PFIZER INC. These results are supplied for informational purpose only. Prescribing decisions should be made based on the approved package insert.

Transcription

1 Public Disclosure Synopsis Protocol A November 24 Final PFIZER INC. These results are supplied for informational purpose only. Prescribing decisions should be made based on the approved package insert. PROPRIETARY DRUG NAME / GENERIC DRUG NAME: Xeljanz / Tofacitinib PROTOCOL NO.: A3924 PROTOCOL TITLE: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Confirm Dose Responsiveness Following 2 Weeks of the Administration of CP-69,55 (5 Doses) or Placebo in Subjects With Active Rheumatoid Arthritis Inadequately Responding to At Least DMARD Study Centers: Forty-seven centers took part in the study and enrolled subjects. All the study centers were in Japan. 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Study Initiation and Final Completion Dates: 26 March 29 to 8 July 2 Phase of Development: Phase 2 Study Objectives: Primary Objective To evaluate the dose-response relationship of 5 tofacitinib (, 3, 5,, and 5 mg twice daily [BID]) doses compared to placebo for the treatment of signs and symptoms in subjects with active rheumatoid arthritis (RA) who failed an adequate trial of therapy with at least disease-modifying antirheumatic drug (DMARD) (including methotrexate) in a 2-week therapy. Secondary Objectives When tofacitinib (, 3, 5, and 5 mg BID) is used in a 2-week study in active RA subjects, to evaluate the safety and tolerability of all dose levels of tofacitinib versus placebo. When tofacitinib (, 3, 5,, and 5 mg BID) is used in a 2-week study in active RA subjects, to evaluate subjects quality of life (QOL) and functional status. When tofacitinib (, 3, 5,, and 5 mg BID) is used in a 2-week study in active RA subjects, to characterize the relationship between plasma concentrations of tofacitinib and efficacy and safety outcomes. When tofacitinib (, 3, 5,, and 5 mg BID) is used in a 2-week study in active RA subjects, to conduct Population pharmacokinetics (PK) analyses in active RA subjects. Template version. Page

2 Public Disclosure Synopsis Protocol A November 24 Final METHODS Study Design: This was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were randomized in a ::::: ratio to receive of 5 doses of tofacitinib (, 3, 5, and 5 mg, BID) or placebo. A total of 3 subjects were required; 5 subjects for each study group. For each subject, the study comprised screening period (at least 3 days but not longer than 28 days prior to first study drug administration) and treatment period (2 weeks). Three tablets of tofacitinib mg or 5 mg, or placebo were administered orally BID (separated by 2±2 hours), for a total of 6 tablets/day per treatment period. The study design is presented in Figure. Figure. Study Design tofacitinib 5 mg BID tofacitinib mg BID 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 tofacitinib 5 mg BID Prior treatment DMARDs wash out tofacitinib 3 mg BID tofacitinib mg BID Placebo Screening ( 28 to 3days) Treatment period (2 weeks) BID = twice daily; DMARDs = disease-modifying antirheumatic drugs. The schedule of activities is presented in Table. Template version. Page 2 +2 Week

3 Protocol A November 24 Final Table. Schedule of Activities 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Items Screening a Baseline Visits During Treatment Phase b EOT b Subjects characteristics Day -28 (-28 to-3 Day) Week () Week 2 (±3 Days) Week 4 (±3 Days) Week 8 (±3 Days) Week 2/Discontinuation (±3 Days) Informed consent X Randomization X Background investigation (eg complications, medical history, treatment conditions) c X Questions/examinations by physician (physical examination etc) d Xd X X X X X d Measurement of height, abdominal Assessments Lab tests/exploratory tests/physiological test circumference X Measurement of body weight X X X X X X RA diagnosis (ACR classification criteria 987) X Eligibility confirmation (eg inclusion/exclusion criteria) X X ACR assessments e X X X X X X DAS 28-3 (CRP),DAS 28-4 (ESR) assessments X X X X X X QOL (SF-36v2, EQ-5D) X X QOL2 (MOS-sleep, FACIT fatigue) X X X Vital signs (sitting blood pressure/pulse rate, axillary body temperature) X X X X X X Adverse event assessment X X X X X ESR (Westergren method) X X X X X X Serum rheumatoid factor X QuantiFERON -TB or Tuberculosis test f X HIV test, Hepatitis test (hepatitis B virus antigen, hepatitis C virus antibody) X Hematology g X X X X X X Biochemistry: standard (fasting) h X X X X X Biochemistry: hepatic/renal function (fasting) i X Biochemistry: lipid special (fasting) j X X X X X CRP X X X X X X Lymphocyte subset markers (FACS analysis) X X Serum IgG, IgM, and IgA levels X X Urinalysis (general/pregnancy) k X X X X X X PK sampling l X X Template version. Page 3

4 Protocol A November 24 Final Table. Schedule of Activities 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Pharmacogenomic sampling (DNA) m Exploratory RNA sampling m X X X X Retained Serum/Plasma sampling m X X X X Standard 2-lead ECG X X X SpO 2 X X X X X X Chest X-rays X n X Serum KL-6, β-d glucan X Study drug dispensing o X X X Study drug recovery, remaining drug check X X X X Confirmation of concomitant medications X X X X X X Instructions on the use of drugs o X X X X X Eligibility confirmation (for subjects who would enter into the continuous study) X X Drug supplies X Template version. Page 4

5 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Table. Schedule of Activities ACR = American College of Rheumatology, ALT = alanine aminotransferase, AST = aspartate aminotransferase, Ca = calcium, Cl - chlorine, CRP = C-reactive protein, DAS = disease activity score,, DNA = deoxyribonucleic acid, ESR = erythrocyte sedimentation rate, EOT = end of treatment, EQ-5D = EuroQol-5dimensions, FSH = follicle-stimulating hormone, FACIT = functional assessment of chronic illness therapy, FACS = fluorescence activated cell sorting, HCO3 = bicarbonate, HAQ-DI = health assessment questionnaire - disability index, HDL = high-density lipoprotein, HIV = human immunodeficiency virus, IgG = immunoglobulin G, IgM = immunoglobulin M, IgA = immunoglobulin A, K = pottasium, MOS = medical outcomes study, Na = sodium, QOL = quality of life, SF-36 = SF-36 health survey, RA = rheumatoid arthritis, SpO2 = percutaneous arterial oxygen saturation., RBC = red blood cell RNA = ribo-nucleic acid,, TB = Mycobacterium tuberculosis, WBC = white blood cell, LDL = low-density lipoprotein, VAS = visual analogue scale. a. The screening visit took place within 28 days prior to the Baseline Visit. Subject s informed consent was obtained before initiating assessments or tests in the screening period. b. The data observed for the observation/test parameters specified for all visits were accepted within a time window of 3 days relative to the Day of Treatment Initiation. c. Subject characteristics (eg complications, past medical history, treatment status) were investigated at the time of the interview. Subjects were questioned about their family history of cardiovascular disease which was developed under 55 and 65 years old in male and female each. Subjects were also questioned about their preferences regarding smoking and the average amount of alcohol consumption in week (eg, presence or absence of alcohol dependency or drug abuse). d. Questioning/examination by physician consisted of weight measurement and the examination of heart, lungs, abdomen, and lymph nodes, which were to be monitored carefully at Screening and the EOT. e. The following assessments based on the ACR core set were to be performed at all visits: painful joint count (68); swollen joint count (66); patients assessment of arthritis pain (VAS); patients Global Assessment of Active Arthritis (VAS); Physician s Global Assessment of Active Arthritis (VAS); HAQ-DI. f. QuantiFERON -TB or tuberculin test was performed only if a tuberculin test had not been performed in the 3 months prior to the start of the study (the assessment of tuberculin test was made within hours). g. WBC, differential WBC, RBC; hemoglobin, hematocrit, reticulocytes, platelet count. h. Biochemistry tests (standard): protein, total bilirubin, albumin, ALP, BUN, creatinine, blood glucose, AST, ALT, Na+, K+, Cl, Ca++, HCO3, uric acid, LDH, (all measured after fasting for at least 9 hours; this may not apply if the informed consent was obtained on the day of screening). i. Biochemistry tests (hepatic/renal function): AST, ALT, total bilirubin, albumin, creatinine (all measured after fasting for at least 9 hours). j. Biochemistry tests (lipid): T-Chol, LDL, HDL, TG (all measured after fasting for at least 9 hours) at Baseline, Weeks 2, 4, 8 and 2/Early Termination. Apolipoprotein A-I and A-II, apolipoprotein B (all measured after fasting for at least 9 hours) at Baseline and Week 2/Early Termination. k. Pregnancy test was performed for women of child-bearing potential (serum FSH [test] was optional). The pregnancy test was qualitative tests using urine test paper. Urinalysis was performed using dipsticks and, if a clinically significant abnormality was observed or at the discretion of the Investigator, additional examination by means of, for example, microscopy was performed. l. Blood samples were obtained for pharmacokinetic measurements at Weeks 4 and 8. The Investigator had the subjects come in for the visit without taking study medication at Weeks 4 and 8, so that blood samples could be collected at hour predose and at.5,, and 2 hours postdose. m. In principle, the blood samples for pharmacogenomic analysis were collected at Baseline concurrently with other blood samples (for the pharmacogenomic sampling, a separate informed consent had to be obtained). If the informed consent was not obtained at Baseline, the samples could be collected at other blood sampling times after obtaining the consent. n. Chest X-rays (frontal, lateral) to check for respiratory disorders in the 3 months prior to Screening. o. Subjects were instructed to start taking study medication after the evening meal on the treatment initiation Day (Baseline). Similarly, at Week 4 and 8 Template version.the study Page 5 visits, when study medications were dispensed, subjects were instructed to take medication after their evening meal. Subjects were instructed to return all remaining study medication to the Investigator at Week 4, 8 and EOT (including the visit following discontinuation).

6 Public Disclosure Synopsis Protocol A November 24 Final Number of Subjects (Planned and Analyzed): The study planned to enroll approximately 3 subjects (5 subjects per group 6 groups). A total of 383 subjects were screened and 38 subjects were randomized to 6 treatment groups. One subject withdrew after randomization but prior to treatment because of protocol violation (Indeterminate QuantiFERON-TB). In each group, 53, 53, 52, 53, 54, and 52 subjects took study medication for the, 3, 5,, and 5 mg tofacitinib BID and placebo groups, respectively. All subjects were enrolled in Japan. Diagnosis and Main Criteria for Inclusion: Male or female subjects aged between 2 years to 7 years and must have failed an adequate trial of therapy with at least DMARD due to lack of efficacy or toxicity. Excluded were the subjects who undergone current therapy with any DMARD. 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Study Treatment: At each visit, the Investigator instructed the subject to take tablet from each 3 bottles, BID (a total of 6 tablets/day) separated by 2 2 hours with a cup of water (about 2 ml), without chewing. At Baseline (Week ), the subject took the study medication just after examination, and the Investigator instructed the subject to take the study medication in next morning and evening. Based on this randomization table, subjects were randomly allocated at treatment initiation (Baseline) to placebo or tofacitinib, 3, 5,, or 5 mg BID, in a ::::: ratio and received, 3, 5, or 5 mg of tofacitinib or placebo administered orally. Template version. Page 6

7 Public Disclosure Synopsis Protocol A November 24 Final Efficacy, Pharmacokinetics, and Safety Endpoints: Efficacy Endpoints Primary Endpoints American college of rheumatology (ACR) 2 responder rate at Week 2. Secondary Endpoints ACR2 responder rate at all other than Week 2. ACR5, 7, and 9 responder rates at all timepoints. Observed values and changes from Baseline of the 7 components of the ACR Core set. 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Tender/painful joint count (68), swollen joint count (66), patient s Assessment of Arthritis Pain visual analogue scale (VAS), patient s Global Assessment of Active Arthritis (VAS), Physician s Global Assessment of Active Arthritis (VAS), health assessment questionnaire - disability index (HAQ DI), C-reactive protein (CRP). Area under the American college of rheumatology N (ACR-N) curve. Disease activity score 28 (DAS28-3) (CRP), DAS28-4 (erythrocyte sedimentation rate [ESR]). QOL assessments (SF-36, HAQ-DI, EQ-5D). Safety Endpoints Incidence and severity of adverse events (AEs) and lab test abnormalities. Vital signs, electrocardiograms (ECG). Safety Evaluations: Safety was assessed by reporting AEs, reporting results of clinical laboratory tests, measuring vital signs (sitting blood pressure, pulse rate, axillary body temperature, performed at Screening, Baseline, and at Weeks 2, 4, 8, and 2 or early termination); all of these assessments were made at Baseline and Weeks 2, 4, 8, and 2 or at early termination. In addition, standard 2-lead ECGs was assessed at Screening, Baseline, and at Week 2 or early termination. Statistical Methods: The primary analysis population for this study was the full analysis set (FAS) of enrolled and randomized subjects. The FAS study population included all subjects who were randomized to the study and received at least dose of study medication. Subjects who had a protocol deviation thought to affect the efficacy analysis were excluded from the Per Protocol (PP) efficacy analysis. The analyses were conducted to evaluate the robustness of the primary Template version. Page 7

8 Public Disclosure Synopsis Protocol A November 24 Final analysis. The safety analysis set was defined as the subjects who received at least dose of study medication. Analysis of Primary Endpoint: For ACR2 response rate at Week 2, the pair-wise comparisons of the tofacitinib, 3, 5,, and 5 mg BID to placebo were conducted using chi-square ( 2) test with 2-sided significance level of.5. The type I error rate for the pair-wise comparisons was protected from being inflated by using a step-down procedure. If the result was not significant, no further tests were carried out for the primary endpoint. If there was a significant difference between 5 mg BID and placebo, the test between mg BID and placebo was applied in the same way. The test between 5, 3, and mg BID versus placebo was also applied in that order in the same way. Missing values were handled using the Last Observation Carried Forward (LOCF) method. This analysis was based on the FAS. 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Analysis of Secondary Endpoints: ACR2 response rates were assessed at Weeks 2, 4, and 8, and at Weeks 2, 4, 8, and 2 for assessment of the response rates after treatment with ACR5, ACR7, and ACR9. Differences in these ACR response rates between each tofacitinib group and versus the placebo group were calculated using normal approximation method (ie, a 95% confidence interval). The LOCF approach also used to address any missing values for these endpoint assessment. In the case of no evaluable ACR data after Baseline, the ACR response was referred to as a Non-response. For the component variables of the ACR criteria (obtained at Weeks 2, 4, 8, 2 or early termination), a longitudinal linear model was employed for change from Baseline values. The actual baseline value was included as a covariate. The fixed effects of treatment, visit, and treatment-by-week interaction were included, along with subject as a random effect. Compound symmetry covariate structure was used. Estimates of mean values and the mean differences from placebo at each week were derived from the model. Contrasts versus placebo were formed at a significance level of 5%, along with 95% confidence intervals. Observed data were used without imputation. Descriptive statistics of the actual and change from baseline values were calculated. For ACR-N, descriptive statistics were used to assess data (ie, area under the ACR-N curve); this analyses plan was also used to assess the DAS of each subject, DAS28-3(CRP) and DAS28-4(ESR), which were measured and categorized at each visit. Numbers and percentages of subjects in each category were displayed for each treatment group at each visit. Safety Parameters: All the safety data was summarized through appropriate data tabulations, descriptive statistics, and graphical presentations. RESULTS Subject Disposition and Demography: Template version. Page 8

9 Protocol A November 24 Final Table 2 summarizes the number of subjects that were included in the efficacy and safety analyses. Table 2. Subject Evaluation Groups Tofacitinib BID Placebo mg 3 mg 5 mg mg 5 mg Number of Subjects (%) Screened: 383 Assigned to study treatment Treated Completed 5 (96.2) 49 (92.5) 5 (96.2) 49 (92.5) 52 (96.3) 48 (9.6) Discontinued 2 (3.8) 4 (7.5) 2 (3.8) 4 (7.5) 2 (3.7) 4 (7.5) Analyzed for efficacy Full analysis set 53 () 53 () 52 () 53 () 54 () 52 (98.) Per protocol set 53 () 5 (94.3) 5 (98.) 5 (96.2) 53 (98.) 5 (94.3) Analyzed for safety Adverse events 53 () 53 () 52 () 53 () 54 () 52 (98.) Laboratory data 53 () 53 () 52 () 53 () 54 () 52 (98.) BID = twice daily. Subject disposition is shown in Table e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Table 3. Subject Disposition Tofacitinib mg BID 3 mg BID 5 mg BID m g BID 5 m g BID Placebo Number (%) of Subjects Screened N =383 Assigned to study treatment Treated Completed 5 (96.2) 49 (92.5) 5 (96.2) 49 (92.5) 52 (96.3) 48 (9.6) Discontinued 2 (3.8) 4 (7.5) 2 (3.8) 4 (7.5) 2 (3.7) 4 (7.5) Related to Study Drug () 2 (3.8) () 2 (3.8) 4 (7.7) Adverse event () () 2 (3.8) 2 (3.8) Lack of efficacy () () 2 (3.8) Not Related to Study Drug () 2 (3.8) () 2 (3.8) 2 (3.7) Adverse event () () Other () 2 (3.8) () 2 (3.7) Total 2 (3.8) 4 (7.5) 2 (3.8) 4 (7.5) 2 (3.7) 4 (7.7) BID = twice daily Template version. Page 9

10 Public Disclosure Synopsis Protocol A November 24 Final Table 4 summarizes the demographic distribution by age, race, sex, weight, body mass index, and height by treatment groups. Table 4. Demography Characteristics Number of Subjects 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 mg BID 53 3 mg BID 53 Tofacitinib 5 mg BID mg BID 5 mg BID Placebo 52 Total 37 Age (years) < (5.) (2.8) 3 (25.) 9 (7.) 2 (22.2) 4 (26.9) 67 (2.) (73.6) 33 (62.3) 3 (59.6) 32 (6.4) 3 (55.6) 29 (55.8) 94 (6.2) 6 (.3) 9 (7.) 8 (5.4) 2 (22.6) 2 (22.2) 9 (7.3) 56 (7.7) 65 Mean SD Range Race Asian 53 () 53 () 52 () 53 () 54 () 52 () 37 () Sex Male Female Weight (kg) Mean SD Range Body Mass Index(kg/m2) Mean SD Range Height (cm) Mean SD Range Body Mass Index was calculated as weight/(height/)2. BID = twice daily, N = number of subjects, n = number of subjects meeting prespecified criteria, SD = standard deviation. Efficacy Results: The ACR2 response rates using LOCF method for handling missing components at Week 2 on the FAS were 37.74%, 67.92%, 73.8%, 84.9% and 9.74% for -, 3-, 5-, -, and 5-mg BID, respectively compared with 5.38% for placebo as shown in Table 5. Template version. Page

11 Public Disclosure Synopsis Protocol A November 24 Final Table 5. Chi-Square Test on ACR 2 Response Rates at Week 2 (FAS, LOCF) Treatment mg BID 3 mg BID 5 mg BID mg BID 5 mg BID Placebo N n Percent Difference From Placebo Difference Chip-Value Square < < < <. BID = twice daily, ACR = American college of rheumatology, FAS = full analysis set, LOCF = last observation carried forward, N = total number of subjects, n = number of subjects in sub group. The ACR2 response rates are shown in Figure e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 2. ACR2 Response Rates (Percent SE) at Baseline and Weeks 2, 4, 8 and 2 (FAS, LOCF) ACR = American college of rheumatology, FAS = full analysis set, LOCF = last observation carried forward CP-69,55 = tofacitinib. The ACR2 response rates at Weeks 2, 4, 8 and 2. are shown in Table 6. Template version. Page

12 Protocol A November 24 Final Table 6. ACR2 Response Rates at Weeks 2, 4, 8 and 2 (FAS, LOCF) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 N n Percent SE Difference (%) Difference From Placebo 95% CI SE Lower Upper p-value Week 2 mg BID mg BID mg BID <. mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo ACR = American college of rheumatology, BID = twice daily, CP-69,55 = tofacitinib, CI = confidence interval, FAS = full analysis set, LOCF = last observation carried forward, SE = standard error. Template version. Page 2

13 Public Disclosure Synopsis Protocol A November 24 Final ACR5 response rates are shown in Figure e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 3. ACR5 Response Rates (Percent SE) at Baseline and Weeks 2, 4, 8 and 2 (FAS, LOCF) ACR = American college of rheumatology, BID = twice daily, FAS = full analysis set, LOCF = last observation carried forward CP-69,55 = tofacitinib, SE = standard error. ACR5 response rates are shown in Table 7. Template version. Page 3

14 Protocol A November 24 Final Table 7. ACR5 Response Rates at Weeks 2, 4, 8 and 2 (FAS, LOCF) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 N n Percent SE Difference (%) Difference From Placebo 95% CI SE Lower Upper p-value Week 2 mg BID mg BID mg BID mg BID <. 5 mg BID <. Placebo 52. Week 4 mg BID mg BID mg BID <. mg BID <. 5 mg BID <. Placebo 52 2 Week 8 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo 52 2 Week 2 mg BID mg BID mg BID <. mg BID <. 5 mg BID <. Placebo ACR = American college of rheumatology, BID = twice daily, SE = standard error, CI = confidence interval, FAS = full analysis set, LOCF = last observation carried forward, N = total number of subjects, n = number of subjects in sub group. Template version. Page 4

15 Public Disclosure Synopsis Protocol A November 24 Final ACR7 response rates are shown in Figure e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 4. ACR7 Response Rates (Percent SE) at Baseline and Weeks 2, 4, 8 and 2 (FAS, LOCF) ACR = American college of rheumatology, BID = twice daily, SE = standard error, FAS = full analysis set, LOCF = last observation carried forward, CP-69,55 = tofacitinib, SE = standard error. ACR7 response rates are shown in Table 8. Template version. Page 5

16 Protocol A November 24 Final Table 8. ACR7 Response Rates at Weeks 2, 4, 8 and 2 (FAS, LOCF) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N n Percent SE Difference (%) SE Lower Upper p-value Week 2 mg BID mg BID mg BID mg BID mg BID Placebo 52. Week 4 mg BID mg BID mg BID mg BID <. 5 mg BID Placebo 52. Week 8 mg BID mg BID mg BID mg BID <. 5 mg BID <. Placebo 52 2 Week 2 mg BID mg BID mg BID mg BID <. 5 mg BID <. Placebo 52 2 ACR = American college of rheumatology, BID = twice daily, SE = standard error, CI = confidence interval, CI = confidence interval, FAS = full analysis set, LOCF = last observation carried forward, N = total number of subjects, n = number of subjects in sub group ACR9 response rates are shown in Table 9. Template version. Page 6

17 Protocol A November 24 Final Table 9. ACR9 Response Rates at Weeks 2, 4, 8 and 2 (FAS, LOCF) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N n Percent SE Difference (%) SE Lower Upper p-value Week 2 mg BID mg BID mg BID mg BID mg BID Placebo 52. Week 4 mg BID mg BID mg BID mg BID mg BID Placebo 52. Week 8 mg BID mg BID mg BID mg BID mg BID Placebo 52. Week 2 mg BID mg BID mg BID mg BID mg BID Placebo 52. ACR = American college of rheumatology, BID = twice daily, SE = standard error, CI = confidence interval, CI = confidence interval, FAS = full analysis set, LOCF = last observation carried forward, N = total number of subjects, n = number of subjects in sub group. The mean changes from Baseline in painful and tender joint counts are presented in Table. Template version. Page 7

18 Protocol A November 24 Final Table. Mean Change From Baseline in Tender-Joint Counts at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 mg BID mg BID mg BID mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and Baseline as fixed effects and subject as a random effect. ACR = American college of rheumatology, BID = twice daily, SE = standard error, CI = confidence interval, FAS = full analysis set, N= total number of subjects, n = number of subjects in sub group. The mean changes from Baseline in painful and tender joint counts are presented in Figure 5. Template version. Page 8

19 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 5. Mean Change (Mean SE) From Baseline in Tender-Joint Counts at Weeks 2, 4, 8 and 2 (FAS) BID = twice daily, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. Template version. Page 9

