Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children (CyNCh)

Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in Children (CyNCh)

CyNCh is a multi-center, placebo-controlled clinical trial of children ages 8 to 17 years with biopsy-confirmed moderate to severe nonalcoholic fatty liver disease (NAFLD). The primary objective is to evaluate whether 52 weeks of treatment with cysteamine bitartrate delayed-release capsules will result in improvement in liver disease severity.

Study Overview

• Status: Completed
• Conditions: Nonalcoholic Fatty Liver Disease (NAFLD)
• Intervention / Treatment: Drug: DR cysteamine bitartrate capsule; Other: DR cysteamine bitartrate placebo

• Study Type: Interventional
• Enrollment (Actual): 169
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92103
      • University of California, San Diego
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611-2605
      • Ann & Robert H. Lurie Children's Hospital of Chicago (NWU)
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • St. Louis University
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • University of Washington, Seattle Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Children age 8-17 years
• Liver biopsy obtained within 90 days of screening visit and not more than 120 days before randomization
• Clinical history consistent with nonalcoholic fatty liver disease (NAFLD)
• Definite NAFLD based upon liver histology
• No evidence of any other liver disease by clinical history or histological evaluation
• A histological severity of: NAFLD Activity Score (NAS) ≥ 4.
• Sexually active female participants of childbearing potential (i.e., not surgically sterile [defined as tubal ligation, hysterectomy, or bilateral oophorectomy]) must agree to utilize the same two acceptable forms of contraception from screening through completion of the study and to complete a serum pregnancy test at each study visit. The acceptable forms of contraception for this study include hormonal contraceptives (oral, implant, transdermal patch, or injection) at a stable dose for at least 3 months prior to screening, and barrier (condom with spermicide, diaphragm with spermicide). Sexual activity will be ascertained at each study visit for post-menarchal females and if sexually active, subject must verify use of the same 2 acceptable forms of contraception. For pre-pubescent children, a documented attestation of abstinence from their parent or guardian will be acceptable.
• Participants must be able to swallow DR Cysteamine tablets with the tablet intact
• Written informed consent from parent or legal guardian
• Written informed assent from the child

Exclusion Criteria:

• There will be no exclusion criteria based on race, ethnicity or gender.

• Participants with a current history of the following conditions or any other health issues that make it unsafe for them to participate in the opinion of the Investigators:

  • Inflammatory bowel disease (if currently active) or prior resection of small intestine
  • Heart disease (e.g., myocardial infarction, heart failure, unstable arrhythmias)
  • Seizure disorder
  • Active coagulopathy
  • Gastrointestinal ulcers/bleeding
  • Renal dysfunction with a creatinine clearance < 90 mL/min/m2
  • History of active malignant disease requiring chemotherapy within the past 12 months prior to randomization
  • History of significant alcohol intake (AUDIT questionnaire) or inability to quantify alcohol consumption
  • Chronic use (more than 2 consecutive weeks) of medications known to cause hepatic steatosis or steatohepatitis (systemic glucocorticoids, tetracycline, anabolic steroids, valproic acid, salicylates, tamoxifen) in the past year.
  • The use of other known hepatotoxins within 90 days of liver biopsy or within 120 days of randomization
  • Initiation of medications with the intent to treat NAFLD/NASH in the time period following liver biopsy and prior to randomization
  • History of total parenteral nutrition (TPN) use in year prior to screening
  • History of bariatric surgery or planning to undergo bariatric surgery during study duration
  • Clinically significant depression (patients hospitalized for suicidal ideations or suicide attempts within the past 12 months)
  • Any female nursing, planning a pregnancy, known or suspected to be pregnant, or who has a positive serum pregnancy screen.

• Non-compensated liver disease with any one of the following hematologic, biochemical, and serological criteria on entry into protocol:

  • Hemoglobin < 10 g/dL;
  • White blood cell (WBC) < 3,500 cells/mm3 of blood;
  • Neutrophil count < 1,500 cells/mm3 of blood;
  • Platelets < 130,000 cells/mm3 of blood;
  • Direct bilirubin > 1.0 mg/dL
  • Total bilirubin >3 mg/dL
  • Albumin < 3.2 g/dL
  • International normalized ratio (INR) > 1.4
• Poorly controlled diabetes mellitus (hemoglobin A1c (HbA1c) > 9%)

• Evidence of other chronic liver disease:

  • Biopsy consistent with histological evidence of autoimmune hepatitis
  • Serum hepatitis B surface antigen (HBsAg) positive.
  • Serum hepatitis C antibody (anti-HCV) positive.
  • Iron/total iron binding capacity (TIBC) ratio (transferrin saturation) > 45% with histological evidence of iron overload
  • Alpha-1-antitrypsin (A1AT) phenotype ZZ or SZ
  • Wilson's disease
• Children who are currently enrolled in a clinical trial or who received an investigational study drug within 180 days of screening or liver biopsy.
• Subjects who are not able or willing to comply with the protocol or have any other condition that would impede compliance or hinder completion of the study, in the opinion of the investigator.
• Failure to give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: DR cysteamine bitartrate capsule; Active DR cysteamine bitartrate capsule	Drug: DR cysteamine bitartrate capsule; 600 mg/day (four 75 mg capsules twice daily) for patients ≤ 65 kg at baseline; 750 mg/day (five 75 mg capsules twice daily) for patients >65 - 80 kg at baseline; 900 mg/day (six 75 mg capsules twice daily) for patients >80 kg at baseline; Other Names: cysteamine bitartrate delayed-release
Placebo Comparator: DR cysteamine bitartrate placebo; Placebo DR cysteamine bitartrate capsule	Other: DR cysteamine bitartrate placebo; 600 mg/day (four 75 mg capsules twice daily) for patients ≤ 65 kg at baseline; 750 mg/day (five 75 mg capsules twice daily) for patients >65 - 80 kg at baseline; 900 mg/day (six 75 mg capsules twice daily) for patients >80 kg at baseline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in Nonalcoholic Fatty Liver Disease (NAFLD)	Centrally scored and masked assessment of histologic improvement in Nonalcholic Fatty Liver Disease (NAFLD) between the baseline liver biopsy and follow-up biopsy after 52 weeks of treatment, where improvement is defined as: (1) decrease in the NAFLD Activity Score (NAS) of 2 or more and (2) no worsening of fibrosis.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS)	Change from baseline in the NAFLD Activity Score (NAS), which is a composite score equal to the sum of the steatosis grade (0-3), lobular inflammation grade (0-3), and hepatocellular ballooning grade (0-2), from centralized pathologist scoring of liver biopsies. The overall scale of the NAS is 0-8, with higher scores indicating more severe disease. The outcome measure, change from baseline in NAFLD Activity Score (NAS), has a possible range from -8 to +8, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome. Components of the NAS are scored as follows: Steatosis grade 0=<5% steatosis, 1=5-33% steatosis, 2=34-66% steatosis, 3=>66% steatosis. Lobular inflammation grade=amount of lobular inflammation (combines mononuclear, fat granulomas, and polymorphonuclear (pmn) foci): 0=0, 1=<2 under 20x magnification, 2=2-4 under 20x magnification, 3=>4 under 20x magnification. Hepatocellular ballooning 0=none, 1=mild, 2=more than mild.	52 weeks
Steatosis: Patients With Improvement	Improvement in steatosis defined as any decrease in steatosis grade comparing 52-week biopsy to baseline.	52 weeks
Steatosis: Change in Score	Change from baseline in steatosis score. Steatosis score is based on central pathologist grading of liver biopsies: 0=<5% steatosis; 1=5-33% steatosis, 2=34-66% steatosis, 3=>66% steatosis. Change in steatosis score has a possible range of -3 to +3, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).	52 weeks
Lobular Inflammation: Patients With Improvement	Improvement in lobular inflammation defined as any decrease in lobular inflammation grade comparing 52-week biopsy to baseline.	52 weeks
Lobular Inflammation: Change in Score	Change from baseline in lobular inflammation score. The amount of lobular inflammation is based on central pathologist grading of liver biopsies, and combines mononuclear, fat granulomas, and polymorphonuclear (pmn) foci: 0=none; 1=<2 under 20x magnification, 2=2-4 under 20x magnification, 3=>4 under 20x magnification. Change in lobular inflammation score has a possible range of -3 to +3, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).	52 weeks
Hepatocellular Ballooning: Patients With Improvement	Improvement in hepatocellular ballooning defined as any decrease in hepatocellular ballooning score comparing 52-week biopsy to baseline.	52 weeks
Hepatocellular Ballooning: Change in Score	Change from baseline in hepatocellular ballooning score. The amount of hepatocellular ballooning is based on central pathologist grading of liver biopsies: 0=none; 1=few ballooned hepatocytes, 2=many ballooned hepatocytes. Change in hepatocellular ballooning score has a possible range of -2 to +2, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).	52 weeks
Portal Inflammation: Patients With Improvement	Improvement in portal inflammation defined as any decrease in portal inflammation score comparing 52-week biopsy to baseline.	52 weeks
Portal Inflammation: Change in Score	Change from baseline in portal inflammation score. The amount of portal inflammation is based on central pathologist grading of liver biopsies: 0=none; 1=mild, 2=more than mild. Change in portal inflammation score has a possible range of -2 to +2, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).	52 weeks
Fibrosis: Patients With Improvement	Improvement in fibrosis stage defined as any decrease in fibrosis stage comparing 52-week biopsy to baseline.	52 weeks
Fibrosis: Change in Stage	Change from baseline in fibrosis stage. The amount of fibrosis is based on central pathologist grading of liver biopsies: 0=none; 1a=mild, zone 3 perisinusoidal, 1b=moderate, zone 3, perisinusoidal, 1c=portal/periportal only, 2=zone 3 and periportal, any combination, 3=bridging, 4=cirrhosis. Fibrosis stages 1a, 1b, 1c recoded as 1, so the possible range of values for fibrosis stage was 0-4. Change in fibrosis stage has a possible range of -4 to +4, with negative values indicating a better outcome (improvement) and positive values indicating a worse outcome (no improvement).	52 weeks
Resolution of NASH	Patients with a change from a histological diagnosis of definite NASH or indeterminate for NASH to not NASH at end of treatment	52 weeks
Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase		52 weeks
Change in Weight (kg)		52 weeks
Change in Body-mass Index		52 weeks
Change in Body-mass Index Z-score		52 weeks
Change in Waist Circumference		52 weeks
Change in Fasting Serum Glucose		52 weeks
Change in Fasting Insulin		52 weeks
Change in HOMA-IR	(Glucose (mmol/L) x insulin (pmol/L))/22.5	52 weeks
Change in Systolic Blood Pressure		52 weeks
Change in Diastolic Blood Pressure		52 weeks
Change in Pediatric Quality of Life Inventory (PedsQL) Score	Pediatric Quality of Life Inventory (PedsQL) version 4.0 is completed by both the child and parent/caregiver, and is composed of 23 items comprising 4 dimensions: Physical Functioning, Emotional Functioning, Social Functioning, and School Functioning. Scores are transformed on a scale from 0 to 100, with higher scores indicating better health-related quality of life. Physical Health Summary Score =Physical Functioning Scale Score. Psychosocial Health Summary Score = Sum of items over the number of items answered in the Emotional, Social, and School Functioning Scales.	52 weeks
Reduction in MRI-determined Hepatic Fat Fraction	Change from baseline in MRI Proton Density Fat Fraction (PDFF) (%).	52 weeks

