STUDY OBJECTIVES:Determine the minimal clinically important change (MCIC), a measure determining the minimum change in scale score perceived as clinically beneficial, for the international restless legs syndrome (IRLS) and restless legs syndrome 6-item questionnaire (RLS-6) in patients with moderate to severe restless legs syndrome (RLS/Willis-Ekbom disease) treated with the rotigotine transdermal system.METHODS:This post hoc analysis analyzed data from two 6-mo randomized, double-blind, placebo-controlled studies (SP790 [NCT00136045]; SP792 [NCT00135993]) individually and as a pooled analysis in rotigotine-treated patients, with baseline and end of maintenance IRLS and Clinical Global Impressions of change (CGI Item 2) scores available for analysis. An anchor-based approach and receiver operating characteristic (ROC) curves were used to determine the MCIC for the IRLS and RLS-6. We specifically compared "much improved vs minimally improved," "much improved/very much improved vs minimally improved or worse," and "minimally improved or better vs no change or worse" on the CGI-2 using the full analysis set (data as observed).RESULTS:The MCIC IRLS cut-off scores for SP790 and SP792 were similar. Using the pooled SP790+SP792 analysis, the MCIC total IRLS cut-off score (sensitivity, specificity) for "much improved vs minimally improved" was -9 (0.69, 0.66), for "much improved/very much improved vs minimally improved or worse" was -11 (0.81, 0.84), and for "minimally improved or better vs no change or worse" was -9 (0.79, 0.88). MCIC ROC cut-offs were also calculated for each RLS-6 item.CONCLUSIONS:In patients with RLS, the MCIC values derived in the current analysis provide a basis for defining meaningful clinical improvement based on changes in the IRLS and RLS-6 following treatment with rotigotine.

Background: The International Restless Legs Scale (IRLS) is the most widely used of the scales rating the severity of restless legs syndrome/Willis-Ekbom disease (RLS/WED). It has been well validated and is the primary end point for most of the therapeutic and nontherapeutic studies of RLS/WED. It has excellent psychometric properties, although it does not capture the severity of RLS under a wide variety of circumstances and times of day. Moreover, the IRLS has a large placebo effect.Methods: The Restless Legs Syndrome-6 Scale (RLS-6), however, takes another potentially valuable approach. Six items are rated on a 0-10 scale from no symptoms at 0 to very severe at 10. In addition to questions on satisfaction with sleep and sleepiness, the scale rates the severity of RLS for the past week under four separate circumstances: while falling asleep, during the night, during the day while sitting or lying, and during the day when moving around. The purpose of the current study is to report the validation of the RLS-6 under baseline and therapeutic conditions.Results: The RLS-6 seems to be an acceptable, reliable, precise, valid, and responsive instrument for the assessment of RLS severity in a specific and pragmatic manner.Conclusions: At present, we view the RLS-6 not as a replacement for the IRLS but as a supplement, as each scale provides information not captured by the other. (C) 2015 The Authors. Published by Elsevier B.V.

Background: Due to the symptoms and the sleep disturbances it causes, Restless Legs Syndrome (RLS) has a negative impact on quality of life. Measurement of such impact can be performed by means of questionnaires, such as the Kohnen Restless Legs Syndrome-Quality of Life questionnaire (KRLS-QoL), a specific 12-item instrument that is self-applied by patients. The present study is aimed at performing a first formal validation study of this instrument.Methods: Eight hundred ninety-one patients were included for analysis. RLS severity was assessed by the International Restless Legs Scale (IRLS), Restless Legs Syndrome-6 scales (RLS-6), and Clinical Global Impression of Severity. In addition the Epworth Sleepiness Scale (ESS) was assessed. Acceptability, dimensionality, scaling assumptions, reliability, precision, hypotheses-related validity, and responsiveness were tested.Results: There were missing data in 3.58% patients. Floor and ceiling effects were low for the subscales, global evaluation, and summary index derived from items 1 to 11 after checking that scaling assumptions were met. Exploratory parallel factor analysis showed that the KRLS-QoL may be deemed unidimensional, ie, that all components of the scale are part of one overall general quality of life factor. Indexes of internal consistency (alpha = 0.88), item-total correlation (rs = 0.32-0.71), item homogeneity coefficient (0.41), and scale stability (ICC = 0.73) demonstrated a satisfactory reliability of the KRLS-QoL. Moderate or high correlations were obtained between KRLS-QoL scores and the IRLS, some components of the RLS-6, inter-KRLS-QoL domains, and global evaluations. Known-groups validity for severity levels grouping and responsiveness analysis results were satisfactory, the latter showing higher magnitudes of response for treated than for placebo arms.Conclusions: The KRLS-QoL was proven an acceptable, reliable, valid, and responsive measure to assess the impact of the RLS on quality of life. (C) 2016 The Authors. Published by Elsevier B.V.

Purpose In patients with newly diagnosed glioblastoma that harbors a nonmethylated O6-methylguanine–DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ. Patients and Methods In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m2 every 2 weeks) or to daily TMZ (75 mg/m2) during RT followed by six courses of TMZ (150-200 mg/m2/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6). Results In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) –C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms. Conclusion BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

Background: Hamilton depression rating scale (HAMD) subscales provide an economic alternative for the full scale; however, their ability to detect onset of improvement in the early course of treatment (El) has not yet been researched. The present study investigated in patients with major depression (MD) whether the subscales are a comparable option to predict treatment remission in the early course of treatment.Methods: Based on data from 210 MD patients of a 6-week randomised, placebo-controlled trial comparing mirtazapine (MIR) and paroxetine (PAR), the discriminative and predictive validity of El for (stable) remission at treatment end was evaluated for seven subscales and the HAMD(17) in the total and in treatment subgroups (MIR vs. PAR). Receiver operating characteristics (ROC) curves (at week 2) and the Clinical Global Impression scales (CGI) (at study endpoint) were used to validate the 20% EI criterion for the subscales.Results: Only the Evans(6) and Toronto(7) subscale had almost the same predictive value as the HAMD(17) (e.g., sensitivities stable remission Evans(6)/Toronto(7): 96/95% vs. 96% HAMD(17)). The optimal cut-off for El to predict remission was just below 20% for most subscales and slightly over 20% for stable remission. Limitations: Study sample representativeness, non-independence of subscales, missing external validation criterion, lack of control group.Conclusions: The Evans and Toronto7 subscales are valuable alternatives in situations, where economic aspects play a larger role. A sum score reduction of >= 20% as definition for EI seems also appropriate for the HAMD subscales, in the total as well as in the antidepressant subgroups. (C) 2015 Elsevier B.V. All rights reserved.

Early improvement (EI), i.e. a symptom reduction from baseline of at least 20% after 2 weeks, has been proven to be a clinically useful predictor for later treatment outcome. In most studies EI is identified by using the sum score of the Hamilton Depression Rating Scale (HAMD). Several unidimensional subscales of the HAMD exist, which have proven to be an economic measure of treatment change. Their ability to detect onset of improvement in comparison to the full HAMD has not been researched yet. The present study investigated in patients with major depression (MD) (1) whether the HAMD subscales are a valid and economic option to predict antidepressant treatment response in the early course of treatment and, (2) to validate the 20% EI criterion. Based on data from 210 patients of a 6-week randomised, placebo-controlled trial comparing mirtazapine (MIR) and paroxetine (PAR) in patients with MD, the discriminative and predictive validity of EI for (stable) response/remission at treatment end was evaluated for the existing subscales in comparison to the HAMD17 in the total group as well as in the different treatment arms (MIR vs. PAR). Receiver operating characteristics (ROC) curves were used to validate the 20% EI criterion for the subscales. Two subscales had similar predictive values than the full HAMD17, but overall, the HAMD17qualifies best for predicting antidepressant treatmentresponse/remission in the early course of treatment. The established 20%threshold of EI of the full HAMD17 scale also seems appropriate for the subscales.

