Rheumatoid Arthritis
Conditions
Brief summary
Primary Objective: To demonstrate the treatment effect of sarilumab and methotrexate (MTX) compared to etanercept and MTX in participants with rheumatoid arthritis (RA) and an inadequate response to adalimumab and MTX by evaluation of the Disease Activity Score for 28 joints (DAS28). Secondary Objectives: To assess the signs and symptoms of RA in participants taking sarilumab in combination with MTX. To assess the quality of life of participants with RA taking sarilumab in combination with MTX. To assess the safety and tolerability of sarilumab in combination with MTX in participants with RA.
Detailed description
The maximum study duration per participant enrolled in the open label run-in phase and was eligible to enroll in the randomized phase of main study was 54 weeks: * open label screening period of up to 4 weeks * open-label treatment period of 16 weeks * randomized screening period of 2 to 4 weeks * randomized treatment post-treatment safety follow-up period of 6 weeks. The maximum study duration per participant enrolled only in the open label run-in phase and was not eligible to enroll in the randomized phase of main study was 26 weeks: * open label screening period of up to 4 weeks * open-label treatment period of 16 weeks * open label treatment post-treatment safety follow-up period of 6 weeks. The maximum study duration per participant enrolled in the open label run-in phase and was eligible to enroll in the sarilumab sub-study was 82 weeks: * open label screening period of up to 4 weeks * open-label treatment period of 16 weeks * screening period of 2 to 4 weeks * sarilumab treatment period of 52 weeks * sub-study post-treatment safety follow-up period of 6 weeks.
Interventions
DRUGSarilumab
Pharmaceutical form: Solution for injection in pre-filled syringe; Route of administration: Subcutaneous
DRUGEtanercept
Pharmaceutical form: Solution for injection in pre-filled syringe; Route of administration: Subcutaneous
DRUGMethotrexate
Dispensed according to local practice.
DRUGPlacebo (for etanercept)
DRUGAdalimumab
Pharmaceutical form: Solution for injection in pre-filled syringe; Route of administration: Subcutaneous
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of RA \>/= 3 months duration. * Continuous treatment of MTX 10 - 25 mg/week (or per local labeling requirements if the dose range differs) for at least 12 weeks before screening visit and on a stable dose for 8 weeks before screening visit. * Active disease defined as: at least 6/66 swollen and 8/68 tender joints and high sensitivity C-reactive protein \> 10 mg/L.
Exclusion criteria
* Age \< 18 years. * Use of parenteral corticosteroids or intra-articular corticosteroids within 4 weeks of the screening visit. * Use of oral corticosteroids in a dose higher than prednisone 10 mg or equivalent per day, or a change in dosage within 4 weeks of the screening visit. * Prior treatment with a tumor necrosis factor (TNF)-alpha inhibitor, or other biological disease modifying anti-rheumatoid drug (DMARD) or Janus Kinase inhibitor. * New treatment with or dose-adjustment of on-going nonsteroidal anti-inflammatory drugs (NSAIDs) or cyclo-oxygenase-2 (COX-2) inhibitors within 4 weeks of the screening visit. * Treatment with traditional oral DMARD /immunosuppressive agents other than MTX within 4 weeks or 12 weeks before the screening visit, depending on DMARD. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Disease Activity Score for 28 Joints - C-Reactive Protein (DAS28-CRP) Score at Week 24 | Baseline, Week 24 |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With at Least 20% Improvement in American College of Rheumatology (ACR20), at Least 50% Improvement in ACR (ACR50) and at Least 70% Improvement in ACR (ACR70) Efficacy Response Rates at Week 12 and Week 24 | Week 12 and Week 24 |
| Percentage of Participants Achieving Clinical Remission Score (DAS28-CRP) <2.6 at Week 12 and Week 24 | Week 12 and Week 24 |
| Change From Baseline in DAS28-CRP Score at Week 12 | Baseline, Week 12 |
Countries
Argentina, Australia, Brazil, Chile, Colombia, Czechia, Ecuador, Finland, France, Germany, Greece, Hungary, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, New Zealand, Peru, Poland, Romania, Russia, South Africa, South Korea, Spain, Taiwan, Thailand, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 228 sites in 31 countries. A total of 1949 participants were screened between 09 May 2013 and 07 Aug 2014 of which 1173 participants were screen failures and a total of 776 participants entered in the adalimumab run-in phase of the study.
Pre-assignment details
Of 776 participants, 365 completed adalimumab run-in phase, of whom 43 non-responders randomized (1:1:1) in double-blind fashion to receive sarilumab 150 mg, sarilumab 200 mg or etanercept 50 mg; 322 responders entered in open label sub-study. 373 participants did not proceed into randomized phase or sub-study and 38 discontinued from run-in phase.
Participants by arm
| Arm | Count |
|---|---|
| Adalimumab Open Label run-in Treatment Only Adalimumab 40 mg SC injection Q2W for 16 weeks added to stable dose of MTX during run-in period. Participants who were not randomized in the main study or did not enter the sub-study were included in this arm for safety assessment. | 411 |
| Etanercept + MTX (Randomized) Etanercept 50 mg SC injection in combination with Placebo for sarilumab Q2W and etanercept 50 mg SC injection on alternating weeks for 24 weeks added to stable dose of MTX. | 17 |
| Sarilumab 150 mg + MTX (Randomized) Sarilumab 150 mg SC injection in combination with placebo for etanercept Q2W and placebo for etanercept on alternating weeks for 24 weeks added to stable dose of MTX. | 13 |
| Sarilumab 200 mg + MTX (Randomized) Sarilumab 200 mg SC injection in combination with placebo for etanercept Q2W and placebo for etanercept on alternating weeks for 24 weeks added to stable dose of MTX. | 13 |
| Sarilumab 150 mg + MTX Open Label Sub-study Sarilumab 150 mg SC injection Q2W for 52 weeks added to stable dose of MTX. | 322 |
| Total | 776 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Run-in Period | Adverse Event | 15 | 0 | 0 | 0 | 0 |
| Run-in Period | Lack of Efficacy | 5 | 0 | 0 | 0 | 0 |
| Run-in Period | Other than specified above | 17 | 0 | 0 | 0 | 0 |
| Run-in Period | Poor compliance to protocol | 1 | 0 | 0 | 0 | 0 |
| Study Drug Treatment Period | Adverse Event | 0 | 1 | 0 | 0 | 24 |
| Study Drug Treatment Period | Lack of Efficacy | 0 | 0 | 0 | 0 | 2 |
| Study Drug Treatment Period | Other than specified above | 0 | 0 | 0 | 0 | 10 |
Baseline characteristics
| Characteristic | Sarilumab 150 mg + MTX (Randomized) | Sarilumab 200 mg + MTX (Randomized) | Adalimumab Open Label run-in Treatment Only | Etanercept + MTX (Randomized) | Sarilumab 150 mg + MTX Open Label Sub-study | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 51 Participants | 3 Participants | 48 Participants | 108 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 10 Participants | 360 Participants | 14 Participants | 274 Participants | 668 Participants |
| Sex: Female, Male Female | 10 Participants | 9 Participants | 342 Participants | 15 Participants | 261 Participants | 637 Participants |
| Sex: Female, Male Male | 3 Participants | 4 Participants | 69 Participants | 2 Participants | 61 Participants | 139 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 132 / 776 | 7 / 17 | 7 / 13 | 8 / 13 | 104 / 322 |
| serious Total, serious adverse events | 25 / 776 | 2 / 17 | 0 / 13 | 0 / 13 | 11 / 322 |
Outcome results
Primary
Change From Baseline in Disease Activity Score for 28 Joints - C-Reactive Protein (DAS28-CRP) Score at Week 24
Time frame: Baseline, Week 24
Population: As the number of participants randomized fell well below target (43 vs. 699), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.
Secondary
Change From Baseline in DAS28-CRP Score at Week 12
Time frame: Baseline, Week 12
Population: As the number of participants randomized fell well below target (43 vs. 699), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.
Secondary
Number of Participants With at Least 20% Improvement in American College of Rheumatology (ACR20), at Least 50% Improvement in ACR (ACR50) and at Least 70% Improvement in ACR (ACR70) Efficacy Response Rates at Week 12 and Week 24
Time frame: Week 12 and Week 24
Population: As the number of participants randomized fell well below target (43 vs. 699), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.
Secondary
Percentage of Participants Achieving Clinical Remission Score (DAS28-CRP) <2.6 at Week 12 and Week 24
Time frame: Week 12 and Week 24
Population: As the number of participants randomized fell well below target (43 vs. 699), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.