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Cholic acid treatment in Peroxisomal Biogenesis Disorders (Zellweger spectrum)
DOI 10.1186/ISRCTN96480891
ClinicalTrials.gov identifier
EudraCT number
Public title Cholic acid treatment in Peroxisomal Biogenesis Disorders (Zellweger spectrum)
Scientific title Cholic acid treatment in Peroxisomal Biogenesis Disorders (Zellweger spectrum): biochemical and clinical effects
Acronym N/A
Serial number at source P1114
Study hypothesis Cholic acid supplementation in mild Zellweger spectrum patients improves intestinal fat absorption and growth by increasing the amount of intraluminal bile acids, thus promoting micellar solubilization. In addition, we hypothesize that cholic acid supplementation improves liver function and alleviates neurological symptoms by suppressing the endogenous bile acid synthesis and stimulating bile flow, thus decreasing the production of potentially toxic and cholestatic bile acid intermediates.

Neurological milestones will be performed by a trained observer not blinded for the patientsí treatment phase. Measurements of weight and height, fibroscan liver elasticity measurements and laboratory tests will be performed by operators blinded for the patientsí treatment phase.
Lay summary Lay summary under review 2
Ethics approval 1. Medical Ethical Committee AMC, March 2011 ref: MEC 10/276
2. Centrale Commissie Mensgebonden Onderzoek (CCMO), December 2010, ref: NL33339.018.10
Study design Single-centre open label pilot study
Countries of recruitment Netherlands, United States of America
Disease/condition/study domain Zellweger spectrum disorder
Participants - inclusion criteria 1. Zellweger spectrum disorder
2. At least one of the following hallmarks:
2.1. Steatorrhea
2.2. Elevated transaminases
2.3. Growth retardation
2.4. Neurological symptoms
Participants - exclusion criteria Short life expectancy (severe multiple organ dysfunction at the time of diagnosis)
Anticipated start date 01/11/2011
Anticipated end date 01/11/2013
Status of trial Completed
Patient information material Not available in web format, please use the contact details below to request a patient information sheet
Target number of participants Twenty
Interventions Investigational product:
Cholic acid is the predominant human bile acid. In this study, cholic acid will be supplemented for 9 months in a regular dose. No placebo will be used.

Use of co-intervention:
Changes in diet during the study period will be recorded. Use of possible hepatotoxic medication should be avoided if an equally effective alternative drug is available. All changes in co-medication will be recorded.

Dosages, dosage modifications and method of administration:
Cholic acid will be administered in doses of 15 mg/kg/day in 2 or 3-divided doses daily orally during meals. In case of incomplete suppression of bile acid intermediates in week 36 the dosage will be increased to 20 mg/kg/day in 2 or 3 divided doses daily. Frequency of administration depends on the number of capsules needed daily, objective is to administer an equal dose over the day.

Cholic acid can de administered as capsules or liquid depending on the participantís preference. Capsules of 250 and 50 mg will allow accurate dosing at 15 mg/kg/day in patients with body weight above 6 kilogram. In case the dosage is increased to 20 mg/kg/day or patients weighting less than 6 kg are included capsules will be prepared adapted to the patientsí weight by the AMC pharmacy. For this cutom-made preparation the same drug substance and addatives as described in the CMC will be used to prepare the drug product. As this is not a standardized preparation procedure, the storage life will be limited to 6 months after custom made preparation.

The medication will be provided by Asklepion Pharmaceuticals and it will be shipped to the pharmacy of the AMC pharmacy who will be responsible for capsule preparation and distribution of the product. At the end of the (premature) end of the studies the remaining medicinal product will be taken in by the treating physician and returned to the AMC pharmacy.
Primary outcome measure(s) 1. Degree of suppression of endogenous bile acid synthesis [Decrease in urine 3 alpha,7 alpha -dihydroxycholestanoic acid (DHCA) and 3 alpha,7alpha,12 alpha - trihydroxycholestanoic acid (THCA) bile acid intermediates and increase in FGF-19]
2. Increase in normal primary bile acids [increase in urine cholic acid (CA)]
3. Change in fat soluble vitamins levels (T= 24 weeks versus T= 42 weeks)
4. Change in weight gain (weight-for-height percentile) (T= 36 weeks versus T=72 weeks)
5. Change total body length growth rate (cm/year; only in those with remaining growth potential)
6. Feasiibility and side effects of cholic acid supplementation; diarrhea, vomiting, liver dysfunction and others
Measured at 0, 24, 36, 48, 72 weeks
Secondary outcome measure(s) 1. Change in seizure frequency
2. Change in the obtained developmental mile stones
3. Change serum transminases and γ-glutamyltrans- peptidase levels
4. Change in fibroscan liver elasticity measurements
5. Change in liver protein synthesis
6. Change in markers of peroxisomal / mitochondrial functioning
Measured at 0, 24, 36, 48, 72 weeks
Sources of funding Emma Paediatric Hospital (Netherlands)
Trial website
Contact name Dr  Bart  Koot
  Address Department of Pediatrics
Suite H7-250
Meibergdreef 9
  City/town Amsterdam
  Zip/Postcode 1105 AZ
  Country Netherlands
  Email b.g.koot@amc.uva.nl
Sponsor Emma Paeditric Hosptial (Netherlands)
  Address Meibergdreef 9 (TKs0-253)
  City/town Amsterdam
  Zip/Postcode 1105 AZ
  Country Netherlands
Date applied 20/11/2011
Last edited 30/01/2012
Date ISRCTN assigned 30/01/2012
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