Effects of Carvedilol on Suppressing the Premature Ventricular Complex/Ventricular Tachycardia From Outflow Tract (FOREVER)

Carvedilol is known to be effective in reducing ventricular arrhythmias and mortality in patients with heart failure. It is suggested that one of the mechanisms is its ability to block store overload-induced Calcium release which activates spontaneous calcium release by Ryanodine receptors. Ventricular outflow tract tachyarrhythmia is known to be associated with calcium overload due to activation of Ryanodine receptors. The aim of this study is to evaluate the efficacy of Carvedilol on premature ventricular complex(PVC)/ventricular tachycardia(VT) originating from outflow tract.

Study Overview

• Status: Unknown
• Conditions: Ventricular Premature Complexes; Outflow Tract; Carvedilol
• Intervention / Treatment: Drug: Carvedilol; Drug: Flecainide

Detailed Description

Carvedilol is one of the third-generation beta-blockers effective in reducing ventricular arrhythmias and mortality in patients with heart failure. Antioxidative and alpha - blocking effects, along with nonselective beta - blockade, have been described as a mechanism of effect in various diseases.

The antiarrhythmic effect of carvedilol inhibiting atrial fibrillation or ventricular arrhythmia has been reported, but its mechanism is not yet clear. Among them, inhibition of store overload-induced Ca2+ release (SOICR) is suggested as an antiarrhythmic mechanism of carvedilol.

Stimulation of the beta receptor leads to the entry of calcium into the sarcoplasmic reticulum (SR) by opening the L-type calcium channel. The influx of calcium through the L-type calcium channel also increases the calcium release through the Ryanodine receptor (RyR) in the sarcoplasmic reticulum. This is called Ca-induced Ca release and is known as a normal physiological response. However, when calcium overload in the myofibrillar body occurs, spontaneous calcium release, known as SOICR, can occur through RyR, which can make triggered activity by inducing Na+/Ca2+ exchanger present in myocardium, leading to severe arrhythmia. Among several beta-blockers, only carvedilol has been known as a drug that can directly inhibit SOICR in combination with beta-blockade effect.

Ventricular tachyarrhythmia originating from the ventricular outflow tract is an arrhythmia occurring in a patient with normal cardiac function. The mechanism of the arrhythmia is known to be triggered activity which is caused by activation of RyR due to increased cyclic adenosine monophasphate, resulting in calcium overload, eventually causing activation of Na+/Ca2+ exchanger. The aim of this study is to evaluate the efficacy of Carvedilol on PVC/VT originating from outflow tract.

• Study Type: Interventional
• Enrollment (Anticipated): 104
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Daegu, Korea, Republic of, 41931
    • Recruiting
    • Keimyung University Dongsan Medical Center
    • Contact: Jongmin Hwang, M.D.; Phone Number: +82-53-250-7333; Email: dsmcep@dsmc.or.kr
    • Principal Investigator: Seongwook Han, MD, PhD
    • Sub-Investigator: Jongmin Hwang, MD, PhD
    • Sub-Investigator: Yoon-Nyun Kim, MD, PhD
    • Sub-Investigator: Hyoung-Seob Park, MD, PhD
  • Daegu, Korea, Republic of, 41944
    • Recruiting
    • Division of Cardiology, Department of Internal Medicine, Kyungpook National University Hospital
    • Contact: Myung Hwan Bae, MD, PhD
  • Daegu, Korea, Republic of, 42415
    • Recruiting
    • Division of Cardiology, Department of Internal Medicine, Yeungnam University Hospital
    • Contact: Dong Gu Shin, MD, PhD
  • Daegu, Korea, Republic of, 42472
    • Recruiting
    • Division of Cardiology, Department of Internal Medicine, Daegu Catholic University Medical Center
    • Contact: Young Soo Lee, MD, PhD
  • Gwangju, Korea, Republic of, 61469
    • Recruiting
    • Chonnam National University Hospital
    • Contact: Hyung Wook Park, MD, PhD
  • Seoul, Korea, Republic of, 03080
    • Recruiting
    • Seoul National University Hospital
    • Contact: Eue-Keun Choi, MD, PhD
  • Seoul, Korea, Republic of, 06591
    • Recruiting
    • Seoul St. Mary's Hospital
    • Contact: Sung-Hwan Kim
  • Seoul, Korea, Republic of, 02841
    • Recruiting
    • Korea University Anam Hospital
    • Contact: Jong-Il Choi, MD, PhD
  • Seoul, Korea, Republic of, 03722
    • Recruiting
    • Severance Cardiovascular Hospital
    • Contact: Boyoung Joung, MD, PhD
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Seoul Samsung Medical Center
    • Contact: Young Keun On, MD, PhD
  • Seoul, Korea, Republic of, 05505
    • Recruiting
    • Seoul Asan Medical Center
    • Contact: Jun Kim, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with ventricular premature complexes/ventricular tachycardias originating from ventricular outflow tract confirmed on the 12-lead surface ECG
• Patients with PVC burden of 5% or more in 24-hour Holter monitoring

• Patients with normal left ventricular function

  • left ventricular ejection fraction ≥50%
• Patients without structural heart disease

Exclusion Criteria:

• Pregnant, trying to become pregnant or breast feeding
• History of bronchial asthma
• History of coronary arterial disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carvedilol group; Patients in this group are taking carvedilol to inhibit outflow tract PVC/VT. Dilatrend® sustained release form of Chong Kun Dang Pharmaceutical will be used (initial dose: 8 mg sustained release form). Outpatient follow-up will be performed every 2 weeks and the dose is increased from the initial dose to a maximal tolerable dose, at the discretion of the investigator.	Drug: Carvedilol; Patients in this group are taking carvedilol to inhibit outflow tract PVC/VT.; Other Names: Dilatrend
Active Comparator: Flecainide group; Patients in this group are taking flecainide to inhibit outflow tract PVC/VT. Tambocor® of JW Pharmaceutical will be used. Outpatient follow-up will be performed every 2 weeks and the dose is increased from the initial dose to a maximal tolerable dose, at the discretion of the investigator.	Drug: Flecainide; Patients in this group are taking flecainide to inhibit outflow tract PVC/VT.; Other Names: Tambocor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PVC burden	Percentage of PVC/VT beat out of 24 hour total heart beat in Holter monitoring	3 months after reaching the maximum tolerated dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptom assessment scale	questionnaire for PVC/VT symptoms using symptom assessment scale (Min 0 to Max 100)	3 months after reaching the maximum tolerated dose
Side effect of drugs	Difference in occurrence of side effects of each drug	3 months after reaching the maximum tolerated dose

Collaborators and Investigators

• Sponsor: Keimyung University Dongsan Medical Center
• Collaborators: Chong Kun Dang Pharmaceutical Corp.
• Investigators: Study Chair: Seongwook Han, M.D., Ph.D., Keimyung University Dongsan Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2017
• Primary Completion (Anticipated): December 31, 2019
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: July 2, 2018
• First Submitted That Met QC Criteria: July 2, 2018
• First Posted (Actual): July 16, 2018

Study Record Updates

• Last Update Posted (Actual): July 18, 2018
• Last Update Submitted That Met QC Criteria: July 16, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: carvedilol; SOICR; triggered activity; outflow tract PVC/VT
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Cardiac Complexes, Premature; Premature Birth; Tachycardia; Tachycardia, Ventricular; Ventricular Premature Complexes; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Protective Agents; Membrane Transport Modulators; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Carvedilol; Flecainide
• Other Study ID Numbers: 2017-07-022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made available.
• IPD Sharing Time Frame: Data will be available within 6 months of study completion.
• IPD Sharing Access Criteria: Data access requests will be reviewed by an external independent Review Panel. Requestors will be required to sign a Data Access Agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

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