Betaine and Peroxisome Biogenesis Disorders

NCT01838941 | Completed Phase 3 Results

• 1 other identifier: RPGDN001
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Peroxisome Biogenesis Disorders

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Peroxisome Biochemical Functions as Measured by Plasma Very Long Chain Fatty Acid

  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.

  6 months

Secondary Outcomes (1)

• Developmental Status

  6 months

Study Arms (1)

Betaine

EXPERIMENTAL

Betaine will be given orally to all participants and dose will be adjusted to body weight.

Drug: Betaine

Interventions

Betaine DRUG

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).

Also known as: Cystadane®

Betaine

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• McGill University Health Centre/Research Institute of the McGill University Health Centre: lead
• Children's Hospital and Medical Center, Omaha, Nebraska: collaborator

Study Sites (1)

Montreal Children's Hospital

Montreal, Quebec, H3H 1P3, Canada

Location

Related 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.

  PMID: 20212125 BACKGROUND

MeSH Terms

Conditions

Peroxisome biogenesis disorders; Zellweger Syndrome; Peroxisomal Disorders; Refsum Disease, Infantile

Interventions

Betaine

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Trimethyl Ammonium Compounds; Quaternary Ammonium Compounds; Amines; Organic Chemicals; Onium Compounds

Limitations and Caveats

Large intra- and inter-individual variations in peroxisome functions, variation in phenotype severity, variation in age, number of participants; blood metabolite markers may be less sensitive than direct measurements of cell responses.

Results Point of Contact

• Title: Dr. Nancy Braverman, Associate Professor, Human Genetics and Pediatrics
• Organization: McGill University Health Centre

nancy.braverman@mcgill.ca

(514) 934-1934

Study Officials

• Nancy Braverman, PhD, MD

  Montreal Children's Hospital, MUHC

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor, Depts. of Human Genetics and Pediatrics

Study Record Dates

• First Submitted: March 29, 2013
• First Posted: April 24, 2013
• Study Start: March 1, 2013
• Primary Completion: January 1, 2015
• Study Completion: June 1, 2015
• Last Updated: June 28, 2016
• Results First Posted: June 28, 2016

Record last verified: 2016-05

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)