Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer Inc
Investigational Product: tofacitinib
Clinical Study Report Synopsis: Protocol A3921288
Protocol Title: A Phase 3b/4, Multi-Center, Double-Blind, Randomized, Parallel Group
Study of Tofacitinib (CP-690,550) in Subjects With Ulcerative Colitis in Stable Remission
Investigators: Refer to Appendix 16.1.4.1 for a list of investigators involved in this study.
Study Center(s): A total of 69 sites randomized subjects from the following countries:
Belgium (1), Canada (2), Czech Republic (1), France (2), Germany (1), Hungary (3), Italy(1), Japan (14), Republic of Korea (3), Netherlands (1), New Zealand (3), Poland (2),Russian Federation (2), Serbia (5), Slovakia (3), South Africa (4), Spain (1), Ukraine (4),
United Kingdom (1), and the United States (15). Refer to Appendix 16.1.4.1 for a list of sites
involved in this study.
Publications Based on the Study: None
Study Initiation Date: First Subject First Visit: 16 November 2017
Study Completion Date: Data Cut Off Date: 20 February 2020
Report Date: 22 July 2020
Previous Report Date(s): Not applicable
Phase of Development: Phase 3b/4
Study Objectives and Endpoints:
Table S1.

Study Objectives and Endpoints

Type
Primary Efficacy
Efficacy

Objective
To evaluate the efficacy of
tofacitinib in subjects in stableremission on 10 mg twice
daily (BID) who decrease thedose to and remain on 5 mg
BID (“5 mg BID dose group”)
compared to subjects
remaining on 10 mg BID.

Secondary Efficacy

PFIZER CONFIDENTIAL
Page 1

Endpoint

Remission based on
modified Mayo score at
Month 6.

Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
Table S1.

Study Objectives and Endpoints
Type

Efficacy

SafetySafetyObjective
To evaluate the efficacy of
tofacitinib in subjects in stableremission on 10 mg BID who
decrease the dose to andremain on 5 mg BID (“5 mg
BID dose group”) compared tosubjects remaining on 10 mg
BID.

To evaluate the safety of
tofacitinib in subjects in stableremission on 10 mg BID who
decrease the dose to andremain on 5 mg BID (“5 mg
BID dose group”) compared to

PFIZER CONFIDENTIAL
Page 2Endpoint
Time to loss of remission
based on modified Mayoscore.



Remission at all
applicable scheduled visits
based on the following:
modified Mayo score(excluding Month 6),
modified partial Mayoscore (PMS), total Mayoscore, and PMS.



Change from baseline (ofStudy A3921288) at all
applicable scheduled visits
in the following: modified
Mayo score, modified
PMS, total Mayo score,and PMS.



Mucosal healing at all
applicable scheduledvisits.



Clinical response based on
Mayo score at all
applicable scheduledvisits.



Change from baseline at
all applicable scheduledvisits in fecal calprotectin(FCP) and high sensitivity
C-reactive protein(hsCRP) levels.



Incidence and severity ofadverse events (AEs).



Incidence of serious
infections.

Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
Table S1.

Study Objectives and Endpoints
Type

Objective
subjects remaining on 10 mg
BID.

Endpoint
Incidence and severity ofclinical laboratory
abnormalities and change
from baseline in clinicallaboratory values.



Incidence of vital signabnormalities and change
from baseline in vital
signs.



Incidence of clinicallysignificant changes inphysical examinations
from baseline.



Adjudicated safety events(eg, opportunistic
infections, malignancy,
gastrointestinal
perforation, andcardiovascular events).

METHODS
Study Design: This study enrolled subjects from the ongoing open-label long-term
extension (LTE) Study A3921139 who were in stable remission (see Diagnosis and Main
Criteria for Inclusion below) on tofacitinib 10 mg BID for at least 6 months and not receiving
any corticosteroids to treat their ulcerative colitis (UC) for at least 4 weeks prior toenrollment. Subjects must have received tofacitinib 10 mg BID for a minimum of
2 consecutive years in the ongoing open-label LTE Study A3921139 prior to enrollment.
Subjects enrolling under Amendment 2 must not have had any risk factors for pulmonary
embolism.
Approximately 130 subjects were estimated to be enrolled into this study (based on
availability of eligible subjects from the ongoing open-label LTE Study A3921139 and basedon the conservative assumptions of the attrition rate of 50% - 60% in the ongoing open-label
LTE Study A3921139). Eligible subjects were randomized in a 1:1 allocation ratio to receive
either tofacitinib 5 mg BID or 10 mg BID at baseline of this study. Subjects were stratified
at baseline based on the endoscopic subscore (ESS) (0 versus 1) of their most recent
endoscopy (Figure S1).

PFIZER CONFIDENTIAL
Page 3Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
This study will have a total of 42 months of treatment duration. The primary analysis was
conducted after the last subject enrolled reached their Month 6 study visit. The initial
treatment assignment at baseline will remain double-blinded to the site and the subject.
Any time after Month 1, subjects who experienced flare could have had their dose escalated.
Flare was defined by meeting 1 of the following 4 criteria:
1. An increase in rectal bleeding subscore by at least 1 point and an increase in ESS by
at least 1 point; OR
2. An increase in rectal bleeding subscore by at least 2 points and an ESS >0; OR
3. An increase in stool frequency subscore by at least 2 points and an increase in the
ESS by at least 1 point; OR
4. An increase in ESS by at least 2 points.
Subjects with confirmed flare were eligible for a dose escalation.
Figure S1. Study Design

Diagnosis and Main Criteria for Inclusion: Key inclusion criteria were as follows:
1. Subjects enrolled in Study A3921139 who had received tofacitinib 10 mg BID for aminimum of 2 consecutive years in Study A3921139 prior to and including baselineof Study A3921288.
2. Subjects who were in stable remission on tofacitinib 10 mg BID for the 6 month
period in Study A3921139 up to and including baseline of Study A3921288, defined
as meeting all of the following criteria:

PFIZER CONFIDENTIAL
Page 4

Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
a. A partial Mayo score 2, with no individual subscore >1 and a rectal bleeding
subscore of 0 at each study visit where data were available during the 6 month
period in Study A3921139 prior to and including baseline of Study A3921288;
b. AND at least 1 assessment of remission based on Mayo score;

If an endoscopy was not completed 6 months prior to baseline of
Study A3921288, then an endoscopy performed in Study A3921139 with an
ESS of 0 or 1, was required prior to randomization into Study A3921288.

All available assessments based on Mayo score during this period must haveshown remission.

c. AND subjects must not have been receiving any corticosteroid therapy for their
UC for at least 4-weeks prior to baseline.
Study Treatment: Eligible subjects were randomized in a 1:1 allocation ratio to receive
either tofacitinib 5 mg BID or 10 mg BID at baseline of Study A3921288. Subjects werestratified at baseline based on the ESS (0 versus 1) of their most recent endoscopy.
Subjects who met the protocol definition for flare could have had a dose increase to
10 mg BID or remained on 10 mg BID, depending on their initial treatment assignment,
provided that the subject did not have any of the risk factors for pulmonary embolism(beginning with Protocol Amendment 2).
Details of the investigational product used in the is study are shown in Table S2.
Table S2. Investigational Product Description
Investigational
Product Description
Placebo for Tofacitinib
Citrate 5 mg Film
Coated Tablet
Placebo for Tofacitinib
Citrate 5 mg Film
Coated Tablet
Tofacitinib Citrate
5 mg Film Coated
TabletTofacitinib Citrate
5 mg Film Coated
TabletVendor Lot
NumberR73682

Pfizer Lot
Number16-005146

Strength/Potency

Dosage Form

0 mg

Tablet

R7368316-005147

0 mg

Tablet

S2691817-000460

5 mg

TabletX20921

18-002302

5 mg

TabletEfficacy Evaluations:

PFIZER CONFIDENTIAL
Page 5Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
Mayo Score
The Mayo score is an instrument designed to measure disease activity of UC. Mayo score
ranges from 0 to 12 points. It consists of 4 subscores, each graded from 0 to 3 with higherscores indicating more severe disease.
stool frequency (0-3).



rectal bleeding (0-3).

findings of flexible sigmoidoscopy (0-3).



physician global assessment (PGA) (0-3).

