Opt-Out Design for an Observational Toxicology Study Involving Intoxicated Patients at a Dance Music Event.

At electronic dance music events in Belgium in 2013 to 2015, seemingly intoxicated patients were included without their informed consent in an observational toxicology study when the attending physicians determined that they needed treatment with an intravenous line. All included patients received an information letter inviting them to contact the principal investigator (PI) to obtain more information about the study and/or to inform the PI that they wanted to be excluded from it. Overall, 238 patients were included in the study. Nine participants (4%) responded to the information letter, either on their own or through their parent; none of them asked to be excluded from the study. All respondents expressed their gratitude for the information they received. The opt-out study design seemed to be acceptable to the patient-participants, and it provided a fuller picture of the drug-related medical incidents at such music events than what could likely be achieved through a study that includes only people who explicitly choose to participate. These findings may help institutional review boards when evaluating study designs involving recreational drug use, especially at electronic dance music events. Nevertheless, we warn against extrapolation to other settings where informed consent is difficult to obtain.

Precompetitive Consensus Building to Facilitate the Use of Digital Health Technologies to Support Parkinson Disease Drug Development through Regulatory Science.

Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pandemic creates a heightened sense of urgency for effective implementation of such strategies. In order for these technologies to be adopted in drug development studies, a regulatory-aligned consensus on best practices in implementing appropriate technologies, including the collection, processing, and interpretation of digital sensor data, is required. A growing number of collaborative initiatives are being launched to identify effective ways to advance the use of DHT in PD clinical trials. The Critical Path for Parkinson's Consortium of the Critical Path Institute is highlighted as a case example where stakeholders collectively engaged regulatory agencies on the effective use of DHT in PD clinical trials. Global regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, are encouraging the efficiencies of data-driven engagements through multistakeholder consortia. To this end, we review how the advancement of DHT can be most effectively achieved by aligning knowledge, expertise, and data sharing in ways that maximize efficiencies.

Pharmacodynamics, Efficacy, and Safety of IPX203 in Parkinson Disease Patients With Motor Fluctuations.

OBJECTIVES: IPX203 is an investigational oral extended-release capsule formulation of carbidopa and levodopa. The pharmacodynamics and efficacy of IPX203 were compared with immediate-release carbidopa-levodopa (IR CD-LD) in this open-label, rater-blinded, multicenter, crossover study in patients with advanced Parkinson disease (PD). METHODS: Twenty-eight patients were randomized to 2 weeks of treatment with IR CD-LD followed by IPX203 or IPX203 followed by IR CD-LD. Pharmacokinetic and motor assessments were conducted on days 1 and 15 of each treatment period. Efficacy was assessed using a 3-day PD diary. Pharmacodynamics were assessed by rater-blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III and Investigator Assessment of Subject's Motor State. RESULTS: After a single dose, levodopa concentrations were sustained above 50% of peak concentration for 4.6 hours with IPX203 versus 1.5 hours with IR CD-LD (P < 0.0001). Based on the PD diary, patients experienced significantly less Off time with IPX203 as a percentage of waking hours than IR CD-LD (mean 19.3% vs 33.5%, respectively; P < 0.0001), translating into 2.3 hours less Off time than IR CD-LD with most of this improvement (1.9 hours) being Good On time. There was no significant difference in the amount of On time with troublesome dyskinesia between treatments. Pharmacodynamic assessments demonstrated similar outcomes in favor of IPX203 on day 1 and a significant predose benefit on motor examination after multiple dosing. CONCLUSIONS: IPX203 demonstrated a sustained effect to reduce Off time and improve Good On time in patients with PD and motor fluctuations. Both treatments were well tolerated.

Single-Dose Pharmacokinetics and Pharmacodynamics of IPX203 in Patients With Advanced Parkinson Disease: A Comparison With Immediate-Release Carbidopa-Levodopa and With Extended-Release Carbidopa-Levodopa Capsules.

OBJECTIVE: IPX203 is an investigational oral extended-release capsule formulation of carbidopa-levodopa (CD-LD). The aim of this study was to characterize the single-dose pharmacodynamics, pharmacokinetics, and safety of IPX203 in subjects with advanced Parkinson disease compared with immediate-release (IR) CD-LD and extended-release CD-LD (Rytary). METHODS: This was a randomized, open-label, rater-blinded, multicenter, single-dose crossover study. Blinded clinicians assessed subject's motor state and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores for up to 10 hours postdose. Duration of effect was determined using improvement thresholds in the MDS-UPDRS part III. RESULTS: Levodopa concentrations increased rapidly and similarly across all 3 treatments and were sustained for a longer duration after IPX203 dosing. All treatments exhibited a rapid onset of pharmacodynamic effect, whereas IPX203 had a significantly longer duration of effect based on MDS-UPDRS part III scores compared with IR CD-LD (P < 0.0001) and Rytary (P ≤ 0.0290). IPX203 had a 2.7-hour advantage over IR CD-LD (P < 0.0001) and a 0.9-hour advantage over Rytary in "off" time (P = 0.023) and in "good on" time (2.6 hours more than IR CD-LD, P < 0.0001; 0.9 hours more than Rytary, P = 0.0259) as measured by the Investigator Assessment of Subject's Motor State. Subjects were 77% more likely to require rescue following IR CD-LD treatment compared with IPX203 (hazard ratio, 0.23; P < 0.0001). More subjects reported treatment-emergent adverse effects during IR CD-LD (28.0%) and IPX203 (19.2%) than during Rytary (8.0%) treatment. CONCLUSIONS: Compared with Rytary and IR CD-LD, IPX203 had a longer pharmacodynamic effect consistent with LD pharmacokinetics for the 3 treatments. The safety and tolerability of IPX203 were similar to those of IR CD-LD and Rytary.

Dosing Patterns during Conversion to IPX066, Extended-Release Carbidopa-Levodopa (ER CD-LD), in Parkinson's Disease with Motor Fluctuations.

BACKGROUND: IPX066 is an extended-release (ER) oral formulation of carbidopa-levodopa (CD-LD). Following an initial peak at about one hour, plasma LD concentrations are maintained for about 4-5 hours. OBJECTIVE: To present dosing factors that may affect the successful conversion to ER CD-LD from other LD formulations. METHODS: Two-phase 3 studies of ER CD-LD vs. immediate-release (IR) CD-LD (ADVANCE-PD) and vs. CD-LD + entacapone (CLE; ASCEND-PD) in subjects with advanced PD included a 6-week, open-label conversion to ER CD-LD prior to treatment randomization. The "converted" daily LD dose ratio and dose frequency for ER CD-LD were compared to the prior LD treatment regimens at study entry. RESULTS: The average daily LD dose ratio at the end of dose conversion to ER CD-LD was approximately 2.1 for IR CD-LD and 2.8 for CLE. The final dose ratios tended to be slightly higher for participants taking lower LD doses at study entry but independent of dose frequency. ER CD-LD dose frequency increased with increasing LD dose and dose frequency at study entry. Participants on higher baseline LD doses ≥800 mg and dose frequencies ≥6 tended to have higher rates of discontinuation during conversion to ER CD-LD. CONCLUSIONS: Converting participants from other LD formulations to ER CD-LD is based on their current LD regimen. For the most common daily doses (≤1250 mg) and dose frequencies (<7) of LD, final mean dose ratios were within tight ranges of 2.1 to 2.4 for IR CD-LD (ADVANCE-PD) and 2.4 to 2.8 for CLE (ASCEND-PD) and were generally independent of the LD dosing frequency at study entry. These trials are registered with NCT00974974, NCT01130493.

Effect of Concomitant Medications on the Safety and Efficacy of Extended-Release Carbidopa-Levodopa (IPX066) in Patients With Advanced Parkinson Disease: A Post Hoc Analysis.

OBJECTIVES: Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in "off" time, "on" time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). METHODS: ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR- and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures ("off" time and "on" time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. RESULTS AND CONCLUSIONS: Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in "off" time and "on" time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD-LD formulation provides approximately an additional hour of "good" on time.

Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson's disease.

BACKGROUND: IPX066 (Rytary®; carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achieve therapeutic LD plasma concentrations within 1h of dosing and maintain LD concentrations for a prolonged duration in early or advanced Parkinson's disease (PD). METHODS: In this open-label study, patients underwent 6weeks of conversion to IPX066 from their prior controlled-release (CR)±immediate-release (IR) CD-LD therapy and 6months of maintenance (with an additional 6months of IPX066 at some sites). Clinical utility was assessed at both the end of conversion and maintenance. RESULTS: Among 43 patients initiated on IPX066, 33 completed conversion. The mean LD conversion ratio was 1.8 among 30 patients previously on CR plus IR (and 1.5 among 3 previously taking CR alone). The mean IPX066 dosing frequency was 3.5times/day compared with 2.6times/day for CR plus 4.6times/day for IR previously (and 4.7times/day for CR alone). By patient and clinician global improvement ratings after 6-month maintenance, ≥43.8% of patients were much or very much improved from their previous treatment, and ≥68.8% were at least minimally improved. Adverse events were consistent with those reported in prior IPX066 studies. CONCLUSIONS: These results suggest that advanced PD patients using CR CD-LD±IR can be safely converted to IPX066, with high likelihood of achieving a stable regimen, less frequent LD dosing, and improved overall clinical benefit. TRIAL REGISTRATION: Clinicaltrials.govNCT01411137.

