INTERVENTION: Product Name: Sarilumab Product Code: SAR153191 (REGN88) Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: Sarilumab Current Sponsor code: SAR153191 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Trade Name: Humira, 40 mg solution for injection in pre‐filled syringe Product Name: adalimumab Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed INN: ADALIMUMAB CAS Number: 331731‐18‐1 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 40‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use CONDITION: Rheumatoid Arthritis ; MedDRA version: 17.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: To demonstrate that sarilumab monotherapy is superior to adalimumab monotherapy with respect to signs and symptoms as assessed by disease activity score 28 (DAS28)‐erythrocyte sedimentation rate (ESR) in patients with active rheumatoid arthritis (RA) who are either intolerant of, or considered inappropriate candidates for continued treatment with methotrexate (MTX), or after at least 12 weeks of continuous treatment with MTX, are determined to be inadequate responders. Primary end point(s): Change from baseline in disease activity score 28 (DAS28) ‐ erythrocyte sedimentation rate (ESR) Secondary Objective: To demonstrate that sarilumab monotherapy is superior to adalimumab monotherapy in patients with active RA who are either intolerant of, or considered inappropriate candidates for continued treatment with methotrexate (MTX), or after at least 12 weeks of continuous treatment with MTX, are determined to be inadequate responders, with respect to:; • Reduction of signs and symptoms of RA ; • Improvement in quality of life assessed by patient reported outcome questionnaires. ; Assessment of the safety and tolerability of sarilumab monotherapy (including immunogenicity) throughout the study. Timepoint(s) of evaluation of this end point: Week 24 SECONDARY OUTCOME: Secondary end point(s): 1‐ American College of Rheumatology 20 (ACR2020, ACR50 and ACR70 response ; 2‐ Change from baseline in each individual ACR component ; 3‐ Change from baseline in DAS28‐CRP ; 4‐ DAS28‐ESR remission (<2.6) ; 5‐ DAS28‐CRP remission (<2.6) ; 6‐ Low disease activity (DAS28‐ESR <3.2) ; 7‐ Remission based on clinical disease activity index (CDAI) (=2.8) ; 8‐ Change from baseline in CDAI ; 9‐ Sarilumab exposure assessed by trough serum sarilumab concentrations. ; 10‐ Change from baseline in: short form 36 (SF‐36) scores ; Change from baseline in: EQ‐5D‐3L scores ; Change from baseline in: rheumatoid arthritis impact of disease (RAID) scores ; Change from baseline in: work productivity survey‐rheumatoid arthritis (WPS‐RA) scores ; Change from baseline in: functional assessment of chronic illness therapy‐fatigue (FACIT‐F) scores ; Change from baseline in: morning stiffness visual analog scale (VAS) scores ; 11‐ Number of patients with adverse events ; Clinically significant changes in laboratory values, ECG and vital signs ; Measurement of anti‐drug antibody (ADA) levels ; Timepoint(s) of evaluation of this end point: 1 to 8: week 24 ; 9: week 54 ; 10: week 24 ; 11: week 54 INCLUSION CRITERIA: Diagnosis of rheumatoid arthritis =3 months duration. American College of Rheumatology (ACR) Class I‐III functional status. Active RA, 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 mm/H, and ‐ DAS28ESR >5.1. Patients who per investigator judgment were either intolerant of, or considered inappropriate candidates for continued treatment with methotrexate (MTX), or after at least 12 weeks of continuous treatment with MTX, or inadequate responders treated with an adequate MTX dose for at least 12 weeks. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 230 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 110
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.
OBJECTIVES: To compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response.
METHODS: MONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24.
RESULTS: Sarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (-3.28 vs -2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences.
CONCLUSIONS: Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects.
TRIAL REGISTRATION NUMBER: NCT02332590.
