Public Disclosure Synopsis
Protocol A3921094 – 16 May 2016 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
GENERIC DRUG NAME and/or COMPOUND NUMBER: Tofacitinib/CP-690,550
PROTOCOL NO.: A3921094

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PROTOCOL TITLE: A Multicentre, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Study of Oral CP-690,550 as an Induction Therapy in Subjects With
Moderate to Severe Ulcerative Colitis
Study Center(s): The study was conducted at 113 study centers: Australia (3), Austria (1),Belgium (1), Canada (4), Colombia (1), Croatia (1), Czech Republic (2), Denmark (2),Estonia (1), France (3), Germany (4), Hungary (4), Israel (2), Italy (4), Japan (23), Latvia (1),Netherlands (1), New Zealand (3), Poland (4), Romania (1), Russian Federation (4), Serbia(4), Slovakia (1), South Africa (2), Spain (4), Ukraine (7), United Kingdom (UK) (2), andUnited States (US) (23). In addition, there were 31 study centers that received study drug but
did not randomize any subjects.
Study Initiation Date and Final Completion Date: 18 April 2012 to 22 May 2015.
Phase of Development: Phase 3
Study Objective(s):The primary objective of this study was:

To demonstrate the efficacy of tofacitinib in inducing remission in subjects withmoderately to severely active ulcerative colitis (UC).

The secondary objectives of this study were:To evaluate the safety and tolerability of tofacitinib in subjects with moderately toseverely active UC;To evaluate the efficacy of tofacitinib in achieving mucosal healing in subjects withmoderately to severely active UC;To evaluate the effect of tofacitinib induction therapy on other clinical outcomes insubjects with moderately to severely active UC;To evaluate tofacitinib pharmacokinetic (PK) exposure during induction therapy insubjects with moderately to severely active UC.

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METHODS
Study Design: This was a Phase 3, randomized, double-blind, placebo-controlled,parallel-group, multicenter study in subjects with moderately to severely active UC.
After the screening period, subjects who met the inclusion and exclusion criteria at thebaseline visit were randomly assigned to receive 9 weeks of either tofacitinib 10 mg twice aday (BID) or matched placebo BID at a 4:1 allocation ratio. This reflected a change put inplace with Protocol Amendment 3, which removed the tofacitinib 15 mg BID arm from thestudy. Subjects who were enrolled prior to Amendment 3 were randomly assigned to receive
either tofacitinib 10 mg BID, tofacitinib 15 mg BID, or matched placebo BID at a 2:2:1
allocation ratio. Subjects who were randomized under the prior protocol and who were still
active in this study at the time of the approval of Protocol Amendment 3 continued to receive
blinded treatment assigned at baseline for the treatment period.

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Subjects were stratified based on the status of prior treatment with tumor necrosis
factor-alpha inhibitor (TNFi) therapy, corticosteroid use at baseline, and geographic region.
Subjects who completed the double-blind treatment and achieved clinical response orremission at Week 8 were eligible to enter a double-blind maintenance study (A3921096).
Clinical response was defined by a decrease from baseline in Mayo score of at least 3 points
and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least
1 point, or an absolute rectal bleeding subscore of 0 or 1. Remission was defined by a total
Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal
bleeding subscore of 0.
Subjects who completed the double-blind treatment but did not achieve clinical response anddid not show improvement on centrally read endoscopic subscores at Week 8 may have had
an opportunity to enter an open-label study (A3921139).
Subjects who were early withdrawals from the study or who were not transferred into themaintenance study or open-label study had a 4-week safety follow-up after the last dose of
study medication. A schematic of the study design is shown in Figure 1.

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Figure 1

Overview of Study Design

BID = twice a day, DB = double-blind.

Number of Subjects (Planned): There were to be 545 subjects enrolled in the study andrandomized in a 4:1 ratio to either tofacitinib 10 mg BID or placebo. Prior to Protocol
Amendment 3, subjects were to be randomized in a 2:2:1 ratio to tofacitinib 10 mg BID,
tofacitinib 15 mg BID, or placebo.
Diagnosis and Main Criteria for Inclusion: Subjects were men and women of at least
18 years of age with a diagnosis of UC that was documented at least 4 months prior toentering the study and who had moderately to severely active UC based on total Mayo scoreof 6 with a rectal bleeding score of 1, and an endoscopic subscore of 2 on the Mayo score
determined within 10 days of baseline visit (Visit 2). All subjects had either failed or been
intolerant of at least 1 of the following UC treatments: oral or intravenous (IV)corticosteroids, azathioprine or 6-mercaptopurine (6-MP), or TNFi therapy (infliximab or
adalimumab).
Study Treatment: Subjects received their study medications as outpatients. Tofacitinib
10 mg or placebo was taken orally BID (approximately every 12 hours) for up to 9 weeks.
Subjects were dispensed 2 bottles containing either 5 mg tofacitinib or placebo tablets.
Subjects were instructed to take 1 tablet from each bottle in the morning and 1 tablet fromeach bottle in the evening, approximately 12 hours apart. Subjects were therefore taking
2 tablets BID.
Subjects enrolled prior to Protocol Amendment 3 who were randomized to 15 mg BID weredispensed 3 bottles containing either 5 mg tofacitinib or placebo tablets. These subjects were
instructed to take their study medication as 1 tablet from each of the 3 bottles in the morning

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and 1 tablet from each bottle in the evening, approximately 12 hours apart for a total of
3 tablets BID until they completed or were prematurely discontinued from the study.
Tofacitinib could be administered with or without food. If a tofacitinib dose was missed andthe interval to the next scheduled dose was to be <6 hours, the missed dose of tofacitinib was
not administered.
Efficacy Endpoints
Primary Efficacy Endpoint:
The primary efficacy endpoint was as follows:

The proportion of subjects in remission at Week 8.

Key Secondary Efficacy Endpoint:
The key secondary efficacy endpoint was as follows:

The proportion of subjects achieving mucosal healing at Week 8.

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Other Secondary Efficacy Endpoints:
The other secondary efficacy endpoints were as follows:

The proportion of subjects achieving clinical response at Week 8;

The proportion of subjects in endoscopic remission at Week 8;

The proportion of subjects in clinical remission at Week 8;

The proportion of subjects in symptomatic remission at Week 8;

The proportion of subjects achieving deep remission at Week 8;

Partial Mayo scores and change from baseline over time;

Change from baseline at Week 8 in total Mayo score.

Safety Evaluations: Safety was assessed by the incidence and severity of spontaneous
reporting of adverse events (AEs) in all subjects who received at least 1 dose of study
medication.

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Statistical Methods:
The data sets summarized and analyzed in this study were the full analysis set (FAS), definedas all subjects randomly assigned to either tofacitinib 10 mg BID or placebo, and the safety
analysis set, defined as all randomized subjects who received at least 1 dose of study
medication.
Efficacy Analyses:

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In order to control the familywise Type I error rate, a fixed sequence procedure was used.
The hypothesis of no treatment effect between the tofacitinib 10 mg BID and the placebo forthe primary endpoint was tested first at the 2-sided significance level 0.05. If it wassignificant, the hypothesis of no treatment effect between the tofacitinib 10 mg BID and theplacebo for the key secondary endpoint was then tested at the significance level 0.05. The
statistical significance was to be claimed for the key secondary endpoint only if the treatment
effect for the primary efficacy endpoint was also significant. All other efficacy endpoints
were evaluated at the 0.05 level of significance, without adjustments for multiple
comparisons.
Both locally and centrally read endoscopic scores were used for the derivation of all efficacy
endpoints. The primary analyses were based on the efficacy endpoints derived from thecentrally read endoscopic scores and are presented in this report.
Analysis of Primary Endpoints
The primary analysis was based on the FAS. The primary endpoint was compared between
treatment groups by the Cochran-Mantel-Haenszel (CMH) Chi-square test stratified by priortreatment with TNFi therapy, corticosteroid use at baseline, and geographic region; in casethe cell frequencies were too small, the Fisher’s exact test was to be used. The difference
between treatment groups was presented along with its 95% 2-sided confidence interval (CI)in the proportion of subjects in remission at Week 8 using the normal approximation for thedifference. Subjects with missing remission data at Week 8 were treated as non-responders.
The non-responder imputation (NRI) method was used to handle missing values in both thesummary presentations and analyses.
Analysis of Secondary Endpoints
The endpoint of mucosal healing at Week 8 was analyzed and summarized using the same
methods as those for the primary endpoint, including the sensitivity analyses.
For the other secondary endpoints, the summary presentations and analyses were performedon the FAS population with no adjustments for multiple comparisons.
The binary endpoints were analyzed by the CMH Chi-square test stratified by prior treatment
with TNFi therapy, corticosteroid use at baseline, and geographical region; Fisher’s exact test
was used in case of small cell frequencies. The difference between treatment groups waspresented along with its 95% 2-sided CI using the normal approximation for the difference.