20 Protocol A November 24 Final The mean changes from Baseline in swollen joint counts are presented in Table. Table. Mean Change From Baseline in Swollen Joint Counts at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 mg BID mg BID mg BID mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and Baseline as fixed effects and subject as a random effect. BID = twice daily, SE = standard error, CI = confidence interval, FAS = full analysis set, N= total number of subjects, n = number of subjects in sub. The mean changes from Baseline in swollen joint counts are presented in Figure 6. Template version. Page 2

21 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 6. Mean Change (Mean SE) from Baseline in Swollen-Joint Counts at Weeks 2, 4, 8 and 2 (FAS) BID = twice daily, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. Template version. Page 2

22 Protocol A November 24 Final The mean changes from Baseline in Patient's assessment of pain VAS scores are presented in Table 2. Table 2. Mean Change from Baseline in Pain Visual Analog Score at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 mg BID mg BID mg BID <. mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and Baseline as fixed effects and subject as a random effect. BID = twice daily, SE = standard error, CI = confidence interval, FAS = full analysis set, N= total number of subjects, n = number of subjects in sub. The mean changes from Baseline in pain VAS scores are presented in Figure 7. Template version. Page 22

23 Protocol A November 24 Final Figure 7. Mean Change (Mean ± SE) From Baseline in Pain Visual Analog (VAS) Score at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 BID = twice daily, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. Template version. Page 23

24 Protocol A November 24 Final The mean changes from Baseline in the subject s global assessment of arthritis are presented in Table 3. Table 3. Mean Change from Baseline in Subjects Global Assessment at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 mg BID mg BID mg BID <. mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and Baseline as fixed effects and subject as a random effect. BID = twice daily, SE = standard error, CI = confidence interval, FAS = full analysis set, N= total number of subjects, n = number of subjects in sub. The mean changes from Baseline in the subject s global assessment of arthritis are presented in Figure 8. Template version. Page 24

25 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 8. Mean Change (Mean SE) From Baseline in Subjects Global Assessment at Weeks 2, 4, 8 and 2 (FAS) BID = twice daily, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. Template version. Page 25

26 Protocol A November 24 Final The mean changes from baseline in the physician s global assessment of arthritis are presented in Table 4. Table 4. Mean Change from Baseline in Physician Global Assessment at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 mg BID mg BID mg BID mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and Baseline as fixed effects and subject as a random effect. BID = twice daily, SE = standard error, CI = confidence interval, FAS = full analysis set, N= total number of subjects, n = number of subjects in sub. The mean changes from baseline in the physician s global assessment of arthritis are presented in Figure 9. Template version. Page 26

27 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 9. Mean Change (Mean SE) From Baseline in Physician Global Assessment at Weeks 2, 4, 8 and 2 (FAS) BID = twice daily, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. Template version. Page 27

28 Protocol A November 24 Final The HAQ-DI values decreased over time and with increased dose of tofacitinib, which was indicative of improved functional status. The changes from Baseline in HAQ-DI values are presented in Table 5. Table 5. Mean Change from Baseline in HAQ-DI at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 mg BID mg BID mg BID mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and Baseline as fixed effects and subject as a random effect. BID = twice daily, SE = standard error, CI = confidence interval, FAS = full analysis set, HAQ-DI = health assessment questionnaire - disability index, N= total number of subjects, n = number of subjects in sub. The changes from Baseline in HAQ-DI values are presented in Figure. Template version. Page 28

29 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure. Mean Change (Mean SE) From Baseline in HAQ-DI at Weeks 2, 4, 8 and 2 (FAS) BID = twice daily, HAQ-DI = health assessment questionnaire - disability index, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. Template version. Page 29

30 Protocol A November 24 Final The mean changes from Baseline in serum CRP level are presented in Table 6. Table 6. Mean Change from Baseline in C-Reactive Protein (mg/l) at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and Baseline as fixed effects and subject as a random effect. BID = twice daily, SE = standard error, CI = confidence interval, FAS = full analysis set, N= total number of subjects, n = number of subjects in sub. The mean changes from Baseline in serum CRP level are presented in Figure. Template version. Page 3

