Public Disclosure Synopsis
Protocol A3921215 – 08 March 2018 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME® / GENERIC DRUG NAME: Xeljanz / Tofacitinib
citratePROTOCOL NO.: A3921215
PROTOCOL TITLE:
A Multicenter, Randomized, Double-Blind, Parallel-Group, Phase 3 Study to Demonstrate
Non-Inferiority for the Efficacy of a Once Daily Dose of Tofacitinib Modified Release
Tablet to a Twice Daily Dose of the Immediate Release Tablet in Adult Patients With
Rheumatoid Arthritis on Background Methotrexate
Study Centers:
090177e18de16b18\Approved\Approved On: 16-Mar-2018 10:25 (GMT)

A total of 36 centers took part in the study and randomized patients in Japan.
Study Initiation and Final Completion Dates:
18 November 2014 and 15 March 2017
Phase of Development:
Phase 3
Study Objectives:
Primary Objective:

To demonstrate the non-inferiority for efficacy of tofacitinib modified release (MR)
11 mg once daily (QD) to immediate release (IR) 5 mg twice daily (BID) for thetreatment of signs and symptoms in patients with active rheumatoid arthritis (RA) on astable background of methotrexate (MTX), as measured by Disease Activity Score (DAS)
defined using 28 joint counts and C-reactive protein (DAS28-4[CRP]) change frombaseline at Week 12.

Secondary Objectives:
To evaluate the similarity in efficacy of tofacitinib MR 11 mg QD and IR 5 mg BID for
the treatment of signs and symptoms of RA, as measured by DAS defined using 28 joint
counts and erythrocyte sedimentation rate (DAS28-4[ESR]) change from Baseline,
American College of Rheumatology (ACR) definition for calculating improvement in RA
calculated as a 20%/50%/70% improvement in tender and swollen joint counts and20%/50%/70% improvement in 3 of the 5 remaining ACR core set measures,Template version 1.7

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Protocol A3921215 – 08 March 2018 – Finalrespectively (ACR20, ACR50, ACR70, respectively) responses, remission, and low
disease activity (LDA), at Week 12.


To evaluate the similarity in efficacy of tofacitinib MR 11 mg QD and IR 5 mg BID for
physical function status as measured by Health Assessment Questionnaire-Disability
Index (HAQ-DI) change from Baseline at Week 12.



To evaluate the similarity in effects on patient’s health outcome measures (change fromBaseline in Short Form-36 [SF-36], Functional Assessment of Chronic Illness Therapy[FACIT] Fatigue and European Quality of Life-5 dimensions questionnaire [EQ-5D]) of
tofacitinib MR 11 mg QD and IR 5 mg BID at Week 12.



To evaluate the safety and tolerability of tofacitinib MR 11 mg QD in comparison withIR 5 mg BID in patients.

METHODSThis was a multicenter, randomized, double-blind, parallel group, Phase 3 study to evaluate
the efficacy and safety of tofacitinib MR 11 mg tablet QD dose compared to IR 5 mg tablet
BID dose at 12 weeks treatment in patients with moderate to severe active RA on a stablebackground MTX.
Patients were randomized in a 1:1 ratio into the tofacitinib MR 11 mg QD group and thetofacitinib IR 5 mg BID group. The study design schematic for the study is presented in
Figure 1. The schedule of activities is presented in Table 1.
Figure 1.

Study Design

Screening

Randomization 1:1
Randomization

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Study Design:−40

Tofacitinib MR 11 mg Tablet, Once Daily

Tofacitinib IR 5 mg Tablet, Twice Daily

48

Approximately 100 per arm, N=200.
Abbreviations: IR=Immediate release; MR=Modified release; N=Number of patients.

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Table 1.

Schedule of Activities

Visit Identifier

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Study Day
Visit Window (Days)
Informed consent

VisitsVisit 3
Week 4

Visit 4
Week 8

Visit 5
Week 12a(EOS/ET)

1

29

57

85

0

3

3

3


X





X

X

X

X

X

X

X

X
X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

Visit 1
Screening

Visit 2
Baseline
Day 1-27+7 (-34 to 0)b

X
XComplete physical examination

X
X
X
X

Medical history
Prior treatments/medications
Concomitant treatments/ medications
Inclusion/exclusion criteria
Targeted physical examination

c

c

d

Vital signs, temperature
Whole blood interferon-gamma release assaye(Quantiferon-3G/QuantiFERON-TB Gold in-tube or T-SPOT)
12-lead electrocardiogram
Chest X-ray (PA and lateral) or chest CT scan
Blood/urine
Rheumatoid factorg

Hematology , chemistry panel

f

h

i

Lipid profile (fasting)Serum pregnancy test (β-HCG)
Urine pregnancy test (β-HCG)

j

X
X
X

X

k

k

Urinalysis
Serum β-D-glucan and KL-6
HIV serology
HBsAg, HBcAb, HBsAb,l
HBV DNA testing (if necessary)
HCV Ab, HCV RNA PCR (if HCV Ab positive)
Varicella-Zoster virus
m

X

X
X
X
X
X
X

Lymphocyte subset markers
Banked biospecimens (PGx sampling)

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Protocol A3921215 – 08 March 2018 – Final

Table 1.

Schedule of Activities

Visit Identifier

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Study Day

Visit 1
Screening

Visit 2
Baseline
Day 1

-27

1

Visit Window (Days)

VisitsVisit 3
Week 4

Visit 4
Week 8

Visit 5
Week 12a(EOS/ET)

29

57

85

+7 (-34 to 0)
0
3
3
3
ACR/DAS
CRP
X
X
X
X
ESR
X
X
X
X
Joint assessment: tender/painful joint count: (68 joints),
X
X
X
X
swollen joint count (66 joints)
Patient Assessment of Arthritis Pain (VAS)
X
X
X
Patient Global Assessment (VAS)
X
X
X
Physician Global Assessment (VAS)X
X
X
HAQ-DI
X
X
X
SF-36 (Version 2, acute)
X
X
X
FACIT-fatigue scale
X
X
European Quality of Life Questionnaire
X
X
Randomization
X
Study drug dispensing-new bottles supplied
X
X
X
Dispense dosing diary
X
X
X
Drug accountability
X
X
X
Review of patient dosing diary
X
X
X
Adverse events
XX
Abbreviations: ACR=American College of Rheumatology; ALP=Alkaline phosphatase; ALT=Alanine aminotransferase; AST=Aspartate aminotransferase; BCG=BacilleCalmette Guérin; β-HCG=Beta-human chorionic gonadotropin; CD=Cluster of differentiation; CK=Creatine kinase; CRP=C reactive protein; CT=Computed tomography;
DAS=Disease Activity Score; DNA=Deoxyribonucleic acid; EOS=End of study; ESR=Erythrocyte sedimentation rate; ET=Early termination; FACIT=Functional Assessmentof Chronic Illness Therapy; GGT=Gamma-glutamyl transferase; HAQ-DI=Health Assessment Questionnaire-Disability Index; HBcAb=Hepatitis B core antibody;
HBsAb=Hepatitis B surface antibody; HBsAg=Hepatitis B surface antigen; HBV=Hepatitis B virus; HCV=Hepatitis C virus; HCV Ab=Hepatitis C virus antibody;
HEENT=Head, eyes, ears, nose and throat; HIV=Human immunodeficiency virus; IFN-γ=Interferon-gamma; IV=Intravenous; PA=Posteroanterior; PCR=Polymerase chain
reaction; PGx=Pharmacogenomics; pH=Negative logarithm of the hydrogen ion concentration; PPD=Purified Protein Derivative; QFT-G=Quantiferon 3G/QuantiFERON-TB
Gold In-tube; RA=Rheumatoid arthritis; RBC=Red blood cell; RNA=Ribonucleic acid; SF-36=Short Form-36; TB=Tuberculosis; VAS=Visual analog scale; WBC=White
blood cell.
a. Study procedures were to be performed at the EOS or ET Visit.
b. Medical history included previous vaccination history, smoking status, average weekly alcohol consumption, family history of premature coronary heart disease, history of
any prior episodes of herpes zoster and confirmation of RA diagnosis.
c. Complete physical exam included height, weight, general appearance, skin (presence of rash), HEENT (head, eyes, ears, nose and throat), lungs (auscultation), heart(auscultation for presence of murmurs, gallops, rubs), lower extremities (peripheral edema), abdominal (palpation and auscultation), neurologic (mental status, station,

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Protocol A3921215 – 08 March 2018 – Final

Table 1.

Schedule of Activities

Visit Identifier

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Study Day

Visit 1
Screening

Visit 2
Baseline
Day 1

-27

1

Visit Window (Days)

VisitsVisit 3
Week 4

Visit 4
Week 8

Visit 5
Week 12a(EOS/ET)

29

57

85

+7 (-34 to 0)
0
3
3
3
gait, reflexes, motor and sensory function, coordination) and lymph nodes. Targeted physical examination included weight, examination of heart, lungs, lower extremities
for peripheral edema, abdomen and lymph nodes.
d. Temperature was collected as axillary temperature. The same method was used throughout the study.
e. Mantoux PPD tuberculin skin test was allowed, if there were 2 consecutive indeterminate results of QFT-G or T-SPOT test in patients who had not received BCG
vaccination during screening period.
f. Chest X-ray (PA and lateral) or chest CT scan (with or without intravenous [IV] contrast) were obtained at screening or within 12 weeks prior to screening and read by aqualified radiologist or respiratologist. If necessary, a chest CT scan (with or without IV contrast) might have been performed during screening following initial
performance of chest radiographs (PA and lateral) at the clinical discretion of the investigator. If pulmonary signs and symptoms were observed at and after baseline visit,unscheduled imaging test (eg, chest X-ray or chest CT scan) might have been performed based on the judgment by investigator as appropriate.
g. Hematology included hemoglobin, hematocrit, RBC count, WBC count with differential and platelet count.
h. Chemistry panel included blood urea nitrogen, creatinine, glucose, calcium, sodium, potassium, bicarbonate, chloride, total protein, total bilirubin, direct bilirubin, indirect
bilirubin, ALT, AST, ALP, GGT, albumin, CK.
i. Lipid profile included total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and triglycerides under fasting condition.
j. Serum pregnancy test for women of childbearing potential only.
k. Dipstick in all cases; urinalysis included specific gravity, pH, protein, glucose, ketones, blood, nitrite, leukocyte esterase and urine sediment (microscopy). Urine culture
was performed if clinically indicated. Urine pregnancy test (β-HCG) was required only for women who were of childbearing potential; could have been repeated more
frequently if a menstrual cycle was missed, or if potential pregnancy was otherwise suspected.
l. HBV DNA assay might have been required for a subset of patients with specified serological test results.
m. Lymphocyte subset markers included CD3+, CD3−CD19+, CD3+CD4+CD8−, CD3+CD4−CD8+, CD3+CD16+CD56+, CD3−CD16+CD56+, CD3−CD16+CD56−,
CD3−CD16−CD56+, CD3−CD16−CD56−, CD4/CD8.

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Protocol A3921215 – 08 March 2018 – Final

Number of Subjects (Planned and Analyzed):
The following assumptions in treatment comparison for the primary endpoint were applied:One-sided type-I error (alpha) of 0.025;

Patients assigned to tofacitinib MR 11 mg QD and IR 5 mg BID groups in a 1:1 ratio;

Difference of treatment means is 0;

A common standard deviation of 1.3 based on the previous tofacitinib studies.

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Based on the forgoing assumptions, a total of at least 200 evaluable patients (100 in eachtreatment arm) were required to demonstrate non-inferiority with a power of 90% and a
non-inferiority margin of 0.6, which was equal to the minimum improvement in diseaseactivity by DAS consistent with a “moderate response” by the European League Against
Rheumatism (EULAR) criteria. However, the minimal clinically important DAS28 change
from baseline is 1.2.
It was anticipated that the sample size of 100 patients in each formulation group would
provide 0.36 half-width of 2-sided 95% confidence interval (CI) for the difference on thechange from baseline in DAS28-4(CRP) at Week 12 assuming a common standard deviationof 1.3.
A total of 333 patients were screened, of which 209 patients were randomized and treated.
One hundred and four (104) patients were randomized to receive tofacitinib 11 mg QD and
105 patients were randomized to receive tofacitinib 5 mg BID.
Diagnosis and Main Criteria for Inclusion and Exclusion:
Main Inclusion Criteria:
Patients having diagnosis of RA and those who were currently taking a stable dose of MTX;
patients having no evidence of active or latent or inadequately treated tuberculosis were
included in this study.
Main Exclusion Criteria:
Patients having evidence or history of clinically significant hematological, renal, endocrine,
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic or allergic
disease; patients having clinically significant infections within the past 6 months were
excluded from this study.
Study Treatment:
Patients were provided with medication instructions relevant to their study treatment arm.
Study drugs were taken according to the instructions provided to the patient.

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Protocol A3921215 – 08 March 2018 – Final

Patients were instructed to take 1 tablet from each bottle in the morning and 1 tablet frombottle of IR in the evening, approximately 12 hours apart. Patients had to take 3 tablets per
day and record drug compliance in the patient dosing diary.
If a tofacitinib dose was missed and the interval to the next scheduled dose was <6 hours, themissed dose of tofacitinib IR was not administered. Patients swallowed the whole study
drug, and did not manipulate or chew the medication prior to swallowing.
Efficacy Endpoints:
Primary Efficacy Endpoint:Change from Baseline in DAS28-4(CRP) at Week 12.

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Secondary Efficacy Endpoints:


Change from Baseline in DAS28-4(ESR) at Week 12;



ACR20, ACR50 and ACR70 response at Week 12;Remission at Week 12, as assessed by: DAS28-4(CRP) <2.6 and DAS28-4(ESR) <2.6;



LDA at Week 12, as assessed by: DAS28-4(CRP) 3.2 and DAS28-4(ESR) 3.2;

Change from Baseline in HAQ-DI at Week 12;

HAQ-DI response (decrease of at least 0.22) at Week 12;

Change from Baseline in the SF-36 8 domain scores and 2 component scores at Week 12;

Change from Baseline in the FACIT-Fatigue scale at Week 12;

Change from Baseline in the EQ-5D at Week 12.

Safety Evaluations:
Safety evaluations included clinical monitoring, vital signs (heart rate, blood pressure [BP]),
12-lead electrocardiograms (ECGs), AEs including serious adverse events (SAEs) and safety
laboratory tests.
Statistical Methods:
Analysis Sets: There were 3 analysis sets in this study:
Full Analysis Set: The full analysis set (FAS) included all patients who were randomized
and received at least 1 dose of the randomized study drug.
Per Protocol Analysis Set: The per protocol analysis set (PPAS) included subset of the FAS
dataset. The PPAS included all randomized patients who completed the 12 week study withno important protocol deviations that could impact the efficacy analysis. The list of
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Protocol A3921215 – 08 March 2018 – Finalpotentially important protocol deviations and the patients to be excluded from the PPAS wereidentified, reviewed, and finalized prior to the release of the database.
Safety Analysis Set: The safety analysis set included all patients who were randomized andreceived at least 1 dose of the randomized study drug. By definition, it is identical to the
FAS defined above.
Analysis of Efficacy Parameters:

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Analysis of Primary Efficacy Endpoints: The analysis was conducted using a linear mixed
effect model with repeated measures (MMRM), which included treatment (tofacitinib
MR 11 mg QD and IR 5 mg BID), visit, and treatment by visit interaction as fixed effects.
Patients were a random effect and unstructured covariance was assumed for thewithin-patient errors. If there were convergence problems with this model, sequential
structures were to be applied until the problems resolved; autoregressive 1 and compound
symmetry.
If there was modeling of actual values, the explanatory variable of visit included baseline as
one of the longitudinal values. When modeling the change from baseline values, the variableof visit started with the first post-baseline visit, and the actual baseline value was included asa covariate. At each visit, estimates of mean values, the mean differences between thetreatment groups and the associated 2-sided 95% CI (Type I error [alpha] of 0.025 in eachtail) was derived from the model. If the upper bound of the 2-sided 95% CI (Type I error of
0.025 in each tail) for the difference in change from baseline in DAS28-4(CRP) between the
2 treatment groups (MR 11 mg QD - IR 5 mg BID) was <0.6, then the treatment with
11 mg QD would be declared non-inferior to that of tofacitinib IR 5 mg BID.
The patient was required to have a baseline and at least 1 non-missing on-study assessment
of DAS28-4(CRP) to be included in the analysis. Missing values were not imputed.
Sensitivity/Robustness Analyses: To support the interpretation of the primary analysis,robust sensitivity analyses were performed for the primary endpoint. However, theconclusions (non-inferiority) for comparison of the primary endpoint between
tofacitinib MR 11 mg QD and IR 5 mg BID group was based on results of the primary
analysis only.
Analysis of Secondary Endpoints: All analyses of secondary endpoints were based on the
FAS.
The change from baseline in longitudinal continuous variables (ie, DAS28-4[ESR], HAQ-DI,
other 6 components of the ACR criteria, the 8 domains and 2 component scores of SF-36)
were analyzed using the MMRM model and the missing values were not imputed.
The change from baseline in non-longitudinal continuous variables (ie, EQ-5D utility scoreand FACIT fatigue scale) were analyzed using an analysis of covariance (ANCOVA) modeland the missing values were not imputed.

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Protocol A3921215 – 08 March 2018 – Final

Binary variables (ie, the ACR variables [ACR20, ACR50 and ACR70], DAS defined using
28 joint counts [DAS28] responses [DAS28 3.2, DAS28 <2.6] which included
DAS28-4[CRP] and DAS28-4[ESR], and decrease [at least 0.22] in HAQ-DI) were analyzed
using the normal approximation to the difference in response rates.
Safety Parameters:
The AEs were listed and summarized within treatment group in accordance with the sponsor
data standards. The AEs, SAEs and discontinuations due to AEs were also summarized bysubsets.

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Laboratory data were listed and summarized within treatment group in accordance with thesponsor data standards. Incidence of laboratory test abnormalities (including without regard
to baseline abnormality) were summarized within each treatment group. For each planned
time point, actual values and changes from baseline values were summarized within eachtreatment with descriptive statistics. The changes from baseline values were analyzed using
the MMRM model. Instead of changes form baseline, percent changes from baseline wereanalyzed in lipid tests (total cholesterol, low-density lipoprotein cholesterol [LDL-C],
high-density lipoprotein cholesterol [HDL-C] and triglyceride).
For each planned time point, actual values and change from baseline values in BP, weightand body mass index (BMI) were summarized within each treatment with descriptive
statistics. The changes from baseline values in BP was analyzed using the MMRM model.
RESULTS
Subject Disposition and Demography:
Patient disposition is summarized in Table 2. A total of 333 patients were screened.
One hundred and four (104) and 105 patients were randomized to receive tofacitinib 11 mg
QD and tofacitinib 5 mg BID, respectively. A total of 14 patients (6.7%) were discontinued
from the study. The reason for discontinuation were treatment related AEs (overall
11 patients [5.3%]: 3 patients [2.9%] in the tofacitinib 11 mg QD group and 8 patients [7.6%]
in the tofacitinib 5 mg BID group), insufficient clinical response (no patient in the tofacitinib
11 mg QD group and 1 patient [1.0%] in the tofacitinib 5 mg BID group), medication error
without associated AE (1 patient [1.0%] in the tofacitinib 11 mg QD group and no patient in
the tofacitinib 5 mg BID group) and AE not related to study drug (1 patient [1.0%] in thetofacitinib 5 mg BID group and no patient in the tofacitinib 11 mg QD group).

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Table 2.

Patient Disposition

Tofacitinib 11 mg QD Tofacitinib 5 mg BID
Total
Screened: 333
Assigned to study treatment
104
105
209
Treated104 (100.0)
105 (100.0)
209 (100.0)
Completed
100 (96.2)
95 (90.5)
195 (93.3)
Discontinued
4 (3.8)10 (9.5)
14 (6.7)
Relation to study drug not
1 (1.0)1 (1.0)2 (1.0)definedInsufficient clinical0
1 (1.0)1 (0.5)
response
Medication error without
1 (1.0)01 (0.5)
associated adverse event
Related to study drug
3 (2.9)8 (7.6)
11 (5.3)
Adverse event
3 (2.9)8 (7.6)
11 (5.3)
Not related to study drug0
1 (1.0)1 (0.5)Adverse event0
1 (1.0)1 (0.5)
Analyzed for efficacy
Full analysis set
104 (100.0)
105 (100.0)
209 (100.0)
Per protocol analysis set
99 (95.2)
94 (89.5)
193 (92.3)
Analyzed for safety
Adverse events
104 (100.0)
105 (100.0)
209 (100.0)
Laboratory data
104 (100.0)
105 (100.0)
209 (100.0)
Discontinuations occurring outside the lag period had been attributed to the last study treatment received.
Abbreviations: BID=Twice daily; QD=Once daily.

The demographic characteristics of the 2 treatment groups were balanced between treatmentgroups (Table 3) with the following exceptions: the proportion of females and CRP and ESRlevels was numerically higher in the tofacitinib 11 mg QD group. The majority of the treatedpatients were female (161/209 patients) and all the enrolled patients were Asian. The overallmean age of patients was 58.0 years (57.1 years in the tofacitinib 11 mg QD group and58.9 years in the tofacitinib 5 mg BID group) (overall range: 27 years to 79 years). The
overall mean weight was 56.7 kg (55.9 kg in the tofacitinib 11 mg QD group and 57.5 kg in
the tofacitinib 5 mg BID group) (overall range: 35.4 kg to 100.8 kg).

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Table 3.

Demographic Characteristics

Number (%) of
Tofacitinib 11 mg QD
Tofacitinib 5 mg BID
Patients
Male
FemaleTotal
Male
Female
Total
N
18
86
104
30
75
105
Age (years)
18-44
6 (33.3)
12 (14.0)
18 (17.3)
4 (13.3)
7 (9.3)
11 (10.5)
45-64
8 (44.4)
49 (57.0)
57 (54.8)
17 (56.7)
41 (54.7)
58 (55.2)
4 (22.2)
25 (29.1)
29 (27.9)9 (30.0)27 (36.0)
36 (34.3)
65
Mean
54.7
57.6
57.1
58.0
59.3
58.9
SD
13.7
10.9
11.4
10.4
10.1
10.2
Range
30-79
27-79
27-79
34-79
33-79
33-79
Abbreviations: BID=Twice daily; N=Number of patients; QD=Once daily; SD=Standard deviation.

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Male
48

Total
Female
161

Total
209

10 (20.8)
25 (52.1)
13 (27.1)
56.8
11.7
30-79

19 (11.8)
90 (55.9)
52 (32.3)
58.4
10.6
27-79

29 (13.9)
115 (55.0)
65 (31.1)
58.0
10.8
27-79

Public Disclosure Synopsis
Protocol A3921215 – 08 March 2018 – Final

Efficacy Results:
Primary Efficacy Results:
Change From Baseline in DAS28-4(CRP) at Week 12: The statistical analysis of change
from baseline in DAS28-4(CRP) (FAS, longitudinal model) at Week 12 is presented inTable 4. The least square (LS) mean change from baseline in DAS28-4(CRP) was -2.43 and-2.85 for MR 11 mg QD and IR 5 mg BID respectively. The point estimate of the difference(MR-IR) between the 2 groups was 0.43 with 95% CI (0.17-0.69). The non-inferiority
criterion was not met for tofacitinib MR 11 mg QD as compared to tofacitinib 5 mg BID.
Upper bound of the CI (0.69) was above the non-inferiority margin of 0.6. The difference inchange from baseline between treatment arms in DAS28-4 CRP was statistically significant.
Table 4.

Statistical Analysis of Change From Baseline in DAS28-4(CRP) at Week 12(FAS, Longitudinal Model)

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Treatment GroupNLS MeanComparison Between 11 mg QD Versus
5 mg BID (11 mg QD – 5 mg BID)
Difference
95% ConfidenceInterval
Lower
Upper
0.43
0.17
0.69

Tofacitinib 11 mg QD
100
-2.43
Tofacitinib 5 mg BID
95-2.85
The fixed effects of actual baseline values, treatment, visit, and treatment-by-visit interaction were included,
unstructured covariance matrices was used.
Abbreviations: BID=Twice daily; DAS28-4(CRP)=Disease activity score defined using 28 joint counts andC-reactive protein; FAS=Full analysis set; LS=Least square; N=Number of patients; QD=Once daily.

Sensitivity analysis of change from baseline in DAS28-4(CRP) at Week 12 for the PPAS also
supported the primary analysis (Table 5). The same finding was observed by sensitivity
analysis with PPAS with an upper bound of 0.71, which was also greater than (outside) the
non-inferiority boundary.
Table 5.

Sensitivity Analysis: Statistical Analysis of Change From Baseline in
DAS28-4(CRP) at Week 12 (PP, Longitudinal Model)

Treatment GroupNLS MeanComparison Between 11 mg QD Versus
5 mg BID (11 mg QD – 5 mg BID)
Difference
95% ConfidenceInterval
Lower
Upper
0.45
0.19
0.71

Tofacitinib 11 mg QD
99-2.42
Tofacitinib 5 mg BID
94-2.87
The fixed effects of actual baseline values, treatment, visit, and treatment-by-visit interaction were included,
unstructured covariance matrices was used.
Abbreviations: BID=Twice daily; DAS28-4(CRP)=Disease activity score defined using 28 joint counts andC-reactive protein; LS=Least square; N=Number of patients; PP=Per protocol; QD=Once daily.

In a subset analysis, the consistent finding was observed in difference between tofacitinib
MR 11 mg QD and tofacitinib IR 5 mg BID in change from baseline of DAS28-4(CRP) at
Week 12 in all subsets evaluated (sex [male, female], body weight [<55 kg, 55 kg],

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Protocol A3921215 – 08 March 2018 – Finalage [<65 years old, 65 years old], rheumatoid factor at screening [negative, positive],disease duration [<5 years, 5 years], MTX dose at baseline [8 mg/week, >8 mg/week] andDAS28-4(CRP) at baseline [5.1, >5.1]).
Secondary Efficacy Results:
Change From Baseline in DAS28-4(ESR) at Week 12:
Statistical analysis of change from baseline in DAS28-4(ESR) per visit for FAS (longitudinalmodel) (at Week 12) is presented in Table 6.
Table 6.

Statistical Analysis of Change From Baseline in DAS28-4(ESR) at Week 12(FAS, Longitudinal Model)

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Treatment GroupNLS MeanComparison Between 11 mg QD Versus
5 mg BID (11 mg QD – 5 mg BID)
Difference
95% ConfidenceInterval
Lower
Upper
0.37
0.11
0.63

Tofacitinib 11 mg QD
99-2.50
Tofacitinib 5 mg BID
95-2.86
The fixed effects of actual baseline values, treatment, visit, and treatment-by-visit interaction were included,
unstructured covariance matrices was used.
Abbreviations: BID=Twice daily; DAS28-4(ESR)=Disease activity score defined using 28 joint counts anderythrocyte sedimentation rate; FAS=Full analysis set; LS=Least square; N=Number of patients; QD=Oncedaily.

ACR20, ACR50 and ACR70 Response at Week 12:
Both treatments had clinically relevant ACR20 response rates that was maintained through to
Week 12 (84.47% for tofacitinib 11 mg QD group and 79.81% for tofacitinib 5 mg BID
group). The difference between the tofacitinib groups was not statistically significant ateither time point.
Both treatments had clinically relevant response rates (FAS, NRI) through to Week 12(67.96% for tofacitinib 11 mg QD group and 68.27% for tofacitinib 5 mg BID group). The
difference (1.28 at Week 4 and -0.29 [last observation carried forward {LOCF}] at Week 12)
between the tofacitinib groups was not statistically significant at either time point.
ACR70 response rates were significantly higher at Week 12 (31.07% fortofacitinib 11 mg QD group and 46.15% for tofacitinib 5 mg BID group) for patients in thetofacitinib 5 mg BID group (p<0.05).
The ACR20/50/70 response rates in MR 11 mg QD and IR 5 mg BID were 84.5/68.0/31.1
and 79.8/68.3/46.2, respectively which are higher than that typically seen in the historicalglobal studies of tofacitinib (IR) 5 mg BID in RA, but consistent with previous results withIR tofacitinib in Japan. These categorical measures such as the ACR20 and ACR50 were
nearly superimposable, while ACR70 seemed higher in the IR arm of this study. The overallmagnitude of these responses was substantial. Due to lack of a placebo arm in the same

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Protocol A3921215 – 08 March 2018 – Finalstudy, the placebo adjusted effect is unknown.Remission at Week 12, as Assessed by
DAS28-4(CRP) <2.6 and DAS28-4(ESR) <2.6:
Table 7 shows the rates of patients achieving DAS28-4(CRP) <2.6 and DAS28-4(ESR) <2.6
at Week 12 (FAS, NRI, LOCF and no imputation).
There was a difference in the proportion of patients achieving remission. Remission
response rate assessed by DAS28-4(CRP) <2.6 and DAS28-4(ESR) <2.6 at Week 12 wasnominally significantly higher in the tofacitinib 5 mg BID group as compared with the
11 mg QD group (p<0.0051). More than 50% of patients in both the treatment groups
achieved remission as assessed by DAS28-4(CRP) <2.6 at Week 12.
Table 7.

Normal Approximation to Rate of Patients (%) Achieving
DAS28-4(CRP) <2.6 and DAS28-4(ESR) <2.6 at Week 12 (FAS, NRI, LOCF
and No Imputation)

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Treatment GroupNn

Response
Rate

Comparison Between 11 mg QD Versus
5 mg BID (11 mg QD – 5 mg BID)
Difference
95% Confidence Interval
Lower
Upper

DAS28-4(CRP) <2.6 rates (NRI)
Tofacitinib 11 mg QD
103
52
50.49
-18.75-31.86-5.63
Tofacitinib 5 mg BID
104
72
69.23
DAS28-4(CRP) <2.6 rates (LOCF)
Tofacitinib 11 mg QD
103
53
51.46
-18.74-31.79-5.68
Tofacitinib 5 mg BID
104
73
70.19
DAS28-4(CRP) <2.6 rates (no imputation)
Tofacitinib 11 mg QD
100
52
52.00
-23.79-36.83-10.75
Tofacitinib 5 mg BID
95
72
75.79
DAS28-4(ESR) <2.6 rates (NRI)
Tofacitinib 11 mg QD
103
18
17.48
-17.14-28.86-5.42
Tofacitinib 5 mg BID
104
36
34.62
DAS28-4(ESR) <2.6 rates (LOCF)
Tofacitinib 11 mg QD
103
18
17.48
-17.14-28.86-5.42
Tofacitinib 5 mg BID
104
36
34.62
DAS28-4(ESR) <2.6 rates (no imputation)
Tofacitinib 11 mg QD
99
18
18.18
-19.71-32.08-7.35
Tofacitinib 5 mg BID
95
36
37.89
Abbreviations: BID=Twice daily; DAS28-4(CRP)=Disease activity score defined using 28 joint counts andC-reactive protein; DAS28-4(ESR)=Disease activity score defined using 28 joint counts and erythrocyte
sedimentation rate; LOCF=Last observation carried forward; N=Total number of patients; n=Number ofpatients; NRI=Non-responder imputation; QD=Once daily.

LDA at Week 12, as Assessed by DAS28-4(CRP) 3.2 and DAS28-4(ESR) 3.2:
Table 8 shows the rate of patients achieving DAS28-4(CRP) 3.2 and DAS28-4(ESR) 3.2
at Week 12 (FAS, NRI, LOCF and no imputation).
LDA response rate as assessed by DAS28-4(CRP) 3.2 and DAS28-4(ESR) 3.2 at Week 12
was higher in tofacitinib 5 mg BID group compared with the 11 mg QD group (p<0.3912).

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More than 40% of patients in both treatment groups achieved LDA as assessed by
DAS28-4(CRP) 3.2 and DAS28-4(ESR) 3.2 at Week 12.

Table 8.

Normal Approximation to Rate of Patients (%) Achieving
DAS28-4(CRP) 3.2 and DAS28-4(ESR) 3.2 at Week 12 (FAS, NRI, LOCF
and No Imputation)

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Treatment GroupNn

Response
Rate

Comparison Between 11 mg QD Versus
5 mg BID (11 mg QD – 5 mg BID)
Difference
95% Confidence Interval
Lower
Upper
Normal approximation to DAS28-4(CRP) 3.2 rates per visit (FAS, NRI)
Tofacitinib 11 mg QD
103
76
73.79
-5.06
-16.62
6.51
Tofacitinib 5 mg BID
104
82
78.85
Normal approximation to DAS28-4(CRP) 3.2 rates per visit (FAS, LOCF)
Tofacitinib 11 mg QD
103
78
75.73
-6.00
-17.13
5.12
Tofacitinib 5 mg BID
104
85
81.73
Normal approximation to DAS28-4(CRP) 3.2 rates per visit (FAS, no imputation)
Tofacitinib 11 mg QD
100
76
76.00
-10.32-21.17
0.54
Tofacitinib 5 mg BID
95
82
86.32
Normal approximation to DAS28-4(ESR) 3.2 rates per visit (FAS, NRI)
Tofacitinib 11 mg QD
103
44
42.72
-17.86-31.26-4.46
Tofacitinib 5 mg BID
104
63
60.58
Normal approximation to DAS28-4(ESR) 3.2 rates per visit (FAS, LOCF)
Tofacitinib 11 mg QD
103
44
42.72
-19.78-33.12-6.45
Tofacitinib 5 mg BID
104
65
62.50
Normal approximation to DAS28-4(ESR) 3.2 rates per visit (FAS, no imputation)
Tofacitinib 11 mg QD
99
43
43.43
-22.88-36.51-9.26
Tofacitinib 5 mg BID
95
63
66.32
Abbreviations: BID=Twice daily; DAS28-4(CRP)=Disease activity score defined using 28 joint counts andC-reactive protein; DAS28-4(ESR)=Disease activity score defined using 28 joint counts and erythrocyte
sedimentation rate; LOCF=Last observation carried forward; N=Total number of patients; n=Number ofpatients; NRI=Non-responder imputation; QD=Once daily.

