Dataset Information

A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine levels and comparison of safety.

ABSTRACT: Immediate-release cysteamine bitartrate (Cystagon; Mylan Pharmaceuticals, Canonsburg, PA) may prevent or delay kidney transplantation and other serious outcomes in patients with cystinosis, but has never been subjected to a prospective clinical trial. Cystagon efficacy requires strict lifelong dosing every 6 hours. Such a dosing schedule and Cystagon-associated side effects are often cited by patients as reasons for nonadherence.This open-label, randomized, controlled, crossover trial was powered to show that a new delayed-release formulation of cysteamine bitartrate, RP103, taken every 12 hours, was noninferior to Cystagon for maintenance of white blood cell (WBC) cystine at levels associated with optimal outcomes in the disease.Forty-three patients were randomized. Using a mixed-effects statistical analysis model, the least-squares mean peak value of WBC cystine level was 0.62±0.05 nmol 1/2 cystine/mg protein after 12 hours under RP103 and 0.54±0.05 nmol 1/2 cystine/mg protein after 6 hours under Cystagon, a difference of 0.08±0.04 nmol 1/2 cystine/mg protein (95.8% confidence interval, 0-0.16). The average steady-state total daily dose of RP103 was 82% of the incoming steady-state total daily dose of Cystagon. There were three-fold more gastrointestinal side effects compared with using Cystagon.A new delayed-release Q12H formulation of cysteamine bitartrate is not inferior to the Q6H formulation (Cystagon) in maintaining low WBC cystine levels in patients with cystinosis but at a lower total daily dose.

SUBMITTER: Langman CB

PROVIDER: S-EPMC3386675 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine levels and comparison of safety.

Langman Craig B CB Greenbaum Larry A LA Sarwal Minnie M Grimm Paul P Niaudet Patrick P Deschênes Georges G Cornelissen Elisabeth E Morin Denis D Cochat Pierre P Matossian Debora D Gaillard Segolene S Bagger Mary Jo MJ Rioux Patrice P

Clinical journal of the American Society of Nephrology : CJASN 20120503 7

<h4>Background and objectives</h4>Immediate-release cysteamine bitartrate (Cystagon; Mylan Pharmaceuticals, Canonsburg, PA) may prevent or delay kidney transplantation and other serious outcomes in patients with cystinosis, but has never been subjected to a prospective clinical trial. Cystagon efficacy requires strict lifelong dosing every 6 hours. Such a dosing schedule and Cystagon-associated side effects are often cited by patients as reasons for nonadherence.<h4>Design, setting, participants ...[more]

PMID: 22554716

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Project description:Background & aimsNo treatment for nonalcoholic fatty liver disease (NAFLD) has been approved by regulatory agencies. We performed a randomized controlled trial to determine whether 52 weeks of cysteamine bitartrate delayed release (CBDR) reduces the severity of liver disease in children with NAFLD.MethodsWe performed a double-masked trial of 169 children with NAFLD activity scores of 4 or higher at 10 centers. From June 2012 to January 2014, the patients were assigned randomly to receive CBDR or placebo twice daily (300 mg for patients weighing ≤65 kg, 375 mg for patients weighing >65 to 80 kg, and 450 mg for patients weighing >80 kg) for 52 weeks. The primary outcome from the intention-to-treat analysis was improvement in liver histology over 52 weeks, defined as a decrease in the NAFLD activity score of 2 points or more without worsening fibrosis; patients without biopsy specimens from week 52 (17 in the CBDR group and 6 in the placebo group) were considered nonresponders. We calculated the relative risks (RR) of improvement using a stratified Cochran-Mantel-Haenszel analysis.ResultsThere was no significant difference between groups in the primary outcome (28% of children in the CBDR group vs 22% in the placebo group; RR, 1.3; 95% confidence interval [CI], 0.8-2.1; P = .34). However, children receiving CBDR had significant changes in prespecified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction, 53 ± 88 U/L vs 8 ± 77 U/L in the placebo group; P = .02) and aspartate aminotransferase (reduction, 31 ± 52 vs 4 ± 36 U/L in the placebo group; P = .008), and a larger proportion had reduced lobular inflammation (36% in the CBDR group vs 21% in the placebo group; RR, 1.8; 95% CI, 1.1-2.9; P = .03). In a post hoc analysis of children weighing 65 kg or less, those taking CBDR had a 4-fold better chance of histologic improvement (observed in 50% of children in the CBDR group vs 13% in the placebo group; RR, 4.0; 95% CI, 1.3-12.3; P = .005).ConclusionsIn a randomized trial, we found that 1 year of CBDR did not reduce overall histologic markers of NAFLD compared with placebo in children. Children receiving CBDR, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.

Dataset Information

A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine levels and comparison of safety.

Publications

A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: effectiveness on white blood cell cystine levels and comparison of safety.

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