Heart and Blood Diseases

Diseases and Abnormalities at or Before Birth

Symptoms and General Pathology

All Conditions

Long QT Syndrome

Anti-Infective Agents

All Drugs and Chemicals

Antineoplastic Agents

Reproductive Control Agents

Anti-Bacterial Agents

Moxifloxacin

Antibiotics, Antitubercular

Fluoroquinolones

Norgestimate, ethinyl estradiol drug combination

Enzyme Inhibitors

Participants will receive orally single dose of study drugs in the sequence of ABC.

A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Participants will receive orally single dose of study drugs in the sequence of ACB.

A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Participants will receive orally single dose of study drugs in the sequence of BAC.

A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Participants will receive orally single dose of study drugs in the sequence of BCA.

A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Participants will receive orally single dose of study drugs in the sequence of CAB.

A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

Participants will receive orally single dose of study drugs in the sequence of CBA.

A - AZD6094 600 mg (3X 200 mg tablet) B - Placebo C - Moxifloxacin 400 mg

A potent and selective small molecule mesenchymal epithelial transition (MET) kinase inhibitor with significant antitumor activity.

AZD6094 200 mg

AZD6094 matching placebo without any pharmacological activity.

Placebo

A fluoroquinolone broad-spectrum antibiotic, produces a mild, but reproducible increase in QT interval corrected (QTc) in healthy normal participants at time to reach maximum concentration (tmax - approximately 2 hours (0.5 to 4 hours)). This effect is close to the ECG interval measured from the onset of the QRS complex (onset of the QRS complex to the J point) to the offset of the T wave (QT)/QTc effect that represents the threshold of regulatory concern, around 5 ms mean QTc interval prolongation.

Ronald Goldwater, MD

This is a randomized, placebo-controlled, double-blind, 3-way crossover phase I study being conducted on healthy volunteers to investigate the effect of single dose of AZD6094 (600 mg) on cardiac repolarization under well-controlled conditions in accordance with the International Council for Harmonization (ICH) E14 guidelines. An open-label Moxifloxacin (400 mg), a fluoroquinolone broad spectrum antibiotic will be used as a appositive control for the time between the start of the Q wave and the end of the T wave (QT) prolongation in accordance with ICH E14 guidelines, to establish assay sensitivity. The core study consists of screening period, 3 treatment period (AZD6094, placebo and moxifloxacin; with a minimum washout period of 14 days between each treatment period) and follow-up. The study drugs will be administered orally. The study is planned to determine effect of AZD6094 at therapeutic dose, safety and tolerability. This study provides adequate and well-controlled mechanisms to deal with potential bias, facilitate identification of effects related to investigational product (IMP) administration and tolerability issues.

The study is planned to include approximately 45 healthy non-Japanese vasectomized male participants aged 18 to 55 years (inclusive) or male participants over 40 (and up to 55) years old not intending to father children will be enrolled. The study consists of 5 visits comprised of 3 treatment periods with 6 treatment sequences and will have a minimum washout period of 14 days between each treatment period.

Visit 1: Screening period (28 days) - Assessments done on Day -1 of treatment period 1.

Visits 2 to 4: 3 Treatment periods - Participants will be resident form day before IMP (single oral dose of AZD6094 (600 mg) tablet/AZD6094 matching placebo/moxifloxacin (400 mg) capsule) dosing (Day -1) until at least 48 hours post-dose and will be discharged on Day 3.

Visit 5: Follow-up - Participants will have clinical visit 14 days after discharge from the treatment period 3.

Participants will be randomized to 6 treatment sequences (ABC, ACB, BAC, BCA, CAB and CBA). In each sequence, participants will receive single oral dose of all 3 treatments (A - AZD6094 600 mg (3X 200 mg tablet), B - Placebo tablet, C - Moxifloxacin 400 mg capsule) with a washout period (14 days) between each treatment period.

The study duration will be approximately 84 days.

