What is CHANGE AFib?
CHANGE AFib is a pragmatic randomized clinical trial investigating whether the early use of dronedarone can improve outcomes in patients with first-detected atrial fibrillation (AFib).
Who is conducting the trial?
CHANGE AFib is a collaboration between the American Heart Association and the Duke Clinical Research Institute with support from Sanofi US.
Why is this trial important?
Although several clinical trials have addressed the optimal treatment strategy for patients with symptomatic and recurrent AFib, we do not yet have support on the best early treatment plan for those who have just been diagnosed. CHANGE AFib seeks to fill this gap in evidence and determine whether we can better deliver early treatment to help improve long-term outcomes in patients with first-detected AFib.
What treatment is being used?
Eligible, first-detected AFib patients, who provide informed consent to participate, will be randomly assigned to one of two different groups. One group of participants will receive the study intervention – dronedarone – in addition to usual care. The second group will receive usual care alone – medicines that they would receive as part of their usual care (as decided by the care team) per routine clinical practice.
The trial is not blinded. This means that both the participants and the study team know to which group the patient has been assigned.
How does a pragmatic clinical trial differ from an explanatory clinical trial?
Pragmatic clinical trials are designed to test the effectiveness of interventions in real-world practice conditions. Explanatory clinical trials test whether an intervention works under ideal situations. The intention of pragmatic clinical trials is to analyze results that can be applied to generalized settings.
Why is the trial using Dronedarone?
Dronedarone is a rhythm control medicine (antiarrhythmic drug) and has been approved by the U.S. Food and Drug Administration (FDA) in certain patients with atrial fibrillation since 2009. In addition, dronedarone:
- is well-tolerated
- is effective in preventing recurrent AFib
- has been shown to reduce cardiovascular hospitalization
- is safe
- post-hoc analyses suggest it performs well in persons with early AFib
What is considered first-detected atrial fibrillation?
First-detected AFib is defined as atrial fibrillation diagnosed in the previous 120 days.
What is usual care?
Usual care is defined as best-practice, guideline-directed therapy of AFib, including but not limited to (a) stroke prevention therapy, (b) rate-control, and (c) treatment of risk factors. More specifically, oral anticoagulation in those men with a CHA2DS-2VASc score of 2 or greater or women with a CHA2DS-2VASc score of 3 or greater, rate control, and treatment of concomitant cardiovascular conditions (e.g., coronary artery disease or heart failure).
What is CHANGE AFIB trying to accomplish in light of the findings from EAST?
EAST was a landmark and critically important clinical trial that demonstrated the long-term value of rhythm control (predominantly with antiarrhythmic drug therapy). Alongside EAST, there have also been a fair number of trials focused on catheter ablation as first-line therapy for atrial fibrillation. However, none of these trials focused exclusively on patients with first-detected AF, which accounts for 1 out of 5 hospital admissions for atrial fibrillation in US hospitals. These patients often get prescribed oral anticoagulation and an AV nodal blocker and then go on to have several recurrences before they are referred to a cardiovascular specialist or EP or are offered rhythm control. At present, there are no guideline recommendations for rhythm control in patients with first-detected AF.
The goal of CHANGE AFIB is to determine if up-front rhythm control with a well-tolerated antiarrhythmic medication in patients with a first diagnosis of AF can reduce CV hospitalization or death. One might ask why not randomize to ablation or some other form of rhythm control. It would be unlikely for someone with a first occurrence/diagnosis of AF to immediately undergo ablation. However, if rhythm control therapy is initiated with antiarrhythmic drug therapy up front and they continue to have AF despite medical therapy, then they might be referred earlier for other forms of rhythm control. Thus, the hypothesis is that up-front initiation of rhythm control with dronedarone, will reduce CV events in persons with first-detected AF. We believe that this question is relevant even in practices where catheter ablation is considered after symptomatic recurrences. Said another way, we also think that up-front rhythm control will have benefits even in patients who might otherwise have received rhythm control at 3, 6, or 12 months following their first diagnosis.
Finally, in reference back to EAST, if CHANGE AFIB demonstrates improved CV outcomes, there would be two randomized trials demonstrating benefit to early initiation of rhythm control and this would likely lead to a change in the guidelines with stronger advocacy for early initiation of rhythm control.
Is there someone I can contact if I have questions about CHANGE AFib?
What are the requirements for a site to participate in the trial?
- 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.
How many trial sites and patients can be a part of the trial?
The trial is targeting 200 U.S. based trial sites to enroll 3,000 patients.
How are data collected for the trial?
Data are collected in the American Heart Association’s Get With The Guidelines® – AFib (GWTG-AFib) Registry.
Will participating trial sites receive help and support from the AHA for the duration of the trial?
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.
My hospital already participates in GWTG-AFib and submits data to the registry; will we have to collect and abstract additional data to participate in 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:
- A mid-way time point, approximately 6 months post discharge
- An end-of-study time point at 12 months post discharge
How can a site sign up for CHANGE AFib and how does contracting work?
- 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.
Is any financial support provided for sites that contract to participate in CHANGE AFib?
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.
Is IRB oversight necessary?
Does my site need to establish our own IRB?
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.
Patient Enrollment and Follow Up
What are the patient eligibility inclusion and exclusion 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
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 2nd degree or 3rd 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
Why are patients being enrolled early with the condition?
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.
How long is the enrollment period?
Patients may be enrolled through December 2024.
Can we enroll patients on an outpatient basis?
