The effect can be measured as prolongation of the QT interval in the ECG. Since the duration of QT interval is reversely related to heart rate, different formulae for correction exist:

i) Bazett: QTc = QT/RR^0.5
ii) Fridericia: QTc = QT/RR^0.33
iii) Individual correction based on analysis of regression of QT and RR at various heart rates

The criteria of a negative TQT study are fulfilled when the one-sided 95% confidence interval of the mean effect on QTc interval excludes 10 ms. The TQT study should be conducted relatively early, but not before all the data are available that are needed for designing the trial. This mainly concerns information on PK and clinical dose. Inamed’s clinical development experts would be pleased to provide you further advice in this regard taking into account not only the scientific and regulatory needs, but also the principles of a cost-efficient clinical project development.

Design elements:

• Usually two dose levels: the clinical dose and a so-called supra-therapeutic dose level.
• Placebo as negative control.
• FDA is asking for “establishment of assay sensitivity“, which is usually achieved by a positive control, e.g., moxifloxacin.
• Study conduct will be randomized and double-blind regarding investigational compound and placebo. Moxifloxacin does not need to be blinded (CAVE: This is currently under discussion).
• Crossover design or parallel group design.
• Standardization of the study conditions and good quality of study conduct is of paramount importance (control of the “intrinsic variability“).
• PK measurements should be done at the same times as the ECG recordings.
• Evaluation of the ECG recordings should be done by “few skilled readers“.
• Technical standards: “Triplicate 12-lead ECG“, or 12-lead “Holter“ ECG.
• Some standard IN/EX criteria for TQT studies exist, e.g., no subjects with baseline QT interval of >450 ms or certain arrhythmia should be included.
• During the course of the study, an increase of QT/QTc to >500 ms or by >60 ms above baseline is an individual stopping criterion.

Some peer-reviewed papers and articles on TQT study conduct published by Inamed's employees:

W. Timmer
Cardiac Safety - Dr Wolfgang Timmer examines the conduct of thorough QTc trials in practice from a Phase I CRO's perspective
European Pharmaceutical Contractor, Summer '08 Issue, Samedan Ltd. Pharmaceutical Publishers 2008

T. Spinelli, C. Moresino, S. Baumann, W. Timmer, A. Schultz
Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial SpringerPlus 2014, 3: 389. DOI: 10.1186/2193-1801-3-389

M. Hartmann, W. Timmer, A. Schultz, R. Nave, R. Lühmann, S. Krause, G. Lahu, J. Scholpp
A Thorough QT Study of Teduglutide in Healthy Subjects
Clinical Pharmacology in Drug Development 2012; 1: 57-66

More publications by Inamed