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The NRI method was used to handle missing values in both the summary presentations andanalyses.
Continuous secondary endpoints measured at baseline and Week 8, such as total Mayo score,
were analyzed at Week 8 as changes from baseline using an analysis of covariance(ANCOVA) model with prior treatment with TNFi therapy, corticosteroid use at baseline,
and geographic region as factors and baseline score as a covariate based on the observed-casedata. Both the actual values and change from baseline were summarized by treatment groupusing descriptive statistics at each visit. Estimates of the differences and associated 95% CIs
for the comparison of tofacitinib 10 mg BID to placebo were computed.
For continuous secondary endpoints that were measured repeatedly over time, such as partial
Mayo score, the changes from baseline were analyzed using a linear mixed-effects modelwith baseline, treatment group, prior treatment with TNFi therapy, corticosteroid use atbaseline, geographic region, visit, and treatment group by visit interaction as fixed effects,
and subject as a random effect.

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Safety Analysis:
Safety evaluations were analyzed using the safety analysis set. Missing data for safety
endpoints were not imputed and were left as missing. All safety data were summarizedaccording to the sponsor’s data standards.
RESULTS
Subject Disposition and Demography: Subject disposition is summarized in Table 1. Of
990 subjects screened for entry into the study, 614 subjects were randomized to study
treatment. Of these, 598 subjects were randomized to tofacitinib 10 mg BID or placebo(FAS): 476 subjects were randomized to tofacitinib 10 mg BID, and 122 subjects wererandomized to placebo. All randomized subjects received at least 1 dose of study drug
(safety analysis set). There were 16 (2.4%) subjects who were randomized to and received
tofacitinib 15 mg BID prior to Protocol Amendment 3.
The numbers of subjects that discontinued and completed the study are included in Table 1.
The proportion of subjects who discontinued the study was low in all treatment groups.

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Table 1.

Subject Disposition by Treatment Group
Tofacitinib 10 mg
BID
n (%)

Tofacitinib 15 mg
BID
n (%)

Placebon (%)

Screened (N = 990)
Randomized (N = 614)aPrior to Protocol Amendment 3
After Protocol Amendment 3

476 (77.5)
14 (2.3)
462 (75.2)

16 (2.6)
16 (2.6)0122 (19.9)
8 (1.3)114 (18.6)

Full Analysis Set
Per Protocol Analysis Set
Safety Analysis Set
Adverse eventsb

476 (100.0)
443 (93.1)
476 (100.0)476 (100.0)

16 (100.0)
15 (93.8)
16 (100.0)
16 (100.0)

122 (100.0)
117 (95.9)
122 (100.0)
122 (100.0)

TreatedCompleted
Discontinuedc

476 (100.0)445 (93.5)
31 (6.5)

16 (100.0)
15 (93.8)
1 (6.3)122 (100.0)
118 (96.7)
4 (3.3)

