RESEARCH ARTICLE

A Randomized, Double-Blind, Placebo-Controlled Trial of Safinamide

as Add-on Therapy in Early Parkinson’s Disease Patients
Fabrizio Stocchi, MD,1* Rupam Borgohain, DM,2 Marco Onofrj, MD,3 Anthony H.V. Schapira, MD,4
Mohit Bhatt, MD,5 Valentina Lucini, MD,6 Rodolfo Giuliani, MD,6 Ravi Anand, MD,7 and for the Study 015 Investigators8

1
Department of Neuroscience, IRCCS San Raffaele, Rome, Italy
2
Department of Neurology, Nizam’s Institute of Medical Sciences, Hyderabad, India
3
Department of Neurology, Chieti-Pescara University, Chieti, Italy
4
Department of Clinical Neurosciences, UCL Institute of Neurology, London, United Kingdom
5
Movement Disorder Clinic, Mumbai, India
6
Development Department, Newron Pharmaceuticals, Milan, Italy
7
APC, St. Moritz, Switzerland
8
Investigators are listed at the end of the manuscript.

A B S T R A C T : Safinamide is an a-aminoamide with
both dopaminergic and nondopaminergic mechanisms
of action evaluated as an add-on to dopamine agonist
(DA) therapy in early-stage PD. In this 24-week, double-
blind study, patients with early PD receiving a stable
dose of a single DA were randomized to once-daily
safinamide 100 mg, safinamide 200 mg, or placebo.
The primary efficacy variable was UPDRS part III (motor
examination) total score. Analysis was hierarchical:
200 mg of safinamide versus placebo was tested first;
the success of safinamide 100 mg versus placebo was
contingent on this. Two hundred sixty-nine patients
received safinamide 100 mg (n 5 90), safinamide
200 mg (n 5 89), or placebo (n 5 90); 70, 81, and 81
ference between safinamide 200 mg and placebo was
not significant [point estimate: 20.4; 95% confidence
interval (CI): 22.3–1.4; P 5 0.6504]. Although the differ-
ence between 100 mg/day and placebo was significant
(point estimate: 21.9; 95% CI: 23.7 to 20.1; P 5
0.0419), these results are considered exploratory. No
clinically meaningful differences from placebo were
observed for any safety variables. This study did not
demonstrate a significant improvement of the primary
endpoint for safinamide 200 mg/day. Exploratory analy-
sis of the primary endpoint for 100 mg/day demon-
strated that the addition of safinamide to a stable dose
of DA improves motor symptoms in early PD and war-
rants further investigation. V
C 2011 Movement Disorder

patients, respectively, completed the study. Mean Society

improvements from baseline to week 24 in UPDRS III
total scores were 23.90 for safinamide 200 mg, 26.0 Key Words: safinamide; Parkinson’s disease; add-on;
for safinamide 100 mg and 23.60 for placebo. The dif- motor function; a-aminoamide; dopamine

------------------------------------------------------------------------------------------------------------------------------
*Correspondence to: Dr. Fabrizio Stocchi, Department of Neuroscience, IRCCS San Raffaele, Via Della Pisana, 235, 00163 Rome, Italy; fabstocc@tin.it

Funding agencies: The sponsor, Newron Pharmaceuticals S.p.A., was responsible for the study design, investigator selection, general oversight of the
trial, and identification of the contract research organization responsible for day-to-day study management, monitoring, data management, and statistical
analysis. Professor Pablo Martinez-Martin provided training for the UPDRS. The interpretation of the data and preparation of the manuscript were
performed by the authors with the assistance of an independent medical writing agency, funded by Merck Serono. The decision to submit to Movement
Disorders was made by the authors.

Relevant conflicts of interest/financial disclosures: F.S. and all the other participants of the clinical study received payment according to the number
of patients included in the trial. F.S. has received honoraria for educational symposia and consultancy for Newron and Merck Serono. A.H.V.S. has
received honoraria from Merck Serono for medical education symposia and for providing advice in the development of safinamide. R.A. has received
honoraria for acting as a consultant for Newron Pharmaceuticals in the development of safinamide, in the conception and organization of this clinical trial,
in the statistical design and critical review of the analysis, and in the conception, review, and critique of the manuscript for this article. M.O. has received
honoraria for acting as a consultant for Newron Pharmaceuticals and from Merck Serono for an educational symposium. V.L. and R.G. are employees of
Newron. R.B. and M.B. have nothing else to disclose.

