Abstracts

Rationale: A novel nasal spray (NS) formulation of controlled drug midazolam (MDZ) has been approved by the Food and Drug Administration for the treatment of seizure clusters. This trial aimed to evaluate the abuse liability of MDZ-NS versus oral MDZ syrup and placebo (PBO) in healthy, adult, recreational benzodiazepine users. Methods: This was a phase 1, randomized, double-blind, double-dummy, active- and PBO-controlled, crossover trial (P261-101). Participants who distinguished and liked subjective effects of oral MDZ 10mg in a qualification phase (QP) entered a 7-treatment period dose-evaluation phase (DEP), receiving MDZ-NS 5/10/15mg; oral MDZ 5/10/15mg; or matching PBO in a random order. In each period, participants underwent evaluations up to 24h post-dose. The final safety evaluation was 2–7d following last treatment. The primary pharmacodynamic endpoint was Drug Liking Visual Analog Scale (VAS) Emax in the DEP. Key secondary endpoints were Overall Drug Liking VAS Emax and High VAS Emax. Pharmacokinetic endpoints were Cmax, Tmax. Treatment-emergent adverse events (TEAEs) were assessed in the QP and DEP. Results: The safety population (randomized participants who received any trial treatment in DEP) comprised 47 volunteers; demographic and baseline characteristics are shown in Table 1. The pharmacodynamic population (randomized participants who received all trial treatments and had sufficient data for primary endpoint) comprised 38 volunteers. Median Drug Liking VAS Emax was significantly different for each oral MDZ dose (5mg 74.0, 10mg 77.5, 15mg 82.0) versus PBO (51.0; all p<0.001), confirming trial validity. No differences were observed between equivalent-dose MDZ-NS and oral MDZ (all p>0.05) in median Drug Liking VAS Emax (5mg 74.0 vs 74.0, 10mg 88.5 vs 77.5, 15mg 83.5 vs 82.0), Overall Drug Liking VAS Emax (5mg 71.5 vs 73.0, 10mg 76.0 vs 74.0, 15mg 81.5 vs 79.5), or High VAS Emax (5mg 76.0 vs 71.0, 10mg 94.5 vs 80.5, 15mg 86.0 vs 84.0). At equivalent doses, geometric mean Cmax were 38–61% higher and median Tmax earlier (0.21–0.22h vs 0.45–0.47h) for MDZ-NS versus oral MDZ. No serious or severe TEAEs or discontinuations due to AEs occurred. The most commonly reported TEAE was somnolence, which increased in a dose dependent manner for both MDZ-NS and oral MDZ. The incidence of abuse-related TEAEs, CNS depressant effects, and euphoria-related TEAEs of special interest were similar between the active formulations of MDZ when considered at the same dose level. Conclusions: MDZ-NS has similar abuse potential to oral MDZ in recreational benzodiazepine users. Funding: Study sponsored by Proximagen LLC and abstract sponsored by UCB Pharma