Vol.97 (2003) (SUPPLEMENT A), S9-$21 IIIml~l~lllll[t]UJ~lll][lll~i Early clinical investigation ofViozanTM (sibenadet HCI), a novel D 2 dopamine receptor, 1 2-adrenoceptor agonist for the treatment of chronic obstructive pulmonary disease symptoms RW. IND, I L. LAITINEN, 2 L. LAURSEN, 3 S.WENZEL, 4 E.WOUTERS, 5 L. DEAMER 6 AND P. NYSTROM 6 I National Heart and Lung Institute, London, U.K.; 2Hospital District of Helsinki and Uusimaa, Helsinki, Finland; 3Department of Lung Medicine, KAS Gentofte, Niels Andersensvej 65, 2900 Hellerup, Denmark; 4National Jewish Medical Research Centre, Denver, CO, U.S.A.; SAcademisch Ziekenhuis, Maastricht~ Holland; 6AstraZeneca, Charnwood, Loughborough, U.K. Abstract Viozan TM, (Sibenadet HCI, AR-C68397AA) is a dual D 2 dopamine receptor, ~2-adrenoceptor agonist that combines bronchodilator activity with the sensory afferent modulating effects associated with D2-receptor agonism. Investigation in animal models of key chronic obstructive pulmonary disease (COPD) symptoms has demonstrated that sibenadet effectively inhibits sensory nerve activity, thereby reducing reflex cough, mucus production and tachypnoea. The results of the early clinical evaluation of this novel agent are reported. An initial proof of concept study (Study I) aimed to determine the clinical potential of this novel agent by assessingthe effects of three doses of sibenadet therapy relative to placebo, with two commonly used bronchodilators, intended to provide a benchmark against which sibenadet activity could be judged. In all, 701 patients were randomized to one of three sibenadet dose groups (400, 600 or 1000 lig ex valve), salbutamol 200 ~g, ipratropium bromide (IB) 40 pg or placebo, all three times daily via pressurized metered dose inhaler (pMDI) for 4 weeks. Once the results of Study I had been evaluated, a dose-ranging, study (Study 2) involving 872 patients randomized to receive sibenadet (45, 270, or 495 I~g ex actuator), or placebo all three times daily via pMDI, for 6 weeks commenced. Both studies were preceded by a 2-week baseline phase and followed by a 2-week follow up period.The primary efficacy variable identified changes in key COPD symptoms over the treatment period (compared with baseline data) as determined by the novel Breathlessness, Cough and Sputum Scale (BCSS©). In addition, data on lung function, health-related quality of life and adverse events were collected. Patients receiving sibenadet therapy three times daily exhibited statistically significantly greater improvements in BCSStotal score than those receiving placebo or bronchodilator therapy alone. A clear dose-response was evident in Study 2. Symptom improvement in this study was also accompanied by improved lung function and health-related quality of life. Sibenadet therapy was well tolerated with an adverse events profile comparable to current bronchodilator therapy, These data were viewed as extremely encouraging, warranting further, large-scale clinical investigation. © 2003 Elsevier Science Ltd INTRODUCTION Chronic obstructive pulmonary disease (COPD) refers to a disease spectrum with slowly progressive, poorly reversible airways obstruction due to chronic bronchitis, Correspondenceshouldbe addressed to: Dr PhilipW.Ind,MA FRCP, Senior LecturerRespiratory Medicine, National Heartand Lung Institute, HammersmithHospital, Du CaneRd,London,Wl2 0HS, U.K.TeI:+44 (0)208383 3269; Fax: +44 (0)208743 9733, Email: p.ind@ic.ac.uk emphysema, small airways disease or a combination of these conditions. The single greatest risk factor for the development of COPD is long-term tobacco smoking, which accounts for 80-90% of all cases (I). However, only around 15% of smokers go on to develop COPD. In non-smokers, COPD can be attributed to environmental pollution, occupational hazards and genetic abnormalities (2). Although many patients remain undiagnosed, the global prevalence is thought to be 4-6% in those over 45 years of age (2). The impact of COPD continues to