Obstructive Sleep Apnea patients adhering to Continuous positive Airway Pressure: A randomized trial.

BACKGROUND: Excessive daytime sleepiness (EDS) in individuals with obstructive sleep apnea syndrome persisting despite good adherence to continuous positive airway pressure (CPAP) is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects. RESEARCH QUESTION: Is pitolisant efficacious and safe in reducing daytime sleepiness in individuals presenting moderate to severe OSA adhering to CPAP treatment but having residual EDS? STUDY DESIGN AND METHODS: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/day and taken over 12 weeks. The primary endpoint was change in the Epworth Sleepiness Scale (ESS) score in intention to treat. Key secondary endpoints were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test (OSleR), clinical global impressions of severity, the patient's global opinion, EQ-5D quality-of-life, Pichot Fatigue questionnaire scores and safety. RESULTS: 244 OSA participants (82.8% male; mean age: 53.1 years, mean apnea+hypopnea index under CPAP: 4.2/hour, baseline ESS score: 14.7, were randomized to pitolisant (n=183) or placebo (n=61). ESS significantly decreased with pitolisant compared to placebo -2.6 (95%CI: [-3.9;-1.4]) (p<0.001) and the rate of responders to therapy (ESS≤10 or ΔESS≥3) was significantly higher with pitolisant (71.0% vs 54.1%; p=0.013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared to the placebo group (47.0% and 32.8%, p=0.03). 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 reduces subjective and objective sleepiness and improves participant-reported outcomes and physician-reported disease severity.status: Published onlin

Pitolisant for Residual Excessive Daytime Sleepiness in OSA Patients Adhering to CPAP

International audienceBackground: 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

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P &lt; 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)