An Acetylcholine M<sub>1</sub> Receptor–Positive Allosteric Modulator (TAK-071) in Parkinson Disease With Cognitive Impairment
Notice bibliographique
Résumé
Importance: Fall risk and cognitive impairment are prevalent and burdensome in Parkinson disease (PD), requiring efficacious, well-tolerated treatment. Objective: To evaluate the safety and efficacy of TAK-071, a muscarinic acetylcholine M1 positive allosteric modulator, in participants with PD, increased fall risk, and cognitive impairment. Design, Setting, and Participants: 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. Intervention: One-to-one randomization to once-daily oral TAK-071 or placebo for 6 weeks, followed by washout and 6 weeks of crossover treatment. Main Outcomes and Measures: The primary end point was change from baseline in gait variability (stride time variability [STV]) during a 2-minute walk test with or without cognitive load. The secondary efficacy end point was change from baseline in a cognitive composite score consisting of tests of attention, executive function, and memory. Results: 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; P = .16) or without cognitive load (geometric mean ratio, 1.02; 95% CI, 0.88-1.18; P = .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; P = .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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT04334317.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».