Minimal Clinically Important Difference in Parkinson’s Disease as Assessed in Pivotal Trials of Pramipexole Extended Release

Abstract

Background. The minimal clinically important difference (MCID) is the smallest change in an outcome measure that is meaningful for patients. Objectives. To calculate the MCID for Unified Parkinson's Disease Rating Scale (UPDRS) scores in early Parkinson's disease (EPD) and for UPDRS scores and “OFF” time in advanced Parkinson's disease (APD). Methods. We analyzed data from two pivotal, double-blind, parallel-group trials of pramipexole ER that included pramipexole immediate release (IR) as an active comparator. We calculated MCID as the mean change in subjects who received active treatment and rated themselves “a little better” on patient global impression of improvement (PGI-I) minus the mean change in subjects who received placebo and rated themselves unchanged. Results. MCIDs in EPD (pramipexole ER, pramipexole IR) for UPDRS II were −1.8 and −2.0, for UPDRS III −6.2 and −6.1, and for UPDRS II + III −8.0 and −8.1. MCIDs in APD for UPDRS II were −1.8 and −2.3, for UPDRS III −5.2 and −6.5, and for UPDRS II + III −7.1 and −8.8. MCID for “OFF” time (pramipexole ER, pramipexole IR) was −1.0 and −1.3 hours. Conclusions. A range of MCIDs is emerging in the PD literature that provides the basis for power calculations and interpretation of clinical trials.

Post Hoc Analysis of Data from Two Clinical Trials Evaluating the Minimal Clinically Important Change in International Restless Legs Syndrome Sum Score in Patients with Restless Legs Syndrome (Willis-Ekbom Disease)

“…6,13,16 The current level of MCIC analysis, however, has not previously been performed for RLS studies.…”

The improvement of MAO-B inhibitors in Parkinson’s disease is clinically irrelevant: a review

“…More specifically, UPDRS Part III (Motor Examination Part) is used to evaluate the antiparkinsonian effect of the intervention on the patients' motor abilities, which are, after all, the most important aspect of their everyday lives affected by the disease. Alternatively, in LD-treated, advanced disease patients, OFF-time reduction during 24h can be used as a measure [21,22].…”

“…The most widely accepted anchor for PD patients for MCID determination is the Clinician-rated Global Impression of Improvement (CGI-I) scale (1=very much improved; 2=much improved; 3=minimally improved; 4=unchanged; 5=minimally worsened; 6=much worsened; 7=very much worsened) [21,22,[26][27][28]. Determining the MCID done either by calculating mean change on the UPDRS among patients with score 4 (unchanged) and 3 (minimally improved) on the CGI-I scale or by Receiver Operating Characteristic (ROC) curve analysis were developed, where cutoff values for UPDRS and OFF-time changes best distinguished minimally improvement patients from those with no change [22,29], estimated as the point on the ROC curve closest to (0,1), calculated as the minimum value of the square root of (1 -sensitivity)2 + (1 -specificity)2. Distribution-based approach is based on the distribution of the measure in the study population, but is mainly used to calculate the effect size [26,28].…”

“…First, these methods can give different MCID, even on the same sample, while, conversely, the same method can give different MCIDs in different samples [22,29]. Furthermore, Hauser et al [21,22] pointed out the importance of the placebo effect in the MCID, while highlighting that the MCID varies from drug to drug, as studies using drugs with larger efficacy tend to calculate larger MCIDs.…”

“…The studies by Hauser et al [21,22] are the most relevant for our discussion, since their data are derived from clinical trials that include a placebo control group, include patients in early PD as well, evaluate an intervention that is mildly efficacious, utilize also subject-rated impression of change and, finally, used data from two double-blind, randomized Rasagiline studies. According to Hauser's anchor-based analysis (using both mean change within patients and ROC curve analysis) the lower limit for the MCID is -2.0 for UPDRS Part III, -3.8 for UPDRS Total and -1.0 hours (h) for reduction in OFF-time [21].…”