Item response theory in early phase clinical trials: Utilization of a reference model to analyze the Montgomery-Åsberg Depression Rating Scale.
Marije E. Otto, Kirsten R Bergmann, Marieke L De Kam, Kasper Recourt, Gabriël E. Jacobs, Michiel J. van Esdonk
CPT: Pharmacometrics & Systems Pharmacology October 2023 DOI: 10.1002/psp4.13018 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Methodological case study using data from a crossover, placebo-controlled trial Case report Peer reviewed |
|---|---|
| Sample size | 17 |
| Population | Patients with treatment-resistant major depressive disorder |
| Intervention | Intravenous racemic ketamine |
| Duration | Five timepoints from predose to 2 weeks after dosing |
| Measures | Montgomery-Åsberg Depression Rating Scale (MADRS) |
| Topics | Depression |
| Key findings | Applying a reference IRT model to MADRS data from a small early-phase trial produced latent severity scores that differed significantly between reference models but not between assumed data distributions. Estimated treatment effect size was not significantly affected by the chosen approach or reference population, and IRT yielded increased precision for determining treatment effect compared with total scores, which the authors present as demonstrating the usefulness of reference IRT models in early-phase trials. |
Abstract
In clinical trials, Montgomery-Åsberg Depression Rating Scale (MADRS) questionnaire data are added up to total scores before analysis, assuming equal contribution of each separate question. Item Response Theory (IRT)-based analysis avoids this by using individual question responses to determine the latent variable (ψ), which represents a measure of depression severity. However, utilization of IRT in early phase trials remains difficult, because large datasets are needed to develop IRT models. Therefore, we aimed to evaluate the application and assumptions of a reference IRT model for analysis of an early phase trial. A cross-over, placebo-controlled study investigating the effect of intravenous racemic ketamine on MADRS scores in patients with treatment-resistant major depressive disorder was used as a case study. One hundred forty-seven MADRS responses were measured in 17 patients at five timepoints (predose to 2 weeks after dosing). Two reference IRT models based on different patient populations were selected from literature and used to determine ψ, while testing multiple approaches regarding assumed data distribution. Use of ψ versus total score to determine treatment effect was compared through linear mixed model analysis. Results showed that determined ψ values did not differ significantly between assumed distributions, but were significantly different when changing reference IRT model. Estimated treatment effect size was not significantly affected by chosen approach nor reference population. Finally, increased precision to determine treatment effect was achieved by using IRT versus total scores. This demonstrates the usefulness of reference IRT model application for analysis of questionnaire data in early phase clinical trials.
Comparable studies
Other randomized controlled trials on depression, most cited first.