A randomised, double blind, placebo-controlled, parallel group Trial of low-dose adjunctive alTeplase during prIMary PCI Running title: T-TIME Protocol Version: 7.0 Date: 15.03.2018 EudraCT Number: 2014-004405-32 REC Reference Number: 13/WS/0119 Sponsor’s Protocol Number: GN12CA450 Sponsors: NHS Greater Glasgow & Clyde and The University of Glasgow Funder: Medical Research Council / National Institute for Health Research – Efficacy and Mechanism Evaluation Programme This study will be performed according to the Research Governance Framework for Health and Community Care (Second edition, 2006) and The Medicines for Human Use (Clinical Trials) Regulations, 2004 SI 2004:1031 (as amended) and WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles for Medical Research Involving Human Subjects 1964 (as amended). Version 7.0 Page 1 of 128 15.03.2018 Downloaded From: https://jamanetwork.com/ on 09/25/2021 CONTACTS Chief Investigator Professor Colin Berry Honorary Consultant Physician and Cardiologist Institute of Cardiovascular and Medical Sciences BHF Glasgow Cardiovascular Research Centre 126 University Place University of Glasgow Glasgow G12 8TA Tel: 0141 330 1671 Fax: 0141 330 7335 E-mail: [email protected] Co-investigators Dr Campbell Tait Coagulation and Haemostasis Laboratory MacEwan Building 16 Alexandra Parade Glasgow Royal Infirmary Glasgow G31 2ER Email: [email protected] Tel: 0141 211 4000 Professor Peter Macfarlane Emeritus Professor Institute of Cardiovascular and Medical Sciences, Electrocardiology Group, Level 1 New Lister Building, 10 Alexandra Parade Royal Infirmary, Glasgow, G31 2ER. Version 7.0 Page 2 of 128 15.03.2018 Downloaded From: https://jamanetwork.com/ on 09/25/2021 Tel 44 (0)141 211 4724 Fax 44 (0)141 552 6114 e-mail: [email protected] Professor Naveed Sattar Honorary Consultant Physician Institute of Cardiovascular and Medical Sciences BHF Glasgow Cardiovascular Research Centre 126 University Place University of Glasgow Glasgow G12 8TA Email: [email protected] Dr Sylvia Wright Consultant Pathologist Department of Pathology Queen Elizabeth University Hospital Govan Road, Glasgow G51 4TF Email: [email protected] Dr Andrew Walker Health Economist Robertson Centre for Biostatistics University of Glasgow Glasgow G12 8QQ Telephone: 0141 330 4044 Email [email protected] Dr Aleksandra Radjenovic BHF Glasgow Cardiovascular Research Centre 126 University Place University of Glasgow Glasgow G12 8TA Tel: 0141 330 2537 or 0141 330 3006 Fax: 0141 330 6997 Version 7.0 Page 3 of 128 15.03.2018 Downloaded From: https://jamanetwork.com/ on 09/25/2021 Email: [email protected] Trial Statistician Professor Ian Ford Robertson Centre for Biostatistics University of Glasgow Glasgow G12 8QQ Telephone: 0141 330 4048 Email: [email protected] Data Centre Robertson Centre for Biostatistics University of Glasgow Boyd Orr Building University Avenue Glasgow G12 8QQ Tel: 0141 330 4048 Chair of Data Safety Monitoring Committee Professor Gary Ford, Chief Executive Officer, Oxford Academic Health Science Network Consultant Physician, Oxford University Hospitals NHS Foundation Trust Visiting Professor of Clinical Pharmacology, University of Oxford Chair of the Trial Steering Committee Professor Keith Fox, Emeritus Professor, University of Edinburgh Pharmacovigilance Pharmacovigilance Office Glasgow Clinical Trials Unit Robertson Centre for Biostatistics Boyd Orr Building Version 7.0 Page 4 of 128 15.03.2018 Downloaded From: https://jamanetwork.com/ on 09/25/2021 University of Glasgow Glasgow G12 8QQ Tel: +44(0)141 330 4744 Fax: +44(0)141 357 5588 E-mail: [email protected] Sponsor Pharmacy Dr Elizabeth Douglas PhD MR PharmS Senior Pharmacist, Clinical Trials Clinical Research & Development NHS Greater Glasgow & Clyde West Glasgow Ambulatory Care Hospital Dalnair Street Glasgow G3 8SJ Tel: 0141 232 1792 E-mail: [email protected] Sponsor’s Representative Dr Maureen Travers Research Co-ordinator NHS Greater Glasgow & Clyde Research and DevelopmentManagementOffice WestGlasgowAmbulatoryCareHospital Dalnair Street Glasgow G3 8SW Tel: 0141 232 1813 E-mail:[email protected] Funding Body National Institute for Health Research Efficacy and Mechanism Evaluation Programme Alpha House University of Southampton Science Park Southampton, SO16 7NS Tel: 023 8059 4303 Version 7.0 Page 5 of 128 15.03.2018 Downloaded From: https://jamanetwork.com/ on 09/25/2021 Fax: 023 8059 5639 E-mail: [email protected] Version 7.0 Page 6 of 128 15.03.2018 Downloaded From: https://jamanetwork.com/ on 09/25/2021 PROTOCOL APPROVAL A randomised, double blind, placebo-controlled, parallel group, dose-ranging Trial of low-dose adjunctive alteplase during prIMary PCI (T-TIME) Chief Investigator Professor Colin Berry