BACKGROUND: In the GLARIUS trial, progression-free survival was significantly prolonged and overall survival was similar in both arms. The present report focuses on quality of life (QoL), Karnofsky performance score (KPS) and cognitive functioning during first-line and postprogression therapy. METHODS: Patients (n = 170) with newly diagnosed, MGMT-non-methylated glioblastoma were randomized 2:1 for bevacizumab (BEV)/irinotecan (IRI) therapy or standard temozolomide (TMZ) therapy. Every 3 months, KPS, QoL (EORTC-QLQ C30 and BN20) and cognitive functioning (MMSE) was determined. Analysis included a longitudinal mixed model analysis and a Kaplan-Meier analysis of the time to deterioration (10 points in QoL, points, 3 points in MMSE, 20% in KPS; tumor progression not regarded as an event). RESULTS: In KPS, MMSE and all 5 prespecified dimensions of QoL (global health status, physical functioning, social functioning, motor dysfunction, communication deficit) mixed model analyses and time to first deterioration analyses did not detect differences between the treatment arms. Time to deterioration of nausea/vomiting was shorter with BEV/IRI (p = 0.024). At progression, the crossover rate in the BEV/IRI arm (to TMZ) and in the standard TMZ arm (to BEV/(IRI) was identical with 65%. Time to postprogression deterioration was significantly longer in the standard TMZ arm receiving crossover BEV/(IRI) in the majority of patients regarding 13 of 26 QoL dimensions including prespecified global health status, social functioning, motor dysfunction, communication deficit. Time to postprogression deterioration was similar for MMSE, but for KPS it tended to be prolonged in the standard arm receiving crossover BEV/(IRI) (p = 0.09). CONCLUSION: Except for IRI-induced nausea/vomiting, first-line BEV/IRI therapy was not associated with any detrimental effects on QoL, performance status or cognition as compared to TMZ standard therapy. After progression, patients pretreated with TMZ in the standard arm had a prolonged stabilization of QoL in many dimensions presumably due to a high rate of crossover BEV therapy.

BACKGROUND:The efficacy of topical ophthalmic corticosteroids depends upon small modifications in preparations, such as drug concentration.The aim of this study was to confirm that hydrocortisone acetate (HC-ac) ophthalmic ointments of 2.5% and 1% are more effective than a 0.5% eye ointment.METHODS:In this randomized, double-blind, placebo-controlled, parallel-group clinical study, the change of signs and symptoms of acute inflammation of the ocular surface and adnexa was evaluated in 411 subjects.RESULTS:Median time to clinically relevant response as estimated by 50% reduction in clinical signs and symptoms (CSS) total score over the entire trial was similar for subjects treated with HC-ac 2.5% (73.5 h) and for subjects treated with HC-ac 1.0% (67.7 h) and was considerably and significantly longer for subjects treated with HC-ac 0.5% (111.8 h) [p < 0.001 for both dosages]. All trial medications were safe and well tolerated.CONCLUSION:Hydrocortisone acetate 2.5% and Hydrocortisone acetate 1% eye ointments are efficacious and safe treatments for acute inflammations of the ocular surface or adnexa, and showed significantly better efficacy than a control group treated with Hydrocortisone acetate 0.5% therapy.TRIAL REGISTRATION:Current Controlled Trials ISRCTN15464650.

2042^ Background: There is a need for more effective therapies in newly diagnosed glioblastoma (GBM) patients with an MGMT-non-methylated tumor. The GLARIUS trial explored the efficacy of bevacizumab (BEV) + Irinotecan (IRI) as compared to standard TMZ in the first-line therapy of MGMT-non-methylated GBM. The primary endpoint progression-free survival after 6 months (PFS-6) has already been reported as being markedly increased in the BEV/IRI arm (Herrlinger et al., ASCO 2013, LBA 2000). The present report focuses on progression-free survival, overall survival (OS) and quality of life (QoL). OS and QoL are particularly important parameters since previous randomized trials investigating BEV in primary therapy of GBM have not been able to demonstrate an OS benefit and have yielded conflicting results regarding QoL. Methods: Patients (n=170) with newly diagnosed, MGMT-non-methylated glioblastoma received local radiotherapy (RT, 30 x 2 Gy) and were randomized (2:1) for experimental therapy with BEV (10 mg/kg q2w) during RT followed by maintenance BEV (10 mg/kg q2w) + IRI (125 mg/m² q2w) or standard therapy with daily TMZ (75 mg/m2) during RT followed by 6 courses of TMZ (150-200 mg/m2/day for 5 days q4w). For 5 prespecified domaines of the EORTC-QLQ C30 and BN20 questionnaires (global health status, physical functioning, social functioning, motor dysfunction, communication deficit as prespecified domaines), the time to deterioration by at least 10 points was analyzed using Kaplan-Meier statistics. Results: With BEV/IRI, PFS was significantly prolonged from a median of 5.9 months (95%CI 2.7-6.2 months) to 9.7 months (95%CI 8.7-10.5 months, p=0.0004; hazard ratio 0.56, 95%CI 0.4-0.79). At progression, the crossover rate was similar in both arms (60.8 and 61.9%). Final OS results will be presented. In all prespecified dimensions of QoL, the time to deterioration was not significantly different between the treatment arms. Data of post-progression QoL will be presented. Conclusions: BEV/IRI therapy was superior to TMZ regarding PFS. BEV/IRI therapy did not alter QoL as compared to TMZ therapy. Clinical trial information: No.: 2009-010390-21.

Corrigendum to “What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications” [Sleep Med Rev 18 (2014) 153e164] Magdolna Hornyak *, Hanna Scholz **, Ralf Kohnen , Juergen Bengel e, , Jan Kassubek , Claudia Trenkwalder f,g, j Oberer Eselsberg 45, 89081 Ulm, Germany Department of Psychiatry and Psychotherapy, University Medical Center, Hauptstrasse 6, 79095 Freiburg, Germany RPS Research Germany GmbH, 520 Virginia Drive, Fort Washington, PA 19034, USA Department of Psychology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany e Institute for Psychology, University of Freiburg, Engelberger Strasse 41, 79085 Freiburg, Germany f Paracelsus-Elena-Klinik, Center for Movements Disorders, Klinikstrasse 16, 34128 Kassel, Germany University of Goettingen, 37073 Gottingen, Germany

Opioids are mainstay for pain therapy and used in several countries as off-label therapy in RLS after failure of first-line therapy. This study investigated the efficacy and safety of oxycodone/naloxone prolonged-release fixed-combination (OXNPR) in severely affected RLS patients (International RLS Study Group Rating Scale (IRLS) score ¡'Ý21 at randomization) with previously insufficient RLS therapy. Patients (N = 304, mean age 62.4¡'À11.2 years) were randomized to OXNPR twice daily (mean oxycodone dose 21.9¡'À15.0 mg/day) or placebo after screening and a 7 day washout period. After the 12-week double-blind (DB) phase, 197 patients participated in a 40-week open-label extension (mean oxycodone dose 18.1¡'À10.5 mg/day). The primary objective of the DB phase was to demonstrate superior efficacy of OXNPR compared with placebo in reducing RLS symptom severity using the universally accepted IRLS. Secondary endpoints included assessment of RLS severity using the RLS-6 Rating scale, and RLS- specific quality of life (QoL) using the QoL-RLS Scale. Mean IRLS total score was significantly reduced from 31.6¡'À4.5 at randomization (indicating severe symptom load) to 15.1¡'À10.6 after 12 weeks of OXNPR treatment. The 12-week OXNPR treatment resulted in a statistically significant reduction in symptom severity compared to placebo with a clinically relevant treatment difference of 8.15 in the mean IRLS total score (95% CIs: ¡'°5.46; 10.85¡'±; p < 0.001; n=269). The beneficial effects of OXNPR during the night and day when at rest were maintained throughout the extension phase. The mean IRLS total score was 9.7¡'À7.8 at end of study (n = 152), representing a mild RLS symptom severity level, on average. RLS-6 scores (0–10 scale) supported the IRLS results and showed a clinically relevant decrease in RLS symptom severity for OXNPR versus placebo (reduction RLS-6 daytime at rest severity after 12 weeks: OXNPR 6.7¡'À2.2–2.5¡'À2.7 vs placebo 6.7¡'À2.5–4.4¡'À3.3). Despite a prospective augmentation assessment during the trial, no case of augmentation was verified in the DB or extension phases. OXNPR treatment was well tolerated in accordance with the expected safety profile of opioid treatment. Oxycodone/naloxone prolonged-release effectively reduces RLS symptom severity over the short- and long-term in patients with severe RLS, inadequately controlled with previous medications, with accompanying quality of life benefits. Karen Paine provided medical writing services on behalf of Mundipharma Research. (Funded by Mundipharma Research; ClinicalTrials.gov number, NCT01112644).

STUDY OBJECTIVES To validate the Multiple Suggested Immobilization Test (m-SIT), a symptom-provocation test measuring restless legs syndrome (RLS) severity multiple times a day while the patient is awake and resting under controlled conditions. The m-SIT was designed to overcome some limitations in measuring RLS severity with rating scales. DESIGN Patients completed two m-SITs on 2 consecutive days while on 24-h dopaminergic medication. After treatment discontinuation, they completed one more m-SIT 3 days later. Controls performed only one m-SIT. SETTING Sleep laboratory. PARTICIPANTS Nineteen patients with RLS and 10 healthy controls. INTERVENTIONS The original m-SIT consisted of seven modified 60-min SITs performed every 2 h between noon and midnight. During each SIT, the subject reclined quietly but could move his or her legs without restriction to alleviate symptoms. Every 10 min, periodic leg movements during wakefulness (PLMW) were evaluated and the m-SIT Disturbance Scale (m-SIT-DS; range 0-10) was completed. MEASUREMENTS AND RESULTS The m-SIT, composed of 6:00pm, 8:00pm, 10:00pm, and 12:00pm SITs, discriminated patients from controls (mean m-SIT-DS: 2.68 ± 2.35 versus 0.08 ± 0.26; mean PLMW/h, P = 0.0001) and between treatment groups (on medication versus taken off medication; mean m-SIT-DS, P = 0.0001; mean PLMW/h, P < 0.01). It proved reliable on retest and covariated well with the International Restless Legs Scale (IRLS) and scales measuring daytime symptoms (Spearman ρ > 0.4). CONCLUSIONS The m-SIT is a valid and reliable test to evaluate RLS severity and treatment response, and could be useful in the future to confirm diagnosis and identify daytime symptoms. Although it was primarily designed for clinical trials, it might be useful in clinical settings because it provides a standardized testing condition to measure RLS symptoms. CITATION Garcia-Borreguero D; Kohnen R; Boothby L; Tzonova D; Larrosa O; Dunkl E. Validation of the Multiple Suggested Immobilization Test: a test for the assessment of severity of restless legs syndrome (Willis-Ekbom disease). SLEEP 2013;36(7):1101-1109.

Background: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL.Methods: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n = 458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed.Results: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM.Conclusion: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials. (C) 2013 Elsevier B. V. All rights reserved.

