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

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ClinicalTrials.gov Identifier: NCT03005184
Recruitment Status : Withdrawn (Study is being redesigned and submitted as a new study.)
First Posted : December 29, 2016
Last Update Posted : January 11, 2018
Sponsor:
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University Medical Center

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

Condition or disease Intervention/treatment Phase
Heart Failure NYHA Class I Heart Failure NYHA Class II Heart Failure NYHA Class III Drug: Valsartan 80 mg bid Drug: Enalapril 10 mg bid Drug: Sacubitril-Valsartan 200 mg bid Drug: Icatibant Drug: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2
Estimated Study Start Date : September 2017
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2020

Arm Intervention/treatment
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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication

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
oral medication during run-in and washout period

Drug: Enalapril 10 mg bid
oral medication

Drug: Sacubitril-Valsartan 200 mg bid
oral medication

Drug: Icatibant
intravenous medication

Drug: Placebo
intravenous medication




Primary Outcome Measures :
  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 Outcome Measures :
  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 ]


Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03005184


Locations
Layout table for location information
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University Medical Center

Layout table for additonal information
Responsible Party: Nancy J. Brown, Hugh J. Morgan Professor of Medicine and Pharmacology, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT03005184     History of Changes
Other Study ID Numbers: IRB#161306
First Posted: December 29, 2016    Key Record Dates
Last Update Posted: January 11, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Icatibant
Heart Failure
Heart Diseases
Cardiovascular Diseases
Valsartan
Enalapril
Enalaprilat
LCZ 696
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Bradykinin B2 Receptor Antagonists
Bradykinin Receptor Antagonists
Complement Inactivating Agents
Immunosuppressive Agents
Immunologic Factors