Dataset Information

Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: a Phase III study extension.

ABSTRACT: OBJECTIVE:This extension study of the Phase III, randomized, placebo-controlled Belimumab International SLE Study (BLISS)-52 and BLISS-76 studies allowed non-US patients with SLE to continue belimumab treatment, in order to evaluate its long-term safety and tolerability including organ damage accrual. METHODS:In this multicentre, long-term extension study (GlaxoSmithKline Study BEL112234) patients received i.v. belimumab every 4 weeks plus standard therapy. Adverse events (AEs) were assessed monthly and safety-associated laboratory parameters were assessed at regular intervals. Organ damage (SLICC/ACR Damage Index) was assessed every 48 weeks. The study continued until belimumab was commercially available, with a subsequent 8-week follow-up period. RESULTS:A total of 738 patients entered the extension study and 735/738 (99.6%) received one or more doses of belimumab. Annual incidence of AEs, including serious and severe AEs, remained stable or declined over time. Sixty-nine (9.4%) patients experienced an AE resulting in discontinuation of belimumab or withdrawal from the study. Eleven deaths occurred (and two during post-treatment follow-up), including one (cardiogenic shock) considered possibly related to belimumab. Laboratory parameters generally remained stable. The mean (s.d.) SLICC/ACR Damage Index score was 0.6 (1.02) at baseline (prior to the first dose of belimumab) and remained stable. At study year 8, 57/65 (87.7%) patients had no change in SLICC/ACR Damage Index score from baseline, indicating low organ damage accrual. CONCLUSION:Belimumab displayed a stable safety profile with no new safety signals. There was minimal organ damage progression over 8 years. TRIAL REGISTRATION:ClinicalTrials.gov, https://clinicaltrials.gov, NCT00424476 (BLISS-52), NCT00410384 (BLISS-76), NCT00732940 (BEL112232), NCT00712933 (BEL112234).

SUBMITTER: van Vollenhoven RF

PROVIDER: S-EPMC7571485 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: a Phase III study extension.

van Vollenhoven Ronald F RF Navarra Sandra V SV Levy Roger A RA Thomas Mathew M Heath Amy A Lustine Todd T Adamkovic Anthony A Fettiplace James J Wang Mei-Lun ML Ji Beulah B Roth David D

Rheumatology (Oxford, England) 20200201 2

<h4>Objective</h4>This extension study of the Phase III, randomized, placebo-controlled Belimumab International SLE Study (BLISS)-52 and BLISS-76 studies allowed non-US patients with SLE to continue belimumab treatment, in order to evaluate its long-term safety and tolerability including organ damage accrual.<h4>Methods</h4>In this multicentre, long-term extension study (GlaxoSmithKline Study BEL112234) patients received i.v. belimumab every 4 weeks plus standard therapy. Adverse events (AEs) we ...[more]

PMID: 31302695

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Project description:OBJECTIVE:Long-term extension (LTE) studies of belimumab in SLE do not include a comparator arm, preventing comparisons between belimumab plus standard therapy and standard therapy alone for organ damage accrual. Propensity score matching can be used to match belimumab-treated patients from LTE studies with standard therapy-treated patients from observational cohort studies. This analysis was designed to compare organ damage progression between treatment groups (belimumab plus standard therapy vs standard therapy alone) in patients with SLE with ?5 years of follow-up, reproducing our previous study with more generalisable data. METHODS:This exploratory post hoc analysis used a heterogeneous population of US and non-US patients receiving monthly intravenous belimumab from pooled BLISS LTE trials (BEL112234/NCT00712933) and standard therapy-treated patients from the Toronto Lupus Cohort. Sixteen clinical variables were selected to calculate the propensity score. RESULTS:The 592 LTE and 381 Toronto Lupus Cohort patients were highly dissimilar across the 16 variables; an adequately balanced sample of 181 LTE and 181 matched Toronto Lupus Cohort patients (mean bias=3.7%) was created using propensity score matching. Belimumab treatment was associated with a smaller increase in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) over 5 years than standard therapy alone (mean treatment difference=-0.453 (95% CI -0.646 to -0.260); p<0.001). Patients treated with belimumab were 60% less likely to progress to a higher SDI score over any given year of follow-up, compared with standard therapy alone (HR (95% CI) 0.397 (0.275 to 0.572); p<0.001). CONCLUSION:Using propensity score matching, this highly heterogeneous sample was sufficiently matched to the Toronto Lupus Cohort, suggesting that patients treated with intravenous belimumab may have reduced organ damage progression versus standard therapy alone. This analysis of a large and diverse pooled SLE population was consistent with our previously published US-focused study.

Project description:Background and objectiveIntravenous (IV) belimumab is the first treatment approved for children ≥5 years of age with active autoantibody-positive systemic lupus erythematosus (SLE) in the USA, Europe, and Japan. Pharmacokinetic data for belimumab were collected from several clinical trials in Chinese and non-Chinese adults and non-Chinese pediatric patients with SLE. This study aimed to predict the belimumab dose-exposure relationship to Chinese pediatric patients with SLE, as part of the belimumab registration process for this population in China, using a population PK modeling approach.MethodsAn initial linear two-compartment population pharmacokinetic model was built using data from adults only, and considering and adjusting for the covariates age, body weight, body mass index, fat-free mass, race, baseline albumin and immunoglobulin G levels. The model was used to study possible ethnic differences between Chinese and non-Chinese adults and to predict pediatric pharmacokinetic data in a study of non-Chinese pediatric patients (PLUTO study; NCT01649765). The predicted data were compared with the observed data from PLUTO. The model was then updated with pediatric data from PLUTO to predict steady-state belimumab exposure in Chinese pediatric patients with SLE receiving belimumab 10 mg/kg IV every 4 weeks.ResultsThe dataset comprised 9650 sampled concentration values from 1783 patients. The pharmacokinetics of belimumab were adequately described by the final model using all adult and pediatric data with the estimated typical clearance of 238 ml/day in adult and pediatric patients and steady-state volume of distribution of 4915 ml in adults. Between-patient variability was modest (coefficients of variation: 26.1% for clearance; 8.9% and 28.5%, respectively, for volumes of distribution of the central and peripheral compartments). Six covariates were identified that influenced pharmacokinetics: age, fat-free mass, an indicator of North East Asian race, baseline albumin, immunoglobulin G, and an early study indicator (two early phase I and phase II belimumab studies: LBSL01 and LBSL02). The analysis showed no apparent difference in steady-state exposure between Chinese and non-Chinese populations and between pediatric and adult populations receiving belimumab 10 mg/kg IV.ConclusionsIn Chinese pediatric patients with SLE, belimumab 10 mg/kg IV every 4 weeks is expected to have exposure similar to that in Chinese adults and non-Chinese pediatric patients with SLE, supporting the use of this regimen in Chinese pediatric patients with SLE.Clinical trial registration numbersNCT01649765, NCT00657007, NCT00071487, NCT01345253, NCT01516450, NCT00410384, NCT00424476, NCT02880852, NCT01583530.

Dataset Information

Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: a Phase III study extension.

Publications

Long-term safety and limited organ damage in patients with systemic lupus erythematosus treated with belimumab: a Phase III study extension.

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