Alzheimer's Disease Neuroimaging Initiative. Requiring an amyloid-β(1-42) biomarker for prodromal Alzheimer's disease or mild cognitive impairment does not lead to more efficient clinical trials

Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Alzheimer's & dementia: the journal of the Alzheimer's Association (Impact Factor: 12.41). 09/2010; 6(5):367-77. DOI: 10.1016/j.jalz.2010.07.004
Source: PubMed


Low cerebrospinal fluid (CSF) amyloid-beta(1-42) concentration and high total-tau/Abeta(1-42) ratio have been recommended to support the diagnosis of prodromal Alzheimer's disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials (Shaw et al, Ann Neurol 2009;65:403-13; Dubois et al, Lancet Neurol 2007;6:734-46).
We tested this recommendation with clinical trials simulations using patients from the Alzheimer Disease Neuroimaging Initiative who fulfilled the following entry criteria: (1) aMCI, (2) aMCI with CSF Abeta(1-42) <or=192 mg/mL, (3) and aMCI with total-tau/Abeta(1-42) >0.39. For each criterion, we randomly resampled the database obtaining samples for 1000 trials for each trial scenario, planning for 1 or 2 year trials with samples from 50 to 400 patients per treatment or placebo group, with up to 40% dropouts, outcomes after using the AD assessment scale-cognitive subscale and clinical dementia rating scale with effect sizes ranging from 0.15 to 0.75, and calculated statistical power.
Approximately 70% to 74% of aMCI patients with CSF measures met biomarker criteria. The addition of the low Abeta(1-42) or high tau/Abeta(1-42) requirement resulted in minimal or no increase in the power of the trials compared with enrolling aMCI without requiring the biomarker criteria. Slightly larger mean differences between the placebo and treatment groups fulfilling biomarker criteria were offset by increased outcome variability within the groups.
Although patients with aMCI or patients with prodromal AD meeting CSF biomarkers criteria were slightly more cognitively impaired and showed greater decline than patients with aMCI diagnosed without considering the biomarkers, the requirement of biomarker-positive patients would most likely not result in more efficient clinical trials, and trials would take longer because fewer patients would be available. A CSF Abeta(1-42) marker, however, could be useful as an explanatory variable or covariate when warranted by the action of a drug.

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Available from: Gary R Cutter, Jul 14, 2014
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    • "Direct comparison of neuropsychological and biomarker data has suggested that neuropsychological data may actually be superior to biomarker data in predicting conversion from MCI to AD (Gomar et al., 2011; Schmand, Eikelenboom, & van Gool, 2012). Furthermore, modeling of biomarker enrichment strategies for clinical trials has concluded that these may not significantly improve enrollment of appropriate patients and that cost– benefit ratios may be unacceptably high (Lorenzi et al., 2010; Schneider, Kennedy, & Cutter, 2010). Although clinical assessments therefore are likely to remain critical for diagnosing MCI (and possibly for predicting progression/conversion ), there is no consensus regarding which tests, or battery of tests, are best suited to this purpose. "
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    ABSTRACT: Current diagnostic criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) require standardized tests that are capable of measuring a range of neurocognitive abilities in healthy elderly individuals and sensitive to detect change over time. There currently is no clearly-established "gold standard" for this purpose. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a widely used neuropsychological test battery for the clinical diagnosis/tracking of dementia also recently incorporated into clinical trials of new investigational medications for AD treatment. The RBANS has a number of design features that suggest possible utility in diagnosis/tracking of MCI. Eighty-one patients with MCI completed the RBANS and their scores were compared with 81 demographically matched healthy controls. RBANS Total Scale scores in both groups were normally distributed, demonstrating no floor/ceiling effects. The MCI group was most impaired on the Delayed Memory Index (DMI). Receiver operating characteristic analyses reflected good discrimination, with an area under the curve of 0.88 for the Total Scale score and 0.90 for the DMI score. The profile of performance for the MCI group was similar to that previously reported for mild AD patients. The RBANS may be a suitable neurocognitive battery for the detection and tracking of MCI presumed to be due to AD.
    Full-text · Article · Jul 2013 · Archives of Clinical Neuropsychology
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    • "Simulations were conducted under a detailed protocol [7], similar to our previously published approach [5] [8], to reflect clinical trials for an experimental drug for AD or MCI with one treatment group and one placebo group, 1:1 allocation ratio, and parameters for the distribution of ADAS-Cog were selected to be consistent with previously published trials and Alzheimer's Disease Neuroimaging Initiative (ADNI) ADNI [9] [10]. "
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    ABSTRACT: Introduction The sample size re-estimation (SSR) adaptive design allows interim analyses and resultant modifications of the ongoing trial to preserve or increase power. We investigated the applicability of SSR in Alzheimer's disease (AD) trials using a meta-database of clinical studies. Methods Based on six studies, we simulated clinical trials using Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) as primary outcome. A single SSR based on effect sizes or based on variances was conducted at 6 months and 12 months. Resultant power improvement and sample size adjustments were evaluated. Results SSR resulted in highly variable outcomes for both sample size increases and power improvement. The gain in power after SSR varies by initial sample sizes, trial durations, and effect sizes. Conclusions SSR adaptive designs can be effective for trials in AD and mild cognitive impairment with small or medium initial sample sizes. However, SSR in larger trials (>200 subjects per arm) generates no major advantages over the typical randomized trials. © 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
    Full-text · Article · Jul 2013 · Alzheimer's and Dementia
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    • "The simulation study reported by Schneider and colleagues is a valuable contribution to the field of Alzheimer's disease. The study was conducted under a detailed protocol and clearly lays out the assumptions that were made and the criteria that were used for each set of simulations [1]. The article makes the point that some situations are complicated enough that standard power calculations do not capture the whole picture, because they require simplifying assumptions that may not hold. "
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    ABSTRACT: A recent article by Schneider and colleagues has generated a lot of interest in simulation studies as a way to improve study design. The study also illustrates the foremost principal in simulation studies, which is that the results of a simulation are an embodiment of the assumptions that went into it. This simulation study assumes that the effect size is proportional to the mean to standard deviation ratio of the Alzheimer Disease Assessment Scale - cognitive subscale in the population being studied. Under this assumption, selecting a subgroup for a clinical trial based on biomarkers will not affect the efficiency of the study, despite achieving the desired increase in the mean to standard deviation ratio.
    Full-text · Article · Mar 2011 · Alzheimer's Research and Therapy
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