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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

Arch Neurol. 2008;65(5):577-583.

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.

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).

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