Study to Assess Change in Disease Activity and Adverse Events of Oral Upadacitinib Compared to Subcutaneous Adalimumab in Adult Participants With Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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Rheumatoid Arthritis (RA) is a chronic inflammatory disease causing pain, stiffness, swelling and loss of joint function. This study will assess how safe and effective upadacitinib is in treating RA when compared to adalimumab in adult participants with inadequate response or intolerance to one TNF-inhibitor who are on a stable dose of methotrexate (MTX). Adverse events and change in disease activity will be assessed. Upadacitinib is an approved drug for the treatment of RA. This study is double-blinded means that neither the participants nor the study doctors will know who will be given upadacitinib and who will be given adalimumab. Study doctors put the participants in 1 of the 2 groups, called treatment arms randomly, to receive either upadacitinib or adalimumab. There is 1 in 2 chance that participants will receive adalimumab. Each group consists of 2 periods. Approximately 480 participants diagnosed with RA will be enrolled in approximately 250 sites across the world. Participants will receive the oral upadacitinib once daily and matching adalimumab placebo every other week, or the subcutaneous adalimumab every other week and matching upadacitinib placebo once daily during Period 1. Eligible participants will continue to receive same study treatment in Period 2 as assigned in Period 1 and will be followed for 30 days and 70 days. There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, checking for side effects and completing questionnaires.

Official Title
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A Phase 3b/4 Randomized, Double-Blind, Double Dummy, Active Comparator-Controlled Study, Comparing the Efficacy and Safety of Upadacitinib Versus Adalimumab in Subjects With Moderate to Severe Rheumatoid Arthritis on a Stable Background of MTX and Who Had an Inadequate Response or Intolerance to a Single TNF Inhibitor (SELECT- SWITCH)

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Upadacitinib
* Drug: Adalimumab
* Drug: Upadacitinib Matching Placebo
* Drug: Adalimumab Matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Rheumatoid Arthritis (RA) for >= 3 months based on the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for RA. Treated for >= 3 consecutive months prior to screening with 1 tumor necrosis factor inhibitor (TNFi) (originator or biosimilar) for RA (except adalimumab [originator or biosimilar]), but continue to exhibit active RA, or had to discontinue due to intolerability, irrespective of treatment duration. Up to 15% of participants who were intolerant to 1 TNFi will be allowed to enroll. On oral or parenteral methotrexate (MTX) therapy >= 3 months and on a stable prescription of 15 to 25 mg/week (or >= 10 mg/week in participants intolerant of MTX at doses >= 15 mg/week) for >= 4 weeks prior to the first dose of study drug. In addition, all participants should take a dietary supplement of folic acid or folinic acid throughout the study participation. For participants in China, Japan, Korea, or Taiwan, a stable dose of MTX >= 7.5 mg/week is acceptable. Additional local requirements for MTX may apply. Meets both of the following disease activity criteria: >= 6 swollen joint (based on 66 joint counts) and >= 6 tender joints (based on 68 joint counts) at screening and baseline; High-sensitivity C-reactive protein (hsCRP) >= 3 mg/L (central lab, upper limit of normal [ULN] 2.87 mg/L) at screening. Exclusion Criteria: History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint disease other than Rheumatoid Arthritis (RA). Prior exposure to any janus kinase (JAK) inhibitor. Prior exposure to adalimumab (original or biosimilar). Prior exposure to a non-TNFi biologic disease modifying anti-rheumatic drug (bDMARD).

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: Upadacitinib+ Adalimumab matching Placebo<br>Participants will receive upadacitinib once a day along with matching placebo for adalimumab at eow (every other week) in Period 1. Eligible participants will continue to receive same study treatment in Period 2 as assigned in Period 1. | Drug: Upadacitinib<br>* Oral Tablets<br>* Other names: RINVOQ;Drug: Adalimumab Matching Placebo<br>* Subcutaneous Injection<br>|
| Experimental: Adalimumab + Upadacitinib matching Placebo<br>Participants will receive adalimumab at eow (every other week) along with matching placebo for upadacitinib once a day in Period 1. Eligible participants will continue to receive same study treatment in Period 2 as assigned in Period 1. | Drug: Adalimumab<br>* Subcutaneous Injection<br>* Other names: Humira;Drug: Upadacitinib Matching Placebo<br>* Oral Tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) <= 3.2 | The DAS28-CRP 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 (NRS), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. Low Disease Activity (LDA) based on DAS28 (CRP) is defined as achieving a DAS28 (CRP) of less than or equal to 3.2. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 50 % (ACR50) Response | Participants who met the following 3 conditions for improvement from baseline were classified as meeting the ACR50 response criteria: 50% improvement in tender joint count (TJC68); 50% improvement in swollen joint count (SJC66); and 50% improvement in at least 3 of the 5 following parameters: Physician's Global Assessment of Disease Activity measured on a Numerical Rating Scale of 0 to 10 (NRS) Patient's Global Assessment of Disease Activity (NRS) Patient's Assessment of Pain (NRS) Health Assessment Questionnaire - Disability Index (HAQ-DI) High-sensitivity C-reactive protein (hsCRP). | Week 12 | 
| Percentage of Participants Achieving Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) < 2.6 | The DAS28-CRP 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 (NRS), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. Clinical remission (CR) based on DAS28 (CRP) is defined as achieving a DAS28 (CRP) of less than 2.6. | Week 12 | 
| Change from Baseline in Disease Activity Score 28 C-reactive Protein [DAS28-CRP]) | The DAS28-CRP 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 (NRS), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. | Week 12 | 
| Change from Baseline in Participants Assessment of Pain | Participants indicated their level of pain over the last 7 days using the Patient's Global Assessment Pain NRS. The range is 0 to 10 with no activity being indicated by 0 and severe activity by 10. | Week 12 | 
| Change from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score | The HAQ-DI assesses physical function in RA. The HAQ-DI score is the average of the highest score in each of eight categories. The total score is between 0-3.0, in 0.125 increments. Increasing scores indicate worse functioning with 0 indicating no functional impairment and 3 indicating complete impairment. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid Arthritis, RA, Upadacitinib, Adalimumab, Methotrexate, MTX, TNF Inhibitor