Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson's disease
Relevant conflicts of interest/financial disclosures: Dr R. Borgohain has served on the scientific advisory board of Neuronova. Dr. J Szasz serves on the scientific advisory board of Abbott Pharmaceuticals, received funding for travel from the following pharmaceutical companies: Boehringer Ingelheim, Novartis, UCB pharmaceuticals and Lundbeck, and received honoraria for speaking engagements from the following pharmaceutical companies: Abbott, UCB, Novartis, TEVA, Boehringer Ingelheim, and GSK. Dr P. Stanzione serves on the scientific advisory board of UCB pharmaceuticals, received travel expenses and/or honoraria for lectures or educational activities not funded by industry, has received honoraria for speaking engagements from UCB, GlaxoSmithKline, Boehringer Ingelheim, and Chiesi, was the principal investigator for research sponsored by UCB pharmaceuticals in 2012 and received institutional support from Yale university for the IRIS trial, 2010-11-12. Dr. C. Meshram reports no conflicts of interest. Dr. M Bhatt has received honoraria for speaking engagements from the Movement Disorders Society. Dr. D. Chirilineau has received funding for travel to participate in scientific meetings from the following pharmaceutical companies: GlaxoSmithKline, Merck Sereno, Novartis, Ever Neuro Pharma, Lundbeck and Sanofi Aventis. Dr. F. Stocchi has served on scientific advisory boards for TEVA, Novartis, GSK, Lundbeck, IMPAX, Merk Serono, MSD, UCB and Chiesi pharmaceutical and has received research support for research on the pathophysiology of motor fluctuations in PD sponsored by Novartis, GSK. Dr. V. Lucini is an employee of Newron Pharmaceuticals. Dr. R. Giuliani is an employee of Newron Pharmaceuticals. Dr. E. Forrest is an employee of Newron Pharmaceuticals. Ms. P. Rice is an employee of Premier Research. Dr. R. Anand served on the scientific advisory boards of Astra Zeneca 2012, Hoffman LaRoche (AB member) 2011, 2012 and served on the scientific board of Sonexa 2011, is a reviewer and a member of the editorial board of the journal ‘European Neuropsychopharmacology' and reviewer for the journal ‘Experimental Neurology' and is a corporate consultant to: Abbot, Newron, Shire, Roche, Erydel, Takeda, Bioline, and Teva Pharmaceuticals.
Full financial disclosures and author roles may be found in the online version of this article.
Funding agencies: This study was supported by Newron and Merck Serono S.A., Geneva, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.
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. © 2014 International Parkinson and Movement Disorder Society
Levodopa (l-dopa) is considered the most effective treatment for the motor symptoms of Parkinson's disease (PD)1; long-term limitations include development of motor complications and dyskinesia.2 Approximately 40% of patients develop motor fluctuations after 4 to 6 years of l-dopa treatment,3 many of whom will require add-on therapy with other PD medications to improve motor fluctuations, ideally without exacerbating dyskinesia.
Safinamide is a novel therapy in development as add-on therapy to dopamine agonists in early PD4, 5 and to l-dopa in mid- to late-stage PD.6 An orally active α-aminoamide 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 state-dependent 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, placebo-controlled extension to Study 016. The primary objective of both studies was to assess the long-term efficacy and safety of safinamide as an add-on to l-dopa in patients with mid- to late PD and motor fluctuations.
Patients and Methods
This was an 18-month multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group extension study to the pivotal phase III study, Study 016 (Study 018; clinicaltrials.gov identifier NCT01286935), and was conducted at 52 sites in India, Romania, and Italy. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki, and the protocol and its amendments were approved by all appropriate independent ethics committees and regulatory authorities.
Study Protocol
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 computer-generated randomization schedule. Patients were included in the extension study (Study 018) if they completed Study 016, were treatment compliant and willing to continue, or if they had discontinued from Study 016 but had completed scheduled efficacy evaluations at weeks 12 and 24. They were excluded if they had experienced clinically significant adverse events (AEs) or shown clinically significant deterioration in motor symptoms during Study 016.
Patients continued in the same treatment group to which they were randomized in Study 016. Doses were given orally once daily in the morning with breakfast. All patients continued treatment with l-dopa and other PD treatments, and new medicines could be added if considered necessary. In the event of intolerable AEs, the dose of safinamide and levodopa could be reduced, and safinamide treatment could be interrupted or discontinued, if necessary.
