Safety and Tolerability of GTX-104 (Nimodipine Injection for IV Infusion) Compared With Oral Nimodipine in Patients With Aneurysmal Subarachnoid Hemorrhage: A Prospective, Randomized Trial
Loch Macdonald1, Huimahn Choi2, Sherry Chou3, Andrew Ducruet4, W. Kimberly5, Alejandro Rabinstein6
1Grace Therapeutics, 2The University of Texas Health Science Center At Houston, 3Northwestern Memorial Hospital, 4Barrow Neurological Institute, 5Massachusetts General Hospital, 6Mayo Clinic
Objective:
To conduct a randomized, open label, blinded endpoint study of GTX-104 (intravenous [IV] nimodipine) compared with oral nimodipine in patients with aSAH.
Background:
Oral nimodipine is the only drug approved for aneurysmal subarachnoid hemorrhage (aSAH). However, bioavailability is poor and peak plasma concentrations fluctuate widely, leading to dose-limiting hypotension. Administration is problematic in patients who cannot swallow. GTX-104 is an IV nimodipine formulation that has 100% bioavailability and is not affected by swallowing, gastrointestinal absorption and first pass effects. When administered in pharmacokinetically-equivalent doses to oral nimodipine in healthy humans, GTX-104 has more consistent plasma concentrations and causes less hypotension than oral nimodipine.
Design/Methods:
Multicenter, prospective, randomized, open-label safety and tolerability study of GTX-104 compared to oral nimodipine in aSAH. Inclusion/exclusion criteria matched prescribing information for oral nimodipine and included adults with aSAH of all Hunt/Hess grades. Subjects were randomized 1:1 to GTX-104 or oral nimodipine. The primary endpoint was the proportion of participants with clinically significant hypotension (hypotension requiring treatment, with a reasonable likelihood of being due to study drug, as determined by an independent, blinded committee). Secondary endpoints included all episodes of hypotension, adverse events, EQ-5D-3L and modified Rankin scale within 90 days of aSAH.
Results:
102 participants were randomized at 24 sites in the USA. Demographics reflected those of aSAH. There was a 20% relative reduction in clinically significant hypotension with GTX-104 compared to oral nimodipine (28% versus 35%). 54% of GTX-104 subjects got >95% of the prescribed dose compared to 8% on oral nimodipine. Favorable outcome (90-day mRS 0-2) was 62% in the GTX-104 and 48% in the oral nimodipine group. Fewer patients on GTX-104 (36% versus 48% oral nimodipine) had serious adverse events.
Conclusions:
GTX-104, an IV formulation of nimodipine that can be administered through central or peripheral veins, is safer and potentially more efficacious than oral nimodipine.
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