Tesofensine (NS 2330), a Monoamine Reuptake Inhibitor, in Patients with Advanced Parkinson Disease and Motor Fluctuations the ADVANS Study

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 tesofen- Results: The adjusted mean differences (relative to placebo) sine, a triple monoamine reuptake inhibitor, in patients were −4.7 points in UPDRS subscale II plus subscale III total with advanced Parkinson disease (PD). score (P=.005) with tesofensine, 0.5 mg, and −7.1% in off time (−68 minutes, P=.02) with tesofensine, 0.25 mg. Other Design: A pilot phase 2, randomized, double-blind, pla- dosages did not induce statistically significant effects. The cebo-controlled, parallel-group trial. The study oc- plasma concentration increased with the dosage, but no clear curred in hospital-based outpatient clinics and in clini- dose-response relationship was observed. Gastrointesti- cal trial units. Patients with advanced PD and levodopa- nal tract and neuropsychiatric adverse events were more related motor fluctuations were enrolled. Tesofensine frequent with tesofensine than with placebo, especially at (0.125, 0.25, 0.5, or 1 mg) or placebo tablets were ad- the higher dosages. ministered once daily for 14 weeks. Conclusions: Patients with PD in advanced stages showed Main Outcome Measures: Coprimary end points were modest improvements in UPDRS subscale II plus sub- the changes from baseline in Unified Parkinson Disease scale III total score and in off time when treated with Rating Scale (UPDRS) subscale II (activities of daily liv- tesofensine, but a dose-response relationship could not ing) plus subscale III (motor function) total score and be established for efficacy, while adverse drug reactions in percentage of waking hours spent in “off” time noted tended to be more frequent at higher dosages. in self-scoring diaries. Secondary end points were safety, pharmacokinetics, responder analysis (Ն20% reduc- Trial Registration: clinicaltrials.gov Identifier: tion in UPDRS score and in off time), and changes in per- NCT00148512. centage of waking hours spent in “on” time with and without troublesome dyskinesia. Arch Neurol. 2008;65(5):577-583

ATIENTS WITH PARKINSON DIS- ages tested, and the estimated absolute bio- ease (PD) frequently experi- availability after oral administration is ence levodopa-related motor greater than 90%.3 With a half-life in hu- fluctuations. Levodopa dos- mans of approximately 8 days, tesofensine ing adjustments, sustained- has the potential to increase striatal dopa- releaseP levodopa formulations, dopamine mine concentrations without phasic fluc- agonists, monoamine oxidase B inhibitors, tuations. The ADVANS (Proof of Concept and catechol-O-methyltransferase inhibi- in Advanced Parkinson Disease of NS 2330) tors provide incomplete relief.1,2 Blocking study explored the safety and efficacy of presynaptic dopamine reuptake is a new tesofensine in patients with advanced PD therapeutic approach. Tesofensine (NS and levodopa-related motor fluctuations. 2330) inhibits reuptake of dopamine, nor- adrenaline, and serotonin and stimulates METHODS cholinergic neurons in the prefrontal cor- tex and hippocampus.3 In the marmoset Author Affiliations are listed at ORGANIZATION the end of this article. model, it reduced parkinsonian symptoms 4 Group Information: The without inducing dyskinesia. The pharma- The ADVANS study (49 active sites in Aus- ADVANS Study Group members cokinetic profile of the drug is linear after tria, England, France, Germany, Spain, and the are listed on page 582. single and multiple doses across all dos- Netherlands) was planned and coordinated by

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 5), MAY 2008 WWW.ARCHNEUROL.COM 577

©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 a steering committee consisting of the coordinating investiga- and percentage of patients responding with at least 20% reduc- tor (O.R.), 2 movement disorder specialists with experience in tion in percentage of waking hours spent in off time. clinical trials (W.P. and A.L.), and 2 representatives of the study Safety measures included the incidence and severity of ad- sponsor (L.S. and J. Reess, MD). verse events and withdrawals owing to adverse events. Vital signs, body weight, clinical laboratory values, and pharmacokinetic ETHICS variables were also monitored. Patients were evaluated at investigators’ centers (at baseline The protocol was approved by independent ethics committees and at weeks 2, 4, 6, 8, 10, and 14), with additional telephone at each site and complied with local laws, the Declaration of interviews at weeks 1, 5, 7, and 12. Unified Parkinson Disease Helsinki (version 1996), and the International Conference on Rating Scale subscale II was scored for best (on) and worst (off) Harmonisation “Guidelines for Good Clinical Practice.” Each status. Unified Parkinson Disease Rating Scale subscale III was patient provided written informed consent before enrollment. assessed when patients were receiving levodopa. Investigators were trained and certified in UPDRS rating. Off time was calcu- STUDY DESIGN AND TREATMENT lated from the patients’ diaries for 2 consecutive days before each clinic visit. Each patient was trained to recognize on and off times The ADVANS trial was a 14-week pilot, proof-of-concept, phase and was asked to make diary entries at 30-minute intervals from 2, randomized, double-blind, placebo-controlled, parallel- 6 AM to midnight. Test diaries of concordance between the pa- group study of tesofensine in patients with advanced PD. Pa- tient and the investigator were used to verify successful comple- tients received tablets of tesofensine (0.125, 0.25, 0.5, or 1 mg) tion of patient diary training. or placebo once daily. This range of dosages was chosen based Blood samples for pharmacokinetic and laboratory analyses on (1) single oral dose tolerability data for tesofensine (up to were taken at baseline and at weeks 4, 6, 8, 10, and 14. Plasma 10 mg) in healthy volunteers demonstrating sleep difficulties concentrations of tesofensine were analyzed using a fully validated at high dosages3 and (2) positron emission tomography data high-performance liquid chromatography tandem mass spec- showing receptor occupancy of 77% at the 1-mg dosage.4 trometry method at Boehringer Ingelheim, Biberach, Germany.

PARTICIPANTS RANDOMIZATION AND BLINDING

Eligible patients were between 40 and 80 years of age, had been The randomization code was generated by the sponsor using a diagnosed as having idiopathic PD at least 2 years previously, commercially available program (ClinPro/LBL Clinical Label had a modified Hoehn and Yahr stage of II to III during “on” Generation System; Clinical Systems, Inc, Garden City, New time,5 were treated with levodopa 3 to 8 times daily at an op- Jersey). Patients were randomized by receiving the medica- timal and stable dosage for at least 4 weeks, experienced mo- tion kit with the lowest number. Patients, investigators, and tor fluctuations with 2.0 to 6.0 hours daily “off” time during sponsor personnel were blinded to the study treatments. Emer- waking hours (on 2 consecutive days before baseline), and were gency envelopes containing each patient’s treatment code were able to comply with the study protocol. Concomitant treat- provided to the investigators. ment with dopamine agonists, entacapone, antiparkinsonian anticholinergics, amantadine hydrochloride, hypnotics, or anx- SAMPLE SIZE CALCULATION iolytics was allowed at a stable dosage from at least 4 weeks before screening until the end of the study. A sample size of 50 patients per group was planned to detect Exclusion criteria were electrocardiographic abnormalities; (at any dosage at a 5% significance level) a treatment effect of atypical or secondary causes of parkinsonism; treatment with di- 7 points in UPDRS subscale II plus subscale III total score (as- goxin in the 7 days before screening; dementia (Mini-Mental State suming a 13.9 SD) and a treatment effect of 80 minutes in off Examination score, Ͻ26); treatment with selegiline hydrochlo- time (assuming a 2.6-hour SD). A similar reduction in off time ride within 8 weeks before screening; a history of mental disor- was observed in a comparable population using the mono- der, psychosis, or central nervous system injury or disease; hy- amine oxidase type B inhibitor rasagiline mesylate,8 while smaller potension or uncontrolled hypertension or any other significant but potentially clinically relevant UPDRS changes have been medical comorbidity; and regular use of antidepressants, psy- described in others.9 chotropic drugs, or drugs with central dopaminergic antagonist activity within 4 weeks before screening. STATISTICAL ANALYSIS

END POINTS The null hypothesis was that there was no difference between patients treated with placebo and patients treated with tesofen- Because the ADVANS study was a pilot exploratory, nonpiv- sine at any dosage. The alternative was that tesofensine at any otal, phase 2 trial and no previous relevant data were avail- dosage was superior to placebo. The statistical tests used for able, there were 2 coprimary efficacy outcome measures. These the regression coefficient and for the comparison of tesofen- were (1) the changes from baseline to end of study in Unified sine and placebo were 1-sided 2-sample tests at a 5% signifi- Parkinson Disease Rating Scale (UPDRS) subscale II (activi- cance level. No statistical adjustment for having 2 coprimary ties of daily living) and subscale III (motor functioning) total results or multiple comparisons was made. Statistical analyses score and (2) the changes in percentage of waking hours spent were considered descriptive only because of the exploratory de- in off time as recorded on diaries.6,7 sign of the pilot trial. Secondary exploratory efficacy measures were changes from Safety analyses were based on the safety set, defined as pa- baseline to end of study in the following: percentage of wak- tients who received at least 1 dose of treatment. Efficacy analy- ing hours spent in on time without troublesome dyskinesia (ie, ses were based on the full-analysis set, defined as patients with without dyskinesia or with nontroublesome dyskinesia), per- at least 1 posttreatment efficacy evaluation for at least 1 of the centage of waking hours spent in on time with troublesome dys- coprimary end points. The last-observation-carried-forward kinesia, percentage of patients responding with at least 20% im- method was used to estimate missing efficacy data. Analysis of provement in UPDRS subscale II plus subscale III total score, covariance was used to perform linear regressions and pair-

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 5), MAY 2008 WWW.ARCHNEUROL.COM 578

60 Not eligible

254 Randomized

49 Randomized 49 Randomized 52 Randomized 56 Randomized 48 Randomized to placebo to tesofensine, 0.125 mg to tesofensine, 0.25 mg to tesofensine, 0.5 mg to tesofensine, 1 mg

9 AE 11 AE 6 AE 14 AE 13 AE 2 LOE 1 LOE 1 LOE 0 LOE 1 LOE 2 Others 2 Others 2 Others 3 Others 3 Others

36 Completed 35 Completed 43 Completed 39 Completed 31 Completed placebo tesofensine, 0.125 mg tesofensine, 0.25 mg tesofensine, 0.5 mg 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 Placebo Group 0.125 mg 0.25 mg 0.5 mg 1mg Variable (n=49) (n=49) (n=52) (n=56) (n=48) Male sex 74 57 64 63 58 Age, mean (SD), y 65 (7) 65 (7) 63 (9) 63 (8) 64 (9) Duration, mean (SD), y Parkinson disease 9 (4) 10 (6) 10 (5) 8 (4) 10 (5) Motor fluctuations 3.7 (2.8) 3.9 (3.3) 4.7 (3.8) 3.8 (3.2) 4.5 (4.1) Unified Parkinson Disease Rating Scale total score, 34 (13) 34 (15) 33 (14) 32 (16) 31 (16) mean (SD) Off time, mean (SD) % 35 (13) 35 (14) 31 (11) 32 (12) 33 (12) Hours 5.1 (1.8) 5.3 (2.2) 4.6 (1.4) 5.1 (1.9) 4.9 (1.7) Levodopa Dosage, mean (SD), mg/d 562 (286) 778 (502) 589 (283) 737 (428) 659 (365) Doses per day, mean (SD), No. 4.2 (1.1) 4.8 (1.5) 4.4 (1.2) 4.6 (1.5) 4.8 (1.2) Patients receiving, % Dopamine agonist 82 84 98 89 83 Catechol-O-methyltransferase inhibitor 39 35 44 55 48 Amantadine hydrochloride 31 31 50 34 27

