Stephen M. Davis

A Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Effects of a Targeted Exposure of Intravenous Repinotan in Patients With Acute Ischemic Stroke Modified Randomized Exposure Controlled Trial (mRECT)

Background and Purpose— Repinotan hydrochloride is a serotonin (5-HT)1A receptor full agonist with evidence of neuroprotection in animal models of permanent and transient focal ischemia. The purpose of this Phase IIb study was to investigate the efficacy, safety, and tolerability of a targeted exposure to repinotan in patients with acute ischemic stroke. Methods— This was a double-blind, placebo-controlled, parallel-group, multicenter study of 681 patients stratified according to whether or not tissue plasminogen activator was administered and then randomly assigned to treatment with repinotan or placebo. A continuous 72-hour intravenous infusion of repinotan or placebo was to be started within 4.5 hours from the onset of ischemic symptoms. A Point-of-Care test was used to adjust the infusion rate if appropriate. The goal of Modified Randomized Exposure Controlled Trial (mRECT) was to show whether repinotan is statistically superior to placebo (&agr;≤0.10) as measured by the response rate on the primary efficacy variable, Barthel Index (≥85) at 3 months, using a Cochran-Mantel-Haenszel test. Results— For the intention-to-treat population at 3 months, the response rate on the Barthel Index was 37.1% (127 of 342) for patients on repinotan and 42.4% (143 of 337) for patients taking the placebo (Cochran-Mantel-Haenszel probability value=0.149). No apparent safety concerns were identified. Conclusions— mRECT demonstrated the feasibility of conducting a rigorous trial using a short therapeutic window demanding clinical and radiographic criteria to optimize patient selection and a Point-of-Care test to achieve a targeted exposure to repinotan. The study failed to demonstrate a clinical benefit of repinotan. The development of repinotan in acute ischemic stroke was discontinued.

Chapter 1 – Acute Ischemic Stroke

Major progress has occurred in the therapy of ischemic stroke, predominantly in the field of reperfusion with intravenous thrombolysis and endovascular thrombectomy. Challenges remain in implementation with underutilization of thrombolysis and rapidly evolving systems for delivery of endovascular thrombectomy, which brings new resource challenges. Multiple trials of putative neuroprotective compounds have been disappointing but there is new enthusiasm in the era of highly effective endovascular reperfusion and more rigorous preclinical evaluation.

Intracerebral Hemorrhage: MRI of intracerebral hemorrhage

Acute hypertensive response is the elevation of blood pressure above normal and premorbid values that initially occurs within the first 24 hours of symptom onset in patients with intracerebral hemorrhage (ICH). Hypertension is the most frequent and most important risk factor for ICH. Hypertensive patients suspected of primary intraparenchymal hematoma died and were subsequently autopsied in order to assess the alterations of extraparenchymal and intraparenchymal vascular structures. Stroke patients with a history of hypertension are at risk of critical hypoperfusion for mean arterial pressure levels usually well tolerated by normotensive individuals. Drugs recommended for use in lowering blood pressure in acute stroke include labetalol, hydralazine, nicardipine, and nitroprusside. The Antihypertensive Treatment in Acute Cerebral Hemorrhage (ATACH) trial is a prospective, open label phase I safety and tolerability study started in 2005 that plans to study 60 patients.