Protocol-Specified Responder Analyses eAppendix 2. GUID:?FC196110-B4CC-4776-B59A-27A23AD0C43D Key Points Question Is edonerpic maleate, an experimental drug that protects against neurotoxic effects, preserves synapses, and improves memory deficits in preclinical models related to Alzheimer disease, efficacious and safe for patients with Alzheimer disease? Findings In this randomized phase 2 clinical trial that included 484 patients with mild to moderate Alzheimer disease treated with cholinesterase inhibitors with or without memantine, neither dose of edonerpic improved cognition or function over 52 weeks compared with placebo. Edonerpic also did not have obvious effects on amyloid, tau, or brain magnetic resonance imaging biomarkers. Meaning In advancing from preclinical screening, edonerpic has not demonstrated clinical proof of concept in Alzheimer disease. Abstract Importance Edonerpic maleate (T-817MA) protects against A40-induced neurotoxic effects and memory deficits, promotes neurite outgrowth, and preserves hippocampal synapses and spatial memory in tau transgenic mice. These effects may be mediated via sigma-1 receptor activation, delivery of synaptic AMPA receptors, or modulation of microglial function and may benefit patients with Alzheimer disease. Objective To assess the efficacy, security, and tolerability of edonerpic for patients with moderate to moderate Alzheimer disease. Design, Setting, and Participants Randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial conducted over 52 weeks from June 2, 2014, to December 14, 2016, at 52 US clinical and academic centers. Of 822 outpatients screened, 484 met the following criteria and were randomly assigned to treatment: 55 to 85 years of age, probable Alzheimer disease, Mini-Mental State Examination scores from 12 to 22, and taking stable doses of donepezil or rivastigmine with or without memantine. Interventions Random assignment (1:1:1 allocation) to placebo or 224 mg or 448 mg of edonerpic Urapidil hydrochloride maleate, once per day. Main Outcomes and Steps Coprimary outcomes were scores around the Alzheimer Disease Assessment ScaleCCognitive Subscale (ADAS-cog) and Alzheimers Disease Cooperative StudyCClinical Impression of Switch (ADCS-CGIC) at week 52. Biomarkers were brain, lateral ventricular, and hippocampal volumes, as decided on magnetic resonance imaging, and cerebrospinal fluid A40, A42, total tau, and phospho-tau181. The primary efficacy analysis was performed around the coprimary end points for the altered intention-to-treat population. Results Of 482 participants in the security populace, 140 of 158 participants (88.6%) assigned to placebo, 117 of 166 participants (70.5%) to 224 mg of edonerpic maleate, and 120 of 158 participants (76.0%) to 448 mg of edonerpic maleate completed the trial. The mean ADAS-cog score switch at week 52 was 7.91 for the placebo group, 7.45 for the 224-mg group, and 7.08 for the 448-mg group. Mean differences from placebo were ?0.47 (95% CI, ?2.36 to 1 1.43; criteria and National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria,8 brain MRI or computed tomography scan consistent with the clinical diagnosis, MMSE9 score from 12 to 22, altered Hachinski score10 of 4 or less, and a study partner. Participants were required to be taking donepezil or rivastigmine transdermal system, with or without memantine, for at least BAIAP2 4 months and be at stable doses for at least 3 months prior to baseline. Other medications for Alzheimer disease, including other cholinesterase inhibitors and donepezil doses greater than 10 mg/d were not permitted (see the statistical analysis plan for eligibility criteria and trial protocol in Product 1). Randomization and Masking Study medication was dispensed as identically appearing, film-coated tablets each made up of edonerpic maleate, 112 mg (80-mg free base), or placebo. Participants were randomized to 1 1 of 3 treatment groups: placebo, 224 mg/d of edonerpic maleate, or 448 mg/d of edonerpic maleate in a 1:1:1 allocation using a permuted block randomization, stratified by site and MMSE score. Medication was to be taken once daily after breakfast. The 448-mg group in the beginning received Urapidil hydrochloride two 112-mg edonerpic maleate tablets and 2 placebo tablets for 4 weeks and then four 112-mg edonerpic maleate tablets for 48 weeks. The 224-mg group received two 112-mg edonerpic maleate tablets and 2 placebo tablets for 52 weeks. The placebo group received 4 placebo tablets for 52 weeks. Medication was manufactured by the