Evaluation of Sarilumab (SAR153191/REGN88) on Top of Methotrexate in Rheumatoid Arthritis Patients

Study Overview
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Brief Summary
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Primary Objectives: Part A (dose ranging study): To demonstrate that sarilumab (SAR153191/REGN88) on top of MTX was effective on reduction of signs and symptoms of rheumatoid arthritis at 12 weeks. Part B (pivotal study): To demonstrate that sarilumab added to MTX was effective in: reduction of signs and symptoms of rheumatoid arthritis at 24 weeks inhibition of progression of structural damage at 52 weeks improvement in physical function at 16 weeks Secondary Objectives: Part B: To demonstrate that sarilumab added to MTX was effective in induction of a major clinical response at 52 weeks To assess the safety of sarilumab added to MTX To document the pharmacokinetic profile of sarilumab added to MTX in participants with active rheumatoid arthritis who were inadequate responders to MTX therapy.

Detailed Description
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The total study duration for a participant was 16-22 weeks (Part A) and 56-62 weeks (Part B) broken down as follows: Screening: Up to 4 weeks Treatment: 12 weeks (Part A) and 52 weeks (Part B)* Follow-up: 6 weeks (for participants who would not continue in the long-term extension study). '*' Participants successfully completing their treatment period would be offered the opportunity to enter the long term extension study LTS11210 (SARIL-RA-EXTEND) (NCT01146652).

Official Title
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A Randomized, Double-blind, Placebo-controlled, Multicenter, Two-part, Dose Ranging and Confirmatory Study With an Operationally Seamless Design, Evaluating Efficacy and Safety of SAR153191 on Top of Methotrexate (MTX) in Patients With Active Rheumatoid Arthritis Who Are Inadequate Responders to MTX Therapy

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Sarilumab
* Drug: Placebo (for sarilumab)
* Drug: Methotrexate
* Drug: Folic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Diagnosis of rheumatoid arthritis ≥3 months duration Active disease defined as: at least 8/68 tender joints and 6/66 swollen joints, high sensitivity C-reactive protein (hs-CRP) >6 mg/l, continuous treatment with MTX for at least 12 weeks prior to baseline visit and on stable dose for at least 6 weeks prior to screening visit. Part B only: Bone erosion based on documented X-ray prior to first study drug intake, or Cyclic Citrullinated Peptide (CCP) positive, or Rheumatoid Factor (RF) positive. Exclusion criteria: Age <18 years or >75 years. Treatment with disease-modifying antirheumatic drugs (DMARDs) other than MTX within 4 weeks or 12 weeks prior to screening (depending on DMARDs). Past history of non-response to prior Tumor Necrosis Factor (TNF) or biologic treatment. Any past or current biologic agents for the treatment of rheumatoid arthritis within 3 months. Use of parenteral glucocorticoids or intraarticular glucocorticoids within 4 weeks prior to screening visit. Use of oral glucocorticoid greater than 10mg/day or equivalent/day, or a change in dosage within 4 weeks prior to baseline visit. The above information is 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
Maximum Age: 75 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: SAR 100 mg qw<br>Sarilumab 100 mg subcutaneous (SC) injection weekly (qw) on top of MTX for 12 weeks. | Drug: Sarilumab<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>* Other names: REGN88;Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|
| Experimental: Part A: SAR 150 mg qw<br>Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks. | Drug: Sarilumab<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>* Other names: REGN88;Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|
| Experimental: Part A: SAR 100 mg q2w<br>Sarilumab 100 mg SC injection every other week (q2w) alternating with placebo on top of MTX for 12 weeks. | Drug: Sarilumab<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>* Other names: REGN88;Drug: Placebo (for sarilumab)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|
| Experimental: Part A: SAR 150 mg q2w<br>Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. | Drug: Sarilumab<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>* Other names: REGN88;Drug: Placebo (for sarilumab)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|
| Experimental: Part A: SAR 200 mg q2w<br>Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks. | Drug: Sarilumab<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>* Other names: REGN88;Drug: Placebo (for sarilumab)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|
| Placebo Comparator: Part A: Placebo qw<br>Placebo (for sarilumab) qw on top of MTX for 12 weeks. | Drug: Placebo (for sarilumab)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|
| Experimental: Part B Cohort 1: Non-selected Doses<br>Sarilumab 100 mg qw, 150 mg qw or 100 mg q2w SC injections as in Part A on top of MTX up to dose selection. After dose selection, participants were not continued but were allowed to participate in the open-label, long-term, extension study SARIL-RA-EXTEND (LTS11210). | Drug: Sarilumab<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>* Other names: REGN88;Drug: Placebo (for sarilumab)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|
| Experimental: Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2)<br>Sarilumab 150 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab. | Drug: Sarilumab<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>* Other names: REGN88;Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|
| Experimental: Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2)<br>Sarilumab 200 mg SC injection q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab. | Drug: Sarilumab<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>* Other names: REGN88;Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|
| Experimental: Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2)<br>Placebo (for sarilumab) q2w on top of MTX for a maximum of 52 weeks. Participants with inadequate response from Week 16 could be rescued with open-label highest dose of sarilumab. | Drug: Placebo (for sarilumab)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Same weekly dose as received prior to enrollment<br>Drug: Folic Acid<br>* According to local standard<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | ACR20 response was defined, based on guidelines set forth by the American College of Rheumatology (ACR), as ≥20 % improvement in tender joint count and swollen joint count as well as ≥20% improvement in at least 3 of 5 following measures: C-Reactive Protein (CRP), Participant assessment of pain; Participant's global assessment of disease activity; Physician global assessment of disease activity; and Health Assessment Question-Disability Index (HAQ-DI). Missing data imputed by Last Observation Carried Forward (LOCF). | Baseline to Week 12 | 
| Part B: Percentage of Participants Achieving ACR20 Response at Week 24 | ACR20 improvement responses were determined without imputation of missing post-baseline values. In addition data collected after treatment discontinuation or rescue was set to missing. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment. | Baseline to Week 24 | 
| Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 | HAQ-DI was a participant-reported questionnaire that assesses the difficulty of performing daily activities: dress/groom, arise, eat, walk, reach, grip, hygiene and common activities. Overall score range from 0=least difficulty to 3=extreme difficulty. An increase in the score indicates a worsening of physical function while a decrease in the score represents improvement. Data collected after treatment discontinuation was set to missing. | Baseline, Week 16 | 
| Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 | The Sharp method modified by D. van der Heijde involves separate scores for erosions and joint space narrowing based on radiographs to assess the degree of structural damage. Total score range from 0 (normal) to 448 (worst possible total score). An increase in total score represents progression of structural damage. Missing data were imputed by the linear extrapolation method. | Baseline, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52 | Major clinical response was defined as an ACR70 response maintained for at least 24 consecutive weeks. ACR70 response uses the same criteria as for ACR20 but requires 70% improvement. In the primary approach, data collected after treatment discontinuation or rescue was set to missing. No imputation of missing post-baseline values was performed. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment. | Baseline up to Week 52 |