Using an external control to contextualize efficacy data from patients with prodromal and mild Alzheimer’s disease treated with gantenerumab in SCarlet RoAD and Marguerite RoAD open‐label extension studies

Abstract

AbstractBackgroundGantenerumab, a human monoclonal antibody targeting aggregated beta‐amyloid (Abeta), is a potential disease‐modifying treatment for early (prodromal‐to‐mild) Alzheimer’s disease (AD). SCarlet RoAD (SR) (NCT01224106) and Marguerite RoAD (MR) (NCT02051608) were two Phase III trials with open‐label extensions (OLEs), during which participants were treated with up to 1,200 mg/month of subcutaneous gantenerumab for up to 5 years. Substantial Abeta removal was confirmed without new or unexpected safety findings. This work aims to evaluate the gantenerumab treatment effect during the SR and MR uncontrolled OLE studies by using an external control group based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.MethodParticipants from the ADNI studies were weighted using the inverse probability of treatment weighting method1 to make their demographics and baseline characteristics more comparable to the patients in the OLE stages of the pooled SR and MR studies. In the weighted sample, the treatment effects of gantenerumab, per change from the OLE Baseline in Clinical Dementia Rating – Sum of Boxes (CDR‐SB), Alzheimer’s Disease Assessment Scale – Cognitive subscale 13 (ADAS‐Cog13), and Mini‐Mental State Exam (MMSE) at Weeks 104 and 156 were investigated by a mixed‐effect model of repeated measure.ResultsApplying inclusion and exclusion criteria from the ongoing GRADUATE gantenerumab trials (NCT03444870, NCT03443973) to the SR and MR OLE cohorts, 164 participants from the SR and MR OLE studies and 1,218 participants from ADNI were selected. After weighting, the demographics and baseline characteristics were comparable between the two populations. A comparison of relative reductions between the pooled participants in SR and MR OLE studies and weighted ADNI participants can be found in Table 1.ConclusionsWhen comparing participants in the SR and MR OLE studies to a matched ADNI control group, a slower progression was observed with gantenerumab treatment. Specifically, gantenerumab showed effects on slowing cognitive decline in the SR and MR OLE studies compared with weighted ADNI participants on the CDR‐SB and ADAS‐Cog13 scales, although with a smaller effect on MMSE. The efficacy and safety of gantenerumab in early AD participants will be assessed in the two ongoing Phase III GRADUATE trials.1. Austin PC & Stuart EA, 2015; Stat Med. 34:28