wise comparisons between placebo and each dosage of tesofen- (53 patients [20.9%]). The percentages of patients who sine and to test for differences in the secondary end points. prematurely withdrew because of adverse events were 22.4%, 11.5%, 25.0%, and 27.1% in the groups receiv- RESULTS ing tesofensine, 0.125, 0.25, 0.5, and 1 mg, respectively, compared with 18.4% in the placebo group. Patient de- PATIENT FLOW mographics, baseline disease characteristics, and concomitant PD therapy are given in Table 1. The patient flow is illustrated in Figure 1. Overall, 314 patients were screened; 60 patients were excluded pri- PRIMARY OUTCOMES marily because their daily off time did not fall between 2.0 and 6.0 hours or because they had clinically signifi- Compared with the placebo group, the adjusted mean cant electrocardiographic abnormalities. Therefore, 254 changes in UPDRS subscale II plus subscale III total score patients were randomized and received treatment (safety in the tesofensine treatment groups ranged from −1.2 set). Three of these patients did not have an efficacy as- points in the 0.25-mg–treated group to −4.7 points in the sessment; therefore, the full-analysis set comprised 251 0.5-mg–treated group (Table 2). There was a trend to patients. Seventy of 254 patients (27.6%) discontinued greater efficacy with the 2 highest dosages, but the dif- treatment prematurely, primarily because of adverse events ference relative to placebo reached statistical signifi-

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 5), MAY 2008 WWW.ARCHNEUROL.COM 579

Tesofensine Treatment Group Placebo Group 0.125 mg 0.25 mg 0.5 mg 1mg Variable (n=49) (n=48) (n=52) (n=55) (n=47) Change in Unified Parkinson Disease Rating Scale total score Mean (SD) −0.6 (8.3) −3.2 (11.1) −1.5 (9.5) −5.0 (10.6) −2.6 (9.1) Adjusted meanb . . . −2.3 −1.2 −4.7 −2.8 P value . . . .10 .24 .005 .07 Change in percentage of waking hours spent in off time Mean (SD) −2 (18) 1 (20) −8 (16) −1 (16) −5 (13) Adjusted mean (change in minutes)b . . . 3.6 (35) −7.1 (−68) 0.1 (1) −4.4 (−42) P value . . . .14 .02 .49 .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 0.125 mg 0.25 mg 0.5 mg 1mg Variable (n=49) (n=48) (n=52) (n=55) (n=47) Responder Analysis Unified Parkinson Disease Rating Scale total score Ն20% Improvement, % 14 40 31 35 26 P value . . . .007 .04 .02 .27 % of Waking hours spent in off timea Ն20% improvement, % 33 25 52 40 56 P value . . . .63 .08 .46 .02 Percentage of Waking Hours Spent in on Time Without troublesome dyskinesia Mean change (SD) 3.2 (18.1) −1.5 (21.3) 4.6 (18.9) 1.3 (17.3) 2.9 (14.4) Adjusted mean change . . . −6 1 −2 0 P value . . . .06 .34 .26 .49 With troublesome dyskinesia Mean change (SD) −1.1 (7.9) 0.3 (8.7) 2.9 (13.7) −0.2 (9.8) 2.3 (11.6) Adjusted mean change . . . 2 5 2 4 P value . . . .19 .005 .18 .03

a Without receiving tesofensine.

cance only in the 0.5-mg–treated group (P=.005). The cebo was statistically significant only in the group receiv- adjusted mean changes in percentage of waking hours ing tesofensine, 1 mg. Improvements relative to placebo spent in off time from baseline to study end in the tesofen- in on time without troublesome dyskinesia were observed sine treatment groups varied from 3.6% (35 minutes vs only in the group receiving tesofensine, 0.25 mg. Patients placebo) with tesofensine, 0.125 mg, to −7.1% (−68 min- in the groups receiving tesofensine, 0.25 and 1 mg, expe- utes vs placebo) with tesofensine, 0.25 mg. The differ- rienced increases in on time with troublesome dyskinesia. ence relative to placebo was statistically significant (P=.02) No dose-response relationship was apparent for any sec- only in the 0.25-mg–treated group. No dose-response re- ondary end point. lationship could be established. PHARMACOKINETICS SECONDARY END POINTS Steady-state plasma concentrations of tesofensine were A greater proportion of patients responded with at least 20% reached at 4 to 6 weeks. The concentration increased in (range, 26%-40%) improvement in UPDRS subscale II plus a log-linear relationship with the dosage administered subscale III total score in all the tesofensine arms of the trial (Figure 2). compared with placebo (14%) (Table 3). However, there was no dose-response relationship. A greater proportion SAFETY of patients responded with at least 20% improvement in off time in the 3 highest-dosage tesofensine treatment groups More patients in the pooled tesofensine treatment groups than in the placebo group. The difference relative to pla- (81.5%) than in the placebo group (73.5%) experienced

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 5), MAY 2008 WWW.ARCHNEUROL.COM 580

©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 adverse events (Table 4). Patients in the tesofensine treat- Decreases in the mean body weight were observed in ment groups experienced a higher rate of nervous system patients in all treatment groups except the group receiv- disorders (dyskinesia and headache), gastrointestinal tract ing tesofensine, 0.125 mg (−0.2 kg in the placebo group, disorders (nausea and constipation), and psychiatric dis- −0.3 kg in the 0.125-mg–treated group, −0.7 kg in the orders (hallucinations and insomnia). Most adverse events 0.25-mg–treated group, −0.6 kg in the 0.5-mg–treated were assessed as mild. The incidences of severe adverse group, and −1.1 kg in the 1-mg–treated group). No clini- events were 20.4% in the placebo group and 16.6% in the cally significant changes were observed in any laboratory pooled tesofensine treatment groups. The most fre- variables. quently reported severe adverse event in the tesofensine treatment groups was dyskinesia (2% in the 0.125-mg– COMMENT 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). Patients with advanced PD receiving the monoamine Serious adverse events were more frequently re- reuptake blocker tesofensine experienced modest ported with placebo (12.2%) than with tesofensine treat- improvements in some parkinsonian symptoms. Drug- ment (5.9%). Three patients experienced serious ad- plasma concentrations increased linearly with dosage, verse events that were considered drug related: 1 patient while no dose-response relationship was observed. The 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 ane- Tesofensine, 0.125 mg Tesofensine, 0.5 mg Tesofensine, 0.25 mg Tesofensine, 1 mg mia, respectively. Two patients died during the study, both 40 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 myocar- 30 dial infarction. Neither death was considered drug related. Overall, the mean changes in supine systolic blood pres- 20 sure 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 10 with a small increase in blood pressure (0.75 mm Hg) in NS 2330 Plasma Concentration, ng/mL the placebo group. A clinically relevant decrease (a reduc- 0 tion of Ն20 mm Hg, with a final value of Յ90 mm Hg) in Visit 4 Visit 6 Visit 8 Visit 9 Visit 10 Visit 11 the mean systolic blood pressure was recorded in 6 of 205 (wk 4) (wk 6) (wk 8) (wk 10) (wk 14) (wk 20) Time Point patients (2.9%) in the tesofensine treatment groups but in Tesofensine, mg no patients in the placebo group. A dose-dependent in- 0.125 43 40 33 36 32 20 crease in heart rate was observed in patients in all 4 tesofen- 0.25 45 45 38 43 40 36 sine treatment groups (mean change in heart rate, −0.8 beats/ 0.5 47 44 32 39 34 34 1 34 33 26 29 27 28 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, Figure 2. Plasma concentrations of tesofensine (NS 2330) are shown as the 5.6 beats/min in the 0.5-mg–treated group, and 6.7 beats/ mean concentration for each treatment group at the time points indicated. min in the 1-mg–treated group). 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 Patientsa

Tesofensine Treatment Group, % Placebo Pooled Tesofensine Group, % Treatment Groups, % 0.125 mg 0.25 mg 0.5 mg 1mg Variable (n=49) (N=205) (n=49) (n=52) (n=56) (n=48) Any adverse event 73.5 81.5 85.7 82.7 78.6 79.2 Nervous system disorder 40.8 45.9 38.8 40.4 57.1 45.8 Dyskinesia 14.3 22.9 14.3 23.1 28.6 25.0 Headache 2.0 7.3 4.1 5.8 12.5 6.3 Gastrointestinal tract disorder 20.4 34.1 30.6 40.4 30.4 35.4 Nausea 10.2 17.1 20.4 17.3 16.1 14.6 Dry mouth 4.1 5.4 2.1 3.8 8.9 6.3 Constipation 0.0 8.8 0.0 11.5 8.9 14.6 Psychiatric disorder 18.4 30.2 28.6 30.8 30.4 31.3 Insomnia 6.1 11.7 6.1 9.6 17.9 12.5 Hallucinations 4.1 4.9 4.1 3.8 5.4 6.3 Ear and labyrinth disorder 4.1 8.3 10.2 3.8 12.5 6.3 Vertigo 4.1 6.3 8.2 1.9 8.9 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.

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 5), MAY 2008 WWW.ARCHNEUROL.COM 581

©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 effective dosage of tesofensine was different for each of mine reuptake inhibitor tesofensine in advanced PD. The the coprimary outcome measures, namely, 0.5 mg in effective dosages of 0.25 mg/d and 0.5 mg/d exhibited reducing UPDRS subscale II and subscale III total score an acceptable safety profile, while higher dosages may and 0.25 mg in reducing percentage of waking hours induce adverse reactions of clinical concern in this older spent in off time. Dopaminergic adverse drug reactions population. These pilot results deserve further explora- such as dyskinesias and gastrointestinal tract and neuro- tion to better assess the benefit-risk ratio of tesofensine psychiatric symptoms tended to be more frequent in the in the treatment of PD. groups receiving higher tesofensine dosages. The modest antiparkinsonian response, the lack of a Accepted for Publication: October 17, 2007. dose-response effect, and the worsening of dyskinesia were Author Affiliations: Laboratoire de Pharmacologie Me´di- unexpected findings, contrasting with the clear antipar- cale et Clinique, Poˆle Neurosciences, Centre d’Investigations kinsonian effect and the low propensity to induce dys- Cliniques, Institut National de la SanteétdelaRećherche kinesia of tesofensine4 and of a related reuptake inhibi- Me´dicale, Unite´ 825, University Hospital, Toulouse tor, brasofensine maleate, in animal models of PD.10 (Dr Rascol and Ms Aristin), and Medical and Drug Regu- Clinical studies failed to demonstrate superiority of latory Affairs, Boehringer Ingelheim, Reims (Dr Salin and tesofensine over placebo in patients with early11 and ad- Ms Juhel), France; Department of Neurology, Universi- vanced12 PD, while small and variable effects have been ta¨tskliniken, Innsbruck, Austria (Dr Poewe); Reta Lila Wes- reported with methylphenidate hydrochloride, an in- ton Institute for Neurological Studies, Institute of Neurol- hibitor of the dopamine transporter.13,14 Nevertheless, sev- ogy, University College London, London, England (Dr Lees); eral results of the ADVANS study preclude an outright and Clinical Research, Boehringer Ingelheim, Biberach, Ger- dismissal of a potential benefit of the tesofensine and pro- many (Drs Waldhauser and Schindler). vide clinical signs of antiparkinsonian efficacy. The 0.5-mg Correspondence: Olivier Rascol, MD, PhD, Laboratoire dosage was statistically superior to placebo in improv- de Pharmacologie Me´dicale et Clinique, Poˆle Neurosci- ing UPDRS scores, and UPDRS responder rates were ences, Centre d’Investigations Cliniques, Institut Na- higher in all 4 tesofensine treatment groups compared tional de la SanteétdelaRećherche Me´dicale, Unite´ 825, with the placebo group. The adverse effect profile of University Hospital, 37 Alleé J Guesde, 31000 Tou- tesofensine treatment was consistent with clinical amin- louse, France ([email protected]). ergic activity: tachycardia, insomnia, and weight loss sug- Author Contributions: All authors had full access to the gest noradrenergic activation, while dyskinesia, nausea, data and reported and discussed the results of the study and hallucinations are indicative of dopaminergic ef- without restrictions. Ms Aristin performed an indepen- fects. Because the ADVANS trial is a small proof-of- dent statistical analysis using the sponsor database. Study concept study, it is plausible that larger and better- concept and design: Rascol and Salin. Acquisition of data: powered trials could demonstrate in a more consistent Rascol and Poewe. Analysis and interpretation of data: manner the antiparkinsonian properties of tesofensine. Rascol, Poewe, Lees, Aristin, Salin, Juhel, Waldhauser, Moreover, the high dropout rate observed in this popu- and Schindler. Drafting of the manuscript: Rascol, Lees, lation of patients with advanced PD may have contrib- Aristin, Waldhauser, and Schindler. Critical revision of uted to reduce the effect size reported in the trial. the manuscript for important intellectual content: Rascol, Previous positron emission tomography investiga- Poewe, Lees, Salin, and Juhel. Statistical analysis: Rascol tions of dopamine transporter occupancy by tesofensine and Juhel. Administrative, technical, and material sup- demonstrated 18% occupancy at 0.125-mg dosages, 42% port: Poewe, Lees, Salin, and Schindler. Study supervi- at 0.25-mg dosages, 61% at 0.5-mg dosages, and 77% at sion: Poewe and Schindler. 1-mg dosages.4 In the ADVANS study, the lowest tesofen- ADVANS Study Group Investigators: Austria: F. Aich- sine dosage (0.125 mg) elicited no tolerability or efficacy ner, MD, U. Baumhackl, MD, I. Kloiber, MD, E. Ott, signal, while the 0.25-mg dosage seemed to be the small- MD, W. Poewe, MD, G. Ransmayr, MD, F. Reisecker, est active dosage. Safety data suggest that dosages of tesofen- MD, P. Schwingenschuh, MD, K. Seppi, MD, M. Steffel- sine above 1 mg/d might pose tolerability concerns in pa- bauer, MD, and O. Toman, MD. England: D. Burn, MD, tients with advanced PD, including cardiovascular effects C. Clarke, MD, S. Ellis, MD, D. Grosset, MD, M. (tachycardia) and psychiatric effects (hallucinations and Steiger, MD, P. Tidswell, MD, and R. Weiser, MD. insomnia). It is unclear why this study failed to show a France: Y. Agid, MD, S. Arguillère, MD, J. P. Azulay, clear dose-response relationship for any of the primary or MD, I. Benatru, MD, F. Bloch, MD, E. Broussolle, MD, secondary outcomes. This may be related to cumulative P. Damier, MD, B. Debelly, MD, A. Destee, MD, dopamine transporter blockade in the striatum because of E. Doury, MD, F. Durif, MD, M. Galitzky, MD, the long half-life of the drug or because of dose- J. L. Houeto, MD, V. Mesnage, MD, O. Rascol, MD, dependent changes in dopaminergic relative to noradren- F. Tison, MD, F. Viallet, MD, T. Witjas, MD, and ergic reuptake blockade, with different responses of vari- F. Yekhlef, MD. Germany: K. Anvari, MD, G. Arnold, ous parkinsonian symptoms to dopaminergic vs MD, R. Benecke, MD, M. Bick-Sander, MD, K. Boetzel, noradrenergic mechanisms. Other clinical paradoxes such MD, D. Brandsta¨dter, MD, M. Canelo, MD, C. Daniels, as the lack of tesofensine motor effects in patients with early MD, G. Deuschl, MD, R. Ehret, MD, W. H. Jost, MD, PD,11 despite the high number of striatal dopamine trans- E. Kraft, MD, D. Krug, MD, H. Lipp, MD, W. Lueer, porters at this stage,15,16 may have similar explanations. MD, S. Muhlack, MD, T. Mu¨ ller, MD, M. Mu¨ ngersdorf, In conclusion, the ADVANS study provided some in- MD, C. Oehlwein, MD, W. Oertel, MD, M. Sabolek, MD, dications of an antiparkinsonian activity of the dopa- J. Schwarz, MD, M. Simonov, MD, A. Storch, MD, K.

