Participation

• Trial Sites must participate in the American Heart Association’s Get With The Guidelines^® – AFib (GWTG-AFib) Registry for use of the CHANGE AFib trial database. Participation in GWTG-AFib for in-hospital quality improvement purposes is NOT required.
• Trial Sites must be research-ready (e.g., have processes and systems for obtaining IRB approval).
• If your trial site is not already participating in GWTG-AFib, this is not an issue for CHANGE AFib trial participation. The AHA trial team will work with your site thru the required GWTG-AFib registration process during site onboarding.

The trial is targeting 200 U.S. based trial sites to enroll 3,000 patients.

Data are collected in the American Heart Association’s Get With The Guidelines® – AFib (GWTG-AFib) Registry.

Yes. The AHA trial team will actively support all participating trial sites and will be available to address any trial-related questions. Once a site is signed up for the trial, the site can expect in depth training on trial protocols, patient selection, and data entry as well as ongoing support throughout the trial.

There will be a minimal amount of additional data collection for the hospitalization episode. You will also collect data at two follow-up points:

1. A mid-way time point, approximately 6 months post discharge
2. An end-of-study time point at 12 months post discharge

• All sites will be required to fully execute a Clinical Trial Agreement (CTA) between the American Heart Association and the Participating Trial Site. This agreement allows the site to participate in the CHANGE AFib trial. The Clinical Trial Agreement details what the CHANGE AFib trial will cover and formally outlines each parties understanding and responsibilities for conducting the trial.
• Trial sites will also be required to enroll and have access to AHA’s Get With The Guidelines on the registry platform so to access the trial database, GWTG-AFib. Sites already participating in GWTG-AFib do not need to sign up for anything additional. Sites that do not participate in any of the GWTG modules will be required to sign the GWTG contract, Unified Participation Agreement (UPA), as a part of site contracting. Sites enrolled in other GWTG modules, other than AFib, will sign an amendment to their existing UPA.
• A Participating Site is required to sign both the UPA and the Site Agreement in order to participate in the CHANGE AFib trial.

Yes. Sites will receive a trial budget comprised of both site-level and subject-level funds to cover site and personnel time and effort conducting the CHANGE AFib trial.

Yes.

No. A central IRB has been established for CHANGE AFib; the AHA trial team can help a site navigate the process. As the trial sponsor, the AHA is providing access to a Central IRB thru Advarra. The CHANGE AFib Central IRB is sponsor-provided and all Advarra IRB fees will be covered by the AHA.

Some sites participating in CHANGE AFib may have institutional requirements preventing use of a Central IRB. Your site may use your own IRB to participate in the trial. For those sites that must utilize their own IRBs, IRB costs and fees are not covered or reimbursed by the AHA.

Inclusion Criteria
Participants are eligible to be included in the trial if ALL the following apply:

• Age 21 years or older
• First-detected AFib (defined as AFib diagnosed in the previous 120 days)
• Electrocardiographic documentation of atrial fibrillation
• Estimated life expectancy of at least 1 year
• Patient or legal authorized representative capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) of the trial protocol

Exclusion Criteria
Participants are excluded from the trial if ANY of the following criteria apply:

• Patients with prior or planned treatment with rhythm control, either catheter ablation or chronic (>7 days) antiarrhythmic drug therapy
• Planned cardiothoracic surgery
• New York Heart Association class III or IV heart failure or a hospitalization for heart failure in the last 4 weeks
• Reduced ejection fraction (LVEF ≤40%)
• Permanent atrial fibrillation
• Ineligible for oral anticoagulation, unless CHA₂DS₂-VASc is less than 3, in women, or 2, in men.
• Bradycardia with a resting heart rate < 50 bpm
• PR interval >280 msec or 2^nd degree or 3^rd degree atrioventricular block without a permanent pacemaker/cardiac implanted electronic device
• Corrected QT interval ³500 msec
• Pregnancy or breast feeding
• Severe hepatic impairment in the opinion of the investigator

There are no randomized clinical trials that address first-detected AFib treatment. Patients are often started on an atrioventricular nodal blocking agent (beta-blocker or non-dihydropyridine calcium channel blocker). The trial is investigating if earlier administration of a well-tolerated antiarrhythmic drug, shown to reduce hospitalization, may result in improved cardiovascular outcomes and quality of life in patients.

Patients may be enrolled through December 2024.

• YES. While GWTG-AFib is an in-hospital registry, outpatient enrollment is allowed in the CHANGE AFib trial.
• As long as the patient’s diagnosis of their first-detected AFib was within 120-days of enrollment via approved electrocardiographic documentation, they are eligible for trial participation in both the inpatient and outpatient settings.

No. A patient whose first-detected AFib was diagnosed in either the inpatient OR outpatient setting via approved electrocardiographic documentation is eligible for CHANGE AFib.

A cardioversion is allowed at any time during the conduct of the trial (in either arm).

YES.

• All subjects randomized to the intervention arm will have the study drug provided to them throughout their full participation in the trial.
• If a subject is randomized to the intervention (dronedarone) arm, they must be registered in the Almac Simplify^TM IRT System to facilitate study drug shipment and dispensation.
• Study teams are responsible for registration of intervention arm subjects in the IRT System, completing the study drug order request process, and conducting confirmation conversations of study drug delivery and dosing initiation.

Patients in the usual care arm should be treated as they would be in general clinical practice. Thus, if someone has escalating symptoms from atrial fibrillation and their treating physician feels they would benefit from rhythm control then they can be started on an antiarrhythmic medication. A physician could choose to use dronedarone in that instance. This would be expected to be a rare occurrence.

In the EAST AFNET 4 trial that compared early rhythm control vs usual care alone, at two-years of follow-up, only 14% of subjects were on rhythm control (85% were on rate control).

There are a few other items worth mentioning:

• Planned rhythm control therapy or ablation is an exclusion criterion. Therefore, prescription of antiarrhythmic medications in the usual care arm should NEVER occur immediately after randomization.
• In the rare event someone in the usual care arm is ultimately treated with dronedarone (for example, a patient develops worsening symptoms and is treated with dronedarone 9 months after randomization), then the drug would not be covered by the trial as the subject is in the usual care arm.

CHANGE AFIB is comparing the initiation of early rhythm control versus usual care. Specifically, patients are randomized to DRONEDARONE + USUAL CARE versus USUAL CARE ALONE. As a result, it is expected that many patients will be on atrioventricular nodal blocking agents in both arms, including beta-blockers and calcium channel blockers. Patients treated with beta-blockers, CCBs, or digoxin are eligible. Digoxin should be discontinued in those randomized to dronedarone. Throughout the course of the trial, patients may experience progression of their AF and their physician may conclude that antiarrhythmic drug therapy is required. This could include initiation of rhythm control in the usual care arm or transition to a new rhythm control therapy in the dronedarone arm.

Patients who have definitive plans for initiation of an antiarrhythmic drug other than dronedarone (e.g. patient is scheduled for dofetilide loading next week) or definitive plans for catheter ablation are not eligible since they already have plans for specific rhythm control interventions. However, if a patient has been recommended rhythm control, without plans for specific intervention, then they would be an excellent candidate. Patients deemed to have “permanent” AF by definition are not considered to be eligible for rhythm control (as per the definition of permanent AF) and therefore are not eligible.

Consistent with the current FDA label for dronedarone, patients who have been hospitalized in the last 4 weeks with acute heart failure are not eligible for treatment with dronedarone. If a patient has no recent HF hospitalization but has advanced HF (class III or IV) they are also ineligible. Thus, persons with NYHA 1-2 heart failure and no hospitalization for HF in the last 4 weeks are eligible for CHANGE AFIB.