Nuventra provides a wide range of services to support your TQT study and overall development program, including: The timing of a TQT clinical study during the development program can depend on a variety of factors such as the outcome of relevant nonclinical investigations (e.g., hERG assay results) and therapeutic class considerations related to the potential to induce heart arrhythmias, as well as sponsor-related variables like risk tolerance and budget.įor example, TQT clinical studies can be conducted early in a development program (i.e., in Phase 1) to de-risk continued development of a compound, or later in a development program if prior proof-of-concept efficacy data is needed to justify the expense of conducting a TQT study, which often costs upwards of $5 million to conduct, interpret, and report. When to Execute Thorough QT Studies in Development Programs If investigational drugs cannot be administered to healthy volunteers (this is common for oncology drugs, which are typically cytotoxic), then other strategies can be employed to gain insight into the potential for pharmacological QT/QTc interval prolongation. Sponsors may also wish to consider methods for assessing cardiac QT/QTc prolongation and corresponding PK/PD relationships within the context of other early phase healthy volunteer studies and/or late phase clinical trials, including the use of intensive ECG sampling and of sparse sampling of blood concentrations in a population PK approach. Treatment 4: Supratherapeutic dose of investigational drug.Treatment 3: Therapeutic dose of investigational drug.Treatment 2: Positive Control (e.g., moxifloxacin 400 mg IV).For crossover studies, subjects are randomized to 1 of 4 treatment sequences and receive each of the following treatments in random order, with appropriate washout periods determined by the drug’s pharmacokinetics: Parallel study designs for TQT investigations are also a consideration depending on the pharmacokinetics of the investigational drug. Thorough QT/QTc Study DesignĪ thorough QT/QTc study is typically designed as a double-blind (except for the use of a positive control such as moxifloxacin in most studies), randomized, single-site, crossover study in healthy male and female subjects.
For example, a crossover TQT study design (see section on study design below) can allow for characterization of intrinsic intra-subject PK variability, which can be applied to the design of future clinical pharmacology studies that require statistical power (e.g., bioequivalence studies to support formulation changes). Depending upon the depth of existing knowledge around the PK behavior of the drug, pre-study simulations may be helpful for guiding study design and optimizing PK sample collection times.īecause TQT studies typically require a large number of study subjects, Nuventra views these studies not only as a means of assessing potential pharmacological impacts on QT/QTc interval, but also as an opportunity to obtain additional PK data and build a more robust portfolio of PK knowledge for the drug. As such, careful consideration must be given to the timing of electrocardiogram (ECG) acquisition, the PK sampling schedule, and other study design elements. Characterization of the pharmacokinetic/pharmacodynamic concentration-response relationship ( PK/PD) for QT/QTc prolongation is essential during these investigations. Pharmacokinetics (PK) is an integral part of TQT clinical studies. Because the QT interval is strongly influenced by heart rate, the QT interval is often expressed as a “corrected” value (QTc) that takes heart rate into account.įor most drugs, the potential for pharmacologic prolongation of the QT interval involves performing a standalone thorough QT/QTc clinical study (TQT study). This assessment involves examination of the QT interval, which is the time during the heart’s electrical cycle from the beginning of the Q wave (depolarization of the interventricular septum) to the conclusion of the T wave (ventricular repolarization).
As part of a typical drug development program, a sponsor must assess the potential for cardiac repolarization delays following administration of their investigational product. Delays in cardiac repolarization can lead to life-threatening heart arrhythmias.
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