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2017 (English)In: AAPS Journal, E-ISSN 1550-7416, Vol. 19, no 1, p. 172-179Article in journal (Other academic) Published
Abstract [en]
In this study, we report the development of the first IRT model within a NLME (Non Linear Mixed Effect) framework to characterize the disease progression in MS (as measured by EDSS). Data were collected from a 96-week Phase III clinical study, involving 104206 item-level observations from 1319 patients with relapsing-remitting MS, treated with placebo or cladribine. Observed scores for each EDSS item were modelled describing the probability of a given score as a function of patients’ (unobserved) disability using a logistic model. Longitudinal data from placebo arms were used to describe the disease progression over time and the model was then extended to cladribine arms in order to characterize the drug effect. Sensitivity with respect to patient disability was calculated as Fisher information for each EDSS item, which were ranked according to the amount of information they contained. IRT model was able to describe baseline and longitudinal EDSS data on item and total level. Final model suggested that cladribine treatment significantly slows disease-progression rate, with a 20% decrease in disease-progression rate compared to placebo, irrespective of exposure, and effects an additional exposure-dependent reduction in disability progression. Four out of 8 items contained 80% of information for the given range of disabilities. This study has illustrated that IRT modelling is specifically suitable for accurate quantification of disease status and description and prediction of disease progression in Phase 3 studies on RRMS, by integrating EDSS item-level data in a meaningful manner.
Keywords
multiple sclerosis, disease progression model, Expanded Disability Status Scale, Item Response Theory, cladribine tablets
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-315622 (URN)10.1208/s12248-016-9977-z (DOI)000392210900017 ()27634384 (PubMedID)
Funder
EU, European Research Council
Note
CLINICAL PHARMACOKINETICS, Volume: 58, Issue: 3, Pages: 401-401, DOI: 10.1007/s40262-018-0706-x
2017-02-162017-02-162023-08-28Bibliographically approved