Abstract
Background: Detecting subtle-to-moderate biomarker changes such as those in amyloid PET imaging becomes increasingly relevant in the context of primary and secondary prevention of Alzheimer’s disease (AD). This work aimed to determine if and when distribution volume ratio (DVR; derived from dynamic imaging) and regional quantitative values could improve statistical power in AD prevention trials. Methods: Baseline and annualized % change in [11C]PIB SUVR and DVR were computed for a global (cortical) and regional (early) composite from scans of 237 cognitively unimpaired subjects from the OASIS-3 database (www.oasis-brains.org). Bland-Altman and correlation analyses were used to assess the relationship between SUVR and DVR. General linear models and linear mixed effects models were used to determine effects of age, sex, and APOE-ε4 carriership on baseline and longitudinal amyloid burden. Finally, differences in statistical power of SUVR and DVR (cortical or early composite) were assessed considering three anti-amyloid trial scenarios: secondary prevention trials including subjects with (1) intermediate-to-high (Centiloid > 20.1), or (2) intermediate (20.1 < Centiloid ≤ 49.4) amyloid burden, and (3) a primary prevention trial focusing on subjects with low amyloid burden (Centiloid ≤ 20.1). Trial scenarios were set to detect 20% reduction in accumulation rates across the whole population and in APOE-ε4 carriers only. Results: Although highly correlated to DVR (ρ =.96), cortical SUVR overestimated DVR cross-sectionally and in annual % change. In secondary prevention trials, DVR required 143 subjects per arm, compared with 176 for SUVR. Both restricting inclusion to individuals with intermediate amyloid burden levels or to APOE-ε4 carriers alone further reduced sample sizes. For primary prevention, SUVR required less subjects per arm (n = 855) compared with DVR (n = 1508) and the early composite also provided considerable sample size reductions (n = 855 to n = 509 for SUVR, n = 1508 to n = 734 for DVR). Conclusion: Sample sizes in AD secondary prevention trials can be reduced by the acquisition of dynamic PET scans and/or by restricting inclusion to subjects with intermediate amyloid burden or to APOE-ε4 carriers only. Using a targeted early composite only leads to reductions of sample size requirements in primary prevention trials. These findings support strategies to enable smaller Proof-of-Concept Phase II clinical trials to better streamline drug development.
| Original language | English |
|---|---|
| Article number | 82 |
| Journal | Alzheimer's Research and Therapy |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 19 Apr 2021 |
Bibliographical note
Funding Information:JDG has received speaker’s fees from Biogen and Philips. In addition, he holds a “Ramón y Cajal” fellowship (RYC-2013-13054) and has received research support from the EU/EFPIA Innovative Medicines Initiative Joint Undertaking AMYPAD grant agreement n° 115952 and from Ministerio de Ciencia y Universidades (grant agreement RTI2018-102261).
Funding Information:
FB received payment and honoraria from Bayer-Schering Pharma, Sanofi-Aventis, Genzyme, Biogen-Idec, TEVA, Merck-Serono, Novartis, Roche, Jansen Research, IXICO Ltd., GeNeuro, Combinostics, and Apitope Ltd. for consulting; payment from the Serono Symposia Foundation, IXICOLtd, and MedScape for educational presentations; and research support via grants from EU/EFPIA Innovative Medicines Initiative Joint Undertaking (AMYPAD consortium), EuroPOND (H2020), UK MS Society, Dutch MS Society, PICTURE (IMDI-NWO), NIHR UCLH Biomedical Research Centre (BRC), and ECTRIMS-MAGNIMS.
Funding Information:
NV-T is funded by a post-doctoral grant, Juan de la Cierva Programme (FJC2018-038085-I), Ministry of Science and Innovation– Spanish State Research Agency. All CRG authors acknowledge the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya.
Funding Information:
Main authors of this paper have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115952. This Joint Undertaking receives the support from the European Union’s Horizon 2020 research and innovation program and EFPIA.This communication reflects the views of the authors and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.
Publisher Copyright:
© 2021, The Author(s).