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

Alzheimers Res Ther. 2017 Dec 8;9(1):95. doi: 10.1186/s13195-017-0318-y.


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.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / genetics
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Apolipoprotein E4 / genetics
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Humans
  • Immunologic Factors / therapeutic use*
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Middle Aged
  • Neuropsychological Tests
  • Positron-Emission Tomography
  • Prodromal Symptoms*
  • Psychiatric Status Rating Scales
  • Treatment Outcome


  • Amyloid beta-Peptides
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Apolipoprotein E4
  • Immunologic Factors
  • gantenerumab

Associated data

  • ClinicalTrials.gov/NCT01224106