Efficacy and Safety of Sarilumab and Adalimumab Monotherapy in Patients With Rheumatoid Arthritis (SARIL-RA-MONARCH)
- Conditions
- Rheumatoid Arthritis
- Interventions
- Registration Number
- NCT02332590
- Lead Sponsor
- Sanofi
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 369
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Sarilumab 200 mg/Sarilumab 200 mg Placebo (for adalimumab) Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of participants with inadequate response (\<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Participants who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). Adalimumab 40 mg/Sarilumab 200 mg Placebo (for sarilumab) Adalimumab 40 milligrams (mg) subcutaneous (SC) injection in combination with placebo for sarilumab every 2 weeks (q2w) for 24 weeks during the double-blind (DB) period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of participants with inadequate response (less than \[\<\] 20% improvement from baseline in tender joint count \[TJC\] and swollen joint count \[SJC\] for 2 consecutive visits) at or after Week 16 until Week 23. Participants who completed 24 weeks in the DB period had the option to continue in open label extension (OLE) period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). Adalimumab 40 mg/Sarilumab 200 mg Adalimumab Adalimumab 40 milligrams (mg) subcutaneous (SC) injection in combination with placebo for sarilumab every 2 weeks (q2w) for 24 weeks during the double-blind (DB) period. The dosing frequency of adalimumab was adjusted to 40 mg every week (qw) dosing in case of participants with inadequate response (less than \[\<\] 20% improvement from baseline in tender joint count \[TJC\] and swollen joint count \[SJC\] for 2 consecutive visits) at or after Week 16 until Week 23. Participants who completed 24 weeks in the DB period had the option to continue in open label extension (OLE) period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300). Sarilumab 200 mg/Sarilumab 200 mg Sarilumab Sarilumab 200 mg SC injection in combination with placebo for adalimumab q2w for 24 weeks during the DB period. The dosing frequency of placebo for adalimumab was adjusted to 40 mg qw dosing in case of participants with inadequate response (\<20% improvement from baseline in TJC and SJC for 2 consecutive visits) at or after Week 16 until Week 23. Participants who completed 24 weeks in the DB period had the option to continue in OLE period and received sarilumab 200 mg q2w until commercial availability of sarilumab in their country or up to a maximum of an additional 276 weeks (i.e. up to Week 300).
- Primary Outcome Measures
Name Time Method DB Period: Change From Baseline in Disease Activity Score for 28 Joints - Erythrocyte Sedimentation Rate (DAS28-ESR) Score at Week 24 Baseline, Week 24 DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the participant assessed from the ACR and RA core set questionnaire (participant global assessment) in 100 mm VAS; Marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Least square (LS) mean and standard error (SE) at Week 24 were obtained using Mixed-effect model with repeated measures (MMRM) approach.
- Secondary Outcome Measures
Name Time Method DB Period: Percentage of Participants Achieving Clinical Remission Score (DAS28-ESR <2.6) at Week 24 Week 24 DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the participant assessed from the ACR RA core set questionnaire (participant global assessment) in 100 mm VAS; Marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Participants who discontinued treatment prior to Week 24 were analyzed as non-responders.
DB Period: Percentage of Participants Achieving ACR50 Criteria at Week 24 Week 24 ACR responses are assessed with a composite rating scale of the ACR that includes 7 variables: TJC (68 joints); SJC (66 joints); levels of an acute phase reactant (C-reactive protein \[CRP\] level); participant's assessment of pain (measured on 0 \[no pain\]-100 mm \[worst pain\] 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 \[better physical function\] - 3 \[worst physical function\]). ACR50 is defined as achieving at least 50% improvement in both TJC and SJC, and at least 50% improvement in at least 3 of the 5 other assessments of the ACR. Participants were analyzed as non-responders from the time they discontinued treatment.
DB Period: Percentage of Participants Achieving ACR70 Criteria at Week 24 Week 24 ACR responses are assessed with a composite rating scale of the ACR that includes 7 variables: TJC (68 joints); SJC (66 joints); levels of an acute phase reactant (CRP level); participant's assessment of pain (measured on 0 \[no pain\]-100 mm \[worst pain\] 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 HAQ-DI, with scoring range of 0 \[better physical function\] - 3 \[worst physical function\]). ACR70 was defined as achieving at least 70% improvement in both TJC and SJC, and at least 70% improvement in at least 3 of the 5 other assessments. Participants were analyzed as non-responders from the time they discontinued treatment.
DB Period: Percentage of Participants Achieving ACR20 Criteria at Week 24 Week 24 ACR responses are assessed with a composite rating scale of the ACR that includes 7 variables: TJC (68 joints); SJC (66 joints); levels of an acute phase reactant (CRP level); participant's assessment of pain (measured on 0 \[no pain\]-100 mm \[worst pain\] 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 HAQ-DI, with scoring range of 0 \[better physical function\] - 3 \[worst physical function\]). ACR20 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. Participants were analyzed as non-responders from the time they discontinued treatment.
DB Period: Change From Baseline in HAQ-DI at Week 24 Baseline, Week 24 Physical function was assessed by HAQ-DI. It consisted of at least 2 or 3 questions per category, participant reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week rated on a 4-point scale where 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of category scores and divided by the number of categories answered, ranging from 0 to 3, where 0 = no disability and 3 = unable to do, high-dependency disability. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in Short-Form-36 (SF-36) - Physical Component Summary (PCS) Score at Week 24 Baseline, Week 24 SF-36 is a generic 36-item questionnaire consisting of 8 sub-scales, measures health-related quality of life (HRQL) in the last 4 weeks covering 2 summary measures: PCS and mental component summary (MCS). PCS with 4 sub-scales: physical function, role limitations due to physical problems, pain, and general health perception; and MCS with 4 sub-scales: vitality, social function, role limitations due to emotional problems, and mental health. Participants self-report on items in a sub-scale that have between 2-6 choices per item using Likert-type responses (e.g. none of the time, some of the time, etc.). Summations of item scores of the same sub-scale give the sub-scale scores, which are transformed into a range from 0 to 100; 0= worst HRQL, 100=best HRQL. Both PCS and MCS range from 0-100 with higher scores indicating better physical and mental health. LS mean and SE at Week 24 by MMRM approach.
DB Period: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score at Week 24 Baseline, Week 24 The FACIT-F is a 13-item questionnaire assessing fatigue where participants scored each item on a 5-point scale (0-4): 0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much. A total score ranged from 0 to 52, where higher score corresponds to a lower level of fatigue. A positive change from baseline score indicates an improvement. LS mean and SE at Week 24 by MMRM approach.
DB Period: Change From Baseline in SF-36 - Mental Health Component Summary Score at Week 24 Baseline, Week 24 SF-36 is a generic 36-item questionnaire consisting of 8 sub-scales, measures HRQL in the last 4 weeks covering 2 summary measures: PCS and MCS. PCS with 4 subscales: physical function, role limitations due to physical problems, pain, and general health perception; and MCS with 4 subscales: vitality, social function, role limitations due to emotional problems, and mental health. Participants self-report on items in a subscale that have between 2-6 choices per item using Likert-type responses (e.g. none of the time, some of the time, etc.). Summations of item scores of the same sub-scale give the sub-scale scores, which are transformed into a range from 0 to 100; 0= worst HRQL, 100=best HRQL. Both PCS and MCS range from 0-100 with higher scores indicating better physical and mental health. LS mean and SE at Week 24 by MMRM approach.
DB Period: Change From Baseline in Disease Activity Score for 28 Joints Based on C-Reactive Protein (DAS28-CRP Score) at Week 24 Baseline, Week 24 DAS28-CRP is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the participant assessed from the ACR RA core set questionnaire (participant global assessment) in 100 mm VAS; Marker of inflammation assessed by high sensitivity C-reactive protein (hs-CRP) in mg/L. The DAS28-CRP score provides a number indicating the current disease activity of the RA. DAS28-CRP total score ranges from 2-10. A DAS28-CRP score above 5.1 means high disease activity, whereas a DAS28-CRP score below 3.2 indicates low disease activity and a DAS28-CRP score below 2.6 means disease remission. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Percentage of Participants Achieving Clinical Remission Score (DAS28-CRP <2.6) at Week 24 Week 24 DAS28-CRP is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the participant assessed from the ACR RA core set questionnaire (participant global assessment) in 100 mm VAS; Marker of inflammation assessed by hs-CRP in mg/L. The DAS28-CRP score provides a number indicating the current disease activity of the RA. DAS28-CRP total score ranges from 2-10. A DAS28-CRP score above 5.1 means high disease activity, whereas a DAS28-CRP score below 3.2 indicates low disease activity and a DAS28-CRP score below 2.6 means disease remission. Participants were analyzed as non-responders from the time they discontinued treatment.
DB Period: Percentage of Participants Achieving Low Disease Activity (DAS28-ESR < 3.2) at Week 24 Week 24 DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the participant assessed from the ACR RA core set questionnaire (participant global assessment) in 100 mm VAS; Marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Participants were analyzed as non-responders from the time they discontinued treatment.
DB Period: Percentage of Participants Achieving Clinical Disease Activity Index (CDAI) Remission (CDAI ≤2.8) at Week 24 Week 24 CDAI is a composite index constructed to measure clinical remission in RA that does not include a laboratory test, and is a numerical summation of 4 components: SJC (28 joints), TJC (28 joints), participant's global assessment of disease activity (in cm), and physician's global assessment of disease activity (in cm). Total score ranges from 0 to 76 with a lower score indicating less disease activity. Participants were analyzed as non-responders from the time they discontinued treatment.
DB Period: Change From Baseline in CDAI at Week 24 Baseline, Week 24 CDAI is a composite index constructed to measure clinical remission in RA that does not include a laboratory test, and is a numerical summation of 4 components: SJC (28 joints), TJC (28 joints), participant's global assessment of disease activity (in cm), and physician's global assessment of disease activity (VAS in cm). Total score ranges from 0 to 76 with a lower score indicating less disease activity. A negative change in CDAI score indicates an improvement in disease activity and a positive change in score indicates a worsening of disease activity. LS means and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in Individual ACR Component - CRP Level at Week 24 Baseline, Week 24 ACR components were: TJC, SJC, physician global VAS, participant global VAS, pain VAS, HAQ-DI \& acute phase reactant (hs-CRP and ESR levels). An elevated CRP level is considered a non-specific "marker" for RA. A decrease indicates improvement. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in European Quality of Life-5 Dimension 3 Level (EQ-5D-3L) Scores at Week 24 Baseline, Week 24 EQ-5D-3L is a standardized, generic measure of health outcome. EQ-5D was designed for self-completion by participants. EQ-5D was specifically included to address concerns regarding the health economic impact of RA. EQ-5D-3L comprises of 5 questions on mobility, self-care, pain/discomfort, usual activities, and psychological status with 3 possible answers for each item (1=no problem, 2=moderate problems, 3=severe problems). The 5-dimensional 3-level systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-3L-VAS records the participant's self-rated health on a vertical VAS that allows the participants to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable). LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in Rheumatoid Arthritis Impact of Disease (RAID) at Week 24 Baseline, Week 24 RAID is a composite measure of the impact of RA on participants that takes into account 7 domains: pain, functional disability, fatigue, physical and emotional well-being, quality of sleep, and coping. The RAID is calculated based on 7 numerical rating scales (NRS) questions. Each NRS is assessed as a number between 0 and 10 that corresponds to the 7 domains. The values for each of these domains are weighed by participant assessment of relative importance and combined in a single score with a total score range of 0 (not affected, very good) to 10 (most affected). LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in Work Productivity Survey - Rheumatoid Arthritis (WPS-RA) at Week 24: Work Days Missed Due to Arthritis Baseline, Week 24 The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on participant self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of work days missed in the last month by the participant was reported. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in WPS-RA at Week 24: Days With Work Productivity Reduced by ≥ 50% Due to Arthritis Baseline, Week 24 The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on participant self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of work days with reduced productivity by \>= 50% in the last month by the participants was reported. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in WPS-RA at Week 24: Arthritis Interference With Work Productivity Baseline, Week 24 The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on participant self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Interference in the last month with work productivity was measured on a scale that ranges from 0 (no interference) to 10 (complete interference). LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in WPS-RA at Week 24: House Work Days Missed Due to Arthritis Baseline, Week 24 The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on participant self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with no household work in the last month by the participants was reported. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in WPS-RA at Week 24: Days With Household Work Productivity Reduced by >= 50% Due to Arthritis Baseline, Week 24 The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on participant self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with reduced household work productivity by \>= 50% in the last month by the participants was reported. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in WPS-RA at Week 24: Days With Family/Social/Leisure Activities Missed Due to Arthritis Baseline, Week 24 The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on participant self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days missed of family/social/leisure activities in the last month by the participants was reported. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in WPS-RA at Week 24: Days With Outside Help Hired Due to Arthritis Baseline, Week 24 The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on participant self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). Number of days with outside help hired in the last month by the participant was reported. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in WPS-RA at Week 24: RA Interference With Household Work Productivity Baseline, Week 24 The WPS-RA is a validated questionnaire that evaluates productivity limitations within work and within home associated with RA over the previous month. The questionnaire is interviewer-administered and based on participant self-report. It contains 9 questions addressing employment status (1 item), productivity at work (3 items), and within and outside the home (5 items). The RA interference in the last month with household work productivity was measured on a scale that ranges from 0 (no interference) to 10 (complete interference). LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in Morning Stiffness VAS at Week 24 Baseline, Week 24 RA is associated with stiffness of joints, especially in the morning after prolonged stationery state. The degree of stiffness can be an indicator of disease severity. The severity of morning stiffness was assessed on a VAS scale from 0 mm (no problem) to 100 mm (major problem). LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in Individual ACR Component - TJC and SJC at Week 24 Baseline, Week 24 ACR components were: TJC, SJC, physician global VAS, participant global VAS, pain VAS, HAQ-DI \& acute phase reactant (hs-CRP and ESR levels). 68 joints were assessed for tenderness (TJC scoring 0-68) and 66 joints for swelling (SJC scoring 0-66). The 66 SJC evaluated the following joints: temporomandibular, sternoclavicular, acromioclavicular, shoulder, elbow, wrist, metacarpophalangeal, interphalangeal of thumb, distal interphalangeal, proximal interphalangeal, knee, ankle mortise, ankle tarsus, metatarsophalangeal, interphalangeal of great toe, and proximal/distal interphalangeal of the toes. The TJC examined hip joints, in addition to the joints assessed for SJC. Increase in number of tender joints/swollen joints indicated severity. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in Individual ACR Component - Physician Global VAS, Participant Global VAS and Pain VAS at Week 24 Baseline, Week 24 ACR components were: TJC, SJC, physician global VAS, participant global VAS, pain VAS, HAQ-DI \& acute phase reactant (hs-CRP and ESR levels). Physician global VAS \& participant global VAS was done on 100 mm horizontal anchored VAS, ranging from 0 "no arthritis activity" to 100 "maximal arthritis activity" and Pain VAS on 100 mm VAS, ranging from 0 "no pain" to 100 "worst pain". LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Change From Baseline in Individual ACR Component- ESR Level at Week 24 Baseline, Week 24 ACR components were: TJC, SJC, physician global VAS, participant global VAS, pain VAS, HAQ-DI \& acute phase reactant (hs-CRP and ESR levels). The ESR is a blood test that can reveal inflammatory activity. Inflammation can cause the cells to clump together. The farther the red blood cells have descended, the greater the inflammatory response. LS mean and SE at Week 24 were obtained using MMRM approach.
DB Period: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) From Week 0 to Week 24 Adverse event (AE) was defined as any untoward medical occurrence in participant who received investigational medicinal product (IMP) and did not necessarily had to have causal relationship with treatment. All reported AEs are TEAEs developed/worsened during 'on treatment period' (time from first dose of study drug up to day before first dose of open-label treatment for participants who completed 24-week randomized//DB treatment). SAEs were AEs 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.
OLE Period: Number of Participants With Treatment-emergent Adverse Events and Serious Adverse Events 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) AE was defined as any untoward medical occurrence in participant who received IMP and did not necessarily had to have causal relationship with treatment. All reported AEs are TEAEs developed/worsened during 'on treatment period' (from end of week 24 \[Baseline of OLE Period\] up to last dose in OLE period + 6 weeks \[follow-up\], regardless of unplanned intermittent discontinuations). SAEs were AEs 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.
DB Period: Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) - Hematological Parameters From Week 0 to Week 24 Criteria for potentially clinically significant laboratory abnormalities included:
* Hemoglobin (Hb): less than or equal to (\<=) 115 grams per liter (g/L) (Male), \<= 95 g/L (Female); greater than or equal to (\>=) 185 g/L (18.5 g/dL) (Male), \>= 165 g/L (16.5 g/dL) (Female); Decrease From Baseline (DFB) = 20 g/L (2 g/dL).
* Hematocrit: \<= 0.37 volume/volume (v/v) (Male); \<= 0.32 v/v (F); \>= 0.55 v/v (Male); \>= 0.5 v/v (Female).
* Red Blood Cells (RBCs): \>=6 Tera/ liter (L).
* Platelets: \< 50 Giga/L, 50 - 100 Giga/L, \>= 700 Giga/L.
* White blood cells (WBC): \< 3.0 Giga/L (Non-Black); \< 2.0 Giga/L (Black), \>= 16.0 Giga/L.
* Neutrophils: \< 1.0 Giga/L, \< 1.5 Giga/L (Non-Black); \< 1.0 Giga/L (Black).
* Lymphocytes: \< 0.5 Giga/L, \>= 0.5 Giga/L - 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).DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Liver Function Tests From Week 0 to Week 24 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.
* Unconjugated bilirubin: \>1.5 ULN, \>2 ULN.
* ALT \>3 ULN and TBILI \>2 ULN.
* CBILI \>35% TBILI and TBILI \>1.5 ULN.
* Albumin: \<=25 g/L.OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Liver Function Tests From end of Week 24 (Baseline of OLE Period) up to Week 300 Criteria for potentially clinically significant abnormalities:
* 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.
* 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.
* TBILI: \>1.5 ULN; \>2 ULN.
* CBILI: \>1.5 ULN.
* Unconjugated bilirubin: \>1.5 ULN, \>2 ULN.
* ALT \>3 ULN and TBILI \>2 ULN.
* CBILI \>35% TBILI and TBILI \>1.5 ULN.
* Albumin: \<=25 g/L.DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Metabolic Parameters From Week 0 to Week 24 Criteria for potentially clinically significant abnormalities:
* Glucose: \<=3.9 millimole/liter (mmol/L) and \<LLN; \>=11.1 mmol/L (unfasted \[unfas\]) or \>=7 mmol/L (fasted \[fas\]).
* 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.OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Metabolic Parameters From end of Week 24 (Baseline of OLE Period) up to Week 300 Criteria for potentially clinically significant abnormalities:
* Glucose: \<=3.9 mmol/L and \<LLN; \>=11.1 mmol/L (unfas) or \>=7 mmol/L (fas).
* 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.DB Period: Number of Participants With Different Post-baseline Categories of High-density Lipoprotein (HDL) From Week 0 to Week 24 Number of participants with different post-baseline status of HDL: \< 40 mg/dL, 40 - \< 60 mg/dL, \>= 60 mg/dL, is reported here.
OLE Period: Number of Participants With Different Post-baseline Categories of High-density Lipoprotein From end of Week 24 (Baseline of OLE Period) up to Week 300 Number of participants with different post-baseline status of HDL: \< 40 mg/dL, 40 - \< 60 mg/dL, \>=60 mg/dL, is reported here.
DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Renal Function From Week 0 to Week 24 Criteria for potentially clinically significant abnormalities:
* Creatinine: \>=150 micromol/L (adults); \>=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.OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Renal Function From end of Week 24 (Baseline of OLE Period) up to Week 300 Criteria for potentially clinically significant abnormalities:
* Creatinine: \>=150 micromol/L (adults); \>=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.DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Urinalysis From Week 0 to Week 24 Criteria with potentially clinically significant urine abnormalities:
pH: \<= 4.6; pH: \>= 8.0.OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Urinalysis From end of Week 24 (Baseline of OLE Period) up to Week 300 Criteria with potentially clinically significant urine abnormalities:
pH: \<= 4.6; pH: \>= 8.0.DB Period: Number of Participants With Potentially Clinically Significant Abnormalities - Electrolytes From Week 0 to Week 24 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.OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Electrolytes From end of Week 24 (Baseline of OLE Period) up to Week 300 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.OLE Period: Number of Participants With Potentially Clinically Significant Abnormalities - Hematological Parameters From end of Week 24 (Baseline of OLE Period) up to Week 300 Criteria for potentially clinically significant laboratory abnormalities included:
* Hb: \<=115 g/L (Male), \<= 95 g/L (Female); \>=185 g/L (18.5 g/dL) (Male), \>= 165 g/L (16.5 g/dL) (Female); DFB \>= 20 g/L (2 g/dL).
* Hematocrit: \<= 0.37 v/v (Male); \<= 0.32 v/v (Female); \>= 0.55 v/v (Male); \>= 0.5 v/v (Female).
* RBCs: \>=6 Tera/ L.
* Platelets: \< 50 Giga/L, \>=50 - 100 Giga/L, \>= 700 Giga/L.
* WBC: \< 3.0 Giga/L (Non-Black); \< 2.0 Giga/L (Black), \>= 16.0 Giga/L.
* Neutrophils: \< 1.0 Giga/L, \< 1.5 Giga/L (Non-Black); \< 1.0 Giga/L (Black).
* Lymphocytes: \< 0.5 Giga/L, \>= 0.5 Giga/L - LLN, \> 4.0 Giga/L.
* Monocytes: \> 0.7 Giga/L.
* Basophils: \> 0.1 Giga/L.
* Eosinophils: \> 0.5 Giga/L or \> ULN (if ULN \>= 0.5 Giga/L).DB Period: Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Abnormalities From Week 0 to Week 24 Criteria for potentially clinically significant ECG abnormalities:
* Heart rate (HR): \<50 beats per minute (bpm); \<50 bpm and DFB \>=20 bpm; \<40 bpm; \<40 bpm and DFB \>=20 bpm; \<30 bpm; \<30 bpm and DFB \>=20 bpm; \>90 bpm; \>=90 bpm and increase from baseline (IFB) \>=20 bpm; \>100 bpm; \>=100 bpm and IFB \>=20 bpm; \>120 bpm; \>=120 bpm and IFB \>=20 bpm.
* 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.OLE Period: Number of Participants With Potentially Clinically Significant Electrocardiogram Abnormalities From end of Week 24 (Baseline of OLE Period) up to Week 300 Criteria for potentially clinically significant ECG abnormalities:
* HR: \<50 bpm; \<50 bpm and DFB \>=20 bpm; \<40 bpm; \<40 bpm and DFB \>=20 bpm; \<30 bpm; \<30 bpm and DFB \>=20 bpm; \>90 bpm; \>=90 bpm and IFB \>=20 bpm; \>100 bpm; \>=100 bpm and IFB \>=20 bpm; \>120 bpm; \>=120 bpm and IFB \>=20 bpm.
* PR Interval: \>200 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 B: \>450 ms; \>480 ms; \>500 ms; IFB \>30 and \<=60 ms; IFB \>60 ms.
* QTc F: \>450 ms; \>480 ms; \>500 ms; IFB \>30 and \<=60 ms; IFB \>60 ms.DB Period: Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities From Week 0 to Week 24 Criteria for potentially clinically significant vital sign abnormalities:
Systolic blood pressure (SBP) supine: \<=95 mmHg and DFB\>=20 mmHg; \>=160 mmHg and IFB \>=20 mmHg.
Diastolic blood pressure (DBP) supine: \<=45 mmHg and DFB \>=10 mmHg; \>=110 mmHg and IFB \>=10 mmHg.
SBP (Orthostatic): \<=-20 mmHg. DBP (Orthostatic): \<=-10 mmHg. HR supine: \<=50 bpm and DFB \>=20 bpm; \>=120 bpm and IFB \>=20 bpm. Weight: \>=5% DFB; \>=5% IFB.OLE Period: Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities From end of Week 24 (Baseline of OLE Period) up to Week 300 Criteria for potentially clinically significant vital sign abnormalities:
SBP supine: \<=95 mmHg and DFB \>=20 mmHg; \>=160 mmHg and IFB \>=20 mmHg. DBP supine: \<=45 mmHg and DFB \>=10 mmHg; \>=110 mmHg and IFB \>=10 mmHg. SBP (Orthostatic): \<=-20 mmHg. DBP (Orthostatic): \<=-10 mmHg. HR supine: \<=50 bpm and DFB \>=20 bpm; \>=120 bpm and IFB \>=20 bpm. Weight: \>=5% DFB; \>=5% IFB.DB Period: Number of Participants With Treatment-emergent and Treatment-boosted Anti-drug Antibody (ADA) Response From Week 0 to Week 24 Anti-drug antibody response was categorized as: Treatment emergent and Treatment-boosted. Treatment emergent ADAs was defined as a participant with no positive assay response at baseline but with a positive assay response during the TEAE period. Treatment boosted ADAs: defined as participants with a positive ADA assay response at baseline and with at least a 4-fold increase in titer compared to baseline during the TEAE period. TEAE period: time from first dose of study drug up to day before first dose of open-label treatment for participants who completed 24-week randomized/DB treatment.
