The TQT Study

To serve as a basis for discussion on the design of recent TQT studies, a PubMed search was done (December 31) using the search terms thorough QT study 2012 and thorough QTc QT study 2012. Eighteen TQT studies published in 2012 were identified the key features of these studies and the response to the positive control, in all cases moxifloxacin, are summarized in Table 1. The limitations of this approach should be acknowledged The list is most likely not complete only a 

The SD of AQTc was estimated based on the assumptions that the 90 % Cl for peak moxifloxacin AAQTc was calculated from a 2-sample /-test with equal variance for moxifloxacin and placebo data 

healthy volunteers M, males F, females XO, crossover SD, single dose MD, multiple dose T, therapeutic dose ST, supratherapeutic dose P, placebo M, moxifloxacin, single oral dose of 400 mg nested XO, nested crossover comparison for moxifloxacin lacebo within a parallel group study T + keto, therapeutic dose concomitant with ketoconazole. TKI, tyrosine kinase inhibitor, Cl, confidence interval LB, lower bound. Negative upper bound of Cl 10 ms for doses studied 

---

The TQT study is a randomized, placebo- and positive-controlled clinical trial that can adopt a crossover design or a parallel-group design. The traditional four treatment arms are as follows ... 

Even given all of these considerations, we are nonetheless left with the fundamental tenet that the TQT study employs QTc prolongation as the biomarker of proarrhythmic risk. There is widespread acknowledgement that QT interval prolongation is not the most accnrate predictor of such risk. Indeed, some researchers have commented that if it were not relatively easy to measure (at least theoretically, precise identification of the offset of the T wave can be very difficult for some waveforms), it may have been discarded aU together some time ago. 

Among these initiatives, the project of the HESI Cardiovascular Safety Subcommittee represented an analysis of the largest database among the different consortia, a survey of 150 molecules studied in the clinic for QT prolongation (Koemer et al. 2013). This initiative is comparing the concordance between preclinical cardiac repolarization assays and the results from the TQT study data were collected from INDs and NDAs submitted to the FDA between the periods of March 2006 and July 2012. Due to the proprietary namre of these datasets, the FDA populated the spreadsheets with the data and carried out a quality control and statistical analysis based on a methodology that was devised by the subcommittee in advance of the collection of data. The summary results of this analysis of 150 compounds has been presented at conferences and is due for publication in 2015 (Koemer et al. 2013). 

Dose A high, supratherapeutic dose of the NCE, which results in plasma levels in excess of what would be observed in patients with impaired clearance of the drug, should be used in the TQT study. The E14 states If not precluded by consideratimis of safety or tolerability due to adverse effects, the drug should be tested at substantial multiples of the anticipated maximum therapeutic exposure. The overriding principle is that plasma levels achieved with the supratherapeutic dose should exceed the worst-case scenario in patients, taking into account both intrinsic (e.g., renal impairment) and extrinsic factors (e.g., drug interactions). As an example, for NCEs that are CYP 3A4 or 2D6 substrates, the achieved exposure must exceed that observed with concomitant administration with potent 3A4 inhibitors, and in 2D6 poor metabolizers (Abbas et al. 2012 Boyce et al. 2012 Chaikin et al. 2005 Dalen et al. 2010 Malhotra et al. 2007 Robert et al. 2007 Tyl et al. 2012 Zhu et al. 2010). For a renally cleared drug, plasma levels that are only... 

The objective of the TQT study is to demonstrate that an NCE does not prolong the QTc interval by more than 5 ms, as evidenced by the upper bound (UB) of the 2-sided 90 % Cl of the placebo-adjusted change-from-baseline QTc (AAQTc) being below 10 ms. 

The TQT study is formally powered to exclude a small (around 5 ms) QTc prolongation. The variability of other ECG parameters (such as the PR and QRS intervals) are in fact lower than for the QTc interval, and it has become increasingly apparent that these studies also can and should be used for assessment of other ECG effects. These data, unfortunately, are not always given in publications on TQT studies, which makes it difficult to independently evaluate the QTc effect, or lack thereof. As an example, there is no mention of effects on heart rate, PR, or QRS interval in the publication on the TQT study with liraglutide (Chatterjee et al. 2009),... 

Exposure-response (ER) analysis has become an important tool to interpret QT data from TQT studies and has been used to predict QT effects in patients for the targeted indication, including patients with impaired clearance of the dmg (Garnett et al. 2008 Piotrovsky 2005). ER analysis has also been applied to QT data derived from early SAD/MAD studies. Since the doses in SAD studies are often escalated to MTD, high plasma levels often are obtained, which allows for the evaluation of potential ECG effects over a wide range of plasma concentrations. With increasing confidence in data derived from these types of studies, the relevant question as to whether early QT assessment can replace the TQT study has been raised (Darpo... 

---