Mean Maintenance Of Wakefulness Test Research Articles

0609 Samelisant, Histamine 3 Receptor Agonist for the Potential Treatment of Excessive Daytime Sleepiness in Patients with Narcolepsy

Abstract Introduction Samelisant (SUVN-G3031) is a potent and selective histamine 3 receptor inverse agonist. In orexin knockout mice, samelisant produced wake-promoting and anticataplectic effects suggesting its potential therapeutic utility in the treatment of narcolepsy. Safety and tolerability studies in animals and healthy human volunteers suggested a favorable risk/benefit profile for samelisant. Methods Samelisant is currently being evaluated in a double blind, Phase-2 proof of concept study in USA and Canada for narcolepsy with or without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). The study is recruiting subjects diagnosed with narcolepsy as per ICSD-3 criteria, aged between 18 to 65 years with an Epworth Sleepiness Scale (ESS) score of ≥12 and mean Maintenance of Wakefulness Test (MWT) time of < 12 min. A total of 171 subjects are expected to be randomized into 3 treatment arms (placebo, samelisant 2 mg and samelisant 4 mg) in 1:1:1 ratio. Each subject will receive either placebo or study drug once daily for 2 weeks. The primary efficacy endpoint is change in MWT score from baseline to week 2. Key secondary endpoint is change in ESS from baseline to week 2. Safety will be monitored throughout the study by medical monitor and by data safety monitoring committee. As the study is still recruiting, demographics and baseline characteristic data for the currently enrolled subjects is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion. Results At the data cutoff date of Nov 30, 2022, a total of 155 subjects were randomized in the study. The median age of subjects was 30 years (range: 18-57 years) with mean BMI of 28.5 kg/m2 (range: 18.3- 43.9 kg/m2). Overall, 57% subjects were of narcolepsy type-1, 71% were female and 71% were Caucasian. Mean (SD) baseline values of MWT and ESS scores were 6.1 (4.4) and 17.2 (2.8), respectively. Conclusion Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling subjects with narcolepsy and the data readout is expected in Q2 2023. Support (if any)  

Safety and pharmacodynamics of a single infusion of danavorexton in adults with obstructive sleep apnea experiencing excessive daytime sleepiness despite adequate use of CPAP

BackgroundSleep disruptions experienced by patients with obstructive sleep apnea (OSA) can lead to excessive daytime sleepiness (EDS) and significantly impact patients’ quality of life. EDS may persist despite use of continuous positive airway pressure (CPAP) therapy. Small molecules that target the orexin system, which has a known role in sleep-wake regulation, show therapeutic potential for the treatment of EDS in patients with hypersomnia. This randomized, placebo-controlled, phase 1b study aimed to investigate the safety of danavorexton, a small-molecule orexin-2 receptor agonist, and its effects on residual EDS in patients with OSA. MethodsAdults with OSA aged 18–67 years with adequate CPAP use were randomized to one of six treatment sequences of single IV infusions of danavorexton 44 mg, danavorexton 112 mg, and placebo. Adverse events were monitored throughout the study. Pharmacodynamic assessments included maintenance of wakefulness test (MWT), Karolinska Sleepiness Scale (KSS), and the psychomotor vigilance test (PVT). Results and conclusionAmong 25 randomized patients, 16 (64.0%) had treatment-emergent adverse events (TEAEs) and 12 (48.0%) had TEAEs considered related to treatment, all mild or moderate. Seven patients (28.0%) had urinary TEAEs: three, seven, and none while taking danavorexton 44 mg, danavorexton 112 mg, and placebo, respectively. There were no deaths or TEAEs leading to discontinuation. Improvements in mean MWT, KSS, and PVT scores were observed with danavorexton 44 mg and 112 mg vs placebo. These findings show that danavorexton can improve subjective and objective measures of EDS in patients with OSA and residual EDS despite adequate CPAP use.

0607 Improvement in Sleep Latency With FT218 (Once-Nightly Sodium Oxybate): Analysis From the Phase 3 REST-ON Clinical Trial

Abstract Introduction In the phase 3 REST-ON trial (NCT02720744), mean sleep latency on the Maintenance of Wakefulness Test (MWT) was significantly improved vs placebo with investigational, extended-release once-nightly sodium oxybate (FT218 [ON-SXB]; P< 0.001). This post hoc analysis assessed response to treatment and improvement in excessive daytime sleepiness (EDS). Methods Participants (≥16 years) with narcolepsy type 1/2 were randomized 1:1 to double-blind ON-SXB or placebo. Doses were 4.5 g week 1, 6 g weeks 2‒3, 7.5 g weeks 4‒8, and 9 g weeks 9‒13. Mean sleep latency on the MWT was measured in 5 trials up to 30 minutes each at baseline and weeks 3, 8, and 13. Percentage of participants with improvement of ≥5, ≥10, ≥15, and ≥20 minutes from baseline and with mean sleep latency=30 minutes were assessed. Two-sided P values were calculated using Fisher exact test. Results The modified intent-to-treat population included 190 participants (ON-SXB, n=97; placebo, n=93). At baseline, mean (SD) sleep latency was as follows: ON-SXB, 5.0 (3.1) minutes; placebo, 4.7 (2.6) minutes. More participants receiving ON-SXB vs placebo had mean MWT=30 minutes at weeks 3 (6 g; 5.7% vs 0%; P< 0.05), 8 (7.5 g; 10.5% vs 1.3%; P< 0.05), and 13 (9 g; 13.2% vs 5.1%; P=0.14). A significantly greater percentage of participants receiving ON-SXB vs placebo had improved mean sleep latency ≥5 to ≥20 minutes over baseline at all doses (6 g: ≥5 min, 57.5% vs 25.0%; ≥10 min, 35.6% vs 9.1%; ≥15 min, 18.4% vs 3.4%; ≥20 min, 10.3% vs 1.1% [all P< 0.01]; 7.5g: ≥5 min, 63.2% vs 28.2%; ≥10 min, 43.4% vs 11.5%; ≥15 min, 31.6% vs 3.8%; ≥20 min, 15.8% vs 1.3% [all P< 0.001]; 9 g: ≥5 min, 66.2% vs 37.2% [P< 0.001]; ≥10 min, 50.0% vs 19.2% [P< 0.001]; ≥15 min, 32.4% vs 10.3% [P< 0.01]; ≥20 min, 17.6% vs 6.4% [P< 0.05]). Conclusion Clinically significant improvements in EDS occurred with 6-, 7.5-, and 9-g doses of ON-SXB. At the 2 highest doses, >10% of participants remained awake for the entire MWT. If ON-SXB is granted FDA approval, adults with narcolepsy will have a once-nightly treatment to improve EDS. Support (if any) Avadel Pharmaceuticals

0624 Samelisant (SUVN-G3031), Baseline Characteristics from a Phase-2 Study Evaluating Efficacy and Safety in Patients with Narcolepsy

Abstract Introduction Histamine H3 receptor (H3R) antagonists/inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant (SUVN-G3031) is a potent H3R inverse agonist and exhibits very high selectivity over other targets. In orexin knockout mice, samelisant produced wake-promoting and anticataplectic effects suggesting its potential therapeutic utility in the treatment of excessive daytime sleepiness and cataplexy associated with narcolepsy. It showed dose-dependent H3R occupancy at efficacy doses. Safety and tolerability studies in animals and healthy human volunteers suggested a favorable risk/benefit profile for samelisant.Samelisant is being evaluated in a Phase-2, multicenter, double-blind, placebo controlled, parallel-group study in patients with narcolepsy with or without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Methods Eligibility criteria for the study include subjects diagnosed with narcolepsy as per ICSD-3, aged between 18 to 50 years with an Epworth Sleepiness Scale (ESS) score of ≥12 and mean maintenance of Wakefulness Test (MWT) time of <12 min. A total of 171 subjects will be randomized into 3 treatment arms (placebo, samelisant 2 mg and samelisant 4 mg) in a fixed 1:1:1. Further, the randomization will be stratified according to the type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks. The primary efficacy endpoint is change in MWT score from baseline to week 2. Secondary endpoints are change in ESS and Clinical Global Impressions of Severity (CGI-S) from baseline to week 2. Safety will be monitored throughout the study by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion. Results At the data cutoff date of Nov30, 2021, a total of 108 subjects were randomized in the study. The median age of subjects was 30 years (range: 18-50 years) with mean BMI of 26.4 (range: 18.3- 43.1 kg/m2). Overall, 58% subjects were of narcolepsy type-1, 69% were female and 74% were Caucasian. Mean (SD) baseline values of MWT and ESS were 6.20 (4.53) and 17.17 (2.93), respectively. Conclusion Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling subjects with narcolepsy and the data readout is expected in Q3 2022. Support (If Any) None

SLEEP LATENCY RESPONSE WITH FT218, A ONCE-NIGHTLY SODIUM OXYBATE: POST-HOC RESPONDER ANALYSES FROM THE PHASE 3 REST-ON CLINICAL TRIAL

TOPIC: Sleep Disorders TYPE: Original Investigations PURPOSE: Sodium oxybate is efficacious across multiple narcolepsy symptom domains, including excessive daytime sleepiness; currently approved formulations require twice-nightly dosing. The efficacy and safety of FT218, an investigational, extended-release formulation of once-nightly sodium oxybate (ON-SXB), were analyzed in adults with narcolepsy in the pivotal REST-ON trial (NCT02720744). ON-SXB treatment was associated with significant improvements vs placebo on the coprimary endpoints of Maintenance of Wakefulness Test (MWT), Clinical Global Impression-Improvement, and weekly cataplexy attacks at all 3 tested doses (6, 7.5, and 9 g; all P<0.001). This post hoc responder analysis from REST-ON assessed improvement in mean sleep latency on the MWT. METHODS: REST-ON was a 13-week, phase 3, double-blind, placebo-controlled, multicenter, randomized clinical trial. Participants with narcolepsy age ≥16 years were randomized 1:1 to receive ON-SXB (4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and then 9 g for 5 weeks) or matching placebo once nightly before bedtime. Efficacy and safety assessments were completed at the end of each dosing period. Mean sleep latency was measured using the MWT across 5 trials of up to 30 minutes each. The percentage of participants in each treatment arm whose sleep latency improved ≥5, ≥10, ≥15, and ≥20 min from baseline and percentage with a mean MWT=30 min was determined. Two-sided P-values were calculated (Fisher's exact test). RESULTS: In total, 212 participants enrolled in REST-ON (ON-SXB, n=107; placebo, n=105). Baseline mean (SD) sleep latency on the MWT was 5.0 (3.1) min and 4.7 (2.6) min for the ON-SXB and placebo arms, respectively. Mean MWT was =30 min for 5.7% vs 0% (P<0.05), 10.5% vs 1.3% (P<0.05), and 13.2% vs 5.1% (P=0.14) of participants receiving ON-SXB 6, 7.5, and 9 g vs placebo, respectively. A significantly greater proportion of participants in the ON-SXB treatment group had increased mean sleep latency vs placebo at the 6-g dose (week 3; ≥5 min, 57.5% vs 25.0%, P<0.001; ≥10 min, 35.6% vs 9.1%, P<0.001; ≥15 min, 18.4% vs 3.4%, P=0.001; ≥20 min, 10.3% vs 1.1%, P<0.01), 7.5-g dose (week 8; ≥5 min, 63.2% vs 28.2%, P<0.001; ≥10 min, 43.4% vs 11.5%, P<0.001; ≥15 min, 31.6% vs 3.8%, P<0.001; ≥20 min, 15.8% vs 1.3%, P<0.001), and 9-g dose (week 13; ≥5 min, 66.2% vs 37.2%, P<0.001; ≥10 min, 50.0% vs 19.2%, P<0.001; ≥15 min, 32.4% vs 10.3%, P<0.01; ≥20 min, 17.6% vs 6.4%, P<0.05). CONCLUSIONS: ON-SXB treatment was associated with significant improvement vs placebo as shown by the mean sleep latency on the MWT; significantly more participants who received ON-SXB than placebo experienced increased mean sleep latency ranging between ≥5 min to ≥20 min. This improvement was evident as early as week 3 at the 6-g dose and continued to improve for the 7.5- and 9-g doses at week 8 and 13, respectively. CLINICAL IMPLICATIONS: ON-SXB is an efficacious treatment for daytime sleepiness in adults with narcolepsy. 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506 Samelisant: Baseline Characteristics from a Phase 2 Study Evaluating Efficacy and Safety in Patients with Narcolepsy

Abstract Introduction histamine H3 receptor (H3R) antagonists/ inverse agonists increase histaminergic neurotransmission and offer a therapeutic option for the treatment of narcolepsy. Samelisant (SUVN-G3031) is a potent and selective H3R inverse agonist exhibited selectivity over 70 other targets. Samelisant showed wake-promoting and anticataplectic effects in orexin knockout mice suggesting its potential therapeutic utility in the treatment of EDS and cataplexy associated with narcolepsy. Safety and tolerability studies in animals and healthy humans suggested a favorable risk/benefit profile. Methods The current study is a 2 week treatment, multicenter, double-blind, placebo controlled, parallel-group study in patients with Narcolepsy with or without Cataplexy. Eligibility criteria include age between 18 to 50 years old, an ESS score of ≥ 12; and mean MWT time of &amp;lt; 12 minutes and a confirm diagnosis of narcolepsy as per ICSD-3. Further, the randomization will be stratified according to type of narcolepsy (Type-1 or Type-2). Each subject will receive either placebo or study drug once daily for 2 weeks in a fixed ratio of 1:1:1. The primary efficacy endpoint is change in maintenance of wakefulness test (MWT) score from baseline to week 2. Key secondary endpoints include change from baseline to week 2 in ESS and an improvement in CGI-S scores. Safety will be monitored by medical monitor and by an independent data safety monitoring committee. Baseline clinical and demographic data for the currently enrolled study is summarized descriptively. Since the study is blinded, a breakdown of baseline characteristics by treatment group will not be available until after completion. Results As of data cutoff date of Dec 20, 2020, a total of 54 subjects were completed in the study. The median age of subjects was 30 years (range: 18 - 50 years) with mean BMI of 28.6 (range: 18.3 - 43.1 kg/m2). Overall, 74% of subjects were female and 83% were Caucasian. Mean (SD) baseline values of MWT and ESS are 5.65 (3.5) and 16.7 (2.5), respectively. Conclusion Baseline characteristics are consistent with the general narcolepsy population. The study is currently enrolling the subjects with Narcolepsy with or without Cataplexy, and the Data readout is expected in the second half of 2021. Support (if any):

Profile of Solriamfetol in the Management of Excessive Daytime Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea: Focus on Patient Selection and Perspectives.

Excessive sleepiness (ES) is a symptom of obstructive sleep apnea (OSA) and narcolepsy that has severe consequences. Wake-promoting drugs and stimulants are utilized as accessory treatment in OSA to reduce propensity to sleep but they do not improve sleep-disordered breathing. Solriamfetol is a first-line therapeutic agent to combat sleepiness in OSA and narcolepsy patients that is approved both by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). For excessively sleepy adult patients with OSA despite primary treatment or narcolepsy patients without cataplexy, solriamfetol may be used as initial therapy or as replacement therapy in patients who fail treatment or experience unacceptable side effects with modafinil, armodafinil, pitolisant, or stimulants. It can also be used as add-on therapy in OSA or narcolepsy patients when ES is only partially controlled with modafinil, armodafinil, pitolisant, sodium oxybate, or stimulants. Solriamfetol is a phenylalanine derivative whose wake-promoting action may be mediated through its selective dopamine and norepinephrine reuptake inhibition. This paper reviews the profile of solriamfetol in treating ES associated with OSA or narcolepsy and discusses patient selection and clinical perspectives. Mechanism of action, pharmacology, pharmacokinetics, clinical efficacy, and tolerability of solriamfetol are described. The Treatment of OSA and Narcolepsy Excessive Sleepiness (TONES) solriamfetol trials demonstrated the efficacy of solriamfetol in reducing propensity to sleep and maintaining wakefulness, with significant improvements in mean maintenance of wakefulness test (MWT) sleep latencies and significant reduction in Epworth Sleepiness Scale (ESS) scores compared to placebo. With solriamfetol, significantly higher percentages of patients showed improvement in patient’s and clinician’s global impression of change.

0759 Phase 2 Proof Of Concept Study Of SUVN-G3031, A Histamine H3 Receptor Inverse Agonist For The Potential Treatment Of Narcolepsy

Abstract Introduction SUVN-G3031 is a potent inverse agonist at histamine H3 receptor (H3R) with selectivity over 70 other targets. SUVN-G3031 has excellent pharmacokinetics in rats and dogs. SUVN-G3031 demonstrated dose dependent receptor occupancy in rats with marked wake-promoting and anticataplectic effects in orexin knockout mice supporting its potential therapeutic utility in the treatment of narcolepsy. Long-term safety studies in animals and Phase 1 evaluation for safety, tolerability and pharmacokinetics demonstrated no concern for further development of SUVN-G3031. Methods SUVN-G3031 is currently being evaluated in a Phase 2 proof of concept study in USA for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). This is a double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the safety, tolerability, pharmacokinetics and efficacy of SUVN-G3031 in comparison to placebo in patients with narcolepsy with and without cataplexy. Participants with an ESS score of ≥ 12; and mean MWT time of &amp;lt; 12 min are being randomized at a ratio of 1:1:1 to 2 mg SUVN-G3031, 4 mg SUVN-G3031 or placebo. Patients are to be stratified based on the type of narcolepsy. Each patient will receive study drug once daily for 14 days. The primary objective of the study is to evaluate the effectiveness of SUVN-G3031 compared to placebo as measured by an improvement in the maintenance of wakefulness test (MWT) score. Various secondary, exploratory, safety endpoints and steady state plasma concentrations will be evaluated. Results This study has been initiated in Q3 2019 and subject recruitment is expected to be completed by Q2 2020. Conclusion This study is a phase 2 clinical trial evaluating the efficacy and safety of SUVN-G3031 as a monotherapy in patients with narcolepsy with and without cataplexy. Safety and efficacy results from the study are expected in Q3 2020. Support None

Evaluation of the effect of JZP-110 in patients with narcolepsy assessed using the Maintenance of Wakefulness Test censored to 20 minutes

ObjectiveTo evaluate the effects of JZP-110 on the Maintenance of Wakefulness Test (MWT) with data censored to include only the first 20 min of a 40-min MWT. MethodsIn a 4-week, placebo-controlled crossover design (Study 201; N = 33) and a 12-week parallel-group design (Study 202; N = 93), JZP-110 was evaluated in narcolepsy patients using changes from baseline in the 40-min MWT as the primary endpoint. Effect sizes based on the change from baseline in mean MWT sleep latency were calculated using 20-min censored MWT data and compared to 40-min MWT data. ResultsIn Study 201, mean (standard deviation) changes in MWT sleep latency were 12.7 (10.6) min with JZP-110 versus 0.9 (6.0) min with placebo (P = 0.0002) for 40-min data, and 8.9 (6.3) versus 0.4 (4.6) min for 20-min censored data (P < 0.0001). In Study 202, mean changes in MWT sleep latency were 12.8 (10.3) min with JZP-110 versus 2.1 (7.9) min with placebo (P < 0.0001) for 40-min data, and 8.9 (5.5) versus 1.1 (5.6) min for 20-min censored data (P < 0.0001). In Studies 201 and 202, respectively, Cohen's d effect sizes were large and numerically greater for 20-min censored data (1.54 and 1.41) versus 40-min data (1.37 and 1.17). ConclusionsIn patients with narcolepsy, JZP-110 significantly improved the ability to stay awake compared with placebo, with large effect sizes using both the 40-min and 20-min censored MWT data.

Impact of sodium oxybate, modafinil, and combination treatment on excessive daytime sleepiness in patients who have narcolepsy with or without cataplexy

BackgroundEffects of sodium oxybate (SXB) on patients with narcolepsy with cataplexy (NC) or without cataplexy (NWOC) have not been separately evaluated in clinical trials. MethodsRetrospective analysis evaluated data from a phase 3, randomized, placebo-controlled trial of SXB, modafinil, and SXB + modafinil versus placebo in adult NC patients (n = 95) or NWOC patients (n = 127). NC patients were identified based on medical history, concomitant medications, and sleep-onset REM periods on nocturnal polysomnography. The studied outcomes were changes from baseline at eight weeks on the Epworth Sleepiness Scale (ESS), the Maintenance of Wakefulness Test (MWT), and the Clinical Global Impression of Change (CGI-C). ResultsAmong NC and NWOC patients, ESS improvement was significantly greater with SXB and SXB + modafinil versus placebo. In NC patients, mean MWT sleep latency was significantly increased with SXB + modafinil versus placebo. In NWOC patients, mean MWT sleep latency significantly increased in all groups versus placebo. Higher percentages of patients in the SXB and SXB + modafinil groups were “very much improved” or “much improved” on the CGI-C versus placebo in both NC and NWOC populations, although the difference did not reach statistical significance in the NWOC populations. Adverse events were consistent with previously-reported profiles for modafinil and SXB. Nausea was more common in the SXB and SXB + modafinil groups. Dizziness and tremor were more common in the SXB + modafinil group only. ConclusionsSXB alone and in combination with modafinil improved subjective ratings of excessive sleepiness and an objective measure of the ability to stay awake to similar extents in NC patients and NWOC patients.

Effect of oral JZP-110 (ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy

BackgroundJZP-110 is a wake-promoting agent with dopaminergic and noradrenergic activity. MethodsThis double-blind, crossover study, randomized adults with narcolepsy with or without cataplexy (N = 33) to placebo or JZP-110 at 150 mg/day (weeks 1 and 3) increased to 300 mg/day (weeks 2 and 4). Patients had to have baseline Epworth Sleepiness Scale (ESS) scores ≥10 and mean sleep latencies ≤10 min on the Maintenance of Wakefulness Test (MWT). Efficacy end points included MWT sleep latency and ESS, and the percentage of patients improved on the Clinical Global Impression of Change. ResultsPatients were primarily male (57.6%) and white (69.7%), with a mean (standard deviation) age of 37.1 (12.4) years. At two weeks, the change in the mean MWT sleep latency was 11.8 min longer with JZP-110 than with placebo (P = 0.0002); JZP-110 resulted in greater changes in sleep latency on each MWT trial (P < 0.001). For ESS, JZP-110 was more efficacious relative to placebo after 1 (P < 0.0001) and two weeks (P = 0.0002); final ESS scores were 10.8 with JZP-110 and 15.2 with placebo, changes of −6.7 and −2.4, respectively. JZP-110 was generally well tolerated; the most common adverse events with JZP-110 were nausea (12%), noncardiac chest discomfort (9.1%), and headache (9.1%). ConclusionsThe efficacy of JZP-110 for impaired wakefulness and excessive sleepiness was observed at 150–300 mg/day and as early as one week after initiating treatment (Clinicaltrials.gov identifier NCT01485770).

Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: A multicenter, prospective, randomized, double-blind, placebo-controlled, 4-week trial

Background: Myotonic muscular dystrophy type 1 (MMD1) is the most common form of adult MD, with a mean prevalence of 1 in 8000. Excessive daytime sleepiness (ie, hypersomnia) is a common complication of MMD1. Objective: The aim of this study was to evaluate the efficacy and tolerability of modafinil for the treatment of hypersomnia in adults with MMD1. Methods: This multicenter, prospective, randomized, double-blind, placebo-controlled study consisted of a prerandomization period (90 to 2 days before randomization) and a 4-week randomization period in which patients were assigned to receive either active treatment (modafinil 300 mg/d) or placebo. The study was conducted at 3 clinics in France between February 2000 and June 2002. Adult patients aged ≥18 years, with genetically proven MMD1, an Epworth Sleepiness Scale (ESS) score >10, and a mean latency to sleep onset ≤8 minutes measured by the Multiple Sleep Latency Test (MSLT) were eligible. The primary efficacy end point was the Maintenance of Wakefulness Test (MWT) score at 4 weeks. Secondary end points included the mean MSLT score and scores from the ESS, physician's assessment of the therapeutic effect and the patient's global self-assessment via visual analog scale, the 17-item Hamilton Depression Rating Scale, and the Short Form Health Survey (SF-36) quality-of-life assessment. Results: A total of 28 patients (15 men, 13 women; mean [SD] age, 40 [12.7] years [range, 18–69 years]; 100% white; modafinil group, 13; placebo group, 15) completed the study without protocol violations. Of the 28 patients with MMD1 included in the analysis, 21 had adult-onset MMD1. At 4 weeks, the mean MWT score was 16.4 (3.3) minutes in the modafinil group and 15.8 (3.8) minutes in the placebo group ( P = NS). At the end of the randomization period, there were no significant between-group differences in any secondary outcome. A total of 8 patients (4 in each group) reported ≥1 adverse event, including digestive, neurologic, and skin symptoms. Weight loss was reported in 1 patient (2 kg). Conclusion: In this small study conducted in an adult population with MMD1 and a high prevalence of hyper-somnia, modafinil had no significant effects on daytime somnolence measured using objective MWTs.

Maintenance of wakefulness test in military personnel with upper airway resistance syndrome and mild to moderate obstructive sleep apnea

Sleep-disordered breathing (SDB) and the associated symptom of excessive daytime sleepiness (EDS) in military personnel has influential consequences in both the garrison and the deployed environments. The maintenance of wakefulness test (MWT) is a daytime study used to evaluate the tendency to stay awake. We evaluated consecutive patients diagnosed with mild to moderate obstructive sleep apnea (OSA) and upper airway resistance syndrome (UARS) to provide an objective measure of their EDS using the MWT. All military personnel referred between February 2004 and March 2005 with a clinical evaluation suspicious for SDB were evaluated with an overnight polysomnography (PSG). After overnight PSG, military personnel with mild to moderate OSA and UARS were evaluated with a 40-min protocol MWT. Abnormal MWT was defined as sleep onset latency mean below 19.4 min (<2 SD below the mean). Sixty-two military personnel met entry criteria. Fifty-nine were men. Nineteen patients (32%) were diagnosed with UARS with a mean respiratory disturbance index of 11/h (5-20/h). Forty-one (68%) of the military personnel had OSA with a mean apnea-hypopnea index of 12/h (5-29/h). As a collective group, the mean Epworth Sleepiness Scale was elevated at 13/24 (1-24). This subjective excessive sleepiness was assessed with the MWT test, which resulted in a group mean MWT sleep onset latency of 27 min (5-40 min). Eighteen soldiers (30% of the total patients) had abnormal MWTs [six patients (33.3%) with UARS and 12 (67%) with OSA]. Military personnel with mild to moderate OSA and UARS often have abnormal MWTs and therefore have a pathological tendency to fall asleep. This EDS could pose a safety hazard in those personnel, military or civilian, who operate dangerous vehicles, machinery, or carry a firearm. Military personnel with untreated SDB are also at risk for the consequences of decreased mental alertness and decreased cognitive functioning due to daytime sleepiness.

Armodafinil improves wakefulness and long-term episodic memory in nCPAP-adherent patients with excessive sleepiness associated with obstructive sleep apnea.

Residual excessive sleepiness (ES) and impaired cognition can occur despite effective and regular nasal continuous positive airway pressure (nCPAP) therapy in some patients with obstructive sleep apnea (OSA). A pooled analysis of two 12-week, randomized, double-blind studies in nCPAP-adherent patients with ES associated with OSA evaluated the effect of armodafinil on wakefulness and cognition. Three hundred and ninety-one patients received armodafinil (150 or 250 mg) and 260 patients received placebo once daily for 12 weeks. Efficacy assessments included the Maintenance of Wakefulness Test (MWT), Cognitive Drug Research cognitive performance battery, Epworth Sleepiness Scale, and Brief Fatigue Inventory. Adverse events were monitored. Armodafinil increased mean MWT sleep latency from baseline to final visit by 2.0 min vs a decrease of 1.5 min with placebo (P < 0.0001). Compared with placebo, armodafinil significantly improved quality of episodic secondary memory (P < 0.05) and patients’ ability to engage in activities of daily living (P < 0.0001) and reduced fatigue (P < 0.01). The most common adverse events were headache, nausea, and insomnia. Armodafinil did not adversely affect desired nighttime sleep, and nCPAP use remained high (approximately 7 h/night). Adjunct treatment with armodafinil significantly improved wakefulness, long-term memory, and patients’ ability to engage in activities of daily living in nCPAP-adherent individuals with ES associated with OSA. Armodafinil also reduced patient-reported fatigue and was well tolerated.

Does arousal frequency predict daytime function?

Patients with the sleep apnoea/hypopnoea syndrome (SAHS) have impaired daytime function with demonstrable sleepiness and impaired cognition. The hypothesis that brief arousals from sleep cause these daytime impairments was tested. One hundred and fifty patients with sleep disordered breathing were studied prospectively, comparing overnight polysomnography with daytime measures of objective sleepiness, psychological well-being and cognitive performance. Significant, but weak (r2<0.1), relationships were seen between several nocturnal measures (apnoea/hypopnoea index, arousals and desaturation variables) and daytime measures of quality of life, well-being, subjective sleepiness, symptoms and cognitive performance. The only significant relationship between nocturnal variables and objective sleepiness was a very weak correlation (r2<0.05) between the lowest oxygen saturation and mean maintenance of wakefulness test (MWT) result. The MWT was better correlated with daytime function than the multiple sleep latency test. This study shows a lack of strong relationships between conventional nocturnal measures and daytime function in patients with sleep disordered breathing.

Sleep latency on the maintenance of wakefulness test (MWT) for 530 patients with narcolepsy while free of psychoactive drugs

Objectives: To compare maintenance of wakefulness test (MWT) data gathered at baseline in the course of two, multicenter studies on the therapeutic efficacy of modafinil with published MWT norms. Methods: The MWT is a procedure that uses electrophysiological measures to determine the ability to remain awake while sitting in a quiet, darkened room. The test consists of 4 20 min trials conducted 4 times at 2 h intervals commencing 2 h after awakening from a night of sleep. MWT data were gathered at baseline in the course of two, multicenter studies on the therapeutic efficacy of modafinil. Subjects were 17–68 year old men ( n=239) and women ( n=291) diagnosed with narcolepsy according to the International Classification of Sleep Disorders (ICSD). All patients were free of psychoactive medication for a minimum of 14 days. Results: Mean MWT sleep latency was 6.0±4.8 min. However, the mean for the first MWT trial was 7.0 min which was longer that the means for the following 3 trials (5.8, 5.6 and 5.7 min, respectively). The 4 distributions of the individual MWT trials were similar and adequately summarized by the distribution of the average MWT sleep latency. As a group, patients with narcolepsy were less able to remain awake than normals; only 8 of 530 (1.5%) patients were able to remain awake on 4 20 min MWT trials compared with 35 of 64 (54.7%) normals in another study. However, using a mean MWT sleep latency of 12 min (the 5th percentile for normals) as the lowest cut-point for normalcy, 15% of patients with narcolepsy appeared to have an unimpaired ability to remain awake. Conclusions: The diagnosis of narcolepsy did not always predict inability to remain awake on the MWT. Age, gender and the duration of illness did not predict ability to remain awake. Patients with severe cataplexy and other ancillary symptoms were least able to remain awake on MWT trials. Patients who used tobacco and caffeine moderately had the lowest MWT sleep latencies relative to patients with heavy and light use.