Gopichand Gottipati(1), Alienor C. Berges(2), Shuying Yang(2), Chao Chen(2), Mats O. Karlsson(1), Elodie L. Plan(1)
(1) Dept of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. (2) GlaxoSmithKline, London, UK
Objectives: Unified Parkinson’s Disease Rating Scale (UPDRS) has been used for assessing disease severity in Parkinson’s Disease (PD) trials for several decades. More recently, a Movement Disorder Society sponsored revision (MDS-UPDRS) had been proposed [1]. The objective of this work was to develop a framework to leverage historical data through the application of Item Response Theory (IRT) methodology.
Methods: An IRT model with three (hidden) latent variables [2], was previously developed using the MDS–UPDRS data of the De Novo PD cohort from the Parkinson’s Progression Markers Initiative database [3]. This model was adapted to describe the baseline UPDRS data from two clinical trials, one in subjects with early PD [4] and the other in subjects with advanced PD [5]. Assuming that the same underlying latent variables reflected the disease severity, items of the original version were mapped to those of the new version. For 41 shared items the parameters were fixed except for aspects related to minor differences in item categorization. For the remaining 14 items, new item parameters were estimated. Modeling was performed using NONMEM7.3 and evaluated with PsN and R.
Results: The parameters reflecting differences in the shared items between scales or characterization of new item parameters, were estimated successfully. The mean (and variance) of the latent variables for the patient reported items, non-dexterous items, dexterous items according to the affected side were 0.535 (0.774), 0.219 (1.23), 0.353 (0.821) in the early PD patients respectively and 1.23 (1.88), 1.58 (2.63), 0.734 (1.50) in the advanced PD patients respectively. EBE and simulation based diagnostics indicated that mapping between the two versions was better for early PD subjects (close to De Novo cohort of PPMI) than advanced PD subjects. Background (L-dopa) therapy in one of the two studies seemed to induce differences in some item characteristic curves, which could be described as a covariate effect.
Conclusions: The two versions of the main clinical endpoint in PD trials, UPDRS and MDS-UPDRS, can be integrated together in a unique framework using IRT methodology. This can facilitate improved utilization of the data by integrating data from diverse sources, including different versions of the endpoint (as long as they are mapped to the same underlying latent variables), and potentially lead to better characterization of disease progression and drug effects in PD.
References:
[1] Goetz C., Tilley B, Shaftman S, Stebbins G, Fahn S, Martinez M, Werner Poewe et al. Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): Scale presentation and clinimetric testing results. Movement Disorders 2008; 23(15): 2129-2170.
[2] Gottipati G, Karlsson MO, Plan EL., Modeling of a Composite Score in Parkinson’s Disease using Item Response Theory. PAGE 24 (2015) Abstract 3596 [www.page-meeting.org/?abstract=3596]
[3] The Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org
[4] Stocchi F, Hersh BP, Scott BL, Nausieda PA, Giorgi L; Ease-PD Monotherapy Study Investigators. Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson’s disease: a randomized, double-blind, non-inferiority crossover study. Curr Med Res Opin. 2008; 24(10):2883-95
[5] Pahwa R, Stacy MA, Factor SA, Lyons KE, Stocchi F, Hersh BP, Elmer LW, Truong DD, Earl NL; EASE-PD Adjunct Study Investigators. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology. 2007; 68(14):1108-15.
Reference: PAGE 25 () Abstr 5990 [www.page-meeting.org/?abstract=5990]
Poster: Methodology - New Modelling Approaches