Public Disclosure Synopsis
Protocol A3921096 – 14 February 2017 – 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-690550
PROTOCOL NO.: A3921096
PROTOCOL TITLE: A Multicentre, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Study of Oral CP-690,550 as a Maintenance Therapy in Subjects With
Ulcerative Colitis

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Study Centers: The study was conducted at 196 study centers in 31 countries: Australia (4),Austria (1), Belgium (4), Brazil (1), Canada (5), Colombia (1), Croatia (1), Czech Republic(3), Denmark (5), Estonia (3), France (8), Germany (7), Hungary (12), Israel (3), Italy (3),Japan (20), Korea (5), Latvia (1), Netherlands (4), New Zealand (7), Poland (10), Romania(2), Russian Federation (7), Serbia (6), Slovakia (4), South Africa (5), Spain (4), Taiwan (1),Ukraine (13), United Kingdom (UK) (5), and United States (US) (40).
Study Initiation Date and Final Completion Date: 20 July 2012 to 27 May 2016
Phase of Development: Phase 3
Study Objectives:
Primary Objective

To demonstrate the efficacy of tofacitinib as maintenance therapy in subjects withulcerative colitis (UC).

Secondary Objectives
To evaluate the safety and tolerability of tofacitinib as maintenance therapy in subjects
with UC;To evaluate the efficacy of tofacitinib maintenance therapy in achieving mucosal healing
in subjects with UC;

To evaluate the tofacitinib pharmacokinetic (PK) exposure during maintenance therapy insubjects with UC;

To evaluate the effect of tofacitinib as maintenance therapy on quality-of-life in subjects
with UC.

METHODS
Study Design:This was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group,
multicenter study in subjects with UC who had completed 1 of the induction studies
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Protocol A3921096 – 14 February 2017 – Final(A3921094 or A3921095) and had demonstrated clinical response. Clinical response wasdefined by a decrease from induction study 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. This study consisted of a 53 week
double-blind treatment period followed by a 4 week safety follow-up for subjects who did
not participate in the open-label study (A3921139).

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Approximately 654 subjects were to be enrolled in the study. The eligibility of a subject forthe study was assessed based on study data collected at the Week 8 visit of Study A3921094
or Study A3921095, which were considered and recorded as the baseline visit forStudy A3921096. Subjects who demonstrated clinical response after completing either
Study A3921094 or Study A3921095 were eligible to be randomly assigned to receive 1 of
3 treatments: tofacitinib 10 mg twice a day (BID), tofacitinib 5 mg BID, or the matchingplacebo BID with an allocation ratio of 1:1:1. Subjects were stratified according to thetreatment assignments in the induction study (A3921094 or A3921095) and whether they
were in remission or not. Subjects enrolled into this study received double-blind
maintenance treatment for up to 53 weeks.
Subjects were required to remain on stable doses of their concomitant medications for UC
during the study treatment period, with the exception of corticosteroids. For subjects taking
corticosteroids at the baseline visit of this study, tapering of the corticosteroids was tocommence from Week 0.
At the end of the double-blind treatment period, subjects who completed the study may havebeen eligible to enter the open-label study (A3921139). Subjects who withdrew early due totreatment failure may have also been eligible to enter the open-label study. Treatment failure
was defined by an increase in Mayo score of at least 3 points from the baseline of themaintenance study, accompanied by an increase in rectal bleeding subscore by at least
1 point, and an increase of endoscopic subscore of at least 1 point yielding an absoluteendoscopic subscore of at least 2 after a minimum treatment of 8 weeks in the study.
Centrally-read endoscopic subscores were used to determine treatment failure.
Subjects who did not participate in the open-label study concluded this study and had a
4-week safety follow-up after the last dose of study drug. These subjects were given the
post-treatment UC-Healthcare Resource Utilization questionnaires to be completed every
4 weeks and sent back to the site on a monthly basis until the anniversary of the study(Week 52).
A schematic of the study design is shown in Figure 1.

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Protocol A3921096 – 14 February 2017 – Final

Figure 1. Study Design
Week 0 = Week 9 visit
from Study A3921094
and Study A3921095

Week 0 4

8

16

24

32

Tofacitinib 10 mg BID

40

52 53

57

Tofacitinib 5 mg BID
Placebo

Follow-Up

End of Treatment

Re-Randomization

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Follow-Up(4 weeks)

DB Treatment Period × 53 weeks

Treatment Assignment for
OLE Study A3921139
Tofacitinib 5 mg BID or 10 mg BID

BID = twice a day; DB = double-blind; OLE = open-label extension.

Number of Subjects (Planned and Analyzed):
Approximately 654 subjects were to be enrolled in the study and randomized in a 1:1:1 ratio
to either tofacitinib 10 mg BID, tofacitinib 5 mg BID, or the matching placebo BID. Overall,
593 subjects were randomized to study treatment.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Eligible subjects must have met the study entry criteria, completed a 9-week induction
treatment, and demonstrated a clinical response in Study A3921094 or Study A3921095.
Women of childbearing potential had to have tested negative for pregnancy prior to study
enrollment. Subjects must have been willing and able to comply with scheduled visits,
treatment plan, laboratory tests, bowel movement diary calls, and other study procedures.
Subjects were required to have an evidence of a personally signed and dated informed
consent document(s) indicating that the subject (or a legally acceptable representative) had
been informed of all pertinent aspects of the study.
Ineligible subjects included subjects who had a major protocol violation (as determined by
the sponsor) in Study A3921094 or Study A3921095; subjects who had the presence ofindeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinicalfindings suggestive of Crohn's disease; subjects who had surgery for UC or who, in theopinion of the investigator, were likely to require surgery for UC during the study period.

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Protocol A3921096 – 14 February 2017 – Final

Study Treatment:
Subjects received their study medications as outpatients and were randomized into 1 of the
3 treatment groups: tofacitinib 10 mg BID, tofacitinib 5 mg BID, or placebo BID, with anallocation ratio of 1:1:1. Study drug was taken orally BID (approximately every 12 hours)for 53 weeks. Subjects were dispensed 2 bottles containing either 5 mg tofacitinib or placebo
tablets and given clear dosing instructions. Subjects were instructed to take 1 tablet fromeach bottle in the morning and 1 tablet from each bottle in the evening, approximately
12 hours apart. Subjects were therefore taking 2 tablets BID.
At baseline (Visit 1), the first dose was taken approximately 12 hours after the last dose of
study drug of Study A3921094 or Study A3921095, at home. On Week 8 (Visit 3), Week 24(Visit 5), and Week 52 (Visit 8), the subject took the first dose of the day at the site. It was
important that on the days of PK sampling, the subject took 1 dose of the study drug at thesite when instructed to take the dose by a member of the investigational site to allow fortimely performance of the PK sampling.

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Tofacitinib could be administered with or without food. If a tofacitinib dose was missed andthe interval to the next scheduled dose was <6 hours, the missed dose of tofacitinib was not
to be administered.
Efficacy Endpoints:
The primary efficacy endpoint was as follows:Remission at Week 52, defined by a Mayo score of 2 points or lower, with no individual
subscore exceeding 1 point and a rectal bleeding subscore of 0.

The key secondary endpoints were as follows:

Mucosal healing at Week 52, defined by a Mayo endoscopic subscore of 0 or 1.

Sustained corticosteroid-free remission among subjects in remission at baseline of thisstudy (ie, remission and corticosteroid free at both Week 24 and 52), defined by a Mayoscore of 2 points or lower, with no individual subscore exceeding 1 point and a rectal
bleeding subscore of 0, in addition to not requiring any treatment with corticosteroids forat least 4 weeks prior to the visit.

The other secondary endpoints were as follows:Remission at Week 24 and sustained remission (ie, remission at both Week 24 andWeek 52);

Remission at Week 24 and Week 52 and sustained remission, among subjects withremission at baseline of this study;

Mucosal healing at Week 24, and sustained mucosal healing (ie, mucosal healing at both
Week 24 and 52);
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Public Disclosure Synopsis
Protocol A3921096 – 14 February 2017 – Final

Mucosal healing at Week 24 and Week 52 and sustained mucosal healing, among
subjects with mucosal healing at baseline of this study;

Corticosteroid-free remission at Week 24 and Week 52 among subjects in remission atbaseline;

Clinical response at Week 24 and Week 52 and sustained clinical response (ie, clinicalresponse at both Week 24 and 52), defined by a decrease from induction
study (A3921094 or A3921095) baseline 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
absolute subscore for rectal bleeding of 0 or 1;



Clinical remission at Week 24 and Week 52 and sustained clinical remission (ie, clinicalremission at both Week 24 and 52), defined by a Mayo score of 2 points or lower, withno individual subscore exceeding 1 point;

Deep remission at Week 24 and Week 52 and sustained deep remission (ie, deep
remission at both Week 24 and 52), defined by a Mayo score of 2 points or lower, withno individual subscore exceeding 1 point and both absolute endoscopic and rectal
bleeding subscores of 0;

Symptomatic remission at Week 24 and Week 52 and sustained symptomatic remission(ie, symptomatic remission at both Week 24 and 52), defined by a Mayo score of 2 points
or lower, with no individual subscore exceeding 1 point, and both rectal bleeding andstool frequency subscores of 0;

Endoscopic remission at Week 24 and Week 52 and sustained endoscopic remission (ie,endoscopic remission at both Week 24 and 52), defined by a Mayo endoscopic subscore
of 0;



Mayo score and change from baseline in Mayo score over time;Corticosteroid-free remission at Week 24 and Week 52 and sustained corticosteroid-freeremission (ie, corticosteroid-free remission at both Week 24 and 52) among subjects
receiving corticosteroids at baseline.

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.
Statistical Methods:
The data sets summarized and analyzed in this study were as follows:

Full analysis set (FAS): The primary analysis population for efficacy endpoints was the
FAS defined as all subjects randomly assigned to either tofacitinib 10 mg BID, tofacitinib
5 mg BID, or placebo.

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Protocol A3921096 – 14 February 2017 – Final

Modified full analysis set (mFAS): The mFAS was defined as a subset of FAS including
only subjects that received tofacitinib in the induction studies.

Per protocol analysis set (PPAS): The PPAS was defined as a subset of FAS who had no
major protocol violations. The subjects excluded from the PPAS were determined anddocumented before the study was unblinded.

Safety analysis set: The safety analysis set consisted of all randomized subjects who
received at least 1 dose of study medication.

Efficacy Analyses:
The primary endpoint was remission at Week 52, defined by a Mayo score of 2 points orlower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0.
The 2 key secondary efficacy endpoints were mucosal healing at Week 52 and sustained
corticosteroid-free remission among subjects in remission at baseline.

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Both centrally-read and locally-read endoscopic subscores were used for the derivation of all
efficacy endpoints. The primary analyses were based on the efficacy endpoints derived fromthe centrally-read endoscopic subscores.
In order to control the family-wise Type I error rate at 0.05 level, a sequentially rejective
Bonferroni-based iterative multiple test procedure was used for the comparisons between
each of the 2 active doses and placebo in the primary endpoint and the 2 key secondary
efficacy endpoints.
Analysis of Primary Efficacy Endpoint
The primary endpoint of remission at Week 52 was analyzed in the FAS population using astratified Cochran-Mantel-Haenszel (CMH) Chi-square test unless cell frequencies were too
small (wherein a Fisher’s exact test was to be used). The primary analysis was stratified bytreatment received in the induction study and status of remission (remission or not) at
Study A3921096 baseline. The non-responder imputation (NRI) method was used to handle
missing values in summaries and analyses. The difference in the proportion of responders
and associated 95% confidence intervals (CIs) were presented for active versus placebogroups using the normal approximation for the difference in binomial proportions. In
addition, the primary endpoint analysis was also conducted using the mFAS and PPAS.

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Protocol A3921096 – 14 February 2017 – Final

Analysis of Key Secondary Efficacy Endpoints
The 2 key secondary endpoints of the study were mucosal healing at Week 52 and sustained
corticosteroid-free remission among subjects in remission at baseline of Study A3921096.
Both of these binary endpoints were analyzed and summarized using the same methods (ifapplicable) as those for the primary endpoint. Note, the analysis for sustained corticosteroid
free remission among subjects in remission at baseline was only to be stratified by treatment
received in the induction study as, by definition of the endpoint, the status of remission(remission or not) at baseline stratification was not applicable.

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Analysis of Other Secondary Efficacy Endpoints
For all other secondary endpoints, the summary presentations and analyses were performedon the FAS population. All binary secondary endpoints derived from the Mayo score were
descriptively summarized by treatment group using frequency counts and percentages at each
visit. Week 24 and Week 52 data and the endpoints derived by the data of both visits wereanalyzed using the stratified CMH test. For endpoints of remission among subjects withremission at baseline or mucosal healing in subjects with mucosal healing at baseline, theanalysis was stratified by treatment received in the induction study only. For all otherendpoints the stratification also included status of remission (remission or not) at baseline.
For all of these binary secondary endpoints, the NRI method was used to handle missing
values in both the summary presentations and analyses.
Descriptive summaries of the continuous Mayo scores were presented by treatment groupand each visit for both the observed values and change from baseline. The changes frombaseline for Mayo scores at Week 24 and Week 52 were analyzed using a linear
mixed-effects model. Treatment assignment in the induction study was included as abaseline stratification factor in the model. The status of remission at baseline was notincluded as a fixed effect in the analyses for Mayo scores since it was likely to be highly
correlated with the baseline value. Missing data were assumed missing at random.
Additional analyses were conducted based on mFAS.
Safety Analysis:
Safety evaluations were summarized and analyzed using the safety analysis set. Missing data
for safety endpoints were not imputed and were left as missing. All the safety data weresummarized through appropriate data tabulations and descriptive statistics.
RESULTS
Subject Disposition and Demography:
Subject disposition by treatment group is summarized in Table 1. Overall, 593 subjects wererandomized to study treatment (FAS). This included 198 subjects randomized to thetofacitinib 5 mg BID group, 197 subjects to the tofacitinib 10 mg BID group, and198 subjects randomized to the placebo group. Of the 593 randomized subjects, 592 subjects
received at least 1 dose of study drug (safety analysis set). Of the 592 subjects included in
the safety analysis set, 290 (49.0%) completed the study and 302 (51.0%) discontinued thePage 7

Public Disclosure Synopsis
Protocol A3921096 – 14 February 2017 – Finalstudy (including 43.9% of subjects in the tofacitinib 5 mg BID group, 35.7% of subjects inthe tofacitinib 10 mg BID group, and 73.2% in the placebo group).
Table 1.

Subject Disposition by Treatment Group – FAS

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Tofacitinib
5 mg BIDn (%)
198 (100.0)
198

Tofacitinib
10 mg BIDn (%)
197 (100.0)
196

Placebo

Total

n (%)
n (%)
Randomizeda
198 (100.0)
593 (100.0)
Treatedb,c198
592
Analyzed for efficacy
FAS
198 (100.0)
197 (100.0)
198 (100.0)
593 (100.0)
PPAS
183 (92.4)
186 (94.4)
188 (94.9)
557 (93.9)
mFAS
176 (88.9)
173 (87.8)
174 (87.9)
523 (88.2)
Analyzed for safety
Safety analysis set
198 (100.0)
196 (99.5)
198 (100.0)
592 (99.8)
mFAS
176 (88.9)
173 (87.8)
174 (87.9)
523 (88.2)
AEs
198 (100.0)
196 (99.5)
198 (100.0)
592 (99.8)
Laboratory datad
198 (100.0)
195 (99.0)
198 (100.0)
591 (99.7)
Completedc
111 (56.1)
126 (64.3)
53 (26.8)
290 (49.0)
Discontinuedc
87 (43.9)
70 (35.7)e145 (73.2)
302 (51.0)
Primary reason for discontinuationc
Subject died
0000
Related to study drug
74 (37.4)
61 (31.1)
134 (67.7)
269 (45.4)
AE
4 (2.0)8 (4.1)2 (1.0)14 (2.4)
Insufficient clinical responsef
70 (35.4)
53 (27.0)
132 (66.7)
255 (43.1)
Not related to study drug
13 (6.6)9 (4.6)
11 (5.6)
33 (5.6)
AE
1 (0.5)1 (0.5)5 (2.5)7 (1.2)
No longer willing to participate in study
6 (3.0)3 (1.5)5 (2.5)14 (2.4)
Protocol violation01 (0.5)0
1 (0.2)
Lost to follow-up
3 (1.5)2 (1.0)1 (0.5)6 (1.0)Discontinued due to pregnancy
1 (0.5)1 (0.5)02 (0.3)Other
2 (1.0)1 (0.5)03 (0.5)AE = adverse event; BID = twice a day; FAS = full analysis set; mFAS = modified full analysis set; n = numberof subjects meeting prespecified criteria; PPAS = per protocol analysis set; UC = ulcerative collitis.
a. One subject was misrandomized to tofacitinib 5 mg BID (did not achieve clinical response) and was
de-randomized after receiving 2 days of study drug. This subject had no reported AEs and was not included in
the analysis sets.
b. One subject was randomized to tofacitinib 10 mg BID but withdrew consent and did not receive any dosesof study drug.
c. The percentages for completed, discontinued, and primary reason for discontinuation were based on thenumber of subjects treated (ie, the safety analysis set).
d. Laboratory data consisted of all randomized subjects that have lab data collected at both baseline and 1 ofthe post-baseline visits. One of the subjects with only baseline labs was not counted.
e. Percentage for discontinued in the tofacitinib 10 mg BID group was based on the safety analysis set (thenumber of subjects treated).
f. AEs of worsening of UC leading to discontinuation were designated as insufficient clinical response.

A summary of demographic and other baseline characteristics for the FAS is presented inTable 2. Overall, demographic characteristics were similar across treatment groups. For all
subjects included in the FAS, there were more male (329/593, 55.5%) than female subjects(264/593, 44.5%). Overall, the mean age of subjects was 42.7 years, (range: 18 to 80 years);
the mean weight of subjects was 74.8 kg (range: 31.3 to 154.9 kg), and the mean body massindex was 25.5 kg/m2 (range: 11.8 to 55.6 kg/m2).
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Protocol A3921096 – 14 February 2017 – Final

Table 2.

