Title: Tranexamic acid for hyperacute primary Intracerebral Haemorrhage (TICH-2)
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: Stroke is a devastating condition that is the most common cause of adult disability in this country. Most strokes are caused by clots blocking the blood supply to part of the brain. These can be treated with ‘clot busting’ (thrombolysis). However, 1 stroke in 10 is caused by a blood vessel bursting and bleeding into the brain (haemorrhage) . Haemorrhages cause the most severe strokes and two thirds of patients will die or be left with major disability. There is no effective treatment for strokes caused by brain haemorrhage. Haemorrhagic strokes often deteriorate within the first 24 hours of onset because the bleeding continues. Tranexamic acid is a drug that stops bleeding by speeding up the formation of blood clots. This drug has recently been shown in the very large CRASH-2 trial to reduce death and disability in patients with multiple severe injuries or traumatic brain haemorrhage. This proposal is for a large clinical trial to test whether tranexamic acid will reduce the risk of death and disability in patients with stroke caused by a brain haemorrhage. We have recently shown that it is possible to give tranexamic acid to people within 24 hours after haemorrhagic stroke in a small pilot trial (TICH-1). This helped us to design the present study, but was not large enough to show clinical benefits. This study, ‘Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage-2’ (TICH-2) will enroll a much larger number of participants to confirm or exclude a definite benefit. TICH-2 will recruit 2,000 patients in 80 UK hospitals and 40 hospitals across the world. Adult patients who have had a haemorrhagic stroke within the last 8 hours will be eligible. Patients will be given information about the trial and included if they agree to take part and fit the trial criteria. Participants will be allocated randomly (by chance) to one of two treatment groups: Group 1: tranexamic acid injection; Group 2: identical placebo (salt water) injection. The treatment will be given as soon as possible after treatment allocation. Neither the participant or the doctor will know if the participant received tranexamic acid or the placebo (called ‘double blind’) and avoids any bias in the care given to the participants and in the outcome assessments of the study. The main outcome of the study will be to see if tranexamic acid reduces the number of people who die or who are left dependent after haemorrhagic stroke. Participants will be interviewed 90 days after the stroke to assess their disability, using a set of questions known as the modified Rankin Scale – this is the commonest outcome measure in stroke trials. The Rankin Scale scores people according to how badly they are affected by the stroke, ranging from a score of 0 (meaning no symptoms at all) to 6 (death). We will assess how well the patient has recovered at one week by doing a standardised neurological examination and comparing the results with those on admission. The amount of bleeding in the brain (known as haematoma volume) will be assessed by performing a CT brain scan 24 hours after treatment. Potential harm: because tranexamic acid works by stopping bleeding there is a chance it could cause an increase in blood clot formation (thrombosis) leading to life threatening or fatal complications with heart attack, or clots in the legs or lungs. Participants will be closely monitored for signs of thrombosis and the independent Data Monitoring Committee will review the rate of complications in the study. However, the CRASH-2 study, which included 20,000 participants with bleeding problems, did not show any increased risk of thrombosis. The research will be performed according to International Guidelines following approval from national authorities and ethics committees. All participants must give permission (consent) to take part in the study. Sometimes in the first few hours after stroke patients have communication problems or are too unwell to give consent, and in this situation we will ask permission from a close family member or friend – this is known as proxy consent and is common in acute stroke trials. Where no family member or friend is available, permission may be sought from an independent doctor. Stroke survivors are supportive of this. Our research group is well placed to carry out this study as we already have a long track record of carrying out similar research in acute stroke units. One on the co-applicants led the study CRASH-2 which showed that tranexamic acid reduced dying in patients with bleeding due to trauma. We have a large number of contacts already in place within acute stroke units. This will help us organise a training programme and start research quickly when the project begins. Tranexamic acid is inexpensive (£10 per patient), easy to administer (via an injection into the veins) and is already used in the NHS for other conditions such as bleeding after trauma or surgery. If this research shows that tranexamic acid reduces the number of people who die or who are left dependent after haemorrhagic stroke, it could be rapidly introduced to stroke care across the NHS. This would result in benefit to patients, carers and society.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: STROKE