Change From Baseline in HAQ-DI at Week 12:
Table 9 represents the LS mean changes from baseline at Weeks 4 and 12 (FAS) in HAQ-DI
for the treatment groups. The tofacitinib 5 mg BID and tofacitinib 11 mg QD patientsdemonstrated similar and clinically meaningful changes in HAQ-DI scores at Week 4 andWeek 12 (p0.0612).

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Table 9.

Statistical Analysis of Change From Baseline in HAQ-DI per Visit (FAS,Longitudinal Model)

Visit

Treatment Group

N

LS
Mean

Week 4Comparison Between
11 mg QD Versus 5 mg BID(11 mg QD – 5 mg BID)
Difference
95% ConfidenceInterval
Lower
Upper
0.09
0.00
0.19

Tofacitinib 11 mg QD
103
-0.26
Tofacitinib 5 mg BID
104
-0.35
Week 12
Tofacitinib 11 mg QD
99
-0.44
0.02
-0.09
0.13
Tofacitinib 5 mg BID
95-0.46
The fixed effects of actual baseline values, treatment, visit, and treatment-by-visit interaction were included,
unstructured covariance matrices was used.
Abbreviations: BID=Twice daily; HAQ-DI=Health assessment questionnaire-disability index; FAS=Fullanalysis set; LS=Least square; N=Number of patients; QD=Once daily.

090177e18de16b18\Approved\Approved On: 16-Mar-2018 10:25 (GMT)HAQ-DI Response (Decrease of at Least 0.22) at Week 12:
Table 10 shows the normal approximation to rates of at least 0.22 improvement in HAQ-DI
Week 12. A majority of patients in each treatment arm achieved this level of improvement.
There was no statistically significant treatment difference observed in HAQ-DI response(decrease of at least 0.22). Both treatment arms achieved the minimal clinically importantdifference (0.22) for the HAQ-DI by Week 4, and responses were nearly identical between
tofacitinib 11 mg QD and tofacitinib 5 mg BID at Week 12.
Table 10. Normal Approximation to Rates of Patients (%) With at Least 0.22
Improvement in HAQ-DI at Week 12 (FAS, NRI, LOCF and no Imputation)
Treatment GroupNn

Response
Rate

Comparison Between 11 mg QD Versus
5 mg BID (11 mg QD – 5 mg BID)
Difference
95% Confidence Interval
Lower
Upper

NRI
Tofacitinib 11 mg QD
103
65
63.11
5.41
-7.89
18.72
Tofacitinib 5 mg BID
104
60
57.69
LOCF
Tofacitinib 11 mg QD
103
67
65.05
2.55
-10.54
15.64
Tofacitinib 5 mg BID
104
65
62.50
No imputation
Tofacitinib 11 mg QD
99
64
64.65
1.49
-12.03
15.01
Tofacitinib 5 mg BID
95
60
63.16
Abbreviations: BID=Twice daily; FAS=Full analysis set; HAQ-DI=Health assessment questionnaire-disability
index; LOCF=Last observation carried forward; N=Number of patients; n=Number of patients with specified
criteria; NRI=Non-responder imputation; QD=Once daily.

Change From Baseline in the SF-36 8 Domain Scores and 2 Component Scores at Week 12:
Table 11 shows the statistical analysis of change from baseline in SF-36 Mental Component
at Week 12.

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In general, improvements in SF-36 scores for patients who received tofacitinib 5 mg BID
were numerically greater than for those who received tofacitinib 11 mg QD but this did notreach statistical significance.
Table 11. Statistical Analysis of Change From Baseline in SF-36 Mental Component
Score per Visit (FAS, Longitudinal Model)
Visit

Treatment GroupNLS Mean

Week 4Comparison Between 11 mg QD Versus
5 mg BID (11 mg QD – 5 mg BID)
Difference
95% Confidence Interval
Lower
Upper
-0.78
-2.72
1.16

Tofacitinib 11 mg QD
103
3.25
Tofacitinib 5 mg BID
104
4.03
Week 12
Tofacitinib 11 mg QD
99
5.29
0.21
-1.92
2.34
Tofacitinib 5 mg BID
95
5.08
The fixed effects of actual baseline values, treatment, visit, and treatment-by-visit interaction were included,
unstructured covariance matrices was used.
Abbreviations: BID=Twice daily; FAS=Full analysis set; LS=Least square; N=Number of patients; QD=Oncedaily; SF-36=Short Form-36.

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Change From Baseline in the FACIT-Fatigue Scale at Week 12:
Table 12 shows the statistical analysis of change from baseline in FACIT-fatigue scale at
Week 12.
There were no statistically significant changes observed between the treatments for
FACIT-fatigue scale at Week 12 (p=0.3753).
Table 12. Statistical Analysis of Change From Baseline in FACIT-Fatigue Scale per
Visit (FAS, ANCOVA Model)
Visit

Treatment Group

N

LS
Mean

Week 12Comparison Between 11 mg QD Versus
5 mg BID (11 mg QD – 5 mg BID)
Difference
95% Confidence Interval
Lower
Upper
-0.84
-2.70
1.02

Tofacitinib 11 mg QD
995.28
Tofacitinib 5 mg BID
95
6.12
The fixed effects of actual baseline values and treatment were included.
Abbreviations: ANCOVA=Analysis of covariance; BID=Twice daily; FACIT= Functional assessment ofchronic illness therapy; FAS=Full analysis set; LS=Least square; N=Number of patients; QD=Once daily.

Change From Baseline in the EQ-5D at Week 12:
Table 13 shows the statistical analysis of change from baseline in EuroQol EQ-5D healthstate profile-utility score at Week 12.
Change in EuroQol EQ-5D health state profile-utility score was significantly greater forpatients who received tofacitinib 5 mg BID compared with tofacitinib 11 mg QD (p=0.0483).

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Table 13. Statistical Analysis of Change From Baseline in EuroQol EQ-5D HealthState Profile-Utility Score per Visit (FAS, ANCOVA Model)
Visit

Treatment Group

Week 12

N

LS
Mean

Comparison Between 11 mg QD Versus 5 mg BID(11 mg QD – 5 mg BID)
Difference
95% Confidence Interval
Lower
Upper
-0.05
-0.10
0.00

Tofacitinib 11 mg QD
990.20
Tofacitinib 5 mg BID
95
0.25
The fixed effects of actual baseline values and treatment were included.
Abbreviations: ANCOVA=Analysis of covariance; BID=Twice daily; EuroQol EQ-5D= European Quality ofLife-5 dimensions questionnaire; FAS=Full analysis set; LS=Least square; N=Number of patients; QD=Oncedaily.

Safety Results:
Serious Adverse Events:

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Overall, 5 patients in the tofacitinib 11 mg QD group and 4 patients in thetofacitinib 5 mg BID group experienced at least 1 SAE after dosing. The treatment-emergent
SAEs by system organ class (SOC) and preferred term is presented in Table 14.

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Table 14. Treatment-Emergent Serious Adverse Events by System Organ Class andPreferred Term (All-Causalities)
Number (%) of Subjects With Adverse Events by:
Tofacitinib 11 mg QD
Tofacitinib 5 mg BID
System Organ Class and
MedDRA (Version 19.1) Preferred Term
Evaluable for Adverse Events
104
105
With Adverse Events
5 (4.81)
4 (3.81)
Blood and lymphatic system disorders01 (0.95)
Anaemia01 (0.95)
Infections and infestations
3 (2.88)
3 (2.86)
Pneumocystis jirovecii pneumonia
2 (1.92)
1 (0.95)
Pneumonia
1 (0.96)1 (0.95)
Pneumonia bacterial01 (0.95)
Injury, poisoning and procedural complications
1 (0.96)0Femoral neck fracture
1 (0.96)
0
Neoplasms benign, malignant and unspecified (incl
1 (0.96)0
cysts and polyps)
Rectal cancer
1 (0.96)0
Respiratory, thoracic and mediastinal disorders01 (0.95)
Interstitial lung disease01 (0.95)
Subjects were only counted once per treatment for each row.
Included data up to 999 days after last dose of study drug.
Percentages of gender specific events were calculated using the corresponding gender count as denominator.
MedDRA (Version 19.1) coding dictionary applied.
Abbreviations: BID=Twice daily; incl=inclusive; MedDRA=Medical Dictionary for Regulatory Activities;
QD=Once daily.

Adverse Events:
All-causality and treatment-related treatment-emergent AEs (TEAEs) are summarized inTable 15 and Table 16, respectively. The most frequently reported all-causalities andtreatment-related AEs by preferred term were nasopharyngitis, blood creatine phosphokinase
increased, and hepatic function abnormal (in both treatment groups).

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Table 15. Treatment-Emergent Non Serious Adverse Events by System OrganClass and Preferred Term (All-Causalities)
Number (%) of Subjects With Adverse Events by:
System Organ Class and
MedDRA (Version 19.1) Preferred Term
Evaluable for Adverse Events
With Adverse Events
Blood and lymphatic system disorders
Iron deficiency anaemia
Leukopenia
Cardiac disorders
Cardiac failure
Palpitations
Ear and labyrinth disorders
Sudden hearing loss
Tinnitus
VertigoEye disorders
Dry eye
Keratitis
Vision blurred
Gastrointestinal disorders
Abdominal discomfort
Abdominal pain upper
Constipation
Diarrhoea
Duodenal ulcer
Gastric polyps
Gastrooesophageal reflux disease
Large intestine polyp
Mouth ulceration
NauseaStomatitis
Tooth loss
Vomiting
General disorders and administration site conditions
Feeling hot
MalaisePyrexia
Hepatobiliary disorders
Hepatic function abnormal
Liver disorder
Immune system disorders
Seasonal allergy
Infections and infestations
Bronchitis
Bursitis infective
CystitisEnteritis infectious
Helicobacter infection
Herpes virus infection

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Tofacitinib 11 mg
QD

Tofacitinib 5 mg
BID

104
54 (51.92)
2 (1.92)
1 (0.96)1 (0.96)1 (0.96)1 (0.96)01 (0.96)00
1 (0.96)
2 (1.92)
1 (0.96)01 (0.96)
15 (14.42)
3 (2.88)
3 (2.88)
1 (0.96)
3 (2.88)
1 (0.96)1 (0.96)1 (0.96)01 (0.96)1 (0.96)
2 (1.92)01 (0.96)
2 (1.92)01 (0.96)1 (0.96)
4 (3.85)
3 (2.88)
1 (0.96)1 (0.96)1 (0.96)
18 (17.31)
1 (0.96)00
1 (0.96)1 (0.96)0105
52 (49.52)
000
1 (0.95)01 (0.95)
2 (1.90)1 (0.95)
1 (0.95)01 (0.95)01 (0.95)0
11 (10.48)
02 (1.90)
2 (1.90)1 (0.95)000
2 (1.90)01 (0.95)
3 (2.86)
1 (0.95)
1 (0.95)
3 (2.86)
1 (0.95)
1 (0.95)
1 (0.95)
4 (3.81)
4 (3.81)00025 (23.81)
3 (2.86)
1 (0.95)
1 (0.95)00
1 (0.95)

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Protocol A3921215 – 08 March 2018 – Final

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Table 15. Treatment-Emergent Non Serious Adverse Events by System OrganClass and Preferred Term (All-Causalities)
Number (%) of Subjects With Adverse Events by:
System Organ Class and
MedDRA (Version 19.1) Preferred Term
Evaluable for Adverse Events
With Adverse Events
Herpes zoster
Infective tenosynovitis
Influenza
Nasopharyngitis
Oral herpes
Periodontitis
Pharyngitis
Sinusitis
Tinea pedis
Upper respiratory tract infection
Urinary tract infection
Injury, poisoning and procedural complications
Bone contusion
Contusion
Fall
Post-traumatic neck syndrome
Skin abrasion
Spinal compression fracture
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood cholesterol increased
Blood creatine phosphokinase increased
Blood triglycerides increased
Blood urine present
Gamma-glutamyl transferase increased
Hepatic enzyme increased
Lipids abnormal
Low density lipoprotein increased
Lymphocyte count decreased
Weight increased
Metabolism and nutrition disorders
Dyslipidaemia
Hypercholesterolaemia
Hyperuricaemia
Musculoskeletal and connective tissue disorders
Back pain
Musculoskeletal stiffness
Pain in extremity
Rheumatoid arthritis
Spinal osteoarthritis
Nervous system disorders
Dizziness postural
Dysgeusia

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Tofacitinib 11 mg
QD

Tofacitinib 5 mg
BID

104
54 (51.92)
1 (0.96)00
10 (9.62)
1 (0.96)01 (0.96)00
1 (0.96)1 (0.96)
2 (1.92)00
1 (0.96)00
1 (0.96)
12 (11.54)
00
3 (2.88)
4 (3.85)
1 (0.96)01 (0.96)1 (0.96)1 (0.96)
2 (1.92)
1 (0.96)1 (0.96)
2 (1.92)
1 (0.96)1 (0.96)03 (2.88)
1 (0.96)1 (0.96)1 (0.96)1 (0.96)08 (7.69)
1 (0.96)1 (0.96)105
52 (49.52)
1 (0.95)
1 (0.95)
2 (1.90)
13 (12.38)
2 (1.90)1 (0.95)01 (0.95)
2 (1.90)003 (2.86)
1 (0.95)
1 (0.95)
2 (1.90)1 (0.95)
1 (0.95)
1 (0.95)
13 (12.38)
2 (1.90)
3 (2.86)
2 (1.90)
2 (1.90)
2 (1.90)1 (0.95)
2 (1.90)1 (0.95)
2 (1.90)0001 (0.95)00
1 (0.95)
1 (0.95)00001 (0.95)
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Protocol A3921215 – 08 March 2018 – Final

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Table 15. Treatment-Emergent Non Serious Adverse Events by System OrganClass and Preferred Term (All-Causalities)
Number (%) of Subjects With Adverse Events by:
Tofacitinib 11 mg
Tofacitinib 5 mg
System Organ Class and
QD
BID
MedDRA (Version 19.1) Preferred Term
Evaluable for Adverse Events
104
105
With Adverse Events
54 (51.92)
52 (49.52)
Head discomfort
2 (1.92)
0
Headache
1 (0.96)
2 (1.90)
Post herpetic neuralgia
1 (0.96)1 (0.95)
Sciatica
1 (0.96)0Somnolence
1 (0.96)0
Psychiatric disorders
1 (0.96)0
Alcoholic hangover
1 (0.96)0
Respiratory, thoracic and mediastinal disorders
3 (2.88)
6 (5.71)Cough0
1 (0.95)
Oropharyngeal pain
2 (1.92)
0Rhinitis allergic01 (0.95)
Upper respiratory tract inflammation
1 (0.96)
3 (2.86)
Vasomotor rhinitis
01 (0.95)
Skin and subcutaneous tissue disorders
4 (3.85)
4 (3.81)
Alopecia
01 (0.95)
Dermatitis contact
1 (0.96)0
Drug eruption
1 (0.96)1 (0.95)
Eczema0
1 (0.95)
Ingrowing nail0
1 (0.95)
Pruritus
01 (0.95)
Rash
2 (1.92)
0
Vascular disorders01 (0.95)
Hot flush
0
1 (0.95)
Subjects were only counted once per treatment for each row.
Included data up to 999 days after last dose of study drug.
Percentages of gender specific events were calculated using the corresponding gender count as denominator.
MedDRA (Version 19.1) coding dictionary applied.
Abbreviations: BID=Twice daily; MedDRA=Medical Dictionary for Regulatory Activities; QD=Once daily.

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Table 16. Incidence of Treatment-Emergent Adverse Events – Treatment-Related
Number (%) of Subjects With Adverse Events by:
System Organ Class and
MedDRA (Version 19.1) Preferred Term
Evaluable for Adverse Events
Blood and lymphatic system disorders
Anaemia
Iron deficiency anaemia
Leukopenia
Cardiac disorders
Cardiac failure
Palpitations
Ear and labyrinth disorders
Sudden hearing loss
Tinnitus
VertigoEye disorders
Dry eye
Keratitis
Vision blurred
Gastrointestinal disorders
Abdominal discomfort
Abdominal pain upper
Constipation
Diarrhoea
Duodenal ulcer
Gastric polyps
Gastrooesophageal reflux disease
Large intestine polyp
Mouth ulceration
NauseaStomatitis
Tooth loss
Vomiting
General disorders and administration site conditions
Feeling hot
MalaisePyrexia
Hepatobiliary disorders
Hepatic function abnormal
Liver disorder
Immune system disorders
Seasonal allergy
Infections and infestations
Bronchitis
Bursitis infective
CystitisEnteritis infectious
Helicobacter infection
Herpes virus infection
Herpes zoster

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104
1 (1.0)001 (1.0)000
1 (1.0)001 (1.0)0000
4 (3.8)1 (1.0)2 (1.9)
0
0
0
0
0
0
0
1 (1.0)1 (1.0)0
1 (1.0)2 (1.9)0
1 (1.0)1 (1.0)4 (3.8)3 (2.9)1 (1.0)0014 (13.5)
000
1 (1.0)001 (1.0)105
1 (1.0)1 (1.0)001 (1.0)0
1 (1.0)0000
1 (1.0)0
1 (1.0)03 (2.9)00
2 (1.9)00
0
0
00
1 (1.0)1 (1.0)002 (1.9)1 (1.0)1 (1.0)04 (3.8)4 (3.8)000
19 (18.1)
2 (1.9)1 (1.0)000
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Protocol A3921215 – 08 March 2018 – Final

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Table 16. Incidence of Treatment-Emergent Adverse Events – Treatment-Related
Number (%) of Subjects With Adverse Events by:
System Organ Class and
MedDRA (Version 19.1) Preferred Term
Evaluable for Adverse Events
Infective tenosynovitis
Influenza
Nasopharyngitis
Oral herpes
Periodontitis
Pharyngitis
Pneumocystis jirovecii pneumonia
Pneumonia
Pneumonia bacterial
Sinusitis
Tinea pedis
Upper respiratory tract infection
Urinary tract infection
Injury, poisoning and procedural complications
Bone contusion
Contusion
Fall
Femoral neck fracture
Post-traumatic neck syndrome
Skin abrasion
Spinal compression fracture
Investigations
Alanine aminotransferase increased
Aspartate aminotransferase increased
Blood cholesterol increased
Blood creatine phosphokinase increased
Blood triglycerides increased
Blood urine present
Gamma-glutamyltransferase increased
Hepatic enzyme increased
Lipids abnormal
Low-density lipoprotein increased
Lymphocyte count decreased
Weight increased
Metabolism and nutrition disorders
Dyslipidaemia
Hypercholesterolaemia
Hyperuricaemia
Musculoskeletal and connective tissue disorders
Back pain
Musculoskeletal stiffness
Pain in extremity
Rheumatoid arthritis
Spinal osteoarthritis
Neoplasms benign, malignant and unspecified (inclcysts and polyps)

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104
00
6 (5.8)1 (1.0)0
1 (1.0)2 (1.9)1 (1.0)0000
1 (1.0)
0
0
0
0
0
0
0
0
9 (8.7)00
3 (2.9)3 (2.9)1 (1.0)0
1 (1.0)0
1 (1.0)2 (1.9)1 (1.0)0
1 (1.0)0
1 (1.0)
0
0
0
0
0
0
0
1 (1.0)105
1 (1.0)2 (1.9)7 (6.7)2 (1.9)1 (1.0)0
1 (1.0)1 (1.0)1 (1.0)1 (1.0)1 (1.0)
0
0
0
0
0
0
0
0
0
0
13 (12.4)
2 (1.9)3 (2.9)2 (1.9)2 (1.9)2 (1.9)1 (1.0)2 (1.9)1 (1.0)2 (1.9)000
1 (1.0)001 (1.0)
0
0
0
0
0
0
0

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Protocol A3921215 – 08 March 2018 – Final

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Table 16. Incidence of Treatment-Emergent Adverse Events – Treatment-Related
Number (%) of Subjects With Adverse Events by:
Tofacitinib 11 mg QD
Tofacitinib 5 mg BID
System Organ Class and
MedDRA (Version 19.1) Preferred Term
Evaluable for Adverse Events
104
105
Rectal cancer
1 (1.0)0
Nervous system disorders
3 (2.9)2 (1.9)Dizziness postural00Dysgeusia
00Head discomfort
2 (1.9)0
Headache1 (1.0)2 (1.9)
Post herpetic neuralgia00Sciatica
00Somnolence00Psychiatric disorders00
Alcoholic hangover00
Respiratory, thoracic and mediastinal disorders
1 (1.0)2 (1.9)Cough
00Interstitial lung disease0
1 (1.0)Oropharyngeal pain
1 (1.0)0Rhinitis allergic00Upper respiratory tract inflammation0
1 (1.0)
Vasomotor rhinitis
00Skin and subcutaneous tissue disorders0
2 (1.9)Alopecia01 (1.0)Dermatitis contact00Drug eruption00
Eczema0
1 (1.0)Ingrowing nail00Pruritus
0
0
Rash
0
0
Vascular disorders0
1 (1.0)
Hot flush
0
1 (1.0)Total preferred term events
46
61
Patients were counted only once per treatment in each row.
Percentages of gender specific events were calculated using the corresponding gender count as denominator.
MedDRA (Version 19.1) coding dictionary applied.
Abbreviations: BID=Twice daily; incl=inclusive; MedDRA=Medical Dictionary for Regulatory Activities;
QD=Once daily.

Permanent Discontinuations due to Adverse Events: The incidence of TEAEs leading todiscontinuations is presented in Table 17. The most frequent AEs resulting in
discontinuation overall were in the infections and infestations SOC (which occurred in
2 [1.9%] patients in the tofacitinib 11 mg QD group and 6 [5.7%] patients in thetofacitinib 5 mg BID group). The AEs leading to discontinuations were more frequent in thetofacitinib 5 mg BID group (13 TEAEs) as compared to the tofacitinib 11 mg QD group(3 TEAEs).

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Table 17. Incidence of Treatment-Emergent Adverse Events Leading to
Discontinuations
Number (%) of Patients With Adverse Events by:
Tofacitinib 11 mg QD
Tofacitinib 5 mg BID
System Organ Class(N=104)(N=105)
MedDRA Preferred Term
n (%)
n (%)
Blood and lymphatic system disorders0
1 (1.0)Anaemia0
1 (1.0)General disorders and administration site conditions
0
2 (1.9)Feeling hot
0
1 (1.0)
Malaise0
1 (1.0)
Infections and infestations
2 (1.9)6 (5.7)
Bursitis infective0
1 (1.0)
Cystitis01 (1.0)
Infective tenosynovitis
0
1 (1.0)Pneumocystis jirovecii pneumonia
1 (1.0)1 (1.0)Pneumonia
1 (1.0)1 (1.0)Pneumonia bacterial01 (1.0)Sinusitis0
1 (1.0)Investigations
1 (1.0)0
Lymphocyte count decreased
1 (1.0)0
Nervous system disorders0
1 (1.0)
Headache01 (1.0)Respiratory, thoracic and mediastinal disorders0
1 (1.0)Interstitial lung disease0
1 (1.0)
Vascular disorders0
1 (1.0)
Hot flush
0
1 (1.0)Total preferred term events
3
13
Patients were counted only once per treatment in each row.
Percentages of gender specific events were calculated using the corresponding gender count as denominator.
MedDRA (Version 19.1) coding dictionary applied.
Abbreviations: BID=Twice daily; MedDRA=Medical dictionary for Regulatory Activities; N=Number ofpatients in the treatment group; n=Number of patients with specified criteria; QD=Once daily.

Dose Reductions or Temporary Discontinuations due to Adverse Events: The most frequent
AE resulting in temporary discontinuations or dose reductions overall was nasopharyngitis(which occurred in 3 [2.9%] patients in the tofacitinib 11 mg QD group and 2 [1.9%] patientsin the tofacitinib 5 mg BID group).
Deaths: There were no deaths among patients who participated in this study.
Clinical Laboratory Evaluation:
Creatine Kinase: The mean change from baseline in creatinine kinase levels at Week 12 waslower in the tofacitinib 11 mg QD group (42.91 U/L) as compared to the tofacitinib 5 mg
BID group (52.23 U/L).
Hemoglobin: At Week 4, 2 (1.9%) patients in both tofacitinib groups had mild to moderately
decreased hemoglobin. However, at Week 12, the proportion of patients with mild tomoderately decreased hemoglobin was more than twice that in the tofacitinib 5 mg BID
group (7 [7.4%] patients) as compared to the tofacitinib 11 mg QD group (3 [3.0%] patients).

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Neutrophil Counts:
Overall, the proportion of patients with mild neutropenia was 4.9%. One (1) patient at
Week 4 in the tofacitinib 11 mg QD group and 1 patient at Week 12 in the tofacitinib
5 mg BID group had moderate to severe neutropenia. No patient had potentiallylife-threatening neutropenia in either of the treatment groups.
Lymphocyte Counts:
Overall, the proportion of patients with mild and moderate lymphopenia was similar in both
treatment groups. However, severe lymphopenia was reported more than twice as frequently
in the tofacitinib 11 mg QD group as compared to the tofacitinib 5 mg BID group. No
patient had potentially life-threatening lymphopenia in either of the treatment groups.

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Platelets: A numerically greater mean decrease from baseline in platelets was observed in
the tofacitinib 11 mg QD group as compared to the tofacitinib 5 mg BID group.
Increases in Transaminases and Bilirubin: Overall, the proportions of patients (without
regard to baseline abnormality) who had AST and bilirubin values 1 × upper limit of normal(ULN) were greater in the tofacitinib 11 mg QD group (18.3% for AST and 14.4% forbilirubin) than in the tofacitinib 5 mg BID group (15.2% for AST and 4.8% for bilirubin),however the proportions of patients who had ALT increased was greater in the tofacitinib
5 mg BID group (12.4%) than in the tofacitinib 11 mg QD group (7.7%).
Mean AST, ALT and total bilirubin concentrations were similar in both treatment groups.
Serum Creatinine: A numerically greater mean increase from baseline in serum creatinine
was observed in the tofacitinib 5 mg BID group as compared to the tofacitinib 11 mg QD
group; the difference was not statistically significant.
Creatinine Clearance: A numerically greater mean decrease from baseline in creatinine
clearance was observed in the tofacitinib 5 mg BID group as compared to thetofacitinib 11 mg QD group at Week 4.
Lipids:Low-Density Lipoprotein Cholesterol: A numerically smaller mean increase from baseline
in LDL-C was observed in the tofacitinib 11 mg QD group as compared to the tofacitinib
5 mg BID group, however, the difference was not statistically significant.
High-Density Lipoprotein Cholesterol: A numerically smaller mean increase from baseline
in HDL-C was observed in the tofacitinib 11 mg QD group as compared to the tofacitinib
5 mg BID group, however, the difference was not statistically significant.
Low-Density Lipoprotein Cholesterol/High-Density Lipoprotein Cholesterol Ratio: A
numerically larger mean decrease from baseline in LDL-C/HDL-C ratio was observed in thetofacitinib 11 mg QD group as compared to the tofacitinib 5 mg BID group at Week 4. By

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Week 12, however, the ratio was approaching baseline values. There were no statisticallysignificant differences between the treatment groups.
Triglycerides: A numerically greater mean increase from baseline in triglycerides wasobserved in the tofacitinib 5 mg BID group as compared to the tofacitinib 11 mg QD group,
however, the difference was not statistically significant.
Total Cholesterol: A numerically smaller mean increase from baseline in total cholesterol
was observed in the tofacitinib 5 mg BID group as compared to the tofacitinib 11 mg QD
group, however, the difference was not statistically significant.
Patients With Hyperlipidemia: A greater shift towards higher LDL-C values was observed inboth treatment groups between the baseline and maximum observed values on treatment.
Vital Signs:

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Blood Pressure Measurements: A numerically greater mean increase from baseline insystolic BP (SBP) up to Week 4 was observed in the tofacitinib 11 mg QD group ascompared to the tofacitinib 5 mg BID group, however, the difference was not statisticallysignificant. From Week 4 until Week 12, SBP declined to baseline levels in both groups.
A numerically greater mean increase from baseline in diastolic BP up to Week 4 wasobserved in the tofacitinib 5 mg BID group as compared to the tofacitinib 11 mg QD groupand declined until Week 12 in both groups, however, these differences were not statisticallysignificant.
Electrocardiogram: No clinically significant abnormalities in ECG data were found in eitherof the treatment groups.
Physical Examination: No clinically significant abnormalities in physical examination were
found in either of the treatment groups.
Weight: The mean increase from baseline in weight and BMI was numerically similar inboth treatment groups.
CONCLUSIONS:

Non-inferiority was not demonstrated for tofacitinib MR 11 mg QD + MTX compared totofacitinib IR 5 mg BID + MTX as the upper bound of the 95% CI for the change frombaseline DAS28-4(CRP) was 0.69 and was greater than the pre-specified non-inferiority
margin of 0.6.

Both formulations resulted in clinically meaningful responses across all
primary/secondary endpoints. Results are robust using various sensitivity analyses.



The LS mean changes from baseline in DAS28-4(ESR) at Week 4 (-1.76 and -2.03 forMR 11 mg QD and 5 mg BID, respectively) and Week 12 (-2.50 and -2.86 forTemplate version 1.7

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090177e18de16b18\Approved\Approved On: 16-Mar-2018 10:25 (GMT)MR 11 mg QD and 5 mg BID, respectively) showed clinically meaningful decreases frombaseline (improvements).


The overall magnitude of ACR20/50/70 response rates (NRI) in MR 11 mg QD and
IR 5 mg BID was substantial and nearly superimposable for ACR20 (Week 12: 84.47%
for tofacitinib 11 mg QD group and 79.81% for tofacitinib 5 mg BID group) and ACR50(Week 12: 67.96% for tofacitinib 11 mg QD group and 68.27% for tofacitinib 5 mg BID
group) while ACR70 (31.07 for tofacitinib 11 mg QD group and 46.15 fortofacitinib 5 mg BID group) seemed higher in the IR arm of this study.

Remission response rate (NRI) assessed by DAS28-4(CRP) <2.6 and DAS28-4(ESR)<2.6 at Week 12 for tofacitinib 11 mg QD versus (vs) 5 mg BID was 50.49% vs 69.23%
for DAS28-4(CRP) <2.6 and 17.48% vs 34.62% for DAS28-4(ESR) <2.6.



LDA response rate as assessed by DAS28-4(CRP) 3.2 and DAS28-4(ESR) 3.2 at
Week 12 for tofacitinib 11 mg QD vs 5 mg BID was 73.79% vs 78.85% for
DAS28-4(CRP) 3.2 and 42.72% vs 60.58% for DAS28-4(ESR) 3.2.



Remission response rate assessed by DAS28-4(CRP) <2.6 and DAS28-4(ESR) <2.6 at
Week 12 was nominally significantly higher in the tofacitinib 5 mg BID group ascompared with the 11 mg QD group (p<0.0051). As had been reported previously, there
was a difference in the proportion of patients achieving remission. The overallmagnitude of the clinical responses was higher than typically seen in the historical global
studies of tofacitinib in RA, but consistent with RA-BID studies previously conducted inJapan. Overrepresentation of profound responders in Japan, may have facilitated thedetection of even minimal differences between the 2 formulations.



LDA response rate as assessed by DAS28-4(CRP) 3.2 and DAS28-4(ESR) 3.2 at
Week 12 was higher in tofacitinib 5 mg BID group compared with the 11 mg QD group(p<0.3912).



There was no statistically significant treatment difference observed in HAQ-DI response(decrease of at least 0.22) and FACIT-fatigue scale at Week 12.



There was nominal significant difference observed in Simplified Disease Activity Index,
Clinical Disease Activity Index, and ACR/EULAR Boolean-based remission at Week 12.

Numerically greater improvements in SF-36 scores was observed for patients who
received tofacitinib 5 mg BID as compared to tofacitinib 11 mg QD but the difference
was not statistically significant.

Change in EuroQol EQ-5D health state profile-utility score was significantly greater forpatients who received tofacitinib 5 mg BID compared with tofacitinib 11 mg QD(p=0.0483).

Tofacitinib was well tolerated in this study. There were no new safety signals in thisstudy. Safety profiles of the IR and MR formulations were similar.

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There were no deaths among patients who participated in this study.

Overall, 5 patients in the tofacitinib 11 mg QD group and 4 patients in thetofacitinib 5 mg BID group experienced at least 1 SAE after dosing. The most frequently
reported SAE by preferred term were pneumocystis jirovecii pneumonia (intofacitinib 11 mg QD group) and pneumonia (in both treatment groups).

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