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Verubecestat, an orally administered inhibitor of BACE-1, reduces amyloid concentration in the cerebrospinal fluid. In a randomized, 78-week trial involving patients with mild or moderate Alzheimer’s disease, the drug did not slow cognitive decline as compared with placebo.

In a randomized trial, patients with brain amyloid deposition but no dementia who received a β-site amyloid precursor protein–cleaving enzyme 1 inhibitor had no benefit with respect to clinical outcomes and worsening on some measures of cognition and daily function.

Calcitonin gene-related peptide (CGRP) probably has a role in migraine pathophysiology, and antagonism of its receptors might provide treatment without the vasoconstrictor effects of triptans. We aimed to assess the clinical profile of MK-0974 (telcagepant), an orally bioavailable antagonist of CGRP receptor. In a randomised, parallel-treatment, placebo-controlled, double-blind, trial at 81 sites in the Europe and the USA, adults with migraine diagnosed by International Headache Society criteria treated moderate or severe attacks with either oral telcagepant 150 mg or 300 mg, zolmitriptan 5 mg, or placebo. The five co-primary endpoints were pain freedom, pain relief, or absence of photophobia, phonophobia, or nausea at 2 h after treatment. Analysis was by the full analysis set and multiplicity was controlled for with a step-down closed-testing procedure. This trial is registered with ClinicalTrials.gov, number NCT00442936. 1380 patients were randomly assigned to receive telcagepant 150 mg (n=333) or 300 mg (354), zolmitriptan (345), or placebo (348). Telcagepant 300 mg was more effective than placebo for pain freedom (95 [27%] of 353 patients vs 33 [10%] of 343 [p<0·0001]), pain relief (194 [55%] of 353 vs 95 [28%] of 343 [p<0·0001]), and absences of phonophobia (204 [58%] of 353 vs 126 [37%] of 342 [p<0·0001]), photophobia (180 [51%] of 353 vs 99 [29%] of 342 [p<0·0001]), and nausea (229 [65%] of 352 vs 189 [55%] of 342 [p=0·0061]). Efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same, and both were more effective than telcagepant 150 mg. Adverse events were recorded for 31% taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo. Telcagepant 300 mg is effective as an acute treatment for migraine with efficacy comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects. Merck Research Laboratories.

Background Verubecestat, a BACE1 inhibitor that reduces Aβ levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH. Methods EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically. The trial was terminated due to futility close to its scheduled completion. Of 1957 participants who were randomized and took treatment, 652 were assigned to verubecestat 12 mg, 652 to verubecestat 40 mg, and 653 to placebo. Adverse events and relevant laboratory, vital sign, and ECG findings were assessed. Results Verubecestat 12 mg and 40 mg were associated with an increase in the percentage of participants reporting adverse events versus placebo (89 and 92% vs. 82%), although relatively few participants discontinued treatment due to adverse events (8 and 9% vs. 6%). Adverse events that were increased versus placebo included falls and injuries, suicidal ideation, weight loss, sleep disturbance, rash, and hair color change. Most were mild to moderate in severity. Treatment differences in suicidal ideation emerged within the first 3 months but did not appear to increase after 6 months. In contrast, treatment differences in falls and injuries continued to increase over time. Conclusions Verubecestat was associated with increased risk for several types of adverse events. Falls and injuries were notable for progressive increases over time. While the mechanisms underlying the increased adverse events are unclear, they may be due to BACE inhibition and should be considered in future clinical development programs of BACE1 inhibitors. Trial registration ClinicalTrials.gov NCT01739348 , registered on 29 November 2012.

Exposure to methylmercury (MeHg) before birth can adversely affect children's neurodevelopment. The most common form of prenatal exposure is aternal fish consumption, but whether such exposure harms the fetus is unknown. We aimed to identify adverse neurodevelopmental effects in a fish-consuming population. We investigated 779 mother-infant pairs residing in the Republic of Seychelles. Mothers reported consuming fish on average 12 meals per week. Fish in Seychelles contain much the same concentrations of MeHg as commercial ocean fish elsewhere. Prenatal MeHg exposure was determined from maternal hair growing during pregnancy. We assessed neurocognitive, language, memory, motor, perceptual-motor, and behavioural functions in children at age 9 years. The ssociation between prenatal MeHg exposure and the primary endpoints was investigated with multiple linear regression with adjustment for covariates that affect child development. Mean prenatal MeHg exposure was 6·9 parts per million (SD 4·5ppm). Only two endpoints were associated with prenatal MeHg exposure. Increased exposure as associated with decreased performance in the grooved pegboard using the non-dominant hand in males and improved scores in the hyperactivity index of the Conner's teacher rating scale. Covariates affecting child development were appropriately associated with endpoints. These data do not support the hypothesis that there is a neurodevelopmental risk from prenatal MeHg exposure resulting solely from ocean fish consumption.

