Desmopressin for reversal of Antiplatelet drugs in Stroke due to intracerebral Haemorrhage 2 (DASH-2)

Background Intracerebral haemorrhage causes 3.4 million deaths per year. Outcome is worse in patients with intracerebral haemorrhage who are taking antiplatelets.

The number of people taking antiplatelets is rising but there is no effective treatment to reverse the effects of antiplatelet drugs after ICH. Desmopressin is a haemostatic drug that reduces bleeding after surgery in patients taking antiplatelet drugs.

We successfully conducted a feasibility trial assessing desmopressin for the reversal of antiplatelet drugs in intracerebral haemorrhage and are running Tranexamic acid for hyper acute spontaneous intracerebral haemorrhage (TICH-3) trial NIHR129917.

Tranexamic and desmopressin are commonly used in combination for the treatment of inherited bleeding disorders and the combination is recommended in national guidelines for platelet disorders.

Aims and objectives To assess whether desmopressin could reduce death or dependency for patients with intracerebral haemorrhage taking antiplatelet drugs.

Methods Overall research design: A multicentre, blinded, randomised trial of desmopressin compared to placebo for patients with intracerebral haemorrhage taking antiplatelet drugs.

The trial will be a randomised controlled comparison, in a partial factorial design, nested within the master protocol of the ongoing Tranexamic acid for hyper acute spontaneous intracerebral haemorrhage (TICH-3) trial.

The existing trial infrastructure of TICH-3 enables this desmopressin comparison to be conducted much more efficiently than a standalone trial. Setting: Sixty-five UK stroke centres participating in TICH-3.

Participant: Adults with intracerebral haemorrhage on imaging; < 24 hours from onset; taking antiplatelet drug; with verbal consent (patient or relative). Exclusions: Secondary causes of intracerebral haemorrhage; risk of fluid retention; systolic blood pressure <90mmHg; known acute coronary syndrome in previous three months; allergy to desmopressin; pregnant or breastfeeding; life-expectancy <24 hours or planned for palliative care only; Glasgow coma score <5 Intervention: Intravenous desmopressin 20 mcg in 50ml 0.9% sodium chloride administered over 20 minutes. Comparator: Non identical placebo 50ml 0.9% sodium chloride administered over 20 minutes.

Allocation will be concealed using central randomisation (internet-based minimisation 1:1) and blinded central telephone follow-up will minimise performance and detection bias.

A total sample size of 1,000 (500 per group) participants are required, assuming overall significance (alpha) = 0.05; power (1-beta) = 0.90; ordinal odds ratio of 0.71; increases due to losses to follow-up of 5%; and a reduction of 20% for baseline covariate adjustment.

Primary outcome: Death or dependency at day 180 (modified Rankin scale, shift analysis) Secondary outcomes: safety, health economic assessment (EQ-5D).

Timelines for delivery 3-years; 3 months set-up, 24 months recruitment, 6 month follow-up, 3 months data lock, analysis dissemination.

This timeline is only possible due to the nested design &ndash; enabling the coordinating team to open all 65 UK sites at once.

PPIE This partial factorial design, nested within TICH-3, using emergency consent is supported by those with lived experience of stroke.

Anticipated impact and dissemination Clear trajectory for patient benefit - If the trial demonstrates efficacy, the results can be rapidly implemented into routine practice as the drug is inexpensive and already utilised within the NHS. Dissemination through publications, conference presentations, social media, videos co-designed with patient groups.