TY - JOUR
T1 - Evaluation of dose-dependent treatment effects after mid-trial dose escalation in biomarker, clinical, and cognitive outcomes for gantenerumab or solanezumab in dominantly inherited Alzheimer's disease
AU - for the DIAN-TU Study Team
AU - Wang, Guoqiao
AU - Li, Yan
AU - Xiong, Chengjie
AU - McDade, Eric
AU - Clifford, David B.
AU - Mills, Susan L.
AU - Santacruz, Anna M.
AU - Aschenbrenner, Andrew J.
AU - Hassenstab, Jason
AU - Benzinger, Tammie L.S.
AU - Gordon, Brian A.
AU - Fagan, Anne M.
AU - Coalier, Kelley A.
AU - Libre-Guerra, Jorge J.
AU - McCullough, Austin
AU - Joseph-Mathurin, Nelly
AU - Chen, Charles D.
AU - Mummery, Catherine
AU - Wendelberger, Barbara A.
AU - Gauthier, Serge
AU - Masellis, Mario
AU - Holdridge, Karen C.
AU - Yaari, Roy
AU - Chatterjee, Saptarshi
AU - Sims, John
AU - Delmar, Paul
AU - Kerchner, Geoffrey A.
AU - Bittner, Tobias
AU - Hofmann, Carsten
AU - Bateman, Randall J.
N1 - Funding Information:
The authors gratefully acknowledge the outstanding commitment of the participants, family members, and caregivers whose participation was critical to the success of the DIAN‐TU trial. We thank the DIAN‐TU study team for their exceptional dedication and accomplishments, which ensured the success of the trial. We thank the DIAN‐EXR and DIAN‐OBS study teams for their support on recruitment and commitment to family members. We appreciate the robust intellectual collaboration between the DIAN‐TU investigators, participants and family members, F. Hoffmann‐La Roche, Ltd./Genentech, and Eli Lilly and Company, the DIAN‐TU Pharma Consortium ( https://dian.wustl.edu/our‐research/the‐pharma‐consortium/ ), the NIH, and regulatory representatives who were critical in making this study possible. We thank the Alzheimer's Association, GHR Foundation, an anonymous organization, other industry partners (Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company, Signant, and Cogstate), and regulatory representatives for their support. We also acknowledge Dr. Laurie Ryan from the National Institute on Aging for her key contributions in leadership and scientific guidance on this project. Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under Award Numbers U01AG042791, U01AG042791‐S1 (FNIH and Accelerating Medicines Partnership), R01AG046179, R01AG053267‐S1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This research was also supported by the Alzheimer's Association, Eli Lilly and Company, F. Hoffman‐LaRoche Ltd., Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly and Company, GHR Foundation, an anonymous organization. Cogstate, and Signant offered in‐kind support. The DIAN‐OBS was supported by the National Institute on Aging of the National Institutes of Health (DIAN, U19AG032438), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI).
Publisher Copyright:
© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.
PY - 2022
Y1 - 2022
N2 - Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect. Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes. Results: Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions: Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights: We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies. Dose-dependent treatment effects were observed in some biomarkers. No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.
AB - Introduction: While the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) was ongoing, external data suggested higher doses were needed to achieve targeted effects; therefore, doses of gantenerumab were increased 5-fold, and solanezumab was increased 4-fold. We evaluated to what extent mid-trial dose increases produced a dose-dependent treatment effect. Methods: Using generalized linear mixed effects (LME) models, we estimated the annual low- and high-dose treatment effects in clinical, cognitive, and biomarker outcomes. Results: Both gantenerumab and solanezumab demonstrated dose-dependent treatment effects (significant for gantenerumab, non-significant for solanezumab) in their respective target amyloid biomarkers (Pittsburgh compound B positron emission tomography standardized uptake value ratio and cerebrospinal fluid amyloid beta 42), with gantenerumab demonstrating additional treatment effects in some downstream biomarkers. No dose-dependent treatment effects were observed in clinical or cognitive outcomes. Conclusions: Mid-trial dose escalation can be implemented as a remedy for an insufficient initial dose and can be more cost effective and less burdensome to participants than starting a new trial with higher doses, especially in rare diseases. Highlights: We evaluated the dose-dependent treatment effect of two different amyloid-specific immunotherapies. Dose-dependent treatment effects were observed in some biomarkers. No dose-dependent treatment effects were observed in clinical/cognitive outcomes, potentially due to the fact that the modified study may not have been powered to detect such treatment effects in symptomatic subjects at a mild stage of disease exposed to high (or maximal) doses of medication for prolonged durations.
KW - Dominantly Inherited Alzheimer Network
KW - autosomal dominant Alzheimer's disease
KW - dose escalation
KW - gantenerumab
KW - solanezumab
UR - http://www.scopus.com/inward/record.url?scp=85145067806&partnerID=8YFLogxK
U2 - 10.1002/dad2.12367
DO - 10.1002/dad2.12367
M3 - Article
C2 - 36348972
AN - SCOPUS:85145067806
SN - 2352-8729
VL - 14
JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
IS - 1
M1 - e12367
ER -