Serotonin-norepinephrine reuptake inhibitors, tri- or tetracyclic antidepressants, neuroleptics, MAO-B inhibitors, tramadol, meperidine, and agents that inhibit or induce hepatic enzymes were not permitted. All other medications were permitted, including selective serotonin reuptake inhibitors, provided that the dose remained stable and low during the study.
Study visits occurred every 12 weeks.
Study Outcomes
The primary efficacy endpoint was mean change from baseline (at Study 016 start) to endpoint of the total score of the Dyskinesia Rating Scale (DRS)14 during ON time, calculated as the sum of the severities across all items collected at a particular time point. Secondary efficacy endpoints included mean change from baseline to endpoint in diary ON time without troublesome dyskinesia (i.e., with no or only nontroublesome dyskinesia), diary responder rates, Unified Parkinson's Disease Rating Scales (UPDRS) Part IV (complications of therapy) total score and scores of 32 to 35 (dyskinesia and dystonia) and 32 to 34 (dyskinesia), UPDRS Part II (activities of daily living) scores, UPDRS Part II response rates, change in l-dopa dose, UPDRS Part III (motor) scores, Clinical Global Impression—Change (CGI-C), Clinical Global Impression-Severity (CGI-S), change in individual diary categories (ON with no dyskinesia, ON with nontroublesome dyskinesia, ON with troublesome dyskinesia, OFF, asleep). Mean changes from baseline to endpoint on the total scores for the tertiary efficacy variables, Hamilton Rating Scale for Depression (GRID-HAM-D), Parkinson's Disease Questionnaire (PDQ-39), and Hoehn & Yahr (H & Y) were also analyzed.
Safety was assessed by the incidence of AEs reported by the patient or observed by the investigator (at all post-screening visits), vital signs (at all visits), laboratory tests (at screening and all post-baseline visits), 12-lead electrocardiogram (at screening, baseline, and 12 and 24 weeks), and physical, neurological, and ophthalmologic examinations (at screening and 24 weeks). All safety data were monitored by an independent safety monitoring board.
Statistical Analyses
Based on the number of patients randomized in Study 016 and assuming an attrition rate of approximately 14% in Study 016, approximately 550 patients would be eligible to enter Study 018. The following populations were analyzed: intent to-treat (ITT) (all patients enrolled in Study 018) and safety (all patients enrolled in Study 018 with at least one dose of study medication and safety assessment during Study 018). For the safety endpoints, two sets of data were considered: 2-year data from the cohort of patients who entered 018 and newly emergent AEs during the 18-month extension (defined as AEs not reported during 016 or AEs reported during 016 but that worsened during 018).
For all efficacy endpoints, the baseline value was the value at the start of Study 016. The change from baseline to endpoint for the primary efficacy variable (DRS) was analyzed using a mixed linear model with baseline as a covariate. A sequence of comparisons approach was used: safinamide 100 mg/d versus placebo was tested first, and if significant, safinamide 50 mg/d was tested versus placebo.
Each secondary variable was analyzed sequentially as long as the difference between safinamide 100 mg/d and placebo was significant. Also, if the difference between safinamide 100 mg/d and placebo was significant, safinamide 50 mg/d and placebo were compared. If any of the tests were not significant (alpha = 0.05), subsequent tests were considered exploratory. The remaining variables were analyzed using analysis of covariance with baseline values as covariates.
Treatment-emergent AEs (TEAEs) were compared across groups using Cochran-Mantel-Haenszel test stratified by center.
Ad-hoc analyses on the primary and secondary variables were carried out in a subpopulation of patients who presented moderate-to-severe dyskinesia (i.e., DRS score > 4) at baseline of Study 016.
Results
Patient Disposition and Baseline Characteristics
Patient disposition and flow of patients through the study is presented in in Figure 1. The first patient entered Study 018 on 24 August 2007, and the last patient completed the study on 29 April 2010.
CONSORT diagram of patients' disposition and flow through Study 016 and Study 018. The intent-to-treat (ITT) population was composed of all randomized patients from Study 016 (primary analysis population for efficacy). None of the deaths reported during the study were considered related to the study drug. AE, adverse event; SAE, serious adverse event.
In summary, 50 of the 594 patients who completed Study 016 did not enter Study 018. Overall, 65.8% of Study 016 patients completed the whole 2-year treatment period, and 80.9% of Study 018 patients completed the 18-month extension period. No meaningful differences were found amongst patient groups in the percentage of deaths or discontinuations attributable to AEs.
Table 1 shows the demographic and baseline characteristics for the ITT population. No statistically significant between-group differences were found.
| Characteristic | Placebo (n = 222) | Safinamide 50 mg/d (n = 223) | Safinamide 100 mg/d (n = 224) |
|---|---|---|---|
| Gender, male, n (%) | 160 (72.1) | 157 (70.4) | 163 (72.8) |
| Race, n (%) | |||
| Asian | 180 (81.1) | 180 (80.7) | 179 (79.9) |
| White | 42 (18.9) | 43 (19.3) | 45 (20.1) |
| Age, years, mean (SD) | 59.4 (9.41) | 60.1 (9.65) | 60.1 (9.19) |
| Hoehn and Yahr stage, mean (SD) | 2.8 (0.7) | 2.8 (0.6) | 2.8 (0.6) |
| Disease duration, years, mean (SD) | 8.3 (3.8) | 7.9 (4.0) | 8.2 (3.8) |
| Levodopa dose, mg, mean (SD) | 619.20 (338.03) | 622.87 (327.88) | 572.49 (288.30) |
| Daily OFF time, hours, mean (SD) | 5.30 (2.06) | 5.2 (2.08) | 5.2 (2.16) |
| Daily ON time, hours, mean (SD) | 9.30 (2.155) | 9.37 (2.259) | 9.52 (2.246) |
| UPDRS II score, mean (SD) | 12.3 (5.9) | 11.8 (5.7) | 12.1 (5.8) |
| UPDRS III score ON, mean (SD) | 28.7 (12.02) | 27.3 (12.66) | 28.3 (13.30) |
| GRID-HAM-D-17 total score, mean (SD) | 5.5 (4.01) | 5.3 (3.75) | 5.0 (3.43) |
| DRS scores, mean (SD) | |||
| ITT population | 3.4 (3.93) | 3.9 (3.89) | 3.7 (4.07) |
| DRS >4a | 7.9 (3.08) | 8.0 (2.74) | 8.4 (2.81) |
| Concomitant PD medication, n (%) | |||
| Levodopab | 222 (100) | 223 (100) | 224 (100) |
| Dopamine agonist | 137 (61.7) | 142 (63.7) | 128 (57.1) |
| Entacapone | 56 (25.2) | 52 (23.3) | 55 (24.6) |
| Anticholinergic | 87 (39.2) | 74 (33.2) | 87 (38.8) |
| Amantadine | 34 (15.3) | 29 (13.0) | 30 (13.4) |
- DRS, Dyskinesia Rating Scale; GRID-HAM-D-17, Hamilton Rating Scale for Depression—17-item scale; ITT, intent-to-treat; SD, standard deviation; UPDRS, Unified Parkinson's Disease Rating Scales.
- a In 242 patients; 76 in the placebo group, 86 in the safinamide 50 mg/d group, and 80 in the safinamide 100 mg/d group.
- b Includes Stalevo.
At the study start, most patients were taking more than one drug other than l-dopa for PD treatment; approximately 60% of the patients at least one dopamine agonist, 24% entacapone, 36% anticholinergic drugs, and 13% amantadine, respectively.
Primary Efficacy Endpoint
A decrease occurred in mean total DRS score during ON in the active treatment groups. Safinamide 50 and 100 mg/d reduced mean DRS scores by 31% and 27% from baseline, respectively, compared with 3% for placebo. The least squares (LS) mean change in DRS was −0.19 in the safinamide 50 mg/d group at week 78 and −0.28 in the safinamide 100 mg/d group, compared with +0.32 with placebo. However, the primary endpoint was not met (LS mean difference vs placebo, −0.51; 95% confidence interval [CI], −1.32, 0.29; P = 0.2125 and −0.59; −1.40, 0.21; P = 0.1469 for the safinamide 50 mg/d and 100 mg/d groups, respectively).
Secondary and Tertiary Efficacy Evaluations
The mean total daily ON time without troublesome dyskinesia for the ITT population showed a statistically significant improvement from baseline (Study 016, week 0) to Study 018 week 78 in both the safinamide 50 mg/d and the safinamide 100 mg/d groups (Fig. 2). The LS increase from baseline was 1.01 hours for the safinamide 50 mg/d group (95% CI, 0.23, 1.11; P = 0.0031) and 1.18 hours for the safinamide 100 mg/d group (95% CI; 0.39, 1.27; P = 0.0002), compared with placebo (0.34 hours).
Principal secondary endpoint: Mean change in ON time without troublesome dyskinesia over 2 years (from baseline Study 016 to end of Study 018 (patient diary data).
- ON time without troublesome dyskinesia, OFF time, ON time without dyskinesia, and CGI-S (both doses)
- UPDRS part II, part III, and part IV total scores, PDQ-39 total score, and GRID-HAM-D score (safinamide 100 mg/d only), and
- CGI-C improvement (safinamide 50 mg/d) (data not shown).
Reduction in l-dopa dose from Study 016 baseline until the end of Study 018 was 11.3%, 17.0%, and 18.3% in the placebo, safinamide 50 mg/d, and safinamide 100 mg/d groups, respectively. Concurrently, the overall mean dose of l-dopa increased during the same period in the placebo and safinamide 50 mg/d groups (618.5 ± 335.7 mg to 650.6 ± 338.0 mg for the placebo and 621.4 ± 329.7 mg to 635.2 ± 410.4 mg for the safinamide 50 mg/d groups at baseline and endpoints, respectively) but decreased in the safinamide 100 mg/d group (579.6 ± 310.0 mg to 556.0 ± 381.9 mg).
Change in DRS Scores in Patients with Moderate-to-Severe Dyskinesia
Most of the study population (74%) had no to mild dyskinesia at baseline (DRS ≤ 4) (Table 1), allowing minimal if any room for improvement on the DRS. Therefore, an ad hoc analysis of the DRS data from the 242 patients (36%) who entered Study 016 with moderate to severe dyskinesia at baseline (i.e., DRS total score > 4) was conducted. Overall, compared with patients with a DRS total score of 4 or less at baseline, patients with a DRS total score greater than 4 had a longer mean duration of PD (9.3 ± 4.3 vs 7.8 ± 3.4 years); similar mean ON time (9.4 ± 2.1 vs 9.4 ± 2.3 hours); shorter OFF time (4.8 ± 2.0 vs 5.5 ± 2.1 hours); longer ON time with non-troublesome dyskinesia (3.9 ± 2.3 vs 1.5 ± 2.4 hours); longer ON time with troublesome dyskinesia (1.6 ± 1.9 vs 0.4 ± 1.2 hours); and higher mean UPDRS total and subscale scores. For patients with a DRS total score greater than 4, the mean DRS score was 8.1 ± 2.9, compared with 1.2 ± 1.6 for patients with a DRS total score of 4 or less. With regard to antiparkinsonian drug doses at baseline of both Study 016 and Study 018, patients with a DRS total score greater than 4 had higher mean l-dopa dose (660.0 ± 335.9 mg/d vs 574.6 ± 303.0 mg/d) and amantadine dose, compared with patients with a DRS total score of 4 or less. In patients with DRS greater than 4, a decrease from baseline DRS scores was observed in all three treatment groups at all visits, in particular in the active treatment groups. The mean (standard deviation) reduction from baseline (Study 016) to week 78 in Study 018 was −1.4 (3.37), a decrease of 17.5%, in the safinamide 50 mg/d group, and −2.0 (4.73), a decrease of 23.8%, in the safinamide 100 mg/d group, compared with −0.8 (3.60) in the placebo group. The LS mean change in the DRS scores from baseline to week 78 for the safinamide 100 mg/d group (−1.50) was significantly different (−1.50; 95% CI, −2.33, −0.11; P = 0.0317) from the placebo group (−0.28). Interestingly, an analysis excluding patients who experienced a reduction in their l-dopa dose indicated a continued and enhanced benefit in the safinamide 100 mg/d group, suggesting that the antidyskinetic effect was independent of the l-dopa dose reduction (Table 2).
| Characteristic | Placebo (n=222) | Safinamide 50 mg/day (n=223) | Safinamide 100 mg/day (n=224) | |
|---|---|---|---|---|
| ON time without troublesome dyskinesia, mean (hours) | Baseline | 9.301 | 9.373 | 9.520 |
| LS diff vs. placebo (95% CI) | 0.67 (0.23, 1.11) | 0.83 (0.39, 1.27) | ||
| P-value vs. placebo | 0.0031 | 0.0002 | ||
| ON time with troublesome dyskinesia, mean (hours) | Baseline | 0.964 | 0.938 | 0.731 |
| LS diff vs. placebo (95% CI) | 0.04 (−0.24, 0.32) | 0.02 (−0.26, 0.29) | ||
| P-value vs. placebo | NS | NS | ||
| OFF time, mean (hours) | Baseline | 5.301 | 5.166 | 5.193 |
| LS diff vs. placebo (95% CI) | −0.62 (−0.98, −0.25) | −0.75 (−1.11, −0.38) | ||
| P-value vs. placebo | 0.0011 | <0.0001 | ||
| DRS, mean (SD) | Baseline | 3.4 | 3.9 | 3.7 |
| LS diff vs. placebo (95% CI) | −0.51 (−1.32, 0.29) | −0.59 (−1.40, 0.21) | ||
| P-value vs. placebo | NS | NS | ||
| DRS, mean (SD) population with DRS >4 at baselineb | Baseline | 7.9 | 8.0 | 8.4 |
| LS diff vs. placebo (95% CI) | −0.73 (−1.84, 0.39) | −1.22 (−2.23, −0.11) | ||
| P-value vs. placebo | NS | 0.0317 | ||
| DRS, mean (SD) population with DRS >4 at baseline with no change in levodopa dosec | Baseline | 8.0 | 8.0 | 8.4 |
| LS diff vs. placebo (95% CI) | −0.93 (−2.07, 0.22) | −2.04 (−3.23, −0.84) | ||
| P-value vs. placebo | NS | 0.0010 |
- DRS, Dyskinesia Rating Scale; LS, least squares; NS, not statistically significant; SD, standard deviation.
- a Intent-to-treat (ITT) population unless otherwise indicated.
- b In 242 patients; 76 in the placebo group, 86 in the safinamide 50 mg/d group, and 80 in the safinamide 100 mg/d group.
- c In 192 patients; 64 in the placebo group, 69 in the safinamide 50 mg/d group, and 59 in the safinamide 100 mg/d group.
Safety
Safinamide at doses of 50 mg/d and 100 mg/d was safe and well tolerated, and no major or unexpected safety concerns were identified. Overall, dyskinesia occurred more frequently in patients in the safinamide 50 mg/d and 100 mg/d groups (31.2% and 27.8%, respectively, vs 21.7% in the placebo group). However, the incidence of other individual TEAEs, both newly emergent and re-emergent, was generally similar across all groups (Table 3). Only cataract, asthenia, pyrexia, fall, back pain, dyskinesia, worsening of PD, headache, and insomnia occurred in more than 10% of patients. In the 18-month extension, the incidence of new/worsening dyskinesia AEs was similar to placebo, and the risk of other dopaminergic side effects in safinamide-treated patients was not increased versus placebo patients.
| Adverse Event Category, n (%) | Placebo (n = 175) | Safinamide 50 mg/d (n = 189) | Safinamide 100 mg/d (n = 180) |
|---|---|---|---|
| Any TEAE | 160 (91.4) | 168 (88.9) | 163 (90.6) |
| Newly emergent during Study 018 | 149 (85.1) | 145 (76.7) | 141 (78.3) |
| Re-emergent during Study 018 | 21 (12.0) | 18 (9.5) | 19 (10.6) |
| Any serious TEAE | 28 (16.0) | 32 (16.9) | 34 (18.9) |
| Discontinuation due to TEAEs | 10 (5.7) | 10 (5.3) | 12 (6.7) |
| Most frequent TEAEs (occurring in ≥5% of patients in any group) | |||
| Worsening of Parkinson's disease | 42 (24.0) | 42 (22.2) | 43 (23.9) |
| Dyskinesia | 38 (21.7) | 59 (31.2) | 50 (27.8) |
| Cataract | 27 (15.4) | 27 (14.3) | 25 (13.9) |
| Back pain | 21 (12.0) | 17 (9.0) | 12 (12.8) |
| Asthenia | 21 (12.0) | 14 (7.4) | 21 (11.7) |
| Pyrexia | 21 (12.0) | 22 (11.6) | 15 (8.3) |
| Insomnia | 11 (6.3) | 21 (11.1) | 13 (7.2) |
| Headache | 13 (7.4) | 20 (10.6) | 15 (8.3) |
| Fall | 17 (9.7) | 20 (10.6) | 15 (8.3) |
| Hypertension | 12 (6.9) | 19 (10.1) | 18 (10.0) |
- TEAE, treatment-emergent adverse event.
The rate of serious TEAEs in Study 016 and Study 018 combined was similar among treatment groups, and the discontinuation rate from Study 018 because of TEAEs was similar across groups (Table 3). No specific pattern of occurrence of serious AEs was observed. No treatment-related deaths occurred in either study.
A higher proportion of patients in the placebo group (85.1%) than in the safinamide 50 and 100 mg/d groups (76.7% and 78.3%, respectively) experienced newly emergent TEAEs in Study 018 (P = 0.0329 vs placebo). The most commonly reported newly emergent TEAEs that occurred in over 5.0% of patients in any treatment group were cataract, constipation, asthenia, pyrexia, fall, weight decrease, back pain, pain in extremity, arthralgia, worsening of PD, dyskinesia, insomnia, and hypertension. The incidence of other dopaminergic side effects (i.e., hallucinations, fatigue, somnolence) was low (≤6.1% cumulative) and similar between treatment groups, and the incidence of new/worsening (re-emergent) dyskinesia was not statistically different from placebo.
No clinically meaningful differences were seen between treatment groups for measurements of vital signs, electrocardiogram variables, or physical, neurological, or ophthalmologic examinations.
Discussion
This is the first 2-year, prospective, placebo-controlled study in patients with mid-to-late PD and motor fluctuations despite optimized antiparkinsonian treatment.
Patients were selected on the basis of l-dopa–induced motor fluctuations rather than l-dopa–induced dyskinesia, and only approximately one third of patients entered into the 016/018 study presented with moderate to severe dyskinesia (DRS > 4) at baseline, and the mean baseline DRS score was lower than 4. This may explain why the primary study endpoint, a statistically significant decrease of DRS score in favor of active study drug, was not met. However, in moderate-to-severe dyskinetic patients, safinamide 100 mg/d significantly improved dyskinesia (P < 0.05 vs placebo).
Both safinamide doses improved ON time without troublesome dyskinesia when used as an add-on to l-dopa in these PD patients with motor fluctuations, despite optimized PD therapy as shown by patient diary data. Importantly, improvements seen at 6 months in Study 016 were still present at the end of the extension study, showing that safinamide, especially at a dose of 100 mg/d, remains more effective than placebo after 2 years of treatment.
In the 100 mg/d group, these clinical benefits were accompanied by long-term improvements in motor function, activities of daily living, depressive symptoms, patients' clinical status, and some aspects of quality of life, such as activities of daily living, emotional well-being, communication, and bodily discomfort.
Both safinamide doses were well tolerated during 2 years' treatment, as shown by similar incidences of AEs, AEs related to treatment, serious AEs, AEs leading to discontinuation, and other measurements of clinical and laboratory variables versus placebo. Indeed, during the 18-month study the tolerability profile was similar to placebo, indicating that there is no additional risk of new AEs or worsening of existing AEs after the first 6 months of treatment with safinamide. Nor was there increased risk of newly developing or worsening dyskinesia.
This study is the longest placebo-controlled study of safinamide in patients with mid-to-late PD. The completion rate was high.
This is the first demonstration of long-term (2-year) effects of safinamide on diary parameters such as ON and OFF time, motor functions, and activities of daily living. The study was designed to be as similar to clinical practice as possible, allowing the use of other PD medication (i.e., dose increase or addition ex novo) and providing the opportunity both to detect additional clinical benefit of safinamide with respect to an optimized PD treatment and to confirm the good tolerability profile of safinamide in patients on polypharmacy. The findings in this study, in a patient population that comprised a mainly Indian population, together with approximately 20% Europeans, confirm and extend the data obtained with safinamide as add-on therapy in early PD,4, 5, 15 and in the mid-to-late PD population in the 6-month SETTLE Study, in which most patients (over 65%) were white.16 A recent meta-analysis of the comparative efficacy and safety of adjuvant treatment to l-dopa in PD patients with motor complications found that adjuvant therapy with other agents (dopamine agonists, MOA-B inhibitors, or catechol-O-methyltransferase inhibitors) was effective in the management of later PD,17 but, in contrast to our findings, the benefits came at the expense of an increase in dyskinesia and numerous other side effects.
Although the primary endpoint (improvement in DRS score) was not met in the ITT population because of the small number of patients with dyskinesia at baseline, safinamide 50 and 100 mg/d improved motor fluctuations without worsening dyskinesia, as evidenced by the patient diary data, as well as motor symptoms, activities of daily living, and quality of life. Long-term safinamide treatment did not increase the risk of dyskinesia compared with placebo. Importantly, safinamide 100 mg/d improved dyskinesia in patients with more severe dyskinesia at baseline. Both doses of safinamide were generally well tolerated over 2 years despite the use of polypharmacy in these patients, without increasing the risk of other dopaminergic side effects.
Conclusion
This 2-year, prospective, placebo-controlled study of safinamide in patients with mid to late PD experiencing motor fluctuations demonstrated a clinical benefit of safinamide as an add-on to levodopa and other PD medication versus those only on an optimized PD treatment (placebo group).
Acknowledgments
We thank Ray Hill, an independent medical writer, who provided copy editing and journal styling before submission. We thank especially the Study 018 Investigators:
INDIA: M. Illiyas Sahadulla, U. Kardan, B.S. Keshava, A. Kishore, S.S. Kothari, J.M. Krishna Murthy, S. Kumar, P. Kumar Pal, N. Mehta, S. Prabhakar, S.Kr. Prabhakar, S. Pradhan, A.K. Roy, C. Sankhla, P.K. Sethi, A.B. Shah, N. Shankar, R. Shukla, A. Sowani, R. Srinivasa, M. Varma, D. Vasudevan, P. Vavilikolanu Sreenivas, C.U. Velmurugendran, K. Vijayan
ROMANIA: O. Bajenaru, A. Bulboaca, A. Campeanu, D. Chirileanu, D. Muresanu, C. Panea, C. Popescu, M. Simu, J. Szasz, M. Ticmeanu
ITALY: T. Avarello, U. Bonuccelli, R. Eleopra, M. Onofrj, R. Quatrale, P. Stanzione, F. Stocchi
Author Roles
1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.
R.B.: 1C, 2B, 3A
J.S.: 1C, 2B
P.S.: 1C, 2B
C.M.: 1C, 2B
M.B.: 1C, 2B
D.C.: 1C, 2B
F.S.: 1C, 2B, 3A
V.L.: 1B, 1C, 2B, 2C, 3A
R.G.: 1B, 1C, 2B, 2C, 3A
E.F.: 1B, 1C, 2B, 2C
P.R.: 2B, 3A
R.A.: 1B, 1C, 2B, 2C, 3A
Financial Disclosures
Dr. Borgohain has served on the scientific advisory board of Neuronova. Dr. Szasz serves on the scientific advisory board of Abbott Pharmaceuticals, received funding for travel from the following pharmaceutical companies: Boehringer Ingelheim, Novartis, UCB pharmaceuticals, and Lundbeck, and received honoraria for speaking engagements from the following pharmaceutical companies: Abbott, UCB, Novartis, TEVA, Boehringer Ingelheim, and GSK. Dr. Stanzione serves on the scientific advisory board of UCB pharmaceuticals, received travel expenses and/or honoraria for lectures or educational activities not funded by industry, has received honoraria for speaking engagements from UCB, GlaxoSmithKline, Boehringer Ingelheim, and Chiesi, was the principal investigator for research sponsored by UCB pharmaceuticals in 2012 and received institutional support from Yale university for the IRIS trial, 2010-11-12. Dr. C. Meshram reports no conflicts of interest. Dr. M Bhatt has received honoraria for speaking engagements from the Movement Disorders Society. Dr. Chirilineau has received funding for travel to participate in scientific meetings from the following pharmaceutical companies: GlaxoSmithKline, Merck Sereno, Novartis, Ever Neuro Pharma, Lundbeck and Sanofi Aventis. Dr. Stocchi has served on scientific advisory boards for TEVA, Novartis, GSK, Lundbeck, IMPAX, Merk Serono, MSD, UCB and Chiesi pharmaceutical and has received research support for research on the pathophysiology of motor fluctuations in PD sponsored by Novartis, GSK. Dr. Lucini is an employee of Newron Pharmaceuticals. Dr. Giuliani is an employee of Newron Pharmaceuticals. Dr. Forrest is an employee of Newron Pharmaceuticals. Ms. Rice is an employee of Premier Research. Dr. Anand served on the scientific advisory boards of Astra Zeneca 2012, Hoffman LaRoche (AB member) 2011, 2012 and served on the scientific board of Sonexa 2011, is a reviewer and a member of the editorial board of the journal ‘European Neuropsychopharmacology' and reviewer for the journal ‘Experimental Neurology' and is a corporate consultant to: Abbot, Newron, Shire, Roche, Erydel, Takeda, Bioline, and Teva Pharmaceuticals.
