Rotigotine in Hemodialysis-Associated Restless Legs Syndrome: A Randomized Controlled Trial.

BACKGROUND: Restless legs syndrome (RLS) has been associated with insomnia, decreased quality of life, and increased morbidity and mortality in end-stage renal disease. This randomized controlled trial investigated effects of rotigotine in patients with RLS and end-stage renal disease. STUDY DESIGN: Double-blind placebo-controlled study. SETTING & PARTICIPANTS: Adults with moderate to severe RLS (International RLS Study Group Rating Scale [IRLS] ≥ 15) and Periodic Limb Movement Index (PLMI) ≥ 15 who were receiving thrice-weekly hemodialysis enrolled from sites in the United States and Europe. INTERVENTION: Following randomization and titration (≤21 + 3 days) to optimal-dose rotigotine (1-3mg/24 h) or placebo, patients entered a 2-week maintenance period. Polysomnography was performed at baseline and the end of maintenance. OUTCOMES & MEASUREMENTS: Primary efficacy outcome: reduction in PLMI, assessed by ratio of PLMI at end of maintenance to baseline. Secondary/other outcomes (P values exploratory) included mean changes from baseline in PLMI, IRLS, and Clinical Global Impression item 1 (CGI-1 [severity of illness]) score. RESULTS: 30 patients were randomly assigned (rotigotine, 20; placebo, 10); 25 (15; 10) completed the study with evaluable data. Mean (SD) PLMI ratio (end of maintenance to baseline) was 0.7±0.4 for rotigotine and 1.3±0.7 for placebo (analysis of covariance treatment ratio, 0.44; 95% CI, 0.22 to 0.88; P=0.02). Numerical improvements were observed with rotigotine versus placebo in IRLS and CGI-1 (least squares mean treatment differences of -6.08 [95% CI, -12.18 to 0.02; P=0.05] and -0.81 [95% CI, -1.94 to 0.33; P=0.2]). 10 of 15 rotigotine and 2 of 10 placebo patients were CGI-1 responders (≥50% improvement). Hemodialysis did not affect unconjugated rotigotine concentrations. The most common adverse events (≥2 patients) were nausea (rotigotine, 4 [20%]; placebo, 0); vomiting (3 [15%]; 0); diarrhea (1 [5%]; 2 [20%]); headache (2 [10%]; 0); dyspnea (2 [10%]; 0); and hypertension (2 [10%]; 0). LIMITATIONS: Small sample size and short duration. CONCLUSIONS: Rotigotine improved periodic limb movements and RLS symptoms in the short term among ESRD patients requiring hemodialysis in a small-scale study. No dose adjustments are necessary for hemodialysis patients.

Modafinil in the treatment of idiopathic hypersomnia without long sleep time--a randomized, double-blind, placebo-controlled study.

In 2010 the European Medicines Agency withdrew the indication of modafinil for the treatment of obstructive sleep apnea, shift work sleep disorder and for idiopathic hypersomnia (IH). In uncontrolled studies, modafinil has been reported to be efficacious in the treatment of sleep disorders. We therefore performed a randomized, placebo-controlled study with the aim of proving the efficacy of modafinil treatment in these patients. Drug-free IH patients without long sleep according to ICSD2 criteria, age >18 years and disease duration >2 years were included. After a washout phase, patients at baseline received placebo or 100 mg modafinil in the morning and at noon over 3 weeks, followed by 1 week without medication. At each visit the Epworth Sleepiness Scale (ESS) and Clinical Global Impression (CGI) rating scale were performed. At baseline and on days 8 and 21 four Maintenance of Wakefulness Tests (MWTs)/day or per day were performed. Patients kept a sleep-wake diary throughout the study. Between 2009 and 2011 three sleep centres recruited 33 participants. Compared to placebo, modafinil decreased sleepiness significantly and improved mean sleep latency in the MWT non-significantly. The CGI improved significantly from baseline to the last visit on treatment. The most frequent adverse events were headaches and gastrointestinal disorders; skin and psychiatric reactions were not reported. The number of reported naps and duration of daytime sleepiness decreased significantly. Total sleep time of nocturnal sleep was slightly reduced. The sleep diaries showed increases in feeling refreshed in the morning; the diurnal diaries showed significant improvement of performance and of exhaustion. Modafinil is an effective and safe medication in the treatment of IH. Adverse events are mild to moderate.

Summary of Research: Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ).

This is a summary of the original article 'Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ)'. Individuals with insomnia are best positioned to assess the impact of insomnia on their quality of life. Patient reported outcomes (PROs) are self-reported health measures created to allow people to record their experience of their disease. Chronic insomnia has a major impact on daytime functioning for patients, and on their quality of life. This summary of research provides an overview of a previously published article detailing the development and evaluation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), as a tool to allow people with insomnia to report their experience of the impact on their daytime functioning.

Solriamfetol real world experience study (SURWEY): Initiation, titration, safety, effectiveness, and experience during follow-up for patients with narcolepsy from Germany.

BACKGROUND: Excessive daytime sleepiness (EDS) is a core narcolepsy symptom, for which solriamfetol (Sunosi®) was recently approved in the European Union. SURWEY characterises real-world strategies used by physicians when initiating solriamfetol, and patient outcomes after follow-up. METHODS: SURWEY is an ongoing retrospective chart review conducted by physicians in Germany/France/Italy. Here, data are reported from 70 German patients with EDS and narcolepsy. Eligibility included age ≥18 years, reached a stable solriamfetol dose, and completed ≥6 weeks of treatment. Patients were classified (based on existing EDS treatment) into changeover, add-on, or new-to-therapy subgroups. RESULTS: Patients' mean ± SD age was 36.9 ± 13.9 years. Changeover from prior EDS medication was the most common initiation strategy. Initial solriamfetol dose was typically 75 mg/day (69%). In 30 patients (43%), solriamfetol was titrated; 27/30 (90%) completed titration as prescribed, most within 7 days. Mean ± SD Epworth Sleepiness Scale (ESS) score was 17.6 ± 3.1 at initiation (n = 61) and 13.6 ± 3.8 at follow-up (n = 51). Slight/strong improvements in EDS were perceived for >90% of patients (patient and physician report). Sixty-two percent reported an effect duration of 6 to <10 h; 72% reported no change in perceived nighttime sleep quality. Common adverse events included headache (9%), decreased appetite (6%), and insomnia (6%); no cardiovascular events were reported. CONCLUSIONS: Most patients in this study were switched from a prior EDS medication to solriamfetol. Solriamfetol was typically initiated at 75 mg/day; titration was common. ESS scores improved after initiation, and most patients perceived improvement in EDS. Common adverse events were consistent with those reported in clinical trials. GOV REGISTRATION: N/A.

Long-Term Safety and Tolerability of Daridorexant in Patients with Insomnia Disorder.

BACKGROUND AND OBJECTIVE: Daridorexant is a dual orexin receptor antagonist for the treatment of insomnia. In two phase III, 12-week studies in patients with insomnia disorder, daridorexant improved sleep and daytime functioning while maintaining a favorable safety profile. The objective of this 40-week extension study was to assess the long-term safety and tolerability of daridorexant. METHODS: Adults with insomnia disorder who completed the 12-week studies were invited to enroll in this double-blind extension study. Patients originally randomised to daridorexant (10 mg/25 mg/50 mg) remained on their respective treatments; patients randomised to placebo were re-randomised to daridorexant 25 mg or placebo. The 40-week treatment period was followed by a 7-day placebo run-out. The primary objective was to assess safety/tolerability. Exploratory objectives were to evaluate the efficacy of daridorexant on sleep (self-reported total sleep time) and daytime functioning (Insomnia Daytime Symptoms and Impacts Questionnaire). RESULTS: In total, 804 patients were enrolled in the study, of whom 801 received at least one dose of the study treatment and 550 patients (68.4%) completed the study. Overall incidence of treatment-emergent adverse events was similar across groups (35-40%). Daridorexant did not induce next-morning sleepiness and no withdrawal-related symptoms or rebound were observed after treatment discontinuation. Improvements in sleep and daytime functioning were maintained through to the end of the study and were most pronounced with daridorexant 50 mg. Daridorexant 50 mg, compared with placebo, increased self-reported total sleep time by a least-squares mean of 20.4 (95% confidence interval [CI] 4.2, 36.5), 15.8 (95% CI - 0.8, 32.5) and 17.8 (95% CI - 0.4, 35.9) minutes and decreased (i.e., improved) Insomnia Daytime Symptoms and Impacts Questionnaire total scores by a least-squares mean of - 9.3 (95% CI - 15.1, - 3.6), - 9.5 (95% CI - 15.4, - 3.5) and - 9.1 (95% CI - 15.6, - 2.7), at weeks 12, 24 and 36 of the extension study, respectively. CONCLUSIONS: Treatment with daridorexant, for up to 12 months, was generally safe and well tolerated. Exploratory efficacy analyses suggest that the sustained improvements in sleep and daytime functioning with daridorexant 50 mg support its use for long-term treatment of insomnia disorder, without concerns of new safety signals. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT03679884) [first posted: 21 September, 2018], https://clinicaltrials.gov/ct2/show/NCT03679884 .

