Randomized Phase I Trial of the α-Synuclein Antibody Lu AF82422.

BACKGROUND: Immunotherapy targeting pathological α-synuclein (α-syn) species is a promising strategy for slowing disease progression in neurodegenerative synucleinopathies, including Parkinson's disease (PD). OBJECTIVE: The aim was to evaluate the safety, tolerability, pharmacokinetics, and target engagement of ascending doses of Lu AF82422. METHODS: In this first-in-human study (NCT03611569), healthy participants (18-55 years, cohort A) and patients with PD (40-80 years, Hoehn and Yahr stage ≤3, cohort B) were enrolled in ascending-dose cohorts and randomly assigned to receive single intravenous infusions of Lu AF82422 (cohorts A1-A6: 75, 225, 750, 2250 4500, and 9000 mg, respectively; cohorts B1 and B2: 2250 and 9000 mg, respectively) or placebo. Participants were monitored during a 12-week observational period. RESULTS: Overall, single intravenous infusions of Lu AF82422 were safe and well tolerated, and no serious adverse events (AE) were observed; the most common AEs were related to the study on lumbar punctures, headache, and common infections. Lu AF82422 concentrations (in plasma and cerebrospinal fluid [CSF]) increased in a dose-proportional manner with no observable differences between cohorts; mean plasma half-life was 700 h. Plasma concentrations of Lu AF82422 had an immediate, concentration-dependent lowering effect on the plasma concentration of free α-syn and on the ratio of free to total α-syn in all cohorts and lowered the free-to-total α-syn ratio in CSF in the high-dose PD cohort. CONCLUSIONS: The safety and pharmacokinetic profile of Lu AF82422 were appropriate for further clinical development, and results indicated peripheral target engagement. The central target engagement observed in participants with PD indicates that the doses of Lu AF82422 tested may provide CSF concentrations sufficient to target aggregated forms of α-syn. © 2024 H. Lundbeck A/S. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A Randomized, Double-Blind, Controlled Phase II Study of Foliglurax in Parkinson's Disease.

BACKGROUND: Agents targeting the metabotropic glutamate receptor 4 have emerged as a potentially attractive new class of drugs for the treatment of Parkinson's disease (PD). OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of foliglurax in reducing off time and dyskinesia in patients with PD. METHODS: This was a 28-day, multicenter, randomized, placebo-controlled, double-blind clinical trial of foliglurax 10 and 30 mg as adjunct to levodopa in 157 randomly assigned patients with PD and motor complications. RESULTS: Although dose-dependent decreases in daily awake off time were apparent following treatment with foliglurax, the change from baseline to day 28 in off time (primary endpoint) and dyskinesia (secondary endpoint) did not improve significantly compared with placebo for either foliglurax dose. Treatment with foliglurax was generally safe, and there were no relevant safety signals. CONCLUSIONS: There was no evidence in this study that foliglurax has efficacy in improving levodopa-induced motor complications in PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Diagnostic criteria for apathy in neurocognitive disorders.

INTRODUCTION: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed. METHODS: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. RESULTS: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. DISCUSSION: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

Efficacy and Safety of Brexpiprazole for the Treatment of Agitation in Alzheimer's Dementia: Two 12-Week, Randomized, Double-Blind, Placebo-Controlled Trials.

