To Evaluate The Safety of SAR153191 (REGN88) and Tocilizumab Added to Other RA Drugs in Patients With RA Who Are Not Responding to or Intolerant of Anti-TNF Therapy (SARIL-RA-ASCERTAIN)

A Randomized, Double-Blind, Double-Dummy Study Assessing The Safety and Tolerability of Sarilumab and Tocilizumab In Patients With Rheumatoid Arthritis Who Are Inadequate Responders to or Intolerant of TNF Antagonists

Primary Objective:

To assess, in the same study, the safety of sarilumab and tocilizumab in participants with rheumatoid arthritis (RA) who were inadequate responders to or intolerant of tumor necrosis factor (TNF) antagonists.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: sarilumab SAR153191 (REGN88); Drug: hydroxychloroquine; Drug: methotrexate; Drug: sulfasalazine; Drug: leflunomide; Drug: intravenous placebo; Drug: tocilizumab; Drug: subcutaneous placebo

Detailed Description

Total study duration was up to 34 weeks: Screening up to 28 days, treatment phase of 24 weeks, and post-treatment follow-up of 6 weeks.

After completion of the treatment phase of this study, participants were eligible to enter a long term safety study (LTS11210) for active treatment with SAR153191 (REGN88).

• Study Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina, C1015ABO
    • Investigational Site Number 032006
  • Ramos Mejia, Argentina, B1704ETD
    • Investigational Site Number 032010
  • Rosario, Argentina, S200PBJ
    • Investigational Site Number 032013
  • San Fernando, Argentina
    • Investigational Site Number 032015
  • San Miguel De Tucuman, Argentina, 4000
    • Investigational Site Number 032004
  • Tucuman, Argentina, 4000
    • Investigational Site Number 032005
• Belgium
  • Leuven, Belgium, 3000
    • Investigational Site Number 056010
• Brazil
  • Curitiba, Brazil, 80060-240
    • Investigational Site Number 076001
  • Sao Jose Do Rio Preto, Brazil, 15090-000
    • Investigational Site Number 076030
• Czechia
  • Liberec, Czechia, 46063
    • Investigational Site Number 203009
  • Praha 2, Czechia, 12850
    • Investigational Site Number 203011
  • Praha 4, Czechia, 140 00
    • Investigational Site Number 203010
• Estonia
  • Tallinn, Estonia, 10138
    • Investigational Site Number 233010
  • Tallinn, Estonia, 13419
    • Investigational Site Number 233002
• Finland
  • Helsinki, Finland, 00290
    • Investigational Site Number 246001
  • Riihimäki, Finland, 11120
    • Investigational Site Number 246010
• Hungary
  • Budapest, Hungary, 1027
    • Investigational Site Number 348014
  • Budapest, Hungary, 1036
    • Investigational Site Number 348022
  • Esztergom, Hungary, 2500
    • Investigational Site Number 348021
  • Kistarcsa, Hungary, 2143
    • Investigational Site Number 348016
  • Szolnok, Hungary, 5000
    • Investigational Site Number 348009
  • Szombathely, Hungary, 9700
    • Investigational Site Number 348015
• Israel
  • Haifa, Israel, 31096
    • Investigational Site Number 376010
  • Tel Aviv, Israel, 64239
    • Investigational Site Number 376011
• Italy
  • Firenze, Italy, 50141
    • Investigational Site Number 380002
  • Genova, Italy, 16132
    • Investigational Site Number 380005
• Mexico
  • Durango, Mexico, 34080
    • Investigational Site Number 484008
  • Leon, Mexico, 37000
    • Investigational Site Number 484035
  • Merida, Mexico, 97000
    • Investigational Site Number 484009
  • México, D.F., Mexico, 11850
    • Investigational Site Number 484001
  • Zapopan, Mexico, 44280
    • Investigational Site Number 484036
• Netherlands
  • Amsterdam, Netherlands, 1056 AB
    • Investigational Site Number 528010
  • Leiden, Netherlands, 2333 ZA
    • Investigational Site Number 528001
• Norway
  • Kristiansand, Norway, 4604
    • Investigational Site Number 578010
  • Tønsberg, Norway, 3105
    • Investigational Site Number 578006
• Poland
  • Bydgoszcz, Poland, 85-168
    • Investigational Site Number 616019
  • Bytom, Poland, 41-902
    • Investigational Site Number 616054
  • Lublin, Poland, 20-090
    • Investigational Site Number 616030
  • Warszawa, Poland, 01-518
    • Investigational Site Number 616031
  • Warszawa, Poland, 02-653
    • Investigational Site Number 616017
• Romania
  • Braila, Romania, 810019
    • Investigational Site Number 642006
  • Bucharest, Romania
    • Investigational Site Number 642010
  • Bucharest, Romania, 020125
    • Investigational Site Number 642020
  • Bucuresti, Romania, 010584
    • Investigational Site Number 642021
  • Bucuresti, Romania, 010976
    • Investigational Site Number 642001
  • Targoviste, Romania, 130083
    • Investigational Site Number 642022
• Russian Federation
  • Kemerovo, Russian Federation, 650066
    • Investigational Site Number 643017
  • Moscow, Russian Federation, 115404
    • Investigational Site Number 643020
  • Moscow, Russian Federation, 115522
    • Investigational Site Number 643001
  • Moscow, Russian Federation, 117997
    • Investigational Site Number 643002
  • Moscow, Russian Federation, 121374
    • Investigational Site Number 643031
  • Moscow, Russian Federation, 125284
    • Investigational Site Number 643030
  • St-Petersburg, Russian Federation, 191186
    • Investigational Site Number 643032
• Spain
  • Barcelona, Spain, 08035
    • Investigational Site Number 724020
  • Santander, Spain, 39008
    • Investigational Site Number 724021
  • Sevilla, Spain, 41010
    • Investigational Site Number 724022
• Sweden
  • Malmö, Sweden, 205 02
    • Investigational Site Number 752004
  • Uppsala, Sweden, 751 85
    • Investigational Site Number 752002
• United Kingdom
  • Doncaster, United Kingdom, DN2 5LT
    • Investigational Site Number 826004
  • Edinburgh, United Kingdom, EH4 2XU
    • Investigational Site Number 826006
  • Leeds, United Kingdom, LS7 4SA
    • Investigational Site Number 826001
  • London, United Kingdom, E11 1NR
    • Investigational Site Number 826002
  • Southampton, United Kingdom, SO16 6YD
    • Investigational Site Number 826005
  • Wigan, United Kingdom, WN6 9EP
    • Investigational Site Number 826025
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Investigational Site Number 840152
  • Colorado
    • Colorado Springs, Colorado, United States, 80903
      • Investigational Site Number 840151
  • Florida
    • Aventura, Florida, United States, 33180
      • Investigational Site Number 840153
    • Fort Lauderdale, Florida, United States, 33334
      • Investigational Site Number 840033
    • Miami, Florida, United States, 33155
      • Investigational Site Number 840048
    • Palm Harbor, Florida, United States, 34684
      • Investigational Site Number 840155
  • Maryland
    • Wheaton, Maryland, United States, 20902
      • Investigational Site Number 840013
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Investigational Site Number 840154
  • Michigan
    • Lansing, Michigan, United States, 48910
      • Investigational Site Number 840150
  • Pennsylvania
    • Reading, Pennsylvania, United States, 19611
      • Investigational Site Number 840062
  • Texas
    • Austin, Texas, United States, 78705
      • Investigational Site Number 840038
    • Dallas, Texas, United States, 75235
      • Investigational Site Number 840022
    • Dallas, Texas, United States, 75246
      • Investigational Site Number 840156
    • Mesquite, Texas, United States, 75150
      • Investigational Site Number 840074

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

Diagnosis of RA was, according to the American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) 2010 Rheumatoid Arthritis Classification Criteria with ≥ 3 months disease duration

