Betaine and Peroxisome Biogenesis Disorders

• ClinicalTrials.gov Identifier: NCT01838941
• Recruitment Status: Completed
• First Posted: April 24, 2013
• Results First Posted: June 28, 2016
• Last Update Posted: June 28, 2016
• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
• Collaborator: Children's Hospital and Medical Center, Omaha, Nebraska
• Information provided by (Responsible Party): Nancy Braverman, McGill University Health Centre/Research Institute of the McGill University Health Centre

Study Description

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12 participants
• Allocation: N/A
• 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

Arms and Interventions

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®

Outcome Measures

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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Canada, Quebec

Montreal Children's Hospital

Montreal, Quebec, Canada, H3H 1P3

Sponsors and Collaborators

McGill University Health Centre/Research Institute of the McGill University Health Centre

Children's Hospital and Medical Center, Omaha, Nebraska

Investigators

• Principal Investigator: Nancy Braverman, PhD, MD; Montreal Children's Hospital, MUHC

More Information

Publications:

Zhang R, Chen L, Jiralerspong S, Snowden A, Steinberg S, Braverman N. Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds. Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5569-74. doi: 10.1073/pnas.0914960107. Epub 2010 Mar 8.

• Responsible Party: Nancy Braverman, Associate Professor, Depts. of Human Genetics and Pediatrics, McGill University Health Centre/Research Institute of the McGill University Health Centre
• ClinicalTrials.gov Identifier: NCT01838941
• Other Study ID Numbers: RPGDN001
• First Posted: April 24, 2013
• 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 Centre/Research Institute of the McGill University Health Centre:

Peroxisome Biogenesis Disorder; PBD; neonatal adrenoleukodystrophy; infantile Refsum disease; PEX1 mutation; Betaine

Additional relevant MeSH terms:

Peroxisomal Disorders; Disease; Pathologic Processes; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Betaine; Gastrointestinal Agents; Lipotropic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents