A NOVEL STUDY DESIGN FOR PARALLEL GROUP THOROUGH QT STUDIES: THE NESTED CROSS-OVER FOR POSITIVE CONTROL

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Authors: Boaz Mendzelevski, MD Dennis O Chanter, DPhil, CStat

BioClinica Inc., United Kingdom Statisfaction, United Kingdom

INTRODUCTION:

Drugs interacting with the hERG potassium channel are associated with a prolongation of the QT interval, which can lead to life-threatening arrhythmias and death1. ICH-E142, a global regulatory guidance, requires that almost all new drugs undergo a Thorough QT (TQT) study to assess their cardiac safety, or pro-arrhythmia risk, as a condition for regulatory approval and market access.

STATISTICAL METHODS (IP):

Primary Pharmacodynamic endpoints
QTcSS = QT/RR, Where is the median value of the regression coefcient from individual subject regressions of log (QT) on log (RR) using drug-free data only Analysis of covariance (ANCOVA) was performed on the time-matched change from baseline in QTcSS, separately at each time-point (mean of triplicate ECGs) Treatment and gender as categorical variables Time-matched baseline QTcSS as a linear covariate Absence of effects of IP on cardiac repolarization (i.e. non-inferiority vs. placebo) was concluded if the upper limit of the 95% one-sided CI for the difference from placebo, for all time-points, was below the NI margin of 10 ms. The QTcSS time-matched change from baseline

RESULTS SUMMARY:
Both the IP therapeutic and supratherapeutic doses were associated with a small, but statistically signicant, increase in HR, of no clinical relevance. Time-matched QTcSS change from baseline and placebo was below the non-inferiority margin of the 95% Upper CI 10 ms at all time-points, for both therapeutic and supra-therapeutic doses. Assay sensitivity was demonstrated by moxioxacin baseline- and placebo-adjusted QTcSS mean effect and lower 95% CI limit being above the 5 ms regulatory threshold at all time-points, except at 1 h post-dose for the lower 95% CI.

BACKGROUND:

Although cross-over design is most efcient for TQT studies, drugs with long half-life, potential carry-over effects, or those necessitating a slow up-titration, may require a parallel group (PG) study design. To be sufciently powered3, PG TQT studies, typically conducted in healthy volunteers (HV), may require between 200 to 300 subjects. We report herein a successful application of an innovative TQT study design, involving a cross-over design for positive control nested within one arm of a parallel group study, that leads to higher efciency and lower sample size for parallel group TQT studies.

RESULTS:

Heart Rate Changes

ddQTcSS

TQT STUDY OBJECTIVES:

Primary Objectives
To demonstrate that treatment with a therapeutic and supratherapeutic doses of an investigational product (IP) in healthy male and female volunteers does not increase the QTc interval by more than 10 ms compared to placebo at any time point.

STATISTICAL METHODS (MOXI):

QTcSS endpoint same as above Analysis uses data from only the two placebo/moxi arms [M:P and P:M] Various ANCOVA models are available. Whilst not the most efcient, following denition of the main effect meets FDA requirement concerning time between baseline and response being similar to that for IP Main effect of moxi is average of estimates from the two arms: M:P arm; [QTcMoxi(D1) - QTcPlac(D15)] [QTcPlac(D13) - QTcPlac(D0)] P:M arm; [QTcMoxi(D15) - QTcPlac(D1)] [QTcPlac(D0) - QTcPlac(D13)]
HR difference in time-matched change from baseline between a) IP 2 mg and placebo, and b) IP 10 mg and placebo, by time-point. Error bars indicate 90% CIs Mean QTcSS differences (ms) in time-matched change from baseline between a) IP 2 mg dose and placebo, and b) IP 10 mg dose and placebo, by time-point. Error bars represent 90% CIs. The solid line indicates the 10 ms regulatory threshold

C:E Analysis

Assay Sensitivity

Secondary Objectives

To demonstrate assay sensitivity by showing that the positive control (moxioxacin 400 mg) treatment, produces a QTc change > 5 ms at at least one time point. Further secondary objectives were: to assess PK parameters of IP to perform a PK/PD assessment of IP to assess safety and tolerability of IP

ECG SAMPLING PLAN:

Day Day Day Day Day

TQT STUDY RESULTS: DEMOGRAPHICS

Number of subjects, n Sex: M, n (%) F, (%) Race: Caucasian, n (%) Asian, n (%) African/Black, n (%) Oriental/Mixed, n (%) Age, meanSD Height, meanSD Weight, meanSD BMI, meanSD Inv. Product (Group 1) 60 34 (56.7%) 26 (43.3%) 46 (76.7%) 5 (8.3%) 5 (8.3%) 4 (6.7%) 29.98.0 172.89.0 70.510.9 23.62.6 Moxi/Placebo (Group 2a) 30 17 (56.7%) 13 (43.3%) 20 (66.7%) 3 (10%) 3 (10%) 4 (6.7%) 28.45.4 171.89.9 73.012.7 24.63.0 Placebo/Moxi (Group 2b) 30 17 (56.7%) 13 (43.3%) 21 (70%) 3 (10%) 1 (3.3%) 5 (16.7%) 27.75.9 174.49.5 72.911.5 23.92.4

12-lead ECGs were recorded continuously using a 12-Lead Holter recorder (H12+, Mortara Instruments) ECGs were extracted in triplicates on the following time-points: 1 (baseline): 0, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12 & 23.5 hours 1: 0, 1, 2, 3, 4, 5 and 6 hours post-dose 5: 0, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12 and 23.5 h post-dose 13: 0, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 23.5, 36, 48 h post-dose 15: 0, 1, 2, 3, 4, 5 and 6 hours post-dose.

Change in QTcSS (ms) vs. plasma concentration (ng ml), for the IP 2 mg (black) and 10 mg (red) doses. Data represent the time-matched change from baseline in QTcSS with the mean placebo effect subtracted. The dotted line indicates the tted mixed-effects linear regression analysis (predicted QTc prolongation) for each dose

Mean QTcSS difference (ms) in time-matched change from baseline between moxioxacin (400 mg) and placebo, and placebo by time-point. Error bars represent 90% CIs. The solid line indicates the 5 ms regulatory threshold

SUMMARY AND CONCLUSIONS:

We hereby present a novel design for Parallel Group (PG) Thorough QT (TQT) studies. By combining the 2 investigational product dose groups (therapeutic and supratherapeutic) and, separately, the 2 control groups (placebo and positive control) and by nesting the positive control treatment within the placebo arm of the study, we have successfully reduced the number of subjects required to meet the primary endpoint in a PG TQT study by half. Likewise, this new design offered an overall cost saving of 40% compared with a corresponding conventional design. Furthermore, the logistics of running a large PG TQT study were largely reduced, allowing smaller CPUs to participate in PG TQT studies. The parallel group with nested cross-over for positive control TQT study design has been validated, published4 and accepted by both the EU (EMA) and US (FDA) regulators. To date, we have completed 4 PG TQT studies with this design.

Note: Baseline ECG assessments were time-matched to Day 5 (therapeutic steady-state, or placebo) and Day 13 (supra-therapeutic steady-state, or placebo).

NESTED CROSS-OVER PARALLEL-GROUP TQT DESIGN*:

N = 120 Subjects IP N=60 IP dose titration Baseline Day Moxi 2 mg 10 mg No Treatment

TQT STUDY RESULTS: SUBJECT DISPOSITION

SaS: safety analysis set EaS: electrocardiogram analysis set PKaS: pharmacokinetic analysis set Subjects Screened = 352 Subjects Enrolled = 120 Group 2a Moxioxacin/Placebo Randomized = 30 Completed n = 27 Sas = 30 EaS = 30 PKaS = 0 Withdrawn n=3 Group 2b Placebo/Moxioxacin Randomized = 30 Completed n = 30 Sas = 30 EaS = 30 PKaS = 0 Withdrawn n=0

PLA N=30

PLA

PLA

Group I Inv. Product Randomized = 60 Completed n = 59 Sas = 60 EaS = 60 PKaS = 60 Withdrawn n=1

REFERENCES:
[1] Roden DM. Drug-Induced Prolongation of the QT Interval. N Engl J Med 2004;350:1013-22. [2] Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. October 2005. ICH. http://www.fda.gov/downloads/ RegulatoryInformation/Guidances/ucm129357.pdf [3] Zhang J, Machado SG. Statistical issues including design and sample size calculation in thorough QT/QTc studies. J Biopharm Stat. 2008;18(3):451-67. [4] Mendzelevski B, Ausma J, Chanter DO, Robinson P, Kerstens R, Vandeplassche L, Camm J. Assessment of the cardiac safety of prucalopride in healthy volunteers: a randomized, double-blind, placebo- and positive-controlled thorough QT study. Br J Clin Pharmacol. 2012;73(2):203-9.

PLA N=30 ECG Day 0

PLA ECG Day 1 ECG Day 5

PLA ECG Day 13

Moxi ECG Day 15

ECG = Electrocardiogram; IP = Investigation Product; PLA = Placebo; Moxi = Moxioxacin

*Originally proposed by Dr Joanne Zhang, FDA, at the 2009 DIA USA Cardiac Safety Conference

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ACCP 2013 Annual Meeting Clinical Pharmacology in Optimizing Drug Development and Therapeutics Bethesda, MD, USA