Betaine and Peroxisome Biogenesis Disorders

Peroxisome Biogenesis Disorder (PBD) Clinical Trial

Official title:

A Pilot, Open Label Trial Assessing the Safety and Efficacy of Betaine in Children With Peroxisome Biogenesis Disorders.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01838941
• Other study ID #: RPGDN001
• Status: Recruiting
• Phase: Phase 3
• First received: March 29, 2013
• Last updated: August 7, 2013
• Start date: March 2013
• Est. completion date: June 2014

Study information

• Verified date: August 2013
• Source: McGill University Health Center
• Contact: Francois Plourde, MSc, MSc
• Phone: (1) 514 934 1934
• Email: francois.plourde[@]mail.mcgill.ca
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial 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.

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. These changes result in abnormalities of organ formation that a child is born with, such as changes in bone, brain and eye formation. 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 have developed a test to be used in laboratories, aiming 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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/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//I700fs or PEX1-G843D and any second PEX1 mutation that is predicted to be null

• Patient already treated with betaine

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Peroxisomal Disorders
• Peroxisome Biogenesis Disorder (PBD)

Intervention

Drug:
• Betaine

Locations

Country	Name	City	State
Canada	Montreal Children's Hospital	Montreal	Quebec

Sponsors (2)

Lead Sponsor	Collaborator
McGill University Health Center	Orphan Europe

Country where clinical trial is conducted

Canada, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Peroxisome biochemical functions as measured by plasma very long chain fatty acid	C26/C22 ratio in plasma which is a recognized biomarker for very long chain fatty acid.	6 months	No
Secondary	Growth developmental status	Denver Developmental Screening Test expressed in years and months.	6 months	No