Tesofensine (NS 2330), a Monoamine Reuptake Inhibitor, in Patients With Advanced

CLINICAL TRIALS
SECTION EDITOR: IRA SHOULSON, MD
Tesofensine (NS 2330), a Monoamine
Reuptake Inhibitor, in Patients With Advanced
Parkinson Disease and Motor Fluctuations
The ADVANS Study
Olivier Rascol, MD, PhD; Werner Poewe, MD; Andrew Lees, MD; Marina Aristin; Laurence Salin, MD;
Nolwenn Juhel; Lisa Waldhauser, PhD; Thomas Schindler, PhD; for the ADVANS Study Group
Objective: To assess the safety and efficacy of tesofensine, a triple monoamine reuptake inhibitor, in patients
with advanced Parkinson disease (PD).
Design: A pilot phase 2, randomized, double-blind, pla-
cebo-controlled, parallel-group trial. The study occurred in hospital-based outpatient clinics and in clinical trial units. Patients with advanced PD and levodoparelated motor fluctuations were enrolled. Tesofensine
(0.125, 0.25, 0.5, or 1 mg) or placebo tablets were administered once daily for 14 weeks.
Results: The adjusted mean differences (relative to placebo)
were −4.7 points in UPDRS subscale II plus subscale III total
score (P=.005) with tesofensine, 0.5 mg, and −7.1% in off
time (−68 minutes, P=.02) with tesofensine, 0.25 mg. Other
dosages did not induce statistically significant effects. The
plasma concentration increased with the dosage, but no clear
dose-response relationship was observed. Gastrointestinal tract and neuropsychiatric adverse events were more
frequent with tesofensine than with placebo, especially at
the higher dosages.
Conclusions: Patients with PD in advanced stages showed
Main Outcome Measures: Coprimary end points were
the changes from baseline in Unified Parkinson Disease
Rating Scale (UPDRS) subscale II (activities of daily living) plus subscale III (motor function) total score and
in percentage of waking hours spent in “off ” time noted
in self-scoring diaries. Secondary end points were safety,
pharmacokinetics, responder analysis (ⱖ20% reduction in UPDRS score and in off time), and changes in percentage of waking hours spent in “on” time with and without troublesome dyskinesia.
modest improvements in UPDRS subscale II plus subscale III total score and in off time when treated with
tesofensine, but a dose-response relationship could not
be established for efficacy, while adverse drug reactions
tended to be more frequent at higher dosages.
Trial Registration: clinicaltrials.gov Identifier:
NCT00148512.
Arch Neurol. 2008;65(5):577-583
P
Author Affiliations are listed at
the end of this article.
Group Information: The
ADVANS Study Group members
are listed on page 582.
ATIENTS WITH PARKINSON DISease (PD) frequently experience levodopa-related motor
fluctuations. Levodopa dosing adjustments, sustainedrelease levodopa formulations, dopamine
agonists, monoamine oxidase B inhibitors,
and catechol-O-methyltransferase inhibitors provide incomplete relief.1,2 Blocking
presynaptic dopamine reuptake is a new
therapeutic approach. Tesofensine (NS
2330) inhibits reuptake of dopamine, noradrenaline, and serotonin and stimulates
cholinergic neurons in the prefrontal cortex and hippocampus.3 In the marmoset
model, it reduced parkinsonian symptoms
without inducing dyskinesia.4 The pharmacokinetic profile of the drug is linear after
single and multiple doses across all dos-
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577
ages tested, and the estimated absolute bioavailability after oral administration is
greater than 90%.3 With a half-life in humans of approximately 8 days, tesofensine
has the potential to increase striatal dopamine concentrations without phasic fluctuations. The ADVANS (Proof of Concept
in Advanced Parkinson Disease of NS 2330)
study explored the safety and efficacy of
tesofensine in patients with advanced PD
and levodopa-related motor fluctuations.
METHODS
ORGANIZATION
The ADVANS study (49 active sites in Austria, England, France, Germany, Spain, and the
Netherlands) was planned and coordinated by
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The ADVANS trial was a 14-week pilot, proof-of-concept, phase
2, randomized, double-blind, placebo-controlled, parallelgroup study of tesofensine in patients with advanced PD. Patients received tablets of tesofensine (0.125, 0.25, 0.5, or 1 mg)
or placebo once daily. This range of dosages was chosen based
on (1) single oral dose tolerability data for tesofensine (up to
10 mg) in healthy volunteers demonstrating sleep difficulties
at high dosages3 and (2) positron emission tomography data
showing receptor occupancy of 77% at the 1-mg dosage.4
and percentage of patients responding with at least 20% reduction in percentage of waking hours spent in off time.
Safety measures included the incidence and severity of adverse events and withdrawals owing to adverse events. Vital signs,
body weight, clinical laboratory values, and pharmacokinetic
variables were also monitored.
Patients were evaluated at investigators’ centers (at baseline
and at weeks 2, 4, 6, 8, 10, and 14), with additional telephone
interviews at weeks 1, 5, 7, and 12. Unified Parkinson Disease
Rating Scale subscale II was scored for best (on) and worst (off )
status. Unified Parkinson Disease Rating Scale subscale III was
assessed when patients were receiving levodopa. Investigators
were trained and certified in UPDRS rating. Off time was calculated from the patients’ diaries for 2 consecutive days before each
clinic visit. Each patient was trained to recognize on and off times
and was asked to make diary entries at 30-minute intervals from
6 AM to midnight. Test diaries of concordance between the patient and the investigator were used to verify successful completion of patient diary training.
Blood samples for pharmacokinetic and laboratory analyses
were taken at baseline and at weeks 4, 6, 8, 10, and 14. Plasma
concentrations of tesofensine were analyzed using a fully validated
high-performance liquid chromatography tandem mass spectrometry method at Boehringer Ingelheim, Biberach, Germany.
PARTICIPANTS
RANDOMIZATION AND BLINDING
Eligible patients were between 40 and 80 years of age, had been
diagnosed as having idiopathic PD at least 2 years previously,
had a modified Hoehn and Yahr stage of II to III during “on”
time,5 were treated with levodopa 3 to 8 times daily at an optimal and stable dosage for at least 4 weeks, experienced motor fluctuations with 2.0 to 6.0 hours daily “off” time during
waking hours (on 2 consecutive days before baseline), and were
able to comply with the study protocol. Concomitant treatment with dopamine agonists, entacapone, antiparkinsonian
anticholinergics, amantadine hydrochloride, hypnotics, or anxiolytics was allowed at a stable dosage from at least 4 weeks
before screening until the end of the study.
Exclusion criteria were electrocardiographic abnormalities;
atypical or secondary causes of parkinsonism; treatment with digoxin in the 7 days before screening; dementia (Mini-Mental State
Examination score, ⬍26); treatment with selegiline hydrochloride within 8 weeks before screening; a history of mental disorder, psychosis, or central nervous system injury or disease; hypotension or uncontrolled hypertension or any other significant
medical comorbidity; and regular use of antidepressants, psychotropic drugs, or drugs with central dopaminergic antagonist
activity within 4 weeks before screening.
The randomization code was generated by the sponsor using a
commercially available program (ClinPro/LBL Clinical Label
Generation System; Clinical Systems, Inc, Garden City, New
Jersey). Patients were randomized by receiving the medication kit with the lowest number. Patients, investigators, and
sponsor personnel were blinded to the study treatments. Emergency envelopes containing each patient’s treatment code were
provided to the investigators.
a steering committee consisting of the coordinating investigator (O.R.), 2 movement disorder specialists with experience in
clinical trials (W.P. and A.L.), and 2 representatives of the study
sponsor (L.S. and J. Reess, MD).
ETHICS
The protocol was approved by independent ethics committees
at each site and complied with local laws, the Declaration of
Helsinki (version 1996), and the International Conference on
Harmonisation “Guidelines for Good Clinical Practice.” Each
patient provided written informed consent before enrollment.
STUDY DESIGN AND TREATMENT
END POINTS
Because the ADVANS study was a pilot exploratory, nonpivotal, phase 2 trial and no previous relevant data were available, there were 2 coprimary efficacy outcome measures. These
were (1) the changes from baseline to end of study in Unified
Parkinson Disease Rating Scale (UPDRS) subscale II (activities of daily living) and subscale III (motor functioning) total
score and (2) the changes in percentage of waking hours spent
in off time as recorded on diaries.6,7
Secondary exploratory efficacy measures were changes from
baseline to end of study in the following: percentage of waking hours spent in on time without troublesome dyskinesia (ie,
without dyskinesia or with nontroublesome dyskinesia), percentage of waking hours spent in on time with troublesome dyskinesia, percentage of patients responding with at least 20% improvement in UPDRS subscale II plus subscale III total score,
SAMPLE SIZE CALCULATION
A sample size of 50 patients per group was planned to detect
(at any dosage at a 5% significance level) a treatment effect of
7 points in UPDRS subscale II plus subscale III total score (assuming a 13.9 SD) and a treatment effect of 80 minutes in off
time (assuming a 2.6-hour SD). A similar reduction in off time
was observed in a comparable population using the monoamine oxidase type B inhibitor rasagiline mesylate,8 while smaller
but potentially clinically relevant UPDRS changes have been
described in others.9
STATISTICAL ANALYSIS
The null hypothesis was that there was no difference between
patients treated with placebo and patients treated with tesofensine at any dosage. The alternative was that tesofensine at any
dosage was superior to placebo. The statistical tests used for
the regression coefficient and for the comparison of tesofensine and placebo were 1-sided 2-sample tests at a 5% significance level. No statistical adjustment for having 2 coprimary
results or multiple comparisons was made. Statistical analyses
were considered descriptive only because of the exploratory design of the pilot trial.
Safety analyses were based on the safety set, defined as patients who received at least 1 dose of treatment. Efficacy analyses were based on the full-analysis set, defined as patients with
at least 1 posttreatment efficacy evaluation for at least 1 of the
coprimary end points. The last-observation-carried-forward
method was used to estimate missing efficacy data. Analysis of
covariance was used to perform linear regressions and pair-
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314 Assessed for eligibility
60 Not eligible
254 Randomized
49 Randomized
to placebo
49 Randomized
to tesofensine, 0.125 mg
9 AE
2 LOE
2 Others
36 Completed
placebo
52 Randomized
to tesofensine, 0.25 mg
11 AE
1 LOE
2 Others
35 Completed
tesofensine, 0.125 mg
56 Randomized
to tesofensine, 0.5 mg
6 AE
1 LOE
2 Others
43 Completed
tesofensine, 0.25 mg
48 Randomized
to tesofensine, 1 mg
14 AE
0 LOE
3 Others
39 Completed
tesofensine, 0.5 mg
13 AE
1 LOE
3 Others
31 Completed
tesofensine, 1 mg
Figure 1. Patient flow from screening to last visit. AE indicates adverse event; LOE, lack of efficacy. Seventeen patients withdrew from the study
for various reasons.
Table 1. Patient Demographics, Baseline Disease Characteristics, and Concomitant Parkinson Disease Therapy
Based on the Safety Set of 254 Patients
Tesofensine Treatment Group
Variable
Male sex
Age, mean (SD), y
Duration, mean (SD), y
Parkinson disease
Motor fluctuations
Unified Parkinson Disease Rating Scale total score,
mean (SD)
Off time, mean (SD)
%
Hours
Levodopa
Dosage, mean (SD), mg/d
Doses per day, mean (SD), No.
Patients receiving, %
Dopamine agonist
Catechol-O-methyltransferase inhibitor
Amantadine hydrochloride
Placebo
Group
(n = 49)
0.125 mg
(n = 49)
0.25 mg
(n = 52)
0.5 mg
(n = 56)
1 mg
(n=48)
74
65 (7)
57
65 (7)
64
63 (9)
63
63 (8)
58
64 (9)
9 (4)
3.7 (2.8)
34 (13)
10 (6)
3.9 (3.3)
34 (15)
10 (5)
4.7 (3.8)
33 (14)
8 (4)
3.8 (3.2)
32 (16)
10 (5)
4.5 (4.1)
31 (16)
35 (13)
5.1 (1.8)
35 (14)
5.3 (2.2)
31 (11)
4.6 (1.4)
32 (12)
5.1 (1.9)
33 (12)
4.9 (1.7)
562 (286)
4.2 (1.1)
778 (502)
4.8 (1.5)
589 (283)
4.4 (1.2)
737 (428)
4.6 (1.5)
659 (365)
4.8 (1.2)
82
39
31
84
35
31
98
44
50
89
55
34
83
48
27
wise comparisons between placebo and each dosage of tesofensine and to test for differences in the secondary end points.
RESULTS
PATIENT FLOW
The patient flow is illustrated in Figure 1. Overall, 314
patients were screened; 60 patients were excluded primarily because their daily off time did not fall between
2.0 and 6.0 hours or because they had clinically significant electrocardiographic abnormalities. Therefore, 254
patients were randomized and received treatment (safety
set). Three of these patients did not have an efficacy assessment; therefore, the full-analysis set comprised 251
patients. Seventy of 254 patients (27.6%) discontinued
treatment prematurely, primarily because of adverse events
(53 patients [20.9%]). The percentages of patients who
prematurely withdrew because of adverse events were
22.4%, 11.5%, 25.0%, and 27.1% in the groups receiving tesofensine, 0.125, 0.25, 0.5, and 1 mg, respectively,
compared with 18.4% in the placebo group. Patient demographics, baseline disease characteristics, and concomitant PD therapy are given in Table 1.
PRIMARY OUTCOMES
Compared with the placebo group, the adjusted mean
changes in UPDRS subscale II plus subscale III total score
in the tesofensine treatment groups ranged from −1.2
points in the 0.25-mg–treated group to −4.7 points in the
0.5-mg–treated group (Table 2). There was a trend to
greater efficacy with the 2 highest dosages, but the difference relative to placebo reached statistical signifi-
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Table 2. Primary Outcomes Based on the Full-Analysis Set of 251 Patients a
Tesofensine Treatment Group
Variable
Change in Unified Parkinson Disease Rating Scale total score
Mean (SD)
Adjusted mean b
P value
Change in percentage of waking hours spent in off time
Mean (SD)
Adjusted mean (change in minutes) b
P value
Placebo
Group
(n = 49)
0.125 mg
(n = 48)
0.25 mg
(n = 52)
0.5 mg
(n = 55)
1 mg
(n=47)
−0.6 (8.3)
...
...
−3.2 (11.1)
−2.3
.10
−1.5 (9.5)
−1.2
.24
−5.0 (10.6)
−4.7
.005
−2.6 (9.1)
−2.8
.07
−2 (18)
...
...
1 (20)
3.6 (35)
.14
−8 (16)
−7.1 (−68)
.02
−1 (16)
0.1 (1)
.49
−5 (13)
−4.4 (−42)
.10
Abbreviation: Ellipses, not applicable.
a Negative values in Unified Parkinson Disease Rating Scale total score and percentage of waking hours spent in off time represent improved outcomes.
b Adjusted for baseline and pooled centers.
Table 3. Secondary Outcomes Based on the Full-Analysis Set of 251 Patients
Tesofensine Treatment Group
Placebo
Group
(n = 49)
Variable
0.125 mg
(n = 48)
0.25 mg
(n = 52)
0.5 mg
(n = 55)
1 mg
(n=47)
Responder Analysis
Unified Parkinson Disease Rating Scale total score
ⱖ 20% Improvement, %
P value
% of Waking hours spent in off time a
ⱖ 20% improvement, %
P value
14
...
40
.007
31
.04
35
.02
26
.27
33
...
25
.63
52
.08
40
.46
56
.02
−1.5 (21.3)
−6
.06
4.6 (18.9)
1
.34
1.3 (17.3)
−2
.26
2.9 (14.4)
0
.49
0.3 (8.7)
2
.19
2.9 (13.7)
5
.005
Percentage of Waking Hours Spent in on Time
Without troublesome dyskinesia
Mean change (SD)
Adjusted mean change
P value
With troublesome dyskinesia
Mean change (SD)
Adjusted mean change
P value
a Without
3.2 (18.1)
...
...
−1.1 (7.9)
...
...
−0.2 (9.8)
2
.18
2.3 (11.6)
4
.03
receiving tesofensine.
cance only in the 0.5-mg–treated group (P =.005). The
adjusted mean changes in percentage of waking hours
spent in off time from baseline to study end in the tesofensine treatment groups varied from 3.6% (35 minutes vs
placebo) with tesofensine, 0.125 mg, to −7.1% (−68 minutes vs placebo) with tesofensine, 0.25 mg. The difference relative to placebo was statistically significant (P=.02)
only in the 0.25-mg–treated group. No dose-response relationship could be established.
cebo was statistically significant only in the group receiving tesofensine, 1 mg. Improvements relative to placebo
in on time without troublesome dyskinesia were observed
only in the group receiving tesofensine, 0.25 mg. Patients
in the groups receiving tesofensine, 0.25 and 1 mg, experienced increases in on time with troublesome dyskinesia.
No dose-response relationship was apparent for any secondary end point.
PHARMACOKINETICS
SECONDARY END POINTS
A greater proportion of patients responded with at least 20%
(range, 26%-40%) improvement in UPDRS subscale II plus
subscale III total score in all the tesofensine arms of the trial
compared with placebo (14%) (Table 3). However, there
was no dose-response relationship. A greater proportion
of patients responded with at least 20% improvement in
off time in the 3 highest-dosage tesofensine treatment groups
than in the placebo group. The difference relative to pla-
Steady-state plasma concentrations of tesofensine were
reached at 4 to 6 weeks. The concentration increased in
a log-linear relationship with the dosage administered
(Figure 2).
SAFETY
More patients in the pooled tesofensine treatment groups
(81.5%) than in the placebo group (73.5%) experienced
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Decreases in the mean body weight were observed in
patients in all treatment groups except the group receiving tesofensine, 0.125 mg (−0.2 kg in the placebo group,
−0.3 kg in the 0.125-mg–treated group, −0.7 kg in the
0.25-mg–treated group, −0.6 kg in the 0.5-mg–treated
group, and −1.1 kg in the 1-mg–treated group). No clinically significant changes were observed in any laboratory
variables.
COMMENT
Patients with advanced PD receiving the monoamine
reuptake blocker tesofensine experienced modest
improvements in some parkinsonian symptoms. Drugplasma concentrations increased linearly with dosage,
while no dose-response relationship was observed. The
Tesofensine, 0.125 mg
Tesofensine, 0.25 mg
NS 2330 Plasma Concentration, ng/mL
adverse events (Table 4). Patients in the tesofensine treatment groups experienced a higher rate of nervous system
disorders (dyskinesia and headache), gastrointestinal tract
disorders (nausea and constipation), and psychiatric disorders (hallucinations and insomnia). Most adverse events
were assessed as mild. The incidences of severe adverse
events were 20.4% in the placebo group and 16.6% in the
pooled tesofensine treatment groups. The most frequently reported severe adverse event in the tesofensine
treatment groups was dyskinesia (2% in the 0.125-mg–
treated group, 6% in the 0.25-mg–treated group, 4% in the
0.5-mg–treated group, and 0% in the 1-mg–treated group).
Serious adverse events were more frequently reported with placebo (12.2%) than with tesofensine treatment (5.9%). Three patients experienced serious adverse events that were considered drug related: 1 patient
in the group receiving tesofensine, 1 mg, experienced severe tightness of the chest, possibly due to exacerbation
of the “wearing-off” effect, and 2 patients in the placebo
group developed visual hallucinations and acute anemia, respectively. Two patients died during the study, both
of whom had received tesofensine: 1 patient in the 0.25mg–treated group died after aspirating food, and 1 patient in the 0.5-mg–treated group died of acute myocardial infarction. Neither death was considered drug related.
Overall, the mean changes in supine systolic blood pressure in the tesofensine treatment groups were minimal
(ranging from −0.29 mm Hg in the 0.125-mg–treated group
to −1.95 mm Hg in the 0.5-mg–treated group) compared
with a small increase in blood pressure (0.75 mm Hg) in
the placebo group. A clinically relevant decrease (a reduction of ⱖ20 mm Hg, with a final value of ⱕ90 mm Hg) in
the mean systolic blood pressure was recorded in 6 of 205
patients (2.9%) in the tesofensine treatment groups but in
no patients in the placebo group. A dose-dependent increase in heart rate was observed in patients in all 4 tesofensine treatment groups (mean change in heart rate, −0.8 beats/
min in the placebo group, 4.7 beats/min in the 0.125-mg–
treated group, 4.7 beats/min in the 0.25-mg–treated group,
5.6 beats/min in the 0.5-mg–treated group, and 6.7 beats/
min in the 1-mg–treated group).
Tesofensine, 0.5 mg
Tesofensine, 1 mg
40
30
20
10
0
Visit 4
(wk 4)
Visit 6
(wk 6)
Visit 8
(wk 8)
Visit 9
(wk 10)
Visit 10
(wk 14)
Visit 11
(wk 20)
32
40
34
27
20
36
34
28
Time Point
Tesofensine, mg
0.125
0.25
0.5
1
43
45
47
34
40
45
44
33
33
38
32
26
36
43
39
29
Figure 2. Plasma concentrations of tesofensine (NS 2330) are shown as the
mean concentration for each treatment group at the time points indicated.
Data are given as arithmetic mean (SD) at visits 4, 6, 8, 9, 10, and 11.
Table 4. Adverse Events Based on the Safety Set of 254 Patients a
Tesofensine Treatment Group, %
Variable
Any adverse event
Nervous system disorder
Dyskinesia
Headache
Gastrointestinal tract disorder
Nausea
Dry mouth
Constipation
Psychiatric disorder
Insomnia
Hallucinations
Ear and labyrinth disorder
Vertigo
Placebo
Group, %
(n=49)
Pooled Tesofensine
Treatment Groups, %
(N = 205)
0.125 mg
(n = 49)
0.25 mg
(n = 52)
0.5 mg
(n = 56)
1 mg
(n=48)
73.5
40.8
14.3
2.0
20.4
10.2
4.1
0.0
18.4
6.1
4.1
4.1
4.1
81.5
45.9
22.9
7.3
34.1
17.1
5.4
8.8
30.2
11.7
4.9
8.3
6.3
85.7
38.8
14.3
4.1
30.6
20.4
2.1
0.0
28.6
6.1
4.1
10.2
8.2
82.7
40.4
23.1
5.8
40.4
17.3
3.8
11.5
30.8
9.6
3.8
3.8
1.9
78.6
57.1
28.6
12.5
30.4
16.1
8.9
8.9
30.4
17.9
5.4
12.5
8.9
79.2
45.8
25.0
6.3
35.4
14.6
6.3
14.6
31.3
12.5
6.3
6.3
6.3
a Adverse events are listed that were observed in at least 5.0% (or 4.9% for hallucinations) of patients in all tesofensine treatment groups, as well as those
observed more frequently with tesofensine than with placebo.
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effective dosage of tesofensine was different for each of
the coprimary outcome measures, namely, 0.5 mg in
reducing UPDRS subscale II and subscale III total score
and 0.25 mg in reducing percentage of waking hours
spent in off time. Dopaminergic adverse drug reactions
such as dyskinesias and gastrointestinal tract and neuropsychiatric symptoms tended to be more frequent in the
groups receiving higher tesofensine dosages.