Endpoints based on total Mayo score are defined below:Remission: total Mayo score of 2 points or lower, with no individual subscoreexceeding 1 point and a rectal bleeding subscore of 0.



Clinical response: decrease from baseline in total Mayo score of the Induction study,of at least 3 points and at least 30%, with an accompanying decrease in the subscore
for rectal bleeding of at least 1 point, or absolute subscore for rectal bleeding of
0 or 1.

Mucosal healing: an ESS of 0 or 1.

Modified Mayo score consists of stool frequency subscore, rectal bleeding subscore and ESS(ie, total Mayo score without PGA).
Endpoints based on modified Mayo score are defined below:Remission: an ESS of 0 or 1, stool frequency subscore of 0 or 1, and rectal bleeding
subscore of 0.

Partial Mayo Score
A PMS is an instrument designed to measure disease activity of UC without endoscopy.
PMS ranges from 0 to 9 points. It consists of 3 subscores, each graded from 0 to 3 withhigher scores indicating more severe disease.
stool frequency (0-3);



rectal bleeding (0-3);

physician global assessment (PGA) (0-3).
PFIZER CONFIDENTIAL
Page 6

Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
Endpoints based on PMS are defined below:Remission: PMS of 2 points or lower, with no individual subscore exceeding 1 point
and a rectal bleeding subscore of 0.

Modified PMS consists of stool frequency and rectal bleeding subscores (ie, PMS without
PGA).
Endpoints based on modified PMS are defined below:Remission: stool frequency subscore of 0 or 1, and a rectal bleeding subscore of 0.

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, clinical laboratory tests (including FCP and hsCRP) andthe spontaneous reporting of AEs, in all subjects who received at least 1 dose ofinvestigational product.
Statistical Methods:
Analysis of the Primary Endpoint
The primary efficacy endpoint was remission based on modified Mayo score at Month 6. For
dose comparison between tofacitinib 10 mg BID and 5 mg BID, the stratified estimation of
the treatment difference between tofacitinib 10 mg BID and 5 mg BID in the proportion ofsubjects was presented along with its 95% confidence interval (CI) with the ESS at baseline(0 versus 1) as the stratification factor. The Cochran Mantel Haenszel (CMH) weight
method was used for the stratified estimation of the treatment difference. The stratified CI
was constructed using the NewCombe method by Yan and Su.
In addition, p-values based on CMH Chi-square test stratified by ESS at baseline (0 versus 1)
were presented.
Analysis of the Secondary Endpoints
Binary secondary efficacy endpoints were analyzed using the same approach as described forthe primary efficacy endpoint.
For continuous efficacy endpoints based on total Mayo score evaluated for primary objectiveat Month 6, the change from baseline was analyzed using an analysis of covariance(ANCOVA) model with dose group, the ESS at baseline (0 versus 1) as factors and baseline
score as a covariate. Otherwise, for continuous efficacy endpoints, the change from baseline
was analyzed using linear mixed effects model with baseline value, dose group, the ESS at
PFIZER CONFIDENTIAL
Page 7

Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
baseline (0 versus 1), visit, and dose group by visit interaction all as fixed effects, and subject
as a random effect. The adjusted estimations and associated 95% CI for the overall
difference between the 2 dose groups was computed for each visit.
Time to loss of remission (flare) based on modified Mayo score was estimated using a
log-rank test stratified by ESS at baseline (0 versus 1). In addition, cumulative event rates
and associated CIs were estimated from the Kaplan-Meier curves for each dose group. The
dose comparison for the proportions of the event were made using Wald test statistics.
FCP and hsCRP, and their change from baseline were summarized descriptively for each
visit by dose group.
The FCP and hsCRP data were also log-transformed (natural logarithm) for the analyses.
The change from baseline was analyzed using the same approach as the continuous efficacy
endpoints.
The safety data were summarized in accordance with Pfizer Data Standards.
RESULTS
Subject Disposition and Demography: Subject disposition is presented in Figure S2.


A total of 140 subjects were randomized into the study, with 70 subjects randomized toeach treatment group.

Discontinuation rates were similar between treatment groups.



The most common reasons for discontinuation were AEs (5 subjects) and withdrawal bysubject (5 subjects) in the tofacitinib 5 mg BID group, and withdrawal by subject(10 subjects) in the tofacitinib 10 mg BID group.

PFIZER CONFIDENTIAL
Page 8Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
Figure S2. Subject Disposition

Subjects who discontinued due to an AE of ‘worsening UC’ were summarized under lack of efficacy.

Efficacy Results:
Primary Endpoint Result
Remission Based on Modified Mayo Score at Month 6
The proportion of subjects in remission based on modified Mayo score at Month 6 washigher for the tofacitinib 10 mg BID (90.0%) group compared with the tofacitinib 5 mg BID
group (77.1%) with a difference of 12.9% (95% CI: 0.5, 25.0).
Secondary Endpoint Results
Consistent results were observed in the secondary endpoints to support the results of the
primary endpoint.
Remission (Based on Total Mayo Score)

PFIZER CONFIDENTIAL
Page 9Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
The proportion of subjects in remission based on total Mayo score at Month 6 was higher forthe tofacitinib 10 mg BID (87.1%) group compared with the tofacitinib 5 mg BID group(75.7%) with a difference of 11.4% (95% CI: -1.5, 24.1).
Mucosal Healing
The proportion of subjects with mucosal healing at Month 6 was higher for the tofacitinib
10 mg BID (91.4%) group compared with the tofacitinib 5 mg BID group (80.0%) with adifference of 11.4% (95% CI: -0.3, 23.1).
Clinical Response
The proportion of subjects with a clinical response at Month 6 was higher for the tofacitinib
10 mg BID (95.7%) group compared with the tofacitinib 5 mg BID group (84.3%) with adifference of 11.4% (95% CI: 1.3, 22.0).
Remission Based on Modified Partial Mayo Score and Partial Mayo ScoreFor all subjects, the proportions of subjects in remission based on modified partial Mayoscore (PMS) and PMS were higher for the tofacitinib 10 mg BID group compared withthe tofacitinib 5 mg BID group at each time point assessed (Months 1, 3 and 6).
At Month 1, 91.4% in the tofacitinib 10 mg BID group and 88.6% in the tofacitinib
5 mg BID group with a difference of 2.9% (95% CI:-7.5, 13.4) for both modified
PMS and PMS.

At Month 3, 92.9% in the tofacitinib 10 mg BID group and 81.4% in the tofacitinib
5 mg BID group with a difference of 11.4% (95% CI: 0.1, 22.8) for both modified
PMS and PMS.

At Month 6, 95.7% in the tofacitinib 10 mg BID group and 81.4% in the tofacitinib
5 mg BID group with a difference of 14.3% (95% CI: 2.9, 25.2) for modified PMS
and 94.3% in the tofacitinib 10 mg BID group and 80.0% in the tofacitinib 5 mg BID
group with a difference of 14.3% (95% CI: 2.4, 25.6) for PMS.

Change From Baseline of Modified Mayo and Total Mayo Score at Month 6
The least square (LS) mean [standard error (SE)] for the change from baseline ofmodified Mayo score at Month 6 was lower for the tofacitinib 10 mg BID group (0.3[0.2]) compared with the tofacitinib 5 mg BID group (0.6 [0.2]) based on ANCOVA.

The LS mean [SE] for the change from baseline of total Mayo score at Month 6 waslower for the tofacitinib 10 mg BID group (0.4 [0.3]) compared with the tofacitinib 5 mg
BID group (0.9 [0.2]) based on ANCOVA.

