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Background New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. Methods We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p  < 0.0001; effect size 0.531) after 36 weeks of treatment. Treatment-emergent adverse event incidence was comparable between active treatment and placebo (73.9%, 75.4%). Two deaths determined to be unrelated to drug effects occurred in the GV-971 group. Conclusions GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. Trial registration ClinicalTrials.gov, NCT0229391 5. Registered on November 19, 2014

Preladenant is an adenosine 2A (A 2A) receptor antagonist. In animal models of Parkinson's disease, preladenant monotherapy improves motor function without causing dyskinesia and, as an adjunct to levodopa, it improves motor function without worsening dyskinesia. We aimed to assess the efficacy and safety of preladenant in patients with Parkinson's disease and motor fluctuations who were receiving levodopa and other antiparkinsonian drugs. In this phase 2, dose-finding trial, patients with Parkinson's disease who were receiving levodopa were enrolled and treated at 44 sites in 15 countries between December, 2006, and November, 2008. Assignment to treatment was done centrally with an interactive voice response system, according to a block randomisation schedule that was computer generated by the sponsor. Patients were assigned to receive 1, 2, 5, or 10 mg oral preladenant twice daily, or matching placebo for 12 weeks. Patients, study staff, investigators, and all sponsor personnel were masked to treatment assignment. The primary outcome was change in mean daily off time from baseline to week 12, as assessed by home diaries. Efficacy analysis included all patients who received at least one dose of study drug and had data for assessments after baseline. This trial is registered with ClinicalTrials.gov, number NCT00406029. 253 patients were randomised to receive preladenant (1 mg [n=49], 2 mg [n=49], 5 mg [n=49], 10 mg [n=57]) or placebo (n=49), of whom 234 on preladenant (1 mg [n=47], 2 mg [n=48], 5 mg [n=45], 10 mg [n=49]) and placebo (n=45) were eligible for the efficacy analysis. Mean daily off time from baseline to week 12 was reduced versus placebo in patients on 5 mg preladenant (difference −1·0 h, 95% CI −2·1 to 0·0; p=0·0486) and 10 mg preladenant (−1·2 h, −2·2 to −0·2; p=0·019). Changes in mean daily off time versus placebo were not significant for 1 mg preladenant (0·2 h, −0·9 to 1·2; p=0·753) or 2 mg preladenant (−0·7 h, −1·7 to 0·3; p=0·162). The most common adverse events in the combined preladenant group versus placebo were worsening of Parkinson's disease (22 [11%] vs 4 [9%]), somnolence (20 [10%] vs 3 [6%]), dyskinesia (18 [9%] vs 6 [13%]), nausea (17 [9%] vs 5 [11%]), constipation (15 [8%] vs 1 [2%]), and insomnia (15 [8%] vs 4 [9%]). 5 and 10 mg preladenant twice daily might be clinically useful to reduce off time in patients with Parkinson's disease and motor fluctuations. Schering-Plough, a subsidiary of Merck.

Purpose Oral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration. Methods Subjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m² of oral temozolomide on days 1, 2 and 5. On days 3 and 4, subjects received 150 mg/m² temozolomide either as a 90-min intravenous infusion on one day or by oral administration on an alternate day. Results Ratio of log-transformed means (intravenous:oral) of area under the concentration-time curve and maximum concentration of drug after dosing for temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) met exposure equivalence criteria (90% confidence interval = 0.8-1.25). Treatment-emergent adverse events were consistent with those reported previously in subjects with recurrent glioma treated with oral temozolomide, except for mostly mild and transient injection site reactions with intravenous administration. Conclusions This study demonstrated an exposure equivalence of a 90-min intravenous infusion of temozolomide and an equivalent oral dose.

Affective and emotional symptoms such as depression, anxiety, euphoria, and irritability are common neuropsychiatric symptoms (NPS) in pre-dementia and cognitively normal older adults. They comprise a domain of Mild Behavioral Impairment (MBI), which describes their emergence in later life as an at-risk state for cognitive decline and dementia, and as a potential manifestation of prodromal dementia. This selective scoping review explores the epidemiology and neurobiological links between affective and emotional symptoms, and incident cognitive decline, focusing on recent literature in this expanding field of research. Existing literature in prodromal and dementia states was reviewed, focusing on epidemiology, and neurobiology. Search terms included: “mild cognitive impairment,” “dementia,” “prodromal dementia,” “preclinical dementia,” “Alzheimer's,” “depression,” “dysphoria,” “mania,” “euphoria,” “bipolar disorder,” and “irritability.” Affective and emotional dysregulation are common in preclinical and prodromal dementia syndromes, often being harbingers of neurodegenerative change and progressive cognitive decline. Nosological constraints in distinguishing between pre-existing psychiatric symptomatology and later life acquired NPS limit historical data utility, but emerging research emphasizes the importance of addressing time frames between symptom onset and cognitive decline, and age of symptom onset. Affective symptoms are of prognostic utility, but interventions to prevent dementia syndromes are limited. Trials need to assess interventions targeting known dementia pathology, toward novel pathology, as well as using psychiatric medications. Research focusing explicitly on later life onset symptomatology will improve our understanding of the neurobiology of NPS and neurodegeneration, enrich the study sample, and inform observational and clinical trial design for prevention and treatment strategies.

