An extensive literature search was undertaken in MEDLINE with the search terms “Alzheimer and clinical trial”, “Alzheimer and disease modifying”, “Alzheimer and therapeutic trials”, “Alzheimer and study design”, “MCI and treatment”, “dementia and therapeutic trials”, “Alzheimer and biomarkers”, “Alzheimer and economic aspects”, “Alzheimer and neuroimaging”, “prevention and Alzheimer”, “prevention and cognitive decline”, “prevention and dementia”, and “prevention and cognitive impairment”.
ReviewEndpoints for trials in Alzheimer's disease: a European task force consensus
Introduction
Endpoints are used to measure disease outcomes in clinical studies, and the selection of endpoints that represent the outcomes of interest accurately is a major challenge. Definition of the primary outcome is probably the most important decision in the design of a clinical trial. The size and type of population to be targeted, the clinical relevance of the drug therapy, the rationale for its use in clinical practice, and cost-effectiveness all depend on the primary outcome.
Outcomes for trials in Alzheimer's disease (AD) are still subject to discussion, partly because patients are increasingly being diagnosed during the earliest stages of the disease.1 For example, the cognitive subscale of the AD assessment scale (ADAS-cog), traditionally thought of as the standard primary cognitive outcome for symptomatic trials, is probably not appropriate for trials in very early AD. Likewise, subjective measures of global improvement, which have long been recommended by regulatory agencies, are difficult to assess in trials of 18 months or longer, and are probably not suitable in such studies. Clinical assessment methods should also be reconsidered because many trials now add a new treatment to an existing standard-of-care regimen, so characteristics of patients are likely to differ from those in previous trials.
The most suitable outcomes should therefore be redefined on the basis of better knowledge of AD, in light of its well characterised stages, the large number of trials in development, and the negative results from some recent trials.2 These results sometimes contrast with positive effects in animal models,3 which could mean that the trial methods are at fault or that effects in a subgroup of patients are being missed.
Because the AD phenotype is complex, a single type of measurement is unlikely to capture adequately all the domains of the disease in its different stages.4 The solution is to use more than one measurement in a particular context and to attempt an integrated interpretation of the results. Once a set of measurements is obtained, it must be assigned a meaning in terms of relevance to the patient's life and daily living abilities.
In this Review, we provide critical analysis of the endpoints that are judged to be valid and have already been used in clinical studies to evaluate outcomes at different stages of AD. We also present recommendations from an international task force on outcomes, which follows on from our task force on disease-modifying trials.5 We do not make recommendations about the specific development of new endpoints, although we do mention the need for such development where appropriate.
Section snippets
Methods
Under the auspices of the European Alzheimer Disease Consortium (EADC), a network of excellence in the field of AD financed by the European Commission (5th FP QLAM 2001-00003), the organising committee (SA, CS, BV, and GW) set up a task force to propose a European consensus on endpoints for trials in AD. Task force members were chosen for their academic, regulatory, or pharmaceutical experience. The task force included researchers from the USA in addition to Europe because many research and
Primary prevention trials
Prevention is currently a major issue in AD, and it will continue to be so until there is a cure. Preventive strategies have the potential to decrease the incidence of AD substantially.17, 18 Primary prevention trials in AD19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 are relatively new (table 1), and the most widely used outcomes have been developed on the basis of experience from other contexts and expert judgment. Usually, primary prevention trials for dementia
Secondary prevention trials
Secondary prevention trials in AD involve patients with a certain degree of cognitive impairment (eg, MCI; table 2).43, 44, 45 Patients with MCI are often divided into two groups: those with amnestic MCI, who are more likely to develop AD, and those with non-amnestic MCI. Here, we focus on amnestic MCI.46, 47
Symptomatic trials in very early, mild, and moderate AD
About 75–80% of people with an established diagnosis of probable AD fall into the mild or moderate category.51 A significant proportion of patients with MCI have very early AD and go on to fulfil the criteria for probable AD.1 At this stage of the disease, symptomatic trials probably require the development of more sensitive outcome paradigms than those currently available (table 3).52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 The low efficacy in recent trials could be as much due to
Disease-modifying trials in very early, mild, and moderate AD
Disease modification implies arrest or retardation of the processes that led to neuronal loss or malfunction, to produce clinical benefit. This approach, which is being explored mainly in mild and moderate rather than severe AD, has been discussed in detail previously.5 By definition, symptomatic effects can be difficult to distinguish from disease modification, and some drugs might have both symptomatic and disease-modifying properties. The outcome measures chosen will depend on the trial
Trials in severe AD
Around 20% of patients with AD are estimated to be at the severe dementia stage (MMSE <10).51 Patients with severe dementia have both severe cognitive impairment and functional loss in basic ADL. Aggressive forms of the disease, with rapid cognitive decline and functional loss, must be assessed in a different way to severe AD and are not discussed in this Review. However, reduction of the percentage of patients with rapid progression could be an important outcome for new drugs. Severe dementia
Discussion
According to the guidelines recently released for consultation by the European Committee for Human Medicinal Products (CHMP),83 outcomes for symptomatic trials need to address the following domains: cognition, as measured by objective tests (cognitive endpoint); ADL (functional endpoint); and overall clinical response (global endpoint). The global endpoint should not be one of the two co-primary outcomes, because this position should be reserved for the cognitive and functional outcomes. To
Search strategy and selection criteria
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