GRAPHICAL ABSTRACT

INTRODUCTION

Motor fluctuations are a frequent complication of levodopa treatment in Parkinson’s disease (PD) patients, with a reported prevalence of 40% at 4–6 years and 80% at 10 years of disease [1]. A troublesome symptoms in PD patients with motor fluctuations is a delayed effect of levodopa after dose intake, known as delayed ON [2,3]. Although parkinsonian symptoms usually begin to improve 10 to 30 min after levodopa medication is administered, in patients with delayed ON the improvement of symptoms is delayed sometimes for hours. This phenomenon is associated with delayed absorption of levodopa, as both the disease (PD) and antiparkinsonian drugs contribute to delayed gastric emptying [4,5].

To improve delayed ON, increasing the dose of levodopa or improving its pharmacokinetics is often necessary [5,6] Nonpharmacological interventions such as dietary manipulations (taking medications before meals on an empty stomach, avoiding protein-containing meals, or avoiding foods that delay gastric emptying), relieving constipation, and exercising are recommended [6]. However, delayed ON is not easily overcome by one approach, and multiple strategies are often needed. However, despite these strategies there is no improvement in many cases. Delaying ON at the early morning dose, which is administered under overnight fasting conditions, may be even more challenging. Helicobacter pylori (H. pylori) infection is thought to affect the time-to-ON and plasma levodopa T_max and C_max [7,8]. Eradication of H. pylori was shown to improve these pharmacokinetic parameters of levodopa, resulting in improved time-to-ON in affected patients [8,9]. However, there is still one caveat: eradication of H. pylori is often practically intolerable for PD patients with multiple daily medications and comorbid dyspepsia symptoms.

A levodopa-benserazide dispersible formulation (DSP) was developed to be easily dissolved in a small amount of water to facilitate drug administration [8]. Pharmacokinetic studies have shown that DSP has a shorter levodopa T_max than the regular formulation, resulting in faster absorption [10,11]. In several openlabel studies, the latency to “ON” was faster with DSP than with regular tablets, whereas the quality and “ON” duration were similar for both formulations [11,12]. Previous studies have evaluated the efficacy of DSP in reversing afternoon “OFF” [12], and there is only a simple observation study for early morning akinesia [13]. However, no study has compared the efficacy of DSP with that of the regular formulation on delayed “ON” in the morning. Therefore, the aim of this study was to demonstrate the efficacy of DSP on delayed ON to the first-morning dose compared with regular formulations in PD patients with motor fluctuations and to further investigate whether the efficacy is affected by an individual’s H. pylori infection status.

MATERIALS & METHODS

Study subjects

The trial protocol was registered at ClinicalTrials.gov (NCT02769793). Study participants were recruited from two referral hospitals in Seoul, South Korea, between August 2015 and August 2018. The inclusion criteria were a diagnosis of PD (according to the UK PD Brain Bank diagnostic criteria [14]) and stable antiparkinsonian medication use for at least 2 weeks. The patients had to be aged between 31 and 80 years and confirmed to have delayed “ON” (defined as >40 minutes before reaching the “ON” state or no “ON” after the first-morning dose, which appeared at least once a week). Antiparkinsonian medications, except the investigational drugs, were kept unchanged during the trial, and any prokinetics were not allowed during the trial. We excluded patients from this study if they had cognitive impairment with a Mini-Mental State Examination score <24, contraindications to blood sampling, a history of hypersensitivity or adverse events related to investigational drug use, the use of nonselective monoamine oxidase inhibitors, or gastrointestinal diseases, including active peptic ulcers, gastroenteritis, gastrointestinal tumors, etc. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (IRB No. 2016-2015-52) and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all the patients included in the study.

Randomization

After enrollment, randomization was performed at the baseline visit according to a predesigned randomization table by a consultant biomedical statistician (S.O.) at Seoul National University Boramae Medical Center via an unstratified permuted block design [15].

Sample size estimation

We estimated the sample size presuming a 10-minute reduction in the time-to-ON for the first-morning dose. The required sample size was 17 for each arm with α=0.05 and 80% power. Assuming a drop-out rate of 15%, the final sample size per group was set to 20.

Procedures

After enrollment, the participants were randomized 1:1 to either treatment group: one group was first treated with levodopa/benserazide 100/25 mg DSP tablets followed by levodopa/benserazide 100/25 mg regular tablets, and the other group was first treated with regular tablets followed by DSP. The investigational drugs were taken together with the participants’ usual first-morning dose every day for 4 weeks, while keeping other antiparkinsonian regimens unchanged. Both groups had a one-week wash-out period between the two treatment phases. At baseline, we obtained demographic and clinical information, including PD duration, daily levodopa dose, and levodopa equivalent daily dose. Outcome measure evaluation and adverse event monitoring were performed at baseline, four, and nine weeks after the intervention, and during any unscheduled visits prompted by adverse events or other patient needs.

Outcome measures

Specialized diary for time-to-ON

The participants kept a specialized diary for three consecutive days before each scheduled visit (Supplementary Figure 1 in the online-only Data Supplement). This diary was recorded every 10 minutes for 90 minutes from the first morning dose intake. Diaries were used to record the onset time of the “ON” state, but in the case of no “ON” until 90 minutes, patients were instructed to keep recording their time-to-ON for an extra 150 minutes. If no “ON” was observed until 240 minutes, the time-to-ON was recorded as 240 minutes.

Parkinsonian symptoms and quality of life

We assessed the effects of the study medications on parkinsonian motor symptoms via the Unified Parkinson’s Disease Rating Scale (UPDRS) [16] and Hoehn and Yahr (H&Y) stages in the “ON” state at each of the scheduled visits. For dyskinesia symptoms, we used the Unified Dyskinesia Rating Scale (UDysRS) [17] Part III and Part IV, which are related to the objective evaluation of dyskinesia disability and consist of an intensity and disability scale. PD-related quality of life (QoL) was assessed via the Korean Version 39-item Parkinson’s Disease Questionnaire (K-PDQ39), which consists of eight domains with scores ranging from 0 to 100 (worse PD-related QoL with higher scores) [18].

Primary and secondary outcomes

The primary outcome was the change in time-to-ON (average data for three consecutive days before the 4th and 9th weeks). The secondary outcomes were changes in the UPDRS and UDysRS scores, K-PDQ39 scores, and patient global impression of change (PGI-C) scores.

Serological tests for H. pylori

Serum samples were collected from 3 mL of venous blood collected from each participant. H. pylori immunoglobulin G antibodies were detected via an enzyme-linked immunosorbent assay as previously described [19]. The serology was determined to be positive if the antibody titers were ≥8 arbitrary units (AU)/mL and negative if the antibody titers were <8 AU/mL [20].

Statistical analysis

For the comparison of clinical variables between the two groups, we used an independent two-sample t test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. The phase effect of each medication was corrected via repeated-measures analysis of variance. Multivariate analysis was performed to confirm the factors affecting time-to-ON. Intention‒to‒treat analysis was adopted for changes from baseline after either treatment, whereas per-protocol analysis was adopted for comparisons of outcomes between the two treatments. A linear mixed model (LMM) was used to analyze the primary and secondary endpoints between the two treatments, adjusting for baseline values (age, sex, PD duration, levodopa equivalent dose [LED], and baseline UPDRS), study phase, and treatment sequence. The LMM accounts for missing data under the missing-at-random assumption and adjusts for baseline differences by including baseline scores as covariates, ensuring unbiased and efficient estimation of treatment effects [21,22]. Statistical analyses were performed via SPSS version 25.0 (IBM Corp.), with the significance level set at 0.05.

RESULTS

Baseline characteristics of the participants

We screened 40 participants who were randomly allocated to either the DSP-first group or the regular-first group. During the interventions, nine participants dropped out (Figure 1), and 31 participants completed the trial.

There were no group differences in age or sex distribution, PD duration, H&Y stages, antiparkinsonian medication doses, UPDRS scores, UDysRS scores, or K-PDQ39 indices (Table 1). In addition, there was no difference in the baseline time-to-ON between the two groups. At baseline, LED did not differ between the two treatment groups, although LED was a significant contributor to the time-to-ON (p=0.014, multiple linear regression) in the total study population.

Efficacy: primary outcomes

After the 4th and 9th weeks of intervention, the time-to-ON was significantly shorter in both the DSP and regular treatment groups than at baseline (34.72 minutes, p<0.001 and 23.81 minutes, p=0.005, respectively) (Table 2). When we analyzed the outcomes of the two medications considering the potential phase effect, the DSP tablet shortened the time-to-ON by 11.72 minutes (p=0.014), which was greater than that of the regular tablet (Figure 2). No phase effects were observed (p=0.594).

Efficacy: secondary outcomes

The secondary outcomes are presented in Table 3. Compared with that at baseline, the UPDRS Part III score was improved for both medications (-3.08±7.23, p=0.022 and -1.89±4.76, p=0.035, respectively), and the total UPDRS score was improved for both medications compared with that at baseline but not significantly (-3.23±9.85, p=0.073 and -2.34 ± 7.56, p=0.095, respectively). However, there were no significant differences in the UPDRS score changes between the two medications (all UPDRS scores; p>0.05).

The UDysRS score tended to increase with both medications, but there were no significant differences from baseline (1.25± 4.73, p=0.145 and 1.18±3.55, p=0.074) or between the two medications (p=0.902). K-PDQ39 was not significantly changed by either medication (p=0.937). On the PGI-C scale (Supplementary Figure 2 in the online-only Data Supplement), 21 (67.7%) participants reported improvement with DSP tablets and 18 (58.1%) with regular tablets, whereas 3 (9.7%) participants reported worsening with DSP tablets and 9 (29.0%) with regular tablets (no significant difference between the two tablets, p=0.229).

Outcomes and H. pylori status

Blood tests for H. pylori status were performed on 39 participants, excluding one individual due to a blood sample issue. In total, 30 (76.9%) participants contracted H. pylori infections. There were no significant differences in any baseline characteristics, including time-to-ON, between the H. pylori-positive and H. pylori-negative groups (Supplementary Table 1 in the online-only Data Supplement). A favorable response in time-to-ON to DSP medication over the regular tablet was demonstrated in both H. pylori groups (positive group, DSP: -26.7 minutes vs. regular: -18.3 minutes; negative group, DSP: -45.0 minutes vs. regular: -29.1 minutes) (Table 4). The amount of change in shortening time-to-ON by adding levodopa/benserazide tablets tended to be greater in H. pylori-negative patients than in H. pylori-positive patients, although we could not demonstrate a significant difference owing to the small sample sizes. There were no significant differences in the UPDRS motor or dyskinesia score changes between the H. pylori-positive and H. pylori-negative groups. However, UDysRS scores after DSP medication in H. pylori-positive patients tended to increase, whereas those in H. pylori-negative patients tended to decrease (Table 4).

Adverse events

The incidence of adverse drug reactions was 7.5% (3/40) for the DSP tablet and 12.5% (5/40) for the regular tablet during both phases (p=0.456). Only one patient had aggravated dyskinesia on DSP, three patients had aggravated dyskinesia on the regular tablet, and two of the three patients dropped out due to dyskinesia (Supplementary Table 2 in the online-only Data Supplement). No serious adverse events were reported throughout the trial.

DISCUSSION

This multicenter, crossover, randomized trial showed that, compared with regular formulations, levodopa/benserazide DSP tablets could improve early morning delayed ON in patients with PD with motor fluctuations. There was no exacerbation of levodopa-induced dyskinesia by the addition of DSP, while the UPDRS Part III and total scores improved simultaneously.

DSP tablets of levodopa/benserazide have several pharmacokinetic advantages, such as rapid absorption and short latency to onset. However, there have been concerns about the possibility of a shortened duration of the levodopa effect and increased peak dose complications. In one study [9], the maintenance period of levodopa concentration was found to be comparable between DSP and regular formulations, and there was no difference in the “ON” duration reported by patients. The peak levodopa concentration was not much greater with DSP than with the regular formulation, and dyskinesia was not aggravated by the DSP formulation. Although we did not assess changes in “ON” duration during the study, the PGI-C did not significantly differ between the two tablet groups overall. However, a detailed comparison of the PGI-C results revealed that 67.7% of the subjects reported improvement with the DSP formulation, whereas 58.1% reported improvement with the regular formulation. Conversely, 9.7% of the subjects reported worsening on the DSP formulation, whereas 29.0% reported worsening on the regular formula. These findings suggest that “ON” duration can be similarly maintained by adding both DSP and regular tablets and that the quality of “ON” may also be similar. Notably, fewer subjects reported worsening after taking the DSP tablet. Moreover, dyskinesia did not increase with the addition of DSP to the first-morning dose in patients with delayed ON.

Another levodopa regimen is available as a liquid formulation, consisting of a solution composed of levodopa, carbidopa, and ascorbic acid (vitamin C) (LCAS). This formulation involves the preparation of a solution by dissolving levodopa/carbidopa tablets in water with ascorbic acid overnight, followed by administering the solution to patients as needed, typically at intervals of 1–2 hours [23]. This method leads to a shorter time to peak plasma levodopa levels and improves motor complications. Previous research has demonstrated that this liquid form of levodopa reduces off periods, does not exacerbate dyskinesia, and enhances the quality of “ON” time [24]. However, a long-term follow-up study for 2 years reported that only 14 out of 38 patients maintained LCAS for more than 1 year, mostly due to poor drug adherence [25]. Frequent dosing and time-consuming preparation for patients and caregivers were the major reasons for the discontinuation of therapy. The current study revealed an advantage of the DSP formulation in patients suffering from “OFFs” in the morning and delayed on to the first morning dose. Compared with LCAS, the DSP tablet offers the advantage of easier solution preparation, although the rationale of the DSP tablet and LCAS regimens shares a common principle in the pharmacokinetics of levodopa absorption. Our study results support that the DSP regimen can be utilized in specific situations to induce short-term immediate levodopa effects where patients experience delayed “ON” or failure to “ON” to regular medications.

Delayed gastric emptying and decreased levodopa absorption can contribute to delayed ON in patients with PD [26]. H. pylori infection is one factor that can affect these processes. Previous studies have shown that H. pylori-infected patients have longer times to “ON” and shorter “ON” durations than noninfected patients do [5,6]. H. pylori eradication improved both parameters in infected patients [6]. Another study revealed that the area under the plasma levodopa concentration‒time curve and C_max of levodopa could increase by more than 50% after H. pylori eradication [7]. In the present study, there was no difference in baseline time-to-ON between the H. pylori-positive and H. pylori-negative groups, but we observed that the shortening of time-to-ON by the addition of DSP or regular tablets tended to be more pronounced in H. pylori-negative patients than in H. pylori-positive patients. These data support the hypothesis that H. pylori infection interferes with levodopa absorption and the clinical response. Nevertheless, the benefit of DSP over regular tablets was demonstrated in both H. pylori-positive and H. pylori-negative patients, which emphasizes the usefulness of DSP in controlling delayed ON regardless of H. pylori positivity. Notably, changes in the dyskinesia score with the addition of DSP were intriguing in our patients. The dyskinesia score tended to worsen in H. pylori-positive patients but tended to mildly improve in H. pylori-negative patients, although there was no significant difference between the two groups. This finding suggests the possibility of a divergent effect of DSP on diphasic dyskinesia caused by H. pylori infection. However, further studies with large sample sizes are needed to address this issue.

Although we report here several interesting findings, our results should be interpreted with caution. First, because this was an open-label, crossover trial, a double-blind, double-dummy trial is worth conducting. Second, because the plasma levodopa level was not checked, we could only assess the clinical efficacy but not the pharmacokinetic parameter changes. Finally, this trial focused on the time-to-ON in the morning, but a comprehensive evaluation of the quality of the “ON” state during the entire day needs to be conducted in the future.

In conclusion, this study is the first randomized trial showing that a levodopa dispersible formulation can shorten the time-to-ON at the first-morning dose in PD patients with a delayed ON phenomenon more efficiently than can regular levodopa formulations.

Supplementary Materials

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This study was supported by Handok Inc., Seoul, Republic of Korea. The sponsor had no role in the study design, data collection, analysis, decision to publish, or manuscript preparation.

Acknowledgments

We thank to Prof. Cheol Min Shin (Division of Gastroenterology, Internal Medicine Department, Seoul National University Bundang Hospital) for providing valuable comments in study design and interpretation of the data.

Author Contributions

Conceptualization: Jee-Young Lee, Jin Whan Cho. Data curation: Jee-Young Lee, Jin Whan Cho, Sohee Oh, Hee Jin Chang. Formal analysis: Jee-Young Lee, Sohee Oh, Hee Jin Chang. Funding acquisition: Jee-Young Lee, Jin Whan Cho. Investigation: Jee-Young Lee, Jin Whan Cho, Jongkyu Park, Chaewon Shin, Ji Won Kim, Sohee Oh. Methodology: Jee-Young Lee, Jin Whan Cho, Jongkyu Park, Chaewon Shin, Ji Won Kim, Sohee Oh. Project administration: Jee-Young Lee, Jin Whan Cho. Resources: Jee-Young Lee, Jin Whan Cho, Jongkyu Park, Chaewon Shin. Supervision: Jee-Young Lee, Jin Whan Cho. Validation: Jee-Young Lee, Sohee Oh, Hee Jin Chang. Visualization: Jee-Young Lee, Hee Jin Chang. Writing—original draft: Hee Jin Chang, Jee-Young Lee. Writing—review & editing: Hee Jin Chang, Jee-Young Lee, Jin Whan Cho, Jongkyu Park, Chaewon Shin.

Figure 1.

Flowchart of the study subjects. A total of 40 participants were screened and randomized at a 1:1 ratio to the dispersible-first group or the regular-first group. Among them, 14 participants in the dispersible-first group and 18 participants in the regular-first group completed the first 4-week parallel intervention. 13 participants in the dispersible-first group and 18 participants in the regular-first group completed all the study visits.

Figure 2.

Changes in time-to-ON after each investigational drug treatment. The dark circles represent the dispersible-first group, and the blank squares represent the regular-first group. Each data point represents the change from baseline and the corresponding p value from the t test. The time-to-ON after the first morning dose was significantly lower with the dispersible tablet than with the regular tablet (-34.72 vs. -23.81 minutes, p=0.014). DSP, dispersible formulation.

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