MRI as a biomarker of disease progression in a therapeutic trial of milameline for AD.

Abstract

OBJECTIVE:

To assess the feasibility of using MRI measurements as a surrogate endpoint for disease progression in a therapeutic trial for AD.

METHODS:

A total of 362 patients with probable AD from 38 different centers participated in the MRI portion of a 52-week randomized placebo-controlled trial of milameline, a muscarinic receptor agonist. The therapeutic trial itself was not completed due to projected lack of efficacy on interim analysis; however, the MRI arm of the study was continued. Of the 362 subjects who underwent a baseline MRI study, 192 subjects underwent a second MRI 1 year later. Hippocampal volume and temporal horn volume were measured from the MRI scans.

RESULTS:

The annualized percent changes in hippocampal volume (-4.9%) and temporal horn volume (16.1%) in the study patients were consistent with data from prior single-site studies. Correlations between the rate of MRI volumetric change and change in behavioral/cognitive measures were greater for the temporal horn than for the hippocampus. Decline over time was more consistently seen with imaging measures, 99% of the time for the hippocampus, than behavioral/cognitive measures (p < 0.001). Greater consistency in MRI than behavioral/clinical measures resulted in markedly lower estimated sample size requirements for clinical trials. The estimated number of subjects per arm required to detect a 50% reduction in the rate of decline over 1 year are: AD Assessment Scale-cognitive subscale 320; Mini-Mental Status Examination 241; hippocampal volume 21; temporal horn volume 54.

CONCLUSION:

The consistency of MRI measurements obtained across sites, and the consistency between the multisite milameline data and that obtained in prior single-site studies, demonstrate the technical feasibility of using structural MRI measures as a surrogate endpoint of disease progression in therapeutic trials. However, validation of imaging as a biomarker of therapeutic efficacy in AD awaits a positive trial.

• Authors: C R Jack Jr, M Slomkowski, S Gracon, T M Hoover, J P Felmlee, K Stewart, Y Xu, M Shiung, P C O'Brien, R Cha, D Knopman, R C Petersen
• Journal: Neurology (Neurology) Vol. 60 Issue 2 Pg. 253-60 (Jan 28 2003) ISSN: 1526-632X [Electronic] United States
• PMID: 12552040 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Dihydropyridines
• Muscarinic Agonists
• Neuroprotective Agents
• Oximes
• milameline

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Alzheimer Disease (drug therapy, pathology)
• Biomarkers
• Brain (pathology)
• Dihydropyridines (therapeutic use)
• Disease Progression
• Feasibility Studies
• Female
• Hippocampus (pathology)
• Humans
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Muscarinic Agonists (therapeutic use)
• Neuroprotective Agents (therapeutic use)
• Neuropsychological Tests
• Oximes (therapeutic use)
• Predictive Value of Tests
• Reference Values
• Sample Size
• Sex Distribution
• Treatment Outcome