Abstract WMP2: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial in Acute Non-Cardioembolic Ischemic Stroke With Adrenomedullin

Abstract

Background: Adrenomedullin (AM), a vasoactive peptide, has strong anti-inflammatory and angiogenic properties, which have been reported to ameliorate the consequences of ischemic stroke (IS) in several animal models. This phase II clinical trial aimed to test the safety and tolerability of intravenous (IV) AM administration in acute IS (AIS) patients within 24 hours of onset. Methods: The AdrenoMedullin For Ischemic Stroke study is an investigator-initiated, randomized, double-blind, phase II trial. Patients with non-cardioembolic IS within 24 hours after stroke onset and baseline NIH Stroke Scale (NIHSS) score ≥1 were randomly allocated to the intermittent IV AM (I-AM group) (30 μg/kg in total for 7 days, n=20) or placebo group (n=10) in the first cohort and a combination of continuous (the first 3 days) and intermittent (the following 4 days) IV AM (C/I-AM group) (56 μg/kg in total for 7 days, n=20) or placebo group (n=10) in the second cohort. The primary endpoint was serious adverse events related to the protocol treatment and secondary efficacy endpoints were favorable outcomes (mRS 0-2 at 90 days) and good outcomes (mRS 0-3 at 90 days). Results: The population of 60 patients had a median age of 75 years, 21 patients (35%) were female, and the median NIHSS score was 3. The primary endpoint did not occur in all groups. In the secondary efficacy endpoints, the rates of favorable outcome (75.0% vs. 68.9%, adjusted odds ratio [aOR], 1.45; 95% confidential interval [CI], 0.32-6.53) and good outcome (90.0% vs. 73.7%, aOR 3.86; 95% CI, 0.67-22.11) in the I-AM group were not statistically different from those in the placebo group. The rates of good outcomes in the C/I-AM group were comparable with those in the placebo group (85.0% vs. 73.7%, aOR 1.56; 95% CI, 0.72-3.39). Conclusions: Treatment with IV AM within 24 hours of AIS onset is safe. Intermittent IV AM may contribute to improved AIS prognosis. The efficacy and safety of AM will need confirmation in the next phase of clinical trials.