Insomnia disorder is the long-term inability to fall asleep or stay asleep with a significant impact on daily life. Left inadequately treated, this disorder may increase the risk of other health problems. For patients with insomnia disorder who require a sleep medication, many drugs are not recommended for long-term use and there is an unmet need for one that can be used safely and effectively over the long term. Daridorexant is a new insomnia treatment that was approved for adults following positive results in two 12-week clinical studies. Both studies showed that, in patients with insomnia disorder, daridorexant improved night-time sleep and patients' ability to function during the day, while avoiding major safety concerns. Patients who completed these two studies could continue into a 40-week extension study enabling the safety and tolerability of daridorexant to be investigated for up to 1 year. Treatment remained double blind for the entire 1-year period. The extension study showed that daridorexant, at all doses studied (10 mg, 25 mg, 50 mg), continued to be generally safe and well tolerated. Patients showed no signs of tolerance, physical dependence, rebound nor any excessive daytime sleepiness. Exploratory efficacy analyses suggest that improved night-time and daytime symptoms of insomnia were sustained, in particular with the highest approved dose, 50 mg, and there were no signs that the benefits of the drug were wearing off at the end of the 1 year. These results support the use of daridorexant 50 mg for the long-term treatment of insomnia disorder in adults.

Characterization of the central nervous system penetrant and selective purine P2X7 receptor antagonist JNJ-54175446 in patients with major depressive disorder.

JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1ß/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1ß release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) (N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1-3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1ß release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT).

European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society.

BACKGROUND: Since the publication of the first European Federation of Neurological Societies (EFNS) guidelines in 2005 on the management of restless legs syndrome (RLS; also known as Willis-Ekbom disease), there have been major therapeutic advances in the field. Furthermore, the management of RLS is now a part of routine neurological practice in Europe. New drugs have also become available, and further randomized controlled trials have been undertaken. These guidelines were undertaken by the EFNS in collaboration with the European Neurological Society and the European Sleep Research Society. OBJECTIVES: To provide an evidence-based update of new treatments published since 2005 for the management of RLS. METHODS: First, we determined what the objectives of management of primary and secondary RLS should be. We developed the search strategy and conducted a review of the scientific literature up to 31 December 2011 (print and electronic publications) for the drug classes and interventions employed in RLS treatment. Previous guidelines were consulted. All trials were analysed according to class of evidence, and recommendations made according to the 2004 EFNS criteria for rating. RECOMMENDATIONS: Level A recommendations can be made for rotigotine, ropinirole, pramipexole, gabapentin enacarbil, gabapentin and pregabalin, which are all considered effective for the short-term treatment for RLS. However, for the long-term treatment for RLS, rotigotine is considered effective, gabapentin enacarbil is probably effective, and ropinirole, pramipexole and gabapentin are considered possibly effective. Cabergoline has according to our criteria a level A recommendation, but the taskforce cannot recommend this drug because of its serious adverse events.

Algorithms for the diagnosis and treatment of restless legs syndrome in primary care.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder with a lifetime prevalence of 3-10%. in European studies. However, the diagnosis of RLS in primary care remains low and mistreatment is common. METHODS: The current article reports on the considerations of RLS diagnosis and management that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored task force consisting of experts and primary care practitioners. The task force sought to develop a better understanding of barriers to diagnosis in primary care practice and overcome these barriers with diagnostic and treatment algorithms. RESULTS: The barriers to diagnosis identified by the task force include the presentation of symptoms, the language used to describe them, the actual term "restless legs syndrome" and difficulties in the differential diagnosis of RLS. CONCLUSION: The EURLSSG task force reached a consensus and agreed on the diagnostic and treatment algorithms published here.

Psychological distress of patients suffering from restless legs syndrome: a cross-sectional study.

