Clinical trial NCT02332590: Efficacy and Safety of Sarilumab and Adalimumab Monotherapy in Patients With Rheumatoid Arthritis (SARIL-RA-MONARCH)
Official title: A Randomized, Double-blind, Parallel-group Study Assessing the Efficacy and Safety of Sarilumab Monotherapy Versus Adalimumab Monotherapy in Patients With Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Regeneron Pharmaceuticals
First posted: 2015-01-07
Enrollment: 369
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: During the OLE period of this study, all participants received sarilumab 200 mg or 150 mg q2w via prefilled syringe.
Primary purpose: TREATMENT

Brief summary: Primary Objective:

To demonstrate that sarilumab monotherapy was superior to adalimumab monotherapy with respect to signs and symptoms as assessed by disease activity score 28 (DAS28)-erythrocyte sedimentation rate (ESR) in participants with active rheumatoid arthritis (RA) who were either intolerant of, or considered inappropriate candidates for continued treatment with methotrexate (MTX), or after at least 12 weeks of continued treatment with MTX, were determined to be inadequate responders.

Secondary Objectives:

To demonstrate that sarilumab monotherapy was superior to adalimumab monotherapy in participants with active RA who were either intolerant of, or considered inappropriate candidates for continued treatment with MTX, or after at least 12 weeks of continued treatment with MTX, were determined to be inadequate responders, with respect to:

* Reduction of signs and symptoms of RA.
* Improvement in quality of life assessed by participant reported outcome questionnaires.

Assessment of the safety and tolerability of sarilumab monotherapy (including immunogenicity) throughout the study.

Detailed description: Total study duration was up to 310 weeks: Up to a 4 week screening period, 24 week randomized double-blind treatment phase, 276-week open-label extension, and 6 weeks post-treatment final study visit.

Eligibility criteria: Inclusion criteria:

* Diagnosis of RA greater than or equal to (\>=)3 months duration.
* American College of Rheumatology (ACR) Class I-III functional status.
* Active RA was defined as:

At least 6 of 66 swollen joints and 8 of 68 tender joints, high sensitivity C-reactive protein (hs-CRP) \>=8 mg/L or ESR \>=28 millimeter per hour (mm/H), and DAS28-ESR greater than (\>) 5.1.

* Participants as per Investigator judgment were either intolerant of, or considered inappropriate candidates for continued treatment with MTX, or after at least 12 weeks of continued treatment with MTX, or inadequate responders treated with an adequate MTX dose for at least 12 weeks.

Exclusion criteria:

