Clinical trial NCT01800968: Functional Impact of GLP-1 for Heart Failure Treatment (FIGHT)
Official title: Functional Impact of GLP-1 for Heart Failure Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Heart Failure
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2013-02-28
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective is to test the hypothesis that, compared with placebo, therapy with Subcutaneous (SQ) GLP-1 agonist in the post-Acute Heart Failure Syndrome (AHFS) discharge period will be associated with greater clinical stability at six months as assessed by a composite clinical endpoint.

Detailed description: Hospitalization for AHFS identifies individuals at increased risk of death and re-hospitalization following discharge. This increased risk justifies intervention with novel therapy during the vulnerable post-discharge period to enhance clinical stability and prevent early HF mortality and readmissions.

As heart failure (HF) progresses, impairments in metabolism render the heart substrate constrained, limiting cardiac metabolism. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin peptide that enhances cellular glucose uptake by stimulating insulin secretion and insulin sensitivity in target tissues. Preclinical and early-phase clinical data support GLP-1 as an effective therapy for advanced HF while use of GLP-1 receptor agonists in large numbers of patients with diabetes reveal a good safety profile and reductions in adverse cardiac outcomes.

Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years
2. AHFS as defined by the presence of at least 1 symptom (dyspnea, orthopnea, or edema) AND 1 sign (rales on auscultation, peripheral edema, ascites, pulmonary vascular congestion on chest radiography)
3. AHFS is the primary cause of hospitalization
4. Prior clinical diagnosis of HF
5. Left Ventricular Ejection Fraction(LVEF) ≤ 40% during the preceding 3 months (if no echo within the preceding 3 months, an LVEF ≤ 30% during the preceding three years is acceptable)
6. On evidence-based medication for HF (including beta-blocker and ACE-inhibitor/ARB) or previously deemed intolerant
7. Use of at least 80 mg or furosemide total daily dose (or equivalent) prior to admission for AHFS (a lower dose of a loop diuretic combined with a thiazide will count as an "equivalent")
8. Willingness to provide informed consent

Exclusion Criteria:

1. AHFS due to acute myocarditis or acute Myocardial Infarction
2. Ongoing hemodynamically significant arrhythmias contributing to HF decompensation
3. Inotrope, intra-aortic balloon pump (IABP) or other mechanical circulatory support use at the time of consent. Prior use will not exclude a patient.
4. Current or planned left ventricular assist device therapy in next 180 days
5. United Network for Organ Sharing status 1A or 1B
6. B-type natriuretic peptide(BNP)\< 250 or NT-proBNP\<1,000 (Not required per protocol but if available and too low would be an exclusion; within 48 hours of consent)
7. Hemoglobin (Hgb) \< 8.0 g/dl
8. Glomerular filtration rate(GFR) \< 20 ml/min/1.73 m2 within 48 hours of consent
9. Systolic blood pressure \< 80 mmHg at consent
10. Resting Heart Rate \> 110 at consent
11. Acute coronary syndrome within 4 weeks as defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g. troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)
12. Percutaneous Coronary Intervention, coronary artery bypass grafting or new biventricular pacing within past 4 weeks
13. Primary hypertrophic cardiomyopathy
14. Infiltrative cardiomyopathy
15. Constrictive pericarditis or tamponade
16. Complex congenital heart disease
17. Non-cardiac pulmonary edema
18. More than moderate aortic or mitral stenosis
19. Intrinsic (prolapse, rheumatic) valve disease with severe mitral, aortic or tricuspid regurgitation
20. Sepsis, active infection (excluding cystitis) or other comorbidity driving the HF decompensation
21. Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, International Normalized Ration (INR) \> 1.7 in the absence of anticoagulation treatment
22. Terminal illness (other than HF) with expected survival of less than 1 year
23. Previous adverse reaction to the study drug
24. Receipt of any investigational product in the previous 30 days.
25. Enrollment or planned enrollment in another randomized therapeutic clinical trial in next 6 months.
26. Inability to comply with planned study procedures
27. Pregnancy or breastfeeding mothers
28. Women of reproductive age not on adequate contraception
29. History of acute or chronic pancreatitis
30. History of symptomatic gastroparesis
31. Familial or personal history of medullary thyroid cancer or multiple endocrine neoplasia type-2 (MEN2)
32. Prior weight-loss surgery (i.e., Roux-en-Y gastric bypass) or other gastric surgery associated with increased endogenous GLP-1 production
33. Prior or ongoing treatment with GLP-1 receptor agonists
34. Ongoing treatment with dipeptidyl peptide-IV inhibitors (1 week washout required)
35. Ongoing treatment with thiazolidinedione
36. Oxygen-dependent chronic obstructive pulmonary disease
37. Diabetic patients with history of 2 or more severe hypoglycemia, Diabetic Ketoacidosis(DKA) or hyperglycemic, hyperosmotic nonketotic coma in the preceding 12 months.
38. Diagnosis of Type 1 Diabetes Mellitus

40. If diabetic, inadequate glycemic control with glucose level \> 300 mg/dL within 24 hours of randomization

Primary outcomes:
measure: Global Ranking of Predefined Events
timeFrame: Randomization to 180 days
Secondary outcomes:
measure: Change in Left Ventricular End-Diastolic Volume Index
timeFrame: Baseline to 180 days
measure: Change in Left Ventricular End-systolic Volume Index
timeFrame: Baseline to 180 days
measure: Change in Left Ventricular Ejection Fraction
timeFrame: Baseline to 180 days
measure: Change in Medial Filling Pressure
timeFrame: Baseline to 180 days
measure: Change in Lateral Filling Pressure
timeFrame: Baseline to 180 days
measure: Change in 6 Minute Walk Distance
timeFrame: Baseline to day 30
measure: Change in 6 Minute Walk Distance
timeFrame: Baseline to 90 days
measure: Change in 6 Minute Walk Distance
timeFrame: Baseline to 180 days
measure: Change in Clinical Summary Score Using the Kansas City Cardiomyopathy Questionnaire (KCCQ)
timeFrame: Baseline to 30 days
measure: Change in Clinical Summary Score Using the Kansas City Cardiomyopathy Questionnaire (KCCQ)
timeFrame: Baseline to 90 days
measure: Change in Clinical Summary Score Using the Kansas City Cardiomyopathy Questionnaire (KCCQ)
timeFrame: Baseline to day 180
measure: Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score
timeFrame: Baseline to 30 days
measure: Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score
timeFrame: Baseline to 90 days
measure: Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score.
timeFrame: Baseline to 180 days
measure: Individual Component of the Primary Endpoint- Mortality
timeFrame: Randomization to 180 days
measure: Individual Component of the Primary Endpoint- Heart Failure Hospitalization
timeFrame: Randomization to 180 days
measure: Individual Component of the Primary Endpoint- Time-averaged Proportional Change in NT-proBNP
timeFrame: Baseline to 180 days
measure: Global Ranking of Predefined Events
timeFrame: Baseline to 180 days
Other outcomes:
Locations:
city: Newark
country: United States
facility: Christiana Care Health Services
state: Delaware
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: West Roxbury
country: United States
facility: Boston VA Healtcare System
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Louis
country: United States
facility: Washington University
state: Missouri
city: St. Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Lumberton
country: United States
facility: Southeast Regional Medical Center
state: North Carolina
city: Cleveland
country: United States
facility: University Hospitals- Case Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Metro Health System
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Lancaster
country: United States
facility: Lancaster Heart and Stroke Foundation
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvaina
state: Pennsylvania
city: Philadelphia
country: United States
facility: Jefferson Medical College
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Houston
country: United States
facility: Michael Debakey VA Medical Center
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah School of Medicine
state: Utah
city: Salt Lake City
country: United States
facility: Utah VA Medical Center
state: Utah
city: Burlington
country: United States
facility: The University of Vermont- Fletcher Allen Health Care
state: Vermont
Study officials:
affiliation: Duke University
name: Adrian Hernandez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Harvard University
name: Eugene Bruanwald, MD
role: STUDY_CHAIR
References:
citation: Lerman JB, Giamberardino SN, Hernandez AF, Felker GM, Shah SH, McGarrah RW. Plasma metabolites associated with functional and clinical outcomes in heart failure with reduced ejection fraction with and without type 2 diabetes. Sci Rep. 2022 Jun 2;12(1):9183. doi: 10.1038/s41598-022-12973-0.
citation: Redouane B, Greene SJ, Fudim M, Vaduganathan M, Ambrosy AP, Sun JL, DeVore AD, McNulty SE, Mentz RJ, Hernandez AF, Felker GM, Cooper LB, Borlaug BA, Velazquez EJ, Margulies KB, Sharma A. Effects of Liraglutide on Worsening Renal Function Among Patients With Heart Failure With Reduced Ejection Fraction: Insights From the FIGHT Trial. Circ Heart Fail. 2020 May;13(5):e006758. doi: 10.1161/CIRCHEARTFAILURE.119.006758. Epub 2020 May 4.
citation: Sharma A, Ambrosy AP, DeVore AD, Margulies KB, McNulty SE, Mentz RJ, Hernandez AF, Michael Felker G, Cooper LB, Lala A, Vader J, Groake JD, Borlaug BA, Velazquez EJ. Liraglutide and weight loss among patients with advanced heart failure and a reduced ejection fraction: insights from the FIGHT trial. ESC Heart Fail. 2018 Dec;5(6):1035-1043. doi: 10.1002/ehf2.12334. Epub 2018 Aug 17.
citation: Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, Mann DL, Whellan DJ, Kiernan MS, Felker GM, McNulty SE, Anstrom KJ, Shah MR, Braunwald E, Cappola TP; NHLBI Heart Failure Clinical Research Network. Effects of Liraglutide on Clinical Stability Among Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):500-8. doi: 10.1001/jama.2016.10260.