MR GENTLE-multicentre randomised controlled trial of ghrelin in anterior circulation ischaemic stroke treated with endovascular thrombectomy: a phase 2 trial

BACKGROUND AND AIMS: About half of the patients with acute ischaemic stroke treated with endovascular thrombectomy (EVT) remains dependent or dies in the first 90 days. Ghrelin is a naturally occurring hormone and mildly excitatory neurotransmitter that improved functional, histological, and cytological recovery in in vitro and in vivo ischaemia-reperfusion models. Acylated ghrelin (i.e. the bioactive form) has shown safety in a range of populations, including patients with cardiovascular or neurodegenerative disease. We hypothesise that treatment with acylated ghrelin improves early recovery and long-term functional outcome in patients with ischaemic stroke treated with EVT.

METHODS: We propose an investigator-initiated, phase 2, randomised, clinical trial with open-label treatment and blinded endpoint assessment in 80 patients with anterior circulation ischaemic stroke treated with EVT and a pre-EVT National Institutes of Health Stroke Scale (NIHSS) score ≥ 10. Patients will be randomised to intravenous acylated ghrelin, 600 µg twice daily for 5 days and started within 6 h of symptom onset, in addition to standard care vs. standard care alone. The primary outcome is the NIHSS score on day 7 adjusted for pre-EVT NIHSS and other relevant baseline characteristics. Secondary outcomes include infarct size on MRI at day 3, adverse events, and functional recovery at 90 days. The primary analysis will be a single comparison between the treatment groups of the primary outcome according to the intention-to-treat principle. The primary effect variable will be the adjusted beta for the difference in NIHSS score, estimated with multi-variable linear regression analysis.

DISCUSSION: If administration of acylated ghrelin is found safe and potentially effective in patients with ischaemic stroke treated with EVT, this study can inform the sample size calculation for a subsequent randomised phase 3 trial to assess efficacy.

TRIAL REGISTRATION: The trial has been approved and registered on ClinicalTrials.gov (NCT05726240). The first patient has been included in November 2024.