title: In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores.
abstract: 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.
  
  
  
  We 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.
  
  
  
  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% 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).
  
  
  
  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, however, had significant reductions in serum aminotransferase levels and lobular inflammation. ClinicalTrials.gov no: NCT01529268.
authors: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California; Department of Gastroenterology, Rady Children's Hospital, San Diego, California. Electronic address: jschwimmer@ucsd.edu.
authors: Jeffrey B
authors: JB
authors: Schwimmer
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University, and Morgan Stanley Children's Hospital of New York Presbyterian, New York, New York.
authors: Joel E
authors: JE
authors: Lavine
authors: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors: Laura A
authors: LA
authors: Wilson
authors: Division of Gastroenterology and Hepatology, St. Louis University, St. Louis, Missouri.
authors: Brent A
authors: BA
authors: Neuschwander-Tetri
authors: Steatohepatitis Center, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Stavra A
authors: SA
authors: Xanthakos
authors: Steatohepatitis Center, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors: Rohit
authors: R
authors: Kohli
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas.
authors: Sarah E
authors: SE
authors: Barlow
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia.
authors: Miriam B
authors: MB
authors: Vos
authors: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia.
authors: Saul J
authors: SJ
authors: Karpen
authors: Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, Indiana.
authors: Jean P
authors: JP
authors: Molleston
authors: Department of Pediatrics, Feinberg Medical School of Northwestern University and the Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors: Peter F
authors: PF
authors: Whitington
authors: Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Francisco Benioff Children's Hospital, San Francisco, California.
authors: Philip
authors: P
authors: Rosenthal
authors: Department of Pediatrics, St. Louis University, St. Louis, Missouri.
authors: Ajay K
authors: AK
authors: Jain
authors: Division of Gastroenterology and Hepatology, Department of Pediatrics, University of Washington School of Medicine and Seattle Children's, Seattle, Washington.
authors: Karen F
authors: KF
authors: Murray
authors: Department of Pathology, Washington University in St. Louis, St. Louis, Missouri.
authors: Elizabeth M
authors: EM
authors: Brunt
authors: National Cancer Institute, Bethesda, Maryland.
authors: David E
authors: DE
authors: Kleiner
authors: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors: Mark L
authors: ML
authors: Van Natta
authors: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors: Jeanne M
authors: JM
authors: Clark
authors: Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors: James
authors: J
authors: Tonascia
authors: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
authors: Edward
authors: E
authors: Doo
mesh_terms: D000293:Adolescent; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D001706:Biopsy; D001835:Body Weight; D002648:Child; D003543:Cysteamine / Q000008:administration & dosage / Q000627:therapeutic use*; D065104:Cystine Depleting Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D005260:Female; D006505:Hepatitis / Q000209:etiology / Q000473:pathology; D006801:Humans; D057194:Intention to Treat Analysis; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D012720:Severity of Illness Index
chemical_list: D065104:Cystine Depleting Agents; D003692:Delayed-Action Preparations; D003543:Cysteamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: ALT; AST; Obesity; Pediatrics