Number of Participants With Treatment-emergent and Treatment-boosted Anti-drug Antibody Response During Entire Treatment-emergent Adverse Event Period From Week 0 up to last dose in OLE + 6 weeks of follow-up (i.e. up to Week 306) Anti-drug antibody response was categorized as: Treatment emergent and Treatment-boosted. Treatment emergent ADAs was defined as a participant with no positive assay response at baseline but with a positive assay response during the entire TEAE period. Treatment boosted ADAs: defined as participants with a positive ADA assay response at baseline and with at least a 4-fold increase in titer compared to baseline during the entire TEAE period. Entire TEAE period: last OLE dose - first DB dose date + 6 weeks (follow-up), regardless of unplanned intermittent discontinuations.
DB Period: Pharmacokinetics: Serum Trough (Pre-dose) Concentrations of Functional Sarilumab Pre-dose at Week 0 (Baseline), 2, 4, 12, 16, 20, and 24 Data for this outcome measure was not planned to be collected and analyzed for "Adalimumab 40 mg/Sarilumab 200 mg" arm.
OLE Period: Pharmacokinetics: Serum Trough (Pre-dose) Concentrations of Functional Sarilumab Pre-dose at Week 24 (Baseline of OLE period), 36, 48, 60, 84, 108, 132, 156, 180, 204, 228, 252, 276, 300 and 306
Trial Locations
- Locations (86)
Investigational Site Number 840403
🇺🇸Saint Petersburg, Florida, United States
Investigational Site Number 840229
🇺🇸Coral Gables, Florida, United States
Investigational Site Number 840140
🇺🇸Tampa, Florida, United States
Investigational Site Number 376031
🇮🇱Haifa, Israel
Investigational Site Number 604003
🇵🇪Lima, Peru
Investigational Site Number 410001
🇰🇷Seoul, Korea, Republic of
Investigational Site Number 616016
🇵🇱Szczecin, Poland
Investigational Site Number 642006
🇷🇴Braila, Romania
Investigational Site Number 710011
🇿🇦Cape Town, South Africa
Investigational Site Number 710007
🇿🇦Cape Town, South Africa
Investigational Site Number 616004
🇵🇱Warszawa, Poland
Investigational Site Number 642010
🇷🇴Bucharest, Romania
Investigational Site Number 643031
🇷🇺Moscow, Russian Federation
Investigational Site Number 643030
🇷🇺Moscow, Russian Federation
Investigational Site Number 643008
🇷🇺Saint-Petersburg, Russian Federation
Investigational Site Number 643011
🇷🇺Saratov, Russian Federation
Investigational Site Number 804014
🇺🇦Kyiv, Ukraine
Investigational Site Number 804047
🇺🇦Kyiv, Ukraine
Investigational Site Number 804046
🇺🇦Lviv, Ukraine
Investigational Site Number 840202
🇺🇸Hagerstown, Maryland, United States
Investigational Site Number 840232
🇺🇸Flint, Michigan, United States
Investigational Site Number 840074
🇺🇸Mesquite, Texas, United States
Investigational Site Number 840130
🇺🇸Lewes, Delaware, United States
Investigational Site Number 840400
🇺🇸Long Beach, California, United States
Investigational Site Number 840407
🇺🇸Covina, California, United States
Investigational Site Number 840141
🇺🇸Whittier, California, United States
Investigational Site Number 840404
🇺🇸Middleburg Heights, Ohio, United States
Investigational Site Number 840112
🇺🇸Lincoln, Nebraska, United States
Investigational Site Number 840127
🇺🇸Oklahoma City, Oklahoma, United States
Investigational Site Number 840402
