Placebo and drug response assessment on Unified Parkinson’s Disease Rating Scale using longitudinal Item Response Modelling
Siv Jönsson (1), Gopichand Gottipati (1), Shuying Yang (2), Chao Chen (2), Mats O. Karlsson (1), Elodie L. Plan (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. (2) GlaxoSmithKline, London, UK
Objectives: To employ an Item Response Model (IRM) to describe the time course and drug effect in advanced Parkinson’s disease (PD) subjects based on longitudinal Unified Parkinson’s Disease Rating Scale (UPDRS) data.
Methods: An IRM with 3 latent variables [1] has been used to describe baseline 44-item UPDRS data from 2 clinical trials in early [2] and advanced [3] PD. The IRM was applied to extended data with longitudinal UPDRS recordings collected in the randomized advanced PD study [3], comparing ropinirole to placebo as adjunct therapy to L-dopa over 24 weeks at individually titrated doses between 6 and 24 mg/day. For placebo, a linear model assessed the disease progression (Slope), or an exponential model the extent (Extent) and onset rate (Onset) of symptom relief over time. Exposure independent disease modifying (DM) and symptomatic (SY) drug effects were assessed as follows: Linear: Baseline+(Slope+DM)·time; Exponential: Baseline+(Extent+SY)·(1-exp[-Onset*time]). Modelling was performed using NONMEM 7.3 [4].
Results: The data comprised of 72,167 (552 patients) UPDRS recordings, whereof placebo and ropinirole data from [3] accounted for 31,212 (190 patients) and 33,951 (201 patients) records. The exponential model resulted in statistically significantly better description of the longitudinal data than the linear model. Placebo time course parameters were estimated for each latent variable, defining the observed small improvement in disease over time (Extent ranging from -0.30 to -0.058) corresponding to a change in total UPDRS of -2 ([-4; -1] 95% CI) points in the placebo group. Drug effects could not be differentiated statistically among latent variables and one common drug effect (SY ‑0.54 [-0.61;-0.47] 95% CI) was estimated disclosing additional improvement corresponding to a change in total UPDRS of -10 ([-11; -8.5] 95% CI) points in the ropinirole group.
Conclusions: The longitudinal IRM model adequately described the data, reflecting a gradual onset of symptom relief from baseline by the drug, in addition to the placebo effect. The progression of the symptoms during placebo treatment or the drug effect on this progression could not be reliably assessed, due to the insufficient trial duration. The use of multiple latent variables revealed the differentiated nature of symptom relief by placebo among various aspects of the clinical endpoint. This model can be further extended to allow simulations for drugs with differentiated pharmacological profiles.
References:
[1] Gottipati G, Berges AC, Yang S, Chen C, Karlsson MO, Plan EL. Item response modelling to leverage data from historical Parkinson’s disease trials while integrating data from a newer version of the clinical endpoint. PAGE 25 (2016) Abstr 5990 [www.page-meeting.org/?abstract=5990].
[2] 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.
[3] 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’s disease. Neurology. 2007; 68(14):1108-15.
[4] Beal S, Sheiner LB, Boeckmann A, Bauer, RJ, NONMEM User's Guides. (1989-2009), Icon Development Solutions, Ellicott City, MD, USA, 2009.
