Clinical trial NCT01529268: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Nonalcoholic Fatty Liver Disease (NAFLD)
Keywords: Nonalcoholic Fatty Liver Disease (NAFLD)
Cysteamine bitartrate delayed release
Children
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: National Center for Advancing Translational Sciences (NCATS)
name: National Cancer Institute (NCI)
name: Raptor Pharmaceuticals
First posted: 2012-02-08
Enrollment: 169
Sex: ALL
Minimum age (years): 8
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Improvement in Nonalcoholic Fatty Liver Disease (NAFLD)
timeFrame: 52 weeks
Secondary outcomes:
measure: Change in Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS)
timeFrame: 52 weeks
measure: Steatosis: Patients With Improvement
timeFrame: 52 weeks
measure: Steatosis: Change in Score
timeFrame: 52 weeks
measure: Lobular Inflammation: Patients With Improvement
timeFrame: 52 weeks
measure: Lobular Inflammation: Change in Score
timeFrame: 52 weeks
measure: Hepatocellular Ballooning: Patients With Improvement
timeFrame: 52 weeks
measure: Hepatocellular Ballooning: Change in Score
timeFrame: 52 weeks
measure: Portal Inflammation: Patients With Improvement
timeFrame: 52 weeks
measure: Portal Inflammation: Change in Score
timeFrame: 52 weeks
measure: Fibrosis: Patients With Improvement
timeFrame: 52 weeks
measure: Fibrosis: Change in Stage
timeFrame: 52 weeks
measure: Resolution of NASH
timeFrame: 52 weeks
measure: Change in Serum Aminotransferase and Gamma-glutamyl Transpeptidase
timeFrame: 52 weeks
measure: Change in Weight (kg)
timeFrame: 52 weeks
measure: Change in Body-mass Index
timeFrame: 52 weeks
measure: Change in Body-mass Index Z-score
timeFrame: 52 weeks
measure: Change in Waist Circumference
timeFrame: 52 weeks
measure: Change in Fasting Serum Glucose
timeFrame: 52 weeks
measure: Change in Fasting Insulin
timeFrame: 52 weeks
measure: Change in HOMA-IR
timeFrame: 52 weeks
measure: Change in Systolic Blood Pressure
timeFrame: 52 weeks
measure: Change in Diastolic Blood Pressure
timeFrame: 52 weeks
measure: Change in Pediatric Quality of Life Inventory (PedsQL) Score
timeFrame: 52 weeks
measure: Reduction in MRI-determined Hepatic Fat Fraction
timeFrame: 52 weeks
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago (NWU)
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Saint Louis
country: United States
facility: St. Louis University
state: Missouri
city: New York
country: United States
facility: Columbia University
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: University of Washington, Seattle Children's Hospital
state: Washington
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Edward Doo, MD
role: STUDY_DIRECTOR
References:
citation: 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.