Rheumatoid Arthritis
Conditions
Brief summary
Primary Objective: To assess, in the same study, the safety of sarilumab and tocilizumab in participants with rheumatoid arthritis (RA) who were inadequate responders to or intolerant of tumor necrosis factor (TNF) antagonists.
Detailed description
Total study duration was up to 34 weeks: Screening up to 28 days, treatment phase of 24 weeks, and post-treatment follow-up of 6 weeks. After completion of the treatment phase of this study, participants were eligible to enter a long term safety study (LTS11210) for active treatment with SAR153191 (REGN88).
Interventions
Pharmaceutical form: solution Route of administration: subcutaneous
DRUGtocilizumab
Pharmaceutical form: solution Route of administration: intravenous
DRUGhydroxychloroquine
Dispensed according to local practice.
DRUGmethotrexate
Dispensed according to local practice.
DRUGsulfasalazine
Dispensed according to local practice.
DRUGleflunomide
Dispensed according to local practice.
Pharmaceutical form: solution Route of administration: subcutaneous
DRUGintravenous placebo
Pharmaceutical form: solution Route of administration: intravenous
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 was, according to the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) 2010 Rheumatoid Arthritis Classification Criteria with ≥ 3 months disease duration ACR Class I-III functional status, was based on the 1991 revised criteria. Moderate-to-severely active RA. Anti-TNF therapy failures, was defined as participants with an inadequate clinical response was defined by the investigator, after being treated for at least 3 consecutive months, and/or intolerance to at least 1 TNF-antagonist, resulting in or requiring their discontinuation. TNF-antagonists were include, but were not limited to, etanercept, infliximab, adalimumab, golimumab and/or certolizumab pegol Continuous treatment with one or a combination of non-biologic disease modifying antirheumatic drugs (DMARDs) for at least 12 consecutive weeks prior to screening and on a stable dose(s) for at least 6 consecutive weeks prior to screening: * Methotrexate - 10 to 25 milligram/week orally or parenteral (or per local labelling requirements if the dose range differs) * Leflunomide - 10 to 20 mg orally daily * Sulfasalazine (SSZ) - 1000 to 3000 mg orally daily * Hydroxychloroquine (HCQ) - 200 to 400 mg orally daily
Exclusion criteria
Participants \<18 years of age. Use of parenteral corticosteroids or intra-articular corticosteroids within 4 weeks prior to screening Use of oral corticosteroids in a dose higher than prednisone 10 mg or equivalent per day, or a change in dosage within 4 weeks prior to screening Past history of, or current, autoimmune or inflammatory systemic or localized joint disease(s) other than RA History of juvenile idiopathic arthritis or arthritis onset prior to age 16. Severe systemic RA, including but not limited to vasculitis, pulmonary fibrosis, and/or Felty's syndrome Participation in any clinical research study that evaluated an investigational drug or therapy within 5 half-lives or 60 days of the Screening Visit, whichever was longer Participants with active tuberculosis or latent tuberculosis infection. Prior or current history of interstitial lung disease. Prior treatment with anti-interleukin (IL) -6 or anti-IL-6R therapies, including but not limited to tocilizumab or sarilumab Treatment with anti-TNF agents, as follows: * Etanercept: within 28 days prior to randomization * Infliximab, adalimumab, golimumab, certolizumab pegol: within 42 days prior to randomization Treatment with RA-directed biologic agents with non- TNF-α antagonist mechanisms without adequate washout as follows: * Anakinra: within 28 days prior to randomization * Abatacept: within 42 days prior to randomization * Rituximab or other cell depleting agent: Within 6 months prior to randomization or until total lymphocyte count and CD 19+ lymphocyte count were normalized, or whichever was longer Prior treatment with a janus kinase (JAK) inhibitor (eg, tofacitinib). Participants with a history of invasive opportunistic infection. Prior or current history of malignancy, including lymphoproliferative diseases, other than adequately-treated carcinoma in-situ of the cervix, nonmetastatic squamous cell or basal cell carcinoma of the skin, within 5 years prior to the randomization (baseline) visit Prior or current history of other significant concomitant illness(es) that, according to Investigator's judgement, was adversely affect the participant's participation in the study. 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 | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Up to 211 days | Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and does not necessary have to have a causal relationship with treatment. All adverse events that occurred from the first dose of the study drug administration up to 60 days after the end of treatment visit were considered as TEAEs. Serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. A summary of SAEs, all other non-serious AEs, regardless of causality, are reported in AE section. |
Countries
Argentina, Belgium, Brazil, Czechia, Estonia, Finland, Hungary, Israel, Italy, Mexico, Netherlands, Norway, Poland, Romania, Russia, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 78 centers in 19 countries. A total of 389 participants were screened between 25 March 2013 and 02 April 2014, 187 of whom were screen failures. Screen failures were mainly due to failure to meet inclusion and exclusion criteria.
Pre-assignment details
Randomization of participants were stratified by region and screening value of absolute neutrophil count. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in 1:1:2 (sarilumab 150 mg q2w: sarilumab 200 mg q2w: tocilizumab q4w). 202 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Sarilumab 150 mg q2w Sarilumab 150 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD for 24 weeks. | 49 |
| Sarilumab 200 mg q2w Sarilumab 200 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD for 24 weeks. | 51 |
| Tocilizumab q4w Tocilizumab 4 mg/kg or 8 mg/kg IV infusion q4w and placebo SC injection q2w was added to one or a combination of the nonbiologic DMARD for 24 weeks. Dose for tocilizumab could be up-titrated to 8 mg/kg or down-titrated to 4 mg/kg based on clinical response as per Investigator's discretion. | 102 |
| Total | 202 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 8 | 4 |
| Overall Study | Lack of Efficacy | 1 | 3 | 1 |
| Overall Study | Other, Not due to an adverse event | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Sarilumab 150 mg q2w | Sarilumab 200 mg q2w | Tocilizumab q4w | Total |
|---|---|---|---|---|
| Age, Continuous | 54.8 years STANDARD_DEVIATION 12.1 | 51.7 years STANDARD_DEVIATION 13.1 | 50.4 years STANDARD_DEVIATION 13 | 51.8 years STANDARD_DEVIATION 12.8 |
| Disease Activity Score for 28 Joints- C-reactive protein (DAS28-CRP) | 5.85 score on scale STANDARD_DEVIATION 0.92 | 5.88 score on scale STANDARD_DEVIATION 0.97 | 5.91 score on scale STANDARD_DEVIATION 1.01 | 5.89 score on scale STANDARD_DEVIATION 0.97 |
| Duration of rheumatoid arthritis (RA) since diagnosis | 13.59 years STANDARD_DEVIATION 8.24 | 10.45 years STANDARD_DEVIATION 7.57 | 10.84 years STANDARD_DEVIATION 8.91 | 11.41 years STANDARD_DEVIATION 8.48 |
| Health Assessment Questionnaire Disability Index (HAQ-DI) | 1.63 units on a scale STANDARD_DEVIATION 0.66 | 1.71 units on a scale STANDARD_DEVIATION 0.6 | 1.78 units on a scale STANDARD_DEVIATION 0.63 | 1.72 units on a scale STANDARD_DEVIATION 0.63 |
| RA functional class I | 10 participants | 4 participants | 16 participants | 30 participants |
| RA functional class II | 25 participants | 33 participants | 62 participants | 120 participants |
| RA functional class III | 14 participants | 14 participants | 24 participants | 52 participants |
| RA functional class IV | 0 participants | 0 participants | 0 participants | 0 participants |
| Sex: Female, Male Female | 41 Participants | 39 Participants | 82 Participants | 162 Participants |
| Sex: Female, Male Male | 8 Participants | 12 Participants | 20 Participants | 40 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 | 33 / 49 | 36 / 51 | 66 / 102 |
| serious Total, serious adverse events | 1 / 49 | 3 / 51 | 7 / 102 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and does not necessary have to have a causal relationship with treatment. All adverse events that occurred from the first dose of the study drug administration up to 60 days after the end of treatment visit were considered as TEAEs. Serious AE (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. A summary of SAEs, all other non-serious AEs, regardless of causality, are reported in AE section.
Time frame: Up to 211 days
Population: The safety population consisted of all randomized participants who received at least 1 dose or a partial dose of study drug analyzed according to the treatment actually received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sarilumab 150 mg q2w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 33 participants |
| Sarilumab 150 mg q2w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any treatment-emergent SAE | 1 participants |
| Sarilumab 150 mg q2w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 0 participants |
| Sarilumab 150 mg q2w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation | 6 participants |
| Sarilumab 200 mg q2w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation | 8 participants |
| Sarilumab 200 mg q2w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 36 participants |
| Sarilumab 200 mg q2w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 0 participants |
| Sarilumab 200 mg q2w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any treatment-emergent SAE | 3 participants |
| Tocilizumab q4w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to discontinuation | 4 participants |
| Tocilizumab q4w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any treatment-emergent SAE | 7 participants |
| Tocilizumab q4w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE leading to death | 1 participants |
| Tocilizumab q4w | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 68 participants |