Dementia: Trial Design and Experience with Large Multicentre Trials

Abstract

Dementia is common, being estimated to affect up to 50% of the population who are aged over 85 years [1]. Rarely, reversible causes, such as a frontal meningioma, normal pressure hydrocephalus or vitamin B₁₂ deficiency lead to specific treatments. The majority of cases, however, are due to one of the neurodegenerative diseases, of which Alzheimer’s disease (AD) is by far the commonest. The identification of specific cholinergic deficits in the brains of patients with AD in the late 1970s and early 1980s provided considerable impetus to the hope that treatment for the dementias might be possible [2,3]. The development and expansion of world-wide drug development programmes since that time have been dramatic, culminating in the licensing of tacrine in the United States in 1993 [4,5], and more recently, the approval of donezepil [6]. The diseases that cause dementia are defined neuropathologically, yet in life the diagnosis can usually only be made clinically. Moreover, the considerable heterogeneity and broad spectrum of impairment that occurs is difficult to measure in a reliable way. From the earliest clinical trials in AD, drug regulatory authorities, and particularly the US Food and Drug Administration (FDA) have taken a proactive interest in the methodology being used to prove the efficacy of drugs treatments for dementia. This interest has ensured broad standardisation of clinical trial designs, and has promoted the development of standardised guidelines through processes such as the International Working Group on the Harmonization of Dementia Drug Guidelines [7].