ACR Class I-III functional status, was based on the 1991 revised criteria. Moderate-to-severely active RA. Anti-TNF therapy failures, was defined as participants with an inadequate clinical response was defined by the investigator, after being treated for at least 3 consecutive months, and/or intolerance to at least 1 TNF-antagonist, resulting in or requiring their discontinuation. TNF-antagonists were include, but were not limited to, etanercept, infliximab, adalimumab, golimumab and/or certolizumab pegol

Continuous treatment with one or a combination of non-biologic disease modifying antirheumatic drugs (DMARDs) for at least 12 consecutive weeks prior to screening and on a stable dose(s) for at least 6 consecutive weeks prior to screening:

• Methotrexate - 10 to 25 milligram/week orally or parenteral (or per local labelling requirements if the dose range differs)
• Leflunomide - 10 to 20 mg orally daily
• Sulfasalazine (SSZ) - 1000 to 3000 mg orally daily
• Hydroxychloroquine (HCQ) - 200 to 400 mg orally daily

Exclusion criteria:

Participants <18 years of age. Use of parenteral corticosteroids or intra-articular corticosteroids within 4 weeks prior to screening

Use of oral corticosteroids in a dose higher than prednisone 10 mg or equivalent per day, or a change in dosage within 4 weeks prior to screening

Past history of, or current, autoimmune or inflammatory systemic or localized joint disease(s) other than RA

History of juvenile idiopathic arthritis or arthritis onset prior to age 16. Severe systemic RA, including but not limited to vasculitis, pulmonary fibrosis, and/or Felty's syndrome

Participation in any clinical research study that evaluated an investigational drug or therapy within 5 half-lives or 60 days of the Screening Visit, whichever was longer

Participants with active tuberculosis or latent tuberculosis infection. Prior or current history of interstitial lung disease. Prior treatment with anti-interleukin (IL) -6 or anti-IL-6R therapies, including but not limited to tocilizumab or sarilumab

Treatment with anti-TNF agents, as follows:

• Etanercept: within 28 days prior to randomization
• Infliximab, adalimumab, golimumab, certolizumab pegol: within 42 days prior to randomization

Treatment with RA-directed biologic agents with non- TNF-α antagonist mechanisms without adequate washout as follows:

• Anakinra: within 28 days prior to randomization
• Abatacept: within 42 days prior to randomization
• Rituximab or other cell depleting agent: Within 6 months prior to randomization or until total lymphocyte count and CD 19+ lymphocyte count were normalized, or whichever was longer

Prior treatment with a janus kinase (JAK) inhibitor (eg, tofacitinib). Participants with a history of invasive opportunistic infection. Prior or current history of malignancy, including lymphoproliferative diseases, other than adequately-treated carcinoma in-situ of the cervix, nonmetastatic squamous cell or basal cell carcinoma of the skin, within 5 years prior to the randomization (baseline) visit

Prior or current history of other significant concomitant illness(es) that, according to Investigator's judgement, was adversely affect the participant's participation in the study.