* Age \<18 years or the legal age of consent in the country of the study site, whichever was higher.
* Current treatment with disease-modifying antirheumatic drug (DMARDs)/immunosuppressive agents including MTX, cyclosporine, mycophenolate, tacrolimus, gold, penicillamine, sulfasalazine or hydroxychloroquine within 2 weeks prior to the baseline (Randomization Visit) or azathioprine, cyclophosphamide within 12 weeks prior to baseline (Randomization Visit) or leflunomide within 8 weeks prior to the Randomization Visit, or 4 weeks after cholestyramine washout.
* Treatment with any prior biologic agent, including anti-interleukin 6 (IL-6), IL-6 receptor (IL-6R) antagonists, and prior treatment with a Janus kinase inhibitor.
* Use of parenteral corticosteroids or intra-articular corticosteroids within 4 weeks prior to screening.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: DB Period: Change From Baseline in Disease Activity Score for 28 Joints - Erythrocyte Sedimentation Rate (DAS28-ESR) Score at Week 24
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: DB Period: Percentage of Participants Achieving Clinical Remission Score (DAS28-ESR <2.6) at Week 24
timeFrame: Week 24
measure: DB Period: Percentage of Participants Achieving ACR50 Criteria at Week 24
timeFrame: Week 24
measure: DB Period: Percentage of Participants Achieving ACR70 Criteria at Week 24
timeFrame: Week 24
measure: DB Period: Percentage of Participants Achieving ACR20 Criteria at Week 24
timeFrame: Week 24
measure: DB Period: Change From Baseline in HAQ-DI at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Short-Form-36 (SF-36) - Physical Component Summary (PCS) Score at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in SF-36 - Mental Health Component Summary Score at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Disease Activity Score for 28 Joints Based on C-Reactive Protein (DAS28-CRP Score) at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Percentage of Participants Achieving Clinical Remission Score (DAS28-CRP <2.6) at Week 24
timeFrame: Week 24
measure: DB Period: Percentage of Participants Achieving Low Disease Activity (DAS28-ESR < 3.2) at Week 24
timeFrame: Week 24
measure: DB Period: Percentage of Participants Achieving Clinical Disease Activity Index (CDAI) Remission (CDAI ≤2.8) at Week 24
timeFrame: Week 24
measure: DB Period: Change From Baseline in CDAI at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in European Quality of Life-5 Dimension 3 Level (EQ-5D-3L) Scores at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Work Productivity Survey - Rheumatoid Arthritis (WPS-RA) at Week 24: Work Days Missed Due to Arthritis
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in WPS-RA at Week 24: Days With Work Productivity Reduced by ≥ 50% Due to Arthritis
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in WPS-RA at Week 24: Arthritis Interference With Work Productivity
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in WPS-RA at Week 24: House Work Days Missed Due to Arthritis
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in WPS-RA at Week 24: Days With Household Work Productivity Reduced by >= 50% Due to Arthritis
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in WPS-RA at Week 24: Days With Family/Social/Leisure Activities Missed Due to Arthritis
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in WPS-RA at Week 24: Days With Outside Help Hired Due to Arthritis
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in WPS-RA at Week 24: RA Interference With Household Work Productivity
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Morning Stiffness VAS at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Individual ACR Component - TJC and SJC at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Individual ACR Component - Physician Global VAS, Participant Global VAS and Pain VAS at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Individual ACR Component - CRP Level at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Change From Baseline in Individual ACR Component- ESR Level at Week 24
timeFrame: Baseline, Week 24
measure: DB Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Treatment-emergent Adverse Events and Serious Adverse Events
timeFrame: From end of Week 24 (Baseline of OLE Period) up to last dose in OLE + 6 weeks of follow up (i.e. up to Week 306)
measure: DB Period: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) - Hematological Parameters
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Hematological Parameters
timeFrame: From end of Week 24 (Baseline of OLE Period) up to Week 300
measure: DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Liver Function Tests
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Liver Function Tests
timeFrame: From end of Week 24 (Baseline of OLE Period) up to Week 300
measure: DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Metabolic Parameters
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Metabolic Parameters
timeFrame: From end of Week 24 (Baseline of OLE Period) up to Week 300
measure: DB Period: Number of Participants With Different Post-baseline Categories of High-density Lipoprotein (HDL)
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Different Post-baseline Categories of High-density Lipoprotein
timeFrame: From end of Week 24 (Baseline of OLE Period) up to Week 300
measure: DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Renal Function
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Renal Function
timeFrame: From end of Week 24 (Baseline of OLE Period) up to Week 300
measure: DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Urinalysis
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Urinalysis
timeFrame: From end of Week 24 (Baseline of OLE Period) up to Week 300
measure: DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Electrolytes
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Electrolytes
timeFrame: From end of Week 24 (Baseline of OLE Period) up to Week 300
measure: DB Period: Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Potentially Clinically Significant Electrocardiogram Abnormalities
timeFrame: From end of Week 24 (Baseline of OLE Period) up to Week 300
measure: DB Period: Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities
timeFrame: From Week 0 to Week 24
measure: OLE Period: Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities
timeFrame: From end of Week 24 (Baseline of OLE Period) up to Week 300
measure: DB Period: Number of Participants With Treatment-emergent and Treatment-boosted Anti-drug Antibody (ADA) Response
timeFrame: From Week 0 to Week 24
measure: Number of Participants With Treatment-emergent and Treatment-boosted Anti-drug Antibody Response During Entire Treatment-emergent Adverse Event Period
timeFrame: From Week 0 up to last dose in OLE + 6 weeks of follow-up (i.e. up to Week 306)
measure: DB Period: Pharmacokinetics: Serum Trough (Pre-dose) Concentrations of Functional Sarilumab
timeFrame: Pre-dose at Week 0 (Baseline), 2, 4, 12, 16, 20, and 24
measure: OLE Period: Pharmacokinetics: Serum Trough (Pre-dose) Concentrations of Functional Sarilumab
timeFrame: Pre-dose at Week 24 (Baseline of OLE period), 36, 48, 60, 84, 108, 132, 156, 180, 204, 228, 252, 276, 300 and 306
Other outcomes:
Locations:
city: Covina
country: United States
facility: Investigational Site Number 840407
state: California
city: Long Beach
country: United States
facility: Investigational Site Number 840400
state: California
city: Whittier
country: United States
facility: Investigational Site Number 840141
state: California
city: Lewes
country: United States
facility: Investigational Site Number 840130
state: Delaware
city: Coral Gables
country: United States
facility: Investigational Site Number 840229
state: Florida
city: Ormond Beach
country: United States
facility: Investigational Site Number 840128
state: Florida
city: Saint Petersburg
country: United States
facility: Investigational Site Number 840403
state: Florida
city: Tampa
country: United States
facility: Investigational Site Number 840140
state: Florida
city: Cumberland
country: United States
facility: Investigational Site Number 840073
state: Maryland
city: Hagerstown
country: United States
facility: Investigational Site Number 840202
state: Maryland
city: Flint
country: United States
facility: Investigational Site Number 840232
state: Michigan
city: Lincoln
country: United States
facility: Investigational Site Number 840112
state: Nebraska
city: Charlotte
country: United States
facility: Investigational Site Number 840402
state: North Carolina
city: Hickory
country: United States
facility: Investigational Site Number 840406
state: North Carolina
city: Middleburg Heights
country: United States
facility: Investigational Site Number 840404
state: Ohio
city: Oklahoma City
country: United States
facility: Investigational Site Number 840127
state: Oklahoma
city: Mesquite
country: United States
facility: Investigational Site Number 840074
state: Texas
city: Osorno
country: Chile
facility: Investigational Site Number 152005
city: Puerto Varas
country: Chile
facility: Investigational Site Number 152001
city: Santiago
country: Chile
facility: Investigational Site Number 152002
city: Santiago
country: Chile
facility: Investigational Site Number 152050
city: Talca
country: Chile
facility: Investigational Site Number 152014
city: Temuco IX Region
country: Chile
facility: Investigational Site Number 152015
city: Viña Del Mar
country: Chile
facility: Investigational Site Number 152007
city: Praha 11
country: Czechia
facility: Investigational Site Number 203033
city: Praha 2
country: Czechia
facility: Investigational Site Number 203001
city: Praha 4
country: Czechia
facility: Investigational Site Number 203030
city: Uherske Hradiste
country: Czechia
facility: Investigational Site Number 203002
city: Köln
country: Germany
facility: Investigational Site Number 276058
city: Osnabrück
country: Germany
facility: Investigational Site Number 276021
city: Budapest
country: Hungary
facility: Investigational Site Number 348025
city: Budapest
country: Hungary
facility: Investigational Site Number 348020
city: Budapest
country: Hungary
facility: Investigational Site Number 348022
city: Szombathely
country: Hungary
facility: Investigational Site Number 348024
city: Veszprém
country: Hungary
facility: Investigational Site Number 348023
city: Ashkelon
country: Israel
facility: Investigational Site Number 376032
city: Haifa
country: Israel
facility: Investigational Site Number 376031
city: Ramat Gan
country: Israel
facility: Investigational Site Number 376030
city: Tel Aviv
country: Israel
facility: Investigational Site Number 376011
city: Daegu
country: Korea, Republic of
facility: Investigational Site Number 410005
city: Daejeon
country: Korea, Republic of
facility: Investigational Site Number 410004
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410006
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410001
city: Lima
country: Peru
facility: Investigational Site Number 604003
city: Lima
country: Peru
facility: Investigational Site Number 604005
city: Lima
country: Peru
