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     

Efficacy of levodopa/carbidopa/entacapone versus levodopa/carbidopa in patients with early Parkinson’s disease experiencing mild wearing-off: a randomised,double-blind trial

To compare the efficacy and safety of levodopa/carbidopa/entacapone (LCE) with levodopa/carbidopa (LC) on Parkinson’s disease (PD) patients with mild, or only minimally disabling motor complications. A prospective 3-month, multicentre, parallel-group, double-blind, and randomised phase IV study was performed. The primary endpoint was to assess the efficacy of LCE compared to LC on ADLs using the UPDRS part II. Secondary endpoints were assessed by the UPDRS (I, III and IV) scores, QUICK and PDQ-39 questionnaires, and patient and investigator clinical global impression (CGI). Ninety-five patients were randomly assigned to treatment with LCE (100/25/200 or 150/37.5/200 mg tablets, n = 46) or LC (100/25 mg tablets, n = 49), at the same levodopa dose that were administered before randomization. Treatment with LCE resulted in significantly greater improvement in UPDRS part II (ADLs) scores compared to treatment with LC (adjusted mean difference between groups of ?1.5 points) (p = 0.0288). Amelioration was also observed in UPDRS part III scores (p = 0.010), and CGI (patient and investigator) scores (p = 0.015, and p = 0.028, respectively). LCE and LC were generally well tolerated with 78 % of subjects completing the study. Most AEs (50 % in LCE and 71.4 % in LC) were classified as mild. No serious AEs were related to the treatment. Treatment with LCE results in improved efficacy compared to LC in PD patients with mild, or minimally disabling motor fluctuations, maintaining a good safety and tolerability profile.     

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     

Randomized trial of IPX066, carbidopa/levodopa extended release,in early Parkinson's disease

ObjectiveIPX066 is an extended release carbidopa/levodopa formulation designed to rapidly attain and maintain therapeutic plasma concentrations for a prolonged duration, allowing dosing intervals of approximately 6 h. The objective was to assess the efficacy, safety, and impact on quality of life of IPX066 in the treatment of levodopa-naive Parkinson's disease (PD) patients.MethodsThis was a randomized, double-blind, placebo-controlled, 30-week study of 381 levodopa-naïve patients assigned to placebo or IPX066 containing 145, 245 or 390 mg of levodopa administered three times daily (TID). The primary efficacy measure was change from Baseline in Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living (Part II) + motor scores (Part III), at 30 weeks. Secondary outcome measures included UPDRS total and subscores, patient and clinician global impressions (PGI-I, CGI-I), and the Parkinson's Disease Questionnaire (PDQ-39).ResultsAll IPX066 dosages were superior to placebo throughout the study and at 30 weeks (P < 0.0001). The mean improvement in UPDRS Parts II + III at 30 weeks compared to baseline was 11.7, 12.9, and 14.9 points for the three dosages and 0.6 points for placebo (P < 0.0001, all dosages). PDQ-39 total scores improved with IPX066 (P ≤ 0.034, all dosages). The most commonly reported adverse events with IPX066 included nausea, dizziness, and headache. No unexpected drug-related serious adverse events were reported.ConclusionIPX066 provided significant clinical benefits at the three dosages tested compared to placebo and was well tolerated in levodopa-naive PD patients. Of the dosages tested, IPX066 145 mg TID appeared to provide the best overall balance between efficacy and safety.     

Transcutaneous port for continuous duodenal levodopa/carbidopa administration in Parkinson's disease

Motor fluctuations in Parkinson's disease (PD) can be reduced by intraduodenal infusion of levodopa‐carbidopa (Duodopa®) via percutaneous endoscopic gastrojejunostomy (PEG). We applied the transcutaneous soft‐tissue anchored titanium port (T‐port) in 15 PD patients with motor fluctuations; 7 Duodopa‐naive (non‐PEG), and 8 previously receiving Duodopa (former‐PEG). Motor scores (UPDRS‐III) and quality of life (QOL, PDQ‐8) were assessed at baseline and 6 month follow‐up. Six patients had local irritation shortly after implantation, persisting in one patient at 6 month follow‐up, which led to explantation. After having finished the protocol, four T‐ports were explanted in total. UPDRS‐III and PDQ‐8 scores improved moderately in the non‐PEG patients, but remained similar in the former‐PEG users. Two former‐PEG users developed polyneuropathy. No obstructions, retractions, or leakages occurred. Technical and hygienic properties of the T‐port were preferred by most patients. The T‐port seems to be suitable for most PD patients qualifying for Duodopa therapy, although local infection may lead to explantation during longer‐term follow‐up. © 2010 Movement Disorder Society.     

