Articles www.thelancet.com Published online October 23, 2008 DOI:10.1016/S0140-6736(08)61525-1 1 Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial Arne Astrup, Sten Madsbad, Leif Breum, Thomas J Jensen, Jens Peter Kroustrup, Thomas Meinert Larsen Summary Background Weight-loss drugs produce an additional mean weight loss of only 3–5 kg above that of diet and placebo over 6 months, and more effective pharmacotherapy of obesity is needed. We assessed the efficacy and safety of tesofensine—an inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin—in patients with obesity. Methods We undertook a phase II, randomised, double-blind, placebo-controlled trial in five Danish obesity management centres. After a 2 week run-in phase, 203 obese patients (body-mass index 30–≤40 kg/m²) were prescribed an energy restricted diet and randomly assigned with a list of randomisation numbers to treatment with tesofensine 0·25 mg (n=52), 0·5 mg (n=50), or 1·0 mg (n=49), or placebo (n=52) once daily for 24 weeks. The primary outcome was percentage change in bodyweight. Analysis was by modified intention to treat (all randomised patients with measurement after at least one dose of study drug or placebo). The study is registered with ClinicalTrials.gov, number NCT00394667. Findings 161 (79%) participants completed the study. After 24 weeks, the mean weight loss produced by diet and placebo was 2·0% (SE 0·60). Tesofensine 0·25 mg, 0·5 mg, and 1·0 mg and diet induced a mean weight loss of 4·5% (0·87), 9·2% (0·91), and 10·6% (0·84), respectively, greater than diet and placebo (p<0·0001). The most common adverse events caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhoea, and insomnia. After 24 weeks, tesofensine 0·25 mg and 0·5 mg showed no significant increases in systolic or diastolic blood pressure compared with placebo, whereas heart rate was increased by 7·4 beats per min in the tesofensine 0·5 mg group (p=0·0001). Interpretation Our results suggest that tesofensine 0·5 mg might have the potential to produce a weight loss twice that of currently approved drugs. However, these findings of efficacy and safety need confirmation in phase III trials. Funding Neurosearch A/S, Denmark. Introduction The prevalence of obesity has increased to 15–35% of the adult population in most developed countries and in several developing countries, 1 resulting in an increasing number of people with diseases such as type 2 diabetes, cardiovascular disease, musculoskeletal disorders, and cancers. Weight loss of 5–10% of bodyweight, irrespective of how it is achieved, is associated with improvements in cardiovascular risk profiles and reduced incidence of type 2 diabetes. 2 Furthermore, major weight loss as a result of bariatric surgery (eg, 20–25% weight loss by gastric bypass) substantially reduces obesity comorbidities, increases longevity, 3 and can often cure type 2 diabetes in patients who are obese. 4 Non- pharmacological treatment can be effective, but the success rate in the long term is low. 5 Pharmacological drugs for weight loss are effective in the long term, but after 1 year of treatment, the weight loss produced above that achieved by diet and lifestyle management is 2·9 kg for orlistat, 4·2 kg for sibutramine, and 4·7 kg for rimonabant. 6,7 Pharmacotherapy with agents that are more effective has so far been limited because of adverse effects and difficulties with tolerability. 7 A gap is therefore evident between the efficacy provided by bariatric surgery and present pharmacotherapy for obesity management. We report a phase II study on tesofensine—an inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin—that has been shown to be safe and effective in animal models and to produce unintended weight loss in obese patients with Parkinson’s or Alzheimer’s disease. 8 In these patients, tesofensine produced a placebo-subtracted weight loss of about 4% over 14 weeks without any diet and lifestyle therapy, which is similar to the effect of sibutramine and rimonabant, but with no effect on blood pressure or mood. On the basis of these short-term results, we aimed to assess the weight-loss efficacy and safety in patients with obesity over 24 weeks. Methods Study design and patients We undertook a randomised, double-blind, placebo- controlled, parallel-group, multicentre study of the effect of tesofensine on bodyweight in obese patients (body- mass index [BMI] 30–≤40 kg/m²). Five Danish obesity Published Online October 23, 2008 DOI:10.1016/S0140- 6736(08)61525-1 Department of Human Nutrition, Faculty of Life Sciences (Prof A Astrup MD, T M Larsen PhD) and Department of Endocrinology (Prof S Madsbad MD), University of Copenhagen, Denmark; Department of Medicine, Køge Hospital, Køge, Denmark (L Breum MD); Cyncron Clinical Research Unit, Copenhagen, Denmark (T J Jensen MD); and Department of Endocrinology, Aalborg Hospital, Aalborg, Denmark (J P Kroustrup MD) Correspondence to: Prof Arne Astrup, The Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Rolighedsvej 30, DK-1958 Frederiksberg, Denmark ast@life.ku.dk