Primary Reason for Discontinuation
Subject died
1 (0.2)00
Related to study drug
19 (4.0)02 (1.6)Adverse event
8 (1.7)0
1 (0.8)Insufficient clinical responsed
11 (2.3)
01 (0.8)
Not related to study drug
11 (2.3)
1 (6.3)2 (1.6)Adverse event
1 (0.2)00
No longer willing to participate in study
4 (0.8)0
1 (0.8)
Protocol violation
4 (0.8)1 (6.3)1 (0.8)Other
2 (0.4)00
BID = twice a day, N = total number of subjects, n = number of subjects meeting prespecified criteria.
a.
Percentage of randomized subjects in each treatment group and in prior and after Protocol Amendment 3 rows
was calculated using the total number randomized (614) as the denominator. All other percentages were
calculated using the total number randomized in each respective treatment group.
b.
Adverse events (AEs) – all randomized subjects for which the Adverse Event case report form (CRF) wascompleted in the database.
c.
One subject in the tofacitinib 10 mg BID treatment group completed the Week 8 visit and was then withdrawn
for an AE. This subject was counted as discontinued instead of completed.
d.
AEs of worsening of ulcerative colitis leading to discontinuation were designated as insufficient clinicalresponse.

Overall, demographic characteristics were similar across treatment groups (Table 2). For all
subjects randomized, there were more male than female subjects and the majority werewhite.

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Table 2.

Baseline Demographic Characteristics by Treatment Group

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Tofacitinib 10 mg BID(N = 476)

Tofacitinib 15 mg BID(N = 16)

Placebo(N = 122)

Age (years)
Mean (SD)41.3 (14.1)
39.9 (12.8)
41.8 (15.3)
Range
18, 77
21, 6819, 81
Sex, n (%)
Men
277 (58.2)
9 (56.3)
77 (63.1)
Women
199 (41.8)
7 (43.8)45 (36.9)
Race, n (%)
White
395 (83.0)
12 (75.0)
98 (80.3)
Black
3 (0.6)0
3 (2.5)Asian
54 (11.3)
3 (18.8)
14 (11.5)
Other
15 (3.2)
1 (6.3)3 (2.5)
Unspecified
9 (1.9)04 (3.3)Weight (kg)
Mean (SD)72.9 (16.8)
78.1 (19.3)
72.7 (16.7)
Range
37.0, 156.5
55.0, 127
37.4, 130
Height (cm)Mean (SD)
171.4 (9.6)
168.1 (5.0)
172.4 (10.4)
Range
145.5, 196.0
160.0, 175.3
143.0, 199.0
Race was not collected for French subjects.
BID = twice a day, N = number of subjects randomized, n = number of subjects meeting prespecified criteria,
SD = standard deviation.

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Efficacy Results:
Primary Efficacy Endpoint:
The proportion of subjects achieving remission at Week 8 (FAS, NRI) was statisticallysignificantly greater in the tofacitinib 10 mg BID group compared with the placebo group(Table 3).
Table 3.

Proportion of Subjects in Remission at Week 8 (FAS, NRI)
Tofacitinib 10 mg BID(N = 476)n (%)

Placebo(N = 122)n (%)

Difference From Placebo
Difference (95% CI)a
P-ValuebRemission
Central read88 (18.5)
10 (8.2)
10.3 (4.3, 16.3)
0.0070
BID = twice a day, CI = confidence interval, FAS = full analysis set, N = number of subjects in the analysis set,n = number of subjects meeting prespecified criteria, TNFi = tumor necrosis factor-alpha inhibitor.
a.
95% CI was based on the normal approximation for the difference.
b.
P-value was based on Cochran-Mantel-Haenszel (CMH) Chi-squared test stratified by prior treatment with
TNFi, corticosteroid use at baseline, and geographical region.

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Key Secondary Efficacy Endpoint:
The proportion of subjects achieving mucosal healing at Week 8 (FAS, NRI) was statisticallysignificantly greater in the tofacitinib 10 mg BID group compared with the placebo group(Table 4).
Table 4.