Full financial disclosures and author roles may be found in the online version of this article.
Received: 25 March 2011; Revised: 29 July 2011; Accepted: 14 August 2011
Published online 12 September 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.23954

106 Movement Disorders, Vol. 27, No. 1, 2012

 S A F I N A M I D E
Dopamine agonists (DAs) are commonly used as ini-
tial therapy in patients with newly diagnosed PD,1–3
because they are associated with a low risk of motor
complications, such as dyskinesia.4,5 The efficacy of
DAs declines with disease progression, and most
patients eventually require additional therapy.6 Fur-
thermore, DAs may be associated with side effects,
such as somnolence, peripheral edema, cognitive dis-
turbances, and impulse control disorders (ICDs).7,8
Some of these may be improved by a reduction in
dose, although at the risk of a decline in motor con-
trol. Levodopa (L-dopa) is commonly added to DAs
when an improvement in motor function is required.
However, once L-dopa therapy is initiated, the risk of
dyskinesia is similar to that for patients initially
treated with L-dopa.9,10 The addition of alternative
adjunct therapy to DAs is an attractive strategy
that may allow the use of a lower dose of DA while
maintaining efficacy and delaying the introduction of
L-dopa.
Safinamide is an a-aminoamide with both dopami-
nergic and nondopaminergic mechanisms of action,
including monoamine oxidase-B (MAO-B) and dopa-
mine reuptake inhibition, activity-dependent sodium-
channel antagonism, and inhibition of glutamate
release in vitro.11–13
This article reports on the results of a phase III
trial (Study 015) evaluating the efficacy, safety, and
tolerability of safinamide as add-on therapy in early
PD patients treated with a stable dose of a single
DA.
Patients and Methods
Patients
This 24-week, randomized, double-blind, placebo-
controlled, parallel-group trial was conducted at
26 centers in Italy, Spain, the United Kingdom, India,
Argentina, Chile, and Colombia. The study protocol
was approved by all ethics committees and regulatory
authorities. The study was conducted in accord with
the International Conference on Harmonization Good
Clinical Practice guidelines and the Declaration of
Helsinki. All patients provided written informed con-
sent before their participation.
Eligible patients were 30 to 80 years in age, with a
clinical diagnosis of idiopathic PD <5 years in dura-
tion, and Hoehn and Yahr stage I to III. Patients were
required to be on a stable dose of a single DA for at
least 4 weeks before screening. Recruitment was car-
ried out by the principal and coinvestigators at each
center and took place between December 21, 2004
and July 22, 2005; the last patient completed the trial
on January 23, 2006.
Exclusion criteria included the following: current
diagnosis or recent history of substance abuse; end-of-
A S A D D - O N T H E R A P Y I N E A R L Y P D
dose wearing off, on/off phenomena, disabling dyski-
nesia, or wide fluctuations; previous safinamide treat-
ment; history or current diagnosis of psychosis or
depression; hypersensitivity to anticonvulsants or anti-
parkinsonian agents; severe postural hypotension; use
of other PD medications (except for a single DA) dur-
ing the 4 weeks before screening; or concomitant
use of MAO inhibitors. Based on its selectivity for
MAO-B and results indicating a lack of tyramine
potentiation by safinamide, there were no restrictions
on tyramine intake.14
Procedures
After a 10-day screening and run-in period, eligible
patients were randomized using a computer-generated
code (1:1:1) to receive safinamide 100 mg/day,
200 mg/day, or placebo as add-on therapy to a single
DA. An interactive voice-response system was used to
assign blinded medication and make dose changes.
The patients, caregivers, and raters remained blinded
to the identity of the assigned medications throughout
the study. Randomization was carried out on a coun-
try-specific basis; a minimization procedure was used
to ensure that the range of Hoehn and Yahr scores
were evenly distributed across treatment groups. Daily
doses were achieved using combinations of 50-mg cap-
sules of safinamide and matching placebo capsules
(both manufactured by MiPharm S.p.A., Milan, Italy),
with 4 capsules being taken orally, once-daily, with
breakfast.
Patients assigned to 100 mg/day of safinamide
received 50 mg/day for 2 weeks, before being titrated
up to their target dose of 100 mg/day, whereas
patients assigned to 200 mg/day of safinamide initially
received 100 mg/day and had their dose increased to
150 mg/day on day 7, and to the target dose of
200 mg/day on day 14. Dose reductions were permit-
ted for patients who could not tolerate their assigned
dose. The dose of DA was to remain constant
throughout the trial; however, a dose increase or addi-
tion of another PD medication was permitted for
patients who were receiving the maximum dose
of study medication, but whose motor symptoms
were worsening. All final efficacy and safety evalua-
tions were performed before this intervention. A
decrease in the dose of DA was permitted, if clinically
indicated.
Patients returned for scheduled visits at 2, 4, 8, 12,
18, and 24 weeks. Patients who completed 24 weeks
of treatment, and those who discontinued prematurely
but returned for scheduled efficacy evaluations at
weeks 12 and 24, were eligible to continue treatment
in a 52-week, double-blind, extension study (Study
017; NCT00642889).
Blood samples were taken before the administration
of the first dose of study medication, 5 hours
