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WithdrawnNCT03005184Updated Jan 11, 2018

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

A Phase 2 interventional study of Valsartan 80 mg bid and Enalapril 10 mg bid in Heart Failure NYHA Class I, Heart Failure NYHA Class II and Heart Failure NYHA Class III, sponsored by Vanderbilt University Medical Center. Withdrawn at 1 site in United States. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2018-01-11.

Sponsored by Vanderbilt University Medical Center · Phase 2, Interventional, and Basic science

Why this study was withdrawn
Study is being redesigned and submitted as a new study.
Phase
Phase 2
Study type
Interventional
Enrollment
0
Allocation
Randomized
Ages
18 Years to 75 Years
Sex
All
01

Study summary

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

Read the detailed 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.

02

Conditions studied

  • Heart Failure NYHA Class I
  • Heart Failure NYHA Class II
  • Heart Failure NYHA Class III
03

In context

Lead sponsor

Vanderbilt University Medical Center is the lead sponsor of 833 studies on the registry; 159 are open to participants now.

Of its 124 completed or terminated interventional studies of FDA-regulated products, 92 (74%) have results posted.

Browse Vanderbilt University Medical Center studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 75 Years
Sexes eligible
All
Accepts healthy volunteers
No

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

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

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
05

Study design

Phase
Phase 2
Primary purpose
Basic science
Allocation
Randomized
Intervention model
Crossover assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
0 participants (actual)

Study arms

  • Experimental
    S/V+Pla, S/V+I, Enal+Pla, Enal+I

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    S/V+Pla, Enal+I, S/V+I, Enal+Pla

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    S/V+Pla, Enal+Pla, Enal+I, S/V+I

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    S/V+I, S/V+Pla, Enal+I, Enal+P

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    S/V+I, Enal+Pla, S/V+Pla, Enal+I

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    S/V+I, Enal+I, Enal+Pla, S/V+Pla

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    Enal+Pla, S/V+Pla, S/V+I, Enal+I

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    Enal+Pla, S/V+I, Enal+I, S/V+Pla

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    Enal+Pla, Enal+I, S/V+Pla, S/V+I

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    Enal+I, S/V+Pla, Enal+Pla, S/V+I

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    Enal+I, S/V+I, S/V+Pla, Enal+Pla

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

  • Experimental
    Enal+I, Enal+Pla, S/V+I, S/V+Pla

    Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days. Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment. Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.

    Drug: Valsartan 80 mg bid · Drug: Enalapril 10 mg bid · Drug: Sacubitril-Valsartan 200 mg bid · Drug: Icatibant · Drug: Placebo

Interventions

06

What researchers measure

Primary outcomes

  1. change in systolic blood pressure

    Time frame: 7-hour period after 7-day intervention

  2. change in plasma cGMP

    Time frame: 7-hour period after 7-day intervention

Secondary outcomes

  1. heart rate

    Time frame: 7-hour period after 7-day intervention

  2. renal plasma flow

    Time frame: 7-hour period after 7-day intervention

  3. glomerular filtration rate

    Time frame: 7-hour period after 7-day intervention

  4. change in diastolic blood pressure

    Time frame: 7-hour period after 7-day intervention

  5. fractional excretion of sodium

    Time frame: 7-hour period after 7-day intervention

  6. urine albumin-to-creatinine ratio

    Time frame: 7-hour period after 7-day intervention

  7. brain natriuretic peptide (BNP) to N-terminal pro-BNP ratio

    Time frame: 7-hour period after 7-day intervention

  8. plasminogen activator inhibitor-1

    Time frame: 7-hour period after 7-day intervention

  9. tissue plasminogen activator

    Time frame: 7-hour period after 7-day intervention

  10. aldosterone

    Time frame: 7-hour period after 7-day intervention

  11. urine cGMP

    Time frame: 7-hour period after 7-day intervention

07

Study locations

1 site
  • Vanderbilt University Medical Center
    Nashville, Tennessee 37232, United States
08

References and documents

Individual participant data

Plan to share: No

No publications or documents are linked to this record.

09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jan 11, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT03005184
Lead sponsor
Vanderbilt University Medical Center
Responsible party
Nancy J. Brown (Hugh J. Morgan Professor of Medicine and Pharmacology, Vanderbilt University Medical Center) — Principal investigator
First posted
Dec 29, 2016
Start date
Sep 2017 (estimated)
Primary completion
Jan 2020 (estimated)
Completion
Jan 2020 (estimated)
Last update
Jan 11, 2018

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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Studies of the drugs tested here: Valsartan · Enalapril · Icatibant

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