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

Nonalcoholic Fatty Liver Disease (NAFLD) Clinical Trial

— CyNCh  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01529268
• Other study ID #: NASH-CyNCh
• Secondary ID: U01DK061718U01DK
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: June 2012
• Est. completion date: September 2015

Study information

• Verified date: August 2017
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 169
• Est. completion date: September 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• 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:
• 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

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Ann & Robert H. Lurie Children's Hospital of Chicago (NWU)	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Texas Children's Hospital	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	Columbia University	New York	New York
United States	St. Louis University	Saint Louis	Missouri
United States	University of California, San Diego	San Diego	California
United States	University of California, San Francisco	San Francisco	California
United States	University of Washington, Seattle Children's Hospital	Seattle	Washington

Sponsors (4)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	National Cancer Institute (NCI), National Center for Advancing Translational Science (NCATS), Raptor Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Steatosis: Patients With Improvement	Improvement in steatosis defined as any decrease in steatosis grade comparing 52-week biopsy to baseline.	52 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Fibrosis: Patients With Improvement	Improvement in fibrosis stage defined as any decrease in fibrosis stage comparing 52-week biopsy to baseline.	52 weeks
Secondary	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
Secondary	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
Secondary	Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase		52 weeks
Secondary	Change in Weight (kg)		52 weeks
Secondary	Change in Body-mass Index		52 weeks
Secondary	Change in Body-mass Index Z-score		52 weeks
Secondary	Change in Waist Circumference		52 weeks
Secondary	Change in Fasting Serum Glucose		52 weeks
Secondary	Change in Fasting Insulin		52 weeks
Secondary	Change in HOMA-IR	(Glucose (mmol/L) x insulin (pmol/L))/22.5	52 weeks
Secondary	Change in Systolic Blood Pressure		52 weeks
Secondary	Change in Diastolic Blood Pressure		52 weeks
Secondary	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
Secondary	Reduction in MRI-determined Hepatic Fat Fraction	Change from baseline in MRI Proton Density Fat Fraction (PDFF) (%).	52 weeks

External Links

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