title: Modeling and stimulation for clinical trial design involving a categorical response: a phase II case study with naratriptan.
abstract: OBJECTIVE
  The overall aim of the present study was to investigate retrospectively the feasibility and utility of model-based clinical trial simulation as applied to the clinical development of naratriptan with effect measured on a categorical scale.
  
  
  METHODS
  A PK-PD model for naratriptan was developed by using information gathered from previous naratriptan and sumatriptan preclinical and clinical trials. The phase IIa naratriptan data were used to check the PK-PD model in its ability to describe future data. A further PK-PD model was developed by using the phase IIa naratriptan data, and a phase IIb trial was designed by simulation with the use of Matlab. The design resulting from clinical trial simulation was compared with that derived by using D-optimal design.
  
  
  RESULTS
  The PK-PD model showed reasonable agreement with the data observed in the phase IIa naratriptan clinical trial. Clinical trial simulation resulted in a design with four or five arms at 0 mg, 2.5 and/or 5 mg, 10 mg, and 20 mg, PD measurements to be taken at 0, 2, and 4 or 6 h and at least 150 patients per arm. A sub-D-optimal design resulted in two dosing arms at 0 and 10 mg and PD measurements to be taken at 1 and 2 h.
  
  
  CONCLUSIONS
  Clinical trial simulation is a useful tool for the quantitative assessment of the influence of the controllable factors and is the only tool for the quantitative assessment of the uncontrollable factors on the power of a clinical trial.
authors.affiliation: Centre for Applied Pharmacokinetic Research, Manchester University, United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Nestorov
authors.forename: G
authors.initials: G
authors.lastname: Graham
authors.forename: S
authors.initials: S
authors.lastname: Duffull
authors.forename: L
authors.initials: L
authors.lastname: Aarons
authors.forename: E
authors.initials: E
authors.lastname: Fuseau
authors.forename: P
authors.initials: P
authors.lastname: Coates
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008954:Models, Biological; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012107:Research Design; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012984:Software; D014363:Tryptamines
chemical_list: D007211:Indoles; D010880:Piperidines; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C106783:naratriptan