BACKGROUND: Restless legs syndrome (RLS) is a chronic disorder with substantial impact on quality of life similar to that seen in diabetes mellitus or osteoarthritis. Little is known about the psychological characteristics of RLS patients although psychological factors may contribute to unfavourable treatment outcome. METHODS: In an observational cross-sectional design, we evaluated the psychological features of 166 consecutive RLS patients from three outpatient clinics, by means of the Symptom Checklist 90-R (SCL-90-R) questionnaire. Additionally, the Beck Depression Inventory-II (BDI-II) and the International RLS Severity Scale (IRLS) were measured. Both treated and untreated patients were included, all patients sought treatment. RESULTS: Untreated patients (n = 69) had elevated but normal scores on the SCL-90-R Global Severity Index (GSI; p = 0.002) and on the sub-scales somatisation (p < 0.001), compulsivity (p = 0.003), depression (p = 0.02), and anxiety (p = 0.004) compared with a German representative sample. In the treated group, particularly in those patients who were dissatisfied with their actual treatment (n = 62), psychological distress was higher than in the untreated group with elevated scores for the GSI (p = 0.03) and the sub-scales compulsivity (p = 0.006), depression (p = 0.012), anxiety (p = 0.031), hostility (p = 0.013), phobic anxiety (p = 0.024), and paranoid ideation (p = 0.012). Augmentation, the most serious side effect of dopaminergic, i.e. first-line treatment of RLS, and loss of efficacy were accompanied with the highest psychological distress, as seen particularly in the normative values of the sub-scales compulsivity and anxiety. Generally, higher RLS severity was correlated with higher psychological impairment (p < 0.001). CONCLUSION: Severely affected RLS patients show psychological impairment in multiple psychological domains which has to be taken into account in the treatment regimen.

An algorithm for actigraphy-based sleep/wake scoring: Comparison with polysomnography.

OBJECTIVE: To evaluate the accuracy of actigraphy against polysomnography (PSG) as gold standard using a newly developed algorithm for sleep/wake discrimination that explicitly models the temporal structure of sleep. METHODS: PSG was recorded in 11 men and 9 women (age 71.1±5.0) to evaluate suspected neuropsychiatric sleep disturbances. Simultaneously, wrist actigraphy was recorded, from which 37 features were computed for each 1-min epoch. We compared prediction of PSG-derived sleep/wake states for each of these features between our newly developed algorithm, and four state-of-the-art algorithms. The algorithms were evaluated using a leave-one-subject out cross validation. RESULTS: The new algorithm classified 84.9% of sleep epochs (sensitivity) and 74.2% of wake epochs correctly (specificity), leading to a sleep/wake scoring accuracy of 79.0%. Four out of five sleep parameters were estimated more accurately by the new algorithm than by state-of-the-art algorithms. CONCLUSION: The proposed algorithm achieved a significantly higher specificity than state-of-the-art algorithm, with only minor decrease in sensitivity for patients with sleep disorders. We assume this reflects the capability of the algorithm to explicitly model sleep architecture. SIGNIFICANCE: The unobtrusive assessment of sleep/wake cycles is particularly relevant for patients with neuropsychiatric diseases that are associated with sleep disturbances, such as depression or dementia.

Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ).

BACKGROUND AND OBJECTIVE: Chronic insomnia has major consequences for daytime functioning, yet no fully validated patient-reported outcome instrument for once-daily assessments is available to measure these consequences. This study describes the development and psychometric evaluation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). METHODS: The Daytime Insomnia Symptom Scale (DISS), an existing 20-item instrument for assessing daytime functioning, was modified to give an 18-item version of the IDSIQ (IDSIQ-18) based on iterative qualitative interviews with 54 subjects with insomnia and expert input. The construct validity and other psychometric properties of the IDSIQ-18 were analyzed based on an interventional study (NCT03056053) in which subjects with insomnia received zolpidem (5 or 10 mg) daily for 2 weeks and an observational study among subjects with no diagnosis of insomnia (good sleepers). Participants in both studies completed the IDSIQ-18 daily for 2 weeks. Exit interviews were conducted with a sample of subjects who completed the interventional study to elicit concepts defining the experience of insomnia, to assess understanding of the response scales, and to determine meaningful change thresholds. Exploratory factor analysis and Rasch analysis were conducted to further assess the structure and latent model for the scoring of the final IDSIQ instrument. Further psychometric evaluation of the final IDSIQ was then conducted. RESULTS: Subjects in both the interventional study (N = 114) and observational study (N = 103) were predominantly female (65% for subjects with insomnia and 60% for good sleepers). Mean age was 51 years for subjects with insomnia and 45 years for good sleepers. Subjects in the exit interviews (N = 41) demonstrated a good understanding of the IDSIQ-18 response scales. Day 1 mean scores were higher (worse) in subjects with insomnia compared with good sleepers. Based on inter-item correlation, exploratory factor, and Rasch analyses and review of the qualitative data, four items were removed. This yielded the final IDSIQ, with 14 items comprising three domains: Alert/Cognition, Mood, and Sleepiness. The domain structure was determined in a confirmatory factor analysis. Evidence of internal consistency reliability was strong: day 1 Cronbach's alpha was 0.917 for IDSIQ total score and 0.806-0.918 for the domains. Test-retest reliability, assessed for subjects with insomnia with no change on the Patient Global Assessment of Disease Severity scale between day 1 and day 8, was also good (intra-class correlation coefficient 0.856-0.911). Meaningful change thresholds derived for this sample using anchor-based approaches were 20 for IDSIQ total score, 9 for the Alert/Cognition domain, 4 for the Mood domain, and 4 for the Sleepiness domain. CONCLUSIONS: These studies, which closely followed Food and Drug Administration Guidance for Industry on patient-reported outcome measures, support use of the IDSIQ as a fit-for-purpose measure for deriving valid and reliable endpoints in insomnia clinical research trials and real-world studies.

Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch.

BACKGROUND: Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS). METHODS: Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS. RESULTS: Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2. CONCLUSIONS: Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy. TRIAL REGISTRATION: NCT00498186.

Effects of Solriamfetol on Quality-of-Life Measures from a 12-Week Phase 3 Randomized Controlled Trial.

Rationale: Excessive daytime sleepiness in patients with obstructive sleep apnea is associated with substantial burden of illness.Objectives: To assess treatment effects of solriamfetol, a dopamine/norepinephrine reuptake inhibitor, on daily functioning, health-related quality of life, and work productivity in participants with obstructive sleep apnea and excessive daytime sleepiness as additional outcomes in a 12-week phase 3 trial (www.clinicaltrials.gov identifier NCT02348606).Methods: Participants (N = 476) were randomized to solriamfetol 37.5, 75, 150, or 300 mg or to placebo. Outcome measures included the Functional Outcomes of Sleep Questionnaire short version, Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, and 36-item Short Form Health Survey version 2. A mixed-effects model with repeated measures was used for comparisons with placebo.Results: Demographics, baseline disease characteristics, daily functioning, health-related quality of life, and work productivity were similar across groups. At Week 12, increased functioning and decreased impairment were observed with solriamfetol 150 and 300 mg (mean difference from placebo [95% confidence interval]) on the basis of Functional Outcomes of Sleep Questionnaire total score (1.22 [0.57 to 1.88] and 1.47 [0.80 to 2.13], respectively), overall work impairment (-11.67 [-19.66 to -3.69] and -11.75 [-19.93 to -3.57], respectively), activity impairment (-10.42 [-16.37 to -4.47] and -10.51 [-16.59 to -4.43], respectively), physical component summary (2.07 [0.42 to 3.72] and 1.91 [0.22 to 3.59], respectively), and mental component summary (150 mg only, 2.05 [0.14 to 3.96]). Common adverse events were headache, nausea, decreased appetite, and anxiety.Conclusions: Solriamfetol improved measures of functioning, quality of life, and work productivity in participants with obstructive sleep apnea and excessive daytime sleepiness. Safety was consistent with previous studies.Clinical trial registered with www.clinicaltrials.gov (NCT02348606).

Validation of an algorithm for the diagnosis of Restless Legs Syndrome: The Restless Legs Syndrome-Diagnostic Index (RLS-DI).

