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Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial.

ABSTRACT: To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA).This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ?6?months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4?weeks (8 or 10?mg/kg for body weight (BW) <30?kg; 8?mg/kg for BW ?30?kg). At week 16, patients with ?JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab.In part 1, 188 patients received tocilizumab (<30?kg: 10?mg/kg (n=35) or 8?mg/kg (n=34); ?30?kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: -0.21; 95% CI -0.35 to -0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY).Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis.NCT00988221.

SUBMITTER: Brunner HI

PROVIDER: S-EPMC4431348 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial.

Brunner Hermine I HI Ruperto Nicolino N Zuber Zbigniew Z Keane Caroline C Harari Olivier O Kenwright Andrew A Lu Peng P Cuttica Ruben R Keltsev Vladimir V Xavier Ricardo M RM Calvo Inmaculada I Nikishina Irina I Rubio-Pérez Nadina N Alexeeva Ekaterina E Chasnyk Vyacheslav V Horneff Gerd G Opoka-Winiarska Violetta V Quartier Pierre P Silva Clovis A CA Silverman Earl E Spindler Alberto A Baildam Eileen E Gámir M Luz ML Martin Alan A Rietschel Christoph C Siri Daniel D Smolewska Elzbieta E Lovell Daniel D Martini Alberto A De Benedetti Fabrizio F

Annals of the rheumatic diseases 20140516 6

<h4>Objective</h4>To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA).<h4>Methods</h4>This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg f ...[more]

PMID: 24834925

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Project description:BACKGROUND:Few clinical trials have investigated the prevention of radiographic progression in children with juvenile idiopathic arthritis treated with antirheumatic drugs. This study aimed to investigate radiographic progression in patients with systemic juvenile idiopathic arthritis (sJIA) and patients with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with the anti-interleukin-6 receptor antibody tocilizumab for 2?years in the TENDER and CHERISH randomized controlled trials, respectively. METHODS:Standard radiographs of both wrists and both hands in the posteroanterior view were obtained within 4?weeks of baseline and were repeated at weeks 52?±?4 and 104?±?4 in both trials. All films were scored by two independent readers using the adapted Sharp-van der Heijde (aSH) and Poznanski scoring methods. Although the Poznanski score indicates bone growth limitation or cartilage growth decrease, which are not the same as joint space narrowing in rheumatoid arthritis, its change reflects damage to cartilage. Therefore, impairment in the Poznanski score as well as the aSH score was considered as a measure of structural joint damage. Radiographic progression was defined as worsening of radiographic scores beyond the smallest detectable difference. RESULTS:Poznanski and aSH scores were available at baseline and at one or more postbaseline time points for 33 and 47 of 112 sJIA patients and 61 and 87 of 188 pcJIA patients, respectively, providing a representative subset of the study populations. The inter-reader and intra-reader agreement intra-class correlation coefficient was >?0.8. Median baseline Poznanski and aSH scores, respectively, were -?2.4 and 24.6 for sJIA patients and -?1.5 and 8.0 for pcJIA patients. Compared with baseline, aSH scores remained stable for all sJIA patients at week 52, whereas 9.4% of sJIA patients had radiographic progression according to Poznanski scores at week 52; at 104?weeks, radiographic progression according to aSH and Poznanski scores was observed in 5.4% and 11.5%, respectively. In pcJIA patients, radiographic progression from baseline at 52?weeks and at 104?weeks was 12.5% and 2.9%, respectively, using aSH scoring and 6.5% and 4%, respectively, using Poznanski scoring. CONCLUSION:Tocilizumab may delay radiographic progression in children with sJIA and children with pcJIA. TRIAL REGISTRATION:Trial registration numbers and dates: TENDER, NCT00642460 (March 19, 2008); CHERISH, NCT00988221 (October 1, 2009).

Project description:OBJECTIVE:To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). METHODS:In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6-17 years and cohort 2, ages 2-5 years) in whom treatment with ?1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to <50 kg (87.5 mg), ?50 kg (125 mg). Patients who had met the JIA-American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (Cminss ) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71-CRP) over time, safety, and immunogenicity. RESULTS:The median abatacept Cminss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 ?g/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n = 173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n = 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71-CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS-71-CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects. CONCLUSION:Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.

Project description:BackgroundTo investigate efficacy and safety of intravenous abatacept in Japanese patients with active polyarticular-course juvenile idiopathic arthritis (pJIA).MethodsIn this phase III, open-label, multicenter, single-arm study, patients with pJIA aged 4-17 years who failed ≥1 biologic or methotrexate received weight-tiered (< 75 kg: 10 mg/kg; 75-100 kg: 750 mg; > 100 kg: 1000 mg) intravenous abatacept at Weeks 0, 2, 4, and every 4 weeks thereafter. The study comprised a short-term period (16 weeks) and ongoing long-term period. Primary endpoint: Week 16 JIA-American College of Rheumatology criteria 30 (JIA-ACR30) response rate. Secondary endpoints/outcomes included Week 16 JIA-ACR50/70/90 response and inactive disease rates, Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI), pharmacokinetics, safety, and immunogenicity. Proportions of patients achieving Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS27-CRP) remission (score < 1) and minimal disease activity (MDA; score < 3.8), were among exploratory endpoints.ResultsAll 20 patients who received study medication completed the short-term period. During the long-term period, two patients discontinued due to insufficient efficacy or patient decision. Median age and disease duration at baseline were 10.5 and 0.75 years, respectively. Week 16 JIA-ACR30 response rate (primary endpoint) was 90.0% (18/20). JIA-ACR50/70/90 response and inactive disease rates at Week 16 were 75.0% (15/20), 70.0% (14/20), 35.0% (7/20), and 25.0% (5/20), respectively. At Week 52, JIA-ACR30/50/70/90 response and inactive disease rates were observed by 88.9% (16/18), 88.9% (16/18), 83.3% (15/18), 66.7% (12/18) and 44.4% (8/18), respectively. CHAQ-DI improved after Week 12. JADAS27-CRP remission and MDA were achieved by 15.0% (3/20) and 45.0% (9/20) of patients at Week 16, and by 50.0% (9/18) and 78.0% (14/18) of patients at Week 52, respectively. The mean abatacept pre-dose serum concentration was above the target therapeutic exposure (10 μg/ml) from Week 8 through Week 16. All adverse events were of mild/moderate intensity, except for one case of severe gastroenteritis. No deaths, malignancies, or autoimmune disorders were observed. No antidrug antibodies were detected through Week 16; one patient had a positive immunogenic response during the cumulative period.ConclusionIntravenous abatacept was efficacious and well tolerated in Japanese patients with active pJIA.Trial registrationClinicalTrials.gov: NCT01835470 . Date of registration: April 19, 2013.

Dataset Information

Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial.

Publications

Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial.

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