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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.

Patient flow from screening to last visit. AE indicates adverse event; LOE, lack of efficacy. Seventeen patients withdrew from the study for various reasons.

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.

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 1. 
Patient Demographics, Baseline Disease Characteristics, and Concomitant Parkinson Disease Therapy Based on the Safety Set of 254 Patients
Patient Demographics, Baseline Disease Characteristics, and Concomitant Parkinson Disease Therapy Based on the Safety Set of 254 Patients
Table 2. 
Primary Outcomes Based on the Full-Analysis Set of 251 Patientsa
Primary Outcomes Based on the Full-Analysis Set of 251 Patientsa
Table 3. 
Secondary Outcomes Based on the Full-Analysis Set of 251 Patients
Secondary Outcomes Based on the Full-Analysis Set of 251 Patients
Table 4. 
Adverse Events Based on the Safety Set of 254 Patientsa
Adverse Events Based on the Safety Set of 254 Patientsa
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Rascol  OGoetz  CKoller  WPoewe  WSampaio  C Treatment interventions for Parkinson's disease: an evidence based assessment. Lancet 2002;359 (9317) 1589- 1598
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Goetz  CGPoewe  WRascol  OSampaio  C Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004. Mov Disord 2005;20 (5) 523- 539
PubMedArticle
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Thatte  U NS-2330 (NeuroSearch). Curr Opin Investig Drugs 2001;2 (11) 1592- 1594
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 Tesofensine [investigator's brochure].  Ingelheim, Germany Boehringer Ingelheim GmbH2000;
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Hauser  RADeckers  FLehert  P Parkinson's disease home diary: further validation and implications for clinical trials. Mov Disord 2004;19 (12) 1409- 1413
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Rascol  OBrooks  DJMelamed  E  et al. LARGO (Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily) Study Group, Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations. Lancet 2005;365 (9463) 947- 954
PubMedArticle
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Parkinson Study Group, A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of Off) study. Arch Neurol 2005;62 (2) 241- 248
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Pearce  RKBSmith  LAJackson  MJBanerji  TScheel-Krüger  JJenner  P The monoamine reuptake blocker brasofensine reverses akinesia without dyskinesia in MPTP-treated and levodopa-primed common marmosets. Mov Disord 2002;17 (5) 877- 886
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Hauser  RASalin  LJuhel  NKonyago  VLNS 2330 Monotherapy Study Group, Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease. Mov Disord 2007;22 (3) 359- 365
PubMedArticle
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Bara-Jimenez  WDimitrova  TSherzai  AFavit  AMouradian  MMChase  TN Effect of monoamine reuptake inhibitor NS 2330 in advanced Parkinson's disease. Mov Disord 2004;19 (10) 1183- 1186
PubMedArticle
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Camicioli  RLea  ENutt  JGSexton  GOken  BS Methylphenidate increases the motor effects of L-dopa in Parkinson's disease: a pilot study. Clin Neuropharmacol 2001;24 (4) 208- 213
PubMedArticle
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Nutt  JGCarter  JHCarlson  NE Effects of methylphenidate on response to oral levodopa: a double-blind clinical trial. Arch Neurol 2007;64 (3) 319- 323
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Rinne  UKLaihinen  ARinne  JONågren  KBergman  JRuotsalainen  U Positron emission tomography demonstrates dopamine D2 receptor supersensitivity in the striatum of patients with early Parkinson's disease. Mov Disord 1990;5 (1) 55- 59
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Turjanski  NLees  ABrooks  DJ In vivo studies on striatal dopamine D1 and D2 site binding in L-dopa–treated Parkinson's disease patients with and without dyskinesia. Neurology 1997;49 (3) 717- 723
PubMedArticle
Clinical Trials
May 2008

Tesofensine (NS 2330), a Monoamine Reuptake Inhibitor, in Patients With Advanced Parkinson Disease and Motor FluctuationsThe ADVANS Study

Author Affiliations

Author Affiliations:Laboratoire de Pharmacologie Médicale et Clinique, Pôle Neurosciences, Centre d’Investigations Cliniques, Institut National de la Santé et de la Récherche Médicale, Unité 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, Universitätskliniken, 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).

 

IRASHOULSONMD

Arch Neurol. 2008;65(5):577-583. doi:10.1001/archneur.65.5.577
Abstract

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, placebo-controlled, parallel-group trial. The study occurred in hospital-based outpatient clinics and in clinical trial units. Patients with advanced PD and levodopa-related motor fluctuations were enrolled. Tesofensine (0.125, 0.25, 0.5, or 1 mg) or placebo tablets were administered once daily for 14 weeks.

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 (≥20% reduction in UPDRS score and in off time), and changes in percentage of waking hours spent in “on” time with and without troublesome dyskinesia.

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 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.

Patients with Parkinson disease (PD) frequently experience levodopa-related motor fluctuations. Levodopa dosing adjustments, sustained-release levodopa formulations, dopamine agonists, monoamine oxidase B inhibitors, and catechol-O-methyltransferase inhibitors provide incomplete relief.1,2Blocking 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.3In the marmoset model, it reduced parkinsonian symptoms without inducing dyskinesia.4The pharmacokinetic profile of the drug is linear after single and multiple doses across all dosages tested, and the estimated absolute bioavailability after oral administration is greater than 90%.3With 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 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

The ADVANS trial was a 14-week pilot, proof-of-concept, phase 2, randomized, double-blind, placebo-controlled, parallel-group 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 dosages3and (2) positron emission tomography data showing receptor occupancy of 77% at the 1-mg dosage.4

PARTICIPANTS

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,5were 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.

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, 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 AMto 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.

RANDOMIZATION AND BLINDING

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.

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,8while 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 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 significance 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.

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 placebo 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

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 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 0.25-mg–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 ≥20 mm Hg, with a final value of ≤90 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).

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 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 tesofensine4and of a related reuptake inhibitor, brasofensine maleate, in animal models of PD.10Clinical studies failed to demonstrate superiority of tesofensine over placebo in patients with early11and advanced12PD, while small and variable effects have been reported with methylphenidate hydrochloride, an inhibitor of the dopamine transporter.13,14Nevertheless, 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 theADVANS trial is a small proof-of-concept study, it is plausible that larger and better-powered 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.4In 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 dose-dependent 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,11despite the high number of striatal dopamine transporters at this stage,15,16may have similar explanations.

In conclusion, theADVANS study provided some indications of an antiparkinsonian activity of the dopamine 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.

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Article Information

Correspondence:Olivier Rascol, MD, PhD, Laboratoire de Pharmacologie Médicale et Clinique, Pôle Neurosciences, Centre d’Investigations Cliniques, Institut National de la Santé et de la Récherche Médicale, Unité 825, University Hospital, 37 Allée J Guesde, 31000 Toulouse, France (rascol@cict.fr).

Accepted for Publication:October 17, 2007.

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. Brandstädter, 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. Müller, MD, M. Müngersdorf, MD, C. Oehlwein, MD, W. Oertel, MD, M. Sabolek, MD, J. Schwarz, MD, M. Simonov, MD, A. Storch, MD, K. Strecker, MD, C. Trenkwalder, MD, and A. Wolters, MD. Spain: A. Castro, MD, A. Esquivel, MD, F. Grandas, MD, J. Kulivesky, MD, J. Martí, 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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