A 52-week, Phase 3, Multicentre, Randomised, Double Blind, Efficacy and Safety Study Comparing GSK3196165 With Placebo and With Tofacitinib, in Combination With Methotrexate in Participants With Moderately to Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Methotrexate
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- GlaxoSmithKline
- Enrollment
- 1,537
- Locations
- 1
- Primary Endpoint
- Percentage of Participants Achieving 20 Percentage (%) Improvement in American College of Rheumatology Criteria (ACR20) at Week 12 Superiority Comparison With Placebo
Study Overview
Brief Summary
This study [contRAst 1 (201790: NCT03980483)] is a phase 3, randomized, multicenter, double blind study to assess the safety and efficacy of GSK3196165, in combination with methotrexate (MTX), for the treatment of adult participants with moderate to severe active rheumatoid arthritis (RA) who have had an inadequate response to MTX. The study will consist of a screening phase of up to 6 weeks followed by a 52-week treatment phase in which participants will be randomized in a ratio of 6:6:3:1:1:1 to receive GSK3196165 150 milligrams (mg) subcutaneous (SC) weekly, GSK3196165 90 mg SC weekly, tofacitinib capsules (cap) 5 mg twice a day or placebo (three arms, each placebo arm will have 12 weeks placebo followed by 40 weeks active treatment) respectively, all in combination with MTX. Participants who, in investigator's judgement will benefit from extended treatment with GSK3196165, may be included in the long-term extension study [contRAst X (209564: NCT04333147)]. For those participants who do not continue into the long term-extension study, there will be an 8 week safety follow-up visit following the treatment phase.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Masking Description
Double blinded
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
GSK3196165 90mg + MTX
Participants received GSK3196165 90 mg subcutaneous (SC) injection once weekly for 52 weeks in combination with methotrexate (MTX).
Intervention: GSK3196165 (Otilimab) (Biological)
GSK3196165 150mg + MTX
Participants received GSK3196165 150 mg subcutaneous (SC) injection once weekly for 52 weeks in combination with MTX.
Intervention: GSK3196165 (Otilimab) (Biological)
Tofacitinib 5mg + MTX
Participants received Tofacitinib 5mg capsule, orally, twice daily (BID) in combination with MTX plus placebo injection weekly to maintain the blind for 52 weeks.
Intervention: Tofacitinib 5 mg (Drug)
Placebo + MTX and GSK3196165 90mg + MTX
Participants received Placebo weekly SC injection in combination with MTX for 12 weeks. At Week 12, participants were switched from placebo to GSK3196165 90 mg, SC injection, once weekly in combination with MTX until Week 52.
Intervention: GSK3196165 (Otilimab) (Biological)
Placebo + MTX and GSK3196165 90mg + MTX
Participants received Placebo weekly SC injection in combination with MTX for 12 weeks. At Week 12, participants were switched from placebo to GSK3196165 90 mg, SC injection, once weekly in combination with MTX until Week 52.
Intervention: Placebo (Drug)
Placebo + MTX and GSK3196165 150mg + MTX
Participants received Placebo weekly SC injection in combination with MTX for 12 weeks. At Week 12, participants were switched from placebo to GSK3196165 150 mg, SC injection, once weekly in combination with MTX until Week 52.
Intervention: GSK3196165 (Otilimab) (Biological)
Placebo + MTX and GSK3196165 150mg + MTX
Participants received Placebo weekly SC injection in combination with MTX for 12 weeks. At Week 12, participants were switched from placebo to GSK3196165 150 mg, SC injection, once weekly in combination with MTX until Week 52.
Intervention: Placebo (Drug)
Placebo + MTX and Tofacitinib 5mg + MTX
Participants received Placebo capsule weekly in combination with MTX for 12 weeks. At Week 12, participants were switched from placebo capsule to Tofacitinib 5mg, capsule, orally, BID in combination with MTX plus placebo injection to maintain the blind for 52 weeks.
Intervention: Tofacitinib 5 mg (Drug)
Placebo + MTX and Tofacitinib 5mg + MTX
Participants received Placebo capsule weekly in combination with MTX for 12 weeks. At Week 12, participants were switched from placebo capsule to Tofacitinib 5mg, capsule, orally, BID in combination with MTX plus placebo injection to maintain the blind for 52 weeks.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Percentage of Participants Achieving 20 Percentage (%) Improvement in American College of Rheumatology Criteria (ACR20) at Week 12 Superiority Comparison With Placebo
Time Frame: Week 12
ACR20 is calculated as a 20% improvement from Baseline in Tender Joint Count 68 (TJC68) and Swollen Joint Count 66 (SJC66) and a 20% improvement in 3 of the following 5 measures: Patient's Global Assessment of Arthritis Disease Activity (PtGA) \[visual analogue scale (VAS) with values from 0=best to 100=worst\], Physician Global Assessment of Arthritis Disease Activity (PhGA) (VAS with values from 0=best to 100=worst), Patient Assessment of Arthritis Pain (VAS with values from 0=no pain and 100=most severe pain), Health Assessment Questionnaire-Disability Index (HAQ-DI) (ranges from 0 to 3 where 0 = least difficulty and 3 = extreme difficulty) and an acute-phase reactant \[high sensitivity C-reactive Protein milligram per liter (mg/L) (hsCRP)\]. For the purpose of all analyses up to week 12, the placebo arms were pooled into a single placebo arm to primarily serve as a reference for the comparison of active treatment arms.
