Kimberly, W.

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. An enteral liquid formulation exists but causes severe diarrhea. GTX‐104 is an intravenous (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. To conduct a randomized, open label, blinded endpoint study to determine the safety and tolerability of GTX‐104 compared with oral nimodipine in patients with aSAH We conducted a 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 subjects 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. 102 subjects 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 more common in the GTX‐104 group compared with oral nimodipine (62% versus 48%). Fewer patients on GTX‐104 (36% versus 48% oral nimodipine) had serious adverse events. There were no safety issues with GTX‐104. 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.