ABSTRACT

Background Obstructive sleep apnea (OSA) pharmacological interventions like the noradrenergic muscle stimulant atomoxetine have wake-promoting properties. Pimavanserin, a promising serotonin 2A receptor antagonist, may help counteract atomoxetine’s noradrenergic effects by increasing arousal threshold and possibly reduce OSA severity.

Research question In a randomized, crossover, two-period, double-blind clinical trial, we tested the effect of this drug combination on apnea-hypopnea index (AHI; primary outcome), arousal index and nadir oxygen saturation (SpO2; secondary outcomes).

Study design and methods Following baseline polysomnography, 18 OSA participants (AHI>15events/h) took pimavanserin-plus-atomoxetine (34/80mg; 34/40mg for the first 3 days) or placebo for one-week; follow-up polysomnography was performed to provide study outcomes. Safety outcomes, subjective sleep quality, and flow-estimated endotypes (using oronasal pneumotachograph flow) were also explored.

Results Eleven and seven 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<0.001). Absolute AHI reduction was 16.9 [8.1, 23.6] events/h greater than placebo. Nadir SpO2 and arousal index were also improved, by 5.0 [1, 8] % and 10.9 [2.4, 18.1] events/h vs. placebo. Overnight heart rate was increased (+4.8 [1.5, 8.1]), but no other change in subjective sleep quality or next-morning vital signs was evident. There was no increased risk for side effects on the combination vs. placebo. Treatment vs. placebo improved pharyngeal collapsibility (+7.9 [1.6, 14.1]%VEUPNEA), reduced loop gain by 20% (0.15 [-0.23, -0.07]), and did not reduce the arousal threshold.

Interpretation Pimavanserin with atomoxetine is a strong pharmacological therapy candidate for OSA.

Competing Interest Statement

Conflicts of interest: LM received grant support from Apnimed, Inc. and ProSomnus. AA receives grant support from Somnifix and serves as a consultant for Somnifix, Inspire, and Apnimed; SS receives personal fees as a consultant for Nox Medical, Apnimed, Merck, and Inspire outside the submitted work, and he has received grant support from Apnimed, Prosomnus, and Dynaflex; SS received grant support from Apnimed, Prosomnus, and Dynaflex, and has served as a consultant for Apnimed, Nox Medical, Inspire Medical Systems, Eli Lilly, Respicardia, LinguaFlex, and Forepont. He receives royalties for intellectual property pertaining to combination pharmacotherapy for sleep apnea via his Institution. He is also co-inventor of intellectual property pertaining to wearable sleep apnea phenotyping, also via his Institution. His industry interactions are actively managed by his Institution; AW works as a consultant for Apnimed, Nox, Inspire, Mosanna, and Takeda. He has received grants from Prosomnus. He also has a financial interest in Apnimed Corp., a company developing pharmacologic therapies and wearable oximetry devices for sleep apnea. Dr. Wellman's interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. LG contributed to the current study under her ongoing academic role at the Brigham and Women's Hospital, but her primary employment is currently as a consultant for Apnimed. DPW is a consultant for Apnimed, Philips-Respironics, Cryosa, Xtrodes, Cerebra Health, Bairitone, Mosanna, Onera, SleepRes and LinguaFlex. DV, AA, NE, MK, IB and TC have no conflicts of interest.

Clinical Trial

NCT04538755

Funding Statement

This study was funded by NHLBI P01 149630

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval was provided by the Brigham and Women's Hospital Institutional Review Board

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors

ABBREVIATION LIST5HT2A5-hydroxytryptamine receptor, type 2A.AHIapnea hypopnea indexAHI4hypopneas required oxyhemoglobin desaturation of at least 4%Ato-pimaatomoxetine and pimavanserinBMIbody mass indexCO2carbon dioxideEKGelectrocardiogramESSEpworth sleepiness scaleGABAgamma-aminobutyric acidNREMnon REMOSAobstructive sleep apneaPSGpolysomnographyQTccorrected QTREMrapid eye movementsSpO2oxyhemoglobin saturationTSTtotal sleep timeVASvisual analog scaleWASOwake after sleep onset