To Evaluate The Safety of SAR153191 (REGN88) and Tocilizumab Added to Other RA Drugs in Patients With RA Who Are Not Responding to or Intolerant of Anti-TNF Therapy (SARIL-RA-ASCERTAIN)

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Randomized, Double-Blind, Double-Dummy Study Assessing The Safety and Tolerability of Sarilumab and Tocilizumab In Patients With Rheumatoid Arthritis Who Are Inadequate Responders to or Intolerant of TNF Antagonists

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: sarilumab SAR153191 (REGN88)
* Drug: tocilizumab
* Drug: hydroxychloroquine
* Drug: methotrexate
* Drug: sulfasalazine
* Drug: leflunomide
* Drug: subcutaneous placebo
* Drug: intravenous placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sarilumab 150 mg q2w<br>Sarilumab 150 mg subcutaneous (SC) injection once every 2 weeks (q2w) and placebo intravenous (IV) infusion once every 4 weeks (q4w) was added to one or a combination of the nonbiologic disease modifying antirheumatic drug (DMARD), hydroxychloroquine, methotrexate, sulfasalazine and/or leflunomide for 24 weeks, except for the simultaneous use of leflunomide and methotrexate. | Drug: sarilumab SAR153191 (REGN88)<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>Drug: hydroxychloroquine<br>* Dispensed according to local practice.<br>Drug: methotrexate<br>* Dispensed according to local practice.<br>Drug: sulfasalazine<br>* Dispensed according to local practice.<br>Drug: leflunomide<br>* Dispensed according to local practice.<br>Drug: intravenous placebo<br>* Pharmaceutical form: solution Route of administration: intravenous<br>|
| Experimental: Sarilumab 200 mg q2w<br>Sarilumab 200 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD, hydroxychloroquine, methotrexate, sulfasalazine and/or leflunomide for 24 weeks, except for the simultaneous use of leflunomide and methotrexate. | Drug: sarilumab SAR153191 (REGN88)<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>Drug: hydroxychloroquine<br>* Dispensed according to local practice.<br>Drug: methotrexate<br>* Dispensed according to local practice.<br>Drug: sulfasalazine<br>* Dispensed according to local practice.<br>Drug: leflunomide<br>* Dispensed according to local practice.<br>Drug: intravenous placebo<br>* Pharmaceutical form: solution Route of administration: intravenous<br>|
| Active Comparator: Tocilizumab q4w<br>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, hydroxychloroquine, methotrexate, sulfasalazine and/or leflunomide for 24 weeks, except for the simultaneous use of leflunomide and methotrexate. | Drug: tocilizumab<br>* Pharmaceutical form: solution Route of administration: intravenous<br>Drug: hydroxychloroquine<br>* Dispensed according to local practice.<br>Drug: methotrexate<br>* Dispensed according to local practice.<br>Drug: sulfasalazine<br>* Dispensed according to local practice.<br>Drug: leflunomide<br>* Dispensed according to local practice.<br>Drug: subcutaneous placebo<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 211 days |