{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T18:11:57Z","timestamp":1789150317273,"version":"build-2803163510"},"reference-count":61,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2025,2,1]]},"abstract":"<jats:sec><jats:title>Importance<\/jats:title><jats:p>Fall risk and cognitive impairment are prevalent and burdensome in Parkinson disease (PD), requiring efficacious, well-tolerated treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To evaluate the safety and efficacy of TAK-071, a muscarinic acetylcholine M<jats:sub>1<\/jats:sub> positive allosteric modulator, in participants with PD, increased fall risk, and cognitive impairment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This phase 2 randomized double-blind placebo-controlled crossover clinical trial was conducted from October 21, 2020, to February 27, 2023, at 19 sites in the US. Participants included patients aged 40 to 85 years with a diagnosis of PD, with at least 1 fall in the prior 12 months, with a Montreal Cognitive Assessment score of 11 to 26, and receiving stable antiparkinsonian medications and no acetylcholinesterase inhibitors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Intervention<\/jats:title><jats:p>One-to-one randomization to once-daily oral TAK-071 or placebo for 6 weeks, followed by washout and 6 weeks of crossover treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>The primary end point was change from baseline in gait variability (stride time variability [STV]) during a 2-minute walk test with or without\u2009cognitive load. The secondary efficacy end point was change from baseline in a cognitive composite score consisting of tests of attention, executive function, and memory.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among the 54 participants included in the analysis, 45 (83%) were male, mean (SD) age was 69.7 (6.9) years, and median Montreal Cognitive Assessment score was 24 (range, 17-26). After 6 weeks of treatment, the primary outcome was negative: the change from baseline in STV did not differ between participants receiving TAK-071 or placebo, with cognitive load (geometric mean ratio, 1.15; 95% CI, 0.94-1.41; <jats:italic>P<\/jats:italic>\u2009=\u2009.16) or without cognitive load (geometric mean ratio, 1.02; 95% CI, 0.88-1.18; <jats:italic>P<\/jats:italic>\u2009=\u2009.78). TAK-071 improved the secondary efficacy outcome (cognitive composite score) vs placebo. The least squares mean difference of the change from baseline was 0.22 (95% CI, 0.05-0.38; <jats:italic>P<\/jats:italic>\u2009=\u2009.01). Treatment-emergent adverse events occurred in 18 of 49 participants (37%) while receiving placebo and in 19 of 53 (36%) while receiving TAK-071. Four participants (8%) receiving TAK-071 had adverse events resulting in withdrawal of study drug; 4 had gastrointestinal tract adverse events.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Relevance<\/jats:title><jats:p>In this study, in participants with PD, risk for falls, and cognitive impairment, TAK-071 was well-tolerated. The treatment did not improve the primary outcome of gait variability, but did improve cognition compared with placebo. Larger and longer studies in more diverse populations are needed to better understand the safety and efficacy of TAK-071 in broader populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial Registration<\/jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT04334317\">NCT04334317<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamaneurol.2024.4519","type":"journal-article","created":{"date-parts":[[2025,1,6]],"date-time":"2025-01-06T16:01:50Z","timestamp":1736179310000},"page":"152","source":"Crossref","is-referenced-by-count":24,"title":["An Acetylcholine M<sub>1<\/sub> Receptor\u2013Positive Allosteric Modulator (TAK-071) in Parkinson Disease With Cognitive Impairment"],"prefix":"10.1001","volume":"82","author":[{"given":"Niraj M.","family":"Shanbhag","sequence":"first","affiliation":[{"name":"Takeda Development Center Americas, Inc, 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