Opicapone Improves Global Non-Motor Symptoms Burden in Parkinson’s Disease: An Open-Label Prospective Study

Patients with Parkinson’s disease (PD) can improve some non-motor symptoms (NMS) after starting treatment with opicapone. The aim of this study was to analyze the effectiveness of opicapone on global NMS burden in PD. OPEN-PD (Opicapone Effectiveness on Non-motor symptoms in Parkinson’s Disease) is a prospective open-label single-arm study conducted in 5 centers from Spain. The primary efficacy outcome was the change from baseline (V0) to the end of the observational period (6 months ± 30 days) (V2) in the Non-Motor Symptoms Scale (NMSS) total score. Different scales were used for analyzing the change in motor, NMS, quality of life (QoL), and disability. Thirty-three patients were included between JUL/2019 and JUN/2021 (age 63.3 ± 7.91; 60.6% males; 7.48 ± 4.22 years from symptoms onset). At 6 months, 30 patients completed the follow-up (90.9%). The NMSS total score was reduced by 27.3% (from 71.67 ± 37.12 at V0 to 52.1 ± 34.76 at V2; Cohen’s effect size = −0.97; p = 0.002). By domains, improvement was observed in sleep/fatigue (−40.1%; p < 0.0001), mood/apathy (−46.6%; p = 0.001), gastrointestinal symptoms (−20.7%; p = 0.029), and miscellaneous (−44.94%; p = 0.021). QoL also improved with a 18.4% reduction in the 39-item Parkinson’s Disease Quality of Life Questionnaire Summary Index (from 26.67 ± 17.61 at V0 to 21.75 ± 14.9 at V2; p = 0.001). A total of 13 adverse events in 11 patients (33.3%) were reported, 1 of which was severe (not related to opicapone). Dyskinesias and nausea were the most frequent (6.1%). Opicapone is well tolerated and improves global NMS burden and QoL in PD patients at 6 months.


Introduction
Parkinson's disease (PD), the second most common neurodegenerative disease after Alzheimer's disease, is a progressive neurodegenerative disorder causing motor and nonmotor symptoms (NMS) that result in disability, loss of patient autonomy and caregiver burden [1]. The understanding of PD has changed over recent years, with the disease currently considered to be a neurodegenerative disorder involving a diversity of pathways and neurotransmitters that may explain, in part, the wide range of NMS that patients may have such as depression, anxiety, pain, cognitive impairment, apathy, gastrointestinal, urinary or cardiovascular symptoms, fatigue, or sleep problems [2,3]. NMS are frequent, disabling, and impact negatively on the quality of life (QoL) of PD patients [4], and strategies designed to improve NMS are necessary [5]. In clinical practice, the identification of NMS by the neurologist is very important, as well as knowing how they affect the patient.

Material and Methods
OPEN-PD, Opicapone Effectiveness on Non-motor symptoms in Parkinson's Disease, is a multicenter, observational (phase IV), prospective, open-label, follow-up study conducted in 5 centers from Spain. A total of 40 PD patients were expected to be included in the study. Inclusion criteria were: (1) diagnosis of PD according to the United Kingdom Parkinson's Disease Society Brain Bank criteria [19]; (2) to be under levodopa therapy and have indication for receiving opicapone according to the neurologist criteria in his/her clinical practice; (3) NMSS total score at baseline > 40; (4) age > 30 years old; (5) voluntary participation and signed informed consent form. Exclusion criteria were: (1) to be taking opicapone at the inclusion evaluation moment or to have been taking opicapone before; (2) to be under other COMT inhibitor therapy (entacapone or tolcapone) at the inclusion evaluation moment or to have received it in the previous month; (3) any contraindication to be treated with opicapone according to product data; (4) incapacity to complete the questionnaires adequately; (5) other disabling concomitant neurological disease (stroke, severe head trauma, neurodegenerative disease, etc.); (6) other severe and disabling concomitant non-neurological disease (oncological, autoimmune, etc.); (7) expected impossibility of long-term follow-up; (8) to be participating in a clinical trial and/or other type of study. All the neurologists who participated in the study of each center were experts on PD/movement disorders.
Opicapone was administered as a once-daily 50 mg capsule. This study did not contemplate the switching of entacapone or tolcapone (COMT inhibitors) to opicapone. So, patients with PD who were being treated with another COMT inhibitor different from opicapone should take at least 1 month without taking a COMT inhibitor (entacapone and/or tolcapone) to be considered a candidate to participate in the study. During follow-up, any other medications different from opicapone should not have been modified (regimen, doses, etc.) except if the neurologist considered these changes absolutely necessary. All the changes including PD and not-PD related medications and levodopa-equivalent daily dose (LEDD) [31] of levodopa were recorded.

