Orodispersible sublingual piribedil to abort OFF episodes: A single dose placebo-controlled, randomized, double-blind, cross-over study

Authors

  • Olivier Rascol MD, PhD,

    Corresponding author
    1. Departments of Clinical Pharmacology and Neurosciences, INSERM Clinical Investigation Center CIC-9302 and UMR-825, CHU Toulouse-Purpan and University Paul Sabatier, Toulouse, France
    • Department of Clinical Pharmacology, Faculty of Medicine, 37 Allées Jules Guesde, Toulouse 31000, France===

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  • Jean-Philippe Azulay MD,

    1. Service de Neurologie et Pathologie du Mouvement, Pôle Neurosciences cliniques, CHU Timone, Marseille, France
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  • Olivier Blin MD, PhD,

    1. Clinical Investigation Centre (CIC-UPCET) and Department of Clinical Pharmacology, UMR-CNRS 6193 Institute of Cognitive Neurosciences, CHU Timone, Marseille, France
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  • Anne-Marie Bonnet MD,

    1. Centre d'Investigation Clinique, Fédération des maladies du Système Nerveux, INSERM U 679, CHU Pitié-Salpétrière, Paris, France
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  • Christine Brefel-Courbon MD, PhD,

    1. Departments of Clinical Pharmacology and Neurosciences, INSERM Clinical Investigation Center CIC-9302 and UMR-825, CHU Toulouse-Purpan and University Paul Sabatier, Toulouse, France
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  • Pierre Césaro MD,

    1. Department of Clinical Neurosciences, INSERM U 841, CHU Henri Mondor, Créteil 94000, France
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  • Philippe Damier MD, PhD,

    1. INSERM, Clinical Investigation Center CIC, and Clinique Neurologique, CHU Nantes, Nantes, France
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  • Bérengère Debilly MD,

    1. Service de Neurologie, Hôpital Gabriel Montpied, CHU Clermont-Ferrand, Faculty of Medecine, University of Clermont, 1, EA 3845, Clermont-Ferrand, France
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  • Frank Durif MD, PhD,

    1. Service de Neurologie, Hôpital Gabriel Montpied, CHU Clermont-Ferrand, Faculty of Medecine, University of Clermont, 1, EA 3845, Clermont-Ferrand, France
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  • Monique Galitzky MD,

    1. Departments of Clinical Pharmacology and Neurosciences, INSERM Clinical Investigation Center CIC-9302 and UMR-825, CHU Toulouse-Purpan and University Paul Sabatier, Toulouse, France
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  • Jean-Marie Grouin PhD,

    1. Laboratoire de Biostatistiques, INSERM U 657, Université de Rouen, Rouen, France
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  • Sylvie Pennaforte MD,

    1. Institut de Recherches Internationales Servier, Courbevoie, France
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  • Gabriel Villafane MD,

    1. Department of Clinical Neurosciences, INSERM U 841, CHU Henri Mondor, Créteil 94000, France
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  • Sadek Yaici MD,

    1. Centre d'Investigation Clinique, Fédération des maladies du Système Nerveux, INSERM U 679, CHU Pitié-Salpétrière, Paris, France
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  • Yves Agid MD, PhD

    1. Centre d'Investigation Clinique, Fédération des maladies du Système Nerveux, INSERM U 679, CHU Pitié-Salpétrière, Paris, France
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  • Potential conflict of interest: Nothing to report.

Abstract

S90049, a novel sublingual formulation of the non-ergoline D2-D3 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 × 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 (ΔUPDRS 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 wassuperior to placebo on ΔUPDRS 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, ΔUPDRS 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. © 2009 Movement Disorder Society

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