Functional Impact of GLP-1 for Heart Failure Treatment (FIGHT) (FIGHT)

Functional Impact of GLP-1 for Heart Failure Treatment

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.

Study Overview

• Status: Completed
• Conditions: Acute Heart Failure
• Intervention / Treatment: Drug: Placebo; Drug: Liraglutide

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.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care Health Services
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • West Roxbury, Massachusetts, United States, 02132
      • Boston VA Healtcare System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University
    • St. Louis, Missouri, United States, 63117
      • Saint Louis University Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University
    • Lumberton, North Carolina, United States, 28538
      • Southeast Regional Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44109
      • Metro Health System
    • Cleveland, Ohio, United States, 44106
      • University Hospitals- Case Medical Center
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17603
      • Lancaster Heart and Stroke Foundation
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson Medical College
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvaina
  • Texas
    • Houston, Texas, United States, 77030
      • Michael DeBakey VA Medical Center
  • Utah
    • Murray, Utah, United States, 84157
      • Intermountain Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah School of Medicine
    • Salt Lake City, Utah, United States, 84132
      • Utah VA Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • The University of Vermont- Fletcher Allen Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Liraglutide; Increasing dose from 0.6mg, 1.2mg to 1.8mg SQ daily.	Drug: Liraglutide; Active Drug; Other Names: Victoza
Placebo Comparator: Placebo; Placebo dose increasing from 0.6mg, 1.2mg to 1.8 mg SQ daily.	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global Ranking of Predefined Events	A rank score based on time to death, time to adjudicated heart failure hospitalization, and time-averaged proportional change in NTproBNP through d180. For patients that died, the patient with the shortest time from randomization to death is assigned rank 1, the second shortest time is assigned rank 2, etc. The patient with the longest time from randomization to death is assigned rank X. For patients that did not die but had a heart failure hospitalization, the patient with the shortest time from randomization to re-admission is assigned rank X+1 and the patient with the longest time from randomization to heart failure hospitalization is assigned rank Y. For patients that did not die or have a heart failure hospitalization, increases in time-averaged proportional change in NTproBNP indicate a worse result and the largest increase is assigned rank Y+1. The patient with the largest decrease is assigned rank N, where N is the sample size.	Randomization to 180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Left Ventricular End-Diastolic Volume Index	Change in Left Ventricular End-Diastolic Volume Index from baseline to 180 days.	Baseline to 180 days
Change in Left Ventricular End-systolic Volume Index	Change in left ventricular end-systolic volume index from baseline to day 180.	Baseline to 180 days
Change in Left Ventricular Ejection Fraction	Change in left ventricular ejection fraction from baseline to day 180	Baseline to 180 days
Change in Medial Filling Pressure	Change in medial filling pressure baseline to day 180.	Baseline to 180 days
Change in Lateral Filling Pressure	Change in lateral filling pressure baseline to day 180.	Baseline to 180 days
Change in 6 Minute Walk Distance	Change in 6 minute walk distance baseline to day 30	Baseline to day 30
Change in 6 Minute Walk Distance	Change in 6 minute walk distance baseline to 90 days.	Baseline to 90 days
Change in 6 Minute Walk Distance	Change in 6 minute walk distance baseline to 180 days.	Baseline to 180 days
Change in Clinical Summary Score Using the Kansas City Cardiomyopathy Questionnaire (KCCQ)	Change in clinical summary score using the Kansas City Cardiomyopathy Questionnaire (KCCQ) baseline to 30 days. The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life.In the KCCQ, an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Each question is answered by the subject on a 6 point scale (Extremely limited, quite a bit limited, moderately limited, slightly limited, not at all limited, Limited for other reasons or did not do this activity).Scores are transformed to a range of 0-100, in which higher scores reflect better health status.	Baseline to 30 days
Change in Clinical Summary Score Using the Kansas City Cardiomyopathy Questionnaire (KCCQ)	Change in clinical summary score using the Kansas City Cardiomyopathy Questionnaire (KCCQ) baseline to 90 days.The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life.In the KCCQ, an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Each question is answered by the subject on a 6 point scale (Extremely limited, quite a bit limited, moderately limited, slightly limited, not at all limited, Limited for other reasons or did not do this activity).Scores are transformed to a range of 0-100, in which higher scores reflect better health status.	Baseline to 90 days
Change in Clinical Summary Score Using the Kansas City Cardiomyopathy Questionnaire (KCCQ)	Change in clinical summary score using the Kansas City Cardiomyopathy Questionnaire (KCCQ) from baseline to day 180.The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life.In the KCCQ, an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Each question is answered by the subject on a 6 point scale (Extremely limited, quite a bit limited, moderately limited, slightly limited, not at all limited, Limited for other reasons or did not do this activity).Scores are transformed to a range of 0-100, in which higher scores reflect better health status.	Baseline to day 180
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score	Kansas City Cardiomyopathy Questionnaire (KCCQ) change in overall summary score baseline to 30 days.The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life.In the KCCQ, an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Each question is answered by the subject on a 6 point scale (Extremely limited, quite a bit limited, moderately limited, slightly limited, not at all limited, Limited for other reasons or did not do this activity).Scores are transformed to a range of 0-100, in which higher scores reflect better health status.	Baseline to 30 days
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score	Kansas City Cardiomyopathy Questionnaire (KCCQ) change in overall summary score baseline to 90 days.The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life.In the KCCQ, an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Each question is answered by the subject on a 6 point scale (Extremely limited, quite a bit limited, moderately limited, slightly limited, not at all limited, Limited for other reasons or did not do this activity).Scores are transformed to a range of 0-100, in which higher scores reflect better health status.	Baseline to 90 days
Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score.	Kansas City Cardiomyopathy Questionnaire (KCCQ) change in overall summary score baseline to 180 days.The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life.In the KCCQ, an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Each question is answered by the subject on a 6 point scale (Extremely limited, quite a bit limited, moderately limited, slightly limited, not at all limited, Limited for other reasons or did not do this activity).Scores are transformed to a range of 0-100, in which higher scores reflect better health status.	Baseline to 180 days
Individual Component of the Primary Endpoint- Mortality	Individual component of the primary endpoint of mortality at 180 days after randomization	Randomization to 180 days
Individual Component of the Primary Endpoint- Heart Failure Hospitalization	Individual component of the primary endpoint- Heart Failure hospitalization from randomization to 180 days	Randomization to 180 days
Individual Component of the Primary Endpoint- Time-averaged Proportional Change in NT-proBNP	Individual component of the primary endpoint- time-averaged proportional change in NT-proBNP from baseline to 180 days	Baseline to 180 days
Global Ranking of Predefined Events	A rank score based on time to death, time to adjudicated heart failure hospitalization, time to emergency department visit and time-averaged proportional change in NTproBNP through d180. See Outcome Measure 1 for a general description of the outcome derivation.	Baseline to 180 days

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Study Chair: Eugene Bruanwald, MD, Harvard University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: February 7, 2013
• First Submitted That Met QC Criteria: February 26, 2013
• First Posted (Estimate): February 28, 2013

Study Record Updates

• Last Update Posted (Actual): February 15, 2017
• Last Update Submitted That Met QC Criteria: February 14, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: Pro00042633; 5U10HL084904-09 (U.S. NIH Grant/Contract)