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

Study Overview
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Brief Summary
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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.

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

Conditions
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Nonalcoholic Fatty Liver Disease (NAFLD)

Intervention / Treatment
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* Drug: DR cysteamine bitartrate capsule
* Other: DR cysteamine bitartrate placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DR cysteamine bitartrate capsule<br>Active DR cysteamine bitartrate capsule | Drug: DR cysteamine bitartrate capsule<br>* 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<br>* Other names: cysteamine bitartrate delayed-release;|
| Placebo Comparator: DR cysteamine bitartrate placebo<br>Placebo DR cysteamine bitartrate capsule | Other: DR cysteamine bitartrate placebo<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonalcoholic Fatty Liver Disease (NAFLD), Cysteamine bitartrate delayed release, Children