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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01529268
First Posted: February 8, 2012
Last Update Posted: September 4, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
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)
  Purpose
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.

Condition Intervention Phase
Nonalcoholic Fatty Liver Disease (NAFLD) Drug: DR cysteamine bitartrate capsule Other: DR cysteamine bitartrate placebo Phase 2 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) in Children (CyNCh)

Resource links provided by NLM:


Further study details as provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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) (%).


Enrollment: 169
Study Start Date: June 2012
Study Completion Date: September 2015
Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   8 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01529268


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

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT01529268     History of Changes
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 )
First Submitted: January 18, 2012
First Posted: February 8, 2012
Results First Submitted: April 10, 2017
Results First Posted: September 4, 2017
Last Update Posted: September 4, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Public use database deposited with the NIDDK Central Repository
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
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/

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

Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):
Nonalcoholic Fatty Liver Disease (NAFLD)
Cysteamine bitartrate delayed release
Children

Additional relevant MeSH terms:
Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases
Cysteamine
Cystine Depleting Agents
Molecular Mechanisms of Pharmacological Action