Quality of life in early Parkinson's disease treated with levodopa/carbidopa/entacapone

We aimed to investigate whether treatment with levodopa/carbidopa/entacapone when compared with levodopa/carbidopa improves quality of life in Parkinson's disease (PD) patients with no or minimal, nondisabling motor fluctuations. This is a multicenter, randomized, double‐blind study. One hundred eighty‐four patients on 3 to 4 equal doses of 100/25 to 200/50 mg levodopa/carbidopa or levodopa/benserazide, 0 to 3 hours of nondisabling OFF time over a 48 hour period and no dyskinesia were randomized to levodopa/carbidopa/entacapone or levodopa/carbidopa treatment for 12 weeks. The primary outcome measure was quality of life as assessed by the PDQ‐8. Secondary outcome measures were the UPDRS parts I–IV, and the Wearing Off Card. Treatment with levodopa/carbidopa/entacapone resulted in significantly greater improvements in PDQ‐8 scores compared to treatment with levodopa/carbidopa (mean difference 1.4 points, P = 0.021). Statistically significant improvements were seen predominantly in nonmotor domains (depression, personal relationships, communication, stigma, all P < 0.05; dressing P = 0.056). Patients who were randomly assigned to levodopa/carbidopa/entacapone also showed significantly greater improvement in UPDRS part II scores (P = 0.032) with UPDRS part III scores showing borderline significance. Differences in UPDRS parts I and IV and Wearing Off Card scores were not significant. Treatment with levodopa/carbidopa/entacapone results in improved quality of life compared with levodopa/carbidopa in PD patients with mild or minimal, nondisabling motor fluctuations. © 2007 Movement Disorder Society     

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     

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, 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.     

Entacapone improves motor fluctuations in levodopa- treated Parkinson's disease patients

Motor fluctuations associated with levodopa therapy are common problems encountered in the long-term treatment of Parkinson's disease (PD). Entacapone, a peripherally acting, reversible inhibitor of catechol-O-methyltransferase, slows the elimination of levodopa in humans by reducing the formation of 3-O-methyldopa. We conducted a placebo-controlled, double-blind, parallel-group, multicenter trial of entacapone in PD patients with motor fluctuations. Two hundred five patients were randomized to receive either entacapone 200 mg or matching placebo with each dose of levodopa and were followed for 24 weeks. The primary measure of efficacy was the change in percentage of “on” time (relief of parkinsonism) while awake, as recorded by subjects at home in diaries completed at 30-minute intervals. At baseline, patients averaged approximately 10 hours of “on” time per day while awake (60.5% “on” time), and entacapone treatment increased the percent “on” time by 5.0 percentage points. The effect of entacapone was more prominent in patients with a smaller percent “on” time (<55%) at baseline, and increased as the day wore on. Entacapone is effective at increasing the duration of response to levodopa and at relieving parkinsonism in patients experiencing motor flucturations and was well tolerated during the 24 weeks of treatment.     

Early versus delayed initiation of entacapone in levodopa‐treated patients with Parkinson’s disease: a long‐term,retrospective analysis

Background: We analysed data from three clinical trials in Parkinson’s disease (PD) patients with wearing‐off to determine whether early enhancement of levodopa therapy with entacapone can lead to better long‐term outcomes than delayed entacapone treatment. Methods: Post‐hoc analysis of pooled data from three randomized, double‐blind, placebo‐controlled studies and their long‐term, open‐label extension phases. In all three studies, patients on levodopa/dopa‐decarboxylase inhibitor (DDCI) were first randomized to entacapone (‘early‐start’ group) or placebo (‘delayed‐start’ group) for the initial 6‐month double‐blind phase, after which all patients received open‐label levodopa/DDCI and entacapone treatment for up to 5 years. Results: A total of 488 PD patients with wearing‐off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and entacapone was found, with an improvement in Unified Parkinson’s Disease Rating Scale Part III (motor) score of ?1.66 (95% confidence intervals [?3.01, ?0.31]) points compared with the delayed‐start treatment group (P < 0.05). Levodopa/DDCI and entacapone therapy was well tolerated. There was no excess of dyskinesia in the early‐start group. Conclusions: These data suggest that early rather than delayed addition of entacapone to levodopa/DDCI in PD patients with wearing‐off provides a modest clinical benefit over levodopa/DDCI that is maintained for up to 5 years.     

Effect of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, on the motor response to acute treatment with levodopa in patients with Parkinson''s disease.

