Safety and efficacy of Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke: the TARDIS randomised controlled trial

Design: International collaborative prospective randomised (1:1) open blinded end-point controlled phase III trial of one month of intensive (triple: aspirin [Asp], dipyridamole [Dip], clopidogrel [Clop]) versus guideline [Asp+Dip or Clop alone] antiplatelet therapy in participants with acute ischaemic stroke or TIA. The primary outcome is frequency and severity of stroke/TIA. Setting: 4,100 well phenotyped (stroke/TIA; clinical and imaging) participants from UK and overseas hospital-based stroke/TIA services (3,500 from main phase and ~600 participants from start up phase). UK participants (1,750) will be recruited from NIHR Stroke Research Network sites. Target population: Age>=50. <=48 hours of ictus (30-48 hours if thrombolysed). Non-cardioembolic ischaemic stroke, with new motor weakness, or dysphasia, or hemianopia. TIA with one or more of ABCD2 score >3, crescendo TIA (>1 TIA within 1 week), or on dual antiplatelet therapy. Limb weakness and/or dysphasia must be present for >10 mins if a TIA, or at enrolment if a stroke. CT scan to exclude haemorrhage/other pathology if a stroke. Health technology: Open-label IMPs for 30 days: oral Asp (load 300 mg, then 75 mg daily), Clop (load 300 mg, then 75 mg daily), Dip (modified release 200 mg twice daily). Standard evidence-based vascular and gastro prophylaxis are given as appropriate. Costs/outcomes: The overall hypothesis is that acute triple antiplatelets will reduce early stroke recurrence and its severity, and hence resource costs. The primary outcome is stroke/TIA recurrence and its severity. Secondary and safety outcomes include vascular events, bleeding and death. Outcome data will also include cognition, mood and quality of life. Key costs and outcomes will be collected at each centre and resource utilisation determined locally including length of stay, drug cost and discharge disposition. Incremental Cost Effectiveness Ratios and Cost Effectiveness Acceptability Curves will be calculated for both groups. Sample size: Total size =4,100 (3,500 from HTA main phase, ~600 from ongoing BHF start-up phase), assuming alpha=5%; power =90%; distribution of 5-level stroke/TIA ordinal outcome (%): death 0.51 / severe (mRS 2-5) 0.77 / mild (mRS 0,1) 1.53 / TIA 3.57 / no event 93.62 (total events =262); odds ratio =0.68; treatment crossovers 5%; losses 2%; adjustment for baseline covariates = 20%; and assuming proportionality of odds. Timetable: TARDIS has 50 active UK sites and 479 (stroke 61%, TIA 39%) of 350 planned participants in the BHF-funded start-up phase (at 28 of 36 months). To ensure a seamless transition, we are now seeking additional sites to make 140+ in total (UK 70+; overseas 70+ from 15 countries). Recruitment: 140 active centres x0.5 participants per month=50 per month x1 year then 70 per month x3.5 years ~3,540 participants. The existing approvals from MHRA, MREC, R&D, and SRN, cover the whole trial.