Safety, Tolerability, and Efficacy of GS-9876 in Participants With Active Rheumatoid Arthritis on Background Therapy With Methotrexate

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the effect of GS-9876 versus placebo for the treatment of signs and symptoms of rheumatoid arthritis (RA) in participants with active RA as measured by change from baseline in Disease Activity Score for 28 joint count using C-reactive protein (CRP) (DAS28 (CRP)) at Week 12.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 2 Proof-of-Concept Study to Evaluate Safety, Tolerability, and Efficacy of GS-9876 in Subjects With Active Rheumatoid Arthritis on Background Therapy With Methotrexate

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: GS-9876
* Drug: Filgotinib
* Drug: GS-9876 placebo
* Drug: Filgotinib placebo
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Active RA disease as defined by: a tender joint count (TJC) of ≥ 6 (out of 68), a swollen joint count (SJC) of ≥ 6 (out of 66) at screening and Day 1 Inadequate response to treatment with oral or parenteral methotrexate (MTX) 7.5 to 25 mg/week continuously for at least 12 weeks No evidence of active or latent tuberculosis Key Exclusion Criteria: Prior treatment with B-cell depleting agents (eg, rituximab), unless more than 6 months prior to the first dose of study drug and documented return of CD19+ cells at screening Prior treatment with any commercially available or investigational spleen tyrosine kinase (SYK) inhibitor Concurrent treatment with any other conventional synthetic DMARD (csDMARD) other than MTX and/or hydroxychloroquine (HCQ) (prior csDMARD treatment allowed if appropriate wash out as defined in the protocol) Concurrent treatment with any biological disease modifying anti-rheumatic drug (bDMARD)(prior bDMARD treatment allowed if appropriate wash out as defined in the protocol). Prior failure to treatment with bDMARDs is not an exclusion criterion. Note: Other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GS-9876 - 30 mg<br>GS-9876 30 mg + filgotinib placebo for 12 weeks | Drug: GS-9876<br>* One tablet administered orally once daily<br>Drug: Filgotinib placebo<br>* Two tablets administered orally once daily<br>Drug: Methotrexate<br>* Background therapy with methotrexate administered orally or parenterally once weekly<br>|
| Experimental: GS-9876 - 10 mg<br>GS-9876 10 mg + filgotinib placebo for 12 weeks | Drug: GS-9876<br>* One tablet administered orally once daily<br>Drug: Filgotinib placebo<br>* Two tablets administered orally once daily<br>Drug: Methotrexate<br>* Background therapy with methotrexate administered orally or parenterally once weekly<br>|
| Experimental: Filgotinib<br>Filgotinib + GS-9876 placebo for 12 weeks | Drug: Filgotinib<br>* Two tablets administered orally once daily<br>Drug: GS-9876 placebo<br>* One tablet administered orally once daily<br>Drug: Methotrexate<br>* Background therapy with methotrexate administered orally or parenterally once weekly<br>|
| Placebo Comparator: Placebo<br>GS-9876 placebo + filgotinib placebo for 12 weeks | Drug: GS-9876 placebo<br>* One tablet administered orally once daily<br>Drug: Filgotinib placebo<br>* Two tablets administered orally once daily<br>Drug: Methotrexate<br>* Background therapy with methotrexate administered orally or parenterally once weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Disease Activity Score 28 C-Reactive Protein (DAS28 (CRP)) at Week 12 | Disease Activity Score 28 C-Reactive Protein (DAS28 (CRP)) is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), participant's global assessment of disease activity (visual analog scale: 0 = no disease activity to 100 = maximum disease activity) and C-Reactive Protein (CRP) for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. A negative change from baseline indicates improvement. | Baseline; Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved American College of Rheumatology (ACR)20 Improvement at Week 12 | American College of Rheumatology (ACR)20 response was defined as having ≥ 20% improvement from baseline in the number of tender and the number of swollen joints, and a 20% improvement in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity (PhGA), Participant's Global Assessment of Disease Activity (PtGA), Participant's pain assessment, Participant's assessment of physical function (HAQ-DI) score, and C-reactive protein (CRP). | Week 12 | 
| Percentage of Participants Who Achieved ACR50 Improvement at Week 12 | ACR50 response was defined as having ≥ 50% improvement from baseline in the number of tender and the number of swollen joints, and a 50% improvement in at least 3 of the following 5 criteria: PhGA, PtGA, Participant's pain assessment, HAQ-DI score, and CRP. | Week 12 | 
| Percentage of Participants Who Achieved ACR70 Improvement at Week 12 | ACR70 response was defined as having ≥ 70% improvement from baseline in the number of tender and the number of swollen joints, and a 70% improvement in at least 3 of the following 5 criteria: PhGA, PtGA, Participant's pain assessment, HAQ-DI score, and CRP. | Week 12 | 
| Change From Baseline in The Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 12 | The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a self-reported tool used to assess the ability to perform tasks in 8 functional categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and common daily activities. Responses in each functional category were collected as 0 (without any difficulty) to 3 (unable to do a task in that area). The HAQ-DI score ranges from 0 (no disability) to 3 (completely disabled), when 6 or more categories are non-missing. | Baseline; Week 12 |