Betaine and Peroxisome Biogenesis Disorders

• Sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre (Other)
• Overall Status: Completed
• CT.gov ID: NCT01838941
• Collaborator: Children's Hospital and Medical Center, Omaha, Nebraska (Other)
• Enrollment: 12
• Location: 1
• Arm: 1
• Duration (Months): 27
• Patients Per Site Per Month: 0.4

Study Details

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
• 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: Mar 1, 2013
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jun 1, 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 Names: Cystadane®

Outcome Measures

Primary Outcome Measures

1. Peroxisome Biochemical Functions as Measured by Plasma Very Long Chain Fatty Acid [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 [6 months]

   Denver Developmental Screening Test expressed in years and months.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

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: Apr 24, 2013
• Last Update Posted: Jun 28, 2016
• Last Verified: May 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Nancy Braverman, Associate Professor, Depts. of Human Genetics and Pediatrics, 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; Betaine

Study Results

Participant Flow

Arm/Group Title	Betaine
Arm/Group Description	Betaine will be given orally to all participants and dose will be adjusted to body weight. 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).
Period Title: Overall Study
STARTED	12
COMPLETED	10
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Betaine
Arm/Group Description	Betaine will be given orally to all participants and dose will be adjusted to body weight. Betaine: Betaine given orally (mixed with food or dissolved in water, juice, milk, or formula) or through gastrostomy tube: 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).
Overall Participants	12
Age (Count of Participants)
<=18 years	11 91.7%
Between 18 and 65 years	1 8.3%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	4.75
Sex: Female, Male (Count of Participants)
Female	7 58.3%
Male	5 41.7%
Region of Enrollment (participants) [Number]
Canada	2 16.7%
United States	10 83.3%
Mutation status (participants) [Number]
PEX1 G843D homozygous mutation	2 16.7%
PEX1 G843D/null mutations	10 83.3%

Outcome Measures

1. Primary Outcome

Title	Peroxisome Biochemical Functions as Measured by Plasma Very Long Chain Fatty Acid
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betaine
Arm/Group Description	Betaine will be given orally to all participants and dose will be adjusted to body weight. 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).
Measure Participants	10
Baseline	0.180
At 6 months	0.188

2. Secondary Outcome

Title	Developmental Status
Description	Denver Developmental Screening Test expressed in years and months.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

The Denver Developmental Screening Test was not performed.

Arm/Group Title	Betaine
Arm/Group Description	Betaine will be given orally to all participants and dose will be adjusted to body weight. 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).
Measure Participants	0

Adverse Events

Arm/Group Title	Betaine
Arm/Group Description	Betaine will be given orally to all participants and dose will be adjusted to body weight. 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).
All Cause Mortality
	Betaine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Betaine
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	Betaine
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Ear and labyrinth disorders
Ear infection/Otitis media	2/12 (16.7%)	9
Eye disorders
Eye discharge	1/12 (8.3%)	1
Gastrointestinal disorders
Diarrhea	2/12 (16.7%)	3
Gas	1/12 (8.3%)	1
Constipation	4/12 (33.3%)	4
Vomiting	1/12 (8.3%)	1
Decreased appetite	2/12 (16.7%)	2
Upset stomach	1/12 (8.3%)	1
General disorders
Dry mouth	1/12 (8.3%)	1
Fatigue	3/12 (25%)	3
Infections and infestations
Viral syndrome	3/12 (25%)	4
Investigations
Elevated INR levels	1/12 (8.3%)	1
Nervous system disorders
Increase in seizure activity	1/12 (8.3%)	1
Febrile seizure	1/12 (8.3%)	2
Respiratory, thoracic and mediastinal disorders
Croup	1/12 (8.3%)	1
Respiratory tract infection	2/12 (16.7%)	2
Skin and subcutaneous tissue disorders
Change in body odor (skin, urine, and/or breath)	3/12 (25%)	4

Limitations/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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.