WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Amnestic mild cognitive impairment MCI) represents the prodromal stage of Alzheimer's dementia and this disease progresses in a non-linear fashion.• Disease progression depends on a variety of demographic, biochemical, genetic and cognitive factors. WHAT THIS STUDY ADDS• Baseline CSF biomarkers carry information about disease pathology and critical thresholds for these markers (Ab and p-tau181P) have been identified that allow segregation of the population into MCI progressers and non-progressers. AIMThe objective is to develop a semi-mechanistic disease progression model for mild cognitive impairment (MCI) subjects. The model aims to describe the longitudinal progression of ADAS-cog scores from the Alzheimer's disease neuroimaging initiative trial that had data from 198 MCI subjects with cerebrospinal fluid (CSF) information who were followed for 3 years. METHODVarious covariates were tested on disease progression parameters and these variables fell into six categories: imaging volumetrics, biochemical, genetic, demographic, cognitive tests and CSF biomarkers. RESULTSCSF biomarkers were associated with both baseline disease score and disease progression rate in subjects with MCI. Baseline disease score was also correlated with atrophy measured using hippocampal volume. Progression rate was also predicted by executive functioning as measured by the Trail B-test. CONCLUSIONCSF biomarkers have the ability to discriminate MCI subjects into sub-populations that exhibit markedly different rates of disease progression on the ADAS-cog scale. These biomarkers can therefore be utilized for designing clinical trials enriched with subjects that carry the underlying disease pathology.

Topiramate is generally safe and reasonably well tolerated for the prevention of migraine in adults. The most common topiramate-associated AEs were mild or moderate in severity and occurred more frequently during titration to target doses.

IMPORTANCE Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs). OBJECTIVE To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior.DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment. INTERVENTIONS Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185). MAIN OUTCOMES AND MEASURES Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study. RESULTSOf 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, −1.09; 95% CI, −1.66 to −0.53; P < .001) and month 12 (least-square mean, −1.62; 95% CI, −2.49 to −0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, −3.70; 95% CI, −5.76 to −1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups.CONCLUSIONS AND RELEVANCE Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment.

The results of 3 proof-of-concept studies to evaluate carisbamate's efficacy and safety in treating neuropathic pain are presented. In studies 1 (postherpetic neuralgia, n = 91) and 2 (diabetic neuropathy, n = 137), patients received carisbamate 400 mg/day or placebo for 4 weeks and then crossed over to the other treatment for 4 weeks. In study 3 (diabetic neuropathy, higher carisbamate doses), patients (n = 386) were randomized (1:1:1:1) to receive either carisbamate 800 mg/day, 1200 mg/day, pregabalin 300 mg/day or placebo for 15 weeks. Primary efficacy end point was the mean of the last 7 average daily pain scores obtained on days the study drug was taken, for all 3 studies. Least square mean (95% CI) differences between carisbamate and placebo groups on the primary end point were as follows: study 1: -0.512 (-1.32, 0.29) carisbamate 400 mg/day; study 2: -0.307 (-0.94, 0.33) carisbamate 400 mg/day; and study 3: -0.51 (-1.10, 0.08), carisbamate 800 mg/day; -0.55 (-1.13, 0.04), carisbamate 1200 mg/day; and -0.43 (-1.01, 0.15), pregabalin 300 mg/day. Neither carisbamate (all 3 studies) nor pregabalin (study 3) significantly differed from placebo, although multiple secondary end points showed significant improvement in efficacy with carisbamate in studies 1 and 2. Dizziness was the only treatment-emergent adverse event occurring at ≥10% difference in carisbamate groups versus placebo (study 1: 12% vs. 1%; study 3: 14% vs. 4%; study 2: 1% vs. 2%). Carisbamate, although well tolerated, did not demonstrate efficacy in neuropathic pain across these studies, nor did the active comparator pregabalin (study 3).

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