Does tranexamic acid lead to changes in MRI measures of brain tissue health in patients with spontaneous intracerebral haemorrhage? Protocol for a MRI substudy nested within the double-blind randomised controlled TICH-2 trial

Abstract

Objectives: To test whether administration of the antifibrinolytic drug tranexamic acid (TXA) in patients with spontaneous intracerebral haemorrhage (SICH) leads to increased prevalence of diffusion-weighted MRI-defined hyperintense ischaemic lesions (primary hypothesis) or reduced perihaematomal oedema volume, perihaematomal diffusion restriction and residual MRI-defined SICH-related tissue damage (secondary hypotheses).

Design: MRI substudy nested within the double-blind randomised controlled Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 trial (ISRCTN93732214).

Setting: International multicentre hospital-based study.

Participants: Eligible adults consented and randomised in the TICH-2 trial who were also able to undergo MRI scanning. To address the primary hypothesis, a sample size of n=280 will allow detection of a 10% relative increase in prevalence of diffusion-weighted imaging (DWI) hyperintense lesions in the TXA group with 5% significance, 80% power and 5% imaging data rejection.

Interventions: TICH-2 MRI substudy participants will undergo MRI scanning using a standardised protocol at day ~5 and day ~90 after randomisation. Clinical assessments, randomisation to TXA or placebo and participant follow-up will be performed as per the TICH-2 trial protocol.

Conclusion: The TICH-2 MRI substudy will test whether TXA increases the incidence of new DWI-defined ischaemic lesions or reduces perihaematomal oedema or final ICH lesion volume in the context of SICH.

Ethics and dissemination: The TICH-2 trial obtained ethical approval from East Midlands - Nottingham 2 Research Ethics Committee (12/EM/0369) and an amendment to allow the TICH-2 MRI sub study was approved in April 2015 (amendment number SA02/15). All findings will be published in peer-reviewed journals. The primary outcome results will also be presented at a relevant scientific meeting.

Trial registration number: ISRCTN93732214; Pre-results.

Keywords: diffusion weighted imaging; hyperacute primary intracerebral haemorrhage; magnetic resonance imaging; perihaematomal oedema; tranexamic acid.

Figure 1

TICH-2 MRI substudy flowchart. Details of participant flow for the TICH-2 trial, including the schedule for randomisation, treatment, cranial CT, clinical assessments and non-MRI follow-up assessments have been described in Sprigg et al. TICH-2, Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage 2 trial.

Figure 2

Summary of image processing and outputs in the TICH-2 MRI substudy. 3D, three dimensional; ADC, apparent diffusion coefficient; CMB, cerebral microbleed; DWI, diffusion-weighted image; DWIHL, diffusion-weighted image hyperintense lesion; FLAIR, fluid-attenuated inversion recovery; MNI, montreal neurological institute; PHO, perihaematomal oedema; ROI, region of interest; SWI, susceptibility weighted imaging; TICH-2, Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage 2 trial; WMHL, white matter hyperintense lesion.

Figure 3

Measurement of PHO volume and ADC. (A) Axial FLAIR image in native T1 space showing the PHO delineation from which the PHO volume can be derived. (B) ADC map in native T1 space. PHO ADC values are calculated from the voxels within the PHO delineation in the ADC map. ADC, apparent diffusion coefficient; FLAIR, fluid-attenuated inversion recovery; PHO, perihaematomal oedema.