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

Duke University300 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

300

Conditions

Acute Heart Failure

Interventions

LiraglutideDRUG

Active Drug

PlaceboDRUG

Placebo

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (25)

Christiana Care Health Services

Outcomes

Primary Outcomes

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.

Time frame: Randomization to 180 days

Secondary Outcomes

Change in Left Ventricular End-Diastolic Volume Index

Change in Left Ventricular End-Diastolic Volume Index from baseline to 180 days.

Time frame: 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.

Time frame: Baseline to 180 days

Change in Left Ventricular Ejection Fraction

Change in left ventricular ejection fraction from baseline to day 180

Time frame: Baseline to 180 days

Change in Medial Filling Pressure

Change in medial filling pressure baseline to day 180.

Time frame: Baseline to 180 days

Data from ClinicalTrials.gov

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Newark, Delaware, United States

Emory University School of Medicine

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

Johns Hopkins Hospital

Baltimore, Maryland, United States

Tufts Medical Center

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham and Women's Hospital

Boston, Massachusetts, United States

Boston VA Healtcare System

West Roxbury, Massachusetts, United States

Mayo Clinic

Rochester, Minnesota, United States

Washington University

St Louis, Missouri, United States

...and 15 more locations

Change in Lateral Filling Pressure

Change in lateral filling pressure baseline to day 180.

Time frame: Baseline to 180 days

Change in 6 Minute Walk Distance

Change in 6 minute walk distance baseline to day 30

Time frame: Baseline to day 30

Change in 6 Minute Walk Distance

Change in 6 minute walk distance baseline to 90 days.

Time frame: Baseline to 90 days

Change in 6 Minute Walk Distance

Change in 6 minute walk distance baseline to 180 days.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline to 180 days

Individual Component of the Primary Endpoint- Mortality

Individual component of the primary endpoint of mortality at 180 days after randomization

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: Baseline to 180 days