The modest antiparkinsonian response, the lack of a
dose-response effect, and the worsening of dyskinesia were
unexpected findings, contrasting with the clear antiparkinsonian effect and the low propensity to induce dyskinesia of tesofensine4 and of a related reuptake inhibitor, brasofensine maleate, in animal models of PD.10
Clinical studies failed to demonstrate superiority of
tesofensine over placebo in patients with early11 and advanced12 PD, while small and variable effects have been
reported with methylphenidate hydrochloride, an inhibitor of the dopamine transporter.13,14 Nevertheless, several results of the ADVANS study preclude an outright
dismissal of a potential benefit of the tesofensine and provide clinical signs of antiparkinsonian efficacy. The 0.5-mg
dosage was statistically superior to placebo in improving UPDRS scores, and UPDRS responder rates were
higher in all 4 tesofensine treatment groups compared
with the placebo group. The adverse effect profile of
tesofensine treatment was consistent with clinical aminergic activity: tachycardia, insomnia, and weight loss suggest noradrenergic activation, while dyskinesia, nausea,
and hallucinations are indicative of dopaminergic effects. Because the ADVANS trial is a small proof-ofconcept study, it is plausible that larger and betterpowered trials could demonstrate in a more consistent
manner the antiparkinsonian properties of tesofensine.
Moreover, the high dropout rate observed in this population of patients with advanced PD may have contributed to reduce the effect size reported in the trial.
Previous positron emission tomography investigations of dopamine transporter occupancy by tesofensine
demonstrated 18% occupancy at 0.125-mg dosages, 42%
at 0.25-mg dosages, 61% at 0.5-mg dosages, and 77% at
1-mg dosages.4 In the ADVANS study, the lowest tesofensine dosage (0.125 mg) elicited no tolerability or efficacy
signal, while the 0.25-mg dosage seemed to be the smallest active dosage. Safety data suggest that dosages of tesofensine above 1 mg/d might pose tolerability concerns in patients with advanced PD, including cardiovascular effects
(tachycardia) and psychiatric effects (hallucinations and
insomnia). It is unclear why this study failed to show a
clear dose-response relationship for any of the primary or
secondary outcomes. This may be related to cumulative
dopamine transporter blockade in the striatum because of
the long half-life of the drug or because of dosedependent changes in dopaminergic relative to noradrenergic reuptake blockade, with different responses of various parkinsonian symptoms to dopaminergic vs
noradrenergic mechanisms. Other clinical paradoxes such
as the lack of tesofensine motor effects in patients with early
PD,11 despite the high number of striatal dopamine transporters at this stage,15,16 may have similar explanations.
In conclusion, the ADVANS study provided some indications of an antiparkinsonian activity of the dopa-
mine reuptake inhibitor tesofensine in advanced PD. The
effective dosages of 0.25 mg/d and 0.5 mg/d exhibited
an acceptable safety profile, while higher dosages may
induce adverse reactions of clinical concern in this older
population. These pilot results deserve further exploration to better assess the benefit-risk ratio of tesofensine
in the treatment of PD.
Accepted for Publication: October 17, 2007.
Author Affiliations: Laboratoire de Pharmacologie Me´dicale et Clinique, Poˆle Neurosciences, Centre d’Investigations
Cliniques, Institut National de la Sante´ et de la Re´cherche
Me´dicale, Unite´ 825, University Hospital, Toulouse
(Dr Rascol and Ms Aristin), and Medical and Drug Regulatory Affairs, Boehringer Ingelheim, Reims (Dr Salin and
Ms Juhel), France; Department of Neurology, Universita¨tskliniken, Innsbruck, Austria (Dr Poewe); Reta Lila Weston Institute for Neurological Studies, Institute of Neurology, University College London, London, England (Dr Lees);
and Clinical Research, Boehringer Ingelheim, Biberach, Germany (Drs Waldhauser and Schindler).
Correspondence: Olivier Rascol, MD, PhD, Laboratoire
de Pharmacologie Me´dicale et Clinique, Poˆle Neurosciences, Centre d’Investigations Cliniques, Institut National de la Sante´ et de la Re´cherche Me´dicale, Unite´ 825,
University Hospital, 37 Alle´e J Guesde, 31000 Toulouse, France ([email protected]).
Author Contributions: All authors had full access to the
data and reported and discussed the results of the study
without restrictions. Ms Aristin performed an independent statistical analysis using the sponsor database. Study
concept and design: Rascol and Salin. Acquisition of data:
Rascol and Poewe. Analysis and interpretation of data:
Rascol, Poewe, Lees, Aristin, Salin, Juhel, Waldhauser,
and Schindler. Drafting of the manuscript: Rascol, Lees,
Aristin, Waldhauser, and Schindler. Critical revision of
the manuscript for important intellectual content: Rascol,
Poewe, Lees, Salin, and Juhel. Statistical analysis: Rascol
and Juhel. Administrative, technical, and material support: Poewe, Lees, Salin, and Schindler. Study supervision: Poewe and Schindler.
ADVANS Study Group Investigators: Austria: F. Aichner, MD, U. Baumhackl, MD, I. Kloiber, MD, E. Ott,
MD, W. Poewe, MD, G. Ransmayr, MD, F. Reisecker,
MD, P. Schwingenschuh, MD, K. Seppi, MD, M. Steffelbauer, MD, and O. Toman, MD. England: D. Burn, MD,
C. Clarke, MD, S. Ellis, MD, D. Grosset, MD, M.
Steiger, MD, P. Tidswell, MD, and R. Weiser, MD.
France: Y. Agid, MD, S. Arguillère, MD, J. P. Azulay,
MD, I. Benatru, MD, F. Bloch, MD, E. Broussolle, MD,
P. Damier, MD, B. Debelly, MD, A. Destee, MD,
E. Doury, MD, F. Durif, MD, M. Galitzky, MD,
J. L. Houeto, MD, V. Mesnage, MD, O. Rascol, MD,
F. Tison, MD, F. Viallet, MD, T. Witjas, MD, and
F. Yekhlef, MD. Germany: K. Anvari, MD, G. Arnold,
MD, R. Benecke, MD, M. Bick-Sander, MD, K. Boetzel,
MD, D. Brandsta¨dter, MD, M. Canelo, MD, C. Daniels,
MD, G. Deuschl, MD, R. Ehret, MD, W. H. Jost, MD,
E. Kraft, MD, D. Krug, MD, H. Lipp, MD, W. Lueer,
MD, S. Muhlack, MD, T. Mu¨ller, MD, M. Mu¨ngersdorf,
MD, C. Oehlwein, MD, W. Oertel, MD, M. Sabolek, MD,
J. Schwarz, MD, M. Simonov, MD, A. Storch, MD, K.
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Strecker, MD, C. Trenkwalder, MD, and A. Wolters, MD.
Spain: A. Castro, MD, A. Esquivel, MD, F. Grandas, MD,
J. Kulivesky, MD, J. Martı´ , MD, F. Miquel, MD,
B. Pascual, MD, A. Sesar, MD, E. Tolosa, MD, and
F. Valldeoriola, MD. The Netherlands: H.W. M. Anten, MD,
M. A. M. Bomhof, MD, A. W. F. Rutgers, MD, J. P. Ter
Bruggen, MD, and C. R. B. Willems, MD.
Financial Disclosure: Drs Rascol, Poewe, and Lees received honoraria from Boehringer Ingelheim for scientific advice. Dr Rascol has also received grants for scientific research programs or honoraria for participation in
advisory boards, steering committees, or consultant activities from Eisai, GlaxoSmithKline, Kyowa, Lilly, Lundbeck, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough,
Servier, Solvay, and Teva.
Funding/Support: The study was sponsored by
Boehringer Ingelheim, Reims, France.
Role of the Sponsor: Boehringer Ingelheim contributed
to the design and conduct of the study and in the collection of data. Analysis and interpretation of the data were
conducted independently. The authors were free in the
preparation, review, and approval of the manuscript.
Additional Contributions: Robert Hauser, MD, and Christopher Goetz, MD, read draft versions of the manuscript.
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