A Study To Evaluate The Safety And Efficacy Of Tofacitinib Modified Release Tablets Compared To Tofacitinib Immediate Release Tablets In Adult Patients With Rheumatoid Arthritis

• ClinicalTrials.gov Identifier: NCT02281552
• Recruitment Status: Completed
• First Posted: November 2, 2014
• Results First Posted: October 12, 2018
• Last Update Posted: October 12, 2018
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

This is a 12 week study that will evaluate the efficacy and safety of the 11 mg tofacitinib modified release tablet taken once a day in patients with rheumatoid arthritis who continue taking methotrexate. Results for the modified release tablets will be compared to the efficacy and safety of the 5 mg tofacitinib immediate release tablets taken twice a day in patients with rheumatoid arthritis who continue taking methotrexate.

Condition or disease	Intervention/treatment	Phase
Rheumatoid Arthritis	Drug: Tofacitinib	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 209 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: November 18, 2014
• Actual Primary Completion Date: March 15, 2017
• Actual Study Completion Date: March 15, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: tofacitinib modified release tablet	Drug: Tofacitinib; tofacitinib modified release 11 mg tablet administered once time a day for 12 weeks
Active Comparator: tofacitinib immediate release tablet	Drug: Tofacitinib; tofacitinib immediate release 5 mg tablet administered twice a day for 12 weeks

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Disease Activity Score in 28 Joints Using 4 Variables (DAS28-4) (C-Reactive Protein [CRP]) at Week 12 [ Time Frame: Baseline, Week 12 ]
   DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (CRP) was calculated from swollen joint count (SJC) and tender/painful joint count (TJC) using 28 joints count, CRP (milligrams per liter [mg/L]) and patient global assessment of disease activity on a 100 millimeter (mm) visual analog scale (VAS: scores ranging from 0 mm [very well] to 100 mm [extremely bad], higher scores indicate worse health condition). Total DAS28-4 (CRP) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (CRP) [less than or equal to] <= 3.2 implied low disease activity and greater than (>) 3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (CRP) less than (<) 2.6 implied remission.

Secondary Outcome Measures :

1. Change From Baseline in Disease Activity Score in 28 Joints Using 4 Variables (DAS28-4) (Erythrocyte Sedimentation Rate [ESR]) at Week 12 [ Time Frame: Baseline, Week 12 ]
   DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (millimeters per hour [mm/hr]) and patient global assessment of disease activity on a 100 mm visual analog scale (VAS: scores ranging from 0 mm [very well] to 100 mm [extremely bad], higher scores indicate worse health condition). Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (ESR) <2.6 implied remission.
2. Number of Participants Achieving an American College of Rheumatology 20 Percent [%] (ACR20) Response at Week 12 [ Time Frame: Week 12 ]
   Participants with 20% improvement in 68-tender and 66-swollen joint counts and 20% improvement in at least 3 of the 5 measures: patient's global assessment of arthritis, physician global assessment of arthritis, patient's assessment of arthritis pain, health assessment questionnaire-disability index(HAQ-DI) and CRP. Patient's global assessment of arthritis: participant assessed arthritis by 100 mm VAS, score: 0 mm (no arthritis) to 100 mm (extreme arthritis), higher score implied more arthritis. Physician global assessment of arthritis: physician judged participants arthritis by 100 mm VAS, score: 0 mm (no arthritis) to 100 mm (extreme arthritis), higher score implied more arthritis. Patient's assessment of arthritis pain: participant assessed arthritis pain by 100 mm VAS, score: 0 mm (no pain) to 100 mm (most severe pain), higher score implied more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score implied more disability.
3. Number of Participants Achieving an American College of Rheumatology 50% (ACR50) Response at Week 12 [ Time Frame: Week 12 ]
   Participants with 50% improvement in 68-tender and 66-swollen joint counts and 50% improvement in at least 3 of the 5 measures: patient's global assessment of arthritis, physician global assessment of arthritis, patient's assessment of arthritis pain, health assessment questionnaire-disability index(HAQ-DI) and CRP. Patient's global assessment of arthritis: participant assessed arthritis by 100 mm VAS, score: 0 mm (no arthritis) to 100 mm (extreme arthritis), higher score implied more arthritis. Physician global assessment of arthritis: physician judged participants arthritis by 100 mm VAS, score: 0 mm (no arthritis) to 100 mm (extreme arthritis), higher score implied more arthritis. Patient's assessment of arthritis pain: participant assessed arthritis pain by 100 mm VAS, score: 0 mm (no pain) to 100 mm (most severe pain), higher score implied more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score implied more disability.
4. Number of Participants Achieving an American College of Rheumatology 70% (ACR70) Response at Week 12 [ Time Frame: Week 12 ]
   Participants with 70% improvement in 68-tender and 66-swollen joint counts and 70% improvement in at least 3 of the 5 measures: patient's global assessment of arthritis, physician global assessment of arthritis, patient's assessment of arthritis pain, health assessment questionnaire-disability index(HAQ-DI) and CRP. Patient's global assessment of arthritis: participant assessed arthritis by 100 mm VAS, score: 0 mm (no arthritis) to 100 mm (extreme arthritis), higher score implied more arthritis. Physician global assessment of arthritis: physician judged participants arthritis by 100 mm VAS, score: 0 mm (no arthritis) to 100 mm (extreme arthritis), higher score implied more arthritis. Patient's assessment of arthritis pain: participant assessed arthritis pain by 100 mm VAS, score: 0 mm (no pain) to 100 mm (most severe pain), higher score implied more pain. HAQ-DI: functional disability evaluation, score: 0 (no difficulty) to 3 (extreme difficulty), higher score implied more disability.
5. Number of Participants With DAS Remission (DAS28-4-CRP <2.6) at Week 12 [ Time Frame: Week 12 ]
   DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (CRP) was calculated from SJC and TJC using 28 joints count, CRP (mg/L) and patient global assessment of disease activity on a 100 mm visual analog scale (VAS: scores ranging from 0 mm [very well] to 100 mm [extremely bad], higher scores indicate worse health condition). Total DAS28-4 (CRP) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (CRP) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (CRP) <2.6 implied remission. Number of participants with DAS remission (DAS28-4-CRP<2.6) were reported in this outcome measure.
6. Number of Participants With DAS Remission (DAS28-4-ESR <2.6) at Week 12 [ Time Frame: Week 12 ]
   DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hr) and patient global assessment of disease activity on a 100 mm visual analog scale (VAS: scores ranging from 0 mm [very well] to 100 mm [extremely bad], higher scores indicate worse health condition). Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) <= 3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (ESR) <2.6 implied remission. Number of participants with DAS remission (DAS28-4-ESR<2.6) were reported in this outcome measure.
7. Number of Participants With Low Disease Activity (DAS28-4-CRP <=3.2) at Week 12 [ Time Frame: Week 12 ]
   DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (CRP) was calculated from SJC and TJC using 28 joints count, CRP (mg/L) and patient global assessment of disease activity on a 100 mm visual analog scale (VAS: scores ranging from 0 mm [very well] to 100 mm [extremely bad], higher scores indicate worse health condition). Total DAS28-4 (CRP) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (CRP) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (CRP) <2.6 implied remission. Number of participants with low disease activity (DAS28-4-CRP<=3.2) were reported in this outcome measure.
8. Number of Participants With Low Disease Activity (DAS28-4-ESR <=3.2) at Week 12 [ Time Frame: Week 12 ]
   DAS28 is a measure of disease activity in participants with rheumatoid arthritis. DAS28-4 (ESR) was calculated from SJC and TJC using 28 joints count, ESR (mm/hr) and patient global assessment of disease activity on a 100 mm visual analog scale (VAS: scores ranging from 0 mm [very well] to 100 mm [extremely bad], higher scores indicate worse health condition). Total DAS28-4 (ESR) score range: 0 (none) to 9.4 (extreme disease activity), higher score indicated more disease activity. DAS28-4 (ESR) <=3.2 implied low disease activity and >3.2 to <=5.1 implied moderate disease activity, >5.1 implied high disease activity, and DAS28-4 (ESR) <2.6 implied remission. Number of participants with low disease activity (DAS28-4-ESR<=3.2) were reported in this outcome measure.
9. Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12 [ Time Frame: Baseline, Week 12 ]
   HAQ-DI assesses the degree of difficulty a participant has experienced during the past week in 8 categories of daily living activities: dressing/grooming; arising; eating; walking; reach; grip; hygiene; and other activities over past week. Each activity category consisted of 2-3 items. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0 (least difficulty) and 3 (extreme difficulty), where higher scores indicate more difficulty while performing daily living activities.
10. Number of Participants Achieving an Improvement of at Least 0.22 Units in Health Assessment Questionnaire (HAQ Scores) at Week 12 [ Time Frame: Week 12 ]
    HAQ-DI assesses the degree of difficulty a participant has experienced during the past week in 8 categories of daily living activities: dressing/grooming; arising; eating; walking; reach; grip; hygiene; and other activities over past week. Each activity category consisted of 2-3 items. Each item scored on 4-point scale from 0 to 3: 0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range 0 (least difficulty) and 3 (extreme difficulty), where higher scores indicate more difficulty while performing daily living activities. Number of participants with an improvement of at least 0.22 units in HAQ scores from baseline to Week 12 were reported in this outcome measure.
11. Change From Baseline in the Short Form 36 (SF-36) Health Survey Domain Scores at Week 12 [ Time Frame: Baseline, Week 12 ]
    SF-36 is a participant reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: physical functioning, role physical, bodily pain, social functioning, mental health, role emotional, vitality, and general health. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of 8 health aspects were aggregated to derive the two component scores (physical component scores [PCS], mental component scores [MCS]) ranging from 0 (worst) to 100 (best), where higher scores indicated good health condition.
12. Change From Baseline in the Short Form 36 (SF-36) Health Survey Component Scores at Week 12 [ Time Frame: Baseline, Week 12 ]
    SF-36 is a participant reported standardized survey designed to assess generic health related quality of life. It consisted of 36 items evaluating 8 aspects of functional health and well-being: physical functioning, role physical, bodily pain, social functioning, mental health, role emotional, vitality, and general health. The score range for each of the 8 health aspects was from 0 (poor health) to 100 (better health), higher scores indicating good health condition. Scores of 8 health aspects were aggregated to derive the two component scores PCS and MCS ranging from 0 (worst) to 100 (best), where higher scores indicated good health condition.
13. Change From Baseline in the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale Scores at Week 12 [ Time Frame: Baseline, Week 12 ]
    The FACIT-Fatigue Scale was a participant completed questionnaire consisted of 13 items that assessed fatigue. Each item was scored on a scale of 0 (not at all) to 4 (very much), Total score ranging from 0 (not at all) to 52 (very much), higher scores represented lower level of fatigue.
14. Change From Baseline in the European Quality of Life - 5 Dimensions Questionnaire (EQ-5D) Scores at Week 12 [ Time Frame: Baseline, Week 12 ]
    EQ-5D was a participant completed instrument designed to assess impact on quality of life in terms of a single utility score in five domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression with 3 possible answers for each item (1=no problem, 2=moderate problems, 3=severe problems). The 5-dimensional systems are converted into a single index utility score between 0 and 1, where higher score indicated a better health state.

Other Outcome Measures:

1. Number of Participants With Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 12 weeks ]
   An Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between first dose of study drug and up to 12 weeks that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non- serious adverse events.
2. Number of Participants With Clinically Significant Laboratory Test Abnormalities [ Time Frame: Baseline up to 12 weeks ]
   Criteria: lipids(cholesterol[CH] milligrams/deciliter[mg/dL] >1.3*upper limit normal(ULN), high-density lipoprotein CH mg/dL <0.8*lower limit normal(LLN), Low-density lipoprotein CH mg/dL >1.2* ULN, triglycerides mg/dL >1.3*ULN); neutrophil count(NC) <1000 cells/cubic milliliters(mm^3), platelet counts(PC) <100,000 P/mm^3, lymphocyte counts(LC) <500 L/mm^3, any single (aspartate transaminase elevation(ASTE)/alanine transaminase elevation(ALTE) >=3*ULN, hemoglobin(Hb) value <8.0 grams(g)/dL or >=2 g/dL below baseline, any serum creatinine(SC) increase(inc) >50% or inc >0.5 mg/dL over the average of screening(OAS) and baseline values(BV), 2 sequential ASTE/ALTE>=3*ULN with total bilirubin value(TBV) >=2*ULN, ASTE/ALTE >=3*ULN, ASTE/ALTE >=5*ULN, Hb <8.0 g/dL or decrease of >30% from BV, PC <75,000 P/mm^3, NC <1000 cells/mm^3, LC <500 L/mm^3, confirmed inc in SC >50% OAS and BV and detection of hepatitis B virus-deoxyribonucleic acid(HBV-DNA) by the two sequential quantitative tests.