RP5063 is a multimodal dopamine (D)‐serotonin (5‐HT) stabilizer with a high affinity for D2/3/4 and 5‐HT1A/2A/2B/7 receptors and moderate affinity for the serotonin transporter. Single‐dose (10 and 15 mg fasting, 15 mg fed) safety in healthy volunteers and multiple‐dose (10, 20, 50, and 100 mg fed, 10 days) safety and pharmacodynamics in patients with stable schizophrenia were defined in two phase I studies. In the single‐dose study, 32 treatment‐emergent adverse events (TEAEs) were observed. Orthostatic hypotension (n = 6), nausea (n = 5), and dizziness (n = 4) were the most common. One serious adverse event (SAE), seen in a patient who should not have been in the study due to a history of seizures, involved brief seizure‐like symptoms. In the multiple‐dose study, 75 TEAEs were reported. Akathisia (n = 20) and somnolence (n = 14) were the most frequent. No clinically significant changes were seen in glucose or prolactin levels, lipid profiles, weight, or electrocardiographic recordings. In both studies, all TEAEs resolved and none led to withdrawal from the study or death. A pharmacodynamic evaluation reflected significant improvements with RP5063 (P < 0.05) over placebo in an analysis of patients with a baseline Positive and Negative Syndrome Scale (PANSS) score ≥50 for positive subscale scores. Improvements of the Trail Making A and Trail Making B test results were observed for patients treated in the 50 mg dose group for days 5, 10, and 16. These findings indicate that RP5063 is well‐tolerated up to 100 mg and displays promising preliminary clinical behavioral and cognition activity signals in patients with stable disease over a 10‐day period.

RP5063, a multimodal dopamine (D)–serotonin (5‐HT) stabilizer, possesses high affinity for D2/3/4 and 5‐HT1A/2A/2B/2C/6/7 receptors and moderate affinity for the serotonin transporter. Two phase I studies characterized the pharmacokinetics of a single dose (10 and 15 mg fasting, 15 mg fed/fasting) in healthy volunteers and multiple doses (10, 20, 50, and 100 mg fed) over 10 days in patients with stable schizophrenia. RP5063 displayed a dose‐dependent Cmax at 4 to 6 h, linear dose proportionality for both Cmax and AUC, and a half‐life between 40 and 71 h. In the single‐dose study, food slightly increased the extent of drug absorption. In the multiple‐dose study, steady‐state was approached after 120 h of daily dosing. Pooled data in the single‐dose study indicate that the pharmacokinetic profile appears to be comparable between Japanese and Caucasians. RP5063 appears to have a straightforward pharmacokinetic profile that supports for phase II and III evaluation as a once‐daily oral administered agent.

Depression occurs in ~50% of Parkinson's disease (PD) patients, increases in severity and duration as the disease progresses, and is associated with increased morbidity. Improvement of depression in PD patients is correlated with reduced physical disability and improved quality of life. We are assessing use of pimavanserin (PIM) for treatment of depression in adults with PD. A Phase-2, 8-week, open-label, single-arm study is being conducted to evaluate the safety and efficacy of PIM as an adjunct to SSRI/SNRI or as monotherapy in adults with both PD and symptoms of depression (baseline Hamilton Depression Scale [17-items] total score [HAMD-17] ≥15). The primary endpoint of the study is change from Baseline to Week 8 in the HAMD-17. Secondary measures included the Clinical Global Impression (CGI) scales (improvement and severity) and Scales of Outcomes in PD-Sleep (SCOPA). Interim results based on the first 34 of 40 planned patients have been evaluated: 55.9% of patients were male, and average age was 68.1 years, with 19 patients on adjunctive therapy and 15 on monotherapy. At baseline, patients had a mean (SE) HAMD-17 of 19.8(0.6). Change from Baseline to Week 8 (least squares mean [LSM] [SE]) in the HAMD-17 was -10.7(1.0) (95% CI; -12.7,-8.7; P<0.001), with significant improvement seen as early as Week 2 (-8.4[1.0]; 95% CI; -10.5,-6.4; P<0.001). Significant improvement was seen for both adjunctive treatment and monotherapy: 45.2% of patients responded to treatment (≥50% improvement on the HAMD-17) at Week 8, and 35.5% reached remission (HAMD-17 ≤7). On the Clinical Global Impressions-Improvement scale, 54.8% were much/very much improved at Week 8. Significant improvement was seen in change from Baseline to Week 8 SCOPA-Global Sleep Quality, -Nighttime Sleep, and -Daytime Sleepiness: -1.0(0.4) (95% CI; -1.7,-0.3; P=0.010), -2.1(0.7) (95% CI; -3.6,-0.6; P=0.008), -2.1(0.4) (95% CI; -3.0,-1.2; P<0.001) respectively. Twenty-one of the 34 enrolled patients have completed the study to date, and another 7 are still continuing. Thirteen patients reported adverse events, the most common being falls, UTI, diarrhea, and nausea. These interim data suggest that PIM as adjunctive treatment or monotherapy is associated with early improvement of depressive symptoms in patients with PD and is well tolerated. This is consistent with recently reported data of PIM in major depressive disorder. Final data will be shared at the time of this presentation. However, additional placebo-controlled data will be needed to determine fully the efficacy of PIM in patients with comorbid PD and depression. ACADIA Pharmaceuticals Inc.

To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable “QoL responders”/“non-responders”. At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as “QoL non-responders”. Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as ‘difficulties experiencing pleasure’ and ‘problems sustaining concentration’. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy.