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Betaine and Peroxisome Biogenesis Disorders

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. Identifier: NCT01838941
Recruitment Status : Completed
First Posted : April 24, 2013
Results First Posted : June 28, 2016
Last Update Posted : June 28, 2016
Children's Hospital and Medical Center, Omaha, Nebraska
Information provided by (Responsible Party):
Nancy Braverman, McGill University Health Center

Brief Summary:
The PBD are a rare group of inherited disorders due to the failure to form functional cellular peroxisomes. Most patients have progressive hearing and visual loss, leading to deafness and blindness, as well as neurological deterioration. There are no therapies for this disorder. A misfolded protein with residual function, PEX1-Gly843Asp, represents one third of all mutant alleles. Using patient cell lines with this mutation, we reported the recovery of peroxisome functions by treatment with Betaine, acting as a nonspecific chemical chaperone for the misfolded PEX1 protein. Betaine, or trimethylglycine, is a Health Canada and FDA approved orphan drug for the treatment of homocystinuria and is used by us safely and regularly in genetic medicine. We will perform a 6 month pilot study with 12 patients to test the hypothesis that Betaine, at recommended doses, can recover peroxisome biochemical functions in blood.

Condition or disease Intervention/treatment Phase
Peroxisome Biogenesis Disorders Drug: Betaine Phase 3

Detailed Description:

Peroxisome biogenesis disorders (PBD) are a group of inherited conditions caused by faulty assembly of peroxisomes, structures located inside cells that regulate levels of important fats and lipids in the body. When there is faulty peroxisome assembly, as in PBD, these important fats and lipids either accumulate or are not made. There is no specific treatment for these disorders, and management is supportive. In order to complement existing supportive therapies, physicians and researchers are still actively looking for new treatments acting on the root cause of PBD: the peroxisome function. To identify drugs that help recover peroxisome function a group of scientists developed a laboratory-based research test aimed at reviewing the activity of the large number of potential treatments. Using this test, they have uncovered that Betaine can improve the function of the peroxisome, when the defect is caused by a PEX1-Gly843Asp mutation, and as such may improve the overall health of child suffering from PBD.

Betaine is a medication already available as a powder for oral solution, for another rare disease. It is approved in many countries, including Health Canada for Canada and the Food and Drug Administration for the USA. Paediatric genetic physicians are used to prescribing this medication and know it well.

At the current stage of scientific knowledge, it is a critical next step to evaluate the benefit of betaine in children having a PBD due to a PEX1-Gly843Asp mutation, to ensure that the medication is safe and to measure the level of improvement of the function of the peroxisome.

Thus, the principal objective of the study is to determine the improvement in the key peroxisome functions (plasma very long chain fatty acid profiles red cell plasmalogen levels, plasma pipecolic acid levels and plasma bile acid profiles). Another objective is to measure the growth of your child and his / her development.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot, Open Label Trial Assessing the Safety and Efficacy of Betaine in Children With Peroxisome Biogenesis Disorders.
Study Start Date : March 2013
Actual Primary Completion Date : January 2015
Actual Study Completion Date : June 2015

Arm Intervention/treatment
Experimental: Betaine
Betaine will be given orally to all participants and dose will be adjusted to body weight.
Drug: Betaine

Betaine will be given orally (mixed with food or dissolved in water, juice, milk, or formula) or through gastrostomy tube as follows:

  • 6 g/day in children < 30 kg, in 3 divided doses (2 g at meal time)
  • 12 g/day in children > 30 kg, in 4 divided doses (3 g at meal time and bed time).
Other Name: Cystadane®

Primary Outcome Measures :
  1. Peroxisome Biochemical Functions as Measured by Plasma Very Long Chain Fatty Acid [ Time Frame: 6 months ]
    C26/C22 ratio in plasma is a recognized biomarker for very long chain fatty acid (normal range: 0.002-0.018). It was measured twice before the beginning of treatment and measured once at the end.

Secondary Outcome Measures :
  1. Developmental Status [ Time Frame: 6 months ]
    Denver Developmental Screening Test expressed in years and months.

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Males or females
  • Any age
  • Peroxisome Biogenesis Disorder (PBD) confirmed by biochemical analysis of at least two peroxisomal enzyme parameters:

    • Elevated plasma VLCFA (C26/22) > 0.02
    • Elevated plasma branched chain pristanic acid > 0.3 μg/ml
    • Reduced red blood cell plasmalogen levels (C16:0DMA/C16:0 Fatty acid) < 0.07
  • PBD clinical syndromes: neonatal adrenoleukodystrophy (NALD) or infantile Refsum disease (IRD)
  • Genotype PEX1-G843D/G843D, PEX1-G843D/I700fs, or PEX1-G843D and any second PEX1 mutation that is predicted to be null
  • Expected survival of at least 6 months

Exclusion Criteria:

  • Genotypes other than PEX1 G843D/G843D, PEX1-G843D//I700fs, or PEX1-G843D and any second PEX1 mutation that is predicted to be null
  • Patient already treated with betaine

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 identifier (NCT number): NCT01838941

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Canada, Quebec
Montreal Children's Hospital
Montreal, Quebec, Canada, H3H 1P3
Sponsors and Collaborators
McGill University Health Center
Children's Hospital and Medical Center, Omaha, Nebraska
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Principal Investigator: Nancy Braverman, PhD, MD Montreal Children's Hospital, MUHC

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Responsible Party: Nancy Braverman, Associate Professor, Depts. of Human Genetics and Pediatrics, McGill University Health Center Identifier: NCT01838941     History of Changes
Other Study ID Numbers: RPGDN001
First Posted: April 24, 2013    Key Record Dates
Results First Posted: June 28, 2016
Last Update Posted: June 28, 2016
Last Verified: May 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Nancy Braverman, McGill University Health Center:
Peroxisome Biogenesis Disorder
neonatal adrenoleukodystrophy
infantile Refsum disease
PEX1 mutation

Additional relevant MeSH terms:
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Peroxisomal Disorders
Pathologic Processes
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Gastrointestinal Agents
Lipotropic Agents
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents