Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations

The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW‐6002) is an adenosine A_2A receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12‐week, multicenter, double‐blind, placebo‐controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti‐Parkinson's medications. Istradefylline‐treated subjects had significant placebo‐corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline‐treated and 7 (6.1%) placebo‐treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations. © 2008 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     

Amantadine extended release for levodopa‐induced dyskinesia in Parkinson's disease (EASED Study)

ADS‐5102 is a long‐acting, extended‐release capsule formulation of amantadine HCl administered once daily at bedtime. This study investigated the safety, efficacy, and tolerability of ADS‐5102 in Parkinson's disease (PD) patients with levodopa‐induced dyskinesia. This was a randomized, double‐blind, placebo‐controlled, parallel‐group study of 83 PD patients with troublesome dyskinesia assigned to placebo or one of three doses of ADS‐5102 (260 mg, 340 mg, 420 mg) administered daily at bedtime for 8 weeks. The primary efficacy analysis compared change from baseline to week 8 in Unified Dyskinesia Rating Scale (UDysRS) total score for 340 mg ADS‐5102 versus placebo. Secondary outcome measures included change in UDysRS for 260 mg, 420 mg, Fatigue Severity Scale (FSS), Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS), patient diary, Clinician's Global Impression of Change, and Parkinson's Disease Questionnaire (PDQ‐39). ADS‐5102 340 mg significantly reduced dyskinesia versus placebo (27% reduction in UDysRS, P = 0.005). In addition, ADS‐5102 significantly increased ON time without troublesome dyskinesia, as assessed by PD patient diaries, at 260 mg (P = 0.004), 340 mg (P = 0.008) and 420 mg (P = 0.018). Adverse events (AEs) were reported for 82%, 80%, 95%, and 90% of patients in the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. Constipation, hallucinations, dizziness, and dry mouth were the most frequent AEs. Study withdrawal rates were 9%, 15%, 14%, and 40% for the placebo, 260‐mg, 340‐mg, and 420‐mg groups, respectively. All study withdrawals in the active treatment groups were attributable to AEs. ADS‐5102 was generally well tolerated and resulted in significant and dose‐dependent improvements in dyskinesia in PD patients. © 2015 Adamas Pharmaceuticals, Inc. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Helicobacter pylori infection and motor fluctuations in patients with Parkinson's disease

To investigate whether Helicobacter pylori (HP) infection affects the clinical response to levodopa and whether its eradication could improve motor fluctuation in patients with Parkinson's disease (PD). Using the [¹³C] urea breath test, we monitored HP infection in 65 patients with PD and motor fluctuations of the “wearing‐off” or delayed “on” types, with or without dyskinesia. We compared the clinical features and response to L ‐dopa between HP noninfected (n = 30) and HP infected patients (n = 35) by reviewing home diaries kept for 72 hours. Among HP infected patients, we compared the differences in L ‐dopa “onset” time, “on‐time” duration, and scores on the motor examination section of the Unified PD Rating Scale (UPDRS‐III) during the medication “on” phase before and after HP eradication. There were no differences in the age, disease duration, Hoehn and Yahr stage, UPDRS‐III score, L ‐dopa daily dose, and frequency of dyskinesia between HP noninfected and HP infected groups. However, L ‐dopa “onset” time was longer and “on‐time” duration was shorter in HP infected patients than in HP noninfected patients (78.4 ± 28.2 vs. 56.7 ± 25.1 and 210.0 ± 75.7 vs. 257.7 ± 68.9 min, respectively, P < 0.05). HP eradication improved the delay L ‐dopa “onset” time and short “on‐time” duration (to 58.1 ± 25.6 and to 234.4 ± 66.5 min, respectively, P < 0.05). These data demonstrated that HP infection could interfere with the absorption of L ‐dopa and provoke motor fluctuations. HP eradication can improve the motor fluctuations of HP infected patients with PD. © 2008 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     

Safety and efficacy of perampanel in advanced Parkinson's disease: A randomized,placebo‐controlled study

Perampanel, a novel, noncompetitive, selective AMPA‐receptor antagonist demonstrated evidence of efficacy in reducing motor symptoms in animal models of Parkinson's disease (PD). We assessed the safety and efficacy of perampanel for treatment of “wearing off” motor fluctuations in patients with PD. Patients (N = 263) were randomly assigned to once‐daily add‐on 0.5, 1, or 2 mg of perampanel or placebo. The primary objective was to determine whether there was a dose‐response relationship for efficacy among the 3 perampanel doses and placebo. The primary efficacy endpoint for each treatment was measured as the least‐squares (LS) mean change from baseline to week 12 in percent “off” time reduction during the waking day, as recorded by patient diaries. The primary efficacy analysis was a 1‐sided Williams test for dose‐response trend at the 0.025 level of significance. At week 12, dose‐response trends, as determined by the Williams test, were not statistically significant for LS mean reduction in percent “off” time during the waking day (P = 0.061, with significance defined as P ≤ 0.025). The 2 higher perampanel doses (ITT population; n = 258) produced nonsignificant reductions from baseline to week 12 in percent “off” time during the waking day versus placebo (7.59%, P= 0.421 [1 mg], 8.60%, P = 0.257 [2 mg] versus 5.05% [placebo]; significance for pairwise comparisons defined as P ≤ 0.05). There were no significant changes in dyskinesia or cognitive function in any perampanel group versus placebo. Adverse events were similar across treatment groups. Perampanel treatment was well tolerated and safe, but failed to achieve statistical significance in primary and secondary endpoints. © 2010 Movement Disorder Society     

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.     

Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005)

Objective

Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A_2A receptor antagonist, istradefylline, shows promise for the treatment of PD.

Methods

Istradefylline (40mg/day) was studied in levodopa‐treated PD subjects experiencing prominent wearing‐off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double‐blind, 12‐week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake “off” time, recorded by subjects using a patient PD diary. Secondary end points evaluated “on” time (including “on time with dyskinesia”), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression–Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring.

Results

After randomization, approximately 88% of subjects completed the double‐blind period. Compared with baseline, the decrease of daily awake “off” time for istradefylline was a mean (± standard deviation) of ?10.8 ± 16.6% (95% confidence interval, ?13.46 to ?7.52) and for placebo, ?4.0 ± 15.7% (95% confidence interval, ?7.73–0.31; p = 0.007 using two‐way analysis of variance). This effect corresponded to changes from baseline in total daily awake “off” time of ?1.8 ± 2.8 hours for istradefylline and ?0.6 ± 2.7 hours for placebo (p = 0.005). Treatment‐emergent adverse effects with istradefylline were generally mild.

Interpretation

Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in “off” time without increased troublesome dyskinesia. Ann Neurol 2008

     

Early treatment benefits of ropinirole prolonged release in Parkinson's disease patients with motor fluctuations

We performed a retrospective analysis of the Efficacy And Safety Evaluation in Parkinson's Disease (EASE‐PD) Adjunct Study, assessing the minimum time to symptom improvement after initiation of ropinirole prolonged release (2–24 mg/day) versus placebo in patients with moderate‐to‐advanced PD not optimally controlled with levodopa. Ropinirole prolonged release was superior to placebo at Week 2 for change from baseline in “off” time (adjusted mean treatment difference [AMTD] – 0.7 hours; 95% confidence interval [CI], –1.1, –0.2; P = 0.0029), and “on” time without troublesome dyskinesia (0.4 hours; 95%CI, 0.01, 0.88; P = 0.0444). At Week 4, improvements were seen in change from baseline in Unified Parkinson's Disease Rating Scale total motor score (AMTD, –3.1; 95%CI, –4.4, –1.8; P < 0.0001), activities of daily living score (AMTD, –1.1; 95%CI, –1.7, –0.5; P = 0.0004), and the cardinal symptoms of PD compared with placebo. These analyses indicate that once‐daily, adjunctive ropinirole prolonged release can offer PD symptom control 2 weeks after treatment initiation. © 2010 Movement Disorder Society     

Onset of dyskinesia with adjunct ropinirole prolonged‐release or additional levodopa in early Parkinson's disease

Levodopa‐induced dyskinesia can result in significant functional disability and reduced quality of life in patients with Parkinson's disease (PD). The goal of this study was to determine if the addition of once‐daily ropinirole 24‐hour prolonged‐release (n = 104) in PD patients not optimally controlled with levodopa after up to 3 years of therapy with less than 600 mg/d delays the onset of dyskinesia compared with increasing doses of levodopa (n = 104). During the study, 3% of the ropinirole prolonged‐release group (mean dose 10 mg/d) and 17% of the levodopa group (mean additional dose 284 mg/d) developed dyskinesia (P < 0.001). There were no significant differences in change in Unified Parkinson's Disease Rating Scale activities of daily living or motor scores, suggesting comparable efficacy between the two treatments. Adverse events were comparable in the two groups with nausea, dizziness, insomnia, back pain, arthralgia, somnolence, fatigue, and pain most commonly reported. Ropinirole prolonged‐release delayed the onset of dyskinesia with comparable efficacy to increased doses of levodopa in early PD patients not optimally controlled with levodopa. © 2010 Movement Disorder Society     

Do dyskinesia and pain share common pathophysiological mechanisms in Parkinson's disease?

Plastic changes within the striatum resulting from pulsatile dopaminergic stimulation are thought to lead to dyskinesia in patients with Parkinson's disease (PD). The basal ganglia play a role in processing pain. We hypothesized that the plastic changes that lead to dyskinesia may also mediate pain responses. Our objective was to compare the change in pain sensitivity after levodopa administration between stable responders, fluctuators without dyskinesia, and dyskinetic patients, and to compare pain sensitivity between PD and healthy subjects. Fifty patients with PD were assessed with cold water immersion after overnight withdrawal of dopaminergic medications and again after a standard levodopa challenge, and carefully classified into stable responder (n = 12), fluctuator (n = 15), and dyskinetic (n = 23) groups. Twenty age‐matched controls were also tested. PD patients “off”‐medication had a lower threshold (P = 0.016) and tolerance (P < 0.0001) to cold pain compared to controls. After levodopa administration, dyskinetic patients experienced a large increase in cold pain threshold (48%) and tolerance (66%) that was absent in stable responders (P = 0.038 and P = 0.015); there was no significant difference in pain sensitivity change scores between the fluctuator and either the stable responder or dyskinetic groups. Our results suggest that dyskinesia and pain may share common pathophysiological mechanisms in PD. © 2008 Movement Disorder Society     

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     

AFQ056 treatment of levodopa‐induced dyskinesias: Results of 2 randomized controlled trials

Study objectives were to assess the efficacy, safety, and tolerability of AFQ056 in Parkinson's disease patients with levodopa‐induced dyskinesia. Two randomized, double‐blind, placebo‐controlled, parallel‐group, in‐patient studies for Parkinson's disease patients with moderate to severe levodopa‐induced dyskinesia (study 1) and severe levodopa‐induced dyskinesia (study 2) on stable dopaminergic therapy were performed. Patients received 25–150 mg AFQ056 or placebo twice daily for 16 days (both studies). Study 2 included a 4‐day down‐titration. Primary outcomes were the Lang‐Fahn Activities of Daily Living Dyskinesia Scale (study 1), the modified Abnormal Involuntary Movement Scale (study 2), and the Unified Parkinson's Disease Rating Scale–part III (both studies). Secondary outcomes included the Unified Parkinson's Disease Rating Scale–part IV items 32–33. The primary analysis was change from baseline to day 16 on all outcomes. Treatment differences were assessed. Fifteen patients were randomized to AFQ056 and 16 to placebo in study 1; 14 patients were randomized to each group in study 2. AFQ056‐treated patients showed significant improvements in dyskinesias on day 16 versus placebo (eg, Lang‐Fahn Activities of Daily Living Dyskinesia Scale, P = .021 [study 1]; modified Abnormal Involuntary Movement Scale, P = .032 [study 2]). No significant changes were seen from baseline on day 16 on the Unified Parkinson's Disease Rating Scale‐part III in either study. Adverse events were reported in both studies, including dizziness. Serious adverse events (most commonly worsening of dyskinesias, apparently associated with stopping treatment) were reported by 4 AFQ056‐treated patients in study 1, and 3 patients (2 AFQ056‐treated patient and 1 in the placebo group) in study 2. AFQ056 showed a clinically relevant and significant antidyskinetic effect without changing the antiparkinsonian effects of dopaminergic therapy. © 2011 Movement Disorder Society     

Two‐year,randomized, controlled study of safinamide as add‐on to levodopa in mid to late Parkinson's disease

In a 6‐month double‐blind, placebo‐controlled study of Parkinson's disease patients with motor fluctuations, safinamide 50 and 100 mg/d significantly increased ON‐time without increasing dyskinesia. Further long‐term safinamide use in these patients was evaluated over an additional 18 months. Patients continued on their randomized placebo, 50, or 100 mg/d safinamide. The primary endpoint was change in Dyskinesia Rating Scale total score during ON‐time over 24 months. Other efficacy endpoints included change in ON‐time without troublesome dyskinesia, changes in individual diary categories, depressive symptoms, and quality of life measures. Change in Dyskinesia Rating Scale was not significantly different in safinamide versus placebo groups, despite decreased mean total Dyskinesia Rating Scale with safinamide compared with an almost unchanged score in placebo. Ad hoc subgroup analysis of moderate to severe dyskinetic patients at baseline (36% of patients) showed a decrease with safinamide 100 mg/d compared with placebo (P = 0.0317). Improvements in motor function, activities of daily living, depressive symptoms, clinical status, and quality of life at 6 months remained significant at 24 months. Adverse events and discontinuation rates were similar with safinamide and placebo. This 2‐year, controlled study of add‐on safinamide in mid‐to‐late Parkinson's disease with motor fluctuations, although not demonstrating an overall difference in dyskinesias between patients and controls, showed improvement in dyskinesia in patients at least moderately dyskinetic at baseline. The study additionally demonstrated significant clinical benefits in ON‐time (without troublesome dyskinesia), OFF‐time, activities of daily living, motor symptoms, quality of life, and symptoms of depression. © 2014 International Parkinson and Movement Disorder Society     

Levodopa‐carbidopa intestinal gel in advanced Parkinson's disease: Final 12‐month,open‐label results

Motor complications in Parkinson's disease (PD) are associated with long‐term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l ‐dopa‐carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG‐J), which reduces l‐ dopa‐plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54‐week, open‐label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post‐LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary‐assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health‐related quality‐of‐life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG‐J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty‐seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l‐ dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Task force report on scales to assess dyskinesia in Parkinson's disease: Critique and recommendations

Drug‐induced dyskinesia is a common phenomenon in Parkinson's disease (PD) and is often socially as well as physically disabling for patients. The Movement Disorders Society commissioned a task force to assess available clinical rating scales, critique their clinimetric properties, and make recommendations regarding their clinical utility. A task force composed six clinical researchers who systematically searched the literature for scales measuring dyskinesia in PD, evaluated the scales' previous use, performance parameters, and quality of validation data (if available). A scale was designated “Recommended” if the scale has been used in clinical studies beyond the group that developed it, has been specifically used in PD reports, and if clinimetric studies have established that it is a valid, reliable, and sensitive. “Suggested” scales met two of the above criteria and those meeting one were “Listed.” Based on the systematic review, eight rating scales for dyskinesia that have either been validated or used in PD were identified. These were the Abnormal Involuntary Movement Scale (AIMS), The Unified Parkinson's Disease Rating Scale (UPDRS) part IV, the Obeso Dyskinesia Rating Scale, the Rush Dyskinesia Rating Scale, the Clinical Dyskinesia Rating Scale (CDRS), the Lang‐Fahn Activities of Daily Living Dyskinesia Scale, the Parkinson Disease Dyskinesia Scale (PDYS‐26), and the Unified Dyskinesia Rating Scale (UDysRS). Based on this review, at present two of the reviewed dyskinesia scales (AIMS and the Rush Dyskinesia Rating Scale) fulfill criteria for Recommended for use in PD populations, albeit weakly so; all of the remaining met criteria to be Suggested. However, the two most recent scales (PDYS‐26 and UDysRS) have excellent clinimetric properties and appear to provide a reliable and valid assessment tool of dyskinesia in PD. If they are used successfully beyond the groups that developed them, both have the potential to be re‐ranked as Recommended. As further testing of these scales in PD is warranted, no new scales are needed until the available scales are fully tested clinimetrically. © 2010 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.     

Clinical pattern and risk factors for dyskinesias following fetal nigral transplantation in Parkinson's disease: A double blind video‐based analysis

The objective of this study is to assess dyskinesias in 34 Parkinson's disease patients randomized to receive bilateral fetal nigral transplantation with 4 donors per side (12), 1 donor per side (11), or placebo (11). Videotape recordings were performed at the baseline, 3, 6, 12, 18, and 24 month visits during the “practically defined off” (12 hours after last evening dopaminergic therapy) and “best on” (best response following morning dopaminergic therapy) states. Videotapes were analyzed in random order by a blinded investigator. Dyskinesias during “best on” (on‐medication dyskinesia) were observed in all, but 1 patient at baseline, and in all patients at each subsequent visit. There were no differences between groups. No patient had dyskinesia at baseline in “practically‐defined off” (“off‐medication” dyskinesia). Following transplantation, off‐medication dyskinesia was observed in 13 of 23 patients, but not in any patient in the placebo group (P = 0.019). There was no difference in dyskinesia score between patients in the 1 and 4 donor groups. On‐medication dyskinesias were typically generalized and choreiform, whereas off‐medication dyskinesias were usually repetitive, stereotypic movements in the lower extremities with residual Parkinsonism in other body regions. Off‐medication dyskinesias are common following transplantation and may represent a prolonged form of diphasic dyskinesias. © 2008 Movement Disorder Society     

Long‐term antidyskinetic efficacy of amantadine in Parkinson's disease

Several randomized placebo‐controlled trials have consistently shown antidyskinetic effects of amantadine in levodopa treated patients with advanced Parkinson's disease (PD). However, all of these were of short duration and there have been claims that the effect of amantadine on levodopa induced dyskinesias (LID's) wear off after about 9 months of treatment. This randomized placebo‐controlled parallel‐group study was performed to assess the long‐term antidyskinetic effect of amantadine in 32 PD patients, who after having been on stable amantadine therapy for LID over at least one year‐ were switched in a double blind manner to amantadine or placebo and followed for 3 weeks. Dyskinesia duration and intensity were assessed by UPDRS IV items 32 and 33 as well as by patient's diaries. The primary outcome was the score change of UPDRS IV items 32 + 33 between baseline and 3 weeks after treatment as well as the between treatment group comparison of the score change of UPDRS IV items 32 + 33. There was a significant increase of UPDRS IV items 32 + 33 in patients treated with placebo from 3.06 (95% CI, 2.1–4.03) at baseline to 4.28 (95% CI, 3.1–5.4) at three‐week follow‐up (P = 0.02) compared with no significant change between baseline 3.2 (95% CI, 2.1–4.4) to follow‐up 3.6 (95% CI, 2.3–4.8) in patients staying on amantadine. These findings argue for long‐term antidyskinetic efficacy of amantadine in PD patients with LID's. © 2010 Movement Disorder Society     

Effect of histamine H2 receptor antagonism on levodopa–induced dyskinesia in the MPTP‐macaque model of Parkinson's disease

Levodopa‐induced motor complications, including dyskinesia and wearing off, are troublesome side effects of treatment and impair quality of life in Parkinson's disease (PD) patients. The use of nondopaminergic agents as adjuncts to levodopa are potential options for managing these problems. Here, we asses the ability of the clinically available, selective histamine H₂ antagonist, famotidine (1, 3, and 30 mg/kg) to treat levodopa‐induced dyskinesia and wearing off in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐macaque model of PD. Famotidine (3 mg/kg) increased peak activity, enhanced peak anti‐parkinsonian action (1 and 3 mg/kg), and extended duration of action (3 mg/kg, by 38%) of a low dose of levodopa (compared to low dose levodopa alone). Enhancement of anti‐parkinsonian actions of low dose levodopa by famotidine (3 mg/kg) was associated with only mild, nondisabling dystonia. Famotidine had no effect on the anti‐parkinsonian actions of high dose levodopa (compared to high dose levodopa alone). However, famotidine (1, 3, and 30 mg/kg) had a significant effect on chorea, but not dystonia, induced by high dose levodopa (compared to high dose levodopa alone). Famotidine increased high dose levodopa–induced “good quality” on time, i.e., on time not associated with disabling dyskinesia, by up to 28% (compared to high dose levodopa alone). In conclusion, famotidine, a drug currently available for use in the clinic, can enhance the peak‐dose anti‐parkinsonian actions and extend total duration of action of a low dose of levodopa, without producing disabling dyskinesia. Furthermore, in combination with a higher dose of levodopa, famotidine can reduce peak‐dose levodopa‐induced chorea and improve the quality of on‐time. © 2010 Movement Disorder Society