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

• ClinicalTrials.gov Identifier: NCT01529268
• Recruitment Status: Completed
• First Posted: February 8, 2012
• Results First Posted: September 5, 2017
• Last Update Posted: September 5, 2017
• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: National Center for Advancing Translational Science (NCATS); National Cancer Institute (NCI); Raptor Pharmaceuticals
• Information provided by (Responsible Party): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Tracking Information

• First Submitted Date: January 18, 2012
• First Posted Date: February 8, 2012
• Results First Submitted Date: April 10, 2017
• Results First Posted Date: September 5, 2017
• Last Update Posted Date: September 5, 2017
• Study Start Date: June 2012
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 2, 2017)

Improvement in Nonalcoholic Fatty Liver Disease (NAFLD) [ Time Frame: 52 weeks ]

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.

Original Primary Outcome Measures (submitted: February 6, 2012)

Improvement in NAFLD [ Time Frame: 52 weeks ]

Centrally scored and masked assessment of histologic improvement in NAFLD between the baseline liver biopsy and follow-up biopsy after 52 weeks of treatment, where improvement is defined as: (1) decrease in NAS of 2 or more and (2) no worsening of fibrosis.

Current Secondary Outcome Measures (submitted: August 2, 2017)

• Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) [ Time Frame: 52 weeks ]
  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.
• Steatosis: Patients With Improvement [ Time Frame: 52 weeks ]
  Improvement in steatosis defined as any decrease in steatosis grade comparing 52-week biopsy to baseline.
• Steatosis: Change in Score [ Time Frame: 52 weeks ]
  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).
• Lobular Inflammation: Patients With Improvement [ Time Frame: 52 weeks ]
  Improvement in lobular inflammation defined as any decrease in lobular inflammation grade comparing 52-week biopsy to baseline.
• Lobular Inflammation: Change in Score [ Time Frame: 52 weeks ]
  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).
• Hepatocellular Ballooning: Patients With Improvement [ Time Frame: 52 weeks ]
  Improvement in hepatocellular ballooning defined as any decrease in hepatocellular ballooning score comparing 52-week biopsy to baseline.
• Hepatocellular Ballooning: Change in Score [ Time Frame: 52 weeks ]
  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).
• Portal Inflammation: Patients With Improvement [ Time Frame: 52 weeks ]
  Improvement in portal inflammation defined as any decrease in portal inflammation score comparing 52-week biopsy to baseline.
• Portal Inflammation: Change in Score [ Time Frame: 52 weeks ]
  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).
• Fibrosis: Patients With Improvement [ Time Frame: 52 weeks ]
  Improvement in fibrosis stage defined as any decrease in fibrosis stage comparing 52-week biopsy to baseline.
• Fibrosis: Change in Stage [ Time Frame: 52 weeks ]
  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).
• Resolution of NASH [ Time Frame: 52 weeks ]
  Patients with a change from a histological diagnosis of definite NASH or indeterminate for NASH to not NASH at end of treatment
• Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase [ Time Frame: 52 weeks ]
• Change in Weight (kg) [ Time Frame: 52 weeks ]
• Change in Body-mass Index [ Time Frame: 52 weeks ]
• Change in Body-mass Index Z-score [ Time Frame: 52 weeks ]
• Change in Waist Circumference [ Time Frame: 52 weeks ]
• Change in Fasting Serum Glucose [ Time Frame: 52 weeks ]
• Change in Fasting Insulin [ Time Frame: 52 weeks ]
• Change in HOMA-IR [ Time Frame: 52 weeks ]
  (Glucose (mmol/L) x insulin (pmol/L))/22.5
• Change in Systolic Blood Pressure [ Time Frame: 52 weeks ]
• Change in Diastolic Blood Pressure [ Time Frame: 52 weeks ]
• Change in Pediatric Quality of Life Inventory (PedsQL) Score [ Time Frame: 52 weeks ]
  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.
• Reduction in MRI-determined Hepatic Fat Fraction [ Time Frame: 52 weeks ]
  Change from baseline in MRI Proton Density Fat Fraction (PDFF) (%).

Original Secondary Outcome Measures (submitted: February 6, 2012)

• Reduction in serum aminotransferase and gamma-glutamyl transpeptidase [ Time Frame: 52 weeks ]
• Reduction in MRI-determined Hepatic Fat Fraction [ Time Frame: 52 weeks ]
• Changes to markers of oxidation and anti-oxidant status: maldondialdehyde, F2alpha-isoprostane, total antioxidant capacity, oxidized LDL [ Time Frame: 52 weeks ]
• Changes in fasting insulin and glucose [ Time Frame: 52 weeks ]
• Changes in weight, height, BMI, and waist circumference [ Time Frame: 52 weeks ]
• Changes in the Pedatric Quality of Life score [ Time Frame: 52 weeks ]
• Changes to any symptoms the patient may have experienced [ Time Frame: 52 weeks ]
• Proportion with a change from a histological diagnosis of definite NASH or indeterminate for NASH to not NASH at end of treatment [ Time Frame: 52 weeks ]
• Individual histological characteristics at end of treatment compared to baseline such as steatosis, lobular inflammation, portal chronic inflammation, ballooning, fibrosis score and stage 1a vs 1b fibrosis [ Time Frame: 52 weeks ]
• Change in mean NAFLD Activity Score (NAS) [ Time Frame: 52 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cysteamine Bitartrate Delayed-Release for the Treatment of NAFLD in Children
• Official Title: Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in Children (CyNCh)
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Nonalcoholic Fatty Liver Disease (NAFLD)

Intervention

• 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 Name: cysteamine bitartrate delayed-release
• 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

Study Arms

• Active Comparator: DR cysteamine bitartrate capsule
  Active DR cysteamine bitartrate capsule
  Intervention: Drug: DR cysteamine bitartrate capsule
• Placebo Comparator: DR cysteamine bitartrate placebo
  Placebo DR cysteamine bitartrate capsule
  Intervention: Other: DR cysteamine bitartrate placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 6, 2015): 169
• Original Estimated Enrollment (submitted: February 6, 2012): 160
• Actual Study Completion Date: September 2015
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 8 Years to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01529268
• Other Study ID Numbers: NASH-CyNCh; U01DK061718 ( U.S. NIH Grant/Contract ); U01DK061728 ( U.S. NIH Grant/Contract ); U01DK061731 ( U.S. NIH Grant/Contract ); U01DK061732 ( U.S. NIH Grant/Contract ); U01DK061734 ( U.S. NIH Grant/Contract ); U01DK061737 ( U.S. NIH Grant/Contract ); U01DK061738 ( U.S. NIH Grant/Contract ); U01DK061730 ( U.S. NIH Grant/Contract ); U01DK061713 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Public use database deposited with the NIDDK Central Repository
• Supporting Materials: Study Protocol
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Analytic Code
• Time Frame: Currently available
• Access Criteria: Apply through the NIDDK Central Repository: https://www.niddkrepository.org/home/
• URL: https://www.niddkrepository.org/studies/cynch/

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Study Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborators

• National Center for Advancing Translational Science (NCATS)
• National Cancer Institute (NCI)
• Raptor Pharmaceuticals

Investigators

• Study Director: Edward Doo, MD; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

• PRS Account: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Verification Date: August 2017