Opicapone for the Treatment of Nocturnal Hypokinesia in Patients With Parkinson’s Disease: An Open-Label Pilot Clinical Trial

Abstract

Nocturnal hypokinesia (NH) is common in patients with moderate-stage Parkinson’s disease (PD). This open-label, single-arm pilot study aimed to assess the effect of bedtime opicapone administration on NH and to evaluate the clinical utility of the Nocturnal Hypokinesia Questionnaire (NHQ). The primary endpoint was the change in the NHQ score from baseline to week 6. Fifteen patients were included. The mean change in the NHQ score after the 6-week treatment was -0.9 points (95% confidence interval [CI]: -2.4, 0.5; p=0.187), which was not statistically significant. However, NHQ domain 2 (getting out of bed) significantly improved, with a mean change of -0.3 points (95% CI: -0.6, -0.1; p=0.025). The administration of opicapone in patients with PD and NH did not result in a significant improvement in NH, although it was associated with an improvement in the single domain of getting out of bed. Further studies are needed to establish the efficacy of opicapone for treating NH.

INTRODUCTION

Nocturnal hypokinesia (NH) is defined as a reduced ability to perform sufficient axial rotation and/or trunk flexion to turn in bed or get out of bed, and it occurs in approximately 54%–70% of patients with Parkinson’s disease (PD) [1]. A major challenge in the evaluation and management of NH is that it manifests exclusively at night. Clinical interviews conducted while patients are awake do not provide standardized results, and although PD diaries are practical and useful, they are not specific for assessing NH [1]. Objective evaluations during sleep using polysomnography or electronic devices are not easily applicable in routine practice, are not specifically designed for NH assessment, and lack standardization [1]. To overcome these limitations, the Nocturnal Hypokinesia Questionnaire (NHQ) was introduced to specifically assess NH [2,3].

Opicapone is a third-generation catechol-O-methyltransferase (COMT) inhibitor that has been proven effective in managing wearing-off symptoms in patients with PD [4,5]. Opicapone has a prolonged duration of action, allowing for once-daily dosing, and has significant advantages over previous COMT inhibitors. Given these pharmacological properties, opicapone is expected to improve nocturnal symptoms in patients with PD. A recent post hoc analysis of PD diaries from the BIPARK-1 and BIPARK-2 studies demonstrated that opicapone significantly reduced “off” time during the nighttime sleep period [6]. Additionally, the OASIS trial reported that patients with PD treated with opicapone showed significant improvements in sleep disturbances [7]. However, to date, no study has evaluated the effect of opicapone on NH using an NH-specific questionnaire.

Therefore, this study aimed to assess the effect of bedtime opicapone administration on NH using the Korean version of the NHQ (NHQ-K) and to evaluate the clinical utility of the NHQ-K in patients with PD.

METHODS

Study design

This study was an open-label, single-arm, pilot clinical trial in patients with PD and NH from June 2023 to January 2025. The study consisted of a screening visit (V0), a 6-week treatment period (V1 and V2), and a 4-week safety follow-up (Supplementary Table 1). The study design was approved by the Institutional Review Board of Chungnam National University Sejong Hospital (No. 2022-07-009-001). Informed consent was obtained from all participants at the time of recruitment. This study was registered with the Clinical Research Information Service of South Korea (No. KCT0010294).

Participants and interventions

The detailed inclusion criteria for patients are described in the Supplementary Material. All participants received 50 mg of opicapone once daily at bedtime for 6 weeks. Other antiparkinsonian medications were maintained at stable doses throughout the study period. The concomitant use of other sleep-related medications (e.g., sedative-hypnotics and antidepressants) was permitted if they had already been in use, but the initiation of new medications during the study was prohibited.

Clinical evaluation

The primary endpoint was the change in the NHQ-K score from baseline to week 6 (Supplementary Table 1). Secondary efficacy outcomes included various motor and nonmotor rating scale scores. A detailed list of secondary outcomes is provided in the Supplementary Material. Safety and tolerability were evaluated by assessing treatment-emergent adverse events (TEAEs).

Statistical analysis

Statistical analysis of the efficacy was performed using the full analysis set. Missing data due to patient discontinuation were imputed using a baseline observation-carried forward approach, with the assumption of no change from baseline. Detailed sample size calculations and statistical methods are provided in the Supplementary Material.

