Efficacy of xanomeline in Alzheimer disease: cognitive improvement measured using the Computerized Neuropsychological Test Battery (CNTB).

The cognitive efficacy of the M1-selective muscarinic agonist xanomeline in mild-to-moderate Alzheimer disease (AD) was measured using the Computerized Neuropsychological Test Battery (CNTB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) in this 17-center, double-blind, placebo-controlled study. Three hundred forty-three patients were randomly assigned to receive 25, 50, or 75 mg xanomeline tartrate or placebo three times daily (t.i.d.) for 24 weeks, followed by placebo for 4 weeks in a single-blind washout phase. Cognitive function was assessed at randomization and after 4, 8, 12, 24, and 28 weeks. Three hundred nineteen patients were included in an intent-to-treat (ITT) analysis; 209 completers had evaluable data at week 24. ITT analysis showed a significant (p < or = 0.05) dose-response trend and a significant (p < or = 0.05) between-group comparison favoring 75 mg t.i.d. over placebo for the CNTB summary score but not for the ADAS-cog. In the completer analysis, however, the ADAS-cog showed a significant (p < or = 0.05) dose-response trend and between-group comparison, whereas the CNTB Summary Score did not. The ADAS-cog was less sensitive to treatment effects in mildly impaired patients (ADAS-cog < 21) than in moderately impaired patients (ADAS-cog > or = 21), whereas the CNTB was sensitive in the entire study population (mean ADAS-cog = 22.5+/-9.6). Significant (p < or = 0.05) beneficial treatment effects were seen in measures of simple reaction time and delayed verbal recall, which are included in the CNTB but not in the ADAS-cog. During the single-blind placebo washout period, the ADAS-cog score of the placebo group worsened dramatically (change of 2.63 points; p < or = 0.001), whereas the CNTB score remained stable (change of 1.04 points; p=0.694). Thus, the CNTB appears to be more objective than the ADAS-cog.

Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease.

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 < or = .05), and CIBIC+ (high dose vs placebo; P < or = .02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P < or = .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 < or = .02). In the high-dose 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.

The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease.

The therapeutic effects of selective cholinergic replacement using oral xanomeline, an m1/m4 receptor agonist, were assessed in a multicenter study of 343 patients with Alzheimer disease (AD). Patients were randomized to parallel treatment arms (placebo, 25, 50, and 75 mg t.i.d. xanomeline) and followed through 6 months of double-blind therapy and 1 month of single-blind placebo washout. Completer analysis, using the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), revealed a significant treatment effect (75 mg t.i.d. vs. placebo; p = 0.045). Similar assessment of global status, using the Clinician's Interview-Based Impression of Change, was also significant (75 mg t.i.d. vs. placebo; p = 0.022). Treatment Emergent Signs and Symptoms analysis of the Alzheimer's Disease Symptomatology Scale, revealed highly significant (p < or = 0.002) dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, the Nurses' Observational Scale for Geriatric Patients also showed a significant dose-response relationship (p = 0.018). The improvement in ADAS-Cog provides the first clinical evidence of involvement of the m1 muscarinic receptor in cognition. Furthermore, the favorable effects of xanomeline on disturbing behaviors suggest a novel approach for treatment of the noncognitive symptoms of AD. Although adverse effects (mainly gastrointestinal) associated with the oral formulation appear to limit its use, a large-scale study investigating the safety and efficacy of transdermal xanomeline is under way.