Marc Cerou1,2, Sophie Peigné3, Emmanuelle Comets4,5,6, Marylore Chenel3. 1. Université de Paris, IAME, INSERM, F-75018, Paris, France. marc.cerou@inserm.fr. 2. Division of Clinical Pharmacokinetics and Pharmacometrics, Institut de Recherches Internationales Servier, Suresnes, France. marc.cerou@inserm.fr. 3. Division of Clinical Pharmacokinetics and Pharmacometrics, Institut de Recherches Internationales Servier, Suresnes, France. 4. Université de Paris, IAME, INSERM, F-75018, Paris, France. 5. CIC 1414, INSERM, 35700, Rennes, France. 6. Université Rennes-1, 35700, Rennes, France.
Abstract
INTRODUCTION: In this paper, we studied the effect over time of agomelatine, an antidepressant drug administered in patient with major depressive disorder, through item response theory (IRT), taking into account a strong placebo effect and missing not at random. We also assessed the informativeness of the HAMD-17 scale's item. MATERIALS AND METHODS: The data includes five phase III clinical trials sponsored by Servier Institute, totalling 1549 patients followed during a maximum of 1 year. At each observation, individual scores for the 17 items of the HAMD scale were recorded. The probability for each score was modelled with IRT. A non-linear mixed effects model was used to describe the evolution of the disease and was coupled with a time to event model to predict dropout. Clinical trial simulations were then used to compare placebo and active treatment. Informativeness of each item was evaluated using the Fisher information theory. RESULTS: The best model combined an IRT model, a longitudinal model for underlying depression which describes the remission and then a possible relapse, and a hazard model for dropout depending on the evolution from baseline. The drug effect was best modelled as an effect on the remission and the relapse phases. The median predicted drop in HAMD between baseline and 6 weeks was 8.8 (90% PI, 8.3-9.2) when on placebo and 13.1 (90% PI, 12.8-13.4) when treated. Nine items were found to be the most informative. CONCLUSION: The IRT framework allowed to characterise the evolution of depression with time and estimate the effect of agomelatine, as well as the link between symptoms and disease.
INTRODUCTION: In this paper, we studied the effect over time of agomelatine, an antidepressant drug administered in patient with major depressive disorder, through item response theory (IRT), taking into account a strong placebo effect and missing not at random. We also assessed the informativeness of the HAMD-17 scale's item. MATERIALS AND METHODS: The data includes five phase III clinical trials sponsored by Servier Institute, totalling 1549 patients followed during a maximum of 1 year. At each observation, individual scores for the 17 items of the HAMD scale were recorded. The probability for each score was modelled with IRT. A non-linear mixed effects model was used to describe the evolution of the disease and was coupled with a time to event model to predict dropout. Clinical trial simulations were then used to compare placebo and active treatment. Informativeness of each item was evaluated using the Fisher information theory. RESULTS: The best model combined an IRT model, a longitudinal model for underlying depression which describes the remission and then a possible relapse, and a hazard model for dropout depending on the evolution from baseline. The drug effect was best modelled as an effect on the remission and the relapse phases. The median predicted drop in HAMD between baseline and 6 weeks was 8.8 (90% PI, 8.3-9.2) when on placebo and 13.1 (90% PI, 12.8-13.4) when treated. Nine items were found to be the most informative. CONCLUSION: The IRT framework allowed to characterise the evolution of depression with time and estimate the effect of agomelatine, as well as the link between symptoms and disease.
Entities:
Keywords:
Agomelatine; IRT; MNAR; Major depressive disorder; NLMEM
Authors: Nishant Verma; S Natasha Beretvas; Belen Pascual; Joseph C Masdeu; Mia K Markey Journal: Alzheimers Res Ther Date: 2015-11-12 Impact factor: 6.982