Commentary on “A roadmap for the prevention of dementia II. Leon Thal Symposium 2008.” Prevention Trials in Persons At-Risk for Dominantly-Inherited Alzheimer's Disease: Opportunities and Challenges

Mary S. Easton Center for Alzheimer's Disease Research, UCLA Department of Neurology, Los Angeles, CA, USA.
Alzheimer's & dementia: the journal of the Alzheimer's Association (Impact Factor: 12.41). 04/2009; 5(2):166-71. DOI: 10.1016/j.jalz.2008.12.002
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Available from: Yaneth Rodríguez-Agudelo, Oct 04, 2015
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    • "Additionally, the risk of being placed into the placebo arm of a controlled study may be too high for an individual to risk learning that they will develop the disease [11]. The decision to undergo genetic testing prior to such trial participation is therefore a difficult one and performing prevention studies ethically such that subjects are truly informed regarding the scope of risks and benefits presents challenges [11]. The design of prevention trials in FAD will be improved by enhanced understanding of protocol features that affect at-risk persons' desire to undergo genetic testing. "
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    ABSTRACT: Persons at-risk for autosomal dominant neurodegenerative diseases provide the opportunity to efficiently test preventive interventions. Only a minority of such persons, however, choose to undergo revealing genetic testing, presenting a challenge to enrollment. Thirty-four preclinical Latinos (n = 26) and non-Latinos at-risk for familial Alzheimer's disease (FAD) unaware of their genetic status were administered a questionnaire exploring their interest in undergoing revealing genetic testing at baseline and in the context of eligibility for four prevention trials of increasing invasiveness. Forty-four percent of subjects expressed a baseline interest in undergoing revealing testing which increased to 85% in order to be eligible for a study of an oral drug "felt to be very safe." If there were a 50% chance of receiving placebo, this number dropped to 62% (p = 0.02). For those not interested in a study involving a 50% chance of receiving placebo, a range of 5% to 40% chance of receiving placebo was given as acceptable. For more invasive studies, living in the U.S. (as opposed to Mexico) positively influenced the likelihood of participating. Our data suggests that clinical trial designs in which persons must confront their genetic status prior to enrollment are feasible. Study designs to minimize the likelihood of being placed on placebo or provide the eventual administration of the drug through open-label extensions should be considered.
    Contemporary clinical trials 07/2013; 36(1). DOI:10.1016/j.cct.2013.07.006 · 1.94 Impact Factor
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    • "The latter consists of those for disease-modifying agents which strive to show that the course of AD has been altered and the rate of disease progression has been slowed (Cummings 2006, Aisen 2006, Citron 2004, Mani 2004). Currently, clinical trials on AD have been almost entirely focused on symptomatic trials for which the standard randomized and placebo controlled parallel designs have been used on patients with AD or on subjects at risk of AD (Kryscio et al. 2004, Ringman et al. 2009, Andrieu et al. 2006). All FDA-approved treatments to AD so far have been symptomatic in nature, and their effectiveness has not been established for the long term and disease-modifying benefit of treating AD. "
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    ABSTRACT: Randomized start and withdrawal designs have been recently proposed to test the disease-modifying agents on Alzheimer's disease (AD). This article provides methods to determine the optimum parameters for these designs. A general linear mixed effects model is proposed. This model employs a piecewise linear growth pattern for those in the delayed treatment or early withdrawal arm, and incorporates a potential correlation on the rates of change on efficacy outcome before and after the treatment switch. Based on this model, we formulate the disease-modifying hypothesis by comparing the rate of change on efficacy outcome between treatment arms with and without a treatment switch, and develop a methodology to optimally determine the sample size allocations to different treatment arms as well as the time of treatment switch for subjects whose treatment is changed. We then propose an intersection-union test (IUT) to assess the disease-modifying efficacy, and study the size and the power of the IUT. Finally, we employ two recently published symptomatic trials on AD to obtain pilot estimates to model parameters, and provide the optimum design parameters including total and individual sample size to different arms as well as the time of treatment switch for future disease-modifying trials on AD.
    Statistics in Biopharmaceutical Research 08/2012; 4(3):216-227. DOI:10.1080/19466315.2011.634757 · 0.62 Impact Factor
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    ABSTRACT: Because cerebrospinal fluid (CSF) abnormalities in presymptomatic subjects with PSEN1 (presenilin 1) mutations may be observed 4 to 12 years prior to the estimated age at onset, it is possible to test putative therapies on the CSF analytes that correlate with neurodegeneration during this presymptomatic window of clinical opportunity. It is also possible to test the same therapy on a comparison group with increased risk status conferred by both hyperlipidemia and heterozygosity for apolipoprotein Eε4. To our knowledge, the only putative therapy thus far tested in such a common design has been statin therapy. The results of these tests show increases in soluble amyloid precursor protein (sAPP)α correlating with statin-induced decreases in serum cholesterol levels in the non- PSEN1 subjects. This result could be one functional correlate for part of the substantial risk reduction for late onset Alzheimer's disease recently reported in the Rotterdam study, a large, long-term prospective statin trial. Statin therapy significantly decreased both sAPPα and sAPPβ in presymptomatic PSEN1 subjects. Initially, elevated phospho-tau levels in PSEN1 subjects did not further increase during the 2 to 3 years of statin therapy, possibly indicative of a prophylactic effect. These results suggest that large and longer term trials of statin therapy correlating changes in CSF biomarker levels with clinical course may be warranted in both presymptomatic PSEN1 and non- PSEN1 subjects.
    Alzheimer's Research and Therapy 10/2010; 2(5):31. DOI:10.1186/alzrt55 · 3.98 Impact Factor
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