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

Acute Heart Failure Clinical Trial

— FIGHT  

Official title:

Functional Impact of GLP-1 for Heart Failure Treatment

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01800968
• Other study ID #: Pro00042633
• Secondary ID: 5U10HL084904-09
• Status: Completed
• Phase: Phase 2
• First received: February 7, 2013
• Last updated: February 14, 2017
• Start date: April 2013
• Est. completion date: October 2015

Study information

• Verified date: February 2017
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: October 2015
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Heart Failure
• Heart Failure

Intervention

Drug:
• Liraglutide
Active Drug
• Placebo
Placebo

Locations

Country	Name	City	State
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	The University of Vermont- Fletcher Allen Health Care	Burlington	Vermont
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	Metro Health System	Cleveland	Ohio
United States	University Hospitals- Case Medical Center	Cleveland	Ohio
United States	Duke University	Durham	North Carolina
United States	Michael Debakey VA Medical Center	Houston	Texas
United States	Lancaster Heart and Stroke Foundation	Lancaster	Pennsylvania
United States	Southeast Regional Medical Center	Lumberton	North Carolina
United States	Intermountain Medical Center	Murray	Utah
United States	Christiana Care Health Services	Newark	Delaware
United States	Jefferson Medical College	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvaina	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Utah School of Medicine	Salt Lake City	Utah
United States	Utah VA Medical Center	Salt Lake City	Utah
United States	Saint Louis University Hospital	St. Louis	Missouri
United States	Washington University	St. Louis	Missouri
United States	Boston VA Healtcare System	West Roxbury	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Duke University	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Change in Left Ventricular Ejection Fraction	Change in left ventricular ejection fraction from baseline to day 180	Baseline to 180 days
Secondary	Change in Medial Filling Pressure	Change in medial filling pressure baseline to day 180.	Baseline to 180 days
Secondary	Change in Lateral Filling Pressure	Change in lateral filling pressure baseline to day 180.	Baseline to 180 days
Secondary	Change in 6 Minute Walk Distance	Change in 6 minute walk distance baseline to day 30	Baseline to day 30
Secondary	Change in 6 Minute Walk Distance	Change in 6 minute walk distance baseline to 90 days.	Baseline to 90 days
Secondary	Change in 6 Minute Walk Distance	Change in 6 minute walk distance baseline to 180 days.	Baseline to 180 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Individual Component of the Primary Endpoint- Mortality	Individual component of the primary endpoint of mortality at 180 days after randomization	Randomization to 180 days
Secondary	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
Secondary	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
Secondary	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