Pitolisant for Daytime Sleepiness in Patients with Obstructive Sleep Apnea Who Refuse Continuous Positive Airway Pressure Treatment. A Randomized Trial.

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome.Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment.Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire.Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns.Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

Effect of increasing doses of colchicine on the treatment of 333 COVID-19 inpatients.

BACKGROUND: Previous research done in Bulgaria demonstrated a fivefold reduction in mortality from COVID-19 with increased doses of colchicine from two hospitals in the country. We report here a further 333 cases of COVID-19 inpatients, treated with different doses of colchicine and its effect on mortality. MATERIALS AND METHODS: A case-control comparison from two additional hospitals was conducted between increased doses of colchicine and added bromhexine to standard of care (SOC) versus current SOC. Risk and odds ratio, as well as subgroup analysis, was conducted with newly reported data, alongside aggregate data from all hospital centers to determine the extent of mortality reduction in COVID-19 inpatients. RESULTS: There was a clear reduction in the mortality of inpatients with increasing doses of colchicine-between twofold and sevenfold. Colchicine loading doses of 4 mg are more effective than those with 2 mg. Despite these doses being higher than the so-called "standard doses," colchicine inpatients experienced lower mortality than SOC patients (5.7% vs. 19.53%). This mortality benefit was evident in different age subgroups, with a 4-mg loading dose of colchicine proving slightly superior to a 2-mg loading dose. Colchicine led to an overall relative risk reduction of 70.7%, with SOC patients having 3.91 higher odds of death. The safety of the doses was not different than the reported in the summary of product characteristics. CONCLUSION: Inpatients in Bulgaria with added colchicine and bromhexine to SOC achieved better clinical and mortality outcomes than those on SOC alone. These results question the World Health Organization-recommended strategy to inhibit viral replication. We posit that our treatment strategy to inhibit the Severe acute respiratory syndrome coronavirus 2 entry into the cell with inhaled bromhexine and the hyperactivated NLRP3 inflammasome with higher doses of colchicine, prevents the development of cytokine storm. The timing of the initiation of treatment seems critical.

Pitolisant for Residual Excessive Daytime Sleepiness in OSA Patients Adhering to CPAP: A Randomized Trial.

BACKGROUND: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects. RESEARCH QUESTION: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS? STUDY DESIGN AND METHODS: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to-treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety. RESULTS: Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS ≤ 10 or change in ESS ≥ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported. INTERPRETATION: Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu.