Pragmatic Ischaemic Stroke Thrombectomy Evaluation: PISTE ?· Pragmatic Ischaemic Stroke Thrombectomy…

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  • Version 1.5

    1st

    September 2014 1

    Pragmatic Ischaemic Stroke Thrombectomy Evaluation: PISTE

    Running title: PISTE

    Protocol Version: 1.5

    Date: 1st

    September 2014

    REC Reference Number: Scotland A REC 12/SS/0059

    NRES Committee North East- Newcastle & North

    Tyneside 2 12-NE-0315 Sponsors Protocol Number: GN11NE257

    Sponsor: NHS Greater Glasgow & Clyde

    Funder: The Stroke Association

    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).

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    CONTACTS

    Chief Investigator

    Professor Keith Muir

    SINAPSE Professor of Clinical Imaging & Consultant Neurologist

    Institute of Neurosciences & Psychology

    University of Glasgow

    Southern General Hospital

    Glasgow G51 4TF

    Tel: 0141 201 2494

    Fax: 0141 201 2510

    E-mail: keith.muir@glasgow.ac.uk

    Co-investigators

    Professor Philip White

    Professor of Interventional and Diagnostic Neuroradiology

    Newcastle University

    Institute for Ageing & Health

    3-4 Claremont Terrace

    Newcastle upon Tyne

    NE2 4AE

    E-mail: phil.white@ncl.ac.uk

    Project Manager

    Dr Alicia Murray

    Project Manager

    Glasgow Clinical Research Facility

    Tennent Institute

    38 Church Street

    Western Infirmary

    Glasgow G11 6NT

    Email: Alicia.Murray@ggc.scot.nhs.uk

    Trial Statistician

    Professor Ian Ford

    Robertson Centre for Biostatistics

    University of Glasgow

    Data Centre

    Robertson Centre for Biostatistics

    University of Glasgow

    Boyd Orr Building

    University Avenue

    Glasgow G12 8QQ

    Tel: 0141 330 3991

    Chair of Data Safety Monitoring Committee

    Professor Kennedy Lees

    Professor of Cardiovascular Medicine

    College of Medicine, Veterinary & Life Sciences

    Institute of Cardiovascular and Medical Sciences

    Western Infirmary

    Dumbarton Road

    Glasgow G11 6NT

    Tel: 0141 211 2176

    E-mail: kennedy.lees@glasgow.ac.uk

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    Chair of the Trial Steering Committee

    Professor Gary Ford

    Level 6 Leazes Wing

    Royal Victoria Infirmary

    Newcastle

    NE1 4LP

    Tel: +44 (0) 191 222 7744

    E-mail: g.a.ford@newcastle.ac.uk

    Pharmacovigilance

    Dr Eleanor Dinnett

    Pharmacovigilance Office

    Glasgow Clinical Trials Unit

    Robertson Centre for Biostatistics

    Boyd Orr Building

    University of Glasgow

    Glasgow G12 8QQ

    Tel: +44(0)141 330 4744

    Fax: +44(0)141 357 5588

    Sponsor

    This clinical trial is sponsored by NHS Greater Glasgow & Clyde.

    Sponsors representative

    Dr Erica Packard

    Research Co-ordinator

    NHS Greater Glasgow & Clyde

    Research and Development Management Office

    Tennent Institute

    38 Church Street

    Western Infirmary

    Glasgow G11 6NT

    Tel: 0141 211 6208

    E-mail: erica.packard@ggc.scot.nhs.uk

    Funding Body

    The Stroke Association

    Stroke House

    240 City Road

    London, EC1V 2PR

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    PROTOCOL APPROVAL

    Chief Investigator Professor Keith Muir

    SINAPSE Professor of Clinical Imaging & Consultant Neurologist

    Institute of Neurosciences & Psychology

    University of Glasgow

    Southern General Hospital

    Glasgow G51 4TF

    Signature:

    Date:

    Sponsors representative Dr Erica Packard

    Research Co-ordinator

    NHS Greater Glasgow & Clyde

    Research and Development Management Office

    Tennent Institute

    38 Church Street

    Western Infirmary

    Glasgow G11 6NT

    Signature:

    Date:

  • Version 1.5

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    TABLE OF CONTENTS

    CONTACTS ............................................................................................................................... 2 PROTOCOL APPROVAL ................................................................................................................ 4 TABLE OF CONTENTS .................................................................................................................. 5 ABBREVIATIONS ........................................................................................................................ 7 STUDY SYNOPSIS ....................................................................................................................... 8 STUDY FLOW CHART ................................................................................................................ 10 SCHEDULE OF ASSESSMENTS ...................................................................................................... 11

    1. INTRODUCTION ............................................................................................... 12 1.1 Background ..................................................................................................... 12 1.2 Study rationale hypothesis ............................................................................... 15

    2. STUDY OBJECTIVES ........................................................................................... 16 Primary Endpoint ....................................................................................................... 16 Secondary endpoints .................................................................................................. 16 Safety Outcomes ........................................................................................................ 16

    3. STUDY DESIGN ................................................................................................ 16 3.1 Study Population .............................................................................................. 17 3.2 Main inclusion criteria ....................................................................................... 17 3.3 Main exclusion criteria ....................................................................................... 18 3.4 Centre Qualification .......................................................................................... 18 3.5 Identification of participants and consent .............................................................. 19 3.6 Study schedule ................................................................................................. 20 3.7 Modified Rankin Scale ........................................................................................ 22 3.8 Imaging ........................................................................................................... 22

    3.8.1 Image Processing and Analysis..................................................................... 23 3.9 Blood testing / venepuncture .............................................................................. 23

    4. INVESTIGATIONAL DEVICE INFORMATION ............................................................. 24 5. SAFETY REPORTING .......................................................................................... 25

    5.1 Definitions of adverse events .............................................................................. 25 5.2 Definition of Serious Adverse Event ...................................................................... 25 5.3 Recording and reporting of Adverse Events ............................................................ 25 5.4 Expected Adverse Events .................................................................................... 25 5.5 Reporting to sponsor (Pharmacovigilance (PV) Office) .............................................. 26 5.6 Reporting to the Research Ethics Committee (REC) .................................................. 26 5.7 Annual progress report ...................................................................................... 27 5.8 Reporting to local Research and Development (R&D) Departments ............................ 27

    6. STATISTICS AND DATA ANALYSIS ......................................................................... 28 6.1 Statistical analysis plan....................................................................................... 28 6.2 General considerations ...................................................................................... 28 6.3 Primary efficacy variable .................................................................................... 28 6.4 Secondary efficacy analysis ................................................................................. 28 6.5 Safety analysis .................................................................................................. 28 6.6 Software and statistical analysis ........................................................................... 28 6.7 Sample size ...................................................................................................... 28 6.8 Management and delivery .................................................................................. 29

    7. TRIAL CLOSURE / DEFINITION OF END OF TRIAL ...................................................... 30 8. DATA HANDLING ............................................................................................. 31

    8.1 Randomisation ................................................................................................. 31 8.2 Case Report Forms / Electronic Data Record .......................................................... 31 8.3 Record Retention .............................................................................................. 31

    9. TRIAL MANAGEMENT ....................................................................................... 32 9.1 Routine management of trial: Trial Management Group ........................................... 32 9.2 Trial steering committee (TSC) ............................................................................. 32

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    9.3 Independent Data Monitoring Committee (IDMC) ................................................... 32 10. STUDY MONITORING AND AUDITING ................................................................... 33 11. PROTOCOL AMENDMENTS ................................................................................. 34 12. ETHICAL CONSIDERATIONS................................................................................. 35

    12.1 Ethical conduct of the study ............................................................................ 35 12.2 Informed consent ......................................................................................... 35

    13. INSURANCE AND INDEMNITY ............................................................................. 36 14. FUNDING ....................................................................................................... 36 15. SPONSOR RESPONSIBILITIES ............................................................................... 36 16. ANNUAL REPORTS ............................................................................................ 36 17. DISSEMINATION OF FINDINGS ............................................................................ 36 18. REFERENCES.................................................................................................... 37

    Appendix A: Flowchart for Assessing and Reporting Adverse Events ............................................. 39 Appendix B: Declaration of Helsinki....................................................................................... 40 Appendix C: NIH Stroke Scale ............................................................................................... 44 Appendix D: Modifed Rankin Scale (mRS) ............................................................................... 50 Appendix E: Rating Form Prestroke Rankin Focused Assessment (RFA) ......................................... 51 Appendix F: Rating Form Rankin Focused Assessment (RFA) ....................................................... 55

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    ABBREVIATIONS

    AE Adverse event

    CI Chief Investigator

    CNS Central Nervous System

    eCRF Electronic Case Report Form

    CRN Clinical Research Network

    CT Computed Tomography

    CTA Computed Tomography Angiogram

    CTP Computed Tomography Perfusion

    CV Curriculum Vitae

    DSA Digital Subtraction Angiography

    ECASS European Cooperative Acute Stroke Study

    ECG Electrocardiogram

    eGFR Estimated Glomerular Filtration Rate

    GP General Practitioner

    HI Hemorrhagic Infarct

    IA Intra-arterial

    ICA Internal Carotid Artery

    ICH Intracerebral Haemorrhage

    ICH GCP International Conference on Harmonization of Good Clinical Practice

    IDMC Independent Data Monitoring Committee

    I.V. Intravenous

    IVRS Interactive Voice Recognition System

    MCA Middle Cerebral Artery

    MI Myocardial Infarction

    MRA Magnetic resonance angiography

    MRI Magnetic Resonance Imaging

    mRS Modified Rankin Scale

    mRS-RFA Modified Rankin Scale - Rankin Focussed Assessment

    NIHSS National Institute of Health Stroke Scale

    PH Parenchymal Haemorrhage

    PHr Parenchymal Haemorrhage remote

    r-TPA Recombinant Tissue Plasminogen activator

    RCT Randomised Controlled Trial

    REC Research Ethics Committee

    RFA Rankin Focussed Assessment

    SAE Serious adverse event

    SICH Symptomatic intracranial haemorrhage

    SRN Stroke Research Network

    SOP Standard Operating Procedure

    TSC Trial Steering Committee

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    STUDY SYNOPSIS Title of Study: Pragmatic Ischaemic Stroke Thrombectomy Evaluation: PISTE

    Study Centre: Multicentre UK Trial

    Duration of Study: 2 years

    Primary Objective: To determine if endovascular thrombectomy in addition to IV

    thrombolysis improves the proportion of patients with favourable

    functional 3 month outcome (defined by modified Rankin 0-2) in

    patients with acute ischaemic stroke due to occlusion of the middle

    cerebral or intracranial internal carotid artery.

    Secondary Objective: To determine the safety.

    Primary Endpoint: The proportion with favourable functional outcome at 90 (7) days

    based on the modified Rankin scale. This will be assessed by use of

    the Rankin Focused Assessment tool (RFA).

    Rationale: Use of mechanical thrombectomy devices in acute ischaemic stroke is

    associated with higher rates of recanalisation in large artery

    occlusions (such as the middle cerebral artery main segment or

    intracranial internal carotid artery) compared to historical data for

    intravenous thrombolysis, the current standard of care for eligible

    patients. However, thrombectomy takes significantly longer than IV

    thrombolysis, and may have higher haemorrhagic complications.

    Registry data and studies using historical controls do not support any

    improvement in outcome over routine medical care for

    thrombectomy, but are confounded by the patient group having

    much more severe strokes than would be enrolled in IV thrombolysis

    trials. No randomised controlled trial has yet evaluated whether

    thrombectomy is associated with improved clinical outcome.

    Methodology: Prospective, randomised, controlled, parallel group study with

    blinded outcome evaluation (PROBE).

    Sample Size: 800

    Screening: Patients with acute ischaemi...