A Phase IIb, Double-Blind, Placebo-Controlled, Dose-Adaptive, Study of the Efficacy and Safety of GSK3196165 in Combination With Methotrexate Therapy, in Subjects With Active Moderate-Severe Rheumatoid Arthritis Despite Treatment With Methotrexate
Overview
- Phase
- Phase 2
- Intervention
- GSK3196165
- Conditions
- Arthritis, Rheumatoid
- Sponsor
- GlaxoSmithKline
- Enrollment
- 222
- Locations
- 1
- Primary Endpoint
- Percentage of Participants Who Achieved Disease Activity Score for 28 Different Joints With C-reactive Protein Value (DAS28{CRP}) Remission (DAS28 <2.6) at Week 24
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
This is a randomised, Phase IIb, dose-adaptive, multicentre, double-blind, parallel group, placebo-controlled study with the primary objective to assess the efficacy of GSK3196165, in combination with methotrexate (MTX), in subjects with active moderate severe rheumatoid arthritis (RA) despite treatment with MTX. Approximately 210 subjects will be randomised into the study, following a screening period of up to four weeks. The total treatment period is up to 52 weeks, with a 12-week follow-up period after the last dose (Week 50). Subjects will be randomised (1:1:1:1:1:1) to placebo or one of five subcutaneous (SC) GSK3196165 doses, in combination with MTX (at a weekly dose between 15-25 milligram [mg]), previously received for at least 12 weeks, with a stable and tolerated dose and route of administration for >=4 weeks. Escape therapy is provided at specified timepoints in the protocol for subjects that do not achieve adequate disease improvement.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age \>=18 years at the time of signing informed consent.
- •Meets ACR/EULAR 2010 RA Classification Criteria, with disease duration of \>=12 weeks.
- •Swollen joint count of \>=4 (66-joint count) and tender joint count of \>=4 (68-joint count).
- •DAS28(CRP) \>=3.
- •CRP \>=5.0 milligram per litre (mg/L) at screening.
- •Must have previously received MTX (15-25 mg weekly) for at least 12 weeks before screening, with no change in route of administration, with a stable and tolerated dose for \>=4 weeks prior to Day
- •A stable dose of MTX \>=7.5 mg/week is acceptable, if the MTX dose has been reduced for reasons of documented intolerance to MTX, e.g. hepatic or hematologic toxicity, or per local requirement.
- •Weight \>=45 kilogram (kg).
- •Male or female subjects are eligible to participate so long as they meet and agree to abide by the contraceptive criteria.
- •Diffusing capacity of the lung for carbon monoxide (DLCO) \>=60% predicted; forced expiratory volume in 1 second (FEV1) \>=70% predicted
Exclusion Criteria
- •Pregnant or lactating women.
- •History of other inflammatory rheumatological or autoimmune disorders, other than Sjögren's syndrome secondary to RA.
- •History of any respiratory disease which (in the opinion of the investigator) would compromise subject safety or the ability of the subject to complete the study (e.g. significant interstitial lung disease, such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), moderate-severe asthma, bronchiectasis, previous pulmonary alveolar proteinosis \[PAP\]).
- •Clinically-significant or unstable (in the opinion of the investigator) persistent cough or dyspnea that is unexplained.
- •Significant unstable or uncontrolled acute or chronic disease which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk.
- •A history of malignancy.
- •Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.
- •Current/previous Hepatitis B virus (HBV), Hepatitis C virus (HCV) or human immunodeficiency virus (HIV) 1 or 2 infection.
Arms & Interventions
GSK3196165, Dose 1 + MTX and Folic acid
Subject will receive GSK3196165 Dose 1 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: GSK3196165
GSK3196165, Dose 1 + MTX and Folic acid
Subject will receive GSK3196165 Dose 1 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: MTX
GSK3196165, Dose 1 + MTX and Folic acid
Subject will receive GSK3196165 Dose 1 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: Folic acid
GSK3196165, Dose 2 + MTX and folic acid
Subject will receive GSK3196165 Dose 2 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: GSK3196165
GSK3196165, Dose 2 + MTX and folic acid
Subject will receive GSK3196165 Dose 2 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: MTX
GSK3196165, Dose 2 + MTX and folic acid
Subject will receive GSK3196165 Dose 2 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: Folic acid
GSK3196165, Dose 3 + MTX and folic acid
Subject will receive GSK3196165 Dose 3 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: GSK3196165
GSK3196165, Dose 3 + MTX and folic acid
Subject will receive GSK3196165 Dose 3 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: MTX
GSK3196165, Dose 3 + MTX and folic acid
Subject will receive GSK3196165 Dose 3 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: Folic acid
GSK3196165, Dose 4 + MTX and folic acid
Subject will receive GSK3196165 Dose 4 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: GSK3196165
GSK3196165, Dose 4 + MTX and folic acid
Subject will receive GSK3196165 Dose 4 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: MTX
GSK3196165, Dose 4 + MTX and folic acid
Subject will receive GSK3196165 Dose 4 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: Folic acid
GSK3196165, Dose 5 + MTX and folic acid
Subject will receive GSK3196165 Dose 5 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: GSK3196165
GSK3196165, Dose 5 + MTX and folic acid
Subject will receive GSK3196165 Dose 5 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: MTX
GSK3196165, Dose 5 + MTX and folic acid
Subject will receive GSK3196165 Dose 5 (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: Folic acid
Placebo + MTX and folic acid
Subjects will receive placebo (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: MTX
Placebo + MTX and folic acid
Subjects will receive placebo (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: Folic acid
Placebo + MTX and folic acid
Subjects will receive placebo (initially weekly, then every other week) in combination with MTX (at a dose between 15-25 mg/week) and folic acid \>=5 mg/week.
Intervention: Placebo
Outcomes
Primary Outcomes
Percentage of Participants Who Achieved Disease Activity Score for 28 Different Joints With C-reactive Protein Value (DAS28{CRP}) Remission (DAS28 <2.6) at Week 24
Time Frame: Week 24
DAS28 is a modification of the original DAS and is based on a count of 28 swollen and tender joints and is used to evaluate a participant's response to treatment. DAS 28 CRP utilizing joint scores from the following 28 joints: elbows, shoulders, elbow, wrists, metacarpal- phalangeal I-V, proximal interphalangeal I-V and knees and is calculated using the following formula: DAS28 (CRP) = 0.56\*√(TJC28) +0.28\*√(SJC28)+0.014\*GH+0.36\*ln(CRP+1)+0.96. Where TJC - Tender joint Count, SJC= Swollen Joint Count, (GH=participant assessment of disease activity using a 100 millimeter \[mm\] visual analogue scale with 0 = best, 100 = worst) and CRP= C reactive Protein (in \[milligrams/liter\] mg/L). It ranges between 0.96 and 8.61. High score (worse outcome) and low scores (better outcome). ITT population comprised of all participants who were randomized to treatment and who received at least one dose of study treatment (GSK3196165 or placebo).
Secondary Outcomes
- Percentage of Participants Achieving Categorical DAS28(CRP) Response (Moderate/Good [European League Against Rheumatism] EULAR Response) at All Assessment Time Points(Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up))
- Percentage of Participants With American College of Rheumatology's (ACR) 20/50/70 Response Rates at All Assessment Time Points(Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up))
- Percentage of Participants With Index-based ACR/EULAR Remission Rates at All Assessment Time Points(Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up))
- Percentage of Participants With Boolean-based ACR/EULAR Remission Rates at All Assessment Time Points(Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up))
- Change From Baseline in DAS28(CRP) at Week 12(Baseline and Week 12)
- Percentage of Participants Who Achieved DAS28(CRP) Remission (DAS28 <2.6) at All Time Points(Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up))
- Change From Baseline in DAS28(CRP) at All Assessment Time Points(Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and 24)
- Time to First DAS28(CRP) Remission(Up to Week 62)
- Percentage of Participants in Clinical Disease Activity Index (CDAI) Remission(Weeks 1, 2, 4, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and Week 62 (follow-up))
- Change From Baseline in SDAI at All Assessment Time Points(Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and 24)
- Change From Baseline in CDAI at All Assessment Time Points(Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and 24)
- Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at All Assessment Time Points(Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and 24)
- Change From Baseline in Pain Score at All Assessment Time Points(Baseline and Weeks 1, 2, 4, 6, 8, 12, 16, 20 and Week 24)
- Change From Baseline in Physical and Mental Component Scores (PCS, MCS) and in Domain Scores of Short Form 36 (SF-36) at All Assessment Time Points(Baseline and Weeks 4, 12, 24)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue at All Assessment Time Points(Baseline and Weeks 4, 12, 24)
- Change From Baseline in Brief Fatigue Inventory (BFI) Question 3 at All Assessment Time Points(Baseline and Weeks 4, 12, 24)
- Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs)(Up to 62 weeks)
- Number of Participants With Serious Infections(Up to 62 weeks)
- Number of Participants With Opportunistic Infections(Up to 62 weeks)
- Number of Participants With Pulmonary Events(Up to 62 weeks)
- Number of Participants With Worst-case Post-Baseline Results for Pulse Oximetry(Up to 62 weeks)