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)

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

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Sarilumab; Drug: Sulfasalazine; Drug: Leflunomide; Drug: Bucillamine; Drug: Tacrolimus; Drug: Mizoribine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Asahi-Shi, Japan
    • Investigational Site Number 392010
  • Asahikawa-Shi, Japan
    • Investigational Site Number 392001
  • Beppu-Shi, Japan
    • Investigational Site Number 392070
  • Chiba-Shi, Japan
    • Investigational Site Number 392036
  • Chuo-Ku, Japan
    • Investigational Site Number 392083
  • Fukui-Shi, Japan
    • Investigational Site Number 392004
  • Fukuoka-Shi, Japan
    • Investigational Site Number 392039
  • Ichinomiya-Shi, Japan
    • Investigational Site Number 392030
  • Iizuka-Shi, Japan
    • Investigational Site Number 392002
  • Kagoshima-Shi, Japan
    • Investigational Site Number 392019
  • Kamakura-Shi, Japan
    • Investigational Site Number 392066
  • Kato-Shi, Japan
    • Investigational Site Number 392050
  • Kawachi-Nagano-Shi, Japan
    • Investigational Site Number 392037
  • Kawasaki-Shi, Japan
    • Investigational Site Number 392099
  • Kitakyushu-Shi, Japan
    • Investigational Site Number 392013
  • Kochi-Shi, Japan
    • Investigational Site Number 392097
  • Kushiro-Shi, Japan
    • Investigational Site Number 392065
  • Matsuyama-Shi, Japan
    • Investigational Site Number 392026
  • Miyagi-Gun, Japan
    • Investigational Site Number 392034
  • Nagoya-Shi, Japan
    • Investigational Site Number 392076
  • Nagoya-Shi, Japan
    • Investigational Site Number 392080
  • Narashino-Shi, Japan
    • Investigational Site Number 392046
  • Oita-Shi, Japan
    • Investigational Site Number 392059
  • Okayama-Shi, Japan
    • Investigational Site Number 392062
  • Osaki-Shi, Japan
    • Investigational Site Number 392027
  • Sagamihara-Shi, Japan
    • Investigational Site Number 392049
  • Sapporo-Shi, Japan
    • Investigational Site Number 392014
  • Sapporo-Shi, Japan
    • Investigational Site Number 392073
  • Sapporo-Shi, Japan
    • Investigational Site Number 392041
  • Sasebo-Shi, Japan
    • Investigational Site Number 392006
  • Sendai-Shi, Japan
    • Investigational Site Number 392021
  • Sendai-Shi, Japan
    • Investigational Site Number 392022
  • Sendai-Shi, Japan
    • Investigational Site Number 392033
  • Sendai-Shi, Japan
    • Investigational Site Number 392071
  • Shizuoka-Shi, Japan
    • Investigational Site Number 392029
  • Takaoka-Shi, Japan
    • Investigational Site Number 392023
  • Tomakomai-Shi, Japan
    • Investigational Site Number 392003
  • Urasoe-Shi, Japan
    • Investigational Site Number 392074
  • Urayasu-Shi, Japan
    • Investigational Site Number 392079
  • Yokohama-Shi, Japan
    • Investigational Site Number 392048

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sarilumab 150 mg q2w + DMARDs; 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; Pharmaceutical form:solution; Other Names: SAR153191 (REGN88); Drug: Sulfasalazine; Pharmaceutical form: Tablet Route of administration: Oral; Drug: Leflunomide; Pharmaceutical form: Tablet Route of administration: Oral; Drug: Bucillamine; Pharmaceutical form: Tablet Route of administration: Oral; Drug: Tacrolimus; Pharmaceutical form: Capsule Route of administration: Oral; Drug: Mizoribine; Pharmaceutical form: Tablet Route of administration: Oral
Experimental: Sarilumab 200 mg q2w + DMARDs; 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; Pharmaceutical form:solution; Other Names: SAR153191 (REGN88); Drug: Sulfasalazine; Pharmaceutical form: Tablet Route of administration: Oral; Drug: Leflunomide; Pharmaceutical form: Tablet Route of administration: Oral; Drug: Bucillamine; Pharmaceutical form: Tablet Route of administration: Oral; Drug: Tacrolimus; Pharmaceutical form: Capsule Route of administration: Oral; Drug: Mizoribine; Pharmaceutical form: Tablet Route of administration: Oral
Experimental: Sarilumab 150 mg q2w; Participants received sarilumab 150 mg, SC injection, q2w for up to 52 weeks.	Drug: Sarilumab; Pharmaceutical form:solution; Other Names: SAR153191 (REGN88)
Experimental: Sarilumab 200 mg q2w; Participants received sarilumab 200 mg, SC injection, q2w for up to 52 weeks.	Drug: Sarilumab; Pharmaceutical form:solution; Other Names: SAR153191 (REGN88)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: February 12, 2015
• First Submitted That Met QC Criteria: February 20, 2015
• First Posted (Estimate): February 26, 2015

Study Record Updates

• Last Update Posted (Actual): January 30, 2018
• Last Update Submitted That Met QC Criteria: January 5, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antiprotozoal Agents; Antiparasitic Agents; Antioxidants; Antimalarials; Calcineurin Inhibitors; Leflunomide; Tacrolimus; Sulfasalazine; Mizoribine; Bucillamine
• Other Study ID Numbers: LTS13618; U1111-1160-6525 (Other Identifier: UTN)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• product manufactured in and exported from the U.S.: Yes