RESULTS

Baseline characteristics

Fifteen patients were enrolled in the study, and 14 patients completed the study. One patient discontinued the study because of a TEAE (Supplementary Figure 1). Although we initially planned to recruit 30 participants, we faced difficulties in enrolling eligible patients during the study period. Therefore, the trial ended early once 15 participants had been enrolled. At baseline, the mean age of the participants was 67.7 years, and the mean disease duration was 7.9 years (Supplementary Table 2). The mean initial NHQ-K Part I score was 4.5 points, indicating a moderate level of severity of the patients’ subjective symptoms. The Movement Disorder Society-Sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part IV was assessed only in patients who exhibited dyskinesias or motor fluctuations during the daytime. A total of 10 patients were evaluated, among whom 9 had motor fluctuations and 5 had dyskinesias.

Efficacy

The mean change in the total NHQ-K Part I patient score was -0.9 (95% confidence interval [CI]: -2.4 to 0.5; p=0.187), which was not statistically significant (Figure 1A). However, in the subdomain analyses, the mean change in NHQ-K Part I Domain 3 (getting out of bed) significantly improved by -0.3 (95% CI: -0.6, -0.1; p=0.025) (Figure 1B). No significant changes were observed in the scores of the other domains of the NHQ-K Part I or II (Figure 1B and Supplementary Table 3). There were no significant changes in the secondary outcomes (Table 1 and Supplementary Table 4 for detailed subscores of the Non-Motor Symptoms Scale [NMSS] and Scales for Outcomes in Parkinson’s Disease-Sleep [SCOPA-Sleep]).

Figure 1.

Changes in the mean NHQ total score (A) and score by domain (B) from baseline to week 6 in patients with PD. Bars represent the mean; error bars indicate standard deviation. NHQ, Nocturnal Hypokinesia Questionnaire; PD, Parkinson’s disease.

Table 1.

The mean changes in motor and non-motor scales after 6-week opicapone treatment

Item	Baseline	6 weeks	Difference	95% CI	p value
	Mean±SD	Mean±SD	Mean±SE
MDS-UPDRS Part I	11.5±6.0	11.5±6.1	-0.1±1.0	-2.2–2.1	0.948
MDS-UPDRS Part II	10.5±4.5	10.3±5.2	-0.3±0.9	-2.3–1.8	0.782
MDS-UPDRS Part III	26.5±9.3	24.0±12.0	-2.5±2.8	-8.5–3.5	0.392
MDS-UPDRS Part IV (n=10)	4.0±1.9	3.6±1.8	-0.4±0.4	-1.4–0.6	0.373
NMSS	59.2±44.7	53.6±44.0	-5.6±0.1	-15.8–4.6	0.258
SCOPA-AUT	15.5±7.4	14.5±9.6	-0.9±0.2	-4.1–2.3	0.541
QUIP	0.3±0.5	0.5±0.5	0.1±0.4	-0.2–0.4	0.317*
SCOPA-Sleep Sum score (B-D)	13.1±7.7	11.9±7.6	-1.1±0.2	-6.0–3.7	0.623
PDSS-2	15.8±8.6	14.5±9.7	-1.3±1.5	-4.5–1.8	0.384
KESS	6.7±5.1	5.7±4.1	-0.9±0.2	-3.6–1.7	0.459
RBDSQ	3.4±2.8	2.9±2.4	-0.5±0.3	-1.8–0.9	0.256*
NFOG-Q	5.9±8.5	4.5±8.1	-1.3±0.3	-4.5–1.8	0.237*
PDQ-39	39.7±29.0	36.3±30.1	-3.3±3.9	-11.6–4.9	0.402

^*the Wilcoxon Signed Rank Test was used for the statistical analysis.

CI, confidence interval; KESS, Korean Epworth Sleepiness Scale; MDS-UPDRS, Movement Disorder Society-Sponsored revision of the Unified Parkinson’s Disease Rating Scale; NFOG-Q, New Freezing of Gait Questionnaire; NMSS, Non-Motor Symptoms Scale; PDSS-2, Parkinson’s Disease Sleep Scale-2; PDQ-39, Parkinson’s Disease Questionnaire-39; QUIP, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease; RBDSQ, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire; SCOPA-AUT, Scales for Outcomes in Parkinson’s Disease-Autonomic Dysfunction; SCOPA-Sleep, Scales for Outcomes in Parkinson’s Disease-Sleep; SD, standard deviation; SE, standard error.

Safety

Opicapone treatment was generally well tolerated (Supplementary Table 5). One patient with a serious TEAE (6.7%) was hospitalized because of worsening congestive heart failure during the treatment period. The patient had a history of severe mitral and aortic valve stenoses and underwent valve repair surgeries 4 years prior to participation. He also had atrial fibrillation and was taking warfarin. The patient experienced a transient decrease in ejection fraction with global hypokinesia, which improved after conservative management. Although this event was unlikely to be related to the opicapone treatment, the medication was discontinued.

