Placebo‐controlled,double‐blind dose‐finding study of entacapone in fluctuating parkinsonian patients

We conducted a multicenter randomized, placebo‐controlled double‐blind parallel‐group study in Japanese Parkinson's disease (PD) patients with wearing‐off motor fluctuations to determine the clinical efficacy and safety of entacapone as an adjunct to concomitant treatment with levodopa and a dopa decarboxylase inhibitor (DCI). We randomized 341 patients to receive entacapone 100 or 200 mg or placebo per dose of levodopa/DCI for 8 weeks. The primary efficacy variable was on time change while awake, determined by patients' diaries. Mean baseline on time in each group was approximately 8 hours. Mean on time change at final assessment was 1.4 hours each for entacapone 100‐mg and 200‐mg groups and by 0.5 hours for the placebo group (P < 0.05). The two entacapone doses were equally efficacious. Adverse events occurred in 79 patients (69.9%) in placebo, 82 (72.6%) in 100 mg, and 98 (86.0%) in 200 mg. The most common adverse event with entacapone was an increase in dyskinesias. The overall safety profile was satisfactory in both entacapone groups. In conclusion, both entacapone 100 and 200 mg were equally effective in increasing on time of PD patients with wearing‐off fluctuations, although the safety and tolerability profile appeared more favorable for the 100‐mg dose. © 2006 Movement Disorder Society     

Efficacy of combining levodopa with entacapone on quality of life and activities of daily living in patients experiencing wearing-off type fluctuations

OBJECTIVES: To compare the efficacy of levodopa/dopa decarboxylase inhibitor (DDCI) plus entacapone with levodopa/DDCI plus placebo on measures of parkinsonian disability and health-related quality of life (QoL) in subjects with Parkinson's disease (PD) experiencing motor fluctuations. MATERIALS AND METHODS: A double-blind, placebo-controlled phase IV study was performed in 270 PD patients randomized to receive either entacapone 200 mg or placebo with each dose of their current levodopa regimen. The primary variables were the Unified Parkinson's Disease Rating Scale (UPDRS) part II activities of daily living (ADL) and the Parkinson's Disease Questionnaire (PDQ)-39 summary index. UPDRS parts I, III-VI, Global Assessment of Change, PDQ-39 subscores, and the Short-Form (SF)-36 and the European Quality of Life five-dimension questionnaire (EQ-5D) were included as secondary variables. RESULTS: There was a significant improvement in ADL scores with levodopa/DDCI/entacapone compared with levodopa/DDCI/placebo at 5 and 13 weeks (-2.3 vs -0.7, respectively; P = 0.0001). However, no significant differences were observed between treatments using the PDQ-39 summary index. UPDRS part III (motor) scores significantly decreased in the levodopa/DDCI/entacapone group compared with the levodopa/DDCI/placebo group (-5.0 vs -2.9, respectively; P = 0.03). Similarly, the change in the investigators Global Assessment was significantly greater (P = 0.004) in the levodopa/DDCI/entacapone group. There were no significant differences between treatments for any of the PDQ-39 subscores, the SF-36 variables or the EQ-5D utility score. CONCLUSIONS: Levodopa combined with entacapone demonstrated good efficacy in terms of ADL, global function, motor performance and was well tolerated. However, this short-term study did not generate significant improvements in QoL.     

Trial of dextromethorphan/quinidine to treat levodopa‐induced dyskinesia in Parkinson's disease

Background : Nondopaminergic pathways represent potential targets to treat levodopa‐induced dyskinesia in Parkinson's disease (PD). This pilot‐study (NCT01767129) examined the safety/efficacy of the sigma‐1 receptor‐agonist and glutamatergic/monoaminergic modulator, dextromethorphan plus quinidine (to inhibit rapid dextromethorphan metabolism), for treating levodopa‐induced dyskinesia. Methods : PD patients were randomized to dextromethorphan/quinidine (45 mg/10 mg twice daily)/placebo in two 2‐week double‐blind, crossover treatment periods, with intervening 2‐week washout. After 14 days, a 2‐hour intravenous levodopa‐infusion was administered. Patient examinations were videotaped before infusion (“off” state) and every 30 minutes during and afterwards until patients returned to “off.” The primary endpoint was dyskinesia‐severity during infusion measured by Unified Dyskinesia Rating Scale part 3 area‐under‐curve scores (blinded expert rated). Additional endpoints included other dyskinesia/motor assessments, global measures of clinical‐change, and adverse‐events. Results : A total of 13 patients were randomized and completed the study (efficacy‐evaluable population). Dyskinesia‐severity was nonsignificantly lower with dextromethorphan/quinidine than placebo during infusion (area‐under‐curve 966.5 vs 1048.8; P = .191 [efficacy‐evaluable patients]), and significantly lower in a post‐hoc sensitivity analysis of the per‐protocol‐population (efficacy‐evaluable patients with ≥ 80% study‐drug‐compliance, n = 12) when measured from infusion start to 4‐hours post–infusion completion (area‐under‐curve 1585.0 vs 1911.3; P = .024). Mean peak dyskinesia decreased significantly from infusion‐start to return to “off” (13.3 vs 14.9; P = .018 [efficacy‐evaluable patients]). A total of 9 patients rated dyskinesia “much/very much improved” on dextromethorphan/quinidine versus 1‐patient on placebo. Dextromethorphan/quinidine did not worsen PD‐motor scores, was generally well tolerated, and was associated with more frequent adverse events. Conclusion : This study provides preliminary evidence of clinical benefit with dextromethorphan/quinidine for treating levodopa‐induced dyskinesia in PD. Larger studies with a longer treatment duration need to corroborate these early findings. © 2017 International Parkinson and Movement Disorder Society     

A Double‐Blind,Randomized, Placebo and Active‐Controlled Study of Nebicapone for the Treatment of Motor Fluctuations in Parkinson's Disease

To determine the efficacy, safety and tolerability of nebicapone, a new catechol‐O‐methyltransferase inhibitor for the treatment of motor fluctuations in Parkinson's disease (PD), we conducted a multicenter, randomized, 8‐week double‐blind, placebo‐ and active‐controlled, parallel‐group study comparing nebicapone 50 mg, 100 mg, or 150 mg, entacapone 200 mg (active control) or placebo administered concomitantly with levodopa/carbidopa or levodopa/benserazide. Two hundred and fifty‐two PD patients with motor fluctuations treated with levodopa/carbidopa or levodopa/benserazide (4–8 daily doses) were enrolled and 250 patients were eligible for intention‐to‐treat (ITT) analysis on the basis of having at least one efficacy assessment. The primary endpoint was 8‐week change from baseline in absolute “Off” time duration noted in self‐scoring diaries. At 8 weeks of treatment the mean daily “Off” time decreased significantly compared to placebo for nebicapone 150 mg (?106 min; 95%CI: ?192; ?21) and entacapone 200 mg (?81 min; 95%CI: ?142; ?19). The decrease in “Off” time with nebicapone 50 mg or 100 mg did not reach statistical significance. Treatment‐emergent adverse events were reported by 32% to 49% of patients in any treatment group, with no observed dose relationship in the nebicapone groups. Clinically relevant elevations in aspartate transaminase (AST) and/or alanine transaminase (ALT) were observed in 4 of 46 patients with the nebicapone 150 mg dose. The results of this study show that nebicapone 150 mg is efficacious for the treatment of motor fluctuations in PD patients. However, the risk of increasing liver transaminases and its clinically relevance deserves further evaluation.     

Levodopa/DDCI and entacapone is the preferred treatment for Parkinson's disease patients with motor fluctuations in routine practice: a retrospective, observational analysis of a large French cohort

Levodopa is the gold standard drug for the symptomatic control of Parkinson's disease (PD). However, long-term treatment with conventional formulations [levodopa and a dopa decarboxylase inhibitor (DDCI)], is associated with re-emergence of symptoms because of wearing-off and dyskinesia. Treatment with levodopa/DDCI and entacapone extends the half-life of levodopa, avoiding deep troughs in levodopa plasma levels and providing more continuous delivery of levodopa to the brain. In this open-label, retrospective, observational study we investigated the effects of levodopa/DDCI and entacapone therapy in 800 PD patients with motor fluctuations. Levodopa/DDCI and entacapone treatment was assessed as good/very good in improving motor fluctuations (64%) and activities of daily living (ADL; 62%). The therapeutic utility was considered to be good/very good in 70% of cases. Moreover, there was a reduction in levodopa dose in 20% of patients. Neurologists preferred levodopa/DDCI and entacapone compared with increasing levodopa dosage, dose-fractionation or addition of a dopamine agonist (63%, 29% and 23% of patients respectively). Reasons included achieving more continuous dopaminergic stimulation (40%), reducing motor fluctuations (54%) and improving ADL (41%). This analysis reveals the preference of neurologists for levodopa/DDCI and entacapone over conventional levodopa-modification strategies for the effective treatment of PD motor fluctuations in clinical practice.     

Five-year efficacy and safety of levodopa/DDCI and entacapone in patients with Parkinson’s disease

This was a retrospective pooled analysis of data from four comparably designed, double-blind, placebo-controlled, Phase III studies and their long-term open-label extensions. Patients on levodopa and a dopa decarboxylase inhibitor (DDCI) were randomized to entacapone or to placebo in the 6-month, double-blind phase, with all patients subsequently receiving entacapone in the extension phase. UPDRS III motor scores improved by -2.1 points during the first 6 months of levodopa/DDCI and entacapone therapy, and remained below baseline for up to 2 years. Increased daily 'ON' time, together with response duration to a single morning dose of levodopa and clinical global evaluation, also supported the long-term efficacy of levodopa/DDCI and entacapone. The mean daily dose of levodopa did not increase over the 5-year follow-up period. Long-term therapy with levodopa/DDCI and entacapone was well-tolerated.     

Factors predictive of the development of Levodopa‐induced dyskinesia and wearing‐off in Parkinson's disease

The Stalevo Reduction in Dyskinesia Evaluation in Parkinson's Disease (STRIDE‐PD) study compared the initiation of levodopa (l ‐dopa) therapy with l ‐dopa/carbidopa (LC) versus l ‐dopa/carbidopa/entacapone (LCE) in patients with Parkinson's disease. In the current study, the STRIDE‐PD study population was investigated to determine the effect of l ‐dopa dose and other risk factors on the development of dyskinesia and wearing‐off. Patients were randomized to receive LCE (n=373) or LC (n=372). Blinded assessments for dyskinesia and wearing‐off were performed at 3‐month intervals for the 134‐ to 208‐week duration of the study. The patients were divided into 4 dose groups based on nominal l ‐dopa dose at the time of onset of dyskinesia (or at study conclusion if there was no dyskinesia): group 1, <400 mg/day (n=157); group 2, 400 mg/day (n=310); group 3, 401 to 600 mg/day (n=201); and group 4, >600 mg/day (n=77). Similar analyses were performed with respect to wearing‐off and any motor complication. The times to onset and frequency of dyskinesia, wearing‐off, or any motor complication were compared using the log‐rank test (overall trend test) and a Cox proportional hazards model (pairwise comparisons). A stepwise Cox proportional hazards model was used to screen predictive factors in a multivariate analysis. The risk of developing dyskinesia and wearing‐off increased in an l ‐dopa dose‐dependent manner (P<0.001 for both). Analyses using l ‐dopa equivalent doses produced comparable results. Factors that were predictive of dyskinesia, in rank order, were: young age at onset, higher l ‐dopa dose, low body weight, North American geographic region, LCE treatment group, female gender, and more severe Unified Parkinson's Disease Rating Scale (UPDRS) Part II. Multivariate analyses identified similar predictors for wearing‐off but included baseline UPDRS Part III and excluded weight and treatment allocation. The risk of developing dyskinesia or wearing‐off was closely linked to l ‐dopa dose. The current results suggest that physicians should use the lowest dose of l ‐dopa that provides satisfactory clinical control to minimize the risk of both dyskinesia and wearing‐off. © 2013 Movement Disorder Society     

Long‐term safety and efficacy of levodopa‐carbidopa intestinal gel in advanced Parkinson's disease

