A double-blind, placebo-controlled study of prucalopride in elderly patients with chronic constipation S. MU ¨ LLER-LISSNER,* A. RYKX,  R. KERSTENS & L. VANDEPLASSCHE  *Park-Klinik Weissensee, Berlin, Germany  Movetis NV, Turnhout, Belgium Abstract Background Constipation affects up to 50% of the elderly; this study evaluates the efficacy, safety, and tolerability of the selective 5-HT 4 agonist prucalo- pride in chronically constipated elderly patients. Methods Three hundred chronic constipation patients aged ‡65 years were randomized to prucalopride (1, 2, or 4 mg once daily) or placebo for 4 weeks. The pri- mary endpoint was the percentage of patients with ‡3 spontaneous complete bowel movements (SCBM) per week. Secondary endpoints included the percentage with an increase of ‡1 SCBM per week, BM frequency, constipation-related symptoms, quality of life (QoL), safety, and tolerability. Key Results More patients achieved ‡3 SCBM per week with prucalopride than with placebo. This difference was largest and signifi- cant during the first week of 4 mg prucalopride (P £ 0.05). Significantly more patients in each prucal- opride group achieved an increase of ‡1 SCBM per week from baseline vs placebo (e.g. 60% with 1 mg prucalopride vs 34% with placebo at week 4; P £ 0.05). More patients had improvement in PAC-QOL satis- faction score of ‡1 with 1 mg prucalopride than with placebo (P £ 0.05); the same was true for PAC-SYM stool symptoms (1 and 4 mg prucalopride; P £ 0.05). Treatment-emergent adverse events were similar between groups: the most frequently reported with prucalopride were headache and gastrointestinal events. There were no clinically significant differ- ences between prucalopride and placebo for vital signs, laboratory assessments, or ECG variables. Conclusions & Inferences Prucalopride, in the dose- range tested (1–4 mg once daily), has beneficial effects on bowel movements, symptoms, and QoL, and is safe and well-tolerated in elderly patients with chronic constipation. Keywords 5-HT 4 receptors, colon motility, consti- pation, elderly, enterokinetic, prucalopride. Abbreviations: AE, adverse event; BM, bowel movement; CMH, Cochran–Mantel–Haenszel; HR, heart rate; ITT, intent to treat; PAC-QOL, patient assessment of constipa- tion-quality of life; PAC-SYM, patient assessment of constipation-symptom; QTcF, QT interval corrected according to Fridericia; SAE, serious adverse event; SBM, spontaneous bowel movement; SCBM, spontaneous complete bowel movement. INTRODUCTION Estimates suggest that constipation affects up to 28% of individuals in the Western World, 1,2 with a two-fold higher prevalence in women than in men. 3 Rome III criteria 4 define constipation on the basis of multi- system symptoms, including straining, lumpy or hard stools, a sensation of incomplete evacuation, a sensation of anorectal obstruction, and fewer than three bowel movements (BMs) per week. The symptoms of chronic constipation are unpleasant and have an adverse effect on patients’ quality of life (QoL). 5–7 Longer transit times have been reported in elderly individuals, 8 which may explain why chronic constipa- tion appears to be a particular problem in the elderly, with estimated prevalence of 15–50%. 3 The biological basis of constipation in the elderly is not entirely clear, although there is evidence of enteric neurodegeneration, which affects gut epithelial, muscle and neuronal func- tion. 9 There is evidence of loss of excitatory enteric neurons (e.g. cholinergic) whereas inhibitory enteric neurons appear to be unchanged in aging, leading to decreased motility. 9 In addition, reduced fiber and fluid Address for Correspondence Stefan Mu ¨ ller-Lissner, Professor of Medicine, Park-Klinik Weissensee, Schoenstrasse 80, 13086 Berlin, Germany. Tel: +49 30 9628 3600; fax: +49 30 9628 3605; e-mail: mueli@park-klinik.com; stefan@mueller-lissner.de Received: 3 December 2009 Accepted for publication: 7 May 2010 Neurogastroenterol Motil (2010) 22, 991–e255 doi: 10.1111/j.1365-2982.2010.01533.x Ó 2010 Blackwell Publishing Ltd 991