Early Dronedarone Versus Usual Care to Improve Outcomes in Persons With Newly Diagnosed Atrial Fibrillation

Last updated: January 27, 2025
Sponsor: American Heart Association
Overall Status: Completed

Phase

4

Condition

Atrial Fibrillation

Chest Pain

Arrhythmia

Treatment

Dronedarone

Clinical Study ID

NCT05130268
176131-M
  • Ages > 21
  • All Genders

Study 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.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Age >=21 years.

  2. First-detected atrial fibrillation (defined as atrial fibrillation diagnosed in theprevious 120 days).

  3. Electrocardiographic documentation of atrial fibrillation.

  4. Estimated life expectancy of at least 1 year.

  5. Patient or legal authorized representative capable of giving signed informedconsent, which includes compliance with the requirements and restrictions listed inthe informed consent form (ICF) and in this protocol.

Exclusion

Exclusion Criteria:

  1. Patients with prior or planned treatment with rhythm control, either catheterablation or chronic (>7 days) antiarrhythmic drug therapy.

  2. Planned cardiothoracic surgery. 4. New York Heart Association class III or IV heartfailure or a hospitalization for heart failure in the last 4 weeks.

  3. Patients with reduced ejection fraction (LVEF ≤40%). 6. Permanent atrialfibrillation. 7. Ineligible for oral anticoagulation, unless CHA2DS2-VASc is lessthan 3 in women or 2 in men.

  4. Bradycardia with a resting heart rate < 50 bpm 9. PR interval >280 msec or 2nddegree or 3rd degree atrioventricular block without a permanent pacemaker/cardiacimplanted electronic device.

  5. Corrected QT interval >=500 msec. 11. Pregnancy or breast feeding. 12. Severehepatic impairment in the opinion of the investigator.

Study Design

Total Participants: 339
Treatment Group(s): 1
Primary Treatment: Dronedarone
Phase: 4
Study Start date:
October 29, 2021
Estimated Completion Date:
June 30, 2024

Study Description

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice, accounting for one-third of arrhythmia-related hospitalizations.1 As many as 1 in 4 people develop AF over their lifetime after the age of 40 years. The prevalence and burden of AF in the United States is substantial; the age-adjusted incidence and prevalence has increased over the last 3 decades. Moreover, the number of Americans with AF is expected to increase 150% by 2050. The goals of care in the treatment of AF include (1) the management and reduction of risk factors, (2) prevention of tachycardia (rate control), (3) prevention of stroke, and (4) improvement of symptoms. Reduction or elimination of symptoms often requires rhythm control. Historically, randomized clinical trials have not demonstrated a mortality or stroke benefit with a rhythm control versus a rate control strategy.

Despite the failure of prior randomized clinical trials to demonstrate the superiority of rhythm control, the recent Early Treatment of Atrial Fibrillation for Stroke Prevention 4 (EAST-AFNET 4) trial demonstrated that early introduction of a comprehensive rhythm-control strategy (within one year of diagnosis) is superior to guideline-based usual care in improving cardiovascular (CV) outcomes at a mean follow-up of 5 years. The EAST-AFNET 4 trial found that early rhythm control reduced the primary outcome of CV death, stroke, hospitalization for heart failure (HF), or acute coronary syndrome (HR 0.79, 96% confidence interval (CI) 0.66-0.94, p = 0.005). EAST-AFNET 4 also demonstrated a reduction in the risk of stroke with early introduction of rhythm control (HR 0.65, 95% CI 0.44-0.98), a finding that was also observed with dronedarone in the ATHENA trial. In addition, maintenance of sinus rhythm has been associated with improved quality of life and increased exercise capacity in some patients. Outside of clinical trials, a quality-of-life study from the Registry on Cardiac Rhythm Disorders Assessing the Control of Atrial Fibrillation (RECORD-AF) found that rhythm control was associated with better quality of life.