🇺🇸Charlotte, North Carolina, United States
Investigational Site Number 840406
🇺🇸Hickory, North Carolina, United States
Investigational Site Number 152005
🇨🇱Osorno, Chile
Investigational Site Number 203033
🇨🇿Praha 11, Czechia
Investigational Site Number 152001
🇨🇱Puerto Varas, Chile
Investigational Site Number 152050
🇨🇱Santiago, Chile
Investigational Site Number 203030
🇨🇿Praha 4, Czechia
Investigational Site Number 376011
🇮🇱Tel Aviv, Israel
Investigational Site Number 348020
🇭🇺Budapest, Hungary
Investigational Site Number 152014
🇨🇱Talca, Chile
Investigational Site Number 348023
🇭🇺Veszprém, Hungary
Investigational Site Number 348025
🇭🇺Budapest, Hungary
Investigational Site Number 348022
🇭🇺Budapest, Hungary
Investigational Site Number 203001
🇨🇿Praha 2, Czechia
Investigational Site Number 203002
🇨🇿Uherske Hradiste, Czechia
Investigational Site Number 276058
🇩🇪Köln, Germany
Investigational Site Number 276021
🇩🇪Osnabrück, Germany
Investigational Site Number 376032
🇮🇱Ashkelon, Israel
Investigational Site Number 410005
🇰🇷Daegu, Korea, Republic of
Investigational Site Number 410004
🇰🇷Daejeon, Korea, Republic of
Investigational Site Number 604005
🇵🇪Lima, Peru
Investigational Site Number 376030
🇮🇱Ramat Gan, Israel
Investigational Site Number 410006
🇰🇷Seoul, Korea, Republic of
Investigational Site Number 604022
🇵🇪Lima, Peru
Investigational Site Number 616056
🇵🇱Bytom, Poland
Investigational Site Number 616015
🇵🇱Elblag, Poland
Investigational Site Number 616005
🇵🇱Lublin, Poland
Investigational Site Number 616055
🇵🇱Nadarzyn, Poland
Investigational Site Number 616030
🇵🇱Lublin, Poland
Investigational Site Number 616018
🇵🇱Poznan, Poland
Investigational Site Number 616031
🇵🇱Warszawa, Poland
Investigational Site Number 642001
🇷🇴Bucuresti, Romania
Investigational Site Number 642005
🇷🇴Galati, Romania
Investigational Site Number 643020
🇷🇺Moscow, Russian Federation
Investigational Site Number 643001
🇷🇺Moscow, Russian Federation
Investigational Site Number 804049
🇺🇦Poltava, Ukraine
Investigational Site Number 724012
🇪🇸Santiago De Compostela, Spain
Investigational Site Number 724003
🇪🇸Barakaldo, Spain
Investigational Site Number 724001
🇪🇸Málaga, Spain
Investigational Site Number 804029
🇺🇦Ivano-Frankivsk, Ukraine
Investigational Site Number 804048
🇺🇦Kharkiv, Ukraine
Investigational Site Number 804037
🇺🇦Lutsk, Ukraine
Investigational Site Number 804011
🇺🇦Vinnitsya, Ukraine
Investigational Site Number 804043
🇺🇦Vinnitsya, Ukraine
Investigational Site Number 826001
🇬🇧Leytonstone, United Kingdom
Investigational Site Number 724015
🇪🇸Barcelona, Spain
Investigational Site Number 724011
🇪🇸Barcelona / Sabadell, Spain
Investigational Site Number 724007
🇪🇸Sevilla, Spain
Investigational Site Number 152015
🇨🇱Temuco IX Region, Chile
Investigational Site Number 152002
🇨🇱Santiago, Chile
Investigational Site Number 152007
🇨🇱Viña Del Mar, Chile
Investigational Site Number 840128
🇺🇸Ormond Beach, Florida, United States
Investigational Site Number 348024
🇭🇺Szombathely, Hungary
Investigational Site Number 643006
🇷🇺Kemerovo, Russian Federation
Investigational Site Number 642002
🇷🇴Bucuresti, Romania
Investigational Site Number 710004
🇿🇦Kempton Park, South Africa
Investigational Site Number 840073
🇺🇸Cumberland, Maryland, United States