PFIZER CONFIDENTIAL
Page 10

Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
Change From Baseline of Modified Partial Mayo Score and Partial Mayo Score
The LS mean changes (SE) from baseline for the modified PMS and PMS remained low
over time (Months 1, 3 and 6) and were either the same or similar for both dose groups.


At Month 1, 0.2 (0.1) in the tofacitinib 10 mg BID group and 0.1 (0.1) in thetofacitinib 5 mg BID group for modified PMS and 0.2 (0.1) for both dose groups forPMS.

At Month 3, 0.1 (0.1) in the tofacitinib 10 mg BID group and 0.2 (0.1) in thetofacitinib 5 mg BID group for modified PMS and 0.2 (0.1) in the tofacitinib 10 mg
BID and 0.3 (0.1) in the tofacitinib 5 mg BID group for PMS.

At Month 6, 0.2 (0.1) in the tofacitinib 10 mg BID group and 0.1 (0.1) in thetofacitinib 5 mg BID group for modified PMS and 0.3 (0.1) for both dose groups for
PMS.

Subgroup Analyses
Subgroup analyses were conducted for the primary efficacy and secondary efficacy endpoints
for ESS at baseline (0, 1), prior tumor necrosis factor inhibitor (TNFi) failure (Y/N) and prior
TNFi exposure (Y/N).
Remission Based on Modified Mayo Score at Month 6
The proportion of subjects in remission based on modified Mayo score at Month 6 washigher in both dose groups for subjects with a baseline ESS=0 compared with subjects
with a baseline ESS=1.



For both subgroups based on baseline ESS=0 and ESS=1, the proportion of subjects inremission based on modified Mayo score at Month 6 was higher in the tofacitinib 10 mg
BID group compared with the tofacitinib 5 mg BID group.

The observed difference between tofacitinib 10 mg BID and 5 mg BID in proportions ofsubjects in remission at Month 6 was higher in the subgroup with baseline ESS=1 than
the subgroup with baseline ESS=0.


ESS=0: 92.2% for the tofacitinib 10 mg BID group compared with 82.4% for thetofacitinib 5 mg BID group with a difference of 9.8% (95% CI: -3.0, 22.6).



ESS=1: 84.2% for the tofacitinib 10 mg BID group and 63.2% for the tofacitinib
5 mg BID group with a difference of 21.1% (95% CI: -6.1, 48.2).

PFIZER CONFIDENTIAL
Page 11

Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSISThe proportions of subjects in remission based on modified Mayo score at Month 6 in thesubgroup with prior TNFi failure and the subgroup without prior TNFi failure werehigher in the tofacitinib 10 mg BID group compared with the tofacitinib 5 mg BID group.

The observed difference between tofacitinib 10 mg BID and 5 mg BID in proportions ofsubjects in remission at Month 6 was higher in the subgroup with prior TNFi failure than
the subgroup without prior TNFi failure.

Prior TNFi failure=Yes: 91.4% for the tofacitinib 10 mg BID group compared with
74.1% for the tofacitinib 5 mg BID group with a difference of 17.4% (95% CI: -1.6,
36.3).



Prior TNFi failure=No: 88.6% for the tofacitinib 10 mg BID group and 79.1% for thetofacitinib 5 mg BID group with a difference of 9.5% (95% CI: -6.6, 25.6).

Trends were similar for the subgroup of prior TNFi exposure.

Subgroup results were similar for the secondary endpoints of remission based on total Mayoscore at Month 6, remission based on modified partial Mayo score and partial Mayo score,mucosal healing at Month 6, and clinical response.
Time to Loss of Remission (Flare) Based on Modified Mayo Score
Any time after Month 1, subjects who experienced flare may have had their dose escalated.
In the tofacitinib 10 mg BID group, 4 subjects had a dose escalation action taken
although the dose was not actually changed; 3 subjects prior to or at Month 6 (study
day ≤190).

In the tofacitinib 5 mg BID group, 12 subjects had a dose escalation to 10 mg BID;
9 subjects prior to or at Month 6 (study day ≤190).

The estimated rates (%) of having loss of remission were numerically lower in the tofacitinib
10 mg BID group compared with the tofacitinib 5 mg BID group at Months 1, 3 and 6(Figure S3). Prior to or at Month 6, there were 4 subjects in the tofacitinib 10 mg BID groupand 10 subjects in the tofacitinib 5 mg BID group that experienced loss of remission.
At Month 1: 1.43% in the tofacitinib 10 mg BID group compared with 2.90% in thetofacitinib 5 mg BID group with a difference of -1.47 (95% CI: -6.31, 3.37).

At Month 3: 1.43% in the tofacitinib 10 mg BID group compared with 5.84% in thetofacitinib 5 mg BID group with a difference of -4.41 (95% CI: -10.62, 1.80).

At Month 6: 5.74% in the tofacitinib 10 mg BID group compared with 14.77% in thetofacitinib 5 mg BID group with a difference of -9.03 (95% CI: -19.10, 1.03).
PFIZER CONFIDENTIAL
Page 12Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS
Figure S3. Kaplan‑Meier Plot of Time to Loss of Remission (Flare) based on Modified
Mayo Score by Dose Group (FAS)

Change from Baseline in Fecal Calprotectin and hsCRP Levels
FCP Levels
Median baseline FCP values were similar between the treatment groups, 48.0 µg/g and 54.0µg/g in the tofacitinib 10 mg BID group and tofacitinib 5 mg BID group, respectively.


There were no meaningful differences in FCP values between the dose groups over time.

hsCRP Levels
Baseline median hsCRP values were similar between the treatment groups, 0.7 mg/L and 0.5
mg/L in the tofacitinib 10 mg BID group and tofacitinib 5 mg BID group, respectively.


At Months 1 and 3, the LS mean in the tofacitinib 10 mg BID group showed a decrease
from baseline (-0.3 and -0.1, respectively) in hsCRP compared with the tofacitinib 5 mg
BID group which showed an LS mean increase (0.2 and 0.3, respectively) from baseline
using linear mixed-effects model).

PFIZER CONFIDENTIAL
Page 13

Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSISAt Month 6, the tofacitinib 10 mg BID group showed a lower LS mean increase frombaseline in hsCRP (0.1) compared with the tofacitinib 5 mg BID group (0.3) using linear
mixed-effects model.

Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, Immunogenicity and/or
Other Results: No pharmacokinetic, pharmacodynamic or pharmacogenomic evaluations
were performed in this study.
Safety Results:
Data collected after dose escalation from tofacitinib 5 mg BID to 10 mg BID was notincluded in the safety analyses.
The proportion of subjects who experienced all-causality treatment-emergent adverse
events (TEAEs) was similar between the treatment groups (Table S3).


The majority of reported all-causality TEAEs were mild to moderate in both
treatment groups; with the number of subjects with severe TEAEs lower in thetofacitinib 10 mg BID group (2 [2.9%] subjects) compared with the tofacitinib 5 mg
BID group (6 [8.6%] subjects).



There were 4 (5.7%) subjects with SAEs in each treatment group.

Two (2.9%) subjects discontinued the study due to AEs in the tofacitinib 10 mg BID
group compared with 7 (10.0%) subjects (1 [1.4%] subject discontinued study drug but
continued in the study) in the tofacitinib 5 mg BID group.

Two (2.9%) subjects in the tofacitinib 10 mg BID group and 3 (4.3%) subjects in thetofacitinib 5 mg BID group had temporary discontinuations.



No deaths were reported in this study.

No new or unexpected safety findings were observed.


Two cardiovascular events were confirmed by adjudication (1 pulmonary embolism
in the tofacitinib 10 mg BID group; 1 cerebrovascular accident in the tofacitinib 5 mg
BID group).



Four herpes zoster events were reported (1 in the tofacitinib 5 mg BID group; 3 in thetofacitinib 10 mg BID group); 1 herpes zoster event was reported in the tofacitinib
10 mg BID group that met criteria for an opportunistic infection (OI). No events
classified as serious herpes zoster.