31 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure. Mean Change (Mean SE) From Baseline in C-Reactive Protein (mg/l) at Weeks 2, 4, 8 and 2 (FAS) BID = twice daily, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. Template version. Page 3

32 Protocol A November 24 Final The mean changes from Baseline in ACR-N are presented in Table 7. Table 7. Mean Change From Baseline in ACR-N at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 (LOCF) mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 4 (LOCF) mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 (LOCF) mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 (LOCF) mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and Baseline as fixed effects and subject as a random effect. ACR = American college of rheumatology, BID = twice daily, SE = standard error, CI = confidence interval FAS = full analysis set, N= total number of subjects, n = number of subjects in sub. The mean changes from Baseline in ACR-N are presented in Figure 2. Template version. Page 32

33 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 2. Mean Change (Mean SE) From Baseline in ACR-N at Weeks 2, 4, 8 and 2 (FAS, LOCF) BID = twice daily, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. Template version. Page 33

34 Protocol A November 24 Final The mean changes from Baseline in DAS28-3(CRP) are presented in Table 8. Table 8. Mean Change From Baseline in DAS28-3 (CRP) at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and Baseline as fixed effects and subject as a random effect. BID = twice daily, SE = standard error, CI = confidence interval, DAS = disease activity score, FAS = full analysis set. The mean changes from Baseline in DAS28-3(CRP) are presented in Figure 3. Template version. Page 34

35 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 3. Mean Change (Mean SE) From Baseline in DAS28-3(CRP) at Weeks 2, 4, 8 and 2 (FAS) BID = twice daily, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. Template version. Page 35

36 Protocol A November 24 Final The mean changes from Baseline in DAS28-4(ESR) are presented in Table 9. Table 9. Mean Change From Baseline in DAS28-4 (ESR) at Weeks 2, 4, 8 and 2 (FAS) 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value Week 2 mg BID mg BID mg BID mg BID <. 5 mg BID <. Placebo Week 4 mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 8 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Week 2 mg BID <. 3 mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results were obtained from a longitudinal linear model with the change from Baseline as a dependent variable and treatment, week, treatment-by-week interaction and baseline as fixed effects and subject as a random effect. BID = twice daily, CI = confidence interval, DAS = disease activity score, ESR = erythrocyte sedimentation rate, FAS = full analysis set, SE = standard error. The mean changes from Baseline in DAS28-4(ESR) are presented in Figure 4. Template version. Page 36

37 Public Disclosure Synopsis Protocol A November 24 Final 977e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Figure 4. Mean Change (Mean SE) From Baseline in DAS28-4(ESR) at Weeks 2, 4, 8 and 2 (FAS) BID = twice daily, SE = standard error, FAS = full analysis set, CP-69,55 = tofacitinib, SE = standard error. The SF-36 health survey domain scores (physical function, role physical, bodily pain, general health, vitality, social function, role emotional, and mental health). For all domains the active dose groups had higher scores than the placebo group. Statistically significant differences (p<.5) from placebo in change from Baseline at Week 2 were seen in 3, 5, and 5 mg BID doses for all domain scores, and mg BID dose for physical function, role physical, bodily pain and role emotional. The mean changes from Baseline of EQ-5D utility score at Week 2 are presented in Table 2. Table 2. Mean Change From Baseline EQ-5D Utility Score at Week 2 and Statistical Test From the Mixed-Effects Model (FAS) Difference From Placebo 95% CI N Mean SE Difference SE Lower Upper p-value mg BID mg BID <. 5 mg BID <. mg BID <. 5 mg BID <. Placebo Results are obtained from a Mixed-Effect model with change from Baseline as a dependent variable and Treatment and Baseline as fixed effects and subject as a random effect. BID = twice daily, CI = confidence interval, EQ-5D = EuroQol- 5 demimension FAS = full analysis set, N= total number of subjects, SE = standard error. Template version. Page 37

38 Protocol A November 24 Final The HAQ-DI values decreased over time and with increased dose of tofacitinib, which was indicative of improved functional status. Safety Results: Treatment-emergent non-serious adverse events by system organ class and preferred term (all causalities) in >5 % of subjects is presented in Table e85e57b77\Approved\Approved On: 2-Nov-24 2:2 Template version. Page 38