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 5), MAY 2008 WWW.ARCHNEUROL.COM 582

©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Strecker, MD, C. Trenkwalder, MD, and A. Wolters, MD. 4. Tesofensine [investigator’s brochure]. Ingelheim, Germany: Boehringer Ingel- Spain: A. Castro, MD, A. Esquivel, MD, F. Grandas, MD, heim GmbH, 2000. 5. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology. J. Kulivesky, MD, J. Martı´, MD, F. Miquel, MD, 1967;17(5):427-442. B. Pascual, MD, A. Sesar, MD, E. Tolosa, MD, and 6. Fahn S, Elton R; UPDRS Development Committee. Recent Development in Par- F. Valldeoriola, MD. The Netherlands: H.W. M. Anten, MD, kinson’s Disease: Unified Parkinson’s Disease Rating Scale. In: Fahn S, Marsden M. A. M. Bomhof, MD, A. W. F. Rutgers, MD, J. P. Ter CD, Calne DB, Goldstein M, eds. Vol 2. New York, NY: MacMillan Publishing; Bruggen, MD, and C. R. B. Willems, MD. 1987:153-163. Financial Disclosure: Drs Rascol, Poewe, and Lees re- 7. Hauser RA, Deckers F, Lehert P. Parkinson’s disease home diary: further vali- dation and implications for clinical trials. Mov Disord. 2004;19(12):1409-1413. ceived honoraria from Boehringer Ingelheim for scien- 8. Rascol O, Brooks DJ, Melamed E, et al; LARGO (Lasting Effect in Adjunct Therapy tific advice. Dr Rascol has also received grants for scien- With Rasagiline Given Once Daily) Study Group. Rasagiline as an adjunct to le- tific research programs or honoraria for participation in vodopa in patients with Parkinson’s disease and motor fluctuations. Lancet. 2005; advisory boards, steering committees, or consultant ac- 365(9463):947-954. tivities from Eisai, GlaxoSmithKline, Kyowa, Lilly, Lund- 9. Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in beck, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO (Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of Off ) Servier, Solvay, and Teva. study. Arch Neurol. 2005;62(2):241-248. Funding/Support: The study was sponsored by 10. Pearce RKB, Smith LA, Jackson MJ, Banerji T, Scheel-Kru¨ger J, Jenner P. The Boehringer Ingelheim, Reims, France. monoamine reuptake blocker brasofensine reverses akinesia without dyskine- Role of the Sponsor: Boehringer Ingelheim contributed sia in MPTP-treated and levodopa-primed common marmosets. Mov Disord. 2002; to the design and conduct of the study and in the collec- 17(5):877-886. 11. Hauser RA, Salin L, Juhel N, Konyago VL; NS 2330 Monotherapy Study Group. tion of data. Analysis and interpretation of the data were Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofen- conducted independently. The authors were free in the sine) in early Parkinson’s disease. Mov Disord. 2007;22(3):359-365. preparation, review, and approval of the manuscript. 12. Bara-Jimenez W, Dimitrova T, Sherzai A, Favit A, Mouradian MM, Chase TN. Additional Contributions: Robert Hauser, MD, and Chris- Effect of monoamine reuptake inhibitor NS 2330 in advanced Parkinson’s disease. topher Goetz, MD, read draft versions of the manuscript. Mov Disord. 2004;19(10):1183-1186. 13. Camicioli R, Lea E, Nutt JG, Sexton G, Oken BS. Methylphenidate increases the motor effects of L-dopa in Parkinson’s disease: a pilot study. Clin Neuropharmacol. REFERENCES 2001;24(4):208-213. 14. Nutt JG, Carter JH, Carlson NE. Effects of methylphenidate on response to oral 1. Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment interventions for levodopa: a double-blind clinical trial. Arch Neurol. 2007;64(3):319-323. Parkinson’s disease: an evidence based assessment. Lancet. 2002;359(9317): 15. Rinne UK, Laihinen A, Rinne JO, Na˚gren K, Bergman J, Ruotsalainen U. Posi- 1589-1598. tron emission tomography demonstrates dopamine D2 receptor supersensitiv- 2. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review up- ity in the striatum of patients with early Parkinson’s disease. Mov Disord. 1990; date: pharmacological and surgical treatments of Parkinson’s disease: 2001 to 5(1):55-59.

2004. Mov Disord. 2005;20(5):523-539. 16. Turjanski N, Lees A, Brooks DJ. In vivo studies on striatal dopamine D1 and D2 3. Thatte U. NS-2330 (NeuroSearch). Curr Opin Investig Drugs. 2001;2(11):1592- site binding in L-dopa–treated Parkinson’s disease patients with and without 1594. dyskinesia. Neurology. 1997;49(3):717-723.

Announcement

Online Submission and Peer Review System Avail- able. The Archives of Neurology editorial office has in- troduced an online manuscript submission and peer review system developed by eJournalPress that will serve the needs of authors, reviewers, and editors. The new system went live on November 14, 2005. See http: //archneur.ama-assn.org for more detailed information.

(REPRINTED) ARCH NEUROL / VOL 65 (NO. 5), MAY 2008 WWW.ARCHNEUROL.COM 583