ADS-5102 (Amantadine) Extended-Release Capsules for Levodopa-Induced Dyskinesia in Parkinson Disease (EASE LID Study): A Randomized Clinical Trial.

Importance: Medical treatment of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) is an unmet need. Objective: To evaluate the efficacy and safety of ADS-5102 (amantadine) extended-release 274-mg capsules for treatment of LID in patients with PD. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled clinical trial was conducted between May 7, 2014, and July 22, 2015, at 44 North American sites among patients with PD treated with levodopa who experienced at least 1 hour of troublesome dyskinesia per day with at least mild functional impact. Interventions: Patients were randomized to receive placebo or 274 mg of ADS-5102 administered orally at bedtime for up to 25 weeks. Main Outcomes and Measures: The primary efficacy analysis was the change from baseline to week 12 in the Unified Dyskinesia Rating Scale total score for ADS-5102 vs placebo in the modified intent-to-treat population. OFF time (amount of time the PD medication is not controlling motor symptoms) was a key secondary end point. Safety analyses included all patients who received the study drug (ADS-5102 or placebo). Results: A total of 189 patients were screened, and 126 were randomized; the modified intent-to-treat population included 121 patients (51 women and 70 men; mean [SD] age, 64.7 [9.1] years). At week 12, the least-squares mean (SE) change in the Unified Dyskinesia Rating Scale score was -15.9 (1.6) for ADS-5102 (n = 63) and -8.0 (1.6) for placebo (n = 58) (treatment difference, -7.9; 95% CI, -12.5 to -3.3; P < .001). OFF time decreased by a mean (SE) of 0.6 (0.3) hours for ADS-5102 and increased by 0.3 (0.3) hours for placebo (treatment difference, -0.9 hours; 95% CI, -1.6 to -0.2; P = .02). Common adverse events for ADS-5102 vs placebo included visual hallucinations (15 [23.8%] vs 1 [1.7%]), peripheral edema (15 [23.8%] vs 0), and dizziness (14 [22.2%] vs 0). Adverse events led to treatment discontinuation for 13 patients receiving ADS-5102 (20.6%) vs 4 patients receiving placebo (6.9%). Conclusions and Relevance: ADS-5102, 274 mg at bedtime, may be an effective treatment for LID. An additional benefit is reduced OFF time. To our knowledge, this is the first demonstration of an oral treatment reducing both LID and OFF time in patients with PD with dyskinesia. Trial Registration: clinicaltrials.gov Identifier: NCT02136914.

Conversion to carbidopa and levodopa extended-release (IPX066) followed by its extended use in patients previously taking controlled-release carbidopa-levodopa for advanced Parkinson's disease.

BACKGROUND: IPX066 (Rytary®; carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achieve therapeutic LD plasma concentrations within 1h of dosing and maintain LD concentrations for a prolonged duration in early or advanced Parkinson's disease (PD). METHODS: In this open-label study, patients underwent 6weeks of conversion to IPX066 from their prior controlled-release (CR)±immediate-release (IR) CD-LD therapy and 6months of maintenance (with an additional 6months of IPX066 at some sites). Clinical utility was assessed at both the end of conversion and maintenance. RESULTS: Among 43 patients initiated on IPX066, 33 completed conversion. The mean LD conversion ratio was 1.8 among 30 patients previously on CR plus IR (and 1.5 among 3 previously taking CR alone). The mean IPX066 dosing frequency was 3.5times/day compared with 2.6times/day for CR plus 4.6times/day for IR previously (and 4.7times/day for CR alone). By patient and clinician global improvement ratings after 6-month maintenance, ≥43.8% of patients were much or very much improved from their previous treatment, and ≥68.8% were at least minimally improved. Adverse events were consistent with those reported in prior IPX066 studies. CONCLUSIONS: These results suggest that advanced PD patients using CR CD-LD±IR can be safely converted to IPX066, with high likelihood of achieving a stable regimen, less frequent LD dosing, and improved overall clinical benefit. TRIAL REGISTRATION: Clinicaltrials.govNCT01411137.

Conversion to IPX066 from Standard Levodopa Formulations in Advanced Parkinson's Disease: Experience in Clinical Trials.

BACKGROUND: Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours. OBJECTIVE: To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting. METHODS: Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided. RESULTS: Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE. CONCLUSIONS: Among PD patients with substantial "off" time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

Long-Term Treatment with Extended-Release Carbidopa-Levodopa (IPX066) in Early and Advanced Parkinson's Disease: A 9-Month Open-Label Extension Trial.

BACKGROUND AND OBJECTIVE: IPX066 is a multiparticulate extended-release formulation of carbidopa-levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson's disease (PD). METHODS: Participants were enrolled from two phase III IPX066 studies and one open-label phase II study. Early PD patients were titrated to an appropriate dosing regimen while advanced patients started with regimens established in the antecedent studies. Adjustment was allowed throughout the extension. Clinical utility measures included the Unified Parkinson's Disease Rating Scale (UPDRS) and Patient Global Impression (PGI) ratings. RESULTS: Among 268 early PD patients, 53.4 % reported adverse events (AEs) and 1.1 % (three patients) discontinued due to AEs; the most frequent AEs were nausea (5.6 %) and insomnia (5.6 %). Among 349 advanced patients, 60.2 % reported AEs and 3.7 % (13 patients) discontinued due to AEs; the most frequent AEs were dyskinesia (6.9 %) and fall (6.6 %). At month 9 (or early termination), 78.3 % of early patients were taking IPX066 three times daily (median: 720 mg/day) and 87.7 % of advanced patients were taking IPX066 three or four times daily (median: 1450 mg/day). Adjusting for 70 % bioavailability relative to immediate-release (IR) carbidopa-levodopa, the median dosages correspond to ~500 and ~1015 mg/day of IR levodopa in early and advanced PD, respectively. Based on the plasma profiles previously observed in PD patients, the IPX066 regimens in the extension can be estimated to provide a levodopa Cmax (maximum plasma drug concentration) similar to or lower than that provided by IR regimens during the antecedent trials. UPDRS and PGI findings showed sustained treatment effects throughout the extension. CONCLUSION: During 9 months of extended use, IPX066 exhibited a safety/tolerability profile consistent with dopaminergic PD therapy.

Quantitative analysis of tremors in welders.

BACKGROUND: Workers chronically exposed to manganese in welding fumes may develop an extra-pyramidal syndrome with postural and action tremors. OBJECTIVES: To determine the utility of tremor analysis in distinguishing tremors among workers exposed to welding fumes, patients with Idiopathic Parkinson's Disease (IPD) and Essential Tremor (ET). METHODS: Retrospective study of recorded tremor in subjects from academic Movement Disorders Clinics and Welders. Quantitative tremor analysis was performed and associated with clinical status. RESULTS: Postural tremor intensity was increased in Welders and ET and was associated with visibly greater amplitude of tremor with arms extended. Mean center frequencies (Cf) of welders and patients with ET were significantly higher than the mean Cf of PD subjects. Although both the welders and the ET group exhibited a higher Cf with arms extended, welders could be distinguished from the ET subjects by a significantly lower Cf of the rest tremor than that measured in ET subjects. CONCLUSIONS: In the context of an appropriate exposure history and neurological examination, tremor analysis may be useful in the diagnosis of manganese-related extra-pyramidal manifestations.

Ropinirole 24-hour prolonged release and ropinirole immediate release in early Parkinson's disease: a randomized, double-blind, non-inferiority crossover study.

OBJECTIVE: This study compares once-daily ropinirole 24-h prolonged release and three-times-daily ropinirole immediate release in patients with early Parkinson's disease. METHODS: This multicentre, double-blind, non-inferiority crossover study involved 161 patients randomized to one of four formulation sequences: (1) immediate release-immediate release-prolonged release; (2) immediate release-prolonged release-prolonged release; (3) prolonged release-prolonged release-immediate release; (4) prolonged release-immediate release-immediate release. During a 12-week dose-titration period, ropinirole immediate release was titrated according to the approved labelling; titration of ropinirole 24-h prolonged release started at a higher dose and was more rapid. Patients then entered three consecutive, flexible-dose, 8-week maintenance periods. At the end of the first maintenance period, half of the patients in each formulation group switched to the same or closest dose of the alternative formulation; remaining patients switched at the end of the second maintenance period. RESULTS: At the end of titration, before the first dose switch, there were substantial reductions in mean Unified Parkinson's Disease Rating Scale (UPDRS) motor scores. During maintenance periods, both groups showed similar efficacy on the UPDRS motor score. Overall mean (standard error) change from period baseline was -0.1 (0.28) for ropinirole 24-h prolonged release, and 0.6 (0.30) for ropinirole immediate release (adjusted mean treatment difference -0.7; 95% confidence interval [CI]: -1.51, 0.10; p = 0.0842). The upper limit of the 95% CI was less than the predefined threshold of 3 points for non-inferiority. Ropinirole 24-h prolonged release was well-tolerated when titrated more rapidly than ropinirole immediate release; overnight switching between formulations was also well-tolerated. Study limitations included complexity of the non-inferiority study design and the forced dose-titration schedule. CONCLUSION: Ropinirole 24-h prolonged release was effective and well-tolerated in patients with early Parkinson's disease.

A multicenter, open-label, sequential study comparing preferences for carbidopa-levodopa orally disintegrating tablets and conventional tablets in subjects with Parkinson's disease.

BACKGROUND: Patients with Parkinson's disease (PD) may have difficulty taking their medications for various reasons. In these patients, orally disintegrating tablets (ODTs) can be given without water and may provide greater convenience and ease of use than conventional tablets. OBJECTIVE: This study compared preferences for ODTs with those of the conventional tablet formulation of the antiparkinsonism combination drug carbidopa-levodopa (C.-L.) in subjects with PD. METHODS: Subjects aged > or =18 years with PD controlled using a stable dosage of C-L were enrolled in this multicenter, open-label, sequential study. Subjects received their stable dose of conventional C-L for 7 +/- 3 days. They were then switched to the same dose of C-L in the ODT formulation for 14.+/- 3 days. During the last 3 days of each treatment period, subjects were to record in a diary their "on" and "off" times (asymptomatic and symptomatic parkinsonism, respectively) and medication use. On the final day of each treatment period, the Unified Parkinson's Disease Rating Scale (UPDRS) was administered to subjects before the first morning dose and then after dosing when they mentioned they were experiencing the "on" state. A Global Preference Questionnaire (GPQ) was completed by subjects at the end of the study. The primary variable was response to all GPQ items. Secondary variables were changes in UPDRS score and mean amount of "off" time per 24 hours. Adverse effects (AEs) also were monitored. RESULTS: Sixty-one subjects (31 men, 30 women; mean[SD] age, 71.8 [8.3] years; mean body weight, 76.2 kg) participated in the study and were included in the AE assessment; 60 completed the study and were included in the efficacy assessment. Twenty-seven subjects (45%) preferred ODTs compared with 12 (20%) who preferred the conventional tablets (P < 0.017). The remaining 21 subjects (35%) had no preference. The attributes of the ODTs that influenced subjects' preference for that formulation included accessibility to medication to treat "off" times (30 [50%]); ease of activities of daily living (28 [47%]); reduced concern about swallowing the medication (27 [45%]); and use for nighttime dosing, ease of compliance with dosing schedule, and feeling less self-conscious about others noticing medication use (each, 25 [42%]) (all, P < 0.001). No statistically significant differences in UPDRS scores in the "on" and "off" states were found between the 2 formulations. The incidence of AEs was statistically similar between the 2 formulations. CONCLUSIONS: In this small study of ODT C-L versus conventional C-L tablets in these adult subjects with PD, the results suggest that the ODTs may be of value in certain patients with PD, depending on their personal preferences, disease status, and willingness to alter an aspect of their medication use. For selected patients with PD, the ODT C-L formulation may provide increased convenience, ease of use, and rapid access to medication.

[18F]-Dopa positron emission tomography imaging in early-stage, non-parkin juvenile parkinsonism.

There are few reports of positron emission tomography (PET) in juvenile parkinsonism (JP). We report on the results of (18)F-6-fluoro-L-dopa (FD) PET in a 14-year-old patient with JP of 5 years duration associated with atypical features. This is the youngest subject to be investigated to date. There was a severe asymmetric reduction in striatal FD uptake, with a rostrocaudal gradient in the putamen similar to that seen in adult-onset idiopathic parkinsonism. Extensive DNA analysis in this patient did not show mutations in the parkin gene.