A Study to Investigate the Effect of Single Dose of AZD6094 (600 mg) on Cardiac Repolarization in Healthy Volunteers

A Single-center, Randomized, Double-blind, Placebo-controlled, Three-way Crossover Phase I Study to Investigate the Effect on the QTc Interval of a Single Dose of AZD6094 (600 mg) Compared With Placebo, Using Open-label Moxifloxacin (Avelox®) as a Positive Control, in Healthy Volunteers

To assess the effect of AZD6094 at single therapeutic dose (600mg) on ventricular repolarization by assessing the time matched baseline-adjusted, placebo subtracted QTc interval corrected for RR (R waves on electrocardiogram \[ECG\]) by the Fridericia formula (QTcF). The ECGs -digital (dECG) and page (pECG) would be recorded during the study for the assessment of safety. Paper ECG for safety review will be performed following the dECG recordings and at additional intervals if required.

To assess the effect of AZD6094 at therapeutic dose (600 mg) on additional time matched ECG variables using the dECG and pECG records. The ECG variables includes Bazett corrected QT interval \[QTcB\], onset of the P wave to the onset of the QRS complex (PR), onset of the QRS complex to the J point (QRS), QT and time interval between corresponding points on 2 consecutive R waves on ECG (RR). Paper ECG for safety review will be performed following the dECG recordings and at additional intervals if required.

To assess the effect of moxifloxacin 400 mg on the QTcF interval compared to placebo. Paper ECG for safety review will be performed following the dECG recordings and at additional intervals if required.

To assess AUC(0-∞) after administration of single oral dose of AZD6094, placebo and moxifloxacin. The pharmacokinetic (PK) sampling done post dose must precede with 10 minutes of rest followed by 5 minutes dECG.

To assess AUC(0-t) after administration of single oral dose of AZD6094, placebo and moxifloxacin. The PK sampling done post dose must precede with 10 minutes of rest followed by 5 minutes dECG.

To assess Cmax after administration of single oral dose of AZD6094, placebo and moxifloxacin; Cmax will be taken directly from the individual concentration-time curve. The PK sampling done post-dose must precede with 10 minutes of rest followed by 5 minutes dECG.

To assess tmax after administration of single oral dose of AZD6094, placebo and moxifloxacin; tmax will be taken directly from the individual concentration-time curve. The PK sampling done post-dose must precede with 10 minutes of rest followed by 5 minutes dECG.

To assess lag-time (tlag) after administration of single oral dose of AZD6094, placebo and moxifloxacin; tlag will be taken directly from the individual concentration-time curve. The PK sampling done post-dose must precede with 10 minutes of rest followed by 5 minutes dECG.

To assess λz after administration of single oral dose of AZD6094, placebo and moxifloxacin; λz will be estimated by log-linear least squares regression of the terminal part of the concentration-time curve. The PK sampling done post-dose must precede with 10 minutes of rest followed by 5 minutes dECG.

To assess t½ after administration of single oral dose of AZD6094, placebo and moxifloxacin. The PK sampling done post-dose must precede with 10 minutes of rest followed by 5 minutes dECG.

To assess CL/F after administration of single oral dose of AZD6094, placebo and moxifloxacin. The PK sampling done post-dose must precede with 10 minutes of rest followed by 5 minutes dECG.

To assess apparent volume of distribution for parent drug at terminal phase (Vz/F, extravascular administration) after administration of single oral dose of AZD6094, placebo and moxifloxacin; Vz/F will be estimated by dividing the apparent clearance (CL/F) by λz. 10 min rest + 5 min dECG will always precede the PK sampling when coinciding post-dose.

To assess the effect of AZD6094 and moxifloxacin on ventricular repolarization by assessing the plasma concentration and ECG variables including baseline-adjusted and placebo subtracted QTc interval

To assess AEs as a criteria of safety and tolerability. AEs will be collected from the start of Screening throughout the treatment period up to and including the Follow-up Visit (Visit 5). Serious AEs will be recorded from the time of informed consent.

To assess SBP as criteria of safety and tolerability variables. Blood pressure will be taken after the ECG.

To assess DBP as criteria of safety and tolerability variables. Blood pressure will be taken after the ECG.

To assess pulse rate as criteria of safety and tolerability variables.

To assess the cardiovascular system functioning using 12-Lead dECG and pECG as a criteria of safety and tolerability variables.

To assess the physical examination as a criteria of safety and tolerability variables. Brief physical examination will be performed at pre-dose on Day -1 at each treatment period; includes assessment of general appearance, skin, cardiovascular system, respiratory and abdomen. Full physical examination includes assessment of the general appearance, skin, cardiovascular, respiratory, abdomen, head, and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems.

To assess the hematology (blood cells count, differential count and hemoglobin count) as a criteria of safety and tolerability variables. A reduced safety laboratory screen will be done at Day -1 or pre-dose at Day 1 and at 48 hours post-dose for all treatment periods.

To assess the clinical chemistry (electrolytes, glucose (fasting), C-reactive protein (CRP), liver enzymes, total and unconjugated bilirubin; at screening alone - free thyroxine and thyroid-stimulating hormone) as a criteria of safety and tolerability variables. A reduced safety laboratory screen will be done at Day -1 or pre-dose at Day 1 and at 48 hours post-dose for all treatment periods.

To assess the urinalysis (glucose, protein and blood) as a criteria of safety and tolerability variables. If urinalysis is positive for protein or blood, a microscopy test will be performed to assess red blood cells (RBC), white blood cells (WBC), casts (cellular, granular, hyaline)). A reduced safety laboratory screen will be done at Day -1 or pre-dose at Day 1 and at 48 hours post-dose for all treatment periods.

To assess the effect of AZD6094 at therapeutic dose (600 mg) on additional time matched ECG variable - HR using the dECG and pECG records. Paper ECG for safety review will be performed following the dECG recordings and at additional intervals if required.

Parexel

AstraZeneca

Arrhythmias, Cardiac

Heart Diseases

Participants will be provided with a wearable device on Day 1 and Day 4 whilst admitted in hospital.

The app together with the wearable device will record a V1 (Left wrist) or V2 (left ankle) ECG reading. These measurements will be conducted on Day 1 and Day 4.

ECG application

The 12 lead ECG will measure corrected QT interval by recording RR and QT intervals on Day 1 and Day 4. This will be performed within the same episode of care as the wearable device ECG recording. There is no need to perform both at exactly the same time point, but within a 15 minute window.

12 lead ECG

Lane Collier

A/Prof Rachel Conyers

Dr Claudia Toro

A prospective study in paediatric, adolescent and young adult patients aged 7 to 18 years to evaluate the agreement between QTc measured using 12 lead electrocardiogram (ECG) and the wearable device ECG.

Rationale: Leveraging existing wearable technology has the ability to scale routine screening strategies across large populations and can facilitate ambulatory care. In recent years, wearable technology has rapidly diffused into consumer markets and provides unique opportunities to engage individuals on health issues of personal interest, and to collect personal health data. One example of such technology is the ability to perform electrocardiogram (ECG) type traces on wearable devices. However, utilization of this data source to improve patient outcomes has not been fully realized in the health care field. An app-based heart ECG algorithm that can be remotely analysed for QTc prolongation with potential to then notify the user of such potential irregularities could lead to widespread screening, detection and initiation of treatment solutions (i.e. correction of electrolytes, alteration of exacerbating medications, cardiac monitoring etc).

Trial Design: This will be a prospective, single arm, experimental, non-significant risk study conducted with the assistance of eligible participants. Parents or mature minors will download the Beat to Beat app, once consented.

Once consented the wearable device will be paired to the parent/guardians phone following the steps provided by the wearable device app. Once the device is paired and the study coordinator has assisted with the download of 'Beat to Beat' app, the patients will then be able to commence the ECG readings. A 12 lead ECG will be performed by the study team and immediately following this, an ECG will be recorded on the wearable device. The wearable device will be placed on the left wrist for a Lead I reading, on the left lower abdomen for a Lead II reading and in the fourth intercostal space left parasternal for a chest V2 Lead reading. Recording of the 12 lead ECG and wearable device ECG will be repeated again 4 days later. Once both timepoints (and two device recordings for each time period) have been completed the ECGs will be retrieved from the Beat to Beat app. Both the 12 lead and wearable device ECG will be de-identified and given a patient identifier before being uploaded into the REDCap database.

Beat to Beat A Study in Paediatric, Adolescent and Young Adult Patients Who Are Undergoing or Have Undergone Cancer Therapy to Evaluate the Agreement Between QTc Measured Using 12 Lead Electrocardiogram (ECG) and a Wearable Device ECG

Beat to Beat A Prospective Study in Paediatric, Adolescent and Young Adult Patients Aged 7 to 18 Years of Age Who Are Undergoing or Have Undergone Cancer Therapy to Evaluate the Agreement Between QTc Measured Using 12 Lead Electrocardiogram (ECG) and a Wearable Device ECG

The de-identified data set collected for this analysis of the Beat to Beat trial will be available 12 months after publication of the primary outcome.

The study protocol, analysis plan and consent forms will also be available. The data may be obtained from the Murdoch Children's Research Institute by emailing MCTC@mcri.edu.au.

12 lead ECG and wearable device ECG recordings will be taken at the time point of care. The wearable device ECG will be placed on the left wrist to record a V1 (lead I) ECG and on the left ankle to record a V2 (lead II) ECG reading from which the QT interval can be calculated.

The wearable device ECG and 12 lead ECG will be de-identified and given appropriate study numbers. This data will be listed separately for each patient. The QT interval for each recording will be calculated. This is the time corresponding to beginning of depolarization to repolarization of the ventricles. It is calculated using a standardised approach (Fridericia's formula:QTcF = QT divided by cube root of RR).

From the analysis of QT measurements from Outcome 2, prolonged or abnormal QTc measurement will be noted. An abnormal QTc is greater than 0.48mm. This data will be collected separately for each patient.

Sensitivity is calculated only in the participants who are declared to have QTc prolongation (abnormal QTc) and is calculated as the proportion patients with QTc prolongation on the wearable device among those with QTc prolongation on the 12-lead ECG.

Specificity is calculated only in participants who do not have QTc prolongation and is calculated as the proportion patients who do not have QTc prolongation on the wearable device among those who do not have QTc prolongation on the 12-lead ECG.

The corrected QT interval will be calculated on both the wearable device ECG and the 12 lead ECG for each patient and measured by a health professional. QT interval will be calculated by the health professional by using the QT and RR interval from the ECGs using Frederichia's interval (QTcF = QT divided by cube root of RR). This data will be collected separately for each patient. The standard deviation of the difference in QTc interval between the two observers will be reported.

The corrected QT interval will be calculated on both the wearable device ECG and the 12 lead ECG for each patient and measured by a health professional. QT interval will be calculated by the health professional by using the QT and RR interval from the ECGs using Frederichia's interval (QTcF = QT divided by cube root of RR). This data will be collected separately for each patient for each patient The standard deviation of the difference in QTc interval between the two observers will be reported.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study to Investigate the Effect of Single Dose of AZD6094 (600 mg) on Cardiac Repolarization in Healthy Volunteers	NCT03258515	Solid Tumors	AZD6094 200 mg Placebo Moxifloxacin	18 Years - 55 Years	AstraZeneca
Beat to Beat A Study in Paediatric, Adolescent and Young Adult Patients Who Are Undergoing or Have Undergone Cancer Therapy to Evaluate the Agreement Between QTc Measured Using 12 Lead Electrocardiogram (ECG) and a Wearable Device ECG	NCT05615376	Neoplasms Cardiac Arrhyth...	ECG application 12 lead ECG	7 Years - 18 Years	Murdoch Childrens Research Institute

Spots Global Cancer Trial Database for qt prolongation