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 levodoparelated motor fluctuations were enrolled. Tesofensine (0.125, 0.25, 0.5, or 1 mg) or placebo tablets were administered once daily for

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... 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 (Ն20% 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. Arch Neurol. 2008;65(5):577-583 P 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-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.