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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

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ClinicalTrials.gov Identifier: NCT02281552
Recruitment Status : Completed
First Posted : November 3, 2014
Results First Posted : October 12, 2018
Last Update Posted : October 12, 2018
Sponsor:
Information provided by (Responsible Party):
Pfizer

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

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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

Resource links provided by the National Library of Medicine


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




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.



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02281552


Locations
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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
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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


Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02281552     History of Changes
Other Study ID Numbers: A3921215
TOFACITINIB QD P3 ( Other Identifier: Alias Study Number )
First Posted: November 3, 2014    Key Record Dates
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:
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Protein Kinase Inhibitors
Enzyme Inhibitors
Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Tofacitinib
Molecular Mechanisms of Pharmacological Action