................................139
9.5. Safety Analysis......................................................................................................140
9.6. Exploratory Pharmacodynamic Analysis..............................................................140
9.7. Interim Analysis ....................................................................................................140
9.8. Data Monitoring Committee .................................................................................141
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................141
11. DATA HANDLING AND RECORD KEEPING ...........................................................141
11.1. Case Report Forms/Electronic Data Record .......................................................141
11.2. Record Retention.................................................................................................142
12. ETHICS............................................................................................................................143
12.1. Institutional Review Board/Ethics Committee....................................................143
12.2. Ethical Conduct of the Study ..............................................................................143
12.3. Subject Information and Consent........................................................................143
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................144
13. DEFINITION OF END OF TRIAL.................................................................................145
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................145
15. PUBLICATION OF STUDY RESULTS........................................................................145
15.1. Communication of Results by Pfizer ..................................................................145
15.2. Publications by Investigators ..............................................................................146
16. REFERENCES ................................................................................................................148


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LIST OF TABLES
Table 1.
PF-06651600 Exposure Margins and No Observed Adverse Effects 
Level .........................................................................................................52
Table 2.
Number and Type of Tablets for Each Treatment Sequence....................72
Table 3.
Laboratory Tests .....................................................................................103
Table 4.
Primary and Secondary Endpoints for Overall Study Reporting and 
Publications.............................................................................................125
Table 5.
Primary and Secondary Endpoints Organized by Known Regional 
Regulatory Requirements .......................................................................126
Table 6.
Statistical Methods for the Analysis of the Primary Endpoint for the 
Overall Study, and for the FDA/PMDA.................................................135
Table 7.
Statistical Methods for the Analysis of the Primary Endpoint for the 
EMA and Competent Authorities in the VHP Countries........................136
Table 8.
Windows for Remote Visits and Laboratory Sample Collections if 
Required Due to Disruptions from Public Emergencies.........................170
LIST OF FIGURES
Figure 1.
Study Design Schematic...........................................................................59
Figure 2.
Schematic and Graphical Presentation for Multiple Testing 
Procedure Incorporating a Key Secondary Endpoint .............................130
Figure 3.
Schematic and Graphical Presentation for Multiple Testing 
Procedure ................................................................................................132


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APPENDICES
Appendix 1. Abbreviations....................................................................................................155
Appendix 2. Hepatitis B Testing Algorithm and Full Eligibility Criteria .............................160
Appendix 3. Guidelines for Subject Safety Monitoring and Discontinuation.......................161
Appendix 3.1. Monitoring......................................................................................................161
Appendix 3.2. Discontinuation ..............................................................................................162
Appendix 4. Prohibited and Permitted Concomitant CYP3A Inducers and Substrates ........164
Appendix 4.1. Prohibited Concomitant CYP3A Inducers and Substrates.............................164
Appendix 4.2. Permitted Concomitant CYP3A Substrates ...................................................165
Appendix 5. Country-specific Requirements.........................................................................166
Appendix 5.1. Japan-Specific Requirements for Hepatitis B Testing ...................................166
Appendix 6. Alternative Measures During Public Emergencies ...........................................167
Appendix 6.1. Eligibility........................................................................................................167
Appendix 6.2. Telehealth Visits.............................................................................................168
Appendix 6.3. Alternative Facilities for Safety Assessments................................................169
Appendix 6.4. Investigational Product...................................................................................171
Appendix 6.5. Home Health Visits........................................................................................172
Appendix 6.6. Adverse Events and Serious Adverse Events.................................................173
Appendix 6.7. Efficacy Assessments.....................................................................................173


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PROTOCOL SUMMARY
Background and Rationale:
Alopecia areata (AA) is a chronic relapsing T-cell mediated autoimmune disorder 
characterized by non-scarring hair loss affecting children and adults across all ages, races, 
and sexes.7,8  AA is associated with other immune diseases including asthma, allergic rhinitis, 
atopic dermatitis, and autoimmune diseases such as thyroiditis and vitiligo.8
CD8+ T cells, natural killer (NK) cells, and mast cells are involved in the pathogenesis of 
AA.  The possible inflammatory pathways in AA include cytokines from the type 1 helper 
T cell (TH1) axis, including interferon (IFN) alpha (), IFN gamma (), and IFN-induced 
protein 10 (IP-10).7,9  Mouse models have shown that interleukin (IL)-2 and IL-15 play a role 
in the initiation of auto-reactive CD8+ cells that attack hair follicles.1  IL-12 and IL-23 may 
also play a role in the pathogenesis of AA.11
Clinical presentation of AA can be limited to small, circular patches of scalp hair loss (patchy 
hair loss, alopecia focalis), involve complete loss of hair on the scalp (alopecia totalis [AT]), 
or total loss of hair on the scalp and body (alopecia universalis [AU]).12  AA involving 
50% or greater scalp hair loss, including AT and AU, is considered an advanced form of 
alopecia, according to the United States (US) National Alopecia Areata Foundation.13  Patchy 
alopecia is the most common form of AA which may develop into the more extensive and 
often treatment-resistant forms of AA, especially with earlier age of onset.  It is estimated 
that AA affects as many as 6 to 7 million individuals in the US8 and 147 million worldwide.13  
AA is a disease with a significant pediatric prevalence, in addition to the burden of disease 
seen in adults.  A substantial body of evidence demonstrates a widespread impact of AA on 
the psychological health of both adult and pediatric patients with AA, including impairment 
in self-esteem, increased incidence of anxiety and depressive disorders and other 
psychological conditions,21-25 problems with social relations,26 decreased health-related 
quality of life (HRQoL) and general quality of life (QoL), as well as the QoL of their 
families.27-35
No drugs have been approved for the treatment of AA in most countries/regions, including 
the US and the European Union (EU). Review of treatment guidelines and recommendations 
indicate that a number of off label therapies are frequently used after assessing factors such 
as the age of the patient, disease extent and disease duration.  However, there is neither a cure 
for AA, nor is there a therapy convincingly demonstrated to induce and sustain remission 
long term.38-42
PF-06651600 is an orally bioavailable, small molecule that is currently being investigated in 
patients with AA.  PF-06651600 inhibits, by irreversibly blocking the adenosine triphosphate 
(ATP) binding site, Janus kinase 3 (JAK3) and the tyrosine kinase expressed in 
hepatocellular carcinoma (TEC) kinase family (BTK, BMX, ITK, TEC, TXK), with high 
selectivity over the other three JAK isoforms, JAK1, JAK2, and tyrosine kinase 2 [TYK2], as 
well as over the broader kinome.  PF-06651600 potently inhibits signaling of the common 
-chain receptors for IL-15 and IL-21, which have been implicated in the pathogenic 
pathways of AA.1  Additionally, PF-06651600 inhibits the cytotoxic function of CD8+ T cells 


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and NK cells which have also been implicated in the pathogenic process of AA.2,3  This 
inhibition may be mediated through mechanisms dependent on JAK3 and TEC kinase family 
members.4,5,6
Objectives and Endpoints: 
The following table details the overall study objectives and endpoints.  There are some 
region specific differences noted throughout.  Table 5 in Section 9 lists the primary and 
secondary endpoints of the study organized by known regional requirements.
Primary Objective(s):
Primary Endpoint(s):

To evaluate the efficacy of PF-06651600 compared to 
placebo in adult and adolescent alopecia areata (AA) 
subjects with 50% or greater scalp hair loss on 
regrowth of lost hair (as measured by an absolute 
Severity of Alopecia Tool (SALT) Score ≤20) at 
Week 24.
Note: For the European Medicines Agency (EMA) 
and competent authorities in the Voluntary 
Harmonisation Procedure (VHP) countries,a the 
primary objective is to evaluate the efficacy of 
PF-06651600 compared to placebo in adult and 
adolescent AA subjects with 50% or greater scalp hair 
loss on regrowth of lost hair (as measured by an 
absolute SALT Score ≤10) at Week 24.

Response based on an absolute SALT Score ≤20 at 
Week 24.
Note: For the EMA and competent authorities in the 
VHP countries, response based on an absolute SALT 
Score ≤10 at Week 24 will be analyzed as the 
primary endpoint in a separate analysis.
Key Secondary Objective(s):
Key Secondary Endpoint(s):

To evaluate the efficacy of PF-06651600 compared to 
placebo in adult and adolescent AA subjects with 50% 
or greater scalp hair loss on regrowth of lost hair (as 
measured by an absolute SALT Score ≤10) at Week 
24.
Note: This key secondary objective will be utilized as 
the primary objective for the EMA and competent 
authorities in the VHP countries.  Additionally, this 
key secondary objective will not apply for the United 
States Food and Drug Administration (FDA) /Japan 
Pharmaceuticals and Medical Devices Agency 
(PMDA).

Response based on an absolute SALT Score ≤10 at 
Week 24.
Note: This key secondary endpoint will be utilized as 
the primary endpoint for the EMA and competent 
authorities in the VHP countries.  Additionally, this 
key secondary endpoint will not apply for the 
FDA/PMDA.

To evaluate the effect of PF-06651600 on patient 
centered outcomes (as measured by PGI-C response) 
at Week 24.
Note: This key secondary objective is only applicable 
for the EMA and competent authorities in the VHP 
countries.

PGI-C response defined as a score of “moderately 
improved” or “greatly improved” at Week 24.
Note: This key secondary endpoint is only applicable 
for the EMA and competent authorities in the VHP 
countries.
Secondary Objective(s):
Secondary Endpoint(s):

To characterize the exposure response of 
PF-06651600 on regrowth of lost hair.

Response based on an absolute SALT Score ≤20 at 
Week 24 will be used to characterize the exposure 
response.b


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
To assess the efficacy of PF-06651600 on regrowth of 
lost hair during the treatment period over time.

Response based on an absolute SALT score ≤20 at 
Weeks 4, 8, 12, 18, 28, 34, 40, and 48.c,d

Response based on an absolute SALT score of ≤10 at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.e

Response based on a 75% improvement in SALT 
score from baseline (SALT75) at Weeks 4, 8, 12, 18, 
24, 28, 34, 40, and 48.

Change from baseline in SALT scores at Weeks 4, 8, 
12, 18, 24, 28, 34, 40, and 48.

Response based on at least a 2 grade improvement or 
a score of 3 in Eyebrow Assessment (EBA) score at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Response based on at least a 2-grade improvement or 
a score of 3 in Eyelash Assessment (ELA) score at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

To evaluate the effect of PF-06651600 on 
patient-centered outcomes and payer relevant 
measures to assess treatment benefit from the patient 
perspective and to demonstrate value.f

PGI-C response defined as a PGI-C score of 
“moderately improved” or “greatly improved” at 
Weeks 4, 8, 12, 18, 24, 34, 40, and 48.f

Change from baseline in Alopecia Areata Patient 
Priority Outcomes (AAPPO) scales at Weeks 4, 8, 
12, 18, 24, 34, 40, and 48.
Safety Objective(s)
Safety Endpoint(s)

To evaluate the safety and tolerability of PF-06651600 
in the treatment period over time.

Incidence of treatment-emergent adverse events 
(AEs).

Incidence of serious AEs (SAEs) and AEs leading to 
discontinuation.

The incidence of clinically significant abnormalities 
in vital signs.

The incidence of clinically significant abnormalities 
in clinical laboratory values.
PK Objective(s)
PK Endpoint(s)

To characterize pharmacokinetics of PF-06651600.

Plasma concentrations of PF-06651600 at Weeks 4, 
and 8 or 12.
Exploratory Objective(s):
Exploratory Endpoint(s):

To collect banked biospecimens for exploratory 
research, unless prohibited by local regulations or 
ethics committee decision.

Collection of banked biospecimens unless prohibited 
by local regulations or ethics committee decision.  
Additional information on collection and potential 
use is provided in the Banked Biospecimens section.


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
To assess the efficacy of PF-06651600 on regrowth of 
lost hair during the treatment period over time.

Response based on a 50% improvement in SALT 
score from baseline (SALT50) at Weeks 4, 8, 12, 18, 
24, 28, 34, 40, and 48.

Absolute SALT scores at Baseline, Weeks 4, 8, 12, 
18, 24, 28, 34, 40, and 48.

To evaluate the effect of PF-06651600 on 
patient-centered outcomes and payer relevant 
measures to assess treatment benefit from the patient 
perspective and to demonstrate value.

Improvement on PGI-C defined as “slightly 
improved”, “moderately improved”, or “greatly 
improved” at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.

Improvement on Patient Satisfaction with Hair 
Growth (P-Sat) items defined as slightly, moderately, 
or very satisfied at Weeks 4, 8, 12, 18, 24, 34, 40, 
and 48.

Change from baseline in EuroQoL 5 Dimensions 
(EQ-5D-5L) in adults or 
EuroQoL 5 Dimensions-Youth (EQ-5D-Y) in 
adolescents at Weeks 4, 12, 24, and 48.

Change from baseline in Alopecia Areata Resource 
Utilization (AARU) at Weeks 12, 24, 34, and 48.

Change from baseline in Work Productivity and 
Activity Impairment: Alopecia Areata (WPAI:AA) at 
Weeks 12, 24, 34, and 48.

Change from baseline in the depression subscale 
score of the Hospital Anxiety and Depression Scale 
(HADS) at Weeks 4, 8, 12, 24, and 48.g,87

Change from baseline in the anxiety subscale score 
of the HADS at Weeks 4, 8, 12, 24, and 48.g,87

Improvement on HADS among subjects with a 
baseline subscale score indicative of depression who 
achieved a “normal’ subscale score indicative of an 
absence of depression at Weeks 4, 8, 12, 24, and 
48.g,79,88

Improvement on HADS among subjects with a 
baseline subscale score indicative of anxiety who 
achieved a “normal’ subscale score indicative of an 
absence of anxiety at Weeks 4, 8, 12, 24, and 
48.g,79,88

Change from baseline in 36-Item Short Form Health 
Survey version 2 Acute (SF36v2 Acute) at Weeks 4, 
8, 12, 24, and 48.

To evaluate the effect of PF-06651600 on the clinician 
global impression of severity of scalp hair loss.

Change from baseline in Clinician Global Impression 
– Alopecia Areata (CGI-AA) at Weeks 4, 8, 12, 18, 
24, 28, 34, 40, and 48.

To evaluate efficacy of PF-06651600 in AA nail 
disease over time.

Change from baseline in fingernails affected by AA 
at Weeks 12, 24, 34, 40, and 48.


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
To assess pharmacodynamic and disease-related 
biomarkers over time.

Change from baseline in interferon gamma-induced 
protein 10 (IP-10) at Weeks 4, 8, 12, and 24.

Change from baseline in percent and absolute 
lymphocyte subsets (T-cell, B-cell, and natural killer 
[NK] cells) at Weeks 4, 12, 24, and 48.

Change from baseline in immunoglobulins (IgA, 
IgG, IgM) at Weeks 24 and 48.
a.
The VHP countries participating in this study are Czech Republic, Germany, Hungary, Poland, and Spain.
b.
For the EMA and competent authorities in the VHP countries, when SALT ≤10 is utilized for the primary endpoint, 
exposure response will be analyzed utilizing SALT ≤10 in a separate analysis.
c.
For the EMA and competent authorities in the VHP countries, when SALT ≤10 is utilized for the primary endpoint, 
SALT ≤20 at Week 24 will be analyzed as a secondary endpoint.
d.
When SALT ≤20 response at Week 24 is utilized as the primary endpoint, responses based on absolute SALT score 
≤20 at Weeks 18, 12, 8 and 4 will be analyzed controlling for Type I error utilizing an appropriate testing procedure.  
When SALT ≤10 response at Week 24 is utilized as the primary endpoint, the response based on absolute SALT 
score ≤20 at Week 24 will be analyzed controlling for Type I error utilizing an appropriate testing procedure. 
e.
When SALT ≤20 response at Week 24 is utilized as the primary endpoint, the response based on absolute SALT 
score ≤10 at Week 24 will be analyzed controlling for Type I error utilizing an appropriate testing procedure.  When 
SALT ≤10 response at Week 24 is utilized as the primary endpoint, the responses based on absolute SALT score 
≤10 at Weeks 18, 12, 8 and 4 will be analyzed controlling for Type I error utilizing an appropriate testing procedure.
f.
For the EMA and competent authorities in the VHP countries, the evaluation of the effect of PF-06651600 on 
patient centered outcomes (as measured by PGI-C response at Week 24) is a key secondary objective.  The PGI-C 
response at Week 24 will be analyzed as a key secondary endpoint utilizing an appropriate testing procedure to 
control overall Type I error.
g.
For the EMA and competent authorities in the VHP countries, endpoints utilizing the HADS will be 
analyzed as secondary endpoints.
Study Design:
This is a Phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging study to 
investigate PF-06651600 in AA.  The study will have a maximum duration of approximately 
57 weeks.  This includes an up to 5-week Screening period, a 48-week treatment period, and 
a 4-week follow-up period as shown below.  The treatment period will be comprised of a 
placebo-controlled period that includes a 4-week loading phase and a 20-week maintenance 
phase, followed by a 24-week extension phase.  The study will enroll a total of 
approximately 660 subjects.  The study will be conducted at approximately 120 sites.


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Page 34
To be eligible to enroll in this study, subjects must have moderate to severe AA with 
≥50% hair loss of the scalp (Severity of Alopecia Tool [SALT] score ≥50) at both Screening 
and baseline visits, without evidence of terminal hair regrowth within the previous 6 months 
and with the current episode of hair loss ≤10 years.
Screening will occur within 35 days prior to the first dose of study drug to confirm that 
subjects meet selection criteria for the study.  Eligible subjects will be randomized as 
described below.
A stratified randomization will be used for operational purposes in order to achieve a target 
global composition for AT/AU and adolescent subjects in the enrolled population.  The 
targets for enrollment are approximately 40% AT/AU and approximately 15% adolescents.  
The randomization will be operationalized as follows.  In regions enrolling both adolescents 
and adults, there will be four strata:
<18 years of age and AT/AU;
<18 years of age and not AT/AU;
≥18 years of age and AT/AU; and
≥18 years of age and not AT/AU.
Within each of these strata, subjects will be randomized in a 2:2:2:2:1:1:1 manner to blinded 
PF-06651600 and matching placebo for a total of 7 treatment sequences.  
* Primary endpoint is response based on absolute Severity of Alopecia Tool (SALT) Score ≤20 at Week 24.
1         15         29        57            85              127              169         183      197        239        281         337   365    
BL       2           4          8            12               18                24*          26        28          34                         48   F/U    
40    


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In regions enrolling only adults, there will be two strata:
≥18 years of age and AT/AU; and
≥18 years of age and not AT/AU.
In these regions, subjects will be randomized using the same ratio as described for regions 
enrolling both adolescents and adults.
All subjects will begin dosing during the loading phase according to their assigned sequence.  
Following the 4-week loading phase, subjects will continue dosing according to their 
assigned sequence in the 20-week maintenance phase.  At the end of the maintenance phase, 
placebo-treated subjects will be advanced in a prespecified, blinded manner to one of 2 active 
treatment sequences for the remainder of the study (through Week 48).  Investigators, 
subjects, and the sponsor study team will be blinded to treatment throughout the duration of 
the study.  Following the last dose of study drug, both discontinued and completed subjects 
will enter into a 4-week follow-up period for safety monitoring.  Subjects who complete 
treatment may be eligible for enrollment in a long-term study (Phase 3 study B7981032).  
Subjects who enroll immediately into the B7981032 study will not be required to complete 
the 4-week follow-up period in this study.
Study Treatments:
Blinded PF-06651600 and its matched placebo will be provided as tablets for oral 
administration.  The 50-mg and 10-mg tablets and their matching placebos will be supplied 
in blister cards and labeled according to local regulatory requirements.  Subjects will receive 
blinded labeled supplies throughout the study.
In order to achieve the proper dosage and maintain the blind throughout the study, tablets 
will be dispensed in a blinded fashion to ensure that all subjects, regardless of the assigned 
treatment sequence, will take the same number of tablets/day.  To accomplish this, all 
subjects will take 7 tablets/day during the loading phase, 4 tablets/day during the 
maintenance phase, 7 tablets/day during the first 4 weeks of the extension phase, and 
4 tablets/day for the remainder of the extension phase.
Statistical Methods:
The study may be unblinded for Sponsor internal decision-making purposes when ≥90% of 
subjects have reached 24 weeks post-randomization (or discontinued prior to the Week 24 
visit), and dissemination of these results will be limited to the unblinded reporting team and 
Sponsor management.  The sponsor personnel who are unblinded will be separate from the 
study team.  The sponsor will still maintain the blind for study team members who will be 
involved in daily study conduct, study management, safety, and data monitoring through the 
completion of the study.  Investigators and subjects will remain blinded.  There will be no 
impact on B7981015 study conduct, analysis, or reporting.


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The sample size for the study was based on the consideration to have sufficient power to 
evaluate the primary endpoint.  A sample size of 120 subjects per group (for the 
200 mg/50 mg once daily (QD), 200 mg/30 mg QD, 50 mg/50 mg QD, or 30 mg/30 mg QD 
groups) will provide more than 90% power to demonstrate that at least the 200 mg/50 mg QD 
group is superior to placebo by a difference of 24% in the proportion of subjects achieving 
the primary endpoint (SALT ≤20 at Week 24), assuming a placebo response rate of no more 
than 5%, at α = 0.05 (2-sided significance level).  This sample size accounts for multiplicity 
using a closed testing procedure to ensure strong control of Type I error for all comparisons 
between active treatment groups and placebo.  This sample size additionally provides > 90% 
power for the SALT ≤ 10 at Week 24 endpoint assuming that the 200 mg/50 mg QD group is 
superior to placebo by a difference of 20% in the proportion of subjects achieving SALT 
≤10, assuming a placebo response rate of no more than 5%, at α = 0.05 (2-sided significance 
level).  The assumption of the placebo response rate for both SALT≤20 and SALT≤10, as 
well as the treatment difference, was informed by the Week 24 results from the Phase 2a 
Study B7931005. 
As noted in Section 9, regulatory requirements for a marketing authorization approval 
 
will require significance at an α more stringent than 0.05, although 
the exact level of stringency required may vary (ie, 0.00125 is required by the FDA/PMDA 
for their requested primary endpoint of SALT ≤20 while 0.01 is required by the EMA for 
their requested primary endpoint of SALT ≤10).  The sample size of 120 subjects per group 
provide power >90% for SALT ≤20 (α = 0.00125) and SALT ≤10 (α = 0.01). 
The 10 mg/10 mg QD group is included to address the secondary objective of characterizing 
the exposure response. The sample size of 60 subjects for this group was chosen to allow for 
estimation of the exposure-response parameters. 
For the EMA and competent authorities in the VHP countries,  that request that the PGI-C 
response at Week 24 be analyzed as a key secondary endpoint, a sample size of 120 subjects 
per group also provides more than 90% power for PGI-C response assuming a difference of 
35% and a placebo response rate of 20%, at α = 0.05 (2-sided significance level).  The 
assumptions of the treatment difference and placebo response rate for PGI-C response were 
based on the Concert CTP-543 Phase 2b Study Week 24 data.90  Under the above 
assumptions, the power of the study remains >90% at α = 0.01 (EMA required 2-sided 
significance level).
The primary analysis population for efficacy data will be the Full Analysis Set (FAS) defined 
as all randomized subjects, regardless of whether they received study medication.  In the 
comparison to placebo, the data from the 2 groups, F and G, up to Week 24 will be pooled to 
form the placebo group.
For the overall study and for the FDA/PMDA, the SALT ≤20 response at Week 24 is the 
primary endpoint. The SALT ≤10 response at Week 24 will be analyzed as a key secondary 
endpoint for the overall study but not for the FDA/PMDA. The testing procedures are 
described in Section 9.2.1.1 and Section 9.2.1.2, and the planned analysis of the primary 
endpoint are described in Table 6. The primary analysis of the primary endpoint will be 
CCI


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Page 37
analyzed by Miettinen and Nurminen (MN) method84 for the difference in the proportion of 
responders between each active treatment group and placebo.  Subjects with missing SALT 
score at Week 24 due to coronavirus disease 2019 (COVID-19) related reasons will be 
excluded from the analysis at that timepoint, whereas missing data due to other reasons will 
be counted as non-responders at that time-point.  As supplementary analysis to assess the 
impact of COVID-19-related missing data on the results of the primary analysis, the analysis 
of the primary endpoint will be repeated with all missing data considered as non-responders 
regardless of the reason for missingness.
For the EMA and competent authorities in the VHP countries, the SALT ≤10 response at 
Week 24 will be the primary endpoint and the PGI-C response at Week 24 will be analyzed 
as a key secondary endpoint.  The testing procedures are described in Section 9.2.1.3, and the 
planned analyses of the primary endpoint are described in Table 7. The primary analysis of 
the primary endpoint will be conducted using a generalized linear mixed model (GLMM) 
model for the longitudinal binary data of SALT ≤10 response over time up to Week 24, 
assuming a mechanism of missing at random (MAR) for missing data due to COVID-19. 
Missing data due to reasons not related to COVID-19 will be assumed as non-responders. 
The key secondary endpoint will also be analyzed using this approach.
To characterize the exposure (dose or average steady state drug concentration [Cavg]) 
response in achieving the primary endpoint, a Bayesian three-parameter maximum effect 
attributable to the drug (Emax) exposure-response model will be used as the primary analysis 
approach to characterize the exposure response relationship.  The response function will be 
the log odds (logit) of the proportion of subjects achieving the primary endpoint.  In 
modelling the exposure response, the effect of loading dose will be included as a fixed factor 
in the model.  Model-based estimation of treatment effect for each dose or associated Cavg
compared to placebo will be presented with 95% confidence interval (CI).  The model will be 
described in detail in the Statistical Analysis Plan (SAP).  
For secondary endpoints, all binary endpoints will be analyzed in the same way as the 
primary endpoint for the overall study . For continuous endpoints, a mixed-effect model with 
repeated measures (MMRM) will be used.  This model will include the factors (fixed effects) 
for treatment group, visit, treatment-by-visit interaction, and relevant baseline value when 
modeling the change from baseline.  Within the framework of MMRM, the treatment 
difference will be tested at each time point.
All secondary endpoints will be evaluated at the 5% level of significance, without 
adjustments for multiple comparisons.
The pharmacokinetic (PK) concentration population is defined as all enrolled subjects who 
received at least 1 dose of PF-06651600 and in whom at least 1 concentration value is 
reported.
The safety data will be summarized in accordance with Pfizer Data Standards.  All subjects 
who receive investigational product (safety population) will be included in the safety 
analyses.  All safety data will be summarized descriptively.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the
protocol.  If subject visits or procedures are affected by a public emergency, including the coronavirus disease 2019 (COVID-19) 
pandemic, please refer to Appendix 6.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.
Protocol Activity
Screening 
Period
Treatment Period
Loading Phase
Maintenance Phase
Extension Phase
F/Ub
ETc
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Daya
Day -35 
to -1
Day 1
Day 15
Day 29
Day 
57
Day 
85
Day 
127
Day 
169
Day 183 Day 197
Day 
239
Day 281
Day 337
Week
N/A
W2
W4
W8
W12
W18
W24
W26
W28
W34
W40
W48/EOT EOS
Visit Window
N/A
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
+7 
Days
Enrollment procedure
Informed consent and if applicable 
assent
X
Inclusion/Exclusion criteria
X
X
Demographics 
X
Medical history and AA disease 
historyd
X
X
Medical procedures
Complete physical examinatione
X
X
X
X
X
Targeted physical examinationf
X
X
X
X
X
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECGh
X
X
X
X
X
X
X
Height & Weighti
X
X
X
X
X
Chest radiographsj
X
Audiological Evaluationk
X
X
X
X
Laboratory
Hematology & Serum Chemistryl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting lipid Panelm
X
X
X
X
X
X
X
X
X
Urinalysisn
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum FSHo
X


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Page 39
Protocol Activity
Screening 
Period
Treatment Period
Loading Phase
Maintenance Phase
Extension Phase
F/Ub
ETc
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Daya
Day -35 
to -1
Day 1
Day 15
Day 29
Day 
57
Day 
85
Day 
127
Day 
169
Day 183 Day 197
Day 
239
Day 281
Day 337
Week
N/A
W2
W4
W8
W12
W18
W24
W26
W28
W34
W40
W48/EOT EOS
Visit Window
N/A
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
+7 
Days
Pregnancy test (WOCBP only)p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV testingq
X
Hep B and Hep C Screeningr
X
HBVDNA (applicable countries)s
X
X
X
X
X
X
Varicella-zoster virus 
immunoglobulin G antibody (VZV 
IgG Ab) (adolescents only, if 
applicable)t
X
Collection of baseline sample for 
potential viral screenu
X
Tuberculosis testv
X
Laboratory Pharmacodynamics
IP-10 (CXCL10)
X
X
X
X
X
FACS-TBNK 
X
X
X
X
X
X
Immunoglobulins (IgA, IgG, IgM)
X
X
X
X
Trial treatment
Impala registration
X
Randomization
X
Investigational product dispensing
X
X
X
X
X
X
X
X
X
X
X
Investigational product 
administrationw
X










Investigational product 
accountability
X
X
X
X
X
X
X
X
X
X
X
X
Clinical assessments
SALT
X
X
X
X
X
X
X
X
X
X
X
X
ELA and EBA
X
X
X
X
X
X
X
X
X
X
X
X
Photographyx
X
X
X
X
X
X
X
X
X
Assessment of Fingernails 
Affected by AAy
X
X
X
X
X
X
X
CGI-AA
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRSz
X
X
X
X
X
X
X
X
X
X
X


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Page 40
Protocol Activity
Screening 
Period
Treatment Period
Loading Phase
Maintenance Phase
Extension Phase
F/Ub
ETc
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Daya
Day -35 
to -1
Day 1
Day 15
Day 29
Day 
57
Day 
85
Day 
127
Day 
169
Day 183 Day 197
Day 
239
Day 281
Day 337
Week
N/A
W2
W4
W8
W12
W18
W24
W26
W28
W34
W40
W48/EOT EOS
Visit Window
N/A
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
+7 
Days
Patient reported outcome
AAPPO
X
X
X
X
X
X
X
X
X
X
PGI-C and P-Sat
X
X
X
X
X
X
X
X
X
PHQ-8z
X
HADS
X
X
X
X
X
X
X
SF36v2 Acute
X
X
X
X
X
X
X
EQ-5D-5L (adults) or EQ-5D-Y 
(adolescents)
X
X
X
X
X
X
AARU
X
X
X
X
X
X
WPAI: AA (adults only)
X
X
X
X
X
X
Pharmacokinetic
Predose PK samplingaa
X
Full PK sampling (including 
predose sampling)bb
X
X
Xbb
Banked Biospecimen Collection 
Genomic banked Biospecimen: 
Prep D1cc
X
Other banked biospecimen: 
Prep B1
X
X
X
X
Other banked biospecimen: 
Prep B2
X
X
X
X
Other banked biospecimen: 
Prep R1
X
X
X
X
Other
Prior and current concomitant 
treatment(s) monitoring 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception check, as applicable 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Check for initiation of menarche 
(for premenarchal females only)dd
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Page 41
Protocol Activity
Screening 
Period
Treatment Period
Loading Phase
Maintenance Phase
Extension Phase
F/Ub
ETc
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Daya
Day -35 
to -1
Day 1
Day 15
Day 29
Day 
57
Day 
85
Day 
127
Day 
169
Day 183 Day 197
Day 
239
Day 281
Day 337
Week
N/A
W2
W4
W8
W12
W18
W24
W26
W28
W34
W40
W48/EOT EOS
Visit Window
N/A
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
+7 
Days
Abbreviations: = ongoing/continuous event; AA = alopecia areata; AAPPO = Alopecia Areata Patient Priority Outcomes; AARU = Alopecia Areata Resource Utilization; 
CGI-AA = Clinician Global Impression – Alopecia Areata; C-SSRS = Columbia Suicide Severity Rating Scale; CT = Computed Tomography; CXCL-10 = C-X-C motif 
chemokine 10; EBA = Eyebrow Assessment; ECG = electrocardiogram; ELA = Eyelash Assessment; EOT = End of Treatment; EOS = End of Study; EQ-5D-5L = EuroQoL 5 
Dimensions; EQ5D-Y = EuroQoL 5 Dimensions-Youth; ET = Early Termination; FACS-TBNK = fluorescence-activated cell sorting for T-cells, B-cells, and natural killer (NK) 
cells; FSH = follicle stimulating hormone; F/U = follow-up; HADS = Hospital Anxiety and Depression Scale; HBVDNA = hepatitis B viral DNA; Hep B = hepatitis B; 
Hep C = hepatitis C; HEENT = head, eyes, ears, nose and throat; HIV = human immunodeficiency virus; Ig = Immunoglobulin; IP10 = Interferon gamma-induced protein 10; 
MRI = Magnetic Resonance Imaging; N/A = Not Applicable; PGI-C = Patient’s Global Impression of Change; PHQ-8 = Patient Health Questionnaire – 8 items; 
PK = Pharmacokinetic; P-Sat = Patient Satisfaction with Hair Growth; SALT = Severity of Alopecia Tool; SF-36v2 = 36-Item Short Form Health Survey version 2; 
VZV IgG Ab = varicella-zoster virus immunoglobulin G antibody; WOCBP = women of childbearing potential; WPAI:AA = Work Productivity and Activity Impairment: 
Alopecia Areata.
a.
Day relative to start of study treatment (Day 1).
b.
If a subject discontinues from the study for any reason other than death, lost to follow-up, or withdrawal of consent, a Follow-Up Visit must be performed 
within 28 (+7 days) after the Early Termination visit.  In addition, all subjects who complete the study but do not enter the long-term extension study must 
have a Follow-Up Visit within 28 (+7 days) of End of Treatment visit.
c.
For subjects who discontinue early from the study, the procedures scheduled for ET Visit will be performed on the last day the subject takes the 
investigational product or as soon as possible thereafter.  Subject will then require a Follow-Up Visit within 28 (±7) days.
d.
Medical history and AA disease history includes detailed histories of conditions specified in Study Procedures Section 6.1.
e.
Complete physical examination consists of general appearance, skin, head, eyes, ears, nose and throat (HEENT); mouth, heart, lungs, abdomen, extremities, 
neurologic function, back, and lymph nodes.  In addition, dermatological full body exam must be performed.  Dermatological examinations should include 
visual inspection of the breasts and external genitalia.  When dermatologic adverse events are identified on physical exam, additional procedures may be 
required.  Please refer to Section 7.5.6.2 for additional details.
f.
Targeted physical examination consists of skin, heart, lungs, abdomen, neurologic function, and examination of body systems where there are symptom 
complaints by the subject.
g.
Vital signs, including pulse rate, blood pressure, respiratory rate, and temperature (eg, oral, tympanic, or axillary), should be performed before ECG and 
laboratory blood collection as specified in the protocol.
h.
ECG should be performed before laboratory blood collection.
i.
Height and weight will be measured without shoes or outerwear.


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Protocol Activity
Screening 
Period
Treatment Period
Loading Phase
Maintenance Phase
Extension Phase
F/Ub
ETc
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Daya
Day -35 
to -1
Day 1
Day 15
Day 29
Day 
57
Day 
85
Day 
127
Day 
169
Day 183 Day 197
Day 
239
Day 281
Day 337
Week
N/A
W2
W4
W8
W12
W18
W24
W26
W28
W34
W40
W48/EOT EOS
Visit Window
N/A
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
+7 
Days
j.
Chest X-ray or other appropriate diagnostic imaging (ie, CT or MRI) should be performed at Screening (unless taken within 3 months prior to the Screening 
visit).  Chest X-rays are required and should be performed as per local guidelines and standard of care (eg, posterior-anterior and lateral views).  Official 
reading must be located in the source documentation.
k.
For Screening, the audiological evaluation may be performed within 8 weeks prior to Day 1 but results must be available prior to Day 1 in order to assess 
eligibility.  At Screening, this includes audiological history, otoscopic examination, pure tone audiometry, air and bone conduction, speech audiometry, and 
immittance audiometry.  At subsequent visits, updated audiological history, otoscopic examination, and pure tone audiometry will be performed; based upon 
results, additional audiometry assessments may be required.  For details, refer to the Audiometry Study Guide.  All procedures must be performed as per the 
Audiometry Study Guide.  For subjects who terminate early from the study, efforts must be made to complete the audiological evaluation. 
l.
Hematology includes hemoglobin, hematocrit, red blood cell count, platelet count, white blood cell count, total neutrophils (%, Abs), basophils (%, Abs), 
eosinophils (%, Abs), lymphocytes (%, Abs), monocytes (%, Abs), and reticulocyte count (%, Abs).  Serum chemistry includes BUN/urea, creatinine, 
glucose, calcium, sodium, potassium, chloride, total CO2/bicarbonate, AST, ALT, total bilirubin, direct and indirect bilirubin, alkaline phosphatase, uric acid, 
albumin, total protein, and creatine kinase.  At Weeks 2 and 26, only hematology will be performed.
m. Fasting lipid profile includes total cholesterol, triglycerides, HDL, and LDL.  A minimum of 8-hour fasting is required for fasting lipid profile evaluation.
n.
Urinalysis will be performed by the central laboratory.  Microscopic analysis will be performed if urinalysis is positive for blood, nitrite, leukocyte esterase, 
and/or protein.  Urine culture will be performed if urinalysis is positive for nitrite and/or leukocyte esterase or if clinically indicated.
o.
Follicle stimulating hormone (FSH) test must be performed at Screening to confirm postmenopausal status in female subjects under 60 years old and who 
have been amenorrheic for at least 12 consecutive months with no alternative pathological or physiological cause to confirm postmenopausal status.
p.
Urine pregnancy test must be performed prior to dosing with the investigational product for female subjects of childbearing potential.  In the event that urine 
pregnancy tests are not permitted at an institution, serum pregnancy tests can be utilized.  In addition to urine pregnancy tests performed at each study visit, 
sites in Voluntary Harmonisation Procedure (VHP) countries in the European Medicines Agency (EMA) should instruct female subjects of childbearing 
potential to perform a urine pregnancy test at home between the Week 40 and 48 visits (at approximately Week 44).  In addition, the investigator or designee 
will instruct the subject to contact the site immediately if the urine pregnancy test result is positive or cannot be confirmed as negative.  The VHP countries 
participating in this study are Czech Republic, Germany, Hungary, Poland, and Spain.  
q.
Subjects who are positive for HIV antibodies will be screen-failed.
r.
All subjects will undergo Screening for Hep B and Hep C for eligibility.  All subjects will undergo testing for hepatitis B surface antigen (HBsAg) and 
hepatitis B core antibody (HBcAb).  Subjects who are HBsAg positive will not be eligible for this study.  Subjects who are HBsAg negative but HBcAb 
positive will be reflex-tested for hepatitis B surface antibody (HBsAb).  Additional reflex testing for hepatitis B virus DNA testing (HBVDNA) is also 
required for HBcAb positive subjects in countries in which Hep B prevalence has been reported at a rate of >5.0% or if required by local standard of care.  


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Protocol Activity
Screening 
Period
Treatment Period
Loading Phase
Maintenance Phase
Extension Phase
F/Ub
ETc
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Daya
Day -35 
to -1
Day 1
Day 15
Day 29
Day 
57
Day 
85
Day 
127
Day 
169
Day 183 Day 197
Day 
239
Day 281
Day 337
Week
N/A
W2
W4
W8
W12
W18
W24
W26
W28
W34
W40
W48/EOT EOS
Visit Window
N/A
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
+7 
Days
Please refer to Appendix 2 for testing algorithm, reflex testing, and full eligibility criteria.  For Japan-specific requirements, see Appendix 5.1.  For all 
subjects in the study, Hep C testing will be performed using hepatitis C antibody.  Subjects who are HCVAb positive will be reflex-tested for HCV RNA.  
Subjects who are positive for HCVAb and HCV RNA will not be eligible for this study.
s.
HBVDNA testing will be performed at Weeks 12, 24, 34, 48, and Early Termination for subjects who were enrolled with a positive HBcAb and a negative 
HBVDNA in those regions for which Hep B prevalence has been reported at a rate of >5.0% or if required by local standard of care (refer to Section 7.5.11
for information regarding which screening laboratory results should be used to determine whether HBVDNA testing should be performed).  Testing at 
additional time points may be performed as per the local standard of care.  For Japan-specific requirements see Appendix 5.1.  For all other countries, please 
refer to Appendix 2 for testing algorithm, reflex testing, and full eligibility criteria.
t.
Varicella-zoster virus immunoglobulin G antibody (VZV IgG Ab) testing is required to confirm eligibility only in adolescent subjects who have no 
documented evidence of having received varicella vaccination (2 doses).
u.
A serum sample will be collected at baseline and submitted to the central lab.  The sample will be stored and analyzed at a later date only at the sponsor’s 
request.  For example, in certain cases of suspected viral infection (eg, disseminated herpes zoster or varicella), the sponsor may request to analyze the 
sample to determine if the subject had exposure to that virus.
v.
A documented TB test performed within 12 weeks prior to Day 1 is acceptable.  Subjects with a history of tuberculosis may not require TB testing as per the 
protocol exclusion criteria in Section 4.2 Exclusion Criterion 21.  Perform TB test procedure using the QuantiFERON®-TB Gold In Tube (QFT-G) test.  If 
QFT-G test is not available, the T-SPOT®.TB (T-Spot) test can be used.  A negative Purified Protein Derivative (PPD) test can be substituted for the 
QFT-G test or T-Spot test only under specific circumstances described in Section 7.5.8.
w.
Dosing instructions will be provided to the subject and reviewed by the site at each visit.  Subjects should be encouraged to take the medication in the 
morning whenever possible.  Subjects should take the medication at approximately the same time every day.  However, at study visit days, subjects are to be 
instructed to refrain from dosing at home and are to take the dose in the clinic.
x.
Scalp photographs will be obtained at Screening to verify eligibility.  Scalp areas photographed should be recorded in study documents so that the same scalp 
region(s) is (are) photographed at all time points as applicable.  Photographs of eyelashes and eyebrows will also be taken. 
y.
The number of fingernails affected by AA will be counted.
z.
Subjects who have recent or active suicidal ideation or behavior will be excluded from the study.  For specific criteria regarding subjects with prior suicidal 
ideation or behavior, see Section 4.2.
aa. Only predose blood sample for PK will be collected at baseline (Visit 2 Day 1).


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Protocol Activity
Screening 
Period
Treatment Period
Loading Phase
Maintenance Phase
Extension Phase
F/Ub
ETc
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Daya
Day -35 
to -1
Day 1
Day 15
Day 29
Day 
57
Day 
85
Day 
127
Day 
169
Day 183 Day 197
Day 
239
Day 281
Day 337
Week
N/A
W2
W4
W8
W12
W18
W24
W26
W28
W34
W40
W48/EOT EOS
Visit Window
N/A
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
±3 Days based on 
Day 1 visit
±7 Days based on 
Day 1 visit
+7 
Days
bb. Blood samples for PK will be collected at predose and postdose 0.5 hr, 1 hr and 3 hr at Week 4; blood samples will be collected for predose and postdose 
0.5 hr and 2 hr at Week 8.  For each blood sample collection, the allowable windows are as follows for time postdose: 0.5 hr (±10 min), 1 hr (±15 min), 2 hr 
(±20 min) and 3 hr (±30 min).  If the blood samples for PK were collected at Week 8, no PK samples are required at Week 12.
cc. If not collected on the designated collection day, collect at the next available time point when biospecimens are being collected in conjunction with a subject 
visit.
dd. In female subjects who are premenarchal at the start of the study, the investigator must confirm with the subject at every visit whether menarche has started 
since the last visit.  If menarche has started, the subject must now be considered of childbearing potential; therefore, from that point forward, the subject 
must be required to use contraception as described in Section 4.3.1 and to undergo contraception checks and pregnancy testing according to the Schedule of 
Activities, starting with the current visit.  In addition, the investigator or designee must instruct the subject to call the study site immediately if the subject 
begins menarche between study visits.


