In English

This page is a brief introduction to the TICH-3 Cog trial in English. The full protocol will be published with a full history of amendments.

Every year, 1.7 million, experience a spontaneous Intracerebral haemorrhage, and out of those who manage to survive, one-third of them develop cognitive issues. In Sweden, there is an incidence of 2,700 cases of spontaneous Intracerebral haemorrhage annually.

Currently, there is no hyper-acute medical intervention available except for the reduction of blood pressure. Despite the patients’ emphasis on cognition as the most crucial research area and the European Stroke Organisation’s identification of significant gaps in knowledge, there is a lack of randomized controlled studies investigating the possibility of mitigating cognitive impairment.

We want to carry out a randomised controlled study that investigates whether tranexamic acid can reduce cognitive problems that arise after an intracerebral haemorrhage. Half of the patients will receive an intravenous infusion of tranexamic acid and the other half a placebo. Treatment begins within 4.5 hours of stroke onset.

The hypothesis is that tranexamic acid reduces the size of the haemorrhage and thereby reduces secondary brain damage.

The primary outcome measure is cognition at 1 year as measured by the Montreal Cognitive Assessment scale.

ICH-3 Cog is a Swedish sub-study embedded in the international TICH-3 trial

We will include adults with spontaneous Intracerebral haemorrhage within 4.5 hours of symptom onset. If the exact time of symptom onset is unknown, patients must be within 4.5 hours of discovering their symptoms.

TICH-3 Cog is embedded in the Tranexamic acid for Intracerebral Haemorrhage (TICH-3) trial, a pragmatic phase III prospective randomised placebo-controlled study that aims to include 5,500 individuals from around the world. The full protocol for TICH-3 is available here.
The research plan for TICH-3 Cog is written in collaboration with the principal investigator for TICH-3, Prof Nikola Sprigg, Nottingham, UK. The primary outcome measure for TICH-3 is death within 7 days.

Inclusion and Exclusion criteria

We will exclude patients with known indications for treatment with tranexamic acid – such as traumatic brain injury – and patients with contraindications for tranexamic acid. Moreover, we will exclude individuals with massive intracerebral haemorrhage (typically defined as a hematoma volume estimated to be larger than 60 ml), patients with a Glasgow Coma Scale score of less than 5, and patients who have decisions for palliative (end-of-life) care.

Synopsis

Protocol ID	TICH-3-Cog protocol v2
Brief Title	Tranexamic acid for hyperacute intracerebral haemorrhage on cognition
Acronym	TICH-3-Cog
Swedish title	Rädda hjärnblödningen
Objectives	To assess the clinical effectiveness of tranexamic acid after intracerebral haemorrhage and determine whether tranexamic acid should be used in clinical practice. Primary objective: To assess the effect of tranexamic acid on cognition at 1 year. Secondary objective: To assess the effect of tranexamic acid on death, dependency and dementia up to 10 years after intracranial haemorrhage.
Trial Configuration	Rädda hjärnblödningen is a pragmatic phase III prospective blinded randomised placebo-controlled trial embedded in the Tranexamic acid for Intracerebral Haemorrhage (TICH-3) trial. Rädda hjärnblödningen will include at least 180 patients in Sweden The TICH-3 trial will include 5 500 patients from around the world. The primary outcome for TICH-3 is early death up to and including day 7 after intracerebral haemorrhage onset.
Setting	Emergency departments and acute stroke units in Sweden.
Sample size estimate	Rädda hjärnblödningen has been dimensioned in order to detect a two-unit difference in mean Montreal Cognitive Assessment (23 versus 25) between the two groups with a significance level of 5 per cent (2-sided), an assumed standard deviation of 4.5 and a power of 80 per cent. With 81 patients in each group, these conditions will be met. In order to compensate for included patients not valid for efficacy analysis it is planned to enrol up to 180 patients in the study in order to have 162 patients valid for efficacy analysis. The attrition rate is estimated to be at most 10 per cent.
Number of participants	At least 180.
Eligibility criteria	Inclusion criteria: Adults within 4.5 hours of the onset of acute spontaneous intracerebral haemorrhage 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. Exclusion Criteria: Patient with a known indication for tranexamic acid treatment Patient with contraindication for tranexamic acid treatment Patient known to be taking therapeutic anticoagulation with warfarin or low molecular weight heparin at time of enrolment. Patients taking direct oral anticoagulants can be included and are not excluded. Massive intracerebral haemorrhage for which haemostatic treatment seems futile. This would ordinarily be when haematoma volume is estimated as larger than 60 ml. Severe coma (Glasgow Coma Scale <5) Decision already taken for palliative (end of life) care with withdrawal of active treatment
Description of interventions	Intervention: Intravenous tranexamic acid 2 g: 1 g loading dose given as 100 mls infusion over 10 minutes, followed by 1 g in 250 mls infused over 8 hours. Comparator: Matching placebo (normal saline 0.9%) administered by an identical regimen.
Duration of study	Start date: 2023. Duration of study per participant: 1 year for primary outcome. Up to 10 years for secondary outcomes.
Randomisation and blinding	Randomisation will be to tranexamic acid versus 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 tranexamic acid 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 tranexamic acid and placebo, using random permuted blocks of varying size. The Investigational Medicinal Products manufacturer will prepare blinded individual treatment packs containing four 5 ml glass ampoules of tranexamic acid 500 mg or sodium chloride 0.9% which will be very similar in appearance.
Outcome measures	Primary outcome Cognition at one year measured by Montreal Cognitive Assessment Secondary outcomes Functional outcome assessed with the modified Rankin Scale) Anxiety and depression assessed with the Hospital Anxiety and Depression Scale) Physical Activity measured with Saltin-Grimby Physical Assessment Scale (SGPALS). We will ask the pre-SGPALS (before the bleeding) and SGPALS follow-ups. Cognitive decline and dementia. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). IQCODE is a short questionnaire designed to assess cognitive decline and dementia in elderly people. The questionnaire is filled out by a relative or friend who has known the person for 10 years or more. Caregiver burden. We intend to ask the next of kin if they want to be part of the study (separate consent) and measure their burden with the Caregiver burden Scale.
Approval Ethics	Swedish Ethical Review Authority. Dnr 2021-03497. Date: 8 Sep 2021. Amendment 1: (pending)
Approval MPA	Swedish Medical Product Agency. Dnr 5.1.1-2023-4604 Date: 27 April 2023
EU CT number EudraCT number:	EU CT number for TICH-3: 2022-500587-35-01 EudraCT number for TICH-3: 2021-001050-62
Clinicaltrials.gov number	Pending registration
Funding	Strokeförbundet Neuroförbundet
Contact in Sweden	Professor/PI Erik Lundström. Email: erik.lundstrom@neuro.uu.se. PhD/Trial Manager Eva Isaksson. Email: eva.isaksson@regionstockholm.se.
Protocol version	2