Abstract
Oral nimodipine is the only drug approved in North America for patients with aneurysmal subarachnoid hemorrhage (aSAH). However, bioavailability is variable and frequently poor, leading to fluctuations in peak plasma concentrations that cause dose-limiting hypotension. Furthermore, administration is problematic in patients who cannot swallow. An oral liquid formulation exists but causes diarrhea. An intravenous nimodipine formulation (GTX-104) has been developed that has bioavailability approaching 100% and is not affected by feeding or gastrointestinal absorption. GTX-104 causes less hypotension and has more consistent peak plasma concentrations than oral nimodipine in human volunteers. Herein, we describe the protocol of a prospective, randomized, open-label safety, and tolerability study of GTX-104 compared with oral nimodipine in patients with aSAH (Safety and Tolerability of GTX-104 [Nimodipine Injection for Intravenous Infusion] Compared with Oral Nimodipine; ClinicalTrials.gov identifier: NCT05995405). The study is designed to seek approval of GTX-104 by the Food and Drug Administration 505(b)(2) pathway. Inclusion and exclusion criteria match the prescribing information for oral nimodipine and include adult patients with aSAH of all Hunt and Hess grades who can receive investigational product within 96 h of aSAH. Study participants at imminent risk of death will be excluded. Study participants will be randomly assigned 1:1 to receive GTX-104 or oral nimodipine for up to 21 days. The primary end point is the proportion of study participants with clinically significant hypotension, defined as hypotension requiring treatment that has a reasonable likelihood of being due to investigational product as determined by an independent, blinded end point adjudication committee. No statistical analysis of the end point is planned. Secondary end points include all episodes of hypotension, all adverse events, delayed cerebral ischemia, rescue therapy, and suicidal ideation. Clinical and health economic outcomes include quality of life using the EuroQol 5-dimension/3-level, modified Rankin Scale score at 30 and 90 days after aSAH and hospital resource use. The planned sample size is 100 study participants across 25 sites in the United States and Canada.