Importance:Smoking has been associated with lower risks of Parkinson disease (PD) in epidemiological studies, but the underlying mechanisms remain poorly elucidated. Objective:To investigate the association of exhaled carbon monoxide (CO) with risk of PD. Design, Setting, and Participants:This nationwide prospective cohort study leveraged data from the China Kadoorie Biobank across 10 geographically diverse areas in China. A total of 512 724 adults aged 30 to 79 years were recruited between June 2004 and July 2008. Prospective analyses were restricted to first events occurring between ages 40 and 94 years and before January 1, 2019. Data were analyzed from May 2025 to March 2026. Exposure:Self-reported smoking status and measured exhaled CO. Main Outcomes and Measures:During approximately 12 years' follow-up, 1131 individuals with PD and 2949 with other neurodegenerative diseases were recorded through linkage to national death and disease registries and the health insurance system. Cox regression was used to estimate adjusted hazard ratios (HRs) for associations of smoking and, among individuals who never smoked, exhaled CO levels with PD, other neurodegenerative diseases, and several known smoking-related diseases. Covariates included sociodemographic characteristics, lifestyle factors, and other confounders (ie, solid fuel use and passive exposure to smoking). Results:Among the 512 701 participants included in the main analyses, the mean (SD) age was 52 (11) years and 302 041 (58.9%) were female. Overall, 156 650 male individuals (74.5%) and 9944 female individuals (3.3%) ever smoked regularly, with mean exhaled CO levels higher among those who regularly smoked (11.1 ppm) than those who never smoked (3.5 ppm), those who occasionally smoked (3.8 ppm), and those who formerly smoked regularly (3.7 ppm). Regular smoking was significantly associated with elevated risks of lung cancer, ischemic heart disease, stroke, and all-cause mortality but with lower risk of PD (adjusted HR, 0.70; 95% CI, 0.62-0.79). In individuals who never smoked, higher exhaled CO levels were associated with lower HRs of PD (n = 675) in a broadly dose-dependent manner (exhaled CO <2.0 ppm: 1.00 [95% CI, 0.85-1.18]; 2.0 to <3.0: 0.85 [95% CI, 0.73-0.99]; 3.0 to <5.0: 0.62 [95% CI, 0.53-0.73]; 5.0 to <11.5: 0.68 [95% CI, 0.56-0.83]; ≥11.5: 0.65 [95% CI, 0.45-0.92]; P for trend < .001) but were not associated with risks of smoking-related diseases or other neurodegenerative diseases. The associations with PD were more pronounced in female individuals who never smoked. Similar exhaled CO-PD associations were found in those who regularly smoked. Conclusion and Relevance:Among individuals who never smoked, higher exhaled CO levels were associated with lower PD risk. These findings demonstrate a potentially protective role of CO in PD etiology, which help explain the association between smoking and PD observed in this and other epidemiological studies and support ongoing clinical trials of CO in the treatment of PD.
Importance:Melanocortin 1 receptor (MC1R) is a key regulator of pigmentation and oxidative stress implicated in Parkinson disease (PD). MC1R loss-of-function variants, defined by experimentally demonstrated reductions in MC1R function, are carried by more than 60% of individuals of European descent. Objective:To determine whether MC1R loss-of-function variants are associated with accelerated PD progression. Design, Setting, and Participants:This longitudinal cohort study used data from July 2010 to January 2026 in the Parkinson Progression Markers Initiative (PPMI) cohort and June 2009 to June 2019 in a replication cohort using 3 US-based multicenter randomized clinical trials (SURE-PD phase 2, SURE-PD3, and STEADY-PD III), with up to 12 years of follow-up. Analysis was performed in May 2026. Of 926 PPMI participants with PD and available genomewide sequencing data, 66 without dopamine deficiency and 51 with pathogenic variants in known PD-associated genes were excluded. The remaining 809 participants were stratified by MC1R loss-of-function carrier status (505 carriers and 304 noncarriers) and classified as having sporadic PD (n = 383) or monogenic PD (n = 426) based on LRRK2 and GBA carrier status. The replication cohort included 587 participants with PD (410 carriers and 177 noncarriers). An additional 53 PPMI participants with prodromal PD (34 carriers and 19 noncarriers) were assessed. Exposures:MC1R loss-of-function carrier status. Main Outcomes and Measures:Rate of motor decline per Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score, assessed via linear mixed-effects models adjusted for age at onset, sex, race, baseline score, and levodopa equivalent daily dose. Phenoconversion risk, assessed via Fine-Gray subdistribution hazards model. Results:Among 383 participants with sporadic PD, 130 were female, 253 were male, and the mean (SD) age at onset was 61.3 (9.9) years for MC1R loss-of-function carriers and 64.6 (10.5) for noncarriers. MC1R loss-of-function carriers exhibited 30% faster motor decline (β, 0.57 points/year; 95% CI, 0.16-0.98; P = .006) than noncarriers. In the replication cohort, MC1R loss-of-function carriers exhibited 50% faster motor decline than noncarriers (β, 1.37; 95% CI, 0.28-2.46; P = .01). In a small prodromal cohort, MC1R loss-of-function carriers showed a more than 4-fold increased risk of phenoconversion to PD (subdistribution hazard ratio, 4.75; 95% CI, 1.48-15.27; P = .009). Conclusions and Relevance:The findings of this cohort study suggest that MC1R loss-of-function variants may define a large, readily identifiable genetic subgroup with accelerated progression, highlighting their utility for potential prognostic stratification and clinical trial enrichment in patients of European descent with PD.
Importance:Patients with branch atheromatous disease (BAD)-related stroke are predisposed to early neurological deterioration (END) and disability. However, large-scale clinical trials focused on the prevention of the deterioration and recurrent stroke in this population are currently lacking. Objective:To evaluate the efficacy and safety of intensive antiplatelet therapy combining the tirofiban with aspirin for patients with BAD-related stroke. Design, Setting, and Participants:This randomized clinical trial was the multicenter, double-blind, randomized, placebo-controlled STRATEGY trial, conducted across 38 hospitals in China. Participants were patients with BAD-related acute ischemic stroke confirmed by magnetic resonance imaging within 48 hours of symptom onset were eligible for enrollment. Enrollment occurred from November 15, 2022, to November 19, 2024, with a 90-day follow-up period for all participants. Investigators, patients, and outcome assessors were blinded to treatment assignment. Interventions:Eligible participants were randomized to receive either intravenous tirofiban or placebo (0.4 µg/kg/min for 30 minutes followed by 0.1 µg/kg/min for 24 hours). All patients received a 300-mg loading dose of aspirin on the day of randomization, followed by 100 mg daily until day 90. Main Outcomes and Measures:The primary efficacy end point was END within 7 days or new stroke within 90 days. The primary safety end point was moderate or severe bleeding. Results:Of 1378 patients with acute ischemic stroke screened for eligibility, 408 were excluded for ineligible imaging findings, other exclusion criteria, lack of consent, or additional reasons, leaving 970 participants who underwent randomization (486 assigned to tirofiban plus aspirin, 484 to placebo plus aspirin). The median (IQR) age was 63.0 (56.0-70.0) years; 607 patients (62.6%) were male and 363 (37.4%) female. The incidence of the primary efficacy end point was 79 patients (17.1%) in the tirofiban group and 89 (19.6%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.65-1.19; P = .39). The incidence of the primary safety end point was 1 of 486 patients (0.2%) in the tirofiban group and 0 patients in the placebo group (P > .99). Conclusions and Relevance:This study found that in patients with BAD-related stroke, intravenous tirofiban combined with aspirin did not significantly reduce the risk of END or stroke compared with aspirin alone, nor was it associated with an increased risk of moderate or severe bleeding. Trial Registration:ClinicalTrials.gov Identifier: NCT05310968.
This Viewpoint discusses the importance of and considerations for including benzodiazepines in airline emergency medical kits for treating patients who experience seizure during a flight.
Importance Concomitant use of antiseizure medications (ASMs) and direct oral anticoagulants (DOACs) is common in epilepsy, but comparative safety data remain limited. Objective To compare risks of thromboembolic events, major bleeding, and all-cause mortality across commonly used ASMs in adults with epilepsy receiving DOACs. Design, Setting, and Participants This was a retrospective cohort study emulating a target trial for each ASM group against an active comparator; 1:1 propensity score matching in 4 cohorts emulated randomization to estimate the per-protocol outcome of sustained ASM monotherapy. Participant data were acquired from the TriNetX Global Collaborative Network, a federated, deidentified electronic health record platform of 165 health care organizations internationally. Included in the study were adults 18 years or older with epilepsy. Individuals were excluded if there was evidence of recent use of vitamin K antagonists (VKAs) or strong non-ASM cytochrome P450 3A4/P-glycoprotein modulators and if there was a history of major vascular events in the prior year. Participant follow-up began at a prespecified 90-day landmark. Data were analyzed January to March 2026. Exposures ASM monotherapy with levetiracetam, valproate, moderate enzyme-inducing ASMs, or strong enzyme-inducing ASMs (eg, carbamazepine, phenytoin), each vs lamotrigine or lacosamide (1 pooled reference group of patients taking either drug; hereafter referred to as lamotrigine/lacosamide ). Main Outcomes and Measures The primary outcomes included primary thromboembolic composite (ischemic stroke, myocardial infarction, pulmonary or systemic/peripheral embolism), major bleeding, and all-cause mortality. Sensitivity analyses included patients treated with VKAs. Results Of 2.29 million adults (≥18 years) with epilepsy, 40 932 were DOAC eligible, 26 962 had DOAC-ASM overlap within 6 months, 10 209 were monotherapy eligible, and 9529 initiators formed the analytic cohort. Among 9529 initiators (mean [SD] age, 63 [18] years; 4869 female [51%]), there were 5473 (57%) taking levetiracetam, 1395 (15%) taking strong enzyme-inducing ASMs, 1006 (11%) taking valproate, and 382 (4%) taking moderate enzyme-inducing ASMs. In matched analyses vs lamotrigine/lacosamide, levetiracetam was associated with higher thromboembolic risk (hazard ratio [HR], 1.98; 95% CI, 1.37-2.87) and higher all-cause mortality (HR, 1.60; 95% CI, 1.23-2.08), with comparable major bleeding. Strong enzyme-inducing ASMs were associated with higher thromboembolic risk (HR, 1.55; 95% CI, 1.02-2.36) but lower major bleeding (HR, 0.62; 95% CI, 0.46-0.83). Valproate was associated with higher mortality (HR, 1.49; 95% CI, 1.09-2.04) and higher intracranial major bleeding (HR, 3.01; 95% CI, 1.45-6.26). Approximately 28% of thromboembolic events were potentially preventable under a lamotrigine/lacosamide reference. In VKA-treated adults, thromboembolic risks were near null. Conclusions and Relevance Results suggest that in adults with epilepsy who are treated with DOACs, ASM selection was associated with distinct thromboembolic, bleeding, and mortality risks, supporting ASM choice as a modifiable contributor to clinical outcomes.
