Common Protocol Template Thorough QT/Qtc (TQT) Library V001

Common Protocol Template Thorough QT/QTc (TQT) Library v001

Common Protocol Template Thorough QT/QTc (TQT) Library v001

Section in Common Protocol Template (CPT) / Library Content
1.1.Synopsis / Instructional text to be consistent in meaning with the corresponding text in the main body
2.1. Study Rationale / Description of the purpose of the thorough QT/QTc (TQT) study and the TQT prolongation threshold of regulatory concern
3. Objectives and Endpoints (Main Body) / Objectives and corresponding endpoints for the TQT study
4.1. Overall Design / Instructional text regarding positive control
Text for including the positive control in the protocol
5.2. Exclusion Criteria / Exclusion criteria related to baseline QT/QTc prolongation, additional risk factors, and use of concomitant medications that prolong QT/QTc interval
5.3.1. Meals and Dietary Restrictions / Restrictions relevant for TQT studies
5.3.2. Caffeine, Alcohol, and Tobacco / Restrictions relevant for TQT studies
6.5. Concomitant Therapy / Prohibited use of medications that prolong QT/QTc interval
8. Study Assessments and Procedures / Instructional text specifying things for the study team to consider and things to specify in writing for the investigational unit
9.4. Statistical Analysis / Instructional text referring the protocol author to publications that may guide this section
11. References / References relevant for TQT studies

2. Introduction

2.1. Study Rationale

The objective of the thorough QT/QTc (TQT) study is to determine whether a drug has a threshold effect on cardiac repolarization as detected by QT/QTc prolongation. According to the International Council on Harmonisation (ICH) guideline, the threshold of regulatory concern in a TQT study is a mean increase in the QTc interval of approximately 5 ms as evidenced by an upper limit of the 95% one-sided confidence interval (CI) around the mean effect on QTc of 10 ms (ICH E14 guidance1).

3. Objectives and Endpoints (main body)

Primary Objectives and Endpoints:

The QT interval length (ms) and the RR length (ms), measured on the electrocardiogram (ECG), contribute to the computation of the primary endpoint variable (see the Therapeutic Area User Guide [TAUG] for details of QTc computation). Most commonly, QT measures are corrected for heart rate using Fridericia’s (QTcF) formula. All interventiontimepoints should be indicated.

Primary Objective / Primary Endpoints
To demonstrate that a supratherapeutic dose of [Study Intervention] administered to healthy volunteers does not result in a clinically significant increase in the maximal mean heart rate corrected QT (QTc) interval relative to change observed with [Placebo] / The change from baseline in QTcF[using Fridericia’s formula (]QTcF)]at all timepoints[list timepoints]at all time pointsafter administration of [Study Intervention]

Time-matched change from baseline (QTcF) at all timepoints[list timepoints] after administration of [placebo]

Secondary Objectives and Endpoints:

Consider ECG Quantitative EndpoinThe PR and QRS interval lengths (in ms) and heart rate (HR) are secondary quantitative endpoint variables measured on the ECG. Multiple alternative definitions of baseline might be used (refer to the TAUG).

Secondary Objectives / Secondary Endpoints
To demonstrate that the study has sufficient assay sensitivity to detect a 5 ms increase in QTc with a positive control intervention, relative to [Placebo] / The change from baseline in QTcF[using Fridericia’s formula (]QTcF)]at all timepoints[list timepoints]after administration of [positive control]
Time-matched change from baseline (QTcF) at all timepoints[list timepoints] after administration of [placebo]
To demonstrate a lack of effect on the proportions of participants with QTc changes from baseline greater than pre-specified limits ( 30 ms and 60 ms) compared to[Placebo] / The proportion ofparticipants with absolute change in [QTcF(30 and / or 60 ms)] (from among values obtained at several time points following last treatment administration ([Study Treatment or placebo]) prior to data collection at Weeks [number and number]
To demonstrate the lack of effect of a supratherapeutic dose of [Study Intervention]on the proportions of participants with absolute QTc values of 450, 480, and 500 msec compared to [Placebo] / The proportion of participants with QTcF(from > 450, 480 and 500 ms following last administration [Study Intervention or placebo]
To demonstrate that a supratherapeutic dose of [Study Intervention], administered to participants does not result in clinically relevantchanges in the heart rate (HR), PR and QRS interval, compared to the changes observed with [Placebo] / The proportion of participants with clinically relevant percent changein [HR (beats/min) orPR interval (ms)or QRS interval (ms)] (from among values obtained at several time points following last intervention administration ([Study Interventionor placebo]) prior to data collection at Weeks [number and number]
To describe the proportions of participants with treatment emergent electrocardiogram (ECG) abnormalities (qualitative and/or morphological) in the [Study Intervention] to [Placebo]groups / The proportion of study participants withtreatment emergent ECG abnormalities (qualitative and/or morphological) in each intervention group

Exploratory Objectives and Endpoints:

Basal / resting (sitting) heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) can be collected following each ECG replicate set collection. The participant should stand up for collection of HR, SBP, and DBP at appropriate time points in the 0 to 3minute interval after collection of the resting vital signs to evaluate orthostatic changes in these parameters.

