Multidimensional phenotyping to distinguish among distinct obstructive sleep apnea, chronic obstructive pulmonary disease, and overlap syndrome phenotypes.

OBJECTIVE/BACKGROUND: Chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA) and their comorbid association called Overlap Syndrome (OS) are frequent chronic diseases with high individual and societal burdens. Precise descriptions of the respective symptoms, comorbidities, and medications associated with these three conditions are lacking. We used a multidimensional phenotyping approach to identify relevant phenotypes characterizing these 3 disorders. PATIENTS/METHODS: 308 patients with OSA, COPD and OS were prospectively assessed using a combination of body shape measurements and multidimensional questionnaires evaluating sleep, fatigue, depression and respiratory symptoms. Comorbidities and medications were confirmed by physicians. Patients made home blood pressure self-measurements using a connected wearable device to identify undiagnosed or uncontrolled hypertension. RESULTS: Three distinct relevant phenotypes were identified. OSA patients were round in shape with a balanced waist-to-hip ratio, frequent witnessed apneas, nocturia, daytime sleepiness, depression, and high diastolic blood pressure. COPD patients had a thinner body shape with a high waist-to-hip ratio, complained mainly of fatigue, and exhibited a higher resting heart rate. OS patients were round in shape with a balanced waist-to-hip ratio, reported little sleepiness and depression, but had impaired sleep and the highest rate of cardio-metabolic comorbidities. Diminished fitness-to-drive was most apparent in patients with OSA and OS. Home blood pressure measurements identified undiagnosed hypertension in 80 % of patients and in nearly 80 % of those with hypertension it was uncontrolled by their current medications. CONCLUSIONS: Our systematic multidimensional phenotyping approach identified distinct body shapes, symptoms, and comorbidity profiles among patients with OSA, COPD, and OS.

Long-Term Efficacy and Safety of Pitolisant for Residual Sleepiness Due to OSA.

BACKGROUND: In people with OSA, excessive daytime sleepiness is a prominent symptom and can persist despite adherence to CPAP, the first-line therapy for OSA. Pitolisant was effective in reducing daytime sleepiness in two 12-week randomized controlled trials (RCTs), one in patients adherent to CPAP (BF2.649 in Patients With OSA and Treated by CPAP But Still Complaining of EDS [HAROSA 1]) and the other in patients refusing or not tolerating CPAP (BF2.649 in Patients With OSA, Still Complaining of EDS and Refusing to be Treated by CPAP [HAROSA 2]). RESEARCH QUESTION: Does the efficacy and safety of pitolisant persist when these patients take it long-term? STUDY DESIGN AND METHODS: All adults included in the HAROSA 1 and HAROSA 2 RCTs (both pitolisant and placebo arms) were offered pitolisant (up to 20 mg/d) after completion of the short-term double-anonymized phase (ie, from week 13) in an open-label cohort study. The primary efficacy outcome was the change in Epworth Sleepiness Scale score between baseline and week 52. Safety outcomes were treatment-emergent adverse event(s) (TEAE[s]), serious TEAEs, and special interest TEAEs. RESULTS: Out of 512 adults included in the two RCTs, 376 completed the 1-year follow-up. The pooled mean difference in Epworth Sleepiness Scale score from baseline to 1 year for the intention-to-treat sample was -8.0 (95% CI, -8.3 to -7.5). The overall proportions of TEAEs, serious TEAEs, and TEAEs of special interest were 35.1%, 2.0%, and 11.1%, respectively, without any significant difference between patients in the initial pitolisant and placebo arms. No cardiovascular safety issues were reported. INTERPRETATION: Pitolisant is effective in reducing daytime sleepiness over 1 year in adults with OSA, with or without CPAP treatment. Taken for 1 year, it has a good safety profile (including cardiovascular). TRIAL REGISTRATION: ClinicalTrials.gov; Nos.: NCT01071876 and NCT01072968; URL: www. CLINICALTRIALS: gov.

Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Narcolepsy is a life-long disorder characterised by excessive daytime sleepiness and cataplexy, often arising in childhood or adolescence. Pitolisant, a selective histamine H3 receptor inverse agonist, has been approved in Europe and USA for adults with narcolepsy with or without cataplexy, with a favourable safety profile. This phase 3 study aimed to assess the safety and efficacy of pitolisant in children with narcolepsy with or without cataplexy. METHODS: For this double-blind, randomised, placebo-controlled, multisite study, we recruited patients aged 6-17 years with narcolepsy with or without cataplexy in 11 sleep centres in five countries (Italy, France, Netherlands, Russia, and Finland). Participants were required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and to have not received psychostimulants for at least 14 days before enrolment; participants who needed anticataplectics (including sodium oxybate) were required to have been on a stable dose for at least 1 month. Participants were randomly assigned to treatment with pitolisant or placebo in a 2:1 ratio at the end of screening. Randomisation was stratified by study centre and treatment was allocated using an interactive web response system. After a 4-week screening period including a 2-week baseline period, patients entered in a 4-week individual up-titration scheme from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo; treatment was administered at a stable dose for 4 weeks, followed by a 1-week placebo period. For the primary analysis, we assessed pitolisant versus placebo using change in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of double-blind period in the full analysis set, defined as all randomly allocated patients who received at least one dose of treatment and who had at least one baseline UNS value. A decrease in the UNS total score reflects a reduction in both excessive daytime sleepiness and cataplexy. All adverse events were assessed in the safety population, defined as all participants who took at least one dose of study medication. An open-label follow-up is ongoing. This study is registered at ClinicalTrials.gov, NCT02611687. FINDINGS: Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned (mean age 12·9 [SD 3·0] years, 61 [55%] male, and 90 [82%] with cataplexy; 72 assigned to pitolisant and 38 to placebo); 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. The mean adjusted difference in UNS total score from baseline to the end of the double-blind period was -6·3 (SE 1·1) in the pitolisant group and -2·6 (1·4) in the placebo group (least squares mean difference -3·7; 95% CI -6·4 to -1·0, p=0·007). Treatment-emergent adverse events were reported in 22 (31%) of 72 patients in the pitolisant group and 13 (34%) of 38 patients in the placebo group. The most frequently reported adverse events (affecting ≥5% of patients) in either group were headache (14 [19%] in the pitolisant group and three [8%] in the placebo group) and insomnia (five [7%] in the pitolisant group and one [3%] in the placebo group). INTERPRETATION: Pitolisant treatment resulted in an improvement in narcolepsy symptoms in children, although the UNS was not validated for use in children with narcolepsy when our study began. The safety profile was similar to that reported in adults but further studies are needed to confirm long-term safety. FUNDING: Bioprojet.

Investigation and management of residual sleepiness in CPAP-treated patients with obstructive sleep apnoea: the European view.

Excessive daytime sleepiness (EDS) is a major symptom of obstructive sleep apnoea (OSA), defined as the inability to stay awake during the day. Its clinical descriptors remain elusive, and the pathogenesis is complex, with disorders such as insufficient sleep and depression commonly associated. Subjective EDS can be evaluated using the Epworth Sleepiness Scale, in which the patient reports the probability of dozing in certain situations; however, its reliability has been challenged. Objective tests such as the multiple sleep latency test or the maintenance of wakefulness test are not commonly used in patients with OSA, since they require nocturnal polysomnography, daytime testing and are expensive. Drugs for EDS are available in the United States but were discontinued in Europe some time ago. For European respiratory physicians, treatment of EDS with medication is new and they may lack experience in pharmacological treatment of EDS, while novel wake-promoting drugs have been recently developed and approved for clinical use in OSA patients in the USA and Europe. This review will discuss 1) the potential prognostic significance of EDS in OSA patients at diagnosis, 2) the prevalence and predictors of residual EDS in treated OSA patients, and 3) the evolution of therapy for EDS specifically for Europe.

The Bowel Function Index: a new validated scale for assessing opioid-induced constipation.

BACKGROUND: The management of opioid-induced constipation (OIC) is often complicated by the fact that clinical measures of constipation do not always correlate with patient perception. As the discomfort associated with OIC can lead to poor compliance with the opioid treatment, a shift in focus towards patient assessment is often advocated. SCOPE: The Bowel Function Index * (BFI) is a new patient-assessment scale that has been developed and validated specifically for OIC. It is a physician-administered, easy-to-use scale made up of three items (ease of defecation, feeling of incomplete bowel evacuation, and personal judgement of constipation). An extensive analysis has been performed in order to validate the BFI as reliable, stable, clinically valid, and responsive to change in patients with OIC, with a 12-point change in score constituting a clinically relevant change in constipation. FINDINGS: The results of the validation analysis were based on major clinical trials and have been further supported by data from a large open-label study and a pharmaco-epidemiological study, in which the BFI was used effectively to assess OIC in a large population of patients treated with opioids. Although other patient self-report scales exist, the BFI offers several unique advantages. First, by being physician-administered, the BFI minimizes reading and comprehension difficulties; second, by offering general and open-ended questions which capture patient perspective, the BFI is likely to detect most patients suffering from OIC; third, by being short and easy-to-use, it places little burden on the patient, thereby increasing the likelihood of gathering accurate information. CONCLUSION: Altogether, the available data suggest that the BFI will be useful in clinical trials and in daily practice.

Constipation assessment scales in adults: a literature review including the new Bowel Function Index.

Constipation is a common clinical condition and patient and physician perception of the disorder can vary considerably. The assessment of a symptom-based condition such as constipation is challenging, in terms of making the diagnosis, assessing the severity of symptoms and their impact on a patient's quality of life, and assessing response to therapy or changes to symptoms over time. In order to assist physicians in assessing the severity of constipation and its related discomfort, several rating scales have been developed. During the course of a literature search, 16 studies were identified that reported assessment scales based on a selection of varied symptoms of constipation and that evaluated these scales in different groups of individuals; two studies presented stool form as being key to assessing transit time. In the present article, the characteristics and psychometric evaluation of these different constipation assessment scales, including the new Bowel Function Index, are reported with a view to discussing which assessment tool appears to be most robust and/or useful in daily clinical practice.