Statistical analysis plan for the randomized controlled trial Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST)
Agnethe Eltoft, Tom Wilsgaard, Melinda B Roaldsen, Mary-Helen Søyland, Erik Lundström, Jesper Petersson, Bent Indredavik, Jukka Putaala, Hanne Christensen, Janika Kõrv, Dalius Jatužis, Stefan T Engelter, Gian Marco De Marchis, David J Werring, Thompson Robinson, Arnstein Tveiten, Ellisiv B Mathiesen, Agnethe Eltoft, Tom Wilsgaard, Melinda B Roaldsen, Mary-Helen Søyland, Erik Lundström, Jesper Petersson, Bent Indredavik, Jukka Putaala, Hanne Christensen, Janika Kõrv, Dalius Jatužis, Stefan T Engelter, Gian Marco De Marchis, David J Werring, Thompson Robinson, Arnstein Tveiten, Ellisiv B Mathiesen
Abstract
Background: Patients with wake-up ischemic stroke are frequently excluded from thrombolytic treatment due to unknown symptom onset time and limited availability of advanced imaging modalities. The Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST) is a randomized controlled trial of intravenous tenecteplase 0.25 mg/kg and standard care versus standard care alone (no thrombolysis) in patients who wake up with acute ischemic stroke and can be treated within 4.5 h of wakening based on non-contrast CT findings.
Objective: To publish the detailed statistical analysis plan for TWIST prior to unblinding.
Methods: The TWIST statistical analysis plan is consistent with the Consolidating Standard of Reporting Trials (CONSORT) statement and provides clear and open reporting.
Discussion: Publication of the statistical analysis plan serves to reduce potential trial reporting bias and clearly outlines the pre-specified analyses.
Trial registration: ClinicalTrials.gov NCT03181360 . EudraCT Number 2014-000096-80 . WHO ICRTP registry number ISRCTN10601890 .
Keywords: Acute stroke therapy; Ischemic stroke; TWIST; Tenecteplase; Thrombolysis; Wake-up stroke.
Conflict of interest statement
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The cost of tenecteplase is covered by an unconditional grant from Boehringer Ingelheim Norway KS.
© 2022. The Author(s).
References
- Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J. 2018;379:611–622. doi: 10.1056/NEJMoa1804355.
- Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019;380:1795–1803. doi: 10.1056/NEJMoa1813046.
- Thomalla G, Boutitie F, Ma H, et al. Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data. Lancet. 2020;396:1574–1584. doi: 10.1016/s0140-6736(20)32163-2.
- Roaldsen MB, Lindekleiv H, Eltoft A, et al. Tenecteplase in wake-up ischemic stroke trial: Protocol for a randomized-controlled trial. Int J Stroke. 2021;1747493020984073. 2021/01/16. 10.1177/1747493020984073.
- Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c332. doi: 10.1136/bmj.c332.
- Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 1971;44:793–797. doi: 10.1259/0007-1285-44-526-793.
- Saver JL. Novel end point analytic techniques and interpreting shifts across the entire range of outcome scales in acute stroke trials. Stroke. 2007;38:3055–3062. doi: 10.1161/strokeaha.107.488536.
- Wahlgren N, Ahmed N, Davalos A, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007;369:275–282. doi: 10.1016/s0140-6736(07)60149-4.
- Group ISTc Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial. Lancet Neurol. 2013;12:768–776. doi: 10.1016/S1474-4422(13)70130-3.
- Rv K, Broderick JP, BCV C, et al. The Heidelberg Bleeding Classification. Stroke. 2015;46:2981–2986. doi: 10.1161/STROKEAHA.115.010049.
- Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet. 2012;379:2364–2372. doi: 10.1016/s0140-6736(12)60738-7.
- Zhu RL, Xu J, Xie CJ, et al. Efficacy and safety of thrombolytic therapy for stroke with unknown time of onset: a meta-analysis of observational studies. J Stroke Cerebrovasc Dis. 2020;29:104742. doi: 10.1016/j.jstrokecerebrovasdis.2020.104742.
- Senn S. Statistical Issues in Drug Development. 2. Chichester: Wiley; 2008. p. 173.
- Churilov L, Arnup S, Johns H, et al. An improved method for simple, assumption-free ordinal analysis of the modified Rankin Scale using generalized odds ratios. Int J Stroke. 2014;9:999–1005. doi: 10.1111/ijs.12364.
Source: PubMed