A Study to Compare Upadacitinib (ABT-494) to Placebo in Adults With Rheumatoid Arthritis (RA) Who Are on a Stable Dose of Conventional Synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs) and Have an Inadequate Response to csDMARDs

Study Overview
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Brief Summary
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This is a randomized, double-blind study comparing ABT-494 to placebo in Japanese participants with moderately to severely active rheumatoid arthritis who are on a stable dose of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and have an inadequate response. Following marketing approval of upadacitinib for rheumatoid arthritis in Japan, this study will become a post-marketing clinical study and include a long-term extension period.

Detailed Description
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This study consisted of a 35-day screening period; a 12-week randomized, double-blind, parallel-group, placebo-controlled treatment period (Period 1); a 248-week blinded long-term extension period (Period 2); and a 30-day follow-up period (call or visit). Participants who met eligibility criteria were randomized in a 3:3:3:1:1:1 ratio to one of six treatment groups: Group 1: Upadacitinib 7.5 mg QD (Period 1) → upadacitinib 7.5 mg QD (Period 2) Group 2: Upadacitinib 15 mg QD (Period 1) → upadacitinib 15 mg QD (Period 2) Group 3: Upadacitinib 30 mg QD (Period 1) → upadacitinib 30 mg QD (Period 2) Group 4: Placebo (Period 1) → upadacitinib 7.5 mg QD (Period 2) Group 5: Placebo (Period 1) → upadacitinib 15 mg QD (Period 2) Group 6: Placebo (Period 1) → upadacitinib 30 mg QD (Period 2)

Official Title
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A Phase 2b/3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to Placebo in Japanese Subjects With Moderately to Severely Active Rheumatoid Arthritis Who Are on a Stable Dose of Conventional Synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs) and Have an Inadequate Response to csDMARDs

