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

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ClinicalTrials.gov Identifier: NCT03587558
Recruitment Status : Recruiting
First Posted : July 16, 2018
Last Update Posted : July 18, 2018
Sponsor:
Collaborator:
Chong Kun Dang Pharmaceutical Corp.
Information provided by (Responsible Party):
Keimyung University Dongsan Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Ventricular Premature Complexes Outflow Tract Carvedilol Drug: Carvedilol Drug: Flecainide Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Effects of Carvedilol on Suppressing the Premature Ventricular Complex/Ventricular Tachycardia From Outflow Tract
Actual Study Start Date : September 5, 2017
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : December 31, 2020


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 Name: 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 Name: Tambocor




Primary Outcome Measures :
  1. PVC burden [ Time Frame: 3 months after reaching the maximum tolerated dose ]
    Percentage of PVC/VT beat out of 24 hour total heart beat in Holter monitoring


Secondary Outcome Measures :
  1. Symptom assessment scale [ Time Frame: 3 months after reaching the maximum tolerated dose ]
    questionnaire for PVC/VT symptoms using symptom assessment scale (Min 0 to Max 100)

  2. Side effect of drugs [ Time Frame: 3 months after reaching the maximum tolerated dose ]
    Difference in occurrence of side effects of each drug



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Ages Eligible for Study:   19 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03587558


Contacts
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Contact: Jongmin Hwang, M.D., Ph.D. +82-53-250-7333 dsmcep@dsmc.or.kr

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

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Responsible Party: Keimyung University Dongsan Medical Center
ClinicalTrials.gov Identifier: NCT03587558     History of Changes
Other Study ID Numbers: 2017-07-022
First Posted: July 16, 2018    Key Record Dates
Last Update Posted: July 18, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data for all primary and secondary outcome measures will be made available.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Data will be available within 6 months of study completion.
Access Criteria: Data access requests will be reviewed by an external independent Review Panel. Requestors will be required to sign a Data Access Agreement.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Keimyung University Dongsan Medical Center:
carvedilol
SOICR
triggered activity
outflow tract PVC/VT
Additional relevant MeSH terms:
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Tachycardia
Tachycardia, Ventricular
Premature Birth
Ventricular Premature Complexes
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Cardiac Conduction System Disease
Pathologic Processes
Cardiac Complexes, Premature
Flecainide
Carvedilol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antihypertensive Agents
Antioxidants
Protective Agents
Calcium Channel Blockers
Membrane Transport Modulators
Calcium-Regulating Hormones and Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists