1. 1. BACKGROUND
The IQ-CSRC planning group for the prospective study `Can Early QT assessment replace the
thorough QT (TQT) study?’ will conduct a prospective clinical study with the objective to
evaluate whether confidence in data generated using exposure response (ER) analysis applied to
standard, clinical pharmacology studies with high drug exposure, can be sufficient to allow
replacement of a thorough QT studies. We believe that a comparative evaluation of the ability of
TQT studies and ‘Early QT assessment’ to detect small QTc changes is essential to understand
and define the advantages and disadvantages of different approaches.
Based on the results from this study, the IQ-CSRC group will approach individual regulatory
agencies and the ICH E14 group to present the data and to discuss ‘Early ECG assessment’ as an
optional alternative to the TQT study.
iCardiac Technologies has decided to fund and will act as the sponsor for the study, which will be
conducted during Q1 2014 at Covance clinical site in Evansville. We expect that results from the
study will be available for interactions with regulators and at public meeting early Q3, 2014.
In the following, we are outlining the underlying concept, the design, conduct and analysis of the
clinical study. FDA has taken an active role in choosing the ‘QT-positive’ drugs in the study and
in creating the design and analysis. The design of the study will also be published in Annals of
Non-invasive Electrocardiology within the next 2 to 3 months (Darpo B et al. THE IQ-CSRC
PROSPECTIVE CLINICAL PHASE 1 STUDY: `CAN EARLY QT ASSESSMENT USING
EXPOSURE RESPONSE ANALYSIS REPLACE THE THOROUGH QT STUDY?’.Accepted
for publication in ANE November, 2014).
The underlying concept of ‘Early QT assessment’ is to utilize exposure response analysis as the
primary analysis method. If the E14-defined time-matched approach is applied to a standard SAD
study with dosing groups of 6 to 9 subjects, it will often not have the power to exclude a QT
effect of concern, since the effect of the drug is independently tested at each post-dosing time
point. In contrast, exposure response analysis utilizes data from all time points in one model,
which results in a substantially higher power to exclude small QT effects.
The concordance of the results from this ‘SAD-like’ study and previous QT assessment for the
identified drugs will be evaluated against prospectively agreed success criteria: If the 5 TQTstudy-positive drugs also come out positive in the prospective study, using criteria described
below, it would provide evidence in favor of replacing the TQT study with Early QT assessment.
The study will be conducted at one clinical site and ECGs will be initially analyzed using
iCardiac’s High Precision QT technique [1]. The study will generate digital, continuous ECG
data that will be stored in an independent data warehouse, where the data will be accessible for
research by other core ECG laboratories, sponsors and researchers.
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2. 2. IMPLICATIONS OF THE STUDY
If this study meets the criteria for positive QT assessment for the 5 ‘QT-positive’ drugs and the
criterion for negative QT assessment for the ‘QT-negative’ drug, this would provide evidence in
support of a TQT waiver for drugs with a negative QT assessment in future phase 1 studies
conducted in the same robust fashion (e.g. SAD or MAD studies with exposure response
analysis). It should be acknowledged that therapeutic plasma levels and the pharmacokinetic
variability within the target patient population are not known at the time when a SAD/MAD
study is conducted. A waiver can therefore only be discussed if clinically relevant plasma levels
are covered and exceeded in SAD/MAD study.
The following criterion has been proposed for Early QT assessment to serve as a basis for a
request for a TQT waiver [2]:

The upper bound of the 2-sided 90% confidence interval of the predicted placebocorrected ∆QTcF at the highest clinically relevant plasma level of the drug should be
below 10 ms.
3. STUDY OUTLINE
3.1 Objectives of the study
The primary objective is to study the effect of 6 marketed drugs on the QTc interval using
exposure response modeling. Secondary objectives will include evaluation of the effect of the
drugs on heart rate, QTc, PR and QRS intervals using a descriptive statistical analysis by time
point and dose.
