It is possible to get an accurate baseline QT measurement, while taking the increased heart rate into account. One solution we have implemented is including exercise as part of the baseline ECG collection.

In our experience conducting thorough QT studies, the use of treadmills can mimic the increased heart rate levels that the compound is known to cause. An example of a possible study design incorporating a treadmill includes:

·         Conducting a baseline treadmill test the day before initial dosing to cover the range of heart rate anticipated while on the study drug. Baseline data are amassed a day before to avoid variations associated with data collection at a different part of the day.

·         Setting a goal of achieving the same heart rate in all participants during the treadmill test. If the anticipated heart rate on the study product is 90 to 100bpm, the goal of the treadmill test is to achieve the same heart rate in all of the subjects. Once the heart rate of more than 100bpm is achieved, the test stops.

·         Collecting consistent and reliable data that will be used in the analysis with an H-12 ECG. The core lab will also extract triplicate ECGs for a range of more than 80 to 90bpm and a range of more than 90 to 100bpm.

·         Calculating the subject-specific QTc1 with that data.This will be used when evaluating the QT data while on the study product.

·         Performing a trial run in a small group of participants is recommended to ensure the quality of the data collected.

This approach provides more accurate correction factors, and thus better data for evaluating the real-world applications of a compound as the regulatory process moves forward.

Regardless of your approach to thorough QT trials, key elements that must always be considered in study design include:

·         Parallel or crossover – Dependent on the half-life of the drug or population under evaluation, parallel or crossover study designs must be considered.

·         Number of subjects – Subject numbers can be determined by the variability of the QT measurement and the power needed, based on the estimated QT change. The number of groups participating can affect the variability of a study dramatically. One study split between several smaller groups and conducted at different sites may increase the variability of the QT measurement.

·         Timing of the baseline ECGs – These should be taken multiple times throughout the day before dosing and should correspond to the times of day that the ECGs are measured following dosing.

Regulatory agencies worldwide are increasingly requiring thorough QT studies as a component of marketing application submissions. Precise planning and proper execution can improve cost and time efficiencies of these studies.

In Cetero’s experience, when multiple measurements are to be collected at the same time point, the order of activities should be:

1.    Holter ECG acquisition
2.    PK sample collection
3.    Vital sign measurement

Priority should be given to the collection of the triplicate ECGs from the Holter device because of the amount of time required for the supine resting period prior to collection and the time associated with the actual ECG acquisition.

Typically, the ECG acquisition period is 10 minutes in length. Following completion of this 10-minute period, the PK blood sample should be collected. Finally, the vital signs can be collected in a supine position. The order of collection and time windows allowed for collection should be clearly outlined in the protocol.

A central nervous system compound may require dose titration in order for the dose to be tolerated and to achieve a suprathereapeutic dose. Titration will require multiple doses over multiple days and in some cases, depending on the compound, may require more than 28 days to achieve the supratherapeutic dose. Even with careful dose titration, it still may not be possible for all participants to tolerate the targeted supratherapeutic dose.

Based on Cetero’s experience, one should consider scheduling Holter monitoring days over the course of the titration after designated doses have been achieved. These Holter monitoring days will provide data at doses exceeding the clinical dose, in case participants are not able to continue to the supratherapeutic dose.

Intravenous (IV) or injection delivery in a TQT study requires extra preparation to ensure successful study conduct.

•    Dose administration with an intravenous infusion requires planning to consistently deliver the dose over the defined time interval. Based on Cetero’s experience, we recommend filling empty IV bags with the appropriate volume of diluent and drug. This practice has resulted in more consistent delivery times from participant to participant. Prefilled IV bags tend to have a volume of ± 10% of the labeled volume. This difference can result in variations in the infusion time for the investigational product.

•    Another consideration for an injectable dosage form is the volume of solution to be administered. The volume may require multiple injections to deliver the dose and avoid injection site reactions.

•    Due to the complexity of injectable dosage forms, often it will be necessary to dose smaller groups. The clinical team should work with the pharmacy and nursing teams to plan the dose administration for injectable delivery and the number of subjects that should be dosed in a cohort.

Defining the supratherapeutic dose is dependent on the investigational compound. Because of this, it is essential that you:
•    Know as much as possible about the compound. It is ideal if the maximum tolerated dose (MTD) has been defined. If an MTD has not been identified, a compilation of the adverse events observed during past studies, together with the dose at which the events occurred can be useful in evaluating a potential supratherapeutic dose. Pharmacokinetic data from past studies can be used to simulate exposure of the compound, if the compound was administered with a drug which inhibits the metabolism of the compound or if the patient takes more than the prescribed amount.
•    If the proposed supratherapeutic dose has not been previously administered to healthy participants, consider conducting a small pilot study in eight to 12 subjects to determine tolerability and the exposure levels achieved. The pilot study will document the tolerability of the proposed supratherapeutic dose prior to administration in the TQT study where 36 to 60 subjects would be exposed to the supratherapeutic dose.
•    Decide the route of administration for the compound. Whether it will be delivered orally, topically or by injection may play a role in determining the supratherapeutic dose. In the case of a topical product, if an oral dosage form is available, consideration should be given to conducting the TQT study with the oral dosage form which will achieve much higher exposure than the compound would when administered topically.