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: National Cancer Institute (NCI); National Center for Advancing Translational Sciences (NCATS); Raptor Pharmaceuticals
• Investigators: Study Director: Edward Doo, MD, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Schwimmer JB, Lavine JE, Wilson LA, Neuschwander-Tetri BA, Xanthakos SA, Kohli R, Barlow SE, Vos MB, Karpen SJ, Molleston JP, Whitington PF, Rosenthal P, Jain AK, Murray KF, Brunt EM, Kleiner DE, Van Natta ML, Clark JM, Tonascia J, Doo E; NASH CRN. In Children With Nonalcoholic Fatty Liver Disease, Cysteamine Bitartrate Delayed Release Improves Liver Enzymes but Does Not Reduce Disease Activity Scores. Gastroenterology. 2016 Dec;151(6):1141-1154.e9. doi: 10.1053/j.gastro.2016.08.027. Epub 2016 Aug 26.

Helpful Links

• Nonalcoholic Steatohepatitis Clinical Research Network Centers
• The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): September 1, 2015

Study Registration Dates

• First Submitted: January 18, 2012
• First Submitted That Met QC Criteria: February 6, 2012
• First Posted (Estimate): February 8, 2012

Study Record Updates

• Last Update Posted (Actual): June 10, 2021
• Last Update Submitted That Met QC Criteria: May 30, 2021
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Children; Nonalcoholic Fatty Liver Disease (NAFLD); Cysteamine bitartrate delayed release
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Molecular Mechanisms of Pharmacological Action; Cystine Depleting Agents; Cysteamine
• Other Study ID Numbers: NASH-CyNCh; U01DK061730 (U.S. NIH Grant/Contract); U01DK061732 (U.S. NIH Grant/Contract); U01DK061713 (U.S. NIH Grant/Contract); U01DK061737 (U.S. NIH Grant/Contract); U01DK061728 (U.S. NIH Grant/Contract); U01DK061718 (U.S. NIH Grant/Contract); U01DK061734 (U.S. NIH Grant/Contract); U01DK061738 (U.S. NIH Grant/Contract); U01DK061731 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Public use database deposited with the NIDDK Central Repository
• IPD Sharing Time Frame: Currently available
• IPD Sharing Access Criteria: Apply through the NIDDK Central Repository: https://www.niddkrepository.org/home/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No