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

A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 2 Proof-of-Concept Study to Evaluate Safety, Tolerability, and Efficacy of GS-5718 on Background Therapy With Conventional Synthetic Disease-modifying Antirheumatic Drug(s) (csDMARDs) in Participants With Active Rheumatoid Arthritis Who Have an Inadequate Response to Biologic DMARD(s) Treatment

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 Overview

• Status: Withdrawn
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: GS-5718; Drug: Placebo to match GS-5718; Drug: Placebo to match Tofacitinib; Drug: Tofacitinib 5 mg

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: GS-5718 Dose A; Participants will receive GS-5718 Dose A once daily + placebo to match (PTM) GS-5718 Dose B once daily + PTM tofacitinib twice daily for up to 12 weeks.	Drug: GS-5718; Tablets administered orally; Drug: Placebo to match GS-5718; Tablets administered orally; Drug: Placebo to match Tofacitinib; Tablets administered orally
Experimental: GS-5718 Dose B; Participants will receive GS-5718 Dose B once daily + PTM GS-5718 Dose A once daily + PTM tofacitinib twice daily for up to 12 weeks.	Drug: GS-5718; Tablets administered orally; Drug: Placebo to match GS-5718; Tablets administered orally; Drug: Placebo to match Tofacitinib; Tablets administered orally
Active Comparator: Tofacitinib; Participants will receive tofacitinib 5 mg twice daily + PTM GS-5718 (Dose A + Dose B) once daily for up to 12 weeks.	Drug: Placebo to match GS-5718; Tablets administered orally; Drug: Tofacitinib 5 mg; Tablets administered orally; Other Names: XELJANZ®
Placebo Comparator: Placebo; Participants will receive PTM GS-5718 (Dose A + Dose B) once daily + PTM tofacitinib twice daily for up to 12 weeks.	Drug: Placebo to match GS-5718; Tablets administered orally; Drug: Placebo to match Tofacitinib; Tablets administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Week 12
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.	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.	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.	Baseline, Week 12
Percentage of Participants Who Achieve SDAI ≤ 11 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.	Week 12
Percentage of Participants Who Achieve CDAI ≤ 10 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.	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.	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).	Baseline, Week 12
Percentage of Participants Who Achieve SDAI ≤ 3.3 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.	Week 12
Percentage of Participants Who Achieve CDAI ≤ 2.8 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.	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.	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.	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.	Up to Week 8
PK Parameter: Cmax of GS-5718	Cmax is defined as the maximum observed concentration of drug.	Up to Week 12
PK Parameter: Cmax of MTX	Cmax is defined as the maximum observed concentration of drug.	Up to Week 8

Collaborators and Investigators

• Sponsor: Gilead Sciences

Publications and helpful links

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2022
• Primary Completion (Anticipated): February 1, 2023
• Study Completion (Anticipated): March 1, 2023

Study Registration Dates

• First Submitted: December 8, 2021
• First Submitted That Met QC Criteria: December 8, 2021
• First Posted (Actual): December 21, 2021

Study Record Updates

• Last Update Posted (Actual): May 18, 2022
• Last Update Submitted That Met QC Criteria: May 11, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tofacitinib
• Other Study ID Numbers: GS-US-561-5898; 2021-002664-52 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No