There are several antiarrhythmic drugs (AADs) available for rhythm control of AF. Class I antiarrhythmic agents are predominantly limited to younger patients without coronary artery or structural heart disease. Patients with advanced chronic kidney disease, prolonged QT intervals, and/or severe left ventricular hypertrophy should not be treated with sotalol or dofetilide. Even when sotalol or dofetilide can be used, patients are often hesitant to start a medication that requires an inpatient hospitalization for drug loading and laboratory evaluation every 3 months. Amiodarone has been shown to be the most effective AAD for maintaining sinus rhythm in patients with AF; however, based on its side effect profile, amiodarone is only recommended as a first-line agent under specific clinical circumstances. Moreover, despite its efficacy, amiodarone has high rates of discontinuation due to frequent adverse events. In addition to its unfavorable side effects, several studies, including those of patients at risk for sudden cardiac death, have demonstrated an association between amiodarone use and higher mortality, as well as lower functional status. In contrast to amiodarone, dronedarone is a much better tolerated antiarrhythmic medication. In randomized controlled trials, dronedarone has been shown to prevent recurrent AF, improve rate control, and decrease cardiovascular hospitalization in patients with AF.

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 or new-onset AF. After appropriate evaluation for oral anticoagulation, these patients are often started on an atrioventricular nodal blocking agent (beta-blocker or non-dihydropyridine calcium channel blocker). The investigators hypothesize that earlier administration of a well-tolerated antiarrhythmic drug proven to reduce hospitalization may result in improved quality of life and cardiovascular outcomes in patients with first-detected AF.

Risk Assessment:

Dronedarone is approved by the Food and Drug Administration to reduce the risk of hospitalization for AF in patients with paroxysmal or persistent AF. The efficacy and safety of dronedarone 400 mg twice daily was evaluated in five controlled studies, ATHENA, ANDROMEDA, European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS), ADONIS, and Dronedarone Atrial FibrillatioN study after Electrical Cardioversion (DAFNE), involving more than 6,000 patients with including more than 3200 patients who received dronedarone. As with any therapeutic agent, there are known risks with dronedarone therapy. These risks include hepatic injury, heart failure exacerbation, increased exposure to digoxin, increased plasma concentration of tacrolimus, sirolimus, and other Cytochrome P450, family 3, subfamily A (CYP 3A) substrates, and very rare instances of pulmonary toxicity. The risks of dronedarone are felt to be outweighed by its benefits. The guideline recommendations provided by the European Society of Cardiology and American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) are commensurate with this risk benefit assessment.

Benefit Assessment:

While there are no completed randomized clinical trials to guide selection or initiation of rhythm control therapies in patients with first-detected AF, there are recent trials that suggest benefit with both dronedarone antiarrhythmic therapy and early-initiation of rhythm control in persons with AF. the recent EAST-AFNET 4 trial demonstrated that early introduction of a comprehensive rhythm-control strategy (within one year of diagnosis) is superior to usual guideline-recommended care in improving cardiovascular (CV) outcomes at 5 years. The median time from new-onset AF to randomization in the EAST-AFNET4 trial was 36 days. The trial found that early rhythm control reduced the primary outcome of CV death, stroke, hospitalization for HF, or acute coronary syndrome (HR 0.79, 95% confidence interval 0.66-0.94, p = 0.005). EAST-AFNET 4 also demonstrated a reduction in the risk of stroke with early introduction of rhythm control (HR 0.65, 95% CI 0.44-0.98), a finding that was also observed with dronedarone in the ATHENA trial. Thus, the investigators hypothesize that early initiation of dronedarone in patients with new-onset AF will lead to a reduction in CV hospitalization or death.

Overall Design:

Dronedarone is approved by the Food and Drug Administration to reduce the risk of CV hospitalization in patients with AF or atrial flutter. However, it is unknown if dronedarone (or any antiarrhythmic medication) can reduce CV hospitalization or death in patients with first-detected AF. This trial has been designed to address this important question. In order to facilitate the trial enrollment, data collection, and a generalizability to clinical practice, the CHANGE AFIB study has been designed as an open-label pragmatic clinical trial nested within the Get With The Guidelines (GWTG) Atrial Fibrillation registry. At present the overall GWTG program is being implemented in over 2,300 hospitals across the U.S. and is comprised of over 9 million patient records, with an estimated 650,000 new patient records entered per year. The trial will utilize the existing GWTG registry network, data collection architecture, and experience to facilitate both enrollment and conduct of the trial.

The comparator arm will be "usual care." Thus, this study will compare usual care plus dronedarone versus usual care alone. 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 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.

CHANGE AFIB will leverage several critical advantages as a pragmatic clinical trial. Data collection will be integrated into the Get With The Guidelines AFIB registry. The use of the GWTG-AFIB registry will also enhance subject recruitment and ensure the enrollment of a diverse group of patients. The randomized intervention will be compared with usual care thus further enhancing generalizability. Follow-up visits will be minimized to reduce patient burden. Moreover, follow-up visits will have "windows" to accommodate variation in follow-up intervals at different centers.

Justification for Study Drug Intervention and Dose:

Dronedarone is a non-iodinated benzofuran similar to amiodarone but is not associated with thyroid or pulmonary toxicity in randomized clinical trials or post-marketing observational studies. Dronedarone has electrophysiological characteristics spanning all 4 Vaughan-Williams anti-arrhythmic classes, with primarily class III effects. Initial trials suggested that dronedarone prolonged the time to recurrence of AF and reduced cardiovascular death and hospitalization.

The landmark ATHENA trial evaluated the efficacy and safety of dronedarone in patients with atrial arrhythmias (atrial fibrillation or atrial flutter). This trial did not include patients with a recent history of New York Heart Association (NYHA) class IV heart failure or recent hospitalization for decompensated heart failure (<4 weeks). Approximately, 30% of the ATHENA population had NYHA class I-III heart failure. ATHENA demonstrated that dronedarone 400 mg twice daily (in combination with background therapy) reduced the combined endpoint of CV hospitalization or death from any cause by 24% (p<0.001) compared with placebo. Of course, the ATHENA trial was not conducted in the special population of patients with a new diagnosis of AF. There are no randomized trials or guideline recommendations for antiarrhythmic therapy at the time of first-detected AF. A subgroup analysis from the ATHENA trial suggests that optimal outcomes may be achieved in those patients with shorter duration of AF (time from diagnosis). Similar observations have also been made in patients undergoing other forms of rhythm control, including catheter ablation. In this trial, patients with first-detected AF will be randomized to dronedarone on top of usual care versus usual care alone. Patients randomized to the intervention arm will be prescribed and treated with Dronedarone 400 mg bid. This dose has been chosen as it is the Food and Drug Administration approved dose as well as the dose recommended in current international guidelines. Dronedarone has also been shown to be an effective rate control agent as well. In the ERATO study treatment with dronedarone 400 mg twice daily let to a mean reduction of 24.5 beat/min in patients with permanent AF when compared with placebo. In the EURIDIS/ADONIS studies the mean difference in patients with paroxysmal/persistent AF during AF recurrence was 14 beats/min. Moreover, the dronedarone treated patients experienced improved rate control without any reduction in exercise tolerance as measured by maximal exercise.

Connect with a study center

  • Thomas Hospital

    Fairhope, Alabama 36532
    United States

    Site Not Available

  • Mercy Gilbert Medical Center

    Gilbert, Arizona 85297
    United States

    Site Not Available

  • HonorHealth Scottsdale Shea Medical Center

    Scottsdale, Arizona 85260
    United States

    Site Not Available

  • Cedars Sinai Medical Center

    Los Angeles, California 90048
    United States

    Site Not Available

  • Los Angeles Medical Center (Kaiser Permenente)

    Los Angeles, California 90027
    United States

    Site Not Available

  • West Los Angeles Medical Center

    Los Angeles, California 90034
    United States

    Site Not Available

  • UC Irvine Medical Center (AKA UCI Health)

