A Phase 2 Proof-of-Concept, Randomized, Placebo-Controlled Trial of CX-8998 in Essential Tremor.

BACKGROUND: Available essential tremor (ET) therapies have limitations. OBJECTIVES: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor. METHODS: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry. RESULTS: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%). CONCLUSIONS: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers.

Neuropathic pain affects ~ 6.9-10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage-dependent and use-dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo-controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7-day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax ), area under the concentration-time curve from predose to 24 hours postdose (AUC0-24 ), time to Cmax (Tmax ), and terminal half-life (t1/2), among others, were assessed. Drug-related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug-related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1-2 hours, and t1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady-state was achieved from day 5 onward. These data indicate that oral vixotrigine is well-tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.

Evaluation of the Potential Pharmacokinetic Interactions Between Vixotrigine and an Oral Contraceptive.

BACKGROUND AND OBJECTIVE: Vixotrigine is a voltage- and use-dependent sodium channel blocker in development for neuropathic pain management. This study evaluated the effect of coadministration of vixotrigine (metabolized primarily via uridine diphosphate-glucuronosyltransferases) and an oral contraceptive containing ethinyl estradiol (uridine diphosphate-glucuronosyltransferase inducer) and levonorgestrel on the pharmacokinetics and safety of all three compounds. METHODS: In this phase I, open-label, fixed-sequence, multiple-dose study, 36 healthy women received oral vixotrigine 150 mg three times daily for 6 days and once on day 7. This was followed by a washout period, days 8-11. The oral contraceptive was administered alone on days 12-25 and with vixotrigine 150 mg three times daily on days 26-32. Serial blood samples were collected for pharmacokinetic analysis. Safety was assessed. RESULTS: The geometric least-squares mean ratios (90% confidence intervals) for the area under the concentration-time curve over 8 h and maximum concentration of vixotrigine co-administered with an oral contraceptive vs vixotrigine alone were 0.85 (0.82-0.89) and 0.91 (0.87-0.96), respectively. The geometric least-squares mean ratios (90% confidence interval) for area under the concentration-time curve over 24 h and maximum concentration of ethinyl estradiol with vixotrigine vs ethinyl estradiol alone were 0.94 (0.91-0.97) and 0.89 (0.84-0.94), respectively; the ratios for levonorgestrel with vixotrigine vs levonorgestrel alone were 1.06 (0.98-1.16) and 1.05 (0.98-1.13), respectively. No adverse events occurring with vixotrigine alone were deemed related to the study drug by the investigators. CONCLUSIONS: Coadministration of vixotrigine and an oral contraceptive containing ethinyl estradiol and levonorgestrel had no clinically relevant effect on exposure of all three compounds. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT03324685 (registered 25 October, 2017).

Evaluation of the Pharmacokinetic Interaction Between the Voltage- and Use-Dependent Nav1.7 Channel Blocker Vixotrigine and Carbamazepine in Healthy Volunteers.

Vixotrigine is a voltage- and use-dependent Nav1.7 channel blocker under investigation for the treatment of peripheral neuropathic pain conditions, including trigeminal neuralgia. Vixotrigine is metabolized primarily via uridine diphosphate-glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome P450 3A4 inducer, is a first-line treatment for trigeminal neuralgia. We conducted a double-blind, randomized, placebo-controlled, parallel-group, single-center phase 1 study to investigate the impact of coadministering vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in healthy volunteers, the safety and tolerability of combined treatment, and PK recovery of vixotrigine following carbamazepine discontinuation. Randomly assigned treatments were carbamazepine (100 mg twice a day, days 1-3 and 200 mg twice a day, days 4-21) or placebo on days 1 to 21. All volunteers received vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times, whole-blood samples were collected for PK assessment. Statistical analyses were performed on the log-transformed PK parameters area under the concentration-time curve within a dosing interval (AUC0-tau ) and maximum observed concentration (Cmax ) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC0-tau and Cmax were reduced by 31.6% and 26.3%, respectively, when coadministered with carbamazepine compared with placebo. Seven days after carbamazepine discontinuation, vixotrigine AUC0-tau and Cmax remained 24.5% and 21.4% lower compared with placebo. Carbamazepine AUC0-tau and Cmax were <10% lower when coadministered with vixotrigine compared on days 15 and 21. Vixotrigine/carbamazepine coadministration was well tolerated. These results suggest that vixotrigine does not have an effect on carbamazepine PK, and although carbamazepine has an effect on the exposure of vixotrigine, the effect is not considered clinically relevant.

Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer's Disease.

BACKGROUND: ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule ß-amyloid (Aß) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer's disease (AD). Tramiprosate has been found to inhibit ß-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aß42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers. METHODS: Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [1] a single ascending dose (SAD) study; [2] a 14-day multiple ascending dose (MAD) study; and [3] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study. RESULTS: ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration (C max) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials. CONCLUSIONS: ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

Pain intensity rating training: results from an exploratory study of the ACTTION PROTECCT system.

Clinical trial participants often require additional instruction to prevent idiosyncratic interpretations regarding completion of patient-reported outcomes. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership developed a training system with specific, standardized guidance regarding daily average pain intensity ratings. A 3-week exploratory study among participants with low-back pain, osteoarthritis of the knee or hip, and painful diabetic peripheral neuropathy was conducted, randomly assigning participants to 1 of 3 groups: training with human pain assessment (T+); training with automated pain assessment (T); or no training with automated pain assessment (C). Although most measures of validity and reliability did not reveal significant differences between groups, some benefit was observed in discriminant validity, amount of missing data, and ranking order of least, worst, and average pain intensity ratings for participants in Group T+ compared with the other groups. Prediction of greater reliability in average pain intensity ratings in Group T+ compared with the other groups was not supported, which might indicate that training produces ratings that reflect the reality of temporal pain fluctuations. Results of this novel study suggest the need to test the training system in a prospective analgesic treatment trial.

Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects.

INTRODUCTION: SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing results to duloxetine, a dual reuptake inhibitor of NE and 5-HT. METHODS: Eighteen healthy normal subjects received either SEP-432 (300 mg/day), duloxetine (60 mg/day), or placebo for 14 days in-clinic (double blind) with CSF and plasma collections at baseline (single lumbar puncture) and Day 14 (24-h CSF and plasma collection). Concentrations of monoamines and their metabolites, as well as pharmacokinetic concentrations of SEP-432 and metabolite, were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Compared to placebo in the Day 14 area under the curve 24-h (AUC0-24 h ) analysis, SEP-432 significantly (P < 0.05) decreased the NE metabolite dihydroxyphenylglycol (DHPG) in CSF and plasma, decreased 5-HT in plasma, and did not affect DA metabolites, while duloxetine had significant effects on DHPG and 5-HT. Time-matched baseline to Day 14 biomarker comparisons confirmed these findings. CONCLUSION: CSF monoamine biomarkers confirmed central NET activity for SEP-432 and duloxetine's dual reuptake inhibition.

Inclusion and exclusion criteria for epilepsy clinical trials-recommendations from the April 30, 2011 NINDS workshop.

On April 30th, 2011 the National Institute of Neurological Disorders and Stroke (NINDS) held a workshop to identify key problems in recent epilepsy clinical trials and propose approaches to address the barriers that impede development of new therapeutic options for epilepsy. Preliminary recommendations were made for selection criteria for subjects entered into epilepsy trials that maximize the scientific impact of the trial and increase the ability to recruit appropriate subjects efficiently and safely. These recommendations were further refined by the authors following the workshop, and subsequently shared with all NINDS workshop participants and with the participants of the 2011 AED XI workshop on epilepsy trials (approximately 200 participants) for further comment. The working group agreed to a final set of criteria that include updated considerations of subject age, clinical semiology, EEG and imaging results, use of prior and current therapies, co-occurring conditions, and suicidality, among others.

Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To evaluate the efficacy and safety of ziprasidone adjunctive to a mood stabilizer for the maintenance treatment of bipolar mania. METHOD: Subjects with DSM-IV bipolar I disorder with a Mania Rating Scale score > or = 14 were enrolled. Subjects achieving > or = 8 consecutive weeks of stability with open-label ziprasidone (80-160 mg/d) and lithium or valproate (period 1) were randomly assigned in the 6-month, double-blind maintenance period (period 2) to ziprasidone plus mood stabilizer or placebo plus mood stabilizer. The primary and key secondary end points were the time to intervention for a mood episode and time to discontinuation for any reason, respectively. Inferential analysis was performed using a Kaplan-Meier product-limit estimator (log-rank test). The study was conducted from December 2005 to May 2008. RESULTS: A total of 127 and 113 subjects were randomly assigned to ziprasidone and placebo, respectively. Intervention for a mood episode was required in 19.7% and 32.4% of ziprasidone and placebo subjects, respectively. The time to intervention for a mood episode was significantly longer for ziprasidone than placebo (P = .0104). The median time to intervention for a mood episode among those requiring such an intervention (n = 61) was 43.0 days for ziprasidone versus 26.5 days for placebo. The time to discontinuation for any reason was significantly longer for ziprasidone (P = .0047). Adjunctive ziprasidone treatment was well tolerated. Among treatment-emergent adverse events occurring in > or = 5% of subjects in either treatment group during period 2, only tremor occurred more frequently in the ziprasidone versus placebo group (6.3% vs 3.6%). CONCLUSIONS: Ziprasidone is an effective, safe, and well-tolerated adjunctive treatment with a mood stabilizer for long-term maintenance treatment of bipolar mania. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00280566.

Psychosocial functioning and health-related quality of life in children and adolescents treated with open-label ziprasidone for bipolar mania, schizophrenia, or schizoaffective disorder.

OBJECTIVE: The aim of this study was to examine global functioning, health-related quality of life (HRQOL), and clinical outcome in children and adolescents with bipolar I disorder, schizophrenia, or schizoaffective disorder following ziprasidone treatment. METHODS: Sixty-three subjects (aged 10-17 years) received open-label ziprasidone, titrated from 10 to 40 mg twice a day (b.i.d.) (low-dose group) or from 20 to 80 mg b.i.d. (high-dose group); fixed doses were used until week 3, followed by flexible doses for 6 months. The Children's Global Assessment Scale (CGAS) characterized functional impairment at baseline and following treatment. The Child Health Questionnaire (CHQ) assessed HRQOL at baseline. RESULTS: Baseline CHQ showed greater impairment in psychosocial functioning than in physical health. Baseline mean CGAS scores were substantially below normal (i.e., <70), indicating functional impairment. Improvement in CGAS scores occurred as early as the first week of treatment. The low correlations between both CHQ and CGAS and the efficacy measures at baseline indicate that these scales measure different constructs. Nevertheless, there was good correlation between improvements in the CGAS and changes in Brief Psychiatric Rating Scale-Anchored (BPRS-A) and Young Mania Rating Scale (YMRS) during ziprasidone treatment. CONCLUSION: CHQ and CGAS scales may be useful together with standard efficacy measures for children and adolescents with these disorders.

The impact of calories and fat content of meals on oral ziprasidone absorption: a randomized, open-label, crossover trial.

BACKGROUND: Food is known to increase the bioavailability of ziprasidone. Therefore, we evaluated the effects of meals of differing caloric and fat content on steady-state ziprasidone exposure in a stable, treated group of subjects with DSM-IV diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder, or psychotic disorder (not otherwise specified) who were already receiving oral ziprasidone as their standard therapy. METHOD: Patients took ziprasidone under 6 meal conditions in randomized sequences (fasted, low calorie/low fat, low calorie/high fat, medium calorie/high fat, high calorie/low fat, and high calorie/high fat); each crossover period was separated by at least 3 days for washout of the previous meal condition. Serial blood samples were obtained over the 12 hours postdose. The study was conducted from July 27 to September 28 of 2006. RESULTS: Maximum ziprasidone exposures in this study were observed with high-calorie meals (1000 kcal), which were nearly twice those observed under fasting conditions. The medium-calorie meal (500 kcal) was associated with exposures similar to the high-calorie meals. Low-calorie meals (250 kcal) were associated with exposures that were approximately 60% to 90% lower than those of medium- and high-calorie meals, and approached exposures seen under fasting conditions. Fat content of the meal had no significant effect on ziprasidone absorption. The ziprasidone exposures observed with medium- and high-calorie meals had less variability than those with low-calorie meals and under fasting conditions. CONCLUSIONS: These results confirm that ziprasidone should be taken with food and that a meal equal to or greater than 500 kcal, irrespective of fat content, is required for optimal and reproducible bioavailability of the administered dose.

Tolerability of oral ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder.

