The purpose of this study is to assess the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis (RA) in patients with active RA who are unresponsive or intolerant to treatment with anti-TNF-alpha agents.
INTERVENTION: Product Name: Sirukumab Product Code: CNTO136 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: Sirukumab Current Sponsor code: CNTO 136 Other descriptive name: Human anti‐IL6 monoclonal antibody Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 50 ‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Product Name: Sirukumab Product Code: CNTO136 Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: Sirukumab Current Sponsor code: CNTO136 Other descriptive name: Human anti‐IL6 monoclonal antibody Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use CONDITION: Rheumatoid Arthritis ; MedDRA version: 17.0 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Immune System Diseases [C20] PRIMARY OUTCOME: Main Objective: The primary objective is to assess the efficacy of sirukumab as measured by the reduction of the signs and symptoms of RA in subjects with active RA who are refractory to an anti‐TNF alpha agent. Primary end point(s): Proportion of patients with an ACR 20 response Secondary Objective: The secondary objectives are to assess the following for sirukumab in subjects with active RA who are refractory to anti‐TNF alpha agents: ; ‐Safety ; ‐Physical function; ‐Population pharmacokinetics; ‐Immunogenicity; ‐Pharmacodynamics ; Timepoint(s) of evaluation of this end point: Week 16 SECONDARY OUTCOME: Secondary end point(s): 1. Change from baseline in HAQ‐DI ; 2. Proportion of patients with an ACR 50 response ; 3. Proportion of patients with DAS28 (CRP) remission ; 4. Pharmacogenetics (deoxyribonucleic acid [DNA]) Evaluations ; 5. Health economics avaluations ; 6. Plasma concentrations of Sirukumab Timepoint(s) of evaluation of this end point: 1. Week 24 ; 2. Week 24 ; 3. Week 24 ; 4. Week 0 ; 5. 52 weeks ; 6. 52 weeks INCLUSION CRITERIA: ‐ Have a diagnosis of rheumatoid arthritis (RA) for at least 3 months before screening ‐ Have moderately to severely active RA with at least 4 of 68 tender joints and 4 of 66 swollen joints, at screening and at baseline ‐ Have had anti‐tumor necrosis factor (TNF)‐alpha therapy and were unresponsive by 1 of the following 2 reasons: Lack of benefit to at least 1 anti‐TNF‐alpha biologic therapy, as assessed by the treating physician, after at least 12 weeks of etanercept, yisaipu, adalimumab, golimumab, or certolizumab pegol therapy and/or at least a 14‐week dosage regimen (ie, at least 4 doses) of infliximab; Intolerance to at least 2 anti‐TNF‐alpha biologic therapies, as assessed by the treating physician, to etanercept, yisaipu, adalimumab, golimumab, certolizumab pegol, or infliximab or have documented intolerance to an anti‐TNF‐alpha agent as described above that precludes further administration of anti‐TNF‐alpha agents ‐ If using oral corticostero
BACKGROUND: Sirukumab, a human monoclonal antibody that selectively binds to the interleukin-6 cytokine with high affinity, is under development for the treatment of rheumatoid arthritis and other diseases. We aimed to assess the efficacy and safety of sirukumab for rheumatoid arthritis in a phase 3 study (SIRROUND-T).
METHODS: We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre study at 183 hospitals and private rheumatology clinics in 20 countries (Argentina, Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Lithuania, Mexico, Netherlands, Poland, Portugal, Russia, South Korea, Spain, Taiwan, UK, and USA). Eligible participants were patients with active rheumatoid arthritis aged at least 18 years, with four or more of 68 tender joints and four or more of 66 swollen joints, who were refractory or intolerant to previous treatment with at least one anti-TNF drug. We randomly assigned patients (1:1:1) via a central interactive voice or web response system to either placebo every 2 weeks, 50 mg sirukumab every 4 weeks, or 100 mg sirukumab every 2 weeks, all given for 52 weeks or less. We allowed participants to continue using any concomitant disease-modifying antirheumatic drugs (DMARDs). We based the randomisation on a computer-generated, permuted-block schedule stratified by use of methotrexate at baseline (0, >0 to <12·5 mg/week, or ≥12·5 mg/week). Masking was achieved with the use of multipart labels on the study drug containers which contained directions for use and other information, but not the drug's identity. Treatments were administered by subcutaneous injection; patients assigned to 50 mg sirukumab given every 4 weeks also received a placebo injection every 2 weeks to maintain masking. At week 18, placebo-treated patients meeting early escape criteria (<20% improvement in swollen and tender joint counts) were randomly reassigned to either 50 mg or 100 mg of sirukumab. All remaining placebo-treated patients were subsequently randomly reassigned at week 24 to either sirukumab dose (crossover). The primary outcome was the proportion of patients who achieved a response of at least 20% improvement at week 16 according to American College of Rheumatology criteria (ACR20) in the intention-to-treat population (all randomly assigned participants). Safety analyses included all participants who received at least one dose (partial or complete) of study drug. This study is registered at EudraCT (number: 2010-022243-38) and ClinicalTrials.gov (number: NCT01606761).
FINDINGS: Between July 25, 2012, and Jan 12, 2016, we randomly assigned 878 patients to treatment: 294 to placebo, 292 to 50 mg sirukumab every 4 weeks, and 292 to 100 mg sirukumab every 2 weeks. 523 (60%) of 878 patients had previously received two or more biological treatments including non-TNF drugs, and 166 (19%) of 878 were not taking a DMARD at baseline. The proportions of patients who achieved an ACR20 response at week 16 were 117 (40%) of 292 with 50 mg sirukumab every 4 weeks, and 132 (45%) of 292 with 100 mg sirukumab every 2 weeks versus 71 (24%) of 294 with placebo; differences compared with placebo were 0·16 (95% CI 0·09-0·23) for 50 mg sirukumab every 4 weeks and 0·21 (0·14-0·29) for 100 mg sirukumab every 2 weeks (both p<0·0001). Adverse event incidences in the 24-week placebo-controlled period were similar across groups (at least one event occurred for 182 patients assigned to placebo [62%, including early escape patients switched to sirukumab at week 18] of 294; 194 [66%] of 292 with 50 mg sirukumab every 4 weeks; and 207 [71%] of 292 with 100 mg sirukumab every 2 weeks). The most common adverse events in this period were injection-site erythema (four [1%] with placebo, 22 [8%] with 50 mg sirukumab every 4 weeks, and 41 [14%] with 100 mg sirukumab every 2 weeks). At week 52, of all patients receiving sirukumab including those reassigned from placebo, the most common adverse events were again injection-site erythema (33 [8%] of 416 with 50 mg sirukumab every 4 weeks and 66 [16%] of 418 with 100 mg sirukumab every 2 weeks).
INTERPRETATION: In patients with active rheumatoid arthritis who were refractory or intolerant to anti-TNF drugs and other biological treatments, both dosing regimens of sirukumab were well tolerated and significantly improved signs and symptoms of the disease, compared with placebo, in this difficult-to-treat population.
FUNDING: Janssen Research & Development, LLC, and GlaxoSmithKline.
The purpose of this study is to assess the efficacy of sirukumab as measured by the reduction of the signs and symptoms of rheumatoid arthritis (RA) in patients with active RA who are unresponsive or intolerant to treatment with anti-TNF-alpha agents.
