Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc
Investigational Product: CP-690,550 (Tofacitinib)
Clinical Study Report Synopsis: Protocol A3921139
Protocol Title: A Multi-Center, Open-Label Study of CP-690,550 in Participants With
Moderate to Severe Ulcerative Colitis
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Center(s): A total of 298 sites randomized participants from the following countries:
Australia (8), Austria (3), Belgium (4), Brazil (2), Canada (7), Colombia (3), Croatia (5),Czech Republic (5), Denmark (5), Estonia (5), France (9), Germany (9), Hungary (16), Israel(5), Italy (4), Japan (27), Republic of Korea (9), Latvia (3), Netherlands (5), New Zealand(7), Poland (13), Romania (8), Russian Federation (11), Serbia (8), Slovakia (8), South
Africa (7), Spain (6), Taiwan (1), Ukraine (14), United Kingdom (5), and the United States(76). Refer to Appendix 16.1.4.1 for a list of sites involved in this study.
Publications Based on the Study:
Sandborn WJ, Panés J, D’Haens GR, et al. Safety of tofacitinib for treatment of ulcerative
colitis, based on 4.4 years of data from global clinical trials. Clin Gastroenterol Hepatol
2019; 17(8):1541-50.
Sands BE, Armuzzi A, Marshall JK, et al. Efficacy and safety of tofacitinib dose deescalation and dose escalation for patients with ulcerative colitis: results from OCTAVE
open. Aliment Pharmacol Ther 2020; 51(2):271-80.
Study Initiation Date: 01 October 2012
Study Completion Date: 06 August 2020
Report Date: 16 March 2021
Previous Report Date(s): 20 December 2016
Phase of Development: Phase 3

Page 1

Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Primary and Secondary Study Objectives and Endpoints:
Table S1.

Study Objectives and Endpoints

Type
Primary
SafetyObjective(s)To assess the safety andtolerability of long-term tofacitinib
therapy in participants withulcerative colitis (UC).

Endpoints

Incidence and severity ofadverse events (AEs).



Incidence of serious infections.



Incidence and severity of clinicallaboratory abnormalities andchange from baseline in clinicallaboratory values.



Incidence of vital signabnormalities and change frombaseline in vital signs.

Secondary
Efficacy

To evaluate the efficacy of longterm tofacitinib therapy inparticipants with UC.

Incidence of clinically significant
changes in physical examinations
from baseline.

Incidence of electrocardiogram(ECG) abnormalities during
study intervention.



Summary of adjudicated safety
events (eg, cardiovascular,
malignancy, opportunistic
infections).

Proportion of participants withaddition of lipid lowering agents.



The proportion of participants inremission at Month 2, Month 12,
Month 24, and Month 36.
Remission in this study isdefined as a Mayo score ≤2 withno individual subscore >1, andrectal bleeding subscore of 0.



The proportion of participants inclinical remission at Month 2,

To evaluate the effect of long-term
tofacitinib therapy on quality oflife in participants with UC.

Page 2Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Table S1.

Study Objectives and Endpoints

Type

Objective(s)Endpoints
Month 12, Month 24 and Month
36. Clinical remission in thisstudy is defined as a Mayo score≤2 with no individual subscore>1.
The proportion of participants in
PMS (partial Mayo score)
remission over time. PMS
remission in this study is defined
as a partial Mayo score ≤2 withno individual subscore >1.



The proportion of participants
who achieve mucosal healing at
Month 2, Month 12, Month 24
and Month 36. Mucosal healing
is defined as a Mayo endoscopic

subscore of 0 or 1.


The proportion of participants
with total score in the
Inflammatory Bowel Disease
Questionnaire (IBDQ) ≥170 over
time.



PMS and change from baseline(of Study A3921139) over time.

Total Mayo score and change
from Baseline (of Study
A3921139) at Month 2,
Month 12, Month 24 andMonth 36.

The absolute scores and change
from baseline (of Study
A3921139) in total IBDQ scoreand domains (Bowel Symptoms,
Systemic Symptoms, Emotional
Function and Social Function)over time.

Exploratory

Page 3Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Table S1.

Study Objectives and Endpoints

Type

Objective(s)Page 4

Endpoints
The absolute scores and change
from baseline (of Study
A3921139) in Short Form 36(SF-36), version 2, acute(physical and mental component
summary scores, and 8 domainscores) over time throughMonth 33.

