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ORIGINAL ARTICLE
Year : 2017  |  Volume : 65  |  Issue : 4  |  Page : 746-751

Levodopa dose maintenance or reduction in patients with Parkinson's disease transitioning to levodopa/carbidopa/entacapone


1 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
2 Department of Neurology, Yonsei University College of Medicine, Seoul, Korea
3 Department of Neurology, Korea University College of Medicine at Guro Hospital, Seoul, Korea
4 Department of Neurology, Seoul National University, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
5 Department of Neurology, Sanggye Paik Hospital, Inje University, Seoul, Korea

Date of Web Publication5-Jul-2017

Correspondence Address:
Jin W Cho
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
Korea
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/neuroindia.NI_597_16

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 » Abstract 


Background: Levodopa bioavailability is enhanced by adding entacapone. However, the optimal dose of levodopa while transitioning to levodopa/carbidopa/entacapone (LCE) in Parkinson's disease (PD) during the wearing-off period is unclear.
Aims: The relative therapeutic efficacy and safety of different doses of levodopa were assessed when transitioning to the LCE combination for optimizing combined levodopa therapy.
Materials and Methods: A randomized, multicenter, double-arm, open-label study was conducted in Korea. The patients were randomly assigned to either a maintained levodopa dose (Group 1, n = 66) or a reduced levodopa dose by 15–25% (Group 2, n = 41). Treatment efficacy, safety, and tolerability were assessed during an 8-week treatment period.
Results: Eighty of the 107 (74.8%) participants completed the study (Group 1, n = 50; Group 2, n = 30). The patients' global impression of a change in scores indicated significant benefits of maintaining the levodopa dose (Group 1) compared to reducing the dose (Group 2). Although changes in the unified Parkinson's disease rating scale (UPDRS) scores, Hoehn and Yahr (H and Y) stages, and duration of ON, OFF and dyskinesia were not statistically different between the groups, an increased ON time and a reduced OFF time occurred in both the groups after LCE administration. Twenty-four participants (26.7%) experienced adverse events and 15 of them did not complete the study in the safety population (Group 1, n = 57; Group 2, n = 38). Significant drug-related withdrawal caused troublesome dyskinesia and aggravation of Parkinsonism in both Group 1 and Group 2, respectively.
Conclusions: Direct transitioning to LCE, without levodopa dose reduction, is recommended in Asian patients with PD and wearing-off.


Keywords: Dyskinesia, entacapone, Parkinson's disease, wearing-off


How to cite this article:
Park J, Kim Y, Youn J, Lee PH, Sohn YH, Koh SB, Lee JY, Baik JS, Cho JW. Levodopa dose maintenance or reduction in patients with Parkinson's disease transitioning to levodopa/carbidopa/entacapone. Neurol India 2017;65:746-51

How to cite this URL:
Park J, Kim Y, Youn J, Lee PH, Sohn YH, Koh SB, Lee JY, Baik JS, Cho JW. Levodopa dose maintenance or reduction in patients with Parkinson's disease transitioning to levodopa/carbidopa/entacapone. Neurol India [serial online] 2017 [cited 2019 Mar 23];65:746-51. Available from: http://www.neurologyindia.com/text.asp?2017/65/4/746/209533


Key Message:
This randomized, multicenter, double-arm, open-label study, investigating the relative therapeutic efficacy and safety of reduction of the dose of levodopa when transitioning to the levodopa/carbidopa/entacapone (LCE) combination, revealed that a direct transitioning to LCE therapy, without levodopa dose reduction, is recommended in Asian patients with Parkinson′s disease. This avoids the significant drug withdrawal-related dyskinesia and aggravation of Prakinsonian manifestations. An increased ON time and a reduced OFF time occurred in both the groups (with or without initial levodopa dose reduction) after the initiation of LCE treatment.




Since its introduction, administration of levodopa has been the most effective treatment for the cardinal symptoms of Parkinson's disease (PD), even for patients at advanced stages of the disease.[1],[2],[3],[4] When PD progresses, however, levodopa therapy is frequently accompanied by motor complications, including inadequate dopaminergic tone (wearing-off and dose failures) and excessive dopaminergic tone (levodopa-induced dyskinesia). Increasing degeneration of presynaptic dopaminergic cells and postsynaptic changes result in the fluctuating effects of levodopa.[5],[6],[7] Several treatments have been developed with an intent to mitigate these motor complications by stabilizing or increasing levodopa concentrations, or by stimulating dopamine receptors in the brain. These treatments include administration of monoamine oxidase B (MAO-B) inhibitors,[8],[9],[10] cathecol-O-methyl transferase (COMT) inhibitors,[11],[12],[13] and dopamine agonists.[14],[15],[16]

Entacapone, a COMT inhibitor, increases the plasma half-life and bioavailability of levodopa by blocking the peripheral metabolism of levodopa.[17],[18],[19] Several studies have found that the addition of entacapone to levodopa treatment resulted in an increase in the mean plasma levodopa concentrations by 25–50% and a 20–50% increase in levodopa half-life,[17],[18],[19],[20],[21] which is important because the efficacy of levodopa may increase as a result of enhanced bioavailability. Furthermore, according to the levodopa equivalent daily dose (LEDD) equation,[22],[23] the potency of levodopa is predicted to increase by 120% when administered in conjunction with entacapone. These findings suggest that reducing levodopa doses by as much as 25% is appropriate when transitioning to levodopa/carbidopa/entacapone (LCE) (Stalevo ®, Novartis, Seoul, Republic of Korea).[24],[25] In contrast, some studies have shown an improvement in the activities of daily living by adding entacapone without dose reduction of levodopa in patients as well as in the wearing-off manifestations.[26],[27] Direct transitioning from the regular form of levodopa to LCE without dose reduction in PD without or with only mild-to-moderate wearing-off manifestations was more tolerable and showed a better efficacy.[28],[29] These results do not provide a clear decision regarding the most appropriate dose of levodopa that needs to be maintained when transitioning to LCE. Additionally, there may be Asian-specific ethnic differences in the effects during the transition of medication to LCE.

This study was conducted on Korean patients with Parkinson's disease (PD). We attempted to determine the efficacy, safety, and tolerability of maintaining or reducing the dose of oral levodopa in the patients of PD, who are put on LCE directly during the transition period. The primary objective of this clinical trial was to determine whether maintaining or reducing the oral levodopa doses when transitioning to LCE would be a more appropriate therapeutic strategy to avoid the wearing off phenomenon and the aggravation of other manifestations of Parkinson's disease.


 » Materials and Methods Top


Participants

The participants were in the age range 40–80 years and were diagnosed with idiopathic PD, according to the criteria of the UK Parkinson's Disease Brain Bank.[30] Other inclusion criteria were a stablelevodopa dose for 1 month, confirmed wearing-off documented in a participant diary, and a Hoehn and Yahr (H and Y) stage <4 during the ON state. The use of other anti-Parkinsonian medications, such as amantadine, anticholinergics, (monoamine oxidae) MAO-B inhibitors, and dopamine agonists were permitted if the doses of these drugs had not changed for at least 1 month prior to the conduction of the study.

The exclusion criteria were the existing contraindications against the use of entacapone (hepatic impairment, narrow angle glaucoma, previous history of neuroleptic malignant syndrome, pheochromocytoma, and melanoma); major depression; severe medical illness; psychiatric symptoms related to dopaminergic treatments; or severe dyskinesia that impaired activities of daily living. Participants, who could not complete the PD diary independently, were also excluded.

Study design and procedures

This was a phase IV, randomized, open-label, multicenter, double-arm study of patients with PD. Participants were enrolled from 5 university hospitals in South Korea. The study was conducted between August 2009 and January 2014. The study protocol and amendments were independently approved by the Institutional Review Board of all participating centers, and written informed consent was obtained from all participants before the conduction of the study.

The study protocol included up to a 2-week screening period, followed by an 8-week (±7 days) treatment period. After a screening period, participants who met the eligibility criteria were randomly assigned to either the group with maintained levodopa doses (Group 1) or to the group in which the total levodopa dose was reduced by 15–25% (Group 2), according to a random number table. Randomization was carried out based on a random permuted block design, separately for the two strata, 2:1, to Group 1 and Group 2. After the inclusion of participants in the corresponding group, levodopa was directly transitioned to LCE. The LCE dosage was not modified until the final baseline visit.

Outcome variables

Primary outcome was determined based on the patient global impression of change (PGI-C) scores (1 = much improved, 2 = a little improved, 3 = no change, 4 = a little worse, and 5 = much worse) at the final visits.

Secondary outcomes were evaluated by comparing the clinical changes between the baseline and the final visits. Clinical assessment including administering the H and Y scale and the unified PD rating scale (UPDRS; I, II, III, and IV) were carried out, along with the examining of the Parkinson's diaries, which were completed by the patient 3 days prior to the baseline visit and 3 days prior to the study completion. The patients also recorded ON and OFF time durations, ON with dyskinesia time durations, and sleep periods in their diaries.

The safety and tolerability of the medication were assessed using the safety population, which included all participants who received at least one dose of the study medication. Safety was assessed by monitoring adverse events (AEs) during a telephonic follow up (2 weeks after randomization) and a final visit to the clinic. Tolerability was defined based on the patient not withdrawing from the study due to drug-related AEs, while also being on regular medication.

Study medication

The study medication included 6 types of LCE, with levodopa/carbidopa/entacapone doses as follows: 50/12.5/200 mg, 75/25/200 mg, 100/25/200 mg, 125/25/200 mg, 150/37.5/200 mg, and 200/37.5/200 mg (Stalevo ® 50, Stalevo ® 75, Stalevo ® 100, Stalevo ® 125, Stalevo ® 150, and Stalevo ® 200, respectively).

Statistical analyses

Data analyses for the primary and secondary efficacy variables were performed using the per protocol population (defined as all randomized participants who complied with medication and completed a post-baseline efficacy assessment). Statistical analyses were conducted using Statistical Package for Social Sciences S(PSS) 21 (IBM Corporation, Somers, New York, USA). Efficacy variables were assessed using the univariate analysis (mean ± SD), and 95% confidence intervals were calculated for the change from baseline values. Changes in scale responses were compared between the groups using Mann-Whitney U tests and nonparametric categorical data were analyzed using Fisher's exact tests. Two-sided P values <0.05 were considered statistically significant.


 » Results Top


Participants

One hundred and seven participants fulfilled the inclusion criteria. Out of the 107 participants (5 participants were excluded from the study due to protocol violations and 7 participants withdrew their informed consent for personal reasons), 95 were included in the safety population (Group 1, n = 57; Group 2, n = 38).15 participants discontinued the study protocol due to adverse events. Eighty participants, who completed the study, were included in the per protocol population (Group 1, n = 50; Group 2, n = 30).

Demographics, baseline characteristics, and concomitant medications

The participant demographics and the baseline PD characteristics of all participants (per protocol population) are presented in [Table 1]. The mean age ± standard deviation (SD) was 62.9 ± 9.8 years, and 37 (46.2%) of the participants were men. The mean duration of PD was 95.2 ± 52.0 months, and the mean duration of levodopa treatment was 63.2 ± 41.7 months. The mean total daily levodopa dose was 483.6 ± 214.4 mg, and the mean total daily dopamine agonist dose was 125.8 ± 120.6 mg by levodopa equivalent daily dose (LEDD) calculator. The mean total UPDRS III score was 19.5 ± 10.3, and the mean H and Y stage score was 2.1 ± 0.7. Twenty-two participants (27.5%) were current amantadine users. The baseline clinical characteristics between Groups 1 and 2 were not significantly different.
Table 1: Baseline demographics and characteristics, per protocol population

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Primary outcome

When we assessed the PGI-C score between the two groups, the participants in Group 1 reported a better effect than those in Group 2 (PGI-C mean score 2.2 ± 0.9 and 2.9 ± 0.7 in Group 1 and 2, respectively, P = 0.016). In Group 1, 64% of participants noticed clinical improvement, while 10% reported worsening after adding entacapone. However, 26.6% of Group 2 participants demonstrated clinical improvement and 23.3% reported worsening [Table 2].
Table 2: Result of primary outcome; PGI-C scores at the final visit

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Secondary outcomes

Changes in UPDRS (I, II, III, and IV) scores and H and Y stages after transitioning were not statistically different between the groups. There were improvements in both the groups (mean ± SD) for UPDRS (I, II, III, and IV) scores at the end of the study, compared to the baseline values [Table 3].
Table 3: Result of secondary outcome; changes in H and Y, UPDRS (I, II, III, and IV), daily ON, OFF and dyskinesia duration at final visit

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Increased daily durations of time in the ON state and decreased daily durations of time in the OFF state were observed in both the groups after transitioning to LCE. However, the difference between the groups was not statistically significant. Furthermore, there were no statistically significant differences between the groups for the dyskinesia scores, based on the UPDRS part IV scores, and the duration of ON state, with dyskinesia time [Table 3].

Safety and tolerability

A total of 24 (26.7%; Group 1, n = 12; Group 2, n = 12) participants in the safety population reported 25 AEs. Two serious AEs were reported (femur neck fracture and cardiovascular accident), which were not considered as drug related. Thirteen participants withdrew consent due to drug-related safety issues. In Group 1, one had nausea, one experienced dopamine dysregulation syndrome, one had aggravated Parkinsonism, and two out of three participants with significant dyskinesia withdrew their informed consent. In Group 2, one participant had nausea and 7 reported aggravation of Parkinsonism symptoms and withdrew their informed consent [Table 4]. Overall, 50 of the 57 (87.7%) participants assigned to Group 1 and 30 of the 38 (78.9%) participants assigned to Group 2 completed the study protocol without drug adjustment and the difference in tolerability was not statistically significant (P = 0.092).
Table 4: Adverse events and tolerability, safety population

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 » Discussion Top


This prospective, multicenter, randomized, open-label clinical study aimed to investigate the feasible dosages of levodopa in patients with PD with wearing-off manifestations, who are transitioning to LCE. We found greater clinical benefits with maintained levodopa doses compared to reduced doses of levodopa while transitioning to LCE.

Specifically, maintaining levodopa doses during the transition to LCE resulted in a higher patient satisfaction, as indicated by the primary efficacy variable, the PGI-C scores. The percentage of patients who reported improvement of symptoms was higher in the maintained dose group (Group 1, 64% vs. Group 2, 26.7%), and the percentage of patients who reported worse symptoms was higher in the reduced dose group (Group 1, 10% vs. Group 2, 23.3%).

Both groups experienced a trend toward improvement after transitioning, including for efficacy variables such as the duration of the ON time, the duration of the OFF time, the H and Y stages, as well as the UPDRS I, II, III, and IV scores. Improvements in the wearing-off symptoms of participants in both the groups in the present study were reflected by an increased ON time and a decreased OFF time with the LCE use. Our open label design limits interpretation regarding improvement of secondary outcomes.

Analyses of data from participants in our safety population reflect that a reduced levodopa dose was less well-tolerated, even though the difference was not statistically significant (drug-related attrition; Group 1, 9.1% vs. Group 2, 21.1%). Two participants in Group 1 withdrew due to the occurrence of significant dyskinesia that affected their quality of life, and these patients had initially reported no dyskinesia. The participants reporting dyskinesia were younger (56.5 ± 0.7 years), had relatively longer disease durations (126.0 ± 25.5 months), and were on higher daily levodopa doses (935.0 ± 685.9 mg/d) compared to other study participants in Group 1 (94.7 ± 54.8 months and 462.8 ± 204.6 mg/d). These characteristics of higher levodopa dose and younger age are compatible with previously reported risk factors responsible for the development of dyskinesia.[31]

The previous studies have reported that a direct transition to LCE without levodopa dose reduction showed a relatively higher incidence of increased dyskinesia (Linazasoro et al.,[28] [23.5%], and Tolosa et al.,[29] {17.8%}). However, among the patients who reported a worsened dyskinesia, only one was omitted from the clinical trial in those studies and he was taking a relatively higher dose of levodopa (800 mg/d).[28] This finding was also in agreement with our study; the incidence of patients in whom dyskinesia affected the quality of life was relatively lower (5.6%). Moreover, most participants who initially reported the development of dyskinesia (Group 1, n = 14, 24.6% and Group 2, n = 5, 13.2%) did not report troublesome dyskinesia, with the exception of three participants in Group 1. Based on these results, it is deduced that maintaining the dose of levodopa may increase the dyskinesia; however, it rarely interferes with the quality of life.

Seven of the Group 2 participants (18.4%) reported an aggravation of their Parkinson's symptoms, and all of these participants withdrew from the study. The withdrawn participants were older (72.0 ± 5.8 years), had a higher LEDD (825.2 ± 330.7 mg/d), and had longer daily OFF time (6.4 ± 2.8 h) compared to the other participants (64.0 ± 10.3 years, 518.3 ± 229.0 mg/d, and 4.3 ± 2.2 h). Eggert et al.,[32] directly switched from LC and levodopa/benserazide to LCE by a decreased levodopa equivalent dose; this resulted in 28% of participants again increasing their dose of levodopa due to inadequate efficacy. In our study, aggravation of Parkinsonism was the most common reason for withdrawal of patients from the trial in Group 2 (Group 1, n = 1, 1.8% vs. Group 2, n = 7, 18.4%). There was a favorable trend towards tolerability in the dose maintenance group, although the results were statistically insignificant. (Tolerability: Group 1, 90.9% vs. Group 2, 78.9%)

A previous randomized open-label clinical trial in Europe did not report any meaningful differences in efficacy, safety, and tolerability between the groups in the Western population.[28] We demonstrated a favorable primary outcome and better tolerability in an Asian group with levodopa dose maintenance. Our study supports the recommendation to maintain levodopa doses in patients who are experiencing mild-to-moderate wearing-off, if severe dyskinesia is not disturbing their activities of daily living.

Although our study had a larger sample size than the previously published studies, the open-label study design and high withdrawal rates limit our ability to form strong conclusions. We also excluded patients with a dyskinesia that interfered with activities of daily living. Therefore, interpretations regarding dyskinesia must be approached with caution.

In conclusion, the present study demonstrates that transitioning to LCE while maintaining levodopa doses in patients with wearing-off is tolerable and may increase the efficacy of medications in PD. Thus, we recommend the maintenance of levodopa doses, in order to minimize the manifestations of the wearing-off phenomenon, in Korean patients with PD who do not have severe dyskinesia.

Acknowledgements

This work was supported by a grant from Novartis Korea and Samsung Medical Center (PHO1095531). Novartis Korea had no influence on the study design, data analysis and interpretation, writing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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