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

BackgroundExcessive 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 QuestionIs 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 MethodsIn 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.ResultsTwo 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.InterpretationPitolisant 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 RegistryClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu 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. Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS? 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. 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. 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. ClinicalTrials.gov; No.: NCT01071876; URL: www.clinicaltrials.gov; EudraCT N°: 2009-017248-14; URL: eudract.ema.europa.eu Take-home PointsStudy Question: Is pitolisant effective and safe for reducing daytime sleepiness in patients with moderate to severe OSA adhering to CPAP treatment, but who having residual excessive daytime sleepiness?Results: In a 12-week randomized controlled trial, excessive daytime sleepiness was reduced significantly with pitolisant compared with placebo. No cardiovascular or other significant safety concerns were reported during this study period.Interpretation: Pitolisant can be used safely as an adjunct to CPAP therapy in OSA patients with residual sleepiness, despite good CPAP adherence, to reduce daytime sleepiness. Study Question: Is pitolisant effective and safe for reducing daytime sleepiness in patients with moderate to severe OSA adhering to CPAP treatment, but who having residual excessive daytime sleepiness? Results: In a 12-week randomized controlled trial, excessive daytime sleepiness was reduced significantly with pitolisant compared with placebo. No cardiovascular or other significant safety concerns were reported during this study period. Interpretation: Pitolisant can be used safely as an adjunct to CPAP therapy in OSA patients with residual sleepiness, despite good CPAP adherence, to reduce daytime sleepiness. OSA affects up to 1 billion people worldwide and constitutes a major health concern because it results in multiorgan consequences.1Benjafield A.V. Ayas N.T. Eastwood P.R. et al.Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis.Lancet Respir Med. 2019; 7: 687-698Abstract Full Text Full Text PDF PubMed Scopus (448) Google Scholar, 2Levy P. Kohler M. McNicholas W.T. et al.Obstructive sleep apnoea syndrome.Nat Rev Dis Primers. 2015; 1: 15015Crossref PubMed Scopus (334) Google Scholar, 3McNicholas W.T. Bassetti C.L. Ferini-Strambi L. et al.Challenges in obstructive sleep apnoea.Lancet Respir Med. 2018; 6: 170-172Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Excessive daytime sleepiness (EDS) is the dominant symptom reported for most OSA patients and often is associated with fatigue, impaired attention and vigilance, irritability, and depressive symptoms. This impairment in daily functioning results in considerable economic and societal burdens with loss of productivity at work, deterioration in quality of life, and an increased risk of accidents.4Bucks R.S. Olaithe M. Rosenzweig I. Morrell M.J. Reviewing the relationship between OSA and cognition: where do we go from here?.Respirology. 2017; 22: 1253-1261Crossref PubMed Scopus (45) Google Scholar,5Rosenzweig I. Glasser M. Polsek D. Leschziner G.D. Williams S.C. Morrell M.J. Sleep apnoea and the brain: a complex relationship.Lancet Respir Med. 2015; 3: 404-414Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar CPAP is the primary treatment for symptomatic moderate to severe OSA, effective in suppressing pharyngeal collapse during sleep and thus normalizing oxygen saturation and sleep quality and architecture. CPAP reduces daytime sleepiness and improves alertness, cognitive function, and quality of life in optimally adherent patients.2Levy P. Kohler M. McNicholas W.T. et al.Obstructive sleep apnoea syndrome.Nat Rev Dis Primers. 2015; 1: 15015Crossref PubMed Scopus (334) Google Scholar,6Bratton D.J. Gaisl T. Schlatzer C. Kohler M. Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: a network meta-analysis.Lancet Respir Med. 2015; 3: 869-878Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar,7Schwartz M. Acosta L. Hung Y.L. Padilla M. Enciso R. Effects of CPAP and mandibular advancement device treatment in obstructive sleep apnea patients: a systematic review and meta-analysis.Sleep Breath. 2018; 22: 555-568Crossref PubMed Scopus (62) Google Scholar However, despite well-managed CPAP therapy, residual EDS is reported in 6% to 15% of CPAP-treated OSA patients.8Gasa M. Tamisier R. Launois S.H. et al.Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure.J Sleep Res. 2013; 22: 389-397Crossref PubMed Scopus (81) Google Scholar,9Pepin J.L. Viot-Blanc V. Escourrou P. et al.Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study.Eur Respir J. 2009; 33: 1062-1067Crossref PubMed Scopus (101) Google Scholar Besides CPAP adherence, residual EDS requires appropriate management, including good sleep hygiene. Other sleep disorders and depression should be assessed before considering pharmacologic therapy with stimulants.10Chapman J.L. Serinel Y. Marshall N.S. Grunstein R.R. Residual daytime sleepiness in obstructive sleep apnea after continuous positive airway pressure optimization: causes and management.Sleep Med Clin. 2016; 11: 353-363Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Several wake-promoting agents such as modafinil plus armodafinil and more recently solriamfetol as adjunct to CPAP therapy have shown significant improvement in residual sleepiness in randomized controlled trials.11Schweitzer P.K. Rosenberg R. Zammit G.K. et al.Solriamfetol for Excessive Sleepiness in Obstructive Sleep Apnea (TONES 3): a randomized controlled trial.Am J Respir Crit Care Med. 2019; 199: 1421-1431Crossref PubMed Scopus (53) Google Scholar,12Strollo Jr., P.J. Hedner J. Collop N. et al.Solriamfetol for the Treatment of Excessive Sleepiness in OSA: a placebo-controlled randomized withdrawal study.Chest. 2019; 155: 364-374Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Solriamfetol has been approved for treatment of residual sleepiness in individuals with OSA in the United States and in Europe. The European Medical Agency has removed the indication for modafinil because of potential cardiovascular safety concerns. Pitolisant is a novel selective histamine H3 receptor antagonist and inverse agonist with strong wake-promoting effects that is well tolerated in patients with narcolepsy.13Szakacs Z. Dauvilliers Y. Mikhaylov V. et al.Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial.Lancet Neurol. 2017; 16: 200-207Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, 14Dauvilliers Y. Bassetti C. Lammers G.J. et al.Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial.Lancet Neurol. 2013; 12: 1068-1075Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, 15Dauvilliers Y. Arnulf I. Szakacs Z. et al.Long-term use of pitolisant to treat patients with narcolepsy: Harmony III Study.Sleep. 2019; 42: zsz174Crossref PubMed Scopus (31) Google Scholar We recently reported that pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in the specific phenotype of sleepy individuals with OSA who decline CPAP or are nonadherent to CPAP therapy.16Dauvilliers Y, Verbraecken J, Partinen M, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: a randomized trial. Am J Respir Crit Care Med. 2020;201(9):1135-1145.Google Scholar The evaluation of pitolisant needs to be completed in the different subgroup of OSA individuals: those exhibiting residual sleepiness, despite good adherence to CPAP treatment. The objectives of the present study were to demonstrate the efficacy and safety of pitolisant given at 5 mg, 10 mg, or 20 mg once daily vs placebo over 12 weeks for the treatment of residual EDS in individuals undergoing well-managed CPAP therapy for moderate to severe OSA. This phase 3, double-blind, placebo-controlled, parallel-group multicenter trial evaluated the efficacy and safety of pitolisant treatment over 12 weeks in adults with moderate to severe OSA treated by CPAP for at least 3 months, with at least 4 h of nightly CPAP use, with residual EDS (Epworth Sleepiness Scale [ESS] score, ≥ 12), and without unstable cardiovascular disease as judged by the investigator. The study was conducted in 35 sleep centers in nine European countries between August 12, 2011, and June 21, 2013. The study protocol was approved by the institutional review board or ethics committees of each study site; the study was conducted in accordance with the principles of the Declaration of Helsinki and is registered at ClinicalTrials.gov (Identifier: NCT01071876) and EudraCT (Identifier: 2009-017248-14). All participants provided written informed consent before inclusion. Included participants were adults with OSA diagnosed according to the International Classification of Sleep Disorders 2 criteria and treated with CPAP for at least 3 months with persistence of EDS despite mean nightly CPAP use of ≥ 4 h. Only individuals assessed by polysomnography with CPAP before inclusion or during the previous year with an Apnea Hypopnea Index ≤ 10/h of sleep and EDS, defined as an ESS score of ≥ 12, were eligible for inclusion. Additional inclusion criteria were a periodic limb movement disorder arousal index of ≤ 10/h, a 13-item Beck Depression Inventory score of < 16 and item G (suicidal ideation) of 0, a Mini-Mental State Examination score of ≥ 28, and BMI of ≤ 40 kg/m2 (because of the risk of obesity hypoventilation syndrome and because morbid obesity may be a significant cause for sleepiness). Key noninclusion criteria were: history of a medical disorder other than OSA associated with EDS (such as severe chronic insomnia, narcolepsy, restless leg syndrome, sleep deprivation, and night-time or shift work); previous surgical intervention for OSA, including uvulopalatopharyngoplasty; use of a mandibular advancement device; current or recent history of drug, alcohol, or other substance use or dependence; history or presence of an unstable or clinically significant medical condition, especially those related to the cardiovascular system (recent myocardial infarction, angina, arterial hypertension or dysrhythmia, ECG-Bazett’s corrected QT interval of more than 450 ms, and history of left ventricular hypertrophy or mitral valve prolapse), a psychiatric disorder, or a condition that could affect safety or interfere with study assessments; pregnancy or breast feeding; the use of any treatment that could affect the evaluation of EDS; or a combination thereof. Procedures were similar to those of the companion study.16Dauvilliers Y, Verbraecken J, Partinen M, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: a randomized trial. Am J Respir Crit Care Med. 2020;201(9):1135-1145.Google Scholar Randomization was centralized and performed via a website (Arone Projection; https://www.bioprojet-studies.org/). Randomization was on a 3:1 (three pitolisant for one placebo) basis (e-Appendix 1). Pitolisant and placebo were contained within sealed capsules, similar in appearance and taste, and containing a one-fourth (5 mg), one-half (10 mg), or one full tablet of pitolisant (20 mg) or lactose only (placebo). The participants, their sleep and respiratory physicians, study investigators, and all research staff were masked to the treatment allocation. Treatment was taken once daily on an empty stomach within 1 h of waking. The individual titration began with 5 mg/day during 1 week, then 10 mg/day was proposed during 1 week, and then 20 mg/day during 1 week if necessary, based on efficacy and tolerability. The best adapted and tolerated dose was administered for the 9-week stable dose period (Fig 1). The primary efficacy end point was change in ESS score from baseline to the end of treatment at week 12. The key secondary end point was change from baseline to week 12 in the Oxford Sleep Resistance Test (OSleR), which objectively measures the ability to maintain vigilance. This consisted of three 40-min sessions of sleep-resistance challenges at approximately 9:00 am, 11:00 am, and 1:00 pm. The mean sleep latency and the number of errors (3-6 consecutive errors indicating microsleep and ≥ 7 errors indicating sleep onset) were collected.16Dauvilliers Y, Verbraecken J, Partinen M, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: a randomized trial. Am J Respir Crit Care Med. 2020;201(9):1135-1145.Google Scholar,17Crook S. Sievi N.A. Bloch K.E. et al.Minimum important difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: estimation from three randomised controlled trials.Thorax. 2019; 74: 390-396PubMed Google Scholar Other secondary end points were: responders by other ESS criteria (ESS ≤ 10 or improvement of ≥ 3 points), episodes of sleepiness and daytime sleep recorded in sleep diaries (e-Appendix 1), parts A and B of the Trail Making Test, the clinicians’ Clinical Global Impressions scale of severity and change, the patient’s global opinion, the Leeds Sleep Evaluation Questionnaire, EuroQoL quality-of-life questionnaire, and the Pichot fatigue scale. Safety was assessed through clinical adverse events, clinical laboratory parameters (hematology, biochemistry, and electrolytes), vital signs, physical examination, ECG, 13-item Beck Depression Inventory scale, amphetamine-like withdrawal symptoms, and the patient’s overall evaluation of tolerance. BP measurements were conducted following recommendations of the European Society of Cardiology with at least two measurements obtained at each assessment, both after 15 min in a supine position. The statistical analysis plan was the same as for the companion study.16Dauvilliers Y, Verbraecken J, Partinen M, et al. Pitolisant for daytime sleepiness in obstructive sleep apnea patients refusing CPAP: a randomized trial. Am J Respir Crit Care Med. 2020;201(9):1135-1145.Google Scholar Exploratory study results indicated residual ESS variability with an SD of six points. Before the study, the investigators agreed on a minimum important difference in ESS of -3 corresponding to an effect size of 0.5. Recent independent studies17Crook S. Sievi N.A. Bloch K.E. et al.Minimum important difference of the Epworth Sleepiness Scale in obstructive sleep apnoea: estimation from three randomised controlled trials.Thorax. 2019; 74: 390-396PubMed Google Scholar,18Patel S. Kon S.S.C. Nolan C.M. et al.The Epworth Sleepiness Scale: minimum clinically important difference in obstructive sleep apnea.Am J Respir Crit Care Med. 2018; 197: 961-963Crossref PubMed Scopus (48) Google Scholar established the minimum important difference ESS to lie between -2 and -3. The correlation between final and baseline ESS was estimated conservatively as r = -0.4. Assuming an analysis of covariance 95% CI for the main confirmatory test, a difference of more than three points should be detected with a power of 90% by including at least 60 participants in the placebo group and 180 in the pitolisant group. The intention-to-treat (ITT) population included all randomized participants. The safety population included all participants who received at least one dose of study medication regardless of the outcome and for whom at least one valid evaluation after baseline (including any adverse event) was available. The per-protocol (PP) population included ITT participants without any major protocol violations and who did not discontinue the study drug or placebo prematurely during the 12-week treatment phase of the study. The PP population was determined by a blinded review of the data before database lock. Demographic data and other baseline characteristics were analyzed using the ITT population. Efficacy was analyzed for both the ITT and PP populations, with the ITT population analysis considered the primary analysis. Safety, concomitant medications, exposure, dosing, and compliance were analyzed using the safety population. The statistical analysis was carried out by an independent external statistician. Another third-party statistician independently reviewed the results. Descriptive statistics were used for the quantitative variables, and frequency distribution was used for the ordinal and nominal variables. Exact 95% CIs are given for selected variables. The final ESS score was compared using a linear mixed-effects model, considering treatment as a fixed factor, center as a random factor, and ESS and BMI at baseline as adjustment covariates. The ESS score could be log transformed if necessary, depending on normality of the residuals. The analysis of safety data was descriptive except for comparisons of the frequencies of participants with treatment-emergent adverse events (TEAEs) by logistic regression. Missing data for the primary efficacy variable and for response were allocated using the last observation carried forward (LOCF) method. A sensitivity analysis was performed using the baseline ESS value carried forward adjusting for ESS and BMI at baseline. This trial was conducted considering a single primary end point (ESS) associated with the ITT dataset, with one test comparing pitolisant with placebo via one main statistical analysis (analysis of covariance). All statistical tests were two sided at a 5% level of significance. We screened 298 individuals for inclusion, of whom 244 (82%) were retained for the double-blind phase of the study and randomized to either pitolisant (n = 183) or placebo (n = 61) (Fig 2, e-Table 1). All 244 participants received at least one dose of study medication and had a validated assessment after baseline. In this safety population, 36 participants were considered to have at least one major protocol deviation (e-Table 2), and 12 participants discontinued the study prematurely (4 of them also were considered to have a major deviation). The PP population was 200 participants, 148 in the pitolisant group and 52 in the placebo group. The ITT population primarily comprised men (82.8%) with a mean age of 53.1 years (SD, 10.6 years). Mean Apnea Hypopnea Index with CPAP was 4.2/h (SD, 3.5/h), and mean CPAP pressure was 10.7 cm H2O (SD, 2.8 cm H2O). No significant differences in demographic or clinical characteristics were found between the treatment groups (Table 1).Table 1Baseline CharacteristicsParameterPitolisant (n = 183)Placebo (n = 61)All Participants (N = 244)Age, y Mean ± SD53.8 ± 10.551.0 ± 10.653.1 ± 10.6 Range23-8125-7223-81Sex Male149 (81.4)53 (86.9)202 (82.8) Female34 (18.6)8 (13.1)42 (17.2)Weight at inclusion, kg98.3 ± 18.897.9 ± 14.6…BMI, kg/m232.7 ± 5.232.2 ± 4.3…Time since diagnosis, mo44.8 ± 44.149.0 ± 57.145.9 ± 47.6AHI with CPAP, number/h of sleep4.1 ± 3.54.5 ± 3.14.2 ± 3.5CPAP pressure, cm H2O10.7 ± 2.710.7 ± 3.010.7 ± 2.8History of cardiovascular disease111 (60.7)27 (44.3)138 (56.6)Data are presented as No. (%), mean ± SD, or range. AHI = Apnea Hypopnea Index. Open table in a new tab Data are presented as No. (%), mean ± SD, or range. AHI = Apnea Hypopnea Index. The ESS geometric mean was 14.9 ± 2.7 at baseline and decreased to 9.0 ± 4.8 at the end of the 12-week intervention in the pitolisant group. In the placebo group, the ESS geometric mean decreased from 14.6 ± 2.8 to 12.1 ± 6.1. The change in ESS from baseline to end of treatment was −5.5 (95% CI, −6.2 to −4.9) in the pitolisant group and −2.8 (95% CI, −4.3 to −1.2) in the placebo group (P < .001). A significant difference was found between the two arms in favor of pitolisant: −2.6 (95% CI, −3.9 to −1.4; P < .001) (Fig 3, Table 2). Prespecified sensitivity analyses adjusting for BMI and ESS at baseline did not change the results.Table 2Efficacy Results for the Primary End Point: Change in ESS ScoreParameterPitolisant (n = 183)Placebo (n = 61)P ValueESS score at inclusion14.9 ± 2.714.6 ± 2.8…ESS score at end of treatment9.0 ± 4.812.1 ± 6.1…Final ESS score DB-LOCF< .001 Mean ± SD9.4 ± 4.611.9 ± 5.7 95% CI8.8 to 10.110.4 to 13.3Change in ESS score (DB-LOCF - inclusion)< .001 Mean ± SD−5.5 ± 4.4−2.7 ± 5.9 95% CI−6.2 to −4.9−4.3 to −1.24ESS score ≤ 10.028 No. (%)103 (56.3)26 (42.6) 95% CI48.8% to 63.6%30.0% to 55.9%EES score ≤ 10 or reduction in EESS ≥ 3.013 No. (%)130 (71)33 (54.1) 95% CI63.9% to 77.5%40.8% to 66.9%Data are presented as No. (%), mean ± SD, or 95% CI, unless otherwise indicated. DB-LOCF = database with last observation carried forward; ESS = Epworth Sleepiness Scale. Open table in a new tab Data are presented as No. (%), mean ± SD, or 95% CI, unless otherwise indicated. DB-LOCF = database with last observation carried forward; ESS = Epworth Sleepiness Scale. Pitolisant resulted in normalization of the ESS score (ESS ≤ 10) in 56.3% of participants vs 42.6% in the placebo group (P = .028). ESS response defined as either ESS ≤ 10 or improvement ≥ 3 points was observed in 71.0% and 54.1% in the pitolisant and placebo groups, respectively (Table 2). Baseline OSleR mean sleep latencies were 15.5 minutes (range, 0.3-40.0 minutes) and 19.0 minutes (range, 0.7-40.0 minutes) for the pitolisant and placebo groups, respectively. The ratio of increase in mean latency during OSleR tests was 1.4 in the pitolisant group and 1.2 in the placebo group (P = .050 using a mixed model for repeated measures) (Table 3). Similar results were found in the PP population analysis. A trend was found toward an improvement in sleep diary variables in the pitolisant group compared with the placebo group regarding the number of sleep or sleepiness episodes (P = .06). No between-group differences were found regarding the EuroQoL quality-of-life questionnaire. In the Leeds questionnaire, two items improved significantly in the pitolisant arm: “getting to sleep” (participants showed less propensity to fall asleep; P = .020) and “quality of sleep” (P = .05). No changes were found in mean time to perform parts A or B of the Trail Making Tests. At the end of the double-blind phase, the Clinical Global Impressions scale of severity and change had improved for 78% of the pitolisant group compared with 53.4% of the placebo group (P < .001). Improvement in the patient’s global opinion end point was perceived by 76.4% of the participants in the pitolisant group compared with 56.9% in the placebo group (P = .005).Table 3Efficacy Results for Secondary OutcomesParameterPitolisant (n = 183)Placebo (n = 61)P ValueOSleR test Sleep latency at inclusion, min15.5 (0.3-40.0)18.9 (0.7-40.0)… Sleep latency at end of treatment, min22.3 (1.3-40.0)21.9 (0.7-40.0)… Ratio OSL at visit 6 to OSL at visit 2 (geometric mean)1.441.22.05Sleep diary variables Change in no. of sleep or sleepiness episodes per day−2.1 ± 1.8−1.34 ± 1.7.06 Change in duration of sleep or sleepiness episodes, min/d−51.8 ± 69.3−47.7 ± 66.9.70Pichot fatigue score, change−3.8 ± 5.6−2.9 ± 5.9.70Leeds Sleep Evaluation Questionnaire Change in ease of getting to sleep8.4 ± 20.80.7 ± 23.7.02 Change in quality of sleep9.9 ± 26.615.2 ± 21.9.05 Change in ease of awaking after sleep12.1 ± 24.812.0 ± 26.2.81 Change in behavior after wakening15.7 ± 21.815.7 ± 22.7.37 Change in global score11.6 ± 14.810.9 ± 14.9.78Trail Making Test Part A: change in average time, s−5.9 ± 13.0−6.2 ± 13.3.88 Part B: change in average time, s−11.7 ± 37.0−15.3 ± 34.4.45EQ-5D change in VAS score5.5 ± 14.93.5 ± 18.9.52Clinical Global Impression136 (78.0)31 (53.4)< .001 95% CI71.1%-84.0%39.9%-66.7%… Very much improved19 (11.0)4 (6.9).005 Much improved73 (42.2)16 (27.6) Minimally improved43 (24.9)11 (19.0) No change33 (19.1)18 (31.0) Minimally worse5 (2.9)8 (13.8) Much worse0 (0.0)1 (1.7)Patient global opinion improvement at end of double-blind treatment No. (%)133 (76.4)33 (56.9) 95% CI69.4%-82.5%43.2%-69.8%Data are presented as No. (%), mean (range), mean ± SD, or 95% CI, unless otherwise indicated. EQ-5D = EuroQoL quality-of-life questionnaire; OSL = OSleR sleep latency for OSleR tests; OSleR = Oxford Sleep Resistance Test; PGO = patient’s global opinion; VAS = visual analog scale. Open table in a new tab Data are presented as No. (%), mean (range), mean ± SD, or 95% CI, unless otherwise indicated. EQ-5D = EuroQoL quality-of-life questionnaire; OSL = OSleR sleep latency for OSleR tests; OSleR = Oxford Sleep Resistance Test; PGO = patient’s global opinion; VAS = visual analog scale. The mean Pichot fatigue scale score decreased in both pitolisant and placebo groups (from 13.2 ± 7.2 to 9.4 ± 6.9 and from 11.4 ± 7.2 to 8.6 ± 6.0, respectively) without significant between-group difference (Table 3). During the double-blind phase, the maximum dose was 20 mg/day for 79.8% of participants in the pitolisant group and 88.5% in the placebo group. Safety evaluation was based on the incidence of TEAEs: 47.0% in the pitolisant group and 32.8% in the placebo group (P = .03). The most frequently reported TEAE was headache (14.8% and 11.5% for pitolisant and placebo groups, respectively). Insomnia was reported in a higher proportion of participants treated with pitolisant (9.3%) than with placebo (3.3%) (Table 4). The frequency of treatment-related TEAEs was similar (headache, insomnia, diarrhea) and did not differ between groups (26.8% with pitolisant and 19.7% with placebo; P = .256). The frequency of severe treatment-related TEAEs was similar in both treatment groups (pitolisant, 27%; placebo, 32.8%).Table 4Safety ParametersParameterPitolisant (n = 183)Placebo (n = 61)P ValueAny TEAE86 (47.0)20 (32.8).030 Treatment related49 (26.8)12 (19.7).256 Serious2 (1.1)0 (0.0).998 Leading to study drug withdrawal4 (2.2)2 (3.3).625Systolic BP Baseline (V2)129.3 ± 12.9130.2 ± 11.8…Range100 to 180110 to 163… End of DB treatment (V6)128.7 ± 12.0129.1 ± 12.0…Range98 to 188110 to 166… Change (SD)−0.6 ± 10.1−1.8 ± 10.1.704Range−50 to 25−20 to 33Diastolic BP Baseline (V2)80.3 ± 8.980.6 ± 6.9…Range56 to 10959 t