1 2 3 PROJECT TITLE 4 Anti-viral Prophylaxis for Prevention of Cytomegalovirus (CMV) Reactivation in Immunocompetent 5 Patients in Critical Care 6 7 STUDY ACRONYM 8 Cytomegalovirus Control in Critical Care - CCCC 9 10 APPLICANTS 11 Dr Nicholas Cowley 12 Specialty Registrar Anaesthesia and Intensive Care Medicine, Intensive Care Research Fellow 13 Queen Elizabeth Hospital Birmingham 14 15 Professor Paul Moss 16 Professor of Haematology 17 Queen Elizabeth Hospital Birmingham 18 19 Professor Julian Bion 20 Professor of Intensive Care Medicine 21 Queen Elizabeth Hospital Birmingham 22 23 Trial Virologist Trial Statistician 24 Dr H Osman Dr P G Nightingale 25 Queen Elizabeth Hospital Birmingham University of Birmingham CCCC CMV Protocol V1.7, 18th September 2013 1 Downloaded From: https://jamanetwork.com/ on 09/23/2021 26 CONTENTS 27 Substantial Amendment Sept 18th 2013 4 28 1 SUMMARY OF TRIAL DESIGN .......................................................................................................... 5 29 2 QEHB ICU Duration of Patient Stay ................................................................................................. 6 30 3 SCHEMA - QEHB PATIENT NUMBERS AVAILABLE FOR RECRUITMENT ........................................... 6 31 4 INTRODUCTION ............................................................................................................................... 7 32 4.1 CMV latent infection is widespread ........................................................................................ 7 33 4.2 CMV Reactivation .................................................................................................................... 7 34 4.3 CMV Reactivation in Critical Care ........................................................................................... 7 35 4.4 The Proposed Research is Widely Supported by Experts in the Intensive Care Community . 7 36 4.5 Evidence for Use of Antivirals to Suppress CMV ..................................................................... 8 37 4.6 Antivirals Effective Against CMV ............................................................................................. 8 38 4.7 Acceptable Tolerability and Side Effects ................................................................................. 9 39 4.8 Choice of Antiviral and Dosing for CMV Prophylaxis in Critical Care ...................................... 9 40 5 TRIAL DESIGN ................................................................................................................................ 10 41 5.1 Research Question ................................................................................................................ 10 42 5.2 Trial Summary ....................................................................................................................... 10 43 5.3 Observational Arm of Study ..................................................... Error! Bookmark not defined. 44 5.4 Interventional Arm of Study ................................................................................................. 10 45 5.4.1 Research Objective ....................................................................................................... 10 46 5.4.2 Trial Objectives .............................................................................................................. 10 47 5.4.3 Outcome Measures for Efficacy .................................................................................... 11 48 5.4.3.1 Primary Outcome ...................................................................................................... 1 1 49 5.4.3.2 Secondary Outcomes ................................................................................................ 11 50 5.4.4 Outcome Measures for Safety ...................................................................................... 11 51 5.5 Flow Diagram of Trial ............................................................................................................ 12 52 5.6 Inclusion Criteria ................................................................................................................... 13 53 5.7 Exclusion Criteria ................................................................................................................... 13 54 5.8 Informed Consent ................................................................................................................. 14 55 5.8.1 Obtaining informed consent from participants ............................................................ 14 56 5.8.2 Proposed action where fully informed consent is not possible .................................... 14 57 5.8.3 Retrospective Patient Information ............................................................................... 14 58 5.8.4 Withdrawal of Consent ................................................................................................. 14 CCCC CMV Protocol V1.7, 18th September 2013 2 Downloaded From: https://jamanetwork.com/ on 09/23/2021 59 5.9 Randomisation Procedure .................................................................................................... 15 60 5.10 Trial Treatment Group 1 ....................................................................................................... 15 61 5.10.1 Randomised to receive Valaciclovir/Aciclovir ............................................................... 15 62 5.10.2 Intravenous Aciclovir ..................................................................................................... 15 63 5.11 Trial Treatment Group 2 ....................................................................................................... 15 64 5.11.1 Randomised to receive Valganciclovir/Ganciclovir ....................................................... 15 65 5.11.2 Intravenous Gancilcovir ................................................................................................ 15 66 5.12 Study Drug Dose Adjustment in Renal Failure ...................................................................... 16 67 5.13 Trial Control Group – Randomised not to receive antiviral therapy .................................... 16 68 5.14 Monitoring for Drug Related Side Effects ............................................................................. 16 69 5.15 Assessments .......................................................................................................................... 17 70 5.15.1 Patient Details ............................................................................................................... 17 71 5.15.2 Recruitment Data .......................................................................................................... 17 72 5.15.3 Critical Care Data........................................................................................................... 17 73 5.15.4 Treatment Data ............................................................................................................. 17 74 5.15.5 Monitoring .................................................................................................................... 17 75 5.15.6 Hospital Data ................................................................................................................. 18 76 5.16 Data Management ................................................................................................................ 18 77 5.17 Trial Monitoring and Adverse Event Management ............................................................... 18 78 5.17.1 Adverse Events .............................................................................................................. 18 79 5.17.2 Serious Adverse Events (SAEs) and Suspected Unexpected Serious Adverse Reactions 80 (SUSARs) 18 81 5.17.3 Reporting Procedures of SAEs and SUSARs .................................................................. 19 82 5.18 Trial Closure .......................................................................................................................... 19 83 6 DATA ANALYSIS ............................................................................................................................. 19 84 6.1 Primary Outcome .................................................................................................................. 19 85 6.2 Secondary Outcomes ............................................................................................................ 20 86 6.3 Sample Size Calculation ........................................................................................................ 21 87 7 Ethical and Regulatory Compliance .............................................................................................. 21 88 8 Risks and anticipated benefits for trial participants and society .................................................. 21 89 9 Project Costings ............................................................................................................................ 22 90 10 RERERENCES .............................................................................................................................. 23 91 11 APPENDICES .............................................................................................................................. 26 92 11.1 Appendix One - common side effects ganciclovir/valganciclovir ......................................... 26 CCCC CMV Protocol V1.7, 18th September 2013 3 Downloaded From: https://jamanetwork.com/ on 09/23/2021