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

ABSTRACT: 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 ?-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.

SUBMITTER: Borgohain R

PROVIDER: S-EPMC4285943 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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

Borgohain Rupam R Szasz J J Stanzione P P Meshram C C Bhatt M M Chirilineau D D Stocchi F F Lucini V V Giuliani R R Forrest E E Rice P P Anand R R

Movement disorders : official journal of the Movement Disorder Society 20131209 2

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 patien ...[more]

PMID: 24323641

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Project description:BackgroundLevodopa remains the gold standard for the treatment of Parkinson's disease, but its long-term use is associated with motor complications whose management is still a significant challenge. Safinamide is a multimodal drug with proven efficacy as an adjunct to levodopa.ObjectiveThe objective of this study was to investigate the efficacy and safety of safinamide as an add-on to levodopa in Chinese patients with Parkinson's disease with motor fluctuations.MethodsThe XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter study, with a 2-week screening period and a 16-week treatment period. The starting dose of safinamide (or placebo) was 50 mg once daily, increased to 100 mg once daily at day 15. Patients aged ≥ 18 years, with idiopathic Parkinson's disease of >3 years duration, Hoehn and Yahr stage 1-4, and daily OFF time ≥ 1.5 h, were eligible. Patients should follow a stable oral levodopa regimen and may receive concomitant treatment with stable doses of other anti-Parkinson drugs, except monoamine oxidase-B inhibitors. Patients with severe disabling peak-dose or biphasic dyskinesia, unpredictable or widely swinging fluctuations, other forms of parkinsonism, a history of dementia or severe cognitive dysfunction, major psychiatric illnesses, and/or clinically significant medical illnesses were excluded. The primary efficacy endpoint was the change from baseline to week 16 in the mean daily OFF time. Secondary efficacy endpoints included the Unified Parkinson's Disease Rating Scale, the Numerical Rating Scale, the Clinical Global Impression scale, and the 39-Item Parkinson's Disease Questionnaire scale. The statistical analysis of the efficacy parameters was conducted using an analysis of co-variance, except for the Clinical Global Impression scale scores that were assessed using the Wilcoxon-Mann-Whitney test. Safety was evaluated through the frequency of adverse events and serious adverse events, physical examination, vital signs, 12-lead electrocardiograms, and laboratory exams. All safety endpoints were summarized using descriptive statistics.ResultsThe trial enrolled 307 patients. At week 16, the difference in the change of the mean total daily OFF time between safinamide and placebo groups was 1.10 h (p < 0.0001). This change was significantly greater in the safinamide group starting from week 2, suggesting a rapid onset of drug efficacy. ON time, Unified Parkinson's Disease Rating Scale, Clinical Global Impression scale, and the 39-Item Parkinson's Disease Questionnaire showed statistically significant improvements. There were no significant between-group differences for adverse events or serious adverse events.ConclusionsSafinamide, as add-on therapy to levodopa, significantly reduced motor fluctuations and improved motor symptoms and quality of life of Chinese patients with idiopathic Parkinson's disease. The improvements observed in the Unified Parkinson's Disease Rating Scale total and motor scores were also clinically significant. No safety concerns were identified, confirming the good tolerability profile of the drug.Clinical trial registrationNCT03881371, registered on 19 March, 2019, https://clinicaltrials.gov/NCT03881371 .

Project description:Levodopa-induced dyskinesia gradually emerges during long-term dopamine therapy, causing major disability in patients with Parkinson disease. Using pharmacodynamic functional MRI, we have previously shown that the intake of levodopa triggers an excessive activation of the pre-supplementary motor area in Parkinson disease patients with peak-of-dose dyskinesia. In this pre-registered, interventional study, we tested whether the abnormal responsiveness of the pre-supplementary motor area to levodopa may constitute a 'stimulation target' for treating dyskinesia. A gender-balanced group of 17 Parkinson disease patients with peak-of-dose dyskinesia received 30 min of robot-assisted repetitive transcranial magnetic stimulation, after they had paused their anti-Parkinson medication. Real-repetitive transcranial magnetic stimulation at 100% or sham-repetitive transcranial magnetic stimulation at 30% of individual resting corticomotor threshold of left first dorsal interosseous muscle was applied on separate days in counterbalanced order. Following repetitive transcranial magnetic stimulation, patients took 200 mg of oral levodopa and underwent functional MRI to map brain activity, while they performed the same go/no-go task as in our previous study. Blinded video assessment revealed that real-repetitive transcranial magnetic stimulation delayed the onset of dyskinesia and reduced its severity relative to sham-repetitive transcranial magnetic stimulation. Individual improvement in dyskinesia severity scaled linearly with the modulatory effect of real-repetitive transcranial magnetic stimulation on task-related activation in the pre-supplementary motor area. Stimulation-induced delay in dyskinesia onset correlated positively with the induced electrical field strength in the pre-supplementary motor area. Our results provide converging evidence that the levodopa-triggered increase in pre-supplementary motor area activity plays a causal role in the pathophysiology of peak-of-dose dyskinesia and constitutes a promising cortical target for brain stimulation therapy.

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

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

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