Elsevier

The Lancet Neurology

Volume 7, Issue 5, May 2008, Pages 436-450
The Lancet Neurology

Review
Endpoints for trials in Alzheimer's disease: a European task force consensus

https://doi.org/10.1016/S1474-4422(08)70087-5Get rights and content

Summary

Harmful consequences in health status caused by disease are referred to as outcomes, and in clinical studies the measures of these outcomes are called endpoints. A major challenge when deciding on endpoints is to represent the outcomes of interest accurately, and the accuracy of such representation is assessed through validation. Complex diseases like Alzheimer's disease have many different and interdependent outcomes. We present a consensus for endpoints to be used in clinical trials in Alzheimer's disease, agreed by a European task force under the auspices of the European Alzheimer Disease Consortium. We suggest suitable endpoints for primary and secondary prevention trials, for symptomatic and disease-modifying trials in very early, mild, and moderate Alzheimer's disease, and for trials in severe Alzheimer's disease. A clear and consensual definition of endpoints is crucial for the success of further clinical trials in the field and will allow comparison of data across studies.

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

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”.

References (133)

  • P Polo-Kantola et al.

    The effect of short-term estrogen replacement therapy on cognition: a randomized, double-blind, cross-over trial in postmenopausal women

    Obstet Gynecol

    (1998)
  • EF Binder et al.

    Effects of hormone replacement therapy on cognitive performance in elderly women

    Maturitas

    (2001)
  • DJ Stott et al.

    Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease

    Am J Clin Nutr

    (2005)
  • C Lewerin et al.

    Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study

    Am J Clin Nutr

    (2005)
  • SA Shumaker et al.

    The Women's Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia

    Control Clin Trials

    (1998)
  • BK Martin et al.

    Double placebo design in a prevention trial for Alzheimer's disease

    Control Clin Trials

    (2002)
  • HH Feldman et al.

    Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study

    Lancet Neurol

    (2007)
  • M Grundman et al.

    Alzheimer Association research roundtable meeting on mild cognitive impairment: what we have learned?

    Alzheimer Dement

    (2006)
  • A Wimo et al.

    Validity and reliability of assessments of time. Comparisons of direct observations and estimates of time by the use of the resource utilization in dementia (RUD)-instrument

    Arch Gerontol Geriatr

    (2007)
  • L Schneider

    Prevention therapeutics of dementia

    Alzheimer Dement

    (2008)
  • C Sampaio

    Clinical Relevance on Alzheimer's disease endpoints

    J Nutr Health Aging

    (2007)
  • F Cortes et al.

    Six and 18-month changes in mild to moderate Alzheimer's patients treated with acetylcholinesterase Inhibitors: what can we learn for clinical outcomes of therapeutic trials?

    J Nutr Health Aging

    (2007)
  • J Durga et al.

    What can we learn from the FACIT trial: a randomized, double blind, controlled trial

    J Nutr Health Aging

    (2007)
  • GB Frisoni et al.

    Neuroimaging outcomes for clinical trials

    J Nutr Health Aging

    (2007)
  • V Gardette et al.

    Attrition in geriatric research: how important is it and how should it be dealt with?

    J Nutr Health Aging

    (2007)
  • JE Harrison

    Measuring cognitive change in Alzheimer's disease clinical drug trials

    J Nutr Health Aging

    (2007)
  • L Jönsson

    Assessing health economic outcome in Alzheimer's disease clinical trials

    J Nutr Health Aging

    (2007)
  • P Robert et al.

    Neuropsychiatric outcome for clinical trials

    J Nutr Health Aging

    (2007)
  • E Salmon

    Outcomes for secondary preventive trials

    J Nutr Health Aging

    (2007)
  • B Vellas

    Outcomes for Alzheimer's trials

    J Nutr Health Aging

    (2007)
  • FRJ Verhey et al.

    Caregiver outcomes in disease modifying trials

    J Nutr Health Aging

    (2007)
  • G Wilcock

    Outcomes for disease modifying trials

    J Nutr Health Aging

    (2007)
  • R Brookmeyer et al.

    Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset

    Am J Public Health

    (1998)
  • B Vellas et al.

    The GuidAge study: methodological issues. A 5-year double-blind randomized trial of the efficacy of EGb 761 for prevention of Alzheimer disease in patients over 70 with a memory complaint

    Neurology

    (2006)
  • Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial

    Neurology

    (2007)
  • SA Shumaker et al.

    Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial

    JAMA

    (2003)
  • SA Shumaker et al.

    Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study

    JAMA

    (2004)
  • RJ Kryscio et al.

    Designing a large prevention trial: statistical issues

    Stat Med

    (2004)
  • JH Kang et al.

    A randomized trial of vitamin E supplementation and cognitive function in women

    Arch Intern Med

    (2006)
  • JH Kang et al.

    Low dose aspirin and cognitive function in the women's health study cognitive cohort

    BMJ

    (2007)
  • JA McMahon et al.

    A controlled trial of homocysteine lowering and cognitive performance

    N Engl J Med

    (2006)
  • AD Dangour et al.

    A randomised controlled trial investigating the effect of n-3 long-chain polyunsaturated fatty acid supplementation on cognitive and retinal function in cognitively healthy older people: the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study protocol [ISRCTN72331636]

    Nutr J

    (2006)
  • RC Petersen et al.

    Current concepts in mild cognitive impairment

    Arch Neurol

    (2001)
  • AL Fitzpatrick et al.

    Associations of gait speed and other measures of physical function with cognition in a healthy cohort of elderly persons

    J Gerontol A Biol Sci Med Sci

    (2007)
  • RC Petersen

    Conversion

    Neurology

    (2006)
  • RC Green et al.

    Primary prevention trials in Alzheimer disease

    Neurology

    (2006)
  • LJ Thal et al.

    A randomized, double-blind, study of rofecoxib in patients with mild cognitive impairment

    Neuropsychopharmacology

    (2005)
  • RC Petersen et al.

    Vitamin E and donepezil for the treatment of mild cognitive impairment

    N Engl J Med

    (2005)
  • RC Petersen

    Mild cognitive impairment as a diagnostic entity

    J Intern Med

    (2004)
  • H Tounsi et al.

    Sensitivity to semantic cuing: an index of episodic memory dysfunction in early Alzheimer disease

    Alzheimer Dis Assoc Disord

    (1999)
  • Cited by (0)

    Members listed in full at end of review

    View full text