The scores and change frombaseline (of Study A3921139) in
EQ-5D/VAS over time.

The scores and change frombaseline (of Study A3921139) inthe Work Productivity andActivity Impairment (WPAI)
questionnaire domains(Absenteeism, Presenteeism,
Work Productivity Loss, Activity
Impairment) over time throughMonth 33.

The proportion of subjects who
utilize the healthcare services andthe frequency of utilization ofsuch services specified in the
Ulcerative Colitis Healthcare
Resource Utilization
Questionnaire-All(UC-HCRU-All) over time.

The number and length of
UC-related hospitalizations.



The proportion of subjects
requiring colectomy for UC or
UC-related complications.



Summary of absolute counts andchange from baseline in thefollowing lymphocyte subsets:
CD4+ T cells, CD8+ T cells, B
cells, and natural killer (NK)Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Table S1.

Study Objectives and Endpoints

Type

Objective(s)Endpoints
cells (United Kingdom (UK)only).

METHODS
Study Design: This was a Phase 3, multi-center, open-label study in participants whocompleted or demonstrated treatment failure in the maintenance study A3921096, or who
were non-responders after completing induction studies A3921094 or A3921095. Individual
participant duration of participation varied depending on when the participant was enrolled
into the study and the first market approval.
Eligible participants were assigned to either tofacitinib 5 mg twice daily (BID) or 10 mg BID
depending on whether the participant was in remission at baseline of Study A3921139.
Eligible participants who were in remission at Week 52 of Study A3921096 were assigned toreceive tofacitinib 5 mg BID and comprised the maintenance remission subpopulation.
Participants who completed Study A3921096 but did not meet the remission definition or
who were early withdrawals due to treatment failure in Study A3921096 were eligible toreceive tofacitinib 10 mg BID and comprised the maintenance treatment failures and othermaintenance completers subpopulations. Participants who completed induction studies
A3921094 or A3921095 and were classified as non-responders were also eligible to receive
tofacitinib 10 mg BID and comprised the induction non-responders subpopulation.
The maintenance remission subpopulation was defined as participants who completed themaintenance Study A3921096 in remission. Remission was defined by a total Mayo score ≤2 with no individual subscore >1, and rectal bleeding subscore of 0.
The maintenance treatment failures subpopulation was defined as those participants who
were treatment failures or dropped out due to lack of efficacy from maintenance Study
A3921096 and received tofacitinib 10 mg BID or placebo from induction Study A3921094 or
A3921095.
The other maintenance completers subpopulation was defined as all other completed
participants from maintenance Study A3921096; that is, those participants who were neither
in remission nor fulfilled the definition of treatment failure.
The induction non-responder subpopulation was defined as participants who were enrolledfrom induction Study A3921094 or A3921095 directly, but did not achieve clinical response
and received tofacitinib 10 mg BID or placebo in the induction studies.
Participants from the induction studies A3921094 or A3921095 (ie, non-responders) who
failed to demonstrate clinical response at Month 2 of this study were withdrawn from thePage 5Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
study. Clinical response was defined by a decrease from the induction study baseline(A3921094 or A3921095) Mayo score of at least 3 points and at least 30%, with anaccompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal
bleeding subscore of 0 or 1. The endoscopic subscore based on central reading was used toassess clinical response.
The maximum tofacitinib dose allowed in this study was 10 mg BID. Dose adjustments only
occurred after a participant had received at least 8 weeks of treatment in Study A3921139.
Tofacitinib dose was adjusted from 5 mg BID to 10 mg BID for efficacy and from10 mg BID to 5 mg BID after meeting specific laboratory abnormalities or other protocol
defined criteria regarding efficacy. If a participant who received tofacitinib 5 mg BID
experienced loss of response, then the participant should have been scheduled for endoscopy
to determine if the participant experienced a flare.
In addition, participants were evaluated for pulmonary embolism (PE) risk factors. If aparticipant had a risk factor and was receiving 10 mg BID, the participant was required tohave their dose reduced to 5 mg BID. Participants who were receiving tofacitinib 5 mg BID
and who developed one or more of the risk factors for PE during the study were notpermitted to increase their dose to tofacitinib 10 mg BID.
A schematic of the study design is shown in Figure S1.
Figure S1. Study Design

Page 6

Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Diagnosis and Main Criteria for Inclusion:
Key Inclusion Criteria were as follows:
1. Participants who previously participated in Study A3921096 who either:

completed 52-week maintenance treatment in Study A3921096, or

were early withdrawals from Study A3921096 and met treatment failure criteria
defined by an increase in Mayo score of at least 3 points from baseline value ofthe maintenance study (A3921096), accompanied by an increase in rectal
bleeding subscore by at least 1 point, and an increase of endoscopic subscore of atleast 1 point (yielding an absolute endoscopic subscore of ≥2), after a minimum of
8 weeks of treatment in the maintenance study. In the scenario where theendoscopic subscore was a ‘3’, and the maintenance baseline endoscopic subscore
was already a ‘3’ (maximum value), then an increase by at least 1 point was notneeded in order to meet treatment failure. However, all other components of thetreatment failure criteria still needed to be met. NOTE: endoscopic subscoresbased on central reading were used to assess treatment failure.

2. Participants who previously participated in the induction Study A3921094 or A3921095
who:

did not demonstrate clinical response after completing 8 weeks of study
intervention. Clinical response was defined by a decrease from baseline in Mayoscore of at least 3 points and at least 30%, with an accompanying decrease in therectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscoreof 0 or 1, and

had an endoscopic subscore at Week 8 that was either the same or higher (worse)
than the endoscopic subscore at Week 0 of Study A3921094 or A3921095.
NOTE: endoscopic subscores based on central reading were used to determine
eligibility.

Study Treatment: Tofacitinib was self-administered at 5 or 10 mg BID. Details of thestudy intervention used are shown in Table S2.

Page 7

Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Table S2. Study Intervention Description
Study Intervention
Description

Vendor Lot
Number

Pfizer Lot Number

Strength/Potency

Dosage Form

CP-690,550-10 5 mg
Immediate Release
Filmcoated Tablet

9634233017

11-009938

5 mg

TabletCP-690,550-10 5 mg,
Film-Coated Tablet,
Commercial Image

H9027314-000544

5 mg

TabletCP-690,550-10 5 mg,
Film-Coated Tablet,
Commercial Image

L73080

15-005244

5 mg

TabletCP-690,550-10 5 mg,
Film-Coated Tablet,
Commercial Image

H15758

13-110032

5 mg

TabletCP-690,550-10 5 mg,
Film-Coated Tablet,
Commercial Image

H000005938/
H1462113-108395

5 mg

TabletCP-690,550-10 5 mg
Immediate Release
Filmcoated Tablet

9634233025

12-005920

5 mg

TabletCP-690,550-10 5 mg,
Film-Coated Tablet,
Commercial Image

R3683716-003831

5 mg

TabletCP-690,550-10 5 mg,
Film-Coated Tablet,
Commercial Image

W2088717-00321

5 mg

TabletCP-690,550-10 5 mg,
Film-Coated Tablet,
Commercial Image

H9027414-000545

5 mg

TabletPrimary Efficacy Evaluations: As this was an open-label extension study, there were no
primary efficacy endpoints. The primary analysis was safety.

Page 8Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Secondary Efficacy Evaluations:

The proportion of participants in remission at Month 2, Month 12, Month 24, and Month
36. Remission in this study was defined as a Mayo score ≤2 with no individual subscore>1, and rectal bleeding subscore of 0.



The proportion of participants in clinical remission at Month 2, Month 12, Month 24 andMonth 36. Clinical remission in this study was defined as a Mayo score ≤2 with noindividual subscore >1.



The proportion of participants in PMS remission over time. PMS remission in this study
was defined as a partial Mayo score ≤2 with no individual subscore >1.



The proportion of participants who achieved mucosal healing at Month 2, Month 12,
Month 24 and Month 36. Mucosal healing was defined as a Mayo endoscopic subscore of
0 or 1.

The proportion of participants with total score in IBDQ ≥170 through Month 84.
Exploratory Efficacy Evaluations:

PMS and change from baseline (of Study A3921139) over time.

Total Mayo score and change from baseline (of Study A3921139) at Month 2, Month 12,
Month 24, and Month 36.

The absolute scores and change from baseline (of Study A3921139) in total IBDQ scoreand domains (Bowel Symptoms, Systemic Symptoms, Emotional Function, and Social
Function) over time.

The absolute scores and change from baseline (of Study A3921139) in SF-36, version 2,
acute (physical and mental component summary scores, and 8 domain scores) over timethrough Month 33.

The scores and change from baseline (of Study A3921139) in EQ-5D/VAS over time.