facility: Investigational Site Number 604022
city: Bytom
country: Poland
facility: Investigational Site Number 616056
city: Elblag
country: Poland
facility: Investigational Site Number 616015
city: Lublin
country: Poland
facility: Investigational Site Number 616005
city: Lublin
country: Poland
facility: Investigational Site Number 616030
city: Nadarzyn
country: Poland
facility: Investigational Site Number 616055
city: Poznan
country: Poland
facility: Investigational Site Number 616018
city: Szczecin
country: Poland
facility: Investigational Site Number 616016
city: Warszawa
country: Poland
facility: Investigational Site Number 616004
city: Warszawa
country: Poland
facility: Investigational Site Number 616031
city: Braila
country: Romania
facility: Investigational Site Number 642006
city: Bucharest
country: Romania
facility: Investigational Site Number 642010
city: Bucuresti
country: Romania
facility: Investigational Site Number 642001
city: Bucuresti
country: Romania
facility: Investigational Site Number 642002
city: Galati
country: Romania
facility: Investigational Site Number 642005
city: Kemerovo
country: Russian Federation
facility: Investigational Site Number 643006
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643020
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643001
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643031
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643030
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site Number 643008
city: Saratov
country: Russian Federation
facility: Investigational Site Number 643011
city: Cape Town
country: South Africa
facility: Investigational Site Number 710011
city: Cape Town
country: South Africa
facility: Investigational Site Number 710007
city: Kempton Park
country: South Africa
facility: Investigational Site Number 710004
city: Barakaldo
country: Spain
facility: Investigational Site Number 724003
city: Barcelona / Sabadell
country: Spain
facility: Investigational Site Number 724011
city: Barcelona
country: Spain
facility: Investigational Site Number 724015
city: Málaga
country: Spain
facility: Investigational Site Number 724001
city: Santiago De Compostela
country: Spain
facility: Investigational Site Number 724012
city: Sevilla
country: Spain
facility: Investigational Site Number 724007
city: Ivano-Frankivsk
country: Ukraine
facility: Investigational Site Number 804029
city: Kharkiv
country: Ukraine
facility: Investigational Site Number 804048
city: Kyiv
country: Ukraine
facility: Investigational Site Number 804014
city: Kyiv
country: Ukraine
facility: Investigational Site Number 804047
city: Lutsk
country: Ukraine
facility: Investigational Site Number 804037
city: Lviv
country: Ukraine
facility: Investigational Site Number 804046
city: Poltava
country: Ukraine
facility: Investigational Site Number 804049
city: Vinnitsya
country: Ukraine
facility: Investigational Site Number 804011
city: Vinnitsya
country: Ukraine
facility: Investigational Site Number 804043
city: Leytonstone
country: United Kingdom
facility: Investigational Site Number 826001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Rubbert-Roth A, Furst DE, Fiore S, Praestgaard A, Bykerk V, Bingham CO, Charles-Schoeman C, Burmester G. Association between low hemoglobin, clinical measures, and patient-reported outcomes in patients with rheumatoid arthritis: results from post hoc analyses of three phase III trials of sarilumab. Arthritis Res Ther. 2022 Aug 25;24(1):207. doi: 10.1186/s13075-022-02891-x.
citation: 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.
citation: Strand V, Boklage SH, Kimura T, Joly F, Boyapati A, Msihid J. High levels of interleukin-6 in patients with rheumatoid arthritis are associated with greater improvements in health-related quality of life for sarilumab compared with adalimumab. Arthritis Res Ther. 2020 Oct 20;22(1):250. doi: 10.1186/s13075-020-02344-3.
citation: Genovese MC, Burmester GR, Hagino O, Thangavelu K, Iglesias-Rodriguez M, John GS, Gonzalez-Gay MA, Mandrup-Poulsen T, Fleischmann R. Interleukin-6 receptor blockade or TNFalpha 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.
citation: 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.
citation: 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.
citation: Gabay C, Burmester GR, Strand V, Msihid J, Zilberstein M, Kimura T, van Hoogstraten H, Boklage SH, Sadeh J, Graham NMH, Boyapati A. Sarilumab and adalimumab differential effects on bone remodelling and cardiovascular risk biomarkers, and predictions of treatment outcomes. Arthritis Res Ther. 2020 Apr 7;22(1):70. doi: 10.1186/s13075-020-02163-6.
citation: Burmester GR, Strand V, Rubbert-Roth A, Amital H, Raskina T, Gomez-Centeno A, Pena-Rossi C, Gervitz L, Thangavelu K, St John G, Boklage S, Genovese MC. Safety and efficacy of switching from adalimumab to sarilumab in patients with rheumatoid arthritis in the ongoing MONARCH open-label extension. RMD Open. 2019 Oct 18;5(2):e001017. doi: 10.1136/rmdopen-2019-001017. eCollection 2019.
citation: Gossec L, Strand V, Proudfoot C, Chen CI, Guillonneau S, Kimura T, van Hoogstraten H, Mangan E, Reaney M. Effects of Sarilumab on Rheumatoid Arthritis as Reported by Patients Using the Rheumatoid Arthritis Impact of Disease Scale. J Rheumatol. 2019 Oct;46(10):1259-1267. doi: 10.3899/jrheum.180904. Epub 2019 Mar 15.
citation: Burmester GR, Lin Y, Patel R, van Adelsberg J, Mangan EK, Graham NM, van Hoogstraten H, Bauer D, Ignacio Vargas J, Lee EB. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017 May;76(5):840-847. doi: 10.1136/annrheumdis-2016-210310. Epub 2016 Nov 17.