TICH-3

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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 (at least 18 years old) 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).

Title	Desmopressin for reversal of Antiplatelet drugs in Stroke due to Haemorrhage 2 – UK SITES ONLY
Acronym	DASH-2
Chief investigator	Professor Nikola Sprigg
Objectives	To assess the efficacy of desmopressin for reducing the risk of death or disability from intracerebral haemorrhage associated with antiplatelet drugs
Trial configuration	A phase III single blind ended point randomised placebo-controlled efficacy trial, delivered by the addition of an additional intervention and comparison, nested within the master protocol of the ongoing pragmatic phase III prospective randomised TICH-3 RCT. We have chosen a factorial design because it a more efficient way to evaluate both in a single trial. We hypothesis no interaction between the interventions. If a patient is eligible for both tranexamic acid and desmopressin comparisons, they may be enrolled into both comparisons.
Setting	Secondary care (in the UK only)
Sample size estimate	A total sample size of 1,000 (500 per group) participants with acute antiplatelet related intracerebral haemorrhage are required, assuming overall significance (alpha) = 0.05; power (1-beta) = 0.90; distribution in (mRS 0=1.7%, 1=5.8, % 2=11.6, % 3=12.2, % 4=17.3, % 5=16.7, % 6 (death)= 34.7 %) based on data from control participants with APT related intracerebral haemorrhage in the TICH-2 trial); ordinal odds ratio of 0.71; increases due to losses to follow-up of 5%; and a reduction of 20% for baseline covariate adjustment.
Number of participants	1,000
Eligibility criteria	Inclusions Adults (at least 18 years old) with confirmed intracerebral haemorrhage on imaging Event less than 24 hours from onset of symptoms, or from when last seen free of stroke symptoms (for sleep stroke, take onset as bed time) Prescribed and thought to be taking a daily oral antiplatelet drug in the preceding seven days – Aspirin, Dipyridamole, Clopidogrel, Prasugrel (Efient®) and/or Ticagrelor (Brilique®) (cyclooxygenase inhibitors, phosphodiesterase inhibitors or P2Y12 inhibitors) Signed consent (or waiver of consent) Exclusions Massive ICH for which haemostatic treatment seems futile (this would ordinarily be when haematoma volume is estimated as larger than 60ml) Aneurysmal subarachnoid haemorrhage known at time of randomisation Haemorrhage suspected to be due to transformation of ischaemic stroke or trauma Haemorrhage known to be due to thrombolytic drug or venous thrombosis Risk(s) of fluid retention associated with desmopressin judged clinically significant by the attending physician (for example patients with pulmonary oedema and/or cardiac failure) Significant hypotension (systolic blood pressure under 90 mmHg) Known drug-eluting coronary artery stent in previous three months Known unstable angina, decompensated cardiac insufficiency or acute coronary syndrome in past month Known allergy to desmopressin Pregnant or breastfeeding Life expectancy less than four hours, or planned for palliative care only Severe pre-morbid disability (modified Rankin scale is 5) Glasgow coma scale less than 5 Use of substances that are known to induce syndrome of inappropriate ADH section (SIADH), for example, tricyclic antidepressants, selective serotonin re-uptake inhibitors, chlorpromazine and carbamazepine, may cause an addictive antidiuretic effect leading to increased rick of water retention and/or hyponatremia
Description of interventions	Allocated treatment desmopressin 20µg (20µg in 50ml sodium chloride 0.9% infusion bag) through a venous cannula over 20 minutes) Placebo (50ml sodium chloride 0.9% infusion bag) through a venous cannula over 20 minutes)
Duration of study	30 months / participants will be followed up for 180 days
Randomisation and blinding	Patients will be randomised (1:1) to receive either desmopressin or matching placebo (Sodium Chloride 0.9%) via intravenous injection. Randomisation will be performed by the Stroke Trials Unit, Nottingham (STUN). Standard pharmacy supplies of the IMP will be used. Personnel prescribing and preparing the injection for administration and clinical team will not be masked to the treatment allocation. Patients, relatives, and outcome assessors will be masked to treatment allocation. Blinded central follow-up will minimise performance and detection bias.
Outcome measures	Primary outcome Death or dependency at Day 180 (modified Rankin scale, mRS shift analysis) assessed by modified Rankin Scale at 180 days Secondary outcomes Safety: Symptomatic hyponatraemia or fluid overload at 24 hours (as defined in the protocol); early mortality < 7 days, < 28 days, and up to day 180; serious adverse events (including thrombotic events) up to day 180. Functional/other: Quality of Life (EuroQol, EQ-5D-5L, VAS), and cognition (AD-8) at day 180. Health economics: Health economic assessment (EQ-5D), length of hospital stay, discharge destination.
Statistical methods	The analysis and presentation of the trial results will be in accordance with the CONSORT extension recommendation. Ordinal shift in modified Rankin scale will be assessed as the primary outcome using an intention-to-treat population. The primary outcome will also be investigated in pre-specified subgroups using appropriate interaction terms. The subgroups will be specified in the SAP and will, at a minimum, include age, sex, systolic blood pressure, estimated HV, GCS, the start of treatment (≤ 4.5, > 4.5 hours) and intraventricular haemorrhage (yes, no), Aspirin versus other types of antiplatelet drug, TXA comparison subgroup. Full details will be presented in the SAP.

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
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