Demographic and Baseline Characteristics by Treatment Group – FAS

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Tofacitinib 5 mg BID(N = 198)

Tofacitinib 10 mg BID(N = 197)

Placebo(N = 198)

Total(N = 593)

Age (years)a
Mean (SD)41.9 (13.7)
42.9 (14.4)
43.4 (14.0)
42.7 (14.0)
Median
41.0
40.0
42.0
41.0
Range
18-79
18-79
19-80
18-80
<18, n (%)
0 (0.0)0 (0.0)0 (0.0)0 (0.0)18 to 44, n (%)
114 (57.6)
110 (55.8)
111 (56.1)
335 (56.5)
45 to 64, n (%)
71 (35.9)
70 (35.5)
69 (34.8)
210 (35.4)
13 (6.6)
17 (8.6)
18 (9.1)
48 (8.1)
65, n (%)
Gender, n (%)
Male
103 (52.0)
110 (55.8)
116 (58.6)
329 (55.5)
Female95 (48.0)
87 (44.2)
82 (41.4)
264 (44.5)
Race, n (%)b,c
White
164 (82.8)
153 (77.7)
155 (78.3)
472 (79.6)
Black
2 (1.0)0 (0.0)3 (1.5)5 (0.8)Asian
23 (11.6)
25 (12.7)
26 (13.1)
74 (12.5)Other
5 (2.5)9 (4.6)9 (4.5)23 (3.9)
Unspecified
4 (2.0)10 (5.1)
5 (2.5)
19 (3.2)
Ethnicity, n (%)b
Hispanic/Latino
5 (2.5)7 (3.6)7 (3.5)
19 (3.2)
Not Hispanic/Latino
189 (95.5)
180 (91.4)
186 (93.9)555 (93.6)
Unspecified
4 (2.0)10 (5.1)
5 (2.5)
19 (3.2)
Geographic region, n (%)
N1
198
197
198
593
Europe113 (57.1)
121 (61.4)
112 (56.6)
346 (58.3)
North America
39 (19.7)
44 (22.3)
45 (22.7)
128 (21.6)
Other d46 (23.2)
32 (16.2)
41 (20.7)
119 (20.1)
Weight (kg)a
Mean (SD)73.4 (17.8)
74.6 (15.1)
76.2 (16.7)
74.8 (16.6)
Median
71.3
73.2
74.3
73.0
Range
31.3-154.9
39.4-137.1
44.5-134.0
31.3-154.9
BMI (kg/m2)e
Mean (SD)25.1 (5.1)
25.5 (4.8)
25.8 (4.9)
25.5 (4.9)
Median
24.5
24.9
24.9
24.7
Range
11.8-49.1
17.0-55.6
17.4-43.5
11.8-55.6
BID = twice a day; BMI = body mass index; FAS = full analysis set; N = number of subjects randomized;
n = number of subjects meeting prespecified criteria; N1 = number of subjects in the specified category with
non-missing values; SD = standard deviation.
a. Weight was from Week 8 of induction study, while height and age were from screening of induction study.
b. Race/Ethnicity was not collected for French subjects.
c. Racial designation was collected for those subjects whose race was marked as Asian, other, or unspecified.
d. Geographic regions other than Europe and North America included Asia-Pacific, South America, andAfrica.
e. BMI was defined as weight/(height × 0.01)2, with weight in kg, and height in cm.

A summary of selected Study A3921096 baseline clinical characteristics for the FAS ispresented in Table 3.

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Protocol A3921096 – 14 February 2017 – Final

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Table 3.

Baseline Clinical Characteristics From A3921096 Study – FAS

Tofacitinib
Tofacitinib
PlaceboTotal
5 mg BID
10 mg BID
(N = 198)(N = 593)(N = 198)(N = 197)
Treatment assignment in induction study, n (%)
Placebo
22 (11.1)
24 (12.2)
24 (12.1)
70 (11.8)
Tofacitinib 10 mg and 15 mg
176 (88.9)
173 (87.8)
174 (87.9)
523 (88.2)
Tofacitinib 10 mg
170 (85.9)
167 (84.8)
167 (84.3)
504 (85.0)
Remission at baseline, n (%)
Yes
65 (32.8)
55 (27.9)
59 (29.8)
179 (30.2)
No
133 (67.2)
142 (72.1)
139 (70.2)
414 (69.8)
Mucosal healing at baseline, n (%)
Yes
105 (53.0)
89 (45.2)
101 (51.0)
295 (49.7)
No
93 (47.0)
108 (54.8)
97 (49.0)
298 (50.3)
Mayo score, n (%)<3
71 (35.9)
64 (32.5)
74 (37.4)
209 (35.2)
127 (64.1)
133 (67.5)
124 (62.6)
384 (64.8)
3
Mayo score
Mean (SD)
3.3 (1.8)
3.4 (1.8)
3.3 (1.8)
3.3 (1.8)
Median
3.0
3.0
3.0
3.0
Range
(0.0-10.0)(0.0-7.0)(0.0-8.0)(0.0-10.0)
Partial Mayo score, n (%)<2
89 (44.9)
88 (44.7)
85 (42.9)262 (44.2)
109 (55.1)
109 (55.3)
113 (57.1)
331 (55.8)
2Partial Mayo score
Mean (SD)
1.8 (1.3)
1.8 (1.3)
1.8 (1.4)
1.8 (1.3)
Median
2.0
2.0
2.0
2.0
Range
(0.0-7.0)(0.0-6.0)(0.0-7.0)(0.0-7.0)
hsCRPaMean (SD)
2.2 (3.8)
4.0 (9.3)
3.3 (6.1)
NAMedian
0.69
0.89
1.00
NA
Min
0.1
0.1
0.1
NA
Max
33.7
74.3
45.0
NA
Baseline CRP (mg/L), n (%)
157 (79.3)
147 (74.6)
141 (71.2)
445 (75.0)
3>3
41 (20.7)50 (25.4)
57 (28.8)
148 (25.0)
181 (91.4)
168 (85.3)
166 (83.8)
515 (86.8)
6>6
17 (8.6)
29 (14.7)
32 (16.2)
78 (13.2)
BID = twice a day; CRP = C-reactive protein; FAS = full analysis set; hsCRP = high sensitivity C-reactive
protein; N = number of randomized subjects in the total population; n = number of subjects meeting
prespecified criteria; NA = not available; SD = standard deviation.
a. Values are for the safety analysis set.

Demographic and baseline clinical characteristics of the mFAS population were consistent
with those of the FAS population at baseline. In addition, within the mFAS, thesecharacteristics were similar across treatment groups.

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Protocol A3921096 – 14 February 2017 – Final

Efficacy Results
Primary Efficacy Endpoint:

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Analysis of remission at Week 52 is presented in Table 4 (FAS, NRI), including both
centrally-read and locally-read endoscopy. The proportion of subjects in remission at
Week 52 (FAS, NRI) was statistically significantly (p <0.0001) greater in both the tofacitinib
5 mg BID group (34.3%) and the tofacitinib 10 mg BID group (40.6%) compared with theplacebo group (11.1%). Results based on locally-read endoscopic findings for remission
were consistent with centrally-read findings, with a significant difference (p <0.0001)
observed for both tofacitinib treatment groups (39.4% in the tofacitinib 5 mg BID group and47.7% in the tofacitinib 10 mg BID group) compared with placebo (13.1%). These results
were supported by various sensitivity analyses, including those based on the mFAS
population.

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Table 4.

Proportion of Subjects in Remission at Week 52 –FAS (NRI)

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Placebo(N = 198)

Tofacitinib 5 mg BID(N = 198)
Difference From Placebon (%)
Diff (95% CI)a p-valueb

Tofacitinib 10 mg BID(N = 197)
Difference From Placebon (%)
Diff (95% CI)ap-valueb

N1
n (%)
N1
N1
Remission
Centrally-read198
22 (11.1)
198
68 (34.3)
23.2 (15.3, 31.2) <0.0001
197
80 (40.6)
29.5 (21.4, 37.6)<0.0001
Locally-read198
26 (13.1)
198
78 (39.4)
26.3 (18.0, 34.5) <0.0001
197
94 (47.7)
34.6 (26.2, 43.0)<0.0001
BID = twice a day; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; Diff = difference; FAS = full analysis set; N = number of subjects in theanalysis set; N1 = number of subjects in each group at Week 52, and used as the denominator in the percentage calculation; n = number of subjects meeting
specific criteria; NRI = non-responder imputation.
a. 95% CI was based on the normal approximation for the difference in binomial proportions.
b. P-value was based on CMH Chi-squared test stratified by induction study treatment assignment (tofacitinib, placebo) and remission at baseline (yes, no).

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Key Secondary Endpoints:

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Mucosal Healing at Week 52: Analysis of mucosal healing at Week 52 is presented inTable 5 (FAS, NRI), including both centrally-read and locally-read endoscopy. The
proportion of subjects with mucosal healing at Week 52 (FAS, NRI) was statisticallysignificantly (p <0.0001) greater in both the tofacitinib 5 mg BID group (37.4%) and thetofacitinib 10 mg BID group (45.7%) compared with the placebo group (13.1%). Results
based on locally-read endoscopic findings for mucosal healing were consistent withcentrally-read findings, with a significant difference (p <0.0001) observed for both tofacitinib
treatment groups (44.9% in the tofacitinib 5 mg BID group and 53.8% in the tofacitinib
10 mg BID group) compared with placebo (15.7%). These results were supported by various
sensitivity analyses, including those based on the mFAS population.

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Table 5.

Proportion of Subjects With Mucosal Healing at Week 52 – FAS (NRI)

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Placebo(N = 198)

Tofacitinib 5 mg BID(N = 198)
Difference From Placebon (%)
Diff (95% CI)a p-valueb

Tofacitinib 10 mg BID(N = 197)
Difference From Placebon (%)
Diff (95% CI)a p-valueb

N1
n (%)
N1
N1
Mucosal Healing
Centrally-read198
26 (13.1)
198
74 (37.4) 24.2 (16.0, 32.5) <0.0001
197
90 (45.7)
32.6 (24.2, 41.0) <0.0001
Locally-read198
31 (15.7)
198
89 (44.9) 29.3 (20.7, 37.9) <0.0001
197
106 (53.8) 38.2 (29.5, 46.8) <0.0001
BID = twice a day; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; Diff = difference; FAS = full analysis set; N = number of subjects in theanalysis set; N1 = number of subjects in each group at Week 52, and used as the denominator in the percentage calculation; n = number of subjects meeting
specific criteria; NRI = non-responder imputation.
a. 95% CI was based on the normal approximation for the difference in binomial proportions.
b. P-value was based on CMH Chi-squared test stratified by induction study treatment assignment (tofacitinib, placebo) and remission at baseline (yes, no).

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Protocol A3921096 – 14 February 2017 – Final

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Sustained Corticosteroid-Free Remission Among Subjects in Remission at Baseline:
Analysis of sustained corticosteroid-free remission among subjects in remission at baseline ispresented in Table 6 (FAS, NRI), including both centrally-read and locally-read endoscopy.
The proportion of subjects in sustained corticosteroid-free remission among subjects inremission at baseline (FAS, NRI) was statistically significantly (p <0.0001) greater in boththe tofacitinib 5 mg BID group (35.4%) and the tofacitinib 10 mg BID group (47.3%)
compared with the placebo group (5.1%). Results based on locally-read endoscopic findings
for sustained corticosteroid-free remission among subjects in remission at baseline wereconsistent with centrally-read findings, with a significant difference (p <0.0001) observed forboth tofacitinib treatment groups (47.7% in the tofacitinib 5 mg BID group and 58.2% in thetofacitinib 10 mg BID group) compared with placebo (11.9%). These results were supported
by various sensitivity analyses, including those based on the mFAS population.

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Table 6.

Proportion of Subjects in Sustained Corticosteroid-Free Remission Among Subjects in Remission at Baseline - FAS(NRI)

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Placebo(N = 198)

Tofacitinib 5 mg BID
Tofacitinib 10 mg BID(N = 198)(N = 197)
Difference From Placebo
Difference From Placebo
N1
n (%)
N1
n (%)
%Diff (95% CI)ap-valueb
N1n (%)
Diff (95% CI)ap-valuebCentrally-read59
3 (5.1)65
23 (35.4)
30.3 (17.4, 43.2)<0.000155
26 (47.3)
42.2 (27.9, 56.5)<0.0001
Locally-read59
7 (11.9)65
31 (47.7)
35.8 (21.1, 50.5)<0.000155
32 (58.2)
46.3 (30.9, 61.7)<0.0001
BID = twice a day; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; Diff = difference; FAS = full analysis set; N = number of subjects in theanalysis set; N1 = number of subjects in each group in remission at baseline regardless of corticosteroid use at baseline, and used as the denominator in thepercentage calculation; n = number of subjects in sustained corticosteroid-free remission, defined as being in remission and corticosteroid-free at both Week 24
and Week 52; NRI = non-responder imputation.
a. 95% CI was based on the normal approximation for the difference in binomial proportions.
b. P-value was based on CMH Chi-squared test stratified by induction study treatment assignment in the induction study (tofacitinib, placebo).

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Protocol A3921096 – 14 February 2017 – Final

Other Secondary Endpoints:
Binary Efficacy Endpoints:
The analyses of other secondary binary efficacy endpoints based on centrally-read andlocally-read endoscopy are presented for FAS in Table 7 and Table 8, respectively.

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Remission at Week 24 and Sustained Remission: A statistically significantly (p <0.0001)
greater proportion of subjects in the FAS in both the tofacitinib 5 mg BID group and thetofacitinib 10 mg BID group were in remission based on centrally-read endoscopic subscoresat Week 24 (33.8% and 35.5%, respectively) and sustained remission at both Week 24 andWeek 52 (22.2% and 25.4%, respectively) than those in the placebo group (Week 24: 11.1%;
sustained: 5.1%). The significant difference between tofacitinib treatment groups andplacebo was also observed based on locally-read endoscopic subscores (p <0.0001). For
remission at Week 24 and for sustained remission, results for the mFAS were consistent withthose of the FAS for both the tofacitinib 5 mg BID and 10 mg BID treatment groups
compared with placebo based on centrally-read and locally-read endoscopy.
Remission at Week 24 and Week 52 and Sustained Remission Among Subjects With
Remission at Baseline: A statistically significantly (p <0.0001) greater proportion ofsubjects with remission at baseline in the FAS in both the tofacitinib 5 mg BID group and thetofacitinib 10 mg BID group were in remission based on centrally-read endoscopic subscoresat Week 24 (55.4% and 63.6%, respectively), Week 52 (46.2% and 56.4%, respectively), andsustained remission at both Week 24 and Week 52 (36.9% and 47.3%, respectively) thanthose in the placebo group (Week 24: 15.3%; Week 52: 10.2%; sustained: 5.1%).
Statistically significant difference between treatment groups was also observed based on
locally-read endoscopic subscores (p <0.0001). For remission at Week 24 and Week 52 andsustained remission among subjects with remission at baseline, results for the mFAS wereconsistent with those of the FAS for both the tofacitinib 5 mg BID and 10 mg BID treatmentgroups compared with placebo based on centrally-read and locally-read endoscopic
subscores.
Mucosal Healing at Week 24 and Sustained Mucosal Healing: A statistically significantly(p <0.0001) greater proportion of subjects in the FAS in both the tofacitinib 5 mg BID groupand the tofacitinib 10 mg BID group demonstrated mucosal healing based on centrally-readendoscopic subscores at Week 24 (43.9% and 46.2%, respectively) and sustained mucosal
healing at both Week 24 and Week 52 (27.8% and 33.0%, respectively) than those in theplacebo group (Week 24: 17.2%; sustained: 6.6%). The significant difference between
tofacitinib treatment groups and placebo was also observed based on locally-read endoscopic
subscores (p <0.0001). For mucosal healing at Week 24 and for sustained mucosal healing,
results for the mFAS were consistent with those of the FAS for both the tofacitinib 5 mg BID
and 10 mg BID treatment groups compared with placebo based on centrally-read andlocally-read endoscopy.

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Protocol A3921096 – 14 February 2017 – Final

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Mucosal Healing at Week 24 and Week 52 and Sustained Mucosal Healing Among
Subjects With Mucosal Healing at Baseline: A statistically significantly (p <0.0001) greater
proportion of subjects in the FAS in both the tofacitinib 5 mg BID group and the tofacitinib
10 mg BID group with mucosal healing at baseline based on centrally-read endoscopic
subscores demonstrated mucosal healing at Week 24 (52.4% and 66.3%, respectively), at
Week 52 (41.9% and 55.1%, respectively), and sustained mucosal healing (33.3% and49.4%), than those in the placebo group (Week 24: 21.8%; Week 52: 11.9%; sustained:8.9%). The significant difference between tofacitinib treatment groups and placebo was also
observed based on locally-read endoscopic subscores (p <0.0001). For mucosal healing at
Week 24 and Week 52 and sustained mucosal healing among subjects with mucosal healing
at baseline, results for the mFAS were consistent with those of the FAS for both thetofacitinib 5 mg BID and 10 mg BID treatment groups compared with placebo based on
centrally-read and locally-read endoscopy.
Corticosteroid-Free Remission at Week 24 and Week 52 Among Subjects in Remission at
Baseline: A statistically significantly (p <0.0001) greater proportion of subjects in the FAS
in both the tofacitinib 5 mg BID group and the tofacitinib 10 mg BID group were incorticosteroid-free remission based on centrally-read endoscopic subscores at Week 24(53.8% and 63.6%, respectively) and at Week 52 (44.6% and 56.4%, respectively) than thosein the placebo group (Week 24: 15.3%; Week 52: 10.2%). The significant difference
between tofacitinib treatment groups and placebo was also observed based on locally-readendoscopic subscores (p <0.0001). For corticosteroid-free remission among subjects inremission at baseline at Week 24 and Week 52, results for the mFAS were consistent withthose of the FAS for both the tofacitinib 5 mg BID and 10 mg BID treatment groups
compared with placebo based on centrally-read and locally-read endoscopy.
Clinical Remission at Week 24 and Week 52 and Sustained Clinical Remission: A
statistically significantly (p <0.0001) greater proportion of subjects in the FAS in both thetofacitinib 5 mg BID group and the tofacitinib 10 mg BID group were in clinical remission
based on centrally-read endoscopic subscores at Week 24 (34.3% and 35.5%, respectively)
and Week 52 (34.3% and 41.1%, respectively) and sustained clinical remission (22.2% and25.9%, respectively), than those in the placebo group (Week 24: 11.1%; Week 52: 11.1%;
sustained: 5.1%). The significant difference between tofacitinib treatment groups andplacebo was also observed based on locally-read endoscopic subscores (p <0.0001). For
clinical remission at Week 24 and Week 52 and for sustained clinical remission, results forthe mFAS were consistent with those of the FAS for both the tofacitinib 5 mg BID and
10 mg BID treatment groups compared with placebo based on centrally-read and locally-readendoscopy.

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Protocol A3921096 – 14 February 2017 – Final

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Clinical Response at Week 24 and Week 52 and Sustained Clinical Response: A
statistically significantly (p <0.0001) greater proportion of subjects in the FAS in both thetofacitinib 5 mg BID group and the tofacitinib 10 mg BID group demonstrated clinicalresponse based on centrally-read endoscopic subscores at Week 24 (63.6% and 70.6%,
respectively) and at Week 52 (51.5% and 61.9%, respectively) and sustained clinicalresponse (49.0% and 59.4%, respectively) than those in the placebo group (Week 24: 33.3%;
Week 52: 20.2%; sustained: 19.2%). The significant difference between tofacitinib treatmentgroups and placebo was also observed based on locally-read endoscopic subscores(p <0.0001). For clinical response at Week 24 and Week 52 and for sustained clinicalresponse, results for the mFAS were consistent with those of the FAS for both the tofacitinib
5 mg BID and 10 mg BID treatment groups compared with placebo based on centrally-readand locally-read endoscopy.
Deep Remission at Week 24 and Week 52 and Sustained Deep Remission: A statisticallysignificantly greater proportion of subjects in the FAS in both the tofacitinib 5 mg BID groupand the tofacitinib 10 mg BID group were in deep remission based on centrally-readendoscopic subscores at Week 24 (14.1%, [p = 0.0006] and 10.7% [p = 0.0092],
respectively) and at Week 52 (14.6% [p = 0.0004] and 15.2% [p <0.0001], respectively) andsustained deep remission (6.1% [p = 0.0029] and 3.6%, [p = 0.0350], respectively) than thosein the placebo group (Week 24: 4.0%; Week 52: 4.0%; sustained: 0.5%). Statisticallysignificant difference between the tofacitinib 5 mg and 10 mg BID groups and placebo wasalso observed based on locally-read endoscopic subscores (Week 24: p = 0.0002 andp <0.0001, respectively; Week 52: both p <0.0001; sustained: p = 0.0005 and p <0.0001,
respectively).
Symptomatic Remission at Week 24 and Week 52 and Sustained Symptomatic Remission:
A statistically significantly (p <0.0001) greater proportion of subjects in the FAS in both thetofacitinib 5 mg BID group and the tofacitinib 10 mg BID group were in symptomatic
remission based on centrally-read endoscopic subscores at Week 24 (23.7% and 21.8%,
respectively) and Week 52 (22.7% and 26.9%, respectively), and sustained symptomatic
remission (13.6% and 15.7%, respectively) than those in the placebo group (Week 24: 6.6%;
Week 52: 7.1%; sustained: 2.5%). Statistically significant difference between the tofacitinib
5 mg and 10 mg BID groups and placebo was also observed based on locally-readendoscopic subscores (Week 24, Week 52, and sustained: all p <0.0001).
Endoscopic Remission at Week 24 and Week 52 and Sustained Endoscopic Remission: A
statistically significantly greater proportion of subjects in the FAS in both the tofacitinib
5 mg BID group and the tofacitinib 10 mg BID group were in endoscopic remission based on
centrally-read endoscopic subscores at Week 24 (16.2% [p <0.0001] and 12.2% [p = 0.0021],
respectively) and Week 52 (14.6% [p = 0.0004] and 16.8% [p <0.0001], respectively) andsustained endoscopic remission (6.1% [p = 0.0029] and 5.1% [p = 0.0064], respectively) thanthose in the placebo group (Week 24: 4.0%; Week 52: 4.0%; sustained: 0.5%). Statisticallysignificant difference between tofacitinib 5 mg and 10 mg BID groups and placebo was also
observed based on locally-read endoscopic subscores (Week 24: p = 0.0001 and p <0.0001,
respectively; Week 52: both p <0.0001; sustained: p = 0.0005 and p <0.0001, respectively).

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Protocol A3921096 – 14 February 2017 – Final

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Corticosteroid-Free Remission at Week 24 and Week 52 and Sustained
Corticosteroid-Free Remission Among Subjects Receiving Corticosteroids at Baseline: A
statistically significantly greater proportion of subjects in the FAS receiving corticosteroids
at baseline in both the tofacitinib 5 mg BID group and the tofacitinib 10 mg BID group werein corticosteroid-free remission based on centrally-read endoscopic subscores at Week 24(23.8% [p = 0.0074] and 24.1% [p = 0.0103], respectively) and Week 52 (27.7% [p = 0.0018]
and 27.6% [p = 0.0029], respectively) and sustained (12.9% [p = 0.0419] and 16.1%[p = 0.0121], respectively) than those in the placebo group (Week 24: 10.9%;
Week 52: 10.9%; sustained: 5.0%). Statistically significant difference between tofacitinib
5 mg and 10 mg BID groups and placebo was also observed based on locally-readendoscopic subscores (Week 24: p = 0.0016 and p = 0.0062, respectively;
Week 52: p = 0.0010 and p = 0.0026, respectively; sustained: p = 0.0294 and p = 0.0485,
respectively).

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Table 7.

Summary of Binary Efficacy Endpoints – FAS (NRI, Centrally-Read)

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PlaceboTofacitinib 5 mg BID
Difference From Placebon (%)%Diff (95% CI) p-valuea

N

Tofacitinib 10 mg BID
Difference From Placebon (%)%Diff (95% CI) p-valuea

22.7 (14.8, 30.6)
23.2 (15.3, 31.2)
17.2 (10.6, 23.7)<0.0001<0.0001<0.0001

197
197
197
197

55 (27.9)
70 (35.5)
80 (40.6)
50 (25.4)

24.4 (16.4, 32.4)
29.5 (21.4, 37.6)
20.3 (13.5, 27.1)<0.0001<0.0001<0.000140.1 (25.0, 55.3)
36.0 (21.6, 50.3)
31.8 (18.8, 44.8)<0.0001<0.0001<0.0001

55
55
55
55

55 (100)
35 (63.6)
31 (56.4)
26 (47.3)

48.4 (32.7, 64.1)
46.2 (31.0, 61.4)
42.2 (27.9, 56.5)<0.0001<0.0001<0.000126.8 (18.1, 35.5)
24.2 (16.0, 32.5)
21.2 (14.1, 28.3)<0.0001<0.0001<0.0001

197
197
197
197

89 (45.2)
91 (46.2)
90 (45.7)
65 (33.0)

29.0 (20.3, 37.7)
32.6 (24.2, 41.0)
26.4 (19.0, 33.8)<0.0001<0.0001<0.000130.6 (18.1, 43.1)
30.0 (18.7, 41.4)
24.4 (13.8, 35.0)<0.0001<0.0001<0.0001

89
89
89
89

89 (100)
59 (66.3)
49 (55.1)
44 (49.4)

44.5 (31.8, 57.2)
43.2 (31.1, 55.3)
40.5 (28.7, 52.3)<0.0001<0.0001<0.000138.6 (23.4, 53.8)
34.4 (20.1, 48.8)
30.3 (17.4, 43.2)<0.0001<0.0001<0.000155
55
55

35 (63.6)
31 (56.4)
26 (47.3)

48.4 (32.7, 64.1)
46.2 (31.0, 61.4)
42.2 (27.9, 56.5)<0.0001<0.0001<0.0001

23.2 (15.3, 31.2)
23.2 (15.3, 31.2)
17.2 (10.6, 23.7)<0.0001<0.0001<0.0001

197
197
197
197

56 (28.4)
70 (35.5)
81 (41.1)
51 (25.9)

