Tranexamic acid for hyper acute spontaneous intracerebral haemorrhage TICH-3

Research question: Does tranexamic acid (TXA) improve outcomes when given within 4.5 hours after intracerebral haemorrhage (ICH)?

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.

Aim: To assess the clinical effectiveness of TXA after ICH and determine whether TXA should be used in clinical practice.

Primary objective: To assess the effect of TXA on early death (=7days)

Secondary objective: To assess the effect of TXA on dependency 6 months after ICH.

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.

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.

Participants: Adult patients with ICH confirmed on brain imaging within 4.5 hours of symptom onset. Exclusion: Glasgow coma scale (GCS) 60mls)

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.

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.

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.

We will embed a Study Within A Trial (SWAT) aimed at reducing inequalities in enrolling and retaining participants from minority communities.

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.

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.