OBJECTIVE: To assess the efficacy, safety, and tolerability of brexpiprazole in patients with agitation in Alzheimer's dementia (AAD). DESIGN: Two 12-week, randomized, double-blind, placebo-controlled, parallel-arm studies (NCT01862640; NCT01922258). SETTING: Study 1: 81 sites in 7 countries. Study 2: 62 sites in 9 countries. PARTICIPANTS: Patients with AAD (Study 1: 433 randomized; Study 2: 270 randomized) in a care facility or community-based setting. Stable Alzheimer disease medications were permitted. INTERVENTION: Study 1 (fixed dose): brexpiprazole 2 mg/day, brexpiprazole 1 mg/day, or placebo (1:1:1) for 12 weeks. Study 2 (flexible dose): brexpiprazole 0.5-2 mg/day or placebo (1:1) for 12 weeks. MEASUREMENTS: Cohen-Mansfield Agitation Inventory (CMAI) (Total score range: 29-203; higher scores indicate more frequent agitated behaviors), and Clinical Global Impression - Severity of illness (CGI-S) as related to agitation. Safety was also assessed. RESULTS: In Study 1, brexpiprazole 2 mg/day demonstrated statistically significantly greater improvement in CMAI Total score from baseline to Week 12 than placebo (adjusted mean difference, -3.77; confidence limits, -7.38, -0.17; t(316) = -2.06; p = 0.040; MMRM). Brexpiprazole 1 mg/day did not show meaningful separation from placebo (0.23; -3.40, 3.86; t(314) = 0.12; p = 0.90; MMRM). In Study 2, brexpiprazole 0.5-2 mg/day did not achieve statistical superiority over placebo (-2.34; -5.49, 0.82; t(230) = -1.46; p = 0.15; MMRM). However, a benefit was observed in post hoc analyses among patients titrated to the maximum brexpiprazole dose of 2 mg/day compared with similarly titrated placebo patients (-5.06; -8.99, -1.13; t(144) = -2.54; p = 0.012; MMRM). On the CGI-S, a greater numerical improvement than placebo was demonstrated for brexpiprazole 2 mg/day in Study 1 (-0.16; -0.39, 0.06; t(337) = -1.42; nominal p = 0.16; MMRM), and a greater improvement for brexpiprazole 0.5-2 mg/day in Study 2 (-0.31; -0.55, -0.06; t(222) = -2.42; nominal p = 0.016; MMRM). In Study 1, treatment-emergent adverse events (TEAEs) with incidence ≥5% among patients receiving brexpiprazole 2 mg/day were headache (9.3% versus 8.1% with placebo), insomnia (5.7% versus 4.4%), dizziness (5.7% versus 3.0%), and urinary tract infection (5.0% versus 1.5%). In Study 2, TEAEs with incidence ≥5% among patients receiving brexpiprazole 0.5-2 mg/day were headache (7.6% versus 12.4% with placebo) and somnolence (6.1% versus 3.6%). In both studies, the majority of TEAEs were mild or moderate in severity. CONCLUSIONS: Brexpiprazole 2 mg/day has the potential to be efficacious, safe, and well tolerated in the treatment of AAD.

Open-label Study with Nalmefene as Needed Use in Alcohol-Dependent Patients with Evidence of Elevated Liver Stiffness and/or Hepatic Steatosis.

AIMS: This open-label study in patients with alcohol dependence and evidence of elevated liver stiffness and/or hepatic steatosis was designed to explore the efficacy of nalmefene (18 mg) in reducing alcohol consumption and its subsequent effects on a variety of clinically relevant liver parameters. METHODS: Adult patients with a diagnosis of alcohol dependence and evidence of elevated liver stiffness and/or hepatic steatosis (liver stiffness >6 kPa or controlled attenuation parameter (CAP) >215 dB/m as measured by transient elastography) were recruited at two study sites in Germany. During the 12-week treatment period, patients were instructed to take nalmefene each day they perceived a risk of drinking alcohol. RESULTS: All 45 enrolled patients took at least one dose of nalmefene and 39 completed the study. After 12 weeks of study treatment with nalmefene patients showed a reduction in alcohol consumption of -13.5 days/month heavy drinking days and -45.8 g/day total alcohol consumption. Most liver parameters showed modest changes at Week 12; there was a 13% decrease in liver stiffness and 10% reduction in CAP values. Results indicated non-significant negative associations between alcohol consumption and liver stiffness and/or CAP over this 12-week study. Nalmefene was generally well tolerated, and most adverse events were mild or moderate, the most frequent being dizziness. CONCLUSIONS: Patients treated with nalmefene for 12 weeks had reductions in alcohol consumption by ~50% relative to baseline and showed trends to improvement in liver stiffness and CAP.

Long-term safety and efficacy of nalmefene in Japanese patients with alcohol dependence.

