FormalPara Key Summary Points

Why carry out this study?

Levodopa-carbidopa intestinal gel (LCIG) is a stable gel suspension of levodopa carbidopa (20 mg/mL and 5 mg/mL, respectively) approved for continuous daytime infusion in patients with advanced Parkinson’s disease (PD).

In the 12-week, phase 3b, open-label, randomized DYSkinesia COmparative interventional trial on Duodopa VERsus oral medication (DYSCOVER) study, patients treated with LCIG experienced significant improvements in dyskinesia, pain, health related quality of life (HRQoL), activities of daily living (ADL), and clinical impression versus patients treated with optimized medical treatment (OMT).

To better understand the relationship between dyskinesia, pain, HRQoL, ADL, clinical impression, and “On” time without troublesome dyskinesia, this post hoc analysis of the DYSCOVER study examined correlations between PD outcomes at baseline and after 12 weeks of treatment with LCIG or OMT.

What was learned from the study?

Dyskinesia and pain were both associated with HRQoL at baseline, and improvements in dyskinesia and pain correlated with improvements in HRQoL.

Improvements in dyskinesia also correlated with improvements in ADL and clinical impression, and improvements in “On” time without troublesome dyskinesia correlated with improvements in HRQoL, ADL, and clinical impression.

Introduction

Levodopa remains the gold standard for the treatment of Parkinson’s disease (PD) [1]; however, the progression of disease presents challenges in controlling motor fluctuations and other symptoms despite optimized medical treatment (OMT) [2]. Dyskinesias are among the most prominent and distressing symptoms for patients and can cause pain, impair quality of life, and reduce a patient’s ability to engage in daily activities [3, 4]. Dyskinesias affect approximately 30% of patients within just 2–3 years of levodopa treatment initiation and nearly 90% of patients after 9 years or more [5].

Levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension [CLES]) is a stable gel suspension of levodopa-carbidopa (20 mg/mL and 5 mg/mL, respectively) approved for continuous daytime infusion in patients with advanced PD [6, 7]. Continuous delivery of levodopa with LCIG results in stable levodopa plasma levels and avoids the effects of pulsatile gastric emptying [8,9,10]. Results from multiple clinical trials have demonstrated that LCIG therapy improves dyskinesia, pain, health-related quality of life (HRQoL), and other clinically relevant outcomes in PD [6, 11,12,13]. Furthermore, results from observational studies have shown the effectiveness of LCIG in improving health-related outcomes in routine patient-care settings [14,15,16]. In particular, patients treated with LCIG in the long-term, prospective DUOdopa/Duopa in Patients with Advanced Parkinson’s Disease–a GLobal OBservational Study Evaluating Long-Term Effectiveness (DUOGLOBE) study experienced significant improvements from baseline to month 36 in dyskinesia, “Off” time, and non-motor symptoms [16]. The reduction in dyskinesia observed in the DUOGLOBE study is particularly noteworthy because DUOGLOBE was the first fully prospective, observational study to assess dyskinesia using the newly developed Unified Dyskinesia Rating Scale (UDysRS), which is a validated, comprehensive scale that includes both subjective and objective assessments of dyskinesia [17].

The DYSkinesia COmparative interventional trial on Duodopa VERsus oral medication (DYSCOVER) study was the first randomized trial to evaluate the efficacy of LCIG versus OMT on symptoms of dyskinesia as assessed by the UDysRS [11]. In addition, the DYSCOVER study utilized the recently developed King’s Parkinson’s disease Pain Scale (KPPS), which is the only validated scale that characterizes the various types of pain in PD [18].

In the DYSCOVER study, the primary endpoint (change from baseline to week 12 in UDysRS score) was met with LCIG versus OMT (least squares mean [standard error] difference [based on mixed effect for repeated measures model] − 15.1 [3.2]; p < 0.001). At week 12, patients who received LCIG also experienced significant improvements from baseline in pain, HRQoL, activities of daily living (ADL), and clinical impression versus OMT [11]. However, the exact relationship between dyskinesia and pain and how improvements in one or both measures can impact health-related outcomes are not fully understood. Our post hoc analysis of data from the DYSCOVER study examines the correlations between dyskinesia, pain, HRQoL, ADL, overall condition/clinical impression, and “On” time without troublesome dyskinesia at baseline and after 12 weeks of treatment with LCIG or OMT.

Methods

Study Design and Patients

This is a post hoc analysis of data from female and male patients who participated in the DYSCOVER study (NCT02799381). The methodology of the study is presented in detail elsewhere [11]. Briefly, the DYSCOVER study was a phase 3b, open-label, randomized, 12-week study conducted in 23 movement disorder specialist sites across the USA, Finland, Greece, Hungary, Italy, Slovakia, and Spain (Table S1 in the Supplementary Material). Patients aged ≥ 30 years with advanced levodopa-responsive PD, persistent motor fluctuations, and significant burden of dyskinesia at baseline (UDysRS total score ≥ 30) that were not controlled with OMT were randomized 1:1 to receive open-label LCIG or OMT for 12 weeks. Patients with predominantly diphasic dyskinesia, previous surgery for PD (e.g., deep brain stimulation), or a Mini-Mental State Examination score < 24 were excluded.

Assessments

This analysis assessed correlations between dyskinesia (UDysRS) and PD-specific pain (KPPS total score, KPPS fluctuation-related domain score, and KPPS dyskinesia item score), HRQoL (8-item Parkinson’s Disease Questionnaire [PDQ-8]), ADL (Unified Parkinson’s Disease Rating Scale part II [UPDRS II]), symptomatology and impact of illness on functioning (Clinical Global Impression of Severity [CGI-S]), and overall improvement in clinical impression (Clinical Global Impression of Change [CGI-C]) at baseline and week 12 change from baseline. Correlations of KPPS scores with PDQ-8 and UPDRS II scores were evaluated at baseline and week 12 change from baseline. Further assessments included correlations between “On” time without troublesome dyskinesia (Parkinson’s disease diary) and PDQ-8, UPDRS II, and CGI-S/CGI-C scores at baseline and week 12 change from baseline.

Statistics

We combined data from the LCIG and OMT arms into a single group in all analyses presented here. Patient demographics and disease characteristics at baseline were summarized using descriptive statistics. Categorical variables were summarized by the number and percentage of patients in each category; continuous variables were summarized by mean and standard deviation. Pearson correlation coefficients (r) were used to analyze combined data from both treatment groups at baseline and changes from baseline at week 12. Each correlation was evaluated separately as a marginal correlation without adjustment for any other variables; multivariate regression analyses were not performed. Correlation strength was defined with the following cutoffs: weak, r = 0.20–0.39; moderate, r = 0.40–0.59; strong, r ≥ 0.60. Statistical analyses were conducted using SAS® version 9.4 (SAS Institute Inc., Cary, NC, USA).

Compliance with Ethics Guidelines

Patients provided written informed consent before enrollment. Institutional review boards and ethics committees approved the DYSCOVER study protocol at all study sites in participating countries (Table S2 in the Supplementary Material). This clinical study was conducted in accordance with the Good Clinical Practice guideline as defined by the International Council for Harmonisation guidelines, Declaration of Helsinki of 1964 and its later amendments, institutional review boards, and all applicable regional regulations. Where applicable, permissions were obtained to use the scales and assessment measures employed in this clinical trial (UDysRS, KPPS, PDQ-8, UPDRS II, CGI-S, CGI-C, and PD diary).

Results

Patients

A total of 61 patients were included in this analysis. The mean age was 69.0 years, and 32 (52.5%) patients were female. At baseline, patients had a high dyskinesia burden (mean UDysRS total score 52.1), with a mean KPPS total score of 29.3. Patients had a mean UPDRS II score of 18.3 and a mean PDQ-8 total score of 44.2. Detailed patient demographics and disease characteristics at baseline have been presented previously [11]; baseline values relevant to this analysis are summarized in Table 1.

Table 1 Patient demographics and disease characteristics at baseline
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Correlation of Dyskinesia with Pain

At baseline, there were moderate positive and significant correlations between UDysRS and KPPS total and fluctuation-related domain scores (r = 0.47 and 0.42, respectively; p < 0.001; Fig. 1a). Correlation of baseline UDysRS and KPPS dyskinesia item scores were weakly positive but not statistically significant (r = 0.21; p = 0.114).