Conversion to IPX066 from Standard Levodopa Formulations in Advanced Parkinson's Disease: Experience in Clinical Trials.

BACKGROUND: Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours. OBJECTIVE: To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting. METHODS: Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided. RESULTS: Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE. CONCLUSIONS: Among PD patients with substantial "off" time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing's disease: results from an open-ended, open-label extension trial.

PURPOSE: Report the efficacy and safety of pasireotide sc in patients with Cushing's disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study. METHODS: 162 patients entered the core study. 58 patients who had mean UFC ≤ ULN at month 12 or were benefiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300-1,200 µg bid). Dose titration was permitted according to efficacy or drug-related adverse events. RESULTS: 40 patients completed 24 months' treatment. Of the patients who entered the extension, 50.0% (29/58) and 34.5% (20/58) had controlled UFC (UFC ≤ ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3% (95% CI 40.7-73.9; n = 52) and 62.1% (50.8-73.5; n = 33) after 12 and 24 months' treatment, respectively. Improvements in clinical signs of Cushing's disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received ≥1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6%), nausea (48.1%), hyperglycemia (38.9%), and cholelithiasis (31.5%). No new safety issues were identified during the extension. CONCLUSIONS: Reductions in mean UFC and improvements in clinical signs of Cushing's disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing's disease.

Comparison of IPX066 with carbidopa-levodopa plus entacapone in advanced PD patients.

BACKGROUND: IPX066, an investigational extended-release carbidopa-levodopa (CD-LD) preparation, has demonstrated a rapid attainment and prolonged maintenance of therapeutic LD plasma concentrations in advanced Parkinson's disease (PD). This phase-3 crossover study assessed its efficacy and safety vs. CD-LD plus entacapone (CL + E). METHODS: At baseline, all patients had motor fluctuations despite a stable regimen of CL + E or CD-LD-entacapone combination tablets (CLE). The study included a 6-week conversion from CL + E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL + E), the other on CL + E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily "off" time during waking hours (from patient diaries). RESULTS: Of 91 randomized patients, 84 completed the study. Their median daily LD dosage was 1495 mg from IPX066 and 600 mg from CL + E, corresponding, after correction for bioavailability, to an approximately 22% higher LD exposure on IPX066. Compared with CL + E, IPX066 demonstrated a lower percent "off" time (24.0% vs. 32.5%; p < 0.0001), lower "off" time (3.8 vs. 5.2 h/day; p < 0.0001), and higher "on" time without troublesome dyskinesia (11.4 vs. 10.0 h/day; p < 0.0001). Other endpoints, including patient-reported treatment preference, also favored IPX066 (p < 0.05). During double-blind treatment, 20.2% and 13.6% of patients reported adverse events on IPX066 and CL + E, respectively. The most common were dyskinesia (4 patients), insomnia (3), and confusional state (3) for IPX066, and fall (2) for CL + E. CONCLUSIONS: In advanced PD, IPX066 showed improved efficacy, compared with CL + E, and appeared to be well tolerated.

Karyotyping, is it worthwhile in transsexualism?

INTRODUCTION: Karyotyping is often performed in transsexual individuals. AIM: Quantification and characterization of karyotype findings and abnormalities in transsexual persons. MAIN OUTCOME MEASURES: Karyotypes were listed both in male-to-female and in female-to-male transsexual persons. METHODS: The data were collected through a retrospective study. RESULTS: Karyotypes of 368 transsexual individuals (251 male-to-female, 117 female-to-male) are described. Normal findings were found in 97.55%. Prevalence of abnormal karyotypes was 3.19% among male-to-female, and 0.85% among female-to-male transsexuals. Nine karyotypes showed variations; Klinefelter syndrome was confirmed in three persons, whereas others displayed autosomal aberrations. CONCLUSION: Karyotyping is only of very limited information in the transsexual population.

A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia.

BACKGROUND: Longer-term pharmacologic studies for insomnia in older individuals are sparse. OBJECTIVE: To evaluate the efficacy and safety of 12 weeks of nightly eszopiclone in elderly outpatients with insomnia. METHODS: Participants (65-85 years) met DSM-IV-TR criteria for insomnia with total sleep times (TST) < or = 6 h, and wake time after sleep onset (WASO) > or = 45 min. Participants were randomized to 12 weeks of eszopiclone 2 mg (n = 194) or placebo (n = 194), followed by a 2-week single-blind placebo run-out. Subject-reported measures of sleep (sTST, sleep latency [sSL], sWASO) and daytime function (alertness, concentration, wellbeing, ability to function) were assessed. AEs were monitored. RESULTS: Subjects treated with 2 mg eszopiclone slept longer at night on average and at every individual time point compared to baseline than placebo subjects, as measured by TST over the 12-week double-blind period (P < 0.0001). Mean sTST over the double-blind period for eszopiclone-treated subjects was 360.08 min compared to 297.86 min at baseline, a mean change of 63.24 min. Over the double-blind period, eszopiclone-treated subjects also experienced a significantly greater improvement in sSL compared to placebo, with a mean decrease of 24.62 min versus a mean decrease of 19.92 min, respectively (P = 0.0014). Eszopiclone subjects also experienced a significantly greater decrease in WASO (mean decrease of 36.4 min) compared to placebo subjects (decrease of 14.8 min) (P < 0.0001). Post-discontinuation, sleep parameters were statistically improved versus baseline for eszopiclone (P-values < or = 0.01), indicating no rebound. The most common AEs (> or = 5%) were headache (eszopiclone 13.9%, placebo 12.4%), unpleasant taste (12.4%, 1.5%), and nasopharyngitis (5.7%, 6.2%). CONCLUSION: In this Phase IV trial of older adults with insomnia, eszopiclone significantly improved patient-reported sleep and daytime function relative to placebo. Improvements occurred within the first week and were maintained for 3 months, with no evidence of rebound insomnia following discontinuation. The 12 weeks of treatment were well tolerated. CLINICAL TRIAL INFORMATION: A Long-Term Safety and Efficacy Study of Eszopiclone in Elderly Subjects With Primary Chronic Insomnia; Registration #NCT00386334; URL - http://www.clinicaltrials.gov/ct2/show/NCT00386334?term=eszopiclone&rank=24

Quantification of testosterone undecanoate in human hair by liquid chromatography-tandem mass spectrometry.

Testosterone undecanoate (T-C11) can be used by athletes in order to improve performance. After oral intake, T-C11 is rapidly metabolized, hampering discrimination between exogenous and endogenous testosterone. A possible alternative is to detect the intact ester in hair. A method based on liquid chromatography-tandem mass spectrometry was developed for the determination of T-C11 in hair. The sample procedure consisted of digestion of 200 mg of pulverized hair with tris(2-carboxyethyl)phosphine hydrochloride and liquid-liquid extraction with n-pentane. Several parameters such as the mobile phase, the ionization source and the washing step were optimized. The method was validated at different spiked levels obtaining satisfactory values for accuracy (between 92 and 102%) with relative standard deviations lower than 7% and a limit of detection of 0.2 ng/g. The applicability of the method was checked by the analysis of three samples from patients using T-C11. A peak for the analyte was detected in all samples with concentrations between 0.4 and 8.4 ng/g.

The effect of eszopiclone in patients with insomnia and coexisting rheumatoid arthritis: a pilot study.

