title: Model based design and analysis of phase II HIV-1 trials.
abstract: This work explores the advantages of a model based drug development (MBDD) approach for the design and analysis of antiretroviral phase II trials. Two different study settings were investigated: (1) a 5-arm placebo-controlled parallel group dose-finding/proof of concept (POC) study and (2) a comparison of investigational drug and competitor. Studies were simulated using a HIV-1 dynamics model in NONMEM. The Monte-Carlo Mapped Power method determined the sample size required for detecting a dose-response relationship and a significant difference in effect compared to the competitor using a MBDD approach. Stochastic simulation and re-estimation were used for evaluation of model parameter precision and bias given different sample sizes. Results were compared to those from an unpaired, two-sided t test and ANOVA (p ≤ 0.05). In all scenarios, the MBDD approach resulted in smaller study sizes and more precisely estimated treatment effect than conventional statistical analysis. Using a MBDD approach, a sample size of 15 patients could be used to show POC and estimate ED50 with a good precision (relative standard error, 25.7 %). A sample size of 10 patients per arm was needed using the MBDD approach for detecting a difference in treatment effect of ≥20 % at 80 % power, a 3.4-fold reduction in sample size compared to a t test. The MBDD approach can be used to achieve more precise dose-response characterization facilitating decision making and dose selection. If necessitated, the sample size needed to reach a desired power can potentially be reduced compared to traditional statistical analyses. This may allow for comparison against competitors already in early clinical studies.
authors.affiliation: Unit for Pharmacokinetics and Drug Metabolism, Department of Pharmacology, Sahlgrenska Academy at University of Gothenburg, PO Box 431, 405 30 Gothenburg, Sweden. dinko.rekic@gmail.com
authors.forename: Dinko
authors.initials: D
authors.lastname: Rekić
authors.forename: Daniel
authors.initials: D
authors.lastname: Röshammar
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
mesh_terms: D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery / Q000379:methods*; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D015233:Models, Statistical; D009010:Monte Carlo Method; D012107:Research Design; D018401:Sample Size
chemical_list: D044966:Anti-Retroviral Agents