title: Orodispersible sublingual piribedil to abort OFF episodes: a single dose placebo-controlled, randomized, double-blind, cross-over study.
abstract: S90049, a novel sublingual formulation of the non-ergoline D(2)-D(3) agonist piribedil, has a pharmacokinetic profile promising to provide rapid relief on motor signs in Parkinson's disease (PD). We assessed the efficacy and safety of S90049 in aborting OFF episodes responding to subcutaneous apomorphine in PD patients with motor fluctuations. This was a single-dose double-blind double-placebo 3 x 3 cross-over study. Optimal tested doses were determined during a previous open-label titration phase (S90049 median dose: 60 mg, apomorphine: 5 mg). Primary endpoint was the maximal change versus baseline in UPDRS motor score (Delta UPDRS III) assessed after drug administration following an overnight withdrawal of antiparkinsonian medications. Thirty patients (age: 60 +/- 8 years, PD duration: 12 +/- 6 years, UPDRS III OFF: 37 +/- 15) participated. S90049 was superior to placebo on Delta UPDRS III (-13 +/- 12 versus -7 +/- 9 respectively; estimated difference -5.2, 95% Confidence Interval (CI)[-10.4;0.05], P = 0.05). This was also true for secondary outcomes: number of patients switching from OFF to ON (17 on S90049 vs. 8 on placebo, P = 0.03), time to turn ON (P = 0.013) and duration of the ON phase (P = 0.03). In the 17 patients who switched ON on S90049, Delta UPDRS III was similar on S90049 (-21.2 +/- 10.1) and apomorphine (-23.6 +/- 14.1) (estimated difference: 4.0 95% CI [-2.9;10.9]). S90049 was well tolerated: no serious or unexpected adverse event occurred. A single dose of up to 60 mg of S90049 given sublingually was superior to placebo in improving UPDRS III and aborting a practical OFF in patients with advanced PD. Testing greater doses might improve response rate.
authors.affiliation: Department of Clinical Pharmacology, INSERM Clinical Investigation Center CIC-9302 and UMR-825, CHU Toulouse-Purpan and University Paul Sabatier, Toulouse, France. rascol@cict.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Rascol
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Azulay
authors.forename: Olivier
authors.initials: O
authors.lastname: Blin
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Bonnet
authors.forename: Christine
authors.initials: C
authors.lastname: Brefel-Courbon
authors.forename: Pierre
authors.initials: P
authors.lastname: Césaro
authors.forename: Philippe
authors.initials: P
authors.lastname: Damier
authors.forename: Bérengère
authors.initials: B
authors.lastname: Debilly
authors.forename: Frank
authors.initials: F
authors.lastname: Durif
authors.forename: Monique
authors.initials: M
authors.lastname: Galitzky
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Grouin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pennaforte
authors.forename: Gabriel
authors.initials: G
authors.lastname: Villafane
authors.forename: Sadek
authors.initials: S
authors.lastname: Yaici
authors.forename: Yves
authors.initials: Y
authors.lastname: Agid
mesh_terms: D000286:Administration, Sublingual; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D001058:Apomorphine / Q000008:administration & dosage; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004333:Drug Administration Routes; D005602:France; D006801:Humans; D016015:Logistic Models; D010300:Parkinson Disease / Q000188:drug therapy*; D010891:Piribedil / Q000008:administration & dosage*; D016016:Proportional Hazards Models; D012720:Severity of Illness Index
chemical_list: D000978:Antiparkinson Agents; D010891:Piribedil; D001058:Apomorphine