Lockwood2006_PKPD_AlzheimersDisease

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Short description

This a model from the article:
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.
Lockwood P, Ewy W, Hermann D, Holford N. Pharm Res 2006 Sep;23(9):2050-9 16906456 ,
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 x 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 4 M dollars in direct costs and a firm decision 8-12 months earlier than a 12-week parallel group trial.

This model was taken from the CellML repository and automatically converted to SBML.
The original model was: Lockwood P, Ewy W, Hermann D, Holford N. (2006) - version=1.0
The original CellML model was created by:
James Lawson
j.lawson@auckland.ac.nz
The University of Auckland

This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
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To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Format
SBML (L2V4)
Related Publication
  • 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.
  • Lockwood P, Ewy W, Hermann D, Holford NH
  • Pharmaceutical research , 9/ 2006 , Volume 23 , pages: 2050-2059
  • Pfizer Global Research and Development, Ann Arbor, Michigan, USA. peter.lockwood@pfizer.com
  • 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.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).A 4 x 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.CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US 4 M dollars in direct costs and a firm decision 8-12 months earlier than a 12-week parallel group trial.
Contributors
Camille Laibe

Metadata information

is
BioModels Database MODEL1006230054
isDescribedBy
PubMed 16906456
isVersionOf
Gene Ontology response to drug
Human Disease Ontology Alzheimer's disease
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
Curation status
Non-curated
Original model(s)
http://models.cellml.org/exposure/60366c003dba765e53609eaca35027fd
  • Model originally submitted by : Camille Laibe
  • Submitted: 23-Jun-2010 10:12:15
  • Last Modified: 25-Jun-2010 14:17:54
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 25-Jun-2010 14:17:54
    • Submitted by: Camille Laibe
    • With comment: Current version of Lockwood2006_PKPD_AlzheimersDisease
  • Version: 1 public model Download this version
    • Submitted on: 23-Jun-2010 10:12:15
    • Submitted by: Camille Laibe
    • With comment: Original import of Lockwood2006_PKPD_AlzheimersDisease