Secondary Outcomes
- Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12(Baseline (Day 1) and Week 12)
- Percentage of Participants Achieving CDAI Total Score <=10 (CDAI LDA) at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Percentage of Participants Achieving CDAI Total Score <=2.8 (CDAI Remission) at Week 12(Week 12)
- Percentage of Participants Achieving 20% Improvement in ACR20 at Week 24 (Non-Inferiority Versus Tofacitinib)(Week 24)
- Percentage of Participants Achieving Clinical Disease Activity Index (CDAI) Total Score Less Than or Equal to (<=)10 [CDAI Low Disease Activity (LDA)] at Week 12(Week 12)
- Percentage of Participants Achieving 50%/70% Improvement in American College of Rheumatology Criteria (ACR50/70) at Week 24 and ACR 20/50/70 at and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Percentage of Participants Achieving CDAI Total Score <=10 (CDAI LDA) at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Percentage of Participants Achieving CDAI Total Score <=2.8 (CDAI Remission) at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Percentage of Participants Achieving CDAI Total Score <=2.8 (CDAI Remission) at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Percentage of Participants Achieving ACR20/50/70 at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Percentage of Participants Achieving 50%/70% Improvement in American College of Rheumatology Criteria (ACR50/70) at Week 12(Week 12)
- Percentage of Participants Achieving Disease Activity Score Using 28 Joint Count and C-Reactive Protein (DAS28-CRP) <=3.2 (DAS28-CRP LDA) at Week 12(Week 12)
- Percentage of Participants Achieving DAS28 Erythrocyte Sedimentation Rate (ESR) <=3.2 (DAS28-ESR LDA) at Week 12(Week 12)
- Percentage of Participants Achieving DAS28-CRP <=3.2 (DAS28-CRP LDA) at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Percentage of Participants Achieving DAS28-ESR <=3.2 (DAS28-ESR LDA) at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Percentage of Participants Achieving DAS28-CRP <=3.2 (DAS28-CRP LDA) at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Percentage of Participants Achieving DAS28-ESR <=3.2 (DAS28-ESR LDA) at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Percentage of Participants Achieving DAS28-CRP <2.6 (DAS28-CRP Remission) at Week 12(Week 12)
- Percentage of Participants Achieving DAS28 ESR <2.6 (DAS28-ESR Remission) at Week 12(Week 12)
- Percentage of Participants Achieving DAS28-CRP <2.6 (DAS28-CRP Remission) at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Change From Baseline in SF-36 MCS at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in SF-36 Domain Scores at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Day 1), Week 24 and Week 52)
- Percentage of Participants Achieving DAS28 ESR <2.6 (DAS28-ESR Remission) at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Percentage of Participants Achieving DAS28-CRP <2.6 (DAS28-CRP Remission) at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Number of Participants Achieving ACR/EULAR Remission at Week 12(Week 12)
- Change From Baseline in DAS28-CRP/DAS28-ESR at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in DAS28-CRP/DAS28-ESR at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Percentage of Participants Achieving DAS28 ESR <2.6 (DAS28-ESR Remission) at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Percentage of Participants Achieving a Good/Moderate (European League Against Rheumatism) EULAR Response at Week 12(Week 12)
- Percentage of Participants Achieving a Good/Moderate EULAR Response at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Percentage of Participants Achieving a Good/Moderate EULAR Response at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Number of Participants Achieving ACR/EULAR Remission at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Number of Participants Achieving ACR/EULAR Remission at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Percentage of Participants Achieving no Radiographic Progression (Van Der Heijde Modified Total Sharp Scores (mTSS <= 0.5) at Week 12(Week 12)
- Change From Baseline in CDAI Total Score at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in CDAI Total Score at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in CDAI Total Score at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Van Der Heijde mTSS at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Day 1), Week 24 and Week 52)
- Percentage of Participants Achieving no Radiographic Progression (mTSS <= 0.5) at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Week 24 and Week 52)
- Percentage of Participants Achieving no Radiographic Progression (mTSS <= 0.5) at Week 24 and Week 52 for Placebo Switched Arms(Week 24 and Week 52)
- Change From Baseline in Arthritis Pain VAS at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in SF-36 Domain Scores at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in SF-36 PCS at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in SF-36 PCS at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in DAS28-CRP/DAS28-ESR at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Van Der Heijde mTSS at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in Van Der Heijde mTSS at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in HAQ-DI at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in HAQ-DI at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Arthritis Pain VAS at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in Arthritis Pain VAS at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in SF-36 Mental Component Scores (MCS) at Week 12(Baseline (Day 1) and Week 12)
- Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI)(Up to Week 59)
- Change From Baseline in Short Form (SF)-36 Physical Component Scores (PCS) at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in White Blood Cell (WBC) Count at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in WBC Count at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Clinical Chemistry Parameter of Albumin at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in SF-36 Domain Scores at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in FACIT-Fatigue at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in WBC Count at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Week 12), Week 24 and Week 52)
- Change From Baseline in Hematology Parameter of Platelet Count, Neutrophils, Lymphocytes at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Hematology Parameter of Platelet Count, Neutrophils, Lymphocytes at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Week 12), Week 24 and Week 52)
- Change From Baseline in Hematology Parameter of Hemoglobin at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in SF-36 MCS at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Hematology Parameter of Platelet Count, Neutrophils, Lymphocytes at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in Hematology Parameter of Hemoglobin at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in FACIT-Fatigue at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Day 1), Week 24 and Week 52)
- Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESI) for Placebo Switched Arms(Up to Week 59)
- Change From Baseline in Hematology Parameter of Hemoglobin at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Week 12), Week 24 and Week 52)
- Change From Baseline in Clinical Chemistry Parameter of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Alkaline Phosphatase (AP), Gamma-Glutamyl Transpeptidase (GGT) at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in Clinical Chemistry Parameter of AST, ALT, AP, GGT at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Clinical Chemistry Parameter of AST, ALT, AP, GGT at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Week 12), Week 24 and Week 52)
- Change From Baseline in Clinical Chemistry Parameter of Total Bilirubin at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in Clinical Chemistry Parameter of Total Bilirubin at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Clinical Chemistry Parameter of Total Bilirubin at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Week 12), Week 24 and Week 52)
- Change From Baseline in Lipid Profile Parameter of LDL Cholesterol, High-density Lipoprotein-cholesterol at Week 52 for Placebo Switched Arms(Baseline (Day 1) and Week 52)
- Change From Baseline in Clinical Chemistry Parameter of Albumin at Week 24 and Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1), Week 24 and Week 52)
- Change From Baseline in Clinical Chemistry Parameter of Albumin at Week 24 and Week 52 for Placebo Switched Arms(Baseline (Week 12), Week 24 and Week 52)
- Change From Baseline in Lipid Profile Parameter of Total Cholesterol at Week 24 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1) and Week 24)
- Change From Baseline in Lipid Profile Parameter of Total Cholesterol at Week 52 for Placebo Switched Arms(Baseline (Day 1) and Week 52)
- Change From Baseline in Lipid Profile Parameter of LDL Cholesterol, High-density Lipoprotein-cholesterol at Week 24 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1) and Week 24)
- Change From Baseline in Lipid Profile Parameter of LDL Cholesterol, High-density Lipoprotein-cholesterol at Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1) and Week 52)
- Change From Baseline in Lipid Profile Parameter of Total Cholesterol at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in Lipid Profile Parameter of Total Cholesterol at Week 24 for Placebo Switched Arms(Baseline (Day 1) and Week 24)
- Change From Baseline in Lipid Profile Parameter of Total Cholesterol at Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1) and Week 52)
- Change From Baseline in Lipid Profile Parameter of LDL Cholesterol, High-density Lipoprotein-cholesterol at Week 24 for Placebo Switched Arms(Baseline (Day 1) and Week 24)
- Change From Baseline in Lipid Profile Parameter of Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein-cholesterol at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in Lipid Profile Parameter of Triglycerides at Week 12(Baseline (Day 1) and Week 12)
- Change From Baseline in Lipid Profile Parameter of Triglycerides at Week 24 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1) and Week 24)
- Change From Baseline in Lipid Profile Parameter of Triglycerides at Week 24 for Placebo Switched Arms(Baseline (Day 1) and Week 24)
- Change From Baseline in Lipid Profile Parameter of Triglycerides at Week 52 for Treatment Arms Who Started Study Intervention From Day 1(Baseline (Day 1) and Week 52)
- Number of Participants With National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) >=Grade 3 Hematological/Clinical Chemistry Abnormalities(Up to Week 59)
- Change From Baseline in Lipid Profile Parameter of Triglycerides at Week 52 for Placebo Switched Arms(Baseline (Day 1) and Week 52)
- Number of Participants With National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) >=Grade 3 Hematological/Clinical Chemistry Abnormalities for Placebo Switched Arms(Up to Week 59)
- Concentrations of Granulocyte-macrophage Colony Stimulating Factor (GM-CSF) Autoantibody(At baseline)
- Number of Participants With Anti-GSK3196165 Antibodies(Up to Week 59)