24.4 (16.4, 32.4)
30.0 (21.9, 38.2)
20.8 (14.0, 27.7)<0.0001<0.0001<0.0001Nn (%)
N
Remission
Baseline
198 59 (29.8)
198
65 (32.8)
Week 24
198 22 (11.1)
198
67 (33.8)
Week 52
198 22 (11.1)
198
68 (34.3)
Sustained (Weeks 24 and 52) 198
10 (5.1)
198
44 (22.2)
Remission among subjects in remission at baselineb
Baseline59
59 (100)6565 (100)
Week 2459
9 (15.3)
65
36 (55.4)
Week 5259
6 (10.2)
65
30 (46.2)
Sustained (Weeks 24 and 52)
59
3 (5.1)65
24 (36.9)
Mucosal healing
Baseline
198 101 (51.0) 198
105 (53.0)
Week 24
198 34 (17.2)
198
87 (43.9)
Week 52
198 26 (13.1)
198
74 (37.4)
Sustained (Weeks 24 and 52) 198
13 (6.6)
198
55 (27.8)
Mucosal healing among subjects with mucosal healing at baselineb
Baseline
101 101 (100)105
105 (100)
Week 24
101 22 (21.8)
105
55 (52.4)
Week 52
101 12 (11.9)
105
44 (41.9)
Sustained (Weeks 24 and 52) 101
9 (8.9)105
35 (33.3)
Corticosteroid-free remission among subjects in remission at baselineb
Week 2459
9 (15.3)
65
35 (53.8)
Week 5259
6 (10.2)
65
29 (44.6)
Sustained (Weeks 24 and 52)
59
3 (5.1)65
23 (35.4)
Clinical remission
Baseline
198 60 (30.3)
198
65 (32.8)
Week 24
198 22 (11.1)
198
68 (34.3)
Week 52
198 22 (11.1)
198
68 (34.3)
Sustained (Weeks 24 and 52) 198
10 (5.1)
198
44 (22.2)

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Table 7.

Summary of Binary Efficacy Endpoints – FAS (NRI, Centrally-Read)

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PlaceboTofacitinib 5 mg BID
Difference From Placebon (%)%Diff (95% CI) p-valuea

Tofacitinib 10 mg BID
Difference From Placebon (%)%Diff (95% CI) p-valuea

N
n (%)
N
N
Clinical response
Baseline
198 195 (98.5) 198
193 (97.5)
197 195 (99.0)
Week 24
198 66 (33.3)
198
126 (63.6)
30.3 (20.9, 39.7)<0.0001 197 139 (70.6) 37.2 (28.1, 46.4)<0.0001
Week 52
198 40 (20.2)
198
102 (51.5)
31.3 (22.4, 40.2)<0.0001 197 122 (61.9) 41.7 (32.9, 50.5)<0.0001
Sustained (Weeks 24 and 52) 198 38 (19.2)
198
97 (49.0)
29.8 (20.9, 38.7)<0.0001 197 117 (59.4) 40.2 (31.4, 49.0)<0.0001
Deep remission
Baseline
198 23 (11.6)
198
18 (9.1)
197
16 (8.1)
Week 24
198
8 (4.0)198
28 (14.1)
10.1 (4.5, 15.7)
0.0006
197 21 (10.7)
6.6 (1.5, 11.7)
0.0092
Week 52
198
8 (4.0)198
29 (14.6)
10.6 (5.0, 16.2)
0.0004
197 30 (15.2)
11.2 (5.5, 16.9)<0.0001
Sustained (Weeks 24 and 52) 198
1 (0.5)198
12 (6.1)
5.6 (2.1, 9.0)
0.0029197
7 (3.6)
3.0 (0.3, 5.8)
0.0350Symptomatic remission
Baseline
198 38 (19.2)
198
43 (21.7)
197 35 (17.8)
Week 24198
13 (6.6)
198
47 (23.7)
17.2 (10.3, 24.0)<0.0001 197 43 (21.8)
15.3 (8.5, 22.0)<0.0001
Week 52198
14 (7.1)
198
45 (22.7)
15.7 (8.8, 22.5)<0.0001 197 53 (26.9)
19.8 (12.7, 27.0)<0.0001
Sustained (Weeks 24 and 52) 198
5 (2.5)198
27 (13.6)
11.1 (5.9, 16.4)<0.0001 197 31 (15.7)
13.2 (7.7, 18.7)<0.0001
Endoscopic remission
Baseline
198 26 (13.1)
198
22 (11.1)
197 20 (10.2)
Week 24
198
8 (4.0)198
32 (16.2)
12.1 (6.3, 17.9)<0.0001 197 24 (12.2)
8.1 (2.8, 13.5)
0.0021
Week 52
198
8 (4.0)198
29 (14.6)
10.6 (5.0, 16.2)
0.0004
197 33 (16.8)
12.7 (6.8, 18.6)<0.0001
Sustained (Weeks 24 and 52) 198
1 (0.5)198
12 (6.1)
5.6 (2.1, 9.0)
0.0029197
10 (5.1)
4.6 (1.4, 7.8)
0.0064
Corticosteroid-free remission among subjects receiving corticosteroids at baseline
Week 24
101 11 (10.9)
101
24 (23.8)
12.9 (2.6, 23.2)
0.007487
21 (24.1)
13.2 (2.4, 24.1)
0.0103
Week 52
101 11 (10.9)
101
28 (27.7)
16.8 (6.2, 27.5)0.001887
24 (27.6)
16.7 (5.5, 27.9)
0.0029Sustained (Weeks 24 and 52) 101
5 (5.0)101
13 (12.9)
7.9 (0.1, 15.7)
0.041987
14 (16.1)
11.1 (2.3, 19.9)
0.0121
95% CI was based on the normal approximation for the difference in binomial proportions.
BID = twice a day; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; Diff = difference; FAS = full analysis set; N = number of subjects in theanalysis set; n = number of subjects meeting endpoint criteria; NRI = non-responder imputation.
a. P-value was based on CMH Chi-squared test stratified by treatment assignment in the induction study (tofacitinib, placebo) and remission at baseline (yes,no), unless specified otherwise.
b. P-value was based on CMH Chi-squared test stratified by treatment assignment in the induction study (tofacitinib, placebo).

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Table 8.

Summary of Binary Efficacy Endpoints – FAS (NRI, Locally-Read)

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)

PlaceboTofacitinib 5 mg BID
Difference From Placebon (%)%Diff (95% CI)
p-valuea

N

Tofacitinib 10 mg BID
Difference From Placebon (%)%Diff (95% CI) p-valuea

26.3 (17.5, 35.0)
26.3 (18.0, 34.5)
21.7 (14.1, 29.4)<0.0001<0.0001<0.0001

197
197
197
197

74 (37.6)
91 (46.2)
94 (47.7)
73 (37.1)

28.5 (19.8, 37.3)
34.6 (26.2, 43.0)
27.5 (19.6, 35.4)<0.0001<0.0001<0.000142.3 (26.4, 58.2)
38.9 (24.2, 53.6)
37.4 (22.7, 52.1)<0.0001<0.0001<0.0001

55
55
55
55

50 (90.9)
39 (70.9)
36 (65.5)
32 (58.2)

45.5 (29.1, 61.8)
53.6 (38.6, 68.6)
46.3 (30.9, 61.7)<0.0001<0.0001<0.000131.3 (22.1, 40.5)
29.3 (20.7, 37.9)
28.8 (20.5, 37.1)<0.0001<0.0001<0.0001

197
197
197
197

117 (59.4)
117 (59.4)
106 (53.8)
98 (49.7)

33.1 (23.9, 42.3)
38.2 (29.5, 46.8)
37.1 (28.7, 45.5)<0.0001<0.0001<0.000134.9 (22.1, 47.7)
31.9 (20.2, 43.5)
32.8 (21.3, 44.4)<0.0001<0.0001<0.0001

89
89
89
89

83 (93.3)
62 (69.7)
56 (62.9)
53 (59.6)

37.0 (23.8, 50.2)
49.1 (37.0, 61.1)
46.7 (34.6, 58.8)<0.0001<0.0001<0.000139.2 (23.1, 55.3)
37.4 (22.7, 52.1)
35.8 (21.1, 50.5)<0.0001<0.0001<0.000155
55
55

39 (70.9)
36 (65.5)
32 (58.2)

45.5 (29.1, 61.8)
53.6 (38.6, 68.6)
46.3 (30.9, 61.7)<0.0001<0.0001<0.0001

29.8 (20.4, 39.2)
30.3 (21.3, 39.3)
29.3 (20.4, 38.2)<0.0001<0.0001<0.0001

197
197
197
197

188 (95.4)
140 (71.1)
121 (61.4)
118 (59.9)

35.7 (26.5, 44.9)
40.7 (31.9, 49.5)
40.2 (31.4, 49.0)<0.0001<0.0001<0.0001Nn (%)
N
Remission
Baseline
198 80 (40.4) 198 75 (37.9)
Week 24
198 35 (17.7) 198 87 (43.9)
Week 52
198 26 (13.1) 198 78 (39.4)
Sustained (Weeks 24 and 52) 198
19 (9.6)
198 62 (31.3)
Remission among subjects in remission at baselineb
Baseline59
56 (94.9)
65
57 (87.7)
Week 2459
15 (25.4)
65
44 (67.7)
Week 5259
7 (11.9)65
33 (50.8)
Sustained (Weeks 24 and 52)
59
7 (11.9)65
32 (49.2)
Mucosal healing
Baseline
198 129 (65.2) 198 137 (69.2)
Week 24
198 52 (26.3) 198 114 (57.6)
Week 52
198 31 (15.7) 198 89 (44.9)
Sustained (Weeks 24 and 52) 198 25 (12.6) 198 82 (41.4)
Mucosal healing among subjects with mucosal healing at baselineb
Baseline
101 95 (94.1) 105 96 (91.4)
Week 24
101 33 (32.7) 105 71 (67.6)
Week 52
101 14 (13.9) 105 48 (45.7)
Sustained (Weeks 24 and 52) 101 13 (12.9) 105 48 (45.7)
Corticosteroid-free remission among subjects in remission at baselineb
Week 2459
15 (25.4)
65
42 (64.6)
Week 5259
7 (11.9)65
32 (49.2)
Sustained (Weeks 24 and 52)
59
7 (11.9)65
31 (47.7)
Clinical response
Baseline
198 194 (98.0) 198 194 (98.0)
Week 24
198 70 (35.4) 198 129 (65.2)
Week 52
198 41 (20.7) 198 101 (51.0)
Sustained (Weeks 24 and 52) 198 39 (19.7) 198 97 (49.0)

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Protocol A3921096 – 14 February 2017 – Final

Table 8.

