Tesofensine (NS 2330), a monoamine reuptake inhibitor, in patients with advanced Parkinson disease and motor fluctuations: the ADVANS Study.
OBJECTIVE
To assess the safety and efficacy of tesofensine, a triple monoamine reuptake inhibitor, in patients with advanced Parkinson disease (PD).


METHODS
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.


METHODS
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 (> or =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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00148512.
Rascol
Olivier
O
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, France. rascol@cict.fr
Poewe
Werner
W
Lees
Andrew
A
Aristin
Marina
M
Salin
Laurence
L
Juhel
Nolwenn
N
Waldhauser
Lisa
L
Schindler
Thomas
T
D000203:Activities of Daily Living; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015306:Biogenic Monoamines / Q000819:agonists*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced; D008875:Middle Aged; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D010300:Parkinson Disease / Q000188:drug therapy*; D010865:Pilot Projects; D010919:Placebos; D016896:Treatment Outcome
D015306:Biogenic Monoamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D014179:Neurotransmitter Uptake Inhibitors; D010919:Placebos; C518479:Tesofensine