CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 84 NUMBER 5 | NOVEMBER 2008 595 ARTICLES nature publishing group Thorough QT/QTc Study in Patients With Advanced Parkinson’s Disease: Cardiac Safety of Rotigotine M Malik 1 , J-O Andreas 2 , K Hnatkova 1 , J Hoeckendorff 2 , W Cawello 2 , M Middle 3 , R Horstmann 2 and M Braun 2 The potential effects of the dopamine agonist rotigotine on cardiac repolarization were studied in patients with Parkinson’s disease, which affects electrocardiogram (ECG) quality. The parallel-group trial was double-blind and placebo- and positive (moxifloxacin 400 mg)-controlled. After two 24-h baseline ECGs, patients were randomized to rotigotine (n = 66) or placebo (n = 64). Twenty four–hour ECGs were recorded on days 14/15, 21/22, 28/29, 35/36, and 42/43 of a regimen involving weekly dose escalations of 4 mg/24 h (4 mg/24 h–24 mg/24 h). In 10-s ECGs (n = 357,948) selected from 24-h records, QT measurements were manually verified and individually rate-corrected (QTc). Assay sensitivity showed maximum mean 13.5 ms QTc prolongation after moxifloxacin with 95% confidence interval (CI) 11.8– 15.2 ms. Rotigotine vs. placebo differences in time-matched changes from baseline (54 data points/24 h) showed mean effects close to zero with upper one-sided 95% CI <5 ms. Accurate, thorough QTc studies are possible even in patients with diseases that profoundly affect ECG quality. Rotigotine in supra- and therapeutic doses was shown not to affect cardiac repolarization. Rotigotine ((6S)-6-{propyl[2-(2-thienyl)ethyl]amino}-5,6,7,8- tetrahydro-1-naphthalenol) is a nonergolinic D 3 /D 2 /D 1 dopamine receptor agonist formulated as a silicone-based matrix-type transdermal patch providing continuous drug delivery over 24 h. 1 A rotigotine transdermal system has been developed for early- and advanced-stage Parkinson’s disease with maximum therapeutic doses of 6–8 mg/24 h for early- and 16 mg/24 h for advanced-stage Parkinson’s disease. Rotigotine is also in development for restless legs syndrome at considerably lower doses than are used in Parkinson’s disease. 2,3 The International Conference on Harmonization E14 guideline 4 requires a thorough QT/QTc (TQT) study for all new drugs, including at supratherapeutic doses (that is, well above the maximum clinically expected dose). Given that such high doses of dopamine receptor agonists are not toler- ated by healthy volunteers without a dopaminergic deicit, the TQT study had to be conducted in patients with advanced- stage Parkinson’s disease. Electrocardiogram (ECG) record- ings in these patients are inluenced by muscle tremors, skin conditions, and disease-related autonomic disturbances (Figure 1). 5,6 herefore, the TQT study design had to relect these challenging conditions. Substantial novel experience was obtained during the record- ing and analysis of ECGs for this study. herefore, this article not only presents the results of the TQT study of rotigotine but also describes the details of the methodology used. In several aspects, the study can serve as a model for TQT studies conducted in clinical populations with diseases that substantially afect the character and quality of ECGs. RESULTS Population he study enrolled 130 patients (31.5% female). he mean age of the subjects was 63 (range 29–88) years. Of this popula- tion, 64 and 66 patients were randomized to receive placebo and rotigotine, respectively. A total of 126 patients completed the trial (96.9%); 3 patients dropped out from the placebo arm (2 adverse events; 1 withdrawal of consent) and 1 patient from the rotigotine arm (an adverse event). 1 St. Paul’s Cardiac Electrophysiology, London, England; 2 UCB-Group, Schwarz Biosciences GmbH, Monheim am Rhein, Germany; 3 Parexel ClinPharm, George, South Africa. Correspondence: M Malik (marek.malik@btinternet.com) Received 6 February 2008; accepted 9 June 2008; advance online publication 23 July 2008. doi: 10.1038/clpt.2008.143