Study to Evaluate Safety, Tolerability, and Efficacy of GS-5718 in Participants With Active Rheumatoid Arthritis Who Have an Inadequate Response to Disease-modifying Antirheumatic Drug(s) (bDMARDs) Treatment

Gilead Sciences

Overview

The primary objective of the study is to evaluate the effect of GS-5718 versus placebo for the treatment of rheumatoid arthritis (RA) as measured by change from baseline in Disease Activity Score (DAS) based on 28 joints using C-reactive protein (CRP) (DAS28\[CRP\]) at Week 12.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Conditions

Rheumatoid Arthritis

Interventions

GS-5718DRUG

Tablets administered orally

GS-5718DRUG

Tablets administered orally

Placebo to match GS-5718DRUG

Tablets administered orally

Tofacitinib 5 mg

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Diagnosis of rheumatoid arthritis (RA) ≥ 3 months prior to screening fulfilling the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA * Rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA) positivity * Individual fulfills all of the following minimum disease activity criteria: * ≥ 6 swollen joints (from a swollen joint count based on 66 joints \[SJC66\]) provided this would also fulfill ≥ 4 swollen joints (from a swollen joint count based on 28 joints \[SJC28\]) at screening and Day 1, and * ≥ 6 tender joints (from a tender joint count based on 68 joints \[TJC68\]), provided this would also fulfill ≥ 4 tender joints (from a tender joint count based on 28 joints \[TJC28\]) at screening and Day 1, and * hsCRP \> upper limit of normal at screening * Received at least one bDMARD for the treatment of RA to which there is a lack of efficacy and/or intolerance. Key Exclusion Criteria: * Individuals who do not qualify per the tofacitinib label and/or local guidelines should not be enrolled. * Prior exposure to any Janus kinase inhibitor Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Outcomes

Primary Outcomes

Change From Baseline in Disease Activity Score (DAS) Based on 28 Joints Using C-reactive Protein (CRP) DAS28 (CRP) at Week 12

The DAS28(CRP) is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), subject's global assessment (SGA) of disease activity assessed using visual analog scale (VAS) on a scale of 0-100 (0 indicating no arthritis and 100 indicating extremely active arthritis), and high-sensitivity C-reactive protein (hsCRP) measurement for a total possible score of 1 to 9.4. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

Time frame: Baseline, Week 12

Secondary Outcomes

Percentage of Participants Who Achieve American College of Rheumatology 20% Improvement (ACR20) Response at Week 12

ACR20 response is achieved when the participant has: ≥20% improvement (reduction) from baseline in tender joint count based on 68 joints (TJC68), swollen joint count based on 66 joints (SJC66) and in at least 3 of the following 5 items: physician's global assessment of disease activity (PGA) assessed using VAS on a scale of 0-100 (0 indicating no disease activity and 100 indicating maximum disease activity) and SGA assessed using VAS on a scale of 0-100 (0 indicating no arthritis and 100 indicating extremely active arthritis); participant's pain assessment using VAS on a scale of 0-100 (0 indicating no pain and 100 indicating severe pain); health assessment questionnaire-disability index (HAQ-DI) score contains 20 questions,8 components: dressing/ grooming, arising, eating, walking, hygiene, reach, grip, and errands/chores and scored on a scale of 0-3 (0 and 3 indicating without difficulty and unable to do); hsCRP.

Time frame: Week 12

Percentage of Participants Who Achieve ACR 50% Improvement (ACR50) Response at Week 12

ACR50 response is achieved when the participant has: ≥ 50% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PGA assessed using VAS on a scale of 0-100 (0 indicating no disease activity and 100 indicating maximum disease activity) and SGA assessed using VAS on a scale of 0-100 (0 indicating no arthritis and 100 indicating extremely active arthritis); participant's pain assessment using VAS on a scale of 0-100 (0 indicating no pain and 100 indicating severe pain); HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and errands/chores and scored on a scale of 0-3 (0 and 3 indicating without difficulty and unable to do); hsCRP.

Data from ClinicalTrials.gov

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Tablets administered orally

Placebo to match TofacitinibDRUG

Tablets administered orally

Percentage of Participants Who Achieve ACR 70% Improvement (ACR70) Response at Week 12

ACR70 response is achieved when the participant has: ≥ 70% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PGA assessed using VAS on a scale of 0-100 (0 indicating no disease activity and 100 indicating maximum disease activity) and SGA assessed using VAS on a scale of 0-100 (0 indicating no arthritis and 100 indicating extremely active arthritis); participant's pain assessment using VAS on a scale of 0-100 (0 indicating no pain and 100 indicating severe pain); HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and errands/chores and scored on a scale of 0-3 (0 and 3 indicating without difficulty and unable to do); hsCRP.

Time frame: Week 12

Change From Baseline in Simplified Disease Activity Index (SDAI) at Week 12

SDAI is a composite measure that sums the TJC28, SJC28, SGA, PGA, and the hsCRP (in mg/dL). PGA assessed using VAS on a scale of 0-10 (0 and 10 indicating no disease activity and maximum disease activity) and SGA assessed using VAS on a scale of 0-10 (0 and 10 indicating no arthritis and extremely active arthritis). Higher score indicates more severe disease activity status and total possible score is 0 to 86. A negative change from baseline indicates improvement.

Time frame: Baseline, Week 12

Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 12

CDAI is calculated using formula: CDAI = TJC based on 28 joints (TJC28) + SJC based on 28 joints (SJC28) + SGA + PGA. PGA assessed using VAS on a scale of 0-10 (0 and 10 indicating no disease activity and maximum disease activity) and SGA assessed using VAS on a scale of 0-10 (0 and 10 indicating no arthritis and extremely active arthritis). CDAI can range from 0 to 76, with higher score indicating more severe disease activity status. A negative change from baseline indicates improvement.

Time frame: Baseline, Week 12

Percentage of Participants Who Achieve SDAI ≤ 11 at Week 12

Time frame: Week 12

Percentage of Participants Who Achieve CDAI ≤ 10 at Week 12

Time frame: Week 12

Percentage of Participants Who Achieve DAS28(CRP) ≤ 3.2 at Week 12

The DAS28(CRP) is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), SGA and hsCRP measurement for a total possible score of 1 to 9.4. Higher values indicate higher disease activity.

Time frame: Week 12

Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) Score at Week 12

The HAQ-DI is a 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 domains (dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and errands/chores). Responses are scored on a 4-point Likert scale from 0, indicating no difficulty, to 3, indicating inability to perform a task in that area. The need for aids or help from another person will also be recorded. The HAQ-DI total score ranges from 0 to 3 with higher scores indicating greater dysfunction. Negative change from baseline indicates improvement (less disability).

Time frame: Baseline, Week 12

Percentage of Participants Who Achieve SDAI ≤ 3.3 at Week 12

Time frame: Week 12

Percentage of Participants Who Achieve CDAI ≤ 2.8 at Week 12

Time frame: Week 12

Percentage of Participants Who Achieve DAS28(CRP) < 2.6 at Week 12

The DAS28(CRP) is a measure of the participant's disease activity calculated using the tender joint counts (28 joints), swollen joint counts (28 joints), SGA, and hsCRP measurement for a total possible score of 1 to 9.4. Higher values indicate higher disease activity.

Time frame: Week 12

Pharmacokinetic (PK) Parameter: AUCtau of GS-5718

AUCtau is defined as the area under the curve from time zero to end of dosing interval.

Time frame: Up to Week 12

PK Parameter: AUCtau of Methotrexate (MTX)

AUCtau is defined as the area under the curve from time zero to end of dosing interval.

Time frame: Up to Week 8

PK Parameter: Cmax of GS-5718

Cmax is defined as the maximum observed concentration of drug.

Time frame: Up to Week 12

PK Parameter: Cmax of MTX

Cmax is defined as the maximum observed concentration of drug.

Time frame: Up to Week 8