BACKGROUND: There is a need for structured methods to improve sensitivity and specificity of diagnostic decision making in Restless Legs Syndrome (RLS). We present the RLS-Diagnostic Index (RLS-DI), a diagnostic algorithm which combines essential and supportive diagnostic criteria from patient interviews, polysomnography and neurological examination in an adaptive procedure. METHOD: The RLS-DI consists of 10 items which are related to the essential diagnostic criteria established by the International RLS Study Group (five items) as well as their supportive criteria (3 items) and features associated with RLS (2 items). Items have to be completed using three categories per item that address frequency of occurrence of symptoms or certainty of presence or absence of other diagnostic information. Negative weights were given when the clinically most relevant items were not present. The RLS-DI was administered in a telephone interview to 179 patients (86 with RLS, 93 with other sleep disorders) of the 21 month cohort of one sleep center in Germany. RESULTS: With receiver-operating characteristics, a cut-off of >or= 11 points on a scale ranging from -22 (no RLS) to 20 (definite RLS) was identified by comparing the RLS-DI total score to the diagnosis of two independent sleep experts. Sensitivity was 93.0%, specificity was 98.9%, and 96.1% of the patients could be correctly diagnosed. Specificity was higher in items related to supportive or associated diagnostic information (95.7%) than in those related to the essential diagnostic criteria (81.7%). Patients with RLS scored a higher RLS-DI than those with primary insomnia or other neurological or psychiatric disorders (p < .001). CONCLUSION: The RLS-DI demonstrated the ability to validly diagnose an actual and persistently present Restless Legs Syndrome in patients of a sleep lab population and to exclude those patients whose sleep disturbances have other causes.

Empirical evaluation of the accuracy of diagnostic criteria for Restless Legs Syndrome.

BACKGROUND: In accordance with the diagnostic criteria of the International Restless Legs Syndrome (RLS) Study Group, the diagnosis of RLS is exclusively based on subjective information. Patients must report an urge to move the legs (and arms) with or without unpleasant sensations which is engendered by rest, relieved by movement, and worse in the evening or at night than during the day (essential criteria). Objective information such as excessive periodic leg movements, positive response to dopaminergic medication, family history of RLS or findings of a neurological examination cannot substitute any of the essential criteria but are considered both supportive for the RLS diagnosis and important for decisions on differential diagnoses. In this article, we report a systematic empirical analysis of the accuracy of diagnostic decisions based on all diagnostic criteria being either "essential" or "non-essential." METHODS: We re-analyzed data from a validation study for the RLS Diagnostic Index, in which ten items related to diagnostic criteria were compared with an expert diagnosis of RLS (n = 86) and other sleep-related diagnoses (n = 93). The value of individual diagnostic criteria and features of RLS predictive of the expert diagnoses were analyzed with logistic regression models by increasing the set of diagnostic criteria stepwise based on delta-chi(2) tests. RESULTS: The essential diagnostic criteria share a large amount of variance in the prediction of the expert diagnosis. Three of the four essential criteria (urge to move the legs, which is engendered by rest and worse in the evening) almost completely determine the expert diagnosis. However, adding response to dopaminergic medication to the set of the essential criteria increased the effect size in the logistic regression model from 69.4% to 88.4%, indicating a relevant improvement of the accuracy in supporting or excluding the diagnosis of RLS. CONCLUSION: On the basis of our exploratory empirical analysis we conclude that the accuracy of diagnostic decision making in patients suspicious for RLS can be improved by inclusion of objective information. Response to dopaminergics is the most important criterion which both supports the "true" diagnosis of RLS, if present, and is also relevant to exclude mimics of RLS.

Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome. METHODS: In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28.1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045. FINDINGS: Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 (SE 0.9) in the 1 mg group, -16.2 (0.9) in the 2 mg group, -16.8 (0.9) in the 3 mg group, and -8.6 (0.9) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 (0.14) in the 1 mg group, -2.41 (0.14) in the 2 mg group, -2.55 (0.14) in the 3 mg group, and -1.34 (0.14) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted. INTERPRETATION: 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome. FUNDING: Schwarz Biosciences.

Augmentation in restless legs syndrome is associated with low ferritin.

BACKGROUND AND PURPOSE: Augmentation is a major problem with dopaminergic therapy for restless legs syndrome (RLS), and predictors of augmentation have not yet been identified. We aimed to analyze the relationship between baseline ferritin level and occurrence of augmentation in a retrospective analysis of a prospective double-blind trial of cabergoline versus levodopa on augmentation in RLS. PATIENTS AND METHODS: Patients who experienced augmentation were compared to patients who did not experience augmentation. RESULTS: Augmentation symptoms causing premature discontinuation from the study or which were tolerated (n=36, ferritin: 85+59 ng/ml) were associated with lower levels of serum ferritin compared to patients without augmentation (n=302, ferritin: 118+108 ng/ml, p=0.0062). CONCLUSIONS: Ferritin as a marker of iron storage may play an important role in the pathophysiology of RLS and may prove to be a biomarker for the development of augmentation under dopaminergic therapy.

One year open-label safety and efficacy trial with rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome.

BACKGROUND: Long-term efficacy and tolerability data are not yet available for patch formulations of dopamine agonists in restless legs syndrome. METHODS: Efficacy and safety of rotigotine (0.5-4mg/24h), formulated as a once-daily transdermal system (patch), were investigated in an open extension (SP710) of a preceding 6-week placebo-controlled trial (SP709, 341 randomized patients) in patients with idiopathic restless legs syndrome. For efficacy assessment the international RLS severity scale (IRLS), the RLS-6 scales, the clinical global impressions (CGI) and the QoL-RLS questionnaire were administered. In addition, long-term tolerability and safety were assessed. RESULTS: Of 310 patients who finished the controlled trial, 295 (mean age 58+/-10 years, 66% females) with a mean IRLS score of 27.8+/-5.9 at baseline of SP709 were included. We report results after one year of this ongoing long-term trial. Two hundred twenty patients (retention rate=74.6%) completed the 12-month follow-up period. The mean daily dose was 2.8+/-1.2mg/24h with 4mg/24h (40.6%) being the most frequently applied dose; 14.8% were sufficiently treated with 0.5 or 1.0mg/24h. The IRLS total score improved by ?17.4+/-9.9 points between baseline and end of Year 1 (p<0.001). The other measures of severity, sleep satisfaction and quality of life supported the efficacy of rotigotine (p<0.001 for pre-post-comparisons of all efficacy variables). The tolerability was described as "good" or "very good" by 80.3% of all patients. The most common adverse events were application site reactions (40.0%), which led to withdrawal in 13.2%. Further relatively frequent adverse events were nausea (9.5%) and fatigue (6.4%). Two drug-related serious adverse events, nausea and syncope, required hospitalization. Symptoms of augmentation were not reported by the patients. CONCLUSION: Rotigotine provided a stable, clinically relevant improvement in all efficacy measures throughout one year of maintenance therapy. The transdermal patch was safe and generally well tolerated by the majority of patients. Comparable to any transdermal therapy, application site reactions were the main treatment complication.

Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in Europe.

BACKGROUND: In a pilot placebo-controlled study, low dosages of 0.5-2mg/24h rotigotine showed a dose-dependent beneficial effect in restless legs syndrome (RLS) patients. METHODS: Efficacy and safety of the dopamine agonist rotigotine, formulated as a once-daily transdermal system (patch), was investigated for five fixed dosages and compared to placebo in patients with idiopathic RLS in a double-blind, randomized, parallel-group, multicenter, six-week dose-finding trial. Primary efficacy measure was the total score of the International RLS Severity Scale (IRLS); in addition, the RLS-6 scales and the Clinical Global Impressions (CGI) were administered. RESULTS: Of 371 enrolled patients, 341 patients (mean age 58+/-10years, 67% females) were randomized. The IRLS total score improved between baseline and end of the six-week treatment period by -10.6 (0.5mg/24h rotigotine; patch area 2.5cm2), -15.1 (1mg/24h; 5cm2), -15.7 (2mg/24h; 10cm2), -17.5 (3mg/24h; 15cm2), and -14.8 (4mg/24h, 20cm2) as compared to placebo (-9.2). The hierarchical statistical test procedure demonstrated superiority of rotigotine over placebo for 4mg/24h, 3mg/24h, 2mg/24h, and 1mg/24h, with p-values of 0.0013, <0.0001, 0.0003, and 0.0004, respectively. Only the 0.5mg/24h dose was not different compared to placebo (p=0.2338). The CGI and the RLS-6 severity items supported the efficacy of the rotigotine doses beyond 0.5mg/24h. The most frequent side effects were application site reactions and nausea and tended to be more frequent with higher doses. CONCLUSIONS: This dose-finding trial identified the range for a maintenance dose of rotigotine from 1mg/24h to 3mg/24h. The lowest dose was ineffective and, with the highest dose, no additional benefit was observed.

A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity.

BACKGROUND: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder. AIMS: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires. RESULTS: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 ( p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) -18.8 (21.3) and -29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) -11.1 (36.4) and -11.3 (46.5). The most common adverse events were headache and somnolence. CONCLUSIONS: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings.