Articles Introduction Most patients with established Parkinson’s disease and sustained treatment with levodopa will eventually have motor fluctuations, defined as periods of the day with poor or absent motor function (off-time) alternating with periods of clearly improved motor function (on-time). 1 Several drugs (pergolide, pramipexole, ropinirole, entacapone, and tolcapone) have been effective in the management of fluctuations. 2–6 However, these drugs produce only part improvement, leaving patients to have clinically significant off-periods, while adding complexity to the treatment schedule. Their adjunct use needs adjustment of levodopa dose and additional drug doses, and might result in adverse reactions. The use of dopamine agonists also needs slow titration. Inhibition of monoamine oxidase B (MAO-B) activity provides an alternative option for the treatment of motor fluctuations, but evidence supporting the effectiveness of the only currently available MAO-B inhibitor selegiline is insufficient. 2,3 Moreover, no study has yet assessed in parallel the effects of MAO-B and catecholamine-O-methyltransferase (COMT) inhibitors in levodopa-treated patients with Parkinson’s disease having motor fluctuations. Rasagiline (N-propargyl-R-aminoindan) mesylate is a selective, irreversible, second-generation MAO-B inhibitor, and has shown effectiveness in early Parkinson’s disease when given as once-daily treatment without dose titration. 7 Preliminary data also lend support to its adjunct use in advanced disease. 8 The aim of this study was to determine the safety and efficacy of rasagiline as an adjunct to levodopa compared with placebo in the treatment of patients with Parkinson’s disease and motor fluctuations. As a comparator drug, this trial also included an adjunct entacapone arm, a COMT inhibitor that is demonstrably effective against motor fluctuations. 2,3,9,10 Methods Patients The LARGO (Lasting effect in Adjunct therapy with Rasagiline Given Once daily) study was an 18-week, randomised, placebo-controlled, double-blind, double- dummy, parallel-group trial, and was undertaken at 74 sites (hospitals or academic centres) in Europe, Israel, and Argentina. The study protocol was approved by ethics committees and regulatory authorities. The study was undertaken in accordance with Good Clinical Lancet 2005; 365: 947–54 See Comment *Investigators listed at end of report Clinical Investigation Centre, Department of Clinical Pharmacology, University Hospital, Toulouse, France (Prof O Rascol MD); Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, UK (Prof D J Brooks MD); Department of Neurology, Rabin Medical Centre, Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel (Prof E Melamed MD); Philipps- University of Marburg, Centre of Nervous Diseases, Marburg, Germany (Prof W Oertel MD); Department of Neurology, University of Innsbruck, Innsbruck, Austria (Prof W Poewe MD); Institute of Neurology, IRCCS Neuromed, Pozzilli, Italy (F Stocchi MD); and Neurology Service, Institut de Malalties del Sistema Nervios, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain (Prof E Tolosa MD) Correspondence to: Prof O Rascol, Department of Clinical Pharmacology, Faculty of Medicine, University Hospital, 37 Allees Jules Guesde, Toulouse 31073, France rascol@cict.fr www.thelancet.com Vol 365 March 12, 2005 947 Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial O Rascol, D J Brooks, E Melamed, W Oertel, W Poewe, F Stocchi, E Tolosa, for the LARGO study group* Summary Background Rasagiline mesylate is a novel drug for Parkinson’s disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinson’s disease and motor fluctuations. Methods In an 18-week, double-blind, multicentre (74 hospitals and academic centres in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline (231 individuals; 1 mg once daily), entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary outcome was change in total daily off- time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinson’s disease rating scale (UPDRS) scores. Analysis was by intention to treat. Findings 88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n=34) and adverse events (n=34). Both rasagiline and entacapone reduced mean daily off-time (–1·18 h rasagiline and –1·2 h entacapone vs placebo –0·4 h; p=0·0001, p0·0001, respectively) and increased daily on-time without troublesome dyskinesia (0·85 h vs placebo 0·03 h; p=0·0005 for both). We recorded significant mean improvements in CGI scores (–0·86 rasagiline and –0·72 entacapone vs –0·37 placebo; p0·0001, p=0·0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (–1·71 and –1·38 vs placebo; p0·0001, p=0·0006, respectively) and motor function during on-time (–2·94 and –2·73 vs placebo; both p0·0001). Frequency of adverse events was similar for all treatments. Interpretation Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinson’s disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.