Treatment of Barth Syndrome by CARDIOlipin MANipulation (CARDIOMAN): A randomised placebo controlled pilot trial conducted by the nationally commissioned Barth Syndrome Service CARDIOMAN IRAS No: 170371 ISRCTN No: EUDRACT no.: 2015-001382-10 R&I No: CS/2015/4775 Details of Sponsor: University Hospitals Bristol NHS Foundation Trust Research and Innovation Level 3, Education & Research Centre Upper Maudlin Street Bristol BS2 8AE Tel: 0117 342 0233 Fax: 0117 342 0239 Chief Investigators & Research Team Contact Details Chief Investigator Emeritus Professor of Paediatric Stem Cell Dr Guido Pieles Transplantation Professor Colin Graham Steward Consultant Paediatric Cardiologist Bristol Royal Hospital for Children Professor Colin G Steward Paul O’Gorman Building School of Cellular & Molecular Medicine Bristol Biomedical Sciences Building BS2 8BJ University of Bristol University Walk Tel: 0117 342 8296 Bristol, BS8 1TD Email: [email protected] Tel: 0117 342 8044 [email protected] Professor in Diabetes and Metabolic Professor of Epidemiology Endocrinology Professor Andrew Robert Ness Professor Julian Paul Hamilton-Shield School of Oral & Dental Sciences School of Clinical Sciences Biomedical Research Unit Offices Level 6 University Hospitals Bristol Education Centre Education Centre Lower Maudlin Street University Hospitals Bristol NHS Foundation Bristol BS1 2LY Trust Upper Maudlin Street Tel: (0117) 34 21751 Bristol, BS2 8AE Email: [email protected] Tel: 0117 342 0159 CARDIOMAN 12 February 2019 Protocol – version 4.0 Page 1 of 39 Fax: 0117 34 20178 Email: [email protected] Senior Statistician Consultant Senior Lecturer Professor Chris Rogers Dr Chiara Bucciarelli-Ducci Clinical Trials and Evaluation Unit University Hospitals Bristol NHS Foundation School of Clinical Sciences Trust/University of Bristol University of Bristol Level 7 Level 7, Bristol Royal Infirmary Bristol Royal Infirmary Upper Maudlin Street Upper Maudlin Street Bristol BS2 8HW Bristol BS2 8HW Tel: 0117 342 2507 Email: [email protected] Tel: 0117 342 3287 Email: [email protected] Professor of Health Services Research Statistical advisor Professor Barnaby Reeves Ms Rosemary Greenwood Clinical Trials and Evaluation Unit Research Design Service School of Clinical Sciences Education Centre University of Bristol University Hospitals Bristol NHS Foundation Level 7 Trust Bristol Royal Infirmary Upper Maudlin Street Upper Maudlin Street Bristol, BS2 8AE Bristol Tel: 0117 342 0234 BS2 8HW Email: [email protected] Tel: 0117 342 3143 Email: [email protected] Clinical Trial Coordinator Ms Lucy Dabner Clinical Trials and Evaluation Unit School of Clinical Sciences University of Bristol Level 7 Bristol Royal Infirmary Upper Maudlin Street Bristol BS2 8HW Tel: 0117 342 2374 Email: [email protected] CARDIOMAN 12 February 2019 Protocol – version 4.0 Page 2 of 39 Table of contents Glossary / abbreviations ......................................................................................................... 4 1. Trial summary ................................................................................................................. 6 2. Background ..................................................................................................................... 7 3. Aims and objectives ....................................................................................................... 9 4. Plan of Investigation ......................................................................................................10 4.1 Study schema .........................................................................................................10 4.2 Trial design .............................................................................................................11 4.3 Key design features to minimise bias ......................................................................11 4.4 Trial population .......................................................................................................12 4.5 Trial interventions ...................................................................................................13 4.6 Primary and secondary outcomes ..........................................................................15 4.7 Sample size calculation ..........................................................................................16 5. Trial methods .................................................................................................................16 5.1 Description of randomisation ..................................................................................16 5.2 Blinding and code breaking ....................................................................................16 5.3 Research procedures .............................................................................................17 5.4 Duration of treatment period ...................................................................................18 5.5 Definition of end of trial ...........................................................................................19 5.6 Data collection ........................................................................................................19 5.7 Source data ............................................................................................................22 5.8 Planned recruitment rate ........................................................................................22 5.9 Participant recruitment ............................................................................................22 5.10 Discontinuation/withdrawal of participants ..............................................................23 5.11 Frequency and duration of follow up .......................................................................23 5.12 Likely rate of loss to follow-up .................................................................................24 5.13 Expenses ...............................................................................................................24 6. Statistical analyses ........................................................................................................24 6.1 Plan of analysis ......................................................................................................24 6.2 Subgroup analyses .................................................................................................25 6.3 Frequency of analyses............................................................................................25 6.4 Economic issues.....................................................................................................25 7. Trial management ..........................................................................................................25 7.1 Day-to-day management ........................................................................................25 7.2 Monitoring of sites ..................................................................................................26 7.3 Trial Steering Committee and Data Monitoring and Safety Committee ...................26 8. Safety reporting .............................................................................................................26 8.1 Expected adverse events .......................................................................................27 8.2 Period for recording serious adverse events ...........................................................29 9. Ethical considerations ...................................................................................................29 9.1 Review by an NHS Research Ethics Committee .....................................................29 9.2 Risks and anticipated benefits ................................................................................29 9.3 Informing potential study participants of possible benefits and known risks ............30 9.4 Obtaining informed consent from participants .........................................................30 9.5 Co-enrolment ..........................................................................................................30 10. Research governance ....................................................................................................31 10.1 Sponsor approval ...................................................................................................31 10.2 NHS approval .........................................................................................................31 10.3 Investigators' responsibilities ..................................................................................31 10.4 Monitoring by sponsor ............................................................................................31 CARDIOMAN 12 February 2019 Protocol – version 4.0 Page 3 of 39 10.5 Indemnity ................................................................................................................31 10.6 Clinical Trial Authorisation ......................................................................................32 11. Data protection and participant confidentiality ...........................................................32 11.1 Data protection .......................................................................................................32 11.2 Data handling, storage and sharing ........................................................................32