3.2 Study design and rationale
The study will be randomized, placebo- and QT positive-controlled and performed in 2 separate
cohorts of 10 healthy adult, male subjects. Six marketed drugs have been selected for the
evaluation: 5 ‘QT-positive’ drugs with a known and well-characterized QT-effect and one
negative drug. Main features of the design will be similar to those of a standard single-ascending
dose study (SAD) with the difference that only 2 doses of each drug will be tested. The design,
sample size and statistical approach is intended to achieve similar power to exclude clinically
relevant QTc effects as a standard SAD First-in-Man study would have.
Twenty healthy subjects will be enrolled and randomized to receive 3 drugs in separate treatment
periods. In each cohort of 10 subjects, 9 will receive 3 of the selected drugs and 3 subjects will
receive placebo in any of the 3 treatment periods. This will ensure at least 6 subjects on each of
the drugs and 6 subjects on placebo, which will be pooled across the 2 cohorts. On Day 1,
subjects will receive the lower dose of the drug and on Day 2, the higher dose of the same drug.
3.3 ECG methodology
ECG recordings, extraction and analysis will be performed using the same approach and scrutiny
as in thorough QT studies. Continuous digital 12-lead ECG recordings will be performed from
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3. predose timepoints on Day 1 to 24 hours after the dose on Day 2, i.e. in the morning of Day 3.
12-lead ECGs will be extracted from the continuous recordings in replicates (triplicates or more)
at 3 pre-dose time points on Day 1 and serially thereafter using the same schedule for all
treatments, designed to capture sufficiently high plasma levels of each drug. At each of these time
points, subjects should be resting for at least 10 minutes prior to and 5 minutes after the time
point. 12-lead ECG strips of appropriate length will be extracted from the continuous recording
during periods of verified stable heart rate during the 15-minute window at each time point. Staff
at the central laboratory performing ECG assessments will remain blinded to all study treatments,
study visits (baseline vs. on drug) and subject identification.
During the protocol-specified ECG extraction windows, ten (10) 12-lead ECG tracings will be
extracted using TQT Plus method. TQT Plus optimizes for selecting ECGs with the least number
of unstable beats, the highest signal to noise ratios (using a proprietary methodology focused on
T-wave signal quality), and the least number of beats where the software could not determine
fiducials in an automated fashion.
High-Precision QT analysis will be performed on all analyzable (non-artifact) beats in the 10
ECG replicates. Statistical quality control procedures will be used to review and assess all beats
and identify “high” and “low” confidence beats using several criteria including QT or QTc values
exceeding or below certain thresholds (biologically unlikely), RR values exceeding or below
certain thresholds (biologically unlikely) and rapid changes in QT, QTc, or RR from beat to beat.
Placement of fiducials and measurements of all primary ECG parameters (QT, QTc, RR) in all
recorded beats of all replicates will be performed using iCardiac’s proprietary COMPAS
software. All low confidence beats will be reviewed manually by an iCardiac ECG Analyst and
adjudicated using pass-fail criteria. The beats found acceptable by manual review will be
included in the analysis.
PR, QRS, T-wave morphology and U-wave presence will be assessed in 3 non-overlapping ECG
replicates with the highest quality score from the ECG extraction window using the COMPAS
software and semi-automated methodology. The iCardiac ECG Analyst will select 3 consecutive,
usable beats for each replicate and review and/or adjust the fiducial placements (onset of P, onset
of Q, offset of S, and offset of T-wave that were electronically marked) of each waveform and
also document the T-wave morphology and the presence of U-waves for each beat. If 3
consecutive usable beats cannot be identified in at least 2 of the 3 replicates, then all beats will be
reviewed for that timepoint for each replicate using a manual analysis. A replicate will only be
reported if it has 3 approved, usable beats.
3.4
Subjects
Twenty (20) healthy male and female adult subjects (18 to 55 years of age) will be enrolled with
the aim to have at least 6 evaluable subjects on both doses of each of the 6 marketed drugs. Dropouts will not be replaced.
