An Open-label, Ascending, Repeated Dose-finding Study of Sarilumab in Children and Adolescents With Polyarticular-course Juvenile Idiopathic Arthritis (pcJIA)
- Registration Number
- NCT02776735
- Lead Sponsor
- Sanofi
- Brief Summary
Primary Objective:
To describe the pharmacokinetic (PK) profile of sarilumab in participants aged 2-17 years with Polyarticular-course Juvenile Idiopathic Arthritis (pcJIA) in order to identify the dose and regimen for adequate treatment of this population
Secondary Objective:
To describe the pharmacodynamic (PD) profile, the efficacy and the long-term safety of sarilumab in participants with pcJIA.
- Detailed Description
For 73 participants enrolled in the dose-finding and second portions, the total study duration per participant was up to 166 weeks that consists of a 4- week screening, a 12-week core treatment phase, a 144-week extension phase, and a 6-week post-treatment follow-up. For 29 participants enrolled in the third portion, the total study duration per participant was up to 106 weeks that consists of a 4- week screening, a 12-week core treatment phase, a 84-week extension phase, and a 6-week post-treatment follow-up.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 102
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Sarilumab Sarilumab Participants received one of three ascending dose regimens of sarilumab by subcutaneous (SC) injection based on body weight. All the participants received the selected dose regimen once this was identified. Sarilumab was given during 12-week core treatment phase followed by an extension treatment phase (144 weeks for 73 participants enrolled in dose-finding and second portions and 84 weeks for approximately 29 participants enrolled in third portion)
- Primary Outcome Measures
Name Time Method Maximum Serum Concentration (Cmax) of Sarilumab at Week 12 Pre-dose on Days 1, 3, 5, 8, 12 and Weeks 2, 4, 8 and 12 The Cmax was defined as maximum serum concentration. The values reported are mean and standard deviation.
Area Under the Serum Concentration Versus Time Curve Using the Trapezoidal Method During a Dose Interval (AUC0-t) of Sarilumab at Week 12 Pre-dose on Days 1, 3, 5, 8, 12 and Weeks 2, 4, 8 and 12 The AUC0-t was defined as area under the concentration in serum versus time curve calculated using the trapezoidal method during a dose interval (tau). The values reported are mean and standard deviation.
Concentration Before Treatment Administration During Repeated Dosing (Ctrough) of Sarilumab at Week 12 Pre-dose on Days 1, 3, 5, 8, 12 and Weeks 2, 4, 8 and 12 The Ctrough was defined as concentration observed before treatment administration during repeated dosing from baseline to Week 12. The values reported are mean and standard deviation.
- Secondary Outcome Measures
Name Time Method Cohorts 1 and 3: Change From Baseline in High-Sensitivity C-reactive Protein (Hs-CRP) at Week 12 Baseline (Day 1) and Week 12 Serum concentrations of hs-CRP was determined to assess the Pharmacodynamic (PD) effects of sarilumab. The values reported are mean and standard deviation.
Cohort 2: Change From Baseline in High-Sensitivity C-reactive Protein at Weeks 12, 24, 48, 96, and 156 Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156 Serum concentrations of hs-CRP was determined to assess the PD effects of sarilumab. The values reported are mean and standard deviation.
Change From Baseline in Interleukin-6 (IL-6) at Week 12 Baseline (Day 1) and Week 12 Serum concentrations of IL-6 was determined to assess the PD effects of sarilumab. The values reported are mean and standard deviation.
Change From Baseline in Total Soluble Interleukin-6 Receptor (sIL-6R) at Week 12 Baseline (Day 1) and Week 12 Serum concentrations of sIL-6R was determined to assess the PD effects of sarilumab. The values reported are mean and standard deviation.
Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology (JIA ACR) 30 Response at Week 12 Week 12 JIA ACR30 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 30% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 30 Response at Weeks 12, 24, 48, 96, and 156 Weeks 12, 24, 48, 96, and 156 JIA ACR30 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 30% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Week 12 Week 12 JIA ACR50 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 50% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 50 Response at Weeks 12, 24, 48, 96, and 156 Weeks 12, 24, 48, 96, and 156 JIA ACR50 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 50% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Week 12 Week 12 JIA ACR70 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 70% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 70 Response at Weeks 12, 24, 48, 96, and 156 Weeks 12, 24, 48, 96, and 156 JIA ACR70 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 70% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Week 12 Week 12 JIA ACR90 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 90% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 90 Response at Weeks 12, 24, 48, 96, and 156 Weeks 12, 24, 48, 96, and 156 JIA ACR90 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 90% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohorts 1 and 3: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Week 12 Week 12 JIA ACR100 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 100% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohort 2: Percentage of Participants With Juvenile Idiopatic Arthritis American College of Rheumatology 100 Response at Weeks 12, 24, 48, 96, and 156 Weeks 12, 24, 48, 96, and 156 JIA ACR100 response was defined as a participant with at least 3 out of the 6 JIA core set variables with \>= 100% improvement from baseline with no more than 1 of the remaining variables worsened by \>= 30%.
Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Week 12 Baseline (Day 1) and Week 12 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using visual analog scale (VAS), Childhood Health Questionnaire Disability Index (CHAQ-DI) and hs-CRP. Activity joint count-71 was calculated as sum (joints with active arthritis)\*(71/number of joints with assessment).
Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Activity Joint Count-71, at Weeks 12, 24, 48, 96, and 156 Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Activity joint count-71 was calculated as sum (joints with active arthritis)\*(71/number of joints with assessment).
Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Week 12 Baseline (Day 1) and Week 12 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Limited motion joint count was calculated as sum (joints with limited motion)\*(67/number of joints with assessment).
Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Limited Motion Joint Count, at Weeks 12, 24, 48, 96, and 156 Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Limited motion joint count was calculated as sum (joints with limited motion)\*(67/number of joints with assessment).
Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Week 12 Baseline (Day 1) and Week 12 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. The CHAQ questionnaire consists of 30 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities. Each domain is scored on a 4 point scale ranges from 0 to 3: 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do). An additional response of "not applicable" is available to indicate activities the participant is unable to perform because he/she is too young. The CHAQ-DI total score is the sum of the domain scores divided by the number of domains that have a non-missing score. This overall score ranges from 0 (best) to 3 (worst). Higher scores indicate worse outcome.
Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Childhood Health Assessment Questionnaire Disability Index, at Weeks 12, 24, 48, 96, and 156 Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. The CHAQ questionnaire consists of 30 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities. Each domain is scored on a 4 point scale ranges from 0 to 3: 0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do). An additional response of "not applicable" is available to indicate activities the participant is unable to perform because he/she is too young. The CHAQ-DI total score is the sum of the domain scores divided by the number of domains that have a non-missing score. This overall score ranges from 0 (best) to 3 (worst). Higher scores indicate worse outcome.
Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Week 12 Baseline (Day 1) and Week 12 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Serum concentrations of hs-CRP was determined to assess the PD effects of sarilumab.
Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, C-Reactive Protein, at Weeks 12, 24, 48, 96, and 156 Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Serum concentrations of hs-CRP was determined to assess the PD effects of sarilumab.
Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Week 12 Baseline (Day 1) and Week 12 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Physician global assessment of disease activity was assessed on an anchored 100 mm horizontal VAS score ranging from 0 to 10 where 0 is considered the best disease activity (no disease activity) and 10 the worst (most disease activity). Higher scores indicate worse outcome.
Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Physician Global Assessment of Disease Activity, at Weeks 12, 24, 48, 96, and 156 Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Physician global assessment of disease activity was assessed on an anchored 100 mm horizontal VAS score ranging from 0 to 10 where 0 is considered the best disease activity (no disease activity) and 10 the worst (most disease activity). Higher scores indicate worse outcome.
Cohorts 1 and 3: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Week 12 Baseline (Day 1) and Week 12 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Participant/parent assessment of overall well-being was rated on an anchored 100 mm horizontal VAS score ranging from 0 to 10 where 0 is considered the best disease activity (no disease activity) and 10 the worst (most disease activity). Higher scores indicate worse outcome.
Cohort 2: Change From Baseline in Juvenile Idiopatic Arthritis American College of Rheumatology Component, Participant/Parent Assessment of Overall Well-Being, at Weeks 12, 24, 48, 96, and 156 Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156 The JIA ACR components included joints with active arthritis (0 to 71 joints), joints with limited motion (0 to 67 joints), physician global assessment of disease activity and participant/parent assessment of overall well-being using VAS, CHAQ-DI and hs-CRP. Participant/parent assessment of overall well-being was rated on an anchored 100 mm horizontal VAS score ranging from 0 to 10 where 0 is considered the best disease activity (no disease activity) and 10 the worst (most disease activity). Higher scores indicate worse outcome.
Cohorts 1 and 3: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score (JADAS-27) at Week 12 Baseline (Day 1) and Week 12 The JADAS is used for assessment of disease activity, and it includes 4 measures: Physician global assessment of disease activity (VAS range: 0 to10; where 0= no activity and 10= maximum activity), parent/participant global assessment of well-being (VAS range: 0 to 10; where 0= no activity and10= maximum activity), count of joints with active disease (range: 0 to 27; where 0= no activity and 27= maximum activity), and index of inflammation determined by hs-CRP or ESR (normalized scale range: 0 to 10; where 0= no disease activity and 10= maximum disease activity). The JADAS total score is calculated as the simple sum of the scores of its 4 components. The total score ranges from 0 to 57 where 0= no disease activity and 57= maximum disease activity. Higher scores indicate higher disease activity. Clinical JADAS-27 is without CRP or ESR component and score ranges from 0 to 47 where 0= no disease activity and 47= maximum disease activity.