- 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.
Does a patient have to be admitted to the hospital to be eligible for CHANGE AFib?
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.
At what point is a Cardioversion allowed after randomization in both the treatment and Usual Care arms?
A cardioversion is allowed at any time during the conduct of the trial (in either arm).
Is the study drug, dronedarone, being provided to subjects randomized to the intervention arm?
- 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 SimplifyTM 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.
Can dronedarone be started in the usual care arm?
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.
Are you regarding anti-nodal blocking agents, such as Dilitazem, and beta blockers, such as Metoprolol, as antiarrhythmic therapy? If these drugs were used as a first line of treatment (SOC) in the ER, would those patients be necessarily excluded from the study?
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.
Considering the exclusion criteria, criteria #1 (patients with prior or planned treatment w/rhythm control, either catheter ablation or antiarrhythmic drug therapy) and criteria #6 (permanent atrial fibrillation) could be contradictory and would limit the study participants.
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.
Exclusion criteria# 4 “New York Heart Association class III or IV heart failure or a hospitalization for heart failure in the last 4 weeks” may be problematic for enrollment. The way that interprets is that anyone hospitalized with HF couldn’t be enrolled regardless of class.
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.
I am a patient recently diagnosed with AFib and want to learn more about my diagnosis. Where can I find this information?
The American Heart Association (AHA) is a great resource for information on AFib. Go to the AHA website to learn about AFib and why it matters. You will also find a variety of tools for you and those helping you manage your health.
How long will patients participate in the trial?
Patients will take part in the trial for approximately 12 months. There will be two follow-up visits. The first will take place between 3- and 9-months after participant enrollment, and the second will take place approximately 12-months after enrollment. These follow-up visits can be performed either virtually or in-person.
Are there any patient benefits for participation?
Patients will not receive direct benefit from taking part in this trial. The main reason for joining is to help researchers learn about treating patients with newly diagnosed AFib. The results may benefit patients in the future.
What happens if a patient in the intervention group stops taking dronedarone?
Dronedarone is required for patients randomized to the intervention group of the trial. If a patient decides to stop taking dronedarone, the reason for dosing discontinuation will be assessed. Patients in the intervention arm who stop taking dronedarone will continue to be followed throughout the full course of their trial participation.
Can a patient choose to withdraw from the trial after being enrolled?
Participation in this trial is completely voluntary. We do ask that patients only enroll if they plan to commit to the trial requirements and duration. This commitment will ensure the trial results are as complete as possible. However, it is understood that circumstances change and participants may change their mind about participating at any time. Patients choosing to stop participating must inform their trial doctor and the trial team. Once this is complete, they will not need to complete any additional follow-up visits, nor will any additional information be collected.
Can a participant choose which treatment group they wish to be assigned to?
No, all treatment assignments are assigned at random by a computer (i.e., similar to flipping a coin). A patient will have a 50% chance of being assigned to the treatment group and a 50% chance of receiving usual care alone. Neither the participant, nor provide, can control which treatment a participant receives.
What are the safety considerations and most common adverse reactions observed with dronedarone?
Dronedarone is subject to a boxed warning regarding increased risk of death, stroke, and heart failure in patients with decompensated heart failure or permanent atrial fibrillation. Please see the label insert for the complete boxed warning. The most common adverse reactions observed with dronedarone were diarrhea, nausea, abdominal pain, vomiting, and weakness or lack of energy. Rare but serious side effects may occur. A detailed list can be found on the label insert.
Is the expectation that the site Principal Investigator (PI) prescribe dronedarone for the entire 12 months?
NO. The PI OR any other prescribing member of the trial team may prescribe dronedarone.
However, the PI does need to assume responsibility for the patient, their participation, and the following of the protocol. In the case of dronedarone, this will include oversight to ensure subjects are taking the medication as prescribed and educating any other providers that are working with the subject. The PI may delegate this monitoring to another member of the trial team
Are there specific labs that need to be drawn, or tests that need to be done on patients in the dronedarone arm during the follow up period?
No, the protocol does not mandate phlebotomy or lab draws beyond those conducted for usual clinical care.
The protocol states, in section 7.3, that loss to follow up needs to be documented. Where should this information be recorded?
Contact attempts should be documented in the participant’s medical record; however, if a site prefers to record this information within the CHANGE AFib follow-up form only, that is acceptable.
Do candidates for CHANGE AFib need to have paroxysmal AFib? Are patients with persistent AFib excluded?
Patients with both paroxysmal and persistent AFib are eligible.
Do patients need to be symptomatic to be eligible for CHANGE AFib?
No, patients do not need to be symptomatic. Eligible patients do need to have first-detected AFib, defined as AFib diagnosed within the previous 120 days.
What is the timeframe for bradycardia, PR interval, and corrected QT interval exclusions?
Providers should evaluate the patient’s most recent ECG(s).
What if a patient only has a single instance of bradycardia? Should the patient be excluded from the trial?
For a single episode of bradycardia, the site Principal Investigator’s judgment can be used. If there is a transient bradycardia that was reversible, then that would not necessarily exclude patient screening and enrollment if otherwise eligible.
How should patients with a contingency plan for ablation be handled?
Patients with planned ablation at the time of enrollment, or those patients where ablation is highly anticipated are NOT candidates for CHANGE AFib. Recurrent AFib requiring escalation of rhythm control (including ablation) is expected. Patients in the dronedarone arm may continue dronedarone after AFib ablation.