A Study Comparing Upadacitinib (ABT-494) Monotherapy to Methotrexate (MTX) Monotherapy in Adults With Rheumatoid Arthritis (RA) Who Have an Inadequate Response to MTX (SELECT-MONOTHERAPY)

Study Overview
=================
Brief Summary
-----------------
The study objective of Period 1 of this study is to compare the safety and efficacy (signs and symptoms) of upadacitinib 30 mg once daily (QD) alone and upadacitinib 15 mg QD alone versus continuing MTX alone adults with moderately to severely active rheumatoid arthritis (RA) with an inadequate response to MTX. The study objective of Period 2 is to evaluate the long term safety, tolerability, and efficacy of upadacitinib 30 mg QD and 15 mg QD in adults with RA who had completed Period 1.

Detailed Description
-----------------
The study includes a 35-day screening period; a 14-week randomized, double-blind, parallel-group, controlled treatment period (Period 1); a 246-week blinded extension period (Period 2); and a 30-day follow-up visit. Participants who met eligibility criteria were to be randomized in a 2:2:1:1 ratio to one of four treatment groups: Group 1: upadacitinib 30 mg QD (Period 1) → upadacitinib 30 mg QD (Period 2) Group 2: upadacitinib 15 mg QD (Period 1) → upadacitinib 15 mg QD (Period 2) Group 3: MTX (Period 1) → upadacitinib 30 mg QD (Period 2) Group 4: MTX (Period 1) → upadacitinib 15 mg QD (Period 2) Starting with implementation of Protocol Amendment 5, all participants in the extension period will receive open-label upadacitinib 15 mg QD, including those currently on upadacitinib 30 mg QD.

Official Title
-----------------
A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) Monotherapy to Methotrexate (MTX) in Adults With Moderately to Severely Active Rheumatoid Arthritis With Inadequate Response to MTX

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: Methotrexate
* Drug: Upadacitinib
* Drug: Placebo Upadacitinib
* Drug: Placebo Methotrexate


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of RA for >= 3 months. Subjects must have been on oral or parenteral MTX therapy >= 3 months and on a stable dose for >= 4 weeks prior to first dose of study drug. Must have discontinued all conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) (other than MTX) >= 4 weeks prior to first dose of study drug. Meets the following minimum disease activity criteria: >= 6 swollen joints (based on 66 joint counts) and >= 6 tender joints (based on 68 joint counts) at Screening and Baseline Visits. Exclusion Criteria: Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, and filgotinib). Prior exposure to any biological disease-modifying anti-rheumatic drugs (bDMARDs). Current diagnosis of inflammatory joint disease other than RA. Current diagnosis of secondary Sjogren's Syndrome is permitted.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Upadacitinib 30 mg<br>Period 1: Participants receive upadacitnib 30 mg once daily and placebo to methotrexate once weekly for 14 weeks. Period 2: Participants receive upadacitinib 30 mg once daily until implementation of Protocol Amendment 5 when participants begin to receive upadacitinib 15 mg once daily up to Week 260. | Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: Rinvoq;Drug: Placebo Methotrexate<br>* Capsule; Oral<br>|
| Experimental: Upadacitinib 15 mg<br>Period 1: Participants receive upadacitnib 15 mg once daily and placebo to methotrexate once weekly for 14 weeks. Period 2: Participants receive upadacitinib 15 mg once daily up to Week 260. | Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: Rinvoq;Drug: Placebo Methotrexate<br>* Capsule; Oral<br>|
| Experimental: Methotrexate / Upadacitinib 30 mg<br>Period 1: Participants receive methotrexate once weekly and placebo to upadacitinib once daily for 14 weeks. Period 2: Participants receive upadacitinib 30 mg once daily until implementation of Protocol Amendment 5 when participants begin to receive upadacitinib 15 mg once daily up to Week 260. | Drug: Methotrexate<br>* Capsule; Oral<br>Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: Rinvoq;Drug: Placebo Upadacitinib<br>* Tablet; Oral<br>Drug: Placebo Methotrexate<br>* Capsule; Oral<br>|
| Experimental: Methotrexate / Upadacitinib 15 mg<br>Period 1: Participants receive methotrexate once weekly and placebo to upadacitinib for 14 weeks. Period 2: Participants receive upadacitinib 15 mg once daily up to Week 260. | Drug: Methotrexate<br>* Capsule; Oral<br>Drug: Upadacitinib<br>* Tablet; Oral<br>* Other names: Rinvoq;Drug: Placebo Upadacitinib<br>* Tablet; Oral<br>Drug: Placebo Methotrexate<br>* Capsule; Oral<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 14 | The primary endpoint for United States (US)/Food and Drug Administration (FDA) regulatory purposes was ACR 20% response (ACR20) at Week 14. 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 14 | 
| Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(CRP) at Week 14 | The primary endpoint for European Union (EU)/European Medicines Agency (EMA) regulatory purposes was low disease activity, based on a Disease Activity Score 28 (DAS28)-CRP score of ≤ 3.2 at Week 14. 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. A DAS28 score less than or equal to 3.2 indicates low disease activity. | Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in in Disease Activity Score 28 (CRP) at Week 14 | 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. A negative change from baseline in DAS28 (CRP) indicates improvement in disease activity. | Baseline to week 14 | 
| Change From Baseline in Heath Assessment Questionnaire and Disability Index (HAQ-DI) at Week 14 | 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 to week 14 | 
| Change From Baseline in Short-Form 36 (SF-36) Physical Component Score (PCS) at Week 14 | 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 to week 14 | 
| Percentage of Participants Achieving Clinical Remission (CR) Based on DAS28(CRP) at Week 14 | 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. A DAS28 score less than 2.6 indicates clinical remission. | Week 14 | 
| Change From Baseline in Duration of Morning Stiffness at Week 14 | Participants were asked to indicate the time it took for them to get as limber as possible after awakening with morning stiffness over the past 7 days. A negative change from Baseline indicates improvement. | Baseline to week 14 | 
| Percentage of Participants With an American College of Rheumatology 50% (ACR50) Response at Week 14 | 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 14 | 
| Percentage of Participants With an American College of Rheumatology 70% (ACR70) Response at Week 14 | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 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 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Musculoskeletal Disease, Arthritis, Joint Disease, Anti-inflammatory agents, Antirheumatic agents, Upadacitinib, ABT-494