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
PF-06651600 is an orally bioavailable, small molecule that is currently being investigated in 
patients with alopecia areata (AA).  PF-06651600 inhibits, by irreversibly blocking the 
adenosine triphosphate (ATP) binding site, JAK3 and the tyrosine kinase expressed in 
hepatocellular carcinoma (TEC) kinase family (BTK, BMX, ITK, TEC, TXK), with high 
selectivity over the other three JAK isoforms, JAK1, JAK2, and tyrosine kinase 2 (TYK2), as 
well as over the broader kinome.  PF-06651600 potently inhibits signaling of the common 
gamma ()-chain receptors for interleukin (IL)-15 and IL-21, which have been implicated in 
the pathogenic pathways of AA.1  Additionally, PF-06651600 inhibits the cytotoxic function 
of CD8+ T cells and natural killer (NK) cells which have also been implicated in the 
pathogenic process of AA.2,3  This inhibition may be mediated through mechanisms 
dependent on JAK3 and TEC kinase family members.4,5,6
1.2. Background and Rationale
1.2.1. Background on Alopecia Areata
Alopecia areata is a chronic relapsing T-cell mediated autoimmune disorder characterized by 
non-scarring hair loss affecting children and adults across all ages, races, and sexes.7,8  AA is 
associated with other immune diseases including asthma, allergic rhinitis, atopic dermatitis, 
and autoimmune diseases such as thyroiditis and vitiligo.8
CD8+ T cells, NK cells, and mast cells are involved in the pathogenesis of AA.  The possible 
inflammatory pathways in AA include cytokines from the type 1 helper T cell (TH1) axis, 
including interferon (IFN) alpha (), IFN gamma (), and IFN-induced protein 
10 (IP-10).9,10  Mouse models have shown that IL-2 and IL-15 play a role in the initiation of 
auto-reactive CD8+ cells that attack hair follicles.1  IL-12 and IL-23 may also play a role in 
the pathogenesis of AA.11
Clinical presentation of AA can be limited to small, circular patches of scalp hair loss (patchy 
hair loss, alopecia focalis), involve complete loss of hair on the scalp (alopecia totalis [AT]), 
or total loss of hair on the scalp and body (alopecia universalis [AU]).12  AA involving 
50% or greater scalp hair loss, including AT and AU, is considered an advanced form of 
alopecia, according to the United States (US) National Alopecia Areata Foundation.13  Patchy 
alopecia is the most common form of AA which may develop into the more extensive and 
often treatment-resistant forms of AA, especially with earlier age of onset.15  It is estimated 
that AA affects as many as 6 to 7 million individuals in the US8 and 147 million worldwide.13
The spontaneous remission rates for AA patients presenting with <50% scalp hair loss 
(patchy hair loss, alopecia focalis) are 30-50% within the first 6-12 months of disease onset, 
and 66% of the patients will show complete regrowth of hair within 5 years.14  The likelihood 
of complete regrowth spontaneously with AT or AU is less than 10%.16


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Further, there is evidence that AA can become refractory to JAK inhibition if it has been 
present for a substantial period of time.  Specifically, a recent case series demonstrated that 
AA patients whose current episode of alopecia totalis or alopecia universalis had lasted more 
than 10 years were highly non-responsive to off-label tofacitinib treatment in comparison 
with patients with shorter duration.17
Depression, anxiety, and panic disorders are often observed in patients with AA and the 
coping mechanisms of AA patients mirror those of grief and bereavement.19,20  A substantial 
body of evidence demonstrates a widespread impact of AA on the psychological health of 
both adult and pediatric patients with AA, including impairment in self-esteem, increased 
incidence of anxiety and depressive disorders and other psychological conditions,21-,25
problems with social relations,26 decreased health-related quality of life (HRQoL) and 
general quality of life (QoL), as well as the QoL of their families.27-35
AA is a disease with significant pediatric prevalence, in addition to the burden of disease 
seen in adults, and ample evidence is available on the impact of AA on the mental health of 
adolescent patients.  In a US study, children with AA had more psychological problems than 
those without AA.  Specifically, those with AA exhibited more anxiety, depression, 
tendencies to withdraw, aggression, and delinquency.  In addition, children with AA were 
more likely to exhibit somatic problems as well as problems in social relations and in 
attention span.  Girls with AA seem to have been affected more in dimensions of total 
problems, anxiety/depression, and internalizing/externalizing syndromes.  Children with 
AA were also less likely to have experienced positive life events in the year prior to 
exhibiting AA symptoms.26
In addition to experiencing a significant mental health burden, children with AA report 
experiencing other negative impacts to their QoL.  Specifically, 75% of children aged 
15-19 years reported instances of effects on QoL, 50% reported that the disease limited their 
participation in activities, 40% reported instances of bullying, and 35% reported that others 
noticed and commented on their condition.  Rates of decrement in QoL, limitations on 
participation in activities, and bullying were heightened in older children aged 15-19 years 
compared to younger children.36
Given the finding that complete scalp hair loss with duration >10 years in adults is less likely 
to respond to treatment, pursuing treatment, even if only intermittently, in adolescents or 
even younger patients with stable, severe AA may prevent future irreversible hair loss.17  
Additionally, an earlier age of first onset has been reported to correspond to an increased 
lifetime risk of extensive disease.  Differences in treatment responses are not expected for 
adolescent versus adult AA patients as suggested in 2 reports of tofacitinib (off-label 
use).17,37
No drugs have been approved for the treatment of AA in most countries/regions, including 
the US and the European Union (EU).  Review of the treatment guidelines and 
recommendations indicate that a number of off-label therapies are frequently used after 
assessing factors such as the age of the patient, disease extent, and disease duration.  
However, there is neither a cure for AA, nor is there a therapy convincingly demonstrated to 
induce and sustain remission long term.38-42


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1.2.2. Drug Development Rationale
The JAK family, including JAK1, JAK2, JAK3 and TYK2, is a group of cytoplasmic 
tyrosine kinases that mediate signal transduction via interactions with Type 1 and Type 2 
cytokine receptors critical for leukocyte activation, proliferation, survival and function.43,44  
Upon binding of the cytokine to its receptor, the associated JAKs are activated, and 
phosphorylate each other and the receptor.  The phosphorylated receptors serve as docking 
sites for the signal transducer and activator of transcription (STAT) family of transcription 
factors.  The STATs are phosphorylated and subsequently translocate to the nucleus where 
they bind to specific gene promoters to activate transcription of a range of target genes.43,44
JAK1 pairs with JAK3 to mediate -common cytokine signaling and also with JAK2 or 
TYK2 to transmit the signals of additional cytokines important in inflammation and immune 
responses including IL-2, IL-4, IL-5, IL-6, IL-12, IL-13, IL-15, IL-21, IL-23, IL-31, IFN, 
and IFN.43
The cytokine signaling pathways of IFNand IL-15, among others, can be blocked via JAK 
inhibition, supporting the rationale of a JAK inhibitor in the treatment of AA.45  Treatment 
with the JAK inhibitors tofacitinib and ruxolitinib are reported to reverse AA in a mouse 
model.2  Clinically, there are case reports and case series reporting that these JAK inhibitors 
demonstrate efficacy in AA.2,17,18,46-51
Based on the mechanism of action of PF-06651600, this candidate is expected to inhibit the 
signaling of multiple soluble cytokines and signaling pathways contributing to the AA 
pathogenesis.
1.3. Nonclinical and Phase 1 Efficacy and Safety Data
Data from nonclinical and Phase 1 programs supports the planned clinical trials with 
PF-06651600.
The no observed adverse effect levels (NOAEL) in the 6-month rat and second 9-month dog 
studies were 200 and 10 mg/kg/day, respectively.  In the second 9-month dog toxicity study, 
the NOAEL of 10 mg/kg/day was based on adverse over-immunosuppression and axonal 
dystrophy (not axonal degeneration) in the central nervous system and peripheral nervous 
system at ≥20 mg/kg/day, accompanied by functional auditory deficits (brainstem auditory 
evoked potentials) at the highest dose of 40 mg/kg/day (a 29-fold exposure multiple relative 
to the clinical dose of 50 mg).  The area under the concentration-time curve (AUC) exposure 
margins in this study at the NOAEL at study end were approximately 1.5x and 6.5x relative 
to the predicted exposure at the 200 mg and 50 mg clinical doses, respectively.
Further information is available in the current version of the Investigator’s Brochure (IB).
The potential for PF-06651600 to be involved in drug-drug interaction (DDI) is being 
investigated.  If results exclude a clinically meaningful DDI (eg, relative to AUC) between 
PF-06651600 and a perpetrator or victim drug then that perpetrator or victim drug will no 
longer be prohibited as a concomitant medication; this information will be communicated via 
an administrative letter.  Refer to Section 5.8.2 for medications prohibited to be used prior to 
and during the study.  


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1.4. Clinical Experience
There are complete and ongoing Phase 2 and 3 studies with PF-06651600 in a number of 
disease indications.  Forty-two (42) patients with rheumatoid arthritis were exposed to 
PF-06651600 in the Phase 2a study B7981006.91  Forty-eight (48) subjects were exposed to 
PF-06651600 in the Phase 2a Alopecia Areata study B7931005 in the initial 24-week 
period.92  There are ongoing studies in subjects with ulcerative colitis (B7981005)93, Crohn’s 
disease (B7981007)94, and vitiligo (B7981019)95.  These studies are expected to expose 
approximately 180, 125, and 330, respectively, to once daily (QD) PF-06651600 treatment.  
The duration of exposure will range from 24 to 32 weeks in B7981005, from 52 to 64 weeks 
in B7981007, and up to 48 weeks in B7981019.  In addition, there is the B7981032 study, an 
ongoing Phase 3 open-label study for subjects with alopecia areata who have previously 
enrolled in either the B7931005 or B7981015 studies as well as de novo subjects who have 
not received study intervention in either of those studies.96  Approximately 450 de novo 
subjects and 510 subjects from B7931005 or B7981015 will be exposed to PF-06651600 in 
the B7981032 study and the duration of exposure will range up to 26 months. 
1.4.1. Phase 2a Study in Alopecia
Study B7931005 is a Phase 2a, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy and safety profile of PF-06651600 and PF-06700841 (a TYK2/JAK1 
inhibitor) compared with placebo in adult (18-75 years-old) subjects with scalp hair loss of 
≥50% at baseline.  The study consisted of an initial 24-week double-blind treatment period, 
an up to 12-month extension period, and a 6-month cross-over open label extension period.  
A total of 142 subjects were randomized to study treatment: 47 subjects received placebo, 
48 subjects received PF-06651600 and 47 subjects received the other study treatment.
During the initial 24-week treatment period, subjects were treated with 200 mg QD during a 
4-week induction phase followed by dosing with 50 mg QD in a maintenance phase in the 
PF-06651600 group.  The primary efficacy endpoint in the study was mean change from 
baseline in SALT score at Week 24.  At Week 24, analysis provided data on both efficacy 
and safety, and indicated clinical improvement for subjects treated with PF-06651600.  
PF-06651600 met the predefined primary decision criterion (mean change from baseline 
[CFB] in SALT score, adjusted p-value <0.025, and point estimate >20% at Week 24).  The 
Mixed effect Model Repeat Measurement (MMRM) estimates for PF-06651600 compared to 
placebo at Week 24 for SALT mean CFB (95% CI) were 33.6 [95% CI= (21.4, 45.7); 
Hochberg p (1-sided) <0.0001].  PF-06651600 differentiates from placebo (statistically 
significant), as early as Week 6.  Overall, the placebo response was almost negligible.  
PF-06651600 also differentiates from placebo on the proportion of responders in eyelash 
assessment (ELA) and eyebrow assessment (EBA). 
During the initial 24-week treatment period of Study B7931005, there were no deaths and no 
subject in the PF-06651600 treatment group experienced a serious adverse event (SAE). The 
proportion of subjects who experienced treatment-emergent adverse events (TEAEs) in the 
placebo treatment group (74.5%) was comparable with the PF-06651600 treatment group 
(62.5%).  The TEAEs reported in more than 5% of subjects with AA receiving PF-06651600 
were headache, infections of upper respiratory tract, acne, diarrhea, nausea, and skin 


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infections.  The majority of events were mild.  No serious infections, malignancies, cases of 
herpes zoster, or cases of herpes simplex were reported in the PF-06651600 group.  
Hematological changes were observed in both active groups during the induction and 
maintenance periods but were not associated with clinically relevant TEAEs.  During the 
induction period, when subjects received PF-06651600 200 mg QD for 4 weeks, decreases in 
mean platelet and lymphocyte counts (-18% and -24% mean CFB, respectively) were 
observed in the PF-06651600 group.  During the maintenance period, when subjects received 
50 mg QD for 20 weeks, there was improvement in the platelet and lymphocyte counts in the 
PF-06651600 group.  Neutrophil counts were increased at Week 4 (12% CFB) and Week 24 
(10% CFB) in the PF-06651600 treatment group.  Two subjects in the PF-06651600 group 
discontinued due to TEAEs.
The final study results, including the results of the two extension periods, are described in the 
current version of the IB. 
1.4.2. Phase 2a Study in Rheumatoid Arthritis
The completed Phase 2a study B7981006 was an 8-week randomized, double-blind, 
placebo-controlled, parallel-group, multi-center study in subjects with moderate-to-severe 
active rheumatoid arthritis (RA) with an inadequate response to methotrexate.  A total of 
70 subjects were randomized to study treatment; 28 subjects received placebo and 
42 subjects received PF-06651600 (200 mg QD). 
PF-06651600 was determined to be generally safe and well tolerated in this study.  There 
were no deaths or SAEs.  TEAEs were numerically higher in subjects receiving PF-06651600 
compared to those receiving placebo.  The TEAEs reported in more than 5% subjects with 
RA receiving PF-06651600 were influenza and lymphopenia.  The majority of the TEAEs 
were mild in severity.  There was 1 mild case of herpes simplex in the PF-06651600 group 
that was considered to be treatment-related with no cases in the placebo group.  There were 
no clinically relevant changes in vital signs, electrocardiogram (ECG), or audiometric 
assessments.  By the Week 8 time point (as early as 2 weeks), in the PF-06651600 group, 
there were decreases in the median platelet counts (25% change from baseline), lymphocyte 
counts (21% change from baseline), neutrophil counts (24% change from baseline), and 
hemoglobin (3% change from baseline).  None of these were deemed to be clinically relevant 
by the investigator and values returned to near baseline by the 12-week follow-up visit.
1.4.3. Clinical Pharmacokinetics and Metabolism
Pharmacokinetics, bioavailability, and food effect have been studied in several Phase 1 
clinical trials.  For a complete description of these studies, please refer to the IB.
These studies demonstrated that the PK profile of PF-06651600 is characterized by rapid 
absorption with time (Tmax) to first occurrence of maximum plasma concentration (Cmax) 
values <1 hour and rapid elimination (half-life [t½] of 1.1–2.5 hours).  Systemic exposures 
increase in an approximately dose proportional manner across 50 mg to 400 mg total daily 
dose with observed accumulation ratios (Rac) ranging from 1-1.8.  A similar PK profile was 
observed in Japanese subjects following administration of 200 mg PF-06651600 QD for 
10 days.  The bioavailability of a solid dose formulation of PF-06651600 relative to a 


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solution formulation under fasting conditions and the effect of food on the bioavailability of 
the solid dosage formulation of PF-06651600 was evaluated.  The relative bioavailability of 
the PF-06651600 tablet as measured by area under the plasma concentration time curve from 
time zero to infinity (AUCinf) is similar to that of an oral solution.  PF-06651600 can be 
administered with or without food. 
In vitro and in vivo metabolite profiling suggested that the primary clearance mechanisms for 
PF-06651600 were glutathione-related conjugation and cytochrome P450 (CYP)-mediated 
oxidation with the major contributing isoform being CYP3A4.  No unique human 
metabolites were observed clinically compared to metabolite profiles in mouse, rat, and dog.  
PF-06651600 showed a low risk of inhibition and induction of the major CYP450 and uridine 
diphosphate glucuronosyltransferase (UGT) enzymes, although time-dependent inhibition of 
CYP1A2 (inhibitory concentration 50% [IC50] = 65 µM) and CYP3A4/5 (IC50 = 11 to 14 M) 
was observed.  PF-06651600 showed a low potential to inhibit organic anion transporting 
polypeptide (OATP) 1B1, OATP1B3, bile salt export pump (BSEP), organic cation 
transporter (OCT)2, organic anion transporter (OAT)1, and OAT3 at clinically relative 
concentrations.  However, PF-06651600 has the potential to inhibit P-glycoprotein (P-gp) 
(systemically and in the gastrointestinal [GI] tract), breast cancer resistance protein (BCRP) 
(systemically and in the GI tract), OCT1, multidrug and toxin extrusion (MATE)1, and 
MATE2K at clinically relevant concentrations.
In general, systemic exposures in the adolescent populations do not differ significantly from 
adults, which justifies similar doses for adults and adolescents.52,53  Based on the current 
knowledge of the disposition of PF-06651600, which is primarily metabolism, adolescents 
are expected to have a similar range of exposures as seen in adults. 
1.5. Study Rationale
This study is being conducted to evaluate the efficacy and safety of multiple doses/regimens 
of PF-06651600 in comparison with placebo over the first 24 weeks treatment duration.  This 
will be followed by an additional 24-week extension period during which all subjects will 
receive active treatment including those subjects who received placebo during the initial 
24 weeks of the study.
This study will test multiple dose regimens, including the dose regimen with demonstrated 
clinical efficacy in the ongoing Phase 2a Study B793100592, as well as several lower doses to 
evaluate dose-response relationships.  The rationale for selection of the dosing regimens in 
this study is further described in Section 1.6.
In addition to dose-ranging, the other objectives of this study are to support registration for 
treatment of patients with moderate to severe AA and to evaluate safety in this population. 
To achieve this, response based on absolute SALT score ≤20 at Week 24 will be the primary 
endpoint for analyzing a dose-response and for confirming a clinically meaningful treatment 
effect in patients with AA.89  SALT is an instrument that is widely used to assess severity of 
AA by visual determination of the amount of terminal hair loss and summing across four 
views of the scalp (left side, right side, top and back; range 0-100%).54,55  This tool has been 
well accepted and used in multiple AA clinical trials (NCT02691117; NCT01950780; and 
NCT01797432) as a reliable and reproducible measure of disease severity.17,18,49,56  


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The extension phase of this study will provide additional blinded safety and efficacy data, 
including long-term data in subjects initially randomized to active treatment as well as data in 
subjects initially randomized to placebo and subsequently advanced to active treatment at 
Week 24.
The total sample size for the study is approximately 660 randomized subjects.
1.6. Dose Rationale
This study will evaluate PF-06651600 administered at a loading dose of 200 mg QD for 
4 weeks followed by maintenance doses of 30 mg and 50 mg QD for 20 weeks relative to 
placebo (until the primary endpoint, Week 24).  The maintenance doses will then be 
continued for an additional 24 weeks.  Additionally, doses of 10 mg, 30 mg and 50 mg QD 
will be evaluated relative to placebo for 24 weeks and continued for an additional 24 weeks 
as a fixed-dose regimen (ie, without loading dose). 
The rationale for the selection of the doses and regimens is based on:
Efficacy and safety results for the initial 24 weeks of PF-06651600 treatment from Study 
B793100592 in subjects with AA.
Dose/Exposure response relationships observed for PF-06651600 relevant biomarkers.
Safety results for PF-06651600 from Study B798100691 in subjects with RA.
Exposure margins of proposed clinical doses relative to nonclinical no observed adverse 
effect level (NOAEL)/lowest observed adverse effect level (LOAEL) exposures
(Table 1). 
An analysis of the initial 24 weeks (primary objective) of the ongoing Phase 2a Study 
B7931005 was performed at Week 24.  In that study, PF-06651600 was evaluated at 200 mg 
QD for 4 weeks followed by 50 mg QD for 20 weeks compared to placebo.  Both safety and 
efficacy data from the analysis suggest that this dosing regimen of PF-06651600 is 
appropriate for further investigation.
Mechanistically, PF-06651600 inhibits signaling of the common-chain receptors for 
IL-15 and IL-21, which have been implicated in the pathogenic pathways of AA.  There is 
also evidence of modulation of IP-10, which is a marker related to IFN.
The need for a loading-dose regimen is based on the hypothesis that maximal inhibition of 
the relevant immunomodulatory pathways at initiation of treatment can accelerate clinical 
response which can be maintained by the subsequent lower maintenance dose.  The 200 mg 
dose chosen as the loading dose is expected to produce a >70% IL-15 and IL-21 in vitro 
signaling inhibition, with ~40% reduction in IP-10 levels from baseline.  The 200 mg dose 
has demonstrated acceptable safety over 4 weeks in B7931005 in AA patients and 8 weeks in 
B7981006 in moderate to severe RA patients as described in Section 1.4.  


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The highest maintenance dose of 50 mg is expected to produce ~30-40% IL-15 and IL-21 in 
vitro signaling inhibition, with ~18% reduction in IP-10 levels from baseline.  The 50 mg 
maintenance dose demonstrated acceptable safety over a 20-week period in Study B7931005 
in AA patients as described in Section 1.4.1. 
Exposure margins of the proposed clinical doses relative to the NOAEL exposures are 
summarized in Table 1.
The dose of 10 mg is likely to be a minimally efficacious dose as it is expected to produce a 
<10% change from baseline in IP-10 levels.
In this study, PF-06651600 doses of 10 mg, 30 mg, and 50 mg will be evaluated as a fixed 
regimen, and 30 mg and 50 mg will also be evaluated following the 200 mg loading dose, in 
order to identify the optimal clinical dose and regimen necessary.
Table 1.
PF-06651600 Exposure Margins and No Observed Adverse Effects Level
Dose/Route
Mean AUC in 
Dogs (unbound, 
ng•hr/ml)
Mean Clinical 
AUC (unbound, 
ng•hr/ml)
Calculated 
Safety Margin
Safety Exposure Margins for Human 200 mg QD Dose (B7931005)
Dog 2-month 
toxicology (Study 1)
NOAEL:
45 mg/kg oral
44100
5464
8.1
Dog 9-month 
toxicology (Study 2)
NOAEL:
10 mg/kg oral
7940
5464
1.5
Safety Exposure Margins for 50 mg QD Dose (B7931005)
Dog 2-month 
toxicology (Study 1)
NOAEL:
45 mg/kg oral
44100
1213
36
Dog 9-month 
toxicology (Study 2)
NOAEL:
10 mg/kg oral
7940
1213
6.5
Abbreviations: AUC = area under the concentration-time curve; NOAEL = no observed adverse effect level; 
QD = once daily.
1.7. Summary of Benefit/Risk Assessment
In the Phase 2a proof-of-concept Study B793100592 in adult patients with AA, PF-06651600 
met its primary endpoint of improvement in SALT score relative to placebo at Week 24.  
PF-06651600 appeared generally safe and well tolerated as suggested by adverse event (AE) 
number and profile.  Reductions in platelet counts and lymphocyte counts were observed 
during treatment with 200 mg QD but were not considered clinically meaningful and 
improved after switching to 50 mg QD during the maintenance phase of the study.  
PF-06651600 is an immunomodulator and, as such, can be associated with the potential risk 
of infection (including serious infection), opportunistic infections, and viral reactivation.  The 
risk of infection will be monitored and evaluated in longer term studies of PF-06651600. 


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These preliminary clinical data indicate that PF-06651600 has a favorable benefit: risk 
profile and provides meaningful clinical benefit in a serious disease with no approved 
treatment options.  The benefit of evaluating PF-06651600 in adolescents is additionally 
supported by prevalence of AA in adolescents, the significant psychological burden of 
disease in this population, and a recent case series suggesting that extended duration of 
AA appears to increase likelihood of being refractory to off-label tofacitinib treatment.
It is not known whether PF-06651600 is secreted into human milk.  In animals, PF-06651600 
was associated with fetal changes in bones and some internal organs, and lower fetal body 
weights.  Because of the investigational nature of PF-06651600, it should not be 
administered to pregnant women, breastfeeding women, or fertile women of childbearing 
potential who are unwilling or unable to use contraception as defined in the study protocol.  
PF-06651600 is not likely to transfer to a partner through semen at pharmacologically 
relevant levels.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure (IB).
1.8. Additional Information
Banked biospecimens will be collected for the purpose of conducting research; specific uses 
are described in the Banked Biospecimens section.  Comparing the deoxyribonucleic acid 
(DNA), ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who
respond well and those who respond poorly to treatment may help to better define the most 
appropriate group of subjects in which to target a given treatment.  Collecting biospecimens 
for exploratory pharmacogenomic/genomic/biomarker analyses and retaining them in the 
Biospecimen Banking System (BBS) make it possible to better understand the investigational 
product’s mechanism of action and to seek explanations for differences in, for example, 
exposure, tolerability, safety, and/or efficacy not anticipated prior to the beginning of the 
study.
Banked biospecimens retained in the BBS also can be used in research on AA.
Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited by local regulations or ethics committee (EC) decision.


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2. STUDY OBJECTIVES AND ENDPOINTS
The following table details the overall study objectives and endpoints.  There are some 
region specific differences noted throughout.  Table 5 in Section 9 lists the primary and 
secondary endpoints of the study organized by known regional requirements. 
Primary Objective(s):
Primary Endpoint(s):

To evaluate the efficacy of PF-06651600 compared to 
placebo in adult and adolescent alopecia areata (AA) 
subjects with 50% or greater scalp hair loss on 
regrowth of lost hair (measured by an absolute 
Severity of Alopecia Tool (SALT) Score ≤20) at week 
24.
Note: For the European Medicines Agency (EMA)
and competent authorities in the Voluntary 
Harmonisation Procedure (VHP) countries,a the
primary objective is to evaluate the efficacy of 
PF-06651600 compared to placebo in adult and 
adolescent AA subjects with 50% or greater scalp hair 
loss on regrowth of lost hair (measured by an absolute 
Severity of Alopecia Tool (SALT) Score ≤10) at 
Week 24.

Response based on an absolute Severity of Alopecia 
Tool (SALT) Score ≤20 at Week 24. 
Note: For the EMA and competent authorities in the 
VHP countries, response based on an absolute SALT 
Score ≤10 at Week 24 will be analyzed as the primary 
endpoint in a separate analysis.
Key Secondary Objective(s)
Key Secondary Endpoint(s):

To evaluate the efficacy of PF-06651600 compared to 
placebo in adult and adolescent AA subjects with 50% 
or greater scalp hair loss on regrowth of lost hair (as 
measured by an absolute SALT Score ≤10) at Week
24.
Note: This key secondary objective will be utilized as 
the primary objective for the EMA and competent 
authorities in the VHP countries.  Additionally, this 
key secondary objective will not apply for the United 
States Food and Drug Administration (FDA)/Japan 
Pharmaceuticals and Medical Devices Agency 
(PMDA).

Response based on an absolute SALT Score ≤10 at 
Week 24.
Note: This key secondary endpoint will be utilized as 
the primary endpoint for the EMA and competent 
authorities in the VHP countries. Additionally, this 
key secondary endpoint will not apply for the 
FDA/PMDA. 

To evaluate the effect of PF-06651600 on patient 
centered outcomes (as measured by PGI-C response) 
at Week 24.
Note: This key secondary objective is only applicable 
for the EMA and competent authorities in the VHP 
countries.

PGI-C response defined as a score of “moderately 
improved” or “greatly improved” at Week 24.
Note: This key secondary endpoint is only applicable 
for the EMA and competent authorities in the VHP 
countries.
Secondary Objective(s):
Secondary Endpoint(s):

To characterize the exposure response of 
PF-06651600 on regrowth of lost hair.

Response based on an absolute SALT Score ≤20 at 
Week 24 will be used to characterize the exposure 
response.b

To assess the efficacy of PF-06651600 on regrowth of 
lost hair during the treatment period over time.

Response based on an absolute SALT score ≤20 at 
Weeks 4, 8, 12, 18, 28, 34, 40, and 48.c,d


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
Response based on an absolute SALT score of ≤10 at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.e

Response based on a 75% improvement in SALT 
score from baseline (SALT75) at Weeks 4, 8, 12, 18, 
24, 28, 34, 40, and 48. 

Change from baseline in SALT scores at Weeks 4, 8, 
12, 18, 24, 28, 34, 40, and 48.

Response based on at least a 2-grade improvement or
a score of 3 in Eyebrow Assessment (EBA) score at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Response based on at least a 2-grade improvement or 
a score of 3 in Eyelash Assessment (ELA) score at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

To evaluate the effect of PF-06651600 on 
patient-centered outcomes and payer relevant 
measures to assess treatment benefit from the patient 
perspective and to demonstrate value.f

PGI-C response defined as a PGI-C score of 
“moderately improved” or “greatly improved” at 
Weeks 4, 8, 12, 18, 24, 34, 40, and 48.f

Change from baseline in Alopecia Areata Patient 
Priority Outcomes (AAPPO) scales at Weeks 4, 8, 12, 
18, 24, 34, 40, and 48.

Safety Objective(s)
Safety Endpoint(s)

To evaluate the safety and tolerability of 
PF-06651600 in the treatment period over time.

Incidence of treatment-emergent adverse events 
(AEs).

Incidence of serious AEs (SAEs) and AEs leading to 
discontinuation.

The incidence of clinically significant abnormalities 
in vital signs.

The incidence of clinically significant abnormalities 
in clinical laboratory values.

PK Objective(s)
PK Endpoint(s)

To characterize pharmacokinetics of PF-06651600.

Plasma concentrations of PF-06651600 at Weeks 4, 
and 8 or 12.
Exploratory Objective(s):
Exploratory Endpoint(s):

To collect banked biospecimens for exploratory 
research, unless prohibited by local regulations or 
ethics committee decision.

Collection of banked biospecimens unless prohibited 
by local regulations or ethics committee decision.  
Additional information on collection and potential 
use is provided in the Banked Biospecimens section.

To assess the efficacy of PF-06651600 on regrowth of 
lost hair during the treatment period over time.

Response based on a 50% improvement in SALT 
score from baseline (SALT50) at Weeks 4, 8, 12, 18, 
24, 28, 34, 40, and 48.

Absolute SALT scores at Baseline, Weeks 4, 8, 12, 
18, 24, 28, 34, 40, and 48.


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
To evaluate the effect of PF-06651600 on 
patient-centered outcomes and payer relevant 
measures to assess treatment benefit from the patient 
perspective and to demonstrate value.

Improvement on PGI-C defined as “slightly 
improved”, “moderately improved”, or “greatly 
improved” at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.  

Improvement on Patient Satisfaction with Hair 
Growth (P-Sat) items defined as slightly, moderately, 
or very satisfied at Weeks 4, 8, 12, 18, 24, 34, 40, and 
48.

Change from baseline in EuroQoL 
5 Dimensions (EQ-5D-5L) in adults or 
EuroQoL 5 Dimensions-Youth (EQ-5D-Y) in 
adolescents at Weeks 4, 12, 24, and 48.

Change from baseline in Alopecia Areata 
Resource Utilization (AARU) at Weeks 12, 24, 
34, and 48.

Change from baseline in Work Productivity and 
Activity Impairment: Alopecia Areata (WPAI:AA) at 
Weeks 12, 24, 34, and 48.

Change from baseline in the depression subscale 
score of the Hospital Anxiety and Depression Scale 
(HADS) at Weeks 4, 8, 12, 24, and 48.g,87

Change from baseline in the anxiety subscale score of 
the HADS at Weeks 4, 8, 12, 24, and 48.g,87

Improvement on HADS among subjects with a 
baseline subscale score indicative of depression who 
achieved a “normal’ subscale score indicative of an 
absence of depression at Weeks 4, 8, 12, 24, and 
48.g,79,88

Improvement on HADS among subjects with a 
baseline subscale score indicative of anxiety who 
achieved a “normal’ subscale score indicative of an 
absence of anxiety at Weeks 4, 8, 12, 24, and 48.g,79,88

Change from baseline in 36-Item Short Form Health 
Survey version 2 Acute (SF36v2 Acute) at Weeks 4, 
8, 12, 24, and 48.

To evaluate the effect of PF-06651600 on the 
clinician global impression of severity of scalp hair 
loss.

Change from baseline in Clinician Global Impression 
– Alopecia Areata (CGI-AA) at Weeks 4, 8, 12, 18, 
24, 28, 34, 40, and 48.

To evaluate efficacy of PF-06651600 in AA nail 
disease over time.

Change from baseline in fingernails affected by AA 
at Weeks 12, 24, 34, 40, and 48.

To assess pharmacodynamic and disease-related 
biomarkers over time.

Change from baseline in interferon gamma-induced 
protein 10 (IP-10) at Weeks 4, 8, 12, and 24.


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
Change from baseline in percent and absolute 
lymphocyte subsets (T-cell, B-cell, and natural killer 
[NK] cells) at Weeks 4, 12, 24, and 48.

Change from baseline in immunoglobulins (IgA, IgG, 
IgM) at Weeks 24 and 48.
a.
The VHP countries participating in this study are Czech Republic, Germany, Hungary, Poland, and Spain.
b.
For the EMA and competent authorities in the VHP countries, when SALT ≤10 is utilized for the primary endpoint, 
exposure response will be analyzed utilizing SALT ≤10 in a separate analysis.
c.
For the EMA and competent authorities in the VHP countries, when SALT ≤10 is utilized for the primary endpoint, 
SALT ≤20 at Week 24 will be analyzed as a secondary endpoint.
d.
When SALT ≤20 response at Week 24 is utilized as the primary endpoint, responses based on absolute SALT score 
≤20 at Weeks 18, 12, 8 and 4 will be analyzed controlling for Type I error utilizing an appropriate testing procedure.  
When SALT ≤10 response at Week 24 is utilized as the primary endpoint, the response based on absolute SALT 
score ≤20 at Week 24 will be analyzed controlling for Type I error utilizing an appropriate testing procedure. 
e.
When SALT ≤20 response at Week 24 is utilized as the primary endpoint, the response based on absolute SALT 
score ≤10 at Week 24 will be analyzed controlling for Type I error utilizing an appropriate testing procedure.  When 
SALT ≤10 response at Week 24 is utilized as the primary endpoint, the responses based on absolute SALT score 
≤10 at Weeks 18, 12, 8 and 4 will be analyzed controlling for Type I error utilizing an appropriate testing procedure. 
f.
For the EMA and competent authorities in the VHP countries, the evaluation of the effect of PF-06651600 on 
patient centered outcomes (as measured by PGI-C response at Week 24) is a key secondary objective.  The PGI-C 
response at Week 24 will be analyzed as a key secondary endpoint utilizing an appropriate testing procedure to 
control overall Type I error.
g.
For the EMA and competent authorities in the VHP countries, endpoints utilizing the HADS will be analyzed as 
secondary endpoints.
3. STUDY DESIGN
Study B7981015 will investigate PF-06651600 in subjects with moderate to severe AA.  This 
is a Phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging study.  The 
study will have a maximum duration of approximately 57 weeks.  This includes an up to 
5-week Screening period, a 48-week treatment period, and a 4-week follow-up period as 
shown in Figure 1.  The treatment period will be comprised of a placebo-controlled period 
that includes a 4-week loading phase and a 20-week maintenance phase, followed by a 
24-week extension phase.  The study will enroll a total of approximately 660 subjects.  The 
study will be conducted at approximately 120 sites. 
To be eligible to enroll in this study, subjects must have moderate to severe AA with 
≥50% hair loss of the scalp (SALT score ≥50) at both Screening and baseline visits, without 
evidence of terminal hair regrowth within the previous 6 months and with the current episode 
of hair loss ≤10 years.  The full list of eligibility criteria for the study is included in 
Section 4.
Screening will occur within 35 days prior to the first dose of study drug to confirm that 
subjects meet selection criteria for the study.  Photographs will be taken at the Screening 
Visit to verify eligibility (AA with ≥50% hair loss of the scalp).  Eligible subjects will be 
randomized as described below.
A stratified randomization will be used for operational purposes in order to achieve a target 
global composition for AT/AU and adolescent subjects in the enrolled population.  The 
targets for enrollment are approximately 40% AT/AU and approximately 15% adolescents.  


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The randomization will be operationalized as follows.  In regions enrolling both adolescents 
and adults, there will be four strata:
<18 years of age and AT/AU;
<18 years of age and not AT/AU;
≥18 years of age and AT/AU; and
≥18 years of age and not AT/AU.
Within each of these strata, subjects will be randomized in a 2:2:2:2:1:1:1 manner to blinded 
PF-06651600 and matching placebo for a total of 7 treatment sequences.  
In regions enrolling only adults, there will be two strata:
≥18 years of age and AT/AU; and
≥18 years of age and not AT/AU.
In these regions, subjects will be randomized using the same ratio as described for regions 
enrolling both adolescents and adults.
Figure 1 provides a schematic of the study design and the 7 treatment sequences.  All 
subjects will begin dosing during the loading period according to their assigned sequence.  
Following the 4-week loading period, subjects will continue dosing according to their 
assigned sequence in the 20-week maintenance period.  At the end of the maintenance period, 
placebo-treated subjects will be advanced in a prespecified, blinded manner to one of two 
active treatment sequences for the remainder of the study (through Week 48).  Investigators, 
subjects, and the sponsor study team will be blinded as to treatment group throughout the 
duration of the study.  Following the last dose of study drug, both discontinued and 
completed subjects will enter into a 4-week follow-up period for safety monitoring.  Subjects 
who complete treatment may be eligible for enrollment in a long-term study (Phase 3 study 
B7981032).  Subjects who enroll immediately into the B7981032 study will not be required 
to complete the 4-week follow-up period in this study.


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Figure 1.
Study Design Schematic
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects 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 subject is suitable for this protocol. 
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 
NOTE: There are certain eligibility requirements specific to subjects within Voluntary 
Harmonisation Procedure (VHP) countries in the EMA.  The VHP countries participating in 
this study are Czech Republic, Germany, Hungary, Poland, and Spain.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject or a legally acceptable representative/parent(s)/legal guardian has been 
informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
* Primary endpoint for the overall study is response based on absolute Severity of Alopecia Tool (SALT) Score ≤20 at 
1         15         29       57            85              127              169         183      197        239        281         337   365    
BL       2            4          8            12               18                24*          26        28          34                        48   F/U    
40    


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3. Male or female subjects age 12 years and older, inclusive, at time of informed 
consent/assent.  Adolescent subjects below the age of 18 years will only be enrolled 
into this study if permitted by the sponsor, local competent authority, and institutional 
review board (IRB)/ethics committee (EC).  Otherwise, only subjects 18 years or 
older (or age specified by applicable reviewer) will be enrolled in those countries, 
regions, or sites.  Within VHP countries in the EMA, subjects must be aged 18 
through 74 years at the time of informed consent.  
4. Subjects must meet/comply with the following reproductive criteria:
Females:
Female subjects are eligible to participate if they are not pregnant or breastfeeding, 
and at least 1 of the following conditions applies: 
a.
Is a woman of childbearing potential (WOCBP) and using a contraceptive method 
that is highly effective (with a failure rate of <1% per year), as described in 
Section 4.3, during the intervention period and for at least 28 days after the last 
dose of study intervention.  The investigator should evaluate the effectiveness of 
the contraceptive method in relationship to the first dose of study intervention.
OR
b. Is not a WOCBP (see definitions below): 
Women in the following categories are not considered WOCBP:

Premenarchal.

Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical 
cause other than the above, (eg, Müllerian 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.


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
Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  In addition, a high follicle stimulating hormone 
(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 hormone replacement therapy (HRT).  Females 
on HRT and whose menopausal status is in doubt will be required to use 
one of the nonestrogen hormonal highly effective contraception methods if 
they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment.
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.  Documentation of this review should be included in the 
participant’s medical record for the study.
Males:
Outside of VHP countries in the EMA, no contraceptive methods are required for 
male subjects in this study.
Within VHP countries in the EMA, male subjects are eligible to participate if they 
agree to the following requirements during the intervention period and for at least 90 
days after the last dose of study intervention: 

Refrain from donating sperm.
AND

Use one acceptable method of contraception as described in Section 4.3.  
5. Must meet the following AA criteria:
a.
Have a clinical diagnosis of AA with no other etiology of hair loss (eg, telogen 
effluvium, androgenetic alopecia, etc.).
b. ≥50% hair loss of the scalp, including alopecia totalis (AT) and alopecia 
universalis (AU), without evidence of terminal hair regrowth within 6 months at 
both the screening and baseline visits. 

AT is defined as complete (100%) scalp hair loss.

AU is defined as complete (100%) scalp, facial, and body hair loss. 

Percentage of hair loss on the scalp will be measured by SALT. 


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
Photographs taken at Screening must be submitted to the Sponsor or designee 
for verification of SALT score ≥50 and hair loss due to AA.  Subjects must 
not be randomized until verification has been confirmed.
c.
Current episode of hair loss ≤10 years.
6. If receiving permitted concomitant medications for any reason other than AA, 
subjects should be on a stable regimen, which is defined as not starting a new drug or 
changing dosage within 7 days or 5 half-lives (whichever is longer) prior to Day 1.  
Subject must be willing to stay on a stable regimen during the duration of the study 
(see Section 5.8). 
7. Must agree to avoid prolonged exposure to the sun and not to use tanning booths, sun 
lamps or other ultraviolet light sources during the study.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
2. Participation in other studies involving investigational drug(s) within 8 weeks or 
within 5 half-lives (if known), whichever is longer, prior to study entry and/or during 
study participation.
3. Other types of alopecia (including, but not limited to traction and scarring alopecia, 
telogen effluvium).  Subjects with known androgenetic alopecia will be excluded. 
4. Other scalp disease that may impact AA assessment (eg, scalp psoriasis, dermatitis, 
etc).
5. Active systemic diseases that may cause hair loss (eg, lupus erythematosus, 
thyroiditis, systemic sclerosis, lichen planus, etc).
6. Any psychiatric condition including recent or active suicidal ideation or behavior that 
meets any of the following criteria: 
a.
Suicidal ideation associated with actual intent and a method or plan in the past 
year: “Yes” answers on items 4 or 5 of the Columbia Suicide Severity Rating 
Scale (C-SSRS). 
b. For subjects who had previous history of suicidal behaviors in the past >1 year to 
<5 years: “Yes” answer (for events that occurred in the past 5 years) to any of the 
suicidal behavior items of the C-SSRS or any lifetime history of serious or 


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recurrent suicidal behavior, a risk assessment must be performed, and 
documented, by a qualified mental health professional to assess whether it is safe 
for the subject to participate in the trial.
c.
Clinically significant depression as indicated by the Patient Health 
Questionnaire - 8 Items (PHQ-8) total score ≥15. 
d. The presence of any current major psychiatric disorder that is not explicitly 
permitted in the inclusion/exclusion criteria. 
NOTE: For any subject who has significant depression or any suicidal behavior, the 
subject will not be randomized and should be referred for appropriate evaluation and 
treatment.
7. Have hearing loss with progression over the previous 5 years, or sudden hearing loss, 
or middle or inner ear disease such as otitis media, cholesteatoma, Meniere’s disease, 
labyrinthitis, or other auditory condition that is considered acute, fluctuating or 
progressive. 
8. Received any of the following treatment regimens specified in the timeframes 
outlined below:
a.
At any time: previous use of any JAK inhibitor for use in any disease indication 
or any non-B-cell selective lymphocyte-depleting agent (eg, alefacept, 
alemtuzumab).
b. Within 6 months of first dose of study drug or 5 half-lives (if known), or until 
lymphocyte count returns to normal, whichever is longer: any B-cell-depleting 
agents including but not limited to rituximab.
c.
Within 12 weeks of first dose of study drug or 5 half-lives (if known), whichever 
is longer: other immunomodulatory biologic agents.
d. Within 8 weeks of first dose of study drug or within 5 half-lives (if known), 
whichever is longer:

Other systemic treatments that could affect AA including:

Immunosuppressants (eg, cyclosporine A, azathioprine, methotrexate 
[MTX], sulfasalazine, mycophenolate mofetil [MMF], everolimus, 
ibrutinib).

Intralesional, oral, or injectable steroids.

5α-Reductase inhibitors (5-ARIs) (eg, finasteride, dutasteride).

Oral minoxidil.

Spironolactone if used specifically for AA.


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e.
Within 6 weeks of first dose of study drug: vaccination with live or attenuated 
live vaccine.
f.
Within 4 weeks of first dose of study drug: Ultraviolet B (UVB) phototherapy, 
Psoralen Ultraviolet A (PUVA) therapy, other phototherapy, contact 
immunotherapy (eg, diphenylcyclopropenone [DPCP], squaric acid dibutylester 
[SADBE], and 1-chloro-2,4-dinitrobenzene [DNCB]), topical irritants (eg, 
anthralin), and liquid nitrogen cryotherapy.
g. Within 4 weeks of first dose of study drug or 5 half-lives (whichever is longer): 
prohibited cytochrome P450 isoenzyme 3A (CYP3A) inducers as described in 
Appendix 4.
h. Within 2 weeks of first dose of study drug: topical treatments on areas under 
assessment (ie, scalp, eyebrows, eyelashes, and fingernails) that could affect AA 
(eg, steroid cream, medicated shampoo, minoxidil).
i.
Within 1 week of first dose of study drug:

Herbal medications with unknown properties or known effects for AA.

Prohibited CYP3A substrates as described in Appendix 4 (within 7 days or 
5 half-lives, whichever is longer).
j.
Subjects with shaved heads must not enter the study until hair has grown back and 
is considered stable by the investigator.
9. Treatment anticipated with prohibited concomitant medication(s) (see Section 5.8.2
and Appendix 4) during the course of the study.
10. Current or recent history of clinically significant severe, progressive, or uncontrolled 
renal (including but not limited to active renal disease or recent kidney stones), 
hepatic, hematological, gastrointestinal, metabolic, endocrine (particularly thyroid 
disease which can be associated with hair loss), pulmonary, cardiovascular, 
psychiatric, immunologic/rheumatologic or neurologic disease; or have any other 
severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational 
product administration, or interfere with the interpretation of study results; or in the 
opinion of the investigator or Pfizer (or designee), the subject is inappropriate for 
entry into this study, or unwilling/unable to comply with STUDY PROCEDURES
and Lifestyle Requirements.
11. Any present malignancies or history of malignancies with the exception of adequately 
treated or excised non-metastatic basal cell or squamous cell cancer of the skin or 
cervical carcinoma in situ.


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12. History of any lymphoproliferative disorder such as Epstein Barr Virus (EBV) related 
lymphoproliferative disorder, history of lymphoma, history of leukemia, or signs and 
symptoms suggestive of current lymphatic or lymphoid disease.
13. History (single episode) of disseminated herpes zoster or disseminated herpes 
simplex, or a recurrent (more than one episode of) localized, dermatomal herpes 
zoster.
14. Adolescent subjects 12 to <18 years-old without one of the following:

Documented evidence of having received varicella vaccination (2 doses); or

Evidence of prior exposure to varicella-zoster virus (VZV) based on 
serological testing (ie, a positive VZV immunoglobulin G antibody [VZV IgG 
Ab] result) at screening.
NOTE: Serological testing must be performed for VZV IgG Ab only in the 
absence of documented evidence of having received varicella vaccination 
(2 doses).  If serological testing is performed in the presence of documented 
evidence of having received varicella vaccination (2 doses), subjects are 
eligible to enter the study regardless of the result of serological testing.
15. History of systemic infection requiring hospitalization, parenteral antimicrobial 
therapy, or as otherwise judged clinically significant by the investigator within 
6 months prior to Day 1 (for criteria regarding Tuberculosis [TB] infection, see 
Exclusion Criterion 21).
16. Active acute or chronic infection requiring treatment with oral antibiotics, antivirals, 
antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to Day 1 or 
superficial skin infection within 1 week prior to Day 1.  NOTE: subjects may be 
rescreened after the infection resolves.
17. Significant trauma or major surgery within 1 month of the first dose of study drug.
18. Considered in imminent need for surgery or with elective surgery scheduled to occur 
during the study. 
19. Known immunodeficiency disorder, including positive serology for human 
immunodeficiency virus (HIV) at screening, or a first-degree relative with a 
hereditary immunodeficiency.
20. Infection with hepatitis B or hepatitis C viruses according to protocol-specific testing 
algorithm. 
a.
For hepatitis B, all subjects will undergo testing for hepatitis B surface antigen 
(HBsAg) and hepatitis B core antibody (HBcAb).  Subjects who are HBsAg 
positive will not be eligible for this study.  Subjects who are HBsAg negative but 
HBcAb positive will be reflex tested for hepatitis B surface antibody (HBsAb).  