Correlations of the NHQ-K score with other motor and nonmotor rating scale scores

The NHQ-K Part I total score was positively correlated with the MDS-UPDRS Part II score (ρ=0.543; p=0.036) (Supplementary Table 6), New Freezing of Gait Questionnaire (NFOG-Q) score (ρ=0.566; p=0.028), and Parkinson’s Disease Questionnaire-39 (PDQ-39) score (ρ=0.548; p=0.035). The NHQ-K Part I Domain 2 (getting out of bed) score was positively correlated with the levodopa equivalent daily dose (ρ=0.619; p=0.014), MDS-UPDRS Part II score (ρ=0.752; p=0.001), Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease (QUIP) score (ρ=0.580; p=0.023), and PDQ-39 score (ρ=0.550; p=0.034).

DISCUSSION

These results provide important insights into the improvement in NH symptoms following opicapone treatment. Specifically, symptoms captured by each NHQ domain may be broadly grouped or overlooked during general assessments or clinical interviews. In a recent study utilizing sleep diaries, opicapone treatment resulted in a significant improvement in “off” periods during nighttime sleep [6]. However, whether these improvements were directly related to general nighttime parkinsonian symptoms or to specific NH-related symptoms such as turning in bed or getting out of bed remains unclear. By precisely separating and assessing symptoms using the NHQ, our findings suggest that the improvement in NH with opicapone treatment is associated mainly with difficulties in getting out of bed.

This study also highlighted the advantages of the NHQ over other sleep-related questionnaires, such as the SCOPA-Sleep, Parkinson’s Disease Sleep Scale-2 (PDSS-2), Korean Epworth Sleepiness Scale (KESS), Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ), which were used as secondary outcomes. These general sleep questionnaires do not include NH-specific questions except Item 9 of the PDSS-2—“Did you feel uncomfortable at night because you were unable to turn around in bed or move due to immobility?” [8] This may partially explain why changes in these secondary outcomes did not reach statistical significance in the present study. Interestingly, in the recent OASIS trial, which has a similar design to the present study, the PDSS-2 score significantly improved by -7.9 points, unlike the findings in our study [7]. One important factor contributing to this discrepancy may be the differences in the study objectives, namely, whether the focus was on NH specifically or on overall sleep disturbance. These differences likely affected how the study objectives were explained to patients, which in turn may have influenced their responses to questionnaires through recall bias or varying degrees of placebo response [9].

In this study, various assessment scales for PD were employed as secondary outcomes, allowing us to explore their correlations with the NHQ, which has not been reported previously. The NHQ Part I score was positively correlated with the MDS-UPDRS Part II, PDQ-39, and NFOG-Q scores. These findings suggest that NH may be associated with patients’ overall mobility, impairment in activities of daily living, and quality of life. In particular, the PDQ-39 score also showed a positive correlation in a previous study, further indicating that NH may be closely linked to quality of life [3]. Further research is necessary to clarify the relationship between NH and motor symptoms in patients with PD.

Limitations

Caution is needed when interpreting the results because of the open-label, single-arm design of this study. Furthermore, the small sample size limits the generalizability of the results. Moreover, the NHQ Part II (caregiver section) could be evaluated in only five patients, which poses considerable limitations in interpreting the results. Finally, although the use of a sleep diary could have provided a more detailed understanding of the characteristics of NH and its relationship with the NHQ, it could not be implemented because of the practical constraints of the study.

Conclusion

The administration of 50 mg of opicapone in patients with PD and NH did not result in a significant improvement in NH, although it was associated with an improvement in the single domain of getting out of bed. These results provide additional evidence supporting the potential utility of opicapone in managing sleep-related symptoms in patients with PD [6,7]. Further studies are needed to establish the efficacy of opicapone for NH in patients with PD.

Supplementary Materials

The Data Supplement is available with this article at https://doi.org/10.14802/jmd.25250.

Supplementary Table 1.

Study visits and evaluations

Supplementary Table 2.

Baseline characteristics

Supplementary Table 3.

The mean changes in the NHQ-K Part I and Part II scores after 6-week opicapone treatment

Supplementary Table 4.

Detailed subscores of NMSS and SCOPA-Sleep

Supplementary Table 5.

Summary of TEAEs

Supplementary Table 6.

Correlations of baseline clinical characteristics with NHQ-K Part I patient score

Supplementary Figure 1.

Correlations of baseline clinical characteristics with NHQ-K Part I patient score