A Study Assessing the Efficacy and Safety of Sarilumab Added to MTX in Japanese Patients With Moderately to Severely Active Rheumatoid Arthritis (SARIL-RA-KAKEHASI)

Study Overview
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Brief Summary
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Primary Objective: -To demonstrate that sarilumab added to methotrexate (MTX) reduce signs and symptoms of rheumatoid arthritis (RA) in Japanese RA participants with an inadequate response to MTX. Secondary Objective: -To assess the safety of sarilumab added to MTX in Japanese RA participants with an inadequate response to MTX.

Detailed Description
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The total duration of study was expected up to 62 weeks (screening period of 4 weeks, treatment period of 52 weeks, and a 6-week post treatment observation).

Official Title
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A Randomized, Double-blind, Multicenter Study With a Placebo-controlled Period Assessing the Efficacy and Safety of Sarilumab Added to Methotrexate (MTX) in Japanese Patients With Moderately to Severely 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 SAR153191 (REGN88)
* Other: Placebo (for sarilumab)
* Drug: Methotrexate
* Drug: Folic acid


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of RA, according to the American College of Rheumatology/The European League Against Rheumatism (ACR/EULAR) 2010 Rheumatoid Arthritis Classification Criteria with >=3 months disease duration. Moderately to severely active RA defined as: At least 8 of 68 tender joints and 6 of 66 swollen joints at screening visit. High sensitivity C-Reactive Protein (hs-CRP) >=6mg/L at screening visit. Exclusion criteria: Participants <20 or >75 years of age. Treatment with any Disease-modifying antirheumatic drug (DMARD) other than MTX or biologic agent without the appropriate off-drug period prior to screening. Prior treatment with anti-interleukin-6 (anti-IL-6) or anti-interleukin-6 receptor (IL-6R) antagonist therapies, including but not limited to tocilizumab or sarilumab. 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: 20 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sarilumab 150 mg/150 mg<br>Sarilumab 150 mg subcutaneous (SC) injection once every 2 weeks (q2w) in combination with MTX and folic acid in double-blind period up to Week 24 followed by single-blind period in which participants continued with the same treatment up to Week 52. Participants with inadequate response (defined as less than 20% improvement from baseline on 2 consecutive visits [at least 4 weeks apart] in either tender joint count [TJC] or swollen joint count [SJC], or with any other clear lack of efficacy based on investigator's judgment) by Week 16, were rescued with open label sarilumab 200 mg q2w treatment. | Drug: Sarilumab SAR153191 (REGN88)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Dispensed according to local practice.<br>Drug: Folic acid<br>* Dispensed according to local practice.<br>|
| Experimental: Sarilumab 200 mg/200 mg<br>Sarilumab 200 mg SC injection q2w in combination with MTX and folic acid in double-blind period up to Week 24 followed by single-blind period in which participants continued with the same treatment up to Week 52. Participants with inadequate response (defined as less than 20% improvement from baseline on 2 consecutive visits [at least 4 weeks apart] in either TJC or SJC, or with any other clear lack of efficacy based on investigator's judgment) by Week 16, were rescued with open label sarilumab 200 mg q2w treatment. | Drug: Sarilumab SAR153191 (REGN88)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Dispensed according to local practice.<br>Drug: Folic acid<br>* Dispensed according to local practice.<br>|
| Placebo Comparator: Placebo/Sarilumab 150 mg<br>Placebo (for sarilumab) SC injection q2w in combination with MTX and folic acid in double-blind period up to Week 24 followed by a single-blind period in which participants were switched and received sarilumab 150 mg SC injection q2w in combination with MTX and folic acid up to Week 52. Participants with inadequate response (defined as less than 20% improvement from baseline on 2 consecutive visits [at least 4 weeks apart] in either TJC or SJC, or with any other clear lack of efficacy based on Investigator's judgment) by Week 16, were rescued with open label sarilumab 200 mg q2w treatment. | Drug: Sarilumab SAR153191 (REGN88)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Other: Placebo (for sarilumab)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Dispensed according to local practice.<br>Drug: Folic acid<br>* Dispensed according to local practice.<br>|
| Placebo Comparator: Placebo/Sarilumab 200 mg<br>Placebo (for sarilumab) SC injection q2w in combination with MTX and folic acid in double-blind period up to Week 24 followed by a single-blind period in which participants were switched and received sarilumab 200 mg SC injection q2w in combination with MTX and folic acid up to Week 52. Participants with inadequate response (defined as less than 20% improvement from baseline on 2 consecutive visits [at least 4 weeks apart] in either TJC or SJC, or with any other clear lack of efficacy based on Investigator's judgment) by Week 16, were rescued with open label sarilumab 200 mg q2w treatment. | Drug: Sarilumab SAR153191 (REGN88)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Other: Placebo (for sarilumab)<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>Drug: Methotrexate<br>* Dispensed according to local practice.<br>Drug: Folic acid<br>* Dispensed according to local practice.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20 (ACR20) Response at Week 24 | American College of Rheumatology (ACR) response is a composite rating scale that includes 7 variables: tender joints count (TJC [68 joints]); Swollen joints count (SJC [66 joints]); levels of an acute phase reactant (high sensitivity C-reactive protein [hs-CRP level]); participant's assessment of pain (measured on 0 [no pain]-100 mm [worst pain] visual analog scale [VAS]); participant's global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); physician's global assessment of disease activity (measured on 0 [no arthritis activity]-100 mm [maximal arthritis activity] VAS); participant's assessment of physical function (measured by health assessment questionnaire disability index [HAQ-DI], with scoring range of 0 [better health] - 3 [worst health]). ACR20 response was defined as achieving at least 20% improvement in both TJC and SJC, and at least 20% improvement in at least 3 of the 5 other assessments. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, In-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AEs that developed or worsened or became serious during double-blind on-treatment period, single-blind on-treatment period up to 6-week post-treatment follow-up period (up to Week 58) were considered treatment-emergent. | For placebo arm: Baseline up to Week 24; For sarilumab 150 mg/150 mg, sarilumab 200 mg/200 mg and sarilumab rescue arm: Baseline up to Week 58; For placebo/sarilumab 150 mg and placebo/sarilumab 200 mg arm: Week 25 up to Week 58 | 
| Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities | Criteria for potentially clinically significant vital sign abnormalities: Systolic blood pressure supine (SBP[S]): <=95 mmHg and decrease from baseline (DFB) >=20 mmHg; >=160 mmHg and increase from baseline (IFB) >=20 mmHg Diastolic blood pressure supine (DBP[S]): <=45 mmHg and DFB >=10 mmHg; >=110 mmHg and IFB >=10 mmHg Orthostatic systolic blood pressure (SBP[O]): <=-20 mmHg Orthostatic diastolic blood pressure (DBP[O]): <=-10 mmHg Heart rate supine (HR[S]): <=50 beats per minute (bpm) and DFB >=20 bpm; >=120 bpm and IFB >=20 bpm Weight: >=5% DFB; >=5% IFB | For placebo arm: Baseline up to Week 24; For sarilumab 150 mg/150 mg, sarilumab 200 mg/200 mg and sarilumab rescue arm: Baseline up to Week 58; For placebo/sarilumab 150 mg and placebo/sarilumab 200 mg arm: Week 25 up to Week 58 | 
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | Criteria for potentially clinically significant ECG abnormalities: PR Interval: >200 millisecond (ms); >200 ms and IFB >=25%; >220 ms; >220 ms and IFB >=25%; >240 ms; >240 ms and IFB >=25% QRS Interval: >110 ms; >110 ms and IFB >=25%; >120 ms; >120 ms and IFB >=25% QT Interval: >500 ms QTc Bazett (QTc B): >450 ms; 480 ms; 500 ms; IFB >30 and <=60 ms; IFB >60 ms QTc Fridericia (QTc F): >450 ms; 480 ms; 500 ms; IFB >30 and <=60 ms; IFB >60 ms | For placebo arm: Baseline up to Week 24; For sarilumab 150 mg/150 mg, sarilumab 200 mg/200 mg and sarilumab rescue arm: Baseline up to Week 58; For placebo/sarilumab 150 mg and placebo/sarilumab 200 mg arm: Week 25 up to Week 58 | 
| Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematological Parameters | Criteria for potentially clinically significant abnormalities: Hemoglobin: <=115 g/L (Male[M]) or <=95 g/L (Female[F]); >=185 g/L (M) or >=165 g/L (F); DFB >=20 g/L Hematocrit: <=0.37 v/v (M) or <=0.32 v/v (F); >=0.55 v/v (M) or >=0.5 v/v (F) Red blood cells (RBC): >=6 Tera/L Platelets: <50 Giga/L; >=50 and <100 Giga/L; >=700 Giga/L White blood cells (WBC): <3.0 Giga/L (Non-Black[NB]) or <2.0 Giga/L (Black[B]); >=16.0 Giga/L Neutrophils: <1.5 Giga/L (NB) or <1.0 Giga/L (B); <1.0 Giga/L Lymphocytes: <0.5 Giga/L; >=0.5 Giga/L and < lower limit of normal (LLN); >4.0 Giga/L Monocytes: >0.7 Giga/L Basophils: >0.1 Giga/L Eosinophils: >0.5 Giga/L or >upper limit of normal (ULN) (if ULN >=0.5 Giga/L) | For placebo arm: Baseline up to Week 24; For sarilumab 150 mg/150 mg, sarilumab 200 mg/200 mg and sarilumab rescue arm: Baseline up to Week 58; For placebo/sarilumab 150 mg and placebo/sarilumab 200 mg arm: Week 25 up to Week 58 | 
| Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Metabolic Parameters | Criteria for potentially clinically significant abnormalities: Glucose: <=3.9 mmol/L and <LLN; >=11.1 mmol/L unfasted or >=7 mmol/L fasted Hemoglobin A1c (HbA1c): >8% Total cholesterol: >=6.2 mmol/L; >=7.74 mmol/L LDL cholesterol: >=4.1 mmol/L; >=4.9 mmol/L Triglycerides: >=4.6 mmol/L; >=5.6 mmol/L | For placebo arm: Baseline up to Week 24; For sarilumab 150 mg/150 mg, sarilumab 200 mg/200 mg and sarilumab rescue arm: Baseline up to Week 58; For placebo/sarilumab 150 mg and placebo/sarilumab 200 mg arm: Week 25 up to Week 58 | 
| Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Electrolytes | Criteria for potentially clinically significant abnormalities: Sodium: <=129 mmol/L; >=160 mmol/L Potassium: <3 mmol/L; >=5.5 mmol/L Chloride: <80 mmol/L; >115 mmol/L | For placebo arm: Baseline up to Week 24; For sarilumab 150 mg/150 mg, sarilumab 200 mg/200 mg and sarilumab rescue arm: Baseline up to Week 58; For placebo/sarilumab 150 mg and placebo/sarilumab 200 mg arm: Week 25 up to Week 58 | 
| Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Renal Function Parameters | Criteria for potentially clinically significant abnormalities: Creatinine: >=150 micromol/L; >=30% change from baseline; >=100% change from baseline Creatinine clearance: <15 mL/min; >=15 to <30 mL/min; >=30 to < 60 mL/min; >=60 to <90 mL/min Blood urea nitrogen: >=17 mmol/L Uric acid: <120 micromol/L; >408 micromol/L | For placebo arm: Baseline up to Week 24; For sarilumab 150 mg/150 mg, sarilumab 200 mg/200 mg and sarilumab rescue arm: Baseline up to Week 58; For placebo/sarilumab 150 mg and placebo/sarilumab 200 mg arm: Week 25 up to Week 58 | 
| Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Liver Function Parameters | Criteria for potentially clinically significant abnormalities: Alanine Aminotransferase (ALT): >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN Aspartate aminotransferase (AST): >1 ULN and <=1.5 ULN; >1.5 ULN and <=3 ULN; >3 ULN and <=5 ULN; >5 ULN and <=10 ULN; >10 ULN and <=20 ULN; >20 ULN Alkaline phosphatase: >1.5 ULN Total bilirubin (TBILI): >1.5 ULN; >2 ULN Conjugated bilirubin (CBILI): >1.5 ULN; >2 ULN Unconjugated bilirubin: >1.5 ULN; >2 ULN ALT and TBILI: ALT >3 ULN and TBILI >2 ULN CBILI and TBILI: CBILI >35% TBILI and TBILI >1.5 ULN Albumin: <=25 g/L | For placebo arm: Baseline up to Week 24; For sarilumab 150 mg/150 mg, sarilumab 200 mg/200 mg and sarilumab rescue arm : Baseline up to Week 58; For placebo/sarilumab 150 mg and placebo/sarilumab 200 mg arm: Week 25 up to Week 58 |