BY SARAH OWENS
The performance of patients with mild cognitive impairment varied greatly in an analysis of seven randomized controlled trials, according to a new study published in the April 5 online edition of Neurology. Variability in the criteria for enrolling patients, study design, and outcomes assessments may have contributed to the wide-ranging results, the study authors said.
"While the studies appeared to be designed in a similar fashion, subtle entry, exit, and procedural differences led to vastly different outcomes for the participants," the study authors, led by Ronald C. Petersen, PhD, MD, wrote. "The implementation of continuous outcome measures rather than clinical states may improve performance of trials," they added, "but clinical meaningfulness needs to be established."
For their study, researchers obtained data on placebo groups from 7 randomized, controlled trials of patients with MCI and collated the data for common measurement instruments. Using the Alzheimer's Disease Assessment Sale-cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and the Clinical Dementia Rating-sum of boxes (CDR-SB), the researchers tracked the performance of patients in the placebo arms and measured their progression to prespecified clinical study endpoints.
They found that although similar criteria for MCI were used in the trials, the implementation of those criteria varied significantly. For example, all studies used the ADAS-cog to measure cognition, but in some studies the patients in the placebo group with MCI had worsening cognition on this scale, while patients in other studies appeared to improve. Results on the MMSE and the CDR-SB "appeared to corroborate the ADAS-cog findings": Some patients appeared to worsen in a predictable manner, but others remained stable or improved.
Additionally, researchers examined the effect of APOE4 carrier status on the results, finding that, as expected, APOE4 carriers had worse cognitive performance on all scales.
The results, the study authors concluded, suggest that minor variations in methodology can lead to significant variations in outcomes among patients in the placebo group, which vastly limits efficacy findings. As for the source of these variations, the researchers suggested that differences in the implementation of instruments like the ADAS-cog in order to characterize participants, and subtle variations in study populations, likely play a role. Differences in language, culture, and the prevalence of comorbidities may also contribute, they noted, adding that future trials should address these issues.
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- Peterson RC, Thomas RG, Aisen PS, et al. Randomized controlled trials in mild cognitive impairment: Sources of variability. Neurology 2017; Epub 2017 Apr 5.