Gene Therapy for Post-Operative Atrial Fibrillation (AFGT01)

AdKCNH2-G628S Gene Therapy for Post-Operative Atrial Fibrillation

This clinical trial will have 2 components: a brief dose-ranging study and a randomized comparison of 2 doses of AdKCNH2-G628S with control cardiac surgery patients. The study will assess safety of the intervention in a population at increased risk for post-operative atrial fibrillation.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation; Post-operative Atrial Fibrillation
• Intervention / Treatment: Biological: AdKCNH2-G628S

Detailed Description

Post-operative AF (POAF) is a specific form of AF occurring in the days after cardiothoracic surgery. A unique element of POAF is the limited duration of risk, which peaks 3 days and dissipates 10 days after surgery. We propose gene therapy for POAF. Our hypothesis is that counteracting AF-related electrical remodeling will disrupt the reentrant electrical circuits integral to maintaining AF. We have extensive preclinical data showing safety and efficacy of adenoviral gene transfer using the gene mutation KNCH2-G628S. When delivered to the atria using adenoviruses and a novel gene painting technique, KCNH2-G628S effectively and specifically prolongs atrial action potential and prevents development of AF for the 10-14-day duration of post-operative AF risk. This clinical trial will have 2 components: a brief dose-ranging study and a randomized comparison of 2 doses of AdKCNH2-G628S with control cardiac surgery patients.

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Kevin Donahue, MD; Phone Number: 508-421-1538; Email: kevin.donahue@umassmed.edu
• Study Contact Backup: Name: Taylor Orwig; Email: taylor.orwig@umassmed.edu

Study Locations

• United States
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Recruiting
      • UMass Memorial Hospital
      • Contact: Kevin Donahue, MD; Phone Number: 508-421-1538; Email: kevin.donahue@umassmed.edu
      • Contact: Taylor Orwig; Email: taylor.orwig@umassmed.edu
      • Principal Investigator: David McManus, MD
      • Principal Investigator: Kevin Donahue, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion:

• Elective valve surgery (alone or with coronary artery bypass grafting surgery) and one of the risk factors listed below, or elective coronary artery bypass grafting surgery with two of the risk factors listed below.

• Risk factors:

  • age greater than 70,
  • increased left atrial size (> 4 cm left atrial diameter or LA volume index > 35 on echocardiogram).
  • obesity (body mass index > 30)

  • history of:

    • paroxysmal AF
    • hypertension
    • chronic pulmonary disease
    • diabetes mellitus
    • clinical heart failure
    • rheumatic heart disease

Exclusion:

• persistent or permanent AF
• QTc > 475 on pre-op ECG or any time in last year (unless due to QT prolonging drug that was stopped > 5 half-lives before surgery with verification of QT normalization after discontinuing drug)
• QTc prolonging drug use (unless stopped > 5 half-lives prior to surgery)
• Any antiarrhythmic drug use in last year (inclusive of Vaughan Williams class I and III drugs, not including β-blocker or calcium channel blocker drugs)
• Any history of inherited arrhythmia syndrome
• Any prior or current sustained ventricular arrhythmias
• Any prior or current clinically significant bradyarrhythmias unless already treated with pacemaker and ventricular pacing <20% (to reliable measure QT interval during the study)
• Any prior gene therapy
• Left ventricular ejection fraction (LVEF) < 35%
• Prior open chest surgery
• History of or current malignancy, unless documented to be cured
• History of or current chemotherapy, radiotherapy, or other immunosuppressive therapy within the past 30 days. Corticosteroid treatment may be permitted at the discretion of the Primary Investigator
• History of infection with human immunodeficiency virus (HIV), hepatitis A, B, or C, or tuberculosis
• Immunizations of any kind in the month prior to surgery
• Underlying defect in immune function or history of multiple or severe life-threatening infections
• Significant liver disease (active hepatitis, AST or ALT greater than twice the upper limit of normal, prior or current liver failure with Pugh-Child category A-C disease)
• Significant renal disease (GFR less than 30)
• Current pregnancy
• Childbearing potential unless participant agrees to prevent pregnancy prior to and for at least 3 months after virus delivery 10
• Any condition that limits life to < 12 months other than the condition to be treated with the planned surgery
• Participation in any other clinical trial within 30 days of surgery
• Incarcerated persons
• Individuals under the age of 18 years
• Unwillingness to undergo the study interventions and follow-up as outlined in the schedule of events
• Ongoing medical or other condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study
• Lack of capacity to provide participant's own informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: dose escalation; initial phase, increasing dose	Biological: AdKCNH2-G628S; adenovirus containing the transgene KCNH2-G628S
Experimental: low dose; second phase, fixed dose 5x10(11) vp	Biological: AdKCNH2-G628S; adenovirus containing the transgene KCNH2-G628S
Experimental: high dose; second phase, fixed dose 2x10(12) vp	Biological: AdKCNH2-G628S; adenovirus containing the transgene KCNH2-G628S
No Intervention: control; second phase, blinded, randomized with no intervention delivered but with testing and monitoring.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proportion of patients having a post-operative complication relative to controls	proportion of patients having a post-operative complication relative to controls	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
proportion of patients having post-operative atrial fibrillation	proportion of patients having post-operative atrial fibrillation	1 month

Collaborators and Investigators

• Sponsor: Kevin Donahue
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Kevin Donahue, MD, University of Massachusetts Chan Medical School

Publications and helpful links

General Publications

• Kikuchi K, McDonald AD, Sasano T, Donahue JK. Targeted modification of atrial electrophysiology by homogeneous transmural atrial gene transfer. Circulation. 2005 Jan 25;111(3):264-70. doi: 10.1161/01.CIR.0000153338.47507.83. Epub 2005 Jan 10.
• Amit G, Kikuchi K, Greener ID, Yang L, Novack V, Donahue JK. Selective molecular potassium channel blockade prevents atrial fibrillation. Circulation. 2010 Jun 1;121(21):2263-70. doi: 10.1161/CIRCULATIONAHA.109.911156. Epub 2010 May 17.
• Liu Z, Hutt JA, Rajeshkumar B, Azuma Y, Duan KL, Donahue JK. Preclinical efficacy and safety of KCNH2-G628S gene therapy for postoperative atrial fibrillation. J Thorac Cardiovasc Surg. 2017 Nov;154(5):1644-1651.e8. doi: 10.1016/j.jtcvs.2017.05.052. Epub 2017 May 23.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2023
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2026

Study Registration Dates

• First Submitted: January 24, 2022
• First Submitted That Met QC Criteria: January 24, 2022
• First Posted (Actual): February 4, 2022

Study Record Updates

• Last Update Posted (Actual): October 13, 2023
• Last Update Submitted That Met QC Criteria: October 11, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation
• Other Study ID Numbers: WIRB1333791; 4R33HL158541 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Data from the clinical trial will be made available to the scientific community and the general public in the following ways:

1. As soon as final data are complete, verified and analyzed, manuscripts will be written and submitted to scientific journals with the highest possible impact factor to achieve the widest possible dissemination within the scientific community.
2. Presentations at scientific meetings within the disciplines of cardiac surgery, cardiology, cardiac electrophysiology and gene therapy will further disseminate the research information gained as a result of the proposed studies.
3. The research data will be uploaded to an openly available research website maintained by UMass for review and use by the scientific community.
4. The research results will be uploaded to clinicaltrials.gov.
5. Press releases, summaries of research findings and interviews with investigators will be released to the general public to publicize the information gained in the proposed research.

• IPD Sharing Time Frame: as per plan description
• IPD Sharing Access Criteria: as per plan description
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No