A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease - Sorbonne Université Access content directly
Journal Articles Alzheimer's Research and Therapy Year : 2017

A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease

Abstract

Background: Gantenerumab is a fully human monoclonal antibody that binds aggregated amyloid-β (Aβ) and removes Aβ plaques by Fc receptor-mediated phagocytosis. In the SCarlet RoAD trial, we assessed the efficacy and safety of gantenerumab in prodromal Alzheimer's disease (AD). Methods: In this randomized, double-blind, placebo-controlled phase III study, we investigated gantenerumab over 2 years. Patients were randomized to gantenerumab 105 mg or 225 mg or placebo every 4 weeks by subcutaneous injection. The primary endpoint was the change from baseline to week 104 in Clinical Dementia Rating Sum of Boxes (CDR-SB) score. We evaluated treatment effects on cerebrospinal fluid biomarkers (all patients) and amyloid positron emission tomography (substudy). A futility analysis was performed once 50% of patients completed 2 years of treatment. Safety was assessed in patients who received at least one dose. Results: Of the 3089 patients screened, 797 were randomized. The study was halted early for futility; dosing was discontinued; and the study was unblinded. No differences between groups in the primary (least squares mean [95% CI] CDR-SB change from baseline 1.60 [1.28, 1.91], 1.69 [1.37, 2.01], and 1.73 [1.42, 2.04] for placebo, gantenerumab 105 mg, and gantenerumab 225 mg, respectively) or secondary clinical endpoints were observed. The incidence of generally asymptomatic amyloid-related imaging abnormalities increased in a dose- and APOE ε4 genotype-dependent manner. Exploratory analyses suggested a dose-dependent drug effect on clinical and biomarker endpoints. Conclusions: The study was stopped early for futility, but dose-dependent effects observed in exploratory analyses on select clinical and biomarker endpoints suggest that higher dosing with gantenerumab may be necessary to achieve clinical efficacy. Trial registration: ClinicalTrials.gov, NCT01224106 . Registered on October 14, 2010.

Dates and versions

hal-04559141 , version 1 (25-04-2024)

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Susanne Ostrowitzki, Robert Lasser, Ernest Dorflinger, Philip Scheltens, Frederik Barkhof, et al.. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimer's Research and Therapy, 2017, 9 (1), pp.95. ⟨10.1186/s13195-017-0318-y⟩. ⟨hal-04559141⟩
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