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

Study Overview
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Brief Summary
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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
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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.

Official Title
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Functional Impact of GLP-1 for Heart Failure Treatment

Conditions
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Acute Heart Failure

Intervention / Treatment
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* Drug: Liraglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years 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) AHFS is the primary cause of hospitalization Prior clinical diagnosis of HF 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) On evidence-based medication for HF (including beta-blocker and ACE-inhibitor/ARB) or previously deemed intolerant 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) Willingness to provide informed consent Exclusion Criteria: AHFS due to acute myocarditis or acute Myocardial Infarction Ongoing hemodynamically significant arrhythmias contributing to HF decompensation Inotrope, intra-aortic balloon pump (IABP) or other mechanical circulatory support use at the time of consent. Prior use will not exclude a patient. Current or planned left ventricular assist device therapy in next 180 days United Network for Organ Sharing status 1A or 1B 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) Hemoglobin (Hgb) < 8.0 g/dl Glomerular filtration rate(GFR) < 20 ml/min/1.73 m2 within 48 hours of consent Systolic blood pressure < 80 mmHg at consent Resting Heart Rate > 110 at consent 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) Percutaneous Coronary Intervention, coronary artery bypass grafting or new biventricular pacing within past 4 weeks Primary hypertrophic cardiomyopathy Infiltrative cardiomyopathy Constrictive pericarditis or tamponade Complex congenital heart disease Non-cardiac pulmonary edema More than moderate aortic or mitral stenosis Intrinsic (prolapse, rheumatic) valve disease with severe mitral, aortic or tricuspid regurgitation Sepsis, active infection (excluding cystitis) or other comorbidity driving the HF decompensation 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 Terminal illness (other than HF) with expected survival of less than 1 year Previous adverse reaction to the study drug Receipt of any investigational product in the previous 30 days. Enrollment or planned enrollment in another randomized therapeutic clinical trial in next 6 months. Inability to comply with planned study procedures Pregnancy or breastfeeding mothers Women of reproductive age not on adequate contraception History of acute or chronic pancreatitis History of symptomatic gastroparesis Familial or personal history of medullary thyroid cancer or multiple endocrine neoplasia type-2 (MEN2) Prior weight-loss surgery (i.e., Roux-en-Y gastric bypass) or other gastric surgery associated with increased endogenous GLP-1 production Prior or ongoing treatment with GLP-1 receptor agonists Ongoing treatment with dipeptidyl peptide-IV inhibitors (1 week washout required) Ongoing treatment with thiazolidinedione Oxygen-dependent chronic obstructive pulmonary disease Diabetic patients with history of 2 or more severe hypoglycemia, Diabetic Ketoacidosis(DKA) or hyperglycemic, hyperosmotic nonketotic coma in the preceding 12 months. Diagnosis of Type 1 Diabetes Mellitus 40. If diabetic, inadequate glycemic control with glucose level > 300 mg/dL within 24 hours of randomization

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Liraglutide<br>Increasing dose from 0.6mg, 1.2mg to 1.8mg SQ daily. | Drug: Liraglutide<br>* Active Drug<br>* Other names: Victoza;|
| Placebo Comparator: Placebo<br>Placebo dose increasing from 0.6mg, 1.2mg to 1.8 mg SQ daily. | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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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 |