BSc, PhD, FRCP, FACC Honorary Consultant Physician and Cardiologist Institute of Cardiovascular and Medical Sciences BHF Glasgow Cardiovascular Research Centre 126 University Place University of Glasgow Glasgow G12 8TA Signature: Date: 15.03.2018 Sponsor’s representative Dr Maureen Travers Research Co-ordinator NHS Greater Glasgow & Clyde Research and Development ManagementOffice WestGlasgowAmbulatoryCareHospital Dalnair Street Glasgow G3 8SW Signature: Date: Version 7.0 Page 7 of 128 15.03.2018 Downloaded From: https://jamanetwork.com/ on 09/25/2021 TABLE OF CONTENTS A randomised, double blind, placebo-controlled, parallel group Trial of low-dose adjunctive alTeplase during prIMary PCI............................................................................. 1 CONTACTS ............................................................................................................................ 2 Chief Investigator .......................................................................................................... 2 Co-investigators ............................................................................................................ 2 PROTOCOL APPROVAL .......................................................................................................... 7 TABLE OF CONTENTS ............................................................................................................ 8 ABBREVIATIONS ................................................................................................................ 10 STUDY SYNOPSIS ............................................................................................................... 12 ............................................................................................................................................ 19 SCHEDULE OF ASSESSMENTS ............................................................................................. 19 1. INTRODUCTION ...................................................................................................... 22 1.1 Background .................................................................................................... 22 1.2 Rationale for reduced dose alteplase as an adjunct to primary PCI ..................... 23 1.3 Alteplase: prior experience and dose selection .................................................. 24 1.4 Study rationale - hypothesis ............................................................................ 33 1.5 Relevance to the NHS ...................................................................................... 40 2. STUDY OBJECTIVES ................................................................................................ 41 2.1 Primary outcome ............................................................................................. 41 2.2 Secondary outcomes ....................................................................................... 41 2. 3 Tertiary outcomes……………………………………………………………………………………….. 3. STUDY DESIGN ....................................................................................................... 46 3.1 Study population ............................................................................................. 46 3.2 Setting ........................................................................................................... 46 3.3 Inclusion criteria ............................................................................................. 46 3.4 Exclusion criteria ............................................................................................. 49 3.5 Identification of participants and consent ......................................................... 51 3.6 Study schedule ............................................................................................... 53 3.7 Assessments and Procedures ........................................................................... 57 4. Study Treatment ..................................................................................................... 74 4.1 Alteplase ........................................................................................................ 74 4.2 Study Drug Supplies ........................................................................................ 75 4.3 Unblinding procedure ...................................................................................... 77 4.4 Optimal standardised anti-thrombotic therapy ................................................... 78 5. PHARMACOVIGILANCE ........................................................................................... 80 5.1 Definitions of adverse events ..........................................................................