Eligibility Criteria

• Ages Eligible for Study: 20 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• diagnosis of rheumatoid arthritis
• currently taking a stable dose of methotrexate
• no evidence of active or latent or inadequately treated tuberculosis

Exclusion Criteria:

• evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic or allergic disease
• clinically significant infections within the past 6 months

Contacts and Locations

Locations

Japan

Japanese Red Cross Nagoya Daiichi Hospital

Nagoya, Aichi, Japan, 453-8511

National Hospital Organization Nagoya Medical Center

Nagoya, Aichi, Japan, 460-0001

National Hospital Organization Toyohashi Medical Center

Toyohashi, Aichi, Japan, 440-8510

Yamada Rheumatology Clinic

Matsuyama, Ehime, Japan, 790-0905

St. Mary's Hospital

Kurume, Fukuoka, Japan, 830-8543

Gunma Rheumatism Clinic

Takasaki-shi, Gunma, Japan, 370-0004

Inoue Hospital

Tohrimachi, Takasaki, Gunma, Japan, 370-0053

Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital

Hiroshima-city, Hiroshima, Japan, 730-8619

National Hospital Organization Asahikawa Medical Center

Asahikawa, Hokkaido, Japan, 070-8644

Katayama Orthopaedic Rheumatology Clinic

Asahikawa, Hokkaido, Japan, 078-8243

Yoshida orthopaedics and rheumatologyclinic

Morioka, Iwate, Japan, 020-0015

Komagamine Rheumatoid Orthopaedic Clinic

Morioka, Iwate, Japan, 020-0034

National Hospital Organization Sagamihara National Hospital

Sagamihara, Kanagawa, Japan, 252-0392

National Hospital Organization Yokohama Medical Center

Yokohama, Kanagawa, Japan, 245-8575

Osaki Citizen Hospital

Oosaki, Miyagi, Japan, 989-6183

Tohoku University Hospital/ Department of Hematology and Rheumatology

Sendai, Miyagi, Japan, 9808574

Nagano Red Cross Hospital

Nagano-shi, Nagano, Japan, 380-8582

Sasebo Chuo Hospital

Sasebo, Nagasaki, Japan, 857-1195

National Hospital Organization Ureshino Medical Center

Ureshino-shi, Saga, Japan, 843-0393

Soshigayaokura clinic

Setagaya-ku, Tokyo, Japan, 157-0073

Showa University Hospital

Shinagawa-ku, Tokyo, Japan, 142-8666

Honjo Rheumatism Clinic

Takaoka-shi, Toyama, Japan, 933-0874

Miyasato Clinic

Shunan, Yamaguchi, Japan, 745-0824

National Hospital Organization Chiba-East Hospital

Chiba, Japan, 260-8712

Sugimoto rheumatology and internal medicine clinic

Fukui, Japan, 910-0068

National Hospital Organization Kyushu Medical Center

Fukuoka, Japan, 810-8563

SHONO Rheumatism Clinic

Fukuoka, Japan, 814-0002

Sagawa Akira Rheumatology Clinic

Hokkaido, Japan, 060-0001

Matsubara Mayflower Hospital

Hyogo, Japan, 673-1462

Yokohama Minami Kyosai Hospital

Kanagawa, Japan, 236-0037

Kumamoto Orthopaedic Hospital

Kumamoto, Japan, 862-0976

Japanese Red Cross Kyoto Daiichi Hospital

Kyoto, Japan, 605-0981

Oribe Clinic of Rheumatology and Internal Medicine

Oita, Japan, 870-0823

Otsuka Clinic of Rheumatism and Medicine

Oita, Japan, 870-1155

Rabbit Clinic

Saitama, Japan, 336-0911

Hirose Clinic

Saitama, Japan, 359-1111

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

  Study Documents (Full-Text)

Documents provided by Pfizer:

Statistical Analysis Plan  [PDF] March 28, 2017

Study Protocol  [PDF] August 13, 2015

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tanaka Y, Sugiyama N, Toyoizumi S, Lukic T, Lamba M, Zhang R, Chen C, Stock T, Valdez H, Mojcik C, Fan H, Deng C, Yuasa H. Modified- versus immediate-release tofacitinib in Japanese rheumatoid arthritis patients: a randomized, phase III, non-inferiority study. Rheumatology (Oxford). 2019 Jan 1;58(1):70-79. doi: 10.1093/rheumatology/key250.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02281552
• Other Study ID Numbers: A3921215; TOFACITINIB QD P3 ( Other Identifier: Alias Study Number )
• First Posted: November 2, 2014
• Results First Posted: October 12, 2018
• Last Update Posted: October 12, 2018
• Last Verified: March 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Information relating to our policy on data sharing and the process for requesting data can be found at the following link:

http://www.pfizer.com/research/clinical_trials/trial_data_and_results/data_requests

Keywords provided by Pfizer:

Tofacitinib, CP-690,550, Janis kinase, JAK inhibitor, modified release, Xeljanz

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Tofacitinib; Janus Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action