Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2

Heart Failure NYHA Class III Clinical Trial

Official title:

Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03005184
• Other study ID #: IRB#161306
• Status: Withdrawn
• Phase: Phase 2
• First received: December 22, 2016
• Last updated: January 9, 2018
• Start date: September 2017
• Est. completion date: January 2020

Study information

• Verified date: January 2018
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study tests the hypothesis that endogenous bradykinin contributes to effects of a combined angiotensin receptor blocker/neprilysin inhibitor (LCZ696 or Entresto)

Description:

Patients with heart failure (HF) with reduced ejection fraction who qualify for the study will undergo a three-week run-in period in which any prior angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker they were taking will be discontinued and they will be given valsartan 80 mg bid in a single-blind fashion. After the run-in, subjects will undergo four study periods in random order. During two study periods they will receive enalapril 10 mg bid and during two they will receive sacubitril/valsartan (LCZ696) 200 mg bid for seven days. On the seventh day or each period, subjects will complete a study day in which they are randomized to receive either the bradykinin B2 receptor blocker icatibant or placebo intravenously. Each study period will be separated by a three-week washout during which subjects receive valsartan 80 mg bid.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: January 2020
• Est. primary completion date: January 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Stable patients with a reduced EF

1. EF less than or equal to 40% (confirmed by echocardiogram within the last six months), and

2. history of symptoms of New York Heart Association class I, II or III HF

3. stable clinical symptoms including no hospitalizations for the last six months

4. treatment with a stable dose of an ACEi or ARB and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks

5. treatment with a stable dose of an MR antagonist for at least four weeks unless not possible due to renal function or serum potassium.

2. For female subjects, the following conditions must be met:

1. postmenopausal status for at least one year, or

2. status post-surgical sterilization

Exclusion Criteria:

1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEi, ARBs, or NEPi, as well as known or suspected contraindications to the study drugs

2. History of angioedema

3. History of pancreatitis or known pancreatic lesions

4. History of decompensated HF within the last six months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization)

5. History of heart transplant or on a transplant list or with left ventricular assistance device

6. Symptomatic hypotension and/or a SBP<100 mmHg at screening or <90 mmHg during the study

7. Serum potassium >5.2 mmol/L at screening or >5.4 mmol/L during the study

8. Acute coronary syndrome, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within six months prior to screening

9. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening

10. History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack within six months

11. History of ventricular arrhythmia with syncopal episodes

12. Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker

13. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to LV dilatation

14. Presence of other hemodynamically significant obstructive lesions of the left ventricular outflow tract, including aortic and subaortic stenosis

15. Type 1 diabetes

16. Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c >9%

17. Hematocrit <35%

18. Impaired renal function (eGFR of <30mL/min/1.73 m2) as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dL and age in years:

eGFR (mL/min/1.73m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742 if female)

19. Use of hormone-replacement therapy

20. Breast feeding and pregnancy

21. History or presence of immunological or hematological disorders

22. History of malignancy other than non-melanoma skin cancer

23. Diagnosis of asthma requiring use of inhaled beta agonist more than once a week

24. Clinically significant gastrointestinal impairment that could interfere with drug absorption

25. Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >3.0 x upper limit of normal range]

26. Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal anti-inflammatory drugs

27. Treatment with chronic systemic glucocorticoid therapy within the last year

28. Treatment with lithium salts

29. History of alcohol or drug abuse

30. Treatment with any investigational drug in the one month preceding the study

31. Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study

32. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure NYHA Class I
• Heart Failure NYHA Class II
• Heart Failure NYHA Class III

Intervention

Drug:
• Valsartan 80 mg bid
oral medication during run-in and washout period
• Enalapril 10 mg bid
oral medication
• Sacubitril-Valsartan 200 mg bid
oral medication
• Icatibant
intravenous medication
• Placebo
intravenous medication

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	change in systolic blood pressure		7-hour period after 7-day intervention
Primary	change in plasma cGMP		7-hour period after 7-day intervention
Secondary	heart rate		7-hour period after 7-day intervention
Secondary	renal plasma flow		7-hour period after 7-day intervention
Secondary	glomerular filtration rate		7-hour period after 7-day intervention
Secondary	change in diastolic blood pressure		7-hour period after 7-day intervention
Secondary	fractional excretion of sodium		7-hour period after 7-day intervention
Secondary	urine albumin-to-creatinine ratio		7-hour period after 7-day intervention
Secondary	brain natriuretic peptide (BNP) to N-terminal pro-BNP ratio		7-hour period after 7-day intervention
Secondary	plasminogen activator inhibitor-1		7-hour period after 7-day intervention
Secondary	tissue plasminogen activator		7-hour period after 7-day intervention
Secondary	aldosterone		7-hour period after 7-day intervention
Secondary	urine cGMP		7-hour period after 7-day intervention