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01.12.2013 | Research article | Ausgabe 1/2013 Open Access

BMC Medical Research Methodology 1/2013

Clinical trial simulation to evaluate power to compare the antiviral effectiveness of two hepatitis C protease inhibitors using nonlinear mixed effect models: a viral kinetic approach

Zeitschrift:
BMC Medical Research Methodology > Ausgabe 1/2013
Autoren:
Cédric Laouénan, Jeremie Guedj, France Mentré
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1471-2288-13-60) contains supplementary material, which is available to authorized users.

Competing interests

All authors declare that they have no competing interests.

Authors’ contributions

CL, JG and FM designed the simulation study and the MODCUPIC trial. CL carried out the simulations and drafted the manuscript. JG participated to the work of estimation (with CL). CL, JG and FM participated in the statistical analysis and helped to draft the manuscript. All authors read and approved the final manuscript.

Abstract

Background

Models of hepatitis C virus (HCV) kinetics are increasingly used to estimate and to compare in vivo drug’s antiviral effectiveness of new potent anti-HCV agents. Viral kinetic parameters can be estimated using non-linear mixed effect models (NLMEM). Here we aimed to evaluate the performance of this approach to precisely estimate the parameters and to evaluate the type I errors and the power of the Wald test to compare the antiviral effectiveness between two treatment groups when data are sparse and/or a large proportion of viral load (VL) are below the limit of detection (BLD).

Methods

We performed a clinical trial simulation assuming two treatment groups with different levels of antiviral effectiveness. We evaluated the precision and the accuracy of parameter estimates obtained on 500 replication of this trial using the stochastic approximation expectation-approximation algorithm which appropriately handles BLD data. Next we evaluated the type I error and the power of the Wald test to assess a difference of antiviral effectiveness between the two groups. Standard error of the parameters and Wald test property were evaluated according to the number of patients, the number of samples per patient and the expected difference in antiviral effectiveness.

Results

NLMEM provided precise and accurate estimates for both the fixed effects and the inter-individual variance parameters even with sparse data and large proportion of BLD data. However Wald test with small number of patients and lack of information due to BLD resulted in an inflation of the type I error as compared to the results obtained when no limit of detection of VL was considered. The corrected power of the test was very high and largely outperformed what can be obtained with empirical comparison of the mean VL decline using Wilcoxon test.

Conclusion

This simulation study shows the benefit of viral kinetic models analyzed with NLMEM over empirical approaches used in most clinical studies. When designing a viral kinetic study, our results indicate that the enrollment of a large number of patients is to be preferred to small population sample with frequent assessments of VL.
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