Importance:Uncontrolled generalized myasthenia gravis (gMG) can lead to exacerbations that often warrant rescue therapy (RT) use, especially in moderate to severe cases. Inebilizumab, a monoclonal antibody that depletes cluster of differentiation 19+ B cells, demonstrated efficacy and safety in patients with gMG enrolled in the Myasthenia Gravis Inebilizumab Trial (MINT); the present analysis evaluated its effect on exacerbations and RT use. Objective:To examine the effect of inebilizumab on exacerbations, including RT use, in participants enrolled in MINT. Design, Setting, and Participants:MINT was a phase 3, international, randomized, placebo-controlled trial that enrolled participants between August 2020 and November 2023. The randomized controlled period was 52 weeks for the anti-acetylcholine receptor antibody positive (AChR+) subpopulation and 26 weeks for the anti-muscle-specific kinase antibody positive (MuSK+) subpopulation with an optional 3-year open-label extension. Participants were enrolled at 81 academic and nonacademic sites in 18 countries. MINT screened 485 patients with gMG (AChR+ or MuSK+) and enrolled adult participants with Myasthenia Gravis Activities of Daily Life (MG-ADL) scores of 6-10. This prespecified analysis was conducted between September 2024 and March 2025. Interventions:Participants were randomized 1:1 to either inebilizumab or placebo and underwent a protocol-specified corticosteroid taper to 5 mg per day or less. Main Outcomes and Measures:The frequency of exacerbations, defined as myasthenic crisis, worsening of individual MG-ADL scores, or RT use (intravenous immunoglobulin or plasma exchange). Results:MINT enrolled 238 participants. The mean (SD) age at baseline was 47.5 (15.3) years, 144 (61%) were female, and the mean (SD) MG-ADL score was 9.1 (2.8). Inebilizumab reduced the risk of exacerbations compared with placebo in the combined population by week 26 (hazard ratio [HR], 0.41; 95% CI, 0.24-0.70), in the AChR+ subpopulation by week 52 (HR, 0.39; 95% CI, 0.23-0.68), and in the MuSK+ subpopulation by week 26 (HR, 0.21; 95% CI, 0.06-0.79). Conclusions and Relevance:In this prespecified analysis of a randomized clinical trial, inebilizumab treatment reduced exacerbation rate, including RT use, in participants with gMG who underwent a protocol-specified corticosteroid taper during MINT. These findings further support the clinical benefits of inebilizumab in AChR+ and MuSK+ gMG. Trial Registration:ClinicalTrials.gov Identifier: NCT04524273.
Importance:Phosphorylated tau-217 (p-tau217) is now an established plasma biomarker for assessing amyloid-β pathology in individuals at risk of Alzheimer disease. However, its performance in identifying advanced neocortical neurofibrillary tangle burden remains suboptimal. Precise assessment of tau pathology is increasingly critical for the rational implementation of anti-amyloid therapies and developing anti-tau interventions. Improved biofluid biomarker-based tau staging could enhance patient stratification and optimize participant selection for clinical care and therapeutic trials. Objective:To develop and validate a multiprotein plasma panel to improve identification of neocortical tau pathology beyond p-tau217 alone. Design, Setting, and Participants:This multicenter cohort study included 2 independent observational cohorts, Swedish BioFINDER study and Translational Biomarkers in Aging and Dementia (TRIAD). Cross-sectional clinical data and blood samples were collected between 2017 and 2024. Participants included 560 individuals spanning the clinical spectrum from cognitively unimpaired to dementia. These data were analyzed from January 2025 to May 2026. Exposures:Plasma concentrations of 125 proteins measured using Nucleic Linked Immuno-Sandwich Assay central nervous system panel. Main Outcome and Measure:Advanced tau pathology defined as tau positron emission tomography (PET) uptake within Braak stage V and VI regions. Predictive performance of biomarker models was evaluated using area under the receiver operating characteristic curve (AUC). Results:The study included 560 amyloid-positive participants (BioFINDER: n = 431; mean [SD] age, 73.6 [7.0] years; 212 female [49.2%] and 219 male [51.8%]; TRIAD: n = 129; mean [SD] age, 70.4 [8.3] years; 76 female [58.9%] and 53 male [41.1%]). Using multivariable logistic regression approaches, a 7-protein panel was found in BioFINDER to identify tau PET uptake within Braak stage V and VI regions. When compared with p-tau217 (AUC, 0.86-0.88; 95% CI, 0.82-0.94), this multiprotein panel was associated with improved identification in both discovery and validation cohorts (AUC, 0.92-0.94; 95% CI, 0.89-0.98; DeLong P < .001). This reduced the proportion of individuals classified within the intermediate-risk range (between paired sensitivity and specificity thresholds) in the validation cohort by 14.7% to 21.0%. Conclusions and Relevance:This multicohort study demonstrated how including additional plasma proteins significantly enhanced the performance of p-tau217 in predicting advanced tau pathology among amyloid-positive individuals. This suggests a multiprotein approach may offer a viable and scalable alternative to tau PET staging in clinical or research settings.
This case report describes a patient with a history of progressive sensory disturbance whose lumbar puncture resulted in acute neurological deterioration due to positional cord compression.
Importance Uncontrolled generalized myasthenia gravis (gMG) can lead to exacerbations that often warrant rescue therapy (RT) use, especially in moderate to severe cases. Inebilizumab, a monoclonal antibody that depletes cluster of differentiation 19+ B cells, demonstrated efficacy and safety in patients with gMG enrolled in the Myasthenia Gravis Inebilizumab Trial (MINT); the present analysis evaluated its effect on exacerbations and RT use. Objective To examine the effect of inebilizumab on exacerbations, including RT use, in participants enrolled in MINT. Design, Setting, and Participants MINT was a phase 3, international, randomized, placebo-controlled trial that enrolled participants between August 2020 and November 2023. The randomized controlled period was 52 weeks for the anti–acetylcholine receptor antibody positive (AChR+) subpopulation and 26 weeks for the anti–muscle-specific kinase antibody positive (MuSK+) subpopulation with an optional 3-year open-label extension. Participants were enrolled at 81 academic and nonacademic sites in 18 countries. MINT screened 485 patients with gMG (AChR+ or MuSK+) and enrolled adult participants with Myasthenia Gravis Activities of Daily Life (MG-ADL) scores of 6-10. This prespecified analysis was conducted between September 2024 and March 2025. Interventions Participants were randomized 1:1 to either inebilizumab or placebo and underwent a protocol-specified corticosteroid taper to 5 mg per day or less. Main Outcomes and Measures The frequency of exacerbations, defined as myasthenic crisis, worsening of individual MG-ADL scores, or RT use (intravenous immunoglobulin or plasma exchange). Results MINT enrolled 238 participants. The mean (SD) age at baseline was 47.5 (15.3) years, 144 (61%) were female, and the mean (SD) MG-ADL score was 9.1 (2.8). Inebilizumab reduced the risk of exacerbations compared with placebo in the combined population by week 26 (hazard ratio [HR], 0.41; 95% CI, 0.24-0.70), in the AChR+ subpopulation by week 52 (HR, 0.39; 95% CI, 0.23-0.68), and in the MuSK+ subpopulation by week 26 (HR, 0.21; 95% CI, 0.06-0.79). Conclusions and Relevance In this prespecified analysis of a randomized clinical trial, inebilizumab treatment reduced exacerbation rate, including RT use, in participants with gMG who underwent a protocol-specified corticosteroid taper during MINT. These findings further support the clinical benefits of inebilizumab in AChR+ and MuSK+ gMG. Trial Registration ClinicalTrials.gov Identifier: NCT04524273
Importance:Primary progressive aphasia (PPA) is defined by relatively isolated speech and language symptoms caused by neurodegeneration of language networks; classification of the different clinical, anatomical, and pathological variants relies on time-intensive, expert-dependent assessments that are not widely available. Scalable, interpretable speech-based tools could support diagnosis and monitoring in clinical care and trials. Objective:To determine whether automated speech analysis of voice recording from a short picture description task can yield clinically interpretable speech and language profiles that (1) distinguish among PPA variants, (2) show variant-specific neuroanatomical correlates, and (3) align with underlying autopsy-confirmed neuropathological diagnoses. Design, Setting, and Participants:This was a cross-sectional observational study of patients seen between 2001 and 2025 using the participants' first visit. The setting was a single referral center with external validation in an independent sample from 2 sites. The primary sample included research cohort participants in the following groups: cognitively healthy controls, nonfluent PPA, logopenic PPA, and semantic PPA. Exposures:Picture description task (1-2 minutes of recorded speech) from which 40 linguistic and acoustic features were automatically extracted. Main Outcomes and Measures:The main outcomes included variant-specific speech profile scores derived from Lasso multinomial logistic regression; classification performance for clinical variants and most common underlying neuropathology; and voxelwise associations between speech-profile scores and gray matter volume. Results:A total of 214 participants (mean [SD] age, 65.9 [7.9] years; 118 female [55%]) were included in this analysis (43 in the control group, 50 with nonfluent PPA, 56 with logopenic PPA, and 65 with semantic PPA). Among those with PPA, 64 had postmortem neuropathological data available. Twenty-five features differed between at least 2 PPA variants in 214 patients. Multinomial logistic regression achieved an AUC of 0.90 (95% CI, 0.84-0.97) and generated 3 variant-specific logit scores (speech profiles) using 4 to 8 selected features per variant. External validation in an independent cohort yielded an AUC of 0.90 (95% CI, 0.83-0.97). Profile scores showed associations consistent with established neuroanatomical patterns (n = 195): left superior and middle frontal and premotor cortex in nonfluent PPA, left posterior temporal cortex and angular gyrus in logopenic PPA, and bilateral (left-predominant) anterior temporal lobes in semantic PPA. In an autopsy-confirmed subset with most common underlying pathology (n = 56), speech profile scores discriminated neuropathology with an AUC of 0.90 (95% CI, 0.80-0.96). Conclusions and Relevance:Results of this cross-sectional study suggest that automated speech analysis of a short audio sample of connected speech yielded interpretable speech profiles that accurately distinguished PPA clinical, anatomical, and neuropathological subtypes. These automated speech profiles may serve as clinical tools to support differential diagnosis and longitudinal monitoring, particularly in settings where specialized speech-language assessment is limited.
This case report describes a 60-year-old woman presenting with sudden loss of muscle tone with preserved consciousness and severe daytime sleepiness.
This cohort study examines data for a large population-based cohort to identify and characterize any cases of primary Epstein-Barr virus infection that occurred after the onset of multiple sclerosis.
Importance:Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation. Objective:To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA). Design, Setting, and Participants:This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements). Exposures:Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months. Main Outcomes and Measures:Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC). Results:The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively. Conclusions and Relevance:In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.
Importance Development of motor fluctuations is common in people with Parkinson disease (PD) treated with oral levodopa, and currently available dopamine (D) agonists adjunctive to levodopa offer additional motor control but may increase risk of adverse events (AEs) via preferential activation of D2/D3 receptors. Tavapadon is a novel, investigational, oral, once-daily, selective D1/D5 agonist that may improve motor control while minimizing AEs commonly associated with D2/D3 receptor activation. Objective To evaluate the efficacy, safety, and tolerability of tavapadon as adjunctive therapy to oral levodopa in adults with PD experiencing motor fluctuations. Design, Setting, and Participants This was a phase 3, double-blind, placebo-controlled randomized clinical trial conducted between September 2020 and February 2024 with a 4-week safety follow-up. Participants were recruited from 148 sites across 14 countries. Participants were enrolled after screening adults with PD who were experiencing fluctuations while receiving stable oral levodopa (≥400 mg daily). Interventions Participants were randomized 1:1 to flexible-dose tavapadon (5-15 mg once daily) or placebo adjunctive to oral levodopa for 27 weeks. Main Outcomes and Measures The primary end point was change from baseline to week 26 in total daily on-time (ie, good mobility, smoother movement, fewer motor/nonmotor symptoms) without troublesome dyskinesia (referred to as good-on-time ). The key secondary end point was change from baseline in total daily off-time (ie, return/worsening of motor/nonmotor symptoms often experienced between medication doses). Results After screening 824 adults with PD, 507 participants (mean [SD] age, 64.9 [8.5] years; 321 male [63%]; mean [SD] disease duration, 6.7 [4.5] years; mean [SD] baseline daily off-time, 5.5 [2.4] hours) were enrolled and received tavapadon (n = 252) or placebo (n = 255). Tavapadon significantly increased daily good-on-time by 1.10 hours compared with placebo (1.70 vs 0.60 hours; 95% CI, 0.60-1.70; P <.001). Daily off-time was significantly reduced from baseline with tavapadon vs placebo (−1.88 vs −0.93 hours; difference, −0.94 hours; 95% CI, −1.48 to −0.41]; P < .001). Tavapadon had a favorable safety profile; although more AEs occurred with tavapadon vs placebo (180 participants [71.7%] vs 140 participants [55.1%]), most were nonserious (93.2%) and mild to moderate in severity. Common AEs with tavapadon (≥5% of participants) were nausea (14.3%), dyskinesia (10.0%), and dizziness (7.6%). Conclusions and Relevance Findings of this randomized clinical trial demonstrate the efficacy, tolerability, and safety profile of tavapadon adjunctive to levodopa for off fluctuations. Trial Registration ClinicalTrials.gov Identifier: NCT04542499
