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Using practice effects for targeted trials or sub-group analysis in Alzheimer's disease: How practice effects predict change over time.

ABSTRACT: OBJECTIVE:To describe the presence of practice effects in persons with Alzheimer disease (AD) or mild cognitive impairment (MCI) and to evaluate how practice effects affect cognitive progression and the outcome of clinical trials. METHODS:Using data from a meta-database consisting of 18 studies including participants from the Alzheimer disease Cooperative Study (ADCS) and the Alzheimer Disease Neuroimaging Initiative (ADNI) with ADAS-Cog11 as the primary outcome, we defined practice effects based on the improvement in the first two ADAS-Cog11 scores and then estimated the presence of practice effects and compared the cognitive progression between participants with and without practice effects. The robustness of practice effects was investigated using CDR SB, an outcome independent the definition itself. Furthermore, we evaluated how practice effects can affect sample size estimation. RESULTS:The overall percent of practice effects for AD participants was 39.0% and 53.3% for MCI participants. For AD studies, the mean change from baseline to 2 years was 12.8 points for the non-practice effects group vs 7.4 for the practice effects group; whereas for MCI studies, it was 4.1 for non-practice effects group vs 0.2 for the practice effects group. AD participants without practice effects progressed 0.9 points faster than those with practice effects over a period of 2 years in CDR-SB; whereas for MCI participants, the difference is 0.7 points. The sample sizes can be different by over 35% when estimated based on participants with/without practice effects. CONCLUSION:Practice effects were prevalent and robust in persons with AD or MCI and affected the cognitive progression and sample size estimation. Planning of future AD or MCI clinical trials should account for practice effects to avoid underpower or considers target trials or stratification analysis based on practice effects.

SUBMITTER: Wang G

PROVIDER: S-EPMC7034859 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Using practice effects for targeted trials or sub-group analysis in Alzheimer's disease: How practice effects predict change over time.

Wang Guoqiao G Kennedy Richard E RE Goldberg Terry E TE Fowler Mackenzie E ME Cutter Gary R GR Schneider Lon S LS

PloS one 20200221 2

<h4>Objective</h4>To describe the presence of practice effects in persons with Alzheimer disease (AD) or mild cognitive impairment (MCI) and to evaluate how practice effects affect cognitive progression and the outcome of clinical trials.<h4>Methods</h4>Using data from a meta-database consisting of 18 studies including participants from the Alzheimer disease Cooperative Study (ADCS) and the Alzheimer Disease Neuroimaging Initiative (ADNI) with ADAS-Cog11 as the primary outcome, we defined practi ...[more]

PMID: 32084191

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Project description:Introduction:Practice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome. Methods:We investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline. Results:On average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run-in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design. Discussion:Assuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials.

Dataset Information

Using practice effects for targeted trials or sub-group analysis in Alzheimer's disease: How practice effects predict change over time.

Publications

Using practice effects for targeted trials or sub-group analysis in Alzheimer's disease: How practice effects predict change over time.

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