In patients with obstructive sleep apnea (OSA) with residual sleepiness, use of the selective histamine H3-receptor antagonist pitolisant as an adjunct to continuous positive airway pressure (CPAP), despite their adherence to CPAP therapy, significantly decreases subjective and objective sleepiness, according to the results of the. 12-week, phase 3, multicenter, double-blind, randomized placebo-controlled, parallel-design HAROSA study (HAROSA I; ClinicalTrials.gov Identifier: NCT01071876 and HAROSA II; ClinicalTrials.gov Identifier: NCT01072968). The study was conducted in 35 sleep centers throughout 9 European countries between August 12, 2011, and June 21, 2013, and the results were published CHEST.
Researchers sought to evaluate the efficacy and safety of pitolisant during a 12-week period in reducing daytime sleepiness in patients with moderate to severe OSA who continued to experience excessive daytime sleepiness (EDS) even though they adhered to CPAP therapy. Participants had been treated with CPAP for at least3 months, with at least 4 hours of CPAP usage each night. Further, per the investigator, patients had residual Epworth Sleepiness Scale (ESS) scores of 12 or higher without any unstable cardiovascular disease.
A total of 244 participants with OSA were randomly assigned in a 3:1 ratio to treatment with pitolisant (n=183) or placebo (n=61). The mean patient age was 53.1±10.6 years; 82.8% of the participants were men. The mean apnea hypopnea index with the use of CPAP was 4.2±3.5 per hour. The baseline ESS score was 14.7. Pitolisant was administered at doses of 5 mg, 10 mg, or 20 mg once daily. The primary efficacy end point was change in ESS score from baseline to the end of the 12-week treatment period. The key secondary end point was change from baseline to week 12 in the Oxford Sleep Resistance Test (OSleR).
Results showed that ESS decreased significantly with pitolisant compared with placebo (-2.6 reduction in ESS score; 95% CI, -3.9 to -1.4; P <.001). Pitolisant was associated with normalization of the ESS score (ie, ESS ≤10) in 56.3% of participants compared with 42.6% treated with placebo (P =.028). Further, the rate of responders to treatment (ESS ≤10 or improvement in ESS of ≥3 points) was significantly greater with pitolisant than with placebo (71.0% vs 54.1%, respectively; P =.013). Baseline OSleR mean sleep latencies were 15.5 minutes in the placebo group and 19.0 minutes in the placebo group.
Treatment-emergent adverse events (primarily headache and insomnia) were reported significantly more often in the pitolisant group compared with the placebo group (47.0% vs 32.8%, respectively; P =.03). No cardiovascular or other significant safety concerns were reported.
The investigators concluded that pitolisant can be safely used as an adjunctive treatment strategy in patients with OSA who have good CPAP adherence as a way to reduce daytime sleepiness. Given the limited 12-week treatment period in the current trial, longer-term studies are warranted to evaluate the long-term efficacy and safety of pitolisant in this patient population.
Disclosure: This clinical trial was supported by Biprojet. Please see the original reference for a full list of authors’ disclosures.
Pépin J-L, Georgiev O, Tiholov R, et al; on behalf of the HAROSA I study group. Obstructive sleep apnea patients adhering to continuous positive airway pressure: a randomized trial. CHEST. Published online October 26, 2020. doi:10.1016/j.chest.2020.09.281