May 26, 2018 - 016 (Borgohain et al., 2014b). ⢠Data from studies 016 and SETTLE were combined to analyse the effects on motor fluctuations. Data from.
Efficacy of safinamide on Parkinson’s Disease motor complications and non-motor symptoms
Medical Department Zambon SpA, Bresso, Italy; 2 R&D Department Zambon SpA, Bresso, Italy; 3 Department of Clinical Science and Community, Section of Medical Statistics and Biometry “GA Maccacaro”, University of Milan, Italy 1
Carlo Cattaneo1, Viviana Tubazio2, Erminio Bonizzoni3, Paola Castellani1
• The objectives of the present post-hoc analyses of the data from 3 safinamide studies (016, 018 and SETTLE) were to investigate the effects of safinamide 100 mg/day versus placebo on motor complications, pain and mood in patients with PD.
Methods • Studies 016 and SETTLE were 6-month, doubleblind, placebo-controlled trials comparing safinamide versus placebo as add-on therapy to levodopa (alone or with other anti-Parkinson drugs) in patients with fluctuating PD (Borgohain et al., 2014a; Schapira et al., 2017). Trial 018 was an 18-month extension of trial 016 (Borgohain et al., 2014b). • Data from studies 016 and SETTLE were combined to analyse the effects on motor fluctuations. Data from studies 016 and 018 were compared to evaluate the long-term effects on mood, and data from study 018 alone were used to detect the effects on pain. • Comparisons of the mean change from baseline to week 24 for the active-treatment group with the placebo group were performed using linear effects models with the treatment group and study index as fixed dummy effects and the baseline value as the continuous covariate (ANCOVA analyses). The reduction in the Table 1. Study 018: risk ratio reduction (% reduction in the number of pain treatments in the safinamide group versus the placebo group) RRR
95% Lower CL
26.2%
8.9%
95% Upper CL
P-value*
40.3%
0.005
* negative binomial regression model.
Subgroup
Motor fluctuations • Safinamide 100 mg/day significantly increased the “good” ON time (ON time with no or non-troublesome dyskinesia) and significantly reduced the OFF time, irrespective of whether or not other drugs were added to the baseline levodopa treatment, thus suggesting that safinamide could be an appropriate choice as first adjunct medication in patients with PD not sufficiently controlled with levodopa (Figure 1). In addition, safinamide improved the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores, and in particular improved bradykinesia, rigidity, tremor and gait (Figure 2). These results are important because the patients were receiving stable, optimized dopaminergic therapy, so further improvements in the UPDRS scores were unexpected. Pain • After 2 years of treatment, safinamide, compared with placebo, significantly reduced the individual number of concomitant pain treatments on average by 26.2% (Table 1). • Moreover, the treatment with safinamide 100 mg/day was associated with statistically significantly greater improvements in 2 of the 3 specific items of the “Bodily discomfort” domain of the PDQ-39, related to musculoskeletal and neuropathic pain (Figure 3). Mood • Use of safinamide also resulted in significantly greater improvements in GRID-HAMD scores from baseline, compared with placebo, at 6 months and after 2 years, maintaining the efficacy in the long term (Figure 4). • The improvements on mood were confirmed by the significantly lower percentage of patients reporting depression as an adverse event at 6 months and at 2 years of treatment (Figure 5).
UPDRS III
(Motor symptoms) 0
Safinamide as first add-on to levodopa
Levodope (a) and other meds
Bradykinesia
-1.39
No use of dopamine agonist Use of dopamine agonist
Improvement
No use of amantadine Use of amantadine
1
2 Placebo Better
Figure 1. Studies 016 and SETTLE (pooled data): Forest plot of the reduction in OFF time.
Tremor
n = 218
-0.89
-5.15
-6 Elaborated from Table 3 from Cattaneo C, et al. J Parkinsons Dis. 2016;6(1):165-73
Figure 2. Studies 016 and SETTLE (pooled data): change from baseline and difference versus placebo in UPDRS III scores and cardinal symptoms of PD.
n = 218
n = 217
-0.02 -0.11 -0.16
-0.10
-0.27
-0.15
p=0.6136*
p=0.0209*
-0.20 p-value (quello del Item 38)
-0.25
Safinamide 100 mg/day Placebo
p=0.0074*
-0.30 # ##
had painful muscle cramps or spasms? had aches and pains in your joints or body?
felt unpleasantly hot or cold? * analysis of covariance (ANCOVA)
###
Figure 3. Study 018: changes (least squares means ± SE) from baseline to 2 years for PDQ-39 items 37–39. Trial 016 (week 24) n = 177
n = 176
Trial 018 (week 102) n = 201
-0.2
-0.49 -0.76
-0.4 -0.6
n = 203
0.11
0.0
-1.06
-0.8
p=0.0027*
-1.0
Safinamide 100 mg/day Placebo
p=0.0408*
-1.2 * two-sided t-test
Figure 4. Trials 016 and 018: changes (least squares means ± SD) in GRID-HAMD scores.
6.00
p=0.0057*
Safinamide 100 mg Placebo
8.0%
p=0.0444*
5.00
5.4%
4.00 3.00 2.00 1.00 0.00
Change with Safinamide 100 mg (n=482) Change with Placebo (n=479)
n = 217
-0.15
-0.18 -0.16
p=0.0001
n = 218
-0.05
7.00
p=0.0118
n = 217
Item 39 ###
-0.04
-0.56 -0.33
p=0.7374
-1.48
Item 38 ##
0.00
Gait
-4
p=0.0003 0
Item 37 #
8.00
-1.90
-3
-5
–2 –1 Safinamide Better
Borgohain R, Szasz J, Stanzione P, et al. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov Disord 2014a; 29(2): 229-37. Schapira AH, Fox S, Hauser RA, et al. Assessment of safety and efficacy of safinamide as a levodopa adjunct in patients with Parkinson Disease and motor fluctuations. JAMA Neurol 2017; 74(2): 216-224. Borgohain R, Szasz J, Stanzione P, et al. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Mov Disord 2014b; 29(10): 1273-80.
Postural Stability
p=0.0102
Mild Fluctuators (b) Non-Mild Fluctuators (b)
-1.24 p=0.0006
-2.06
-2
Use of COMT inhibitor
Rigidity
-0.74 -1
No use of COMT inhibitor
References
0.1
Mean Difference with 95% CI
Levodopa (a) only
• Safinamide 100 mg/day was associated with improvements in motor fluctuations and motor functions without increasing troublesome dyskinesia. • Moreover, safinamide improved pain and mood, 2 important non-motor symptoms often underestimated and undertreated. • These favorable effects may be explained by the activity of safinamide on both dopaminergic and glutamatergic pathways, with a significant impact on the patients’ and caregivers’ quality of life.
Improvement
Objective
Results
Conclusions
Improvement
• Chronic levodopa (L-dopa) treatment of Parkinson’s Disease (PD) is associated with motor complications and non-motor symptoms (e.g. pain and mood disorders): their etiology involves several neurotransmitters in addition to dopamine, including the glutamatergic system. • Safinamide (Xadago®, Zambon SpA, Italy) has a unique mechanism of action, dopaminergic and nondopaminergic, that includes reversible inhibition of the monoamine oxidase-B (MAO-B) enzyme and modulation of glutamate release through the use- and state-dependent blockade of the sodium channels.
number of analgesic treatments was estimated by means of a generalized linear model parameterized with a logarithmic link function and negative binomial distribution. The analyses of the Parkinson’s Disease Questionnaire (PDQ-39) items related to pain and of the GRID Hamilton Rating Scale (GRID-HAMD) were performed using an ANCOVA model. The number and percentage of adverse events relating to depression were evaluated using a two-sided Fisher’s exact test.
Percentage of patients - n (%)
Introduction
1.8% n = 224
1.7% n = 222
Trial 016 (24 week)
n = 180
n = 175
Trial 018 (2 years)
* Two-sided Fisher’s Exact test Elaborated from Table 1 from Cattaneo C, et al. J Parkinsons Dis. 2017;7(4):629-634
Figure 5. Studies 016 and 018: proportion of patients reporting depression as an adverse event.
POSTER PRESENTED AT 4TH CONGRESS OF ACCADEMIA LIMPE-DISMOV (ROMA, MAY 24-26 2018)