OBJECTIVE: To evaluate the efficacy and safety of eszopiclone 3 mg, a nonbenzodiazepine medication/hypnotic indicated for the treatment of insomnia with comorbid rheumatoid arthritis (RA). METHOD: This multicenter, double-blind, placebo-controlled pilot study was conducted in 153 patients aged 25-64 years with American College of Rheumatology-defined RA who met DSM-IV criteria for insomnia. The data were collected from February to November of 2004. Patients were randomly assigned to either eszopiclone or placebo nightly for 4 weeks, followed by a 2-week placebo run out. Efficacy was evaluated using patient reports of sleep (wake time after sleep onset [WASO], sleep latency [SL], and total sleep time [TST]), daytime function, pain, and RA assessments. Insomnia severity was evaluated using the Insomnia Severity Index. Safety was also evaluated. RESULTS: Eszopiclone significantly improved all patient-reported sleep measures (WASO, SL, and TST), sleep quality, depth of sleep, and daytime function (P < .05 vs placebo). At week 4, 48% of eszopiclone-treated patients had no clinically meaningful insomnia as assessed by ISI score (versus 30% of placebo-treated patients, P = .03). Eszopiclone was significantly better than placebo on some RA-associated pain measures: (1) overall (P = .05), pain (P = .006), and pain and other symptoms (P = .02) scores of the Arthritis Self-Efficacy Scale, (2) tender joint counts (P = .03) and pain severity scores (P = .023), (3) the activities domain of the Health Assessment Questionnaire-Disability Index (P = .04), and (4) the role physical (P = .03) and bodily pain (P = .01) scales of the 36-item Medical Outcomes Study Short-Form General Health Survey. The most commonly reported adverse events with eszopiclone were unpleasant taste and transient increases in RA symptoms. CONCLUSIONS: In this pilot study of patients with insomnia comorbid with RA, eszopiclone 3 mg improved all assessed sleep and daytime function measures over the treatment period, as well as some measures of RA-associated pain, disability, and quality of life. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00367965.

The female-to-male transsexual and his female partner versus the traditional couple: a comparison.

In this explorative study, nine stable relationships between female-to-male transsexuals and their biologically female partners were compared to an equal number of "traditional" heterosexual couples. The aim was to investigate any differences between these two groups on three aspects: satisfaction about the partner relationship, sexual satisfaction, and partnership sex typing. Data do not show any significant differences in relational and sexual satisfaction between the transsexuals' female partner and the women in the "traditional" couples. In contrast, the female-to-male transsexuals and their female partners were found to have adopted a more pronounced sex-typed partner relationship than the "traditional" couples.

A polysomnographic placebo-controlled evaluation of the efficacy and safety of eszopiclone relative to placebo and zolpidem in the treatment of primary insomnia.

STUDY OBJECTIVES: To evaluate the polysomnographic efficacy and the safety of a range of doses of eszopiclone relative to placebo in patients with primary insomnia. Zolpidem 10 mg was included as an active control. METHODS: This multicenter, randomized, crossover study enrolled patients aged 21-64 years meeting the DSM-IV criteria for primary insomnia (n = 65). Patients received 2 nights treatment each with placebo, eszopiclone 1 mg, 2 mg, 2.5 mg, or 3 mg, and zolpidem 10 mg after randomization to one of 6 treatment sequences. Visits were separated by a 3-7 day washout. Objective efficacy was assessed by polysomnography (PSG). The primary endpoint was latency to persistent sleep (LPS); key secondary endpoints were sleep efficiency (SE) and wake time after sleep onset (WASO); other endpoints included wake time during sleep (WTDS) and number of awakenings (NAW), as well as patient-reported variables. RESULTS: LPS and SE were significantly different than placebo for all active treatments (p < 0.05 for all). Significant differences from placebo were noted in the 3 objective sleep maintenance measures (WASO, WTDS, and NAW) for eszopiclone 3 mg (p < 0.05), which was not the case for zolpidem 10 mg or the other eszopiclone doses. The incidence of central nervous system adverse events was 23.4% for zolpidem 10 mg, 6.2% to 12.5% for the eszopiclone doses, and 7.9% for placebo. CONCLUSIONS: Relative to placebo, all active treatments were effective in reducing LPS and increasing SE. Eszopiclone 3 mg was significantly different from placebo on the 3 PSG measures of sleep maintenance (WASO, WTDS, and NAW). Significant differences between zolpidem 10 mg and eszopiclone (2 mg or 3 mg) were not observed for PSG-measured outcomes, although the study was not powered to detect differences between the active drug conditions.

Eszopiclone coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder.