Fig. 1
figure 1

KPPS score correlations. a KPPS score correlations with UDysRS total scores at baseline and week 12 CFB. CFB in b KPPS total score versus CFB in UDysRS total score, c PDQ-8 score, and d UPDRS II score at week 12. CFB change from baseline, KPPS King’s Parkinson’s Disease Pain Scale, PDQ-8 8-item Parkinson’s Disease Questionnaire, UDysRS Unified Dyskinesia Rating Scale, UPDRS II Unified Parkinson’s Disease Rating Scale part II. Shaded areas on scatterplots represent 95% confidence limits for regression line. ***p < 0.001, *p < 0.05

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At week 12, there was a strong positive and significant correlation between the change from baseline in UDysRS and KPPS total scores (r = 0.63; p < 0.001; Fig. 1a, b). At week 12, change from baseline in UDysRS score was weakly positively and significantly correlated with change in KPPS fluctuation-related domain score (r = 0.36; p = 0.011) and did not correlate with change in KPPS dyskinesia item score (r = − 0.10; p = 0.484; Fig. 1a).

Correlations of Pain, HRQoL, and ADL

At baseline, there was a moderate positive and significant correlation between KPPS total score and PDQ-8 score (r = 0.46; p < 0.001), and at week 12, there was a strong positive and significant correlation between change from baseline in KPPS total score and change in PDQ-8 score (r = 0.64; p < 0.001; Fig. 1c).

The correlation between baseline KPPS total score and UPDRS II score was weakly positive and statistically significant (r = 0.38; p = 0.003). At week 12, there was a strong positive and significant correlation between the change from baseline in KPPS total score and change in UPDRS II score (r = 0.73; p < 0.001; Fig. 1d).

Correlation of Dyskinesia with HRQoL, ADL, Current Severity of Illness, and Overall Improvement in Clinical Impression

At baseline, there were moderate positive and significant correlations between UDysRS and PDQ-8 scores (r = 0.45), UPDRS II scores (r = 0.45), and CGI-S scores (r = 0.41); all p ≤ 0.001 (Fig. 2a).

Fig. 2
figure 2

UDysRS total score correlations. a UDysRS total score correlations with PDQ-8, UPDRS II, and CGI-S/CGI-C scores at baseline and week 12 CFB. CFB in b UDysRS total score versus CFB in PDQ-8 score, c UPDRS II score, and d CGI-C score at week 12. CFB change from baseline, CGI-C Clinical Global Impression of Change, CGI-S Clinical Global Impression of Severity, PDQ-8 8-item Parkinson’s Disease Questionnaire, UDysRS Unified Dyskinesia Rating Scale, UPDRS II Unified Parkinson’s Disease Rating Scale part II. Shaded areas on scatterplots represent 95% confidence limits for regression line. ***p ≤ 0.001

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At week 12, there were moderate positive and significant correlations between UDysRS and PDQ-8 scores (r = 0.54; Fig. 2b), UPDRS II scores (r = 0.57; Fig. 2c), and CGI-C scores (r = 0.47; Fig. 2d); all p < 0.001.

Correlations of “On” Time Without Troublesome Dyskinesia with HRQoL, ADL, Current Severity of Illness, and Overall Improvement in Clinical Impression

At baseline, “On” time without troublesome dyskinesia was weakly negatively and significantly correlated with PDQ-8 score (r = − 0.32; p = 0.016) and was not correlated with UPDRS II and CGI-S scores (r = 0.01 and − 0.06, respectively; Fig. 3a).

