Validation of a novel cognitive-functional outcome measure optimized for early Alzheimer’s Disease: Evidence from the VIVA-MIND trial

BACKGROUND: Cognitive-functional composite measures are increasingly used as primary efficacy endpoints in early Alzheimer's disease (AD) trials, where greater sensitivity to decline can improve trial efficiency and reduce sample size requirements. OBJECTIVES: To compare sensitivity to decline of the Cognitive Functional Component 2 (CFC2), a novel cognitive-functional composite measure described by Raghavan et al. (2013), against the Clinical Dementia Rating - Sum of Boxes (CDR-SB) and other standard cognitive and functional outcomes including MMSE, FAQ, ADAS Cog 13 and ADCOMS using prospective randomized clinical trial data. DESIGN: The VIVA-MIND trial was a phase 2A/2B randomized controlled trial investigating the safety and efficacy of varoglutamstat in patients with mild cognitive impairment and mild dementia due to AD. SETTING: The VIVA-MIND trial was conducted between 2021-2024. It was prematurely terminated in mid-2024 by the study sponsor. PARTICIPANTS: This secondary analysis uses data from 98 participants in the modified intention-to-treat population from the VIVA-MIND trial with complete neuropsychological test data. MEASUREMENTS: Standard power calculations informed by parameters estimated from linear mixed-effects models were used to determine the relative efficiency of outcome measures. RESULTS: The CFC2 was more sensitive to decline than the CDR-SB in this population. Use of the CFC2 would yield a 15% reduction in required sample size relative to the CDR-SB. Application of an optimal weighting scheme further improved the sensitivity of the CFC2. CONCLUSIONS: Practically significant differences in the efficiency of clinical trials in early AD may be realized by the choice of clinical outcome measure and weighting scheme. Although further verification is needed, we replicate a previous finding that the CFC2 may outperform the CDR-SB in the early AD population.