A 24-week, Phase 3, Multicentre, Randomised, Double-blind, Efficacy and Safety Study, Comparing GSK3196165 With Placebo and With Sarilumab, in Combination With Conventional Synthetic DMARDs, in Participants With Moderately to Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Biological DMARDs and/or Janus Kinase Inhibitors

Official Summary

This study (contRAst 3 \[202018: NCT04134728\]) is a Phase 3, randomized, multicenter, double-blind study to assess the safety and efficacy of GSK3196165 in combination with conventional (cs) DMARD\[s\]) or the treatment of adult participants with moderate to severe active rheumatoid arthritis (RA) who have had an inadequate response to biologic (b) DMARD\[s\]) and/or JAK inhibitors. The study will consist of a screening phase of up to 6 weeks followed by 24 week treatment phase in which participants will be randomized in ratio of 6:6:6:1:1:1 to GSK3196165 150 milligrams (mg) subcutaneously (SC) weekly,GSK3196165 90 mg SC weekly, sarilumab 200 mg SC every other week or placebo (three arms) respectively, all in combination with background csDMARD(s). At Week 12, participants in the three placebo arms will switch from placebo to active intervention (either GSK3196165 150 mg SC weekly, GSK3196165 90 mg SC weekly, or sarilumab 200 mg SC every other week). Participants who, in investigator's judgement will benefit from extended treatment with GSK3196165, may be included in the long-term extension study (contRAst X \[209564: NCT04333147\]). Any participant who does not transition into study 209564 will undergo a safety follow-up visit at Week 34 (corresponding to 12 weeks after the last potential dose of sarilumab, at Week 22).

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: TRIPLE
• Enrollment: 550 participants

Study Arms

• GSK3196165 90 mg (EXPERIMENTAL)
  Entire treatment period (24 Weeks): GSK3196165 90 mg SC injection once weekly. Participants will also receive a stable dose of csDMARD(s) as standard of care (SoC).
• GSK3196165 150 mg (EXPERIMENTAL)
  Entire treatment period (24 Weeks): GSK3196165 150 mg SC injection once weekly. Participants will also receive a stable dose of csDMARD(s) as SoC.
• Sarilumab 200 mg (ACTIVE_COMPARATOR)
  Entire treatment period (24 Weeks): Sarilumab 200 mg SC injection every other week + placebo SC injection in the intervening weeks. Participants will also receive a stable dose of csDMARD(s) as SoC.
• Placebo sequence 1 (PLACEBO_COMPARATOR)
  From Week 0-11: Placebo SC injection once weekly. From Week 12 onwards: GSK3196165 90 mg SC injection once weekly. Participants will also receive a stable dose of csDMARD(s) as SoC.
• Placebo sequence 2 (PLACEBO_COMPARATOR)
  From Week 0-11: Placebo SC injection once weekly. From Week 12 onwards: GSK3196165 150 mg SC injection once weekly. Participants will also receive a stable dose of csDMARD(s) as SoC.
• Placebo sequence 3 (PLACEBO_COMPARATOR)
  From Week 0-11: Placebo SC injection once weekly. From Week 12 onwards: Sarilumab 200 mg SC injection every other week + placebo SC injection in the intervening weeks. Participants will also receive a stable dose of csDMARD(s) as SoC.

Interventions

• BIOLOGICAL: GSK3196165 (Otilimab) — GSK3196165 solution in vial/pre-filled syringe (PFS) to be administered SC.
• BIOLOGICAL: Sarilumab — Sarilumab solution in PFS to be administered SC.
• DRUG: Placebo to GSK3196165/ Sarilumab — Placebo sterile 0.9 percentage (%) weight by volume (w/v) sodium chloride solution in vial/PFS to be administered SC.
• DRUG: csDMARDs — Stable dose of csDMARD(s) as SoC.

Primary Outcomes

• Percentage of Participants With 20% Improvement in American College of Rheumatology Criteria (ACR20) at Week 12 Superiority Comparison With Placebo (Week 12)

Secondary Outcomes

• Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) (Versus Placebo) at Week 12 (Baseline (Day 01) and Week 12)
• Percentage of Participants With Clinical Disease Activity Index (CDAI) Total Score <=10 (CDAI Low Disease Activity [LDA]) at Week 12 (Week 12)
• Percentage of Participants With CDAI Total Score <=10 (CDAI LDA) at Week 24 for Treatment Arms That Started Study Intervention From Day 1 (Week 24)
• Percentage of Participants With CDAI Total Score <=10 (CDAI LDA) at Week 24 for Placebo Switched Arms That Started Study Intervention From Week 12 (Week 24)
• Change From Baseline in CDAI Total Score at Week 12 (Baseline (Day 01) and Week 12)

Eligibility Criteria

Key inclusion criteria:

* \>=18 years of age
* Has had RA for \>=6 months and was not diagnosed before 16 years of age
* Has active disease, as defined by having both:\*

  * \>=6/68 tender/painful joints (tender joint count \[TJC\]), and
  * \>=6/66 swollen joints (swollen joint count \[SJC\])
* Has had an inadequate response despite currently taking at least one and at the most two concomitant csDMARDs for at least 12 weeks, from the following:

  * Methotrexate (MTX)
  * Hydroxychloroquine or chloroquine
  * Sulfasalazine
  * Leflunomide
  * Bucillamine
  * Iguratimod
  * Tacrolimus
* Has had inadequate response to at least one bDMARD at an approved dose and/or at least one JAK inhibitors at an approved dose. In both cases this may be with or without combination with a csDMARD.

  * If surgical treatment of a joint has been performed, that joint cannot be counted in the TJC or SJC.

Key exclusion criteria:

* Has had any active and/or recurrent infections (excluding recurrent fungal infections of the nail bed) or has required management of acute or chronic infections.
* Has received prior treatment with an antagonist of GM-CSF or its receptor.
* Has known infection with human immunodeficiency virus (HIV) or current acute or chronic hepatitis B and/or hepatitis C.

Trial Locations

• GSK Investigational Site, Mesa, Arizona, United States
• GSK Investigational Site, Phoenix, Arizona, United States
• GSK Investigational Site, Sun City, Arizona, United States
• GSK Investigational Site, Tucson, Arizona, United States
• GSK Investigational Site, Covina, California, United States
• GSK Investigational Site, San Diego, California, United States
• GSK Investigational Site, Tujunga, California, United States
• GSK Investigational Site, Upland, California, United States
• GSK Investigational Site, Whittier, California, United States
• GSK Investigational Site, Brandon, Florida, United States
• ...and 10 more locations

Study Officials

• GSK Clinical Trials — STUDY_DIRECTOR
  GlaxoSmithKline

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