Fig. 3
figure 3

“On” time without TSD correlations. a “On” time without TSD correlations with PDQ-8, UPDRS II, and CGI-S/CGI-C scores at baseline and week 12 CFB. CFB in b “On” time without TSD versus CFB in PDQ-8 score, c UPDRS II score, and d CGI-C score at week 12. CFB change from baseline, CGI-C Clinical Global Impression of Change, CGI-S Clinical Global Impression of Severity, PDQ-8 8-item Parkinson’s Disease Questionnaire, TSD troublesome dyskinesia, UPDRS II Unified Parkinson’s Disease Rating Scale part II. Shaded areas on scatterplots represent 95% confidence limits for regression line. ***p < 0.001, *p < 0.05

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At week 12, “On” time without troublesome dyskinesia was moderately negatively and significantly correlated with PDQ-8 score (r = − 0.50; p < 0.001; Fig. 3b), UPDRS II score (r = − 0.45; p < 0.001; Fig. 3c), and CGI-C score (r = − 0.52; p < 0.001; Fig. 3d), meaning that longer “On” times without troublesome dyskinesia were associated with improvements in HRQoL, ADL, and clinical impression.

Discussion

Findings from this post hoc analysis of data from the DYSCOVER study demonstrated that both dyskinesia and pain are associated with HRQoL, and that improvements in dyskinesia and pain correlated with improvements in HRQoL. Similarly, both dyskinesia and pain were positively associated with ADL at baseline, and improvements in dyskinesia and pain corresponded to improvements in ADL.

Results from this present analysis also expand on findings from the randomized trial and affirm that treatment-related improvements in dyskinesia and pain are positively associated with corresponding changes in HRQoL. These results are consistent with findings from a long-term observational study that showed that after 12 months of treatment with LCIG, changes in HRQoL were positively correlated with changes in non-motor symptoms and dyskinesia. The correlation with dyskinesia was weak (r = 0.23; p = 0.011), which may be due to the substantially lower burden of dyskinesia at baseline (mean [standard deviation] UDysRS score 33.7 [21.1] vs. 52.1 [11.8] in the DYSCOVER study) [19]. Furthermore, results from the GLORIA registry also support the findings that non-motor symptoms are associated with HRQoL in patients with PD treated with LCIG [20]. These findings from the aforementioned studies support our findings in the current analysis by providing additional evidence that the impact of treatment on HRQoL may extend beyond improvements solely attributed to changes in motor symptoms [19, 20].

The findings from this analysis also showed that dyskinesia was moderately positively and significantly correlated with pain and severity of illness at baseline, with stronger correlations observed at week 12 change from baseline. Similarly, at baseline, “On” time without troublesome dyskinesia showed weakly negative to no correlations with HRQoL, ADL, and severity of illness; however, at week 12, the change from baseline in “On” time without troublesome dyskinesia was moderately negatively and significantly correlated with changes in HRQoL, ADL, and clinical impression. In nearly all correlations presented here, except for correlations of UDysRS with KPPS subscale scores, stronger correlations were observed at week 12 change from baseline than at baseline.

A strength of this analysis was the use of the UDysRS to assess dyskinesia. Previous studies used PD diaries or the motor section of the UPDRS to assess dyskinesia [12, 21, 22], but these tools have limitations in effectively quantifying the full spectrum of dyskinesia symptoms [11]. The UDysRS provides a valid and reliable assessment of dyskinesia, encompassing the patient’s subjective perception of historical disability and an objective assessment of impairment [17]. The UDysRS is also particularly sensitive to change [23].

The study was limited by the post hoc design, small sample size, and short treatment duration (12 weeks), which may reduce the external validity of the results. Furthermore, although randomized, the DYSCOVER study was an open-label study, and while dyskinesia was assessed by blinded raters, a bias affecting other observed outcomes cannot be fully excluded. Lastly, this analysis indicates a positive correlation between dyskinesia, pain, and HRQoL, but it is not clear if these variables are independently related or if causal relationships exist. Further multivariate assessments exploring the relationship between dyskinesia, pain, and HRQoL are warranted. Nonetheless, results from this analysis are consistent with results from previous studies in that improvements in motor and non-motor symptoms are positively associated with HRQoL [19, 20, 24].

Conclusion

This post hoc analysis of data from the open-label DYSCOVER study demonstrated that dyskinesia and pain are both associated with HRQoL. Improvements in dyskinesia and pain due to LCIG or OMT were moderately positively and significantly correlated with improvements in HRQoL. The results of this analysis, coupled with findings reported in studies in the existing literature, highlight the importance of addressing both motor fluctuations and dyskinesia in PD, as they are closely associated with HRQoL, ADL, and overall condition.