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TICH-3 trial

Tranexamic acid for IntraCerebral Haemorrhage 3

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Title Tranexamic acid for IntraCerebral Haemorrhage 3 (TICH-3)
Acronym TICH-3
Chief investigator Professor Nikola Sprigg
Objectives 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 (≤ 7 days)
Secondary objective: To assess the effect of TXA on dependency 6 months after ICH.
Trial configuration Pragmatic phase III prospective blinded randomised placebo-controlled trial.
Setting Emergency departments, acute stroke services/units across the UK and worldwide.
Sample size estimate 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.  As the primary outcome is death we anticipate there will be minimal loss to follow up.
Number of participants At least 5,500
Eligibility criteria Inclusions
  • Adults within 4.5 hours of onset of acute spontaneous ICH (confirmed on brain imaging)
  • When onset of symptoms is unknown, patient must be within 4.5 hours of symptom discovery and have no other exclusion criteria
  • Patients taking direct oral anticoagulants can be included
  • Informed consent documented
Exclusions
  • Patient with a known indication for TXA treatment (e.g. traumatic brain injury)
  • Patient with contraindication for TXA treatment
  • Patient known to be taking therapeutic anticoagulation at time of enrolment, with the exception of direct oral anticoagulants (patients taking direct oral anticoagulants are not excluded)
  • Massive ICH for which haemostatic treatment seems futile (this would ordinarily be when haematoma volume is estimated as larger than 60ml)
  • Severe coma (Glasgow Coma Scale less than 5)
  • Decision already taken for palliative (end of life) care with withdrawal of active treatment
Description of interventions
  • Intravenous tranexamic acid 2g: 1g loading dose given as 100 mls infusion over 10 minutes, followed by 1g in 250 mls infused over 8 hours.
  • Comparator - matching placebo (normal saline 0.9%) administered by an identical regimen.
Duration of study 7.25 years project; approximately 5.25 years participant recruitment in the UK, 4.75 years in international sites.
Start date 1 January 2022.
Duration of study per participant: 6 months.
Randomisation and blinding Randomisation will be to TXA vs. placebo in a 1:1 ratio.
Due to the emergency situation, a straightforward randomisation process will be used, where sites will simply select the next available treatment pack, which will be a numbered box containing either TXA or placebo according to a computer-defined sequence.
Boxes will be identical with the exception of the treatment pack number.
Randomisation will be stratified by site with supply to each site balanced for TXA and placebo, using random permuted blocks of varying size.
The IMP manufacturer will prepare blinded individual treatment packs containing four 5ml glass ampoules of TXA 500mg or sodium chloride 0.9% which will be identical in appearance.
Outcome measures Primary outcome: mortality at 7 days.
Secondary functional outcome: modified Rankin Scale at (mRS) 180 days.
Other secondary outcomes: Death at 2 days.
Safety outcomes: Recorded in the first 7 days (or death if sooner): venous thromboembolism; ischaemic events; seizures. Quality of Life (EuroQol [Devlin, Shah, Feng, Mulhern, & van Hout, 2018], EQ-5D-5L, VAS), and cognition (AD-8 [Galvin, Roe, Coats, & Morris, 2007]) at day 180.
Statistical methods The analysis and presentation of the trial results will be in accordance with the CONSORT guidelines.  The primary outcome will be compared analysing as randomised without imputation of missing data.  Due emphasis will be placed on the confidence intervals for the between arm comparisons.  A full Statistical Analysis Plan (SAP) will be developed prior to database lock.  The evaluation of the primary outcome will be performed using regression models for binary outcomes, with adjustment for key prognostic factors. The model will be fully specified in the SAP.  Absolute and relative measures of effect and 95% confidence intervals will be presented.  The primary outcome will also be investigated in prespecified subgroups using appropriate interaction terms.  The subgroups will be specified in the SAP and will, at a minimum include age, sex, systolic blood pressure, HV, GCS, the start of treatment (≤2 or >2 hours, ≤3 or >3 hours) and intraventricular haemorrhage (yes, no).
Contact details
Address: Room S/D2108
Stroke Trials Unit
School of Medicine
University of Nottingham
Queen's Medical Centre
Derby Road
Nottingham NG7 2UH
United Kingdom

Tel: +44 (0) 115 823 1782
Email:
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