Data Analysis
Data were processed using SPSS 20.0 for Windows. Continuous variables were expressed as the mean ± SD or median and quartiles. Relationships between variables were evaluated using the Student's t-test, the Mann-Whitney U test, or Spearman's or Pearson's correlation coefficient as appropriate (distribution for variables was verified by one-sample Kolmogorov-Smirnov tests). NMS burden was defined as: mild (NMSS 1-20); moderate (NMSS 21-40); severe (NMSS 41-70); and very severe (NMSS > 70) [32]. The PDQ-39 was expressed as a summary index (PDQ-39SI): (score/156) × 100. Each domain of the NMSS and PDQ-39 was expressed as a percentage: (score/total score) × 100.
The primary efficacy outcome was the change from baseline (V0) to the end of the observational period (6 months; V2) in the NMSS total score. The change from V0 to V2 in NMSS domains, PDSS, AS, KPPS, VAS-PAIN, UPDRS-IV, FOGQ, PDQ-39SI, and ADLS were the secondary efficacy outcome variables. Analyses on efficacy variables were performed with the ITT data set (all subjects who receive at least one pill of opicapone and had a baseline and treatment observation for the primary efficacy outcome measure). A The safety data set consists of all subjects for whom the study device was initiated. Safety analyses was assessed by adverse events (AEs). All AEs was coded using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects with treatment emergent AEs by MedDRA system organ class and preferred term, by severity, and by relationship to study treatment as assessed by the investigator, was provided for overall subjects.

Standard Protocol Approvals, Registrations, and Patient Consents
For this study, we received approval from the Comité de Ética de la Investigación Clínica de Galicia from Spain (2017/475; 31/OCT/2017). Written informed consents from all participants in this study were obtained before the start of the study. OPEN-PD was classified by the AEMPS (Agencia Española del Medicamento y Productos Sanitarios) as a Post-authorization Prospective Follow-up study with the code DSG-OPI-2017-01.

Data Availability
The protocol and the statistical analysis plan are available on request. De-identified participant data are not available for legal and ethical reasons.

Results
A total of 33 out of 35 PD patients were included between July/2019 and June/2021 (age 63.3 ± 7.91; 60.6% males). Two patients selected finally refused to participate by their own decision. Data about sociodemographic aspects, comorbidities, antiparkinsonian drugs, and other therapies are shown in Table 1. The mean time from symptoms onset of PD was 7.48 ± 4.22 years. All patients were receiving oral levodopa, and none were under a second line therapy (pump infusion or deep brain stimulation). About two out of three patients were receiving a MAO-B inhibitor and/or a dopamine agonist and less than 10% amantadine or an anticholinergic agent. Benzodiazepines, antidepressant agents, and analgesic drugs were taken by 36.4%, 24.2%, and 21.2% of the patients, respectively. None were taking an antipsychotic agent. The mean LEDD was 820.89 ± 323.31 mg (range from 350 to 1812 mg).
A total of 13 adverse events in 11 patients (33.3%) were reported, 1 of which was severe (not related to opicapone) ( Table 3). Dyskinesias and nausea were the most fre- A total of 13 adverse events in 11 patients (33.3%) were reported, 1 of which was severe (not related to opicapone) ( Table 3). Dyskinesias and nausea were the most frequent (6.1%). Two patients discontinued due to an adverse event related to opicapone (nausea and insomnia), whereas in the third case it was a personal decision of the patient due to a lack of effect of the drug. At least possibly * related to opicapone SAEs, N 0 Patients with at least possibly related to opicapone SAEs, N (%) 0 (0) Patients with at least one AE leading to discontinuation, N (%) 2 (6.1) Patients with at least one possibly* related to opicapone AE leading to discontinuation N (%) 2 (6.1) Deaths, N (%) 0 (0) * Considered "possibly", "probably" or "definitely" related to treatment (opicapone). AE, adverse event; SAE, serious adverse event.