Toyama Chemical Co Ltd, packaged in blister packs of 28 tablets, and dispensed at each visit to provide for 1 week beyond the next scheduled visit. Procedures The screening prebaseline period consisted of obtaining.Secondary outcomes were scores around the Alzheimers Disease Cooperative StudyCActivities of Daily Living (ADCS-ADL),13 MMSE, Functional Activities Questionnaire,14 and Neuropsychiatric Inventory15 at week 52 and scores around the ADAS-cog and ADCS-CGIC at weeks 12, 24, 36, and 44. did not have clear effects on amyloid, tau, or brain magnetic resonance imaging biomarkers. Meaning In advancing from preclinical screening, edonerpic has not demonstrated clinical proof of concept in Alzheimer disease. Abstract Importance Edonerpic maleate (T-817MA) protects against A40-induced neurotoxic effects and memory deficits, promotes neurite outgrowth, and preserves hippocampal synapses and spatial memory in tau transgenic mice. These effects may be mediated via sigma-1 receptor activation, delivery of synaptic AMPA receptors, or modulation of microglial function and may benefit patients with Alzheimer disease. Objective To assess the efficacy, security, and tolerability of edonerpic for patients with moderate to moderate Alzheimer disease. Design, Setting, and Participants Randomized, double-blind, placebo-controlled, parallel-group, phase 2 clinical trial conducted over 52 weeks from June 2, 2014, to December 14, 2016, at 52 US clinical and academic centers. Of 822 outpatients screened, 484 met the following criteria and were randomly assigned to treatment: 55 to 85 years of age, probable Alzheimer disease, Mini-Mental State Examination scores from 12 to 22, and taking stable doses of donepezil or rivastigmine with or without memantine. Interventions Random assignment (1:1:1 allocation) to placebo or 224 mg or 448 mg of edonerpic maleate, once per day. Main Outcomes and Steps Coprimary outcomes were scores around the Alzheimer Disease Assessment ScaleCCognitive Subscale (ADAS-cog) and Alzheimers Disease Cooperative StudyCClinical Impression of Switch (ADCS-CGIC) at week 52. Biomarkers were brain, lateral ventricular, and hippocampal volumes, as decided on magnetic resonance imaging, and cerebrospinal fluid A40, A42, total tau, and phospho-tau181. The primary efficacy analysis was performed around the coprimary end points for the altered intention-to-treat population. Results Of 482 participants in the security populace, 140 of 158 participants (88.6%) assigned to placebo, 117 of 166 participants (70.5%) to 224 mg of edonerpic maleate, and 120 of 158 participants (76.0%) to 448 mg of edonerpic maleate completed the trial. The mean ADAS-cog score switch at week 52 was 7.91 for the placebo group, 7.45 for the 224-mg group, and 7.08 for the 448-mg group. Mean differences from placebo Urapidil hydrochloride were ?0.47 (95% CI, ?2.36 to 1 1.43; criteria and National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria,8 brain MRI or computed tomography scan consistent with the clinical diagnosis, MMSE9 score from 12 to 22, altered Hachinski score10 of 4 or less, and a study partner. Participants were required to be taking donepezil or rivastigmine transdermal system, with or without memantine, for at least 4 months and become at stable dosages for at least three months ahead of baseline. Other medicines for Alzheimer disease, including additional cholinesterase inhibitors and donepezil dosages higher than 10 mg/d weren’t permitted (start to see the statistical evaluation arrange for eligibility requirements and trial process in Health supplement 1). Randomization and Masking Research medicine was dispensed as identically showing up, film-coated tablets each including edonerpic maleate, 112 mg (80-mg free of charge foundation), or placebo. Individuals were randomized to at least one 1 of 3 treatment organizations: placebo, 224 mg/d of edonerpic maleate, or 448 mg/d of edonerpic maleate inside a 1:1:1 allocation utilizing a permuted stop randomization, stratified by site and MMSE rating. Medicine was to be studied once daily after breakfast time. The 448-mg group primarily received two 112-mg edonerpic maleate tablets and 2 placebo tablets for four weeks and four 112-mg edonerpic maleate tablets for 48 weeks. The 224-mg group received two 112-mg edonerpic maleate tablets and 2 placebo tablets for 52 weeks. The placebo group received 4 placebo tablets for 52 weeks. Medicine was produced by the Toyama Chemical substance Co Ltd, packed in blister packages of 28 tablets, and dispensed at.