AIM: The safety and efficacy of nalmefene in Japanese patients with high or very high World Health Organization drinking risk level of alcohol dependence were assessed in a multicenter, randomized, double-blind, placebo-controlled, phase 3 (lead-in) study. Here, the long-term safety and efficacy of nalmefene in an open-label extension of the lead-in study are presented. METHODS: Patients who completed the 24-week lead-in study were eligible for the extension study, where they were treated with nalmefene 20 mg as needed for 24 weeks. The long-term safety and efficacy of nalmefene 20 mg during the total 48-week period were evaluated. Treatment-emergent adverse events during the study period were recorded and change from baseline in the number of heavy drinking days and total alcohol consumption were calculated. RESULTS: Overall, long-term nalmefene 20 mg was well tolerated; the main treatment-emergent adverse events reported in ≥5% of patients included nasopharyngitis (37.2%), nausea (36.5%), somnolence (21.2%), dizziness (16.8%), malaise (14.6%), and vomiting (12.4%). The number of heavy drinking days and total alcohol consumption decreased from baseline to 48 weeks (mixed model for repeated measures, least squares mean ± standard error, -15.09 ± 0.77 days/month and -53.20 ± 2.29 g/day, respectively) during the study. CONCLUSION: This long-term evaluation in Japanese patients with high or very high drinking risk levels of alcohol dependence indicated that nalmefene was safe, well tolerated, and efficacious.

Nalmefene in alcohol-dependent patients with a high drinking risk: Randomized controlled trial.

AIMS: Reducing alcohol consumption is one treatment approach for alcohol-dependent patients. This study compared nalmefene 20 mg and 10 mg with placebo, combined with psychosocial support, in alcohol-dependent Japanese patients with a high or very high drinking risk level (DRL). METHODS: This was a multicenter, randomized, double-blind, phase 3 study conducted in alcohol-dependent patients with a high or very high DRL. Patients were randomized to 24 weeks of treatment with as-needed nalmefene 20 mg, 10 mg, or placebo with psychosocial support. The primary endpoint was change in heavy drinking days (HDD) from baseline to week 12. A key secondary endpoint was the change in total alcohol consumption (TAC) from baseline to week 12. RESULTS: At week 12, 234, 206, and 154 patients who received placebo, nalmefene 20 mg, and 10 mg were included in the primary endpoint analysis. Compared with placebo, nalmefene was associated with significant reductions in HDD at week 12 (difference in 20 mg group, -4.34 days/month; 95% confidence interval [CI]: -6.05 to -2.62; P < 0.0001; difference in 10 mg group, -4.18 days/month; 95%CI: -6.05 to -2.32; P < 0.0001), as well as a significant reduction in TAC at week 12 (P < 0.0001). The incidence of treatment-emergent adverse events was 87.9%, 84.8%, and 79.2% in the groups receiving nalmefene 20 mg, 10 mg, and placebo, respectively. These events were mostly of mild or moderate severity. CONCLUSIONS: Nalmefene 20 mg or 10 mg effectively reduced alcohol consumption and was well tolerated in alcohol-dependent patients with a high or very high DRL.

Nalmefene, Given as Needed, in the Routine Treatment of Patients with Alcohol Dependence: An Interventional, Open-Label Study in Primary Care.

AIMS: This 12-week, open-label, primary care study (NCT02195817) evaluated the efficacy and safety of nalmefene, taken as needed, to reduce alcohol consumption in adults with a diagnosis of alcohol dependence and drinking at least at high drinking risk levels (DRL, > 60 g/day for men, > 40 g/day for women). METHODS: Following the Screening Visit, patients recorded their daily alcohol consumption for 2 weeks. Patients were then categorised by their self-reported drinking levels; those who maintained at least a high DRL in the 2-week period were included in Cohort-A, and those who reduced their alcohol consumption below high DRL were included in Cohort-B. Cohort-A received simple psychosocial interventions and were supplied with nalmefene 18 mg to be taken on days when they perceived a risk of drinking alcohol. Patients in Cohort-B received a simple psychosocial intervention and were treated per normal practice. RESULTS: Of the 378 enrolled patients, 330 were included in Cohort-A and 48 in Cohort-B. For patients in Cohort-A, the mean change from screening to Week-12 in the number of heavy drinking days/month was -13.1 days/month (95% CI -14.4 to -11.9, p < 0.0001). Overall, 55% of patients reduced their DRL by ≥2 risk levels and 44% of patients reduced to a low DRL. The most common adverse events were nausea (18.3%) and dizziness (17.7%). Patients in Cohort-B maintained their lower level alcohol consumption at the 12-week follow-up. CONCLUSIONS: Patients with alcohol dependence treated in primary care with nalmefene, taken as needed, in conjunction with simple psychosocial support, significantly reduced their alcohol consumption. Treatment was well tolerated.

