Abstract Introduction Current treatments for obstructive sleep apnoea (OSA) typically target the anatomical pathophysiological endotype and are either not tolerated or effective in a significant proportion of patients. Pharmaceuticals may provide an alternative therapeutic option and may address some or all of the remaining endotypes (loop gain, muscle compensation and arousal threshold). This randomised, double-blind, placebo-controlled, cross-over study examined the effect of combination acetazolamide and dronabinol (IHL-42X) at low, medium and high doses on OSA severity and the OSA endotypes. Methods Participants with OSA (apnoea-hypopnoea index; AHI≥15events/hr) received 1-week of IHL-42X at each of the 3 doses and 1-week of placebo, each separated by 1-week washout. The change from baseline in AHI, oxygen desaturation index (ODI), Epworth sleepiness score (ESS), and mood (profile of mood states) on the final night of each treatment arm relative to placebo were the major endpoints. Adverse events (AEs) were monitored throughout. Exploratory analyses examined the change in OSA endotypes determined from polysomnography from baseline values. Results Ten of 11 participants (mean baseline AHI 40.7events/hr) completed the final night of at least one treatment arm. All doses of IHL-42X demonstrated a significant reduction in AHI from baseline when compared with placebo (low, -19.7±27.1; medium, -17.5±23.3; high, -16.4±23.8 versus placebo, -2.8±21.0events/hr; all p< 0.05). The change from baseline in ODI3% at the low, medium and high doses of IHL-42X (-15.2±24.8; -15.4±19.0 and -8.3±13.2events/hr, respectively) were not significantly different from placebo (-2.8±21.0events/hr). IHL-42X did not significantly alter ESS or mood. No serious AEs occurred. However, 31 mild-moderate possibly, probably or treatment related AEs occurred during IHL-42X dosing (4 at the low dose) and 4 occurred during placebo. Relative to baseline, loop gain decreased by 15, 21 and 20% (Cohen’s d all ≥0.59) at the low, medium and high doses, respectively, and collapsibility improved by 12.5% (d=1.06) at the low dose only. Conclusion One week of nightly IHL-42X at all doses was well tolerated, safe and associated with significant reductions in OSA severity. IHL-42X may act to reduce OSA severity by decreasing loop gain and upper airway collapsibility, particularly at the low dose. Support (if any) Incannex Healthcare Ltd supported this study.
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