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

• ClinicalTrials.gov Identifier: NCT01061736
• Recruitment Status: Completed
• First Posted: February 3, 2010
• Results First Posted: June 28, 2017
• Last Update Posted: June 28, 2017
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: February 2, 2010
• First Posted Date: February 3, 2010
• Results First Submitted Date: May 23, 2017
• Results First Posted Date: June 28, 2017
• Last Update Posted Date: June 28, 2017
• Study Start Date: March 2010
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 27, 2017)

• Part A: Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 [ Time Frame: Baseline to 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).
• Part B: Percentage of Participants Achieving ACR20 Response at Week 24 [ Time Frame: Baseline to 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.
• Part B: Change From Baseline in Health Assessment Question Disability Index (HAQ-DI) at Week 16 [ Time Frame: Baseline, 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.
• Part B: Change From Baseline in Van Der Heijde Modified Total Sharp Score (mTSS) at Week 52 [ Time Frame: Baseline, 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.

Original Primary Outcome Measures (submitted: February 2, 2010)

• Part A: Percentage of patients who achieved the American College of Rheumatology criteria for improvement ACR20 [ Time Frame: Week 12 ]
• Part B: Percentage of patients who achieved ACR20 [ Time Frame: Week 24 ]

Current Secondary Outcome Measures (submitted: June 27, 2017)

Part B: Percentage of Participants Achieving a Major Clinical Response at Week 52 [ Time Frame: Baseline up to 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.

Original Secondary Outcome Measures (submitted: February 2, 2010)

• Part B: Change in modified Van der Heijde Sharp score (composite index on X-ray assessed through central reading). [ Time Frame: Week 52 ]
• Part B: Change in physical function as measured by the change from baseline in the Health Assessment Question-Disability (HAQ_DI) [ Time Frame: Week 52 ]
• Part B: Percentage of patients who achieved and maintained (for at least 6 months) an ACR70 response [ Time Frame: Week 52 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Sarilumab (SAR153191/REGN88) on Top of Methotrexate in Rheumatoid Arthritis Patients
• Official Title: 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

Brief Summary

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

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).

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Rheumatoid Arthritis

Intervention

• Drug: Sarilumab

  Pharmaceutical form: solution for injection

  Route of administration: subcutaneous

  Other Names:

  • SAR153191
  • REGN88
• Drug: Placebo (for sarilumab)

  Pharmaceutical form: solution for injection

  Route of administration: subcutaneous

• Drug: Methotrexate
  Same weekly dose as received prior to enrollment
• Drug: Folic Acid
  According to local standard

Study Arms

• Experimental: Part A: SAR 100 mg qw
  Sarilumab 100 mg subcutaneous (SC) injection weekly (qw) on top of MTX for 12 weeks.
  Interventions:

  • Drug: Sarilumab
  • Drug: Methotrexate
  • Drug: Folic Acid
• Experimental: Part A: SAR 150 mg qw
  Sarilumab 150 mg SC injection qw on top of MTX for 12 weeks.
  Interventions:

  • Drug: Sarilumab
  • Drug: Methotrexate
  • Drug: Folic Acid
• Experimental: Part A: SAR 100 mg q2w
  Sarilumab 100 mg SC injection every other week (q2w) alternating with placebo on top of MTX for 12 weeks.
  Interventions:

  • Drug: Sarilumab
  • Drug: Placebo (for sarilumab)
  • Drug: Methotrexate
  • Drug: Folic Acid
• Experimental: Part A: SAR 150 mg q2w
  Sarilumab 150 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
  Interventions:

  • Drug: Sarilumab
  • Drug: Placebo (for sarilumab)
  • Drug: Methotrexate
  • Drug: Folic Acid
• Experimental: Part A: SAR 200 mg q2w
  Sarilumab 200 mg SC injection q2w alternating with placebo on top of MTX for 12 weeks.
  Interventions:

  • Drug: Sarilumab
  • Drug: Placebo (for sarilumab)
  • Drug: Methotrexate
  • Drug: Folic Acid
• Placebo Comparator: Part A: Placebo qw
  Placebo (for sarilumab) qw on top of MTX for 12 weeks.
  Interventions:

  • Drug: Placebo (for sarilumab)
  • Drug: Methotrexate
  • Drug: Folic Acid
• Experimental: Part B Cohort 1: Non-selected Doses
  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).
  Interventions:

  • Drug: Sarilumab
  • Drug: Placebo (for sarilumab)
  • Drug: Methotrexate
  • Drug: Folic Acid
• Experimental: Part B: SAR 150 mg q2w (Cohort 1[Selected Dose]+Cohort 2)
  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.
  Interventions:

