The Combination of Aroxybutynin and Atomoxetine in the Treatment of Obstructive Sleep Apnea (MARIPOSA): A Randomized Controlled Trial

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American journal of respiratory and critical care medicine


RATIONALE: Obstructive sleep apnea (OSA) is a common sleep disorder for which the principal treatment option, continuous positive airway pressure, is often poorly tolerated. There is currently no approved pharmacotherapy for OSA. However, recent studies have demonstrated improvement in OSA with combined antimuscarinic and noradrenergic drugs.

OBJECTIVES: The aim of this study was to evaluate the efficacy and safety of AD109, a combination of the novel antimuscarinic aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine in the treatment of OSA.

METHODS: Phase 2, randomized, double-blind, placebo-controlled, parallel-group, 4-week trial comparing AD109 2.5/75 mg, AD109 5/75 mg, atomoxetine 75 mg alone, and placebo (NCT05071612).

MEASUREMENTS AND MAIN RESULTS: Of 211 randomized patients, 181 were included in the pre-specified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index (AHI(4), 4% desaturation criterion, primary outcome) was reduced from median (IQR) of 20.5 (12.3-27.2) to 10.8 (5.6-18.5) in the AD109 2.5/75 mg arm (-47.1%), from 19.4 (13.7-26.4) to 9.5 (6.1-19.3) in the 5/75 mg arm (-42.9%, both p<0.0001 vs placebo), and from 19.0 (11.8-28.8) to 11.8 (5.5-21.5) with atomoxetine alone (-38.8%, p<0.01 vs placebo). Placebo AHI(4) went from 20.1 (11.9 - 25.9) to 16.3 (11.1 - 28.9). Subjectively, there was improvement in fatigue with AD109 2.5/75 (p<0.05 vs placebo and atomoxetine). Atomoxetine taken alone decreased total sleep time (p<0.05 vs AD109 and placebo). The most common adverse events were dry mouth, insomnia, and urinary hesitancy.

CONCLUSIONS: AD109 showed clinically meaningful improvement in OSA, suggesting further development of the compound is warranted. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT05071612. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (

Medical Subject Headings

Humans; Atomoxetine Hydrochloride; Sleep Apnea, Obstructive; Sleep; Polysomnography; Fatigue; Continuous Positive Airway Pressure; Muscarinic Antagonists

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ePub ahead of print





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