Safety and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: pooled data from randomised, double-blind, placebo-controlled studies.

INTRODUCTION: Extended release quetiapine fumarate (quetiapine XR) is a new formulation that allows once-daily dosing and a titration regimen that is simpler than that of immediate release quetiapine (quetiapine IR) and may potentially increase patients' adherence to their prescribed medication. METHODS: The tolerability of quetiapine XR was examined in an analysis of pooled data from three Phase III, double-blind, placebo-controlled, randomised studies with quetiapine IR as a reference treatment. RESULTS: The overall incidence of adverse events (AEs) was similar for quetiapine XR (69.5%) and quetiapine IR (72.5%). Most AEs were mild to moderate in severity and in line with those observed with quetiapine IR. The more rapid dose titration of quetiapine XR did not produce any new safety concerns and was as well tolerated as the regimen for quetiapine IR. CONCLUSIONS: The results of this pooled analysis show that quetiapine XR administered once daily is generally as well tolerated as quetiapine IR given twice daily. These data, together with the simpler dose-titration of quetiapine XR that allowed therapeutically effective doses to be reached by Day 2, suggest that this formulation potentially may improve adherence in patients with schizophrenia.

Evaluation of Drinking Risk Levels as Outcomes in Alcohol Pharmacotherapy Trials: A Secondary Analysis of 3 Randomized Clinical Trials.

Importance: The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use. Objective: To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes. Design, Setting, and Participants: Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence. Main Outcomes and Measures: Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h). Results: Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, -0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, -0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, -0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, -0.020 to 0.303]; varenicline, 0.146 [95% CI, -0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, -0.021 to 0.302]; varenicline, 0.232 [95% CI, -0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]). Conclusions and Relevance: WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days. Trial Registration: ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925.

Evaluation of the feasibility of switching from immediate release quetiapine to extended release quetiapine fumarate in stable outpatients with schizophrenia.

This double-blind, double-dummy study (D1444C00146) evaluated the efficacy and safety of switching patients with clinically stable schizophrenia from quetiapine immediate release (IR) to the same dose of once-daily extended release quetiapine fumarate (quetiapine XR). Patients received quetiapine IR 400-800 mg/day twice daily for 4 weeks, and were then randomized (2 : 1) to a once-daily equivalent dose of quetiapine XR or maintained on IR for 6 weeks. The primary variable was the proportion of patients who discontinued treatment owing to lack of efficacy or whose Positive and Negative Syndrome Scale scores increased by at least 20% from randomization to any visit. In total, 497 patients were randomized to quetiapine XR (n=331) or IR (n=166). Noninferiority (6% margin; one-sided test, 2.5% significance level) was narrowly missed for the primary efficacy variable for the modified intention-to-treat population (9.1%, quetiapine XR; 7.2%, quetiapine IR; difference 1.86%; 95% confidence interval: -3.78, 6.57; P=0.0431), but was shown for the per-protocol population (5.3%, quetiapine XR; 6.2%, quetiapine IR; difference: -0.83%; 95% confidence interval: -6.75, 3.71; P=0.0017). Serious adverse event incidence was low for quetiapine XR and IR; there were no unexpected adverse events. In conclusion, efficacy was maintained without compromising safety/tolerability when switching patients with stable schizophrenia from twice-daily quetiapine IR to once-daily quetiapine XR (400-800 mg/day).

Nalmefene Reduces Reward Anticipation in Alcohol Dependence: An Experimental Functional Magnetic Resonance Imaging Study.

BACKGROUND: Nalmefene is a µ and δ opioid receptor antagonist, κ opioid receptor partial agonist that has recently been approved in Europe for treating alcohol dependence. It offers a treatment approach for alcohol-dependent individuals with "high-risk drinking levels" to reduce their alcohol consumption. However, the neurobiological mechanism underpinning its effects on alcohol consumption remains to be determined. Using a randomized, double-blind, placebo-controlled, within-subject crossover design we aimed to determine the effect of a single dose of nalmefene on striatal blood oxygen level-dependent (BOLD) signal change during anticipation of monetary reward using the monetary incentive delay task following alcohol challenge. METHODS: Twenty-two currently heavy-drinking, non-treatment-seeking alcohol-dependent males were recruited. The effect of single dose nalmefene (18 mg) on changes in a priori defined striatal region of interest BOLD signal change during reward anticipation compared with placebo was investigated using functional magnetic resonance imaging. Both conditions were performed under intravenous alcohol administration (6% vol/vol infusion to achieve a target level of 80 mg/dL). RESULTS: Datasets from 18 participants were available and showed that in the presence of the alcohol infusion, nalmefene significantly reduced the BOLD response in the striatal region of interest compared with placebo. Nalmefene did not alter brain perfusion. CONCLUSIONS: Nalmefene blunts BOLD response in the mesolimbic system during anticipation of monetary reward and an alcohol infusion. This is consistent with nalmefene's actions on opioid receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.

The Alcohol Clinical Trials Initiative (ACTIVE): purpose and goals for assessing important and salient issues for medications development in alcohol use disorders.

Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some 'standards' for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data). This variability impedes the commercial development of medications to treat alcohol dependence. Using a model similar to that used to develop an expert consensus for medications to improve cognitive aspects of schizophrenia (MATRICS) and in the treatment of pain (IMMPACT), a workgroup has been formed under the auspices of ACNP, known as the ACTIVE (Alcohol Clinical Trials Initiative) group, to evaluate data from completed clinical trials to develop a consensus on key issues in the conduct of clinical trials in alcohol dependence. ACTIVE consists of academic experts, industry representatives, and staff from the Food and Drug Administration, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse. This paper describes the rationale behind the effort, its history and organization, and initial key questions that have been identified as the primary focus of the workgroup. Future papers will focus on knowledge gained from the re-analysis of completed trials and provide consensus opinions regarding the performance of clinical trials that might be undertaken in the future.

A failed 6-week,randomized, double-blind, placebo-controlled study of once-daily extended release quetiapine fumarate in patients with acute schizophrenia: lessons learned.

OBJECTIVE: To demonstrate the efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in adults with acute exacerbation of schizophrenia. METHODS: A 6-week, double-blind, randomized, placebo-controlled study. In- or out-patients with a DSM-IV diagnosis of schizophrenia were randomized to fixed-dose quetiapine XR 400, 600, or 800 mg/day, quetiapine immediate release (IR) 800 mg/day, or placebo. Primary endpoint was change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 6. Other efficacy assessments included Clinical Global Impressions (CGI) of Severity (CGI-S) and of Improvement (CGI-I) ratings. Safety assessments included adverse event (AE) reporting and laboratory measures. RESULTS: 565 patients were randomized; 333 (58.9%) completed the study. Greater numeric improvements in PANSS total score were seen for quetiapine XR (all doses) and quetiapine IR versus placebo at Week 6; the differences were not statistically significant. Secondary efficacy endpoint results were similar. There was not a high placebo response in this study, but rather an attenuation of drug effect. In general, quetiapine XR was well tolerated over 6-weeks' treatment; there were no unexpected AEs. CONCLUSION: The efficacy of quetiapine XR (400, 600, and 800 mg/day) was not established at Week 6. Quetiapine IR, an agent with established efficacy in schizophrenia, also did not separate from placebo at endpoint. Therefore, this is considered a failed study and possible reasons for this are discussed. Quetiapine XR was generally well tolerated and its safety profile was consistent with the known profile of quetiapine.

A 24-week, multicenter, open-label, randomized study to compare changes in glucose metabolism in patients with schizophrenia receiving treatment with olanzapine, quetiapine, or risperidone.