To compare the ratesof treatment emergent adverse events that would reflect a serious arrhythmia or suggest the potential for such an arrhythmia between [Study Intervention]and [Placebo] groups / Therates of the following events for each intervention group:

Torsade de pointes (TdP)
Sudden death
Ventricular tachycardia
Ventricular fibrillation and flutter
Syncope

Exploratory Objectives (Optional) / Exploratory Endpoints
To evaluate the pharmacokinetic / pharmacodynamic (PK/PD) relationships between the plasma concentration of [Study Intervention, specific metabolites (list the relevant molecules)] achieved after a supratherapeutic dose of [Study Intervention] administered to healthy volunteers and the QTc change from baseline / For cross-over design studies:
The placebo-adjusted QTcF change from baseline versus plasma concentration of [Study Interventionand relevant metabolites]
For parallel design studies:
The QTcF change from baseline versus plasma concentration of [Study Intervention and relevant metabolites]
To evaluate the effect of [Study Intervention, specific metabolites (list the relevant molecules)]on hemodynamic parameters compared with placebo when administered to healthy volunteers / Changefrom baseline in basal (resting) and orthostatic hemodynamic parameters (heart rate [HR], systolic blood pressure [SBP], diastolic blood pressure [DBP])

4.Study Design

4.1.Overall Design

A positive control should be included to establish assay sensitivity. The comparator chosen should be well-characterized and consistently produce a QTc effect that is around the threshold of regulatory concern (ICH E14 Q&A). The effect of the fluoroquinolone antibiotic moxifloxacin on QT intervals in humans, together with its low pharmacokinetic (PK) variability, has resulted in it being commonly used as a positive control for TQT studies. However, moxifloxacin is not the only option for a positive control. The requisite characteristics of a positive control, as defined in ICH E14,is that it produces a mean QT prolongation effect of 5msec. The study team needs to consider the positive control that is most appropriate.

This study will use [name of positive control] as the positive control for QTc effect and assay sensitivity.

5. Study Population

5.2.Exclusion Criteria

Medical Conditions

1)A marked baseline prolongation of QTinterval (>450 milliseconds [ms])using Fridericia’s formula (QTcF) at screening or prior to study intervention administration

2)A history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome, history of attack of unconsciousness possibly associated with TdP)

Prior/Concomitant Therapy

3)The use of concomitant medications that prolong QT/QTc interval

5.3.Lifestyle Considerations

5.3.1.Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) for a period of 4 hours prior to any safety laboratory evaluations and 8 hours prior to the collection of the pre-dose pharmacokinetic (PK) sample. Ambient temperature water is permitted until 1.5 hours prior to study intervention administration.

Ambient temperature water may be consumed beginning 2 hours after dosing; participants must abstain from drinking for 0.5 hours prior to an ECG measurement. Participants must be restricted to consuming ambient temperature drinks during each study period until the 24-hour ECG has been collected on Day 2. Non-caffeinated drinks (except grapefruit or grapefruit-related citrus fruit juices – see below) may be consumed with meals and the evening snack.

Subjects must abstain from food for 1.5 hours prior to an ECG measurement.

Subjects must abstain from drinking for 0.5 hours prior to an ECG measurement.

Lunch should be provided approximately 4 hours post-dose immediately after completion of the 4hour ECG and PK blood sampling. Meals should be completed 1.5 hours before the 6hour ECG measurement.

Dinner should be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.

Participantsare not allowed to eat or drink grapefruit or grapefruit-related citrus fruits (e.g., Seville oranges, pomelos) from 7 days prior to the first dose of study intervention through collection of the final PK blood sample.

While confined, the total daily nutritional composition should be approximately 50% carbohydrate, 35% fat, and 15% protein. The daily caloric intake per subject should not exceed approximately 3200 kcal.

5.3.2. Caffeine, Alcohol, and Tobacco

Participants must abstain from alcohol for 24 hours prior to admission to the clinical research unit (CRU) and continue abstaining from alcohol through collection of the final PK sample of each study period. Participants may undergo an alcohol breath test at the discretion of the investigator.

Participants must abstain from caffeine-containing products for 24 hours prior to the start of dosing through collection of the final PK sample of each study period.

Participants must abstain from the use of tobacco or nicotine-containing products within 3months of Screening and through the final PK sample collection for the study.

6.5. Concomitant Therapy

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

8. Study Assessments and Procedures

The study team should specify, in writing, the detailed methods of obtaining either conventional 10-sec ECGs or continuous ECG recordings by the investigative unit. The study team should consider whether a central ECG analysis facility and methodology should be employed.

The study team should also specify, in writing, the detailed methods for measuring all ECG intervals of interest, measuring RR intervals, and identifying qualitative ECG findings (“diagnostic” criteria for ECG findings).

Serial triplicate ECGs are recommended.

9.4.Statistical Analyses

See both the TAUG and the PhUSE Analysis White Paper for guidance on writing this section.

11. References

1. International Councilon Harmonisation (ICH). Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic drugs. October2005. Accessed August 5, 2016.

2. CFAST QT Studies Team. Therapeutic Area Data Standards User Guide for QT Studies, Version 1.0 (provisional). December 8, 2014.

3. International Councilon Harmonisation (ICH). Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs Questions and Answers. November 2008. Accessed August 5, 2016.

4. PhUSE Analysis and Display White Papers Project Team. PhUSE Computational Science Development of Standard Scripts for Analysis and Programming Working Group: Analyses and Displays Associated with Thorough QT/QTc Studies. March 2016.

5. Malik M, Johannesen L, Hnatkova K, Stockbridge N. Universal correction for QT/RR hysteresis. Drug Saf. 2016;39:577-88.

6. Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs Questions and Answers (R1). October 2012.

7. International Council on Harmonisation (ICH). ICH E14 Guideline: The Clinical Evaluation of QUARTQTc Interval Prolongation and Proarrhythmic Potential for Nonantiarrhythmic Drugs Question & Answers (R2). March 2014.

8. International Council on Harmonisation (ICH). ICH E14 Guideline: The Clinical Evaluation of QUARTQTc Interval Prolongation and Proarrhythmic Potential for NonAntiarrhythmic Drugs Question & Answers (R3). December 2015.