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

Abstract

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 agent aroxybutynin and the norepinephrine reuptake inhibitor atomoxetine, in the treatment of OSA. Methods: Phase II 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 (www.clinicaltrials.gov identifier NCT05071612). Measurements and Main Results: Of 211 randomized patients, 181 were included in the prespecified efficacy analyses. Sleep was assessed by two baseline and two treatment polysomnograms. Apnea-hypopnea index with a 4% desaturation criterion (primary outcome) was reduced from a 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 AD109 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). Apnea-hypopnea index with a 4% desaturation criterion decreased from 20.1 (11.9-25.9) to 16.3 (11.1-28.9) in the placebo arm. Subjectively, there was improvement in fatigue with AD109 2.5/75 mg (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 that further development of the compound is warranted. Clinical trial registered with www.clinicaltrials.gov (NCT05071612).

Keywords: drug therapy; obstructive sleep apnea; pharmacology.

Figure 1.

Consolidated Standards of Reporting Trials diagram. Ato75 = atomoxetine 75 mg; ITT = intention-to-treat (all participants who were randomized); mITT = modified intention-to-treat (all participants who were randomized, took at least one dose of any of the study drugs, and had at least one measurement on the primary endpoint).

Figure 2.

Individual data of AHI₄. Lines on the sides indicate medians (IQR). Note that the scale for the placebo arm is larger (to 70 events per hour) than for the other arms. AHI₄ = apnea–hypopnea index (⩾4% desaturation criterion for hypopneas); Ato75 = atomoxetine 75 mg.

Figure 3.

Proportion of patients with a ⩾20% reduction in AHI₄ from baseline (A) and with apnea–hypopnea index (⩾4% desaturation criterion for hypopneas) of fewer than 10 events per hour during treatment (B) in the different treatment arms. Error bars in B indicate 95% confidence intervals. AHI₄ = apnea–hypopnea index (⩾4% desaturation criterion for hypopneas); Ato75 = atomoxetine 75 mg.

Figure 4.

LSmean (standard error of the mean) reduction from baseline in Patient-Reported Outcome Measurement Information System scales (t-score). Higher bars represent greater improvement. Ato75 = atomoxetine 75 mg; PROMIS = Patient-Reported Outcome Measurement Information System. *P < 0.05 versus placebo, ^†P < 0.05 versus Ato75.