The scores and change from baseline (of Study A3921139) in the WPAI questionnairedomains (Absenteeism, Presenteeism, Work Productivity Loss, and Activity Impairment)over time through Month 33.

The proportion of participants who utilize the healthcare services and the frequency ofutilization of such services specified in the UC-HCRQ-All over time.

The number and length of UC-related hospitalizations.

Page 9Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSISThe proportion of participants requiring colectomy for UC or UC-related complications.



Summary of absolute counts and change from baseline in the following lymphocyte
subsets: CD4+ T cells, CD8+ T cells, B cells, and natural killer (NK) cells (United
Kingdom [UK] only).

Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and/or Other Evaluations:
No pharmacokinetic, pharmacodynamic, or pharmacogenomic evaluations were performed inthis study.
Safety Evaluations: Safety was assessed by vital signs (blood pressure, pulse rate, andtemperature), physical examinations, ECGs, clinical laboratory tests, incidence of serious
infections, summary of adjudicated safety events (eg, cardiovascular, malignancy,
opportunistic infections), and the spontaneous reporting of AEs, in all participants who
received at least 1 dose of study drug.
Statistical Methods:
Efficacy Endpoints
Efficacy endpoints were based upon the Mayo score and partial Mayo score. All efficacy
endpoints were considered as secondary or exploratory. Descriptive summary statistics werereported at scheduled visits in the full analysis set (FAS), and in subpopulations of the FAS:
maintenance remission, maintenance treatment failures, other maintenance completers, andinduction non-responders subpopulations. However, the endpoints of proportion ofparticipants with dose increase from tofacitinib 5 mg BID to 10 mg BID were summarized
for the maintenance remission subpopulation only.
For FAS or each subpopulation, the data were summarized as in Table S3.
Table S3. Statistical Summaries for Efficacy Endpoints
Efficacy Analysis
Population/Subpopulation
FAS
Maintenance Remission
subpopulation
Maintenance Treatment Failure
subpopulation

Treatment group (the default isthe assigned dose for initialassignment in A3921139)
OverallTofacitinib 5 mg BID
Tofacitinib 10 mg BID
Tofacitinib 5 mg BID

Tofacitinib 10 mg BID

Page 10

By group
Overall
Overall
By maintenance treatment (4groups: 10 mg, 5 mg, placebo,
5mg+10mg)
Overall
By dose combination received in
induction and maintenance (6groups) and a 7th group ofFinal Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Table S3. Statistical Summaries for Efficacy Endpoints
Efficacy Analysis
Population/Subpopulation

Treatment group (the default isthe assigned dose for initialassignment in A3921139)

Other Maintenance Completers
subpopulation

Tofacitinib 10 mg BID

Induction Non-responder
subpopulation

Tofacitinib 10 mg BID

By group
Tofacitinib 10 mg in induction
and Tofacitinib 5 mg + placebo
in maintenance
Overall
By maintenance treatment (4groups: tofacitinib 10 mg,
Tofacitinib 5 mg, placebo,
Tofacitinib 10 mg and 5 mg
combined)
Overall
By Induction treatment(Tofacitinib 10 mg, Placebo)

In addition, subgroup summaries of prior tumor necrosis factor (TNF) failure and prior TNF
exposure were provided for the 4 subpopulations of the FAS.
PRO Endpoints
Descriptive summary statistics were reported at scheduled visits for the FAS, and for the four
subpopulations of the FAS (maintenance remission, maintenance failure, other maintenancecompleters, and induction non-responders) using the same methods as for the efficacy
endpoints for IBDQ, EQ-5D/VAS, and SF-36.
Descriptive summary statistics were reported in the FAS for the WPAI-UC; the UC-HCRU
was based on observed-case data only.
Frequencies and percentages of missing data for the patient reported outcome (PRO)endpoints, and the reasons for the missing data, were summarized by treatment group basedon the FAS.
Safety Endpoints
The safety data were summarized in accordance with Pfizer data standards. Missing data
were not imputed.
RESULTS
Participant Disposition and Demography: participant disposition is presented in Figure S2.
A total of 944 participants were enrolled into the study and included in the FAS; 175 wereassigned to the tofacitinib 5 mg BID group and 769 to the tofacitinib 10 mg BID group.
Participants were allocated into treatment groups according to randomization via theinteractive voice recording system (IVRS) and baseline stratification factors. The safety
analysis set (SAS) consists of all randomized participants who received at least one dose ofPage 11

Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
study intervention. The laboratory data consists of all participants that had data collected atboth baseline and at least one of the post-baseline visits.
Participants eligible for this study were those who completed or demonstrated treatment
failure in the maintenance Study A3921096, or who were non-responders after completing
Induction Studies A3921094 or A3921095.
Of the 944 participants in the FAS, 84 (48.0%) discontinued from the tofacitinib 5 mg BID
group and 665 (86.5%) discontinued from the tofacitinib 10 mg BID group.
The most frequent reasons for discontinuation in the FAS were insufficient clinicalresponse (20 [11.4%] in the tofacitinib 5 mg BID group and 326 [42.4%] in thetofacitinib 10 mg group) and no longer willing to participate in the study (24 [13.7%] and79 [10.3%], respectively). Insufficient clinical response included those participants who
discontinued due to an AE of worsening UC.

For the induction non-responder subpopulation of the FAS (n=429), the most frequent reason
for discontinuation was insufficient clinical response (214, 49.9%). Participants that were
induction non-responders were mandated to discontinue from the study if they continued toshow no clinical response at the Month 2 study visit.
Discontinuations from the study due to other reasons were as follows:

Enrolled to Study A3921288: 2 participants (1.1%) in the tofacitinib 5 mg BID group and
138 participants (17.9%) in the tofacitinib 10 mg BID group.

Enrolled to post-marketing surveillance (participants in Japan only): 8 participants (4.6%)
and 4 participants (0.5%) respectively.

Regulatory approval (participants in Japan only): 1 participant (0.6%) and 2 participants(0.3%), respectively.

All other reasons for withdrawal: 3 participants (1.7%) and 12 participants (1.6%),
respectively.

Page 12Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Efficacy Results:
Primary Endpoint Result
There were no primary efficacy endpoints in this study.
Secondary Endpoint Results
In the maintenance remission subpopulation, continued treatment with open-label
tofacitinib 5 mg BID in participants in remission after completing the 52-weekmaintenance Study A3921096 with either tofacitinib 10 mg BID or 5 mg BID generally
showed persistency of tofacitinib efficacy through Month 36.

In the maintenance treatment failures subpopulation, treatment with open-label tofacitinib
10 mg BID recaptures efficacy in participants who previously received tofacitinib 10 mg
BID from induction Studies A3921094 or A3921095 and subsequently had treatment
failure on tofacitinib 5 mg BID or placebo in the A3921096 maintenance Study. In
participants who previously received tofacitinib 10 mg BID in the induction Studies andeither tofacitinib 5 mg BID or placebo in the maintenance Study (Induction 10 mg/Main
5 mg and Induction 10 mg/Main Placebo), treatment with tofacitinib 10 mg BID resulted
in a notable increase in the proportion of participants achieving a clinical response at
Month 2.

In the other maintenance completers subpopulation, persistence of tofacitinib efficacy s
measured by clinical response (and improvement of efficacy as measured by remission,clinical remission, and mucosal healing) was observed with continued open-label
tofacitinib 10 mg BID treatment in completed participants from the A3921096
maintenance Study who were neither in remission nor fulfilling the definition oftreatment failure.

In the induction non-responders subpopulation, continued treatment with open-label
tofacitinib 10 mg BID for an additional 2 months resulted in increases from baseline forall binary efficacy endpoints at Month 2 in participants who failed to achieve a clinicalresponse after the initial 8 weeks of tofacitinib 10 mg BID in the induction Studies
A3921094 and A3921095; the increase from baseline was most notable for the proportionof participants who had a clinical response.

The binary efficacy endpoint of PMS remission over time was maintained through Month
36 for the maintenance remission subpopulation. This endpoint increased through Month6, then slightly increased or maintained through the remainder of the study for the othermaintenance completers subpopulation; and increased through Month 9, then slightly
increased or generally maintained for the maintenance treatment failures and induction
non-responder subpopulations.

Page 14Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSISThe exploratory efficacy endpoints of change in PMS over time and change in Mayoscore over time both maintained over the course of the study for the maintenanceremission and other maintenance completers subpopulations, and decreased slightly overthe course of the study for the maintenance treatment failures and induction nonresponder subpopulations.