Direct switch from levodopa/benserazide or levodopa/carbidopa to levodopa/carbidopa/entacapone in Parkinson’s disease patients with wearing-off: efficacy, safety and feasibility—an open-label, 6-week study

The study objective was to assess the efficacy, safety and feasibility of switching from levodopa/benserazide (LB) or levodopa/carbidopa (LC) to levodopa/carbidopa/entacapone (LCE) in Parkinson’s disease (PD) patients with wearing-off. This was a multicenter, open-label, 6-week study; the primary outcome was success rate based on the patient-assessed Clinical Global Impression of Change (P-CGI-C). Secondary outcomes included investigator-assessed CGI-C (I-CGI-C), change from baseline in Unified Parkinson’s Disease Rating Scale (UPDRS), motor/non-motor wearing-off symptoms and quality of life–visual analog scale (QoL-VAS). After switching to LCE, 77% of patients reported an ‘improvement’ (p < 0.0001 vs. patients reporting ‘no change or worsening’). Significant improvements were seen in I-CGI-C, UPDRS and QoL-VAS, regardless of prior therapy. Oral levodopa dosing was increased in 28% of patients; the primary outcome remained significant when these patients were excluded. The data suggest that switching from LB/LC to LCE provided a significant benefit in PD patients with wearing-off.     

Conversion from sustained release carbidopa/levodopa to carbidopa/levodopa/entacapone (stalevo) in Parkinson disease patients

OBJECTIVES: This study was performed to determine if conversion from sustained release carbidopa/levodopa (SR-CL) with or without entacapone to carbidopa/levodopa/entacapone (CLE; Stalevo) improves motor functioning and quality of life in Parkinson disease (PD) patients and to assess patient tolerance and drug preference. METHODS: PD patients reporting suboptimal symptom control with SR-CL were converted to CLE. The basic conversion was 1 SR-CL 25/100 to 1 25/100/200 CLE and 1 SR-CL 50/200 to 1 37.5/150/200 CLE with additional changes as necessary. RESULTS: There were 62 patients with an average age of 68 years and an average disease duration of 11 years. CLE was preferred by 42 patients and SR-CL was preferred by 20 patients. In those that preferred CLE, Unified Parkinson Disease Rating Scale (UPDRS) mentation and motor subscores, Parkinson Disease Questionnaire-39 (PDQ-39) quality-of-life activities of daily living (ADL) and bodily discomfort subscores, and Epworth Sleepiness Scale (ESS) scores were significantly improved. There were no significant changes in any measures in the group that preferred SR-CL. Common adverse effects in the group that preferred CLE included nausea, vomiting, increased dyskinesia or off time, dizziness, and somnolence. The most common adverse events in the group preferring SR-CL were increased off time or dyskinesia, nausea, and vomiting. CONCLUSIONS: A majority of patients suboptimally controlled on SR-CL can be successfully converted to CLE with improvements in motor function, quality of life, and sleepiness. Older patients, with longer disease duration not previously exposed to entacapone, may better tolerate CLE after the addition of entacapone.     

Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease

The objective of the study was to compare the pharmacokinetics, motor effects, and safety of IPX066, a novel extended‐release formulation of carbidopa‐levodopa, with an immediate‐release carbidopa‐levodopa formulation in advanced Parkinson's disease. We performed an open‐label crossover study in 27 subjects with advanced Parkinson's disease experiencing motor fluctuations on levodopa therapy. Subjects were randomized 1:1 to 8 days' treatment with either immediate‐release carbidopa‐levodopa followed by IPX066 or IPX066 followed by immediate‐release carbidopa‐levodopa. Pharmacokinetic and motor assessments were undertaken on day 1 for 8 hours (following a single dose) and on day 8 for 12 hours (during multiple‐dose administration). Following a single dose of IPX066 or immediate‐release carbidopa‐levodopa, plasma levodopa concentrations increased at a similarly rapid rate and were sustained above 50% of peak concentration for 4 hours with IPX066 versus 1.4 hours with immediate‐release carbidopa‐levodopa (P < .0001). Multiple‐dose data showed IPX066 substantially reduced variability in plasma levodopa concentrations despite a lower dosing frequency (mean, 3.5 vs 5.4 administrations per day). In addition, total levodopa exposure during IPX066 treatment was approximately 87% higher, whereas the increase in levodopa C_max was approximately 30% compared with immediate‐release carbidopa‐levodopa. Both products were well tolerated. IPX066 provided more sustained plasma levodopa concentrations than immediate‐release carbidopa‐levodopa. Larger, longer‐term, well‐controlled studies should be conducted to provide rigorous assessment of the clinical effects of IPX066. © 2011 Movement Disorder Society     

Double‐blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease

The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279‐carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate‐release carbidopa‐levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high‐capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279‐carbidopa sustained‐release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa‐levodopa four or five times daily were optimized for 2 weeks each on carbidopa‐levodopa four or five times daily and XP21279‐carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double‐blind/double‐dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double‐blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty‐eight of 35 enrolled patients completed both double‐blind treatments. The mean total daily off time was reduced from baseline by a mean (± standard error) of 2.7 hours (± 0.48 hours) for immediate‐release carbidopa‐levodopa and 3.0 hours (± 0.57 hours) for XP21279‐carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279‐carbidopa than carbidopa‐levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279‐carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa‐levodopa administered four or five times daily, and the difference was not statistically significant. XP21279‐carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa‐levodopa. © 2013 International Parkinson and Movement Disorder Society     

Intrajejunal levodopa infusion in Parkinson's disease: A pilot multicenter study of effects on nonmotor symptoms and quality of life

Switching from oral medications to continuous infusion of levodopa/carbidopa gel reduces motor complications in advanced Parkinson's disease (PD), but effects on nonmotor symptoms (NMSs) are unknown. In this prospective open‐label observational study, we report the effects of intrajejunal levodopa/carbidopa gel infusion on NMS in PD based on standard assessments utilizing the nonmotor symptoms scale (NMSS) along with the unified Parkinson's disease rating scale (UPDRS 3 motor and 4 complications) and quality of life (QoL) using the Parkinson's disease questionnaire (PDQ‐8). Twenty‐two advanced PD patients (mean age 58.6 years, duration of disease 15.3 years) were followed for 6 months. A statistically significant beneficial effect was shown in six of the nine domains of the NMSS: cardiovascular, sleep/fatigue, attention/memory, gastrointestinal, urinary, and miscellaneous (including pain and dribbling) and for the total score of this scale (NMSST) paralleling improvement of motor symptoms (UPDRS 3 motor and 4 complications in “best on” state) and dyskinesias/motor fluctuations. In addition, significant improvements were found using the Parkinson's disease sleep scale (PDSS) and the PDQ‐8 (QoL). The improvement in PDQ‐8 scores correlated highly significantly with the changes in NMSST, whereas a moderately strong correlation was observed with UPDRS changes. This is the first demonstration that a levodopa‐based continuous dopaminergic stimulation is beneficial for NMS and health‐related quality of life in PD in addition to the reduction of motor fluctuations and dyskinesias. © 2009 Movement Disorder Society     

Randomized trial of safinamide add‐on to levodopa in Parkinson's disease with motor fluctuations

Levodopa is effective for the motor symptoms of Parkinson's disease (PD), but is associated with motor fluctuations and dyskinesia. Many patients require add‐on therapy to improve motor fluctuations without exacerbating dyskinesia. The objective of this Phase III, multicenter, double‐blind, placebo‐controlled, parallel‐group study was to evaluate the efficacy and safety of safinamide, an α‐aminoamide with dopaminergic and nondopaminergic mechanisms, as add‐on to l ‐dopa in the treatment of patients with PD and motor fluctuations. Patients were randomized to oral safinamide 100 mg/day (n = 224), 50 mg/day (n = 223), or placebo (n = 222) for 24 weeks. The primary endpoint was total on time with no or nontroublesome dyskinesia (assessed using the Hauser patient diaries). Secondary endpoints included off time, Unified Parkinson's Disease Rating Scale (UPDRS) Part III (motor) scores, and Clinical Global Impression‐Change (CGI‐C). At week 24, mean ± SD increases in total on time with no or nontroublesome dyskinesia were 1.36 ± 2.625 hours for safinamide 100 mg/day, 1.37 ± 2.745 hours for safinamide 50 mg/day, and 0.97 ± 2.375 hours for placebo. Least squares means differences in both safinamide groups were significantly higher versus placebo. Improvements in off time, UPDRS Part III, and CGI‐C were significantly greater in both safinamide groups versus placebo. There were no significant between‐group differences for incidences of treatment‐emergent adverse events (TEAEs) or TEAEs leading to discontinuation. The addition of safinamide 50 mg/day or 100 mg/day to l ‐dopa in patients with PD and motor fluctuations significantly increased total on time with no or nontroublesome dyskinesia, decreased off time, and improved parkinsonism, indicating that safinamide improves motor symptoms and parkinsonism without worsening dyskinesia. © 2013 International Parkinson and Movement Disorder Society     

The effect of tolcapone on levodopa pharmacokinetics is independent of levodopa/carbidopa formulation

Clinical pharmacology studies have shown that the catechol-O-methyltransferase inhibitor tolcapone increases the bioavailability area under the plasma concentration-time curve (AUC) and the plasma elimination half-life (t _1/2) of levodopa. The objective of the study was to evaluate the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after coadministration of tolcapone 200 mg with levodopa/carbidopa in the following doses: 100/10 mg, 100/25 mg, 200/20 mg, 200/50 mg, 250/25 mg (all immediate-release) and 200/50 mg (controlled-release). Thirty healthy male volunteers were divided into four groups: three groups of 8 and one group of 6. Participants in the first three groups received two formulations of levodopa/carbidopa. Each dose was administered on two occasions, once with tolcapone 200 mg andonce with placebo (four-way crossover). In the fourth group, one formulation was given on two occasions, once with tolcapone 200 mg and oncewith placebo (two-way crossover). Dosing days were separated by a 7-day washout. The effect of tolcapone on levodopa and 3-OMD pharmacokinetics was found to be similar with all levodopa/carbidopa formulations. The absorption of levodopa wasunaffected by tolcapone in all treatment groups and the maximum plasma concentration (C _max ) remained unchanged. When tolcapone was given with the immediate-release formulations, levodopa AUC increased by 60–90% and levodopa t _1/2 by 20–60%. With tolcapone and the controlled-release formulation, AUC increased by 80% and t _1/2 by 60%. With all levodopa/carbidopa formulations, 3-OMD C _max decreased by 80% and AUC by 70% with tolcapone. Thetolerability of all treatment combinations was similar. We conclude that adjunctive treatment with tolcapone should have similar levodopa-potentiating clinical effects, regardless of the levodopa/carbidopa formulation.     

Randomized,double‐blind,multicenter evaluation of pramipexole extended release once daily in early Parkinson's disease

The objective of this study was to evaluate the efficacy and safety of pramipexole extended release (ER) administered once daily in early Parkinson's disease (PD). Pramipexole immediate release (IR) administered three times daily (TID) is an efficacious and generally well‐tolerated treatment for PD. A pramipexole ER formulation is now available. We performed a randomized, double‐blind, placebo and active comparator–controlled trial in subjects with early PD. The primary efficacy and safety evaluation of pramipexole ER compared with placebo took place at week 18. Two hundred fifty‐nine subjects were randomized 2:2:1 to treatment with pramipexole ER once daily, pramipexole IR TID, or placebo. Levodopa rescue was required by 7 subjects in the placebo group (14%), 3 subjects in the pramipexole ER group (2.9%, P = 0.0160), and 1 subject in the pramipexole IR group (1.0%, P = 0.0017). Adjusted mean [standard error (SE)] change in Unified Parkinson Disease Rating Scale (UPDRS) II [activities of daily living (ADL)] + III (motor) scores from baseline to week 18, including post‐levodopa rescue evaluations, was ?5.1 (1.3) in the placebo group, ?8.1 (1.1) in the pramipexole ER group (P = 0.0282), and ?8.4 (1.1) in the pramipexole IR group (P = 0.0153). Adjusted mean (SE) change in UPDRS ADL + motor scores, censoring post‐levodopa rescue data, was ?2.7 (1.3) in the placebo group, ?7.4 (1.1) in the pramipexole ER group (P = 0.0010), and ?7.5 (1.1) in the pramipexole IR group (P = 0.0006). Adverse events more common with pramipexole ER than placebo included somnolence, nausea, constipation, and fatigue. Pramipexole ER administered once daily was demonstrated to be efficacious compared with placebo and provided similar efficacy and tolerability as pramipexole IR administered TID. © 2010 Movement Disorder Society     

Levetiracetam for the management of levodopa‐induced dyskinesias in Parkinson's disease

The efficacy and safety of levetiracetam (LEV), administered for management of levodopa‐induced dyskinesias (LID) in Parkinson's disease (PD), was examined using a multicenter, double‐blind, placebo‐controlled, parallel groups, crossover trial. Because of having a period effect, data after crossover point was excluded from analysis. Levodopa‐treated PD participants with LID (n = 38) received LEV 500 mg/day, were assessed, titrated to 1,000 mg/day and reassessed, before and after crossover. The placebo group followed the same routine. Primary efficacy was defined from percent change in “On with LID” time from patient diaries. Secondary efficacy assessment used “On without LID,” “Off” time, unified PD rating scale (UPDRS), clinical global impression (CGI), and Goetz dyskinesia scale after levodopa challenge. Safety measures were also performed. On with LID time decreased 37 minutes (95% confidence interval [CI] 0.59, 7.15; P = 0.02) at 500 mg/day, 7.85% 75 minutes (95% CI 3.3, 12.4; P = 0.002) at 1,000 mg/day. On without LID time increased by 46 minutes (95% CI ?1.55, ?0.03; P = 0.04) at 500 mg/day and 55 minutes (95% CI ?10.39, ?1.14; P = 0.018) at 1,000 mg/day. UPDRS 32 showed decreased dyskinesia duration mean change 0.35 (95% CI 0.09, 0.5; P = 0.009) at 1,000 mg/day. CGI showed LID decreased by 0.7 (95% CI 0.21, 1.18; P = 0.006) at 1,000 mg/day. Patient diaries and UPDRS show no increase in Off time. This exploratory trial provides evidence that LEV in 1,000 mg/day, slowly titrated, could be useful in improving LID as was assessed with patient diaries, UPDRS, and CGI scales, safely, with minimal side effects. © 2010 Movement Disorder Society     

Outpatient titration of carbidopa/levodopa enteral suspension (Duopa)

Carbidopa/levodopa enteral suspension (CLES; Duopa) is a suspension or gel formulation of carbidopa/levodopa that is approved by the USA Food and Drug Administration for the treatment of advanced Parkinson's disease patients with motor fluctuations. CLES is delivered at a constant rate continuously throughout the day into the jejunum through an infusion pump via a PEG-J tube implanted surgically. The efficacy of CLES was established in the USA based on a randomized, double-blind, double-dummy, active controlled, parallel group and 12-week study, in which mean daily OFF time was reduced by 4.0 h, compared to 1.9 h with oral immediate release carbidopa/levodopa. The CLES hardware consists of a cassette containing the drug, a pump to deliver the drug and tubing to connect the PEG-J to the pump. It is critical to understand the appropriate conversion of the carbidopa/levodopa daily dosages to the CLES dosage and how to program the pump and titrate CLES to achieve the most effective dose. We describe one methodology for patient selection, outpatient titration and pump programming.     

Melevodopa/carbidopa effervescent formulation in the treatment of motor fluctuations in advanced Parkinson's disease

Melevodopa hydrochloride plus carbidopa in effervescent tablets (M/C) is a readily soluble antiparkinsonian tablet formulation. A total of 221 patients with Parkinson's disease and motor fluctuations entered a randomized, double‐blind, double‐dummy, controlled parallel group study, which compared the effectiveness of oral M/C effervescent tablets with standard oral formulation levodopa/carbidopa tablets (L/C; Sinemet) in reducing total daily OFF time. The difference of total daily OFF time (intention‐to‐treat population) between the two groups was not statistically significant (P = 0.07): ?39.4 minutes (95%CI: ?67.08 to ?11.73) in M/C group vs. +3.5 minutes (95%CI: ?36.19 to +43.26) in the L/C group. In the intragroup analysis, M/C significantly reduced the baseline daily OFF, which remained unchanged in the L/C group. There were no unexpected adverse events in either treatment arms, and discontinuation rates due to adverse events did not differ between the two groups [M/C: 2 patients (1.3%); L/C: 1 patient (1.4%)]. This study failed to meet the primary endpoint (P = 0.07); however, there was a trend in favour of the M/C preparation, which deserves further attention. © 2010 Movement Disorder Society     

Entacapone in combination with standard or controlled-release levodopa/carbidopa: a clinical and pharmacokinetic study in patients with Parkinson's disease

We investigated clinical response and pharmacokinetics of levodopa when entacapone, a catechol O-methyltransferase (COMT) inhibitor, was administered concomitantly with either a standard (Std) or a controlled-release (CR) levodopa/carbidopa preparation to 12 patients with Parkinson's disease. An open cross-over study consisted of the initial study day without entacapone followed by two 10-day treatment periods with a study day at the end of each period. The patients who received entacapone (200 mg t.i.d. or q.i.d.) concomitantly with Std levodopa/carbidopa (200/50 mg t.i.d. or q.i.d.) during the first period received subsequently entacapone with CR levodopa/carbidopa (200/50 mg t.i.d. or q.i.d.), and vice versa. On the study days, the patients took the medication at 8 a.m. and the second dose 6 h later. We evaluated the disability before drug administration and then 1-h intervals for 8 h. Repeated blood samples were taken for analysis of plasma levodopa, 3-O-methyldopa (3-OMD), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), carbidopa, and entacapone. Entacapone decreased significantly the clinical disability with both Std and CR levodopa, slightly more with Std levodopa. The clinical response started earlier with Std levodopa whereas the “on”-time increased by about 1 h, equally with both levodopa preparations. Std levodopa produced 23% higher area under the curve (AUC) of levodopa than the CR preparation, but entacapone increased the AUC approximately equally, 33% with Std and 36% with CR levodopa. Entacapone slightly decreased C_max of levodopa in combination with Std levodopa, whereas it increased that with CR levodopa. The AUC of 3-OMD was about 20% smaller after Std than after CR levodopa. Entacapone decreased the AUC of 3-OMD by 38–40% with both levodopa preparations. Entacapone did not modify the AUC levels of carbidopa although its bioavailability was less from CR levodopa than from Std levodopa. In three patients levodopa dosage was reduced when on Std levodopa because of nausea. Otherwise, the treatments were well tolerated. The study shows that entacapone is an effective COMT inhibitor when combined with either Std levodopa or CR levodopa.     

Longitudinal study of levodopa in Parkinson's disease: Effects of the advanced disease phase

Thirty‐four patients have been studied from the time of initiation of pharmacological treatment in a long‐term prospective study of levodopa effects and disease progression in Parkinson's disease. Objective motor scoring of the response to levodopa in defined off states was performed every 3 years. The mean time from the initiation of levodopa treatment to the most recent measurements was 18.2 years. Of 8 patients who are still alive, only 3 had none of the features of the advanced disease phase (dementia, hallucinations, frequent falling). Off‐phase motor function worsened at a yearly rate of 1.9% of the maximum disability score, although the plots of the serial scores showed that the magnitude of the levodopa response is well preserved. There was little difference in the rate of progression between patients with tremor‐dominant and non‐tremor‐dominant motor subtypes. Those who developed dementia had more rapid deterioration of motor scores, with significantly worse off‐phase (P = .008) and on‐phase (P = .03) motor function. A graph of serial scores of patients who have died, aligned for time of death, showed an upward curving trend of motor disability in the last 5 years of the disease course. Its advanced phase may reveal that Parkinson's disease has an exponential pattern of progression. © 2013 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     

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