P20: Evaluating xanomeline and trospium as a treatment for psychosis associated with Alzheimer’s disease: design of the phase 3, ADEPT-1, relapse prevention study

Abstract

Background: There are no approved treatments for Alzheimer’s disease psychosis (ADP). Xanomeline, a brain- penetrant M1/M4 preferring muscarinic receptor agonist, showed antipsychotic efficacy in placebo-controlled trials in subjects with AD [Bodick NC et al. 1997; DOI: 10.1001/archneur.1997.00550160091022]. Despite promising efficacy, further development of xanomeline was limited by cholinergic adverse events. The investigational antipsychotic xanomeline and trospium combines xanomeline with trospium, an FDA-approved muscarinic receptor antagonist that does not measurably cross the blood-brain barrier. Trospium acts to mitigate the peripheral procholinergic side effects of xanomeline, providing a strategy for using xanomeline to stimulate brain muscarinic receptors with a decreased side effect burden. Unlike available antipsychotics, xanomeline and trospium have no direct dopamine D2-blocking activity, and as such, its safety and tolerability profile is different.

Methods: The phase 3 ADEPT-1 trial is a double-blind, flexible-dose, placebo-controlled randomized withdrawal study to evaluate the safety and efficacy of xanomeline and trospium in decreasing the risk of relapse in subjects with ADP. Subjects aged 55-90 years with moderate to severe psychosis associated with mild to severe AD (Mini- Mental State Exam score range 8-22) will be enrolled into the study. Subjects will receive single-blind xanomeline and trospium for 12 weeks. Each subject will be flexibly titrated to the maximum dose of xanomeline and trospium 200 mg xanomeline/20 mg trospium/day. At the end of the single-blind treatment, eligible responders will be randomized to either continue xanomeline and trospium or be switched to matched placebo for a 26-week double- blind treatment period. A responder is defined as a subject with a ≥40% decrease (improvement) on the Neuropsychiatric Inventory- Clinician: Hallucinations + Delusions (NPI-C: H+D) score compared with baseline (day 1) and a Clinician Global Impression–Change (CGI-C) score of 1 or 2 (very much improved or improved).

Results: The primary endpoint of the study, time from randomization to relapse during the double-blind, randomized withdrawal treatment, will be evaluated by survival analysis using Kaplan-Meier Methods. The study started in August 2022 and will randomize approximately 200 subjects.

Conclusions: The trial design of the ADEPT-1 study is an efficient way to assess the potential for xanomeline and trospium to provide clinically meaningful benefit in preventing the return of ADP in patients who have responded to xanomeline and trospium.