Abstract Rationale 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. Objectives To evaluate the efficacy/safety of AD109 over 6 months in a diverse OSA population unable to use PAP. Methods 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. Measurements and Main Results 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. Conclusions 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. Clinical trial registration www.clinicaltrials.gov (NCT05813275 SynAIRgy).
Strollo et al. (Fri,) studied this question.