Rheumatoid Arthritis
Conditions
Brief summary
Primary Objective: \- To demonstrate that sarilumab (SAR153191/REGN88) on top of methotrexate (MTX) was superior in efficacy to placebo for the relief of signs and symptoms of rheumatoid arthritis (RA), in participants with active RA who had failed up to 2 tumor necrosis factor-alpha (TNF-α) antagonists. Secondary Objectives: * To assess the safety of sarilumab; * To document the pharmacokinetic profile of sarilumab.
Detailed description
The duration of the study period for each participant was approximately 22 weeks; including up to 4 weeks screening period, 12-week double-blind treatment period and 6-week safety follow-up period. Participants who completed the 12-week treatment period were offered enrollment in a separate long-term extension study (LTS11210/NCT01146652).
Interventions
DRUGSarilumab
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGPlacebo
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGGolimumab
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGmethotrexate (MTX)
Pharmaceutical form: tablet or solution for injection Route of administration: Oral (tablet) or subcutaneous, intramuscular (solution)
Pharmaceutical form: tablet Route of administration: oral Folic/folinic acid continued according to local standard.
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of rheumatoid arthritis ≥6 months duration and American College of Rheumatology (ACR) Class I-III functional status at screening and baseline visits; * Active disease defined as: * At least 6 of 68 tender joints and 6 of 66 swollen joints at screening and baseline visits, and * hs-C-Reactive Protein (hs-CRP) \>10 g/L or Erythrocyte Sedimentation Rate (ESR) \>28 mm/hr at screening visit; * Continuous treatment with Methotrexate for at least 12 weeks and on stable dose (minimum 10 mg/week) for at least 6 weeks prior to the screening visit; * Participant considered as Primary TNF-α blocker nonresponder. i.e.: * Appropriate for previous TNF-α blocker therapy * Lack of adequate clinical response after at least 3 months TNF-α blocker therapy with MTX or other synthetic disease modifying anti-rheumatic drug (DMARD) co-therapy.
Exclusion criteria
* Age \<18 years or \>75 years; * Pregnant or breastfeeding woman or woman of childbearing potential, unwilling to utilize adequate contraception or not to become pregnant during the entire study; * Fever (\>38°C), or chronic, persistent, or recurring infection(s); * History of demyelinating disease; * Current underlying hepatobiliary disease. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants Who Achieved at Least 20% Improvement in American College of Rheumatology (ACR20) Core Set Disease Activity Index at Week 12 | Week 12 |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Participants Who Achieved at Least 70% Improvement in American College of Rheumatology Core (ACR70) Set Disease Activity Index at Week 12 | Week 12 |
| Disease Activity Score for 28 Joints (DAS28) at Week 12 | Week 12 |
| Percentage of Participants Who Achieved at Least 50% Improvement in American College of Rheumatology (ACR50) Core Set Disease Activity Index at Week 12 | Week 12 |
| Percentage of Participants Achieving DAS28 Remission Score < 2.6 at Week 12 | Week 12 |
| Pharmacokinetic (PK) Parameter: Serum Concentration of Functional and Bound Sarilumab | Week 12 |
| European League Against Rheumatism (EULAR) Response at Week 12 | Week 12 |
Countries
Colombia, Czechia, Italy, Mexico, Spain, United States
Participant flow
Recruitment details
The study was conducted at 10 centers in United States and Europe. A total of 41 participants were screened between 15 November 2010 and 18 May 2011 of whom 16 participants were randomized and 25 were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment details
Participants were randomized 2:1:2 (Sarilumab 150 mg : Placebo : Golimumab 50 mg) via a centralized randomization system using an interactive voice response system stratified by region and number of previous anti-tumor necrosis factor-alpha (TNF-α) therapy.
Participants by arm
| Arm | Count |
|---|---|
| Placebo SC injection of placebo 2 mL qw to match sarilumab and 0.5 mL q4w to match golimumab on top of MTX (15-25 mg) qw for 12 weeks. | 4 |
| Golimumab 50 mg Golimumab 50 mg SC injection q4w and placebo (matched to sarilumab) SC injection qw on top of MTX (15-25 mg) qw for 12 weeks. | 5 |
| Sarilumab 150 mg Sarilumab 150 mg SC injection qw and placebo (matched to golimumab) SC injection q4w on top of MTX (15-25 mg) qw for 12 weeks. | 7 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Golimumab 50 mg | Sarilumab 150 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 45.3 years STANDARD_DEVIATION 17.9 | 62.6 years STANDARD_DEVIATION 7.6 | 54.0 years STANDARD_DEVIATION 11.1 | 54.5 years STANDARD_DEVIATION 13.2 |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 4 | 1 / 5 | 3 / 7 |
| serious Total, serious adverse events | 0 / 4 | 0 / 5 | 0 / 7 |
Outcome results
Primary
Percentage of Participants Who Achieved at Least 20% Improvement in American College of Rheumatology (ACR20) Core Set Disease Activity Index at Week 12
Time frame: Week 12
Population: As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.
Secondary
Disease Activity Score for 28 Joints (DAS28) at Week 12
Time frame: Week 12
Population: As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.
Secondary
European League Against Rheumatism (EULAR) Response at Week 12
Time frame: Week 12
Population: As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.
Secondary
Percentage of Participants Achieving DAS28 Remission Score < 2.6 at Week 12
Time frame: Week 12
Population: As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.
Secondary
Percentage of Participants Who Achieved at Least 50% Improvement in American College of Rheumatology (ACR50) Core Set Disease Activity Index at Week 12
Time frame: Week 12
Population: As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.
Secondary
Percentage of Participants Who Achieved at Least 70% Improvement in American College of Rheumatology Core (ACR70) Set Disease Activity Index at Week 12
Time frame: Week 12
Population: As the number of participants randomized fell well below target (16 vs. 250), the efficacy data were not systematically collected or cleaned and no datasets have been created to report.
Secondary
Pharmacokinetic (PK) Parameter: Serum Concentration of Functional and Bound Sarilumab
Time frame: Week 12
Population: Analysis was performed in PK population of all participants with at least one non-missing serum concentration data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Pharmacokinetic (PK) Parameter: Serum Concentration of Functional and Bound Sarilumab | Bound Concentration | 4271.43 ng/mL | Standard Deviation 1328.86 |
| Placebo | Pharmacokinetic (PK) Parameter: Serum Concentration of Functional and Bound Sarilumab | Functional Concentration | 42391.43 ng/mL | Standard Deviation 26168.68 |