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Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure

Information source: Duke University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Heart Failure

Intervention: Spironolactone (Drug); Placebo (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Duke University

Official(s) and/or principal investigator(s):
Adrian Hernandez, MD, Principal Investigator, Affiliation: Duke University Health Systems
Eugene Braunwald, MD, Study Chair, Affiliation: Harvard University

Overall contact:
Doris M Coleman, RN, Phone: (919) 668-8042, Email: doris.coleman@duke.edu

Summary

The primary objective of this study is to test the hypothesis that high-dose spironolactone will lead to greater proportional reduction in NT-proBNP levels from randomization to 96 hours over standard of care.

Clinical Details

Official title: Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy - HF (ATHENA-HF)

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: Change in NT-proBNP

Secondary outcome:

Change in clinical congestion score

Change in dyspnea

Change in renal function

Effect on fluid status

Change in body weight

Effect on serum potassium levels

Need for loop diuretics

Change in acute heart failure symptoms

Detailed description: Mineralocorticoid receptor antagonist (MRA) therapy is recommended in stable chronic systolic heart failure (HF) and post-infarction HF patients for improving morbidity and mortality. MRA therapy in AHF and in high doses is less well studied. The effectiveness and safety of early high dose MRA therapy in AHF is supported by a single-blind study showing lower risk of worsening renal function and need for loop diuretics, and improved congestion. MRA therapy in AHF may improve outcomes by relieving congestion at higher doses through their natriuretic property, in addition to preventing the deleterious effects of exacerbation of neuro-hormonal activation by loop diuretics. This randomized, double blind, placebo-controlled study of high-dose spironolactone vs. placebo (for patients not receiving MRA at home) or low-dose spironolactone (for patients already receiving low-dose spironolactone) in AHF, will enroll 360 participants at approximately 30 clinical centers. After obtaining informed consent, subjects who fulfill all the inclusion criteria and none of the exclusion criteria will be randomized. Randomization will be performed by using procedures determined by the Coordinating Center (CC).

- Patients receiving no MRA therapy at baseline will be randomized to receive either

spironolactone 100 mg or placebo daily for 96 hours.

- Patients already receiving low-dose spironolactone at baseline (12. 5 mg or 25 mg daily)

will be randomized to 100 mg or 25 mg spironolactone daily for 96 hours. Within 24 hours prior to randomization, all study participants will undergo:

- Medical History

- Review of medications including pre-hospital loop diuretics, MRA, and potassium doses

- Physical examination, vital signs and body weight

- Measurement of creatinine, blood urea nitrogen (BUN), and electrolytes

- Dyspnea Relief Assessments (7-point Likert and Visual Analog Scale)

- Serum pregnancy test for all women of childbearing potential

- Collection of samples for measurement of NT-proBNP levels (Core Lab)

Study drug will be initiated as follows:

- Patients receiving no MRA therapy at baseline: 4x25 mg study capsules once daily;

starting dose 100 mg spironolactone or placebo; if dose adjustment is required, active capsules will be adjusted by pharmacy to achieve the required dose.

- Patients already receiving low-dose spironolactone at baseline: 4x25 mg study capsules

once daily; one capsule containing 25 mg spironolactone and 3x25 mg study capsules containing spironolactone or placebo; if dose adjustment is required, active capsules will be adjusted by pharmacy to achieve the required dose. Patients will be followed every 24 hours following randomization through 96 hours. Study drug will be administered daily for 96 hours. Study drug administration time is anchored to time of randomization. Dose adjustments (continue, hold, stop) are permitted according to serum K+ and renal function. Assessment at 24 hours post randomization includes: Review of medications, body weight, fluid intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and adverse events. If the 24 hour assessment is also the day of discharge, include:

- Physical exam / Vital signs

- Dyspnea Relief (7-Point Likert and VAS) worksheets

- Biomarkers (NT-proBNP) (Core Lab)

Assessment at 48 hours post randomization includes: Review of medications, physical exam/vital signs, body weight, fluid intake/urine output, Dyspnea Relief (7-Point Likert and VAS) worksheets, creatinine, blood urea nitrogen (BUN), and electrolytes, biomarker levels (NT-proBNP) by Core Lab. Assessment at 72 hours post randomization includes: Review of medications, body weight, fluid intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, and adverse events. If the 72 hour assessment is also the day of discharge, include:

- Physical exam / Vital signs

- Dyspnea Relief (7-Point Likert and VAS) worksheets

- Biomarkers (NT-proBNP) (Core Lab)

Assessment at 96 hours post randomization includes: Review of medications, physical exam/vital signs, body weight, fluid intake/urine output, creatinine, blood urea nitrogen (BUN), and electrolytes, Dyspnea Relief (7-Point Likert and VAS), and biomarker levels (NT-proBNP) by Core Lab. If patient is clinically euvolemic in less than 96 hours, the investigator may consider changing loop diuretics to oral dose. Study drug will be discontinued after 96 hours and further use of MRA will be left to the treating physician's discretion. Assessment at Discharge: If discharge occurs after the 96 hour assessment but prior to the 30 day follow-up telephone call,the following will be documented: Medication review (prescribed medications at the time of discharge), body weight (if available), creatinine, blood urea nitrogen (BUN), and electrolytes (if available), and adverse events. Ejection fraction data will be obtained from echocardiogram within 6 months prior to randomization. Those patients who do not have an echocardiogram recorded within this time frame will get an echocardiogram, nuclear perfusion study, MRI, or MUGA performed prior to the 96 hour in-hospital assessment to ascertain ejection fraction. Follow-up Telephone Call at Day 30: All participants will be contacted by telephone at day 30 (+3 days) following randomization to assess tertiary endpoints, including medication use and adverse events. Follow-up Telephone Call at Day 60: All participants will be contacted by telephone at day 60 (+/-3 days) following randomization to assess vital status. During the consent process, patients will be asked if interested in donating samples and data for research purposes via a biorepository and/or genetic study. Based on site and IRB preference, this optional part of the study may be incorporated into the main consent or may be a separate consent and IRB application.

Eligibility

Minimum age: 21 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Male or female patient ≥21 years old

- Admitted to hospital for AHF with at least 1 symptom (dyspnea, orthopnea, or

fatigue) and 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest radiography) of congestion

- Patient must be randomized within 24 hours of first IV diuretic dose administered for

the current episode of decompensation (regardless of where the diuretic was given e. g. office, ED, ambulance, hospital etc.)

- Estimated GFR of ≥30 mL/min/1. 73m2 determined by the MDRD equation

- Serum K+ ≤5. 0 mmol/L at enrollment

- NT-proBNP ≥1000 pg/mL or BNP ≥250 pg/mL, measured within 24h from randomization

- Not on MRA or on low-dose spironolactone (12. 5 mg or 25 mg daily) at baseline

Exclusion Criteria:

- Taking eplerenone or >25 mg spironolactone at baseline

- eGFR < 30 ml/min/1. 73m2

- Serum K+ >5. 0 mmol/L. If a repeat measurement within the enrollment window is <5. 0,

the patient can be considered for inclusion.

- Systolic blood pressure <90 mmHg

- Hemodynamically significant arrhythmias or defibrillator shock within 1 week

- Acute coronary syndrome currently suspected or within the past 4 weeks

- Severe liver disease (ALT or AST >3 x normal, alkaline phosphatase or bilirubin >2x

normal)

- Active infection (current use of oral or IV antimicrobial agents)

- Active gastrointestinal bleeding

- Active malignancy other than non-melanoma skin cancers

- Current or planned mechanical circulatory support within 30 days

- Post cardiac transplant or listed for transplant and expected to receive one within

30 days

- Current inotrope use

- Complex congenital heart disease

- Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis,

constrictive pericarditis or tamponade

- Previous adverse reaction to MRAs

- Enrollment in another randomized clinical trial during index hospitalization

Locations and Contacts

Doris M Coleman, RN, Phone: (919) 668-8042, Email: doris.coleman@duke.edu

Emory University School of Medicine, Atlanta, Georgia 30322, United States; Recruiting
Andrew L Smith, MD, Phone: 404-778-5273
Andrew L Smith, MD, Principal Investigator

Johns Hopkins Hospital, Baltimore, Maryland 21287, United States; Recruiting
Ryan Tedford, MD, Phone: 410-955-7534, Email: ryan.tedford@jhmi.edu
Ryan Tedford, MD, Principal Investigator

Brigham and Women's Hospital, Boston, Massachusetts 02115, United States; Recruiting
Michael Givertz, MD, Phone: 617-732-7367, Email: mgivertz@partners.org
Michael Givertz, MD, Principal Investigator

Massachusetts General Hospital, Boston, Massachusetts 02114, United States; Recruiting
Marc Semigran, MD, Phone: 617-726-8862, Email: msemigran@partners.org
Marc Semigran, MD, Principal Investigator

Tufts Medical Center, Boston, Massachusetts 02111, United States; Recruiting
Amanda Vest, MD, Email: avest@tuftsmedicalcenter.org
Amanda Vest, MD, Principal Investigator

Boston VA Healtcare System, West Roxbury, Massachusetts 02132, United States; Recruiting
Neal Lakdawala, MD, Phone: 617-525-9574, Email: nlakdawala@partners.org
Neal Lakdawala, MD, Principal Investigator

Mayo Clinic, Rochester, Minnesota 55905, United States; Recruiting
Margaret Redfield, MD, Phone: 507-284-1281, Email: redfield.margaret@mayo.edu
Margaret Redfield, MD, Principal Investigator

Saint Louis University Hospital, St. Louis, Missouri 63117, United States; Recruiting
Paul Hauptman, MD, Phone: 314-268-5293, Email: hauptmpj@slu.edu
Paul Hauptman, MD, Principal Investigator

Washington University, St. Louis, Missouri 63110, United States; Recruiting
Justin Vader, MD, Phone: 314-677-5302, Email: jvader@dom.wustl.edu
Justin Vader, MD, Principal Investigator

Stony Brook University Medical Center, Stony Brook, New York 11794, United States; Recruiting
Hal Skopicki, MD, Phone: 631-444-1117, Email: hal.skopicki@stonybrook.edu

Duke University, Durham, North Carolina 27705, United States; Recruiting
Michael Felker, MD, Phone: 919-668-8919, Email: michael.felker@duke.edu
Michael Felker, MD, Principal Investigator

Southeastern Regional Medical Center, Lumberton, North Carolina 28358, United States; Recruiting
Melvin Echols, MD, Phone: 910-386-1252, Email: melvin.echols@dm.duke.edu

Cleveland Clinic, Cleveland, Ohio 44195, United States; Recruiting
Wilson Tang, MD, Phone: 216-444-2121, Email: tangw@ccf.org
Wilson Tang, MD, Principal Investigator

Metro Health System, Cleveland, Ohio 44109, United States; Recruiting
Mark Dunlap, MD, Phone: 216-778-2711, Email: mdunlap@metrohealth.org
Mark Dunlap, MD, Principal Investigator

University Hospitals - Case Medical Center, Cleveland, Ohio 44106, United States; Recruiting
Guilherme Oliveria, MD, Phone: 216-444-4036, Email: guilherme.oliveira@uhhospitals.org
Guilherme Oliveria, MD, Principal Investigator

Lancaster General Hospital, Lancaster, Pennsylvania 17603, United States; Recruiting
Mark Etter, MD, Phone: 717-397-5484, Email: mdetter@lghealth.org
Mark Etter, MD, Principal Investigator

Jefferson Medical College, Philadelphia, Pennsylvania 19107, United States; Recruiting
David Whellan, MD, Phone: 215-955-2636, Email: david.whellan@jefferson.edu
David Whellan, MD, Principal Investigator

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Recruiting
Kenneth Margulies, MD, Phone: 215-707-2006, Email: ken.margulies@uphs.upenn.edu
Kenneth Margulies, MD, Principal Investigator

Michael Debakey VA Medical Center, Houston, Texas 77030, United States; Recruiting
Anita Deswal, MD, Phone: 713-794-7441, Email: adeswal@bcm.tmc.edu
Anita Deswal, MD, Principal Investigator

University of Utah School of Medicine, Salt Lake City, Utah 84132, United States; Recruiting
Edward Gilbert, MD, Phone: 801-585-2340, Email: edward.gilbert@hsc.utah.edu
Edward Gilbert, MD, Principal Investigator

Utah VA Medical Center, Salt Lake City, Utah 84132, United States; Not yet recruiting
Edward Gilbert, MD, Phone: 801-585-2340, Email: edward.gilbert@hsc.utah.edu
Edward Gilbert, MD, Principal Investigator

The University of Vermont- Fletcher Allen Health Care, Burlington, Vermont 05401, United States; Recruiting
Peter Van Buren, MD, Phone: 802-847-2879, Email: peter.vanburen@vtmednet.org
Peter Van Buren, MD, Principal Investigator

Additional Information

Starting date: December 2014
Last updated: May 14, 2015

Page last updated: August 23, 2015

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