Early Piribedil Monotherapy of Parkinson’s Disease: A Planned Seven-Month Report of the REGAIN Study Olivier Rascol, MD, PhD, 1 * Bruno Dubois, MD, 2 Alexandre Castro Caldas, MD, 3 Stephen Senn, MD, 4 Susanna Del Signore, MD, 5 and Andrew Lees, MD, 6 on behalf of the Parkinson REGAIN Study Group 1 INSERM U455, Clinical Investigation Center and Departments of Clinical Pharmacology and Neurosciences, Faculte ´ de Me ´decine, Toulouse, France 2 INSERM U610/Groupe Hospitalier Pitie ´-Salpe ˆtrie `re, Paris, France 3 Instituto de Cie ¨nsas da Sau `de, Lisbon, Portugal 4 Department of Statistics, University of Glasgow, Glasgow, United Kingdom 5 Institut de Recherches Internationales Servier, Courbevoie, France 6 Royal Free and University College Medical School, University College London/Reta Lila, Weston Institute of Neurological Studies, London, United Kingdom Abstract: Piribedil is a D 2 dopamine agonist, which has been shown to improve symptoms of Parkinson’s disease (PD) when combined with L-dopa. The objective of this study was to compare the efficacy of piribedil monotherapy to placebo in patients with early PD over a 7-month period. Four hundred and five early PD patients were randomized (double-blind) to piribedil (150 –300 mg/day) or placebo. L-dopa open-label sup- plementation was permitted. Unified Parkinson Disease Rating Scale part III (UPDRS III) score as the last observation on monotherapy over 7 months was the primary outcome measure. Secondary outcomes were proportion of responders (UPDRS III improvement  30%), patients remaining on monotherapy after 7 months, UPDRS III subscores, and UPDRS II. UPDRS III improved on piribedil (-4.9 points) versus a worsening on placebo (2.6 points; estimated effect = 7.26 points; 95% CI = 5.38 –9.14; P  0.0001). The proportion of responders was significantly higher for piribedil (42%) than for placebo (14%) (OR = 4.69; 95% CI = 2.82–7.80; P  0.001). Piribedil significantly improved several UPDRS III subscores. UPDRS II improved on piribedil by -1.2 points, while it deteriorated by 1.5 points on placebo (estimated effect = 2.71; 95% CI = 1.8 –3.62; P  0.0001). The proportion of patients remaining on monotherapy after 7 months was greater in the piribedil group (OR = 3.72; 95% CI = 2.26 – 6.11; P  0.001). Safety was consistent with that reported for other dopamine agonists, gastrointestinal side effects being the most common (22% of patients in piribedil group vs. 14% on placebo). Piribedil is effective and safe as early PD therapy. © 2006 Movement Disorder Society Key words: piribedil; L-dopa; Parkinson’s disease; monotherapy Although L-dopa therapy improves motor symptoms of patients with Parkinson’s disease (PD), the emergence of motor fluctuations and dyskinesias poses a major therapeutic challenge. 1–3 The early use of a dopamine agonist delays or prevents the development of motor complications 4,5 for at least 5 years. Piribedil [(methylenedioxy-3,4-benzyl)-4 pyperazinyl- 1-2 pyrimidine], a centrally acting nonergoline dopamine agonist 6 with affinity for D2 and D3 receptors 7,8 and significant activity on animal models of PD, 9 has been used for many years in the treatment of PD. 10 Controlled studies have demonstrated piribedil efficacy in combina- tion with L-dopa, 11–13 but only one open-label 3-month study has reported a favorable therapeutic profile of piribedil monotherapy in de novo patients. 14 The REGAIN (Early Treatment of Idiopathic PD With the Dopaminergic Agonist Trivastal 50 Retard in Mono- therapy) multicenter randomized double-blind placebo- controlled study was carried out to confirm the therapeu- *Correspondence to: Dr. Olivier Rascol, Pharmacologie Me ´dicale et Clinique, Faculte ´ de Me ´decine, 37 Alle ´e Jules Guesde, 31000 Tou- louse, France. E-mail: rascol@cict.fr Received 20 April 2006; Revised 6 June 2006; Accepted 14 June 2006 Published online 29 September 2006 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21122 Movement Disorders Vol. 21, No. 12, 2006, pp. 2110 –2115 © 2006 Movement Disorder Society 2110