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Gene Therapy for Post-Operative Atrial Fibrillation (AFGT01)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05223725
Recruitment Status : Not yet recruiting
First Posted : February 4, 2022
Last Update Posted : May 8, 2023
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Kevin Donahue, University of Massachusetts, Worcester

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Atrial Fibrillation Post-operative Atrial Fibrillation Biological: AdKCNH2-G628S Phase 1

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: participant is masked due to delivery during general anesthesia, outcomes assessors and investigators are fully masked to study group.
Primary Purpose: Prevention
Official Title: AdKCNH2-G628S Gene Therapy for Post-Operative Atrial Fibrillation
Estimated Study Start Date : July 1, 2023
Estimated Primary Completion Date : August 2025
Estimated Study Completion Date : August 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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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.


Outcome Measures
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Primary Outcome Measures :
  1. proportion of patients having a post-operative complication relative to controls [ Time Frame: 3 months ]
    proportion of patients having a post-operative complication relative to controls


Secondary Outcome Measures :
  1. proportion of patients having post-operative atrial fibrillation [ Time Frame: 1 month ]
    proportion of patients having post-operative atrial fibrillation


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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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): NCT05223725


Contacts
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Contact: Kevin Donahue, MD 508-421-1538 Kevin.Donahue@umassmed.edu

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

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Responsible Party: Kevin Donahue, Professor, University of Massachusetts, Worcester
ClinicalTrials.gov Identifier: NCT05223725    
Other Study ID Numbers: WIRB1333791
4R33HL158541 ( U.S. NIH Grant/Contract )
First Posted: February 4, 2022    Key Record Dates
Last Update Posted: May 8, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Time Frame: as per plan description
Access Criteria: as per plan description

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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
Additional relevant MeSH terms:
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Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes