2. Materials and Methods
2.1. Expert Panel Composition
2.2. The RAND/UCLA Method
2.3. Literature Search Strategy
2.4. Delphi Rounds
3.1.1. De Novo
- Conclusion: There is no current evidence on the benefit of safinamide as de novo or neuroprotector treatment, or to treat hypersomnia. Level of agreement: 88%. LE: 5.
3.1.2. Motor Symptoms
- Conclusion: Clinical trials and observational studies demonstrated that adjunctive treatment with safinamide is associated with motor improvements in patients with mid-to-late PD and motor deficit (treated with levodopa alone or in combination with PD treatment(s)) [6,7,8,13]. Level of agreement: 100%. LE: 2.
- Conclusion: No clear conclusion regarding the direct effect of Safinamide on dyskinesias was achieved.
3.1.3. Non-Motor Symptoms
Depression and cognitive impairment
- Conclusion: No clear conclusion regarding the clinical benefits of safinamide on sleep disturbances was achieved.
3.2.1. Most Common AEs
- Conclusion: Most frequent AEs (≥5% incidence) associated with safinamide treatment are scotoma, blurred vision, dizziness, abdominal and lumbar pain, nausea, and hypertension; they occur in a similar frequency than that observed in patients treated with placebo [6,7,8,11,12,14,23,24,31]. Level of agreement: 100%. LE: 1.
Prevention of de novo dyskinesias
Prevention of worsening of pre-existing dyskinesias
Treatment of developing or worsening dyskinesias
3.2.3. Confusional Syndrome
- Conclusion: In patients with PD receiving safinamide, the emergence of episodes of confusion, visual hallucinations and somnolence could be possible with 50 and 100 mg doses, and they could disappear after safinamide withdrawal . However, there is not enough data to support this association. Leve lof agreement: 88%. LE: 3.
- Conclusion: There might be an increased risk for episodes of confusion in patients treated with safinamide with previous documentation of these complications, older age, and advanced PD . Level of agreement: 100%. LE: 3.
3.3. Patient Profiles
3.3.1. Without Motor Fluctuations
3.3.2. With Motor Fluctuations
3.3.3. With Non-Motor Fluctuations
Depression and cognitive impairment
3.3.4. Other Profiles
3.4. Switch from Rasagiline to Safinamide
- Conclusion: In patients with PD previously treated with rasagiline for whom a switch to safinamide is advisable, the 2-week washout period could be avoided and safinamide could be started from one day to another, although there is not enough evidence to support this conclusion . Level of agreement: 100%. LE: 5.
- Recommendation: In patients with PD previously treated with rasagiline for whom a switch to safinamide is advisable, a starting safinamide dosage of 50 or 100 mg/day could be recommended as in other scenarios. Level of agreement: 100%. LE: 5. RG: D .
3.5. Concomitant Use of Safinamide and Antidepressants
Conflicts of Interest
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|Study–Author||PD Stage||Sample Size||Design||Efficacy||Safety|
|Study 015 |
Stocchi et al. 
|Early||270||Randomized, double-blind, placebo-controlled, parallel-group|
Safinamide 200 mg; Safinamide 100 mg;
|UPDRS-III: significant differences between safinamide 100 mg/day vs placebo (−6.0 vs. −3.6; P = 0.0419), but not 200 mg/day vs. placebo.||Most common TEAEs: nausea, headache, abdominal pain (upper), vomiting, pyrexia, cough, hypertension, blurred vision, gastritis, peripheral edema, nasopharyngitis, dizziness, back pain, and tremor.|
|Study 017 |
Schapira et al. 
|Early||227||Randomized, double-blind, placebo-controlled, parallel-group 12-month extension study of Study 015.|
Safinamide 200 mg; Safinamide 100 mg;
|Difference in median time to intervention safinamide vs. placebo (93 days; P = 0.3342).|
Significantly higher changes in UPDRS-III in the safinamide 100 mg group versus placebo (P = 0.0264).
|Most common TEAEs: back pain, scotoma, dizziness, blurred vision, upper abdominal pain, nausea, and hypertension (100 mg/day safinamide), cataract, upper abdominal pain, gastritis, and pain in extremity (200 mg/day safinamide).|
|Study 016 |
Borgohain et al. 
blind, placebo-controlled, parallel-group.
Safinamide 100 mg; Safinamide 50 mg;
|UPDRS-III: mean difference vs. placebo: safinamide 50 mg/day −1.8, P = 0.0138, safinamide 100 mg/day −2.6, P = 0.0006).|
Increase in ON time without troublesome dyskinesia vs. placebo: 0.51 (50 mg/day) and 0.55 (100 mg/day) h.
Change in OFF time vs. placebo: −0.6 (safinamide 50 and 100 mg/day).
Comparable DRS between safinamide and placebo groups.
|Most common TEAEs were nervous system disorders, general disorders and gastrointestinal disorders.|
Dyskinesia was more common in the safinamide group, worsening of PD and depression in the placebo group.
|Study 018 |
Borgohain et al. 
|Mid-to-late||544||Randomized, double-blind, placebo-controlled, parallel-group, 18-month extension to Study 016.|
Safinamide 100 mg; Safinamide 50 mg;
|Long-term improvements in UPDRS part II, III, and IV total scores with safinamide 100 mg/day.|
Increase in ON time from baseline was 1.01 h in safinamide 50 mg/d group (P = 0.0031) and 1.18 h in the safinamide 100 mg/d group (P = 0.0002), compared with placebo (0.34 h).
Reduction in DRS sores of 31%, 27%, and 3% in safinamide 50 mg/day, 100 mg/day, and placebo, respectively (P = NS).
|Most common TEAEs (≥10 patients): cataract, asthenia, pyrexia, fall, back pain, dyskinesia, worsening of PD, headache, and insomnia.|
Incidence of new/worsening dyskinesia similar to placebo.
|Study Settle |
Schapira et al. 
|Mid-to-late||549||Randomized, placebo-controlled clinical trial.|
Safinamide 50 mg → 100 mg;
|UPDRS-III: difference vs. placebo −1.82; P = 0.003).|
Increase in ON time without troublesome dyskinesia vs. placebo: 0.96 h, P < 0.001.
Decrease in OFF time vs. placebo: 1.03 h, P < 0.001.
Comparable DRS scores between safinamide and placebo groups.
|The most common TEAEs were dyskinesia (14.6% safinamide group vs. 5.5% placebo group), falls (6.6% vs. 3.6%), urinary tract infections (6.2% vs. 4.4%), nausea (5.8% vs. 5.5%), and headache (4.4% vs. 6.2%).|
Dyskinesia was more frequent in the safinamide group vs. the placebo group. Severe dyskinesias: 1.8% in patients receiving safinamide and 0.4% receiving placebo.
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