Background: Levodopa‐carbidopa intestinal gel (designated as carbidopa‐levodopa enteral suspension in the United States) provides stable plasma levodopa concentrations and reduces motor fluctuations in advanced Parkinson's disease patients through continuous delivery of levodopa via percutaneous endoscopic gastrojejunostomy. We report long‐term safety and efficacy outcomes from an open‐label phase 3 treatment program. Methods: PD patients (n = 262) who completed a 12‐week double‐blind study and its 52‐week open‐label extension or a separate 54‐week open‐label study were enrolled in this ongoing phase 3 open‐label, multinational study (NCT00660673). Safety and efficacy assessments were collected every 6 months. Results: Mean total duration of exposure to levodopa‐carbidopa intestinal gel was 4.1 years (range, 1.2 to 6.9 years). The overall discontinuation rate was 34% (average annual discontinuation rate, 10%). Although most patients (94%) reported an adverse event, the rate of adverse events decreased over time; 53% experienced a serious adverse event. Of patients in this extension study, 54% required jejunal tube replacement during the study, and 37% required percutaneous endoscopic gastrostomy tube replacement. Most patients were on levodopa monotherapy. Patients maintained reductions in “off” time and increases in mean “on” time without dyskinesia from initial levodopa‐carbidopa intestinal gel infusion to he study end point (P < 0.001; n = 81). Activities of daily living and quality‐of‐life assessments demonstrated significant improvements that persisted through the study. Conclusions: This long‐term study demonstrates sustained and clinically meaningful benefits from levodopa‐carbidopa intestinal gel in advanced PD patients. Although adverse event rates decreased over time, vigilance is required for device‐related complications and adverse events. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society     

Optimizing levodopa therapy for Parkinson's disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective

After 40 years of clinical experience, levodopa remains the gold standard treatment for Parkinson's disease (PD) despite the recent emergence of a host of new therapies. Some physicians are cautious when prescribing levodopa because of its association with motor complications. Evidence now suggests that levodopa-associated complications are a result of deep troughs in delivery of levodopa to the brain caused by the short plasma half-life of conventional levodopa formulations (levodopa and a dopa decarboxylase inhibitor [DDCI]). Dosing strategies, such as dose increases and dose fractionation, may be effective in the short term. For the longer-term, levodopa/carbidopa/entacapone provides pharmacokinetically optimized levodopa therapy that significantly increases the plasma half-life and bioavailability of levodopa, providing more consistent plasma levodopa levels without deep troughs. Evidence from clinical trials in PD patients experiencing re-emergence of symptoms due to wearing-off has consistently shown that levodopa/DDCI and entacapone significantly increases ON-time and affords greater functionality, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) with conventional levodopa. These trials have also shown that levodopa/DDCI and entacapone is generally well tolerated, with notable adverse events including worsening dyskinesia, nausea and diarrhea. Patients experiencing re-emergence of symptoms due to wearing-off may benefit from optimized levodopa therapy with levodopa/carbidopa/entacapone.     

Effect of rasagiline as adjunct therapy to levodopa on severity of OFF in Parkinson's disease

Background: The LARGO study demonstrated that rasagiline 1 mg/day as adjunct to levodopa significantly reduces OFF time to the same magnitude as adjunct entacapone. This substudy of LARGO aimed to assess the effect of rasagiline and entacapone on the motor symptoms of PD during the practically defined OFF state. Methods: LARGO was a randomized, double‐blind, multicenter trial that assessed the efficacy and safety of rasagiline (1 mg/day), entacapone (200 mg with each levodopa dose), and placebo in 687 levodopa‐treated PD patients with motor fluctuations. A substudy of LARGO measured UPDRS motor scores in the practically defined OFF state in 32 rasagiline, 36 entacapone, and 37 placebo patients. Results: Treatment with rasagiline produced a significant improvement over placebo of 5.64 units in UPDRS motor OFF score (P = 0.013 vs. placebo). By contrast, the effect of adjunct entacapone was not significant (P = 0.14 vs. placebo). Whereas rasagiline also showed a trend in reducing the UPDRS‐ADL OFF score (P = 0.058 vs. placebo), no such trend was noted for entacapone (P = 0.26 vs. placebo). Retrospective analysis, using the Bonferroni correction, of UPDRS motor subdomains further revealed that rasagiline, but not entacapone, significantly improved bradykinesia (P < 0.001) and showed trends for improvements in facial expression, speech, and axial impairment during OFF time. Conclusions: This study provides the first objectively measured evidence that adjunct rasagiline 1 mg/day is effective in reducing the severity of motor symptoms in the OFF state. This suggests a continuous effect of rasagiline 1 mg/day throughout the day and night and is consistent with its extended duration of therapeutic action.     

Treatment of end-of-dose wearing-off in parkinson's disease: stalevo (levodopa/carbidopa/entacapone) and levodopa/DDCI given in combination with Comtess/Comtan (entacapone) provide equivalent improvements in symptom control superior to that of traditional levodopa/DDCI treatment

The aim of this study was to evaluate the efficacy of the new optimised levodopa, Stalevo (levodopa, carbidopa and entacapone) in patients with Parkinson's disease experiencing end-of-dose wearing-off. Treatment with Stalevo was compared to treatment with traditional immediate-release levodopa and dopa-decarboxylase inhibitor (DDCI) formulations along with adjunct entacapone (Comtess/Comtan). A European, open, parallel-group, active treatment-controlled phase IIIb study evaluating 176 patients randomised to switch from their current regimen of levodopa/DDCI to either an equivalent dose of Stalevo or levodopa/DDCI plus entacapone. After 6 weeks, treatments were assessed using the Clinical Global Impression of Change, the Unified Parkinson's Disease Rating Scale and a Motor Fluctuations Questionnaire. Over 70% of patients in both the Stalevo and adjunct entacapone arms felt that they were clinically improved and over 80% experienced a reduction in fluctuations. Although there was no significant difference between Stalevo and levodopa/DDCI plus entacapone with regard to motor improvement and side effects, 81% of patients stated that they preferred treatment with Stalevo compared with taking two separate tablets (i.e. levodopa/DDCI and entacapone). Stalevo was well tolerated and safe when substituted for levodopa DDCI preparations.     

The effect of peripheral enzyme inhibitors on levodopa concentrations in blood and CSF

Levodopa combined with a dopa‐decarboxylase inhibitor, such as carbidopa, shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing‐off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day 1; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg tid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C_max of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C_max in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa. © 2010 Movement Disorder Society     

Double‐blind trial of levodopa/carbidopa/entacapone versus levodopa/carbidopa in early Parkinson's disease

We performed a 39‐week, randomized, double‐blind, multicenter study to compare the efficacy, safety, and tolerability of levodopa/carbidopa/entacapone (LCE, Stalevo) with levodopa/carbidopa (LC, Sinemet IR) in patients with early Parkinson's disease (PD). Four hundred twenty‐three patients with early PD warranting levodopa were randomly assigned to treatment with LCE 100/25/200 or LC 100/25 three‐times daily. The adjusted mean difference in total Unified Parkinson's disease Rating Scale (UPDRS) Parts II and III between groups using the analysis of covariance model (prespecified primary outcome measure) was 1.7 (standard error = 0.84) points favoring LCE (P = 0.045). Significantly greater improvement with LCE compared with LC was also observed in UPDRS Part II activities of daily living (ADL) scores (P = 0.025), Schwab and England ADL scores (blinded rater, P = 0.003; subject, P = 0.006) and subject‐reported Clinical Global Impression (CGI) scores (P = 0.047). There was no significant difference in UPDRS Part III or investigator‐rated CGI scores. Wearing‐off was observed in 29 (13.9%) subjects in the LCE group and 43 (20.0%) in the LC group (P = 0.099). Dyskinesia was observed in 11 (5.3%) subjects in the LCE group and 16 (7.4%) in the LC group (P = 0.367). Nausea and diarrhea were reported more frequently in the LCE group. LCE provided greater symptomatic benefit than LC and did not increase motor complications. © 2008 Movement Disorder Society     

Improvements in nocturnal symptoms with ropinirole prolonged release in patients with advanced Parkinson’s disease

Background: The 24‐week, double‐blind Efficacy and Safety Evaluation in PD–Adjunct (EASE‐PD Adjunct) study randomized patients with advanced Parkinson’s disease (PD) suboptimally controlled with levodopa to once‐daily placebo or adjunctive ropinirole prolonged release (2–24 mg/day). We investigated the effect of ropinirole prolonged release on nocturnal symptoms in these patients. Methods: Total and grouped item PD Sleep Scale (PDSS) scores were analyzed post hoc in patients with baseline PDSS total scores ≤ 100 (troublesome nocturnal symptoms) and >100. Results: Baseline PDSS total score was ≤ 100 in 93 of 198 (47%) and 89 of 189 (47%) patients receiving ropinirole prolonged release and placebo, respectively; this subgroup displayed evidence at baseline of greater daily awake ‘off’ time, reduced night‐time sleep and worse quality of life, than the PDSS >100 subgroup. Significant improvements with ropinirole prolonged release versus placebo in PDSS score from baseline to Week 24 last observation carried forward were observed for those with baseline PDSS ≤ 100 [adjusted mean treatment difference 9.0 (95% CI: 2.76, 15.33; P = 0.0051)], but not >100. The PDSS ≤ 100 subgroup demonstrated treatment benefits for PDSS groupings of motor symptoms on waking and global quality of sleep. Changes in daytime sleepiness were similar between treatment groups. The PDSS >100 subgroup demonstrated significant treatment benefit for global quality of sleep. The unadjusted odds ratio for a positive response with ropinirole prolonged release relative to placebo, for the PDSS ≤ 100 subgroup, was 2.90 (95% CI: 1.42, 5.95, P = 0.004). Conclusions: Once‐daily ropinirole prolonged release improves nocturnal symptoms in patients with advanced PD not optimally controlled with levodopa who suffer troublesome nocturnal disturbance.     

Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease

BACKGROUND: The catechol O-methyltransferase inhibitor entacapone acts by extending the elimination half-life of levodopa and is currently approved as an adjunct to levodopa for the treatment of patients with Parkinson disease (PD) with motor fluctuations. OBJECTIVE: To determine if the addition of entacapone administration provides benefit to levodopa-treated PD patients who have a stable response to levodopa and do not experience motor complications. DESIGN: Prospective, double-blind, placebo-controlled trial. SETTING: Outpatient multicenter study. PATIENTS: Female and male patients 30 years or older with idiopathic PD receiving stable doses of levodopa or carbidopa with or without other dopaminergic therapies and who did not experience motor fluctuations were eligible for the study. MAIN OUTCOME MEASURES: Parkinsonian function and quality of life. RESULTS: The addition of entacapone did not improve motor scores on the Unified Parkinson's Disease Rating Scale in levodopa-treated PD patients who did not experience motor fluctuations. The mean +/- SE adjusted change between baseline and final treatment visit was -0.9 +/- 0.35 in the entacapone group and -0.8 +/- 0.35 in the placebo group (P = .83). Significant improvement with entacapone treatment was detected in several quality-of-life measures, including the Parkinson Disease Questionnaire 39, the 36-item Short-Form Health Survey, the Parkinson's Symptom Inventory, and investigator and subject Clinical Global Assessments. The drug was well tolerated by patients in this population. CONCLUSIONS: The catechol O-methyltransferase inhibitor entacapone, used as an adjunct to levodopa in PD patients who do not experience motor fluctuations, does not improve Unified Parkinson's Disease Rating Scale motor scores but does improve a variety of quality-of-life measures.     

Patient‐reported convenience of once‐daily versus three‐times‐daily dosing during long‐term studies of pramipexole in early and advanced Parkinson’s disease

Background and purpose: In chronic diseases including Parkinson’s disease (PD), complex pharmacotherapy dosing schedules are reported to reduce adherence, perhaps leading to less‐effective symptom control and, in PD, more erratic stimulation of dopamine receptors. However, blinded clinical‐trial designs preclude direct comparisons of adherence to various schedules. Methods: In two double‐blind (DB) studies of early PD and one of advanced PD, subjects received three‐times‐daily (t.i.d.) pramipexole or placebo. In open‐label (OL) extensions, subjects took extended‐release, once‐daily (q.d.) pramipexole. At 24 or 32 OL weeks, q.d. versus t.i.d. dosing preference was surveyed by questionnaire. Results: Of 590 DB‐trial completers with early PD, 511 entered the OL extension. Of 374 survey respondents, 94.4% preferred q.d. dosing (72.2% of them found it ‘very much more convenient’ and 27.8%‘more convenient’), 2.7% preferred t.i.d., and 2.9% chose ‘no difference’. Of 465 DB‐trial completers with advanced PD, 391 entered its OL extension. Of 334 survey respondents, 88.9% preferred q.d. dosing (59.9% of them found it ‘very much more convenient’ and 40.1%‘more convenient’), 5.7% preferred t.i.d., and 5.4% chose ‘no difference’. Results excluding DB‐placebo recipients were highly similar. Conclusions: In this first direct comparison of patient preference for q.d. versus t.i.d. dopamine‐agonist dosing, patients with early or advanced PD had a strong preference for q.d. rather than t.i.d. pramipexole. The high proportion of advanced‐PD patients declaring this preference indicates that it does not depend on whether a patient is taking concomitant PD medications dosed more frequently than q.d.     

Entacapone is beneficial in both fluctuating and non-fluctuating patients with Parkinson's disease: a randomised,placebo controlled,double blind,six month study

OBJECTIVE: To study the effect of entacapone, a specific peripherally acting catechol-O-methyltransferase (COMT) inhibitor used in combination with levodopa treatment, in cases of Parkinson's disease with both fluctuating and non-fluctuating response to treatment. METHODS: A randomised, placebo controlled, double blind, six month study was undertaken in 172 fluctuating and 128 non-fluctuating patients. The clinical efficacy and safety of 200 mg entacapone given with each daily levodopa dose was studied. Efficacy was examined using home diaries, the unified Parkinson disease rating scale (UPDRS), and recording of daily levodopa dose. RESULTS: The primary efficacy variable for fluctuating patients-the proportion of daily ON time-showed a significant increase compared with placebo (p < 0.05). The absolute ON time (mean (SD)) increased from 9.5 (2.5) to 10.8 (2.4) hours (p < 0.01), and the daily OFF time was correspondingly reduced from 7.0 (2.6) to 5.9 (2.5) hours (p < 0.05 v placebo). This improvement was achieved despite a reduction in daily levodopa requirements. The effect was rapidly lost on withdrawal of entacapone. In non-fluctuating patients, the primary efficacy measure was part II of the UPDRS (activities of daily living; ADL). In this group of patients, ADL scores improved in the entacapone group (p < 0.01 v placebo), and there was also a 40 mg reduction in levodopa requirement (p < 0.01 v placebo). Entacapone was well tolerated by both fluctuating and non-fluctuating patients. CONCLUSIONS: The ability of entacapone to provide additional benefits to levodopa treatment in increasing ON time in fluctuating Parkinson's disease patients was confirmed. A novel finding was that patients without fluctuations also obtained benefit from the addition of entacapone to their levodopa treatment, as evidenced by improved ADL scores and a relatively reduced levodopa requirement.     

Motor features and response to oral levodopa in patients with Parkinson’s disease under continuous dopaminergic infusion or deep brain stimulation

Background: Subthalamic nucleus deep brain stimulation (STN DBS) and continuous dopaminergic infusions (jejunal levodopa or subcutaneous apomorphine) are indicated in complicated Parkinson’s disease (PD), although it remains unsettled how they compare to each other. Methods: We investigated the daytime motor condition in patients with advanced PD under monotherapy with jejunal levodopa, subcutaneous apomorphine, or STN DBS and also measured the motor changes produced by an additional standard morning dose of levodopa. Motor performance was assessed with the UPDRS‐III, hand taps, the AIMS dyskinesia score and patients’ diaries. Outcome measures were time to best motor ‘on’ after start of morning treatment, daytime variability of motor condition, motor scores. Results: The time to ‘on’ was longest in the jejunal levodopa group. DBS and jejunal levodopa treatments produced stable motor conditions without appreciable ‘off’ episodes. Continuous apomorphine infusion was associated with the worst motor scores (UPDRS‐III and taps) and the most frequent off‐states. Jejunal levodopa infusion was associated with the highest AIMS scores. Addition of a levodopa dose produced shortening of time to ‘on’ and a transient motor improvement in the jejunal levodopa group without increase in dyskinesias; in the DBS and apomorphine groups, there was an increase in dyskinesias without changes in UPDRS‐III or taps. Conclusions: STN DBS provided adequate trade‐off between motor improvement and dyskinesia control, although dyskinesias could be elicited by adding oral levodopa. Jejunal levodopa infusion produced adequate motor improvement with slow time to ‘on’ and moderate dyskinesias. Apomorphine infusion produced insufficient motor control and negligible dyskinesias.     

Long‐term outcome of early versus delayed rasagiline treatment in early Parkinson's disease

The purpose of this study to compare the long‐term clinical outcome of early versus delayed rasagiline treatment in early Parkinson's disease (PD). Subjects (N = 404) were randomly assigned to initial treatment with rasagiline (early‐start group) or placebo for 6 months followed by rasagiline (delayed‐start group) in the TEMPO study. Subjects who chose to participate in an open‐label extension (N = 306) continued to receive rasagiline as well as other PD medications as needed. Average (±SD) duration in the study was 3.6 ± 2.1 years; 177 subjects received rasagiline for ≥5.0 years. Over the entire 6.5‐year follow‐up period, the adjusted mean difference in change from baseline in total UPDRS scores was 2.5 units (SE 1.1; P = 0.021) or 16% (SE 5.7; P = 0.006) in favor of the early‐start versus delayed‐start rasagiline group. Although the interaction between treatment and time was significant, values for the early‐start group were better than the delayed‐start group across all time points. Significantly less worsening (percent change) in total UPDRS scores was observed in the early‐start group at the time points 0.5, 1.5, 2.0, 3.0, 4.5, 5.0, and 5.5 years (P < 0.05). Compared to delayed start, early initiation of rasagiline provided long‐term clinical benefit, even in the face of treatment with other dopaminergic agents. This might reflect enduring benefits due to neuroprotection or effects on compensatory mechanisms in early PD. © 2008 Movement Disorder Society     

COMT inhibition in the treatment of Parkinson’s disease

A new approach in the treatment of Parkinson’s disease is the inhibition of catechol-O-methyltransferase (COMT) with new generation COMT inhibitors, entacapone and tolcapone. Entacapone acts mainly peripherally whereas tolcapone acts both peripherally and centrally. They induce a dose-dependent inhibition of COMT activity in erythrocytes and a significant decrease in the plasma levels of 3-O-methyldopa, indicating their effectiveness as COMT inhibitors. Consequently, they increase the elimination half-life of levodopa and thus prolong the availability of levodopa to the brain without significantly affecting the C_max or t_max of levodopa. Clinically, the improved levodopa availability is seen as prolonged motor response to levodopa/DDC inhibitor and also as prolonged duration of dyskinesias in Parkinson’s disease patients with end-of-dose fluctuations. The dyskinesias are managed by decreasing the daily levodopa dose in Parkinson’s disease patients with end-of-dose fluctuations. Both pharmacokinetically and clinically the 200-mg dose of entacapone is the most effective dose compared with placebo. For tolcapone 100 and 200 mg have most often proved to be the optimal doses. Based on the duration of COMT inhibition entacapone is administered with each levodopa/DDC inhibitor dose whereas tolcapone is given three times daily. Both entacapone and tolcapone are well-tolerated. However, there seems to be a trend for tolcapone to induce more often diarrhoea and increase in liver transaminases compared with entacapone. Thus, COMT inhibitors are clinically significant and beneficial adjunct to levodopa therapy in Parkinson’s disease patients with end-of-dose fluctuations. Their effects and significance also in the treatment of de novo patients need to be clarified.