Combination pharmacological therapy targeting multiple mechanisms of sleep apnoea: a randomised controlled cross-over trial.

Rationale: Acetazolamide and atomoxetine-plus-oxybutynin ('AtoOxy') can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone.
Methods: In a multicentre randomised crossover trial, 19 patients with moderate-to-severe OSA received AtoOxy (80/5 mg), acetazolamide (500 mg), combined AtoOxy-plus-acetazolamide or placebo at bedtime for three nights (half doses on first night) with a 4-day washout between conditions. Outcomes were assessed at baseline and night 3 of each treatment period. Mixed model analysis compared the reduction in Apnoea-Hypopnoea Index (AHI) from baseline between AtoOxy-plus-acetazolamide and AtoOxy (primary outcome). Secondary outcomes included hypoxic burden and arousal index.
Results: Although AtoOxy lowered AHI by 49 (33, 62)% _baseline (estimate (95% CI)) vs placebo, and acetazolamide lowered AHI by+34 (14, 50)% _baseline vs placebo, AtoOxy-plus-acetazolamide was not superior to AtoOxy alone (difference: -2 (-18, 11)% _baseline , primary outcome p=0.8). Likewise, the hypoxic burden was lowered with AtoOxy (+58 (37, 71)% _baseline ) and acetazolamide (+37 (5, 58)% _baseline ), but no added benefit versus AtoOxy occurred when combined (difference: -13 (-5, 39)% _baseline ). Arousal index was also modestly reduced with each intervention (11% _baseline -16% _baseline ). Mechanistic analyses revealed that similar traits (ie, higher baseline compensation, lower loop gain) were associated with both AtoOxy and acetazolamide efficacy.
Conclusions: While AtoOxy halved AHI, and acetazolamide lowered AHI by a third, the combination of these leading experimental interventions provided no greater efficacy than AtoOxy alone. Failure of acetazolamide to further increase efficacy suggests overlapping physiological mechanisms.
Trial Registration Number: NCT03892772.
Competing Interests: Competing interests: The combination intervention under investigation in the current study was protected by a patent ('Combination pharmacological interventions for multiple mechanisms of obstructive sleep apnoea', WO-2021091902-A1, Sands co-inventor) licensed to Apnimed from the Brigham and Women’s Hospital. SS has received grant funding from Apnimed, Prosomnus and Dynaflex, and has served as a consultant for Apnimed, Nox Medical, Inspire, Eli Lilly, Merck, Forepont, LinguaFlex, Achaemenid. He is also co-inventor on a patent related to wearable oximetry technology. He has received royalties from licensed intellectual property. AA served as a consultant for Somnifix, Respicardia and Apnimed; SS and AA’s industry interactions are managed by the Brigham and Women’s Hospital. SJ and GH has received equipment to support research projects from Resmed, Philips Respironics and Air Liquide Healthcare. BE has received grant funding from Apnimed and Incannex, and received personal fees from Signifier Medical outside the current work.
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