No non-herpes zoster OIs were reported.

PFIZER CONFIDENTIAL
Page 14Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS

One malignancy excluding nonmelanoma skin cancer (NMSC) was confirmed by
adjudication (vulvar cancer in the tofacitinib 5 mg BID group).



One NMSC event was confirmed by adjudication (basal cell carcinoma in thetofacitinib 5 mg BID group).

One hepatic event was adjudicated and assessed as unlikely to be drug induced liver
injury; no potential or confirmed Hy’s Law cases.

No gastrointestinal perforations were reported.

Table S3. Tofacitinib Protocol A3921288 Treatment-Emergent Adverse Events by
Dose Group (All Causalities) - Safety Analysis Set

Number (%) of Subjects
Subjects evaluable for adverse events
Number of adverse events
Subjects with adverse events
Subjects with serious adverse events
Subjects with severe adverse events
Subjects discontinued from study due to adverse events (a)Subjects discontinued study drug due to AE and continue Study(b)
Subjects with dose reduced or temporary discontinuation due toadverse events

Tofacitinib 5 mg
BID
n (%)

Tofacitinib 10 mg
BID
n (%)

Total
n (%)

70

70

140

130
46 (65.7)
4 (5.7)6 (8.6)7 (10.0)
1 (1.4)143
49 (70.0)
4 (5.7)2 (2.9)2 (2.9)0273
95 (67.9)
8 (5.7)8 (5.7)9 (6.4)1 (0.7)3 (4.3)2 (2.9)5 (3.6)

Data cut-off: Feb 20, 2020.
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.
(a) Subjects who have an AE record that indicates that the AE caused the subject to be discontinued from the study.
(b) Subjects who have an AE record that indicates that Action Taken with Study Treatment was Drug Withdrawn but AE
did not Cause the Subject to bediscontinued from Study.
MedDRA v22.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 12MAR2020 (15:21) Source Data: Table 16.2.7.1.1.a
Output File: ./ibd_cdisc/A3921288_pcd/adae_s020 Date of Generation: 15APR2020 (22:07)
Table 14.3.1.2.1.a is for Pfizer internal use.

Conclusion(s):Efficacy

PFIZER CONFIDENTIAL
Page 15

Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSISThe proportion of subjects in modified Mayo remission at Month 6 (primary endpoint)
were 90.0% and 77.1% for the tofacitinib 10 mg BID and tofacitinib 5 mg BID groups,
respectively.

Consistent findings were observed for the secondary efficacy endpoints – remission,
mucosal healing and clinical response.



Observed differences between tofacitinib 10 mg BID and 5 mg BID across efficacy
endpoints at Month 6 were greater in the subgroup with baseline ESS of 1 than thesubgroup with baseline ESS of 0, however the confidence intervals overlap.


Observed differences between tofacitinib 10 mg BID and 5 mg BID across efficacy
endpoints at Month 6 were greater in the prior TNFi treatment failure subgroup than in
the subgroup without prior TNFi treatment failure, however the confidence intervals
overlap.


A higher observed proportion of subjects with an ESS of 0 maintained remission or
achieved other binary efficacy endpoints at Month 6 than the subjects with a baseline
ESS of 1 in the 5 mg BID group (ie, after dose reduction to 5 mg BID).

A slightly higher observed proportion of subjects without prior TNFi failure
maintained remission or achieved other binary efficacy endpoints at Month 6 than thesubjects with prior TNFi failure in the 5 mg BID group (ie, after dose reduction to
5 mg BID).

The biomarker analyses (hsCRP/FCP) performed were generally consistent between
tofacitinib 10 mg BID and tofacitinib 5 mg BID groups.

SafetyThe proportions of subjects with AEs and SAEs were similar between the tofacitinib
10 mg BID and tofacitinib 5 mg BID dose groups.



No deaths were reported in this study.

No new or unexpected safety findings were observed.


Two cardiovascular events were confirmed by adjudication (1 pulmonary embolism
in the tofacitinib 10 mg BID group; 1 cerebrovascular accident in the tofacitinib 5 mg
BID group).



Four herpes zoster events were reported (1 in the tofacitinib 5 mg BID group; 3 in thetofacitinib 10 mg BID group); 1 herpes zoster event was reported in the tofacitinib
10 mg BID group that met criteria for an opportunistic infection (OI). No events
classified as serious herpes zoster.
PFIZER CONFIDENTIAL
Page 16Final Clinical Study Report
Protocol A3921288 (Month 6 Primary Completion)

CLINICAL STUDY REPORT SYNOPSIS

No non-herpes zoster OIs were reported.

One malignancy excluding nonmelanoma skin cancer (NMSC) was confirmed by
adjudication (vulvar cancer in the tofacitinib 5 mg BID group).



One NMSC event was confirmed by adjudication (basal cell carcinoma in thetofacitinib 5 mg BID group).

One hepatic event was adjudicated and assessed as unlikely to be drug induced liver
injury; no potential or confirmed Hy’s Law cases.

No gastrointestinal perforations were reported.

PFIZER CONFIDENTIAL
Page 17

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSISSYNOPSIS
Study Title: A Phase 3b/4, Multi-Center, Double-Blind, Randomized, Parallel Group Studyof Tofacitinib (CP-690,550) in Subjects With Ulcerative Colitis in Stable Remission
Study Number: A3921288
Regulatory Agency or Public Disclosure Identifier Number: 2017-002274-39 (EudraCT)
Study Phase: 3b/4
Name of Study Intervention: CP-690,550
Trade Name: Xeljanz
Name of Sponsor/Company: Pfizer Inc.
CSR Version and Report Date:
Document Version
Report Date
Final CSR (PCD 14 February 2020) Version 1.0
22 July 2020
Supplemental CSR (LPLV 18 March 2022) Version 1.0 01 August 2022
Number of Study Center(s) and Investigator(s):A total of 82 investigators from 82 sites randomized subjects from the following countries:
Belgium (9), Canada (3), Czech Republic (3), France (3), Germany (1), Hungary (7),Italy (1), Japan (16), Republic of Korea (12), Netherlands (1), New Zealand (4), Poland (5),Russian Federation (3), Serbia (9), Slovakia (13), South Africa (9), Spain (5), Ukraine (12),United Kingdom (1), and the United States (23).
Publications:
Vermeire S, Su C, Lawendy N, et al. Outcomes of tofacitinib dose reduction in patients withulcerative colitis in stable remission from the randomised RIVETING trial. J Crohns Colitis.
2021;15(7):1130-41.
Study Period:
16 November 2017 to 18 March 2022

PFIZER CONFIDENTIAL
Page 1

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Rationale:
Prior studies in the ulcerative colitis (UC) Phase 3 program have shown that tofacitinib
10 mg twice daily (BID) as an induction therapy and both tofacitinib 5 mg BID and 10 mg
BID as a maintenance therapy were efficacious, relative to placebo, and had an acceptablesafety and tolerability profile. While the data from a completed open-label long term
extension (LTE) study (A3921139) suggested maintenance of efficacy with dose reduction to
5 mg BID for subjects who are in remission after 52 weeks of receiving tofacitinib 10 mg
BID, this double-blind, randomized study was designed to further evaluate the benefits ofdosing flexibility with tofacitinib, and provide additional data for selecting the mostappropriate regimen for an individual subject. Therefore this study evaluated the efficacy andsafety of tofacitinib in participants in stable remission on 10 mg BID who (1) decreased theirdose to 5 mg BID compared to participants remaining on 10 mg BID; (2) who decreased theirdose to 5 mg BID with option for dose escalation for flare (“flexible dosing regimen”)
compared to subjects staying on 10 mg BID; and (3) evaluated the efficacy and safety of
tofacitinib in the subset of subjects who have flare on maintenance tofacitinib 5 mg BID and
are re-treated with 10 mg BID.
Objectives, Endpoints, and Statistical Methods:
The objectives and endpoints of this study are presented in Table 1.
Table 1.