Cohort 2: Mean Change From Baseline in Juvenile Arthritis Disease Activity Score at Weeks 12, 24, 48, 96, and 156 Baseline (Day 1) and Weeks 12, 24, 48, 96, and 156 The JADAS is used for assessment of disease activity, and it includes 4 measures: Physician global assessment of disease activity (VAS range: 0 to10; where 0= no activity and 10= maximum activity), parent/participant global assessment of well-being (VAS range: 0 to 10; where 0= no activity and10= maximum activity), count of joints with active disease (range: 0 to 27; where 0= no activity and 27= maximum activity), and index of inflammation determined by hs-CRP or ESR (normalized scale range: 0 to 10; where 0= no disease activity and 10= maximum disease activity). The JADAS total score is calculated as the simple sum of the scores of its 4 components. The total score ranges from 0 to 57 where 0= no disease activity and 57= maximum disease activity. Higher scores indicate higher disease activity. Clinical JADAS-27 is without CRP or ESR component and score ranges from 0 to 47 where 0= no disease activity and 47= maximum disease activity.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (SAEs) From the first administration of study treatment (Day 1) up to end of treatment period, maximum of 156 weeks for portions 1 and 2 and 96 weeks for portion 3 An adverse events (AEs) is any untoward medical occurrence in a participant or in a clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with the study treatment. An SAE is any untoward medical occurrence that at any dose results in death or is life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization or results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect or is an important medical event. TEAEs are defined as AEs that develop or worsen during the on-treatment period \[that is, from the time of first dose of study treatment up to 6 weeks after the last administration of the study treatment\].
Number of Participants With Local Site Reactions From the first administration of study treatment (Day 1) up to end of treatment period, maximum of 156 weeks for portions 1 and 2 and 96 weeks for portion 3 Participants were observed for at least 30 minutes after each study treatment administration either on site or at home and any local reactions were noted in the diary regardless of being clinically significant.
Trial Locations
- Locations (30)
Investigational Site Number : 1240112
🇨🇦Montréal, Quebec, Canada
Investigational Site Number : 1520016
🇨🇱Concepcion, Biobío, Chile
Investigational Site Number : 2500040
🇫🇷Paris, France
Investigational Site Number : 6160071
🇵🇱Lodz, Lódzkie, Poland
Investigational Site Number : 2760062
🇩🇪Hamburg, Germany
Children's Hospital Los Angeles Site Number : 8400416
🇺🇸Los Angeles, California, United States
Investigational Site Number : 2760060
🇩🇪Sankt Augustin, Germany
Investigational Site Number : 7240052
🇪🇸Madrid, Madrid, Comunidad De, Spain
Investigational Site Number : 8260033
🇬🇧Liverpool, United Kingdom
Investigational Site Number : 7240053
🇪🇸Madrid, Spain
Investigational Site Number : 7240051
🇪🇸Valencia, Spain
Investigational Site Number : 0320004
🇦🇷Tucumán, Argentina
Investigational Site Number : 2460040
🇫🇮Helsinki, Finland
Investigational Site Number : 2030041
🇨🇿Brno, Czechia
Investigational Site Number : 8260031
🇬🇧London, London, City Of, United Kingdom
Investigational Site Number : 2760064
🇩🇪Berlin, Germany
Investigational Site Number : 3800052
🇮🇹Roma, Italy
Investigational Site Number : 5280020
🇳🇱Utrecht, Netherlands
Investigational Site Number : 6160074
🇵🇱Bydgoszcz, Kujawsko-pomorskie, Poland
Investigational Site Number : 4840060
🇲🇽Monterrey, Nuevo León, Mexico
Investigational Site Number : 6160073
🇵🇱Krakow, Malopolskie, Poland
Investigational Site Number : 6430063
🇷🇺Moscow, Russian Federation
Investigational Site Number : 7240050
🇪🇸Esplugues de Llobregat, Catalunya [Cataluña], Spain
Investigational Site Number : 0320060
🇦🇷Caba, Buenos Aires, Argentina
Investigational Site Number : 2760061
🇩🇪Bremen, Germany
Investigational Site Number : 6160070
🇵🇱Lublin, Lubuskie, Poland
Investigational Site Number : 6160072
🇵🇱Sosnowiec, Slaskie, Poland
Investigational Site Number : 6430001
🇷🇺Moscow, Russian Federation
Investigational Site Number : 6430062
🇷🇺Moscow, Russian Federation
Investigational Site Number : 4840061
🇲🇽Guadalajara, Jalisco, Mexico