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Application of Clinical Trial Simulation to Compare Proof-of-Concept Study Designs for Drugs with a Slow Onset of Effect; An Example in Alzheimer's Disease

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Abstract

Objective

Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200–400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials.

Materials and Methods

A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A ‘positive trial’ reflecting drug activity was declared considering both a dose trend test (p < 0.05) and pair-wise comparisons to placebo (p < 0.025).

Results

A 4 × 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability.

Conclusion

CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US$4M in direct costs and a firm decision 8–12 months earlier than a 12-week parallel group trial.

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Authors and Affiliations

  1. Pfizer Global Research and Development, Ann Arbor, Michigan, USA

    Peter Lockwood & Wayne Ewy

  2. deCODE genetics, Brighton, Michigan, USA

    David Hermann

  3. Department of Pharmacology and Clinical Pharmacology, School of Medicine, University of Auckland, Auckland, New Zealand

    Nick Holford

Authors
  1. Peter Lockwood
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  2. Wayne Ewy
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  3. David Hermann
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  4. Nick Holford
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Correspondence to Peter Lockwood.

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Lockwood, P., Ewy, W., Hermann, D. et al. Application of Clinical Trial Simulation to Compare Proof-of-Concept Study Designs for Drugs with a Slow Onset of Effect; An Example in Alzheimer's Disease. Pharm Res 23, 2050–2059 (2006). https://doi.org/10.1007/s11095-006-9048-8

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