Summary of Binary Efficacy Endpoints – FAS (NRI, Locally-Read)

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)

PlaceboTofacitinib 5 mg BID
Difference From Placebon (%)%Diff (95% CI)
p-valuea

Tofacitinib 10 mg BID
Difference From Placebon (%)%Diff (95% CI) p-valuea

N
n (%)
N
N
Clinical remission
Baseline
198 81 (40.9) 198 75 (37.9)
197
75 (38.1)
Week 24
198 35 (17.7) 198 88 (44.4)
26.8 (18.0, 35.5)<0.0001197
92 (46.7)
29.0 (20.3, 37.8)<0.0001
Week 52
198 26 (13.1) 198 79 (39.9)
26.8 (18.5, 35.1)<0.0001197
95 (48.2)
35.1 (26.7, 43.5)<0.0001
Sustained (Weeks 24 and 52) 198
19 (9.6)
198 62 (31.3)
21.7 (14.1, 29.4)<0.0001197
75 (38.1)
28.5 (20.6, 36.4)<0.0001
Deep Remission
Baseline
198 34 (17.2) 198 28 (14.1)
197
27 (13.7)
Week 24198
19 (9.6)
198 47 (23.7)
14.1 (6.9, 21.3)
0.0002
197
52 (26.4)
16.8 (9.4, 24.2)<0.0001
Week 52198
10 (5.1)
198 43 (21.7)
16.7 (10.2, 23.2)<0.0001197
57 (28.9)
23.9 (16.9, 30.9)<0.0001
Sustained (Weeks 24 and 52) 198
7 (3.5)198 27 (13.6)
10.1 (4.7, 15.5)
0.0005197
32 (16.2)
12.7 (7.0, 18.5)<0.0001
Symptomatic Remission
Baseline
198 50 (25.3) 198 50 (25.3)
197
47 (23.9)
Week 24
198 23 (11.6)
198 60 (30.3)
18.7 (10.9, 26.5)<0.0001197
55 (27.9)
16.3 (8.6, 24.0)<0.0001
Week 52198
18 (9.1)
198 55 (27.8)
18.7 (11.3, 26.1)<0.0001197
61 (31.0)
21.9 (14.3, 29.5)<0.0001
Sustained (Weeks 24 and 52) 198
10 (5.1)
198 39 (19.7)
14.6 (8.3, 21.0)<0.0001197
44 (22.3)
17.3 (10.7, 23.9)<0.0001
Endoscopic Remission
Baseline
198 38 (19.2) 198 31 (15.7)
197
30 (15.2)
Week 24
198 21 (10.6) 198 51 (25.8)
15.2 (7.7, 22.6)
0.0001
197
59 (29.9)
19.3 (11.6, 27.0)<0.0001
Week 52198
11 (5.6)
198 44 (22.2)
16.7 (10.1, 23.3)<0.0001197
58 (29.4)
23.9 (16.8, 31.0)<0.0001
Sustained (Weeks 24 and 52) 198
7 (3.5)198 27 (13.6)
10.1 (4.7, 15.5)
0.0005197
38 (19.3)
15.8 (9.7, 21.8)<0.0001
Corticosteroid-free remission among subjects receiving steroids at baseline
Week 24
101 16 (15.8) 101 34 (33.7)
17.8 (6.2, 29.5)
0.001687
27 (31.0)
15.2 (3.1, 27.2)
0.0062
Week 52
101 14 (13.9) 101 33 (32.7)
18.8 (7.5, 30.2)
0.001087
27 (31.0)
17.2 (5.3, 29.0)
0.0026
Sustained (Weeks 24 and 52) 101 12 (11.9) 101 23 (22.8)
10.9 (0.6, 21.2)
0.029487
18 (20.7)
8.8 (-1.8, 19.4)
0.0485
95% CI was based on the normal approximation for the difference in binomial proportions.
BID = twice a day; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; Diff = difference; FAS = full analysis set; N = number of subjects in theanalysis set; n = number of subjects meeting endpoint criteria; NRI = non-responder imputation.
a. P-value was based on CMH Chi-squared test stratified by treatment assignment in the induction study (tofacitinib, placebo) and remission at baseline (yes,no), unless specified otherwise.
b. P-value was based on CMH Chi-squared test stratified by treatment assignment in the induction study (tofacitinib, placebo).

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Public Disclosure Synopsis
Protocol A3921096 – 14 February 2017 – Final

Change in Mayo Score Over Time:The mean Mayo score at baseline was similar across treatment groups (3.3, 3.4, and 3.3, inthe tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo groups, respectively).

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)The analysis of change from baseline for Mayo score using the linear mixed-effects model(FAS, observed cases) is presented in Table 9. At Week 24, both the tofacitinib 5 mg BID
and tofacitinib 10 mg BID groups demonstrated significant treatment effects in change frombaseline in Mayo score compared with placebo, with adjusted mean differences from placeboof -2.6 (95% CI: -3.2, -1.9; p <0.0001), and -2.8 (95% CI: -3.5, -2.2; p <0.0001),
respectively. Similarly, at Week 52, both the tofacitinib 5 mg BID and 10 mg BID groups
demonstrated significant treatment effects in change from baseline in Mayo score comparedwith placebo, with adjusted mean differences from placebo of -2.6 (95% CI: -3.4, -1.7;
p <0.0001), and -3.3 (95% CI: -4.1, -2.5; p <0.0001), respectively.

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Protocol A3921096 – 14 February 2017 – Final

Table 9.

Analysis of Change From Baseline for Mayo Score Using the Linear Mixed-Effects Model – FAS (Observed Cases)
Placebo

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)N

Adjusted
Mean (SE)N

Tofacitinib 5 mg BID
Difference From Placebo
Adjusted
Diff (95% CI)
p-value
Mean

N

Tofacitinib 10 mg BID
Difference From Placebo
Adjusted
Diff (95% CI)
p-value
Mean

Mayo Score
Week 24181
2.9 (0.3)179
0.3 (0.3)-2.6 (-3.2, -1.9)<0.0001186
0.0 (0.3)-2.8 (-3.5, -2.2)<0.0001
Week 5268
2.9 (0.4)129
0.4 (0.3)-2.6 (-3.4, -1.7)<0.0001137-0.4 (0.3)-3.3 (-4.1, -2.5)<0.0001
Adjusted Means and p-value were derived from the analysis of linear mixed effect model: change from baseline = treatment + baseline partial mayoscore + induction treatment + week + treatment*week with subject as a random effect.
For Mayo score, data on early termination subjects from Week 4, 8, or 16 windowed visits were treated as Week 24 windowed visit data, and data on earlytermination subjects from Week 32 or 40 windowed visits were treated as Week 52 windowed visit data.
BID = twice a day; CI = confidence interval; Diff = difference; FAS = full analysis set; N = number of subjects with non-missing data; SE = standard error.