Proportion of Subjects With Mucosal Healing at Week 8 (FAS, NRI)
Tofacitinib 10 mg BID(N = 476)n (%)

Placebo(N = 122)n (%)

Difference From Placebo
Difference (95% CI)a P-Valueb

Mucosal Healing
Central read149 (31.3)
19 (15.6)
15.7 (8.1, 23.4)
0.0005
Mucosal healing was defined by a Mayo endoscopic subscore of 0 or 1.
BID = twice a day, CI = confidence interval, FAS = full analysis set, N = number of subjects in the analysis set,n = number of subjects meeting specific criteria, TNFi = tumor necrosis factor-alpha inhibitor.
a.
95% CI was based on the normal approximation for the difference.
b.
P-value was based on Cochran-Mantel-Haenszel (CMH) Chi-squared test stratified by prior treatment with
TNFi, corticosteroid use at baseline, and geographical region.

Other Secondary Efficacy Endpoints:
For the other secondary endpoints of both clinical remission and clinical response at Week 8,
tofacitinib 10 mg BID had statistically significantly higher proportions of subjects withclinical remission and clinical response at Week 8 compared with placebo (Table 5).
For the other secondary endpoints of endoscopic remission and deep remission, tofacitinib
10 mg BID had statistically significantly higher proportions of subjects with endoscopic
remission and deep remission at Week 8 compared with placebo (Table 5).

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Table 5.

Summary of Other Secondary Binary Efficacy Endpoints at Week 8 (FAS,
NRI)
Tofacitinib 10 mg BID(N = 476)n (%)

Placebo(N = 122)n (%)

Difference From Placebo
Difference (95% CI)a
P-Valueb

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Clinical remission
Central read88 (18.5)
10 (8.2)
10.3 (4.3, 16.3)
0.0070
Clinical response
Central read
285 (59.9)
40 (32.8)
27.1 (17.7, 36.5)<0.0001
Endoscopic remission
Central read32 (6.7)
2 (1.6)5.1 (1.9, 8.3)
0.0345Symptomatic remission
Central read56 (11.8)
7 (5.7)
6.0 (1.0, 11.1)
0.0601
Deep remission
Central read31 (6.5)0 (0)6.5 (4.3, 8.7)
0.0043
BID = twice a day, CI = confidence interval, FAS = full analysis set, N = number of subjects in the analysis set,n = number of subjects meeting specific criteria, TNFi = tumor necrosis factor-alpha inhibitor.
a.
95% CI was based on the normal approximation for the difference.
b.
P-value was based on Cochran-Mantel-Haenszel (CMH) Chi-squared test stratified by prior treatment with
TNFi, corticosteroid use at baseline, and geographical region; p-value from Fisher’s exact test was also
provided in the source table.

The descriptive statistics (FAS, observed cases) for the partial Mayo score (range: 0 to 9) andpartial Mayo score change from baseline are presented in Table 6. Baseline mean partial
Mayo scores were similar for both the tofacitinib 10 mg BID and placebo groups.
Reductions in partial Mayo scores were greater in the tofacitinib 10 mg BID group than theplacebo group. The analysis of change from baseline for partial Mayo scores using the linear
mixed-effects model (FAS, observed cases) is presented in Table 7. As early as Week 2,
which was the first post-baseline timepoint assessed, the tofacitinib 10 mg BID treatmentgroup showed a statistically significantly greater reduction from baseline in partial Mayoscore than placebo. The difference between treatment groups continued to increase at
Week 4 and Week 8.

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Table 6.

Descriptive Statistics of Partial Mayo Score and Change from Baseline(FAS, Observed Cases)
Tofacitinib 10 mg BID
Change From
Observed Data
Baseline

Placebo
Change From
Observed Data
Baseline

Partial Mayo Score
Baseline
N
475
121
Mean (SD)
6.3 (1.2)
6.5 (1.2)
Week 2
N
465
464
122
121
Mean (SD)
4.2 (2.2)-2.1 (2.0)
5.2 (2.1)-1.3 (1.7)
Week 4
N
461
460
118
117
Mean (SD)
3.5 (2.3)-2.8 (2.1)
4.8 (2.4)-1.7 (1.8)
Week 8
N
449
448
119
118
Mean (SD)
3.2 (2.4)-3.2 (2.3)
4.8 (2.5)-1.7 (2.1)
BID = twice a day, FAS = full analysis set, N = number of observations with non-missing values, SD = standard
deviation.

