Objectively measuring the response to therapy is an unmet need in the management of Parkinson's disease (PD). The Unified Parkinson's Disease Rating Scale1 and, specifically, its motor subscale (UPDRS‐III), is the most widely used evaluation tool. Traditionally, a statistically significant difference with a comparative group (e.g., placebo) has been employed to identify effective therapies. More recently, the concept of the minimal clinically important difference (MCID) is gaining momentum as a means to avoid relying on statistical differences that do not involve a clear clinical impact.2 This concept has been studied in PD drug trials and observational studies.3, 4, 5
We investigated the MCID for UPDRS‐III in early PD in a naturalistic or pragmatic setting (i.e., participants were prescribed dopaminergic medications by their neurologist). The institutional review board at MIT approved the study (#1412006804) and HM Hospitales (#15.05.796‐GHM). All subjects provided written informed consent before study enrolment.
Thirty‐one recently diagnosed PD participants and thirty age‐ and gender‐matched healthy controls were enrolled to receive five evaluations over the course of six months, consisting in UPDRS‐III before starting dopaminergic agents, as well as other standards related to disease progression and quality‐of‐life (Supporting Text S1). The PD patients were evaluated in ON state in all the follow‐up visits. Prescription schemes were collected for the entire follow up and converted to levodopa equivalent dose (LED) in mg.6 For defining MCID, we pre‐specified two cut‐offs based on previous observations.3, 4 To confirm which one was generalizable to a naturalistic or everyday practice setting, we combined distribution‐ and anchor‐based methods to define the MCID at the final visit.7 The anchors were based on the CISI‐PD and SLS scales.8, 9 Also, we derived the “noise” of the scale in the control group (Supporting Text S1).
A total of 29 (93.5%) PD participants and 29 (96.7%) controls completed the follow‐up. The median (interquartile range) LED was 0 (0 to 0) at baseline, which progressively increased to 340 mg (220‐400) at the final visit, or visit four (six months on average after starting the medication). The minimal clinically important improvement at the final visit was ‐4.83 points and the minimal clinically important worsening was 4.38 points (Fig. 1), which was rounded to a five‐point difference in both directions, as the UPDRS‐III is a discrete scale. Using these thresholds, we found that PD participants who responded to medications were six out of 28 (21.4%) at visit one, 12 out of 31 (38.7%) at visit two, 12 out of 27 (44.4%) at visit three, and 15 out of 29 (51.7%) at visit four. None of the controls had a UPDRS‐III change ≥ 5 points.
Figure 1.
UPDRS‐III change from Baseline to visit one (1 to 1.5 months after starting the dopaminergic treatment), visit two (2 to 2.5 months), visit three (4 to 5 months) and visit four (6 to 7 months) in the PD participants who responded (green dots), who did not change (yellow dots), who got worse (red dots) and the controls (blue dots). The horizontal black lines represent the UPDRS‐III MCID for defining improvement (subjects with an improvement equal or greater than ‐4.83 points) and worsening (subjects who scored equal or greater than 4.39 points more at the follow up visits). Regarding the stability of the classification (Supporting Text S1, Table 5), 29 (93.5%) PD patients showed a “logical” response to medication according to routine practice. Two (6.5%) patients had heterogeneous classifications. All the controls remained in the no change category during the follow up.
Defining the MCID for a routine clinical setting is important to inform decisions on therapy. In this study, we have confirmed that a five‐point UPDRS‐III change3 applies to recently diagnosed PD cases in a naturalistic setting. Another important contribution of this work is our estimation of scale variability in healthy controls to avoid underestimating the cut‐off for worsening that has been proven to be non‐linear in previous studies.3, 4, 5
We are confident that a five‐point UPDRSIII difference represents a clinically meaningful difference and could help guide prescription in everyday practice. This work and methodology should be confirmed for the new version of UPDRS.
Author Roles
1. Research project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing of the first draft, B. Review and Critique.
A.S.F.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B
M.M.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B
P.M.M.: 1A, 2A, 2C, 3A, 3B
J.C.M.: 1A, 2A, 2C, 3B
A.G.C.: 1A, 2C, 3B
L.G.: 1A, 1B, 1C, 2A, 2C, 3B
I.B.: 1A, 2C, 3B
C.S.M.: 1A, 2A, 2A, 3B
M.J.C.: 1A, 1B, 1C, 3B
J.A.M.: 1A, 1B, 1C, 3B
F.B.P.: 1A, 3B
M.G.: 1A, 1B, 2A, 2C, 3B
T.A.G: 1B, 1C, 2C, 3B
P.M.: 1B, 1C, 3B
V.P.M.: 1B, 1C, 3B
I.O.: 1B, 1C, 3B
L.L.M: 1C, 3B
A.A.C.: 1C, 3B
A.G.D.: 2A, 3B
J.H.R.: 1C, 3B
Disclosures
Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The institutional review board at MIT (#1412006804) and HM Hospitales (#15.05.796‐GHM) approved this study. All subjects provided written informed consent prior to study enrollment.
Funding Sources and Conflict of Interest: This study was conducted with research funds from the Michael J. Fox Foundation for Parkinson's Research (grant number 10860). Dr. Sánchez‐Ferro has received funding from “Consejería de Educación, Juventud y Deporte of Comunidad de Madrid” and the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007‐2013) under REA Grant 291820. All authors had full access to all data and contributed to the manuscript revision. The corresponding author collaborated in writing the first draft and had final responsibility for the decision to submit for publication. The authors declare that there are no conflicts of interest regarding the publication of this article.
Financial Disclosures for the previous 12 months: The contributors have not received any financial and material support for this research and work during the previous 12 months.
Supporting information
Supporting information may be found in the online version of this article.
Supporting Text S1: Additional background, study description, and definitions
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
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Supplementary Materials
Supporting information may be found in the online version of this article.
Supporting Text S1: Additional background, study description, and definitions