Clinical Trial Simulation Using Therapeutic Effect Modeling: Application to Ivabradine Efficacy in Patients with Angina Pectoris View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2002-08

AUTHORS

Sylvie Chabaud, Pascal Girard, Patrice Nony, Jean-Pierre Boissel

ABSTRACT

Ivabradine is a new bradycardic agent with a potential indication for stable angina pectoris. To investigate the best compromise between efficacy, safety, drug regimen, and number of patients to include in a phase III study, we conducted Monte Carlo simulations using a full therapeutic model. The binary clinical outcome, chest pain, was simulated using a physiologic model in which the coronary reserve was derived from the heart rate. Safety was defined as being heart rate dependent. Using real data to build a pharmacokinetic–pharmacodynamic model controlling drug effect (i.e., heart rate decrease), and resampling heart rate profiles from the database, 100 clinical trials (N=200) were simulated for five oral doses (2.5, 5, 10, 20, and 40 mg QD or BID) of ivabradine. Only 25% of the simulated trials showed a significant effect of ivabradine with doses up to 10 mg QD, and 48 and 55% of the trials with doses of 10 mg BID and 20 mg QD, respectively, and more than 80% of the trials with a 40 mg daily dose. For safety, 4% of patients had at least one adverse event in the untreated group, and from 5 to 13% in the treated groups for the lowest to the highest dose, respectively. The number of subjects to include in a future trial to obtain a 15% decrease in chest pain under the assumption of a 68% base risk, is 239 subjects per group with 10 mg BID or 196 with 20 mg QD. These results illustrate how clinical trial simulations including a PK/PD model as well as a physiopathologic mechanistic model, describing the relationship between the intermediate and clinical endpoint, and the resampling of real patients from a large database can help in designing future phase III trials. More... »

PAGES

339-363

Identifiers

URI

http://scigraph.springernature.com/pub.10.1023/a:1020953107162

DOI

http://dx.doi.org/10.1023/a:1020953107162

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1038688629

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/12518708


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