Evaluation of study design and analysis plan for a clinical trial of Bedaquiline in MDR-TB infected children
Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Introduction: Multi-drug resistant tuberculosis (MDR-TB) is a growing global health problem with long and cumbersome treatment. MDR strains of TB and its high lethality (>40%) urges the need for new drugs with novel mechanism of action. Bedaquiline (BDQ) is such a drug, recently approved by the FDA. A study is planned in order establish appropriate dosing regiments for HIV negative and positive children infected with MDR-TB.
Aim: To evaluate the power to fulfil regulatory requirements of the currently suggested study design of the first pediatric BDQ phase I/II study and to optimize the design and analysis plan if needed.
Materials and Methods: Pharmacokinetic data as should be obtained with the current study design was simulated with NONMEM, based on the adult BDQ model developed by Svensson et. al. Parameters were allometrically scaled and an enzyme maturation function was incorporated into the model in order to describe the youngest subjects. The age-related covariate weight was simulated with a simplified LMS method. Stochastic simulations and re-estimations were used to evaluate the study design. HIV was added as a covariate on clearance (CL) and the risk of type I and II errors was assessed.
Results: The study design fulfilled the FDA requirements when different functions of allometric scaling for CL were tested, but estimation of the enzyme maturation factor and evaluation of the trial after only the initial 2 weeks of the oldest cohort was problematic. The risk of finding an effect that does not really exist for the HIV covariate was found to be 9% and the risk of not finding an effect when one really is present was found to be less than 1%.
Conclusions: The proposed study design is appropriate to fulfil the FDA requirements. However, intermediate analysis of part of the data cannot support estimation of all model parameters. A solution might be to use priors from the adult population in the prediction of doses for younger cohorts.
Place, publisher, year, edition, pages
2015. , 41 p.
bedaquiline, BDQ, TB, tuberculosis, MDR-TB, multi-drug resistant tuberculosis, pediatric, study, design, clinical, trial, evaluation, estimation, simulation, NONMEM, non-linear mixed effects, pharmacometrics, PopPK, PK, pharmacokinetics, population pharmacokinetics, modeling, enzyme maturation, LMS, stochastic simulation and estimation, Uppsala University
Pharmaceutical Sciences Bioinformatics (Computational Biology)
IdentifiersURN: urn:nbn:se:uu:diva-242052OAI: oai:DiVA.org:uu-242052DiVA: diva2:782187
Subject / course
Master of Science Programme in Pharmacy
Svensson, Elin, Master of ScienceKarlsson, Mats, Professor
Hammarlund-Udenaes, Margareta, Professor