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sarilumab 150 mg q2w; Sarilumab 150 mg subcutaneous (SC) injection once every 2 weeks (q2w) and placebo intravenous (IV) infusion once every 4 weeks (q4w) was added to one or a combination of the nonbiologic disease modifying antirheumatic drug (DMARD), hydroxychloroquine, methotrexate, sulfasalazine and/or leflunomide for 24 weeks, except for the simultaneous use of leflunomide and methotrexate.	Drug: sarilumab SAR153191 (REGN88); Pharmaceutical form: solution Route of administration: subcutaneous; Drug: hydroxychloroquine; Dispensed according to local practice.; Drug: methotrexate; Dispensed according to local practice.; Drug: sulfasalazine; Dispensed according to local practice.; Drug: leflunomide; Dispensed according to local practice.; Drug: intravenous placebo; Pharmaceutical form: solution Route of administration: intravenous
Experimental: Sarilumab 200 mg q2w; Sarilumab 200 mg SC injection q2w and placebo IV infusion q4w was added to one or a combination of the nonbiologic DMARD, hydroxychloroquine, methotrexate, sulfasalazine and/or leflunomide for 24 weeks, except for the simultaneous use of leflunomide and methotrexate.	Drug: sarilumab SAR153191 (REGN88); Pharmaceutical form: solution Route of administration: subcutaneous; Drug: hydroxychloroquine; Dispensed according to local practice.; Drug: methotrexate; Dispensed according to local practice.; Drug: sulfasalazine; Dispensed according to local practice.; Drug: leflunomide; Dispensed according to local practice.; Drug: intravenous placebo; Pharmaceutical form: solution Route of administration: intravenous
Active Comparator: Tocilizumab q4w; Tocilizumab 4 mg/kg or 8 mg/kg IV infusion q4w and placebo SC injection q2w was added to one or a combination of the nonbiologic DMARD, hydroxychloroquine, methotrexate, sulfasalazine and/or leflunomide for 24 weeks, except for the simultaneous use of leflunomide and methotrexate.	Drug: hydroxychloroquine; Dispensed according to local practice.; Drug: methotrexate; Dispensed according to local practice.; Drug: sulfasalazine; Dispensed according to local practice.; Drug: leflunomide; Dispensed according to local practice.; Drug: tocilizumab; Pharmaceutical form: solution Route of administration: intravenous; Drug: subcutaneous placebo; Pharmaceutical form: solution Route of administration: subcutaneous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	Adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and does not necessary have to have a causal relationship with treatment. All adverse events that occurred from the first dose of the study drug administration up to 60 days after the end of treatment visit were considered as TEAEs. Serious AE (SAE) was an AE 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. A summary of SAEs, all other non-serious AEs, regardless of causality, are reported in AE section.	Up to 211 days

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Rehberg M, Giegerich C, Praestgaard A, van Hoogstraten H, Iglesias-Rodriguez M, Curtis JR, Gottenberg JE, Schwarting A, Castaneda S, Rubbert-Roth A, Choy EHS; MOBILITY, MONARCH, TARGET, and ASCERTAIN investigators. Identification of a Rule to Predict Response to Sarilumab in Patients with Rheumatoid Arthritis Using Machine Learning and Clinical Trial Data. Rheumatol Ther. 2021 Dec;8(4):1661-1675. doi: 10.1007/s40744-021-00361-5. Epub 2021 Sep 14. Erratum In: Rheumatol Ther. 2021 Oct 29;:
• Kovalenko P, Paccaly A, Boyapati A, Xu C, St John G, Nivens MC, Davis JD, Rippley R, DiCioccio AT. Population Pharmacodynamic Model of Neutrophil Margination and Tolerance to Describe Effect of Sarilumab on Absolute Neutrophil Count in Patients with Rheumatoid Arthritis. CPT Pharmacometrics Syst Pharmacol. 2020 Jul;9(7):405-416. doi: 10.1002/psp4.12534. Epub 2020 Jun 20.
• Emery P, Rondon J, Parrino J, Lin Y, Pena-Rossi C, van Hoogstraten H, Graham NMH, Liu N, Paccaly A, Wu R, Spindler A. Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019 May 1;58(5):849-858. doi: 10.1093/rheumatology/key361.

Study record dates

Study Major Dates

• Study Start: March 1, 2013
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: January 11, 2013
• First Submitted That Met QC Criteria: January 11, 2013
• First Posted (Estimate): January 15, 2013

Study Record Updates

• Last Update Posted (Actual): June 26, 2017
• Last Update Submitted That Met QC Criteria: June 23, 2017
• Last Verified: June 1, 2017

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; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Dermatologic Agents; Reproductive Control Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Methotrexate; Leflunomide; Hydroxychloroquine; Sulfasalazine
• Other Study ID Numbers: SFY13370; 2012-003536-23; U1111-1133-7839 (Other Identifier: UTN)