CONTEXT: Insomnia and generalized anxiety disorder (GAD) are prevalent disorders that may coexist. OBJECTIVE: To determine the efficacy of eszopiclone combined with escitalopram oxalate in treating insomnia comorbid with GAD. DESIGN: Double-blind, randomized, placebo-controlled, parallel-group, add-on therapy 10-week study. SETTING: Multicenter outpatient study from July 2005 to April 2006. PATIENTS: Adults aged 18 to 64 years meeting DSM-IV-TR criteria for GAD and insomnia. INTERVENTIONS: Patients received 10 mg of escitalopram oxolate for 10 weeks and were randomized to also receive either 3 mg of eszopiclone (n = 294) or placebo (n = 301) nightly for 8 weeks. For the last 2 weeks, eszopiclone was replaced with a single-blind placebo. MAIN OUTCOME MEASURES: Sleep, daytime functioning, psychiatric measures, and adverse events. RESULTS: Compared with treatment with placebo and escitalopram, treatment with eszopiclone and escitalopram resulted in significantly improved sleep and daytime functioning (P < .05), with no evidence of tolerance. Patients taking eszopiclone and escitalopram had greater improvements in total Hamilton Anxiety Scale (HAM-A) scores at each week (P < .05) and at weeks 4 through 10 with the insomnia item removed. Clinical Global Impressions (CGI) of Improvement scores were improved with eszopiclone and escitalopram at every point (P < .02), while CGI of Severity of Illness scores were not significantly different after week 1. The HAM-A response (63% vs 49%, respectively, P = .001) and remission (42% vs 36%, respectively, P = .09) rates at week 8 were higher in patients treated with eszopiclone and escitalopram than those treated with placebo and escitalopram, and median time to onset of anxiolytic response was significantly reduced (P < or = .05). After eszopiclone discontinuation, there was no evidence of rebound insomnia, and while treatment differences in anxiety measures were maintained, differences in sleep outcomes were not. Overall adverse event rates were 77.6% with cotherapy and 67.9% with monotherapy. The most common adverse events with cotherapy were unpleasant taste, headache, dry mouth, and somnolence. CONCLUSIONS: Coadministration of eszopiclone and escitalopram was well tolerated and associated with significantly improved sleep, daytime functioning, anxiety, and mood in patients with insomnia and GAD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00235508.

Next-day cognition, psychomotor function, and driving-related skills following nighttime administration of eszopiclone.

OBJECTIVE: To evaluate next-day driving ability, as assessed by brake reaction time (BRT), and cognitive/psychomotor function following nighttime administration of 3 mg eszopiclone. METHODS: Two randomized, double-blind, placebo-controlled, cross-over studies were performed in healthy volunteers (n = 32) and patients with primary insomnia (n = 32). Study participants received nighttime dosing of 3 mg eszopiclone or placebo. BRT and a psychometric test battery were used to assess the next-day effects of eszopiclone treatment. RESULTS: In both studies, driving ability and measures of cognitive and psychomotor function were not impaired the morning after eszopiclone, as compared to placebo. All eszopiclone subjects reported improved ease in getting to sleep and quality of sleep with no significant changes in behavior upon awakening. A significant increase in next-day feelings of sedation was reported in healthy volunteers, but not in patients with primary insomnia, following eszopiclone treatment relative to placebo. Sleep induction, maintenance, duration, and efficiency, as assessed by PSG, were significantly improved following eszopiclone treatment in patients with insomnia. CONCLUSIONS: Nighttime administration of 3 mg eszopiclone improved objective and subjective sleep measures in patients with insomnia (and subjective sleep measures in healthy patients) and did not impair next-day driving-related skills or measures of cognition in either study population relative to placebo.

Hypoactive sexual desire in transsexual women: prevalence and association with testosterone levels.

OBJECTIVE: An unknown proportion of transsexual women (defined as post-operative male-to-female transsexuals on oestrogen replacement) experience hypoactive sexual desire disorder (HSDD). It has been suggested that the absence of ovarian androgen production together with oestrogen treatment-related increase in sex hormone-binding globulin (SHBG) levels could be leading to HSDD, due to low levels of biologically available testosterone. This study wishes to document the HSDD prevalence among transsexual women and the possible association to androgen levels. DESIGN: Cross-sectional study. METHODS: Transsexual women (n=62) and a control group of ovulating women (n=30) participated in this study. Questionnaires measuring sexual desire (sexual desire inventory) and relationship and sexual satisfaction (Maudsley Marital Questionnaire) were completed. Serum levels of total testosterone, LH and SHBG were measured in blood samples obtained at random in transsexual women and in the early follicular phase in ovulating women. RESULTS: The transsexual group had lower levels of total and calculated free testosterone (both P<0.001) than the ovulating women. HSDD was reported in 34% of the transsexual and 23% of the ovulating women (P=0.30). Both groups reported similar levels of sexual desire (P=0.97). For transsexual women, no significant correlation was found between sexual desire and total (P=0.64) or free testosterone (P=0.82). In ovulating women, these correlations were significant (P=0.006, resp. P=0.003). CONCLUSIONS: HSDD is reported in one-third of transsexual women. This prevalence is not substantially different from controls, despite markedly lower (free) testosterone levels, which argues against a major role of testosterone in this specific group.