The Response To Ajmaline Provocation in Healthy Subjects

An Observational Study Into the Variety of Electrocardiographic Responses to an Ajmaline Provocation in a Healthy Subjects. What Are the Genetic and Structural Variations Dictating This Response ?

Standard, high lead and sodium channel provoked electrocardiograms of a healthy volunteers will be performed to observe the various ECG changes. Participants will the undergo detailed imaging with cardiac magnetic resonance imaging and deep genotyping to identify structural or genetic variants which might dictate the electrocardiographic patterns at rest and with sodium channel provocation.

Study Overview

• Status: Unknown
• Conditions: Sudden Death; Brugada Syndrome
• Intervention / Treatment: Drug: Ajmaline

Detailed Description

The investigators will recruit healthy subjects without a history of cardiac symptoms or a family history of sudden death or premature arrhythmogenic cardiac disease. Participants will undergo electrocardiographic phenotype assessment with standard and high lead electrocardiogram and sodium channel provocation. Detailed cardiac structural examination will be performed with cardiac magnetic resonance imaging to look for any variation in mainly right ventricular outflow tract structure and myocardial architecture. Participants will also undergo targeted genomic sequencing to look for variations in genes encoding for cardiac sodium channel.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • St George's University of London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Asymptomatic healthy Volunteers

Exclusion Criteria:

• • Any prior cardiovascular illness

  • Previous cardiac symptoms.
  • History of unexplained syncope
  • Any family history of proven sudden cardiac death or unexplained sudden death either in adulthood or infancy.
  • Those unable to provide a two generation family history
  • Abnormal resting ECG
  • Any contraindications to cardiac magnetic resonance imaging
  • Pregnant or breastfeeding women
  • Intercurrent use of any medication known to be contraindicated in Brugada Syndrome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Healthy Volunteers; Once screened by the investigators, the participants will undergo ajmaline provocation, cardiac magnetic resonance imaging and genotype evaluation	Drug: Ajmaline; Ajmaline 1milligram/kilogram max dose as bolus intravenous over 10 minutes with continuous ECG monitoring; Other Names: GILURYTMAL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The qualitative and quantitative effects of ajmaline provocation on parameters of cardiac conduction in healthy subjects using the surface electrocardiogram	The investigators will be undertaking quantitative analysis of the changes in cardiac conduction observed in the presence of ajmaline. This is measured in time intervals in milliseconds (ms) and magnitude of electrical conduction which will be expressed in millivolts (mv), but can also be expressed in millimetres (mm). The investigators will use the latter to quantify area changes which will be expressed as millimetres squared (mm2). A quantitive description of the electrocardiographic patterns observed will also be performed in addition to further qualitative analysis of vectors created by the variety of ECG morphologies observed, this geometrical assessment will be measured in degrees. As this is a cohort of healthy volunteers the variations observed are anticipated to be part of the "normal" variation, therefore the statistical analysis of these findings will be as a cohort not individual.	ten minutes

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The influence of normal variations in right ventricular outflow tract dimensions on the electrocardiographic response to ajmaline provocation in healthy subjects using cardiac magnetic resonance imaging.	Using existing cardiac magnetic resonance imaging modality, cardiac dimensions will be measured in millimetres (mm). This includes wall thickness and internal cavity size. Additionally volumetric assessment for chamber size will be made using millilitres (ml), this allows for a 3 dimensional appreciation. Using contrast agents, an assessment of the composition of cardiac muscle can be made and can identify the presence or absence of "myocardial fibrosis,"as a binary outcome measure. Further methods will be used to quantify the degree of fibrosis if observed, this will be expressed as a percentage (%) area of fibrosis divided by total area of myocardium multiplied by 100. The location of this fibrosis within the heart will also be noted.	intraoperative
Genotype linkage analysis of the electrocardiographic response to ajmaline provocation in healthy subjects using candidate gene and gene wide association studies.	Targeted genetic sequencing of the sodium channel genes SCN5A and SCN10A and gene wide association studies for rare variations	through study completion, an average of 2 years

Collaborators and Investigators

• Sponsor: St George's, University of London
• Investigators: Principal Investigator: Elijah Behr, MD, St George's, University of London

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2017
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: August 31, 2016
• First Submitted That Met QC Criteria: October 13, 2016
• First Posted (Estimate): October 14, 2016

Study Record Updates

• Last Update Posted (Actual): November 5, 2019
• Last Update Submitted That Met QC Criteria: November 4, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: SCN5A; Brugada syndrome; SCN10A; Ajmaline
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Death; Death, Sudden; Brugada Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Membrane Transport Modulators; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Ajmaline
• Other Study ID Numbers: 16.0012; 2016-004277-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No