Study Objectives and Endpoints

Type
Primary Efficacy
Efficacy

Secondary Efficacy
Efficacy

Objective

Endpoint

To evaluate the efficacy of
tofacitinib in subjects in stableremission on 10 mg BID who
decrease the dose to and remain
on 5 mg BID (“5 mg BID dosegroup”) compared to subjects
remaining on 10 mg BID.

 Remission based on
modified Mayo score at
Month 6.

To evaluate the efficacy of
tofacitinib in subjects in stableremission on 10 mg BID who
decrease the dose to 5 mg BID
with option for dose escalation
for flare (“flexible dosing
regimen”) compared to subjects
staying on 10 mg BID.

 Time to loss of remission
based on modified Mayoscore.
 Remission at all applicable
scheduled visits based on thefollowing: modified Mayoscore (excluding Month 6),
modified partial Mayo score(PMS), total Mayo score,and PMS.
 Change from baseline (ofStudy A3921288) at all
applicable scheduled visits inthe following: modified

To evaluate the efficacy of thesubset of subjects in stableremission on 10 mg BID whohave flare after dose decrease totofacitinib 5 mg BID and are retreated with 10 mg BID.
PFIZER CONFIDENTIAL
Page 2

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Table 1.

Study Objectives and Endpoints
Type

SafetySafetyObjective

Endpoint
Mayo score, modified PMS,
total Mayo score, and PMS.
 Mucosal healing at all
applicable scheduled visits.
 Clinical response based on
Mayo score at all applicable
scheduled visits.
 Change from baseline at all
applicable scheduled visits infecal calprotectin (FCP) andhigh sensitivity C-reactive
protein (hsCRP) levels.

To evaluate the safety of
tofacitinib in subjects in stableremission on 10 mg BID who
decrease the dose to and remain
on 5 mg BID (“5 mg BID dosegroup”) compared to subjects
remaining on 10 mg BID.

 Incidence and severity ofadverse events (AEs).
 Incidence of serious
infections.
 Incidence and severity ofclinical laboratory
abnormalities and change
from baseline in clinicallaboratory values.
 Incidence of vital signabnormalities and change
from baseline in vital signs.
 Incidence of clinicallysignificant changes inphysical examinations frombaseline.
 Adjudicated safety events(eg, opportunistic infections,malignancy, gastrointestinal
perforation, andcardiovascular events).

To evaluate the safety of
tofacitinib in subjects in stableremission on 10 mg BID who
decrease the dose to 5 mg BID
with option for dose escalation
for flare (“flexible dosing
regimen”) compared to subjects
staying on 10 mg BID.
To evaluate the safety of thesubset of subjects in stableremission on 10 mg BID whohave flare after dose decrease totofacitinib 5 mg BID and are retreated with 10 mg BID.

This was an estimation study, with no planned hypothesis testing.
Analysis Sets
The primary analysis population was the full analysis set (FAS) defined as all subjects who
were randomized into the study and received at least 1 dose of investigational product.
The safety analysis set was defined as all subjects who received at least 1 dose ofinvestigational product.
PFIZER CONFIDENTIAL
Page 3

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Determination of Sample Size
Although approximately 130 subjects were estimated to be enrolled into this study (based on
availability of eligible subjects from the open-label LTE Study A3921139 and based on theconservative assumptions of the attrition rate of 50% - 60% in the open-label LTE Study
A3921139), the final sample size was 140 subjects.
With 130 (65 per group) subjects, the estimated half width of the 95% confidence fortreatment difference between tofacitinib 10 mg BID and 5 mg BID in proportion of remission
at Month 6 based on the modified Mayo score was about 16%, assuming the remission rates
were greater than 70% in both groups.
Analysis of Efficacy Parameters
For the primary endpoint, analyses were performed for comparisons of the following 2 dosegroups:

Tofacitinib 10 mg BID dose group: subjects who were initially assigned to tofacitinib
10 mg BID at randomization. For subjects who dose-reduced due to meeting criteria forvenous thromboembolism (VTE) risk factors, data collected after the dose reduction
were not included in the analyses.



Tofacitinib 5 mg BID dose group: subjects who were initially assigned to tofacitinib
5 mg BID at randomization. For subjects who dose-escalated from 5 mg BID to 10 mg
BID, data collected after the dose escalation were not included in the analyses.

For the first secondary objective, analyses were performed for comparisons of the following
2 regimen groups:
Tofacitinib 10 mg BID regimen group: subjects who were initially assigned totofacitinib 10 mg BID at randomization. For subjects with dose reduction due to VTE
risk factors, data collected after the dose reduction were included in the analyses.



Tofacitinib 5 mg BID regimen group: subjects who were initially assigned totofacitinib 5 mg BID at randomization, regardless of whether the dose was escalated totofacitinib 10 mg BID or not. Data collected after the dose escalation were included in
the analyses.

For the second secondary objective (see Table 1), summary descriptive statistics werereported for the subgroup of subjects who were initially assigned to tofacitinib 5 mg BID andlater were re-treated with tofacitinib 10 mg BID based on the observed case data using theoriginal windowing rules. In addition, the efficacy data after the dose escalation weresummarized using the new windowing rule by resetting the baseline (Day 0) at the dose
escalation time.

PFIZER CONFIDENTIAL
Page 4

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Analysis of Primary Endpoint
The primary efficacy endpoint was remission based on modified Mayo score at Month 6. For
dose comparison between tofacitinib 10 mg BID and 5 mg BID, the stratified estimation of
the treatment difference between tofacitinib 10 mg BID and 5 mg BID in the proportion ofsubjects was presented along with its 95% confidence interval (CI) with the endoscopic
subscore (ESS) at baseline (0 versus 1) as the stratification factor. The Cochran-MantelHaenszel (CMH) weight method was used for the stratified estimation of the treatment
difference. The stratified CI was constructed using the Newcombe method.
In addition, p-values based on CMH Chi-square test stratified by ESS at baseline (0 versus 1)
were presented.
The same analysis method was used for comparisons between regimen groups.
As sensitivity analyses for handling of missing data, remission based on modified Mayoscore and remission based on total Mayo score were analyzed using a generalized linear
mixed-effects model with a logit link and with dose group, visit, dose group by visit
interaction, ESS at baseline (0 versus 1) all as fixed effects, and subject as a random effectbased on data collected at Month 6, Month 18, Month 30 and Month 42 if sufficient data are
available at Month 42. The estimated mean, mean difference, with p-values and 95%
confidence interval based on the model are presented at each time point for dose group andregimen group.
Analysis of Secondary Efficacy Endpoints
Binary secondary efficacy endpoints were analyzed using the same approach as described forthe primary efficacy endpoint.
For continuous efficacy endpoints based on total Mayo score evaluated for primary objectiveat Month 6, the change from baseline was analyzed using an analysis of covariance(ANCOVA) model with dose group, the ESS at baseline (0 versus 1) as factors and baseline
score as a covariate. Otherwise, for continuous efficacy endpoints, the change from baseline
was analyzed using linear mixed effects model with baseline value, dose group or regimengroup, the ESS at baseline (0 versus 1), visit, and dose group or regimen group by visit
interaction all as fixed effects, and subject as a random effect. The adjusted estimations andassociated 95% CI for the overall difference between the 2 dose groups or 2 regimen groups
was computed for each visit.
Time to loss of remission (flare) based on modified Mayo score was tested using a log-rank
test stratified by ESS at baseline (0 versus 1). In addition, cumulative event rates andassociated CIs were estimated from the Kaplan-Meier curves for each dose group and eachregimen group. The dose comparison for the proportions of the event were made using Wald
test statistics.

