Objective: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an m1 and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). Design: A 6-month, randomized, double-blind, placebo-controlled, parallel-group trial followed by a 1-month, single-blind, placebo washout. Setting: Outpatients at 17 centers in the United States and Canada. Participants: A total of 343 men and women at least 60 years of age with mild to moderate AD. Interventions: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. Outcome Measures: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). Results: A significant treatment effect existed for ADAS-Cog (high dose vs placebo; P less than or equal to.05), and CIBIC+ (high dose vs placebo; P less than or equal to.02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P less than or equal to.002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P less than or equal to.02). In the high-lose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. Conclusions: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.