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4. 3.5 Study drugs
Two doses of each drug will be given to subjects in order to mimic a dose escalation design of a
SAD study. The dose on Day 1 was chosen to achieve a mean ΔΔQTc of 9 to12 ms for each of
the QT-prolonging drugs, as suggested by FDA. A higher dose will be given on Day 2 as
described in the Table 1 below. The resulting higher plasma levels from the higher dose will
increase the precision of the slope estimate when pooling data from two dose levels (see Sample
size justification below).
Table 1: Selected drugs with dose on Day 1 and 2
Drug
ZOFRAN
(ondansetron
HCl)
Dose Justification
TQT Study Design and Results
Day 1
QTc interval prolongation was studied in a
double blind, single intravenous dose, placeboand positive-controlled, cross-over study in 58
healthy subjects.
The maximum mean (95% upper confidence
bound) difference in QTcF from placebo after
baseline-correction was 19.5(21.8) ms and 5.6
(7.4) ms after 15 minute intravenous infusions
of 32 mg and 8 mg ZOFRAN, respectively.
QUALAQUIN
(quinine
sulphate)
QTc interval prolongation was studied in a
double-blind, multiple dose, placebo- and
positive-controlled crossover study in young
(N=13, 20 to 39 years) and elderly (N=13, 65
to 78 years) subjects. After 7 days of dosing
with QUALAQUIN 648 mg three times daily,
the maximum mean (95% upper confidence
bound) differences in QTcI from placebo after
baseline correction was 27.7 (32.2) ms.
QRS prolongation noted.
ANZEMET
(dolasetron)
QTcF interval was evaluated in a randomized,
single dose, placebo and active (moxifloxacin
400 mg once-daily) controlled crossover study
in 80 healthy adults. The maximum mean (95%
upper confidence bound) differences in QTcF
from placebo after pre-dose baseline-correction
were 14.1 (16.1) and 36.6 (38.6) ms for 100 mg
and supratherapeutic 300 mg ANZEMET
administered intravenously, respectively.
QRS prolongation noted.
4
56 mg oral*
Dose has not been
tested in TQT study.
However, the
anticipated effect is 10
to 12 ms.
Day 2
32 mg given by 15
min IV infusion.
Based on TQT study
results, mean
ΔΔQTc= 19.5 ms.
Cmax:  281 ng/mL
648 mg oral*
In a PK study in HV
(n=24) the mean
change from baseline
QTc at Tmax was
12 ms.
Cmax  3.2 µg/mL.
Expected increase in
QTc of 12 ms based on
the PK/PD model.
100 mg PO*
Hydrodolasetron Cmax
 278 ng/mL.
This value was
extrapolated from the
200 mg oral dose in
the label (556 ng/mL
with 28% coefficient
of variation). The
Cmax from 100 mg IV
was 310 [SD= 65.7]
ng/mL in the TQT
study.
648 mg q8h x 4 (3
doses on Day 1 and a
morning dose on Day
2)
After the 4th dose
(~75% of Cmax), the
anticipated
concentration is 5.1
µg/mL and the
anticipated QTc is ~
20 ms.
150 mg IV by 15 min
infusion
Dose chosen for an
expected QTcF of
about 20 ms, based
on:
- Linear PK in the 50200 mg IV dose range
- From TQT
modeling, plasma
hydrodolasetron
concentrations above
approximately 444
ng/mL will result in

5. increases in QTcF that
are 20 ms or greater.
AVELOX
(moxifloxacin)
NA
400 mg po*
800 mg IV
Cmax:  2.95 µg/mL
Mean ΔΔQTc = ~20
ms,
Mean ΔΔQTc = 10-14
ms
TIKOSYN
(dofetilide)
XYZAL
(levocetirizine;
negative drug)
Increase in QT interval is directly related to
dofetilide dose and plasma concentration. The
relationship in normal volunteers between
dofetilide plasma concentrations and change in
QTc is linear, with a positive slope of
approximately 15-25 ms per ng/mL after the
first dose.
0.125 mg oral*
0.25 mg oral
Cmax:  0.5 ng/mL
QTc ~ 20 ms
A QT/QTc study using a single dose of 30 mg
of levocetirizine did not demonstrate an effect
on the QTc interval.
5 mg (therapeutic
dose) oral
QTc ~ 10 ms
30 mg oral (supratherapeutic dose TQT
study)
Mean ∆∆QTc 1.1 ms
[31]
Cmax:  1.3 µg/mL
* Dose suggested by FDA
The identity of treatments will be blinded to subjects and the investigating site staff involved in
the study assessments (third party dosing).
4. DATA ANALYSIS
A key element for the use of data from SAD studies to replace a TQT study is an appropriate
analysis. Since subjects in a SAD study are divided into a large number of cohorts receiving
different doses of the drug, an ANOVA type per timepoint analysis with treatment as factor
seems inappropriate. In contrast, an exposure-response (ER) analysis can make optimal use of the
totality of doses and timepoints.
4.1 Primary analysis:
The primary analysis of the drug-induced QTc prolongation will be based on the ER analysis of
the relationship between plasma levels and the effect on ∆QTcF. The primary variable for the ER
analysis will be change-from-baseline QTcF (∆QTcF) and adjustment for placebo and circadian
variability will be done within the model. Placebo data will be pooled across both cohorts, i.e. for
a total of 6 subjects.
The primary analysis will be based on a linear mixed effects model with change from baseline of
QTcF as dependent variable, drug plasma concentration as covariate and timepoint as factor.
Predictions of the drug effect at a given concentration using this model have been shown to be
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6. equivalent to those obtained from a model for the difference to time matched placebo, which,
however, can only be applied in a complete block crossover setting1.
Tests will be formulated based on two-sided 90 % confidence intervals (CI). The confidence
intervals for slopes will be derived directly from the model. Confidence intervals for the
predicted effect at the geometric mean Cmax will be obtained by bootstrapping with subject as unit
of observation.
4.2
Criteria for QT assessment
4.2.1 Positive QT assessment:
The following criteria will be used to evaluate whether the study was able to demonstrate a QT
effect of the 5 ‘QT-positive drugs’:
 The upper bound of the 2-sided 90% confidence interval (CI) of the predicted placebocorrected ∆QTcF is above 10 ms at the observed peak plasma level of the lower dose of
the studied drugs.
In addition, the following criterion will be applied to ensure that the study has sufficiently low
variability to allow confidence in the data:

The lower bound of the 2-sided 90% confidence interval for the slope of ∆QTcF with
respect to concentration is above zero.
4.2.2
Negative QT assessment:
The following criterion will be used to evaluate whether the study was able to exclude a QT
effect of concern for the ‘QT-negative’ drug (levocetirizine):

The upper bound of the 2-sided 90% confidence interval of the predicted placebocorrected ∆QTcF at the observed peak plasma level of the higher dose of the negative
drug is below 10 ms.
1
Needleman K, Garnett C: Exposure-Response Modeling of QT Prolongation for Clinical Studies. Presentation to
the OQT on 2011-12-09
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7. 4.3 Criteria for model selection:
The absence of hysteresis will be checked graphically as detailed in the protocol synopsis. If the
maximum of ∆∆QTcF, obtained by subtracting the time matched mean ΔQTcF under placebo
from each individual ΔQTcF, is delayed compared to the peak plasma level of the drug by one
hour or more, a model with an additional effect compartment will be used to replace the linear
mixed effects model described above. The appropriateness of a linear model will be assured by
inspecting the goodness of fit, e.g. by looking at normal QQ-plots for the residuals. If there is an
indication that a linear model is inappropriate, the nonlinearity detected will be taken into account
by an appropriate transformation of the concentration values (e.g. log(conc/lloq)), or an
appropriate nonlinear model.
4.4 Secondary endpoints
Secondary endpoints include projected ∆QTcF based on exposure response modeling at the
expected Cmax of the low dose of each QT-positive drug and of the high dose of the QT-negative
drug (levocetirizine), the effect on the placebo-corrected, change-from-baseline QTc (∆∆QTcF)
by time point, effects on heart rate, PR and QRS intervals and categorical analysis of QTc
outliers. Descriptive statistical analysis will be used to determine the changes from baseline in the
QT, QTc, PR and QRS intervals and the heart rate at each post-dose time point.
