The importance of endpoint selection: How effective does a drug need to be for success in a clinical trial of a possible Alzheimer\u2019s disease treatment?

Stephanie Evans,Christoforos Hadjichrysanthou,Frank De Wolf,Roy Anderson,Mei Mei Wong,Kevin Mcrae-Mckee

doi:10.1007/s10654-018-0381-0

Stephanie Evans, Christoforos Hadjichrysanthou + Show 4 more

Open Access

https://doi.org/10.1007/s10654-018-0381-0

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Abstract

To date, Alzheimer’s disease (AD) clinical trials have been largely unsuccessful. Failures have been attributed to a number of factors including ineffective drugs, inadequate targets, and poor trial design, of which the choice of endpoint is crucial. Using data from the Alzheimer’s Disease Neuroimaging Initiative, we have calculated the minimum detectable effect size (MDES) in change from baseline of a range of measures over time, and in different diagnostic groups along the AD development trajectory. The Functional Activities Questionnaire score had the smallest MDES for a single endpoint where an effect of 27% could be detected within 3 years in participants with Late Mild Cognitive Impairment (LMCI) at baseline, closely followed by the Clinical Dementia Rating Sum of Boxes (CDRSB) score at 28% after 2 years in the same group. Composite measures were even more successful than single endpoints with an MDES of 21% in 3 years. Using alternative cognitive, imaging, functional, or composite endpoints, and recruiting patients that have LMCI could improve the success rate of AD clinical trials.

Highlights

All cause dementias are one of the world’s leading health concerns
The minimum detectable effect size (MDES) was calculated for four cognitive markers, ADAS-Cog11, ADAS-Cog13, mini-mental state evaluation score (MMSE) and Montreal cognitive assessment (MoCA) (Fig. 1)
The data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) suggest that a clinical trials (CTs) that uses ADASCog-11 as an end point would be unable to detect a treatment effect within 6 years if the patients in the trial were either Cognitively Normal (CN) or had early mild cognitive impairment (MCI) (EMCI) at baseline, even if the treatment acted instantly and with 100% efficacy

Summary

Introduction

All cause dementias are one of the world’s leading health concerns. In the absence of effective therapies, is it estimated that the number of people with dementia will reach 131.5 million by 2050. There is currently no treatment or cure, and in 2016 the Office for National Statistics reported that AD had overtaken cardiovascular disease to become the leading cause of death in England and Wales [3]. Unlike cardiovascular disease where 41 drugs have been approved by the U.S Food and Drug Administration (FDA) since 2002, only five drugs that provide short-term symptomatic relief and have no preventative or curative activity, have been marketed in the AD therapy area since 1984. No new drugs have been approved by the FDA since 2002 [4]

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