No abstract

No abstract

Objective-To assess the feasibility of using magnetic resonance imaging (MRI) measurements as a surrogate end point for disease progression in a therapeutic trial for Alzheimer's disease (AD).Methods-Three-hundred-sixty-two 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 one-year later. Hippocampal volume and temporal horn volume were measured from the MRI scans.Results-The annualized percent change 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 one year are: ADASCog 320; MMSE 241; hippocampal volume 21; temporal horn volume fifty-four. Conclusion-The consistency of MRI measurements obtained across sites, and the consistency between the multi-site milameline data and that obtained in prior single site studies, demonstrate the technical feasibility of using structural MRI measures as a surrogate end point of disease progression in therapeutic trials. However, validation of imaging as a biomarker of therapeutic efficacy in AD still awaits a positive trial.The primary outcome measurements for therapeutic trials in Alzheimer's disease (AD) patients are behavioral or cognitive. Due to the inherent test-retest variability in such measurements however, alternatives have been sought. Magnetic resonance imaging (MRI) measurements of rates of whole brain or hippocampal atrophy have been, and are currently being used as outcome measures in several therapeutic trials for AD. Although imaging has been used in clinical trials on AD and vascular disease for diagnostic purposes, to our knowledge, no publication has appeared describing the MRI results of a therapeutic trial in which structural MRI was used as NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript an outcome measure. MRI measures were added to this trial to gain a claim for effects on disease progression as opposed to just symptomatic treatment in those instances where treatment effect was shown on the behavioral/cognitive measures 1-7 .We report the MRI results of a therapeutic trial of milameline, a centrally active muscari...

No abstract

Global assessments are Food and Drug Administration-required primary outcome measures in trials of putative antidementia drugs. Global ratings are intended to provide an index of clinical importance of change that cannot be obtained from quantitative assessment measures such as mental status examinations. We examined the performance of a global assessment of change instrument, the Clinician Interview-Based Impression (CIBI), in the placebo group of a 30-week, randomized, double-blind clinical trial of tacrine in patients with Alzheimer's disease. Initially there were 184 placebo patients, of whom 125 completed the 30-week study. Descriptive statistics, correlations with changes on other assessment instruments, and test-retest reliability were determined for the CIBI. At week 30, clinicians rated more than 40% of patients on the CIBI as unchanged. The CIBI ratings were weakly but significantly correlated, in the expected direction, with change scores on the quantitative cognitive assessments. The CIBI was modestly reliable on test-retest at weeks 22 and 24 but less reliable compared with other quantitative outcome measures. Modifications of the CIBI that might improve its reliability and acceptance include (1) no restrictions on the form of the bedside mental status assessment, (2) inclusion of caregiver input, and (3) better definition of ratings on the global scale. Global instruments, if properly constructed, can provide an index of clinically important change for the assessment of dementia patients.