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1. BACKGROUND
The IQ-CSRC planning group for the prospective study `Can Early QT assessment replace the
thorough QT (TQT) ...
2. IMPLICATIONS OF THE STUDY
If this study meets the criteria for positive QT assessment for the 5 ‘QT-positive’ drugs and...
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 extrac...
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...
increases in QTcF that
are 20 ms or greater.

AVELOX
(moxifloxacin)

NA

400 mg po*

800 mg IV

Cmax:  2.95 µg/mL

Mean Δ...
equivalent to those obtained from a model for the difference to time matched placebo, which,
however, can only be applied ...
4.3 Criteria for model selection:
The absence of hysteresis will be checked graphically as detailed in the protocol synops...
Table 2: False negative rate and fraction of studies with significantly positive slope based on
subsampling of the moxiflo...
Reference List

1. Darpo B, Fossa AA, Couderc JP, Zhou M, Schreyer A, Ticktin M, Zapesochny A.
Improving the precision of ...
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The IQ-CSRC prospective study-draft protocol

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The IQ-CSRC prospective study-draft protocol

  1. 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. 1
  2. 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 2
  3. 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. 3
  4. 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. 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 5
  6. 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 6
  7. 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). 7
  8. 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. 8
  9. 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. 9

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