Title: Treatment of Barth Syndrome by CARDIOlipin MANipulation (CARDIOMAN): A randomised placebo-controlled pilot trial conducted by the nationally commissioned Barth Syndrome Service
Funder: Department of Health and Social Care

Abstract: HYPOTHESIS & AIMS Barth Syndrome patients show a deficiency of L4-cardiolipin (L4-CL) and excess of monolysocardiolipin (MLCL) in their inner mitochondrial membranes. In vitro studies on mouse and human fibroblasts show that the lipid lowering drug bezafibrate can produce major improvement in the abnormal MLCL/L4-CL ratio and has proven clinical efficacy in mitochondrial myopathy. We seek to examine the effect of bezafibrate in boys/young men with Barth Syndrome, looking at peak skeletal muscle oxygen consumption on bicycle exercise testing and a range of secondary outcome measures, including biochemical cardiolipin levels and Quality of Life (QOL). This will be run in parallel with in vitro testing of transformed lymphoblasts, using both bezafibrate and another potentially effective drug called resveratrol, to look for confirmation of biological activity in each patient and predictive correlates of treatment response. In addition we will use qualitative methods to evaluate trial design and participant satisfaction. DESIGN & POPULATION This is a double blinded, randomised, placebo-controlled crossover study in males aged 6 years and over with Barth Syndrome under the care of the nationally commissioned NHS Barth Syndrome Service, to be conducted through the Clinical Trials & Evaluation Unit in Bristol. INTERVENTIONS Four-month treatments each of bezafibrate followed by placebo (or vice versa) with an interim one month washout period between treatments. Centralised outcome assessment will take place in the last week of each 4 month cycle. OUTCOMES Primary: Peak oxygen consumption on graded exercise testing by bicycle ergometry. Secondary include (1) improvement in MLCL/L4-CL ratio/cardiolipin profile, (2) PCr/ATP ratio in cardiac muscle and skeletal muscle oxidative function/ATP production on 31P MRS, (3) quality of life assessed using age-appropriate PedsQL or SF36 questionnaires, (4) absolute neutrophil count, (5) serum arginine and cysteine levels, (6) cardiac function, (7) mitochondrial function, numbers and cristae organisation in lymphocytes and (8) qualitative assessment. SAMPLE SIZE Maximum UK cohort is 18 males; likely recruitment estimated at 12-15. All UK patients aged at least 6 years who are able to swallow tablets will be invited to take part, with exclusions for acute or unstable health problems. ANALYSIS The data analysis will be performed using a mixed effects model. There are substantial differences between Barth Syndrome males and normal parameters such that a small percentage shift towards normal will be obvious. If large shifts are seen, then a binary response defining patients as responders or not may be used and percentage responders and confidence intervals calculated. ECONOMIC BENEFIT During the past three years different patients have spent a total of 20 months as inpatients on cardiac units. G-CSF therapy and monitoring also carries significant expense. Bezafibrate (and resveratrol) are inexpensive compared with usual treatment costs. TIMETABLE Patient recruitment will commence in October 2015, with treatment phases lasting 9 months, followed by one month follow-up. Analysis, write up and dissemination will take approximately 6 months. Total project time (including set-up) of 24 months.

Lay abstract: Barth Syndrome is a life threatening genetic disease which affects young males. It is caused by abnormal fats (lipids) in the powerhouses of cells (mitochondria). Those affected may be stillborn or develop heart failure, bacterial infections, poor growth or feeding problems during childhood. 23 males are alive with the disease in the UK. This disease carries many risks and problems for its sufferers, as well as major healthcare costs. 7 in 10 people require frequent drug injections to boost their white blood count. Almost half have been considered for heart transplantation, but only half of these survive. Even those who have not received transplants can develop life-threatening heart rhythm disturbances. Boys/men living with the disease have severe exercise intolerance, lethargy and fatigue which affect their daily life; many use wheelchairs intermittently to aid mobility. Furthermore, children continue to die from this disease, which has claimed the lives of 4 of the 5 boys born since the start of the national Barth Syndrome Service (BSS). Scientific research has shown that several treatments can improve the fat abnormalities in cells affected by Barth Syndrome in mice or humans. One is a drug (bezafibrate) which is already used in children to lower blood fats as well as in adults with a muscle disease resulting from mitochondrial problems and the other is a food supplement (resveratrol). These treatments have also shown promising effects in a mouse that has heart problems like those seen in Barth Syndrome. The purpose of this project is to see if the more tried and tested of these treatments (bezafibrate) can be given safely and effectively to people with Barth Syndrome in a blinded randomised trial. Bezafibrate or an inactive (placebo) treatment, would be given for 4 months at a time with a one month break between the two phases. Tests would be performed after each treatment period, looking for benefit in blood cells, exercise capacity, heart function or quality of life. These potential treatments would run alongside laboratory work at Bristol University and Great Ormond St Hospital to see the effect of each drug on their cells and mitochondria (powerful electron microscopes show that these are abnormal in Barth Syndrome). This is to see whether we can predict any improvement in symptoms in order to tell us which patients would benefit from this treatment in future. We wish to study up to 18 Barth Syndrome boys/men - all of those with Barth Syndrome in the UK aged 6 years or over. We will use services local to the patients to perform monthly blood tests in order to minimise the amount of travel to Bristol. These studies will only be performed with appropriate permissions from relevant ethics and regulatory authorities and safety will be monitored by an independent committee with the authority to recommend stoppage if obvious problems are seen. Costs have been calculated to cover the staff running the trial/testing procedures, laboratory costs, time on testing machines, blood sampling, data collection, analysis, and writing up for public journals, as well as overnight hotel costs for patients where stays are necessary. If promising results are obtained with either or both drugs, we would share this information with American/European teams so that this work will have worldwide benefit. For this, we have the complete backing of our patients, their families and the respective UK and USA charities.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CONGENITAL DISORDERS;METABOLIC AND ENDOCRINE