A Study Assessing the Safety and Efficacy of Sarilumab Added to Non-MTX DMARDs or as Monotherapy in Japanese Patients With Active Rheumatoid Arthritis (SARIL-RA-HARUKA)

Study Overview
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Brief Summary
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Primary Objective: To document the long-term safety of sarilumab added to non-methotrexate (non-MTX) disease-modifying antirheumatic drugs (DMARDs) or as monotherapy. Secondary Objective: To document the long term efficacy of sarilumab added to non-MTX DMARDs or as monotherapy.

Detailed Description
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Total study duration was up to 62 weeks: Up to 4-week screening period, 52-week treatment period, and 6-week post-treatment follow-up period.

Official Title
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A Randomized, Double-blind, Multicenter Study Evaluating the Safety and Efficacy of Sarilumab Added to Non-MTX DMARDs or as Monotherapy in Japanese Patients With Active Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Sarilumab
* Drug: Sulfasalazine
* Drug: Leflunomide
* Drug: Bucillamine
* Drug: Tacrolimus
* Drug: Mizoribine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of rheumatoid arthritis (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 4 of 68 tender joints and 4 of 66 swollen joints at screening visit. High sensitivity C-Reactive Protein (hs-CRP) >=4 mg/L or Erythrocyte Sedimentation Rate (ESR) >=28 mm/hr at screening visit. For the combination stratum: Participants who had continuous treatment with non-biologic DMARDs other than MTX for at least 12 weeks prior to the randomization and on a stable dose for a minimum of 6 weeks prior to screening. For the monotherapy stratum: Participants who per investigator judgment were any of inappropriate, intolerant or inadequate to MTX treatment. Exclusion criteria: Participants <20 years of age. Prior treatment with tumor necrosis factor (TNF) antagonists or any other RA-directed biologic agents 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

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 + DMARDs<br>Participants received sarilumab 150 mg, subcutaneous (SC) injection, once every two weeks (q2w) along with non-MTX DMARDs (sulfasalazine, leflunomide, bucillamine, tacrolimus, and/or mizoribine) for up to 52 weeks. | Drug: Sarilumab<br>* Pharmaceutical form:solution<br>* Other names: SAR153191 (REGN88);Drug: Sulfasalazine<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>Drug: Leflunomide<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>Drug: Bucillamine<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>Drug: Tacrolimus<br>* Pharmaceutical form: Capsule Route of administration: Oral<br>Drug: Mizoribine<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>|
| Experimental: Sarilumab 200 mg q2w + DMARDs<br>Participants received sarilumab 200 mg, SC injection, q2w along with non-MTX DMARDs (sulfasalazine, leflunomide, bucillamine, tacrolimus, and/or mizoribine) for up to 52 weeks. | Drug: Sarilumab<br>* Pharmaceutical form:solution<br>* Other names: SAR153191 (REGN88);Drug: Sulfasalazine<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>Drug: Leflunomide<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>Drug: Bucillamine<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>Drug: Tacrolimus<br>* Pharmaceutical form: Capsule Route of administration: Oral<br>Drug: Mizoribine<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>|
| Experimental: Sarilumab 150 mg q2w<br>Participants received sarilumab 150 mg, SC injection, q2w for up to 52 weeks. | Drug: Sarilumab<br>* Pharmaceutical form:solution<br>* Other names: SAR153191 (REGN88);|
| Experimental: Sarilumab 200 mg q2w<br>Participants received sarilumab 200 mg, SC injection, q2w for up to 52 weeks. | Drug: Sarilumab<br>* Pharmaceutical form:solution<br>* Other names: SAR153191 (REGN88);|

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) and Serious Adverse Events (SAEs) | Adverse event (AE) was defined as any untoward medical occurrence in a participant who received IMP and did not necessary have to had a causal relationship with treatment. All AEs that occurred from the first dose of the IMP administration up to 6 weeks after last dose of treatment (up to Week 58) were considered as TEAEs. SAEs were AEs 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. TEAEs included both SAEs and non-SAEs. | Baseline 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 (SBP) supine: <=95 mmHg and decrease from baseline (DFB) >=20 mmHg; >=160 mmHg and increase from baseline (IFB) >=20 mmHg Diastolic blood pressure (DBP) supine: <=45 mmHg and DFB >=10 mmHg; >=110 mmHg and IFB ≥10 mmHg SBP (Orthostatic): <=-20 mmHg DBP (Orthostatic): <=-10 mmHg Heart rate (HR) supine: <=50 beats per minute (bpm) and DFB >=20 bpm; >=120 bpm and IFB >=20 bpm Weight: >=5% DFB; >=5% IFB | Baseline up to Week 58 | 
| Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities | Criteria for potentially clinically significant ECG abnormalities: PR Interval: >200 milliseconds (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 | Baseline 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) | Baseline 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 [unfas]) or >=7 mmol/L (fasted [fas]) 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 | Baseline 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 | Baseline 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 (adults); >=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 | Baseline 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 Unconjugated bilirubin: >1.5 ULN ALT >3 ULN and TBILI >2 ULN CBILI >35% TBILI and TBILI >1.5 ULN Albumin: <=25 g/L | Baseline up to Week 58 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology (ACR) 20, 50 and 70 Responses at Week 52 | 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 Question-Disability Index [HAQ-DI], with scoring range of 0 [better health] - 3 [worst health]). ACR20/50/70 response is defined as at least 20/50/70% improvement in both TJC and SJC, and at least 20/50/70% improvement in at least 3 of the 5 other assessments, respectively. | Week 52 | 
| Change From Baseline at Week 52 in Disease Activity Score for 28 Joints Based on C-Reactive Protein (DAS28-CRP) | DAS28-CRP is a composite score that contains 4 variables: TJC (based on 28 joints), SJC (based on 28 joints), participant's assessment of general health on VAS (range 0 [very well] to 100 mm [extremely bad]) and CRP (mg/L). DAS28-CRP total score ranges from 2-10 with a lower score indicating less disease activity. A DAS28-CRP above 5.1 indicates high disease activity, whereas below 3.2 indicates low disease activity and below 2.6 as disease remission. | Baseline, Week 52 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52 | HAQ-DI assessed the degree of difficulty participants experienced in 8 daily living activity domains during a week: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other activities. Each activity category consisted of 2-3 items. Each items's difficulty was scored from 0-3 (0=no difficulty, 1=some difficulty, 2=much difficulty, 3=unable to do). Overall HAQ-DI score was computed as the sum of domain scores divided by the number of domains answered, providing a score from 0-3. Low scores denoted improvement of disability/lower degree of domain difficulty. | Baseline, Week 52 |