Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease

Cash, David M. ; Morgan, Katy E.; O'Connor, Antoinette; Veale, Thomas D.; Malone, Ian B. ; Poole, Teresa; Benzinger, Tammie L. S.; Gordon, Brian A.; Ibanez, Laura; Li, Yan ; Llibre-Guerra, Jorge J.; McDad, Eric; Wang, Guoqiao; Chhatwal, Jasmeer P. ; Day, Gregory S. ; Huey, Edward; Jucker, Mathias; Levin, Johannes ; Niimi, Yoshiki ; Noble, James M. ; Roh, Jee Hoon ; Sánchez-Valle, Racquel ; Schofield, Peter R. ; Bateman, Randall J.; Frost, Chris und Fox, Nick C. (2025): Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease. In: Journal of Prevention of Alzheimer's Disease [Forthcoming]

Abstract

Introduction: Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.

Methods: Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).

Results: Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95 %CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80 % power (5 % statistical significance) to detect a 25 % reduction in absolute levels of pathology, allowing 40 % dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50 % reduction in rate of change. Sample sizes ranged from 250 to 900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).

Discussion: Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2274-5807
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198