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Placebo
* Drug: Upadacitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of rheumatoid arthritis (RA) for >= 3 months who also fulfill the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA. Subjects have been receiving conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) therapy >= 3 months and on a stable dose for >= 4 weeks prior to the first dose of study drug. Subject has >= 6 swollen joints (based on 66 joint counts) and >= 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits. Subjects with prior exposure to at most one biological disease-modifying anti-rheumatic drug (bDMARD) may be enrolled (up to 20% of total number of subjects) after the required washout period. Specifically, prior to enrollment: Subjects with limited exposure to bDMARD (< 3 months) OR Subjects who are responding to bDMARD therapy but had to discontinue due to intolerability (regardless of treatment duration). Exclusion Criteria: Prior exposure to any Janus kinase (JAK) inhibitor Subjects who are considered inadequate responders (lack of efficacy) to bDMARD therapy, after minimum 3 months treatment, as determined by the Investigator. History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic arthritis, axial spondyloarthritis [SpA] including ankylosing spondylitis and non-radiographic axial SpA, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, dermatomyositis, fibromyalgia [currently with active symptoms]). Current diagnosis of secondary Sjogren's Syndrome is permitted.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo / Upadacitinib 7.5 mg<br>Period 1: Participants will receive placebo once daily for 12 weeks. Period 2: Participants will receive Upadacitinib 7.5 mg once daily for 248 weeks. | Drug: Placebo<br>* Tablet; Oral<br>Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: RINVOQ™;|
| Experimental: Placebo / Upadacitinib 15 mg<br>Period 1: Participants will receive placebo once daily for 12 weeks. Period 2: Participants will receive upadacitinib 15 mg once daily for 248 weeks. | Drug: Placebo<br>* Tablet; Oral<br>Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: RINVOQ™;|
| Experimental: Placebo / Upadacitinib 30 mg<br>Period 1: Participants will receive placebo once daily for 12 weeks. Period 2: Participants will receive upadacitinib 30 mg once daily until regulatory approval of RA indication in Japan at which point they will switch to receive upadacitinib 15 mg once daily. Participants will receive upadacitinib for 248 weeks. | Drug: Placebo<br>* Tablet; Oral<br>Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: RINVOQ™;|
| Experimental: Upadacitinib 7.5 mg / Upadacitinib 7.5 mg<br>Period 1: Participants will receive upadacitinib 7.5 mg once daily for 12 weeks. Period 2: Participants will receive upadacitinib 7.5 mg once daily for 248 weeks. | Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: RINVOQ™;|
| Experimental: Upadacitinib 15 mg / Upadacitinib 15 mg<br>Period 1: Participants will receive upadacitinib 15 mg once daily for 12 weeks. Period 2: Participants will receive upadacitinib 15 mg once daily for 248 weeks. | Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: RINVOQ™;|
| Experimental: Upadacitinib 30 mg / Upadacitinib 30 mg<br>Period 1: Participants will receive upadacitinib 30 mg once daily for 12 weeks. Period 2: Participants will receive upadacitinib 30 mg once daily until regulatory approval of RA indication in Japan at which point they will switch to receive upadacitinib 15 mg once daily. Participants will receive upadacitinib for 248 weeks. | Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: RINVOQ™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12 | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 20% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP). | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score 28 (DAS28) (CRP) at Week 12 | The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. | Baseline and Week 12 | 
| Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 12 | The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. A negative change from Baseline in the overall score indicates improvement. | Baseline and Week 12 | 
| Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 12 | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: ≥ 50% improvement in 68-tender joint count; ≥ 50% improvement in 66-swollen joint count; and ≥ 50% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP). | Baseline and Week 12 | 
| Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 12 | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR70 response criteria: ≥ 70% improvement in 68-tender joint count; ≥ 70% improvement in 66-swollen joint count; and ≥ 70% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP). | Baseline and Week 12 | 
| Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 12 | The Short Form 36-Item Health Survey (SF-36) Version 2 is a self-administered questionnaire that measures the impact of disease on overall quality of life during the past 4 weeks. The SF-36 consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). The physical component score is a weighted combination of the 8 subscales with positive weighting for physical functioning, role-physical, bodily pain, and general health. The PCS was calculated using norm-based scoring so that 50 is the average score and the standard deviation equals 10. Higher scores are associated with better functioning/quality of life; a positive change from baseline score indicates an improvement. | Baseline and Week 12 | 
| Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 12 | Low disease activity. was defined as a DAS28 score less than or equal to 3.2. The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. | Week 12 | 
| Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 12 | Clinical remission was defined as a DAS28 (CRP) score less than 2.6. The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and hsCRP (in mg/L). Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity. | Week 12 | 
| Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 1 | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR20 response criteria: ≥ 20% improvement in 68-tender joint count; ≥ 20% improvement in 66-swollen joint count; and ≥ 20% improvement in at least 3 of the 5 following parameters: Physician global assessment of disease activity Patient global assessment of disease activity Patient assessment of pain Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP). | Baseline and Week 1 | 
| Change From Baseline in in Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) at Week 12 | The FACIT Fatigue scale is a 13-item tool that measures an individual's level of fatigue during their usual daily activities over the past 7 days. Each of the fatigue and impact of fatigue items are measured on a four point Likert scale. The FACIT Fatigue Scale is the sum of the individual 13 scores and ranges from 0 to 52 where higher scores indicate better quality of life. A positive change from Baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline in Rheumatoid Arthritis Work Instability Scale (RA-WIS) at Week 12 | RA-WIS is a simple validated tool to evaluate work instability (the consequence of a mismatch between an individual's functional ability and their work tasks). RA-WIS consists of 23 questions relating to the participant's functioning in their work environment, each answered as Yes or No. The total score is the number of questions answered Yes, and ranges from 0 to 23. A score < 10 means low risk and no action is needed, scores between 10 and 17 indicate medium risk and appropriate advice and information should be given. If the score is > 17, it means high risk and it could warrant referral. A negative change from Baseline indicates improvement. | Baseline and Week 12 | 
| Change From Baseline in the Severity of Morning Stiffness at Week 12 | Morning stiffness severity was determined by the Patient's Assessment of Severity and Duration of Morning Stiffness questionnaire. Participants rated the severity of morning stiffness on awakening over the past 7 days on a scale from 0 (No morning stiffness) to 10 (Worst possible morning stiffness). | Baseline and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rheumatoid arthritis, ABT-494, Japanese, Antirheumatic agents