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Reference - SETTLE trial (JAMA Neurol 2017 Feb 1;74(2):216) (level 1 [likely reliable] evidence)
- Continued management of parkinsonian motor features often requires adjunctive therapy to minimize motor fluctuations.
- The efficacy of safinamide, a selective, reversible monoamine oxidase B (MAO-B) inhibitor with additional non-dopaminergic actions, to increase “on” time (relief of parkinsonian motor features) was investigated in 549 patients in the SETTLE trial. Patients with Parkinson disease (PD) taking oral levodopa with or without adjuvant therapy and who experienced motor fluctuations were randomized to adjuvant safinamide 50-100 mg orally once daily vs. placebo for 24 weeks.
- On time without troublesome dyskinesia was increased by 1.42 hours/day with safinamide vs. 0.57 hours/day with placebo (mean difference 0.96 hours/day, 95% CI 0.56-1.37), but dyskinesia was more common in the safinamide group (in 14.6% vs. 5.5%, statistical comparison not reported).
Management of PD is directed at alleviating symptoms. The benefits of levodopa or dopamine agonist monotherapies can wane over time with the patient experiencing motor fluctuations defined as a switch from on time (relief of parkinsonian motor features) to a period of “off” time (return of parkinsonian motor features). In addition, drug-induced involuntary movements (dyskinesia) may develop. In order to reduce off time, adjunctive therapies with catechol-O-methyltransferase (COMT) inhibitors (only in combination with levodopa), MAO-B inhibitors, or dopamine agonists may be given. Safinamide, a selective, reversible MAO-B inhibitor with additional non-dopaminergic mechanisms of action (Front Pharmacol 2016;7:340), was approved by the Food and Drug Administration in March 2017 as an add-on treatment for patients with PD who are taking levodopa/carbidopa and who experience off time. To evaluate its efficacy to reduce off time, the SETTLE trial included 549 patients (mean age 62 years) with idiopathic PD for > 3 years and taking stable oral levodopa with or without adjuvant therapy randomized to adjuvant safinamide 50-100 mg orally once daily at breakfast vs. placebo for 24 weeks. All patients had > 1.5 hours of off time (return of bradykinesia and rigidity other than morning akinesia) per day despite treatment optimization during the run-in phase. Adjunctive therapies included dopamine agonists in 74.3%, amantadine in 30.2%, anticholinergics in 17.3%, and entacapone in 15.1%. The primary outcome was the mean change from baseline to week 24 in on time without troublesome dyskinesia, as determined by diary entries from the 2 days preceding outcome assessments.
Comparing safinamide with placebo, daily on time without troublesome dyskinesia increased from baseline by 1.42 hours vs. 0.57 hours (mean difference 0.96 hours, 95% CI 0.56-1.37). Patients in the safinamide group also had greater improvement in motor function during on time based on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III score (-3.43 vs. -1.83, mean difference -1.82, 95% CI -3.01 to -0.62). Improvements in the activities of daily living UPDRS Part II scores during on time were similar between the groups. Serious adverse events occurred in 6.6% with safinamide vs. 9.5% with placebo (statistical comparison not reported). Rates of dyskinesia were 14.6% with safinamide vs. 5.5% with placebo, falls were reported in 6.6% vs. 3.6%, and discontinuation of study drug due to adverse events occurred in 4.4% vs. 3.6% (statistical comparisons not reported).
The SETTLE trial showed that the addition of safinamide to levodopa significantly increased mean daily on time without troublesome dyskinesia by about 1 hour compared to placebo in patients with PD. The relevance of the statistically significant greater improvement in the UPDRS motor score seen in the safinamide group is unclear as the 95% confidence interval for the difference in improvement between groups includes clinically unimportant values (< 2.3 points, Arch Neurol 2010 Jan;67(1):64). Head-to-head trials to evaluate the comparative efficacy and tolerability of safinamide with the established adjunctive therapies are needed. In the meantime, safinamide is a recently available treatment option to consider as adjunct therapy to increase on time in patients with early- to mid-stage PD who are taking levodopa.
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