4.5
Robustness analyses
The design of the study allows exploration of the power of ER analysis under variations of the
study design. In particular, robustness analyses using only Day 1 data and simulations of studies
with smaller sample sizes can be considered.
4.6 Justification of sample size
The incomplete block design will result on 9 subjects on each active treatment and 6 subjects on
placebo with the aim to obtain ECG and PK data for 6 marketed drugs from at least 6 subjects
and for placebo from 5 to 6 subjects. This sample size is in the same range as for one dose cohort
in a SAD or MAD study, in which often 8 subjects are allocated within each cohort to 6 on active
and 2 on placebo. It should be acknowledged that there is limited experience with respect to the
power of a study of this design. Model based simulations as well as simulations based on
subsampling from existing TQT studies however indicate that for moxifloxacin, a false negative
rate of about 10 % can be expected, while the power to detect a positive slope is well above 90%.
It is expected that with the addition of a higher dose on Day 2, the power of the study should
further increase (Table 2).
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8. Table 2: False negative rate and fraction of studies with significantly positive slope based on
subsampling of the moxifloxacin and placebo arms of 4 TQT studies as a function of sample
sizes.
Sample size Fraction of (false) negative studies Fraction of studies with significantly positive slope
Moxi/Plac
03/03
06/03
09/03
12/03
03/06
06/06
09/06
12/06
Min
7%
7%
9%
8%
7%
6%
8%
6%
Mean
11%
11%
13%
13%
11%
11%
12%
12%
Max
Min
17%
20%
23%
24%
17%
21%
20%
24%
Mean
74%
87%
92%
97%
80%
90%
97%
99%
Max
83%
93%
96%
99%
88%
96%
99%
99%
86%
98%
100%
100%
91%
99%
100%
100%
Based on parametric PK/PD simulations using the model described in Florian et al2 with
moxifloxacin at doses of 800 mg, 400 mg and 200 mg, inclusion of the 800 mg dose level
increased the precision of the slope estimate obtained from a linear mixed effect model of the
concentration and ΔQTc data (Table 3; the planned study corresponds to the 6/6/0/6 scenario).
Inclusion of the higher dose did not affect the point estimate of the slope: the median slope value
ranged from 5.41 to 5.82 ms per mg/L across all scenarios.
Table 3: Precision of slope estimate under various simulation designs
Number Subjects per
Moxifloxacin Dose Arm
False Negative Rate with
95% Binomial CI
Median and 90% CI of
Slope,
ms per mg/L
Median CI Width of
Slope,
ms per mg/L
0/24/0/24
3.5% (0.953, 6.05)
5.82 (3.75, 7.54)
3.10
0/12/0/12
4.5% (1.63, 7.37)
5.71 (3.06, 8.59)
4.43
0/6/0/6
7% (3.46, 10.5)
5.53 (1.91, 10.4)
6.28
0/6/6/6
7.5% (3.85, 11.2)
5.41 (1.87, 8.61)
5.98
5.44 (3.01, 7.91)
3.20
5.64 (3.01, 8.00)
3.13
800 mg/400 mg/200 mg/0 mg
6/6/0/6
6/0/6/6
10% (5.84, 14.2)
8% (4.24, 11.8)
Simulations based on 200 replicates of the PK/PD model.
2
Florian et al. Population Pharmacokinetic and Concentration–QTc Models for Moxifloxacin: Pooled Analysis of 20
Thorough QT Studies. J Clin Pharmacology 2011; 51: 1152-62.
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9. Reference List
1. Darpo B, Fossa AA, Couderc JP, Zhou M, Schreyer A, Ticktin M, Zapesochny A.
Improving the precision of QT measurements. Cardiol J 2011; 18: 401-10.
2. Darpo B, Garnett C. Early QT assessment - how can our confidence in the data be
improved? Br J Clin Pharmacol 2012; 76: 642-8.
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