OBJECTIVE: This randomized, 24-week, flexible-dose study compared changes in glucose metabolism in patients with DSM-IV schizophrenia receiving initial exposure to olanzapine, quetiapine, or risperidone. METHOD: The hypothesized primary endpoint was change (baseline to week 24) in area under the curve (AUC) 0- to 2-hour plasma glucose values during an oral glucose tolerance test (OGTT); primary analysis: olanzapine versus quetiapine. Secondary endpoints included mean change in AUC 0- to 2-hour plasma insulin values, insulin sensitivity index, and fasting lipids. The first patient enrolled on April 29, 2004, and the last patient completed the study on October 24, 2005. RESULTS: Mean weight change (kg) over 24 weeks was +3.7 (quetiapine), +4.6 (olanzapine), and +3.6 (risperidone). Based on data from 395 patients (quetiapine, N = 115 [mean dose = 607.0 mg/day], olanzapine, N = 146 [mean dose = 15.2 mg/day], and risperidone, N = 134 [mean dose = 5.2 mg/day]), mean change in AUC 0- to 2-hour glucose value (mg/dL x h) at week 24 was significantly lower for quetiapine versus olanzapine (t = 1.98, df = 377, p = .048). Increases in AUC 0- to 2-hour glucose values were statistically significant with olanzapine (+21.9 mg/dL x h, 95% CI = 11.5 to 32.4 mg/dL x h) and risperidone (+18.8 mg/dL x h, 95% CI = 8.1 to 29.4 mg/dL x h), but not quetiapine (+9.1 mg/dL x h, 95% CI = -2.3 to 20.5 mg/dL x h). AUC 0- to 2-hour insulin values increased statistically significantly with olanzapine (+24.5%, 95% CI = 11.5% to 39.0%), but not with quetiapine or risperidone. Reductions in insulin sensitivity index were statistically significant with olanzapine (-19.1%, 95% CI = -27.9% to -9.3%) and risperidone (-15.8%, 95% CI = -25.1% to -5.4%), but not quetiapine. Total cholesterol and low-density lipoprotein levels increased statistically significantly with olanzapine (+21.1 mg/dL, 95% CI = 13.0 to 29.2 mg/dL, and +20.5 mg/dL, 95% CI = 13.8 to 27.1 mg/dL, respectively) and quetiapine (+13.1 mg/dL, 95% CI = 4.3 to 21.9 mg/dL, and +13.3 mg/dL, 95% CI = 6.1 to 20.5 mg/dL, respectively), but not risperidone. Statistically significant increases in triglycerides (+30.9 mg/dL, 95% CI = 10.9 to 51.0 mg/dL), total cholesterol/high-density lipoprotein (HDL) ratio (0.5, 95% CI = 0.2 to 0.8), and triglyceride/HDL ratio (0.3, 95% CI = 0.0 to 0.6) were observed with olanzapine only. CONCLUSION: The results indicate a significant difference in the change in glucose tolerance during 6 months' treatment with olanzapine versus quetiapine, with significant reductions on olanzapine and risperidone, but not quetiapine; these differential changes were largely explained by changes in insulin sensitivity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00214578.

The efficacy and tolerability of once-daily extended release quetiapine fumarate in hospitalized patients with acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled study.

OBJECTIVES: This study aimed to demonstrate efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in patients with acute schizophrenia. METHODS: In this 6-week, randomized, double-blind study (5077IL/0041) patients were randomized to receive quetiapine XR (300, 600, or 800 mg/day), quetiapine fumarate immediate release (quetiapine IR) [300 or 600 mg/day], or placebo. Primary endpoint was change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Day 42. Secondary variables included PANSS response rate at Day 42 (>/=30% decrease in PANSS total score from baseline) and Clinical Global Impressions Severity (CGI-S) and Improvement (CGI-I) ratings. Safety assessments included adverse event (AE) reporting and laboratory measures. RESULTS: Of 532 patients randomized, 222 (41.7%) completed the study. Improvements in PANSS total scores from baseline to Day 42 across treatment groups were: quetiapine XR 300 mg/day -5.01, 600 mg/day -13.01 and 800 mg/day -11.17, quetiapine IR 300 mg/day -9.42 and 600 mg/day -6.97, and placebo -5.19; the difference in change was statistically significant only for quetiapine XR 600 mg/day (p = 0.033). There were no statistically significant differences between active treatment groups and placebo for PANSS response rates. Several post hoc analyses were conducted to explain the study efficacy outcome but these were inconclusive. Quetiapine XR was generally well tolerated with the majority of AEs being mild or moderate in intensity and no unexpected AEs. CONCLUSIONS: Superior efficacy of quetiapine XR versus placebo in patients with schizophrenia was demonstrated for quetiapine XR 600 mg/day. The safety and tolerability profile of quetiapine XR was similar to that of quetiapine IR.

