Current clinical trials in AD frequently include imaging substudies that compare rates of change (between baseline and study end) in cerebral volume between treatment groups. Patients who participate in these imaging substudies are self-selected and hence raise questions of selection bias and generalizability of observed treatment effects on the imaging measures.
In this self-selected sample from 2 ongoing trials conducted by the ADCS, we found that imaging substudy enrollers are very similar to those participants who chose not to enroll in the substudy. Baseline comparisons revealed no differences in terms of age, sex, comorbidities, or clinical characteristics, with the exception of lower mean Hachinski score in enrollers in trial 1. Although this could reflect some under-representation of subjects with vascular risk factors in the MRI enroller group, the magnitude of the difference in Hachinski scores (0.26 points) is probably too modest to be considered clinically important. Differences between enrollers and nonenrollers on cognitive and behavioral measures were also not considered to be clinically important (for example, mean difference on MMSE= −0.89 points in trial 1 and 0.24 in trial 2, mean difference on ADAS-cog of 1.96 in trial 1 and −1.23 in trial 2). The relationship between enrollers and nonenrollers on these measures were reversed between the 2 trials (enrollers are more impaired than nonenrollers in trial 1 and less impaired in trial 2) reinforcing the impression that these modest differences are not indicative of systemic bias in substudy selection.
There are certain limitations to this study that must be considered. First, the analyses included data from 2 ongoing clinical trials in AD conducted through 1 coordinating center; and these findings may not generalize to other AD trials with different baseline study populations. However, as there were no specific exclusion criteria for the MRI substudy in both cases, we hypothesize that other trials, including industry sponsored trials will probably show similar results if there are no additional exclusion criterion for substudy participation. This would be consistent with our overall hypothesis that willingness to participate in an imaging trial component does not introduce important bias. However, this is a hypothesis that still needs to be confirmed more widely.
Second, comparisons did not include follow-up data and so did not compare the groups in terms of rate of change in cognition, behavioral or other efficacy measures. Future analyses are planned that include additional trials conducted by the ADCS and analysis of follow-up data.
In summary, the sample of participants who volunteered to enroll in the imaging substudy of these clinical trials had very similar baseline demographic, medical and clinical characteristics compared to the rest of the study sample. This suggests that it may be possible to recruit a representative sample for a longitudinal imaging substudy in AD. We believe that possible reasons for this finding include the lack of specific exclusion criteria for the MRI substudy and the absence of inducements such as financial remuneration. Further research is underway to confirm these results in other AD clinical trials.