MODEL1006230054
units def: 447833
parameter: 273187
parameter: 273191
parameter: 273243
parameter: 273233
compartment: 273157
rule: 273185
units def: 447809
notes: 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. Th…
parameter: 273205
parameter: 273225
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parameter: 273219
parameter: 273241
units def: 447653
rule: 273164
modified:
  W3 CDTF: Fri Jun 25 14:17:54 BST 2010
parameter: 273202
modified:
  W3 CDTF: Fri Jun 25 14:17:54 BST 2010
parameter: 273222
modified:
  W3 CDTF: Fri Jun 25 14:17:54 BST 2010
type: SBMLModel
creator:
  ORG:
    orgname: Auckland Bioengineering Institute
  n:
    given: James
    family: Lawson
parameter: 273194
length unit: 076409
units def: 447725
parameter: 273211
parameter: 273197
parameter: 273249
parameter: 273214
creator:
  ORG:
    orgname: Auckland Bioengineering Institute
  n:
    given: James
    family: Lawson
parameter: 273246
parameter: 273230
parameter: 273252
units def: 447593
parameter: 273188
units def: 447785
parameter: 273200
rule: 273179
rule: 273173
substance units: 178797
units def: 447858
volume units: 290956
rule: 273176
parameter: 273235
rule: 273162
parameter: 273238
parameter: 273227
parameter: 273217
is described by: http://identifiers.org/pubmed/16906456
units def: 447761
area units: 291053
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curated: false
rule: 273161
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units def: 447617
creator:
  ORG:
    orgname: Auckland Bioengineering Institute
  n:
    given: James
    family: Lawson
time units: 447882
rule: 273167
created:
  W3 CDTF: Fri Jun 25 14:17:54 BST 2010
units def: 447882
parameter: 273208
name: Lockwood2006_PKPD_AlzheimersDisease

273200
constant: false
value: NaN
name: ADAS_Cog_p
type: Parameter

273252
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447737
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447821
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273208
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name: Kel_p
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273217
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value: NaN
name: CL
type: Parameter

273191
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name: S0
type: Parameter

273233
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units: 447653
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name: CeA
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447713
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273243
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units: litre
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name: Vp
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273227
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name: PD_CeA
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447617
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273157
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447882
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name: PC
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273219
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value: 1.0
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447653
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unit: 447665
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447701
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273194
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273230
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447593
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name: mg
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273214
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value: 6.0
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447773
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kind: SECOND
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447809
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name: units_per_day
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273249
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value: 115.44
name: k_ab
type: Parameter

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name: year
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447749
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447870
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447797
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273202
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273235
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273197
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447725
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273225
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units: dimensionless
value: NaN
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447605
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447858
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273187
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value: NaN
name: time
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273211
constant: true
units: 447761
value: 7.0
name: t_half_el_p
type: Parameter

273241
constant: true
units: litre
value: 172.0
name: Vc
type: Parameter

447761
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name: day
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447629
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447641
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273205
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447894
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447665
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scale: -9
multipler: 1.0
kind: GRAM
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273222
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value: 40.0
name: age
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447785
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447845
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kind: SECOND
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447689
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unit: 447701
name: mg_per_litre
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273246
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value: 25.0
name: A_in
type: Parameter