A Task Force was established by the International Restless Legs Syndrome Study Group (IRLSSG) to develop evidence-based and consensus-based recommendations for the long-term pharmacologic treatment of restless legs syndrome/Willis-Ekbom disease (RLS/WED). The Task Force reviewed the results of all studies of RLS/WED treatments with durations of 6 months or longer presented at meetings over the past 2 years, posted on Web sites of pharmaceutical companies, or published in peer-reviewed journals, asking the questions, "What is the efficacy of this treatment in patients with RLS/WED?" and "What is the safety of this treatment in patients with RLS/WED?"The Task Force developed guidelines based on their review of 61 papers meeting inclusion criteria, and using a modified evidence-grading scheme. Pregabalin has been established as effective for up to 1 year in treating RLS/WED (Level A evidence). Pramipexole, ropinirole, and rotigotine have been established as effective for up to 6 months in treating RLS/WED (Level A). The following drugs have been established as probably effective (Level B) in treating RLS/WED for durations ranging from 1 to 5 years: gabapentin enacarbil, pramipexole, and ropinirole (1 year); levodopa (2 years); and rotigotine (5 years). Because of associated safety concerns, pergolide and cabergoline should not be used in the treatment of RLS/WED unless the benefits clearly outweigh the risks. Other pharmacologic therapies have insufficient evidence to support their long-term use in treating RLS/WED.The IRLSSG Task Force also developed consensus-based strategies for the prevention and treatment of complications (such as augmentation, loss of efficacy, excessive daytime sleepiness, and impulse control disorders) that may develop with the long-term pharmacologic treatment of RLS/WED. The use of either a dopamine-receptor agonist or alpha(2)delta calcium-channel ligand is recommended as the first-line treatment of RLS/WED for most patients, with the choice of agent dependent on the patient's severity of RLS/WED symptoms, cognitive status, history, and comorbid conditions. (c) 2013 Elsevier B.V. All rights reserved.

Background Opioids are a potential new treatment for severe restless legs syndrome. We investigated the efficacy and safety of a fixed-dose combination of prolonged release oxycodone naloxone for patients with severe restless legs syndrome inadequately controlled by previous, mainly dopaminergic, treatment.Methods This multicentre study consisted of a 12-week randomised, double-blind, placebo-controlled trial and 40-week open-label extension phase done at 55 sites in Austria, Germany, Spain, and Sweden. Patients had symptoms for at least 6 months and an International RLS Study Group severity rating scale sum score of at least 15; patients with severe chronic obstructive pulmonary disease or a history of sleep apnoea syndrome were excluded. Patients were randomly assigned (1:1) to either study drug or matched placebo with a validated interactive response technology system in block sizes of four. Study drug was oxycodone 5.0 mg, naloxone 2.5 mg, twice per day, which was up-titrated according to investigator's opinion to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day; in the extension, all patients started on oxycodone 5.0 mg, naloxone 2.5 mg, twice per day, which was up-titrated to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day. The primary outcome was mean change in severity of symptoms according to the International RLS Study Group severity rating scale sum score at 12 weeks. This study is registered with ClinicalTrials.gov (number NCT01112644) and with EudraCT (number 2009-011107-23).Findings We screened 495 patients, of whom 306 were randomly assigned and 276 included in the primary analysis (132 to prolonged release oxycodone naloxone vs 144 to placebo). 197 patients participated in the open-label extension. Mean International RLS Study Group rating scale sum score at randomisation was 31.6 (SD 4.5); mean change after 12 weeks was -16.5 (SD 11.3) in the prolonged release oxycodone naloxone group and -9.4 (SD 10.9) in the placebo group (mean difference between groups at 12 weeks 8.15, 95% CI 5.46-10-85; p<0.0001). After the extension phase, mean sum score was 9.7 (SD 7.8). Treatment-related adverse events occurred in 109 of 150 (73%) patients in the prolonged release oxycodone naloxone group and 66 of 154 (43%) in the placebo group during the double-blind phase; during the extension phase, 112 of 197 (57%) had treatment-related adverse events. Five of 306 (2%) patients had serious treatment-related adverse events when taking prolonged release oxycodone naloxone (vomiting with concurrent duodenal ulcer, constipation, subileus, ileus, acute flank pain).Interpretation Prolonged release oxycodone naloxone was efficacious for short-term treatment of patients with severe restless legs syndrome inadequately controlled with previous treatment and the safety profile was as expected. Our study also provides evidence of open-label long-term efficacy of this treatment. Opioids can be used to treat patients with severe restless legs syndrome who have had no benefit with first-line drugs.

Background: Opioid use may provide a new treatment approach for patients with severe restless legs syndrome (RLS) after failure of mainly dopaminergic medications.

Objective: To determine nonmotor signs (NMS) and evaluate the utility of several diagnostic tools in patients with de novo Parkinson disease (PD). Methods: This is a large single-center study of the DeNoPa cohort, including frequency-matched healthy controls. This study covers motor signs, NMS, and a combination of diagnostic tests including olfactory testing, transcranial sonography of substantia nigra (TCS), and polysomnography (PSG). We report the frequency and characteristics of NMS and the outcomes of nonmotor tests at the time of diagnosis. Results: Cross-sectional analyses of baseline investigations identified significant differences in the NMS Questionnaire (NMSQuest) and the Scopa-AUT Gastrointestinal score in 159 drug-naïve PD patients vs 110 controls. In addition, patients with PD showed reduced olfactory function, hyperechogenicity on TCS, and higher frequency of REM sleep behavior disorder (RBD). In exploring predictive markers, we found that the combination of several investigations, i.e., the NMSQuest, Scopa-AUT Gastrointestinal score, and Smell Identification Test reached an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval [CI] 0.878–0.948). With the addition of serum cholesterol and mean heart rate values, the AUC value reached 0.919 (95% CI 886–0.953); when TCS and PSG were added, the AUC increased to 0.963 (95% CI 0.943–0.982). Conclusions: We show feasibility and utility of standardized data acquisition in a large, single-center cohort of patients with de novo PD and matched healthy controls. The baseline results from our prospective investigations reached a value of >0.9 sensitivity and specificity for biological markers when we added routine laboratory investigations and quantified nonmotor features including sleep.

LBA2000 Background: In patients with MGMT-nonmethylated glioblastoma (GBM), primary chemotherapy with temozolomide (TMZ) is at best moderately effective. There is an urgent need for more effective therapies in this large subgroup of GBM. Since results of phase II trials with the antiangiogenic agent bevacizumab (BEV) +/- irinotecan (IRI) are promising in recurrent GBM, the GLARIUS trial explored the efficacy of BEV/IRI as compared to standard TMZ in the first-line therapy of MGMT-non-methylated GBM. Methods: In the randomized, multicenter, open-label GLARIUS trial, adult patients with newly diagnosed, histologically confirmed and MGMT-non-methylated GBM received local radiotherapy (RT, 30 x 2 Gy) and were randomized (2:1) for experimental therapy with BEV (10 mg/kg q2w) during RT followed by maintenance BEV (10 mg/kg q2w) + IRI (125 mg/m² q2w (without enzyme-inducing antiepileptic drugs (EIAEDs)) or 340 mg/m² (with EIAEDs)) or standard therapy with daily TMZ (75 mg/m2) during RT followed by 6 courses of TMZ (150-200 mg/m2/day for 5 days q4w). The primary endpoint was progression-free survival rate after 6 months (PFS-6) as determined by central neuroradiological review. Results: The intent-to-treat population included 170 patients (67.1% male, median age 56 years (range 25-78 years), 48.8% complete resection rate, 78.8% of patients with KPS 90% or higher); 116 patients received BEV/IRI, 54 patients had TMZ. The frequencies of adverse events in both arms of the trial were within the expected range. The PFS-6 rate was significantly higher in the BEV/IRI arm (71.1%, 95% CI 58.1-80.8%) than in the TMZ arm (26.2%, 95% CI 13.1-41.4%, p<0.0001 logrank test). Conclusions: The significant and clinically meaningful increase in the primary endpoint PFS-6 upon BEV/IRI chemotherapy suggests that BEV/IRI is superior to standard TMZ therapy in newly diagnosed MGMT-nonmethylated GBM patients. Clinical trial information: 2009-010390-21.