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Details of a prospective protocol for a collaborative meta-analysis of individual participant data from all randomized trials of intravenous rt-PA vs. control: statistical analysis plan for the Stroke Thrombolysis Trialists’ Collaborative meta-analysis

Authors

  • The Stroke Thrombolysis Trialists' Collaborative Group

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    • Jonathan Emberson, Kennedy R Lees, George Howard, Erich Bluhmki, Barbara Tilley, Gregory Albers, Colin Baigent (Steering Committee co-Chair), Lisa Blackwell, Stephen Davis, Geoffrey Donnan, James Grotta, Werner Hacke (Steering Committee co-Chair), Markku Kaste, Ruediger von Kummer, Maarten Lansberg, Richard Lindley, Patrick Lyden, Peter Sandercock, Danilo Toni, Nils Wahlgren, Joanna Wardlaw, William Whiteley, Gregory J del Zoppo.

  • Jonathan Emberson and Kennedy Lees contributed equally.
  • Conflict of interest: EB is an employee of Boehringer Ingelheim. MK has received honoraria and has had travel and accommodation costs covered by Boehringer Ingelheim and Lundbeck A/S for attending the Steering Committee meetings of the ECASS and DIAS trials. KL was the Chairman of the independent data monitoring committee for the DIAS trials (Lundbeck), Plasmin (Grifols), ECASS-IV (Boehringer Ingleheim), ICTUS (Ferrer), NEST-3 (Photothera), ATTEST (Univ. Glasgow) and is a member of the IDMC for REVASCAT (Covidien) and WAKE-UP (EU FP7). He has also received speaker's fees from Boehringer Ingleheim and is the director for acute research in the NIHR Stroke Research Network. RvK has received compensation for serving on the Advisory Board of Lundbeck AC and for serving as Co-Chair on the Steering Committee and adjudication committee for the DIAS-3 and -4 trials. He has also received consultancy fees from Synarc and is Section Editor for Interventional Neuroradiology of the Journal Neuroradiology. PS has received lecture fees (paid to the Department) and travel expenses from Boehringer Ingelheim for occasional lectures given at international conferences. He was a member of the Independent Data and Safety Monitoring Board (DSMB) of the RELY trial funded by Boehringer Ingelheim and received attendance fees and travel expenses for attending DSMB meetings (paid to the Department). He is not a member of the Speakers' Panel of any company. BT is on the Data and Safety Monitoring Committees for various trials funded by Novartis and Pfizer, has received honoraria from the Michael J Fox Foundation for work related to movement disorders, funding from the Movement Disorders Society to validate aspects of the MDS-UPRS, and NIH grants related to trauma, Parkinson's disease, and recruitment of minorities into clinical trials. She receives no speakers fees or other consultancy fees. DT has received fees from Boehringer Ingelheim as National Coordinator for Italy of the ECASS III trial. NW received honoraria and travel and accommodation reimbursement from Boehringer-Ingeheim and Lundbeck. JMW received reimbursement for reading CT scans for European Cooperative Acute Stroke Study III (ECASS III) from Boehringer Ingelheim in the form of funding to her department, the Division of Clinical Neurosciences, University of Edinburgh; is the contact reviewer for the Cochrane systematic reviews of thrombolytic treatment for acute stroke; has attended meetings held by Boehringer Ingelheim as an unpaid independent external adviser during the licensing of rt-PA, but was refunded her travel expenses and the time away from work; has attended and spoken at national and international stroke meetings organised and funded by Boehringer Ingelheim for which she received honoraria and travel expenses; and is director of the Brain Research Imaging Centre for Scotland, which is located within the Department of Clinical Neurosciences at the University of Edinburgh, Edinburgh, Scotland and houses a research MRI scanner, which was funded by the UK Research Councils Joint Research Equipment Initiative, supplemented by grants and donations from various other sources including Novartis, Schering, General Electric, and Boehringer Ingelheim. These commercial sources contributed to the purchase of the scanner, but not the running costs or any individual studies. GdZ has received grant funding for research from Boehringer Ingelheim (2012-2013). All other authors report no conflicts of interest.

Correspondence: STT Secretariat, Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, CTSU, Richard Doll Building, Roosevelt Drive, Old Road Campus, Oxford, OX3 7LF, UK. E-mail: stt@ctsu.ox.ac.uk

Abstract

Rationale

Thrombolysis with intravenous alteplase is both effective and safe when administered to particular types of patient within 4·5 hours of having an ischemic stroke. However, the extent to which effects might vary in different types of patient is uncertain.

Aims and Design

We describe the protocol for an updated individual patient data meta-analysis of trials of intravenous alteplase, including results from the recently reported third International Stroke Trial, in which a wide range of patients enrolled up to six-hours after stroke onset were randomized to alteplase vs. control.

Study Outcomes

This protocol will specify the primary outcome for efficacy, specified prior to knowledge of the results from the third International Stroke Trial, as the proportion of patients having a ‘favorable’ stroke outcome, defined by modified Rankin Score 0–1 at final follow-up at three- to six-months. The primary analysis will be to estimate the extent to which the known benefit of alteplase on modified Rankin Score 0–1 diminishes with treatment delay, and the extent to which it is independently modified by age and stroke severity. Key secondary outcomes include effect of alteplase on death within 90 days; analyses of modified Rankin Score using ordinal, rather than dichotomous, methods; and effects of alteplase on symptomatic intracranial hemorrhage, fatal intracranial hemorrhage, symptomatic ischemic brain edema and early edema, effacement and/or midline shift.

Discussion

This collaborative meta-analysis of individual participant data from all randomized trials of intravenous alteplase vs. control will demonstrate how the known benefits of alteplase on ischemic stroke outcome vary across different types of patient.

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