Aim: Sarilumab is a human mAb blocking the IL‐6Ralpha. Efficacy and safety of sarilumab + non‐biologic DMARDs have been demonstrated. In this phase 3 trial, efficacy and safety of sarilumab monotherapy were compared with adalimumab monotherapy in adult patients with active RA (NCT02332590). Methods: Adults (N = 369) intolerant of, inappropriate for, or inadequate responders to MTX received subcutaneous sarilumab (200 mg q2w) or adalimumab (40 mg q2w) monotherapy for 24 weeks in this doubleblind, double‐dummy, superiority study. Starting at week 16, patients with inadequate response could increase to weekly adalimumab (or matching placebo). The primary endpoint was change from baseline in DAS28‐ESR at week 24. Results: Baseline demographics and disease characteristics were generally comparable between treatment groups. At week 24, significantly greater decrease in DAS28‐ESR (‐3.3 vs 2.2; P < 0.0001), greater incidence of DAS28‐ESR remission (26.6% vs 7.0%; P < 0.0001) and ACR20/50/70 responses (71.7%/45.7%/23.4% vs 58.4%/29.7%/11.9%; all P <= 0.0074), and improvement in HAQ‐DI (‐0.6 vs ‐0.4; P = 0.0037) were observed with sarilumab vs adalimumab; results included patients switching to weekly adalimumab. Patients in the sarilumab group were twice as likely to achieve CDAI remission at week 24 vs adalimumab (nominal P < 0.05). The incidences of AEs and serious AEs were similar in both groups, including incidences of infections and serious infections. The most common AEs were neutropenia and injection site erythema (sarilumab) and headache and worsening of RA (adalimumab). Conclusions: Sarilumab monotherapy demonstrated superiority to adalimumab monotherapy in reduction of disease activity and improvement in physical function in patients with active RA who were inappropriate candidates for continued treatment with MTX due to intolerance or inadequate response. The overall incidences of AEs and serious AEs were similar between groups, as was the rate of infections and serious infections.
BACKGROUND: The phase III MONARCH randomized controlled trial (NCT02332590) demonstrated that in patients with rheumatoid arthritis (RA), sarilumab (anti-interleukin-6 receptor monoclonal antibody) monotherapy is superior to adalimumab monotherapy in reducing disease activity and signs and symptoms of RA, as well as in improving physical function, with similar rates of adverse and serious adverse events. We report the effects of sarilumab versus adalimumab on patient-reported outcomes (PROs).
METHODS: Patients with active RA intolerant of, or inadequate responders to, methotrexate were randomized to sarilumab 200 mg plus placebo every 2 weeks (q2w; n = 184) or adalimumab 40 mg plus placebo q2w (n = 185). Dose escalation to weekly administration of adalimumab or matching placebo was permitted at week 16. PROs assessed at baseline and weeks 12 and 24 included patient global assessment of disease activity (PtGA), pain and morning stiffness visual analogue scales (VASs), Health Assessment Questionnaire Disability Index (HAQ-DI), 36-item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Rheumatoid Arthritis Impact of Disease (RAID), and rheumatoid arthritis-specific Work Productivity Survey (WPS-RA). Between-group differences in least-squares mean (LSM) changes from baseline were analyzed. p < 0.05 was considered significant for PROs in a predefined hierarchy. For PROs not in the hierarchy, nominal p values are provided. Proportions of patients reporting improvements greater than or equal to the minimal clinically important difference (MCID) and achieving normative values were assessed.
RESULTS: At week 24, sarilumab treatment resulted in significantly greater LSM changes from baseline than adalimumab monotherapy in HAQ-DI (p < 0.005), PtGA (p < 0.001), pain VAS (p < 0.001), and SF-36 Physical Component Summary (PCS) (p < 0.001). Greater LSM changes were reported for sarilumab than for adalimumab in RAID (nominal p < 0.001), morning stiffness VAS (nominal p < 0.05), and WPS-RA (nominal p < 0.005). Between-group differences in FACIT-F and SF-36 Mental Component Summary (MCS) were not significant. More patients reported improvements greater than or equal to the MCID in HAQ-DI (nominal p < 0.01), RAID (nominal p < 0.01), SF-36 PCS (nominal p < 0.005), and morning stiffness (nominal p < 0.05), as well as greater than or equal to the normative values in HAQ-DI (p < 0.05), with sarilumab versus adalimumab.
