Gene Therapy for Post-Operative Atrial Fibrillation

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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AdKCNH2-G628S Gene Therapy for Post-Operative Atrial Fibrillation

Conditions
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Atrial Fibrillation, Post-operative Atrial Fibrillation

Intervention / Treatment
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* Biological: AdKCNH2-G628S


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 |