title: Clinical trial simulation using therapeutic effect modeling: application to ivabradine efficacy in patients with angina pectoris.
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.
authors.affiliation: Service de Pharmacologie Clinique, Faculté RTH Laennec, Rue Guillaume Paradin, BP 8071, 69376 Lyon, France. sylvie.chabaud@upcl.univ-lyon1.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chabaud
authors.forename: Pascal
authors.initials: P
authors.lastname: Girard
authors.forename: Patrice
authors.initials: P
authors.lastname: Nony
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Boissel
mesh_terms: D000787:Angina Pectoris / Q000188:drug therapy*; D001552:Benzazepines / Q000009:adverse effects / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D017326:Clinical Trials, Phase III as Topic / Q000379:methods* / Q000706:statistics & numerical data; D004311:Double-Blind Method; D006801:Humans; D000077550:Ivabradine; D008954:Models, Biological; D009010:Monte Carlo Method; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data
chemical_list: D001552:Benzazepines; D000077550:Ivabradine