Discussion
The present study observed that global NMS burden (NMSS total score) improved in PD patients 6 months after starting with opicapone. Specifically, an improvement was detected in domains of the NMSS related to sleep, fatigue, mood, gastrointestinal symptoms, and pain. Moreover, the effect was significant at 2 months after starting with opicapone, and an improvement in QoL was observed as well. This is the first prospective study specifically designed for assessing the change in global NMS burden in PD patients after been treated with this drug.
NMS are frequent in PD, and their recognition is very important because of their negative impact on QoL [4,32]. In this study, PD patients had to present with severe or very severe NMS burden (NMSS total score > 40) at baseline for being included. Recently, it was observed that up to 30.5% and 44.9% of PD patients with a H&Y stage of 1 and 2, respectively, had severe or very severe NMS burden, and, importantly, patients with a lower H&Y stage may be more affected if they had a greater NMS burden than others with a higher H&Y stage [6]. Therefore, strategies designed to improve NMS are necessary [5]. In this context and considering that some NMS can be related to the deficit of other neurotransmitters different than dopamine (e.g., depression and serotonin), a key question is if NMS can improve with a drug with an only dopaminergic effect [33]. Increasing dopamine activity not only in the striatum but also in other areas of the brain could improve some NMS such as attention and executive functions, depression, anxiety, apathy, restless legs and periodic limb movements, urinary urgency, nocturia, dribbling of saliva, constipation, pain, or fatigue [33][34][35][36][37]. Specifically, some studies with first and second generation COMT inhibitors (entacapone and tolcapone) observed a benefit by the patients on some NMS [9,10,38,39], but really the evidence is scarce, possibly in part due to the fact that NMS are an emerging topic and have been much more studied in recent years. Moreover, if COMT inhibitors such as opicapone can improve ON time, non-motor fluctuations [40], NMS related to OFF episodes [41] and global NMS burden as a whole [8] could improve as well.
Opicapone is a third generation COMT inhibitor rationally designed to reduce the risk of toxicity and improve COMT inhibitory potency and peripheral tissue selectivity compared with other COMT inhibitors [42]. The efficacy and safety of opicapone in reducing OFF time in patients with PD and established motor fluctuations has been well established in three randomized, double-blind, placebo-controlled trials (BIPARK I; BIPARK II; COMFORT-PD) [14,15,43] and observational studies [11,[44][45][46]. However, the effect of opicapone on NMS is a relatively unexplored aspect [42]. In the BIPARK II study, NMS were assessed with the NMSS at different time points, including baseline, the end of the double-blind phase, and the end of the open-label phase. At the end of the double-blind period, NMSS scores slightly improved across the opicapone and placebo groups, with no significant differences between them (placebo, −5.2; opicapone 25 mg, −2.0; opicapone 50 mg, −4.9) [16]. At the 1-year open-label endpoint, a mean improvement of −4.2 in NMSS total score was still maintained [16]. However, data about domains of the NMSS and even the NMSS total score at baseline was not provided in all groups. In those patients receiving opicapone 50 mg (N = 325), the mean baseline NMSS total score was 37.9 ± 28.7. In our study, the score was very much higher (71.67 ± 37.12) due to the inclusion criteria and aim proposed, which is important because the probability of having an improvement is related to the baseline score of the scale [47]. Similar results have previously been observed in the BIPARK I study (−5.7, placebo; −2, opicapone 50 mg). In the third pivotal study of opicapone conducted in Japan, NMS were not assessed [43]. In the only other published study analyzing how NMS changed in PD patients treated with opicapone, the OPTIPARK study [11], a decrease in the NMSS total score of 6.8 ± 19.7 points (p < 0.0001) at 3 months was observed. This was a prospective, open-label, single-arm trial conducted in Germany and the United Kingdom under clinical practice conditions, and data about NMS were collected in 393 PD patients. Again, the NMSS total score at baseline was lower than in our study (44.6 ± 30.3), and the change from baseline to the visit at 3 months in the NMS burden was not the primary efficacy outcome. In this study [11], Reichmann et al. reported a significant improvement in all domains of the NMSS except in domain 4 (perceptual problems/hallucinations), but the size effect was not calculated, and it is not clear whether it can be considered clinically relevant, with a decrease in the score that varied from 13.3% (cardiovascular symptoms; -0.2 from 1.5 ± 2.38 at baseline; p = 0.0310) to 22.4% (mood/apathy; −1.5 ± 6.82 from 6.7 ± 9.8; p < 0.0001). In our study, the greatest improvement was observed in the mood/apathy and sleep/fatigue domains, both with large effect. In the BIPARK II study, a significant signal was seen for the sleep/fatigue domain where the 50 mg dose reduced the NMSS sleep/fatigue score by −1.2 points versus −0.5 points with a placebo [42]. The small sample size of our cohort could explain why the change in sleep (PDSS) and pain (KPPS) scales was not significant. The PDSS was used in the BIPARK II study, but differences were not detected compared to a placebo [16]. In this line of research, studies such as OASIS (OpicApone Sleep dISorder; EudraCT number 2020-001176-15) and OCEAN (the OpiCapone Effect on motor fluctuations and pAiN; EudraCT number 2020-001175-32) are currently underway to evaluate the effect of opicapone 50 mg on sleep and pain, respectively. On the other hand, our study is the first prospective one exploring the effect of opicapone on motivation/apathy using a specific validated scale, but we did not find differences. A recent publication that reviewed data of small retrospective series of PD patients treated with opicapone in Spain suggests a possible positive effect of opicapone on NMS after 6 to 12 months, especially on sleep [48]. However, and in agreement with our findings, the frequency of apathy in 60 PD patients treated with opicapone in real clinical practice did not change at 6 months (32%) and 12 months (33%) compared to the baseline visit (32%) [48]. More studies designed to evaluate the effect of opicapone over NMS are really needed.
In addition to NMS, we observed in our study a trend of significant improvement in motor complications (UPDRS-IV; p = 0.083) and a significant improvement in gait problems (p = 0.018). Although the frequency of patients reporting FOG was similar before and after treatment with opicapone, gait problems as a whole may improve due to motor signs improvement and OFF time reduction [49]. Only two small studies looked at the effects of COMT inhibitors on gait parameters, providing support for tolcapone as an effective addon to levodopa to prolong beneficial effects on gait speed [50,51]. In previously published studies of opicapone, its effect on gait was not analyzed. However, as we detected here, QoL improved significantly in PD patients treated with opicapone in real clinical practice [11]. We used the PDQ-39 and observed improvement in emotional well-being, stigmatization, and pain and discomfort. On the contrary, in the OPTIPARK study the brief version (PDQ-8) was used, and data about domains was not provided in the publication [11]. Contrary to this study, we did not find improvement in the autonomy for ADL.
Opicapone was not only effective but also safe and well-tolerated, with a very high drug maintenance rate at 6 months, above 90%. The rate was 79.4% (393/495) at 3 months and 85.3% (81/95) at 6 months for all the cohort and for the United Kingdom subgroup only, respectively, from the real clinical practice OPTIPARK cohort [11], and 92.2% (107/116) and 83.1% (128/154) in the double-blind phase of BIPARK I and BIPAK II studies, respectively [14,15]. The results about adverse events are in line with other studies [11,[13][14][15][16][17][18][43][44][45][46], even with a lower percentage of events reported. Dyskinesia, as in some studies, was the most frequent adverse event in our study. The European public assessment report (EPAR) for opicapone states that dyskinesias were reported in more than 10% of participants receiving opicapone, in which case it may be necessary to reduce the levodopa dose within the first days to first weeks after starting opicapone to prevent severe dyskinesias [44]. This good tolerability of the drug was accompanied by an improvement according to the PGIC in almost 60% of the cases, in line with other reports [43,48].
Our study has some important limitations. The most important one is related to the study design itself, and since there is not a comparative arm with placebo, the results should be interpreted with caution. Second, the sample size is small, and it is possible that the changes observed in some variables are not significant due to this. In fact, due to different problems (i.e., administrative, commercial distribution of the drug in Spain, COVID-19 pandemic), the study was closed before reaching the initially planned sample size (N = 40). Third, the effect of opicapone on NMS was analyzed in PD patients with a severe or very severe NMS burden (NMSS total score > 40); therefore, the results cannot be extrapolated to patients with a mild or moderate NMS burden (NMSS total score ≤ 40). Fourth, mood was not assessed with a specific scale. On the other hand, this is the first study designed to assess the effect of opicapone on NMS burden in PD patients and the first one in which changes in some NMS such as pain, apathy, or sleep have been exhaustively analyzed. Despite some limitations, the results are novel and of great interest because there is a lack of knowledge about what benefits can opicapone produce over many symptoms in PD patients.

Conclusions
In conclusion, opicapone is well tolerated and improves global NMS burden and QoL in PD patients. Well-designed studies are necessary to analyze in detail the possible beneficial effect of opicapone on NMS in patients with PD.

Funding:
The present study is a study promoted by an independent researcher (promoter: Diego Santos García). Bial Spain has financed its expenses.

Institutional Review Board Statement:
The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Comité de Ética de la Investigación Clínica de Galicia from Spain (2017/475; 31/OCT/2017).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The protocol and the statistical analysis plan are available on request. Deidentified participant data are not available for legal and ethical reasons.