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September 20, 2016; 87 (12) Article

Enrichment of clinical trials in MCI due to AD using markers of amyloid and neurodegeneration

Robin Wolz, Adam J. Schwarz, Katherine R. Gray, Peng Yu, Derek L.G. Hill, For the Alzheimer's Disease Neuroimaging Initiative
First published August 24, 2016, DOI: https://doi.org/10.1212/WNL.0000000000003126
Robin Wolz
From IXICO Plc (R.W., K.R.G., D.L.G.H.), London, UK; Department of Computing (R.W., K.R.G.,), Imperial College London, UK; Eli Lilly and Company (A.J.S., P.Y.), Indianapolis, IN; Department of Psychology and Brain Sciences (A.J.S.), Indiana University, Bloomington; and Department of Radiology and Imaging Sciences (A.J.S.), Indiana University School of Medicine, Indianapolis.
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Adam J. Schwarz
From IXICO Plc (R.W., K.R.G., D.L.G.H.), London, UK; Department of Computing (R.W., K.R.G.,), Imperial College London, UK; Eli Lilly and Company (A.J.S., P.Y.), Indianapolis, IN; Department of Psychology and Brain Sciences (A.J.S.), Indiana University, Bloomington; and Department of Radiology and Imaging Sciences (A.J.S.), Indiana University School of Medicine, Indianapolis.
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Katherine R. Gray
From IXICO Plc (R.W., K.R.G., D.L.G.H.), London, UK; Department of Computing (R.W., K.R.G.,), Imperial College London, UK; Eli Lilly and Company (A.J.S., P.Y.), Indianapolis, IN; Department of Psychology and Brain Sciences (A.J.S.), Indiana University, Bloomington; and Department of Radiology and Imaging Sciences (A.J.S.), Indiana University School of Medicine, Indianapolis.
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Peng Yu
From IXICO Plc (R.W., K.R.G., D.L.G.H.), London, UK; Department of Computing (R.W., K.R.G.,), Imperial College London, UK; Eli Lilly and Company (A.J.S., P.Y.), Indianapolis, IN; Department of Psychology and Brain Sciences (A.J.S.), Indiana University, Bloomington; and Department of Radiology and Imaging Sciences (A.J.S.), Indiana University School of Medicine, Indianapolis.
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Derek L.G. Hill
From IXICO Plc (R.W., K.R.G., D.L.G.H.), London, UK; Department of Computing (R.W., K.R.G.,), Imperial College London, UK; Eli Lilly and Company (A.J.S., P.Y.), Indianapolis, IN; Department of Psychology and Brain Sciences (A.J.S.), Indiana University, Bloomington; and Department of Radiology and Imaging Sciences (A.J.S.), Indiana University School of Medicine, Indianapolis.
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From IXICO Plc (R.W., K.R.G., D.L.G.H.), London, UK; Department of Computing (R.W., K.R.G.,), Imperial College London, UK; Eli Lilly and Company (A.J.S., P.Y.), Indianapolis, IN; Department of Psychology and Brain Sciences (A.J.S.), Indiana University, Bloomington; and Department of Radiology and Imaging Sciences (A.J.S.), Indiana University School of Medicine, Indianapolis.
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Enrichment of clinical trials in MCI due to AD using markers of amyloid and neurodegeneration
Robin Wolz, Adam J. Schwarz, Katherine R. Gray, Peng Yu, Derek L.G. Hill, For the Alzheimer's Disease Neuroimaging Initiative
Neurology Sep 2016, 87 (12) 1235-1241; DOI: 10.1212/WNL.0000000000003126

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Abstract

Objective: To investigate the effect of enriching mild cognitive impairment (MCI) clinical trials using combined markers of amyloid pathology and neurodegeneration.

Methods: We evaluate an implementation of the recent National Institute for Aging–Alzheimer's Association (NIA-AA) diagnostic criteria for MCI due to Alzheimer disease (AD) as inclusion criteria in clinical trials and assess the effect of enrichment with amyloid (A+), neurodegeneration (N+), and their combination (A+N+) on the rate of clinical progression, required sample sizes, and estimates of trial time and cost.

Results: Enrichment based on an individual marker (A+ or N+) substantially improves all assessed trial characteristics. Combined enrichment (A+N+) further improves these results with a reduction in required sample sizes by 45% to 60%, depending on the endpoint.

Conclusions: Operationalizing the NIA-AA diagnostic criteria for clinical trial screening has the potential to substantially improve the statistical power of trials in MCI due to AD by identifying a more rapidly progressing patient population.

GLOSSARY

A+=
amyloid positive;
Aβ=
β-amyloid;
AD=
Alzheimer disease;
ADAS-Cog13=
Alzheimer's Disease Assessment Scale Cognitive Subscale;
ADNI=
Alzheimer's Disease Neuroimaging Initiative;
FAQ=
Functional Assessment Questionnaire;
HV=
hippocampal volume;
MCI=
mild cognitive impairment;
MMSE=
Mini-Mental State Examination;
N+=
neurodegeneration positive;
NIA-AA=
National Institute for Aging–Alzheimer's Association;
RAVLT=
Rey Auditory Verbal Learning Test;
SNR=
signal-to-noise ratio

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Data used in preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.usc.edu/ADNI). Therefore, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at Neurology.org.

  • Supplemental data at Neurology.org

  • Received March 1, 2016.
  • Accepted in final form June 7, 2016.
  • © 2016 American Academy of Neurology
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