The story was different among patients who progressed slowly, Dr. Retout said. “Among slow progressers, no exposure-response relationship could be observed, indicating that the slow disease progression over the 2-year treatment period was probably limiting the detection of a drug effect,” she said.
Finding the right trial population
The problem of progression variability, dropout rates, and potentially skewed clinical outcomes is a tough nut for Alzheimer’s drug trials, Dr. Lasser said at the CTAD conference.
“This is likely to continue to surprise us if we still have this 25%-30% in our trials who don’t decline over the course of treatment. There really aren’t any big differences at baseline that stand out so that you could create the inclusion criteria to minimize this population of patients.”
Amyloid imaging, which does at least allow recruitment of a pure Alzheimer’s cohort, was not widely available when the SCARLET ROAD cohort was recruited. And although amyloid imaging is a great tool for predicting conversion to dementia from mild cognitive impairment, it’s not terribly useful as a tool for predicting progression.
Factoring baseline cerebrospinal fluid tau levels into the equation didn’t improve prediction, Dr. Lasser noted. Apolipoprotein E (APOE) allele status was similarly unhelpful.
“We didn’t find very much difference among the allele groups; there was no consistent pattern, and the between-group differences were small. So we’re beginning to hypothesize that while APOE is an excellent risk marker before cognitive decline develops, once it does start, allele status may not be as crucial in determining the patient’s eventual outcome.”
The only hints of progression speed at baseline were in the two functional measures of CDR-sb and FAQ. Fast progressers showed significantly more impairment on both of these at baseline than did slow progressers.
“Progression seems to be more likely in those who have functional decline already present as part of their prodromal presentation,” Dr. Lasser said. “At baseline, the most meaningful difference was not the MMSE, but the CDR-sb. This indicates that functional impairment may be a critical factor to look at when you’re enrolling subjects.”
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