Enrichment through biomarkers in clinical trials of Alzheimer’s drugs in patients with mild cognitive impairment

LENITEM Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS San Giovanni di Dio-FBF, Brescia, Italy.
Neurobiology of aging (Impact Factor: 5.01). 08/2010; 31(8):1443-51, 1451.e1. DOI: 10.1016/j.neurobiolaging.2010.04.036
Source: PubMed


Clinical trials of disease modifying drugs for Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) might benefit from enrichment with true AD cases. Four hundred five MCI patients (143 converters and 262 nonconverters to AD within 2 years) of the Alzheimer's disease Neuroimaging Initiative (ADNI) were used. Markers for enrichment were hippocampal atrophy on magnetic resonance (MRI), temporoparietal hypometabolism on FDG PET, cerebrospinal fluid (CSF) biomarkers (Abeta42, tau, and phospho-tau), and cortical amyloid deposition (11C-PIB positron emission tomography (PET)). Two separate enrichment strategies were tested to A) maximize the proportion of MCI converters screened in, and B) minimize the proportion of MCI converters screened out. Based on strategy A, when compared with no enrichment and ADAS-Cog as an outcome measure (sample size of 834), enrichment with 18F-FDG PET and hippocampal volume lowered samples size to 260 and 277 cases per arm, but at the cost of screening out 1,597 and 434 cases per arm. When compared with no enrichment and clinical dementia rating (CDR-SOB) as an outcome measure (sample size of 674), enrichment with hippocampal volume and Abeta42 lowered sample sizes to 191 and 291 cases per arm, with 639 and 157 screened out cases. Strategy B reduced the number of screened out cases (740 for [11C]-PIB PET, 101 hippocampal volume, 82 ADAS-COG and 330 for [18F]-FDG PET) but at the expense of decreased power and a relative increase size (740 for [11C]-PIB PET, 676 for hippocampal volume, 744 for ADAS-Cog, and 517 for [18F]-FDG PET). Enrichment comes at the price of an often relevant proportion of screened out cases, and in clinical trial settings, the balance between enrichment of screened in and loss of screened out patients should be critically discussed.

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Available from: Marco Lorenzi, Jan 22, 2015
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    • "Recent revisions to diagnostic criteria define three stages of Alzheimer’s disease, namely Alzheimer’s disease dementia [6], MCI due to AD (MCI-AD) [7], and preclinical AD [8]. Broadly speaking, the MCI and dementia stages of AD can be determined by a combination of clinical assessment and biomarkers, while detection of preclinical AD, characterised by the absence of overt symptoms, requires brain-related assays of disease progression [9-11]. Within the MCI population a significant proportion have symptoms due to underlying AD pathology (MCI-AD [7]). "
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    ABSTRACT: Background Intervention and treatment in Alzheimer’s disease dementia (AD-dementia) can be cost effective but the majority of patients are not diagnosed in a timely manner. Technology is now available that can enable the earlier detection of cognitive loss associated with incipient dementia, offering the potential for earlier intervention in the UK health care system. This study aimed to determine to what extent the timing of an intervention affects its cost-effectiveness. Methods Using published data describing cognitive decline in the years prior to an AD diagnosis, we modelled the effects on healthcare costs and quality-adjusted life years of hypothetical symptomatic and disease-modifying interventions. Early and standard interventions were assumed to have equal clinical effects, but the early intervention could be applied up to eight years prior to standard diagnosis. Results A symptomatic treatment which immediately improved cognition by one MMSE point and reduced in efficacy over three years, would produce a maximum net benefit when applied at the earliest timepoint considered, i.e. eight years prior to standard diagnosis. In this scenario, the net benefit was reduced by around 17% for every year that intervention was delayed. In contrast, for a disease-modifying intervention which halted cognitive decline for one year, economic benefits would peak when treatment effects were applied two years prior to standard diagnosis. In these models, the maximum net benefit of the disease modifying intervention was fifteen times larger than that of the symptomatic treatment. Conclusion Timeliness of intervention is likely to have an important impact on the cost-effectiveness of both current and future treatments. Healthcare policy should aim to optimise the timing of AD-dementia diagnosis, which is likely to necessitate detecting and treating patients several years prior to current clinical practice.
    Full-text · Article · May 2014 · BMC Neurology
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    • "CSF t-tau and p-tau are robust predictors of AD outcome, and are also associated with a more rapid progression from MCI to AD [62]. These findings can be applied to enrich clinical trials via recruitment of MCI subjects who are most likely to progress to clinical AD [63]. "
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    ABSTRACT: Fluid biomarkers improve the diagnostic accuracy in dementia and provide an objective measure potentially useful as a therapeutic response in clinical trials. The role of fluid biomarkers in patient care is a rapidly evolving field. Here, we provide a review and recommendations regarding the use of fluid biomarkers in clinical practice as discussed at the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD4) convened in Montreal, 4 to 5 May 2012. At present, there is no consensus regarding the optimal methodology for conducting quantification of plasma amyloid-beta (Aβ) peptides. In addition, since there is insufficient evidence supporting clinical applications for plasma Aβ-peptide measures, the CCCDTD4 does not recommended plasma biomarkers either for primary care or for specialists. Evidence for CSF Aβ1-42, total tau and phosphorylated tau in the diagnosis of Alzheimer pathology is much stronger, and can be considered at the tertiary care level for selected cases to improve diagnostic certainty, particularly in those cases presenting atypical clinical features.
    Full-text · Article · Nov 2013 · Alzheimer's Research and Therapy
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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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