Original articleRandomized, placebo-controlled, parallel group versus crossover study designs for the study of dementia in Parkinson's disease
Introduction
In addition to motor dysfunction, patients with advanced Parkinson's disease frequently develop dementia. Therapies to treat dementia in patients with Parkinson's disease are in an early stage [1]. Because the physiology of dementia in Alzheimer's and Parkinson's disease is similar, previous work in Alzheimer's disease should offer insights into types of therapeutic agents that may be effective in Parkinson's disease as well as suitable study designs 2, 3, 4. In Alzheimer's disease, cholinesterase inhibition dominates therapeutic strategies for treating dementia [5]. Donepezil is a centrally active, reversible acetylcholinesterase inhibitor approved for Alzheimer's disease that may also be effective with Parkinson's disease [6]. Tacrine, its precursor, was extensively studied for its effects on cognitive function, behavioral disturbance and functional autonomy. A recent meta-analysis and review of tacrine discuss 18 separate studies 5, 7. Of these, ten were crossover (CO) designs, seven were parallel group (PG) and one was a mixed PG/CO.
In PG designs, subjects are randomized to receive either active treatment (T) or placebo (P) for single or multiple periods. In CO designs, some or all subjects receive more than one treatment sequentially. For example, in a two-sequence, two-period CO design (PT:TP), subjects randomized to the first sequence (PT) receive P in the first measurement period and T in the second measurement period, while subjects on the second sequence (TP) receive T followed by P. Both Qizilbash et al. and Conway criticize CO designs, warning that they “harbor methodological problems” and that the most convincing studies demonstrating benefits of tacrine therapy in Alzheimer's disease are large-scale PG designs with long treatment phases 5, 7. Similarly, Leber, writing for the Food and Drug Administration in its draft guidelines for the clinical evaluation of antidementia drugs, recommends PG designs [8].
Recent studies of donepezil show improved cognitive function in Alzheimer's disease patients in both PG and CO studies 9, 10. Here we examine the suitability of PG and CO designs for clinical studies of dementia in patients with Parkinson's disease. In theory, CO designs are suitable for chronic diseases, with outcomes that are relatively stable over the study 11, 12. In particular, subjects cannot be “cured” by the treatments of interest, i.e., treatment cannot permanently alter the normal course of disease. CO designs are efficient because treatment effects are estimated, at least in part, from within-subject contrasts, typically requiring fewer subjects than PG designs where treatment effects reflect between-subject contrasts. However, treatment effects in CO designs are potentially confounded with nuisance parameters, such as period effects, or period by treatment interactions. For example, period effects are systematic changes in outcome that apply to all patients, due perhaps to temporal changes in disease or to the measurement instrument [13]. Period by treatment interactions occur when efficacy varies across periods, e.g., treatment is effective in the first but not the second period. Carryover effects, differences in the lingering effect of a treatment administered in one period into the subsequent period, can bias the estimated treatment effect. Thus, PT:TP designs may be recommended only when carryover effects can be eliminated, e.g., by using a washout period between the two treatments 11, 14.
Here we compare several randomized PG and CO designs. Our motivation, illustrated in the proposed study section, is a placebo-controlled trial examining effects of donepezil therapy on cognitive impairment in patients suffering from dementia. The study design and statistical model section introduces the statistical model, uses several designs to illustrate period effects, treatment×period interactions and carryover effects and discusses a two-stage method of analysis. The section on extensions to other designs examines an alternative, but potentially biased, approach and illustrates sample size calculations that are adjusted for losses in power due to carryover, treatment×period interactions and temporal changes in variance.
Section snippets
Study design and statistical model
Patients are randomized to treatment “sequences.” For PG designs each sequence involves one or more periods, and either T or P. For CO designs, treatment sequences require at least two periods, and usually both T and P. Capital letters designate treatment sequences and subscripts designate baselines, e.g., P:T is a two-sequence PG design where patients receive either P or T for a single period; PBTB is identical with baselines for each subject. We compare single-period PG designs with or
Extensions to other designs
For simple carryover, Chinchilli and Esinhart describe unbiased estimates of the treatment effect for certain CO designs with more than two periods and/or sequences [21]. Of these, a two-sequence, four-period CO design (Design 8, Table 1) and Balaam's [29] four-sequence, two-period design with or without baselines (Designs 9 and 10, Table 1) are considered along with two-sequence, two- and four-period repeated-measures PG designs with or without baselines (Designs 5, 6, 7). We show later that μ̂
The proposed study
Of interest is whether donepezil improves mean cognitive function in patients with Parkinson's disease who have mild to moderate cognitive impairment. The cognitive scale of the Alzheimer's disease assessment scale (ADAS-cog), ranging from 0 (normal) to 70 (severely impaired), is the outcome. The primary study site (The Parkinson's Disease and Movement Disorders Center at the Pennsylvania Hospital) specializes in Parkinson's disease. The clinic has an established record of clinical trials, and
Discussion
Research on CO designs has largely focused on unbiased estimators 11, 21. Our work examines the consequences of using estimates of the treatment effect that are potentially biased. In general, CO designs are most efficient compared to PG designs when intraclass correlations are high, and least efficient when intraclass correlations are low and/or CO-carryover is very high. Two-sequence CO designs and sometimes even PG designs are more efficient than Balaam's design. We note, however, that for
Acknowledgements
We thank Drs. Brian Strom and Stephen Senn for thought-provoking discussions about our work and Jesse Berlin, as well as two reviewers and the editor, for comments on the manuscript. The opinions expressed here reflect those of the authors and are not necessarily those of the individuals named above. S. Montimore and S. Smith provided technical word-processing support. Funding provided to M.P. in part by the Mental Retardation and Developmental Disabilities Research Center of the Children's
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