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A systematic review and meta-analysis of safety and efficacy of safinamide for motor fluctuations in patients with Parkinson's disease.

ABSTRACT: Background: Safinamide, a recently developed drug with several mechanisms of action has been investigated as an add-on therapy for Parkinson's disease patients suffering from motor complications due to the usage of anti-Parkinson's medications such as levodopa and dopaminergic drugs. The aim of the study is to investigate the efficacy and safety of Safinamide as add-on therapy for Parkinson's disease patients. Methods: A computerized literature search was conducted of PubMed, EMBASE, ClinicalTrial.gov and Cochrane Library until August 2019. We selected relevant randomized controlled trials comparing safinamide groups to placebo groups. Relevant outcomes were pooled as mean difference (MD) and risk ratio (RR) using Review Manager 5.3. Results: We found that the overall MD of changes in "off-time" and "on time without troublesome dyskinesia" favored the safinamide group over the placebo group (MD -0.72 h, 95% CI -0.89 to -0.56 and MD 0.71 h, 95% CI 0.52 to 0.90, respectively). Additionally, the overall MD of change in Unified Parkinson's Disease Rating Scale part three (UPDRS III) favored the safinamide group (MD -1.83, 95% CI -2.43 to -1.23). In case of adverse events, the pooled meta-analysis did not favor the safinamide group over the placebo group. Conclusions: In this study, we provide class I evidence about the potential role of safinamide as an add-on therapy for Parkinson's disease patients suffering from motor fluctuations. However, a few included studies did not mention the data of important outcomes. Also, we report high risk of bias in individual studies. Future randomized controlled trials with different doses are recommended to provide more evidence for the efficacy and safety of safinamide as a treatment for motor complications of anti-Parkinson's medications.

SUBMITTER: Abdelalem Aziz Ahmed M

PROVIDER: S-EPMC7205357 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A systematic review and meta-analysis of safety and efficacy of safinamide for motor fluctuations in patients with Parkinson's disease.

Abdelalem Aziz Ahmed Mohamed M

F1000Research 20191210

<b>Background:</b> Safinamide, a recently developed drug with several mechanisms of action has been investigated as an add-on therapy for Parkinson's disease patients suffering from motor complications due to the usage of anti-Parkinson's medications such as levodopa and dopaminergic drugs. The aim of the study is to investigate the efficacy and safety of Safinamide as add-on therapy for Parkinson's disease patients. <b>Methods:</b> A computerized literature search was conducted of PubMed, EMB ...[more]

PMID: 32431802

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Project description:BACKGROUND AND OBJECTIVE: Safinamide is a novel anti-parkinsonian drug with possible anti-dyskinetic properties. Parkinson's disease (PD) is a complex disease. The objective of this systematic review and meta-analysis is to evaluate the efficacy and safety of safinamide administration compared to placebo in PD patients on multiple outcomes.MethodsPubMed, EMBASE, Cochrane CENTRAL, LILACS, and trial databases were searched up to 23 December 2020 for randomized controlled studies (RCTs) comparing safinamide to placebo, alone or as add-on therapy in PD. Data were extracted from literature and regulatory agencies. Primary outcomes were ON-time without troublesome dyskinesia, OFF-time, and Unified Parkinson's Disease Rating Scale (UPDRS) section III (UPDRS-III). Secondary outcomes included any dyskinesia rating scale (DRS), ON-time with troublesome dyskinesia, UPDRS-II, and Parkinson's Disease Questionnaire 39 (PDQ-39). In order to estimate mean difference (MD) and odds ratios with 95% confidence intervals (CI), generic inverse variance and Mantel-Haenszel methods were used for continuous and dichotomous variables, respectively. Analyses were performed grouping by PD with (PDwMF) or without (PDwoMF) motor fluctuations, safinamide dose, and concomitant dopaminergic treatment. Summary of findings with GRADE were performed.ResultsSix studies with a total of 2792 participants were identified. In PDwMF patients, safinamide 100 mg as add-on to levodopa (L-dopa) significantly increased ON-time without troublesome dyskinesia (MD = 0.95 h; 95% CI from 0.41 to 1.49), reduced OFF-time (MD = - 1.06 h; 95% CI from - 1.60 to - 0.51), and improved UPDRS-III (MD = - 2.77; 95% CI from - 4.27 to - 1.28) with moderate quality of evidence. Similar results were observed for the 50 mg dose. However, the quality of evidence was moderate only for ON-time without troublesome dyskinesia, whereas for OFF-time and UPDRS-III was low. In PDwoMF patients taking a single dopamine agonist, safinamide 100 mg resulted in little to no clinically significant improvement in UPDRS-III (MD = - 1.84; 95% CI from - 3.19 to - 0.49), with moderate quality of evidence. Conversely, in PDwoMF patients, the 200 mg and 50 mg doses showed nonsignificant improvement in UPDRS-III, with very low and moderate quality of evidence, respectively. In PDwMF patients taking safinamide 100 mg or 50 mg, nonsignificant differences were observed for ON-time with troublesome dyskinesia and DRS, with high and low quality of evidence, respectively. In the same patients, UPDRS-II was significantly improved at the 100 mg and 50 mg dose, with high and moderate quality of evidence. In PDwoMF, UPDRS-II showed a little yet significant difference only at 100 mg, with low quality of evidence. PDQ-39 resulted significantly improved only with the 100 mg dose in PDwMF, with low quality of evidence.ConclusionOverall, safinamide is effective in PDwMF patients taking L-dopa both at 100 and 50 mg daily. Evidence for efficacy in early PD is limited. Further trials are needed to better evaluate the anti-dyskinetic properties of safinamide.

Project description:Background: Movement fluctuations are the main complication of Parkinson's disease (PD) patients receiving long-term levodopa (L-dopa) treatment. We compared and ranked the efficacy and safety of dopamine agonists (DAs) with regard to motor fluctuations by using a Bayesian network meta-analysis (NMA) to quantify information from randomized controlled trials (RCTs). Methods and Findings: We carried out a systematic review and meta-analysis, and only RCTs comparing DAs for advanced PD were included. Electronic databases (PubMed, Embase, and Cochrane Library) were systematically searched for relevant studies published until January 2021. Two reviewers independently extracted individual study data and evaluated studies for risk of bias using the Cochrane Risk of Bias tool. Network meta-analyses using a Bayesian framework were used to calculate the related parameters. The pre-specified primary and secondary outcomes were efficacy ("ON" time without troublesome dyskinesia, "OFF" time, "ON" time, "UPDRS-III," and "UPDRS-II") and safety [treatment-emergent adverse events (TEAE) and other adverse events] of DAs. The results are presented as the surface under the cumulative ranking (SUCRA) curve. A total of 20 RCTs assessing 6,560 patients were included. The general DA effects were ranked from high to low with respect to the amount of "ON" time without troublesome dyskinesia as follows: apomorphine (SUCRA = 97.08%), pramipexole_IR (probability = 79.00%), and ropinirole_PR (SUCRA = 63.92%). The general safety of DAs was ranked from high to low with respect to TEAE as follows: placebo (SUCRA = 74.49%), pramipexole_ER (SUCRA = 63.6%), sumanirole (SUCRA = 54.07%), and rotigotine (SUCRA = 53.84%). Conclusions: This network meta-analysis shows that apomorphine increased "ON" time without troublesome dyskinesia and decreased "OF" time for advanced PD patients. The addition of pramipexole, ropinirole, or rotigotine to levodopa treatment in advanced PD patients with motor fluctuations increased "ON" time without troublesome dyskinesia, improved the UPDRS III scores, and ultimately ameliorated the UPDRS II scores, thereby maximizing its benefit. This NMA of pramipexole, ropinirole, and rotigotine represents an effective treatment option and has an acceptable safety profile in patients with advanced PD.

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:ObjectiveClinical data has recently shown an association between Parkinson's disease (PD), Dementia with Lewy bodies (DLB), and zonisamide. The purpose of this study was to thoroughly evaluate the efficacy and safety of zonisamide in PD and DLB.MethodsPubmed, the Cochrane Library, Web of Science, and Embase databases were searched for all randomized clinical trials (RCTS) on the role of zonisamide in PD and DLB that were completed by April 18, 2022. UPDRS II (off) total score, UPDRS III total score, Daily "off" time, and UPDRS Part IV, Nos. 32, 33, and 34 were used as clinical efficacy endpoints. Adverse events reported in the RCTs will be considered in the final safety analysis. To better understand the effect of zonisamide on the efficacy and safety of PD and DLB, the UPDRS III total score and the six overlapping adverse events were examined in subgroups. Either a fixed effects model analysis (OR) or a random effects model analysis (MD) is used to figure out the mean difference (MD) and the relative risk.ResultsSeven articles involving 1749 patients (916 PD and 833 DLB) were included in this study. Compared to the control group, zonisamide could significantly reduce the UPDRS III total score in patients with PD and DLB (WMD-2.27 [95% CI: -3.06, -1.48], p < 0.0001). For patients with PD, compared to the control group, zonisamide could significantly reduce the UPDRS II (off) total score (WMD-0.81 [95% CI: -1.36, -0.26], p = 0.004), daily "off" time (WMD-0.67 [95% CI: -1.10, 0.24], p = 0.002), and UPDRS part IV, No. 32 worsen (OR-3.48 [95% CI: 1.20, 10.10], p = 0.02). In terms of safety, compared with the control group, for patients with DLB, zonisamide could significantly increase the incidence of contusion (OR-0.60 [95% CI: 0.38, 0.96], p = 0.03) and may increase the probability of reduced appetite (OR-3.13 [95% CI: 1.61, 6.08], p = 0.0008). And for patients with PD, zonisamide may increase the probability of somnolence (OR-2.17 [95% CI: 1.25, 3.76], p = 0.006).ConclusionsFor the analysis of the current study results, our results show that zonisamide could improve the motor function in patients with PD and DLB and improve the activities of daily living (off) and wearing off and decrease the duration of dyskinesia in patients with PD. In terms of safety, the use of zonisamide significantly increases the probability of contusion in patients with DLB and may increase the probability of reduced appetite in patients with DLB and somnolence in patients with PD. Zonisamide appears to be a new treatment option for patients with PD and DLB. However, the effectiveness and safety of zonisamide in the treatment of PD and DLB need to be further investigated.

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A systematic review and meta-analysis of safety and efficacy of safinamide for motor fluctuations in patients with Parkinson's disease.

Publications

A systematic review and meta-analysis of safety and efficacy of safinamide for motor fluctuations in patients with Parkinson's disease.

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