Browsing by Author "Ardayfio, Paul"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial
    (American Medical Association, 2023) Sims, John R.; Zimmer, Jennifer A.; Evans, Cynthia D.; Lu, Ming; Ardayfio, Paul; Sparks, JonDavid; Wessels, Alette M.; Shcherbinin, Sergey; Wang, Hong; Monkul Nery, Emel Serap; Collins, Emily C.; Solomon, Paul; Salloway, Stephen; Apostolova, Liana G.; Hansson, Oskar; Ritchie, Craig; Brooks, Dawn A.; Mintun, Mark; Skovronsky, Daniel M.; TRAILBLAZER-ALZ 2 Investigators; Neurology, School of Medicine
    Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, setting, and participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main outcomes and measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.
  • Thumbnail Image
    Item
    Using Clinical Scales and Digital Measures to Explore Falls in Patients with Lewy Body Dementia
    (Karger, 2023-06-21) Battioui, Chakib; Man, Albert; Pugh, Melissa; Wang, Jian; Dang, Xiangnan; Zhang, Hui; Ardayfio, Paul; Munsie, Leanne; Hake, Ann Marie; Biglan, Kevin; Neurology, School of Medicine
    Introduction: PRESENCE was a phase 2 clinical trial assessing the efficacy of mevidalen, a D1 receptor positive allosteric modulator, for symptomatic treatment of Lewy body dementia (LBD). Mevidalen demonstrated improvements in motor and non-motor features of LBD, global functioning, and actigraphy-measured activity and daytime sleep. Adverse events (AEs) of fall were numerically increased in mevidalen-treated participants. Methods: A subset of PRESENCE participants wore a wrist actigraphy device for 2-week periods pre-, during, and posttreatment. Actigraphy sleep and activity measures were derived per period and analyzed to assess for their association with participants' reports of an AE of fall. Prespecified baseline and treatment-emergent clinical characteristics were also included in the retrospective analysis of falls. Independent-samples t test and χ2 test were performed to compare the means and proportions between individuals with/without falls. Results: A trend toward more falls was observed with mevidalen treatment (31/258 mevidalen-treated vs. 4/86 in placebo-treated participants: p = 0.12). Higher body mass index (BMI) (p < 0.05), more severe disease measured by baseline Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II (p < 0.05), and a trend toward improved Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog13) (p = 0.06) were associated with individuals with falls. No statistically significant associations with falls and treatment-emergent changes were observed. Conclusion: The association of falls with worse baseline disease severity and higher BMI and overall trend toward improvements on cognitive and motor scales suggest that falls in PRESENCE may be related to increased activity in mevidalen-treated participants at greater risk for falling. Future studies to confirm this hypothesis using fall diaries and digital assessments are necessary.