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Clinical Trial
. 2017 Dec 8;9(1):95.
doi: 10.1186/s13195-017-0318-y.

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

Susanne Ostrowitzki  1 , Robert A Lasser  2 , Ernest Dorflinger  3 , Philip Scheltens  4 , Frederik Barkhof  4   5   6 , Tania Nikolcheva  6 , Elizabeth Ashford  7 , Sylvie Retout  8 , Carsten Hofmann  8 , Paul Delmar  9 , Gregory Klein  6 , Mirjana Andjelkovic  8 , Bruno Dubois  10 , Mercè Boada  11 , Kaj Blennow  11 , Luca Santarelli  12 , Paulo Fontoura  13 ; SCarlet RoAD Investigators
Affiliations
Clinical Trial

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

Susanne Ostrowitzki et al. Alzheimers Res Ther. .

Erratum in

  • Correction to: A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease.
    Ostrowitzki S, Lasser RA, Dorflinger E, Scheltens P, Barkhof F, Nikolcheva T, Ashford E, Retout S, Hofmann C, Delmar P, Klein G, Andjelkovic M, Dubois B, Boada M, Blennow K, Santarelli L, Fontoura P; SCarlet RoAD Investigators. Ostrowitzki S, et al. Alzheimers Res Ther. 2018 Sep 27;10(1):99. doi: 10.1186/s13195-018-0409-4. Alzheimers Res Ther. 2018. PMID: 30261916 Free PMC article.

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.

Keywords: Alzheimer’s disease; Gantenerumab; SCarlet RoAD.

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Conflict of interest statement

Ethics approval and consent to participate

SCarlet RoAD was approved by individual institution ethics committees or institutional review boards and was conducted in accordance with the principles of the Declaration of Helsinki and good clinical practice (GCP). Please refer to Additional file 1 for details. Written informed consent was obtained from each patient.

Consent for publication

Not applicable.

Competing interests

SO, RAL, ED, TN, EA, SR, CH, PD, GK, MA, LS, and PF are current or former employees of F. Hoffmann La-Roche and own stock or stock options in Roche. FB has received consultancy fees/honoraria from Bayer-Schering Pharma, Biogen Idec, Teva, Merck-Serono, Novartis, F. Hoffmann-La Roche, Synthon BV, Janssen Research, and Genzyme. FB has received grants from the Dutch Multiple Sclerosis Society and the European Union Seventh Framework Programme/Horizon 2020 (H2020). FB’s institution has received fees from IXICO for educational presentation development. FB is supported by the National Institute for Health Research-UCL Hospitals Biomedical Research Centre. KB reports receipt of a grant to his institution for performing CSF analyses during the conduct of the study. KB reports receiving personal fees from Alzheon, BioArctic, Biogen, Eli Lilly, Fujirebio Europe, IBL International, Pfizer, and Roche Diagnostics. KB is the co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. MB reports receiving grants from Elizabeth Forward School District/Lilly Mental Health and Diabetes Program (2014–2015) and from the H2020-JTI-IMI2-2015-05 (EC) (Eli Lilly and AstraZeneca) Models of Patient Engagement for Alzheimer’s Disease (MOPEAD) Project (2016–2018). KB reports receiving personal fees from Grifols, Janssen, Eli Lilly, MSD, Nutricia, Roche, and Servier. PS reports receiving speaker fees from Roche AG during the conduct of the study and consultancy fees from Axovant Sciences, Probiodrug, and EIP Pharma. BD reports receiving personal fees from Eli Lilly and grants from Pfizer.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Enrollment, randomization, and 2-year completion in the SCarlet RoAD study. AChE Acetylcholinesterase
Fig. 2
Fig. 2
Least squares mean (±95% CI) change from baseline in CDR-SB (a) and ADAS-Cog 13 score (b). CDR-SB Clinical Dementia Rating Sum of Boxes, ADAS-Cog 13 Alzheimer’s Disease Assessment Scale–Cognitive subscale, LS Least squares
Fig. 3
Fig. 3
Mean (±SE) change from baseline in PET SUVr (cerebellar gray reference). *p < 0.01 vs placebo. PET SUVr Positron emission tomography standardized uptake value ratio
Fig. 4
Fig. 4
Percentage changes in median cerebrospinal fluid biomarker levels for Aβ1–42, p-tau, t-tau, and neurogranin. *p ≤ 0.05; **p ≤ 0.005; ***p ≤ 0.0001. Aβ Amyloid-beta, p-tau Phosphorylated tau 181
See this image and copyright information in PMC

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