PFIZER CONFIDENTIAL
Page 5

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Fecal calprotectin and hsCRP, and their change from baseline were summarized descriptively
for each visit by dose group and by regimen group.
The fecal calprotectin and hsCRP data were also log-transformed (natural logarithm) for the
analyses. The change from baseline was analyzed using the same approach as the continuous
efficacy endpoints.
Safety Analysis
Safety data were summarized based on observed-case data by dose group, regimen group andthe subgroup of subjects who are initially assigned to tofacitinib 5 mg BID and later are
retreated with tofacitinib 10 mg BID (retreatment group). Missing data were not imputed.
For the dose group, data collected after the dose escalation from tofacitinib 5 mg BID to
10 mg BID were not included in the analyses. Data collected after the dose reduction from
tofacitinib 10 mg BID to 5 mg BID were not included in the dose group analyses as well.
For the regimen group, data from subjects with dose escalation from tofacitinib 5 mg BID to
10 mg BID were treated as is. For subjects with dose reduction from tofacitinib 10 mg BID to
5 mg BID due to meeting criteria for the presence of VTE risk factors, data collected after thedose reduction were included in the analyses.
The safety data were summarized in accordance with Pfizer Data Standards.
Serious adverse event presentations were derived from a combination of data in the clinicalstudy database and the corporate safety database. The corporate safety database is a separate,
centralized, adverse event monitoring database that is continuously updated based on rapidly
communicated reports from the investigators to the sponsor. The clinical study database wasbased on information provided from the case report forms (CRFs)/ data collection tools(DCTs). Consequently, occasional differences in data may exist between the centralized
safety database and the clinical study database.
Adverse Events
An AE was considered treatment emergent relative to a given treatment if the event starts
after the first dose. The first dose was defined as the first dose in Study A3921288. A 3-tierapproach was used to summarize AEs. Under this approach, AEs were classified into 1 of 3tiers and different analyses were performed for different tiers. Herpes zoster events were prespecified as Tier 1 events; Tier 2 events were events that were reported at least 4 times in any
treatment group; and Tier 3 events were all other events that were not Tier 1 or Tier 2 events.
Clinical Laboratory Parameters
Clinical laboratory data were summarized descriptively by dose group, regimen group andretreatment group.

PFIZER CONFIDENTIAL
Page 6

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Other Safety Parameters
Vitals Signs and Physical Examination
Vital sign and physical examination data were summarized descriptively by dose group.
Methodology:
This study enrolled subjects from the completed open-label LTE Study A3921139 who werein stable remission on tofacitinib 10 mg BID for at least 6 months and not receiving any
corticosteroids to treat their UC for at least 4 weeks prior to enrollment. Subjects must havereceived tofacitinib 10 mg BID for a minimum of 2 consecutive years in the open-label LTE
Study A3921139 prior to enrollment. Subjects enrolled under Amendment 2 must not have
had any risk factors for pulmonary embolism (PE).
One-hundred and forty (140) subjects were enrolled into this study. Eligible subjects wererandomized in a 1:1 allocation ratio to receive either tofacitinib 5 mg BID or 10 mg BID atbaseline of this study. Subjects were stratified at baseline based on the ESS (0 versus 1) of
their most recent endoscopy.
This study had a total of 42 months of treatment duration. The primary analysis was
conducted after the last subject enrolled reached their Month 6 study visit. The initial
treatment assignment at baseline remained double-blinded to the site and the subject. Study
visits occurred at baseline (enrollment), and at Months 1, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30,
33, 36, 39 and 42. All subjects, who withdrew early or who completed this study, had a 4week safety follow up evaluation after the last dose of investigational product.
Any time after Month 1, subjects who experienced flare could have had their dose escalated.
Flare was defined by meeting 1 of the following 4 criteria:
1.

An increase in rectal bleeding subscore by at least 1 point and an increase in ESS by
at least 1 point; OR

2.

An increase in rectal bleeding subscore by at least 2 points and an ESS >0; OR

3.

An increase in stool frequency subscore by at least 2 points and an increase in the
ESS by at least 1 point; OR

4.

An increase in ESS by at least 2 points.

Subjects with confirmed flare were eligible for a dose escalation provided that the subject did
not have any of the risk factors for PE/VTE.
Subjects who were identified to have one or more of the risk factors for PE/VTE had theirtofacitinib dose adjusted to open label 5 mg BID.
PFIZER CONFIDENTIAL
Page 7

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Number of Participants (planned and analyzed):
This study was conducted at 82 sites. A total of 140 participants were enrolled at 93 centersin 20 countries.
A total of 140 participants were randomized into the study, with 70 participants randomized
to each treatment group.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Key inclusion criteria were as follows:
1. Subjects enrolled in Study A3921139 who had received tofacitinib 10 mg BID for aminimum of 2 consecutive years in Study A3921139 prior to and including baseline of
Study A3921288.
2. Subjects who were in stable remission on tofacitinib 10 mg BID for the 6 month period
in Study A3921139 up to and including baseline of Study A3921288, defined asmeeting all of the following criteria:a. A partial Mayo score 2, with no individual subscore >1 and a rectal bleeding
subscore of 0 at each study visit where data were available during the 6 month
period in Study A3921139 prior to and including baseline of Study A3921288;
b. AND at least 1 assessment of remission based on Mayo score;

If an endoscopy was not completed 6 months prior to baseline of
Study A3921288, then an endoscopy performed in Study A3921139 with an
ESS of 0 or 1, was required prior to randomization into Study A3921288.

All available assessments based on Mayo score during this period must haveshown remission.

c. AND subjects must not have been receiving any corticosteroid therapy for their UC
for at least 4 weeks prior to baseline.
Key exclusion criteria were as follows:
1. Subjects who were initially assigned to tofacitinib 10 mg BID at baseline of
Study A3921139 whose tofacitinib dose was reduced to 5 mg BID due to safety or
efficacy reasons.
2. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious
colitis, or clinical findings suggestive of Crohn’s disease.

PFIZER CONFIDENTIAL
Page 8

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

3. Subjects who in the opinion of the investigator are likely to require surgery for UC
during the study period.
4. Subjects with evidence of colonic malignancy or any dysplasia (eg, "flat dysplasia";
polyp) identified on endoscopic exam during Study A3921139. Subjects withcompletely resected adenomatous polyp(s) outside of (proximal to) the extent of colitis
may be eligible upon consultation with the sponsor. Note, pathology report must be
reviewed prior to subject enrollment.
Beginning with Protocol Amendment 2, subjects with any of the following risk factors for PE
at baseline as defined by European Medicines Agency’s Pharmacovigilance Risk Assessment
Committee (this only impacted the last subject enrolled):

had heart failure;

had inherited coagulation disorders;

has had venous thromboembolism, either deep venous thrombosis or PE;

was taking combined hormonal contraceptives or hormone replacement therapy;

had malignancy (association is strongest with cancers other than non-melanoma skincancers);

was undergoing major surgery.

Study Interventions, Dose, Mode of Administration, and Batch Number(s):Table 2.

Study Intervention(s) Administered

Investigational Product
Description
Placebo for Tofacitinib Citrate
5 mg Film Coated Tablet
Placebo for Tofacitinib Citrate
5 mg Film Coated Tablet
Placebo for Tofacitinib Citrate
5 mg Film Coated Tablet
Placebo for Tofacitinib Citrate
5 mg Film Coated Tablet
Tofacitinib Citrate 5 mg Film
Coated Tablet
Tofacitinib Citrate 5 mg Film
Coated Tablet
Tofacitinib Citrate 5 mg Film
Coated Tablet

Vendor Lot
NumberR73682

Pfizer Lot
Number16-005146

Strength/
Potency
0 mg

DosageForm
Tablet

R7368316-005147

0 mg

TabletT9584818-000343

0 mg

Tablet

X8870418-003619

0 mg

Tablet

AJ694719-000910

5 mg

TabletDR845320-002711

5 mg

Tablet

S2691817-000460

5 mg

TabletPFIZER CONFIDENTIAL
Page 9

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Table 2.

