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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02293902
Recruitment Status : Completed
First Posted : November 19, 2014
Results First Posted : January 30, 2018
Last Update Posted : January 30, 2018
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE November 13, 2014
First Posted Date  ICMJE November 19, 2014
Results First Submitted Date  ICMJE October 23, 2017
Results First Posted Date  ICMJE January 30, 2018
Last Update Posted Date January 30, 2018
Study Start Date  ICMJE November 2014
Actual Primary Completion Date October 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 5, 2018)
Percentage of Participants Achieving American College of Rheumatology 20 (ACR20) Response at Week 24 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 18, 2014)
ACR20 response rate [ Time Frame: 24 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2018)
  • Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 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 ]
    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.
  • Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities [ Time Frame: 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 ]
    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
  • Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities [ Time Frame: 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 ]
    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
  • Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematological Parameters [ Time Frame: 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 ]
    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)
  • Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Metabolic Parameters [ Time Frame: 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 ]
    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
  • Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Electrolytes [ Time Frame: 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 ]
    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
  • Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Renal Function Parameters [ Time Frame: 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 ]
    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
  • Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Liver Function Parameters [ Time Frame: 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 ]
    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
Original Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2014)
  • Number of treatment-emergent adverse events [ Time Frame: 58 weeks ]
  • Clinically significant changes in vital signs [ Time Frame: 58 weeks ]
  • Clinically significant changes in electrocardiogram (ECG) [ Time Frame: 58 weeks ]
  • Clinically significant changes in laboratory values [ Time Frame: 58 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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)
Official Title  ICMJE 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
Brief Summary

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 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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Rheumatoid Arthritis
Intervention  ICMJE
  • Drug: Sarilumab SAR153191 (REGN88)
    Pharmaceutical form: solution for injection Route of administration: subcutaneous
  • Other: Placebo (for sarilumab)
    Pharmaceutical form: solution for injection Route of administration: subcutaneous
  • Drug: Methotrexate
    Dispensed according to local practice.
  • Drug: Folic acid
    Dispensed according to local practice.
Study Arms  ICMJE
  • Experimental: Sarilumab 150 mg/150 mg
    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.
    Interventions:
    • Drug: Sarilumab SAR153191 (REGN88)
    • Drug: Methotrexate
    • Drug: Folic acid
  • Experimental: Sarilumab 200 mg/200 mg
    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.
    Interventions:
    • Drug: Sarilumab SAR153191 (REGN88)
    • Drug: Methotrexate
    • Drug: Folic acid
  • Placebo Comparator: Placebo/Sarilumab 150 mg
    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.
    Interventions:
    • Drug: Sarilumab SAR153191 (REGN88)
    • Other: Placebo (for sarilumab)
    • Drug: Methotrexate
    • Drug: Folic acid
  • Placebo Comparator: Placebo/Sarilumab 200 mg
    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.
    Interventions:
    • Drug: Sarilumab SAR153191 (REGN88)
    • Other: Placebo (for sarilumab)
    • Drug: Methotrexate
    • Drug: Folic acid
Publications * Tanaka Y, Wada K, Takahashi Y, Hagino O, van Hoogstraten H, Graham NMH, Kameda H. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a randomized, placebo-controlled phase III trial in Japan. Arthritis Res Ther. 2019 Mar 20;21(1):79. doi: 10.1186/s13075-019-1856-4. Erratum in: Arthritis Res Ther. 2019 Apr 16;21(1):99.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 5, 2016)
243
Original Estimated Enrollment  ICMJE
 (submitted: November 18, 2014)
240
Actual Study Completion Date  ICMJE October 2016
Actual Primary Completion Date October 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02293902
Other Study ID Numbers  ICMJE EFC14059
U1111-1155-7401 ( Other Identifier: UTN )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date January 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP