Randomized trial of safinamide add-on to levodopa in Parkinson's disease with motor fluctuations.
TL;DR: The addition of safinamide 50 mg/day or 100mg/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 thatsafinamide improves motor symptoms and parkinsonistan without worsening dyskineia.
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 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 136 ± 2625 hours for safinamide 100 mg/day, 137 ± 2745 hours for safinamide 50 mg/day, and 097 ± 2375 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
Citations
More filters
TL;DR: The objective of this review was to update evidence‐based medicine recommendations for treating motor symptoms of Parkinson's disease with new recommendations for treatment of central nervous system symptoms.
Abstract: Objective The objective of this review was to update evidence-based medicine recommendations for treating motor symptoms of Parkinson's disease (PD). Background The Movement Disorder Society Evidence-Based Medicine Committee recommendations for treatments of PD were first published in 2002 and updated in 2011, and we continued the review to December 31, 2016. Methods Level I studies of interventions for motor symptoms were reviewed. Criteria for inclusion and quality scoring were as previously reported. Five clinical indications were considered, and conclusions regarding the implications for clinical practice are reported. Results A total of 143 new studies qualified. There are no clinically useful interventions to prevent/delay disease progression. For monotherapy of early PD, nonergot dopamine agonists, oral levodopa preparations, selegiline, and rasagiline are clinically useful. For adjunct therapy in early/stable PD, nonergot dopamine agonists, rasagiline, and zonisamide are clinically useful. For adjunct therapy in optimized PD for general or specific motor symptoms including gait, rivastigmine is possibly useful and physiotherapy is clinically useful; exercise-based movement strategy training and formalized patterned exercises are possibly useful. There are no new studies and no changes in the conclusions for the prevention/delay of motor complications. For treating motor fluctuations, most nonergot dopamine agonists, pergolide, levodopa ER, levodopa intestinal infusion, entacapone, opicapone, rasagiline, zonisamide, safinamide, and bilateral STN and GPi DBS are clinically useful. For dyskinesia, amantadine, clozapine, and bilateral STN DBS and GPi DBS are clinically useful. Conclusions The options for treating PD symptoms continues to expand. These recommendations allow the treating physician to determine which intervention to recommend to an individual patient. © 2018 International Parkinson and Movement Disorder Society.
538 citations
Centre national de la recherche scientifique1, Karolinska Institutet2, Lund University3, Columbia University4, University of British Columbia5, University of Cagliari6, Vanderbilt University Medical Center7, Oklahoma State University Center for Health Sciences8, University of Ferrara9, University of Milan10, Michigan State University11, Toronto Western Hospital12
TL;DR: The present review attempts to provide an overview of the current understanding of dyskinesia and other L-dopa-induced dysfunctions to help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.
365 citations
TL;DR: This 2‐year, controlled study of add‐on safinamide in mid‐to‐late Parkinson's disease with motor fluctuations showed improvement in dyskinesia in patients at least moderately dyskinetic at baseline, and 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.
Abstract: 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.
200 citations
Cites background from "Randomized trial of safinamide add-..."
...Safinamide is a novel therapy in development as addon therapy to dopamine agonists in early PD4,5 and to L-dopa in mid- to late-stage PD.6 An orally active aaminoamide derivative, safinamide has both dopaminergic and nondopaminergic mechanisms of action, and it is a potent, selective, and reversible inhibitor of monoamine oxidase-B (MAO-B) and also exhibits statedependent blockade of voltage-gated sodium channels, interaction with aminoamine transporters, and inhibition of stimulated release of glutamate.7-11 Given the proposed role of glutamate in the development of dyskinesia,12,13 inhibition of glutamate release could contribute to the therapeutic activity of safinamide....
[...]
...Six months’ treatment with safinamide (50 and 100 mg/d) as an L-dopa add-on in PD patients with motor fluctuations significantly improves ON time without troublesome dyskinesia and motor function versus placebo (Study 016).(6) This study (Study 018) was an 18-month, placebocontrolled extension to Study 016....
[...]
...This study is the longest placebo-controlled study of safinamide in patients with mid-to-late PD....
[...]
...In the 24-week study (Study 016), 669 patients with mid- to-late-stage PD and motor fluctuations were randomized to safinamide 50 mg/d, safinamide 100 mg/d, or placebo as add-on therapy to L-dopa and other PD medications.(6) Randomization was performed on a country-specific basis, using a computergenerated randomization schedule....
[...]
...Safinamide is a novel therapy in development as addon therapy to dopamine agonists in early PD(4,5) and to L-dopa in mid- to late-stage PD.(6) An orally active aaminoamide derivative, safinamide has both dopaminergic and nondopaminergic mechanisms of action, and it is a potent, selective, and reversible inhibitor of monoamine oxidase-B (MAO-B) and also exhibits statedependent blockade of voltage-gated sodium channels, interaction with aminoamine transporters, and inhibition of stimulated release of glutamate....
[...]
TL;DR: The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off.
Abstract: IMPORTANCE:
Although levodopa remains the most effective oral pharmacotherapy for Parkinson disease (PD), its use is often limited by wearing off effect and dyskinesias. Management of such complications continues to be a significant challenge.
OBJECTIVE:
To investigate the efficacy and safety of safinamide (an oral aminoamide derivative with dopaminergic and nondopaminergic actions) in levodopa-treated patients with motor fluctuations.
DESIGN, SETTING, AND PARTICIPANTS:
From March 5, 2009, through February 23, 2012, patients from academic PD care centers were randomized (1:1 ratio) to receive double-blind adjunctive safinamide or placebo for 24 weeks. All patients had idiopathic PD with “off” time (time when medication effect has worn off and parkinsonian features, including bradykinesia and rigidity, return) of greater than 1.5 hours per day (excluding morning akinesia). Their pharmacotherapy included oral levodopa plus benserazide or carbidopa in a regimen that had been stable for 4 weeks or longer. During screening, each patient’s regimen was optimized to minimize motor fluctuations. Study eligibility required that after 4 weeks of optimized treatment, the patients still have more than 1.5 hours per day of off time. Adverse events caused the premature study discontinuation of 12 individuals (4.4%) in the safinamide group and 10 individuals (3.6%) in the placebo group.
INTERVENTIONS:
Patients took safinamide or placebo as 1 tablet daily with breakfast. If no tolerability issues arose by day 14, the starting dose, 50 mg, was increased to 100 mg.
MAIN OUTCOMES AND MEASURES:
The prespecified primary outcome was each treatment group’s mean change from baseline to week 24 (or last “on” treatment value) in daily “on” time (relief of parkinsonian motor features) without troublesome dyskinesia, as assessed from diary data.
RESULTS:
At 119 centers, 549 patients were randomized (mean [SD] age, 61.9 [9.0] years; 334 male [60.8%] and 371 white [67.6%]): 274 to safinamide and 275 to placebo. Among them, 245 (89.4%) receiving safinamide and 241 (87.6%) receiving placebo completed the study. Mean (SD) change in daily on time without troublesome dyskinesia was +1.42 (2.80) hours for safinamide, from a baseline of 9.30 (2.41) hours, vs +0.57 (2.47) hours for placebo, from a baseline of 9.06 (2.50) hours (least-squares mean difference, 0.96 hour; 95% CI, 0.56-1.37 hours; P < .001, analysis of covariance). The most frequently reported adverse event was dyskinesia (in 40 [14.6%] vs 15 [5.5%] and as a severe event in 5 [1.8%] vs 1 [0.4%]).
CONCLUSIONS AND RELEVANCE:
The outcomes of this trial support safinamide as an effective adjunct to levodopa in patients with PD and motor fluctuations to improve on time without troublesome dyskinesia and reduce wearing off.
152 citations
TL;DR: The goal of this Review article is to highlight the current state-of-the-art in this area by profiling 42 selected compounds that combine fluorine and amino acid structural elements, including examples of drug-candidates that although withdrawn from development had a significant impact on the progress of medicinal chemistry and/or provided a deeper understanding of the nature and mechanism of biological action.
122 citations
References
More filters
TL;DR: Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson's disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.
567 citations
TL;DR: Motor complications and especially nocturnal akinesia and biphasic dyskinesias worsened the QL of PD patients, and motor complications led to a deterioration of all dimensions of the PDQ‐39.
Abstract: The impact of motor complications of Parkinson's disease (PD), especially levodopa-induced dyskinesias, on quality of life (QL) was studied in 143 patients with PD. All were evaluated on the Hoehn and Yahr (H&Y) scale, and the Motor part of the Unified Parkinson's Disease Rating Scale (UPDRS). Motor complications were analyzed using the UPDRS Parts IVA and IVB and the Abnormal Involuntary Movement Scale. A specific Parkinson's disease quality of life questionnaire (39-item version, PDQ-39) was used. Motor complications significantly worsened the PDQ-39 Summary Index (PDQ-SI) of patients with PD. The dimensions of Mobility, Activities of Daily Living, Stigma, and Communication were the most strongly affected. “Peak dose” dyskinesia decreased Mobility, Emotional Well-Being, and Cognition, whereas biphasic dyskinesia affected Mobility, Stigma, Communication, and Activities of Daily Living. Morning akinesia, end-of-dose fluctuations, and “unpredictable offs” decreased QL on the dimensions of Mobility, Activities of Daily Living, Stigma, and Communication. Nocturnal akinesia led to a deterioration of all dimensions of the PDQ-39. Thus, motor complications and especially nocturnal akinesia and biphasic dyskinesias worsened the QL of PD patients. © 2004 Movement Disorder Society
488 citations
"Randomized trial of safinamide add-..." refers background in this paper
...Dyskinesia is the most disabling side effect of current PD medications and can have a significant impact on patients’ quality of life.(16) The study also showed improvements in motor function and patients’ overall clinical status, activities of daily living, and some aspects of quality of life with safinamide....
[...]
TL;DR: In this paper, a cross-sectional analysis of the CIDs for UPDRS total and motor scores was performed on patients with Parkinson disease (PD) using distribution-and anchor-based approaches based on the following external standards: disability (10% on the Schwab and England Activities of Daily Living Scale), disease stage (1 stage on the Hoehn and Yahr Scale), and quality of life (1 SD on the 12-Item Short Form Health Survey).
Abstract: Objective To determine the estimates of minimal, moderate, and large clinically important differences (CIDs) for the Unified Parkinson's Disease Rating Scale (UPDRS). Design Cross-sectional analysis of the CIDs for UPDRS total and motor scores was performed on patients with Parkinson disease (PD) using distribution- and anchor-based approaches based on the following 3 external standards: disability (10% on the Schwab and England Activities of Daily Living Scale), disease stage (1 stage on the Hoehn and Yahr Scale), and quality of life (1 SD on the 12-Item Short Form Health Survey). Setting University of Maryland Parkinson Disease and Movement Disorders Center, Patients Six hundred fifty-three patients with PD. Results A minimal CID was 2.3 to 2.7 points on the UPDRS motor score and 4.1 to 4.5 on the UPDRS total score. A moderate CID was 4.5 to 6.7 points on the UPDRS motor score and 8.5 to 10.3 on the UPDRS total score. A large CID was 10.7 to 10.8 points on the UPDRS motor score and 16.4 to 17.8 on the UPDRS total score. Conclusions Concordance among multiple approaches of analysis based on subjective and objective data show that reasonable estimates for the CID on the UPDRS motor score are 2.5 points for minimal, 5.2 for moderate, and 10.8 for large CIDs. Estimates for the UPDRS total score are 4.3 points for minimal, 9.1 for moderate, and 17.1 for large CIDs. These estimates will assist in determining clinically meaningful changes in PD progression and response to therapeutic interventions.
403 citations
"Randomized trial of safinamide add-..." refers methods in this paper
...Importantly, the change in UPDRS-III from baseline with safinamide (Table 2) represented a clinically important difference, according to criteria developed by Shulman et al.17 In general, the benefits of safinamide were more often observed with safinamide 100 mg/day, although the lower dose of 50 mg/ day was significantly superior to placebo for most measures....
[...]
...Importantly, the change in UPDRS-III from baseline with safinamide (Table 2) represented a clinically important difference, according to criteria developed by Shulman et al.(17) In general, the benefits of safinamide were more often observed with safinamide 100 mg/day, although the lower dose of 50 mg/ day was significantly superior to placebo for most measures....
[...]
TL;DR: The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neuro-degenerative disorder.
Abstract: Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson’s disease (PD). The substantia nigra pars compacta—the area where the primary pathological lesion is located—is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neuro-degenerative disorder.
315 citations
"Randomized trial of safinamide add-..." refers background in this paper
...Also, as PD progresses, nondopaminergic pathways (eg, glutamate) become involved in the development of dyskinesia.(5,6) Therefore, there is a need for new PD treatments with both dopaminergic and nondopaminergic effects....
[...]
TL;DR: To provide evidence‐based recommendations for the management of late (complicated) Parkinson's disease (PD), based on a review of the literature, a list of therapeutic interventions is provided, including classification of evidence and ratings of efficacy.
Abstract: The aim of the study was to provide evidence-based recommendations for the management of early (uncomplicated) Parkinson's disease (PD), based on a review of the literature. Uncomplicated PD refers to patients suffering from the classical motor syndrome of PD only, without treatment-induced motor complications and without neuropsychiatric or autonomic problems. MEDLINE, Cochrane Library and International Network of Agencies for Health Technology Assessment (INAHTA) database literature searches were conducted. National guidelines were requested from all European Federation of Neurological Societies (EFNS) societies. Non-European guidelines were searched for using MEDLINE. Part I of the guidelines deals with prevention of disease progression, symptomatic treatment of motor features (parkinsonism), and prevention of motor and neuropsychiatric complications of therapy. For each topic, a list of therapeutic interventions is provided, including classification of evidence. Following this, recommendations for management are given, alongside ratings of efficacy. Classifications of evidence and ratings of efficacy are made according to EFNS guidance. In cases where there is insufficient scientific evidence, a consensus statement (good practice point) is made.
305 citations