Tranexamic acid for hyperacute primary Intracerebral Haemorrhage (TICH-2)

Design: Pragmatic phase III prospective double blind randomised placebo controlled trial performed in two phases: an 18 month start up phase (activate 30 centres, recruit a minimum of 300 participants) then main phase (120 centres, recruit to a total of 2,000 participants). There will be no break in recruitment as the trial proceeds from the start up phase to the main phase unless the stopping criteria are met. Setting: Acute stroke units across the UK and worldwide; 30 in the start up phase, 120 in the main phase. Estimated 80 UK sites, 40 non-UK sites. The inclusion of sites outside the UK will enable the recruitment of 2,000 participants over 43 months and increase external validity of the study. Target population: Patients within 8 hours of acute primary intracerebral haemorrhagic stroke. Exclusion criteria will be one or more of: contra-indication to tranexamic acid, severe pre-morbid disability, Glasgow coma scale <5, or life expectancy < 3 months due to other disease (e.g. advanced cancer). Health technologies being assessed: Intravenous tranexamic acid: 1g loading dose given as 100 mls infusion over 10 minutes, followed by another 1g in 250 mls infused over 8 hours. Comparator – matching placebo (normal saline 0.9%) administered by identical regimen. Measurement of cost and outcomes: Primary outcome: death or dependency (modified Rankin Scale, mRS) day 90. Secondary clinical outcomes: At day 7 (or discharge if sooner), neurological impairment (NIHSS). At day 90, disability (Barthel index), Quality of Life (EuroQol), cognition. Safety: death, serious adverse events, thromboembolic events, seizures. Costs: length of stay in hospital, re-admission, institutionalisation. Radiological efficacy/safety (CT scan): change in haematoma volume from baseline to 24 hours, haematoma location, new infarction. Sample size: With alpha=0.05, power=90%, assuming losses to follow up=5% and covariate adjustment reduces sample size by 20%, 2,000 participants will need to be recruited to detect a treatment effect of OR 0.74 by shift analysis of mRS outcome (OR based on trials of tranexamic acid in traumatic intracerebral haemorrhage). Project timetable: Duration 48mths with 43mths recruitment, anticipated grant start date 01/11/2012, first recruitment Dec 2012. Month -6: Refine protocol, seek approvals; Month 0: Training, investigator training meeting (30 sites); Months: 1-18: Start-up phase recruitment; Month 18: Stop/Go decision (based on feasibility and safety); Month 19: Investigator training meeting (90 sites); Months 19-43: Main phase recruitment; Months 43-47: final follow-ups, data clean, analyse; Month 48: Complete primary publication; results dissemination. Provided the Stop/Go criteria are met, there will be no break in recruitment between the start and main phases. The overall require recruitment rate is 47 participants/month; 0.55 participants/site/month in the start up phase and 0.56/site/month in the main phase. Recruitment of 68 patients per month in main phase allows for recruitment of 1700 patients over 25 months. In reality recruitment is likely to be less than this in the early months of both phases of the trial, but will increase as the number of active sties increase. Impact: If the trial confirms that tranexamic acid is effective, these results can be rapidly implemented into routine practice as the drug is inexpensive and already utilised in other fields (trauma, gynaecology, cardiology) within the NHS. Previous experience has shown that trial results within stroke can be implemented rapidly and influence clinical practice. For example; compression stockings were quickly withdrawn from routine clinical practice in stroke units following the publication of the neutral CLOTS-1 study.