In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores

Abstract

Background & Aims No 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. Methods We performed a double-masked trial of 169 children with NAFLD Activity Scores ≥ 4 at 10 centers. From June 2012 to January 2014, the patients were randomly assigned to receive CBDR or placebo twice daily (300 mg for ≤65 kg, 375 mg for >65–80 kg, 450 mg for >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 NAFLD Activity Score ≥ 2 points without worsening fibrosis; patients without biopsies from week 52 (17 in the CBDR group and 6 in the placebo group) were considered non-responders. We calculated relative risks (RR) of improvement using stratified Cochran-Mantel-Haenszel analysis. Results There 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% CI, 0.8–2.1; P=.34). However, children receiving CBDR had significant changes in pre-specified secondary outcomes: reduced mean levels of alanine aminotransferase (reduction of 53±88 U/L vs a reduction of 8±77 U/L in the placebo group; P=.02) and aspartate aminotransferase (reduction of 31±52 vs a reduction of 4±36 U/L in the placebo group; P=.008), and a larger proportion had reduced lobular inflammation (in 36% of patients in the CBDR group vs placebo 21% of patients in the placebo group; RR, 1.8; 95% CI, 1.1–2.9; P=.03). In a post-hoc analyses, of children ≤65 kg, 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). Conclusions In 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 did, however, have significant reductions in serum levels of aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.

Hepatic R2* is more strongly associated with proton density fat fraction than histologic liver iron scores in patients with nonalcoholic fatty liver disease

“…Inclusion and exclusion criteria for the FLINT and CyNCh trials have been published . All subjects included in the FLINT trial had a diagnosis of NASH based on established histopathological criteria for adults, and all subjects included in the CyNCh trial had a diagnosis of NAFLD based on established histopathological criteria for children . For this secondary analysis, we included all 208 MRI substudy subjects (101 from the FLINT trial and 107 from the CyNCh trial) who had baseline MRI.…”

“…The Non‐Alcoholic Steatohepatitis Clinical Research Network (NASH CRN) maintains a rich, well‐curated database of standardized clinical, laboratory, imaging, and histopathological data collected from patients with NAFLD and NASH enrolled in recent treatment trials . These data offer an opportunity to assess, in patients with NAFLD, a comprehensive set of potential clinical, laboratory, and histologic covariates for R2* that were unavailable in previous smaller, single‐center investigations.…”

Designing Clinical Trials in Pediatric Nonalcoholic Steatohepatitis: Tips for Patient Selection and Appropriate Endpoints

“…Based on the success of TONIC in obtaining paired liver biopsy in children with NAFLD, the Cysteamine Bitartrate Delayed‐Release for the Treatment of NAFLD in Children (CyNCh) trial used a histologic endpoint as the primary endpoint, defined as a decrease in NAS of 2 or more points and no worsening of liver fibrosis. This was a multicenter, placebo‐controlled, double‐blind trial of 169 children aged 8 to 17 years with biopsy‐proven NASH, defined as NAS of 4 or greater . Patients were randomized to receive cysteamine bitartrate delayed‐release (CBDR) at 600, 750, or 900 mg/day or placebo for 52 weeks.…”

Current and future pharmacologic treatment of nonalcoholic steatohepatitis

“…In a recent multicenter RDBPCT (CyNCh), 169 children with biopsy-proven NASH (NAS >4) were randomized to 12 months of cysteamine (300 mg for study participants ≤65 kg; 375 mg for study participants 65–80 kg; 450 mg for study participants >80 kg) versus placebo. Although study participants treated with cysteamine showed statistically significant decrease in ALT and lobular inflammation, there was no difference in overall histologic markers of NAFLD or in NAS [47 ■ ]. A post hoc analysis of study participants who weighed less than 65 kg showed that 50% of those in the treatment arm reached the primary outcome of histological improvement, compared with 13% of placebo ( P = 0.005).…”