QT analysis: A guide for statistical programmers Analysis- A Guide for... · QT correction One difficultly of QT interpretation is that the QT interval gets shorter as the heart rate

Prabhakar Munkampalli Statistical Analyst II Hyderabad, 7th September 2012

QT analysis: A guide for statistical programmers

Agenda

ECG

ICH E14

Thorough QT/QTc study

Role of Statistical Programmer

References

Disclaimer

3 | QT analysis: A guide for Statistical Programmers | Prabhakar M. | 7th Sep 2012 | CONSPIC: JAIPUR 2012 | Business Use Only

All opinions expressed in this presentation are the author’spersonal views, and do not reflect the views or opinions ofNovartis

ECG (Electrocardiogram)

A test that records the electrical activity of the heart. Used to test for irregularities in how the heart functions.

P WAVE: DEPOLARIZATION OF ATRIA

QRS: DEPLOLARIZATION OF VENTRICLES

T: REPOLARIZATION OF VENTRICLES


Torsades de pointes

An undesirable property of some drugs is their ability to delay cardiac repolarization, an effect that can be measured as prolongation of the QT interval on the surface electrocardiogram (ECG).

TdP can degenerate into ventricular fibrillation, leading to sudden death.

Most drugs that have caused TdP clearly increase both the absolute QT and the QTc (hereafter called QT/QTc).


ECG example


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Torsades de pointes

Torsades de pointes

Documented cases of TdP (fatal and non-fatal) associated with the use of a drug have resulted in the withdrawal from the market of several drugs and relegation of other drugs to second-line status.


QT correction

One difficultly of QT interpretation is that the QT interval gets shorter as the heart rate increases. [ QT α 1/ RR]

This problem can be solved by correcting the QT time for heart rate using two formulae.

Bazett correction : QTcB= QT / RR0.5

Fridericia’s correction: QTcF= QT / RR0.33

Other correction formulae


ICH E14

QT analysis is necessary......

Systemic bioavailability

Non antiarrhythmic drugs

Approved drugs with new dose or route that results in higher exposure (ie...Cmax or AUC)

New indication

Drugs with chemical or Pharmacological class with associated with QT effect or TdP


Thorough QT/QTc study

Not the first trial

Threshold level of regulatory concern, 5 ms evidenced by the 95% confidence interval around the mean effect of 10 ms

Carried out in healthy volunteers

Provides guidance for later trials


Role of Statistical/Clinical Programmer

Programmer

Review of protocol and RAP

Review of eCRF

Planning for analysis datset

Study design TLF

Cross over/ Parallel


Inclusion / Exclusion Criterion

Excluded Subjects/Patients with -

A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms)

A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

The use of concomitant medications that prolong the QT/QTc interval.


Study design of ‘Thorough QT/QTc’ study

Based on study objectives and PK/PD of compound.

Typically Randomized, controlled trial, appropriate blinding and concurrent placebo group.

Positive control group (pharmacological or non-pharmacological) to establish assay sensitivity. E.g. Moxifloxacin

Crossover: Small number of subjects as individual subject acts as a control. Simples heart rate correction.

Parallel : Drugs with long half lives, and when Multiple dose treatment groups to be compared.


Number and Timings of recordings

First in human study information like Cmax, Tmax should help to estimate peak concentration of relevant analyte and plan for timing of ECG collection.

Optimal timing to cover range of concentration for PK/PD analysis.

Number and timings of ECG recordings depends on patient population , endpoint , statistical model, sample size, and cost effectiveness.

Even though, peak serum concentration does not always correspond to the peak effect on QT/QTc interval, care should be taken to perform ECG recordings at time points around the Cmax.


Examples of Tables, Listings and Figures




Table 4 Newly occurring ECG Qualitative abnormalityAbnormality Type Finding Treat. A Treat. B Treat. C

N=xxx N=xxx N=xxxTotal n % Total n % Total n %

Any new ECG abnormality xx xx xx.x xx xx xx.x xx xx xx.x

Rhythm xx xx xx.x xx xx xx.x xx xx xx.xAtrial flutter xx xx xx.x xx xx xx.x xx xx xx.xAtrial fibrillation xx xx xx.x xx xx xx.x xx xx xx.xJunctional Rhythm xx xx xx.x xx xx xx.x xx xx xx.x…

Morphology xx xx xx.x xx xx xx.x xx xx xx.xRAA xx xx xx.x xx xx xx.x xx xx xx.xLAA xx xx xx.x xx xx xx.x xx xx xx.x…



Data collection : CRF page


Variables

Quantitative variables Qualitative variablesVentricular rate Evaluation typePR interval rhythmQRS duration arrhythmiaQT interval Fridericia ConductionQT interval Bazett morphologyQT interval uncorrected MIRR interval st

t wavesu wavesECG interpretation


Checks related to source data(1) Source data: quantitative and qualitative variables in same database ?

2 possibilities in the data transfer:

Quantitative variables in one dataset + Qualitative variables in one dataset 2 datasets

OR

Quantitative variables + Qualitative variables in one dataset 1 dataset

E.g. 1 Source ECG dataset

Variable: ECG identification can be used to identify the duplicates in the dataset.

Suggestion:

Create 2 different analysis datasets to avoid duplication of information.23 | QT analysis: A guide for Statistical Programmers | Prabhakar M. | 7th Sep 2012 | CONSPIC: JAIPUR 2012 | Business Use Only

Checks related to source data (2) Source data quantitative variables: Multiple / Single measurement(s)

6 lead pre-dose measurements

3 lead post-dose measurements at 1.5, 3, 6 hours

Average of these measurements

collapsed into 1 record eachOR

• Get a confirmation on the type of transfer from ECG providers

• If there are more number records of time-points than expected how to handle ?


Checks related to source data(3) Source data: identification of scheduled and unscheduled visits

Very important to have correct time point variable to be used later in the analysis.


How to report the data, some pointers: (1) Analysis dataset structure:


How to report the data, some pointers: (2) Various abnormality flags

ECG parameter Abnormality flagging1 QT increase of > 30 msec from baseline2 QT increase of > 60 msec from baseline3 QT new > 450 msec and pre-dose value <= 450 msec4 QT new > 480 msec and pre-dose value <= 480 msec5 QT new > 500 msec and pre-dose value <= 500 msec6 PR < 200 msec Normal ranges7 PR increase > 25% to a value > 2008 QRS < 110 msec Normal ranges9 QRS increase > 25% to a value > 110

10 HR 50 - 100 bpm Normal ranges11 RR 600 - 1200 bpm Normal ranges12 RR + HR RR increase > 25% to HR < 5013 RR + HR RR decrease > 25% to HR > 100


Single(Multiple) vs. Replicate ECGs

Depends on Objectives and end points.

If primary objective is to estimate QTc response profile then single ECGs distributed over time is preferable.

If primary objective is to estimate change in QTc at a specific point in time, replicate ECGs should reduce variability.

For QT/QTc analysis , collection of multiple baseline helps to verify diurnal pattern and the QT to heart relationship for each subject in each period an provide more baseline data for individual correction.


Choice of baseline

Time-matched (complete Day -1 profile)

Account for diurnal variation in QTc

May be necessary for parallel group design

Single predose time point (average of triplicates)

May be sufficient for crossover since time-matched comparison with placebo is within a subject


Analysis of QT/QTc Interval Data

• Both central tendency (e.g., means, medians) and categorical analyses. Provide relevant information on clinical risk assessment.

• In clinical trials, a prolongation of QTc > 500 ms during therapy has been a threshold of particular concern.

• Multiple analyses using different limits are a reasonable approach to this uncertainty, including:

• Absolute QTc interval prolongation: • QTc interval > 450 • QTc interval > 480 • QTc interval > 500

• Change from baseline in QTc interval:

• QTc interval increases from baseline > 30 • QTc interval increases from baseline > 60


Interpretation of “Thorough QT/QTc Study”

The results of the ‘thorough QT/QTc study’ will influence the amount of information collected in later stages of development:

A negative ‘thorough QT/QTc study’: Collection of on therapy ECG

A positive ‘thorough QT/QTc study’: Expanded ECG safety evaluation.

A negative ‘thorough QT/QTc study’ but non clinical data is strongly positive: Expanded ECG safety evaluation


References

• http://www.hrsonline.org/patientinfo/heartrhythmdisorders/idisorders/

• http://www.fda.gov/RegulatoryInformation/Guidances/ucm129335.htm

• http://www.diahome.org/Tools/Content.aspx?type=eopdf&file=%2Fproductfiles%2F8357%2Fdiaj_11191.pdf

• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823351/pdf/bph0159-0049.pdf

• http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R1_step4.pdf

• http://en.ecgpedia.org/wiki/Conduction

• http://ecg.utah.edu/lesson/2

• http://atforum.com/SiteRoot/pages/current_pastissues/2007winter.html

• http://jcp.sagepub.com/content/49/12/1436.full.pdf+html


http://www.hrsonline.org/patientinfo/heartrhythmdisorders/idisorders/

http://www.fda.gov/RegulatoryInformation/Guidances/ucm129335.htm

http://www.diahome.org/Tools/Content.aspx?type=eopdf&file=%2Fproductfiles%2F8357%2Fdiaj_11191.pdf

http://www.diahome.org/Tools/Content.aspx?type=eopdf&file=%2Fproductfiles%2F8357%2Fdiaj_11191.pdf

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823351/pdf/bph0159-0049.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R1_step4.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R1_step4.pdf

http://en.ecgpedia.org/wiki/Conduction

http://ecg.utah.edu/lesson/2

http://atforum.com/SiteRoot/pages/current_pastissues/2007winter.html

http://jcp.sagepub.com/content/49/12/1436.full.pdf+html

THANK YOU

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QT analysis: A guide for statistical programmers Analysis- A Guide for... · QT correction One difficultly of QT interpretation is that the QT interval gets shorter as the heart rate