Movement Disorders, Vol. 27, No. 1, 2012 107
S T O C C H I E T A L .
postdosing, and at each subsequent visit for the mea-
surement of plasma concentrations of safinamide and
its main metabolites (i.e., safinamide acid and N-deal-
kylated acid) using liquid chromatography with tan-
dem mass spectrometry (LC-MS/MS).
The primary efficacy measure was the change in
UPDRS part III (motor examination) total score from
baseline to endpoint (week 24). Secondary efficacy
measures included the following: responder analysis,
that is, the proportion of patients showing improve-
ment on the Clinical Global Impression–Change from
baseline (CGI-C) at endpoint and the proportion of
patients with at least 30% improvement on UPDRS
part III from baseline to endpoint with no worsening
of UPDRS part II (activities of daily living; ADL) and
part IV (complications of therapy) total scores; and
mean change from baseline to endpoint on the UPDRS
part II total score and for CGI-C and CGI–Severity of
illness (CGI-S). Mean changes from screening/baseline
to endpoint on the total scores for the tertiary efficacy
variables, Hamilton Rating Scale for Depression
(HAMD),15 UPDRS part I (mentation, behavior, and
mood), UPDRS part IV, and Mini–Mental State Ex-
amination (MMSE), were also analyzed.
Safety was assessed by the incidence of adverse
events (AEs) reported by the patient or observed by
the investigator (at all postscreening visits), vital signs
(at all visits), laboratory tests (at screening and all
postbaseline visits), 12-lead electrocardiogram (ECG;
at screening, baseline, and 12 and 24 weeks), and
physical and neurologic examinations (at screening
and 24 weeks). All safety data were monitored by an
independent safety monitoring board.
The trial is registered with the U.S. National Insti-
tutes of Health clinical trials database (ClinTrials.gov;
no. NCT00643045). Two amendments to the trial
protocol took place after commencement; the first
introduced additional measures to monitor the ocular
safety of patients, and the second was to designate
UPDRS part III as the only primary outcome.
Statistical Analysis
Two primary analysis populations were defined:
intent to treat (all randomized patients) and the safety
population (all patients who received at least one dose
of study medication and had a postbaseline safety
assessment). The sample size was calculated based on
a single primary endpoint, the UPDRS part III, and
assumed a two-tailed probability of type I error of
0.05. The planned sample size of 192 subjects had a
90% power to detect a difference of 3.3 points in the
UPDRS part III, assuming an estimated standard devi-
ation (SD) of 5.5. Based on an anticipated drop-out
rate of 20% during treatment, and a screen failure
rate of 10%, at least 267 patients were to be screened
to ensure a sufficient number of randomized patients.
108 Movement Disorders, Vol. 27, No. 1, 2012
The primary efficacy analysis consisted of two com-
parisons: safinamide 200 mg versus placebo followed
by safinamide 100 mg versus placebo, with the second
comparison being dependent on the success of the
first. If both primary efficacy comparisons were signifi-
cant, then the secondary endpoints were analyzed in a
hierarchical order in the same sequence as the dose
comparisons for the primary endpoint. If any of the
tests were not significant (alpha ¼ 0.05), then the sub-
sequent tests were considered exploratory analyses.
The analysis of change from baseline in UPDRS part
III total score between safinamide 200 mg versus pla-
cebo and safinamide 100 mg versus placebo was per-
formed using a mixed linear model analysis of
covariance (ANCOVA), with treatment, visit, and
treatment by visit interaction as fixed effects, baseline
UPDRS part III total score as covariate, and country
as a random effect. The primary efficacy analysis was
performed without imputation of missing values. Point
estimates and 95% confidence intervals (CIs) for the
mean difference in UPDRS part III total scores were
calculated. Statistical comparisons were two-sided and
were conducted at the 5% significance level.
A secondary efficacy analysis of change from base-
line in UPDRS part III total score between safinamide
200 mg versus placebo and safinamide 100 mg versus
placebo was performed for the intent-to-treat popula-
tion using the following imputation schemes: last ob-
servation carried forward (LOCF); observed case
(OC); retrieved dropout (RDO); and OC and RDO.
Subsequent secondary analyses of UPDRS parts II, III,
and IV and CGI scores utilized LOCF or OC imputa-
tion schemes, whereas tertiary analyses implemented
LOCF only.
Mean changes from baseline to endpoint for tertiary
variables were analyzed using an ANCOVA model,
with baseline value as covariate and treatment group
and country as main effects. The proportion of
patients showing improvement on the CGI-C or meet-
ing responder criteria for the UPDRS was analyzed
using the Cochran-Mantel-Haenszel method, weighted
by country. The Wilcoxon rank sum test was used to
compare mean CGI-C scores at endpoint.
Safety data were summarized for all patients by
treatment group using appropriate summary statistics.
Results
Patient Disposition and Baseline
Characteristics
A total of 270 patients were randomized (Fig. 1).
The first patient was enrolled on December 21, 2004,
and the last patient completed the study on January
23, 2006. All patients were receiving a single dopa-
mine agonist at a stable dose for 4 weeks before
screening, except 1 patient who had received a dose
 S A F I N A M I D E A S A D D - O N T H E R A P Y I N E A R L Y P D

TABLE 1. Baseline Characteristics for the

Intent-to-Treat/Safety Population

Safinamide Safinamide
200 mg/day 100 mg/day Placebo
Characteristic (n ¼ 89) (n ¼ 90) (n ¼ 90)

Age (yr) 58.5 (11.7) 56.5 (11.3) 57.3 (10.8)

Males (%) 54 (61) 59 (66) 56 (62)
Duration of PD (yr) 2.30 (1.32) 2.64 (1.42) 2.41 (1.20)
Race
White (%) 52 (58) 51 (57) 55 (61)
Asian (Indian) (%) 35 (39) 35 (39) 34 (38)
Weight (kg) 68.0 (12.5) 72.3 (13.8) 69.3 (13.9)
Hoehn and Yahr stage (%)
I 18 (20) 14 (16) 10 (11)
I.5 11 (12) 16 (18) 17 (19)
II 43 (48) 45 (50) 48 (53)
II.5 14 (16) 10 (11) 10 (11)
III 3 (3) 5 (6) 5 (6)
IV 0 0 0
V 0 0 0
CGI–Severity of illness 3.1 (0.85) 3.1 (0.79) 3.1 (0.76)
UPDRS part I (mentation, 1.3 (1.23) 1.2 (1.26) 1.3 (1.24)
behavior, and mood)
UPDRS part II (ADL) 7.3 (4.71) 8.2 (4.92) 8.1 (5.32)
UPDRS part III (motor) 19.3 (9.80) 22.0 (10.15) 20.7 (9.63)
UPDRS part IV 0.4 (0.83) 0.4 (0.73) 0.6 (0.95)
(complications
of therapy)
MMSE total score 28.3 (1.54) 28.9 (1.21) 28.4 (1.56)
HAMD total score 4.2 (3.11) 4.0 (3.43) 4.3 (3.22)

FIG. 1. Study profile. Data are presented as mean (SD) or number (%) of patients.
ADL, activities of daily living; CGI, Clinical Global Impression; HAMD,
Hamilton Rating Scale for Depression; MMSE, Mini–Mental State
Examination; SD, standard deviation.
adjustment 3 weeks before screening. The majority of
patients (>90%) reached the target doses of 100 or
200 mg/day and remained at that dose throughout the cebo showed improvement from baseline to week 24 in
study. Withdrawal of consent and AEs were the most UPDRS part III total score (
6.0 versus
3.6; point
common reasons for premature withdrawal from the estimate:
1.9; 95% CI:
3.7 to
0.1; P ¼ 0.0419).
study.
There were no meaningful differences among treat-
ment groups in any of the key demographic and base- TABLE 2. Concomitant Medication for PD
line characteristics (Table 1), except for the finding (Intent-to-Treat Population)
that the mean UPDRS part III score at baseline was
Safinamide Safinamide
2.7 points higher in the safinamide 100 mg/day group,
200 mg/day 100 mg/day Placebo
compared with the 200 mg/day group (not Medication (n ¼ 89) (n ¼ 90) (n ¼ 90)
significant).
Dopamine agonist usea:
Bromocriptine (%) 10 (11) 16 (22) 13 (14)
Efficacy Cabergoline (%) 3 (3) 9 (10) 9 (10)
Lisuride (%) 3 (3) 0 0
The primary efficacy endpoint of mean change from Pramipexole (%) 27 (30) 21 (23) 23 (26)
baseline in UPDRS part III total score at week 24 was Pergolide (%) 2 (2) 1 (1) 0

3.9 (SD 6 6.01),
6.0 (SD 6 7.18), and
3.6 Piribedil (%) 5 (6) 2 (2) 4 (4)
(SD 67.08) for safinamide 200 mg, safinamide Ropinirole (%) 40 (45) 43 (48) 41 (46)
Dopa and dopa 1 (1) 2 (2) 1 (1)
100 mg, and placebo, respectively (Fig. 2). For the first derivatives (%)
comparison of safinamide 200 mg versus placebo, Amantadine (%) 0 1 (1) 1 (1)
there was no significant difference in change from Anticholinergic agents (%) 2 (2) 2 (2) 1 (1)
baseline to week 24 in UPDRS part III total score
between treatment groups (
3.9 versus
3.6; point a
Concomitant dopamine agonist use for PD includes any dopamine agonist
that was started on or after the first administration of safinamide and any
estimate:
0.4; 95% CI:
2.3–1.4; P ¼ 0.65). The dopamine agonist started before the study, but continued after safinamide
second comparison of safinamide 100 mg versus pla- administration.

Movement Disorders, Vol. 27, No. 1, 2012 109

S T O C C H I E T A L .

FIG. 2. Mean change from baseline in the UPDRS part III total scores–mixed linear model (intent-to-treat population).

Similar results for UPDRS part III total scores were pain (upper), vomiting, pyrexia, cough, hypertension,
obtained using the alternative imputation schemes. blurred vision, gastritis, peripheral edema, nasophar-
The proportion of responders at week 24 in each yngitis, dizziness, back pain, and tremor. The inci-
treatment group is shown in Figure 3. A greater propor- dence of these TEAEs was <10% in each group.
tion of patients in the safinamide 200 mg and 100 mg TEAEs were generally of mild or moderate intensity.
groups experienced benefit, compared with those in the The number of patients with TEAEs rated as severe
placebo group (P < 0.05 for CGI-C responders in was 2 (2.2%) for the safinamide 100 mg group,
the OC analysis). 9 (10.1%) for the safinamide 200 mg group, and
Mean (6 SD) CGI-C from baseline score at week 24 6 (6.7%) for the placebo group. Of these, incidences
for the safinamide 200 mg and 100 mg groups and of blurred vision and leg pain in the safinamide
placebo groups were 3.1 (0.98; n ¼ 70), 3.1 (1.06; 200 mg group and vomiting and dizziness in the safi-
n ¼ 80), and 3.4 (1.04; n ¼ 82), respectively, indicating namide 100 mg group were considered to be related
an improvement in CGI score for both active treatment to treatment. Four patients experienced serious
groups versus placebo (P ¼ 0.0325 and P ¼ 0.0293
for safinamide 200 mg and 100 mg versus placebo,
respectively). The CGI-C from baseline score and CGI-S
mean change at endpoint were not statistically different
between groups.
Mean change from baseline to week 24 in UPDRS
part II indicated an improvement in ADL for the safi-
namide 100 mg group versus placebo (
2.2 versus

1.2, respectively; P ¼ 0.0248); there was no signifi-
cant difference between the safinamide 200 mg group
and placebo (
1.4 versus
1.2, respectively). Changes
from baseline to week 24 in HAMD, UPDRS I,
UPDRS IV, and MMSE did not show a significant
benefit for treatment with safinamide.

Safety
The most common treatment-emergent adverse FIG. 3. Secondary efficacy variables: responders at endpoint (week 24;
events (TEAEs) were nausea, headache, abdominal intent-to-treat population).

110 Movement Disorders, Vol. 27, No. 1, 2012

 S A F I N A M I D E
TEAEs. These included retinal vein occlusion and
iron-deficiency anemia (100 mg group) and gastroen-
teritis (200 mg group). There was one death during
the study (gunshot wound). None of these serious
TEAEs were considered by the investigators to be
related to the study medication. Overall, 21.3% of
patients discontinued treatment in the safinamide
200 mg group, compared with 10.0% each for safina-
mide 100 mg and placebo. Six patients discontinued
treatment as a result of TEAEs: 1 in the safinamide
100 mg group, 3 in the safinamide 200 mg group, and
2 in the placebo group. These were all considered to
be possibly or probably related to study medication
and included nausea/anxiety, head tremor/nausea/
gastroesophageal reflux disease, hypotension/diarrhea/
vomiting (200 mg group), parasthesia (100 mg group),
and nausea and headache/dystonia (placebo group).
The incidence of clinically notable values for labora-
tory parameters and vital signs was comparable
between groups.
Pharmacokinetics
Plasma concentrations in both safinamide groups
were consistent with the dose level and showed a lin-
ear dose exposure and a relationship between dose
groups. However, in the blood samples from patients
in the placebo group, safinamide and its metabolites
were detected in 155 of 588 (26%) plasma samples
taken from 79 of 90 patients randomized to placebo.
This indicates that patients in the placebo group were
exposed, at some visits, to a certain amount of safina-
mide and this exposure was most frequently detected
at weeks 8 and 12 (78% and 58% of patients, respec-
tively). At these time points, the average safinamide
concentration in placebo samples with measurable lev-
els was approximately 20% of that observed in sam-
ples from patients receiving safinamide 100 mg. An
audit revealed that 2 of 51 bulk placebo bottles con-
tained a mixture of placebo and safinamide capsules.
No errors in randomization, labeling, or dispensing
were detected.
Discussion
This phase III, randomized, double-blind, placebo-
controlled study compared two once-daily oral dose
ranges of safinamide with placebo as add-on therapy
to a stable dose of a single DA in patients with early
PD. In the primary efficacy analysis, this study failed
to demonstrate a significant difference between safina-
mide 200 mg/day and placebo for the change in motor
symptoms. The subsequent exploratory analysis indi-
cated a significant improvement in UPDRS part III
total scores for safinamide 100 mg/day versus placebo.
A S A D D - O N T H E R A P Y I N E A R L Y P D
In addition, analyses of safinamide 100 mg/day dem-
onstrated improvements in CGI-C and UPDRS part II
(ADL) scores. The proportion of patients considered
to be ‘‘responders’’ was higher in both safinamide
100 mg and 200 mg groups, compared with the pla-
cebo group.
The reason for the lack of efficacy of the higher
dose of safinamide is unknown. The baseline demo-
graphics and characteristics of the two safinamide
groups were similar. It is possible that the higher inci-
dence of discontinuations in the safinamide 200 mg
group (21.3% versus 10.0% each for safinamide
100 mg and placebo) may have prevented the demon-
stration of a significant clinical benefit. It is also possi-
ble that the higher rate of discontinuation in the
safinamide 200 mg group was the result of a lack of
efficacy; only 2 patients in this group were specifically
withdrawn because of lack of efficacy, but 8 patients
were withdrawn for withdrawal of consent/other rea-
sons, and the possibility that these reflect a lack of ef-
ficacy cannot be ruled out. It has previously been
shown that different results may be obtained with dif-
ferent doses of an MAO-B inhibitor.15 Safinamide has
both dopaminergic (including MAO-B inhibition) and
nondopaminergic mechanisms of action.11–13
In this study, an improvement in UPDRS part III
total scores was observed in the placebo group, an
effect that may have contributed to the lack of efficacy
observed with safinamide 200 mg/day. The influence
of placebo in clinical trials in PD patients that investi-
gate motor functional endpoints has been previously
documented.16 This influence may be caused by the
release of neurotransmitters, such as dopamine, or
other physiological mechanisms, which may obscure
the effects of the investigational therapy.16 The devel-
opment of rating scales of motor function that are
able to discern the effects of placebo would be a criti-
cal advantage for future clinical trials investigating do-
paminergic therapies.17
Safinamide treatment was associated with a low
incidence of serious TEAEs and discontinuations
resulting from AEs. In addition, the incidence of the
most common AEs was low (<10%) and comparable
between the three groups, and the proportion of
patients with serious AEs was lowest in the safinamide
100 mg group (2.2%). The extension study (Study
017) will provide additional safety data for safinamide
as add-on to DA therapy.
Pharmacokinetic analysis revealed that some
patients in the placebo group inadvertently received
study medication, because safinamide was detected in
plasma at various time points. At the time points in
which the greatest safinamide exposure was detected,
the average concentrations in samples with measurable
safinamide did not exceed 20% of the levels in plasma
from patients randomized to the 100 mg/day dose
group. These findings need to be considered when
Movement Disorders, Vol. 27, No. 1, 2012 111
S T O C C H I E T A L .
interpreting the results of the placebo group for this
study. However, the effects are likely to be minor, and
it is possible that differences between safinamide and
placebo may have been greater if the placebo group
had remained free from active drug.
In a previous study in early PD, safinamide 1 mg/kg
(median dose: 70 mg/day) was associated with signifi-
cant improvements in motor function.18,19 In the cur-
rent study, treatment with safinamide 100 mg/day was
associated with improvements in motor symptoms and
ADL, with no clinically meaningful differences from
placebo for any safety variables. These findings sug-
gest that the addition of safinamide 100 mg/day to
DA therapy may be an effective treatment strategy
that could allow physicians to improve motor func-
tion, prolong the use of DAs, and/or delay the intro-
duction of L-dopa. Further studies are required to
confirm this; indeed, safinamide is being evaluated fur-
ther in ongoing phase III trials, including a random-
ized, double-blind study evaluating the efficacy and
tolerability of safinamide 50 or 100 mg/day as add-on
therapy to a single DA (MOTION; NCT00605683).
Conclusion
Further investigation is important to evaluate the
potential benefits of safinamide add-on to DAs. It has
been shown that the risk of developing dyskinesia in
patients on dopamine agonists treated with L-dopa/car-
bidopa/entacapone is greater than that in patients initi-
ated on L-dopa/carbidopa/entacapone.20 Furthermore,
the addition of safinamide may provide an alternative
strategy to increasing the DA dose, thereby reducing the
risk of DA-related side effects, such as ICDs.
Acknowledgments: The authors thank Janet Dawson and Kirs-
teen Munn of Complete Medical Communications (supported by Merck
Serono S.A. – Geneva, Switzerland, a branch of Merck Serono S.A.,
Coinsins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany)
for their editorial support.
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