FDA1- quinidine, verapamil, ranolazine, dofetilide


Background: This database was shared by the FDA with the THEW in October 2014. The database includes a unique sets of ECG recordings from healthy indviduals exposed to four drugs: dofetilide, ranolazine, quinidine and verapamil using a randomized controlled five-way single-dose crossover design. This study was developped to test the hypothesis that ECG measures of early repolarization (global J–Tpeakc) and late repolarization (global Tpeak–Tend) can differentiate pure hERG potassium channel block associated with a high torsade risk from combined hERG potassium channel and inward current block (calcium or late sodium), which may lower torsade risk. The results show that hERG potassium channel block equally prolongs early and late repolarization, whereas additional inward current block (calcium or late sodium) preferentially shortens early repolarization. Characterization of multichannel drug effects on human cardiac repolarization is possible and may improve the utility of the electrocardiogram in the assessment of drug-related cardiac electrophysiology.

Study Design: This study is a randomized controlled five-way single-dose crossover clinical trial in 22 healthy volunteers (11 females). The drugs evaluated in this study were dofetilide (500 μg, Tikosyn, Pfizer, New York, NY), quinidine sulfate (400 mg, Watson Pharma, Corona, CA), ranolazine (1,500 mg, Ranexa, Gilead, Foster City, CA), and verapamil hydrochloride (120 mg, Heritage Pharmaceuticals, Edison, NJ). This database includes 10-sec standard 12-lead ECGs.

Protocol: In the morning of each treatment period, the subjects received one of the four drugs or placebo under fasting conditions. There was a 7-day washout period between each 24-h treatment period, so subjects received treatment on days 1, 9, 17, 25, and 33. Prior to dosing, a continuous 12-lead ECG recorder using the Mason–Likar electrode configuration. From the continuous recording, three replicate 10-s ECGs (pre- and postdose) were extracted at 16 predefined time-points (predose and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 14, 24 h postdose), during which the subjects were resting in a supine position for 10 min. After each ECG extraction time-point period, a blood sample was drawn for pharmacokinetic analysis. Plasma drug concentration was determined using a validated liquid chromatography with tandem mass spectroscopy method. At each of the 16 time-points, three optimal ECGs were extracted with stable heart rates and maximum signal quality using Antares software (AMPS, New York, NY). This resulted in a total of 48 ECGs per subject per treatment period and 5,280 planned ECGs in total.

Inclusion criteria: Subjects were in general good health as determined by a physician, without a history of heart disease or unexplained
syncope or a family history of long QT syndrome; to be 18–35 years of age, weigh at least 50 kg, and have a body mass index of 18–27 kg/
m2; and to be able to read and understand the informed consent. In addition, subjects were excluded if they had more than 10 ectopic beats during a 3-h continuous ECG recording at screening.

Number of Leads: standard 12 lead ECGs

Sampling Frequency : 500 Hz

Clinical Information: The list of clinical information available for this study are described in the following table:

RANDID subject identification
SEX gender
AGE in years
HGHT in cm
WGHT in Kg
SYSBP systolic blood pressure in mmHg
DIABP diastolic blood pressurein mmHG
RACE African, Asian , White
ETHNIC "not hispanic or latino" and "hispanic or Latino"
ARMCD study arms order
VISIT dosing period
EXTRT drug 
EXDOSE drug dose
EXDOSU drug dose unit
TPT time point
PCTEST plasma concentration test
PCSTRESN plasma concentration value
PCSTRESU plasma concentration unit
EGREFID ECG recording ID

Related Publication:

Johannesen L, Vicente J, Mason JW, Sanabria C, Waite-Labott K, Hong M, Guo P, Lin J, Sørensen JS, Galeotti L, Florian J, Ugander M, Stockbridge N, Strauss DG. Differentiating Drug-Induced Multichannel Block on the Electrocardiogram: Randomized Study of Dofetilide, Quinidine, Ranolazine, and Verapamil. Clin Pharmacol Ther. 2014 Jul 23. doi: 10.1038/clpt.2014.155. Click here to download the article

Vicente Jose ,Johannesen Lars ,Mason Jay W.,Crumb William J.,Pueyo Esther ,Stockbridge Norman ,Strauss David G.,Comprehensive T wave Morphology Assessment in a Randomized Clinical Study of Dofetilide, Quinidine, Ranolazine, and Verapamil, 2015 April 13, doi: 10.1161/JAHA.114.001615 2015 April 13, doi: 10.1161/JAHA.114.001615. Click here to download the article