Consistent findings were observed for the patient reported outcome efficacy endpoints for the
subpopulations of the FAS as follows:In the maintenance remission subpopulation, continued treatment with open-label
tofacitinib 5 mg BID in participants in remission after completing the 52-weekmaintenance Study A3921096 with either tofacitinib 10 mg BID or 5 mg BID showed
participants maintained HRQoL through Month 48, as demonstrated by the following
PRO endpoints: IBDQ scores over time and change from baseline, and EQ-5D/VAS
scores. Participants also maintained HRQoL through Month 33, as demonstrated by
SF-36 scores.

In the other maintenance completers subpopulation, treatment with open-label tofacitinib
10 mg BID in completed participants from the A3921096 maintenance Study who wereneither in remission nor fulfilling the definition of treatment failure showed participants
maintained HRQoL through Month 48, as demonstrated by the following endpoints:
IBDQ scores over time and change from baseline, and EQ-5D/VAS scores. Participantsalso maintained HRQoL through Month 33, as demonstrated by SF-36 scores.

In the maintenance treatment failures subpopulation, treatment with open-label tofacitinib
10 mg BID in participants with treatment failure on tofacitinib 5 mg BID or placebo in
the A3921096 maintenance Study who received tofacitinib 10 mg BID from induction
Studies A3921094 or A3921095 showed participants experienced an improvement
HRQoL through Month 48, as demonstrated by increases in the following endpoints:
IBDQ scores over time and change from baseline, and EQ-5D/VAS scores. Participantsalso maintained HRQoL through Month 33, as demonstrated by SF-36 scores.

In the induction non-responders subpopulation, continued treatment with open-label
tofacitinib 10 mg BID for an additional 2 months in participants failing to achieve aclinical response after the initial 8 weeks of tofacitinib 10 mg BID in the induction
Studies A3921094 and A3921095 showed participants experienced an improvement in
HRQoL through Month 48, as demonstrated by increases in the following endpoints:
IBDQ scores over time and change from baseline, and EQ-5D/VAS scores. Participantsalso demonstrated improvement in HRQoL as demonstrated by SF-36 scores throughMonth 33.

The observations for the IBDQ and SF-36 domains over time also support the efficacy per
the PRO results described above for all four subpopulations.

Page 15

Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
WPAI-UC scores were not analyzed for the subpopulations of the FAS, but results of thisendpoint in the tofacitinib 5 mg BID and tofacitinib 10 mg BID treatment groups support theoverall conclusions regarding HRQoL, which was maintained (<7% change from baseline forall 4 domains) in the 5 mg BID group and improved (>11% decrease from baseline in the
Absenteeism, Work Productivity Loss, and Non-Work Productivity Impairment domains) in
the 10 mg BID group.
The number of UC-related hospitalizations were both higher in the tofacitinib 10 mg BID
group. No participants in the tofacitinib 5 mg BID group, and only a small percentage ofparticipants in the tofacitinib 10 mg BID group, required UC-related surgery or colectomy.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, Immunogenicity and/or
Other Results: Not applicable.
Safety Results:The proportion of participants who experienced all-causality treatment-emergent adverse
events (TEAEs) was similar between the treatment groups (Table S4).



The majority of reported all-causality TEAEs mild to moderate in both treatment groups,
and the proportion of participants with severe TEAEs was similar between treatmentgroups.



The proportion of participants with serious adverse events (SAEs) in each treatmentgroup were similar.

The proportion of participants who discontinued the study due to AEs in the tofacitinib
was similar between treatment groups.

The proportion of participants with temporary discontinuations was similar between
treatment groups.

The proportions of participants with dosage of lipid-lowering agents increased during thestudy were similar between the two treatment groups.



There were no meaningful changes in vital signs, ECG, or physical examination results.

Page 16Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
Table S4. Summary of Treatment-Emergent Adverse Events, All Causalities
Tofacitinib
5 mg BID
Number (%) of Subjects:nSubjects evaluable for adverse events

175

Number of adverse events
Subjects with adverse events
Subjects with serious adverse events
Subjects with severe adverse events
Subjects discontinued due to adverse events
Subjects with dose reduced or temporary
discontinuation due to adverse events

951
154
39
25
30
16

(%)

Tofacitinib
10 mg BID

n

(%)

769

(88.0)(22.3)(14.3)(17.1)
(9.1)

3461
626
147
104
166
65

Total

n

(%)

944

(81.4)(19.1)(13.5)(21.6)
(8.5)

4412
780
186
129
196
81

(82.6)(19.7)(13.7)(20.8)(8.6)

Includes events from study database, even those that occur after last dose of study drug.
Except for the Number of Adverse Events subjects are counted only once per treatment in each row.
Serious Adverse Events - according to the investigator's assessment.
Severity counts are based on the maximum severity of events.
Per Adverse Event Case Report Form (CRF), the subjects that permanently discontinued the study drug due toAdverse Event are summarized.
Medical Dictionary for Regulatory Activities (MedDRA, v23.0) coding dictionary applied.
PFIZER CONFIDENTIAL Source Data: Table 16.2.7
Date of Reporting Dataset Creation: 26AUG2020
Dateof Table Generation: 17NOV2020 (17:43)
Path: /Volumes/app/cdars/prod/prjA392/ibd_uc/A3921139_finalcsr_intext/ae411s rtf



The mean duration of treatment was approximately 1305 days for the tofacitinib 5 mg
BID group and approximately 823 days for the tofacitinib 10 mg BID group. The
median (range) of duration of treatment was 1529 (36-2422) and 668 (1-2561) days,
respectively.



Most AEs were mild to moderate in severity.



The most frequent AE leading to discontinuation was colitis ulcerative (worsening ofUC).

Six (6) participant deaths occurred during the study, all in the tofacitinib 10 mg BID
group. All deaths occurred in the setting of an underlying malignancy.



The most frequent SAEs were Colitis ulcerative and Condition aggravated (worseningof UC).



Proportions of infection TEAEs were similar in both treatment groups. The mostfrequent infection AE in both treatment groups was Nasopharyngitis.

Page 17

Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS

Proportions of serious infection AEs and treatment-emergent herpes zoster AEs weresimilar in both treatment groups.



Proportions of adjudicated OIs, cardiovascular/neurovascular events, and GI
perforations (all cases) were similar between the two treatment groups. Proportions of
MACE and malignancy events were slightly higher in the tofacitinib 5 mg BID group,
while the proportion of TE events was slightly higher in the tofacitinib 10 mg BID
group. Regarding adjudicated hepatic injury events, proportions of mild events weresimilar between the two treatment groups, while proportions of moderate events wereslightly higher in the tofacitinib 5 mg BID group and proportions of severe eventswere slightly higher in the tofacitinib 10 mg BID group. There were no confirmed
Hy’s Law cases.

Decreases from baseline in ALC were observed over time in both treatment groups.



There were minimal changes from baseline between treatment groups in laboratory
parameters for ANC, CK, serum creatinine, creatinine clearance, hemoglobin, HDLC, LDL-C, LFTs, total cholesterol, and triglycerides.



The proportions of participants with dosage of lipid-lowering agents increased during
the study were similar between the two treatment groups.



There were no meaningful changes in vital signs, ECG, or physical examination
results.

Conclusion(s):Efficacy
Consistent findings were observed for the secondary efficacy endpoints – remission, clinicalremission, mucosal healing, and clinical response. Persistence of tofacitinib efficacy wasobserved for these endpoints in the maintenance remission and other maintenance completers
subpopulations. Recapture of tofacitinib efficacy was observed in the maintenance treatment
failures and induction non-responders subpopulations.
Consistent findings were observed for the patient reported outcome efficacy endpoints.
Participants in the maintenance remission and other maintenance completers subpopulations
maintained HRQoL, while those participants in the maintenance treatment failures andinduction non-responders subpopulations experienced an improvement in HRQoL.

Page 18

Final Clinical Study Report
Protocol A3921139

CLINICAL STUDY REPORT SYNOPSIS
SafetyThis study demonstrated that tofacitinib administered as 5 mg BID or 10 mg BID had an
acceptable safety profile and was well tolerated during long-term therapy for UC. No new or
unexpected safety findings were observed.


Most AEs were mild to moderate in severity. The proportions of participants with AEs,
SAEs, and serious infection AEs were similar between the tofacitinib 5 mg BID andtofacitinib 10 mg BID dose groups.



Proportions of adjudicated OIs, cardiovascular/neurovascular events, and GI perforations(all cases) were similar between the two treatment groups. There were slight differences
between the two treatment groups regarding MACE, as well as TE, malignancy, andhepatic injury events.



Six deaths were reported in this study, all in the tofacitinib 10 mg BID group. All deaths
occurred in the setting of an underlying malignancy.

Page 19