Patrick J Strollo, Ron Farkas, Luigi Taranto-Montemurro, John Cronin, Sanjay R Patel, SynAIRgy Investigators, Akinyemi Ajayi, Bernadette Alejandrino, Jerome Alonso, Najib Ayas, Francisco Badar, Jacob Coleman, William Cooper, Bruce Corser, Ronald Cridland, Dominick D'Aunno, Matthew Davis, Bertrand De Silva, Michael Downing, Alaa El-Gendy, Tomas Fiel, Steven Geller, James Geyer, Andrew Gould, Nella Green, Mario Guillen, Hermandeep Singh, John Hemmersmeier, John Hudson, Monica Jaffe, Thomas Jarrett, John Khoury, John Kimoff, Oleg Kouskov, Michael Lacey, Judith Leech, David Lesch, Michael Lillestol, Reinero Linares - Mera, Alan Lowe, Kinjal Madhav, David Marks, Ronald Mayfield, James Maynard, Jessica McCoun, Tatyana Miroshnikova, Rizwana Mohseni, Andrew Pastewski, Sanjay Patel*, Susheel Patil, Nirupa Paulraj, Enrique Pelayo, Dena Petersen, Alec Platt, Lew Pliamm, Bruce Rankin, Syed Raza, Anne Romaker, Mark Rosenthal, Eugene Ryan, Hector Sanchez, Andrew Schreiber, Sonja Schuetz, Sudhir Sehgal, Colin Shapiro, Craig Shapiro, Gerald Shockey, Sushil Singhi, Steve Sitar, Eileen Sloan, Damien Stevens, Kenneth Stiel, Masayoshi Takashima, Stephen Thein, Patrick Whitten, Paul Wylie, Dragos Zanchi, Brian Mangal, Brendan Lujan, Elaine Liu, Hoyee Leong, John Yee, Laura Gell, Huy Pho, Ana Sanchez-Azofra, Lori Eakes, Andrea Werner
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]).