Browsing by Author "DIAN-TU Study Team"

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    Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials
    (Springer, 2024) Liu, H.; Li, J.; Ziegemeier, E.; Adams, S.; McDade, E.; Clifford, D. B.; Cao, Y.; Wang, G.; Li, Y.; Mills, S. L.; Santacruz, A. M.; Belyew, S.; Grill, J. D.; Snider, B. J.; Mummery, C. J.; Surti, G.; Hannequin, D.; Wallon, D.; Berman, S. B.; Jimenez-Velazquez, I. Z.; Roberson, E. D.; van Dyck, C. H.; Honig, L. S.; Sanchez-Valle, R.; Brooks, W. S.; Gauthier, S.; Galasko, D.; Masters, C. L.; Brosch, J.; Hsiung, G. Y. R.; Jayadev, S.; Formaglio, M.; Masellis, M.; Clarnette, R.; Pariente, J.; Dubois, B.; Pasquier, F.; Bateman, R. J.; Llibre-Guerra, J. J.; DIAN-TU Study Team; Neurology, School of Medicine
    Background: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). Methods: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. Results: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. Conclusion: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.
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    Longitudinal head-to-head comparison of 11C-PiB and 18F-florbetapir PET in a Phase 2/3 clinical trial of anti-amyloid-β monoclonal antibodies in dominantly inherited Alzheimer disease
    (Springer, 2023) Chen, Charles D.; McCullough, Austin; Gordon, Brian; Joseph-Mathurin, Nelly; Flores, Shaney; McKay, Nicole S.; Hobbs, Diana A.; Hornbeck, Russ; Fagan, Anne M.; Cruchaga, Carlos; Goate, Alison M.; Perrin, Richard J.; Wang, Guoqiao; Li, Yan; Shi, Xinyu; Xiong, Chengjie; Pontecorvo, Michael J.; Klein, Gregory; Su, Yi; Klunk, William E.; Jack, Clifford; Koeppe, Robert; Snider, B. Joy; Berman, Sarah B.; Roberson, Erik D.; Brosch, Jared; Surti, Ghulam; Jiménez-Velázquez, Ivonne Z.; Galasko, Douglas; Honig, Lawrence S.; Brooks, William S.; Clarnette, Roger; Wallon, David; Dubois, Bruno; Pariente, Jérémie; Pasquier, Florence; Sanchez-Valle, Raquel; Shcherbinin, Sergey; Higgins, Ixavier; Tunali, Ilke; Masters, Colin L.; van Dyck, Christopher H.; Masellis, Mario; Hsiung, Robin; Gauthier, Serge; Salloway, Steve; Clifford, David B.; Mills, Susan; Supnet-Bell, Charlene; McDade, Eric; Bateman, Randall J.; Benzinger, Tammie L. S.; DIAN-TU Study Team; Neurology, School of Medicine
    Purpose: Pittsburgh Compound-B (11C-PiB) and 18F-florbetapir are amyloid-β (Aβ) positron emission tomography (PET) radiotracers that have been used as endpoints in Alzheimer's disease (AD) clinical trials to evaluate the efficacy of anti-Aβ monoclonal antibodies. However, comparing drug effects between and within trials may become complicated if different Aβ radiotracers were used. To study the consequences of using different Aβ radiotracers to measure Aβ clearance, we performed a head-to-head comparison of 11C-PiB and 18F-florbetapir in a Phase 2/3 clinical trial of anti-Aβ monoclonal antibodies. Methods: Sixty-six mutation-positive participants enrolled in the gantenerumab and placebo arms of the first Dominantly Inherited Alzheimer Network Trials Unit clinical trial (DIAN-TU-001) underwent both 11C-PiB and 18F-florbetapir PET imaging at baseline and during at least one follow-up visit. For each PET scan, regional standardized uptake value ratios (SUVRs), regional Centiloids, a global cortical SUVR, and a global cortical Centiloid value were calculated. Longitudinal changes in SUVRs and Centiloids were estimated using linear mixed models. Differences in longitudinal change between PET radiotracers and between drug arms were estimated using paired and Welch two sample t-tests, respectively. Simulated clinical trials were conducted to evaluate the consequences of some research sites using 11C-PiB while other sites use 18F-florbetapir for Aβ PET imaging. Results: In the placebo arm, the absolute rate of longitudinal change measured by global cortical 11C-PiB SUVRs did not differ from that of global cortical 18F-florbetapir SUVRs. In the gantenerumab arm, global cortical 11C-PiB SUVRs decreased more rapidly than global cortical 18F-florbetapir SUVRs. Drug effects were statistically significant across both Aβ radiotracers. In contrast, the rates of longitudinal change measured in global cortical Centiloids did not differ between Aβ radiotracers in either the placebo or gantenerumab arms, and drug effects remained statistically significant. Regional analyses largely recapitulated these global cortical analyses. Across simulated clinical trials, type I error was higher in trials where both Aβ radiotracers were used versus trials where only one Aβ radiotracer was used. Power was lower in trials where 18F-florbetapir was primarily used versus trials where 11C-PiB was primarily used. Conclusion: Gantenerumab treatment induces longitudinal changes in Aβ PET, and the absolute rates of these longitudinal changes differ significantly between Aβ radiotracers. These differences were not seen in the placebo arm, suggesting that Aβ-clearing treatments may pose unique challenges when attempting to compare longitudinal results across different Aβ radiotracers. Our results suggest converting Aβ PET SUVR measurements to Centiloids (both globally and regionally) can harmonize these differences without losing sensitivity to drug effects. Nonetheless, until consensus is achieved on how to harmonize drug effects across radiotracers, and since using multiple radiotracers in the same trial may increase type I error, multisite studies should consider potential variability due to different radiotracers when interpreting Aβ PET biomarker data and, if feasible, use a single radiotracer for the best results.
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    The CentiMarker Project: Standardizing Quantitative Alzheimer’s disease Fluid Biomarkers for Biologic Interpretation
    (medRxiv, 2024-07-27) Wang, Guoqiao; Li, Yan; Xiong, Chengjie; Cao, Yuchen; Schindler, Suzanne E.; McDade, Eric; Blennow, Kaj; Hansson, Oskar; Dage, Jeffrey L.; Jack, Clifford R., Jr.; Teunissen, Charlotte E.; Shaw, Leslie M.; Zetterberg, Henrik; Ibanez, Laura; Timsina, Jigyasha; Carlos, Cruchaga; DIAN-TU Study Team; Bateman, Randall J.; Neurology, School of Medicine
    Introduction: Biomarkers have been essential to understanding Alzheimer's disease (AD) pathogenesis, pathophysiology, progression, and treatment effects. However, each biomarker measure is a representation of the biological target, the assay used to measure it, and the variance of the assay. Thus, biomarker measures are difficult to compare without standardization, and the units and magnitude of effect relative to the disease are difficult to appreciate, even for experts. To facilitate quantitative comparisons of AD biomarkers in the context of biologic and treatment effects, we propose a biomarker standardization approach between normal ranges and maximum abnormal AD ranges, which we refer to as CentiMarker, similar to the Centiloid approach used in PET. Methods: We developed a standardization scale that creates percentile values ranging from 0 for a normal population to 100 for the most abnormal measures across disease stages. We applied this scale to CSF and plasma biomarkers in autosomal dominant AD, assessing the distribution by estimated years from symptom onset, between biomarkers, and across cohorts. We then validated this approach in a large national sporadic AD cohort. Results: We found the CentiMarker scale provided an easily interpretable metric of disease abnormality. The biologic changes, range, and distribution of several AD fluid biomarkers including amyloid-β, phospho-tau and other biomarkers, were comparable across disease stages in both early onset autosomal dominant and sporadic late onset AD. Discussion: The CentiMarker scale offers a robust and versatile framework for the standardized biological comparison of AD biomarkers. Its broader adoption could facilitate biomarker reporting, allowing for more informed cross-study comparisons and contributing to accelerated therapeutic development.