  • Drug: Sarilumab
  • Drug: Methotrexate
  • Drug: Folic Acid
• Experimental: Part B: SAR 200 mg q2w (Cohort 1[Selected Dose]+Cohort 2)
  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.
  Interventions:

  • Drug: Sarilumab
  • Drug: Methotrexate
  • Drug: Folic Acid
• Experimental: Part B: Placebo q2w (Cohort 1[Selected Dose]+Cohort 2)
  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.
  Interventions:

  • Drug: Placebo (for sarilumab)
  • Drug: Methotrexate
  • Drug: Folic Acid

Publications *

• Strand V, Kosinski M, Chen CI, Joseph G, Rendas-Baum R, Graham NM, van Hoogstraten H, Bayliss M, Fan C, Huizinga T, Genovese MC. Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016 Sep 6;18:198. doi: 10.1186/s13075-016-1096-9.
• Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, Huang X, Yancopoulos GD, Stahl N, Genovese MC. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014 Sep;73(9):1626-34. doi: 10.1136/annrheumdis-2013-204405. Epub 2013 Dec 2.
• Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, Martincova R, Fiore S, Rohane P, van Hoogstraten H, Garg A, Fan C, van Adelsberg J, Weinstein SP, Graham NM, Stahl N, Yancopoulos GD, Huizinga TW, van der Heijde D. Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. Arthritis Rheumatol. 2015 Jun;67(6):1424-37. doi: 10.1002/art.39093.
• Genovese MC, Burmester GR, Hagino O, Thangavelu K, Iglesias-Rodriguez M, John GS, González-Gay MA, Mandrup-Poulsen T, Fleischmann R. Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials. Arthritis Res Ther. 2020 Sep 9;22(1):206. doi: 10.1186/s13075-020-02229-5.
• Genovese MC, Fleischmann R, Kivitz A, Lee EB, van Hoogstraten H, Kimura T, St John G, Mangan EK, Burmester GR. Efficacy and safety of sarilumab in combination with csDMARDs or as monotherapy in subpopulations of patients with moderately to severely active rheumatoid arthritis in three phase III randomized, controlled studies. Arthritis Res Ther. 2020 Jun 10;22(1):139. doi: 10.1186/s13075-020-02194-z.
• Boyapati A, Schwartzman S, Msihid J, Choy E, Genovese MC, Burmester GR, Lam G, Kimura T, Sadeh J, Weinreich DM, Yancopoulos GD, Graham NMH. Association of High Serum Interleukin-6 Levels With Severe Progression of Rheumatoid Arthritis and Increased Treatment Response Differentiating Sarilumab From Adalimumab or Methotrexate in a Post Hoc Analysis. Arthritis Rheumatol. 2020 Sep;72(9):1456-1466. doi: 10.1002/art.41299. Epub 2020 Aug 25.
• Genovese MC, van der Heijde D, Lin Y, St John G, Wang S, van Hoogstraten H, Gómez-Reino JJ, Kivitz A, Maldonado-Cocco JA, Seriolo B, Stanislav M, Burmester GR. Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical function and radiographic progression: 5 years of sarilumab plus methotrexate treatment. RMD Open. 2019 Aug 1;5(2):e000887. doi: 10.1136/rmdopen-2018-000887. eCollection 2019.
• Muszbek N, Proudfoot C, Fournier M, Chen CI, Kuznik A, Kiss Z, Gal P, Michaud K. Economic Evaluation of Sarilumab in the Treatment of Adult Patients with Moderately-to-Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs. Adv Ther. 2019 Jun;36(6):1337-1357. doi: 10.1007/s12325-019-00946-1. Epub 2019 Apr 19.
• Boyapati A, Msihid J, Fiore S, van Adelsberg J, Graham NM, Hamilton JD. Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY. Arthritis Res Ther. 2016 Oct 6;18(1):225.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 19, 2014): 1675
• Original Estimated Enrollment (submitted: February 2, 2010): 1740
• Actual Study Completion Date: October 2013
• Actual Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belarus, Belgium, Brazil, Canada, Chile, Colombia, Czechia, Egypt, Estonia, Finland, Germany, Greece, Hungary, India, Korea, Republic of, Lithuania, Malaysia, Mexico, Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Romania, Russian Federation, South Africa, Spain, Taiwan, Thailand, Turkey, Ukraine, United States
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01061736
• Other Study ID Numbers: EFC11072; 2009-016266-90 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Sanofi
• Study Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Investigators

• Principal Investigator: Mark C Genovese, MD, Professor of Medicine; Division of Immunology and Rheumatology - Stanford University - USA
• Study Chair: TWJ Huizinga, Prof Dr; Dpt of Rheumatology - Leiden University Medical Center - The Netherlands

• PRS Account: Sanofi
• Verification Date: June 2017