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Additional reflex testing for hepatitis B virus DNA testing (HBVDNA) is also 
required for HBcAb positive subjects in countries in which Hep B prevalence has 
been reported at a rate of >5.0% or if required by local standard of care.  Please 
refer to Appendix 2 for testing algorithm, reflex testing, and full eligibility 
criteria.  For Japan-specific requirements, see Appendix 5.1.
b. For hepatitis C, all subjects will undergo testing for hepatitis C antibody 
(HCVAb) during Screening. 

Subjects who are HCVAb positive will be reflex-tested for hepatitis C RNA 
(HCV RNA).  Subjects who are HCVAb and HCV RNA positive are not 
eligible for the study. 
21. Have evidence of untreated or inadequately treated active or latent Mycobacterium 
tuberculosis (TB) infection as evidenced by the following:
a.
A positive QuantiFERON®-TB Gold In-Tube (QFT-G) test or positive or 
borderline T-SPOT®.TB (T-Spot) test performed within the 3 months prior to 
Baseline (Visit 2).  If the laboratory reports the test as indeterminate, the test 
should be repeated.  If the result of the repeat test is indeterminate, a purified 
protein derivative (PPD) test may be substituted for the QFT-G test or T-Spot test 
only with approval from the Pfizer Medical Monitor on a case-by-case basis.
b. Chest radiograph with changes suggestive of active TB infection within 3 months 
prior to Screening.  Chest radiograph should be performed according to local 
standards of care or country-specific guidelines.
c.
History of either untreated or inadequately treated latent or active TB infection.
If a subject has previously received an adequate course of therapy for either latent 
(9 months of isoniazid in a locale where rates of primary multi-drug resistant TB 
infection are <5% or an acceptable alternative regimen) or active (acceptable 
multi-drug regimen) TB infection, neither a QFT-G test, a T-Spot test, nor a PPD 
test need be obtained.  Details of the previous course of therapy (eg, medication(s)
used, dose, duration of therapy) should be documented in the source 
documentation.
A chest radiograph should be obtained if not done within the 3 months prior to 
Screening.  To be considered eligible for the study, the chest radiograph must be 
negative for active TB infection. 
A subject who is currently being treated for active TB infection must be excluded 
from the study.
A subject who is being treated for latent TB infection can only be enrolled with 
confirmation of current incidence rates of multi-drug resistant TB infection, 


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documentation of an adequate treatment regimen, and prior approval of the 
Sponsor.
22. Abnormal findings on the Screening chest radiographs (eg, chest x-ray) including, but 
not limited to, presence of active TB, general infections, cardiomyopathy, or 
malignancy.  NOTE: Chest radiograph examination may be performed up to 3 months 
prior to Screening visit.  Documentation of the reading by a qualified radiologist or 
pulmonologist must be available in the source documentation.
23. ANY of the following conditions at screening:
a.
Screening 12-lead ECG that demonstrates:

Clinically significant abnormalities requiring treatment (eg, acute myocardial 
infarction, serious tachy- or brady-arrhythmias) or indicating serious 
underlying heart disease (eg, cardiomyopathy, Wolff-Parkinson–White 
syndrome); 

Confirmed QT interval corrected using Fridericia’s correction factor QTcF
(QTcF) prolongation (>450 milliseconds).
b. Long QT Syndrome, a family history of Long QT Syndrome, or a history of 
Torsades de Pointes; 
24. ANY of the following abnormalities in clinical laboratory tests at screening, as 
assessed by the study-specific laboratory and confirmed by a single repeat, if deemed 
necessary:
a.
Absolute neutrophil count <1.2 x 109/L (<1200/mm3);
b. Hemoglobin <11.0 g/dL or hematocrit <33%; 
c.
Platelet count <150 × 109/L or <150,000/mm3;
d. Absolute lymphocyte count of <0.8 x 109 /L (<800/mm3); 
e.
Estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 based on the age 
appropriate calculation;
f.
Enzymes aspartate transaminase (AST) or alanine transaminase (ALT) values 
>2 × upper limit of normal (ULN);
g. Total bilirubin >1.5 × ULN; subjects with Gilbert's syndrome would be eligible 
for this study provided the direct bilirubin is ≤ULN;


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h. In the opinion of the investigator or Pfizer (or designee), have any clinically 
significant laboratory abnormality that that could affect interpretation of study 
data or the subject’s participation in the study.
25. Have an active history of alcohol or substance abuse within 1 year prior to Day 1. 
26. Donation of blood in excess of 500 mL within 8 weeks prior to Day 1.
4.3. Lifestyle Requirements
4.3.1. Contraception
The investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject from 
the permitted list of contraception methods, and will confirm that the subject has been 
instructed in its consistent and correct use.  At time points indicated in the Schedule of 
Activities, the investigator or designee will inform the subject of the need to use highly 
effective contraception consistently and correctly and document the conversation and the 
subject’s affirmation in the subject’s chart (subjects need to affirm their consistent and 
correct use of at least 1 of the selected methods of contraception).  In addition, the 
investigator or designee will instruct the subject to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the subject (if 
WOCBP) or partner.
Males
Outside of VHP countries in the EMA, no contraception methods are required for male 
subjects in the study.
Within VHP countries in the EMA, male subjects must agree to one of the following 
contraception requirements during the intervention period and for at least 90 days after the 
last dose of investigational product.
1. Be abstinent from sexual intercourse with a female of childbearing potential as their 
preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree 
to remain abstinent. 
2. Use a male condom during sexual intercourse with a female of childbearing potential.
3. Have undergone a vasectomy (with the confirmed absence of sperm, considering that 
the spermatogenesis cycle is approximately 90 days).
Females
The following applies to female subjects who are considered WOCBP.


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Highly Effective Contraceptive Methods
1. Oral, injectable, or implantable progestogen-only hormone contraception associated 
with inhibition of ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion or bilateral tubal ligation.
5. Oral, intravaginal, transdermal, or injectable combined (estrogen- and 
progestogen-containing) hormonal contraception associated with inhibition of 
ovulation used in combination with a barrier method. 
Acceptable barrier methods include:

Male or female condom with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide.
Male condom and female condoms should not be used together (due to risk of failure 
with friction).
6. Vasectomized partner.
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP, and the absence of sperm has been 
confirmed.  If not, an additional highly effective method of contraception should be 
used.  The spermatogenesis cycle is approximately 90 days.
7. 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.
Additionally, contraceptive use should be consistent with local regulations or guidance 
regarding the use of contraceptive methods for those participating in clinical trials. 
4.3.2. Cosmetic Treatments/Applications
Following screening, subjects must not shave the hair on the scalp, eyebrows, or eyelashes 
for the duration of the study.  Subjects wishing to keep their hair short are permitted to do so 
and an appropriate length should be discussed with the investigator to allow for assessment 
of hair re-growth.


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In addition, the following applies to other cosmetic treatments/applications:
1. Hair transplants and tattooing of scalp, eyebrows, and eyelashes, including 
procedures such as microblading, are not permitted during the course of study but 
these procedures performed prior to screening may not, in the investigator’s opinion, 
exclude a subject from enrollment.
2. Hair prosthetics (eg, wigs, hair extensions) are permitted but must be removed for 
clinical assessments of AA at all study visits.
3. Hair dye is permitted to be used during the study, but subjects should be discouraged 
from undergoing any hair dying process for 7 days prior to a study visit.
4. Mascara and false eyelashes are permitted but must be removed for clinical 
assessments of AA at all study visits.  The use of false eyelashes with adhesive should 
be discouraged, where possible, due to the risk of eyelash loss during removal.
5. Nail polish/varnish is permitted but must be removed for assessments of fingernails 
affected by AA.
6. False fingernails or gel applications to the fingernails should be discouraged, where 
possible, due to the risk of damage to the subject’s natural fingernails and must be 
removed for clinical assessments of fingernails at all study visits.
4.4. 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 supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council for Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 


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ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, the investigational product is PF-06651600.
Subjects will be randomized in a 2:2:2:2:1:1:1 manner to 1 of 7 treatment sequences using 
blinded PF-06651600 and matching placebo which are defined in Section 3.
5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR] called Impala).  
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the subject number.  The site personnel will then be provided with a 
treatment assignment, randomization number, and dispensable unit (DU) or container number 
when investigational product is being supplied via the IRT system.  The IRT system will 
provide a confirmation report containing the subject number, randomization number, and 
DU or container number assigned.  The confirmation report must be stored in the site’s files.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
5.2. Breaking the Blind
The study will be sponsor, subject, and investigator blinded.  
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should be 
broken only in exceptional circumstances when knowledge of the actual treatment code is 
absolutely essential for further management of the subject.  Investigators are encouraged to 
discuss with a member of the study team if they believe that unblinding is necessary.  When 
the blinding code is broken, the reason must be fully documented and entered on the case 
report form (CRF).
5.3. Subject Compliance
Subject compliance will be verified by the accounting of investigational product at each visit.  
When investigational product is administered at the clinic, it will be administered by the 
appropriately designated staff at the investigator site.
Compliance of the investigational product will be monitored by delegated site personnel by 
the accounting of unused medication returned by the subject at the study visits.  Compliance 
will be documented on the CRF and source document.  If compliance is <80%, the 
investigator or designee is to counsel the subject and ensure steps are taken to improve 
compliance.  Subjects interrupting investigational product for more than 10 days between 


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visits must be discussed with the sponsor for possible withdrawal from the study.  If the 
subject is over-compliant (>120%) with study drug (intentional or accidental) the investigator 
or designee is to counsel the subject and ensure correct understanding of the study drug 
dosing regimen.  The investigator should contact the Pfizer Study Clinician promptly with 
any over-compliance that may potentially impact the safe use of study drug or that may result 
in a serious adverse event.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Blinded PF-06651600 and its matched placebo will be provided as tablets for oral 
administration.  The designation “PF-06651600-15” may appear on labeling and indicates a 
salt.  It is equivalent to “PF-06651600” with regard to this protocol.  The 50 mg and 10 
mg tablets and their matching placebos will be supplied in blister cards and labeled according 
to local regulatory requirements.  Subjects will receive blinded labeled supplies throughout 
the study.
In order to achieve the proper dosage and maintain the blind throughout the study, tablets 
will be dispensed in a blinded fashion to ensure that all subjects, regardless of the assigned 
treatment sequence, will take the same number of tablets/day. To accomplish this, all 
subjects will take 7 tablets/day during the loading period, 4 tablets/day during the 
maintenance period, 7 tablets/day during the first 4 weeks of the extension period, and 
4 tablets/day for the remainder of the extension period.  The number and type of tablets taken 
per day for each treatment sequence is detailed in Table 2.
Table 2.
Number and Type of Tablets for Each Treatment Sequence
Treatment 
Sequence
Loading Period
Day 1 to Week 4
(No. of Tablets)
Maintenance Period
Weeks 4 to 24
(No. of Tablets)
First 4 Weeks of 
Extension Period
Weeks 24 to 28
(No. of Tablets)
Remainder of 
Extension Period
Weeks 28 to 48
(No. of Tablets)
A
4 of 50 mg active
3 of 10 mg size pbo
1 of 50 mg active
3 of 10 mg size pbo
1 of 50 mg active
3 of 50 mg size pbo
3 of 10 mg size pbo
1 of 50 mg active
3 of 10 mg size pbo
B
4 of 50 mg active
3 of 10 mg size pbo
1 of 50 mg size pbo
3 of 10 mg active
4 of 50 mg size pbo
3 of 10 mg active
1 of 50 mg size pbo
3 of 10 mg active
C
1 of 50 mg active
3 of 50 mg size pbo
3 of 10 mg size pbo
1 of 50 mg active
3 of 10 mg size pbo
1 of 50 mg active
3 of 50 mg size pbo
3 of 10 mg size pbo
1 of 50 mg active
3 of 10 mg size pbo
D
4 of 50 mg size pbo
3 of 10 mg active
1 of 50 mg size pbo
3 of 10 mg active
4 of 50 mg size pbo
3 of 10 mg active
1 of 50 mg size pbo
3 of 10 mg active
E
4 of 50 mg size pbo
1 of 10 mg active
2 of 10 mg size pbo
1 of 50 mg size pbo
1 of 10 mg active
2 of 10 mg size pbo
4 of 50 mg size pbo
1 of 10 mg active
2 of 10 mg size pbo
1 of 50 mg size pbo
1 of 10 mg active
2 of 10 mg size pbo
F
4 of 50 mg size pbo
3 of 10 mg size pbo
1 of 50 mg size pbo
3 of 10 mg size pbo
4 of 50 mg active
3 of 10 mg size pbo
1 of 50 mg active
3 of 10 mg size pbo


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Table 2.
Number and Type of Tablets for Each Treatment Sequence
Treatment 
Sequence
Loading Period
Day 1 to Week 4
(No. of Tablets)
Maintenance Period
Weeks 4 to 24
(No. of Tablets)
First 4 Weeks of 
Extension Period
Weeks 24 to 28
(No. of Tablets)
Remainder of 
Extension Period
Weeks 28 to 48
(No. of Tablets)
G
4 of 50 mg size pbo
3 of 10 mg size pbo
1 of 50 mg size pbo
3 of 10 mg size pbo
1 of 50 mg active
3 of 50 mg size pbo
3 of 10 mg size pbo
1 of 50 mg active
3 of 10 mg size pbo
Abbreviations: No. = Number; Pbo = placebo.
5.4.2. Preparation and Dispensing
The investigational product will be dispensed using an IRT drug management system at each 
visit.  A qualified staff member will dispense the investigational product via unique container 
numbers on the blister cards provided, in quantities appropriate for the study visit schedule.  
The subject/caregiver should be instructed to maintain the product in the blister cards 
provided, and the tablets should not be removed from the blister until the investigational 
product is to be administered.  Subjects/caregivers will be instructed to return the blister 
cards to the site at the next study visit. 
5.5. Administration
Subjects will be provided clear dosing instructions. 
Sites will be trained on how subjects should take tablets at home through an Investigational 
Product manual and/or other vehicle(s).  Sites are responsible for communicating this 
information and site staff should review the dosing instructions with subjects at every 
study visit.
Subjects should take their tablets from a single row in the blister card each day.  Subjects 
should not take more than one row of tablets out of the blister card at a time as mixing tablets 
between rows may change the amount of active medication taken in that day.  If a tablet is 
dropped or damaged, skip taking that tablet and note this on the diary card.  Subjects should 
not take a tablet from another row.
Subjects should take the tablets orally according to the dosing instructions provided with the 
medication.  Subjects will be encouraged to take the medication in the morning 
whenever possible.  Subjects should take the medication at approximately the same time 
every day.  However, for study visit days, subjects are to be instructed to refrain from 
dosing at home and are to take the dose in the clinic.
If a dose is missed and the interval to the next dose is <8 hours, the missed dose should not 
be administered.  If a dose is missed and the interval to the next dose is ≥8 hours, the missed 
dose should be administered.
PF-06651600 dose may be temporarily withheld for a maximum of 10 days between visits at 
the discretion of the investigator.  Subjects interrupting investigational product for more than 


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10 days between visits must be discussed with the sponsor for possible withdrawal from the 
study.
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (eg, via a log), at a minimum, 
daily minimum and maximum temperatures for all site storage locations (as applicable, 
including frozen, refrigerated, and/or room-temperature products).  This should be captured 
from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (eg, refrigerator), as applicable, should be 
regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct subjects on the proper storage requirements for investigational 
products taken home.


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5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be
accounted for using a drug accountability form/record. 
All study drug, including empty blister cards, must be returned to the investigator by the 
subject at every visit and at the end of the trial.
5.7.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  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, and all destruction must be adequately documented.
For all blisters returned to the investigator by the subject, the investigator will maintain the 
returned supply until destruction is authorized.  Pfizer will provide instructions as to the 
disposition of any unused investigational product.
5.8. Concomitant Medications/Treatment(s)
Medications/treatments that are taken in the Screening period (after informed consent is 
obtained and before the first dose of study drug) as well as any medications/treatments taken 
for the treatment of AA at any time prior to the Screening visit will be documented as prior 
medications/treatments.  Medications/treatments taken after the first dose of study drug has 
been administered will be documented as concomitant medications/treatments.  All 
concomitant medications/treatments taken during the study must be recorded in study records
with indication, daily dose, and start and stop dates of administration.  Subjects will be 
queried about concomitant medication (including topical medications and treatments, 
over-the-counter and prescription medications and treatments, and vaccinations) at each 
study visit.  Any new concomitant medications/treatments or dose changes to current 
concomitant medications should be evaluated for potential new or worsening adverse events.
The start date, stop date, and indication for all therapies will be recorded on the CRF.
5.8.1. Permitted Concomitant Medications
For the purposes of this protocol, dietary supplements are defined as vitamins, minerals, and 
purified food substances with pharmaceutical properties.  Vitamins, minerals and purified 
food substances are allowed in amounts not known to be associated with adverse effects 
(such as hypervitaminosis).
A subject who is receiving a permitted concomitant medication for any reason must be on a 
locally-approved medication and dose for the treated indication, and this must be 
documented on the CRF.  


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With the exception of those medications prohibited for use in Appendix 4, CYP3A inhibitors 
are permitted to be used during the study.  Sensitive and moderate sensitive CYP3A 
substrates permitted to be used during the study are listed in Appendix 4.
Acetaminophen may be used intermittently (not to exceed 3 g/day).  Subjects are not allowed 
any other investigational drugs or treatments during the study. 
Subjects should refrain from starting new or changing doses of permitted prescription or 
non-prescription drugs, vitamins, and dietary supplements within 7 days or 5 half-lives 
(whichever is longer) prior to Day 1 and prior to study visits throughout the study, unless 
otherwise noted below. 
Subjects should report any changes to permitted medications during the study to the 
investigator as soon as they occur.  Medication changes must be documented in the subject’s 
record and CRF. 
Unless a prohibited medication or treatment, subjects may be administered any other 
medications necessary for the treatment of concomitant medical disorders as deemed 
necessary by the treating physician.  Following Day 1, addition of concomitant medications 
or any change in the dosage should be limited to those considered medically essential.
5.8.2. Prohibited Medications and Treatments
Subjects will abstain from all concomitant medications as described in Exclusion Criterion 8
and Section 4 of the protocol and Appendix 4.  Medically necessary medications should not 
be discontinued without prior evaluation of acceptable alternatives, including consultation 
with prescribing health professional.
Subjects should be instructed at each visit to contact the study site investigator promptly if 
there are any intended changes or additions to concomitant medications. 
All medications and treatments that could affect AA must be discontinued.  During the 
study if it is discovered that a subject has been taking a medication or treatment that could 
affect AA, the investigator should contact the Sponsor for each case to determine whether the 
subject should be discontinued. 
Subjects must also avoid prolonged exposure to the sun and avoid the use of tanning booths, 
sun lamps or other ultraviolet light sources during the study.
Prohibited Concomitant Medications/Treatments:
The following medications and treatments are prohibited for use during the study.  Subjects 
who are treated with any prohibited medication or treatment during the course of the study 
may be discontinued.  NOTE: Examples provided do not represent an all-inclusive list of 


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medications and treatments.  If there is a question about whether a particular medication is 
prohibited, the medication should be discussed with the sponsor.

Medications and treatments that could affect AA:

JAK inhibitors for use in any disease indication.

Immunosuppressants (eg, cyclosporine A, azathioprine, methotrexate [MTX], 
sulfasalazine, mycophenolate mofetil [MMF], everolimus, ibrutinib).

Intralesional, oral or injectable steroids.

5α-Reductase inhibitors (5-ARIs) (eg, finasteride, dutasteride).

Oral minoxidil.

Spironolactone if used specifically for AA.

Other systemic treatments that could affect AA.

Topical treatments that could affect AA on areas under assessment (ie, scalp, 
eyebrows, eyelashes, and fingernails) (eg, steroid cream, medicated shampoo, 
minoxidil).

Phototherapy (eg, Ultraviolet B [UVB] phototherapy, Psoralen Ultraviolet A 
[PUVA]).

Contact immunotherapy (eg, diphenylcyclopropenone [DPCP], squaric acid 
dibutylester [SADBE], and 1-chloro-2,4-dinitrobenzene [DNCB]).

Topical irritants (eg, anthralin) and liquid nitrogen cryotherapy.

Cosmetic treatments/applications as described in Section 4.3.2. 

Medications with potential drug-drug interactions or potential safety concerns:

Lymphocyte-depleting agents/therapies, including both non-B-cell selective and 
B-cell-depleting agents (eg, alefacept, alemtuzumab, rituximab).

Other biologics with immunomodulatory properties.

Live (attenuated) vaccines: restrictions on vaccinations are described in more 
detail in Section 5.8.3.

Moderate to potent CYP3A inducers (See Appendix 4).

Specific sensitive to moderate sensitive CYP3A substrates (See Appendix 4).


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
Herbal medications with either unknown properties or pharmaceutical properties 
that impact AA.

Investigational compounds.
5.8.3. Vaccinations
Vaccination with live virus, attenuated live virus, or any live viral components is prohibited 
within the 6 weeks prior to the first dose of study drug, during the study, and for 6 weeks 
after the last dose of investigational product.  Similarly, current routine household contact 
with individuals who have been vaccinated with live vaccine components should be avoided 
during study treatment and for 6 weeks following completion of study treatment.  Following 
vaccination with live component vaccines, the virus may be shed in bodily fluids, including 
stool, and there is a potential risk that the virus may be transmitted. 
Such vaccines include but are not limited to: FluMist® (intranasal influenza vaccine), 
attenuated rotavirus vaccine, varicella (chickenpox) vaccine, attenuated typhoid fever 
vaccine, oral polio vaccine, MMR (measles, mumps, rubella) vaccine, vaccinia (smallpox) 
vaccine, and Zostavax® (zoster vaccine live). 
Vaccines (including COVID-19 vaccines) that are not live attenuated are permitted.  
5.8.4. Surgery
During the study, no elective surgery should occur without first consulting with the Pfizer 
Medical Monitor or designee. Preferably, elective surgery should occur before the study or 
be delayed until participation in the study is completed.  Subjects who have elective surgery 
should temporarily discontinue study intervention for 1 week prior to the surgical procedure 
and remain off study intervention after the surgical procedure until sutures/staples are 
removed. If absorbing sutures or chemical closure methods are utilized, study intervention 
can be resumed when the operative site is sufficiently healed, and risk of infection is 
minimal. 
The Pfizer Medical Monitor or designee should be notified if a subject requires surgery 
(including dental surgery) during the study to determine whether the subject should 
discontinue from the study and/or discontinue investigational product prior to the surgical 
procedure.  The Pfizer Medical Monitor or designee should be notified as soon as possible if 
a subject undergoes a surgical procedure without first informing the study staff.
6. STUDY PROCEDURES 
Refer to the Schedule of Activities for a detailed list of study procedures as they should be 
conducted at each respective visit.  Visit windows are based on Day 1 visit.
Subjects are required to fast for at least 8 hours prior to all visits that include fasting lipid 
profile panel testing.  During the fasting period, subjects should refrain from all food and 
liquids (water and medications other than investigational product are permitted). 


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To assure consistency and reduce variability, visits should occur at approximately the same 
time of day throughout the study.  Subjects should be encouraged to attend visits in the 
morning and prior to the subject’s dosing of investigational product as subjects will receive 
their dose at the clinic during their study visit. 
Urine pregnancy test must be performed at each visit (and must be negative) prior to dosing 
with the investigational product for female subjects of childbearing potential through end of 
study (EOS).  In addition to urine pregnancy tests performed at each study visit, sites in VHP 
countries in the EMA should instruct female subjects of childbearing potential to perform a 
urine pregnancy test at home between the Week 40 and 48 visits (at approximately Week 44).  
In addition, the investigator or designee will instruct the subject to contact the site 
immediately if the urine pregnancy test result is positive or cannot be confirmed as negative.  
The list of VHP countries participating in the protocol can be found in Section 4.
The patient reported outcome assessments should be completed before the other evaluations 
or treatments at the clinical visits whenever it is possible.  Vital signs and electrocardiograms 
(ECGs) should be performed before any laboratory blood collection.  The CGIS-AA should 
be completed after other clinical assessments of AA (ie, SALT, EBA, ELA, and assessment 
of fingernails affected by AA), whenever it is possible.  All other evaluations (unless noted 
otherwise) do not need to be performed in any specific order.
Refer to Appendix 3 for guidelines on subject safety monitoring and discontinuation.
6.1. Screening, Visit 1
Subjects will have up to 35 days of a screening period prior to the first dose of study drug to 
confirm that they meet the subject selection criteria for the study.  The investigator (or an 
appropriate delegate at the investigator site) will obtain informed consent from each subject 
(or parent(s)/legal guardian and assent from the subject, as appropriate) in accordance with 
the procedures described in the Schedule of Activities section.
Due to possible need for tuberculin testing and chest radiograph, as well as to allow time for 
verification of SALT scores, screening procedures may be performed over more than 1 visit 
within the 35 days prior to the Day 1 visit. 
Screening laboratory tests with abnormal results may be repeated once to confirm abnormal 
results (with the same screening number); the last value will be used to determine eligibility.  
If results return to normal within the 5-week screening period, the subject may enter the 
study. 
Sites may be permitted to re-screen subjects (with a new screening number) who initially do 
not meet eligibility criteria once following agreement with the Sponsor.
The following procedures will be completed:

Obtain written informed consent (or parent(s)/legal guardian and assent from the 
subject, as appropriate).


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
Register subject in Impala.

Review Inclusion and Exclusion criteria.

Administer patient reported outcome (PRO) questionnaire: Patient Health 
Questionnaire – 8 items (PHQ-8).

Collect demography. 

Complete AA disease history includes collection of details of AA at Screening: 
AA background, AA history, AA diagnosis, pattern of scalp hair loss, body hair loss, 
nail involvement, the use of topical treatments, systemic treatments and other 
treatments for AA used at any time prior to the Screening visit.

Complete medical history, in addition to AA history, including but not limited to 
comorbidities associated with AA, history of drug, alcohol, tobacco use, skin rash, 
and infection will be collected at Screening.  Smoking status and alcohol 
consumption will also be collected.

Obtain complete medication history of all other prescription or nonprescription drugs, 
and dietary and herbal supplements taken within 35 days prior to the Screening Visit.

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Perform single 12-lead ECG.

Obtain height and weight. 

Conduct complete physical examination including dermatological full body 
examination.

Perform audiological evaluation (unless performed within 8 weeks of Day 1).

Perform chest radiograph (if previous chest radiograph has not been performed within 
3 months prior to Screening visit; this may be performed at a different location 
outside of the study site).

Obtain samples for laboratory testing: hematology, blood chemistry, urinalysis, serum 
FSH (in female subjects under 60 years-old and who have been amenorrheic for at 
least 12 consecutive months with no alternative pathological or physiological cause to 
confirm postmenopausal status), urine pregnancy test (female subjects of childbearing 
potential), and testing for human immunodeficiency virus (HIV), hepatitis B surface 
antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis B reflex testing (if 
applicable) (See Appendix 5.1 for Japan-specific requirements), hepatitis C antibody 
(HCVAb), and hepatitis C reflex testing (if applicable).


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
In all adolescent subjects, confirm presence or absence of documented evidence of 
having received varicella vaccination (2 doses).

Only in adolescent subjects who have no documented evidence of having received 
varicella vaccination (2 doses): perform VZV IgG Ab testing to confirm eligibility.

Perform TB testing (unless performed within 12 weeks of Day 1). QFT-G test is 
preferred; however, the T-Spot is also permitted. If Mantoux PPD tuberculin skin test 
is performed, the subject must return between 48-72 hours post-injection for 
evaluation of induration (see Section 7.5.8 for further details on TB testing).

Take scalp photographs to verify eligibility.  Take eyelash and eyebrow photographs.

Conduct clinical evaluations: Severity of Alopecia Tool (SALT), Eyebrow 
Assessment (EBA), Eyelash Assessment (ELA), and CGI-AA.

Conduct Columbia Suicide Severity Rating Scale (C-SSRS).

Assess need for contraception and adherence to applicable lifestyle requirements (see 
Section 4.3).  Establish willingness and ability to comply with lifestyle requirements 
going forward in study.

Assess for occurrence of SAEs and non-serious AEs: the reporting period starts with 
the signing of the informed consent.
6.2. Study Period
The visit window for all visits during the study period is based on the date of Visit 2, Day 1 
(Randomization).
6.2.1. Visit 2, Day 1 (Randomization)
Prior to randomizing the subject in Impala, the inclusion/exclusion criteria must be reviewed 
against all information/results from Visit 1 (screening) in addition to information collected at 
Visit 2 (randomization) including prior/concomitant medications, changes in medical 
conditions, physical exam findings, pregnancy test results, contraception check, C-SSRS 
results, and SALT score.  NOTE: Subject eligibility, as based on external review of 
Screening photographs, must be available prior to randomization.  At any time during the 
Day 1 visit, if it is determined that the subject does not meet eligibility criteria, it is not 
necessary to perform any further assessments at Day 1. 
The following procedures will be completed:

Administer PRO questionnaires: Alopecia Areata Patient Priority Outcomes 
(AAPPO), Hospital Anxiety and Depression Scale (HADS), 36-Item Short Form 
Health Survey version 2 Acute (SF36v2 Acute), Alopecia Areata Resource 
Utilization (AARU), Work Productivity and Activity Impairment: Alopecia Areata 


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(WPAI:AA) in adults, and EuroQoL 5 Dimensions (EQ-5D-5L) in adults or EuroQol 
5 Dimension – Youth (EQ-5D-Y) in adolescents.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study.

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Capture photographs.

Conduct clinical evaluations: SALT, EBA, ELA, assessment of fingernails affected 
by AA, and CGI-AA.  NOTE: subjects who experience any terminal hair regrowth 
between the Screening and Day 1 visits are not eligible for randomization.

Conduct C-SSRS.

Review any changes in the subject’s prior and concomitant treatment information.

Review medical history and AA disease history.

Assess for occurrence of AEs: The reporting period starts with the signing of the 
informed consent.

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Obtain height and weight.

Conduct complete physical examination. 

Perform single 12-lead ECG.

Obtain fasting samples for fasting lipid panel.

Obtain samples for other laboratory testing: hematology, serum chemistry, urinalysis, 
interferon gamma-induced protein 10 (IP-10), fluorescence-activated cell sorting for 
T-cells, B-cells, and natural killer (NK) cells (FACS-TBNK), and immunoglobulins 
(IgA, IgG, IgM). 

Collect sample for viral screen.


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
Collect a genomic banked biospecimen (Prep D1).  If missed, collect at the next 
available time point when biospecimens are being collected in conjunction with a 
subject visit.

Obtain Prep B1, B2, and R1 samples.

Review of Inclusion/Exclusion Criteria.

If subject meets all Inclusion/Exclusion criteria, randomize subject into the study in 
Impala.

Prior to dosing, obtain samples for PK analysis.

Administer first dose of study drug to subject.

Provide and review dosing instruction.

Dispense study drug supply to the subject.
6.2.2. Visit 3, Day 15/Week 2 (±3 days)
The following procedures will be completed:

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study.

Perform urine pregnancy test (female subjects of childbearing potential only).

Obtain samples for other laboratory testing: hematology.

Confirm proper contraception is being used.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.

Provide and review dosing instruction.

Dispense new study drug to the subject.


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6.2.3. Visit 4, Day 29/Week 4 (±3 days)
The following procedures will be completed:

Administer PRO questionnaires: AAPPO, PGI-C, P-Sat, HADS, SF36v2 Acute, and 
EQ-5D-5L in adults or EQ-5D-Y in adolescents. 

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Perform single 12-lead ECG.

Conduct targeted physical examination.

Obtain fasting samples for fasting lipid panel.

Obtain samples for laboratory testing: hematology, blood chemistry, urinalysis, IP-10, 
and FACS-TBNK.

Obtain Prep B1, B2, and R1 samples.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study.

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Capture photographs.

Conduct clinical evaluations: SALT, EBA, ELA, and CGI-AA.

Conduct C-SSRS.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Prior to dosing, obtain sample for PK analysis and then at 0.5 hour, 1 hour, and 
3 hours after dosing.

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.

Provide and review dosing instruction.

Dispense new study drug to the subject.


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6.2.4. Visit 5, Day 57/Week 8 (±7 days)
The following procedures will be completed:

Administer PRO questionnaires: AAPPO, PGI-C, P-Sat, HADS, and SF36v2 Acute.

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Conduct targeted physical examination.

Obtain samples for laboratory testing: hematology, blood chemistry, urinalysis, and 
IP-10.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study. 

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Conduct clinical evaluations: SALT, EBA, ELA, and CGI-AA.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Prior to dosing, obtain sample for PK analysis and then at 0.5 hour and 2 hours after 
dosing.

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.

Provide and review dosing instruction.

Dispense new study drug to the subject. 
6.2.5. Visit 6, Day 85/Week 12 (±7 days)
The following procedures will be completed:

Administer PRO questionnaires: AAPPO, PGI-C, P-Sat, HADS, SF36v2 Acute, 
AARU, WPAI: AA in adults, and EQ-5D-5L in adults or EQ-5D-Y in adolescents. 

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.


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
Conduct targeted physical examination.

Obtain fasting samples for fasting lipid panel.

Obtain samples for laboratory testing: hematology, blood chemistry, urinalysis, 
HBVDNA (if applicable), IP-10, and FACS-TBNK. 

Obtain Prep B1, B2, and R1 samples.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study.

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Capture photographs. 

Conduct clinical evaluations: SALT, EBA, ELA, assessment of fingernails affected 
by AA, and CGI-AA.

Conduct C-SSRS.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Prior to dosing, obtain sample for PK analysis and then at 0.5 hour and 2 hours after 
dosing.  If PK samples were collected at Week 8, no PK samples are required at 
Week 12. 

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.

Provide and review dosing instruction.

Dispense new study drug to the subject. 
6.2.6. Visit 7, Day 127/Week 18 (±7 days)
The following procedures will be completed:

Administer PRO questionnaires: AAPPO, PGI-C, and P-Sat.


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
Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Conduct targeted physical examination.

Obtain samples for laboratory testing: hematology, blood chemistry, and urinalysis.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study. 

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Conduct clinical evaluations: SALT, EBA, ELA, and CGI-AA.

Conduct C-SSRS.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.

Provide and review dosing instruction.

Dispense new study drug to the subject.
6.2.7. Visit 8, Day 169/Week 24 (±7 days)
The following procedures will be completed:

Administer PRO questionnaires: AAPPO, PGI-C, P-Sat, HADS, SF36v2 Acute, 
AARU, WPAI: AA in adults, and EQ-5D-5L in adults or EQ-5D-Y in adolescents. 

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Perform single 12-lead ECG.

Obtain height and weight.

Conduct complete physical examination.


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
Perform audiological evaluation.

Obtain fasting samples for fasting lipid panel.

Obtain samples for laboratory testing: hematology, blood chemistry, urinalysis, 
HBVDNA (if applicable), IP-10, FACS-TBNK, and immunoglobulins (IgA, IgG, 
IgM). 

Obtain Prep B1, B2, and R1 samples.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study.

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Capture photographs. 

Conduct clinical evaluations: SALT, EBA, ELA, assessment of fingernails affected 
by AA, and CGI-AA.

Conduct C-SSRS.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.

Provide and review dosing instruction.

Dispense new study drug to the subject.
6.2.8. Visit 9, Day 183/Week 26 (±3 days)
The following procedures will be completed:

Perform urine pregnancy test (female subjects of childbearing potential only).

Obtain samples for other laboratory testing: hematology.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 


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willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study.

Confirm proper contraception is being used.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.

Provide and review dosing instruction.

Dispense new study drug to the subject.
6.2.9. Visit 10, Day 197/Week 28 (±3 days)
The following procedures will be completed:

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Conduct targeted physical examination.

Perform single 12-lead ECG.

Obtain fasting samples for fasting lipid panel.

Obtain samples for laboratory testing: hematology, blood chemistry, and urinalysis.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study. 

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Conduct clinical evaluations: SALT, EBA, ELA, and CGI-AA.

Conduct C-SSRS.

Review any changes in the subject’s concomitant treatments information.

Capture photographs.


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
Assess for occurrence of AEs.

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.

Provide and review dosing instruction.

Dispense new study drug to the subject.
6.2.10. Visit 11, Day 239/Week 34 (±7 days)
The following procedures will be completed:

Administer PRO questionnaires: AAPPO, PGI-C, P-Sat, AARU, and WPAI: AA in 
adults. 

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Conduct targeted physical examination.

Obtain fasting samples for fasting lipid panel.

Obtain samples for laboratory testing: hematology, blood chemistry, urinalysis, and 
HBVDNA (if applicable).

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study. 

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Conduct clinical evaluations: SALT, EBA, ELA, assessment of fingernails affected 
by AA, and CGI-AA.

Conduct C-SSRS.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.


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
Provide and review dosing instruction.

Dispense new study drug to the subject.
6.2.11. Visit 12, Day 281/Week 40 (±7 days)
The following procedures will be completed:

Administer PRO questionnaires: AAPPO, PGI-C, and P-Sat. 

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Conduct targeted physical examination.

Obtain samples for laboratory testing: hematology, blood chemistry, and urinalysis.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
going forward in study. 

Perform urine pregnancy test (female subjects of childbearing potential only).  In 
addition to urine pregnancy tests performed at each study visit, sites in VHP countries 
in VHP countries in the EMA should instruct female subjects of childbearing 
potential to perform a urine pregnancy test at home between the Week 40 and 48 
visits (at approximately Week 44).  In addition, the investigator or designee will 
instruct the subject to contact the site immediately if the urine pregnancy test result is 
positive or cannot be confirmed as negative.  The list of VHP countries participating
in the protocol can be found in Section 4.

Confirm proper contraception is being used.

Conduct clinical evaluations: SALT, EBA, ELA, assessment of fingernails affected 
by AA, and CGI-AA.

Conduct C-SSRS.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Collect study drug from subject, administer dose to subject, and perform 
accountability procedures.

Provide and review dosing instruction.


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
Capture photographs.

Dispense new study drug to the subject.
6.2.12. Visit 13, Day 337/Week 48/End of Treatment (±7 days)
The following procedures will be completed:

Administer PRO questionnaires: AAPPO, PGI-C, P-Sat, HADS, SF36v2 Acute, 
AARU, WPAI: AA in adults, and EQ-5D-5L in adults or EQ-5D-Y in adolescents. 

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Perform single 12-lead ECG. 

Obtain height and weight. 

Conduct complete physical examination.

Perform audiological evaluation.

Obtain fasting samples for fasting lipid panel.

Obtain samples for laboratory testing: hematology, blood chemistry, urinalysis, 
HBVDNA (if applicable), FACS-TBNK, and immunoglobulins (IgA, IgG, IgM).

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
through 28 days after the last dose of study medication. 

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Capture photographs. 

Conduct clinical evaluations: SALT, EBA, ELA, assessment of fingernails affected 
by AA, and CGI-AA.

Conduct C-SSRS.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.


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
Collect study drug from subject and perform accountability procedures.
6.3. Follow-up Period
6.3.1. Visit 14, End of Study/Follow-up
If a subject discontinues from the study for any reason other than death, lost to follow-up, or 
withdrawal of consent, a Follow-Up Visit must be performed within 28 (+7 days) after the 
Early Termination visit.  In addition, all subjects who complete the study but do not enter the 
long-term extension study must have a Follow-Up Visit within 28 (+7 days) of End of 
Treatment visit.
The following procedures will be completed:

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.

Conduct targeted physical examination.

Obtain fasting samples for fasting lipid panel.

Obtain samples for laboratory testing: hematology, blood chemistry, and urinalysis.

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test. 

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.
6.3.2. Early Termination Visit
For subjects who discontinue early from the study, the procedures scheduled for early 
termination (ET) Visit will be performed on the last day the subject takes the investigational 
product or as soon as possible thereafter.  Subject will then require a Follow-up visit 
occurring within 28 (+7 days).
The following procedures will be completed:

Administer PRO questionnaires: AAPPO, PGI-C, P-Sat, HADS, SF36v2 Acute, 
AARU, WPAI: AA in adults, and EQ-5D-5L in adults or EQ-5D-Y in adolescents. 

Obtain vital signs: pulse rate, blood pressure, respiratory rate (after at least 5 minutes 
of rest), and temperature.


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
Perform single 12-lead ECG. 

Obtain height and weight. 

Conduct complete physical examination.

Perform audiological evaluation.

Obtain fasting samples for fasting lipid panel.

Obtain samples for laboratory testing: hematology, blood chemistry, urinalysis, 
HBVDNA (if applicable), FACS-TBNK, and immunoglobulins (IgA, IgG, IgM).

Confirm whether menarche has started in previously premenarchal subjects.  If 
menarche has started, the subject must undergo a pregnancy test and establish 
willingness and ability to comply with contraception requirements (see Section 4.3) 
through 28 days after the last dose of study medication. 

Perform urine pregnancy test (female subjects of childbearing potential only).

Confirm proper contraception is being used.

Capture photographs. 

Conduct clinical evaluations: SALT, EBA, ELA, assessment of fingernails affected 
by AA, and CGI-AA.

Conduct C-SSRS.

Review any changes in the subject’s concomitant treatments information.

Assess for occurrence of AEs.

Collect study drug from subject and perform accountability procedures.
6.4. Subject Withdrawal/Early Termination
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
Subjects who discontinue study treatment from the Treatment Period for any reason other 
than death, lost to follow-up, or withdrawal consent will enter into the Follow-up Period (see 
Withdrawal of Consent section below). The procedures scheduled for Early Termination 
Visit will be performed on the last day the subject takes the investigational product or as soon 
as possible thereafter.  Subjects will then require a Follow-Up Visit within 28 (+7 days).  In 


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addition, all subjects who complete the study but do not enter the open-label extension study 
must have a Follow-Up Visit within 28 (+7 days) of End of Treatment visit.
See Appendix 3 for guidelines on subject safety monitoring and discontinuation.  The Early 
Termination Visit only applies to subjects who are randomized, received at least one dose of 
study drug, and then are prematurely withdrawn from the study treatment.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational 
product(s), request that the subject return for a final visit, if applicable, and follow-up with 
the subject regarding any unresolved AEs.
Withdrawal of consent:
Every effort will be made to complete Early Termination and Follow-up Visits as described 
above for subjects who request to discontinue receipt of study treatment during the Treatment 
Period (withdrawal consent).  The only exception to this is when a subject specifically 
withdraws consent for any further contact with him or her or persons previously authorized 
by the subject to provide this information.  Subjects 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 investigational 
product or also from study procedures and/or post treatment study follow-up and entered on 
the appropriate CRF page.  In the event that vital status (whether the subject 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.
If the subject withdraws from the study, and also withdraws consent 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.
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter.  All attempts should be documented in the subject’s medical records.  If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 


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complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
If subject visits or procedures are affected by a public emergency, including the COVID-19 
pandemic, please refer to Appendix 6.
7.1. Check for Initiation of Menarche (for Premenarchal Females Only)
In female subjects who are premenarchal at the start of the study, the investigator must 
confirm with the subject at every visit whether menarche has started since the last visit.  If 
menarche has started, the subject must now be considered of childbearing potential; 
therefore, from that point forward and starting with the current visit, the subject will be 
required to establish willingness and ability to comply with contraception requirements (see 
Section 4.3) and to undergo contraception checks and pregnancy testing according to the 
Schedule of Activities, starting with the current visit.  In addition, the investigator or 
designee will instruct the subject to contact the site immediately if the subject begins 
menarche between study visits.
7.2. Pregnancy Testing
Pregnancy tests are required to be done (if applicable) as specified in the Schedule of 
Activities. 
Pregnancy tests must have a sensitivity of at least 25 mIU/mL.  Pregnancy tests should be 
urine pregnancy tests.  In the event that urine pregnancy tests are not permitted at an 
institution, serum pregnancy tests can be utilized.  Pregnancy tests will be performed in 
WOCBP at the times listed in the Schedule of Activities.  Following a negative pregnancy 


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test result at screening, appropriate contraception must be verified, and a second negative 
pregnancy test result will be required at the baseline visit prior the subject receiving the 
investigational product.  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 
institutional review boards (IRBs)/ethics committees (ECs) or if required by local 
regulations.  If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required.  In such cases, the subject must be excluded if the serum 
pregnancy result is positive.  In the case of a positive confirmed pregnancy, the subject will 
be withdrawn from administration of investigational product but may remain in the study for 
follow-up.
In addition to urine pregnancy tests performed at each study visit, sites in VHP countries in 
the EMA should instruct female subjects of childbearing potential to perform a urine 
pregnancy test at home between the Week 40 and 48 visits (at approximately Week 44).  In 
addition, the investigator or designee will instruct the subject to contact the site immediately 
if the urine pregnancy test result is positive or cannot be confirmed as negative.  The list of 
VHP countries participating in the protocol can be found in Section 4.
7.3. Banked Biospecimens
Banked biospecimens will be collected from subjects for exploratory research relating to the 
drug response and disease/condition under study.  These collections are not typically 
associated with a planned assessment described in the protocol.  They will be handled in a 
manner that protects each subject’s privacy and confidentiality.  Banked biospecimens will 
be assigned the subject’s study identification code (ID) at the site.  The data generated from 
these banked biospecimens will also be indexed by this ID.  Biospecimens will be kept until 
destruction in facilities with access limited to authorized personnel, and biospecimen-derived 
data will be stored on password-protected computer systems.  The key between the subject’s 
ID and the subject’s direct personally identifying information (eg, name, address) will be 
held at the study site.  Biospecimens will be used only for the purposes described in the 
protocol and informed consent document; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored for many years (no time limit) to allow for research in the future, 
including research conducted during the lengthy drug-development process and also 
postmarketing research.  Subjects may withdraw their consent for the use of their banked 
biospecimens at any time by making a request to the investigator; in this case, any remaining 
biospecimens will be destroyed, but data already generated from the biospecimens will 
continue to be available to protect the integrity of existing analyses. 
Unless prohibited by local regulations or ethics committee decision, a 4-mL blood genomic 
banked biospecimen Prep D1 (dipotassium edetic acid [ethylenediaminetetraacetic acid] 
[K2EDTA] whole-blood collection optimized for DNA analysis) will be collected at the 
time specified in the Schedule of Activities section of the protocol to be retained for potential 
pharmacogenomic/genomic/biomarker analyses related to drug response and 
disease/condition under study.  For example, putative safety biomarkers, drug-metabolizing 
enzyme genes, drug-transport protein genes, or genes thought to be related to the mechanism 


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of drug action may be examined.  The primary purpose is to examine DNA; however, the 
biospecimen may also be used to study other molecules (eg, RNA, proteins, and metabolites).
Additional banked biospecimens to be retained for such exploratory analyses in this study 
include the following: 

Prep B1 (K2EDTA plasma collection optimized for 
biomarker/proteomic/metabonomic analysis): a 10-mL blood biospecimen will be 
collected at times specified in the Schedule of Activities section of the protocol. 

Prep B2 (serum collection optimized for biomarker/proteomic/metabonomic 
analysis): a 10-mL blood biospecimen will be collected at times specified in the 
Schedule of Activities section of the protocol. 

Prep R1 (PAXGene whole-blood collection optimized for RNA analysis): A 
2.5 mL blood biospecimen will be collected at times specified in the Schedule of 
Activities section of the protocol.
The banked biospecimens will be collected from all subjects unless prohibited by local 
regulations or IRB/EC decision. 
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document that they will not be compensated 
in this event.
7.4. Additional Research
Unless prohibited by local regulations or IRB/EC decision, subjects will be asked to indicate 
on the consent form whether they will allow banked biospecimens to also be used to design 
and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Banked Biospecimens section will be used.  Subjects may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.
7.5. Safety Assessments
Safety will be assessed by the spontaneous reporting of AEs, physical examinations and 
clinical laboratory results in all subjects who receive at least one dose of the investigational 
product.  Unscheduled safety assessments may be performed at any time during the study to 
assess any perceived safety concerns.  Investigators and Pfizer Clinicians (or designees) will 
review individual subject data throughout the conduct of the study to ensure subjects’ 
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7.5.1. Vital Signs
Vital signs (pulse rate, blood pressure, respiratory rate and oral, tympanic, or axillary 
temperature) will be measured after 5 minutes of rest as indicated in the Schedule of 
Activities. 
Vital signs should be performed before laboratory blood collection and ECG. 
It is preferred that body temperature be collected using the tympanic or oral methods; 
however, the axillary and temporal artery methods are also permitted.  The same method will 
be used consistently throughout the study. 
Blood pressure (BP) will be measured using a standard calibrated blood pressure measuring 
device.  A BP device that uses multiple cuff sizes based on the arm circumference is the 
required type of device.  The appropriate cuff size for the subject must be used to ensure 
accurate measurement.  The arm circumference at the midpoint of the length of the upper arm 
should be measured to determine the appropriate cuff size in accordance with the 
specifications of the BP measuring device.  The same properly sized and calibrated blood 
pressure cuff will be used to measure blood pressure each time. 
Subjects should be seated in a chair, back supported, and arms bared (free of restrictions such 
as rolled-up sleeves, etc.) and supported at heart level.  Measurements should be taken on the 
same arm at each visit (preferably non-dominant).  Subjects should refrain from smoking or 
ingesting caffeine during the 30 minutes preceding the measurements.  Measurements should 
begin after at least 5 minutes of rest. 
Pulse rate should be measured at approximately the same time as BP for a minimum of 
30 seconds.
7.5.2. Medical History, Physical Exam, Height, and Weight
Complete AA disease history includes collection of details of AA at Screening: AA history, 
AA diagnosis, pattern of scalp hair loss, body hair loss, nail involvement, the use of topical 
treatments, systemic treatments and other treatments for AA.  Medical history, in addition to 
AA history, including, but not limited to, comorbid conditions, history of drug, alcohol, 
tobacco use, dermatologic history, and infection will be collected at Screening and baseline 
(if applicable).  Smoking status and average weekly alcohol consumption (units/week) will 
also be collected.
Height and weight will be measured without the subject wearing shoes or outerwear.  Height 
(inches or centimeters) and weight (lbs or kgs) will be measured and recorded in the source 
document at the Screening visit and at various timepoints according to Schedules of 
Activities.
Complete physical examinations must be performed by the investigator, sub-investigator or a 
qualified health professional per local guidelines.  Complete physical examinations consist of 
assessments of general appearance; skin; head, eyes, ears, nose and throat (HEENT); mouth, 
heart; lungs; abdomen; extremities; neurologic function, back, and lymph nodes.  In addition, 


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dermatological full body exam must be performed by the investigator, sub-investigator or a 
qualified health professional per local guidelines.  Dermatological examinations should also 
include visual inspection of the breasts and external genitalia.
Targeted physical examinations must be performed by the investigator, sub-investigator or a 
qualified health professional per local guidelines and should include skin, heart, lung, and 
abdomen, neurologic function, and examination of body systems where there are symptom 
complaints by the subject. 
When dermatologic adverse events are identified on physical exam, additional procedures 
may be required.  Please refer to Section 7.5.6.2 for additional details.
Subjects with clinically meaningful changes from baseline in neurologic signs or symptoms 
should be referred to a neurologist to undergo a formal neurologic evaluation.
Complete and Targeted physical examinations are performed at various time points, see 
Schedules of Activities.
7.5.3. Chest Radiography
Chest X-ray (posterior-anterior and lateral views are recommended, however local guidelines 
should be followed) or other appropriate diagnostic image (ie, computed tomography or 
magnetic resonance imaging [MRI]) should be taken at Screening or within 3 months prior to 
Screening visit and read by a qualified radiologist or pulmonologist and must show no 
evidence of abnormalities including but not limited to current, active TB or previous inactive 
TB, general infections, heart failure or malignancy.  Documentation of the official reading 
must be located and available in the source documentation.
7.5.4. Electrocardiogram (ECG)
Single 12-lead ECGs should be collected at times specified in the Schedule of Activities. 
ECG should be performed before laboratory blood collection.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position and prior to any blood collection. 
The Screening ECG values will serve as each subject’s baseline values.  To ensure safety of 
the subjects, qualified medical personnel will review all ECGs and make comparisons to 
Screening measurements.  A paper or digital copy of the ECG should be filed in the subject’s 
chart and must be available to the sponsor upon request.  Any clinically significant changes 
will be recorded and evaluated further, as clinically warranted.  In some cases, it may be 
appropriate to repeat abnormal ECGs to rule out improper lead placement as contributing to 
the ECG abnormality.  Subjects will be discontinued from study with a confirmed QTcF
>500 milliseconds or a confirmed QTcF change from baseline of >60 milliseconds.


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7.5.5. Audiological Evaluation
All subjects will have an audiological evaluation at times specified in the Schedule of 
Activities.  When possible, the subject should have the audiological evaluation performed at 
the same evaluation center during the study. 
A full audiological evaluation must be completed at Screening or within 8 weeks prior to 
Day 1.  This evaluation includes audiological history, otoscopic examination, pure tone 
audiometry, air and bone conduction, speech audiometry, and immittance audiometry.  All 
audiological results must be available prior to Day 1 to assess eligibility. 
At subsequent visits, updated audiological history, otoscopic examination, and pure tone 
audiometry will be performed; based upon results, additional audiometry assessments may be 
required.
For subjects who terminate early from the study, efforts must be made to complete the 
audiological evaluation.
If there is a clinically meaningful, treatment-emergent decline in hearing from baseline, the 
subject must be promptly evaluated by a medically qualified specialist to assess for possible 
causes.  Evaluation results should then be discussed with the Sponsor to determine if the 
subject should be discontinued from the study.  Discontinued subjects must be followed up 
off-treatment with appropriate testing at regular intervals, until hearing returns to baseline or 
is determined to be clinically stable. 
Refer to the most current version of the Audiometry Study Guide for details on auditory 
evaluation.  All procedures must be performed as per the Audiometry Study Guide.
7.5.6. Special Safety Assessment
7.5.6.1. Suspected Opportunistic Infections
In the event of a suspected opportunistic infection, every effort should be made to identify 
the pathogen utilizing laboratory or other methods appropriate to the clinical situation.
7.5.6.2. Dermatological Events
All subjects will have a dermatological full body exam at Screening Visit and as noted in the 
Schedule of Activities.
Guidelines for the assessment of herpetiform rash and drug-related rash are noted in 
Sections 7.5.6.2.1 and 7.5.6.2.2, respectively.
7.5.6.2.1. Herpetiform Rash
For any occurrence of a suspected herpetiform rash (eg, herpes zoster and herpes simplex) or 
eczema herpeticum specimens for viral DNA analysis will be obtained: a swab of the 
affected area will be collected for confirmation.  Details for this collection will be provided 
in the laboratory manual.


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7.5.6.2.2. Potential Drug-Related Rash and Unexplained Rash
All potential drug-related reports of rash will be followed up until resolution or clinically 
stable or in agreement with the sponsor. 
All events of rash should be treated according to international and local guidelines for the 
treatment of rash, eg, where appropriate, topical corticosteroids and/or agents such as 
antibiotics or antivirals could be prescribed. 
All subjects reporting an unexplained skin rash should undergo a formal comprehensive 
dermatologic evaluation.  In addition, the subject will be asked to rate the severity of pruritus 
within the last 24 hours on a scale from 0 (No itching) to 10 (Worst possible itching).  
A 4 mm punch biopsy will be taken unless there is a clear, non-drug related etiology (eg, 
infection, including herpes virus, pre-existing condition) or other clinical rationale (eg, if the 
rash is present on the face it may not be appropriate to take a biopsy) or subject refuses to 
have biopsy performed.  The biopsy will be sent to the local laboratory for histological 
investigation of the rash in order to gain insight into potential etiology of the rash.
In addition to a biopsy of suspected drug-related rash, a swab (for microbiological 
assessment) of the affected area will also be taken for culture and sensitivity to assess (at the 
local laboratory) for any bacterial, fungal, or viral pathogens, if applicable.
Photographs of the rash will be taken.
All de-identified biopsy results, culture results, photographs, and any additional relevant test 
results should be forwarded to the Sponsor for review.  This should occur within 30 days of 
receipt of results by the principal investigator (PI).
7.5.7. Clinical Laboratory Tests
The following laboratory tests (Table 3) will be performed at time points identified in the 
Schedule of Activities.  Unscheduled clinical labs may be obtained at any time during the 
study to assess any perceived safety concerns at the investigator’s discretion.
Sample collection, labeling, storage, and shipping information can be found in the laboratory 
manual.  All laboratory tests with clinically important changes from baseline identified after 
administration of investigational product will be followed until the value stabilizes.  In 
addition, there are laboratory results which require specific follow-up described in 
Appendix 3.1 Monitoring Criteria. 

Subjects must abstain from all food and drink (except water and non-study 
medications) for an 8-hour fast prior to fasting lipid profile panel collection according 
to Schedule of Activities.  All other labs (including PK sample collections) do not 
require fasting.


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Table 3.
Laboratory Tests
Hematology
Serum Chemistry
Urinalysis 
(performed by the 
central laboratory)
Other
Hemoglobin
Hematocrit
Red blood cell count
Platelet count
White blood cell count
Total neutrophils (%, Abs)
Basophils (%, Abs)
Eosinophils (%, Abs)
Lymphocytes (%, Abs)f
Monocytes (%, Abs)
Reticulocyte count (%, Abs)
BUN or Urea
Creatinine
Glucose 
Calcium
Sodium
Potassium
Chloride
Total CO2 or Bicarbonate
AST
ALT
Total bilirubin
Direct and indirect bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Creatine kinasep
Follow-up testing for 
potential DILI casesq
pH
Glucose
Protein
Blood
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopyh
Urine culturej
FSHa
Pregnancy testsb
HIVc
HBsAg
HBcAb
HBsAbd
HBVDNAe
HCVAb
HCVRNAg
VZV IgG Abi
QFT-G test or T-Spot testk
Viral screenl
Ig subtypes
Skin biopsies/swabsm
IP-10n
Fasting lipid profileo
T cell, B cell and NK cell subsets
a.
In females under 60 years old and who are amenorrheic for at least 12 consecutive months with no alternative 
pathological or physiological cause to confirm postmenopausal status.
b.
Pregnancy tests (urine) for women of childbearing potential.  In the event that urine pregnancy tests are not permitted 
at an institution, serum pregnancy tests can be utilized.
c.
HIV testing per local regulations.  Subjects who are positive for HIV antibodies will be screen-failed.
d.
HBsAb will be performed as reflex testing for any subject who is HBsAg negative but HBcAb positive.  For Japan 
only: In addition to HBsAg and HBcAb, HBsAb testing will be performed at screening for all subjects rather than as a 
reflex test.  For Japan-specific requirements see Appendix 5.1.  For all other countries, please refer to Appendix 2 for 
testing algorithm, reflex testing, and full eligibility criteria. 
e.
HBVDNA testing will be performed at Week 12 for subjects who were enrolled with a positive HBcAb and a negative 
HBVDNA in those regions for which Hep B prevalence has been reported at a rate of >5.0% or if required by local 
standard of care (refer to Section 7.5.11 for information regarding which screening laboratory results should be used to 
determine whether HBVDNA testing should be performed).  Testing at additional time points may be performed as per 
the local standard of care.  For Japan specific requirements see Appendix 5.1.  For all other countries, please refer to 
Appendix 2 for testing algorithm, reflex testing, and full eligibility criteria.
f.
Subjects with absolute lymphocyte counts <500/mm3 (0.5 × 109/L) will be reflex-tested for FACS-TBNK until the 
absolute lymphocyte count resolves or stabilizes at a level acceptable to the investigator and the sponsor.
g.
HCVRNA will be performed as reflex testing for any subject who is HCVAb positive.
h.
Only if urine dipstick is positive for blood, nitrites, leukocyte esterase, and/or protein.
i.
VZV IgG Ab testing is required to confirm eligibility only in adolescent subjects who do not have documented 
evidence of having received varicella vaccination (2 doses).
j.
Urine culture will be performed if urinalysis is positive for nitrite and/or leukocyte esterase or if clinically indicated.
k.
The QFT-G test is preferred; however, the T-Spot test is also permitted.  A negative PPD test can be substituted for the 
QFT-G test or T-Spot test only under specific circumstances described in Section 7.5.8.
l.
A serum sample will be collected at baseline and submitted to the central lab.  The sample will be stored and analyzed 
at a later date only at the sponsor’s request.  In certain cases of suspected viral infection (eg, disseminated herpes zoster 
or varicella), the sponsor may request to analyze the sample to determine if the subject had exposure to that virus.
m.
When required in cases of skin rash adverse events.  See applicable sections for herpetiform rash (Section 7.5.6.2.1) 
and potential drug-related rash (Section 7.5.6.2.2).
n.
After randomization, the investigator and Pfizer study personnel directly involved in the conduct of the trial will be 
kept blinded of the results of this test.
o.
Lipid profile panel will include total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and 
triglycerides.  A minimum of 8-hour fasting is required for lipid profile evaluation.
p.
Urine myoglobin will be performed as reflex testing for any subject with a creatine kinase >10 × ULN.
q.
In cases of suspected potential drug-induced-liver-injury (DILI), follow-up testing should be performed according to 
requirements in Section 8.4.2.


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Clinically significant abnormal findings should be recorded as AEs.  Abnormal test results 
determined to be caused from laboratory error should not be reported as AEs.  Clinically 
significant laboratory findings at the final assessment should be followed up to resolution or 
until determined by the Investigator to be stabilized.  Repeat tests may be indicated to 
establish this.  Refer to Appendix 3 for laboratory discontinuation criteria.
7.5.8. Tuberculosis Testing
During the Screening period, it must be determined and documented that a subject does not 
have evidence of active or latent or inadequately treated infection with Mycobacterium 
tuberculosis (TB) per the Inclusion Criteria.  The results of TB screening conducted in the 
12 weeks prior to Day 1 visit or during the Screening period must be documented in study 
records prior to Baseline (Visit 2).
QuantiFERON®-TB Gold In-Tube (QFT-G) test is the preferred testing method; however, the 
T-SPOT®.TB (T-Spot) test is also permitted.  Borderline results from the T-Spot test should 
be considered an exclusionary test result for this study. 
If the laboratory reports that the QFT-G test or T-Spot test results are indeterminate, the test 
should be repeated.  If the result of the repeat test is indeterminate, then subjects may be 
screened using the Purified Protein Derivative (PPD) Tuberculin Skin Test (Mantoux 
method) with approval of the Pfizer Medical Monitor.
The QFT-G test is an in vitro diagnostic test using a peptide cocktail simulating early 
secreted antigenic target of 6 kiloDalton (ESAT-6), culture filtrate protein 10 kiloDalton 
(CFP-10), and TB 7.7 proteins to stimulate cells in heparinized whole blood.  Detection of 
interferon-gamma by Enzyme-Linked Immunosorbent Assay (ELISA) is used to identify in 
vitro responses to these peptide antigens that are associated with M. tuberculosis infection.  
The T-Spot test is also an in vitro diagnostic test; however, it differs in that it uses a peptide 
cocktail simulating ESAT-6 and CFP-10 proteins to stimulate peripheral blood mononuclear 
cells.  Both the QFT-G test and the T-Spot test are indirect tests for M. tuberculosis infection 
(including disease) and are intended for use in conjunction with risk assessment, radiography 
and other medical and diagnostic evaluations.
A blood sample will be collected at screening for either the QFT-G or the T-Spot testing.  
The site must determine which test will be performed as sample collection and processing 
guidelines differ.  QFT-G testing will be performed at the central laboratory and T-Spot 
testing will be performed at the site’s local laboratory.  Following QFT-G sample processing, 
the sample will be shipped to the central laboratory for testing.  The procedure for processing 
and preparing the sample for shipment is described fully in the laboratory manual, which will 
be provided to investigators.
In addition to TB testing as specified in this clinical protocol, a chest X-ray will be 
performed as described in Section 7.5.3.


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7.5.8.1. Purified Protein Derivative (PPD) Test
If the QFT-G test or T-Spot test cannot be performed, or if the results from the reference 
laboratory are indeterminate, then subjects may be screened using the PPD Tuberculin Test 
(Mantoux method), with the approval of the Pfizer Medical Monitor. 
Subjects must have the PPD test administered and evaluated by a health care professional 
48 to 72 hours later in order to be eligible for the study, unless performed and documented 
within the last 12 weeks.  The test should be performed and interpreted as negative according 
to local standards (eg, induration of <5 mm).
7.5.9. Varicella-Zoster Virus Immunoglobulin G Antibody (VZV IgG Ab) Testing
Only adolescent subjects without documented evidence of having received varicella 
vaccination (2 doses) will be tested for VZV IgG Ab as described in the lab manual.  
7.5.10. Baseline Viral Screen
A serum sample will be collected at baseline and submitted to the central lab.  The sample 
will be stored and analyzed at a later date only at the sponsor’s request.  In certain cases of 
suspected viral infection (eg, disseminated herpes zoster or varicella), the sponsor may 
request to analyze the sample to determine if the subject had exposure to that virus.  
Additional sample collection instructions will be provided in the lab manual.  The retained 
samples will be destroyed upon subject completion of this study or the long-term extension 
study.
7.5.11. Hepatitis B DNA (HBVDNA) Testing
For subjects in countries in which hepatitis B prevalence has been reported at a rate of 
>5.0%59 or if required by local standard of care, HBVDNA testing will be performed as 
reflex testing for any subject who is HbcAb positive at screening.  In addition, HBVDNA 
testing will be performed at Weeks 12, 24, 34, 48, and Early Termination for subjects who 
were enrolled with a positive HBcAb and a negative HBVDNA in those regions for which 
hepatitis B prevalence has been reported as a rate of >5.0% or if required by local standard of 
care.  Testing at additional time points may be performed as per the local standard of care.  
Please refer to Appendix 2 for testing algorithm, reflex testing, and full eligibility criteria; for 
Japan-specific requirements, see Appendix 5.1.
7.5.12. Events for Adjudication/Review Committee Submission
The identification of events requiring submission to an adjudication/review committee will 
be made by the study site and communicated to Pfizer or designee.  In addition, events 
requiring review, including opportunistic infections, cardiovascular, or malignancy events 
may also be identified by the Pfizer Study Team or designee during the review of subject 
data listings or by site monitors during routine monitoring of subject’s study records.  
Additional types of events for review and adjudication may be identified by Pfizer.  The 
Pfizer Study Team or designee will notify the study site of any events should they identify.


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The Pfizer Study Team or designee will provide a listing of specific documents needed to 
support event adjudication by the Adjudication/Review Committees.  Obtaining and 
submitting the documentation will be the responsibility of the study site.  Event 
documentation will vary with the event requiring adjudication and may include (but not be 
limited to): hospital discharge summaries, operative reports, clinic notes, ECGs, diagnostic 
tests, pathology reports, autopsy reports and death certificate information, as applicable.
7.6. Clinical Assessments
7.6.1. Severity of Alopecia Tool (SALT)
Severity of alopecia tool (SALT) is a quantitative assessment of AA severity based on scalp 
terminal hair loss.
Score parameters utilize a visual aid showing the division of the scalp hair into four 
quadrants (back, top of scalp, and both sides), with each of the four quadrants given an 
accurate determination of the % of scalp surface area covered, representing 24%, 40%, 18%, 
and 18% of the total scalp surface area, respectively.  
Subject must have a SALT score ≥50 at both Screening and Baseline to be eligible for 
the study. 
Photographs of scalp taken at the Screening visit will be reviewed by an independent 
consultant to confirm the SALT scores; photographs taken at other study visits may also be 
reviewed.  For more information on photography required for this protocol, see Section 7.9.
Hair prosthetics (eg, wigs, hair extensions) must be removed for clinical assessments of 
AA at all study visits.
7.6.2. Eyelash Assessment (ELA)
The eyelash assessment (ELA) is a numeric rating scale (NRS) developed to characterize 
eyelash hair loss.  The numeric rating scale ranges from 0 (none) to 3 (normal) as described 
below. 


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Score
Description
0
None Eyelash

No eyelashes of both right and left upper and lower eyelashes.
1
Minimal Eyelash

Modestly or severely decreased density of and/or large gap(s) in one or both upper eyelashes.
2
Moderate Eyelash

Normal density of both upper eyelashes without gap(s), and decreased density or gap(s) is 
present in one or both lower eyelashes, OR

Normal density of both upper eyelashes with short gap(s), OR

Mildly decreased density of one or both upper eyelashes with or without short gap(s).
3
Normal Eyelash

Normal density of both right and left upper and lower eyelashes from near medial canthus to 
near lateral canthus without any gap(s).
NOTE: 

Density of lower eyelashes is usually less than upper eyelashes.

A short gap does not significantly distort the appearance of the eyelash(es).

Moderate Eyelash score does not require presence of lower eyelashes.
Mascara and false eyelashes must be removed for clinical assessments of AA at all study 
visits.
7.6.3. Eyebrow Assessment (EBA)
The eyebrow assessment (EBA) is an NRS developed to characterize eyebrow hair loss.  The 
numeric rating scale ranges from 0 (none) to 3 (normal). 
Score
Description
0
None Eyebrow

No eyebrow hair.
1
Minimal Eyebrow

Normal or decreased density of one or both eyebrows with large gap(s).

Severely decreased density of one or both eyebrows with or without gap(s).
2
Moderate Eyebrow

Normal density of both eyebrows with short gap(s) that does not significantly distort the 
appearance of the eyebrows, OR

Mildly decreased density of eyebrows with or without short gap(s), OR 

Moderately decreased density of eyebrows without short gap(s).  There is visual definition of 
eyebrows at a distance of 3 feet. 
3
Normal Eyebrow

Normal density of both right and left eyebrows spanning usual length (ie, from glabella to 
near temple) and width.  There are no gap(s).
NOTE: 

Density of lateral aspect of eyebrows may be mildly less than medial eyebrows.

A short gap does not significantly distort the appearance of the eyebrow(s).


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7.6.4. Assessment of Fingernails Affected by Alopecia Areata
The number of fingernails affected by AA will be counted in all subjects at baseline.  The 
number of affected fingernails will be counted at subsequent visits during the study treatment 
period (see Schedule of Activities).  Fingernails may have any of the following changes to be 
considered “affected”: nail pitting; trachyonychia (roughening of nail surface); onychorrhexis 
(brittle nails); koilonychia (transverse and longitudinal concavity of nail, ie, “spoon shaped”); 
onychomadesis (separation of nail plate from nail bed); longitudinal ridging or striations; 
leuconychia (white lines or spots in nail plate); red spotting of the lunulae.58,60-76
Photographs may be taken of affected nails at baseline visit and during study treatment at 
investigator’s discretion.
Nail polish/varnish, false fingernails, and gel applications must be removed for assessments 
of fingernails affected by AA.
7.6.5. Clinician Global Impression – Alopecia Areata (CGI-AA)
The Clinician Global Impression – Alopecia Areata (CGI-AA) is a single clinician-reported 
item developed to assess the clinical impression of severity of scalp hair loss.  The rater is 
asked to rate the subject’s current hair loss on a scale ranging from “None (no hair loss)” to 
“Very severe or complete hair loss”, with higher scores indicating more severe hair loss.  The 
CGI-AA should be completed after other clinical assessments of AA (ie, SALT, EBA, ELA, 
and assessment of fingernails affected by AA), whenever it is possible.
7.7. Assessment of Suicidal Ideation and Behavior
7.7.1. Columbia Suicide Severity Rating Scale (C-SSRS)
Columbia suicide severity rating scale is a validated tool to evaluate suicidal ideation and 
behavior. 
There are 2 versions of the C-SSRS to be utilized in this study - “C-SSRS for screening and 
baseline visits” and “C-SSRS for any post-baseline visits”.  The version used is dictated by 
the actual study visit.
At Screening or Day 1 visits, if the subject has had suicidal ideation associated with actual 
intent and a method or plan in the past year (“yes” answers on items 4, 5), the subject will not 
be included in the study.  For subjects who have had previous history of suicidal behaviors in 
the past 5 years, a risk assessment must be performed and documented by a qualified mental 
health professional to assess whether it is safe for the subject to participate in the trial. 
For all subjects who screen failure due to suicidal behavior, the subject should be referred for 
appropriate evaluation and treatment.
At any post-baseline visits, if there are “yes” answers on items 4, 5, or on any question in the 
suicidal behavior section of the C-SSRS, the subject will be discontinued from the study and 
referred to a mental health professional for appropriate evaluation and treatment.  If the 
subject cannot be seen by a mental health professional within 24 hours, then the subject 
should be sent to a local emergency room for psychiatric assessment.


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7.8. Patient Reported Outcome (PRO)
Every effort should be made to have the subject complete all patient reported outcome 
questionnaires before any other evaluations.  All PROs should be completed as per Schedule 
of Activities.
7.8.1. Alopecia Areata Patient Priority Outcomes (AAPPO)
The Alopecia Areata Patient Priority Outcomes (AAPPO) scale is a self-administered 
questionnaire that measures hair loss, emotional symptoms, and activity limitations over the 
past week.  This measure was developed based on qualitative patient input as well as review 
of other data sources (eg, literature, expert input, other existing measures, etc.).  The first 
four items of the tool, which cover hair loss from the scalp, eyebrows, eyelashes, and body, 
ask the patient to describe the current amount of hair loss using a 5 point response scale that 
ranges from “no hair loss” to “complete (do not have any hair on my [insert body area]).”  
The remaining items ask the patient to rate the impact of AA over the past week on a 5-point 
scale ranging from “never” to “always.”  The PGI-C and P-Sat enable an anchor-based 
method for interpreting meaningful changes in the AAPPO domain scores.  
7.8.2. Patient’s Global Impression of Change (PGI-C)
The Patient’s Global Impression of Change (PGI-C) asks the subject to evaluate the 
improvement or worsening of their AA as compared to the start of the study using a 
single-item, “Since the start of the study, my alopecia areata has: …”.  The patients will 
select one of seven responses ranging from “greatly improved” to “greatly worsened.”
7.8.3. Patient Satisfaction with Hair Growth (P-Sat)
The Patient Satisfaction with Hair Growth (P-Sat) asks the subject to evaluate his/her 
satisfaction with the hair that has regrown since the start of the study.  This measure is 
comprised of three items asking about satisfaction with the “amount” and “quality” of hair as 
well as “overall” satisfaction with the hair.  The patients will select one of seven responses 
ranging from “very satisfied” to “very dissatisfied.”
7.8.4. Hospital Anxiety and Depression Scale (HADS)
The Hospital Anxiety and Depression Scale (HADS) is a validated 14-item PRO measure 
used to assess states of anxiety and depression over the past week.  Items are rated on a 
4-point severity scale.  The HADS produces 2 scales, one for anxiety (HADS–A) and one for 
depression (HADS–D), differentiating the two states with established normal score 
cut-offs.79,88  The instrument has been validated for use by adolescents aged 12 and older.79


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7.8.5. EuroQoL 5 Dimensions (EQ-5D-5L) and EuroQoL 5 Dimensions—Youth 
(EQ-5D-Y)
The EuroQoL 5 Dimensions (EQ-5D-5L) is a validated, standardized, generic instrument that 
is the most widely used preference-based HRQoL questionnaire in cost-effectiveness and 
health technologies assessment (HTA). 80-82  The measure is a well-established instrument 
used to measure health states and utilities in various disease areas.  The measure contains 
5 items that cover mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression, as well as a visual analogue scale.  A version of the instrument 
specifically developed and validated for use by youths aged 12 through 17 years is called the 
EuroQoL 5 Dimensions—Youth (EQ-5D-Y) will be used for adolescent subjects.
7.8.6. Patient Health Questionnaire – 8 Items (PHQ-8)
The Patient Health Questionnaire – 8 items (PHQ-8) is a patient-reported questionnaire that 
consists of 8 items to assess subject depression level.  Subjects with clinically significant 
depression as noted by a PHQ-8 total score ≥15 at Screening must not be enrolled in the 
study.
7.8.7. 36-Item Short Form Health Survey Version 2 Acute (SF36v2 Acute)
The 36-Item Short Form Health Survey version 2 Acute (SF36v2) is a validated generic 
health status measure which measures concepts of HRQoL over the past week.  It is 36 items 
and measures 8 general health domains: physical functioning, role limitations due to physical 
health, bodily pain, general health perceptions, vitality, social functioning, role limitations 
due to emotional problems, and mental health.  These domains can also be summarized as 
physical and mental component summary scores.  Of note, the Mental Component Score 
(MCS) may be of particular interest to measure change in this patient population.
7.8.8. Alopecia Areata Resource Utilization (AARU)
The Alopecia Areata Resource Utilization (AARU) is a PRO that measures the resource 
utilization associated with AA.  The AARU is a 3-item questionnaire which asks patients 
about medical or nonmedical practitioner visits, cosmetic covering of hair loss, and career 
impact they may have had over the past 3 months.
7.8.9. Work Productivity and Activity Impairment: Alopecia Areata (WPAI: AA)
The Work Productivity and Activity Impairment: Alopecia Areata (WPAI: AA) is a validated 
scale that was developed to measure the effect on work productivity and regular activities 
during the past 7 days, which has been modified specifically for patients with AA.  The 
WPAI: AA will be completed by adult subjects only.  Adolescents aged 12-17 years will not 
complete this assessment.


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7.9. Photography of Alopecia Areata
Photographs of study subjects will be obtained (according to the separately provided 
Photography Instructions) at various time points as per Schedule of Activities.  Photographic 
services will be provided through a central photography lab selected by the sponsor.  
Detailed procedures to assure photographic quality and consistency will be provided 
separately in a central photography laboratory instruction manual.
Scalp photographs will be taken at the Screening Visit to verify eligibility (eg, ≥50% hair 
loss of the scalp).  Scalp areas photographed should be recorded in study documents so that 
the same scalp region(s) will be photographed at all time points as applicable.  Photographs 
of eyelashes and eyebrows will also be taken.  Photographs will also be taken at Baseline, 
Weeks 4, 12, 24, 28, 40, and 48 (or ET) visits.  Photographs of affected fingernails may be 
taken at the investigator’s discretion.
The photographs may be reviewed by an independent consultant(s) to confirm SALT scores.
7.10. Pharmacokinetics
7.10.1. Plasma for Analysis of PF-06651600
During all study periods, blood samples to provide plasma for PK analysis will be collected 
into appropriately labeled tubes containing K2EDTA anticoagulant at times specified in the 
Schedule of Activities section of the protocol.
Blood will be collected at the time points identified in the Schedule of Activities section of 
the protocol.  All efforts will be made to obtain the pharmacokinetic samples at the exact 
nominal time relative to dosing.  For each blood sample collection, the allowable windows 
are as follows for time postdose: 0.5 hr (±10 min), 1 hr (±15 min), 2 hr (±20 min) and 
3 hr (±30 min).  The date and exact time of the sample collection is to be noted on the source 
document and data collection tool (eg, CRF), as well as the date and time of the previous 
dose.  Samples obtained outside the windows specified in the Schedule of Activities will be 
considered a protocol deviation.

The plasma will be stored in appropriately labeled screw-capped polypropylene tubes at 
approximately -20°C or colder within 1 hour of collection.

Further details regarding the collection, processing, storage and shipping of the blood 
samples will be provided in the lab manual.

Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures. 

The PK samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the PK processing steps, 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.  Any sample 
deemed outside of established stability, or of questionable integrity, will be considered a 
protocol deviation.


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
As part of understanding the pharmacokinetics of the study drug, samples may be used 
for metabolite identification and/or evaluation of the bioanalytical method.  These data 
will be used for internal exploratory purposes and will not be included in the clinical 
report.
7.10.2. Shipment of Pharmacokinetic Samples
The shipment address and assay lab contact information will be provided to the Investigator 
site prior to initiation of the study.  The central laboratory will provide collection materials 
and directions for packaging and shipment of samples and will forward samples to the 
contract analytical laboratory.  The contract analytical laboratory will be provided with 
randomization codes so that only samples in the PF-06651600 treatment groups are assayed.  
Placebo samples may be assayed in the event of suspected error in subject randomization.  
Refer to the central lab vendor manual for further information.
7.11. Pharmacodynamics Markers
The pharmacodynamic (PD) samples must be processed and shipped as indicated to maintain 
sample integrity.  Any deviations from the PD processing steps, 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.  Depending on 
sampling and transport constraints, it is possible that not all biomarker samples will be 
collected in all study regions.
All efforts will be made to obtain the PD samples at the exact nominal time relative to 
dosing.  Please consult the laboratory manual(s) for final instructions on sample collection, 
storage, and shipping requirements.  These manual(s) supersede the instructions listed in the 
applicable protocol sections.  Samples that are handled according to the respective manual 
guidance are considered “per protocol”.
Samples will be analyzed using fit for purpose or validated analytical methods in compliance 
with Pfizer standard operating procedures.
As part of understanding the pharmacodynamics of the study drug and the disease under 
study, samples may be used for evaluation of the bioanalytical method.  These data will be 
used for internal (ie, Pfizer) exploratory purposes and may not be included in the clinical 
report.
7.11.1. Samples for Interferon Gamma-Induced Protein – 10 (IP-10) Analysis
Blood samples to provide serum for the analysis of IP-10 will be collected into appropriately 
labeled tubes according to the times outlined in the Schedule of Activities.  IP-10 samples 
will be collected from all subjects unless the exportation of these samples from the country of 
origin is prohibited by local regulators or IRB/EC decision.


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7.11.2. Samples for fluorescence-activated cell sorting (FACS) analysis (T cell, B cell, 
and NK cell subsets)
Blood samples for the assessment of percent and absolute lymphocyte subsets will be 
collected and will be analyzed by FACS to identify T cell, B cell, and NK cell subsets 
according to the times outlined in the Schedule of Activities.
7.11.3. Samples for Immunoglobulins (IgA, IgG, IgM) Analysis
Blood sample for the analysis of immunoglobulin subtypes (IgA, IgG, and IgM) will be 
collected according to the times outlined in the Schedule of Activities. 
7.11.4. Shipment of Pharmacodynamic Samples
The shipment address and assay lab contact information will be provided to the investigator 
site prior to initiation of the study.
7.12. Rater Qualifications
Diagnosis of AA must be performed by a qualified dermatologist (board certified or 
equivalent) who has experience with AA.  The assessment of fingernails affected by AA 
must be performed by a qualified dermatologist (board certified or equivalent).  An 
experienced and qualified physician or healthcare professional may be permitted to perform 
the clinical evaluations of AA (SALT, ELA, EBA, and CGI-AA).  The C-SSRS may be 
performed by site staff.  For all assessments, the rater must be formally delegated to perform 
this assessment by the PI and receive training (with proper documentation) on the protocol 
and applicable assessment scales prior to performing these evaluations.  To assure 
consistency and reduce variability, the same rater should assess dermatological clinical 
evaluations for a given procedure and for an individual subject throughout the study (eg, one 
rater performs all SALT evaluations throughout the study). The same rater must assess the 
SALT and CGI-AA for an individual subject.  A back-up experienced and qualified, 
protocol-trained rater will only be allowed in special situations when the designated rater is 
unable to perform the evaluation. Use of the back-up rater will be documented.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy 
(EDP), exposure via 
breastfeeding, occupational 
exposure (regardless of 
whether associated with an 
AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this 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 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.


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8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  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.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/parent(s)/legal guardian/legally acceptable representative.  In 
addition, each study subject/parent(s)/legal guardian/legally acceptable representative will be 
questioned about the occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Subject 
Withdrawal/Early Termination section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days; except as indicated below after the last administration of the 
investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.


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Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally, the 
facts (evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
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.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;


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
Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result 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; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.


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8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.

Medical and scientific judgment is exercised in determining whether an event is an 
important medical event.  An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization.  However, if it is determined 
that the event may jeopardize the subject or may require intervention to prevent one 
of the other AE outcomes, the important medical event should be reported as serious.
Examples of such events are 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.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;


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
Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes 
of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.


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8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections and will be handled as SAEs in 
the safety database. 
8.4.2. 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 subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (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 lab 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 subject’s 
individual baseline values and underlying conditions.  Subjects 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:

Subjects 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 subjects 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).


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
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).
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 subject 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, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
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 (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, 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 and liver imaging 
(eg, biliary tract) 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 liver function test (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.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.


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8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, 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.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
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.


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Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes 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 investigational product.
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 subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. Exposure during Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding 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’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported 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 does not pertain to a subject 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.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial 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


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Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
For further clarification, a medication error is:

Any preventable event causing or leading to inappropriate medication use or patient 
harm;

When patient misunderstood, could not read, was not aware of, or not given dosing 
instructions.
A medication error is not an inadvertent or intentional missing of a dose or use of extra dose 
of study medication by a subject who understands dosing instructions.  This is a compliance 
issue.  Reporting of compliance issues are described in Section 5.3.
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 immediately.
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 non-serious, are recorded on an 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.
8.4.5. Safety Adjudication Committees
The identification of events requiring submission to an adjudication/review committee will 
be made by the study site and communicated to Pfizer or designee.  Events requiring review, 
including opportunistic infections, cardiovascular, and malignancy events may also be 
identified by the Pfizer Study Team or designee during the review of subject data listings or 
by site monitors during routine monitoring of subject’s study records.  The Pfizer Study 
Team or designee will notify the study site of any events should they identify.
The Pfizer Study Team or designee will provide a listing of specific documents needed to 
support event adjudication by the Adjudication/Review Committees.  Obtaining and 
submitting the documentation will be the responsibility of the study site.  Event 
documentation will vary with the event requiring adjudication and may include (but not be 
limited to): hospital discharge summaries, operative reports, clinic notes, diagnostic tests, 
pathology reports, autopsy reports and death certificate information, as applicable.


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9. DATA ANALYSIS/STATISTICAL METHODS
This section outlines the key planned statistical summaries and analyses for the data collected 
in this study.  Detailed methodology for summary and statistical analyses of the data 
collected in this study is outlined here and further detailed in a statistical analysis plan (SAP), 
which will be maintained by the sponsor.  The SAP may modify what is outlined in the 
protocol where appropriate; however, any major modifications of the primary endpoint 
definitions or their analyses will also be reflected in a protocol amendment.  The SAP will be 
finalized prior to database lock and breaking the blind for the primary analysis of the 
B7981015 study.
Section 2 lists the overall study objectives and endpoints; the primary and secondary 
objectives and endpoints for the overall study reporting and publications are also detailed 
below in Table 4.  Table 5 lists the primary and secondary endpoints of the study organized 
by known regional requirements.
Table 4.
Primary and Secondary Endpoints for Overall Study Reporting and 
Publications
Alpha (α)
0.05 (2-sided significance level)
Primary Endpoint
Response based on an absolute SALT Score ≤20 at Week 24.
Key Secondary Endpoint
Response based on an absolute SALT Score ≤10 at Week 24.
Secondary Endpoints

Response based on an absolute SALT Score ≤20 at Week 24 will be used to 
characterize the exposure response.

Response based on an absolute SALT score ≤20 at Weeks 4, 8, 12, 18, 28, 34, 40, and 
48.
NOTE: Response at Weeks 4, 8, 12, and 18 will be analyzed controlling for Type I 
error.

Response based on an absolute SALT score of ≤10 at Weeks 4, 8, 12, 18, 28, 34, 40, 
and 48.

Response based on a 75% improvement in SALT score from baseline (SALT75) at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Change from baseline in SALT scores at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Response based on at least a 2-grade improvement or a score of 3 in EBA score at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Response based on at least a 2-grade improvement or a score of 3 in ELA score at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

PGI-C response defined as a PGI-C score of “moderately improved” or “greatly 
improved” at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.

Change from baseline in AAPPO scales at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.


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Table 5.
Primary and Secondary Endpoints Organized by Known Regional 
Regulatory Requirements
For the FDA/PMDA
For the EMA
and competent authorities in the VHP 
countries
Alpha (α)
 
0.00125 (2-sided significance level)
0.01 (2-sided significance level)
Primary Endpoint
Response based on an absolute SALT Score 
≤20 at Week 24.
Response based on an absolute SALT Score 
≤10 at Week 24.
Key Secondary Endpoint
Not applicable
PGI-C response defined as a PGI-C score of 
“moderately improved” or “greatly 
improved” at Week 24.
Secondary Endpoints
•
Response based on an absolute SALT 
Score ≤20 at Week 24 will be used to 
characterize the exposure response.
•
Response based on an absolute SALT 
Score ≤10 at Week 24 will be used to 
characterize the exposure response.
•
Response based on an absolute SALT 
score ≤20 at Weeks 4, 8, 12, 18, 28, 34, 
40, and 48.
NOTE: Response at Weeks 4, 8, 12, 
and 18 will be analyzed controlling for 
Type I error.
•
Response based on an absolute SALT 
score ≤20 at Weeks 4, 8, 12, 18, 24, 28, 
34, 40, and 48.
NOTE: Response at Week 24 will be 
analyzed controlling for Type I error.
•
Response based on an absolute SALT 
score of ≤10 at Weeks 4, 8, 12, 18, 24, 
28, 34, 40, and 48.
NOTE: Response at Week 24 will be 
analyzed controlling for Type I error.
•
Response based on an absolute SALT 
score of ≤10 at Weeks 4, 8, 12, 18, 28, 
34, 40, and 48.
NOTE: Response at Weeks 4, 8, 12, 
and 18 will be analyzed controlling for 
Type I error.
•
Response based on a 75% improvement 
in SALT score from baseline (SALT75) 
at Weeks 4, 8, 12, 18, 24, 28, 34, 40, 
and 48.
•
Response based on a 75% improvement 
in SALT score from baseline (SALT75) 
at Weeks 4, 8, 12, 18, 24, 28, 34, 40, 
and 48.
•
Change from baseline in SALT scores 
at Weeks 4, 8, 12, 18, 24, 28, 34, 40, 
and 48.
•
Change from baseline in SALT scores 
at Weeks 4, 8, 12, 18, 24, 28, 34, 40, 
and 48.
•
Response based on at least a 2-grade 
improvement or a score of 3 in EBA 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 
40, and 48.
•
Response based on at least a 2-grade 
improvement or a score of 3 in EBA 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 
40, and 48.
•
Response based on at least a 2-grade 
improvement or a score of 3 in ELA 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 
40, and 48.
•
Response based on at least a 2-grade 
improvement or a score of 3 in ELA 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 
40, and 48.
•
PGI-C response defined as a PGI-C 
score of “moderately improved” or 
“greatly improved” at Weeks 4, 8, 12, 
18, 24, 34, 40, and 48.
•
PGI-C response defined as a PGI-C 
score of “moderately improved” or 
“greatly improved” at Weeks 4, 8, 12, 
18, 34, 40, and 48.
•
Change from baseline in AAPPO scales 
at Weeks 4, 8, 12, 18, 24, 34, 40, and 
48.
•
Change from baseline in AAPPO scales 
at Weeks 4, 8, 12, 18, 24, 34, 40, and 
48.
-
•
Change from baseline in the depression 
subscale score of the HADS at 
Weeks 4, 8, 12, 24, and 48.
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Table 5.
Primary and Secondary Endpoints Organized by Known Regional 
Regulatory Requirements
For the FDA/PMDA
For the EMA
and competent authorities in the VHP 
countries
-
•
Change from baseline in the anxiety 
subscale score of the HADS at 
Weeks 4, 8, 12, 24, and 48.
-
•
Improvement on HADS among 
subjects with a baseline subscale score 
indicative of depression who achieved a 
“normal’ subscale score indicative of 
an absence of depression at Weeks 4, 8, 
12, 24, and 48.
-
•
Improvement on HADS among 
subjects with a baseline subscale score 
indicative of anxiety who achieved a 
“normal’ subscale score indicative of 
an absence of anxiety at Weeks 4, 8, 
12, 24, and 48.
9.1. Sample Size Determination
The sample size for the study was based on the consideration to have sufficient power to 
evaluate the primary endpoint.  A sample size of 120 subjects per group (for the 
200 mg/50 mg once daily (QD), 200 mg/30 mg QD, 50 mg/50 mg QD, or 30 mg/30 mg QD 
groups) will provide more than 90% power to demonstrate that at least the 200 mg/50 mg 
group is superior to placebo by a difference of 24% in the proportion of subjects achieving 
the primary endpoint (SALT ≤20 at Week 24), assuming a placebo response rate of no more 
than 5%, at α = 0.05 (2-sided significance level).  This sample size accounts for multiplicity 
using a closed testing procedure to ensure strong control of Type I error for all comparisons 
between active treatment groups and placebo.  This sample size additionally provides >90% 
power for the SALT ≤10 at Week 24 endpoint assuming that the 200 mg/50 mg QD group is 
superior to placebo by a difference of 20% in the proportion of subjects achieving SALT 
≤10, assuming a placebo response rate of no more than 5%, at α = 0.05 (2-sided significance 
level).  The assumption of the placebo response rate for both SALT ≤20 and SALT ≤10, as 
well as the treatment difference, was informed by the Week 24 results from the Phase 2a 
Study B7931005. 92  
Regulatory requirements for a marketing authorization approval 
 
 will require significance at an α more stringent than 0.05, although the exact level of 
stringency required may vary (ie, 0.00125 is required by the FDA/PMDA for their requested 
primary endpoint of SALT ≤20, while 0.01 is required by the EMA for their requested 
primary endpoint of SALT ≤10). The sample size of 120 subjects per group provides power 
>90% for SALT ≤20 (α = 0.00125) and SALT ≤10 (α = 0.01).
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The 10 mg/10 mg QD group is included to address the secondary objective of characterizing 
the exposure response.  The sample size of 60 subjects for this group was chosen to allow for 
estimation of the exposure response parameters.  
For the EMA and competent authorities in the VHP countries, that request that the PGI-C 
response at Week 24 be analyzed as a key secondary endpoint, a sample size of 120 subjects 
per group  also provides more than 90% power for PGI-C response assuming a difference of 
35% and a placebo response rate of 20%, at α = 0.05 (2-sided significance level).  The 
assumptions of the treatment difference and placebo response rate for PGI-C response were 
based on the Concert CTP-543 Phase 2b Study Week 24 data.90  Under the above 
assumptions, the power of the study remains >90% at α = 0.01 (EMA required 2-sided 
significance level).
9.2. Efficacy Analysis
The primary analysis population for efficacy data will be the Full Analysis Set (FAS) defined 
as all randomized subjects, regardless of whether they received study medication.  In the 
comparison to placebo, the data from the 2 groups F and G up to Week 24 will be pooled to 
form the placebo group. 
9.2.1. Testing Procedure for Multiple Comparisons
This section describes the testing procedure for multiple comparisons.  This 
 
 will support submission in several regions with different requirements; therefore, this 
section is organized into 3 sections: Section 9.2.1.1, Section 9.2.1.2, and Section 9.2.1.3
describe the testing procedure for the overall study, for the FDA/PMDA, and for the EMA
and competent authorities in the VHP countries, respectively.
9.2.1.1. Overall Study (Testing Procedure for Multiple Comparisons Incorporating the 
SALT ≤10 as a Key Secondary Endpoint)
For the overall study the SALT ≤20 response at Week 24 is the primary endpoint and the 
SALT ≤10 response at Week 24 will be analyzed as a key secondary endpoint.  The 
hypotheses to be tested are that each of the active treatment groups is superior to placebo as 
measured by the proportion of subjects achieving the primary endpoint and the key 
secondary endpoint.  There are a total of 8 hypotheses to be tested:
•
Hypothesis 1 (H1) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the primary endpoint; 
•
Hypothesis 2 (H2) is to test whether the 50 mg QD dose regimen is superior to 
placebo for the primary endpoint; 
•
Hypothesis 3 (H3) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the primary endpoint; 
•
Hypothesis 4 (H4) is to test whether the 30 mg QD dose regimen is superior to 
placebo for the primary endpoint;
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
Hypothesis 1p (H1p) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the key secondary endpoint; 

Hypothesis 2p (H2p) is to test whether the 50 mg QD dose regimen is superior to
placebo for the key secondary endpoint; 

Hypothesis 3p (H3p) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the key secondary endpoint; 

Hypothesis 4p (H4p) is to test whether the 30 mg QD dose regimen is superior to 
placebo for the key secondary endpoint.
The family-wise Type I error will be strongly controlled using a gatekeeping approach as 
described in the following order and shown in Figure 2.  The 10 mg group comparison to 
placebo is not included in the Type I error controlled procedure, as this group is only 
included to support the estimation of the exposure response.

The primary endpoint for 200 mg QD/50 mg QD dose regimen (H1) will be tested at 
significance level first.  If significant, then the primary endpoint for 50 mg QD dose 
regimen and the 200 mg QD/30 mg QD dose regimen (H2 and H3) and the key 
secondary endpoint for 200 mg QD/50 mg QD dose regimen (H1p) will be tested 
simultaneously. If both the 50 mg QD dose regimen and the 200 mg QD/30 mg QD 
dose regimen are significant, then the 30 mg QD dose regimen will be tested. 

For the primary endpoint, if both the 50 mg QD dose regimen and the 200 mg QD/30 
mg QD dose regimen are significant at /4 level, or if one of the dose regimens (50 
mg QD dose regimen or 200 mg QD/30 mg QD dose regimen) is significant at /4 
level and the other is significant at /2 level, both dose regimens will be declared as 
significant.  In this case, the 30 mg QD dose regimen will be tested at /2 level.  If 
only one of the regimens (50 mg QD dose regimen or 200 mg QD/30 mg QD dose 
regimen) is significant at /4 level and the other is not significant at /2 level, only 
the one significant at /4 level will be declared as statistically significant.  In this 
case, the testing for the 30 mg QD dose regimen will not proceed.

For the key secondary endpoint, the 200 mg QD/50 mg QD dose regimen will be 
tested at /2 level first.  If significant, then the 50 mg QD dose regimen and the 
200 mg QD/30 mg QD dose regimen will be tested simultaneously.  If both the 50 mg 
QD dose regimen and the 200 mg QD/30 mg QD dose regimen are significant at 
/4 level, or if one of the dose regimens (50 mg QD dose regimen or 
200 mg QD/30 mg QD dose regimen) is significant at /4 level and the other is 
significant at /2 level, both dose regimens will be declared as significant.  In this 
case, the 30 mg QD dose regimen will be tested at /2 level.  If only one of the 
regimens (50 mg QD dose regimen or 200 mg QD/30 mg QD dose regimen) is 
significant at /4 level and the other is not significant at /2 level, only the one 


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significant at /4 level will be declared as statistically significant.  In this case, the 
testing for the 30 mg QD dose regimen will not proceed.

If the primary endpoint for the 200 mg QD/50 mg QD dose regimen is significant at α 
level, and all the remaining hypotheses for the primary endpoint and key secondary 
endpoint are significant at the overall /2 level, then all 8 hypotheses will be declared 
as statistically significant. 

If the primary endpoint for all 4 hypotheses or the primary endpoint for H1 is 
significant and the key secondary endpoint is significant in all 4 hypotheses, then the 
/2 level will be passed to the hypothesis testing for the other hypotheses.  In this 
case, the other hypotheses can be tested at the level instead of the /2 level 
following the same procedures for claiming statistical significance outlined in the 
bullets above with the exception of the increased .
Figure 2.
Schematic and Graphical Presentation for Multiple Testing Procedure 
Incorporating a Key Secondary Endpoint
The numbers on each edge indicate the transition rule for the weights on allocation once a hypothesis is 
rejected. 
The following approach will be used to control the Type I error for SALT ≤20 at earlier time 
points.  For a given dose, if the primary endpoint of SALT ≤20 is declared to be statistically 
significant based on the testing procedure for the primary endpoint, in order to establish the 
onset of efficacy as measured by SALT ≤20 at the earliest time point, a step-down approach 
with SALT ≤20 from Week 24 to earlier time points (order of testing: Weeks 24, 18, 12, 8, 
and 4) will be used for each time point.  Although this testing scheme does not protect the 
Type I error for the family of all possible comparisons, it will provide Type I error protection 
for testing the family of SALT ≤20 time points within the same dose group.


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9.2.1.2. For the FDA/PMDA (Testing Procedure for Multiple Comparisons With no Key 
Secondary Endpoints)
For the FDA/PMDA, the SALT ≤20 response at Week 24 is the primary endpoint and no 
secondary endpoints will be analyzed as key secondary. The hypotheses to be tested are that 
each of the active treatment groups is superior to placebo as measured by the proportion of 
subjects achieving the primary endpoint.  If the hypothesis test is significant at the 
= 0.00125 level, the active treatment group will be declared to be superior to placebo group 
in treating patients with moderate to severe AA and the study will meet its primary endpoint. 
There are a total of 4 hypotheses to be tested. 

Hypothesis 1 (H1) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 2 (H2) is to test whether the 50 mg QD/50 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 3 (H3) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 4 (H4) is to test whether the 30 mg QD/30 mg QD dose regimen is 
superior to placebo for the primary endpoint. 
The family-wise Type I error will be strongly controlled using a gate-keeping approach to 
test these hypotheses in 3 groups.  The first group includes H1; the second group includes H2 
and H3; and the third group includes H4.  The statistical significance of the first hypothesis 
(H1) will allow simultaneous testing of H2 and H3 using Holm’s method.83  Statistical 
significance for both H2 and H3 will enable testing the statistical significance for the fourth 
hypothesis (H4).  The 10 mg group comparison to placebo is not included in the Type I 
error-controlled procedure, as this group is only included to support the estimation of the 
exposure response.
The grouping of the dose regimens in the test hierarchy was based on the hierarchy of 
2 different dose regimens: in the dosing regimens that have a loading dose, the order is 
200 mg QD/50 mg QD 200 mg QD/30 mg QD; in the regimens without a loading dose, 
the order is 50 mg QD/50 mg QD 30 mg QD/30 mg QD.  The testing strategy proposed 
will allow simultaneous testing of the 200 mg QD/30 mg QD and the 50 mg QD/50 mg QD 
dose regimens against placebo given that it is not known which dose regimen will have a 
better response.  Figure 3 shows a schematic of the procedure for testing each of the active 
treatment groups versus the placebo group for the primary endpoint. 


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Figure 3.
Schematic and Graphical Presentation for Multiple Testing Procedure
The numbers on each edge indicate the transition rule for the weights on allocation once a hypothesis is 
rejected.  
In the simultaneous testing of H2 and H3, if both the 50 mg QD/50 mg QD and 
200 mg QD/30 mg QD regimens are not significant at /2 level, the test for statistical 
significance is stopped.  If one of the hypotheses for 50 mg QD/50 mg QD and 
200 mg QD/30 mg QD regimens is significant at /2 level and the other hypothesis is 
significant at level, this family hypothesis is significant.  If one of the hypotheses for 
50 mg QD/50 mg QD and 200 mg QD/30 mg QD is significant at /2 level and the other 
hypothesis is not significant at level, only the hypothesis significant at /2 level will be 
declared as statistically significant.  In this case, the testing for statistical significance for 
H4 will not proceed.
The following approach will be used to control the Type I error for SALT ≤10 at Week 24 
and SALT ≤20 at earlier time points.  For a given dose, if SALT ≤20 at Week 24 is declared 
to be statistically significant based on the testing procedure for the primary endpoint, then 
SALT ≤10 at Week 24 will be tested at the same significance level as the SALT ≤20 at Week 
24 was tested.  Though this testing scheme does not protect the Type I error for the family of 
all possible comparisons, it will provide Type I error protection for testing the endpoints 
within the same dose group.  For a given dose, if the primary endpoint of SALT ≤20 is 
declared to be statistically significant based on the testing procedure for the primary 
endpoint, in order to establish the onset of efficacy as measured by SALT ≤20 at the earliest 
time point, a step-down approach with SALT ≤20 from Week 24 to earlier time points (order 
of testing: Weeks 24, 18, 12, 8, and 4) will  be used for each time point.  Though this testing 
scheme does not protect the Type I error for the family of all possible comparisons, it will 
provide Type I error protection for testing the family of SALT ≤20 time points within the 
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9.2.1.3. For the EMA and Competent Authorities in the VHP Countries (Testing 
Procedure for Multiple Comparisons Incorporating the PGI-C Response as a Key 
Secondary Endpoint)
For the EMA and competent authorities in the VHP countries, the SALT ≤10 response at 
Week 24 will be the primary endpoint and the PGI-C response at Week 24 will be analyzed 
as a key secondary endpoint.  The hypotheses to be tested at =0.01 are that each of the 
active treatment groups is superior to placebo as measured by the proportion of subjects 
achieving the primary endpoint and the key secondary endpoint.  There are a total of 
8 hypotheses to be tested.

Hypothesis 1 (H1) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 2 (H2) is to test whether the 50 mg QD dose regimen is superior to 
placebo for the primary endpoint; 

Hypothesis 3 (H3) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 4 (H4) is to test whether the 30 mg QD dose regimen is superior to 
placebo for the primary endpoint;

Hypothesis 1p (H1p) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the key secondary endpoint; 

Hypothesis 2p (H2p) is to test whether the 50 mg QD dose regimen is superior to 
placebo for the key secondary endpoint; 

Hypothesis 3p (H3p) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the key secondary endpoint; 

Hypothesis 4p (H4p) is to test whether the 30 mg QD dose regimen is superior to 
placebo for the key secondary endpoint.
The family-wise Type I error will be strongly controlled using a gate-keeping approach as 
described in the following order and shown in Figure 2 in Section 9.2.1.1. The 10 mg group 
comparison to placebo is not included in the Type I error-controlled procedure, as this group 
is only included to support the estimation of the exposure response.

The primary endpoint for 200 mg QD/50 mg QD dose regimen (H1) will be tested at 
significance level first.  If significant, then the primary endpoint for 50 mg QD dose 
regimen and the 200 mg QD/30 mg QD dose regimen (H2 and H3) and the key 
secondary endpoint for 200 mg QD/50 mg QD dose regimen (H1p) will be tested 
simultaneously. If both the 50 mg QD dose regimen and the 200 mg QD/30 mg QD 
dose regimen are significant, then the 30 mg QD dose regimen will be tested. 


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
For the primary endpoint, if both the 50 mg QD dose regimen and the 200 mg QD/30 
mg QD dose regimen are significant at /4 level, or if one of the dose regimens (50 
mg QD dose regimen or 200 mg QD/30 mg QD dose regimen) is significant at /4 
level and the other is significant at /2 level, both dose regimens will be declared as 
significant.  In this case, the 30 mg QD dose regimen will be tested at /2 level.  If 
only one of the regimens (50 mg QD dose regimen or 200 mg QD/30 mg QD dose 
regimen) is significant at /4 level and the other is not significant at /2 level, only 
the one significant at /4 level will be declared as statistically significant.  In this 
case, the testing for the 30 mg QD dose regimen will not proceed.

For the key secondary endpoint, the 200 mg QD/50 mg QD dose regimen will be 
tested at /2 level first.  If significant, then the 50 mg QD dose regimen and the 
200 mg QD/30 mg QD dose regimen will be tested simultaneously.  If both the 50 mg 
QD dose regimen and the 200 mg QD/30 mg QD dose regimen are significant at
/4 level, or if one of the dose regimens (50 mg QD dose regimen or 
200 mg QD/30 mg QD dose regimen) is significant at /4 level and the other is 
significant at /2 level, both dose regimens will be declared as significant.  In this 
case, the 30 mg QD dose regimen will be tested at /2 level.  If only one of the 
regimens (50 mg QD dose regimen or 200 mg QD/30 mg QD dose regimen) is 
significant at /4 level and the other is not significant at /2 level, only the one 
significant at /4 level will be declared as statistically significant.  In this case, the 
testing for the 30 mg QD dose regimen will not proceed.

If the primary endpoint for the 200 mg QD/50 mg QD dose regimen is significant at 
level, and all the remaining hypotheses for the primary endpoint and key secondary
endpoint are significant at the overall /2 level, then all 8 hypotheses will be declared 
as statistically significant. 

If the primary endpoint for all 4 hypotheses or the primary endpoint for H1 is 
significant and the key secondary endpoint is significant in all 4 hypotheses, then the 
/2 level will be passed to the hypothesis testing for the other hypotheses.  In this 
case, the other hypotheses can be tested at the level instead of the /2 level 
following the same procedures for claiming statistical significance outlined in the 
bullets above with the exception of the increased .
For the EMA and competent authorities in the VHP countries, for a given dose, if SALT ≤10 
at Week 24 is declared to be statistically significant based on the testing procedure for the 
primary endpoint incorporating  the key secondary endpoint, then SALT ≤20 at Week 24 will 
be tested at the same significance level as SALT ≤10 at Week 24 was tested. Although this 
testing scheme does not protect the Type I error for the family of all possible comparisons, it 
will provide Type I error protection for testing the endpoints within the same dose group.  
For a given dose, if the primary endpoint of SALT ≤10 is declared to be statistically 
significant based on the testing procedure for the primary endpoint incorporating the key 
secondary endpoint, in order to establish the onset of efficacy as measured by SALT ≤10 at 
the earliest time point, a step-down approach with SALT ≤10 from Week 24 to earlier time 


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points (order of testing: Weeks 24, 18, 12, 8, and 4) will be used for each time point.  
Although this testing scheme does not protect the Type I error for the family of all possible 
comparisons, it will provide Type I error protection for testing the family of SALT ≤10 time 
points within the same dose group.
9.2.2. Analysis of the Primary and Key Secondary Endpoints
The analyses of primary and key secondary endpoints are described separately for the overall 
study and for specific regulatory regions in order to address differences in advice received 
from some regulatory agencies.
9.2.2.1. For the Overall Study and the FDA/PMDA (Analysis of the Primary and Key 
Secondary Endpoints)
For the overall study and for the FDA/PMDA, the SALT ≤20 response at Week 24 is the 
primary endpoint. The SALT ≤10 response at Week 24 will be analyzed as a key secondary 
endpoint for the overall study but not for the FDA/PMDA. The testing procedures are 
described in Section 9.2.1.1 and Section 9.2.1.2, and the planned analysis of the primary 
endpoint are described in Table 6.
Table 6.
Statistical Methods for the Analysis of the Primary Endpoint for the 
Overall Study, and for the FDA/PMDA
Analysis 
#
Analysis 
Designation
Statistical 
Method
Approach for 
missing data due 
to COVID-19
Approach for 
missing data due to 
other reasons
1
Primary
MN
Exclude missing
Consider missing as 
non-responders
2
Supplementary
GLMM
MAR
MAR
2a
Supplementary
GLMM/ 
Tipping point
MNAR
MNAR
3
Supplementary
MN
Consider missing 
as non-responders
Consider missing as 
non-responders
Abbreviations: GLMM = generalized linear mixed model; MN = Miettinen and Nurminen; MAR = Missing at random; 
MNAR = Missing not at random
In the primary analysis for the overall study, and for the FDA/PMDA, the primary endpoint 
will be analyzed by the MN method84 for the difference in the proportion of responders 
between each active treatment group and placebo.  Subjects with missing SALT score at 
Week 24 due to COVID-19 related reasons will be excluded from the analysis at that time 
point, whereas missing data due to other reasons will be counted as non-responders at that 
time point (Analysis 1). As a supplementary analysis to assess the impact of COVID-19-
related missing data on the results of the primary analysis, the analysis of the primary 
endpoint will be repeated with all missing data considered as non-responders regardless of 
the reason for missingness (Analysis 3). 


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As a supplementary analysis a GLMM for the longitudinal binary data of SALT ≤20
response over time up to Week 24 will be conducted (Analysis 2) to evaluate the impact of 
the missing data approach to the primary conclusion.  In this analysis, two different missing 
mechanisms will be assumed: MAR and MNAR.  A tipping point analysis will be conducted 
under MNAR (Analysis 2a).
The key secondary endpoint for the overall study (SALT ≤10 response at Week 24) will be 
analyzed using the same approach as Analysis 1. Analysis 4 described in Table 7 will also be 
conducted for this endpoint as supplementary.
9.2.2.2. For the EMA and Competent Authorities in the VHP Countries (Analysis of the 
Primary and Key Secondary Endpoints)
For the EMA and competent authorities in the VHP countries, the SALT ≤10 response at 
Week 24 will be the primary endpoint and the PGI-C response at Week 24 will be analyzed 
as a key secondary endpoint.  The testing procedures are described in Section 9.2.1.3, and the 
planned analysis of the primary endpoint are described in Table 7.
Table 7.
Statistical Methods for the Analysis of the Primary Endpoint for the EMA 
and Competent Authorities in the VHP Countries
Analysis 
#
Analysis 
Designation
Statistical 
Method
Approach for 
missing data due 
to COVID-19
Approach for 
missing data due to 
other reasons
4
Primary
GLMM
MAR
Consider missing as 
non-responders
4a
Supplementary
GLMM/ 
Tipping point
MNAR
Consider missing as 
non-responders
1
Supplementary
MN
Exclude missing
Consider missing as 
non-responders
3
Supplementary
MN
Consider missing 
as non-responders
Consider missing as 
non-responders
Abbreviations: GLMM = generalized linear mixed model; MN = Miettinen and Nurminen; 
MAR = Missing at random; MNAR = Missing not at random
The primary analysis of the primary endpoint for the EMA and competent authorities in the 
VHP countries (Analysis 4) will be conducted using a GLMM model for the longitudinal 
binary data of SALT ≤10 response over time up to Week 24, assuming a missing mechanism 
of MAR for missing data due to COVID-19. Missing data due to reasons not related to 
COVID-19 will be assumed as non-responders. The key secondary endpoint will also be 
analyzed using this approach.
As a supplementary analysis, imputations will be implemented under the framework of the 
same GLMM model as above, using a tipping point analysis (Analysis 4a). For this analysis, 


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the assumption of the missing mechanism for this analysis will be MNAR for cases of 
missing data due to COVID-19, and missing data due to other reasons will be considered as 
non-responders. 
Additional supplementary analyses will use the MN method to estimate 95% CIs and p-
values for the differences in the proportions of response between each active treatment group 
and placebo. In Analysis 1 missing data due to COVID-19 will be excluded from the 
analysis, whereas missing data due to other reasons will be considered as non-responders. In 
Analysis 3, all missing data will be considered as non-responders, regardless of the reason for 
missingness.
9.2.2.3. Per-Protocol Analysis (Analysis of the Primary and Key Secondary Endpoints)
In addition to the analyses described in Section 9.2.2.1 and in Section 9.2.2.2, the primary 
analyses of the primary endpoints and key secondary endpoints will also be performed in the 
Per Protocol Analysis Set (PPAS), defined as all randomized subjects who do not have any 
major protocol deviations related to inclusion/exclusion criteria, compliance with 
investigational product or any other major protocol deviation that might affect the efficacy 
data at Week 24.  
The following protocol deviations will be evaluated for each subject prior to unblinding to 
determine if a subject should be excluded from the PPAS: 
1. Subject did not meet the following inclusion criteria for hair loss due to AA at 
Screening or Day 1:
a.
Clinical diagnosis of AA with no other known etiology of hair loss, including 
no known androgenetic alopecia
b. ≥50% scalp hair loss
c.
Current episode of hair loss ≤10 years duration at time of Screening
d. No evidence of terminal scalp hair regrowth within 6 months at both the 
screening and baseline visits
2. Subject met one of the following exclusion criteria regarding medical history 
diagnoses:
a.
Another scalp disease which could impact hair loss assessments
b. Active systemic disease which can cause hair loss
3. Subjects who were randomized but never received study drug
4. Prior to the date of the Week 24 visit, subject had a dosing interruption of ≥6 weeks 
for any reason
5. Prior to the date of the Week 24 visit, subject used a prior or concomitant prohibited 
medication that could potentially impact efficacy data at Week 24


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6. Week 24 SALT assessment was impacted in one of the following ways:
a.
Visit/assessment was not performed
b. Assessment was not performed properly (including subject had a shaved head)
7. Subjects with other major protocol deviations not listed above that, in the opinion of 
the sponsor study team, could potentially impact efficacy data at Week 24
The subjects excluded from this analysis set will be determined and documented before the 
study is unblinded.
9.2.3. Analysis of Secondary Endpoints
For all regions, analyses of secondary endpoints that are not controlled will use the 
approach outlined below. 
Secondary endpoints that are binary variables will be analyzed using the same approach as 
Analysis 1 in Table 6.  
For continuous endpoints, a mixed-effects model with repeated measures (MMRM) will be 
used.  This model will include the factors (fixed effects) for treatment group, visit, 
treatment-by-visit interaction, and relevant baseline value when modeling change from 
baseline.  Within the framework of MMRM, the treatment difference will be tested at each 
time point.
All secondary endpoints will be evaluated at the 5% level of significance, without adjustment 
for multiple comparisons.
Details on the analysis of individual secondary endpoints will be provided in the SAP.
9.2.3.1. Analysis of Exposure-Response
To characterize the exposure response (dose or average steady state drug concentration 
[Cavg]) in achieving the primary endpoint, a Bayesian three-parameter maximum effect 
attributable to the drug (Emax) exposure-response model will be used as the primary analysis 
approach to characterize the exposure response relationship.  The response function will be 
the log odds (logit) of the proportion of subjects achieving the primary endpoint.  In 
modeling the exposure response, the effect of loading dose will be included as fixed factor in 
the model.  Model-based estimation of treatment effect for each dose or associated Cavg
compared to placebo will be presented with 95% CIs.  The model will be described in detail 
in the SAP.
9.2.4. Analysis of Other Endpoints
Analysis of other endpoints will be conducted using descriptive statistics.  
9.2.5. Subgroup Analyses
Summary statistics for SALT ≤20 response at Week 24, SALT ≤10 response at Week 24, and 
PGI-C response at Week 24 will be presented by subgroups, including but not limited to:

Age (years) at baseline (12-17, ≥18);


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
Age (years) at baseline (12-17, 18-44, 45-64, ≥65);

Body Mass Index (BMI) at baseline (<median, ≥median);

Weight at baseline (<median, ≥median);

Gender (male, female);

Race (White, Black, Asian, other);

Region of enrollment (North America, Europe, Asia, Rest of World) 
Region 
Countries
North America
Canada, United States
Europe
Czech Republic, Germany, Hungary, Poland, Russia, Spain, United 
Kingdom
Asia
China, Japan, South Korea, Taiwan
Rest of World
Australia, Argentina, Chile, Colombia, Mexico

Baseline disease severity (AT/AU, non AT/AU);

AA duration since onset of disease (years) (<median, ≥median);

AA duration since onset of current episode (years) (<median, ≥median); 

Prior pharmacological treatment for AA.
Estimates of the response rates for each dose compared to the placebo group and their 95% 
confidence interval (CI) based on MN method will be presented for each defined category of 
each subgroup.  No p-values will be presented.
The primary purpose of the subgroup analyses is to check for consistency of key efficacy 
results across subgroups.  No inferences will be made within subgroups.  These analyses may 
also be performed on selected country and/or region subpopulation sets in order to meet 
country/region specific regulatory requirements.
9.3. Pharmacokinetic Analysis during the Treatment Period
The PK concentration population is defined as all enrolled subjects who received at least 
1 dose of PF-06651600 and in whom at least 1 concentration value is reported.
PK concentrations listings and summary by visit and nominal collection time will be 
provided. A population PK model will be developed to characterize the PK and estimate 
PK parameters.  The detailed analysis plans will be described in a separate pharmacometric 
analysis plan.
9.4. Pharmacokinetic/Pharmacodynamic Early Unblinding
Early unblinding for PK/PD modeling purposes is planned when ≥90% of subjects have 
reached 24 weeks post-randomization (or discontinued prior to the Week 24 visit). 
Unblinding will be limited to the PK/PD analysts and programmers listed on the early 
unblinding for PK/PD form in accordance with applicable Pfizer standard operating 


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procedures for releasing randomization codes, early unblinding and breaking the study blind. 
These data programmers and analysts will not serve on the B7981015 study team after the 
PK/PD early unblinding.
These PK/PD data analysts and programmers will be unblinded early to build the PK and 
concentration/response models for study readout. Information, such as drug concentration, 
that may unblind the study will not be reported to investigator sites or other Pfizer personnel, 
who will all remain blinded. There will be no impact on B7981015 study conduct, analysis, 
or reporting based on the early unblinding of the PK/PD data. The results of these analyses 
will be reported in a separate pharmacometrics analysis report.
9.5. Safety Analysis
The safety data will be summarized in accordance with Pfizer Data Standards.  All subjects 
who receive investigational product (safety population) will be included in the safety 
analyses.  All safety data will be summarized descriptively through appropriate data 
tabulations, descriptive statistics, categorical summaries, and graphical presentations.  Safety 
data analysis for the study includes:

Incidence and severity of AEs;

Safety events that trigger withdrawal of subject from study;

Incidence of serious infections, defined as any infection (viral, bacterial, and fungal) 
requiring hospitalization or parenteral antimicrobials;

Change from baseline in vital signs;

Incidence of adjudicated safety events (eg, opportunistic infections, cardiovascular 
events, and malignancy);

Safety laboratory tests will be summarized according to Pfizer Standards.
9.6. Exploratory Pharmacodynamic Analysis
Exploratory biomarkers will be listed and summarized by visit and change from baseline for 
these endpoints will also be summarized at specific time points as reported in the Schedule of 
Activities.
Appropriate regression models may be used to look at association between these endpoints 
and any covariates of clinical interest.
9.7. Interim Analysis
The study may be unblinded for Sponsor internal decision-making purposes when ≥ 90% of 
subjects have reached 24 weeks post-randomization (or discontinued prior to the Week 24 
visit), and dissemination of these results will be limited to the unblinded reporting team and 
Sponsor management.  The sponsor personnel who are unblinded will be separate from the 
study team.  The sponsor will still maintain the blind for study team members who will be 


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involved in daily study conduct, study management, safety and data monitoring through the 
completion of the study.  Investigators and subjects will remain blinded.  There will be no 
impact on B7981015 study conduct, analysis, or reporting.
9.8. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC). 
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the charter.  The recommendations made by the E-DMC to alter the conduct of 
the study will be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
that are not endpoints, to regulatory authorities, as appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer 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 subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.


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A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made on the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital or the physician subject chart.  In these 
cases, data collected on the CRFs must match the data in those charts.
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent/assent documents, copies of all CRFs, safety reporting forms, source 
documents, detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.


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12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data.  Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The 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 shall 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 natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and applicable privacy laws.


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The informed consent/assent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent/assent documents used during the informed consent process and any 
subject recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection.
The investigator must ensure that each study subject, or his or her legally acceptable 
representative, or parent(s) or legal guardian if a minor, is fully informed about the nature 
and objectives of the study, the sharing of data relating to the study and possible risks 
associated with participation, including the risks associated with the processing of the 
subject’s personal data.  The investigator further must ensure that each study subject, or his 
or her legally acceptable representative, or parent(s) or legal guardian if a minor, 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.
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited that he or she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide 
his or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the subject’s legally acceptable representative, the consent 
signer’s relationship to the study subject (eg, parent, spouse), and that the subject’s assent 
was obtained or waived.  If assent is obtained verbally, it must be documented in the source 
documents.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must reconsent as adults to remain in the study.  If the 
enrollment of emancipated minors is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, parent(s), or legal 
guardian and the subject’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC.  The 
investigator will retain the original of each subject's signed consent/assent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 


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information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit in the Schedule of Activities.  The end of the study is 
defined as the date of the last visit of the last participant in the study.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
investigational product at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within a time period set by Pfizer.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial 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.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted.  These results are 
submitted for posting in accordance with the format and timelines set forth by US law.


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EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by European Union (EU) requirements.  
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has 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 European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, clinical study reports (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 available data from these trials 
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.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.


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The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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McGarvey EL, Baum LD, Pinkerton RC, et al. Psychological sequelae and alopecia 
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Colon EA, Popkin MK, Callies AL, et al. Lifetime prevalence of psychiatric disorders 
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90.
Cassella J, Hamilton C, von Hehn J, Braman V. CTP-543, an Oral JAK Inhibitor, 
Achieves Primary Endpoint in Phase 2 Randomized, Placebo-Controlled Dose-Ranging 
Trial in Patients with Moderate-to-Severe Alopecia Areata [Conference presentation]. 
In: 28th European Academy of Dermatology and Venereology (EADV) Annual 
Congress; 2019 Oct 9-13, Madrid, Spain. https://www.concertpharma.com/wp-
content/uploads/2019/10/EADV-Late-Breaker-CTP543-Presentation-FINAL-
12OCT2019.pdf 
91.
B7981006. A Phase 2a, Randomized, Double-Blind, Parallel Group, Placebo-
Controlled, Multi-Center Study to Assess the Efficacy and Safety Profile of 
PF-06651600 in Subjects With Moderate to Severe Active Rheumatoid Arthritis With 
an Inadequate Response to Methotrexate. 25 July 2018 CSR.
92.
B7931005. A Phase 2a Randomized, Double-Blind, Placebo-Controlled, Multicenter 
Study to Evaluate the Efficacy and Safety Profile of PF-06651600 and PF-06700841 in 
Subjects With Moderate to Severe Alopecia Areata With a Single-Blind Extension 
Period and a Cross-Over Open Label Extension Period. 20 December 2019 CSR.
93.
B7981005.  A Phase 2b, Double-Blind, Randomized, Placebo-Controlled, Parallel 
Group, Dose Ranging Study of Oral PF-06651600 and PF-06700841 as Induction and 
Chronic Therapy in Subjects With Moderate To Severe Ulcerative Colitis. 
94.
B7981007.  A Phase 2a, Double-Blind, Randomized, Placebo-Controlled, Parallel 
Group Study to Evaluate the Efficacy and Safety of Oral PF-06651600 and 
PF-06700841 as Induction and Open Label Extension Treatment in Subjects With 
Moderate to Severe Crohn’s Disease.
95.
B7981019. A Phase 2b Randomized, Double-Blind, Placebo-Controlled, Multicenter, 
Dose-Ranging Study to Evaluate the Efficacy and Safety Profile of PF-06651600 With 
a Partially Blinded Extension Period to Evaluate the Efficacy and Safety of 
PF-06651600 and PF-06700841 in Subjects With Active Non-Segmental Vitiligo.
96.
B7981032. A Phase 3 Open-Label, Multi-Center, Long-Term Study Investigating the 
Safety and Efficacy of PF-06651600 in Adult and Adolescent Participants With 
Alopecia Areata.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
5-ARIs
5α-reductase inhibitors
AA
Alopecia areata
AE
Adverse event
AAPPO
Alopecia areata patient priority outcomes
AARU
Alopecia areata resource utilization
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AT
Alopecia Totalis
ATP
Adenosine triphosphate
AU
Alopecia Universalis
AUC
Area under the concentration-time curve
AUCinf
Area under the plasma concentration time curve from time zero to 
infinity
BAEP
Brainstem auditory evoked potentials
BBS
Biospecimen Banking System
BCG
Bacille Calmette Guérin
BCRP
Breast cancer resistance protein
BID
Twice daily
BMI
Body mass index
BP
Blood pressure
BSEP
Bile salt export pump
Cavg
Average steady state drug concentration
CFB
Change from baseline
CFP-10
Culture filtrate protein 10 kiloDalton
CGI-AA
Clinician Global Impression – Alopecia Areata
CI
Confidence interval
CK
Creatine kinase
Cmax
Maximum plasma concentration
COVID-19
Coronavirus disease 2019
CRF
Case report form
CRO
Contract research organization
CSA
Clinical study agreement
CSF
Cerebrospinal fluid
C-SSRS
Columbia suicide severity rating scale
CSR
Clinical study report
CT
Clinical Trial
CTA
Clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events


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Abbreviation
Term
CYP
Cytochrome P450
CYP3A
Cytochrome P450 isoenzyme 3A
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DNCB
1-chloro-2,4-dinitrobenzene
DPCP
Diphenylcyclopropenone
DU
Dispensable unit
EBA
Eyebrow Assessment
EBV
Epstein Barr Virus
EC
Ethics committee
ECG
Electrocardiogram
E-DMC
External data monitoring committee 
EDP
Exposure during pregnancy
eGFR
Estimated glomerular filtration rate
ELA
Eyelash assessment
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
Emax
Maximum effect attributable to the drug
EOS
End of study
EOT
End of treatment
EQ-5D-5L
EuroQoL 5 dimensions
EQ-5D-Y
EuroQoL 5 Dimensions—Youth
ESAT-6
Early secreted antigenic target of 6 kiloDalton
ET
Early Termination
EU
European Union
EudraCT
European Clinical Trials Database
FACS-TBNK
Fluorescence-activated cell sorting for T-cells, B-cells, and natural killer 
(NK) cells
FAS
Full analysis set
FDA
United States Food and Drug Administration
FSH
Follicle-stimulating hormone
F/U
Follow-up
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
GLMM
Generalized linear mixed model
GST
Glutathione S transferase
H1
Hypothesis 1
HADS
Hospital Anxiety and Depression scale
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody


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Abbreviation
Term
HBsAg
Hepatitis B surface antigen
HBVDNA
Hepatitis B viral deoxyribonucleic acid
HCRU
Healthcare resource utilization
HCVAb
Hepatitis C antibody
HEENT
Head, eyes, ears, nose, and throat
HIV
Human immunodeficiency virus
HRQoL
Health-related quality of life
HRT
Hormone replacement therapy
HsCRP
High-sensitivity C-reactive protein
HSV1
Herpes simplex virus type 1
HSV2
Herpes simplex virus type 2
HTA
Health technologies assessment
IB
Investigator’s brochure
IC50
Inhibitory concentration 50%
ICH
International Council for Harmonisation
ID
Identification
IFN
Interferon
Ig
Immunoglobulin
IGA-AA
Investigator’s global assessment of alopecia areata
IL
Interleukin
IND
Investigational new drug application
INR
International normalized ratio
IP
Investigational product
IP-10
Interferon gamma-induced protein 10
IRB
Institutional review board
IRC
Internal review committee
IRT
Interactive response technology
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IWR
Interactive web response
JAK
Janus kinase
K2EDTA
Dipotassium ethylenediaminetetraacetic acid
LFT
Liver function test
LOAEL
Lowest observed adverse effect level
Logit
Log odds
LSLV
Last subject last visit 
MAR
Missing at random
MATE
Multi-drug and toxic compound extrusion
MCS
Mental component score
MDR
Multi-drug resistance
MMF
Mycophenolate mofetil
MMR
Measles, mumps, rubella
MMRM
Mixed-effect model with repeated measures


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Abbreviation
Term
MN
Miettinen and Nurminen
mNAPSI
Modified nail psoriasis severity index
MNAR
Missing not at random
MnB
Meningitidis serogroup B
MRI
Magnetic resonance imaging
MTX
Methotrexate
N/A
Not applicable
NK
Natural killer
NOAEL
No observed adverse effect level
NRS
Numerical rating scale
OAT
Organic anion transporting
OATP1B1
Organic anion transporting polypeptide 1B1
OCT
Organic cation transporter
PCD
Primary completion date
PD
Pharmacodynamic(s)
PGI-C
Patient’s global impression of change
P-gp
P-glycoprotein
PGx
Pharmacogenomics(s)
PHQ-8
Patient health questionnaire – 8 items
PI
Principal investigator
PK
Pharmacokinetic
PMDA
Japan Pharmaceuticals and Medical Devices Agency
PPAS
Per Protocol Analysis Set 
PPD
Purified protein derivative
PRO
Patient reported outcome
P-Sat
Patient Satisfaction with Hair Growth
PT
Prothrombin time
PUVA
Psoralen ultraviolet A
QD
Once daily
QFT-G
QuantiFERON®-TB Gold
QoL
Quality of life
QT interval
Time from the beginning of the QRS complex to the end of the T wave
QTcF
QT corrected using Fridericia’s correction factor
QFT-G test
QuantiFERON®-TB Gold In Tube test
RA
Rheumatoid arthritis
Rac
Accumulation ratio
RNA
Ribonucleic acid
SADBE
Squaric acid dibutylester
SAE
Serious adverse event
SALT
Severity of alopecia tool
SALT50
50% improvement in SALT score from baseline
SALT75
75% improvement in SALT score from baseline
SAP
Statistical analysis plan


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Abbreviation
Term
SARS-CoV2
Severe acute respiratory syndrome coronavirus 2
SDAI
Simple disease activity index
SF-36v2 Acute
36-Item Short Form Health Survey version 2 Acute
SOC
System organ class
SOP
Standard operating procedure
SRSD
Single reference safety document
STAT
Signal transducer and activator of transcription
t1/2
Half-life
TB
Tuberculosis
TBili
Total bilirubin
TdP
Torsades de pointes
TEAE
Treatment-emergent adverse event
TEC
Tyrosine kinase expressed in hepatocellular carcinoma
TH1
Type 1 helper
Tmax
Time after administration of a drug when the maximum plasma 
concentration is reached
T-Spot test
T-SPOT®.TB test
TYK2
Tyrosine kinase 2
UGT
Uridine diphosphate glucuronosyltransferase
ULN
Upper limit of normal
URI
Upper respiratory infection
US
United States
UVB
Ultraviolet B
VHP
Voluntary Harmonisation Procedure
VZV
Varicella-zoster virus
VZV IgG Ab
Varicella-zoster virus immunoglobulin G antibody
WOCBP
Woman of childbearing potential
WPAI:AA
Work productivity and activity impairment: alopecia areata


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Appendix 2. Hepatitis B Testing Algorithm and Full Eligibility Criteria
All subjects will undergo screening for hepatitis B for eligibility (See Appendix 5.1 for 
Japan-specific requirements).
For subjects in countries in which hepatitis B prevalence has been reported at a rate of 
>5.0%* or if required by local standard of care, subjects will be tested as follows:
1. At screening, HBsAg and HBcAb will be tested:  
a.
If both tests are negative, the subject is eligible for study inclusion.
b. If HBsAg is positive, the subject must be excluded from participation in the study.
c.
If HBsAg is negative and HBcAb is positive, HBsAb and HBVDNA reflex 
testing is required: 
i.
If HBsAb is negative, the subject must be excluded from participation in the 
study;
ii. If HBV DNA is detected, the subject must be excluded from participation in 
the study;
iii. If HBsAb is positive and HBV DNA is undetectable, the subject is eligible for 
study inclusion.  If the subject is included in the study, for subsequent visits 
HBVDNA testing must be performed according to the Schedule of Activities.
For subjects in all other countries, subjects will be tested as follows:
1. At screening, HBsAg and HBcAb will be tested:
a.
If both tests are negative, the subject is eligible for study inclusion.
b. If HBsAg is positive, the subject must be excluded from participation in the study.
c.
If HBsAg is negative and HBcAb is positive, HBsAb reflex testing is required: 
i.
If HBsAb is negative, the subject must be excluded from participation in the 
study;
ii. If HBsAb is positive, the subject is eligible for study inclusion.  If the subject 
is included in the study, for subsequent visits no hepatitis B testing is required.
* The Polaris Observatory Collaborators.  Global prevalence, treatment, and prevention of hepatitis B virus 
infection in 2016: a modelling study.  Lancet Gastroenterol Hepatol. 2018;3(6): 383-403.


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Appendix 3. Guidelines for Subject Safety Monitoring and Discontinuation
These guidelines for subject safety monitoring and discontinuation are to be applied to all 
subjects in study B7981015.  Additional individual subject monitoring is at the discretion of 
the investigator and dependent on any perceived safety concerns.  Unscheduled clinical labs 
may be obtained at any time during the study to assess such concerns, and a subject may be 
withdrawn at any time at the discretion of the investigator.
Appendix 3.1. Monitoring
All potential treatment-related events of rash will be followed up until resolution or 
agreement with Pfizer. 
The following laboratory abnormalities require re-testing until resolution or agreement 
with Pfizer:
Laboratory Variable
Laboratory Value
Re-testing 
Timeframea
Hematology
Absolute Neutrophil Count
<1000/mm3 (<1.0 × 109/L)
Within 1 week
Hemoglobin
<10.0 g/dL (<6.21 mmol/L or <100 g/L) 
OR
Decrease of ≥2.0 g/dL from baseline
Within 1 week
Platelet count
<100,000/mm3 (<100.0 × 109/L)
Within 1 week
Absolute Lymphocyte Countb
<600/mm3 (<0.6 × 109/L)
Within 1 week
Serum Chemistry
Creatine kinasec
>3 × ULN
Within 1 week
Aspartate aminotransferase
See Section 8.4.2 for potential cases of drug-induced 
liver injury.
Within 48 hours
Alanine aminotransferase
See Section 8.4.2 for potential cases of drug-induced 
liver injury.
Within 48 hours
Total bilirubin
See Section 8.4.2 for potential cases of drug-induced 
liver injury.
Within 48 hours
a.
Based on awareness of the abnormal results.
b.
Subjects with absolute lymphocyte count <500/mm3 (0.5 × 109/L) will be reflex-tested for FACS-TBNK until the 
absolute lymphocyte count resolves or stabilizes at a level acceptable to the investigator and sponsor.
c.
In addition to re-testing creatine kinase >3 × ULN, urine myoglobin will be performed as reflex testing for any 
subject with creatine kinase >10 × ULN.
In case of positive urine pregnancy test, the subject will have study drug interrupted and a 
serum sample collected on the same day (or as soon as possible) and submitted to the central 
laboratory for pregnancy testing.


