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.
OBJECTIVE: We undertook this phase III study to evaluate baricitinib, an orally administered JAK-1/JAK-2 inhibitor, as monotherapy or combined with methotrexate (MTX) compared to MTX monotherapy in patients with active rheumatoid arthritis (RA) who had received no or minimal conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and who were naive to biologic DMARDs.
METHODS: A total of 588 patients were randomized 4:3:4 to receive MTX monotherapy (once weekly), baricitinib monotherapy (4 mg once daily), or the combination of baricitinib and MTX for 52 weeks. The primary end point assessment was a noninferiority comparison of baricitinib monotherapy to MTX monotherapy based on the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 24.
RESULTS: The study met its primary objective. Moreover, baricitinib monotherapy was found to be superior to MTX monotherapy at week 24, with a higher ACR20 response rate (77% versus 62%; P ≤ 0.01). Similar results were observed for combination therapy. Compared to MTX monotherapy, significant improvements in disease activity and physical function were observed for both baricitinib groups as early as week 1. Radiographic progression was reduced in both baricitinib groups compared to MTX monotherapy; the difference was statistically significant for baricitinib plus MTX. The rates of serious adverse events (AEs) were similar across treatment groups, while rates of some treatment-emergent AEs, including infections, were increased with baricitinib plus MTX. Three deaths were reported, all occurring in the MTX monotherapy group. Malignancies, including nonmelanoma skin cancer, were reported in 1 patient receiving MTX monotherapy, 1 receiving baricitinib monotherapy, and 4 receiving baricitinib plus MTX.
CONCLUSION: Baricitinib alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX monotherapy as initial therapy for patients with active RA.
OBJECTIVES: To compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response.
METHODS: MONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24.
RESULTS: Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (-3.28 vs -2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences.
CONCLUSIONS: Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects.
TRIAL REGISTRATION NUMBER: NCT02332590.
OBJECTIVES: The efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, has not previously been evaluated in a population consisting exclusively of patients with early rheumatoid arthritis (RA).
METHODS: In a double-blind randomised controlled trial (FUNCTION), 1162 methotrexate (MTX)-naive patients with early progressive RA were randomly assigned (1:1:1:1) to one of four treatment groups: 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo and placebo+MTX (comparator group). The primary outcome was remission according to Disease Activity Score using 28 joints (DAS28-erythrocyte sedimentation rate (ESR) <2.6) at week 24. Radiographic and physical function outcomes were also evaluated. We report results through week 52.
RESULTS: The intent-to-treat population included 1157 patients. Significantly more patients receiving 8 mg/kg TCZ+MTX and 8 mg/kg TCZ+placebo than receiving placebo+MTX achieved DAS28-ESR remission at week 24 (45% and 39% vs 15%; p<0.0001). The 8 mg/kg TCZ+MTX group also achieved significantly greater improvement in radiographic disease progression and physical function at week 52 than did patients treated with placebo+MTX (mean change from baseline in van der Heijde-modified total Sharp score, 0.08 vs 1.14 (p=0.0001); mean reduction in Health Assessment Disability Index, -0.81 vs -0.64 (p=0.0024)). In addition, the 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX groups demonstrated clinical efficacy that was at least as effective as MTX for these key secondary endpoints. Serious adverse events were similar among treatment groups. Adverse events resulting in premature withdrawal occurred in 20% of patients in the 8 mg/kg TCZ+MTX group.
CONCLUSIONS: TCZ is effective in combination with MTX and as monotherapy for the treatment of patients with early RA.
TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT01007435.
OBJECTIVES: To compare patient-reported outcomes (PROs) in methotrexate (MTX)-naive patients (defined as no prior treatment or ≤3 doses) receiving tofacitinib versus MTX.
METHODS: In the 24-month, phase III, randomised, controlled, ORAL Start trial (NCT01039688), patients were randomised 2:2:1 to receive tofacitinib 5 mg two times per day (n=373), tofacitinib 10 mg two times per day (n=397) or MTX (n=186). PROs assessed included Patient Global Assessment of disease (PtGA), pain, Health Assessment Questionnaire-Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and health-related quality of life (Short Form-36 [SF-36]).
RESULTS: PROs improved following tofacitinib and MTX treatment: benefits were sustained over 24 months. Patients receiving tofacitinib reported earlier responses which were significantly different between each tofacitinib dose and MTX at month 3 through month 24. At month 6 (primary end point), significant improvements versus MTX were observed in PtGA, pain, HAQ-DI, SF-36 Physical Component Summary (PCS), 5/8 domain scores and FACIT-F with tofacitinib 5 mg two times per day; all PROs, except SF-36 Mental Component Summary Score and Medical Outcomes Survey-Sleep, with tofacitinib 10 mg two times per day. At month 6, the proportion of patients reporting improvements ≥minimum clinically important difference were significant versus MTX with tofacitinib 5 mg two times per day in PtGA and 3/8 SF-36 domains; and with tofacitinib 10 mg two times per day in PtGA, pain, HAQ-DI, SF-36 PCS, 4/8 domains and FACIT-F.
CONCLUSIONS: Patients with rheumatoid arthritis receiving tofacitinib 5 and 10 mg two times per day monotherapy versus MTX reported statistically significant and clinically meaningful improvements in multiple PROs over 24 months; onset of benefit with tofacitinib treatment occurred earlier.
TRIAL REGISTRATION NUMBER: NCT01039688.
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.
