Aroxybutynin and atomoxetine (AD109) for obstructive sleep apnea: a randomized phase 3 trial (SynAIRgy).

Abstract

Many patients with obstructive sleep apnea (OSA) are unable to tolerate long-term positive airway pressure (PAP) therapy, highlighting the need for alternative treatments. AD109 (investigational fixed-dose oral combination of aroxybutynin 2.5 mg/atomoxetine 75 mg) is designed to target neuromuscular dysfunction in OSA. To evaluate the efficacy/safety of AD109 over 6 months in a diverse OSA population unable to use PAP. SynAIRgy enrolled adults with mild-to-severe OSA who were intolerant to or refused PAP therapy into a randomized, double-blind, placebo-controlled, 26-week parallel-arm trial of AD109 vs placebo across 69 centers. The primary efficacy endpoint was change from baseline to week 26 in apnea-hypopnea index (AHI). Key secondary endpoints were oxygen desaturation index (ODI), Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue T-score, hypoxic burden (HB), PROMIS-Sleep Impairment T-score, and proportion of participants with  ≥50% AHI reduction. A total of 646 eligible participants (median age 58 years, 49.3% female, median body mass index 32.4 kg/m2) were randomized. Median baseline AHI was 19.6 events/hour with 35% mild, 42% moderate, and 23% severe OSA. At week 26, mean AHI treatment difference was -4.0 events/hour (95% CI, -6.4 to -1.6; P = .001), representing a model-estimated 44.1% vs 17.6% decrease from baseline (P <.0001). AD109 demonstrated improvements in ODI and HB at week 26 vs placebo; however, no statistically significant difference was observed for PROMIS-Fatigue. Overall, 21.2% of participants on AD109 and 3.1% on placebo discontinued therapy due to adverse events. The most common adverse events with AD109 were dry mouth, nausea, insomnia, and urinary hesitation, with no serious treatment-related adverse events. AD109 significantly improved airway obstruction and oxygenation at 26 weeks across a broad range of patients unable to use PAP, suggesting that AD109 could become a potential treatment option for patients with OSA. www.clinicaltrials.gov (NCT05813275 [SynAIRgy]).