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Early Dronedarone Versus Usual Care to Improve Outcomes in Persons With Newly Diagnosed Atrial Fibrillation (CHANGE-AFIB)

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: NCT05130268
Recruitment Status : Recruiting
First Posted : November 23, 2021
Last Update Posted : April 12, 2022
Sponsor:
Collaborators:
Duke Clinical Research Institute
Sanofi
Information provided by (Responsible Party):
American Heart Association

Brief Summary:

While there are several completed clinical trials that address treatment strategy in patients with symptomatic and recurrent AF, there are no randomized clinical trials that address treatment for first-detected AF. In usual care, these patients are started on an atrioventricular nodal blocking agent (beta-blocker or non-dihydropyridine calcium channel blocker) along with stroke prevention therapy. The investigators hypothesize that earlier administration of a well-tolerated antiarrhythmic drug proven to reduce hospitalization may result in improved cardiovascular outcomes and quality of life in patients first-detected AF.

The purpose of this study is to determine if treatment with dronedarone on top of usual care is superior to usual care alone for the prevention of cardiovascular hospitalization or death from any cause in patients hospitalized with first-detected AF. All patients will be treated with guideline-recommended stroke prevention therapy according to the CHA2DS2-VASc score. The treatment follow-up period will be 12 months. There will be two follow-up visits. Consistent with the pragmatic nature of the trial, the first follow-up will occur between 3 -9 months and the 2nd will occur at 12 months (with a window of +/- 30 days). Approximately 3000 patients will be enrolled and randomly assigned (1:1) to study intervention. The study intervention will be dronedarone 400 mg twice daily in addition to usual care versus usual care alone.


Condition or disease Intervention/treatment Phase
Atrial Fibrillation Drug: Dronedarone Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter, prospective, randomized, open-label, pragmatic clinical trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pragmatic Randomized Clinical Trial of Early Dronedarone Versus Usual Care to Change and Improve Outcomes in Persons With First-Detected Atrial Fibrillation
Actual Study Start Date : October 29, 2021
Estimated Primary Completion Date : June 2024
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Dronedarone

Arm Intervention/treatment
Experimental: Dronedarone
In most patients, the investigators anticipate usual care to include an atrioventricular nodal blocking agent (beta-blocker, non-dihydropyridine calcium channel blocker, or digoxin) without an antiarrhythmic. As dronedarone has anti-adrenergic rate controlling properties, a low dose of beta-blocker or calcium-channel blocker is recommended in the United States Prescribing Information (USPI) when starting dronedarone. In the dronedarone arm concomitant digoxin use will be contraindicated due to P-gp interaction based upon data from the PALLAS trial. All patients will receive oral anticoagulation for stroke prevention according to current guideline recommendations.
Drug: Dronedarone
Dronedarone 400 mg twice daily in addition to usual care
Other Name: Multaq

No Intervention: Usual care
In most patients, the investigators anticipate usual care to include an atrioventricular nodal blocking agent (beta-blocker, non-dihydropyridine calcium channel blocker, or digoxin) without an antiarrhythmic. All patients will receive oral anticoagulation for stroke prevention according to current guideline recommendations.



Primary Outcome Measures :
  1. Cardiovascular Hospitalization or Death [ Time Frame: Evaluated through 12 months from randomization ]
    First occurrence of unplanned CV hospitalization or death from any cause within 12 months of randomization. All unplanned hospitalizations (i.e. admission with an overnight stay in an acute care healthcare facility/hospital) for cardiovascular causes will be considered a cardiovascular hospitalization.


Secondary Outcome Measures :
  1. Win Ratio [ Time Frame: Evaluated through 12 months from randomization ]

    Among the randomized patients, every patient in the dronedarone arm will be compared with every patient in the usual care arm. Within each pair of patients, the component outcomes will be compared in descending order of importance until one of the patients in the pair demonstrates a better outcome compared with the other. For the purpose of this trial the hierarchy of component outcomes are shown below. The components in the WIN ratio hierarchy are similar to the endpoints considered in the recent EAST AFNET4 trial.

    Hierarchy of Outcomes for the WIN Ratio:

    1. All-cause mortality
    2. Ischemic stroke or systemic embolism
    3. Hospitalization for new/worsening diagnosis of heart failure
    4. Hospitalization for acute coronary syndrome

  2. All-cause mortality [ Time Frame: Evaluated through 12 months from randomization ]
    For descriptive purposes, deaths will be categorized by the site investigators according to the following categories: cardiovascular and non-cardiovascular. Cardiovascular deaths will be further classified into arrhythmic vs non-arrhythmic according the modified Hinkle-Thaler criteria, as used in several landmark cardiovascular trials. Patients who are well and (1) have a witnessed sudden collapse or (2) those found dead, but known to be alive and well in the previous 24 hours (e.g. no signs or symptoms of cardiorespiratory distress) will be defined as having arrhythmic death.

  3. Ischemic stroke or systemic embolism [ Time Frame: Evaluated through 12 months from randomization ]
    The occurrence of ischemic stroke will be defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. Symptoms or signs must persist ≥24 hours, unless the stroke is documented by CT, MRI or autopsy, in which case the duration of symptoms/signs may be less than 24 hours. Stroke may be classified as ischemic (including hemorrhagic transformation of ischemic stroke), hemorrhagic, or undetermined. Systemic embolism will be defined as acute arterial insufficiency or occlusion of the extremities or any non-CNS organ associated with clinical, imaging, surgical/autopsy evidence of arterial occlusion in the absence of other likely mechanism (e.g., trauma, atherosclerosis, or instrumentation).

  4. Hospitalization for new/worsening diagnosis of heart failure [ Time Frame: Evaluated through 12 months from randomization ]
    Hospitalization for new or worsening heart failure will be defined as any unplanned hospitalization (i.e. admission with an overnight stay in an acute care healthcare facility/hospital) due to a new diagnosis or worsening symptomatic heart failure

  5. Hospitalization for acute coronary syndrome [ Time Frame: Evaluated through 12 months from randomization ]
    Any hospitalization (i.e. admission with an overnight stay in an acute care healthcare facility/hospital) due to acute coronary syndrome.

  6. Time to first unplanned cardiovascular hospitalization [ Time Frame: Evaluated through 12 months from randomization ]
    Given the importance of CV hospitalization as an outcome from a clinical perspective, patient perspective, and economic perspective, there will be two analyses of CV hospitalization. The key secondary endpoint will be time to first unplanned CV hospitalization (similar to the component of the primary endpoint).

  7. Unplanned cardiovascular hospitalizations--secondary analysis using Anderson-Gill extension [ Time Frame: Evaluated through 12 months from randomization ]
    Given the importance of CV hospitalization as an outcome from a clinical perspective, patient perspective, and economic perspective, there will be two analyses of CV hospitalization. The second exploratory analysis of unplanned cardiovascular hospitalization will use a method to account for repeated events (Anderson-Gill extension).


Other Outcome Measures:
  1. Any unplanned arrhythmia-related hospitalization [ Time Frame: Evaluated through 12 months from randomization ]
    Arrhythmia-Related Hospitalization will be defined as any unplanned hospitalization (i.e. admission with an overnight stay in an acute care healthcare facility/hospital) due to any tachy or brady-arrhythmia.

  2. Number of participants who experience AF progression [ Time Frame: Evaluated through 12 months from randomization ]
    AF Progression will be defined as the transition from (a) paroxysmal to persistent or (b) persistent to permanent AF.

  3. Number of participants who undergo cardioversion (pharmacologic or electrical) [ Time Frame: Evaluated through 12 months from randomization ]
    Cardioversion (either pharmacologic or electrical) with or without transesophageal echocardiographic guidance will be a tertiary endpoint.

  4. Number of participants who have ablation of AF (catheter, surgical or hybrid) performed [ Time Frame: Evaluated through 12 months from randomization ]
    Ablation of AF including catheter ablation, surgical ablation, or hybrid (endocardial and epicardial ablation) ablation will be a tertiary endpoint.

  5. Days alive and outside of the hospital [ Time Frame: Evaluated through 12 months from randomization ]
    Days Alive and Out of the Hospital. Days alive and out of the hospital (DAOH, also referred to as "home time") is an emerging clinical trial endpoint that is both pragmatic and patient centered. It is highly correlated with traditional time-to-event mortality and hospitalization outcomes.

  6. Patient-Reported Quality of Life--AFEQT [ Time Frame: At baseline and 12 months ]
    The AFEQT is a 21-item, AF-specific health-related QOL questionnaire that assesses the impact of AF on patient-reported quality of life. The AFEQT includes a summary score (calculated from 18 of the questions) and subscale scores in three domains: symptoms, daily activities, and treatment concern. The summary and subscale scores range from 0 (corresponds to complete AF-related disability) to 100 (no AF-related disability). A change of 5 or more points in the AFEQT has been identified as a benchmark for a clinically meaningful difference in an individual patient.

  7. Patient-Reported Quality of Life--MAFSI [ Time Frame: At baseline and 12 months ]
    The MAFSI was developed as a modification and update of the AF Symptom Checklist. The trial will use a modified MAFSI questionnaire comprised of a 10-item AF symptom checklist that asks about frequency and severity of each symptom. Frequency of symptoms is recorded as 0 (never), 1 (rarely), 2 (sometimes), 3 (often), or 4 (always). These responses are summed for a total Frequency Score that ranges from 0 (no AF symptoms) to 40 (worst score). MAFSI Severity Scores are recorded as 1 (mild), 2 (moderate), or 3 (extreme). Severity scores are summed and range from 0 (no AF symptoms) to 30 (most severe AF symptoms). A clinically meaningful change in the MAFSI has not previously been established and therefore will be considered to be about ¼ of the pooled baseline standard deviation (SD), or 1.6 points for the Frequency Score and 1.3 points for the Severity Score.



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Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age >=60 years
  2. First-detected atrial fibrillation (defined as atrial fibrillation diagnosed in the previous 60 days)
  3. Electrocardiographic documentation of atrial fibrillation.
  4. Estimated life expectancy of at least 1 year
  5. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

  1. Patients with prior or planned treatment with rhythm control, either catheter ablation or antiarrhythmic drug therapy.
  2. Prior hospitalization for AF
  3. Planned cardiothoracic surgery
  4. New York Heart Association class III or IV heart failure or a hospitalization for heart failure in the last 4 weeks
  5. Patients with reduced ejection fraction (LVEF ≤40%)
  6. Permanent atrial fibrillation
  7. Ineligible for oral anticoagulation, unless CHA2DS2-VASc is less than 3 in women or 2 in men.
  8. Bradycardia with a resting heart rate < 50 bpm
  9. PR interval >280 msec or 2nd degree or 3rd degree atrioventricular block without a permanent pacemaker/cardiac implanted electronic device.
  10. Corrected QT interval less than or equal to 500 msec.
  11. Pregnancy
  12. Severe hepatic impairment

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): NCT05130268


Contacts
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Contact: Samantha Johnson, MPH +1 (609) 223-3730 ChangeAFib@heart.org
Contact: Susana Almeida-Peters, BN, RN +1 (919) TBD-0000 ChangeAF@duke.edu

Locations
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United States, Massachusetts
Brigham and Womens Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Christine Pellegrini, RN, MSN/MHSA    617-732-5241    cpellegrini@bwh.harvard.edu   
Principal Investigator: Sunil Kapur, MD         
United States, New Jersey
Cooper University Hospital Recruiting
Camden, New Jersey, United States, 08103
Contact: Stephanie Vasey, BSN, RN    +1 (856) 342-2000 ext 1095558    vasey-stephanie@CooperHealth.edu   
Principal Investigator: Andrea M. Russo, MD, FACC, FHRS, FAHA         
United States, Ohio
Wooster Community Hospital Health System Recruiting
Wooster, Ohio, United States, 44691
Contact: Karrie Boss, MSN, APRN, ACCNS-AG, CCRN    330-263-8495    kboss@wchosp.org   
Principal Investigator: Cyril Ofori, MD, FACC         
Sponsors and Collaborators
American Heart Association
Duke Clinical Research Institute
Sanofi
Investigators
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Principal Investigator: Jonathan P Piccini, MD, MHS Duke Clinical Research Organization
Publications:
Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA 3rd, Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy CM, Fuster V, Rydén LE, Cannom DS, Le Heuzey JY, Crijns HJ, Lowe JE, Curtis AB, Olsson SB, Ellenbogen KA, Prystowsky EN, Halperin JL, Tamargo JL, Kay GN, Wann LS, Jacobs AK, Anderson JL, Albert N, Hochman JS, Buller CE, Kushner FG, Creager MA, Ohman EM, Ettinger SM, Stevenson WG, Guyton RA, Tarkington LG, Halperin JL, Yancy CW; ACCF/AHA/HRS. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (Updating the 2006 Guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2011 Jan 11;57(2):223-42. doi: 10.1016/j.jacc.2010.10.001. Epub 2010 Dec 21.
Connolly SJ, Camm AJ, Halperin JL, Joyner C, Alings M, Amerena J, Atar D, Avezum Á, Blomström P, Borggrefe M, Budaj A, Chen SA, Ching CK, Commerford P, Dans A, Davy JM, Delacrétaz E, Di Pasquale G, Diaz R, Dorian P, Flaker G, Golitsyn S, Gonzalez-Hermosillo A, Granger CB, Heidbüchel H, Kautzner J, Kim JS, Lanas F, Lewis BS, Merino JL, Morillo C, Murin J, Narasimhan C, Paolasso E, Parkhomenko A, Peters NS, Sim KH, Stiles MK, Tanomsup S, Toivonen L, Tomcsányi J, Torp-Pedersen C, Tse HF, Vardas P, Vinereanu D, Xavier D, Zhu J, Zhu JR, Baret-Cormel L, Weinling E, Staiger C, Yusuf S, Chrolavicius S, Afzal R, Hohnloser SH; PALLAS Investigators. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med. 2011 Dec 15;365(24):2268-76. doi: 10.1056/NEJMoa1109867. Epub 2011 Nov 14. Erratum in: N Engl J Med. 2012 Feb 16;366(7):672.
Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021 Feb 1;42(5):373-498. doi: 10.1093/eurheartj/ehaa612. Erratum in: Eur Heart J. 2021 Feb 1;42(5):507. Eur Heart J. 2021 Feb 1;42(5):546-547. Erratum in: Eur Heart J. 2021 Oct 21;42(40):4194.
Calkins H, Hindricks G, Cappato R, Kim YH, Saad EB, Aguinaga L, Akar JG, Badhwar V, Brugada J, Camm J, Chen PS, Chen SA, Chung MK, Nielsen JC, Curtis AB, Davies DW, Day JD, d'Avila A, de Groot NMSN, Di Biase L, Duytschaever M, Edgerton JR, Ellenbogen KA, Ellinor PT, Ernst S, Fenelon G, Gerstenfeld EP, Haines DE, Haissaguerre M, Helm RH, Hylek E, Jackman WM, Jalife J, Kalman JM, Kautzner J, Kottkamp H, Kuck KH, Kumagai K, Lee R, Lewalter T, Lindsay BD, Macle L, Mansour M, Marchlinski FE, Michaud GF, Nakagawa H, Natale A, Nattel S, Okumura K, Packer D, Pokushalov E, Reynolds MR, Sanders P, Scanavacca M, Schilling R, Tondo C, Tsao HM, Verma A, Wilber DJ, Yamane T. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2017 Oct;14(10):e275-e444. doi: 10.1016/j.hrthm.2017.05.012. Epub 2017 May 12.
Willi Maurer & Frank Bretz (2013) Multiple Testing in Group Sequential Trials Using Graphical Approaches, Statistics in Biopharmaceutical Research, 5:4, 311-320.
Jennison C and Turnbull BW. Group Sequential Methods with Applications to Clinical Trials. New York, NY: Chapman & Hall/CRC; 2000.

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Responsible Party: American Heart Association
ClinicalTrials.gov Identifier: NCT05130268    
Other Study ID Numbers: 176131-M
First Posted: November 23, 2021    Key Record Dates
Last Update Posted: April 12, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by American Heart Association:
Arrhythmias, Cardiac
Atrial Fibrillation
Anti-Arrhythmic Agents
Heterocyclic Compounds
Dronedarone
Multaq
Additional relevant MeSH terms:
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Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Dronedarone
Anti-Arrhythmia Agents