WP5 – Neuroprotection

Staff

WP leaders: Jeannette Hofmeijer (UT) & Ido van den Wijngaard (LUMC)
PhD: Quinty Omes (UT)

The workpackage

About half of the patients with acute ischemic stroke treated with EVT remains dependent on the help of others or dies in the first 90 days. This indicates the need for additional effective treatments to promote functional recovery. Neuroprotective treatments are interventions targeting preservation of neuronal structure or functioning other than reperfusion strategies. In a narrower sense, neuroprotective treatments are considered as interventions that prevent irreversible damage of the penumbra before, during, or directly after revascularization. Effective neuroprotective treatments hold potential to modulate infarct growth and improve functional recovery. Ghrelin and 2-IminoBioton (2-IB) are two high potential neuroprotective treatments that improved histological and functional outcomes in ischemia-reperfusion models under a wide range of experimental in vivo and in vivo conditions. Working mechanisms include optimization of energy homeostasis by modulation of mitochondrial respiration (Ghrelin), reduction of apoptosis (Ghrelin) and free radical scavenging (2-IB and Ghrelin). Both had an excellent safety profile in healthy subjects and divergent patient groups. We hypothesize that treatment with either Ghrelin or 2-IB, started in the first six hours after stroke onset, improves early recovery and long-term functional outcome in patients with acute ischemic stroke treated with EVT.

Objectives

The overall aim of the studies proposed with WP5 is to estimate and compare effect sizes of two high potential neuroprotective agents (Ghrelin and 2-IB) to improve early recovery and long-term functional outcome in patients with acute ischemic stroke treated with EVT. The results will be used as input for the design of a subsequent (future) phase 3 trial to provide conclusive evidence of (in)efficacy.

Specific objectives:

  1. Develop protocols for two phase 2b randomized clinical trials (RCTs) in patients with acute ischemic stroke caused by large vessel occlusion of the anterior circulation and treated with EVT.
  2. Execute two phase 2b randomized clinical trials in those patients, running in parallel, each in different stroke centers belonging to the consortium.
  3. Assess the effects of (1) Ghrelin and (2) 2-IB on the severity of the neurological deficit at seven days after symptom onset.
  4. Assess the effects of (1) Ghrelin and (2) 2-IB on functional outcome at 90 days, infarct size at 3 days, cognitive outcome at 90 days, and safety.
  5. Infer the basis and validity of a subsequent phase 3 neuroprotection trial and propose the tentative trial design.