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Protocol A3921096 – 14 February 2017 – Final

Safety Results:
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 in tofacitinib 5 mg BID, tofacitinib 10 mg
BID, and placebo groups (Table 10). Colitis ulcerative was the most frequent non-serious
AE by preferred term (PT) occurring in tofacitinib 5 mg BID (17.68%), tofacitinib 10 mg
BID (14.80%), and placebo groups (32.32%).
Table 10. Treatment-Emergent Non-Serious Adverse Events by System Organ Classand Preferred Term (All Causalities) in >5% of Subjects

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)

Number (%) of subjects
Evaluable for AEs
With AEs

Tofacitinib 5 mg BIDn (%)

Tofacitinib 10 mg BID
n (%)

Placebon (%)

198
87 (43.94)

196
107 (54.59)

198
108 (54.55)

Number (%) of subjects with AEs by:
SOCs and MedDRA PTs
Gastrointestinal Disorders
39 (19.70)
36 (18.37)
72 (36.36)
Abdominal pain
5 (2.53)
7 (3.57)
11 (5.56)
Colitis ulcerative35 (17.68)
29 (14.80)
64 (32.32)
General Disorders and Administration
8 (4.04)
4 (2.04)
11 (5.56)
Site Conditions
Fatigue
8 (4.04)
4 (2.04)
11 (5.56)
Infections and Infestations
32 (16.16)
46 (23.47)
18 (9.09)
Herpes zoster
2 (1.01)10 (5.10)
1 (0.51)
Nasopharyngitis
19 (9.60)
27 (13.78)
11 (5.56)
Upper respiratory tract infection
13 (6.57)
12 (6.12)
7 (3.54)
Investigations
6 (3.03)13 (6.63)
4 (2.02)
Blood creatine phosphokinase
6 (3.03)13 (6.63)
4 (2.02)increased
Metabolism and Nutrition Disorders
4 (2.02)11 (5.61)
2 (1.01)
Hypercholesterolaemia
4 (2.02)11 (5.61)
2 (1.01)
Musculoskeletal and Connective Tissue
17 (8.59)
17 (8.67)
19 (9.60)
Disorders
Arthralgia
17 (8.59)
17 (8.67)
19 (9.60)
Nervous System Disorders
17 (8.59)
6 (3.06)
12 (6.06)
Headache17 (8.59)
6 (3.06)
12 (6.06)
Skin and Subcutaneous Tissue Disorders
6 (3.03)11 (5.61)
8 (4.04)Rash
6 (3.03)11 (5.61)
8 (4.04)
Subjects are only counted once per treatment for each row.
Percentages of gender specific events are calculated using the corresponding gender count as denominator.
Includes events from study database, even those that occur after last dose of study drug.
MedDRA (v19.0) coding dictionary applied.
AE = adverse events; BID = twice a day; MedDRA = Medical Dictionary for Regulatory Activities; n = numberof subjects meeting prespecified criteria; PT = preferred term; SOC = system organ class.

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Protocol A3921096 – 14 February 2017 – Final

All-Causality Treatment-Emergent Serious Adverse Events

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)The incidence of all-causality serious TEAEs were reported in 5.05% and 5.61% of subjects
in the tofacitinib 5 mg BID group and 10 mg BID group, respectively, compared with 6.57%
for subjects treated with placebo Table 11. The most frequent serious adverse event (SAE)
was colitis ulcerative (tofacitinib 5 mg BID: 2 subjects [1.01%]; tofacitinib 10 mg BID:
1 subject [0.51%]; placebo: 8 subjects [4.04%]). For all PTs, SAEs occurred in <2% ofsubjects in either tofacitinib treatment group.

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Protocol A3921096 – 14 February 2017 – Final

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)

Table 11. Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term (All Causalities)

Number (%) of Subjects
Evaluable for AEs
With AEs
Number (%) of Subjects with AEs by: SOCs and MedDRA
PTs
Cardiac Disorders
Myocardial infarction
Gastrointestinal Disorders
Abdominal pain
Colitis ulcerative
Diarrhoea
Gastrointestinal haemorrhage
Pancreatitis
General Disorders and Administration Site Conditions
Chest pain
MalaiseHepatobiliary Disorders
Cholecystitis acute
Infections and Infestations
Bacterial diarrhoea
Diverticulitis
Peritonsillar abscessSubcutaneous abscess
Urinary tract infection
Injury, Poisoning and Procedural Complications
Lower limb fracture
Lumbar vertebral fracture
Spinal compression fracture
Musculoskeletal and Connective Tissue Disorders
Osteoarthritis
Spondylolisthesis
Neoplasms Benign, Malignant and Unspecified (Incl Cysts
and Polyps)

Tofacitinib 5 mg BIDn (%)

Tofacitinib 10 mg BID
n (%)

Placebon (%)

198
10 (5.05)

196
11 (5.61)

198
13 (6.57)

1 (0.51)
1 (0.51)
3 (1.52)02 (1.01)0
1 (0.51)01 (0.51)
1 (0.51)000
2 (1.01)00
1 (0.51)01 (0.51)
2 (1.01)1 (0.51)
1 (0.51)01 (0.51)01 (0.51)000
3 (1.53)
1 (0.51)
1 (0.51)
1 (0.51)000001 (0.51)
1 (0.51)
1 (0.51)
1 (0.51)00001 (0.51)001 (0.51)
1 (0.51)
1 (0.51)01 (0.51)009 (4.55)
08 (4.04)00
1 (0.51)
1 (0.51)01 (0.51)002 (1.01)0
1 (0.51)01 (0.51)
0
0
0
0
0
0
0
0
1 (0.51)

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Protocol A3921096 – 14 February 2017 – Final

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)

Table 11. Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term (All Causalities)
Tofacitinib 5 mg BID
n (%)
0
0
0
0
0
0
0
0
1 (1.05)
1 (1.05)00
0
0
0

Tofacitinib 10 mg BIDn (%)
1 (0.51)01 (0.51)
3 (1.53)
1 (0.51)
1 (0.51)
1 (0.51)
1 (0.51)002 (1.02)
1 (0.51)
1 (0.51)00Placebon (%)
0
1 (0.51)
0
0
0
0
0
0
0
0
0
0
0
1 (0.51)
1 (0.51)

Bowen’s disease
Invasive ductal breast carcinoma
Squamous cell carcinoma of skin
Nervous System Disorders
Generalised tonic-clonic seizure
Haemorrhagic stroke
Sciatica
SeizurePregnancy, Puerperium and Perinatal Conditions
Abortion spontaneous
Skin And Subcutaneous Tissue Disorders
Dermatitis acneiform
Rash maculo-papular
Vascular Disorders
Embolism venous
Subjects are only counted once per treatment for each row.
Percentages of gender specific events are calculated using the corresponding gender count as denominator.
Includes events from study database, even those that occur after last dose of study drug.
MedDRA (v19.0) coding dictionary applied.
AE = adverse events; BID = twice a day; MedDRA = Medical Dictionary for Regulatory Activities; n = number of subjects meeting prespecified criteria;
PT = preferred term; SOC = system organ class.

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Protocol A3921096 – 14 February 2017 – Final

Withdrawals of Subjects from the Study
Discontinuations from the study are listed in Table 12. A greater proportion of subjects inthe placebo group discontinued from the study compared with the tofacitinib 5 mg and 10 mg
BID groups.
Table 12. Discontinuations from Study

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)

Tofacitinib 5 mg
BID
n (%)
198
111 (56.1)
87 (43.9)
74 (37.4)
4 (2.0)70 (35.4)
13 (6.6)
1 (0.5)3 (1.5)6 (3.0)Tofacitinib 10 mg
BID
n (%)
196
126 (64.3)
70 (35.7)
61 (31.1)
8 (4.1)53 (27.0)
9 (4.6)
1 (0.5)2 (1.0)3 (1.5)

Number (%) of subjects
Completed
Discontinuations
Related to study drug
AE
Insufficient clinical response
Not related to study drug
AE
Lost to follow-up
No longer willing to participate in
study
Other
2 (1.0)1 (0.5)
Protocol violation01 (0.5)
Withdrawn due to pregnancy
1 (0.5)1 (0.5)AE = adverse event; BID = twice daily; n = number of subjects meeting prespecified criteria.

Deaths: There were no deaths among subjects who participated in this study.

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Placebon (%)
198
53 (26.8)
145 (73.2)
134 (67.7)
2 (1.0)132 (66.7)
11 (5.6)5 (2.5)1 (0.5)5 (2.5)000Public Disclosure Synopsis
Protocol A3921096 – 14 February 2017 – Final

090177e18b4c4412\Approved\Approved On: 21-Feb-2017 01:40 (GMT)

CONCLUSIONS:This Phase 3 study demonstrated efficacy of tofacitinib 5 mg BID and 10 mg BID as
maintenance therapy for UC, with statistically significantly greater treatment effects forboth treatment groups versus placebo for remission at Week 52 (primary endpoint),
mucosal healing at Week 52, and sustained corticosteroid-free remission among subjects
in remission at baseline (key secondary endpoints).

The efficacy of tofacitinib 5 mg BID and 10 mg BID was supported by all othersecondary efficacy endpoints, various analysis populations, sensitivity analyses, andlocally-read endoscopic findings.

The observed treatment effect was higher in the tofacitinib 10 mg BID group than thetofacitinib 5 mg BID group in the overall population for primary and key secondary
endpoints.

Tofacitinib 5 mg BID and 10 mg BID also demonstrated significantly higher proportionsof subjects with clinical remission and clinical response compared with placebo.

For all efficacy endpoints, the efficacy results based on the mFAS were consistent withthe results based on the FAS.

In this 52-week maintenance study, both the tofacitinib 5 mg BID and 10 mg BID doses
appeared to be well tolerated. Most frequent TEAEs were colitis ulcerative (higher
incidence in the placebo group) and nasopharyngitis (higher incidence in the tofacitinib
groups).



SAEs occurred at similar frequencies across treatment groups, and there were no deaths
reported during this study.

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