Effects of the Combination of Pimavanserin and Atomoxetine on OSA Severity: A Randomized Crossover Trial.

BACKGROUND

OSA pharmacologic interventions like the noradrenergic muscle stimulant atomoxetine have wake-promoting properties. Pimavanserin, a promising serotonin 2A receptor antagonist, may help to counteract atomoxetine's noradrenergic effects by increasing arousal threshold and possibly reducing OSA severity.

RESEARCH QUESTION: What is the effect of the combination of pimavanserin and atomoxetine on apnea-hypopnea index (AHI; primary outcome), arousal index, and nadir oxygen saturation (Spo2; secondary outcomes)?

STUDY DESIGN AND

METHODS

After baseline polysomnography, 18 participants with OSA (AHI > 15 events/h) took pimavanserin plus atomoxetine (34/80 mg; 34/40 mg for the first 3 days) or placebo for 1 week according to a randomized, crossover, 2-period, double-masked clinical trial. Follow-up polysomnography was performed to provide study outcomes. Safety outcomes, subjective sleep quality, and flow-estimated endotypes (using oronasal pneumotachograph flow) also were explored.

RESULTS

Eleven and 7 participants were randomized to atomoxetine plus pimavanserin and placebo first, respectively. The combination reduced AHI by 42% (95% CI, 18%-60%) vs placebo, meeting the primary outcome (P < .001). Absolute AHI reduction was 16.9 events/h (95% CI, 8.1-23.6 events/h) more than placebo. Nadir Spo2 and arousal index also were improved, by 5.0% (95% CI, 1%-8%) and 10.9 events/h (95% CI, 2.4-18.1 events/h) vs placebo. Overnight heart rate was increased (+4.8 beats/min; 95% CI, 1.5-8.1 beats/min), but no other change in subjective sleep quality or next-morning vital signs was evident. No increased risk for side effects was observed for the combination vs placebo. Treatment vs placebo improved pharyngeal collapsibility (+7.9% of stable breathing during sleep; 95% CI, 1.6%-14.1% of stable breathing during sleep), reduced loop gain by 20% (0.15; 95% CI, -0.23 to -0.07), and did not reduce the arousal threshold.

INTERPRETATION: Our results indicate that pimavanserin with atomoxetine is a strong pharmacologic therapy candidate for OSA.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT05350215; URL: www.

CLINICALTRIALS: gov.