CONCLUSIONS: In parallel with the clinical efficacy profile previously reported, sarilumab monotherapy resulted in greater improvements across multiple PROs than adalimumab monotherapy.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT02332590 . Registered on 5 January 2015.
Product Name: Sarilumab Product Code: SAR153191 (REGN88) Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed
INN:
Sarilumab Current Sponsor code: SAR153191 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 200‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use Trade Name: Humira, 40 mg solution for injection in pre‐filled syringe Product Name: adalimumab Pharmaceutical Form: Solution for injection in pre‐filled syringe INN or Proposed
INN:
ADALIMUMAB CAS Number: 331731‐18‐1 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 40‐ Pharmaceutical form of the placebo: Solution for injection in pre‐filled syringe Route of administration of the placebo: Subcutaneous use
Main Objective: To demonstrate that sarilumab monotherapy is superior to adalimumab monotherapy with respect to signs and symptoms as assessed by disease activity score 28 (DAS28)‐erythrocyte sedimentation rate (ESR) in patients with active rheumatoid arthritis (RA) who are either intolerant of, or considered inappropriate candidates for continued treatment with methotrexate (MTX), or after at least 12 weeks of continuous treatment with MTX, are determined to be inadequate responders. Primary end point(s): Change from baseline in disease activity score 28 (DAS28) ‐ erythrocyte sedimentation rate (ESR) Secondary Objective: To demonstrate that sarilumab monotherapy is superior to adalimumab monotherapy in patients with active RA who are either intolerant of, or considered inappropriate candidates for continued treatment with methotrexate (MTX), or after at least 12 weeks of continuous treatment with MTX, are determined to be inadequate responders, with respect to:; • Reduction of signs and symptoms of RA ; • Improvement in quality of life assessed by patient reported outcome questionnaires. ; Assessment of the safety and tolerability of sarilumab monotherapy (including immunogenicity) throughout the study. Timepoint(s) of evaluation of this end point: Week 24
SECONDARY OUTCOME:
Secondary end point(s): 1‐ American College of Rheumatology 20 (ACR2020, ACR50 and ACR70 response ; 2‐ Change from baseline in each individual ACR component ; 3‐ Change from baseline in DAS28‐CRP ; 4‐ DAS28‐ESR remission (<2.6) ; 5‐ DAS28‐CRP remission (<2.6) ; 6‐ Low disease activity (DAS28‐ESR <3.2) ; 7‐ Remission based on clinical disease activity index (CDAI) (=2.8) ; 8‐ Change from baseline in CDAI ; 9‐ Sarilumab exposure assessed by trough serum sarilumab concentrations. ; 10‐ Change from baseline in: short form 36 (SF‐36) scores ; Change from baseline in: EQ‐5D‐3L scores ; Change from baseline in: rheumatoid arthritis impact of disease (RAID) scores ; Change from baseline in: work productivity survey‐rheumatoid arthritis (WPS‐RA) scores ; Change from baseline in: functional assessment of chronic illness therapy‐fatigue (FACIT‐F) scores ; Change from baseline in: morning stiffness visual analog scale (VAS) scores ; 11‐ Number of patients with adverse events ; Clinically significant changes in laboratory values, ECG and vital signs ; Measurement of anti‐drug antibody (ADA) levels ; Timepoint(s) of evaluation of this end point: 1 to 8: week 24 ; 9: week 54 ; 10: week 24 ; 11: week 54
INCLUSION CRITERIA:
Diagnosis of rheumatoid arthritis =3 months duration. American College of Rheumatology (ACR) Class I‐III functional status. Active RA, 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 mm/H, and ‐ DAS28ESR >5.1. Patients who per investigator judgment were either intolerant of, or considered inappropriate candidates for continued treatment with methotrexate (MTX), or after at least 12 weeks of continuous treatment with MTX, or inadequate responders treated with an adequate MTX dose for at least 12 weeks. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 230 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 110