Prevention of schizophrenia relapse with extended release quetiapine fumarate dosed once daily: a randomized, placebo-controlled trial in clinically stable patients.

INTRODUCTION: This long-term, randomized, double-blind, placebo-controlled study examined the efficacy of extended release quetiapine fumarate (quetiapine XR) in preventing psychotic relapse in schizophrenia. METHODS: Three hundred twenty-seven clinically stable patients with schizophrenia were switched to open-label quetiapine XR (300mg on Day 1, 600mg on Day 2, followed by flexible dosing [400-800mg/day]) for a 16-week stabilization phase. Thereafter, patients who were clinically stable for four months were randomized to flexible doses of quetiapine XR (400-800mg/day) or placebo. Primary endpoint was time to first schizophrenia relapse after randomization. Secondary endpoints included risk of relapse at six months. Interim analyses were planned after 45 and 60 relapses and final analysis after 90 relapses. Maximal treatment time was one year. RESULTS: The study was terminated after the first interim analysis showed a significant difference between randomized treatment groups. Time to relapse was significantly longer in quetiapine XR-treated patients versus placebo (hazard ratio 0.16 [95% confidence interval 0.08, 0.34]; p=0.001). Fewer quetiapine XR-treated patients relapsed versus those receiving placebo (10.7% vs. 41.4%, respectively). Estimated risk of relapse at six months was significantly lower with quetiapine XR (14.3%) compared with placebo (68.2%; p=0.0001). The incidence of treatment-related adverse events (AEs) was similar between quetiapine XR and placebo groups (18% and 21% of patients, respectively) and only one percent of patients in each group withdrew because of AEs. CONCLUSION: Once-daily quetiapine XR (400-800mg/day) was effective in preventing relapse in patients with clinically stable schizophrenia. Quetiapine XR was well tolerated during longer-term use.

Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) in a 6-week, double-blind, randomized study. METHOD: Patients with a DSM-IV diagnosis of acute schizophrenia were randomly assigned to fixed-dose quetiapine XR 400, 600, or 800 mg/day (once daily in the evening), quetiapine immediate release (IR) 400 mg/day (200 mg twice daily), or placebo. Dual-matched placebo was used to maintain blinding. Quetiapine XR target doses were reached by day 2 (400 and 600 mg) and day 3 (800 mg). The primary endpoint was least squares mean change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score. PANSS response rate (percentage of patients with > or = 30% reduction in total score), Clinical Global Impressions-Improvement scale (CGI-I) response rate (percentage of patients with score < or = 3), change in CGI-Severity of Illness (CGI-S), and adverse events (AEs) were also assessed. The study was conducted from November 2004 to December 2005. RESULTS: 588 patients were enrolled and 446 (76%) completed the study. Improvement in PANSS total score at week 6 was significant versus placebo (-18.8) in all groups: -24.8 (p = .03), -30.9 (p < .001), and -31.3 (p < .001) for quetiapine XR 400, 600, and 800 mg, respectively, and -26.6 (p = .004) for quetiapine IR. There were also statistically significant differences in PANSS and CGI-I response rates for all active treatments versus placebo (all p < .05). The most common AEs in all quetiapine groups were somnolence and dizziness; there were no unexpected AEs with quetiapine XR. Incidence of AEs potentially related to extrapyramidal symptoms was similar to placebo. CONCLUSION: Once-daily quetiapine XR (400-800 mg/day) was effective versus placebo in patients with acute schizophrenia. Treatment, including rapid dose escalation, was well tolerated, with a therapeutically effective dose reached by day 2. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00206115.