Modeling and Simulation for Clinical Trial Design Involving a Categorical Response: A Phase II Case Study with Naratriptan
Abstract
Purpose 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.
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- Authors
- Nestorov, I., Graham, G., Duffull, S., Aarons, L., Fuseau, E., & Coates, P.
- Affiliations
- University of Manchester (GB)
- The University of Queensland (AU)
- Corresponding author
- Graham, Gordon
- Venue
- Pharmaceutical Research
- Published
- 2001-08
- Volume
- 18
- Issue
- 8
- Pages
- 1210-1219
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- OpenAlex
- W321073894
- Cited by
- 41
- References
- 20
- Citations by year
- 2018: 1 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 3
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Pharmaceutical Research (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Social Sciences › Decision Sciences › Management Science and Operations Research › Optimal Experimental Design Methods
- Keywords
- clinical trial simulation, pharmacokinetic-pharmacodynamic modeling, naratriptan, sumatriptan, categorical response, migraine, D-optimal design, trial power, dose selection
- MeSH terms
- Administration, Oral, Algorithms, Computer Simulation, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Humans, Indoles, Injections, Subcutaneous, Models, Biological, Piperidines, Research Design, Software, Tryptamines, Clinical Trials, Phase II as Topic, Serotonin Receptor Agonists
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