Catechol-O-methyltransferase (COMT) inhibitors may be useful in the treatment of Parkinson's disease by improving the bioavailability of levodopa and by prolonging its effects. Entacapone (OR-611), a novel COMT inhibitor, which does not cross the blood brain barrier, was assessed in 12 patients with Parkinson's disease and motor fluctuations in a randomised, double-blind, cross-over, single dose study. The magnitude and duration of the therapeutic response to a single dose of 200 mg levodopa/50 mg carbidopa was evaluated after concomitant placebo, or 200 or 800 mg entacapone. A significant increase in the duration of the motor response to levodopa was seen when 200 mg entacapone was given with levodopa/carbidopa. Plasma levodopa concentrations were increased with both doses of the COMT inhibitor. The latency to onset of motor response did not differ significantly between active drug and placebo. Entacapone may prove useful in prolonging the duration of the benefit obtained from individual doses of levodopa.     

Catechol-O-methyltransferase inhibition with entacapone: Evidence from controlled clinical trials in Parkinson's disease

Adjunct therapy with the catechol-O-methyltransferase inhibitor entacapone is a first-line approach to treat wearing-off type motor fluctuations in levodopa-treated Parkinson's disease (PD) patients. Five randomized placebo-controlled trials including a total of >1000 patients have established its efficacy, showing increases in ON time between 0.7 and 1.6 h, with corresponding OFF-time reductions. These and other trials also found improvements in ON motor function and quality of life. Additional trials have tested the efficacy of adjunct entacapone in patients either without or with early and mild motor fluctuations and also found enhanced motor control and improved activities of daily living function and quality of life, whereas the STRIDE-PD trial failed to show efficacy of early entacapone use in delaying the onset of dyskinesias. Adjunct entacapone enhances dopaminergic activity and may increase levodopa-induced adverse events like dyskinesias, which can usually be controlled by modest levodopa dose reductions. There is no formal requirement to monitor liver function during entacapone treatment. Entacapone can be a rare cause of lymphocytic colitis with severe diarrhoea and need for treatment discontinuation. In 2003, a triple-combination pill of levodopa, carbidopa, and entacapone (LCE) was first introduced onto the market, and since then proprietary LCE (Stalevo^®) is indicated on the basis of those trials for patients with idiopathic PD to (i) substitute for immediate-release carbidopa/levodopa and entacapone previously administered as individual products or (ii) replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients taking a total daily dose of levodopa of ≤600 mg and not experiencing dyskinesias experience signs and symptoms of end-of-dose wearing off.     

Inhibition of the COMPT with entacapone in the treatment of motor fluctuations in Parkinson disease

Motor fluctuations are a common problem in the long-term treatment of Parkinson's disease (PD). Entacapone (Comtan) is a potent, peripherally acting, reversible and selective inhibitor of catechol-O-methyltransferase (COMT). Used as an adjuvant to levodopa therapy, entacapone slows the elimination of levodopa by decreasing peripheral conversion to 3-O-methyldopa, increasing central extracellular levodopa and striatal dopamine concentrations. Coadministered with levodopa/carbidopa or levodopa/benserazide, at doses of 200 mg 2 to 10 times daily in patients with end-of-dose fluctuations, entacapone may increase the duration of clinical response, both after the first single dose and after repeated dosing. At this dosage, it has a time to peak plasma concentration of 1.2 h and an elimination half life of 3.4 h. In two multicentric, long-term (24 weeks), parallel, randomized and placebo-controlled studies, entacapone increased the duration of 'on' time (by approximately 1 hour daily) and decreased the duration of 'off' time with a concomitant reduction in the mean daily levodopa dose. In these and other phase III studies, entacapone was generally well tolerated, with most adverse effects being dyskinesias and gastrointestinal disorders. Increased dyskinesia were generally controlled by reducing levodopa doses. Entacapone appears to be a useful adjunct in extending the benefit of each levodopa dose in PD patients with end-of-dose fluctuations.     

Efficacy and safety of entacapone in Parkinson's disease patients with suboptimal levodopa response: a 6-month randomized placebo-controlled double-blind study in Germany and Austria (Celomen study)

OBJECTIVES: To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. PATIENTS AND METHODS: In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries ('on' and 'off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. RESULTS: In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P < 0.05) by entacapone vs placebo. In fluctuating patients, 'on' time increased (1.7 h) and 'off' time decreased (1.5 h) significantly more with entacapone than with placebo (0.5 and 0.6 h, respectively; P < 0.05), and the daily levodopa dose was reduced by 54 mg with entacapone and increased by 27 mg with placebo (P < 0.05). Entacapone benefit was lost on withdrawal. Entacapone efficacy was comparable between patients using CR and standard levodopa preparations. Increased dyskinesias (entacapone 34%, placebo 26%) and nausea (10 and 5%, respectively), mostly occurring shortly after treatment initiation, were generally managed by reducing the levodopa dose. Diarrhoea (entacapone 8%, placebo 4%) was seldom severe. There were no differences in vital signs, ECG or laboratory results. CONCLUSION: Entacapone is an effective and safe levodopa extender and enhancer, improving the symptomatic efficacy of levodopa in PD and adding to the patients' benefit.     

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     

Efficacy and tolerability of entacapone in patients with Parkinson's disease treated with levodopa plus a dopamine agonist and experiencing wearing-off motor fluctuations. A randomized,double-blind,multicentre study

The efficacy and tolerability of entacapone was investigated in a randomized, double-blind, placebo-controlled, 3-month study of 162 patients with Parkinson's disease (PD) treated with levodopa and a dopamine agonist and experiencing wearing-off motor fluctuations. Patients were randomized in a 3 : 2 ratio to entacapone 200 mg or placebo, administered with each dose of levodopa. Efficacy was judged on the improvement of "on" and "off" time while awake (Patient Diary and UPDRS part IV Item 39), Investigators' Global Assessment, the SF-36 Health Survey, and changes in levodopa dosages. Patients were monitored for adverse events, laboratory safety and vital signs throughout the study. Improvements in "on" time as assessed using patient diary data showed a trend in favour of entacapone, however these did not reach statistical significance. "Off" time while awake (UPDRS part IV Item 39) showed an improvement of at least one category in 36% of entacapone-treated patients, compared with 22% in the control group (p = 0.0038). The proportion of patients showing an improvement at the Investigators' Global Assessment was significantly higher (p = 0.0006) in the entacapone-treated group of patients. Also, the proportion of patients with a reduction in their daily levodopa dose was significantly higher (p = 0.02) in the entacapone group (28%) compared with placebo (13%). As expected, the most frequent adverse events were dopamine-mediated (dyskinesia: entacapone 31% versus placebo 13%), and harmless urinary discoloration. The modest increase in dyskinesias could be readily managed by levodopa down-adjustment, and, at study end there was no significant difference for the UPDRS "overall dyskinesia score" between entacapone and placebo. In conclusion, although the primary efficacy variable did not reach statistical significance, the present results demonstrate that entacapone provides additional antiparkinsonian benefits to levodopa therapy and is well tolerated in levodopa-treated PD patients experiencing wearing-off motor fluctuations despite adjunct dopamine agonist therapy.     

Fewer fluctuations,higher maximum concentration and better motor response of levodopa with catechol-O-methyltransferase inhibition

Catechol-O-methyltransferase inhibitor addition to levodopa/carbidopa formulations improves motor symptoms and reduces levodopa fluctuations in patients with Parkinson’s disease. Objectives were to investigate the effects of entacapone and tolcapone on plasma behaviour of levodopa, its metabolite 3-O-methyldopa and on motor impairment. 22 patients orally received levodopa/carbidopa first, then levodopa/carbidopa/entacapone and finally levodopa/carbidopa plus tolcapone within a 4.5 h interval twice. Maximum concentration, time to maximum level and bioavailability of levodopa did not differ between all conditions each with 200 mg levodopa application as a whole. Catechol-O-methyltransferase inhibition caused less fluctuations and higher baseline levels of levodopa after the first intake and less 3-O-methyldopa appearance. The maximum levodopa concentrations were higher after the second levodopa intake, particularly with catechol-O-methyltransferase inhibition. The motor response to levodopa was better with catechol-O-methyltransferase inhibition than without, tolcapone was superior to entacapone. More continuous levodopa brain delivery and lower 3-O-methyldopa bioavailability caused a better motor response during catechol-O-methyltransferase inhibition.     

Clinical advantages of COMT inhibition with entacapone – a review

Two catechol- O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were developed during the 1990's to be used as adjuncts to levodopa (LD) - dopa decarboxylase (DDC) inhibitors in the treatment of Parkinson's disease (PD). Entacapone is currently in wide clinical use, while tolcapone can be used in restricted indications only, due to its hepatotoxicity. COMT inhibitors prolong the elimination of LD, while DDC inhibitors mainly increase its absorption; both mechanisms leading to increased bioavailability of LD. The pharmacokinetic properties of LD, carbidopa and entacapone are quite similar, and entacapone is administered concomitantly with LD plus carbidopa. Entacapone prolongs the clinical effect of each LD dose by 30 to 40 minutes; this effect is seen already after the first entacapone dose. When LD is administered in several frequent daily doses, addition of entacapone reduces the daily fluctuations of plasma LD by 30 to 40%.Based on studies with home diaries, entacapone increases the daily ON-time by an average of one to two hours, and reduces the daily OFF-time correspondingly in patients with PD with motor fluctuations. The daily LD dose has been reduced by 10 to 30%. These positive effects are sustained in long term use over several years. There is still scant information of the benefit of entacapone in patients without motor fluctuations.Entacapone can cause both dopaminergic and non-dopaminergic adverse events. Increased dyskinesias are most frequently recorded in patients with motor fluctuations. The dopaminergic adverse events can usually be diminished by reducing the LD dose. Non-dopaminergic adverse events are abdominal pain and diarrhea. Diarrhoea has led to discontinuation in 3 to 4% of the patients in clinical trials. Entacapone has not been connected to liver toxicity and there are no indications to follow laboratory safety during treatment. The benefit-risk ratio of entacapone is considered favorable.A triple LD/carbidopa/entacapone combination tablet has recently been developed. Three LD strengths (50, 100 and 150 mg) are available, each contains 200 mg of entacapone. The majority of the patients can be managed with these three LD strengths. Entacapone has today an established position in treatment of PD patients with motor fluctuations, either as a separate tablet or as the triple LD combination.     

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.     

ND0612 (levodopa/carbidopa for subcutaneous infusion) in patients with Parkinson's disease and motor response fluctuations: A randomized,placebo-controlled phase 2 study

IntroductionND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system under development for patients with Parkinson's disease (PD) and motor fluctuations.MethodsThis was a randomized, placebo-controlled, double-blind, 2-period study evaluating the safety and pharmacokinetics of ND0612 in PD patients on an optimized oral levodopa regimen and experiencing ≥2 h/day of OFF time. During Period-1, patients received their current standard of care (SoC) levodopa/carbidopa and were randomized (2:1) to 14 days treatment with adjunct ND0612 (daily levodopa/carbidopa dose of 270/63 mg) or placebo infusion +SoC. During Period-2, 16 patients were randomized to receive 7 days treatment with ND0612 or ND0612 plus oral entacapone. Reduction in OFF time was analyzed as an exploratory measure using a futility design with a predefined margin of 1.6 h.ResultsND0612 was well-tolerated; most patients experienced infusion site nodules (95% vs. 56% with placebo), which all resolved without sequelae. Patients treated with adjunct ND0612 during Period-1 avoided deep troughs in levodopa plasma levels and had a decreased fluctuation index versus placebo (1.6 ± 0.5 vs 3.1 ± 1.6 at end of Period-1, respectively). In Period-2, the coadministration of entacapone with continuous ND0612 SC infusion translated to an increase in mean levodopa AUC_0–10h compared to baseline. Exploratory efficacy analysis of Period 1 showed mean ± SD OFF time reductions of −2.13 ± 2.24 [90%CI: -2.8, ∞] hours (p = 0.84 using H₀ of μ₀ ≤-1.6).ConclusionLevodopa/carbidopa infusion with ND0612 was generally well-tolerated and resulted in reduced fluctuations in plasma levodopa concentrations when given with SoC oral levodopa. ND0612 met the efficacy endpoint for the futility design.     

Pharmacokinetic‐pharmacodynamic crossover comparison of two levodopa extension strategies

Controlled‐release carbidopa and levodopa (CL‐CR) and the combination of carbidopa, levodopa, and entacapone (CLE) are used for extending levodopa (L ‐dopa) effects. In a randomized, open‐label crossover study of 17 PD subjects with wearing‐off responses, we compared 8‐hour L ‐dopa pharmacokinetics (PK) and clinical effects after two doses of CL‐CR (50 and 200 mg, respectively) and CLE (37.7, 150, 200 mg, respectively). PK analysis revealed the anticipated near‐equivalent mean L ‐dopa area‐under‐the‐concentration‐curve values (639,490 ng min/mL for two doses of CLE, and 662,577 for CL‐CR, P = 0.86). The mean hourly fluctuation index for L ‐dopa concentration was 235% for CLE and 196% for CL‐CR (P = 0.004). The mean maximal concentration for the first CLE dose was 1,926 ± 760 ng/mL and for CL‐CR, 1,840 ± 889 (P = 0.33). During the PK studies, the mean time that L ‐dopa concentration was ≥1,000 ng/mL for CLE was 291 ± 88 minutes and for CL‐CR, 306 ± 86 (P = 0.33). The mean percent‐time in “off” state was 18% for CLE and 28% for CL‐CR (P = 0.017), “on state without dyskinesia” was 64% for CLE and 65% for CL‐CR (P = 0.803), and “on state with nontroublesome dyskinesia” was 18% for CLE and 7% for CL‐CR (P = 0.03). Despite less “off” time with CLE, both formulations demonstrated similar mean PK values and marked intersubject PK variability. © 2009 Movement Disorder Society     

Orodispersible sublingual piribedil to abort OFF episodes: A single dose placebo‐controlled,randomized, double‐blind,cross‐over study

S90049, a novel sublingual formulation of the non‐ergoline D₂‐D₃ agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single‐dose double‐blind double‐placebo 3 × 3 cross‐over study. Optimal tested doses were determined during a previous open‐label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (ΔUPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 ± 8 years, PD duration: 12 ± 6 years, UPDRS III OFF: 37 ± 15) participated. S90049 wassuperior to placebo on ΔUPDRS III (?13 ± 12 versus ?7 ± 9 respectively; estimated difference ?5.2, 95% Confidence Interval (CI)[?10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, ΔUPDRS III was similar on S90049 (?21.2 ± 10.1) and apomorphine (?23.6 ± 14.1) (estimated difference: 4.0 95% CI [?2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate. © 2009 Movement Disorder Society     

Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: A single‐dose,double‐blind,double‐dummy,placebo‐controlled,crossover trial

Levodopa use in fluctuating Parkinson's disease (PD) is complicated by an inconsistent and prolonged onset to clinical improvement. An orally dissolved carbidopa/levodopa (OD C/L) preparation (Parcopa UCB Pharma) is available in the United States. This offers potential advantages to shorten the duration from ingestion to clinical improvement. Surprisingly, this has never been clinically assessed. We tested 20 patients with fluctuating PD and a Unified Parkinson's Disease Rating Scale (UPDRS) “off” motor score of ≥25 in a 2‐day, single‐dose, double‐blind, double‐dummy, crossover study. Patients arrived in the morning in the practically defined “off” state and were randomly assigned to receive identical doses of either oral C/L and OD placebo or OD C/L and oral C/L placebo on 1st day and the reverse combination on a 2nd day. After training, patients underwent bilateral hand tapping at baseline and every 5 minutes for 60 minutes after dose ingestion. Stride length (SL) was recorded at 5‐minute intervals with an ambulatory gait monitor. Patients identified their subjective latency to “on” and noted drug preferences and adverse events. They also underwent a UPDRS motor examination at baseline and 60 minutes after dose. Twenty subjects [15 male, age 68.7 (9.7), PD duration 13.4 (6.8)] completed. There were no significant group differences in tapping speed, subjective time to “on,” latency of increased SL, or overall preference. However, all trends did favor OD C/L. Adverse events were similar. This small pilot study did not show significant group differences favoring OD C/L; however, larger studies may be justified, and individual patients may benefit. © 2010 Movement Disorder Society     

Efficacy and safety of tolcapone in levodopa-treated Parkinson's disease patients with “wearing-off” phenomenon: a multicentre,double-blind,randomized, placebo-controlled trial

To assess the effect of tolcapone added to levodopa plus benserazide or carbidopa on the “wearing-off” phenomenon in patients with Parkinson's disease, we undertook a double-blind, randomized, placebo-controlled, parallel-group study of tolcapone 50, 200, or 400 mg three times daily (t.i.d.) for 6 weeks in addition to levodopa therapy. We studied 154 parkinsonian patients, aged 40 years or more, who presented with the “wearing-off” phenomenon despite “optimal” antiparkinsonian therapy. The main outcome measures were “on”- and “off”-time, Investigator's Global Assessments, Subscales of the Unified Parkinson's Disease Rating Scale, changes in levodopa dosage, and safety and tolerability. Tolcapone was more effective than placebo in reducing the “wearing-off” phenomenon between baseline and week 6 at all three dosages. Tolcapone 200 mg t.i.d. increased “on”-time from 37.9% of the waking day to 50.8% (p < 0.01) and reduced “off”-time from 26.7% of the waking day to 16.4% (p < 0.05). Tolcapone treatment was generally well tolerated at all dosages. Initial exacerbation of adverse dopaminergic effects was controlled by levodopa dosage adjustment; at week 6, the mean total daily levodopa dosage had decreased by 80 mg, from 694 mg at baseline, in the tolcapone 200 mg t.i.d. group (p < 0.01). We conclude that the addition of tolcapone to levodopa plus a decarboxylase inhibitor effectively and safely reduces the “wearing-off” phenomenon in parkinsonian patients.