Targeted Treatment of Obstructive Sleep Apnea with Dronabinol: Proof of Concept and Phase II Clinical Trial

Obstructive sleep apnea (OSA) is highly prevalent in Veterans, a population at high risk for neuropsychiatric and cardiovascular sequelae of OSA. Continuous positive airway pressure and other device-based or surgical treatments are limited by low adherence or are invasive. There is an urgent unmet clinical need for effective medications to treat OSA. We have previously shown that six weeks of Dronabinol, an FDA approved non-selective cannabimimetic medication, improves OSA compared to placebo. While the overall effect was modest, some participants had a significant reduction in OSA severity indicated by the apnea hypopnea index (AHI). This proposal aims to develop a prediction model for AHI reduction after Dronabinol treatment, based on the participant’s polysomnographic and clinical characteristics, in a proof-of-concept study (POC). In a subsequent phase II randomized controlled trial (RCT), we will use the POC prediction model to randomize participants likely to respond to Dronabinol. Alternatively, suppose the POC does not provide a robust prediction model. In that case, we will randomize Veterans with moderate to severe OSA to determine the efficacy of twelve weeks of Dronabinol treatment. We will also use the RCT data to develop a prediction model for a future phase III RCT. Veterans will be enrolled at Jesse Brown VA Medical Center for the POC and RCT. We propose the following specific aims: Aim 1. To develop a prediction model for a reduction in AHI after 2-week Dronabinol treatment vs. pretreatment AHI. The POC study will enroll Veterans with OSA (N=45, AHI 15-50/hour). Participant clinical and polysomnographic characteristics from the POC data, or POC plus our preliminary study, will be used to develop the prediction model. A predictive score threshold satisfied by ≥30% of participants and with ≥80% positive predictive value to reduce AHI ≥10/hour will be determined. Aim 2. To determine the efficacy of 12-week Dronabinol treatment in reducing AHI compared to placebo (N=72). The enrollment criteria for the RCT will be like the POC study. If a robust prediction model is achieved in Aim 1, participants achieving the predictive score threshold will be randomized. Alternatively, participants with moderate to severe OSA will be randomized to determine efficacy, and the data will be used to generate a predictive model for a future phase III RCT. Aim 3. To explore changes in sleep symptoms, sleep architecture by electroencephalography, daytime alertness, and 24-hour blood pressure after twelve-week Dronabinol treatment in Veterans with moderate to severe OSA. The clinical characteristics included in the prediction model will be demographics, symptoms, comorbidity, pretreatment AHI, and Dronabinol blood levels. The polysomnographic characteristics considered in the model will include quantitative pathophysiologic traits (endotypes: upper airway collapsibility and compensation, loop-gain, and arousal threshold), respiratory, oximetry, and sleep architecture metrics. The proposal includes a multidisciplinary team of collaborators with expertise in OSA neuroscience (Carley, DW), computational measurement of OSA endotypes via polysomnography (Mateika, JH), and advanced statistical modeling (Basu, S). The proposal leverages the research and clinical resources at the University of Illinois at Chicago and Jesse Brown VAMC, which serves a large pool of Veterans with OSA. The strengths of this study are: 1. Innovation: the potential to develop a novel targeted pharmacologic management strategy for OSA, 2. Clinical applicability: using patient characterization tools that are employable in clinical practice, and 3. Scientific rigor: a 12-week placebo controlled RCT to test the effectiveness of Dronabinol treatment of OSA. Project Number: 1I01CX002632-01A2 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Bharati Prasad | Institution: JESSE BROWN VA MEDICAL CENTER, CHICAGO, IL | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 PULM-T (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/10923565