Pregnant Sprague-Dawley rats received a single oral dose of 0, 20, 60, or 180 ng/kg 2,3,7,8-tetra-chlorodibenzo-p-dioxin on day 8 of gestation. Each litter contributed a single male-female pair trained to press a lever to obtain food pellets under two operant behavior procedures. Initially, each lever press was reinforced. The fixed-ratio (FR) requirement was then increased every four sessions from the initial setting of 1 to values between 6 and 71. We then studied responses for 30 days under a multiple schedule combining FR 11 and another schedule requiring a pause of at least 10 sec between responses (DRL 10-sec). TCDD evoked a sexually dimorphic response pattern. Generally, TCDD-exposed males responded at lower rates than control males. In contrast, exposed females responded at higher rates than controls. Each response measure from the mult-FR DRL schedule yielded a male-female difference score. We used the differences in response rate to calculate benchmark doses based on the relative displacement from modeled zero-dose performance of the effective dose at 1% ( ED01) and 10% ( ED10), as determined by a second-order polynomial fit to the dose-effect function. For the male-female difference in FR rate of responding, the mean ED10was 2.77 ng/kg with a 95% lower bound of 1.81 ng/kg. The corresponding ED01was 0.27 ng/kg with a 95% lower bound of 0.18 ng/kg. For the male-female difference in DRL rate, the mean ED10was 2.97 ng/kg with a 95% lower bound of 2.02 ng/kg. The corresponding ED01was 0.30 ng/kg with a 95% lower bound of 0.20 ng/kg. These values fall close to, but below, current estimates of human body burdens of 13 ng/kg, based on TCDD toxic equivalents.

Telcagepant proved well tolerated, with an adverse event rate similar to that of placebo and lower than that for zolmitriptan. [...] for migraine patients who are not satisfied with other acute treatments owing to limited efficacy, poor tolerability, cardiovascular risk factors, or contraindications, telcagepant, if approved, might offer an additional treatment option.

The likelihood ratio test for equality of means that are subject to a partial order constraint is known to have power characteristics that are generally superior to those of competing procedures. Difficulties in implementing this test have led to the development of alternative approaches, many of which are based on multiple contrasts among the sample means. Mukerjee, Robertson, and Wright (1987) were the first to formally propose the use of such tests, basing them on the maximum of the contrasts. Orthogonal contrasts can be chosen to simplify the distribution theory. While tests based on orthogonal contrasts have good power properties and are generally easier to implement than the likelihood ratio test, difficulties persist in the computation of the appropriate contrasts. We propose a class of tests based on contrasts that are not necessarily orthogonal. Instead of using the maximum of these contrasts, the p-values from each contrast are computed and then combined using an adaptation of Fisher's combination statistic for dependent p-values. Extensions are made to the original combination procedure to accommodate dependent p-values based on test statistics when σ2 is unknown. Examples of contrasts for use with the proposed tests include, but are not limited to, the generators of the polyhedral cone, the center of the cone, or any linear combinations of these. The proposed class of tests are referred to as generalized multiple contrast tests (GMCTs), because of the flexibility allowed in combining and consequently choosing the contrasts. We specifically study two members of this class, tests that use the generators of the polyhedral cone as the contrasts and tests that use both the generators and the center. An algorithm is provided to determine the generators and center of these cones that can be applied to a wide range of order restrictions. Robust methods based on ranks and trimmed means can be incorporated into the testing procedure to relax the assumption of normality. Generalizations of this method also allow for the testing of order restricted parameters from distributions other than normal (e.g., binomial proportions). Robust tests for equality of ordered variances using GMCTs based on either Winsorized variances or on jackknife theory are also proposed. The GMCT can be easily implemented and has power that compares well with those of the likelihood ratio test and other existing tests. Furthermore, the GMCT is easily extended to many other testing problems involving general order restrictions. The simplicity, power, and flexibility of the GMCT make it an attractive approach to a wide range of order restricted testing problems.