    Orange, California 92868
    United States

    Site Not Available

  • Los Robles Health System - Los Robles Regional Medical Center

    Thousand Oaks, California 91360
    United States

    Site Not Available

  • UCLA Medical Center - Harbor

    Torrance, California 90502
    United States

    Site Not Available

  • Colorado Heart & Vascular Group - St. Anthony's Hospital

    Lakewood, Colorado 80228
    United States

    Site Not Available

  • Colorado Heart & Vascular Group - St. Anthony's North Health Campus

    Westminster, Colorado 80023
    United States

    Site Not Available

  • Christiana Hospital

    Newark, Delaware 19718
    United States

    Site Not Available

  • First Coast Cardiovascular Institute

    Jacksonville, Florida 32256
    United States

    Site Not Available

  • Enmanuel Advanced Research Center, LLC

    Miami, Florida 33126
    United States

    Site Not Available

  • Excellence Medical And Research, LLC

    Miami, Florida 33169
    United States

    Site Not Available

  • Golden Touch Clinical Research

    Miami, Florida 33144
    United States

    Site Not Available

  • Life Spring Research Foundation, LLC

    Miami, Florida 33130
    United States

    Site Not Available

  • Nouvelle Clinical Research LLC

    Miami, Florida 33130
    United States

    Site Not Available

  • The Miami Research Group

    Miami, Florida 33186
    United States

    Site Not Available

  • Ocean Wellness Center, LLC

    Miami Gardens, Florida 33169
    United States

    Site Not Available

  • Pharma Medical Innovations

    Miami Lakes, Florida 33014
    United States

    Site Not Available

  • The Angel Medical Research

    Miami Lakes, Florida 33156
    United States

    Site Not Available

  • Northside Hospital

    Saint Petersburg, Florida 33709
    United States

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  • Guardian Angel Research Center

    Tampa, Florida 33614
    United States

    Site Not Available

  • Northeast Georgia Medical Center

    Gainesville, Georgia 30501
    United States

    Site Not Available

  • Georgia Arrhythmia Consultants and Research Institute

    Macon, Georgia 31201
    United States

    Site Not Available

  • Wellstar Kennestone Hospital

    Marietta, Georgia 30062
    United States

    Site Not Available

  • Mt Sinai Hospital Medical Center

    Chicago, Illinois 60608
    United States

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  • Rush University Medical Center

    Chicago, Illinois 60612
    United States

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  • University of Illinois Hospital

    Chicago, Illinois 60612
    United States

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  • Riverside Medical Center

    Kankakee, Illinois 60901
    United States

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  • Loyola University Medical Center

    Maywood, Illinois 60153
    United States

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  • Captain James A Lovell Federal Health Care Center

    North Chicago, Illinois 60064
    United States

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  • Methodist Medical Center of Illinois

    Peoria, Illinois 61636
    United States

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  • Proctor Community Hospital

    Peoria, Illinois 61614
    United States

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  • Trinity Rock Island

    Rock Island, Illinois 61201
    United States

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  • St. Elizabeth's Hospital of the Hospital Sisters of the Third Order of St. Francis

    Springfield, Illinois 62769
    United States

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  • St. John's Hospital of the Hospital Sisters of the Third Order of St. Francis

    Springfield, Illinois 62769
    United States

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  • Carle Foundation Hospital

    Urbana, Illinois 61801
    United States

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  • Parkview Hospital, Inc.

    Fort Wayne, Indiana 46845
    United States

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  • Ascension St Vincent Hospital - Indianapolis

    Indianapolis, Indiana 46260
    United States

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  • Kansas City Heart and Vascular Specialists at Providence Medical Center

    Kansas City, Kansas 66112
    United States

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  • Overland Park Regional Medical Center

    Overland Park, Kansas 66215
    United States

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  • Baptist Health Lexington

    Lexington, Kentucky 40223
    United States

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  • Saint Joseph Hospital

    Lexington, Kentucky 40504
    United States

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  • Heart Clinic of Hammond

    Hammond, Louisiana 70403
    United States

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  • Tulane Medical Center

    New Orleans, Louisiana 70112
    United States

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  • Luminis Health Anne Arundel Medical Center

    Annapolis, Maryland 21401
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    Baltimore, Maryland 21229
    United States

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    Rockville, Maryland 20850
    United States

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  • Brigham and Womens Hospital

    Boston, Massachusetts 02115
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  • McLaren Bay Region

    Bay City, Michigan 48708
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  • DMC Harper University Hospital (AKA Wayne State University Hospital)

    Detroit, Michigan 48201
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  • Sparrow Hospital

    Lansing, Michigan 48912
    United States

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  • McLaren Macomb

    Mount Clemens, Michigan 48043
    United States

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  • Trinity Health Ann Arbor Hospital - Michigan Heart

    Ypsilanti, Michigan 48197
    United States

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  • Minneapolis VA Health Care System

    Minneapolis, Minnesota 55417
    United States

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  • University Hospital - University of Missouri

    Columbia, Missouri 65211
    United States

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  • Barnes-Jewish Hospital (AKA Washington Univ)

    Saint Louis, Missouri 63110
    United States

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  • SSM Health Saint Louis University Hospital

    Saint Louis, Missouri 63110
    United States

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  • Mercy Hospital Springfield

    Springfield, Missouri 65804
    United States

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  • CHI Health Creighton University Medical Center - Bergan Mercy

    Omaha, Nebraska 68124
    United States

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  • Cooper University Hospital

    Camden, New Jersey 08103
    United States

    Site Not Available

  • The Valley Hospital

    Ridgewood, New Jersey 07450
    United States

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  • Albany Medical Center

    Albany, New York 12208
    United States

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  • NYC Health and Hospitals - Jacobi

    Bronx, New York 10461
    United States

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  • NYC Health and Hospitals - Lincoln

    Bronx, New York 10451
    United States

    Site Not Available

  • NYC Health and Hospitals - North Central Bronx

    Bronx, New York 10467
    United States

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  • Memorial Sloan Kettering

    New York, New York 10065
    United States

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  • NewYork-Presbyterian/Columbia University Irving Medical Center

    New York, New York 10032
    United States

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  • DiGiovanna Institute for Medical Education & Research

    North Massapequa, New York 11758
    United States

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  • Duke University Hospital

    Durham, North Carolina 27705
    United States

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  • Durham VA Health Care System

    Durham, North Carolina 27705
    United States

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  • WakeMed Raleigh Campus

    Raleigh, North Carolina 27610
    United States

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  • New Hanover Regional Medical Center

    Wilmington, North Carolina 28411
    United States

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  • Trinity Hospital

    Minot, North Dakota 58702
    United States

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  • The MetroHealth System

    Cleveland, Ohio 44109
    United States

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  • Kettering Health Dayton

    Dayton, Ohio 45405
    United States

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  • Miami Valley Hospital

    Dayton, Ohio 45409
    United States

    Site Not Available

  • Kettering Medical Center

    Kettering, Ohio 45429
    United States

    Site Not Available

  • McLaren - St Lukes Hospital

    Maumee, Ohio 43537
    United States

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  • Wooster Community Hospital Health System

    Wooster, Ohio 44691
    United States

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  • Oklahoma City VA Health Care System

    Oklahoma City, Oklahoma 73104
    United States

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  • University of Oklahoma Health Sciences Center

    Oklahoma City, Oklahoma 73104
    United States

    Site Not Available

  • Penn State Health Holy Spirit Medical Center

    Camp Hill, Pennsylvania 17011
    United States

    Site Not Available

  • Penn State Health Milton S Hershey Medical Center

    Hershey, Pennsylvania 17033
    United States

    Site Not Available

  • Penn State Health St Joseph Medical Center - Main Campus

    Reading, Pennsylvania 19605
    United States

    Site Not Available

  • Ascension Saint Thomas Midtown

    Nashville, Tennessee 37236
    United States

    Site Not Available

  • Ascension Seton Medical Center Austin

    Austin, Texas 78723
    United States

    Site Not Available

  • Texas Health Fort Worth (FKA Texas Health Harris Methodist Hospital Fort Worth)

    Fort Worth, Texas 76104
    United States

    Site Not Available

  • Memorial Hermann - Texas Medical Center

    Houston, Texas 77030
    United States

    Site Not Available

  • Texas Institute of Cardiology

    McKinney, Texas 75071
    United States

    Site Not Available

  • Synapse Clinical Research

    Missouri City, Texas 77549
    United States

    Site Not Available

  • University Hospital at University of Texas San Antonio

    San Antonio, Texas 78229
    United States

    Site Not Available

  • University of Utah Hospital

    Salt Lake City, Utah 84132
    United States

    Site Not Available

  • Chippenham and Johnston Willis Medical Center

    Richmond, Virginia 23225
    United States

    Site Not Available

  • Hunter Holmes McGuire VA Medical Center (AKA Richmond VA Medical Center)

    Richmond, Virginia 23249
    United States

    Site Not Available

  • JW Ruby Memorial Hospital

    Morgantown, West Virginia 26506
    United States

    Site Not Available

  • Mayo Clinic Hospital - Franciscan Healthcare La Crosse

    La Crosse, Wisconsin 54601
    United States

    Site Not Available

  • UW Health at the American Center (AKA UW Health East Madison Hospital)

    Madison, Wisconsin 53718
    United States

    Site Not Available

  • University Hospital - University of Wisconsin-Madison

    Madison, Wisconsin 53792
    United States

    Site Not Available

  • Marshfield Medical Center

    Marshfield, Wisconsin 54449
    United States

    Site Not Available

  • Marshfield Medical Center

    Weston, Wisconsin 54476
    United States

    Site Not Available

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