Title: Tranexamic acid for hyper acute spontaneous intracerebral haemorrhage TICH-3
Funder: Department of Health and Social Care

Abstract: Aim: To assess whether tranexamic acid (TXA) given within 4.5 hours after stroke due to bleeding in the brain (intracerebral haemorrhage: ICH) reduces the risk of early death (within 7 days). We also want to assess if TXA has any effect on disability 6 months later. _x000D_ Background: ICH is a medical emergency which causes millions of deaths worldwide each year. Many of the survivors are disabled and their quality of life is affected. The commonest cause of death after ICH is continued bleeding, haematoma growth, which occurs within the first few hours. There is currently no effective treatment for ICH._x000D_ TXA is standard treatment in other bleeding emergencies such as trauma and childbirth, where it reduces deaths from bleeding. In the recently completed TICH-2 study we have shown that TXA given within 8 hours of ICH is safe and prevents haematoma growth. There was also a small reduction in the number of patients who died within the first 7 days. The study was not large enough to show whether there were effects on long-term disability. Tranexamic is cheap (£12) and easy to administer. If we can show that it is effective it could make a difference to ICH patients and their families worldwide._x000D_ Design and methods: Results of the TICH-2 study have shown a larger trial is needed to be certain that TXA saves lives. We therefore propose a large international randomised controlled trial in adults with ICH. We will include people most likely to benefit from the treatment; those within 4.5 hours of stroke onset, and exclude people who cannot benefit because their ICH is already too large. Patients will be approached about the study in the emergency department as soon as the brain scan confirms bleeding in the brain. Because the bleeding is most likely to worsen within the first few hours of onset every minute counts. We will therefore use a rapid emergency consent process, in accordance with ethical guidelines. After enrolment, half the participants are given TXA by injection into a vein and the other half receive saline as placebo. It will be decided by chance which treatment the participants receive and it will not be possible for the doctor or the patient to know if they receive the TXA or placebo as the treatment packs look identical._x000D_ The main outcome will be the number of participants in each treatment group who die within the first 7 days after stroke. We will also contact people via post 6 months after stroke to assess their level of recovery and quality of life. _x000D_ The study will enrol 5500 participants, from 100 hospitals in the UK and 65 hospitals in other countries worldwide and will take 7.25 years._x000D_ PPI: We have worked closely with stroke survivors and their carers to design this study. The people we worked with told us that increased survival is important, but most people would not want to be alive at the expense of very severe disability, also that 3 months is too early to measure recovery after stroke 6 months is more appropriate. We discussed emergency consent in detail, and our advisors suggested that most people would be happy with emergency consent procedure for this study. They also would prefer a blinded study where participants do not know which treatment they receive._x000D_ Dissemination: Results will be presented at major international stroke conference, in a leading medical journal, and to Stroke survivors and public, including the Stroke Assembly Lay conference in the UK.

Lay abstract: Research question: Does tranexamic acid (TXA) improve outcomes when given within 4.5 hours after intracerebral haemorrhage (ICH)?_x000D_ Background: ICH can be devastating with high early mortality and disability in survivors, with outcome related to volume of haematoma and haematoma growth. TXA reduces mortality in other bleeding conditions when given early and reduced haematoma growth in previous study, TICH-2._x000D_ Aim: To assess the clinical effectiveness of TXA after ICH and determine whether TXA should be used in clinical practice._x000D_ Primary objective: To assess the effect of TXA on early death (=7days)_x000D_ Secondary objective: To assess the effect of TXA on dependency 6 months after ICH._x000D_ Methods: Pragmatic phase III prospective blinded randomised placebo-controlled trial performed in two phases: a 36-month internal pilot phase with pre-specified progression criteria then main phase. Using a pragmatic design with emergency consent processes, simple randomisation and minimal data collection will optimise enrolment and the blinded design will minimise bias._x000D_ Setting: Emergency departments, acute stroke units across the UK and worldwide. Estimated 100 UK sites, 65 non-UK sites. The inclusion of sites outside the UK will enable the recruitment of 5500 participants and increase external validity of the study._x000D_ Participants: Adult patients with ICH confirmed on brain imaging within 4.5 hours of symptom onset. Exclusion: Glasgow coma scale (GCS) <5, massive haematoma (volume estimated (HV) > 60mls)_x000D_ Intervention: intravenous TXA 2g given as 100 ml infusion over 10 min or placebo (normal saline 0.9%) administered by an identical regimen. Randomisation will be to TXA vs. placebo in a 1:1 ratio._x000D_ Primary outcome: mortality at 7 days, Secondary outcome: modified Rankin Scale at (mRS) 180 days. Sample size: 2750 participants per group would allow detection of a difference of 2.57% in the proportion of deaths at day 7 between the placebo and TXA groups (7.74% deaths on TXA, OR of 0.73), at the 5% significance level (2-sided) with 90% power._x000D_ Analysis: The primary outcome will be compared between TXA and saline by intention-to-treat using binary logistic regression with adjustment for key prognostic factors. The effect of TXA on the secondary outcome of dependency 6 months after ICH will be compared using shift analysis of the mRS at day 180 ordinal logistic regression (OLR) with adjustment for key prognostic factors. _x000D_ We will embed a Study Within A Trial (SWAT) aimed at reducing inequalities in enrolling and retaining participants from minority communities._x000D_ Timelines for delivery: 7.25 year project; 3 month develop protocol ready for submissions, 9 month set up to obtain regulatory approvals, team recruitment and produce the trial treatment, 5.25 years participant recruitment in the UK, 4.75 years in International sites, 6 months final follow-up, 6 months data clean, analysis and dissemination._x000D_ Anticipated impact and dissemination: TXA is affordable, widely available, already utilised in other fields (trauma, gynaecology, cardiology) within the NHS and worldwide. If the trial confirms that TXA is effective, TXA could be rapidly implemented into the clinical pathway for ICH and has the potential for global impact reducing mortality. Simultaneous oral presentation at a large international stroke conference, publication in high impact journal and a public roadshow will ensure maximum impact and rapid dissemination with incorporation into guidelines.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: STROKE