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Appendix 3.2. Discontinuation
Treatment will be discontinued, and the subject withdrawn from this study following 
completion of the Early Termination visit and the Follow-up Visit (whenever possible) 
for:
Adverse Events:

Serious infections, defined as any infection (viral, bacterial, and fungal) requiring 
parenteral antimicrobial therapy or hospitalization for treatment or meeting other 
criteria that require the infection to be classified as serious adverse event;

Treatment-related SAEs;

Clinically meaningful, treatment-emergent declines in hearing from baseline (refer to 
Audiometry Study Guide for details) are to be discussed with the Sponsor for possible 
withdrawal from the study;

Other serious or severe AEs, at the discretion of the investigator or sponsor.
ECG Findings:

Confirmed QTcF >500 milliseconds;

Confirmed increase from baseline in QTcF of >60 milliseconds.
Investigational Product Interruptions:

Subjects interrupting investigational product for more than 10 days between visits are 
to be discussed with the sponsor for possible withdrawal from the study.
Laboratory Abnormalities:
All the following laboratory abnormalities require discontinuation if they are confirmed by 
re-test.  Refer to the associated re-testing timeframes for laboratory abnormalities in 
Appendix 3.1:

Absolute Neutrophil Count <750/mm3 (<0.75 × 109/L).

Hemoglobin <9.0 g/dL (<5.59 mmol/L or <90 g/L) or a decrease of >30% from 
baseline (either criterion or both).

Platelet count <75,000/mm3 (<75.0 × 109/L).

Absolute Lymphocyte Count <500/mm3 (<0.5 × 109/L).
NOTE: Subjects with absolute lymphocyte count <500/mm3 (0.5 × 109/L) will be 
reflex tested for FACS-TBNK until the absolute lymphocyte count resolves or 
stabilizes at a level acceptable to the investigator and sponsor.


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
Creatine kinase >10 × ULN.
NOTE: In addition to re-testing creatine kinase >3 × ULN, urine myoglobin will be 
performed as reflex testing for any subject with creatine kinase >10 × ULN.

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) that meet ANY 
of the following:

>3 times the upper limit of normal with at least one total bilirubin value >2 times 
the upper limit of normal;

>3 times the upper limit of normal accompanied by signs or symptoms consistent 
with hepatic injury (eg, new onset elevated PT/INR); 

Two sequential AST or ALT elevations >5 times the upper limit of normal, 
regardless of total bilirubin or accompanying signs or symptoms.
NOTE: In each case, there is a need for additional investigations, such as review 
of ethanol, recreational drug and dietary supplement consumption; testing for 
acute hepatitis A, B or C infection and biliary tract imaging should be promptly 
discussed with the sponsor or designee.
Pregnancy:

Female subjects confirmed as pregnant during the study (see Section 8.4.3.1).
Prohibited Medications:

Subjects who are treated with any prohibited medication during the course of the 
study may require discontinuation.  Subjects who are administered a prohibited 
medication are to be discussed with the sponsor for possible withdrawal from the 
study.
Suicidal Ideation:

Subjects with a “yes” answer on items 4, 5, or on any question in the suicidal 
behavior section of the C-SSRS must be discontinued.  The subject must be referred 
to a mental health professional for appropriate evaluation and treatment.  If the 
subject cannot be seen by a mental health professional within 24 hours, then the 
subject should be sent to a local emergency room for psychiatric assessment.
Discontinuation/End of Treatment Monitoring:
Any subject meeting discontinuation criteria must enter into the Follow-up Period with their 
first follow-up visit occurring 1 week after their last dose whenever possible, until the event 
has returned to normal or baseline levels or is deemed clinically stable.  The procedures 
scheduled for Early Termination Visit will be performed on the last day the subject takes the 
investigational product or as soon as possible thereafter.  The only exception to this is when a 
subject specifically withdraws consent for any further contact with him or her or persons 
previously authorized by the subject to provide this information.  Additional follow-up visits 
may occur as needed until any clinically relevant abnormalities or adverse events have 
resolved, returned to a baseline state, or are deemed clinically stable. 


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Appendix 4. Prohibited and Permitted Concomitant CYP3A Inducers and Substrates
Please note that this list addresses only CYP3A inducers and CYP3A substrates. Other 
prohibited medications for this trial are listed in Section 5.8.2.  Refer to Section 5.8.1 for 
additional information regarding permitted medications for this trial, including CYP3A 
inhibitors.
This is not an all-inclusive list.  Study personnel should stay current and consult with their 
pharmacy to exclude all concomitant medications that are moderate to potent CYP3A 
inducers or sensitive or moderate sensitive CYP3A substrates.  If a medication is a sensitive 
or moderate sensitive CYP3A substrate and is not listed below as prohibited or permitted, 
consultation with the Sponsor is required.
Appendix 4.1. Prohibited Concomitant CYP3A Inducers and Substrates
Sensitive CYP3A Substrates##
Moderate Sensitive CYP3A 
Substrates§
Moderate to Potent CYP3A 
Inducers**
Dasatinib
Aprepitant
Avasimibe#
Dronedarone
Eliglustat
Bosentan
Ebastine
Pimozide
Barbiturates
Lomitapide
Rilpivirine
Carbamazepine#
Nisoldipine
Efavirenz 
Sirolimus
Etravirine
Tacrolimus
Mitotane#
Tolvaptan
Modafinil
Nafcillin
Phenobarbital#
Phenytoin#
Rifabutin#
Rifampin #
St. John’s Wort#
Talviraline
** All prohibited drugs that are CYP3A inducers require at least a 28 day or 5 half-lives (whichever is 
longer) washout prior to the first dose of study intervention.
In a situation where appropriate medical care of a participant requires the use of a prohibited CYP3A 
inducer: Moderate to potent inducers of CYP3A are not permitted in the study EXCEPT in emergency 
situations.  Note: Mitotane is not permitted for any duration due to its long half-life; however, if necessary 
mitotane may be used in an emergency, however the participant will then be discontinued from the study.  
Topical (including skin or mucous membranes) application of antimicrobial and antifungal medications is 
permitted.
# 
Notated as potent inducers. 
## Sensitive CYP3A substrates are drugs that demonstrate an increase in concentration-time curve (AUC) 
of ≥5-fold with strong index inhibitors of a given metabolic pathway in clinical drug-drug interaction (DDI) 
studies.
§ 
Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold.


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Appendix 4.2. Permitted Concomitant CYP3A Substrates
Sensitive CYP3A Substrates##
Moderate Sensitive CYP3A 
Substrates§
Alfentanil 
Midazolam
Alprazolam
Avanafil
Naloxegol
Atorvastatin
Buspirone
Quetiapine
Colchicine
Darifenacin
Sildenafil
Rivaroxaban
Eletriptan
Simvastatin
Tadalafil
Eplerenone
Ticagrelor
Felodipine
Triazolam
Lovastatin
Vardenafil
Lurasidone
## Sensitive CYP3A substrates are drugs that demonstrate an increase in concentration-time curve (AUC) of ≥5-fold 
with strong index inhibitors of a given metabolic pathway in clinical drug-drug interaction (DDI) studies.
Topical (including skin or mucous membranes) application of antimicrobial and antifungal medications is permitted.
§ 
Moderate sensitive substrates are drugs that demonstrate an increase in AUC of ≥2 to <5-fold.


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Appendix 5. Country-specific Requirements
Appendix 5.1. Japan-Specific Requirements for Hepatitis B Testing
1. At screening, HBsAg, HBcAb, and HBsAb will be tested for all subjects in Japan:
a.
If all three tests are negative, the subject is eligible for study inclusion. 
b. If HBsAg is positive, the subject must be excluded from participation in the study.
c.
If HBsAg is negative, HBcAb is positive, and HBsAb is negative, the subject 
must be excluded from participation in the study.
d. If HBsAg is negative, HBcAb is negative, HBsAb is positive, and prior HBV 
vaccination is unequivocally documented, the subject is eligible for the study and 
does not require HBVDNA monitoring during the study. 
e.
If HBsAg is negative, HBcAb is negative, HBsAb is positive, and no unequivocal 
documentation of prior HBV vaccination is available, the subject is required to 
undergo HBVDNA reflex testing:
i. If HBVDNA is detected, the subject must be excluded from participation in the 
study;
ii. If HBVDNA is undetectable, the subject is eligible for study inclusion.  If the 
subject is included in the study, for subsequent visits HBVDNA testing must be 
performed according to the Schedule of Activities.
f.
If HBsAg is negative, HBcAb is positive, and HBsAb is positive, the subject is 
required to undergo HBVDNA reflex testing:
i. If HBVDNA is detected, the subject must be excluded from participation in the 
study;
ii. If HBVDNA is undetectable, the subject is eligible for study inclusion. If the 
subject is included in the study, for subsequent visits HBVDNA testing must be 
performed according to the Schedule of Activities.


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Appendix 6. Alternative Measures During Public Emergencies 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic.  This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer.  NOTE: Any deviations from the Schedule of 
Activities or the protocol (eg, missed or partially completed procedures or assessments) must 
be reported to the Sponsor in a timely manner and will be reported by the Sponsor as a 
protocol deviation.
Procedures which are missed due to COVID-19 disruptions are required to be performed at 
the next available opportunity, even if outside of a protocol-specified visit window.
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories). 
Appendix 6.1. Eligibility
While severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) testing is not 
mandated for this study, local clinical practice standards for testing should be followed.  A 
subject should be excluded if he/she has a positive test result for SARS-CoV2 infection, is 
known to have asymptomatic infection, or is suspected of having SARS-CoV2.  Subjects 
with active infections are excluded from study participation per Exclusion #16.  When the 
infection resolves, the patient may be considered for re-screening.  In addition, the following 
criteria apply:
The subject must be able to perform all Screening and Day 1 procedures per the Schedule 
of Activities at the study site and/or designated ancillary facility (eg, for audiological 
evaluations and chest radiographs) in order to determine whether the subject meets 
eligibility criteria for the study.  This includes collection and resulting of laboratory 
assessments through the central laboratory vendor.
The subject must meet eligibility criteria for the study.
It must be anticipated that the subject will be able to have the Week 2 and Week 4 safety 
laboratory tests collected/performed at the study site or an alternative clinical 
laboratory facility according to the windows in Appendix 6.3
If a subject does not meet the criteria described above, the subject cannot be enrolled in 
the study.


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Appendix 6.2. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow up on the safety of study subjects at scheduled visits per the Schedule of Activities or 
unscheduled visits.  Telehealth visits may be used to continue to assess subject safety and 
collect data points.  Telehealth includes the exchange of healthcare information and services 
via telecommunication technologies (eg, audio, video, video-conferencing software) 
remotely, allowing the subject and the investigator to communicate on aspects of clinical 
care, including medical advice, reminders, education, and safety monitoring.  The following 
assessments must be performed during a telehealth visit:
Review dosing logs and record investigational product, including doses taken and any 
interruptions in intake of investigational product (ie, missed doses) since the last 
contact, and calculate compliance.
Review and record any AEs and SAEs since the last contact.  Refer to Section 8.
Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.
For WOCBP: Review and record contraceptive method and results of pregnancy testing.  
Confirm that the subject is adhering to the contraception method(s) required in the 
protocol Section 4.3.1.  Refer to Section 7.2 of the protocol and Appendix 6.3
regarding pregnancy tests.
For premenarchal female subjects: Check for initiation of menarche.
Collection of updated audiological history (Part 1 in the Audiometry Study Guide 
Worksheet for Post Day 1 visits) at visits requiring audiological evaluation.
Body temperature and collection method (eg, oral, tympanic, axillary), pulse rate, and 
respiratory rate (measured by study subject/caregiver).
Administration of the C-SSRS performed by a qualified rater.  Per Section 7.7.1, if there 
are “yes” answers on items 4 or 5 of the suicidal ideation section or on any question 
in the suicidal behavior section of the C-SSRS, the subject will be discontinued from 
the study and referred to a mental health professional for appropriate evaluation and 
treatment.
NOTE: If the investigator determines that additional evaluation is warranted based on the 
information collected during the remote visit described above, follow-up is required 
to be performed, with results submitted to and reviewed by the investigator prior to 
shipping investigational product to the subject.
Study subjects must be reminded to promptly notify site staff about any change in their 
health status.


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Appendix 6.3. Alternative Facilities for Safety Assessments
Laboratory Testing
With the exceptions noted in Appendix 6.1 for Screening and Day 1, if a study subject is 
unable to visit the site for protocol-specified safety laboratory evaluations, testing may be 
conducted at a local laboratory if permitted by local regulations.  The local laboratory may be 
a standalone institution or within a hospital.  Collection of blood and urine samples may also 
be performed at the subject’s home per Appendix 6.5.  The following safety laboratory 
evaluations may be performed at a local laboratory or in the subject’s home:
Hematology;
Serum chemistry; 
Fasting lipid panel;
Urinalysis;
Pregnancy testing (for WOCBP);
Refer to the Schedule of Activities for visits at which these tests are required and to 
Section 7.5.7 for additional details regarding these tests.
If it is not possible for the subject to have the above tests completed within the visit window 
specified in the Schedule of Activities, an extended window may be allowed to collect 
samples for these laboratory tests, provided that the investigator has performed the remote 
visit as described above, assessed each case, and determined that it would not increase risk to 
a subject.  The extended windows for laboratory sample collection for each study visit are 
noted in Table 8.  These windows apply only to laboratory samples collected during 
interruptions due to public emergencies, including the COVID-19 pandemic, based upon 
written notification from Pfizer.  If the laboratory samples are not collected within the 
specified extended window for the visit, the subject must temporarily withhold 
investigational product until the required laboratory samples can be collected. 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results.  Site staff must collect the local laboratory reference ranges and 
certifications/accreditations for filing at the site.  Laboratory test results are to be provided to 
the site staff as soon as possible and must be received and reviewed by the investigator 
within 14 days after they are collected in order to determine eligibility to continue dosing.  In 
addition, laboratory test results from the previous visit must be available and reviewed by the 
investigator prior to shipping investigational product at the current visit.  The local laboratory 
reports must be filed in the subject’s source documents/medical records.  Relevant data from 
the local laboratory report must be recorded on the CRF.


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Special attention should be paid to ensure that laboratory results are checked against the 
Guidelines for Subject Safety Monitoring and Discontinuation in Appendix 3 and that 
required follow-up is performed as applicable.
If a subject requiring pregnancy testing cannot visit a local laboratory for pregnancy testing, 
a home urine pregnancy testing kit with a sensitivity of at least 25 IU/mL may be used by the 
subject to perform the test at home, if compliant with local regulatory requirements.  Urine 
pregnancy test results may be collected based on information provided by the subject (or 
their legally authorized representative, if appropriate) during the remote visit.  The urine 
pregnancy test result must be available prior to dispensing or shipping investigational 
product to a subject.  The pregnancy test outcome must be documented in the subject’s 
source documents/medical records and relevant data recorded on the CRF.  Confirm that the 
subject is adhering to the contraception method(s) required in the protocol. 
NOTE: Pregnancy testing (for WOCBP) between the Week 40 and 48 visits (at 
approximately Week 44) and study site contact with subjects to obtain pregnancy test results 
is required for WOCBP in VHP countries outlined in the Schedule of Activities and 
Section 7.2.
Table 8.
Windows for Remote Visits and Laboratory Sample Collections if 
Required Due to Disruptions from Public Emergencies
Visit (Day in Study)
Remote Visit Window
(Day in Study)a
Lab Collection Window
(Day in Study)b
Week 2 (Day 15)
±3 days (Day 12-18)
±3 days (Day 12-18)
Week 4 (Day 29)
±3 days (Day 26-32)
-3/ +7 days (Day 26-36)
Week 8 (Day 57)
±7 days (Day 50-64)
-7/+14 days (Day 50-71)
Week 12 (Day 85)
±7 days (Day 82-88)
-7/+21 days (Day 82-106)
Week 18 (Day 127)
±7 days (Day 120-134)
-7/+21 days (Day 120-148)
Week 24 (Day 169)
±7 days (Day 162-176)
±7 days (Day 162-176)
Week 26 (Day 183)
±3 days (Day 180-186)
±3 days (Day 180-186)
Week 28 (Day 197)
±3 days (Day 194-200)
-3/+21 days (Day 194-218)
Week 34 (Day 239)
±7 days (Day 232-246)
-7/+21 days (Day 232-260)
Week 40 (Day 281)
±7 days (Day 274-288)
-7/+30 days (Day 274-311)
Week 48 (Day 337)c
±7 days (Day 330-344)
-7/+30 days (Day 330-367)
a. These are the same as the windows in the protocol Schedule of Activities. 
b.Laboratory results must be received and reviewed by the investigator within 14 days after they are 
collected to determine eligibility to continue dosing.  In addition, laboratory test results from the previous 
visit must be available and reviewed by the investigator prior to shipping investigational product at the 
current visit.
c. If subject is rolling over into B7981032, labs must be collected prior to enrollment in B7981032.


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Electrocardiograms
If the subject is unable to visit the study site for an ECG after Day 1, the subject may visit an 
alternative facility to have the ECG performed according to the guidelines in Section 7.5.4.  
Qualified study site personnel must order, receive, and review results. 
Audiological Evaluation
At visits after Screening which require audiological evaluation, if the subject is unable to 
visit the study site or designated ancillary center for audiological evaluation, the audiological 
history (Part 1 in the Audiometry Study Guide Worksheet for Post Day 1 visits) must be 
collected during the remote visit per Appendix 6.2 (or during the home health visit per 
Appendix 6.5).  The audiological evaluation must be performed per Section 7.5.5 at the next 
available opportunity, even if outside of a protocol-specified visit window.
Appendix 6.4. Investigational Product
If the safety of a trial subject is at risk because they cannot complete required evaluations or 
adhere to critical mitigation steps, then discontinuing that subject from investigational 
product must be considered.
Investigational product may be shipped by courier to study subjects if permitted by local 
regulations and in accordance with storage and transportation requirements for the 
investigational product.  Pfizer does not permit the shipment of investigational product by 
mail.  The tracking record of shipments and the chain of custody of investigational product 
must be kept in the subject’s source documents/medical records.
If a third-party courier engaged by Pfizer or Pfizer’s contract research organization (CRO) is 
used for shipping the investigational product, written consent must be documented in the 
informed consent document prior to shipping investigational product.  If a third-party courier 
engaged by Pfizer or Pfizer’s CRO is not used for shipping the investigational product, 
consent must be verbally obtained (or per local guidelines/regulations) and documented in 
site’s source documents prior to shipping investigational product.
Prior to shipping investigational product to a subject, 1) consent must be obtained and 
documented as described above, 2) all required safety information listed in Appendix 6.2
must have been collected and reviewed by the investigator, 3) the required laboratory tests 
from the previous visit must have been reviewed by the investigator, and 4) any additional 
evaluation (if requested based on investigator judgment) must have been performed, with 
results submitted to and reviewed by the investigator.
Investigational product cannot be shipped to the subject and must be temporarily 
discontinued if 1) the laboratory tests from the previous visit have not been reviewed by the 
investigator OR 2) after reviewing the required information (including that from a remote 
visit), the investigator cannot make an assessment of whether it is safe for the subject to 
continue investigational product.  Refer to Section 5.5 regarding temporary withholding of 
investigational product.


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The study site may deliver the investigational product to subjects using an acceptable 
delivery method only if this is consistent with local laws and regulations and the site is able 
to ship the investigational product according to the guidelines provided by the Sponsor in a 
separate document.
The amount of investigational product to be shipped should correspond to the amount 
dispensed per the Impala Quick Reference Guide at the specific study visit which is being 
conducted remotely.  Dispensing and/or shipment of additional investigational product to 
extend the visit window is not permitted.  
Subjects should continue taking the current supply of investigational product until the new 
supply is received (unless temporary withholding of investigational product is required).
Dosing logs should be shipped with the investigational product.
Study sites should follow up with the subject once the investigational product is received by 
the subject to review when to start using the new blister cards, the dosing instructions, and 
completion of the dosing logs.
Subjects should be instructed not to re-use or dispose of any blister cards dispensed at a 
previous visit.  
All blister cards and dosing logs must be returned to the study site at the next on-site visit.
Appendix 6.5. Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities if operationally feasible and will be conducted according to local regulations.  
Home health visits include a healthcare provider conducting an in-person study visit at the 
subject’s location, rather than an in-person study visit at the site. 
If a third-party engaged by Pfizer or Pfizer’s CRO is used for home health visits, written 
consent must be documented in the informed consent document prior to conducting the first 
home health visit.  If a third-party engaged by Pfizer or Pfizer’s CRO is not used for home 
health visits, consent must be verbally obtained and documented in site’s source documents 
(or per local guidelines/regulations) prior to conducting the first home health visit.
The following may be performed during a home health visit:
Review dosing logs and record investigational product, including doses taken and any 
interruptions in intake of investigational product (ie, missed doses) since the last 
contact, and calculate compliance.
Review and record any AEs and SAEs since the last contact.  Refer to Section 8.
Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.


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For WOCBP: Review and record contraceptive method and results of pregnancy testing.  
Confirm that the subject is adhering to the contraception method(s) required in the 
protocol Section 4.3.1.  Refer to Section 7.2 of the protocol and Appendix 6.3
regarding pregnancy tests.
For premenarchal female subjects: Check for initiation of menarche.
Collection of updated audiological history (Part 1 in the Audiometry Study Guide 
Worksheet for Post Day 1 visits) at visits requiring audiological evaluation.
Body temperature and collection method (eg, oral, tympanic, axillary), pulse rate, and 
respiratory rate (measured by study subject/caregiver).
ECG per Section 7.5.4.
Hematology.
Serum chemistry. 
Fasting lipid panel.
Urinalysis.
Pregnancy testing (for WOCBP).
Physical examination.
Appendix 6.6. Adverse Events and Serious Adverse Events
If a subject has a confirmed or suspected COVID-19 infection during the study, this should 
be reported as an adverse event (AE) or serious adverse events (SAE) and appropriate 
medical intervention provided.  For non-serious COVID-19 infections, temporary 
discontinuation of the investigational product may be medically appropriate until the subject 
has recovered from the COVID-19 infection.  If this is a serious infection (ie, requires 
parenteral antimicrobial therapy or hospitalization for treatment or meeting other criteria that 
require the infection to be classified as a serious adverse event), the subject must be 
permanently discontinued from investigational product per Appendix 3.2 of the protocol.  
Appendix 6.7. Efficacy Assessments
Efficacy assessments listed in Section 7.6 and Section 7.8 are only to be collected during 
on-site visits.  This includes SALT, ELA, EBA, fingernail assessment, CGI-AA, and all 
patient reported outcomes.

SAP_001.pdf: 
Protocol B7981015 (PF-06651600) Statistical Analysis Plan
PFIZER CONFIDENTIAL
Page 1
Protocol B7981015
A PHASE 2B/3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
DOSE-RANGING STUDY TO INVESTIGATE THE EFFICACY AND SAFETY OF
PF-06651600 IN ADULT AND ADOLESCENT ALOPECIA AREATA (AA) 
SUBJECTS WITH 50% OR GREATER SCALP HAIR LOSS
Statistical Analysis Plan 
(SAP)
Version:
4
Date:
23 April 2021


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PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION ...............................................................................................................11
2.1. Study Objectives .....................................................................................................11
2.2. Study Design ...........................................................................................................14
2.2.1. Sample Size Determination ........................................................................16
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................17
3.1. Primary and Secondary Endpoints ..........................................................................17
3.2. Other Endpoints.......................................................................................................19
3.2.1. Exploratory Endpoints................................................................................19
3.2.2. PK Endpoint................................................................................................22
3.3. Baseline Variables...................................................................................................22
3.4. Safety Endpoints .....................................................................................................22
3.4.1. Adverse Events...........................................................................................22
3.4.2. Laboratory Data..........................................................................................22
3.4.3. Vital Signs, Including Height and Weight..................................................22
3.4.4. Physical Examinations................................................................................22
3.4.5. Electrocardiogram (ECG)...........................................................................23
4. ANALYSIS SETS ...............................................................................................................23
4.1. Full Analysis Set .....................................................................................................23
4.2. Per Protocol Analysis Set........................................................................................23
4.3. Safety Analysis Set..................................................................................................24
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................25
5.1. Hypotheses and Decision Rules ..............................................................................25
5.1.1. Overall Study (Testing Procedure for Multiple Comparisons 
Incorporating the SALT ≤10 as a Key Secondary Endpoint)..........................25
5.1.2. For the FDA/PMDA (Testing Procedure for Multiple Comparisons 
with no Key Secondary Endpoints) .................................................................28
5.1.3. For the EMA and Competent Authorities in the VHP Countries 
(Testing Procedure for Multiple Comparisons Incorporating the PGI-C 
Response as a Key Secondary Endpoint).........................................................30


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5.2. General Methods .....................................................................................................32
5.2.1. Binary Endpoints ........................................................................................33
5.2.1.1. Miettinen and Nurminen – Analysis 1 and Analysis 3..............33
5.2.1.2. Generalized Linear Mixed Model and Tipping Point –
Analyses 2 and 2a..............................................................................34
5.2.1.3. Generalized Linear Mixed Model and Tipping Point –
Analyses 4 and 4a..............................................................................34
5.2.1.4. Descriptive Analysis of Binary Endpoints................................35
5.2.2. Exposure response analysis ........................................................................35
5.2.2.1. Logistic regression analysis for the evaluation of effect of 
loading dose.......................................................................................35
5.2.2.2. Emax models for exposure response analysis .............................36
5.2.2.3. Bayesian Estimation of Dose Response Models.......................36
5.2.3. Continuous Endpoints.................................................................................36
5.3. Methods to Manage Missing Data ..........................................................................37
5.3.1. Binary Endpoints ........................................................................................37
5.3.2. Continuous Endpoints.................................................................................38
6. ANALYSES AND SUMMARIES ......................................................................................38
6.1. Primary Endpoints, Key Secondary and -controlled Endpoints ...........................38
6.1.1. Response Based on SALT Score 20 at Week 24......................................39
6.1.2. Response Based on SALT Score 10 at Week 24......................................39
6.1.3. PGI-C Response at Week 24 ......................................................................40
6.2. Secondary Endpoints...............................................................................................40
6.2.1. Exposure Response for Response Based on SALT Score 20 at 
Week 24 ...........................................................................................................40
6.2.2. Exposure Response for Response Based on SALT Score 10 at 
Week 24 ...........................................................................................................40
6.2.3. Response Based on SALT Score 20 at all Visits......................................41
6.2.4. Response Based on SALT Score 10 at all Visits......................................41
6.2.5. 75% Improvement in SALT Score (SALT75)............................................41
6.2.6. Change From Baseline in SALT Score ......................................................41
6.2.7. Eyebrow Assessment Score........................................................................42
6.2.8. Eyelash Assessment Score..........................................................................42
6.2.9. PGI-C Response..........................................................................................42


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6.2.10. Alopecia Areata Patient Priority Outcomes (AAPPO) Scale ...................42
6.3. Exploratory Endpoints.............................................................................................43
6.3.1. 50% Improvement in SALT Score (SALT50)............................................43
6.3.2. Absolute SALT Score.................................................................................43
6.3.3. Improvement on PGI-C ..............................................................................44
6.3.4. Improvement on P-Sat ................................................................................44
6.3.5. Change From Baseline in the EQ-5D-5L/EQ-5D-Y ..................................44
6.3.6. Change From Baseline in the AARU Questions ........................................44
6.3.7. Change From Baseline in the WPAI:AA Items..........................................45
6.3.8. Change From Baseline in the Depression Subscale Score of HADS.........45
6.3.9. Change From Baseline in the Anxiety Subscale Score of HADS ..............45
6.3.10. Improvement on Depression Subscale of HADS .....................................46
6.3.11. Improvement on Anxiety Subscale of HADS ..........................................46
6.3.12. Change From Baseline in SF36v2 Acute..................................................46
6.3.13. Change From Baseline in CGI-AA...........................................................46
6.3.14. Change From Baseline in Number of Fingernails Affected by AA .........47
6.3.15. Change From Baseline in IP-10................................................................47
6.3.16. Change From Baseline in T-cell, B-cell, and NK Cells ...........................47
6.3.17. Change From Baseline in IgA, IgG, IgM .................................................47
6.4. PK Endpoints...........................................................................................................48
6.5. Subset Analyses.......................................................................................................48
6.6. Baseline and Other Summaries and Analyses.........................................................49
6.6.1. Baseline Summaries....................................................................................49
6.6.2. Study Conduct and Subject Disposition .....................................................49
6.6.3. Study Treatment Exposure .........................................................................49
6.6.4. Concomitant Medications and Non-Drug Treatments................................49
6.7. Safety Summaries and Analyses .............................................................................49
6.7.1. Adverse Events...........................................................................................50
6.7.2. Laboratory Data..........................................................................................50
6.7.3. Vital Signs, including Height and Weight..................................................50
6.7.4. Electrocardiogram.......................................................................................50
6.7.5. Physical Examination .................................................................................50
6.7.6. Hearing Examination..................................................................................50


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7. INTERIM ANALYSES.......................................................................................................51
8. REFERENCES ....................................................................................................................52
9. APPENDICES .....................................................................................................................53
9.1. Definition and Use of Visit Windows in Reporting................................................53
9.2. Details on Selected PRO Endpoints........................................................................54
9.3. Laboratory Data Criteria for Discontinuation and Abnormalities...........................56
9.4. List of Countries by Region ....................................................................................58
9.5. List of Targeted Medical History Terms.................................................................58
9.6. Tipping Point Analysis for Binary Data..................................................................58
9.7. Prior Pharmacological Treatments for AA – Definition of Subgroups...................60
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................6
Table 2.
Study Objectives and Endpoints...............................................................11
Table 3.
Primary and Secondary Endpoints for Overall Study Reporting and 
Publications...............................................................................................17
Table 4.
Primary and Secondary Endpoints Organized by Known Regional 
Regulatory Requirements .........................................................................18
Table 5.
Statistical Methods of Planned Analysis for Primary and Key 
Secondary Endpoints for the Study and for each Regulatory Region ......33
Table 6.
Visit Windows ..........................................................................................53
Table 7.
Laboratory Values Meeting Discontinuation Criteria ..............................56
Table 8.
Laboratory Test Abnormalities.................................................................56
Table 9.
Countries by Region .................................................................................58
Table 10.
Targeted Medical History Terms..............................................................58
LIST OF FIGURES
Figure 1.
Study Design Schematic...........................................................................15
Figure 2.
Schematic and Graphical Presentation for Multiple Testing 
Procedure Incorporating a Key Secondary Endpoint ...............................27
Figure 3.
Schematic and Graphical Presentation for Multiple Testing 
Procedure ..................................................................................................29


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1. VERSION HISTORY
Table 1.
Summary of Major Changes in SAP Amendments
Version/Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
1 NOV 2018
Original
17 SEP 2018
Not Applicable
Not Applicable
2
11 Aug 2020
Amendment 3
14 July 2020

To be consistent with 
the protocol 
amendments 1-3.

To provide additional 
details and 
clarification.

Changed primary endpoint from 
SALT ≤10 at Week 24 to SALT 
≤20 at Week 24. It was also 
noted that SALT ≤10 will be 
analyzed as the primary endpoint 
in a separate analysis where 
required (Sections 2.1, 2.2, 3.1, 
5.1, 6.1).

Added PGI-C response at Week 
24 will be analyzed as a key 
secondary endpoint where 
required (Section 2.1. 2.2, 3.2, 
5.1, 6.2). 

Updated endpoints according to 
the protocol and provided 
additional details (Sections 2.1, 
3, 6).

Added stratified randomization
(Section 2.2).

Updated power estimation 
(Section 2.2).

Added the study may be 
unblinded for internal 
decision-making purposes 
(Sections 2.2, 7).

Added Per protocol analysis set 
(Section 4.2).

Added testing procedure for 
multiple comparisons for SALT 
≤10 at Week 24 and SALT 
≤20 at earlier timepoints if SALT 
≤20 at Week 24 is the primary 
endpoint. It was also noted that 
for regions that request a primary 
endpoint of SALT ≤10 at week 
24, a similar approach will be 
used to control the Type I error 
for SALT ≤20 at Week 24 and 
SALT ≤10 at earlier time points
(Section 5.1).

Added testing procedure for 
multiple comparisons 
incorporating a key secondary 
endpoint for regions that request 
PGI-C response at week 24 as a 
key secondary endpoint where 
required (Section 5.1.1).


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
Added details on data summary 
in the extension phase (Sections 
5.2, 6). 

Updated visit windows 
(Appendix 1).

Added Appendices 4-6.
Version 3
13 November 
2020
Protocol 
Amendment 4
20 October 2020

To comply with the 
VHP feedback that 
EU specific 
endpoints and 
analysis should be 
explicitly stated 
(beyond the verbatim 
that already existed 
to manage region 
specific preferences) 
in a consistent 
manner and to align 
with the protocol 
Amendment 4 which 
was updated given 
this VHP feedback

It has been specifically clarified 
that for the European Union (EU) 
(including the Voluntary 
Harmonisation Procedure [VHP] 
countries), the primary objective 
and primary endpoint will utilize 
an absolute Severity of Alopecia 
Tool (SALT) Score of ≤10 and 
not 
≤ 20 at Week 24.

Sections 2.1 (study objectives), 
2.2 (sample size), 3.1 (primary 
endpoint), 3.2 (secondary 
endpoints), 6.1 (analysis of 
primary endpoint), and 
6.2 (analysis of secondary 
endpoints).

It has been specifically clarified 
that for the EU (including VHP 
countries), the evaluation of the 
effect of PF-06651600 on patient 
centered outcomes (as measured 
by Patient’s Global Impression of 
Change [PGI-C] response at 
Week 24) is a key secondary 
objective. The PGI-C response at 
Week 24 will be analyzed as a 
key secondary endpoint utilizing 
an appropriate testing procedure 
to control overall Type I error.

Sections 2.1 (study objectives), 
2.2 (sample size), 3.2 (secondary 
endpoints), 5.1 (hypotheses and
decision rules), 5.1.1 (testing 
procedure for multiple 
comparisons incorporating a key 
secondary endpoint) and 6.2.8 
(analysis of PGI-C response).

Objectives and Endpoints table 
(including footnotes) was
updated to clarify which 
secondary endpoints will be 
controlled for Type I error based 
on which SALT parameter at 
Week 24 (ie, ≤20 or ≤10) is 
utilized as the primary endpoint.

Section 2.1 (study objectives).

Endpoints tables was updated to 
clarify that for the EU (including 


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VHP countries), the endpoints 
utilizing the HADS will be 
analyzed as secondary endpoints.

Sections 2.1 (study objectives), 
and 3.3.1 (exploratory 
endpoints).

Added text to clarify that more 
stringent alpha levels have been 
advised for regulatory 
submission of B7981015 in the 
EU and for the FDA.

Sections 2.2 (sample size) and 
5.1 (hypothesis and decision 
rules).

General changes, 
typographical 
corrections, and 
clarifications

Changed the utility weights for 
the derivation of EQ-5D scores 
(Section 3.3.1). US utility 
weights will be used for all 
participants so that all patients 
are on the same weighted scale 
for modeling purposes

Added clarification of the 
definition of baseline for ECG 
assessments (Sections 3.4 and 
3.5.5).

Correction of grammatical and 
typographical errors in Sections 
2.1, 2.2, 3.3.1, 5.2.1, 5.2.2, 5.3.1, 
6.3.8, 6.3.9, 6.3.14, 6.5, 6.6.1, 
6.7, 6.7.1, and Appendix 1.

Replaced all text from Sections 
5.2.1, 6.1 and 6.2 that mentioned 
approach for missing data of 
binary endpoints by a general 
sentence that refers to Section 
5.3.1 

Added Section 6.1.2 to describe 
the analysis of the primary 
endpoint in the per protocol 
analysis set (PPAS).

A standard sentence was used to 
describe the approach for missing 
data throughout Section 6.2 to 
refer back to the missing data 
approach described in Section 
5.3.

HADS cut off values were added 
to sections 6.3.10 and 6.3.11 for 
consistency with Section 3.3.1.

Added subset of subjects who 
received prior pharmacological 
treatment to AA to Section 6.5 
and deleted “requiring 
discontinuation at any time” in 
Section 6.7.4.


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Version 4
23 April 2021
Protocol 
Amendment 5
13 April 2021

To align with 
protocol Amendment 
5, specifically to 
define the endpoints 
and alpha levels and 
hypothesis testing for 
the overall study and 
to clarify the 
endpoints and alpha 
and hypothesis 
testing for 
FDA/PMDA and for 
EMPA and 
competent authorities 
in VHP countries and 
to incorporate 
changes to the 
analysis and 
approach for 
handling missing due 
to COVID-19 after 
feedback received 
from regulatory 
agencies.

The FAS was revised 
based on regulatory 
feedback to include 
all subjects who were 
randomized 
regardless of whether 
they received 
treatment

To provide further 
details on the 
definition of the per 
protocol population 
based on regulatory 
feedback

Also, further details 
of the Emax models
for the exposure 
response, and tipping 
point analysis were 
provided

Planned COVID-19 
related summaries 
and listings were 
added

Unblinding of data 
for PK/PD modelling 
was added

Several places in this 
document were 
corrected for 
typographical errors.

Early unblinding for PK/PD 
modelling was added to Section 
2.2

Further clarification was added to 
the sample size section 2.2.1 to 
account for the alphas for the 
different regions.

Tables 3 and 4 were added to 
Section 3 to define the endpoints 
and alpha for the overall study, 
and clarify the endpoints and 
alpha for FDA/PMDA and for 
EMPA and competent authorities 
in VHP

FAS and PPAS were updated in 
Sections 4.1 and 4.2

Hypothesis testing for the overall 
study was added to Section 5.1 
and was further clarified for 
FDA/PMDA and for and for 
EMPA and competent authorities 
in VHP

Tables 5 was added to Section 
5.2.1 to clarify the primary and 
supportive analyses specifically 
to address handling of missing 
data due to COVID-19 for the 
overall study and for 
FDA/PMDA and for EMPA and 
competent authorities in VHP


Section 5.2.1 was reorganized 
into subsections 5.2.1.1, 5.2.1.2, 
5.2.1.3 and 5.2.1.4 after the 
introduction of the primary 
analysis for the EMA and 
competent authorities in VHP 
countries, following advice from 
regulatory agency


Section 5.2.2. was expanded to 
provide further details of the Emax
models for the analysis for 
exposure response.

Section 5.3.1 was expanded to 
clarify handling of missing data 
due to COVID-19

Section 6.1 was modified to 
summarize all analyses that are 
planned for each primary, key 
secondary and -controlled 
endpoints.

Section 6.2 additional detail was 
provided to clarify handling of 


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missing data due to COVID-19 
for secondary endpoints

COVID-19 related planned 
summaries and listings were 
added to Section 6.7

In Section 6.7.1, clarification on 
analyses of AEs of special 
interest was provided, and the 
planned summaries of COVID-
19 related AEs, and AE 
summaries by COVID-19 anchor 
date were added

Analysis of Columbia Suicide 
Severity Rating Scale analysis 
was removed from Section 6.7.7 
since this scale was only intended 
for monitoring

Further detail was provided for 
the interim analysis in Section 7, 
with regards to the  dissemination 
of results, and to clarify that the 
interim will have no impact on 
B7981015 study conduct, 
analysis, or reporting  

Tipping point and Emax references 
were added

Section 9.6 was added to provide 
further details and specifications 
of the tipping point analysis.

Section 9.7 was added to provide 
further specifications for the 
definition of subgroups for 
analysis


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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B7981015. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
The study objectives and corresponding endpoints are listed below in Table 2. There are 
some region specific differences noted throughout. Table 3 and Table 4 in Section 3.1 lists 
the primary and secondary endpoints of the study (re)organized by known regional 
requirements.
Table 2.
Study Objectives and Endpoints
Primary Objective(s):
Primary Endpoint(s):
To evaluate the efficacy of PF-06651600 compared 
to placebo in adult and adolescent alopecia 
areata (AA) subjects with 50% or greater scalp 
hair loss on regrowth of lost hair (measured by 
an absolute Severity of Alopecia Tool (SALT) 
Score ≤20) at Week 24.
Note: For the European Medicines Agency 
(EMA) and competent authorities in the 
Voluntary Harmonisation Procedure (VHP)
countries,a the primary objective is to evaluate 
the efficacy of PF-06651600 compared to 
placebo in adult and adolescent AA subjects 
with 50% or greater scalp hair loss on regrowth 
of lost hair (as measured by an absolute SALT 
Score ≤10) at Week 24.

Response based on an absolute Severity of Alopecia 
Tool (SALT) Score 20 at Week 24.
Note: For the EMA and competent authorities in the 
VHP countries response based on an absolute SALT 
Score ≤10 at Week 24 will be analyzed as the 
primary endpoint in a separate analysis.
Key Secondary Objective(s)
Key Secondary Endpoint(s)

To evaluate the efficacy of PF-06651600 compared 
to placebo in adult and adolescent AA subjects with 
50% or greater scalp hair loss on regrowth of lost 
hair (as measured by an absolute SALT Score ≤10) 
at Week 24.
Note: This key secondary objective will be utilized 
as the primary objective for the EMA and competent 
authorities in the VHP countries. Additionally, this 
key secondary objective will not apply for the United 
States Food and Drug Administration (FDA)/Japan 
Pharmaceuticals and Medical Devices Agency 
(PMDA).

Response based on an absolute SALT Score ≤10 at 
Week 24.
Note: This key secondary endpoint will be utilized 
as the primary endpoint for the EMA and competent 
authorities in the VHP countries. Additionally, this 
key secondary endpoint will not apply for the
FDA/PMDA. 

To evaluate the effect of PF-06651600 on patient 
centered outcomes (as measured by PGI-C response) 
at Week 24.
Note: This key secondary objective is only 
applicable for the EMA and competent authorities in 
the VHP countries.

PGI-C response defined as a score of “moderately 
improved” or “greatly improved” at Week 24.
Note: This key secondary endpoint is only 
applicable for the EMA and competent authorities in 
the VHP countries.


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Secondary Objective(s):
Secondary Endpoint(s):
To characterize the exposure response of 
PF-06651600 on regrowth of lost hair.
Response based on an absolute SALT Score 20 at 
Week 24 will be used to characterize the 
exposure response.b
To assess the efficacy of PF-06651600 on regrowth 
of lost hair during the treatment period over 
time.
Response based on an absolute SALT score ≤20 at 
Weeks 4, 8, 12, 18, 28, 34, 40, and 48.c,d
Response based on an absolute SALT score of 10 
at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.e
Response based on a 75% improvement in SALT 
score from baseline (SALT75) at Weeks 4, 8, 
12, 18, 24, 28, 34, 40, and 48.
Change from baseline in SALT scores at Weeks 4, 
8, 12, 18, 24, 28, 34, 40, and 48.
Response based on at least a 2-grade improvement 
or a score of 3 in Eyebrow Assessment (EBA) 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 
48.
Response based on at least a 2-grade improvement
or a score of 3 in Eyelash Assessment (ELA) 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 
48.
To evaluate the effect of PF-06651600 on 
patient-centered outcomes and payer relevant 
measures to assess treatment benefit from the 
patient perspective and to demonstrate value. f
PGI-C response defined as a PGI-C score of 
“moderately improved” or “greatly improved” 
at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.f
Change from baseline in Alopecia Areata Patient 
Priority Outcomes (AAPPO) scales at 
Weeks 4, 8, 12, 18, 24, 34, 40, and 48.
Safety Objective(s)
Safety Endpoint(s)
To evaluate the safety and tolerability of 
PF-06651600 in the treatment period over time.
Incidence of treatment-emergent adverse events 
(AEs).
Incidence of serious AEs (SAEs) and AEs leading 
to discontinuation.
The incidence of clinically significant abnormalities 
in vital signs.
The incidence of clinically significant abnormalities 
in clinical laboratory values.
PK Objective(s)
PK Endpoint(s)
To characterize pharmacokinetics of PF-06651600.
Plasma concentrations of PF-06651600 at Weeks 4, 
and 8 or 12.
Exploratory Objective(s):
Exploratory Endpoint(s):
To collect banked biospecimens for exploratory 
research, unless prohibited by local regulations 
or ethics committee decision.
Collection of banked biospecimens unless 
prohibited by local regulations or ethics 
committee decision. Additional information on 
collection and potential use is provided in the
Banked Biospecimens section in the protocol.
To assess the efficacy of PF-06651600 on regrowth 
of lost hair during the treatment period over 
time.
Response based on a 50% improvement in SALT 
score from baseline (SALT50) at Weeks 4, 8, 
12, 18, 24, 28, 34, 40, and 48.


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Absolute SALT scores at Baseline, Weeks 4, 8, 12, 
18, 24, 28, 34, 40, and 48.
To evaluate the effect of PF-06651600 on patient-
centered outcomes and payer relevant measures 
to assess treatment benefit from the patient 
perspective and to demonstrate value.
Improvement on PGI-C defined as “slightly 
improved”, “moderately improved”, or “greatly 
improved” at Weeks 4, 8, 12, 18, 24, 34, 40, 
and 48.
Improvement on Patient Satisfaction with Hair 
Growth (P-Sat) items defined as slightly, 
moderately, or very satisfied at Weeks 4, 8, 12, 
18, 24, 34, 40, and 48.
Change from baseline in EuroQoL 5 Dimensions 
(EQ-5D-5L) in adults or 
EuroQoL 5 Dimensions-Youth (EQ-5D-Y) in 
adolescents at Weeks 4, 12, 24, and 48.
Change from baseline in Alopecia Areata Resource 
Utilization (AARU) at Weeks 12, 24, 34, and 
48.
Change from baseline in Work Productivity and 
Activity Impairment: Alopecia Areata 
(WPAI:AA) at Weeks 12, 24, 34, and 48.
Change from baseline in the depression subscale 
score of the Hospital Anxiety and Depression 
Scale (HADS) at Weeks 4, 8, 12, 24, and 48.g
Change from baseline in the anxiety subscale score 
of the HADS at Weeks 4, 8, 12, 24, and 48.g
Improvement on HADS among subjects with a 
baseline subscale score indicative of depression 
who achieved a “normal’ subscale score 
indicative of an absence of depression at 
Weeks 4, 8, 12, 24, and 48.g
Improvement on HADS among subjects with a 
baseline subscale score indicative of anxiety 
who achieved a “normal’ subscale score 
indicative of an absence of anxiety at Weeks 4, 
8, 12, 24, and 48.g
Change from baseline in 36-Item Short Form 
Health Survey version 2 Acute (SF36v2 Acute) 
at Weeks 4, 8, 12, 24, and 48.
To evaluate the effect of PF-06651600 on the 
clinician global impression of severity of scalp 
hair loss.
To evaluate efficacy of PF-06651600 in AA nail 
disease over time.
Change from baseline in Clinician Global 
Impression – Alopecia Areata (CGI-AA) at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.
Change from baseline in fingernails affected by AA 
at Weeks 12, 24, 34, 40, and 48.
To assess pharmacodynamic and disease-related 
biomarkers over time.
Change from baseline in interferon gamma-induced 
protein 10 (IP-10) at Weeks 4, 8, 12, and 24.
Change from baseline in percent and absolute 
lymphocyte subsets (T-cell, B-cell, and natural 
killer [NK] cells) at Weeks 4, 12, 24, and 48.
Change from baseline in immunoglobulins (IgA, 
IgG, IgM) at Weeks 24 and 48.
a.
The VHP countries participating in this study are Czech Republic, Germany, Hungary, Poland, and Spain.
b.
For the EMA and competent authorities in the VHP countries, when SALT ≤10 is utilized for the primary 
endpoint, exposure response will be analyzed utilizing SALT ≤10 in a separate analysis.


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c.
For the EMA and competent authorities in the VHP countries, when SALT ≤10 is utilized for the primary 
endpoint, SALT ≤20 at Week 24 will be analyzed as a secondary endpoint.
d.
When SALT ≤20 response at Week 24 is utilized as the primary endpoint, responses based on absolute SALT 
score ≤20 at Weeks 18, 12, 8 and 4 will be analyzed controlling for Type I error utilizing an appropriate testing 
procedure. When SALT ≤10 response at Week 24 is utilized as the primary endpoint, the response based on 
absolute SALT score ≤20 at Week 24 will be analyzed controlling for Type I error utilizing an appropriate testing 
procedure. 
e.
When SALT ≤20 response at Week 24 is utilized as the primary endpoint, the response based on absolute SALT 
score ≤10 at Week 24 will be analyzed controlling for Type I error utilizing an appropriate testing procedure.
When SALT ≤10 response at Week 24 is utilized as the primary endpoint, the responses based on absolute SALT 
score ≤10 at Weeks 18, 12, 8 and 4 will be analyzed controlling for Type I error utilizing an appropriate testing 
procedure.
f.
For the EMA and competent authorities in the VHP countries, the evaluation of the effect of PF-06651600 on 
patient centered outcomes (as measured by PGI-C response at Week 24) is a key secondary objective. The PGI-C 
response at Week 24 will be analyzed as a key secondary endpoint utilizing an appropriate testing procedure to 
control overall Type I error. 
g.
For the EMA and competent authorities in the VHP countries, endpoints utilizing the HADS will be analyzed as 
secondary endpoints.
2.2. Study Design
This is a Phase 2b/3, randomized, double-blind, placebo-controlled, dose-ranging study to 
investigate PF-06651600 in subjects with AA. The study will have a maximum duration of 
approximately 57 weeks. This includes an up to 5-week Screening period, a 48-week 
treatment period, and a 4-week follow-up period as shown below. The treatment period will 
be comprised of a placebo-controlled period that includes a 4-week loading phase and a 
20-week maintenance phase, followed by a 24-week extension phase. The study will enroll a 
total of approximately 660 subjects. The study will be conducted at approximately 120 sites.


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Figure 1.
Study Design Schematic
To be eligible to enroll in this study, subjects must have moderate to severe AA with 
50% hair loss of the scalp (Severity of Alopecia Tool [SALT] score 50) at both Screening 
and baseline visits, without evidence of terminal hair regrowth within the previous 6 months,
and with the current episode of hair loss 10 years.
Screening will occur within 35 days prior to the first dose of study drug to confirm that 
subjects meet selection criteria for the study. Eligible subjects will be randomized as 
described below. 
A stratified randomization will be used for operational purposes in order to achieve a target 
global composition for AT/AU and adolescent subjects in the enrolled population. The 
targets for enrollment are approximately 40% AT/AU and approximately 15% adolescents.
The randomization will be operationalized as follows. In regions enrolling both adolescents 
and adults, there will be four strata:

<18 years of age and AT/AU;

<18 years of age and not AT/AU;


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
≥18 years of age and AT/AU; and

≥18 years of age and not AT/AU.
Within each of these strata, subjects will be randomized in a 2:2:2:2:1:1:1 manner to blinded 
PF-06651600 and matching placebo for a total of 7 treatment sequences. In regions enrolling 
only adults, there will be two strata:

≥18 years of age and AT/AU; and

≥18 years of age and not AT/AU.
In these regions, subjects will be randomized using the same ratio as described for regions 
enrolling both adolescents and adults.
All subjects will begin dosing during the loading phase according to their assigned sequence.
Following the 4-week loading phase, subjects will continue dosing according to their 
assigned sequence in the 20-week maintenance phase. At the end of the maintenance phase, 
placebo-treated subjects will be advanced in a prespecified, blinded manner to one of 2 active 
treatment sequences for the remainder of the study (through Week 48). Investigators, 
subjects, and the sponsor study team will be blinded to treatment throughout the duration of 
the study. Following the last dose of study drug, both discontinued and completed subjects 
will enter a 4-week follow-up period for safety monitoring. Subjects who complete treatment 
may be eligible for enrollment in a long-term study (Phase 3 study B7981032). Subjects who 
enroll immediately into B7981032 study will not be required to complete the 4-week 
follow-up period in this study.
The study may be unblinded for internal decision-making purposes when ≥90% of subjects 
have reached 24 weeks post-randomization (or discontinued prior to the Week 24 visit). The 
sponsor personnel who are unblinded will be separate from the study team. The sponsor 
will still maintain the blind for study team members who will be involved in daily study 
conduct, study management, safety, and data monitoring through the completion of the study.
Investigators and subjects will remain blinded. 
Early unblinding for PK/PD modeling purposes is planned when ≥90% of subjects have 
reached 24 weeks post-randomization (or discontinued prior to the Week 24 visit). There will 
be no impact on B7981015 study conduct, analysis, or reporting based on the early 
unblinding of the PK/PD data. The results of these analyses will be reported in a separate 
pharmacometrics analysis report.
2.2.1. Sample Size Determination
The sample size for the study was based on the consideration to have sufficient power to 
evaluate the primary endpoint. A sample size of 120 subjects per group (for the 200 mg/50 
mg once daily (QD), 200 mg/30 mg QD, 50 mg/50 mg QD, or 30 mg/30 mg QD groups) will 
provide more than 90% power to demonstrate that at least the 200 mg/50 mg QD group is 
superior to placebo by a difference of 24% in the proportion of subjects achieving the 
primary endpoint (SALT score 20 at Week 24), assuming a placebo response rate of no 


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more than 5%, at α = 0.05 (2-sided significance level). This sample size accounts for 
multiplicity using a closed testing procedure to ensure strong control of Type I error for all 
comparisons between active treatment groups and placebo. This sample size additionally 
provides > 90% power for the SALT ≤10 at Week 24 endpoint assuming that the 200 mg/50 
mg QD group is superior to placebo by a difference of 20% in the proportion of subjects 
achieving SALT ≤10, assuming a placebo response rate of no more than 5%, at α = 0.05 (2-
sided significance level). The assumption of the placebo response rate for both SALT ≤20 
and SALT ≤10, as well as of the treatment difference, were informed by the Week 24 results 
from the Phase 2a Study B7931005.
Regulatory requirements for a marketing authorization approval 
 
 will require significance at an α more stringent than 0.05, although the exact level of 
stringency required may vary (ie, 0.00125 is required by the FDA/PMDA for their requested 
primary endpoint of SALT ≤20 while 0.01 is required by the EMA for their requested 
primary endpoint of SALT ≤10). The sample size of 120 subjects per group provides >90% 
power for responses based on SALT ≤20 (α = 0.00125) and SALT ≤10 (α = 0.01).
The 10 mg/10 mg QD group is included to address the secondary objective of characterizing 
the exposure response. The sample size of 60 subjects was chosen to allow for estimation of 
the exposure response parameters.
For the EMA and competent authorities in the VHP countries that request that the PGI-C 
response at Week 24 be analyzed as a key secondary endpoint, a sample size of 120 subjects 
per group also provides more than 90% power for PGI-C response assuming a difference of 
35% and a placebo response rate of 20%, at α = 0.05 (2-sided significance level). The 
assumptions of the treatment difference and placebo response rate for PGI-C response were 
based on the Concert10 CTP-543 Phase 2b Study Week 24 data. Under the above 
assumptions, the power of the study remains >90% at α = 0.01 (EMA required 2-sided 
significance level).
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary and Secondary Endpoints
Section 2.1 lists the overall study objectives and endpoints. The primary, key secondary and 
secondary endpoints for the purpose of overall study reporting and publications are also 
detailed in Table 3. Table 4 lists the primary and secondary endpoints of the study organized 
by known regional requirements.
Table 3.
Primary and Secondary Endpoints for Overall Study Reporting and 
Publications
Alpha (α)
0.05 (2-sided significance level)
Primary Endpoint
Response based on an absolute SALT Score ≤20 at Week 24.
Key Secondary Endpoint
Response based on an absolute SALT Score ≤10 at Week 24.
Secondary Endpoints
•
Response based on an absolute SALT Score ≤20 at Week 24 will be used to 
characterize the exposure response.
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Table 3.
Primary and Secondary Endpoints for Overall Study Reporting and 
Publications
•
Response based on an absolute SALT score ≤20 at Weeks 4, 8, 12, 18, 28, 34, 40, and 
48.
NOTE: Response at Weeks 4, 8, 12, and 18 will be analyzed controlling for Type I 
error.
•
Response based on an absolute SALT score of ≤10 at Weeks 4, 8, 12, 18, 28, 34, 40, 
and 48.
•
Response based on a 75% improvement in SALT score from baseline (SALT75) at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.
•
Change from baseline in SALT scores at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.
•
Response based on at least a 2-grade improvement or a score of 3 in EBA at Weeks 4, 
8, 12, 18, 24, 28, 34, 40, and 48.
•
Response based on at least a 2-grade improvement or a score of 3 in ELA at Weeks 4, 
8, 12, 18, 24, 28, 34, 40, and 48.
•
PGI-C response defined as a PGI-C score of “moderately improved” or “greatly 
improved” at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.
•
Change from baseline in AAPPO scales at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.
Table 4.
Primary and Secondary Endpoints Organized by Known Regional 
Regulatory Requirements
For the FDA/PMDA
For the EMA
and competent authorities in 
the VHP countries
Alpha (α)
 
0.00125 (2-sided significance level)
0.01 (2-sided significance level)
Primary Endpoint
Response based on an absolute SALT Score 
≤20 at Week 24.
Response based on an absolute SALT Score 
≤10 at Week 24.
Key Secondary Endpoint
Not applicable
PGI-C response defined as a PGI-C score of 
“moderately improved” or “greatly 
improved” at Week 24.
Secondary Endpoints
•
Response based on an absolute SALT 
Score ≤20 at Week 24 will be used to 
characterize the exposure response.
•
Response based on an absolute SALT 
Score ≤10 at Week 24 will be used to 
characterize the exposure response.
•
Response based on an absolute SALT 
score ≤20 at Weeks 4, 8, 12, 18, 28, 34, 
40, and 48.
NOTE: Response at Weeks 4, 8, 12, 
and 18 will be analyzed controlling for 
Type I error.
•
Response based on an absolute SALT 
score ≤20 at Weeks 4, 8, 12, 18, 24, 28, 
34, 40, and 48.
NOTE: Response at Week 24 will be 
analyzed controlling for Type I error.
•
Response based on an absolute SALT 
score of ≤10 at Weeks 4, 8, 12, 18, 24, 
28, 34, 40, and 48.
NOTE: Response at Week 24 will 
be analyzed controlling for Type I 
error.
•
Response based on an absolute SALT 
score of ≤10 at Weeks 4, 8, 12, 18, 28, 
34, 40, and 48.
NOTE: Response at Weeks 4, 8, 12, 
and 18 will be analyzed controlling for 
Type I error.
•
Response based on a 75% improvement 
in SALT score from baseline (SALT75) 
at Weeks 4, 8, 12, 18, 24, 28, 34, 40, 
and 48.
•
Response based on a 75% improvement 
in SALT score from baseline (SALT75) 
at Weeks 4, 8, 12, 18, 24, 28, 34, 40, 
and 48.
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Table 4.
Primary and Secondary Endpoints Organized by Known Regional 
Regulatory Requirements
For the FDA/PMDA
For the EMA
and competent authorities in 
the VHP countries

Change from baseline in SALT scores 
at Weeks 4, 8, 12, 18, 24, 28, 34, 40, 
and 48.

Change from baseline in SALT scores 
at Weeks 4, 8, 12, 18, 24, 28, 34, 40, 
and 48.

Response based on at least a 2-grade 
improvement or a score of 3 in EBA 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 
40, and 48.

Response based on at least a 2-grade 
improvement or a score of 3 in EBA 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 
40, and 48.

Response based on at least a 2-grade 
improvement or a score of 3 in ELA 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 
40, and 48.

Response based on at least a 2-grade 
improvement or a score of 3 in ELA 
score at Weeks 4, 8, 12, 18, 24, 28, 34, 
40, and 48.

PGI-C response defined as a PGI-C 
score of “moderately improved” or 
“greatly improved” at Weeks 4, 8, 12, 
18, 24, 34, 40, and 48.

PGI-C response defined as a PGI-C 
score of “moderately improved” or 
“greatly improved” at Weeks 4, 8, 12, 
18, 24, 34, 40, and 48.

Change from baseline in AAPPO scales 
at Weeks 4, 8, 12, 18, 24, 34, 40, and 
48.

Change from baseline in AAPPO scales 
at Weeks 4, 8, 12, 18, 24, 34, 40, and 
48.
-

Change from baseline in the depression 
subscale score of the HADS at 
Weeks 4, 8, 12, 24, and 48.
-

Change from baseline in the anxiety 
subscale score of the HADS at 
Weeks 4, 8, 12, 24, and 48.
-

Improvement on HADS among 
subjects with a baseline subscale score 
indicative of depression who achieved a 
“normal’ subscale score indicative of 
an absence of depression at Weeks 4, 8, 
12, 24, and 48.
-

Improvement on HADS among 
subjects with a baseline subscale score 
indicative of anxiety who achieved a 
“normal’ subscale score indicative of 
an absence of anxiety at Weeks 4, 8, 
12, 24, and 48.
3.2. Other Endpoints
3.2.1. Exploratory Endpoints

Collection of banked biospecimens unless prohibited by local regulations or ethics 
committee decision. Additional information on collection and potential use is 
provided in the Banked Biospecimens section in the protocol.

Response based on a 50% improvement in SALT score from baseline (SALT50) at
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.


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
Absolute SALT scores at Baseline, Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Improvement on PGI-C defined as “slightly improved”, “moderately improved”, or 
“greatly improved” at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.

Improvement on Patient Satisfaction with Hair Growth (P-Sat) items defined as 
slightly, moderately, or very satisfied at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.
o
Will be analyzed for each individual item.

Change from baseline in EuroQoL 5 Dimensions (EQ-5D-5L) in adults or 
EuroQoL 5 Dimensions-Youth (EQ-5D-Y) in adolescents at Weeks 4, 12, 24, and 48.
o
Will be analyzed for adults and adolescents separately. US specific utility 
weights1 will be applied for the scoring of these endpoints;

Change from baseline in Alopecia Areata Resource Utilization (AARU) at Weeks 12, 
24, 34, and 48.
o
Proportion of subjects with any healthcare professional (HCP) visits. 
o
Among those with HCP visits, mean total number of visits for any reason, 
mean change from baseline in total number of visits for any reason, mean total 
number of visits related to AA and mean change from baseline in AA-related 
visits. 

Change from baseline in Work Productivity and Activity Impairment: Alopecia 
Areata (WPAI:AA) at Weeks 12, 24, 34, and 48.
o
Change from baseline in absenteeism, presenteesism, work productivity loss 
(overall) and activity impairment in adults.

Change from baseline in the depression subscale score of the Hospital Anxiety and 
Depression Scale (HADS) at Weeks 4, 8, 12, 24, and 48.
o
For the EMA and competent authorities in the VHP countries this endpoint 
will be analyzed as a secondary endpoint.

Change from baseline in the anxiety subscale score of the Hospital Anxiety and 
Depression Scale (HADS) at Weeks 4, 8, 12, 24, and 48.
o
For the EMA and competent authorities in the VHP countries this endpoint 
will be analyzed as a secondary endpoint.

Improvement on HADS among subjects with a baseline subscale score indicative of 
depression who achieved a “normal” subscale score indicative of an absence of 
depression at Weeks 4, 8, 12, 24, and 48.


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o
For the EMA and competent authorities in the VHP countries this endpoint 
will be analyzed as a secondary endpoint.
o
Among adults, a score of 0-7 is considered normal, a score of >7 is indicative 
of depression. Among adolescents (at baseline age), a score of 0-6 is 
considered normal, a score of >6 is indicative of depression;2,3

Improvement on HADS among subjects with a baseline subscale score indicative of 
anxiety who achieved a “normal” subscale score indicative of an absence of anxiety 
at Weeks 4, 8, 12, 24, and 48.
o
For the EMA and competent authorities in the VHP countries this endpoint 
will be analyzed as a secondary endpoint.
o
Among adults, a score of 0-7 is considered normal, a score of >7 is indicative 
of anxiety. Among adolescents (at baseline age), a score of 0-8 is considered 
normal, a score of >8 is indicative of anxiety.2,3

Change from baseline in 36-Item Short Form Health Survey version 2 Acute (SF36v2 
Acute) at Weeks 4, 8, 12, 24, and 48.
o
8 domain scales: physical function (PF), bodily pain (BP), role physical (RP), 
role emotional (RE), Vitality (VT), general health (GH), social function (SF), 
and mental health (MH).
o
2 summary scales: Mental Component Summary Score (MCS) and Physical 
Component Summary Score (PCS).

Change from baseline in Clinician Global Impression – Alopecia Areata (CGI-AA) at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.
o
CGI-AA scored as 0=‘None (no hair loss)’, 1=‘Minimal hair loss’, 
2-4= ‘Moderate-very severe or complete hair loss’.
o
Improvement among participants with a baseline score 2-4 indicating 
Moderate-very severe or complete hair loss who achieved a score of 0=‘None 
(no hair loss)’ or 1=‘Minimal hair loss’. 

Change from baseline in fingernails affected by AA at Weeks 12, 24, 34, 40, and 48.

Change from baseline in interferon gamma-induced protein 10 (IP-10) at Weeks 4, 8, 
12, and 24.

Change from baseline in percent and absolute lymphocyte subsets (T-cell, B-cell, and 
natural killer [NK] cells) at Weeks 4, 12, 24, and 48.

Change from baseline in immunoglobulins (IgA, IgG, IgM) at Weeks 24 and 48.


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3.2.2. PK Endpoint

Plasma concentrations of PF-06651600 at Weeks 4 and 8 (or Week 12).
3.3. Baseline Variables
Baseline is defined as pre-dose on Day 1. Data from the screening period may be used if 
Day 1 data are missing. If multiple data points are available, we will use the observation 
closest but no later than Day 1.
For the analysis of ECG data, subject’s baseline values will be the ECG assessment at the 
Screening visit. Data from the Day 1 may be used if screening data are missing.
3.4. Safety Endpoints
The safety endpoints are:

Incidence of treatment-emergent adverse events (AEs).

Incidence of serious AEs (SAEs) and AEs leading to discontinuation.

The incidence of clinically significant abnormalities in vital signs.

The incidence of clinically significant abnormalities in clinical laboratory values.
3.4.1. Adverse Events
An AE is considered a treatment emergent adverse event (TEAE) if the event starts on or 
after the first dosing day.
3.4.2. Laboratory Data
See Table 3 in the protocol for the list of clinical laboratory tests to be performed. Laboratory
data Criteria for discontinuation and abnormalities are specified in Section 9.3. 
3.4.3. Vital Signs, Including Height and Weight
Vital sign measurements are pulse rate, blood pressure.
Height and weight are also collected pre- and post-treatment.
3.4.4. Physical Examinations
Complete physical examinations consist of assessments of general appearance; skin
(dermatological full body exam); head, eyes, ears, nose, and throat (HEENT); mouth, heart; 
lungs; abdomen; extremities; neurologic function, back, and lymph nodes. Targeted physical 
examinations should include skin, heart, lung, and abdomen, neurologic function, and 
examination of body systems where there are symptom complaints by the subject.


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3.4.5. Electrocardiogram (ECG)
ECG measurements will be collected at Screening, Day 1, Week 4, Week 24, Week 28, and 
Week 48.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population described below prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
4.1. Full Analysis Set
The Full Analysis Set (FAS) is defined as all subjects who have been randomized, regardless 
of whether they received study medication. Subjects will be analyzed in the treatment groups 
as they are randomized. If a subject was randomized but received the incorrect treatment, 
then the subject will be reported under their randomized treatment group for all efficacy 
analyses. If a subject is treated but not randomized, then the subject will be excluded from 
the FAS.
4.2. Per Protocol Analysis Set 
The Per Protocol Analysis Set (PPAS) is defined as all randomized subjects who do not have 
any major protocol deviation related to inclusion/exclusion criteria, compliance with 
investigational product, or any other major protocol deviations that might affect the efficacy 
data through Week 24. The following deviations will be evaluated for each subject prior to 
unblinding to determine if a subject should be excluded from the PPAS: 
1. Subject did not meet the following inclusion criteria for hair loss due to AA at 
Screening or Day 1:
a.
Clinical diagnosis of AA with no other known etiology of hair loss, including 
no known androgenetic alopecia;
b. ≥50% scalp hair loss;
c.
Current episode of hair loss ≤10 years duration at time of Screening;
d. No evidence of terminal scalp hair regrowth within 6 months at both the 
screening and baseline visits.
2. Subject met one of the following exclusion criteria regarding medical history 
diagnoses:
a.
Another scalp disease which could impact hair loss assessments;
b. Active systemic disease which can cause hair loss.
3. Subjects who were randomized but never received study drug.
4. Prior to the date of the Week 24 visit, subject had a dosing interruption of ≥6 weeks 
for any reason.
5. Prior to the date of the Week 24 visit, subject used a prior or concomitant prohibited 
medication that could potentially impact efficacy data at Week 24.


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6. Week 24 SALT assessment was impacted in one of the following ways:
a.
Visit/assessment was not performed;
b. Assessment was not performed properly (including subject had a shaved 
head).
7. Subjects with other major protocol deviations not listed above that, in the opinion of 
the sponsor study team, could potentially impact efficacy data at Week 24.
The subjects excluded from this analysis set will be determined and documented before the 
study is unblinded.
4.3. Safety Analysis Set
The Safety Analysis Set (SAS) will be defined as all subjects who receive at least one dose of 
study medication. The safety analysis set is the primary population for treatment 
administration/compliance and safety. A randomized but not treated subject will be excluded 
from the safety analyses. If a subject was randomized but received partially incorrect 
treatment, then the subject will be summarized under the treatment received for most of the 
time during the study, for all safety analyses.


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5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis and reporting of results will be performed after the completion of the study 
and after the database is locked.
5.1. Hypotheses and Decision Rules
This section describes the testing procedure for multiple comparisons. This 
 
will support submission in several regions with different requirements; therefore, this 
section is organized into 3 sections: Section 5.1.1 describes the testing procedure for the 
overall study, Section 5.1.2, for the FDA/PMDA, and Section 5.1.3 for the EMA and 
competent authorities in the VHP countries.
The study is tested at an overall α = 0.05. While the 5% significance level is deemed 
sufficient for a declaration of effect, more stringent levels have been advised for regulatory 
submission of B7981015 
, ie, 1% for EMA and competent authorities 
in the VHP countries, and 0.125% for the FDA/PMDA.
The hypotheses to be tested are that each of the active treatment groups (200 mg QD/50 mg 
QD, 50 mg QD/50 mg QD, 200 mg QD/30 mg QD, and 30 mg QD/30 mg QD) is superior to 
placebo as measured by the proportion of subjects achieving the primary endpoint at
Week 24 and key secondary endpoints where applicable.
The grouping of the dose regimens in the test hierarchy was based on the hierarchy of 
2 different dose regimens: in the dosing regimens that have a loading dose, the order is 
200 mg QD/50 mg QD →200 mg QD/30 mg QD; in the regimens without a loading dose, 
the order is 50 mg QD/50 mg QD →30 mg QD/30 mg QD. The testing strategy proposed 
will allow simultaneous testing of the 200 mg QD/30 mg QD and the 50 mg QD/50 mg QD 
dose regimens against placebo, given that it is not known which dose regimen will have a 
better response.
5.1.1. Overall Study (Testing Procedure for Multiple Comparisons Incorporating the 
SALT ≤10 as a Key Secondary Endpoint)
For the overall study the SALT ≤20 response at Week 24 is the primary endpoint and the 
SALT ≤10 response at Week 24 will be analyzed as a key secondary endpoint. The 
hypotheses to be tested are that each of the active treatment groups is superior to placebo as 
measured by the proportion of subjects achieving the primary endpoint and the key 
secondary endpoint. There are a total of 8 hypotheses to be tested:
•
Hypothesis 1 (H1) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the primary endpoint; 
•
Hypothesis 2 (H2) is to test whether the 50 mg QD dose regimen is superior to 
placebo for the primary endpoint; 
•
Hypothesis 3 (H3) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the primary endpoint; 
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
Hypothesis 4 (H4) is to test whether the 30 mg QD dose regimen is superior to 
placebo for the primary endpoint;

Hypothesis 1p (H1p) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the key secondary endpoint; 

Hypothesis 2p (H2p) is to test whether the 50 mg QD dose regimen is superior to 
placebo for the key secondary endpoint; 

Hypothesis 3p (H3p) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the key secondary endpoint; 

Hypothesis 4p (H4p) is to test whether the 30 mg QD dose regimen is superior to 
placebo for the key secondary endpoint.
The family-wise Type I error will be strongly controlled using a gatekeeping approach as 
described in the following order and shown in Figure 2. The 10 mg group comparison to 
placebo is not included in the Type I error controlled procedure, as this group is only 
included to support the estimation of the exposure response.

The primary endpoint for 200 mg QD/50 mg QD dose regimen (H1) will be tested at 
significance level first. If significant, then the primary endpoint for 50 mg QD dose 
regimen and the 200 mg QD/30 mg QD dose regimen (H2 and H3) and the key 
secondary endpoint for 200 mg QD/50 mg QD dose regimen (H1p) will be tested 
simultaneously. If both the 50 mg QD dose regimen and the 200 mg QD/30 mg QD 
dose regimen are significant, then the 30 mg QD dose regimen will be tested. 

For the primary endpoint, if both the 50 mg QD dose regimen and the 
200 mg QD/30 mg QD dose regimen are significant at /4 level, or if one of the dose 
regimens (50 mg QD dose regimen or 200 mg QD/30 mg QD dose regimen) is 
significant at /4 level and the other is significant at /2 level, both dose regimens 
will be declared as significant. In this case, the 30 mg QD dose regimen will be tested 
at /2 level. If only one of the regimens (50 mg QD dose regimen or 
200 mg QD/30 mg QD dose regimen) is significant at /4 level and the other is not 
significant at /2 level, only the one significant at /4 level will be declared as 
statistically significant. In this case, the testing for the 30 mg QD dose regimen will 
not proceed.

For the key secondary endpoint, the 200 mg QD/50 mg QD dose regimen will be 
tested at /2 level first. If significant, then the 50 mg QD dose regimen and the 
200 mg QD/30 mg QD dose regimen will be tested simultaneously. If both the 
50 mg QD dose regimen and the 200 mg QD/30 mg QD dose regimen are significant 
at /4 level, or if one of the dose regimens (50 mg QD dose regimen or 
200 mg QD/30 mg QD dose regimen) is significant at /4 level and the other is 
significant at /2 level, both dose regimens will be declared as significant. In this 
case, the 30 mg QD dose regimen will be tested at /2 level. If only one of the 


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regimens (50 mg QD dose regimen or 200 mg QD/30 mg QD dose regimen) is 
significant at /4 level and the other is not significant at /2 level, only the one 
significant at /4 level will be declared as statistically significant. In this case, the 
resting for the 30 mg QD dose regimen will not proceed.

If the primary endpoint for the 200 mg QD/50 mg QD dose regimen is significant at α 
level, and all the remaining hypotheses for the primary endpoint and key secondary 
endpoint are significant at the overall /2 level, then all 8 hypotheses will be declared 
as statistically significant.

If the primary endpoint for all 4 hypotheses or the primary endpoint for H1 is 
significant and the key secondary endpoint is significant in all 4 hypotheses, then the 
/2 level will be passed to the hypothesis testing for the other hypotheses. In this 
case, the other hypotheses can be tested at the level instead of the /2 level 
following the same procedures for claiming statistical significance outlined in the 
bullets above with the exception of the increased .
Figure 2.
Schematic and Graphical Presentation for Multiple Testing Procedure 
Incorporating a Key Secondary Endpoint
The numbers on each edge indicate the transition rule for the weights on allocation once a hypothesis is 
rejected.


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The following approach will be used to control the Type I error for SALT 20 at earlier time 
points:

For a given dose, if the primary endpoint of SALT 20 is declared to be statistically 
significant based on the testing procedure for the primary endpoint, in order to 
establish the onset of efficacy as measured by SALT 20 at the earliest time point, a 
step-down approach with SALT 20 from Week 24 to earlier time points (order of 
testing: Weeks 24, 18, 12, 8, and 4) will be used for each time point. Although this 
testing scheme does not protect the Type I error for the family of all possible 
comparisons, it will provide Type I error protection for testing the family of SALT 
20 time points within the same dose group.
5.1.2. For the FDA/PMDA (Testing Procedure for Multiple Comparisons with no Key 
Secondary Endpoints)
For the FDA/PMDA, the SALT ≤20 response at Week 24 is the primary endpoint and no 
secondary endpoints will be analyzed as key secondary. The hypotheses to be tested at = 
0.00125 are that each of the active treatment groups is superior to placebo as measured by the 
proportion of subjects achieving the primary endpoint. There are a total of 4 hypotheses to be 
tested. 

Hypothesis 1 (H1) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 2 (H2) is to test whether the 50 mg QD/50 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 3 (H3) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 4 (H4) is to test whether the 30 mg QD/30 mg QD dose regimen is 
superior to placebo for the primary endpoint.
The family-wise Type I error will be strongly controlled using a gate-keeping approach to 
test these hypotheses in 3 groups as shown in Figure 3. The first group includes H1; the 
second group includes H2 and H3; and the third group includes H4. The statistical 
significance of the first hypothesis (H1) will allow simultaneous testing of H2 and H3 using 
Holm’s method. Statistical significance for both H2 and H3 will enable testing the statistical 
significance for the fourth hypothesis (H4). The 10 mg group comparison to placebo is not 
included in the Type I error controlled procedure, as this group is only included to support 
the estimation of the exposure response.
Figure 3 shows a schematic of the procedure for testing each of the active treatment groups 
versus the placebo group for the primary endpoint.


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Figure 3.
Schematic and Graphical Presentation for Multiple Testing Procedure
The numbers on each arrow indicate the transition rule for the weights on allocation once a hypothesis is 
rejected.
In the simultaneous testing of H2 and H3, if both the 50 mg QD/50 mg QD and
200 mg QD/30 mg QD regimens are not significant at α/2 level, the test for statistical 
significance is stopped. If one of the hypotheses for 50 mg QD/50 mg QD and 
200 mg QD/30 mg QD regimens is significant at α/2 level and the other hypothesis is 
significant at α level, this family hypothesis is significant. If one of the hypotheses for 
50 mg QD/50 mg QD and 200 mg QD/30 mg QD is significant at α/2 level and the other 
hypothesis is not significant at α level, only the hypothesis significant at α/2 level will be 
declared as statistically significant. In this case, the testing for statistical significance for 
H4 will not proceed.
The following approach will be used to control the Type I error for testing SALT ≤10 at 
Week 24:

For a given dose, if SALT ≤20 at Week 24 is declared to be statistically significant 
based on the testing procedure for the primary endpoint(s), then SALT ≤10 at Week 
24 will be tested at the same significance level as the SALT ≤20 at Week 24 was 
tested. Though this testing scheme does not protect the Type I error for the family of 
all possible comparisons, it will provide Type I error protection for testing the
endpoints within the same dose group.
The following approach will be used to control the Type I error for testing SALT ≤20 at 
earlier time points:


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
For a given dose, if the primary endpoint of SALT ≤20 at Week 24 is declared to be 
statistically significant based on the testing procedure for the primary endpoint, in 
order to establish the onset of efficacy as measured by SALT ≤20 at the earliest time 
point, a step-down approach with SALT ≤20 from Week 24 to earlier time points 
(order of testing: Weeks 24, 18, 12, 8, and 4) will be used for each time point. Though 
this testing scheme does not protect the Type I error for the family of all possible 
comparisons, it will provide Type I error protection for testing the family of SALT 
≤20 time points within the same dose group. 
5.1.3. For the EMA and Competent Authorities in the VHP Countries (Testing 
Procedure for Multiple Comparisons Incorporating the PGI-C Response as a Key 
Secondary Endpoint)
For the EMA and competent authorities in the VHP countries, the SALT ≤10 response at 
Week 24 will be the primary endpoint and the PGI-C response at Week 24 will be analyzed 
as a key secondary endpoint. The hypotheses to be tested at = 0.01 are that each of the 
active treatment groups is superior to placebo as measured by the proportion of subjects 
achieving the primary endpoint and the key secondary endpoint. There are a total of 
8 hypotheses to be tested:

Hypothesis 1 (H1) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 2 (H2) is to test whether the 50 mg QD dose regimen is superior to 
placebo for the primary endpoint; 

Hypothesis 3 (H3) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the primary endpoint; 

Hypothesis 4 (H4) is to test whether the 30 mg QD dose regimen is superior to 
placebo for the primary endpoint;

Hypothesis 1p (H1p) is to test whether the 200 mg QD/50 mg QD dose regimen is 
superior to placebo for the key secondary endpoint; 

Hypothesis 2p (H2p) is to test whether the 50 mg QD dose regimen is superior to 
placebo for the key secondary endpoint; 

Hypothesis 3p (H3p) is to test whether the 200 mg QD/30 mg QD dose regimen is 
superior to placebo for the key secondary endpoint; 

Hypothesis 4p (H4p) is to test whether the 30 mg QD dose regimen is superior to 
placebo for the key secondary endpoint.
The family-wise Type I error will be strongly controlled using a gate-keeping approach as 
described in the following order and shown in Figure 2. The 10 mg group comparison to 
placebo is not included in the Type I error controlled procedure, as this group was only 
included in the study design to support the estimation of the exposure response.


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
The primary endpoint for 200 mg QD/50 mg QD dose regimen (H1) will be tested at 
significance level first. If significant, then the primary endpoint for 50 mg QD dose 
regimen and the 200 mg QD/30 mg QD dose regimen (H2 and H3) and the key 
secondary endpoint for 200 mg QD/50 mg QD dose regimen (H1p) will be tested 
simultaneously. If both the 50 mg QD dose regimen and the 200 mg QD/30 mg QD 
dose regimen are significant, then the 30 mg QD dose regimen will be tested. 

For the primary endpoint, if both the 50 mg QD dose regimen and the 200 mg QD/30 
mg QD dose regimen are significant at /4 level, or if one of the dose regimens (50 
mg QD dose regimen or 200 mg QD/30 mg QD dose regimen) is significant at /4 
level and the other is significant at /2 level, both dose regimens will be declared as 
significant. In this case, the 30 mg QD dose regimen will be tested at /2 level. If 
only one of the regimens (50 mg QD dose regimen or 200 mg QD/30 mg QD dose 
regimen) is significant at /4 level and the other is not significant at /2 level, only 
the one significant at /4 level will be declared as statistically significant. In this case, 
the testing for the 30 mg QD dose regimen will not proceed.

For the key secondary endpoint, the 200 mg QD/50 mg QD dose regimen will be 
tested at /2 level first. If significant, then the 50 mg QD dose regimen and the 
200 mg QD/30 mg QD dose regimen will be tested simultaneously. If both the 50 mg 
QD dose regimen and the 200 mg QD/30 mg QD dose regimen are significant at /4
level, or if one of the dose regimens (50 mg QD dose regimen or 200 mg QD/30 mg
QD dose regimen) is significant at /4 level and the other is significant at /2 level, 
both dose regimens will be declared as significant. In this case, the 30 mg QD dose 
regimen will be tested at /2 level. If only one of the regimens (50 mg QD dose 
regimen or 200 mg QD/30 mg QD dose regimen) is significant at /4 level and the 
other is not significant at /2 level, only the one significant at /4 level will be
declared as statistically significant. In this case, the testing for the 30 mg QD dose 
regimen will not proceed.

If the primary endpoint for the 200 mg QD/50 mg QD dose regimen is significant at
level, and all the remaining hypotheses for the primary endpoint and key secondary
endpoint are significant at the overall /2 level, then all 8 hypotheses will be declared
as statistically significant.

If the primary endpoint for all 4 hypotheses or the primary endpoint for H1 is
significant and the key secondary endpoint is significant in all 4 hypothesis, then the
/2 level will be passed to the hypothesis testing for the other hypotheses. In this
case, the other hypotheses can be tested at level instead of the /2 level following
the same procedures for claiming statistical significance outlined in the bullets above
with the exception of the increased .
For the EMA and competent authorities in the VHP countries, the following approach will be 
used to control the Type I error for SALT ≤20 at Week 24:


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
For a given dose, if SALT ≤10 at Week 24 is declared to be statistically significant based 
on the testing procedure for the primary endpoint incorporating the key secondary 
endpoint, then SALT ≤20 at Week 24 will be tested at the same significance level as 
SALT ≤10 at Week 24 was tested. Although this testing scheme does not protect the 
Type I error for the family of all possible comparisons, it will provide Type I error 
protection for testing the endpoints within the same dose group.
The following approach will be used to control the Type I error for SALT ≤10 at earlier 
timepoints:

For a given dose, if the primary endpoint of SALT ≤10 is declared to be statistically 
significant based on the testing procedure for the primary endpoint incorporating the key 
secondary endpoint, in order to establish the onset of efficacy as measured by SALT ≤10 
at the earliest time point, a step-down approach with SALT ≤10 from Week 24 to earlier 
time points (order of testing: Weeks 24, 18, 12, 8, and 4) will be used for each time point.
Although this testing scheme does not protect the Type I error for the family of all 
possible comparisons, it will provide Type I error protection for testing the family of 
SALT ≤10 time points within the same dose group.
5.2. General Methods 
In general, number and percent will be presented for binary variables. Number, mean, 
standard deviation (or standard error of the mean), median, minimum, and maximum will be 
presented for continuous variables.
For analyses up to Week 24, in the comparison to placebo, the data from both placebo groups 
(F and G) will be pooled to form a combined placebo group. For analyses up to Week 48, 
data will be summarized by 7 treatment sequences (Figure 1) without combining two placebo 
groups.


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5.2.1. Binary Endpoints
Planned analysis for the overall study, for the FDA/PMDA and for the EMA and competent 
authorities in the VHP countries are summarized in Table 5. 
Table 5.
Statistical Methods of Planned Analysis for Primary and Key 
Secondary Endpoints for the Study and for each Regulatory Region
Study or
Region
Endpoint/ 
designation
Analysis #
Analysis 
Designation
Statistical 
Method
Missing due to 
COVID-19
Missing due to 
other reasons
Overall 
Study
SALT ≤20 at 
Week 24/ 
primary
Analysis 1
Primary
MN
Exclude 
non-responders
Analysis 2
Supplementary
GLMM
MAR 
MAR
Analysis 2a
Supplementary
GLMM/TP
MNAR 
MNAR
Analysis 3
Supplementary
MN
non-responders 
non-responders
SALT ≤10 at 
Week 24/ 
key 
secondary
Analysis 1
Key Secondary
MN
exclude
non-responders
Analysis 3
Supplementary
MN
non-responders
non-responders
FDA/ 
PMDA
SALT ≤20 at 
Week 24/ 
primary
Analysis 1
Primary
MN
exclude 
non-responders
Analysis 2
Supplementary
GLMM
MAR 
MAR
Analysis 2a
Supplementary
GLMM/TP
MNAR 
MNAR
Analysis 3
Supplementary
MN
non-responders 
non-responders
EMA and 
competent 
authorities 
in VHP 
countries
SALT ≤10 at 
Week 24/ 
primary
Analysis 4
Primary
GLMM
MAR
non-responders
Analysis 4a
Supplementary
GLMM/TP
MNAR
non-responders
Analysis 1
Supplementary
MN
exclude 
non-responders
Analysis 3
Supplementary
MN
non-responders
non-responders
PGI-C 
Response at 
Week 24/ 
key 
secondary
Analysis 4
Key Secondary
GLMM
MAR
non-responders
Abbreviations: GLMM = Generalized linear mixed model; MN = Miettinen and Nurminen; MAR = Missing at 
random; MNAR = Missing not at random; TP = Tipping point
5.2.1.1. Miettinen and Nurminen – Analysis 1 and Analysis 3
The Miettinen and Nurminen (MN) method will be used to calculate 95% confidence 
intervals (CI) and p-values for the difference in the proportion of responders between each 
active treatment group and placebo. Subjects with missing SALT score at Week 24 due to 
COVID-19 related reasons will be excluded from the analysis at that time point, whereas 
subjects with missing SALT scores due to other reasons will be counted as non-responders at 
that time point (Analysis 1). 
As a supplementary analysis to assess the impact of COVID-19-related missing data on the 
results of the primary analysis, a similar analysis will be conducted with all missing data 
considered as non-responders regardless of the reason for missingness (Analysis 3).


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5.2.1.2. Generalized Linear Mixed Model and Tipping Point – Analyses 2 and 2a
As a supplementary analysis, the primary endpoint for the overall study and for the 
FDA/PMDA will also be analyzed utilizing a generalized linear mixed model (GLMM) for 
longitudinal binary data of response based on SALT ≤20 over time up to Week 24. This 
binary outcome will be modeled using a logistic-normal distribution. Fixed factors in this 
model are treatment (6 levels), visit (5 levels) and treatment-by-visit interaction. Visit will be 
modeled as a categorical covariate. A subject-specific random intercept will be used to model 
the correlation within a subject over time. Due to the expected negligible placebo response, a 
Bayesian estimation will be carried out in which diffusive priors will be used and the placebo 
response probability will be bounded away from 0 to avoid the potential convergency issues. 
From this model, one can derive the estimates of the marginal probability of response for 
each treatment group at each visit as well as inferential comparisons (the proportional 
difference between active and placebo groups, CIs and p-values) between treatment groups 
after the random effect is integrated out from the posterior samples. Given that this random 
intercept model specifies the full joint distribution for the outcome, the inference for the 
marginal proportions will be valid in the presence of missing data when the missing 
mechanism is missing at random (MAR). This inference will be with respect to the difference 
in treatments assuming all subjects maintained their randomized therapy. This analysis will 
be referred to as Analysis 2.
A tipping point analysis will be conducted under the assumption of missing not at random 
(MNAR). The imputations will be implemented under the framework of the same logit 
normal GLMM as above. Imputation of missing SALT response is performed only at Week 
24 based on the predictive distribution of the GLMM. Under MNAR assumption, a fixed 
MNAR quantity (favorable or unfavorable), delta, will be applied to the probability of 
response at Week 24 for subjects with missing SALT response in the PF 06651600 dose 
groups and placebo group independently to assess when the conclusion might change (ie,
tipping). Imputations will be repeated to obtain completed datasets. The Rubin’s rules4,6 will 
be used to combine the results of multiple imputed samples for inference. This analysis will 
be referred to as Analysis 2a.
A scenario included in the tipping point analysis framework is an analysis under MAR, if 
there is no fixed quantity applied to the probability of response for each subject in the 
PF-06651600 dose groups or the placebo group, ie, when delta is zero.
Detailed descriptions of the tipping point analyses are provided in Section 9.6.
5.2.1.3. Generalized Linear Mixed Model and Tipping Point – Analyses 4 and 4a
The primary analysis of the primary endpoint for the EMA and competent authorities in the 
VHP countries will be based on a MAR assumption and use multiple imputation methods
similar to those described in Section 5.2.1.2. In this analysis, while subjects with missing 
SALT scores due to COVID-19 will be assumed to be MAR, subjects with missing SALT 
scores due to other reasons will be treated as non-responders. This analysis will be referred to 
as Analysis 4.


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A tipping point analysis will be conducted similar to that described in Section 5.2.1.2. While 
the analysis for the study and for the FDA/PMDA will treat missing as MNAR regardless of 
the reason for missingness, the analysis for the EMA will treat missing due to COVID-19 as 
MNAR but missing due to other reasons will be considered as non-responders. This analysis 
will be referred to as Analysis 4a.
The key secondary endpoint, PGI-C response at Week 24, will also be analyzed using this 
approach. 
5.2.1.4. Descriptive Analysis of Binary Endpoints
All secondary binary endpoints in the placebo-controlled phase will be analyzed in the same 
way as Analysis 1 in Section 5.2.1.1.
Exploratory binary endpoints will be summarized using descriptive statistics unless specified 
otherwise.
Summaries of data from baseline to Week 48 (over the entire study) will include number of 
responders, percent, standard error, 95% CI based on normal approximation. These 
summaries will be based on observed cases, and data will be presented by 7 treatment 
sequences (ie, without combining the placebo groups F and G, Figure 1).
5.2.2. Exposure response analysis 
A Bayesian three-parameter maximum effect attributable to the drug (Emax) exposure-
response model will be used as the primary analysis approach to characterize the dose-
response relationship. The response function will be the log odds (logit) of the proportion of 
subjects with response based on SALT ≤20 at Week 24 (or SALT ≤10 at Week 24, as 
applicable). In modeling the exposure response, the effect of loading dose will be included as 
a fixed factor in the model. Model-based estimation of the treatment effect for each dose 
compared to placebo will be presented.
5.2.2.1. Logistic regression analysis for the evaluation of effect of loading dose
The evaluation of the effect of loading versus no loading dose on the response at Week 24 
will be assessed by logistic regression applied to the data from the 30 mg and 50 mg 
maintenance doses, with and without the loading dose. Data from placebo and the 10 mg 
dose will not be included in this analysis. There will be a single indicator variable for loading 
(treatment during the first 24 weeks) versus no-loading dose, and a single indicator variable 
for the effect of the 30 mg versus 50 mg maintenance doses. If there is evidence of a loading 
dose effect, an Emax model as specified in Model 1 will be used. In this case, an additional 
term for the effect of loading dose is added to the Emax model.
Although an interaction effect large enough to produce a significant interaction would be 
surprising, a check for interaction will be conducted using a similar logistic regression 
model, which includes interaction terms between the loading and maintenance doses. If the 
interaction effect is significant, exploratory analyses and follow-up work will be needed, and 
Emax modeling will not be performed. No models will be pre-specified for this condition. 


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5.2.2.2. Emax models for exposure response analysis
a.
If the loading dose is significant in the logistic regression model in Section 5.2.2.1, then 
an indicator variable will be added representing the loading dose effect to the Emax model.
log ቀ
గ
ଵିగቁൌܧ଴൅
ா೘ೌೣ∗஽௢௦௘
ா஽ఱబା஽௢௦௘൅ߚܫሺ௟௢௔ௗ௜௡௚ሻ(Model 1)
b. If the effect of loading dose is not significant in the logistic regression model in Section 
5.2.2.1, the data with/without loading doses will be pooled for each maintenance dose 
and analyzed using the Emax model.5
ܔܗ܏ቀ
࣊
૚ି࣊ቁൌࡱ૙൅
ࡱ࢓ࢇ࢞∗ࡰ࢕࢙ࢋ
ࡱࡰ૞૙ାࡰ࢕࢙ࢋ(Model 2)
In either case, the results on the logistic scale of the Emax model will be back-transformed to 
the probability scale to improve interpretability and the posterior distribution for the 
difference on the proportion of SALT responders between the treatment groups determined 
by each dose and placebo will also be displayed.
5.2.2.3. Bayesian Estimation of Dose Response Models
The Bayesian estimation of the Emax model uses prior distributions on the placebo response 
(E0), the dose that produces half the maximal drug effect (ED50), Emax parameters, and the β 
loading dose parameter, if it is included. 
The specification of the Emax model and the prior distributions for some of its parameters are 
based on three meta-analyses of clinical dose response from more than 100 compounds.7,8,9
The Emax model specification is also supported by data from another compound with similar 
target biology, for which dose finding studies were performed in three indications.
We will use a t prior distribution for the logit of the placebo response centered at logit(0.05).
A prior scale parameter (analogous to the standard deviation) of 4.0 (logistic scale) will be 
used, which yields a diffuse prior distribution for the placebo response. A t prior distribution 
for the Emax parameter is used, which is also specified on the logistic scale. It is centered at 0.
This prior distribution will also be diffuse on the logistic scale with a prior scale parameter of 
4.0. If a loading dose effect is included, its t prior distribution will also be centered at 0 with 
a prior scale parameter of 4.0. Our current projected value for the ED50 is P50=30 mg. The 
prior distribution for the ED50 is derived from a t prior distribution for the normalized 
parameter, log(ED50/ P50). The t distribution for log(ED50/ P50) is centered at 0 with scale 
parameter, 1.73. This is the recommended distribution derived from the meta-analyses, and 
implemented in the R package, clinDR. It implies the ED50 is likely to be within 30-fold of its 
initial projected value (P50). The degrees of freedom (df) for each prior t-distribution is 5, 
also obtained from the meta-analyses of dose response data.
5.2.3. Continuous Endpoints
For continuous secondary endpoints up to Week 24, a mixed-effect model with repeated 
measures (MMRM) will be used. This model will include the factors (fixed effects) for 
treatment group, visit, treatment-by-visit interaction, and relevant baseline value when 


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modeling the change from baseline. Within the framework of MMRM, the treatment 
difference will be tested at each time point. Visit will be modeled as a categorical covariate.
Unstructured covariance matrix will be assumed for the model errors. 
When modeling the change from baseline values, the variable for visit will start with the first 
post-baseline visit, and the actual baseline value will be included as a covariate. At each visit, 
estimates of least square mean (LSM) values and the LSM differences between the 
PF-06651600-treated groups and the placebo group will be derived from the model. The 
corresponding p-values, standard errors and 95% CIs will also be derived from the model.
Estimates of the difference in LSMs along with the two-sided 95% CI will also be provided 
for the treatment groups versus placebo group for the initial 24 weeks.
Exploratory endpoints will be summarized using descriptive statistics unless specified 
otherwise.
The MMRM method described above will also be applied to the continuous data up to 
Week 48 (over the entire study) for initial active treatment groups. LSM, standard error and 
95% CI will be presented for each treatment group without treatment comparison.
Descriptive statistics based on the observed case data will also be provided from baseline to 
Week 48 by 7 treatment sequences (Figure 1), without combining two placebo groups, as 
supportive.
5.3. Methods to Manage Missing Data
In general, for analyses using descriptive statistics, missing values will not be imputed.
Missing values for exploratory endpoints will not be imputed unless specified otherwise. In 
addition, for safety endpoints, missing values will not be imputed. Other methods for 
handling missing values are discussed below.
5.3.1. Binary Endpoints
The same rule will be used for any missing data whether it is a missed visit, or it is a missing 
value due to early discontinuation. Depending on the analysis and the endpoint being 
analyzed, the following approaches will be used for managing missing data in binary 
endpoints:
a.
Subjects with missing SALT scores due to COVID-19 in a given visit will be excluded 
from the analysis at that timepoint, whereas subjects with missing SALT scores due to 
other reasons will be treated as non-responders at that timepoint (Analysis 1, Section 
5.2.1.1).
b. Subjects with missing SALT scores due to any reason in a given visit will be treated as 
non-responders at that timepoint (Analysis 3, Section 5.2.1.1).
c.
Imputation of missing SALT response at Week 24 is performed based on the predictive 
distribution of the GLMM under MAR (Analysis 2, Section 5.2.1.2).


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d. Imputation of missing SALT response at Week 24 is performed based on the predictive 
distribution of the GLMM under MNAR using tipping point analysis (Analysis 2a, 
Section 5.2.1.2).
e.
Imputation of missing SALT response is performed based on the predictive distribution 
of the GLMM under MAR for subjects with missing data due to COVID-19, whereas 
subjects with missing SALT scores due to other reasons will be treated as non-responders 
at that timepoint (Analysis 4, Section 5.2.1.3).
f.
Imputation of missing SALT response is performed based on the predictive distribution 
of the GLMM under MNAR using tipping point analysis for patients with missing data 
due to COVID-19, whereas subjects with missing SALT scores due to other reasons will 
be treated as non-responders at that timepoint (Analysis 4a, Section 5.2.1.3).
5.3.2. Continuous Endpoints
For continuous endpoints such as absolute SALT score or change from baseline in SALT 
score measured longitudinally, missing values post-baseline will not be imputed. For 
longitudinal continuous endpoints, assuming that the missing data mechanism is MAR, the 
data will be analyzed based on the full likelihood using a linear mixed-effect model with 
repeated measures for these continuous variables (see Section 5.2.3). This model will yield 
unbiased estimates and valid inferences in the presence of a missing data mechanism that is 
MAR.
For the continuous PRO variables such as AAPPO, HADS, EQ-5D-5L/EQ-5D-Y, SF-36v2, 
and WPAI:AA, rules suggested by Pfizer (for AAPPO) or the developers of these 
instruments will be followed in calculating the missing item-level and scale values. If these 
rules are not enough for imputing a value, then the missing values will be handled in the 
same way as efficacy variables.
6. ANALYSES AND SUMMARIES
Analysis will be done by testing the difference between each of the PF-06651600 QD-treated 
groups and placebo for the first 24 weeks. For the 25-48 week period, point estimates of the 
PF-06651600 QD-treated groups and the associated 95% CIs will be presented without 
testing any hypotheses.
Visit windows to be used for all efficacy analyses and some relevant safety analyses are 
detailed in Section 9.1.
The analyses of the primary endpoint(s) are described separately for the overall study and for 
specific regulatory regions in order to address differences in advice received from some 
regulatory agencies.
6.1. Primary Endpoints, Key Secondary and α-controlled Endpoints
Since this 
 supports submission in several regions with different 
regulatory requirements the analyses of some endpoints may overlap to support multiple 
regions with different designations. This section describes the analyses planned for endpoints 
CCI


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that are either primary, key secondary or -controlled endpoints for the overall study 
reporting or for at least one of the known regional regulatory requirement.
6.1.1. Response Based on SALT Score 20 at Week 24

Response based on SALT Score 20 at Week 24

Population: FAS

Statistical methods:

Analysis 1, Section 5.2.1.1 – this is the primary analysis and primary endpoint 
for the study and for the FDA/PMDA. This analysis will be repeated in the 
PPAS. This method will be also used for the analysis of earlier timepoints.

Analyses 2 and 2a, Section 5.2.1.2 – this is a supplementary analysis for the 
study and for the FDA/PMDA

Analysis 3, Section 5.2.1.1 – this is a supplementary analysis for the study, for 
the FDA/PMDA, and for the EMA and competent authorities in the VHP 
countries.

Analysis 4, Section 5.2.1.3 – this is an -controlled analysis for the EMA and 
competent authorities in the VHP countries. 
6.1.2. Response Based on SALT Score 10 at Week 24

Response based on SALT Score 0 at Week 24

Population: FAS

Statistical methods:

Analysis 4, Section 5.2.1.3– this is the primary analysis and primary endpoint 
for the EMA and competent authorities in the VHP countries. This analysis 
will be repeated in the PPAS. This method will be also used for the analysis of 
earlier timepoints. This analysis could also be considered as supplementary 
for the overall study.

Analysis 1, Section 5.2.1.1 – this is the key secondary endpoint for the study, 
and considered a supplementary analysis for the EMA and competent 
authorities in the VHP countries. For the FDA/PMDA this is an -controlled 
analysis. This analysis will be repeated in the PPAS.

Analysis 3, Section 5.2.1.1 – this is considered a supplementary analysis for 
the study and for the EMA and competent authorities in the VHP countries.


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
Analysis 4a, Section 5.2.1.3 – this analysis is supplementary for the EMA and 
competent authorities in the VHP countries.
6.1.3. PGI-C Response at Week 24

PGI-C response at Week 24

PGI-C response is defined as PGI-C score of “moderately improved” or “greatly 
improved” at Weeks 4, 8, 12, 18, 24, 34, 40, and 48. 

Population: FAS

Statistical methods:

Analysis 4, Section 5.2.1.3 – this is the key secondary endpoint for the EMA 
and competent authorities in the VHP countries. This analysis will be repeated 
in the PPAS. 

Section 6.2.9 describes other analysis that will be conducted for the PGI-C as 
a secondary endpoint the overall study and for the FDA/PMDA.
6.2. Secondary Endpoints
The analysis of binary secondary endpoints in the placebo-controlled phase will use the same 
approach in Analysis 1 (Section 5.2.1.1).
6.2.1. Exposure Response for Response Based on SALT Score 20 at Week 24

Response based on SALT Score 20 at Week 24.

Population: FAS.

Statistical Method: Bayesian three-parameter Emax model with the log odds (logit) of the 
probability of response based on SALT score ≤20 at Week 24 (Section 5.2.2).

Missing Data: Exclude missing due to COVID-19, consider missing due to other as non-
responders.
6.2.2. Exposure Response for Response Based on SALT Score 10 at Week 24

Response based on SALT Score 10 at Week 24.

Population: FAS.

Statistical Method: Bayesian three-parameter Emax model with the log odds (logit) of the 
probability of response based on SALT score ≤10 at Week 24 (Section 5.2.2).

Missing Data: Exclude missing due to COVID-19, consider missing due to other as non-
responders.


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6.2.3. Response Based on SALT Score 20 at all Visits

Response based on SALT Score 20 at all visits except Week 24.

Population: FAS.

Statistical Method: MN up to week 24. Descriptive method for entire duration.

Missing Data: Exclude missing due to COVID-19, consider missing due to other as non-
responders.
6.2.4. Response Based on SALT Score 10 at all Visits

Response based on an absolute SALT Score 10 at Weeks 4, 8, 12, 18, 24, 28, 34, 40, 
and 48.

Population: FAS.

Statistical Method: MN up to week 24. Descriptive method for entire duration.

Missing Data: Exclude missing due to COVID-19, consider missing due to other as 
non-responders.
6.2.5. 75% Improvement in SALT Score (SALT75)

Response based on a 75% improvement in SALT score from baseline (SALT75) at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Population: FAS.

Statistical Method: MN up to week 24. Descriptive method for entire duration

Missing Data: Exclude missing due to COVID-19, consider missing due to other as 
non-responders.
6.2.6. Change From Baseline in SALT Score 

Change from baseline in SALT scores at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Population: FAS.

Statistical Method: MMRM up to Week 24. MMRM for initial active treatment groups
for entire duration. Descriptive statistics for all treatment groups over the entire duration.

Missing Data: Handled in MMRM model. Observed Cases will be used for the 
descriptive analysis.


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6.2.7. Eyebrow Assessment Score

Response based on at least a 2-grade improvement or a normal EBA score at Weeks 4, 8, 
12, 18, 24, 28, 34, 40, and 48.

Population: FAS on the subset of subjects who do not have normal (score of 3 on the 
EBA) eyebrow at baseline.

Statistical Method: MN up to week 24. Descriptive method for entire duration.

Missing Data: Exclude missing due to COVID-19, consider missing due to other as 
non-responders.
6.2.8. Eyelash Assessment Score

Response based on at least a 2-grade improvement or a normal ELA score at Weeks 4, 8, 
12, 18, 24, 28, 34, 40, and 48.

Population: FAS on the subset of subjects who do not have normal (score of 3 on the 
ELA) eyelash at baseline.

Statistical Method: MN up to week 24. Descriptive method for entire duration.

Missing Data: Exclude missing due to COVID-19, consider missing due to other as 
non-responders.
6.2.9. PGI-C Response
The analysis of PGI-C as a key secondary endpoint for the EMA and competent authorities in 
the VHP countries was described in Section 6.1.3. This section describes the analysis of the 
PGI-C response at all timepoints as a secondary endpoint for the overall study and for the 
FDA/PMDA.

PGI-C response defined as PGI-C score of “moderately improved” or “greatly improved”
at Weeks 4, 8, 12, 18, 24, 34, 40, and 48. 

Population: FAS.

Statistical Methods: MN up to week 24. A descriptive summary of the distribution of 
subjects according to each category of PGI-C will be provided.

Missing Data: Exclude missing due to COVID-19, consider missing due to other as non-
responders.
6.2.10. Alopecia Areata Patient Priority Outcomes (AAPPO) Scale
AAPPO was measured at baseline, Weeks 4, 8, 12, 18, 24, 34, 40, and 48. Endpoints include:


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
Current hair loss on scalp, eyebrows, eyelash, and body hair (Items 1-4) for each 
individual item scored as 0=‘no hair loss’, 1=‘little hair loss’ and 
2-4=‘moderate-complete hair loss’.

Improvement on AAPPO items 1-4 among participants with a baseline score 
2-4 indicating moderate-complete hair loss who achieved a score of 0=‘no hair 
loss’ or 1=’little hair loss’.

Change from baseline in AAPPO Emotional Symptoms domain score, where 
Emotional Symptoms domain score is defined as mean of items 5-8.

Change from baseline in AAPPO Activity Limitations subscore, where Activity 
Limitations subscore is defined as mean of items 9-11.

Population: FAS.

Statistical Methods: 

MN for Proportion of patients with Improvement on Items 1-4. A descriptive 
summary of the distribution of subjects according to each category of AAPPO 
Items 1-4 will be provided.

MMRM for change from baseline in AAPPO Emotional Symptoms and Activity
Limitations up to week 24. MMRM for initial active treatment groups for entire 
duration. Descriptive statistics for all treatment groups over the entire duration.

Missing Data: Exclude missing due to COVID-19, consider missing due to other 
as non-responders. For change from baseline, missing values are handled in the 
MMRM model. Observed Cases will be used for the descriptive analysis.
6.3. Exploratory Endpoints
Exploratory binary endpoints will be summarized using descriptive statistics unless specified 
otherwise.
6.3.1. 50% Improvement in SALT Score (SALT50)

Response based on a 50% improvement in SALT score from baseline (SALT50) at 
Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Population: FAS.

Statistical Method: Descriptive statistics.

Missing Data: Observed Case.
6.3.2. Absolute SALT Score 

Absolute SALT scores at Baseline, Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.


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
Population: FAS.

Statistical Method: Descriptive statistics.

Missing Data: Observed Case.
6.3.3. Improvement on PGI-C 

Improvement on PGI-C defined as “slightly improved”, “moderately improved”, or 
“greatly improved” at Weeks 4, 8, 12, 18, 24, 34, 40, and 48.

Population: FAS.

Statistical Method: Descriptive statistics.

Missing Data: Observed Case.
6.3.4. Improvement on P-Sat

Improvement on each item of the P-Sat (ie, amount of hair, quality of new hair, and 
overall) defined as slightly, moderately, or very satisfied for each item at Weeks 4, 8, 
12, 18, 24, 34, 40, and 48.

Population: FAS.

Statistical Method: Descriptive statistics.

Missing Data: Observed Case.
6.3.5. Change From Baseline in the EQ-5D-5L/EQ-5D-Y

Change from baseline in EuroQoL 5 Dimensions (EQ-5D-5L) in adults or 
EuroQoL 5 Dimensions-Youth (EQ-5D-Y) in adolescents at Weeks 4, 12, 24, and 48. 

Population: FAS.

Statistical Method: Descriptive statistics for EQ-5D VAS score and Index Value for 
adults and adolescents separately. Counts and percent of patients in each category of 
for each of the 5 Dimensions, separately for adults and adolescents.

Missing Data: Observed Case.
6.3.6. Change From Baseline in the AARU Questions

Proportion of subjects with any HCP visits at Weeks 12, 24, 34, and 48. 

Among those with HCP visits, mean total number of visits for any reason, mean 
change from baseline in total number of visits for any reason, mean total number of 
visits related to AA and mean change from baseline in AA-related visits at Weeks 12, 
24, 34, and 48. 


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
Population: FAS.

Statistical Method: Descriptive Statistics.

Missing Data: Observed Case.
6.3.7. Change From Baseline in the WPAI:AA Items

Change from baseline in absenteeism (% work time missed due to AA), 
presenteesism (% impairment while working due to AA), work productivity loss 
(overall) due to AA and activity impairment due to AA at Weeks 12, 24, 34, and 48. 

Population: Adults in FAS.

Statistical Method: Descriptive Statistics.

Missing Data: Observed Case.
6.3.8. Change From Baseline in the Depression Subscale Score of HADS

Change from baseline in the depression subscale score of the HADS at Weeks 4, 8, 
12, 24, and 48. 

Population: FAS.

Statistical Method: MMRM up to week 24. MMRM for initial active treatment 
groups for entire duration. Descriptive statistics for all treatment groups over the 
entire duration.

Missing Data: handled in MMRM model. Observed Cases will be used for the 
descriptive analysis.
6.3.9. Change From Baseline in the Anxiety Subscale Score of HADS

Change from baseline in the anxiety subscale score of the HADS at Weeks 4, 8, 12, 
24, and 48. 

Population: FAS.

Statistical Method: MMRM up to week 24. MMRM for initial active treatment 
groups for entire duration. Descriptive statistics for all treatment groups over the 
entire duration.

Missing Data: handled in MMRM model. Observed Cases will be used for the 
descriptive analysis.


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6.3.10. Improvement on Depression Subscale of HADS

Improvement on HADS among subjects with a baseline subscale score indicative of 
depression who achieved a “normal” subscale score indicative of an absence of 
depression at Weeks 4, 8, 12, 24, and 48.

Population: Subjects from the FAS with a baseline subscale score indicative of 
depression (ie, depression subscale score >7 for adults, depression subscale score 
>6 for adolescents). 

Statistical Method: MN up to week 24. Descriptive method for entire duration.

Missing Data: Observed Case.
6.3.11. Improvement on Anxiety Subscale of HADS

Improvement on HADS among subjects with a baseline subscale score indicative of 
anxiety who achieved a “normal” subscale score indicative of an absence of anxiety 
at Weeks 4, 8, 12, 24, and 48.

Population: Subjects from the FAS with a baseline subscale score indicative of 
anxiety (ie, anxiety subscale score >7 for adults, anxiety subscale score >8 for 
adolescents).

Statistical Method: MN up to week 24. Descriptive method for entire duration.

Missing Data: Observed Case.
6.3.12. Change From Baseline in SF36v2 Acute

Change from baseline in the physical and mental component scores, and 8 domain 
scores of the SF36v2 Acute at Weeks 4, 8, 12, 24, and 48.

Population: FAS.

Statistical Method: Descriptive statistics.

Missing Data: Observed Case.
6.3.13. Change From Baseline in CGI-AA

CGI-AA scored as 0=‘None (no hair loss)’, 1=‘Minimal hair loss’, 
2-4=‘Moderate-very severe or complete hair loss’ at Weeks 4, 8, 12, 18, 24, 28, 34, 
40, and 48.

Improvement among participants with a baseline score 2-4 indicating moderate-very 
severe or complete hair loss, who achieved a score of 0=‘None (no hair loss)’ or 
1=‘Minimal hair loss’ at Weeks 4, 8, 12, 18, 24, 28, 34, 40, and 48.

Population: FAS.


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
Statistical Method: Descriptive statistics. 

Missing Data: Observed Case.
6.3.14. Change From Baseline in Number of Fingernails Affected by AA

Change from baseline in the number of fingernails affected by AA at Weeks 12, 24, 
34, 40, and 48.

Population: FAS: on the subset of subjects who have at least one affected fingernail at 
baseline.

Statistical Method: Descriptive statistics.

Missing Data: Observed Case.
6.3.15. Change From Baseline in IP-10

Change from baseline in IP-10 at Weeks 4, 8, 12, and 24. 

Population: FAS.

Statistical Method: Descriptive statistics.

Missing Data: Observed Case.
6.3.16. Change From Baseline in T-cell, B-cell, and NK Cells

Change from baseline in percent and absolute lymphocyte subsets (T-cell, B-cell, and 
natural killer [NK] cells) at Weeks 4, 12, 24, and 48. 

Population: FAS.

Statistical Methods: Descriptive statistics for absolute or percent change from 
baseline. Counts and percent of patients in each category of CTCAE grade.

Missing Data: Observed Case.
6.3.17. Change From Baseline in IgA, IgG, IgM

Change from baseline in immunoglobulins (IgA, IgG, IgM) at Weeks 24 and 48. 

Population: FAS.

Statistical Method: Descriptive statistics for change from baseline. Counts and 
percent of patients categories determined by clinical team.

Missing Data: Observed Case.


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6.4. PK Endpoints

Plasma concentrations of PF-06651600 at Weeks 4, and 8 or 12.

Population: PK analysis set.

Statistical Method: Descriptive statistics of plasma concentrations of PF-06651600 at 
Weeks 4, and 8 or 12. Population PK model detailed in a separate PK analysis plan.
6.5. Subset Analyses 
Summary statistics for SALT ≤20 at week 24, SALT ≤10 at week 24 and PGI-C response at 
Week 24 will be presented by subgroups as below:

Age (years) at baseline (12-17, ≥18);

Age (years) at baseline (12-17, 18-44, 45-64, ≥65);

Body Mass Index (BMI) group at baseline (25, 25-30, ≥30);

Weight at baseline (<median, ≥median);

Gender (Male, Female);

Race (White, Black, Asian, Other);

Region of enrollment (North America, Europe, Asia, Rest of World) as specified in
Section 9.4;

Baseline disease severity (AT/AU, non AT/AU);

AA duration since first diagnosis (years) (<median, ≥median);
o
The median of the entire sample will be used as the cut-off value.

Duration of onset of current AA episode (years) (<median, ≥median);
o
The median of the entire sample will be used as the cut-off value.

Prior pharmacological treatment of AA (yes, no); Section 9.7.
Estimates of the response rates for each dose compared to the placebo group and its 95% CI
based on MN method, will be presented for each defined category of each subgroup. No 
p-values will be presented. 
The primary purpose of the subgroup analyses is to check for consistency of results across 
subgroups. There is no intention to have any specific inference within subgroups. The 
analysis described in this SAP may be repeated on the specific country and/or region 
subpopulation sets in order to meet country-specific regulatory requirements. 


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6.6. Baseline and Other Summaries and Analyses
6.6.1. Baseline Summaries
Medical history will be summarized by treatment group using frequency and percentage of 
subjects for each medical condition according to Pfizer Standards. Demographics will be 
summarized by treatment group. Continuous demographics characteristics data, such as age 
will be summarized using descriptive statistics. Categorical data such as gender will be 
summarized using frequency and percentages.
Targeted medical history using the list in Section 9.5 will also be summarized.
6.6.2. Study Conduct and Subject Disposition
Subjects evaluation, disposition, discontinuation will be summarized according to Pfizer 
standards.
6.6.3. Study Treatment Exposure
A summary of compliance and the number of doses received as well as the median total dose 
by treatment group will be provided.
The exposure to study drug will be summarized by the total number of days of dosing.
6.6.4. Concomitant Medications and Non-Drug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer standards.
6.7. Safety Summaries and Analyses
Safety analysis will be based on the safety analysis set (SAS).
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate. All safety endpoints will be listed and summarized in 
accordance with Pfizer Standards. Categorical outcomes (eg, AEs) will be summarized by 
subject counts and percentage. Continuous outcome will be summarized using N, mean, 
median, standard deviation, etc. Selected subject listings will be produced for these safety 
endpoints accordingly.
In order to report the impact of COVID-19 on clinical trial populations and study data, the 
following additional listings and summaries will be produced:

Listing of subjects affected by COVID-19 related study disruption;

Protocol deviations related to COVID-19;

Summary of drug interruption before and after the COVID-19 pandemic anchor date 
(09 January 2020 for Taiwan/China sites, and 11 March 2020 for the remaining 
countries);


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
Discontinuations from study drug due to COVID-19 related AEs.
6.7.1. Adverse Events
The safety data will be summarized in accordance with Pfizer Standards. Adverse events of 
special interest will be summarized based on a list of preferred terms that will be provided by 
safety risk lead to the programming team prior to database lock. All safety data will be 
summarized descriptively through appropriate data tabulations, descriptive statistics, 
categorical summaries, and graphical presentations. Safety endpoints for the study include:

Treatment-emergent (including treatment-related) AEs and SAEs;

AEs leading to discontinuation;

AEs will be displayed for the following periods: Baseline to Week 24, and Baseline 
to Week 48;

Treatment-emergent COVID-19 related AEs by SOC and PT;

Summary of TEAE before and after the COVID-19 pandemic anchor date.
6.7.2. Laboratory Data
Laboratory data will be listed and summarized in accordance with the Pfizer reporting 
standards. Summaries of incidence of clinically significant abnormalities will include 
frequency and percentages. Laboratory data criteria for discontinuation and abnormalities can 
be found in Section 9.3. 
6.7.3. Vital Signs, including Height and Weight
Vital signs will be summarized at baseline and all post-baseline visits. The data will be listed 
and summarized in accordance with the Pfizer reporting standards. Summaries of incidence 
of clinically significant abnormalities will include frequency and percentages. 
Height and weight will be summarized at enrollment/baseline, Week 24, and Week 48.
6.7.4. Electrocardiogram
Abnormal ECG findings will be summarized.
6.7.5. Physical Examination
Physical examinations will be summarized at baseline and all-available post-baseline visits.
6.7.6. Hearing Examination
Audiometry will be performed at screening, Week 24, and Week 48 visits. Summaries of 
incidence of clinically significant worsening in hearing from screening, as assessed by the 
investigator following review of the audiometry reports, will be presented. 


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7. INTERIM ANALYSES
The study may be unblinded for Sponsor internal decision-making purposes when ≥90% of 
subjects have reached 24 weeks post-randomization (or discontinued prior to the Week 24 
visit), and dissemination of these results will be limited to the unblinded reporting team and 
Sponsor management. The sponsor personnel who are unblinded will be separate from the 
study team. The sponsor will still maintain the blind for study team members who will be 
involved in daily study conduct, study management, safety, and data monitoring through the 
completion of the study. Investigators and subjects will remain blinded. There will be no 
impact on B7981015 study conduct, analysis, or reporting.
This study will use an external data monitoring committee (E-DMC). 
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the charter.


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8. REFERENCES
1.
EQ5D country specific weights.
https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-standard-value-
sets/crosswalk-index-value-calculator/.
2.
Snaith RP, Zigmond AS. The Hospital Anxiety and Depression Scale with the 
Irritability-Depression-Anxiety Scale and the Leeds Situational Anxiety Scale Manual. 
GL Assessment, 1994.
3.
White et al. Validation of the Hospital Anxiety and Depression Scale for use with 
adolescents. Br J Psy, 1999; 175:452-54.
4.
Rubin, D. B. (1987) “Multiple Imputation for Nonresponse in Surveys.” (1st ed.) New 
York: Wiley. 
5.
Kallen A. (2007). PK/PD modelling (Chapter 6). Computational Pharmacokinetics. 
CRC. Boca Raton, Florida
6.
Rubin, D. B. (2004) “Multiple Imputation for Nonresponse in Surveys.” (2nd ed.) New 
York: Wiley Interscience.
7.
Thomas N, Sweeney K, Somayaji V. (2014) Meta-analysis of clinical dose response in a 
large drug development portfolio. Statistics in Biopharmaceutical Research. 6(4):302-
17.
8.
Thomas N, Roy D (2017) Analysis of clinical dose-response in small-molecule drug 
development: 2009-2014. Statistics in Biopharmaceutical Research. 9(2):137-46.
9.
Wu J, Banerjee A, Jin B et al.(2018) Clinical dose-response for a broad set of 
biological products: A model-based meta-analysis. Stat Methods in Med Res. 
27(9):2694 721.
10.
Cassella J, Hamilton C, von Hehn J, Braman V. CTP-543, an Oral JAK Inhibitor, 
Achieves Primary Endpoint in Phase 2 Randomized, Placebo-Controlled Dose-Ranging 
Trial in Patients with Moderate-to-Severe Alopecia Areata [Conference presentation]. 
In: 28th European Academy of Dermatology and Venereology (EADV) Annual 
Congress; 2019 Oct 9-13, Madrid, Spain. https://www.concertpharma.com/wp-
content/uploads/2019/10/EADV-Late-Breaker-CTP543-Presentation-FINAL-
12OCT2019.pdf 


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9. APPENDICES 
9.1. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy and PRO variables, and for any safety data that 
display or summarize by study visit.
Table 6.
Visit Windows
Visit Label
Target Day
Definition 
Baseline
1
<=Day 1
Week 2
15
Days 2 to 21
Week 4
29
Days 22 to 42
Week 8
57
Days 43 to 70
Week 12
85
Days 71 to 105
Week 18
127
Days 106 to 147
Week 24
169
Day 148 to 179 and <=EDaya 1
Week 26
183
Days 180 to 189 and >EDay 1
Week 28
197
Days 190 to 217 and >EDay 1
Week 34
239
Days 218 to 259 and >EDay 1
Week 40
281
Days 260 to 308 and >EDay 1
Week 48
337
≥Day 309 and >EDay 1
a.
EDay =relative day of the first dose date in the extension phase based on dosing log data 
after week 24 visit. If Week 24 dose log is missing, earliest dosing date from Week 26 and 
onward will be considered start of Extension.
The Baseline value is defined in Section 3.3.
Some endpoints were not scheduled to be assessed at each visit. In this case, the unscheduled 
‘windowed’ visit will be moved to the next scheduled windowed visit for analysis and 
reporting. For example, HADS were not to be assessed at Week 18, Week 28, Week 34 and
Week 40, if data falls under Week 18 it will be treated as Week 24; and data that falls under 
Weeks 28, 34, 40 will be treated as Week 48. 
If more than one observation falls within a visit window, the observation that is the closest to 
the targeted day will be used for the summary tables. If two visits are equally distant from the 
target day, the data from the later visit will be used.


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9.2. Details on Selected PRO Endpoints
AAPPO 
The AAPPO is a 11-item scale. Items 1-4 are an assessment of current hair loss, eyebrow 
loss, eyelash loss and body hair loss and will be as such analyzed separately on a scale of 0-4,
with 0 =‘no hair loss’ and 4=‘complete hair loss’. Items 5-8 are an assessment of emotional 
symptoms. Response choices on these items are scored from 0 =‘never’ to 4=‘always’. Items 
9-11 are an assessment of activity limitations. Response choices on these items are scored 
from 0=‘not at all’ to 4= ‘completely’. 

AAPPO Items 1 through 4 are scored separately as 0=‘no hair loss’, 1=‘little hair 
loss’ and 2-4=‘moderate-complete hair loss’.

Improvement on AAPPO items (1-4) among participants with a baseline score 2-4,
indicating moderate-complete hair loss who achieved a score of 0=‘no hair loss’ or 
1=‘little hair loss’.

Emotional Symptoms: Mean of Items 5, 6, 7, 8 (missing rule: requires at least 
2 non-missing responses; otherwise missing).

Activity Limitations: Mean of Items 9, 10, 11 (missing rule: requires at least 
2 non-missing responses; otherwise missing).
AARU:

Assessment of total in-person and remote healthcare visits.

Assessment of AA-related in-person and remote healthcare visits.

Assessment of utilization of hair prostheses or camouflaging agents.

Assessment of # of days hair prostheses or camouflaging agents were utilized.

Percentage of patients not currently employed.

Percentage of patients who have not sought employment due to alopecia areata.

Number of opportunities for employment not sought due to alopecia areata.
WPAI –AA:
WPAI-AA is an adaptation of the WPAI:SHP (Specific Health Problem) version. Outcomes 
from this scale are expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity. The questionnaire is scored as follows:
Questions:

1 = currently employed.


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
2 = hours missed due to specified problem.

3 = hours missed other reasons.

4 = hours actually worked.

5 = degree problem affected productivity while working.

6 = degree problem affected regular activities.
Scoring.

Multiply scores by 100 to express in percentages.

Percent work time missed due to problem (Absenteeism): Q2/(Q2+Q4).

Percent impairment while working due to problem (Presenteeism): Q5/10.

Percent overall work impairment due to problem (Overall Work Impairment):
Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4)))x(Q5/10)].

Percent activity impairment due to problem (Activity Impairment): Q6/10.


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9.3. Laboratory Data Criteria for Discontinuation and Abnormalities 
Labs Meeting Discontinuation Criteria, as per Appendix 3.2 of the protocol
Table 7.
Laboratory Values Meeting Discontinuation Criteria
Criterion #1
Criterion #2
Hematology
Hemoglobin 
<90 g/L or a decrease 
of >30% from baseline
n/a
Platelets
<75 × 10^9/L
n/a
Lymphocytes (ABSOLUTE)
<0.5 × 10^9/L
n/a
Neutrophils (ABSOLUTE)
<0.75 × 10^9/L
n/a
Chemistry
Aspartate Aminotransferase
>3× ULN W/Bilirubin 
>2× ULN
Two Sequential 
Elevations >5× ULN
Alanine Aminotransferase
>3× ULN W/Bilirubin 
>2× ULN
Two Sequential 
Elevations >5× ULN
Creatine Kinase
>10× ULN
Lab Test Abnormalities
Table 8.
Laboratory Test Abnormalities
Lower Limit
Upper Limit
Hematology
Hemoglobin
<0.8× LLN
n/a
Hematocrit
<0.8× LLN
n/a
Red Blood Cell Count
<0.8× LLN
n/a
MCV
<0.9× LLN
>1.1× ULN
MCH
<0.9× LLN
>1.1× ULN
MCHC
<0.9× LLN
>1.1× ULN
Platelets
<0.5× LLN
>1.75× ULN
White Blood Cell Count
<0.6× LLN
>1.5× ULN
Reticulocytes
<0.5× LLN
>1.5× ULN
Reticulocytes/Erythrocytes
<0.5× LLN
>1.5× ULN
Leukocytes
<0.6× LLN
>1.5× ULN
Lymphocytes (ABSOLUTE)
<0.8× LLN
>1.2× ULN
Lymphocytes/Leukocytes
<0.8× LLN
>1.2× ULN
Neutrophils (ABSOLUTE)
<0.8× LLN
>1.2× ULN
Neutrophils/Leukocytes
<0.8× LLN
>1.2× ULN
Basophils/Leukocytes
n/a
>1.2× ULN 
Eosinophils
n/a
>1.2× ULN
Eosinophils/Leukocytes
n/a
>1.2× ULN
Monocytes
n/a
>1.2× ULN
Monocytes/Leukocytes
n/a
>1.2× ULN
Prothrombin Time
n/a
>1.1× ULN
Basophils
n/a
>1.2× ULN


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Table 8.
Laboratory Test Abnormalities
Lower Limit
Upper Limit
Prothrombin Intl. Normalized 
Ratio
n/a
>1.1× ULN
Chemistry
Blood Urea Nitrogen
n/a
>1.3× ULN
Urea
n/a
>1.3× ULN
Creatinine
n/a
>1.3× ULN
Glucose
<0.6× LLN
>1.5× ULN
Calcium
<0.9× LLN
>1.1× ULN
Sodium
<0.95× LLN
>1.05× ULN
Potassium
<0.9× LLN
>1.1× ULN
Chloride
<0.9× LLN
>1.1× ULN
Bicarbonate
<0.9× LLN
>1.1× ULN
Aspartate Aminotransferase
n/a
>3.0× ULN
Alanine Aminotransferase
n/a
>3.0× ULN
Bilirubin
n/a
>1.5× ULN
Direct Bilirubin
n/a
>1.5× ULN
Indirect Bilirubin
n/a
>1.5× ULN
Alkaline Phosphatase
n/a
>3.0× ULN
Uric Acid
n/a
>1.2× ULN
Albumin
<0.8× LLN
>1.2× ULN
Creatine Kinase
n/a
>2.0× ULN
Cholesterol
n/a
>1.3× ULN
HDL Cholesterol
<0.8× LLN
n/a
LDL Cholesterol
n/a
>1.2× ULN
Triglycerides
n/a
>1.3× ULN
Protein
<0.8× LLN
>1.2× ULN
Gamma Glutamyl Transferase
n/a
>3.0× ULN
Urinalysis
pH (Scalar)
<4.5
>8
Glucose (Scalar)
n/a
≥1
Ketones (Scalar)
n/a
≥1
Protein (Scalar)
n/a
≥1
Hemoglobin (No Unit)
n/a
≥1
Nitrite (No Unit)
n/a
≥1
Leukocyte Esterase (No Unit)
n/a
≥
Urobilinogen
n/a
≥1
Erythrocytes (Scalar)
n/a
≥20
Leukocytes (Scalar)
n/a
≥20
Epithelial Cells (Scalar)
n/a
≥6
Granular Casts (Scalar)
n/a
>1
Hyaline Casts (Scalar)
n/a
>1
Bacteria (No Unit)
n/a
>20


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9.4. List of Countries by Region
Table 9.
Countries by Region
Region 
Countries
North America
Canada, United States
Europe
Czech Republic, Germany, Hungary, Poland, Russia, Spain, United Kingdom
Asia
China, Japan, South Korea, Taiwan
Rest of World
Australia, Argentina, Chile, Colombia, Mexico
9.5. List of Targeted Medical History Terms
Table 10.
Targeted Medical History Terms
Term
PT
Atopic dermatitis
DERMATITIS ATOPIC
Diabetes mellitus Type I
TYPE 1 DIABETES MELLITUS
Crohn’s disease
CROHN'S DISEASE
Ulcerative colitis
COLITIS ULCERATIVE
Systemic lupus 
erythematosus
SYSTEMIC LUPUS 
ERYTHEMATOSUS
Sjogren's syndrome
SJOGREN'S SYNDROME
Rheumatoid arthritis
RHEUMATOID ARTHRITIS
Psoriatic arthritis
PSORIATIC ARTHROPATHY
Psoriasis
PSORIASIS
Vitiligo
VITILIGO
Hashimoto’s thyroiditis
AUTOIMMUNE THYROIDITIS
Graves' disease
BASEDOW'S DISEASE
9.6. Tipping Point Analysis for Binary Data 
The primary endpoint for the study and for the FDA/PMDA is response based on SALT ≤20 
(a binary endpoint) at Week 24; for the EMA and competent authorities in the VHP countries 
the primary endpoint is response based on SALT ≤10 at Week 24. This tipping point analysis 
will be conducted for both endpoints, with a subtle difference: while the analysis for the 
study and for the FDA/PMDA will treat missing as MNAR regardless of the reason for 
missingness, the analysis for the EMA will treat missing due to COVID-19 as MNAR but 
missing due to other reasons will be considered as non-responders. 
Treatment comparisons are performed for each PF-06651600 dose group versus placebo. 
These binary endpoints are also assessed at post-baseline visits of Weeks 4, 8, 12, and 18. 
And are coded as a numeric variable with values of 1 if SALT score is ≤20 or 0 if SALT 
score is 20. When there is insufficient information to evaluate the endpoint at a visit 
(eg, due to discontinuation of study participation or other reasons), they will be coded as 


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missing at that visit. Tipping point analysis is used to evaluate the impact of these missing 
values on the trial conclusion based on the primary endpoints. Since the focus is on the 
Week 24 visit, this analysis will use longitudinal data of these endpoints from Week 4 up to 
Week 24 only (5 post-baseline visits) without imputation of the missing responses. Data of 
visits after Week 24 will not be included in these analyses.
A SAS macro “alopbinarytippingV2.sas” (Version 2) is developed to fit the purpose of 
implementing the tipping point analysis for this study. Longitudinal data of the endpoints are 
imported into the macro. 
The prior density specified for the baseline logit is Normal(-1.7, sd=3) and those for all other 
logit effect parameters are Normal(0, sd=1). This gives the prior median and mean of 15% 
and 32% respectively for the probability of response (SALT ≤20) for the placebo group at the 
post-baseline visits. The prior density for variance of random effects is Inverse-
Gamma(shape=1, scale=1). In this prior, the prior 90th percentile for 2 is approximately 9.
The following values will be specified for the implementation of the analyses for each of the 
active treatment and placebo groups.

Active treatment group: deltat = -0.5, -0.3, -0.1, 0, 0.1, 0.3, 0.5 (7 of them)

Placebo group: deltac = -0.9, -0.7, -0.5, -0.3, -0.1, 0 (6 of them)
Since the delta value is subtracted from the MAR probability, a negative delta value means
favoring the probability; a positive delta value means penalizing the probability; and a 0 
value means the same MAR probability. The values of these sensitivity parameters (deltat, 
deltac) may be adjusted if needed.
The number of imputations/imputed datasets per combination of sensitivity parameters for 
the tipping point analysis will be at least 100.
The seeds used for tipping point analysis are defined below:
Endpoint
Seed for MCMC
(seed4mcmc)
Seed for imputation
(seed4imp)
Response based on SALT ≤20
3355
6688
Response based on SALT ≤10 
1286
9276
PGI-C Response
4562
1520


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9.7. Prior Pharmacological Treatments for AA – Definition of Subgroups
The following categories of medications for AA were identified by the Sponsor as relevant 
for the determination of the subgroup ‘Prior Pharmacological Treatment for AA’ in Section 
6.5. A list of medications in each of these categories will be reviewed by the clinical team 
before the study is unblinded.

Biologics 

Intralesional corticosteroid injection

Intralesional minoxidil

Oral anti-inflammatory

Oral immunosuppressant

Oral vasodilator

Oral/IV/IM Steroids

Other (non-oral) systemic immunosuppressant

Other immunotherapy

Other topical anti-inflammatory

Subcutaneous immunotherapy

Topical anthralin/dithranol

Topical corticosteroid

Topical immunotherapy

Topical JAK

Topical vasodilators

Unknown steroid

Unknown methotrexate

Unknown minoxidil