CARDIOMAN
Research type
Research Study
Full title
Treatment of Barth Syndrome by CARDIOlipin MANipulation (CARDIOMAN): A randomised placebo controlled pilot trial conducted by the nationally commissioned Barth Syndrome Service
IRAS ID
170371
Contact name
Diana Benton
Contact email
Sponsor organisation
University Hospital Bristol NHS Trust
Eudract number
2015-001382-10
Clinicaltrials.gov Identifier
U1111-1168-5327, WHO Universal Trial Number
Duration of Study in the UK
years, months, days
Research summary
Research Summary
Barth Syndrome is a rare, life threatening, genetic disease which affects young males. It is caused by abnormal fats (lipids) in the powerhouses of cells (mitochondria) and those who suffer with it often develop heart failure, heart rhythm abnormalities, bacterial infections, poor growth or feeding, weak muscles, developmental delay, severe exercise intolerance, lethargy and fatigue; all of which affect their daily life. In addition, approximately one third of males living with this disease in the UK have required heart transplantation.
Research has shown that several treatments can improve the fat abnormalities in Barth Syndrome, one of which is a drug called bezafibrate. This study will investigate if bezafibrate can be given safely and effectively to people with Barth Syndrome in a blinded randomised trial.
Bezafibrate or an inactive (placebo) treatment will be given for 4 months, followed by a one month break, and then 4 months of the alternate treatment (e.g. placebo if bezafibrate taken for the first 4 months and vice versa). Half of the participants will take bezafibrate first; the other half will take placebo first. Participants and research staff will not know the order in which the treatments are given.
Tests will be performed after each 4 month treatment period, looking for benefit in blood cells, exercise capacity, heart function or quality of life. Laboratory work will also be conducted to see the effect of bezafibrate on participants’ cells and mitochondria. We hope this will help us predict which patients would benefit from treatment in the future. Laboratory work will also be carried out using another drug called resveratrol to see if this could provide an alternative treatment.
We wish to study up to 18 Barth Syndrome boys and young men aged 6 years or over.Summary of Results
Barth syndrome is a rare genetic disease that causes a variety of life-long significant health issues, including heart problems, severe exercise intolerance, fatigue, low neutrophil numbers (neutropenia), poor feeding and growth delay. Affected people are at risk of life-threatening infections, reduced mobility and psychological challenges, resulting in a reduced quality of life. Barth syndrome is almost entirely present in males and is caused by a change in the levels of two lipids (fats) in the mitochondria of the cells, called a cardiolipin ratio.
Currently, there is no cure for the disease. Only symptoms are treated so medicines targeting the cause of the disease in the mitochondria are urgently needed. Previous laboratory studies have shown that a drug called bezafibrate can improve the cardiolipin ratio in the cells, shifting it towards more normal levels. This is thought to be important because some people with Barth syndrome with better cardiolipin ratios have been reported to have less severe disease, with better exercise ability and mild or non-existent neutropenia, so they are less susceptible to infections.
Between March-December 2019 a Randomised Controlled Trial (RCT) was conducted to find out if bezafibrate could improve cardiolipin ratios in Barth syndrome patients. Eleven individuals aged 9 to 27 years from across the United Kingdom were recruited from a potential population of 20 patients aged 6 years or above. Participants were randomised to receive either bezafibrate for four months and a placebo for four months (with a break in between) or to receive the placebo for four months (with a break in between) followed by the bezafibrate. The participants did not know in which order they received the bezafibrate and placebo. To determine if the bezafibrate had any affect, participants were tested for their exercise capacity, heart function and the mitochondrial function of cells. Quality of life was also assessed by questionnaires that were completed by the participants and their caregivers.
The study found that bezafibrate did not significantly improve exercise capacity or the mitochondrial function of participants’ cells. Heart function also remained largely unchanged, apart from some improvements in a sub-set of the tests (known as heart ‘strain’). However, heart strain is a very sensitive measure of heart muscle function and improvements in strain do not always translate into improvement felt by the patient, which was reflected in no difference seen in quality of life. Bezafibrate was shown to be well tolerated by participants, with few side-effects recorded.
The trial had a limited capacity to detect an effect of the bezafibrate in statistical terms because of low participant numbers and the relatively short duration that participants took the bezafibrate. Low participant numbers remain a challenge of conducting research in rare disease populations. However, the trial did prove that complex randomised controlled drug trials are feasible in people with rare diseases and it could serve as a template for future studies. To date only one other drug trial has been conducted in Barth syndrome, and data from that study suggests that it could take much longer than the four months of therapy (as used in CARDIOMAN) to achieve detectable improvement in mitochondrial function. Therefore, it may be that a longer duration of treatment or a higher bezafibrate dose may have produced better outcomes.REC name
South West - Central Bristol Research Ethics Committee
REC reference
15/SW/0228
Date of REC Opinion
12 Nov 2015
REC opinion
Further Information Favourable Opinion