Wang, G; Li, Y; Xiong, C; McDade, E; Clifford, DB; Mills, SL; Santacruz, AM; ... Bateman, RJ; + view all Wang, G; Li, Y; Xiong, C; McDade, E; Clifford, DB; Mills, SL; Santacruz, AM; Aschenbrenner, AJ; Hassenstab, J; Benzinger, TLS; Gordon, BA; Fagan, AM; Coalier, KA; Libre-Guerra, JJ; McCullough, A; Joseph-Mathurin, N; Chen, CD; Mummery, C; Wendelberger, BA; Gauthier, S; Masellis, M; Holdridge, KC; Yaari, R; Chatterjee, S; Sims, J; Delmar, P; Kerchner, GA; Bittner, T; Hofmann, C; Bateman, RJ; - view fewer (2022) 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. Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring , 14 (1) , Article e12367. 10.1002/dad2.12367.

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Abstract

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.

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