Study Intervention(s) Administered

Investigational Product
Description
Tofacitinib Citrate 5 mg Film
Coated Tablet

Vendor Lot
Number
X20921

Pfizer Lot
Number18-002302

Strength/
Potency
5 mg

DosageForm
TabletDuration of Study Intervention:
Subjects were randomized into 1 of 2 dosing groups at baseline of Study A3921288:
 Tofacitinib 5 mg BID.
 Tofacitinib 10 mg BID.
Subjects who met the protocol definition for flare may have had a dose increase to
10 mg BID or remained on 10 mg BID, depending on their initial treatment assignment
provided that the subject did not have any of the risk factors for PE/VTE. Subjects who wereidentified to have one or more of the risk factors for PE/VTE had their tofacitinib dose
adjusted to open label 5 mg BID.
The manufacturing lot numbers for the study intervention(s) dispensed in this study areprovided in Table 2. Prior studies in the UC Phase 3 program have shown that tofacitinib
10 mg BID as an induction therapy and both tofacitinib 5 mg BID and 10 mg BID as amaintenance therapy were efficacious, relative to placebo, and had an acceptable safety andtolerability profile.
Summary of Results:
Demographic and Other Baseline Characteristics:
Selected demographic characteristics were as follows:

The mean age of subjects between both treatment groups was 47.8 years.

The majority of subjects were White (71.4 %); 20.7% of all subjects were of Asiandescent and 4.3% of subjects in the tofacitinib 5 mg BID group (0.0% in the tofacitinib
10 mg BID group) were Black or African American.

Selected baseline and clinical characteristics were as follows:

There were 70 (100.0%) and 68 (97.1%) subjects in remission at baseline in thetofacitinib 10 mg BID and tofacitinib 5 mg BID groups, respectively (Table 3).

At baseline, 51 (72.9%) subjects in each dose group had ESS of 0 (Table 3).

PFIZER CONFIDENTIAL
Page 10

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Mean and median baseline partial Mayo and baseline total Mayo scores were similar
between the treatment groups (Table 3).

Table 3.

Tofacitinib Protocol A3921288 Baseline and Clinical Characteristics, perdata from baseline of A3921288 study - FAS
Tofacitinib 5 mg BID(N=70)

Tofacitinib 10 mg BID(N=70)

Total(N=140)

n (%)

n (%)

n (%)

N1

70

70

140

0

51 (72.9)

51 (72.9)102 (72.9)

1

19 (27.1)

19 (27.1)

38 (27.1)

70

70

140

Endoscopic Subscore at baseline

Remission at baseline
N1No

2 (2.9)02 (1.4)Yes

68 (97.1)

70 (100.0)

138 (98.6)

70

70

140

Modified Mayo Remission at baseline
N1No

1 (1.4)0

1 (0.7)Yes

69 (98.6)

70 (100.0)

139 (99.3)

70

70

140

Mucosal Healing at baseline
N1
No

0

0

0

Yes

70 (100.0)

70 (100.0)

140 (100.0)

70

70

140

Clinical Response at baseline
N1
No

0

0

0

Yes

70 (100.0)

70 (100.0)

140 (100.0)

70

70

140

Mean(SD)

0.6 (0.7)

0.6 (0.7)

0.6 (0.7)

Median

0.0

0.0

0.0

Min-Max(0.0- 2.0)

(0.0- 2.0)

(0.0- 2.0)

Modified Mayo score
N1

Total Mayo score
N1
Mean(SD)

70

70

140

0.6 (0.7)

0.7 (0.8)

0.6 (0.8)

PFIZER CONFIDENTIAL
Page 11

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Table 3.

Tofacitinib Protocol A3921288 Baseline and Clinical Characteristics, perdata from baseline of A3921288 study - FAS
Tofacitinib 5 mg BID(N=70)

Tofacitinib 10 mg BID(N=70)

Total(N=140)

n (%)

n (%)

n (%)

Median

0.0

0.0

0.0

Min-Max(0.0- 3.0)

(0.0- 2.0)

(0.0- 3.0)

Partial Mayo score
N1
Mean(SD)

70

70

140

0.4 (0.5)

0.4 (0.5)

0.4 (0.5)

Median

0.0

0.0

0.0

Min-Max(0.0- 2.0)

(0.0- 2.0)

(0.0- 2.0)

N1

70

70

140

< 25

29 (41.4)

23 (32.9)

52 (37.1)

25 - < 30

24 (34.3)

32 (45.7)

56 (40.0)>= 30

17 (24.3)

15 (21.4)

32 (22.9)

70

70

140

Mean(SD)

12.5 (7.9)

13.6 (7.7)

13.0 (7.8)

Median

10.3

11.2

10.6

Min-Max(4.4- 45.9)(4.6- 44.8)(4.4- 45.9)

BMI (kg/m**2)

Primary Diagnosis - Duration Since Onset(Years)*N1

Data cut-off: Final Data.
N = number of randomized subjects in the total population.
N1 = number of subjects in the specified category with non-missing values.
n = number of subjects with the specified response within the given category. % = n/N1.
* Duration of diagnosis is computed per A3921288 randomization date.
PFIZER CONFIDENTIAL SDTM Creation: 13APR2022 (12:03) Source Data: adsl
Output File: ./ibd_cdisc/A3921288_finalcsr/baseclin_1288 Date of Generation: 02JUN2022 (03:20)
Table 14.1.2.1.1 is for Pfizer internal use.

Exposure:
The duration of treatment for the majority of all participants was between 991 and 1260 days.
The median (range) duration of treatment was 1225.5 (29, 1288) days in the tofacitinib 5 mg
BID group and 1179.5 (267, 1269) days in the tofacitinib 10 mg BID group.

PFIZER CONFIDENTIAL
Page 12

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Efficacy Results
EfficacyThe proportion of subjects in modified Mayo remission at Month 6 (primary endpoint)by dose group was 90.0% and 77.1% for the tofacitinib 10 mg BID and tofacitinib 5 mg
BID group, respectively, with a difference (95% CI) of 12.9% (0.5%, 25.0%). When
analyzed by regimen group, the proportion of subjects in modified Mayo remission at
Month 6 was 90.0% and 85.7% for the tofacitinib 10 mg BID and tofacitinib 5 mg BID
group, respectively, with a difference (95% CI) of 4.3% (-6.9%, 15.5%).

While the proportion of subjects in remission based on modified Mayo score gradually
declined numerically over time, efficacy was maintained with the majority of subjects inremission through Month 30 when evaluated by either dose group or regimen group.



Evaluating by either dose group or regimen group, the proportion of subjects inremission based on modified Mayo score was higher for the tofacitinib 10 mg BID groupcompared with the tofacitinib 5 mg BID group, at both Month 18 and Month 30. Data at
Month 42 were impacted by early study termination.

Consistent findings were observed for the additional secondary efficacy endpoints –remission based on total Mayo score, mucosal healing and clinical response whenanalyzed by either dose group or regimen group.



Observed differences between tofacitinib 10 mg BID and 5 mg BID across efficacy
endpoints were generally greater in the subgroup with baseline ESS of 1 than thesubgroup with baseline ESS of 0; however, the confidence intervals overlap.

Generally, a higher observed proportion of subjects with a baseline ESS of 0 maintained
remission or achieved other binary efficacy endpoints up to Month 30 than the subjects
with a baseline ESS of 1 in the 5 mg BID group (ie, after dose reduction to 5 mg BID).



Except for clinical response, observed differences between tofacitinib 10 mg BID and
5 mg BID across the timepoints for the additional efficacy endpoints were generally
greater in the prior tumor necrosis factor inhibitor (TNFi) treatment failure subgroupthan in the subgroup without prior TNFi treatment failure; however, the confidence
intervals overlap.

Generally, a slightly higher observed proportion of subjects without prior TNFi failure
maintained remission or achieved other binary efficacy endpoints up to Month 30 than
the subjects with prior TNFi failure in the 5 mg BID group (ie, after dose reduction to
5 mg BID).

PFIZER CONFIDENTIAL
Page 13

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSISThe biomarker analyses (FCP/hsCRP) performed were generally consistent between
tofacitinib 10 mg BID and tofacitinib 5 mg BID groups when evaluated by either dosegroup or regimen group.

Safety Results:
By dose group or regimen group, the number of participants with all causality treatmentemergent adverse events (TEAEs) was 55 (78.6%) and 58 (82.9%) in the tofacitinib 5 mg
BID and tofacitinib 10 mg BID treatment groups, respectively. When evaluated by either
dose group or regimen group, the majority of the TEAEs in each treatment group were mild
to moderate.
For the TEAEs by dose group, the following observations were noted:
The proportion of participants with severe TEAEs was 11.4% (8 participants) and 14.3%(10 participants) in the tofacitinib 5 mg BID group and tofacitinib 10 mg BID group,
respectively (Table 4).



The number of participants with serious adverse events (SAEs) was lower in thetofacitinib 5 mg BID group (7 [10.0%]) compared with the tofacitinib 10 mg BID group(16 [22.9%]) (Table 4).

Eleven (11) participants (15.7%) discontinued the study due to AEs in the tofacitinib
5 mg BID group compared with 13 participants (18.6%) in the tofacitinib 10 mg BID
group (Table 4).



Six (6) participants (8.6%) in the tofacitinib 5 mg BID group and 8 participants (11.4%)
in the tofacitinib 10 mg BID group had dose reduced or temporary discontinuation due toAEs (Table 4).

For the TEAEs by regimen group, the following observations compared to the analysis bydose group were noted in the tofacitinib 5 mg BID group:

One (1) additional participant reported a severe TEAE.



Three (3) additional participants reported SAEs.



Two (2) additional participants discontinued the study due to AEs.

PFIZER CONFIDENTIAL
Page 14

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

Table 4.

Tofacitinib Protocol A3921288 Treatment-Emergent Adverse Events by
Dose Group (All Causalities) - Safety Analysis Set
Tofacitinib 5 mg
BID

Tofacitinib 10 mg
BID

Total

Number (%) of Subjects

n (%)

n (%)

n (%)

Participants evaluable for adverse events

70

70

140

Number of adverse events

206

241

447

Participants with adverse events55 (78.6)

58 (82.9)

113 (80.7)

Participants with serious adverse events

7 (10.0)

16 (22.9)

23 (16.4)

Participants with severe adverse events

8 (11.4)

10 (14.3)

18 (12.9)

Participants discontinued from study due to adverse events (a)11 (15.7)

13 (18.6)

24 (17.1)

Participants with dose reduced or temporary discontinuation
due to adverse events

6 (8.6)8 (11.4)

14 (10.0)

Data cut-off: Final Data.
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.
(a) Subjects who have an AE record that indicates that the AE caused the subject to be discontinued from the study.
MedDRA v24.1 coding dictionary applied.
PFIZER CONFIDENTIAL SDTM Creation: 13APR2022 (14:45) Source Data: adae
Output File: ./ibd_cdisc/A3921288_finalcsr/adae_s020 Date of Generation: 02JUN2022 (03:19)
Table 14.3.1.2.1.a is for Pfizer internal use.

Safety

When evaluated by either dose group or regimen group, the proportions of participants
with TEAEs were similar between the tofacitinib 10 mg BID and tofacitinib 5 mg BID
groups. The proportion of participants with SAEs in the tofacitinib 10 mg BID group
was numerically higher than that of the tofacitinib 5 mg BID group.



There were 24 participants who discontinued from the study due to adverse events bydose group. Two (2) additional participants discontinued from the study due to adverse
events when evaluated by regimen group.



One (1) death was reported in the tofacitinib 10 mg BID group in this study. The causeof death was respiratory failure and cardiac arrest due to complications of coronavirus
disease 2019 (COVID-19) pneumonia.

No new or unexpected safety findings were observed.


Serious infections were reported in 9 participants when evaluated by dose group (3 inthe tofacitinib 5 mg BID group; 6 in the tofacitinib 10 mg BID group). One (1)PFIZER CONFIDENTIAL
Page 15

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSIS

additional serious infection (appendicitis) was reported in the tofacitinib 5 mg BID
group when evaluated by regimen group (ie, while receiving tofacitinib 10 mg BID).


When evaluated by dose group, herpes zoster infections were reported in 8
participants (2 in the tofacitinib 5 mg BID group; 6 in the tofacitinib 10 mg BID
group). In the tofacitinib 10 mg BID group, 1 herpes zoster event met criteria for an
opportunistic infection (OI), 1 herpes zoster event met criteria for a special interest
infection, and 1 herpes zoster event (herpes zoster oticus) classified as serious herpes
zoster. An additional herpes zoster event (mild severity) was reported in thetofacitinib 10 mg BID group when evaluated by regimen group (ie, while receiving
tofacitinib 5 mg BID).



No non-herpes zoster OIs were reported.



Four (4) CV/neurovascular events were confirmed by adjudication in the dose group(1 PE in the tofacitinib 10 mg BID group; 1 fatal COVID-19 pneumonia in thetofacitinib 10 mg BID group; 1 deep vein thrombosis [DVT] in the tofacitinib 5 mg
BID group; 1 cerebrovascular accident in the tofacitinib 5 mg BID group). No
additional events were reported when evaluated by regimen group.



Four (4) malignancies excluding non-melanoma skin cancer (NMSC) were confirmed
by adjudication in the dose group (vulvar cancer in the tofacitinib 5 mg BID group;colorectal cancer in the tofacitinib 5 mg BID group; non-Hodgkin lymphoma in thetofacitinib 10 mg BID group; prostate cancer in the tofacitinib 10 mg BID group). No
additional events were reported when evaluated by regimen group.



Three (3) subjects reported NMSC events confirmed by adjudication in the dosegroup (cutaneous squamous cell carcinoma in the tofacitinib 5 mg BID group (4events in 1 participant); basal cell carcinoma in the tofacitinib 5 mg BID group; basal
cell carcinoma in the tofacitinib 10 mg BID group). No additional events werereported when evaluated by regimen group.



One (1) hepatic event in the tofacitinib 10 mg BID group was adjudicated andassessed as unlikely to be drug-induced liver injury; no potential or confirmed Hy’s
Law cases.

No gastrointestinal perforations were confirmed by adjudication.

Clinical laboratory values remained stable throughout the treatment period. Two (2)participants met criteria for discontinuation of study drug for laboratory values whenevaluated by dose group (1 in each of the tofacitinib 5 mg BID and tofacitinib
10 mg BID groups). An additional participant met criteria in the tofacitinib 5 mg BID
group when evaluated by regimen group (ie, while receiving tofacitinib 10 mg BID).

PFIZER CONFIDENTIAL
Page 16

Supplemental Full Clinical Study Report
Protocol A3921288

CLINICAL STUDY REPORT SYNOPSISNo clinically meaningful findings in the vital signs measurements, or physicalexamination assessments were observed in this study.

Conclusions:

The primary efficacy endpoint results (proportion of subjects in remission based on
modified Mayo score at Month 6) were 90.0% and 77.1% for the tofacitinib 10 mg BID
and tofacitinib 5 mg BID groups, respectively, when evaluated by dose group. Whenevaluated by regimen group, the proportion of subjects in remission based on modified
Mayo score was 90.0% and 85.7% for the tofacitinib 10 mg BID and 5 mg BID groups,
respectively.

The majority of subjects in the tofacitinib 5 mg BID and tofacitinib 10 mg BID groups
maintained modified Mayo remission up to Month 30 when evaluated by either dosegroup or regimen group.

No new safety signals specific to the UC population treated with tofacitinib wereidentified.

PFIZER CONFIDENTIAL
Page 17