OBJECTIVE: This study characterizes the tolerability of ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. METHOD: Sixty-three subjects (aged 10-17 years) entered an open-label study consisting of a 3-week fixed-dose period (Period 1) and a subsequent 24-week flexible-dose period (Period 2). In Period 1, subjects received ziprasidone 80 or 160 mg/d in two divided doses, titrated over 10 days. In Period 2, subjects received flexible doses (20-160 mg/d). Tolerability was evaluated using movement rating scales, laboratory tests, and electrocardiograms. Clinical response was assessed using the Young Mania Rating Scale, the Brief Psychiatric Rating Scale-Anchored Version, and the Clinical Global Impressions-Severity scale. RESULTS: Adverse events (AEs) occurred mostly during dose titration and in the high-dose (160 mg/d) group. The most common AEs during Period 1 were sedation (32%), somnolence (30%), and nausea (25%) and during Period 2 were sedation (30%), somnolence (30%), and headache (25%). The incidence of movement disorder AEs was 22% and 16% during Periods 1 and 2, respectively. Six percent of study participants discontinued study participation due to AEs during Period 1 and 20% discontinued in Period 2. Thirty-three percent of subjects gained >or=7% of their baseline weight. No Fridericia-corrected QT (QTcF) intervals of >450 ms were observed during Period 1 and only one occurred during Period 2. No QTcF increase >or=60 ms from baseline was observed. Symptom reductions were observed in all patient groups. CONCLUSIONS: No unexpected tolerability findings were observed in this prospective trial of ziprasidone in children and adolescents with bipolar mania, schizophrenia, or schizoaffective disorder. On the basis of the results, a starting dose of 20 mg/d titrated to between 80 and 160 mg/d over 1-2 weeks appears optimal for most patients.

Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study.

Seven published, randomized, placebo-controlled clinical trials with pregabalin have shown robust efficacy for relief of neuropathic pain from DPN and PHN. An investigation of the efficacy and safety of twice daily pregabalin enrolled 395 adults with painful DPN for > or = 1 year in a 12-week, double-blind, placebo-controlled trial. Patients were randomized to placebo, 150, 300, or 600 mg/day pregabalin (n = 96, 99, 99, and 101). Primary efficacy measure was change from baseline in endpoint mean pain score from patients' daily pain diaries. Secondary efficacy measures included pain-related sleep-interference scores, Patient and Clinical Global Impressions of Change (PGIC, CGIC), and the EuroQOL Health Utilities Index (EQ-5D). Statistically significant reduction in pain was observed in patients receiving pregabalin 600 mg/day, and 46% of patients treated with 600 mg/day pregabalin reported > or = 50% improvement in mean pain scores from baseline (vs 30% of placebo patients, p = 0.036). Number needed to treat to achieve such response was 6.3. Pregabalin 600 mg/day was significantly superior to placebo in improving pain-related sleep-interference scores (p = 0.003), PGIC (p = 0.021), and CGIC (p = 0.009). (Neither pregabalin 150 nor 300 mg/day separated from placebo on these measures, largely because of an atypically large placebo response in one country representing 42% of patients.) All pregabalin dosages were superior to placebo in improving EQ-5D utility scores (all p > or = 0.0263 vs placebo). Pregabalin was well tolerated at all dosages; adverse events were generally mild to moderate. Number needed to harm (discontinuation because of adverse events) was 10.3 for pregabalin 600 mg/day.

Efficacy and tolerability of sumanirole in restless legs syndrome: a phase II, randomized, double-blind, placebo-controlled, dose-response study.

OBJECTIVE: To compare the efficacy, safety and tolerability of sumanirole with placebo in patients with idiopathic restless legs syndrome (RLS). METHODS: In this double-blind, placebo-controlled, randomized, parallel-group, dose-response study, 270 patients with idiopathic RLS were enrolled and randomized to receive sumanirole 0.5, 1.0, 2.0, or 4.0mg, or placebo. The primary efficacy endpoint was mean change of the total score of the International Restless Legs Scale (IRLS-10), a 10-item scale, from baseline to end of maintenance. Secondary assessments included polysomnography (PSG) variables. RESULTS: Treatment with sumanirole was well tolerated. Mean change in IRLS-10 showed no statistically significant change compared with placebo at any dose, although the mean change with the 4.0-mg dose was numerically greater than the other doses and placebo. PSG variables, specifically the periodic leg movements during sleep, showed statistically significant dose-related improvement in favor of sumanirole. Consistent with earlier multinational, multicenter studies in RLS, high placebo response rates were seen with IRLS-10 but not with PSG variables. CONCLUSIONS: Given data published in Parkinson's disease, the dose range of sumanirole selected here may have been too low. Alternatively, dopamine D(2) selective agents could be intrinsically less effective than agonists with combined D(2)/D(3) activity. Sumanirole demonstrated an excellent safety profile.

Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial.

OBJECTIVE: This trial evaluated the efficacy and safety of pregabalin dosed twice daily (BID) for relief of neuro-pathic pain associated with postherpetic neuralgia (PHN). RESEARCH DESIGN AND METHODS: The 13-week, double-blind, placebo-controlled study randomized 370 patients with PHN to pregabalin (150, 300, or 600 mg/day BID) or placebo. MAIN OUTCOME MEASURES: Primary efficacy measure was endpoint mean pain score from daily pain diaries. Secondary efficacy measures included endpoint mean sleep-interference score from daily sleep diaries and Patient Global Impression of Change (PGIC). Safety evaluations included adverse events (AEs), physical and neurologic examinations, 12-lead ECG, vital signs, and laboratory testing. RESULTS: Pregabalin provided significant, dose-proportional pain relief at endpoint: difference from placebo in mean pain score, 150 mg/day, -0.88, p = 0.0077; 300 mg/day, -1.07, p = 0.0016; 600 mg/day, -1.79, p = 0.0003. Weekly mean pain scores significantly improved as early as week 1. Sleep interference in all pregabalin groups was also significantly improved at endpoint, compared with placebo (p < 0.001), beginning at week 1 (p < 0.01). At study termination, patients in the 150 (p = 0.02) and 600 mg/day (p = 0.003) groups were more likely to report global improvement than were those in the placebo group. Most AEs were mild or moderate. Among pregabalin-treated patients, 13.5% withdrew due to AEs, most commonly for dizziness (16 patients, 5.8%), somnolence (8, 2.9%), or ataxia (7, 2.5%). CONCLUSIONS: Pregabalin, dosed BID, reduced neuropathic pain associated with PHN and was well tolerated. It also reduced the extent to which pain interfered with sleep. Pregabalin's effects were seen as early as week 1 and were sustained throughout the 13-week study.

The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study.

BACKGROUND AND PURPOSE: ZK 200775 is a selective competitive AMPA receptor antagonist. It has demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers. We tested the safety and tolerability of ZK 200775 in patients with acute ischaemic stroke. METHODS: In a multicentre double-blind, randomised, placebo-controlled phase II trial, 61 ischaemic stroke patients were treated with either placebo or active drug in a dose finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 h (group 1) and 13 patients received a total dose of 525 mg in 48 h (group 2), and 11 patients received a total dose of 105 mg over a period of 6 h (group 3). We studied the pharmacokinetics of the compound and the effect of the infusion on the neurologic and haemodynamic parameters of the patients. The study was not powered to detect neuroprotective efficacy. RESULTS: In group 2 there was a significant transient worsening in the mean NIH stroke scale score 14- 18 h after the start of treatment. This was due to reduction of consciousness (stupor and coma) in 8 out of 13 patients. Level of consciousness improved approximately 6 h after cessation of infusion. No significant haemodynamic responses were observed. Even after reduction of the administered dose and duration of infusion to 6 h (group 3), 2 patients experienced a reduction in level of consciousness. The effect of ZK 200775 on level of consciousness gave cause for concern and the trial was stopped prematurely for safety reasons. CONCLUSIONS: The AMPA antagonist ZK 200775 reversibly worsened the neurological condition in patients with acute ischaemic stroke. Our results suggest that ZK 200775 exerts significant sedative effects in patients with acute stroke which preclude its further development as a neuroprotective agent in this indication.

Concentration-effect relationships of alcohol in a computerised psychometric test system.

The purpose of this study was to validate a computerised psychometric test system by demonstrating the change of the test variables of the Bochum Diagnostic System after administration of alcohol. Twenty-four healthy young male or female volunteers participated in a doubleblind, randomised, placebo-controlled study in a 3-way cross-over design. The volunteers took single doses of placebo, 0.4 and 0.7 g alcohol/kg body weight (females: 10% less) in a random sequence. Psychometric tests were performed before as well as 1 and 3 h after the administration of alcohol. The effects of alcohol on the psychometric performance were most pronounced 1 h after administration. At this time a significant dose-dependent impairment of performance in the concentration test, the simple and complex reaction tests, the vigilance test and the coordination test was observed. 3 h after administration, significant effects were only observed in the complex reaction test and the concentration test. Maximal alcohol serum concentrations of 0.47 +/- 0.05 % per thousand and of 0.90 +/- 0.15 % per thousand were reached after administration of 0.4 g/kg and 0.7 g/kg, respectively. The correlations between individual serum alcohol concentrations and differences of psychometric variables from baseline were significant. It is concluded that the tests of the Bochum Diagnostic System can quantitatively measure the effects of alcohol. The most sensitive tests are the complex reaction test and the concentration test.

Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial.

This study was designed to assess the efficacy and safety of pregabalin-a novel alpha(2)-delta ligand with analgesic, anxiolytic, and anticonvulsant activity-for treating neuropathic pain in patients with post-herpetic neuralgia (PHN). Two hundred and thirty-eight patients were randomised into this multicentre, doubleblind, placebo-controlled trial to receive 150 (n=81), 300 mg/day (n=76) pregabalin, or placebo (n=81) for 8 weeks. Among the exclusion criteria was failure to respond to previous treatment for PHN with gabapentin at doses > or =1200 mg/day. Endpoint mean pain scores were significantly reduced in patients receiving 150 or 300 mg/day pregabalin compared with placebo. Efficacy was observed as early as week 1 and was maintained throughout the study. Significantly more patients in both pregabalin groups (150 mg, 26%; 300 mg, 28%) were responders (> or =50% decrease in mean pain score from baseline to endpoint) than in the placebo group (10%). Additionally, by week 1 and for the study's duration, 150 and 300 mg/day pregabalin significantly reduced weekly mean sleep interference scores. More pregabalin-treated patients than placebo-treated patients reported that they were 'much improved' or 'very much improved'. Health-related quality-of-life (HRQoL) measurements using the SF-36 Health Survey demonstrated improvement in the mental health domain for both pregabalin dosages, and bodily pain and vitality domains were improved in the 300 mg/day group. The most frequent adverse events were dizziness, somnolence, peripheral oedema, headache, and dry mouth. Pregabalin efficaciously treated the neuropathic pain of PHN. Additionally, pregabalin was associated with decreased sleep interference and significant improvements in HRQoL measures.

AMPA antagonist ZK200775 in patients with acute ischemic stroke: possible glial cell toxicity detected by monitoring of S-100B serum levels.

BACKGROUND AND PURPOSE: S-100B and neuron-specific enolase (NSE) serum concentrations can be used as peripheral markers of glial cell and neuronal damage, respectively. We investigated these markers in a clinical trial with the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) antagonist ZK200775 in acute ischemic stroke patients. METHODS: In a multicenter, double-blind, randomized, placebo-controlled phase 2 trial, 61 ischemic stroke patients were treated with either placebo or active drug in a dose-finding design. Twenty-five patients received placebo, 12 patients received a total dose of 262.5 mg in 48 hours (dose group 1), and 13 patients received a total dose of 525 mg in 48 hours (dose group 2). Eleven patients received a total dose of 105 mg over a period of 6 hours (dose group 3; reduction of total dose and infusion time because of adverse events in group 2). Serum concentrations of S-100B and NSE were analyzed with the use of a monoclonal sandwich immunoluminometric assay. Neurological outcome was assessed with the National Institutes of Health Stroke Scale (NIHSS). RESULTS: In group 2 there was a significant transient worsening in the mean NIHSS score 48 hours after the start of treatment. The mean increase was 11 points. This was due to reduction of consciousness (stupor and coma) in 8 of 13 patients. Neurological deterioration in group 2 was associated with a higher increase of S-100B concentrations, but not of NSE concentrations, than in the placebo group. The trial was stopped prematurely for safety reasons. CONCLUSIONS: The AMPA antagonist ZK200775 transiently worsened the neurological condition in patients with acute ischemic stroke. Our results suggest that in addition to neuronal dysfunction, glial cell toxicity may have occurred. It may be useful to introduce monitoring of serum markers of brain damage in phase 2 trials with glutamate receptor antagonists.