SETTLE
Assessment of Safety and Efficacy of Safinamide as a Levodopa Adjunct in Patients With Parkinson Disease and Motor Fluctuations: A Randomized Clinical Trial
Clinical Question
Does safinamide, an oral aminoamide with both MAO-B inhibitory and nondopaminergic (sodium/calcium channel blocking, glutamate release inhibition) properties, improve on time without troublesome dyskinesia when added to levodopa in PD patients with motor fluctuations?
Bottom Line
Safinamide 100 mg/d as a levodopa adjunct significantly increased daily on time without troublesome dyskinesia by 0.96 hour more than placebo over 24 weeks. It also significantly reduced off time (−1.03 h vs placebo), improved motor function (UPDRS Part III), CGI scores, and quality of life. The benefit was established by week 2 and maintained throughout. Dyskinesia was more common with safinamide (14.6% vs 5.5%) but was rarely troublesome, and overall tolerability was good with high completion rates (~89%). The results support safinamide as an effective once-daily oral adjunct for fluctuating PD, with effects comparable or superior to rasagiline and entacapone in cross-trial comparisons.
Major Points
- SETTLE was a 24-week, randomized, double-blind, placebo-controlled phase 3 trial of safinamide as levodopa adjunct in 549 PD patients with motor fluctuations across 119 centers in 21 countries
- Primary endpoint met: on time without troublesome dyskinesia increased by +1.42 h/d with safinamide vs +0.57 h/d with placebo (LS mean difference 0.96 h; 95% CI 0.56–1.37; P<.001)
- Key secondary endpoints: off time reduced by 1.03 h/d more than placebo (P<.001); UPDRS Part III improved by 1.82 points more (P=.003); CGI-C improvement 57.7% vs 41.8% (OR 1.92; nominal P<.001); but UPDRS Part II was not significant (P=.15), causing hierarchical testing failure for subsequent endpoints
- PDQ-39 quality of life improved by 2.33 points more than placebo (nominal P=.006); EQ-5D improved (nominal P<.001)
- Benefit was established by week 2 on the starting dose of 50 mg/d and maintained at all subsequent assessments on 100 mg/d
- Off-time reduction of 1.03 hours compares favorably with PRESTO (0.49 h for rasagiline 0.5 mg, 0.94 h for 1 mg) and LARGO (0.78 h for rasagiline 1 mg, 0.80 h for entacapone)
- Importantly, 92% of the on-time increase was without troublesome dyskinesia (only +0.08 h increase in on time with troublesome dyskinesia, not significant)
- Dyskinesia was the most commonly reported TEAE (14.6% vs 5.5%), comparable to rasagiline in PRESTO (18% vs 10%); severe dyskinesia was uncommon (1.8% vs 0.4%)
- Only 11 patients (4.0%) on safinamide vs 21 (7.6%) on placebo required a change in antiparkinsonian treatment during the study
- Small but nominally significant worsening on UPDRS Part IV dyskinesia subscores (items 32–34 and 32–35; +0.26 difference for both; nominal P=.04)
Design
Study Type: Randomized, double-blind, placebo-controlled, parallel-group, multicenter phase 3 trial
Randomization: 1
Blinding: Double-blind. Centralized computerized interactive voice-response system for randomization; matching tablets in matching blister packs for each dose level. Raters administering efficacy instruments were unaware of trial group assignments.
Enrollment Period: March 5, 2009 through February 23, 2012
Follow-up Duration: 24 weeks (with 1-week taper at week 25 and 4-week follow-up safety assessment at week 29 for non-continuing patients)
Centers: 119
Countries: 21 countries across Western Europe, Eastern Europe, Asia-Pacific, and North America
Sample Size: 549
Analysis: Intention-to-treat population (all randomized patients). Primary analysis: ANCOVA with treatment and country/region as fixed effects and baseline value as covariate. LOCF for missing data. Hierarchical testing for key secondary endpoints; if any test non-significant, remaining analyses yield nominal P values only. Sensitivity analysis: mixed-effects repeated-measures model (no imputation). CGI-C improvement assessed by logistic regression with Wald χ2 test. Sample size based on PRESTO data: 416 patients (208/group) for 90% power to detect 0.75-hour difference (SD 2.35, α=0.05); 484 randomized accounting for 14% dropout.
Inclusion Criteria
- Age 30–80 years
- Diagnosis of idiopathic PD by Queen Square Brain Bank criteria
- PD duration >3 years since diagnosis
- Hoehn and Yahr stages 1–4 during off phase
- Daily off time >1.5 hours (excluding morning akinesia)
- Levodopa responsive, on stable oral levodopa regimen (3–10 doses/day, with or without COMT inhibitor) for ≥4 weeks
- Motor fluctuations persisting after pharmacotherapy optimization during screening
- Could be taking stable dopamine agonist, anticholinergic, COMT inhibitor, and/or amantadine
Exclusion Criteria
- Severe, disabling peak-dose or biphasic dyskinesia
- Wide or unpredictable symptom fluctuations
- MAO-B inhibitor use within 8 weeks before screening
- Additional exclusion criteria summarized in supplemental materials
Arms
| Field | Control | Safinamide 50–100 mg/d |
|---|---|---|
| Intervention | Matching placebo tablet orally once daily with breakfast for 24 weeks | Safinamide 50 mg orally once daily with breakfast, increased to 100 mg/d by day 14 if no tolerability issues; continued for 24 weeks total as adjunct to stable levodopa and other PD medications |
| Duration | 24 weeks | 24 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change from baseline to week 24 in mean daily on time without troublesome dyskinesia (patient diary, hours/day) | Primary | +0.57 (SD 2.47) h/d from baseline 9.06 h | +1.42 (SD 2.80) h/d from baseline 9.30 h | <.001 | |
| Daily off time change (key secondary; h/d) | LS Mean Difference: −1.03 (95% CI −1.40 to −0.67) | Secondary | −0.54 (SD 2.21) | −1.56 (SD 2.35) | <.001 | |
| UPDRS Part III (motor) score change during on (key secondary) | LS Mean Difference: −1.82 (95% CI −3.01 to −0.62) | Secondary | −1.83 (SD 8.23) | −3.43 (SD 7.72) | .003 | |
| UPDRS Part II (ADL) score change during on (key secondary) | LS Mean Difference: −0.43 (95% CI −1.02 to 0.16) | Secondary | −0.75 (SD 3.95) | −1.07 (SD 3.63) | .15 (not significant; hierarchy failed here) | |
| CGI-C improvement (scores 1–3; key secondary) | Secondary | 41.8% | 57.7% | 1.92 (95% CI 1.36–2.70) | <.001 (nominal) |
| PDQ-39 summary index score change (key secondary) | LS Mean Difference: −2.33 (95% CI −3.98 to −0.68) | Secondary | −0.68 (SD 10.51) | −3.17 (SD 10.86) | .006 (nominal) | |
| CGI-C rating | LS Mean Difference: −0.44 (95% CI −0.62 to −0.27) | Secondary | <.001 (nominal) | |||
| PGI-C rating | LS Mean Difference: −0.40 (95% CI −0.57 to −0.22) | Secondary | <.001 (nominal) | |||
| Off time after morning levodopa dose (h/d) | LS Mean Difference: −0.18 (95% CI −0.28 to −0.09) | Secondary | <.001 (nominal) | |||
| EQ-5D index score change | LS Mean Difference: +0.06 (95% CI 0.03 to 0.09) | Secondary | <.001 (nominal) | |||
| Levodopa dose change (%) | Safinamide: −1.11% (SD 11.43); Placebo: +0.78% (SD 6.45); LS Mean Difference: −1.89 (95% CI −3.44 to −0.33) | Secondary | .02 (nominal) | |||
| DRS (Dyskinesia Rating Scale) score change | LS Mean Difference: +0.23 (95% CI −0.14 to 0.60) | Secondary | .22 (nominal; not significant) | |||
| UPDRS Part IV items 32–34 (dyskinesia duration/disability/pain) | LS Mean Difference: +0.26 (95% CI 0.02 to 0.50) | Secondary | −0.15 (SD 1.38) | +0.10 (SD 1.79) | .04 (nominal) | |
| UPDRS Part IV items 32–35 (dyskinesia items + clinical fluctuations) | LS Mean Difference: +0.26 (95% CI 0.01 to 0.52) | Secondary | −0.20 (SD 1.47) | +0.08 (SD 1.86) | .04 (nominal) | |
| Any TEAE | Adverse | 69.1% | 67.9% | ||
| Dyskinesia | Adverse | 5.5% | 14.6% | ||
| Dyskinesia - severe | Adverse | 0.4% (1 patient) | 1.8% (5 patients) | ||
| Fall | Adverse | 3.6% | 6.6% | ||
| Nausea | Adverse | 5.5% | 5.8% | ||
| Study drug-related TEAE | Adverse | 27.6% | 28.5% | ||
| Serious adverse events | Adverse | 9.5% | 6.6% | ||
| Severe TEAEs | Adverse | 9.1% | 6.9% | ||
| Discontinuation due to TEAE | Adverse | 3.6% | 4.4% | ||
| Death | Adverse | 0.7% (2 patients: myocardial ischemia, acute lymphocytic leukemia) | 0.4% (1 patient: PD worsening, unlikely related) |
Subgroup Analysis
Post hoc analysis showed significant on-time benefit was already present at the 50 mg/d dose at week 2 (first postbaseline assessment) and was maintained at all subsequent time points on 100 mg/d. Approximately 90.9% in the safinamide group and 94.1% in the placebo group were uptitrated to the 100 mg target dose by day 14. No significant changes on Questionnaire for Impulsive-Compulsive Disorders or Epworth Sleepiness Scale.
Criticisms
- Only one dose level (100 mg) was prespecified; the 50 mg dose was only a transient starting dose, so dose-response cannot be formally assessed
- 24-week duration limits long-term efficacy and safety assessment, though a prior safinamide study showed 2-year maintained benefit
- UPDRS Part II (ADL) was not significant (P=.15), causing hierarchical testing failure; all subsequent key secondary P values are nominal only
- Dyskinesia as a TEAE was nearly 3× more frequent with safinamide (14.6% vs 5.5%); while mostly non-troublesome, a small nominally significant worsening on UPDRS Part IV dyskinesia subscores was observed
- Diary-based outcomes are subject to patient reporting variability and may not capture overnight symptoms (no overnight diary data collected)
- Only days 2 and 3 of each 3-day diary period were analyzed (day 1 excluded); rationale provided but potentially reduces data
- Asian patients constituted ~31% of enrollment, but no specific ethnic subgroup analyses were presented
- Patients requiring change in PD treatment had their last pre-change assessment used for primary outcome (LOCF), which could bias results
- Open-label extension availability may have influenced patient behavior or willingness to continue in the placebo arm
- Cross-trial comparisons to rasagiline and entacapone have inherent limitations due to different populations, designs, and time periods
Funding
Study supported by Newron Pharmaceuticals and Merck Serono; the funding sources provided facilities for patient recruitment, study design, conduct, data management, analysis, interpretation, manuscript preparation, review, and approval. Editorial support (Michael Feirtag and Linnéa Elliott of The Curry Rockefeller Group LLC) was funded by Zambon.
Based on: SETTLE (JAMA Neurology, 2017)
Authors: Anthony H. V. Schapira, Susan H. Fox, Robert A. Hauser, ..., Ravi Anand
Citation: JAMA Neurol. 2017;74(2):216-224
Content summarized and formatted by NeuroTrials.ai.