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Table 7.

Analysis of Change From Baseline for Partial Mayo Score Using Linear
Mixed-Effects Model (FAS, Observed Cases)
N

Change From Baseline
Adjusted Mean
SE

Diff

Difference From Placebo
SE
95% CI
P-Value

Week 2
Tofacitinib 10 mg BID 464
-2.1
0.1
-0.9
0.2
(-1.3, -0.5)<0.0001
Placebo
121
-1.2
0.2
Week 4
Tofacitinib 10 mg BID 460
-2.8
0.1
-1.1
0.2
(-1.5, -0.7)<0.0001
Placebo
117
-1.6
0.2
Week 8
Tofacitinib 10 mg BID 448
-3.1
0.1
-1.5
0.2
(-1.9, -1.1)<0.0001
Placebo
118
-1.6
0.2
P-value was obtained from the mixed-effects model: Change from baseline = treatment + prior treatment withTNFi + corticosteroid use at baseline + geographic region + week + treatment*week + baseline with subjects as
random effect.
BID = twice a day, CI = confidence interval, Diff = difference, FAS = full analysis set, N = number ofobservations with non-missing values, SE = standard error, TNFi = tumor necrosis factor-alpha inhibitor.

The analysis of change from baseline for total Mayo scores at Week 8 using the ANCOVA(FAS, observed cases) is presented in Table 8. At Week 8, the tofacitinib 10 mg BID group
showed statistically significantly greater reduction from baseline in total Mayo scorecompared with the placebo group.

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Table 8.

Analysis of Change From Baseline for Total Mayo Score at Week 8 Using
the ANCOVA Model (FAS, Observed Cases)
N

Change From Baseline
Adjusted Mean
SE

Diff

Difference From Placebo
SE
95% CI
P-Value

Week 8
Tofacitinib 10 mg BID
446
-3.8
0.1
-1.9
0.3
(-2.5, -1.4)<0.0001
Placebo
117
-1.8
0.3
Adjusted means and p-value were obtained from the ANCOVA model: change from baseline = treatment+ baseline total Mayo score + prior treatment with TNFi + corticosteroid use at baseline + geographic region.
ANCOVA = analysis of covariance, BID = twice a day, CI = confidence interval, Diff = difference, FAS = fullanalysis set, N = number of observations with non-missing values, SE = standard error, TNFi = tumor necrosis
factor-alpha inhibitor.

Safety Results:

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All-Causality Treatment-Emergent Non-Serious Adverse Events
The incidence (>5% of subjects) of all-causality non-serious treatment-emergent adverse
events (TEAEs) was similar for subjects treated with tofacitinib 10 mg BID compared withsubjects treated with placebo (Table 9). The most frequent non-serious TEAEs by preferredterm (PT) reported were headache and nasopharyngitis in the tofacitinib 10 mg BID andplacebo groups.

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Table 9.

Treatment-Emergent Non-Serious Adverse Events by System Organ Classand Preferred Term (All Causalities) in >5% of Subjects

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Number (%) of Subjects
Evaluable for adverse events
With adverse events

Tofacitinib 10 mg BIDn (%)

Tofacitinib 15 mg BID
n (%)

Placebon (%)

476
148 (31.1)

16
12 (75.0)

122
38 (31.1)

Subjects with AEs by: SOCs and
MedDRA PTs
Blood and Lymphatic System Disorders
11 (2.3)
1 (6.3)6 (4.9)Anaemia
11 (2.3)
1 (6.3)6 (4.9)Gastrointestinal Disorders
23 (4.8)
3 (18.8)9 (7.4)
Colitis ulcerative
6 (1.3)1 (6.3)3 (2.5)
Flatulence
2 (0.4)1 (6.3)1 (0.8)Gastrooesophageal reflux disease0
1 (6.3)0
Nausea15 (3.2)
1 (6.3)5 (4.1)
General Disorders and Administration
Site Conditions
24 (5.0)
2 (12.5)7 (5.7)
Fatigue
10 (2.1)
1 (6.3)4 (3.3)Pyrexia
14 (2.9)
1 (6.3)3 (2.5)
Infections and Infestations
65 (13.7)
6 (37.5)
13 (10.7)
Folliculitis
9 (1.9)1 (6.3)0
Gastroenteritis
7 (1.5)1 (6.3)2 (1.6)
Nasopharyngitis
34 (7.1)
3 (18.8)9 (7.4)Sinusitis
2 (0.4)2 (12.5)
1 (0.8)Upper respiratory tract infection
15 (3.2)
1 (6.3)1 (0.8)Investigations
12 (2.5)
3 (18.8)
0
Blood creatine phosphokinase
increased
12 (2.5)
1 (6.3)0
Liver function test abnormal0
1 (6.3)0White blood cell count increased0
1 (6.3)0
Musculoskeletal and Connective Tissue
Disorders
2 (0.4)1 (6.3)2 (1.6)
Myalgia2 (0.4)1 (6.3)2 (1.6)
Nervous System Disorders
37 (7.8)08 (6.6)
Headache37 (7.8)08 (6.6)
Psychiatric Disorders
1 (0.2)2 (12.5)
1 (0.8)
Anxiety0
1 (6.3)0Depressed Mood
1 (0.2)
1 (6.3)1 (0.8)
Renal and Urinary Disorders
1 (0.2)
1 (6.3)0
Dysuria
1 (0.2)
1 (6.3)0
Haematuria
0
1 (6.3)0
Skin and Subcutaneous Tissue Disorder
15 (3.2)
6 (37.5)
1 (0.8)Acne
10 (2.1)
3 (18.8)0
Alopecia
5 (1.1)1 (6.3)1 (0.8)
Dermatitis acneiform
01 (6.3)0
Night sweats0
1 (6.3)0Subjects were only counted once per treatment for each row.
Includes events from study database, even those that occurred after last dose of study drug.
MedDRA (v18.0) coding dictionary applied.
AE = adverse event, BID = twice daily, MedDRA = Medical Dictionary for Regulatory Activities, n = numberof subjects meeting prespecified criteria, PT = preferred term, SOC = system organ class.

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All-Causality Treatment-Emergent Serious Adverse Events

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The incidence of all-causality serious TEAEs was similar for subjects treated with tofacitinib
10 mg BID compared with subjects treated with placebo (Table 10). No subjects treated withtofacitinib 15 mg BID experienced serious TEAEs.

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Table 10. Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term (All Causalities)

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Tofacitinib 10 mg BID
n (%)
n1
n2
Number (%) of Subjects
Evaluable for adverse events
With adverse events476
16 (3.4)

Subjects with AEs by: SOCs and MedDRA PTs
Cardiac Disorders
Acute coronary syndrome
Gastrointestinal Disorders
Colitis ulcerative
Intestinal perforation
General Disorders and Administration Site Conditions
MalaiseImmune System Disorders
Drug hypersensitivity
Infections and Infestations
Anal abscessCellulitis
Clostridium difficile infection
Febrile infection
Otitis externa
Pneumonia
Injury, Poisoning and Procedural Complications
Animal bite
Joint injury
Musculoskeletal and Connective Tissue Disorders
Arthralgia
Reproductive system and Breast Disorders
Vulva cyst
Respiratory, Thoracic, and Mediastinal Disorders
Pulmonary embolism
Skin and Subcutaneous Tissue Disorders
Drug eruption

1 (0.2)1 (0.2)6 (1.3)5 (1.1)1 (0.2)1 (0.2)1 (0.2)1 (0.2)1 (0.2)6 (1.3)1 (0.2)1 (0.2)1 (0.2)1 (0.2)1 (0.2)1 (0.2)1 (0.2)0
1 (0.2)1 (0.2)1 (0.2)0000
1 (0.2)1 (0.2)

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Tofacitinib 15 mg BID
n (%)
n1
n2
16
0

