Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Sep;2(3):177-181.
doi: 10.1016/j.trci.2016.05.002.

Proof of concept demonstration of optimal composite MRI endpoints for clinical trials

Steven D Edland  1 , M Colin Ard  2 , Jaiashre Sridhar  3 , Derin Cobia  4 , Adam Martersteck  5 , M Marsel Mesulam  6 , Emily J Rogalski  3
Affiliations

Proof of concept demonstration of optimal composite MRI endpoints for clinical trials

Steven D Edland et al. Alzheimers Dement (N Y). 2016 Sep.

Abstract

Background: Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures.

Methods: We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by two years. Rogalski et al. [Neurology 2014;83:1184-1191] previously demonstrated that atrophy of the left perisylvian temporal cortex (PSTC) is a highly sensitive measure of disease progression in this population and a promising endpoint for clinical trials. Using methods described by Ard et al. [Pharmaceutical Statistics 2015;14:418-426], we constructed a composite atrophy index composed of a weighted sum of volumetric measures of 10 regions of interest within the left perisylvian cortex using weights that maximize signal-to-noise and minimize sample size required of trials using the resulting score. Sample size required to detect a fixed percentage slowing in atrophy in a two-year clinical trial with equal allocation of subjects across arms and 90% power was calculated for the PSTC and optimal composite surrogate biomarker endpoints.

Results: The optimal composite endpoint required 38% fewer subjects to detect the same percent slowing in atrophy than required by the left PSTC endpoint.

Conclusions: Optimal composites can increase the power of clinical trials and increase the probability that smaller trials are informative, an observation especially relevant for PPA, but also for related neurodegenerative disorders including Alzheimer's disease.

Keywords: Alzheimer’s Disease; Clinical Trial; Composite Endpoint; MRI; PPA; Power Calculations; Primary Progressive Aphasia; Region of Interest; Sample Size; Structural Magnetic Resonance Imaging.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Regions of interest used to examine longitudinal cortical atrophy in PPA. Top: The perisylvian temporal cortex region of interest defined in Rogalski et al.. Bottom: the regions of interest used to create the composite outcome measure.
See this image and copyright information in PMC

References

    1. Ard M.C., Edland S.D. Power calculations for clinical trials in Alzheimer's disease. J Alzheimers Dis. 2011;26 Suppl 3:369–377. - PMC - PubMed
    1. Mesulam M.M. Primary progressive aphasia–a language-based dementia. N Engl J Med. 2003;349:1535–1542. - PubMed
    1. Mesulam M., Weintraub S. Primary progressive aphasia and kindred disorders. Handb Clin Neurol. 2008;89:573–587. - PubMed
    1. Gorno-Tempini M.L., Hillis A.E., Weintraub S., Kertesz A., Mendez M., Cappa S.F. Classification of primary progressive aphasia and its variants. Neurology. 2011;76:1006–1014. - PMC - PubMed
    1. Rogalski E., Cobia D., Martersteck A., Rademaker A., Wieneke C., Weintraub S. Asymmetry of cortical decline in subtypes of primary progressive aphasia. Neurology. 2014;83:1184–1191. - PMC - PubMed

LinkOut - more resources