1
1
6
5
1
1
1
1
1
6
1
1
1
1
1
1
1
0
1
1
1
0
0
0
0
1
1

0
0
2
1
1
0
0
0
0
2
0
0
0
1
0
1
0
0
0
0
0
0
0
0
0
0
0

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0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

n (%)

Placebo
n1

n2

0
0
2
2
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
0
0
1
1
1
1
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
0

122
5 (4.1)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

0
0
2 (1.6)2 (1.6)
0
0
0
0
0
0
0
0
0
0
0
0
1 (0.8)1 (0.8)000
1 (2.2)1 (2.2)1 (0.8)1 (0.8)00

Public Disclosure Synopsis
Protocol A3921094 – 16 May 2016 – Final

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Table 10. Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term (All Causalities)
Tofacitinib 10 mg BID
Tofacitinib 15 mg BID
Placebo
n (%)
n1
n2
n (%)
n1
n2
n (%)
n1
n2
Vascular Disorders
2 (0.4)
2
1
0
0
0
0
0
0
Aortic dissection
1 (0.2)
1
0
0
0
0
0
0
0
Temporal arteritis
1 (0.2)
1
1
0
0
0
0
0
0
Except for n1 and n2, subjects were only counted once per treatment for each row.
Includes events from study database, even those that occurred after last dose of study drug.
Percentages of gender-specific events were calculated using the corresponding gender count as the denominator.
MedDRA (v18.0) coding dictionary applied.
AE = adverse event, BID = twice daily, MedDRA = Medical Dictionary for Regulatory Activities, n = number of subjects in this reporting group affected by anoccurrence of this all-causality AE, n1 = number of occurrences of all-causality TEAEs, n2 = number of occurrences of treatment-related TEAEs, PT = preferredterm, SOC = system organ class.

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Withdrawals of Subjects from the Study
Discontinuations from the study are listed in Table 11. A greater proportion of subjects inthe tofacitinib 10 mg BID group discontinued from the study compared with the placebogroup.
Table 11. Discontinuations from Study

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Tofacitinib 10 mg
BID
n (%)
476
445 (93.5)
31 (6.5)

Tofacitinib 15 mg BIDn (%)
16
15 (93.8)
1 (6.3)

Placebon (%)
122
118 (96.7)
4 (3.3)

Number (%) of Subjects
Completed
Discontinuations
Reason for Discontinuation
Subject died
1 (0.2)00
Related to study drug
19 (4.0)02 (1.6)Adverse event
8 (1.7)0
1 (0.8)Insufficient clinical response
11 (2.3)
01 (0.8)
Not Related to Study Drug
11 (2.3)
1(6.3)
2 (1.6)Adverse event
1 (0.2)00
No longer willing to participate in study
4 (0.8)0
1 (0.8)Other
2 (0.4)0
0
Protocol violation
4 (0.8)1 (6.3)1 (0.8)Insufficient clinical response includes subjects who discontinued due to AE of worsening UC.
AE = adverse event, BID = twice daily, n = number of subjects meeting prespecified criteria, UC = ulcerative
colitis.

Deaths: One death occurred during the study in the tofacitinib 10 mg BID group due to aortic
dissection, which was assessed by the investigator as not related to the study drug.
CONCLUSIONS:This Phase 3 study demonstrated efficacy of tofacitinib 10 mg BID as an induction therapy
for subjects with moderate to severe UC.
Treatment effects for the tofacitinib 10 mg BID group were statistically significantly
greater compared with the placebo group for both remission (primary endpoint) andmucosal healing (key secondary endpoint).



Significant improvements in partial Mayo score from treatment with tofacitinib 10 mg
BID were observed as early as Week 2.

The tofacitinib 10 mg BID dose appeared to be well tolerated.


The most frequent all-causality TEAEs were headache and nasopharyngitis, with similar
rates between the tofacitinib 10 mg BID and placebo groups.

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The most frequent all-causality SAE was colitis ulcerative (worsening of UC), withsimilar rates between the tofacitinib 10 mg BID and placebo groups. One death occurred
during the study in the tofacitinib 10 mg BID group due to aortic dissection, which wasassessed by the investigator as not related to the study drug.

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