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

NCT03005184 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: IRB#161306
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

Heart Failure NYHA Class I; Heart Failure NYHA Class II; Heart Failure NYHA Class III

Outcome Measures

Primary Outcomes (2)

• change in systolic blood pressure

  7-hour period after 7-day intervention

• change in plasma cGMP

  7-hour period after 7-day intervention

Secondary Outcomes (11)

• heart rate

  7-hour period after 7-day intervention

• renal plasma flow

  7-hour period after 7-day intervention

• glomerular filtration rate

  7-hour period after 7-day intervention

• change in diastolic blood pressure

  7-hour period after 7-day intervention

• fractional excretion of sodium

  7-hour period after 7-day intervention

Study Arms (12)

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

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

EXPERIMENTAL

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

Valsartan 80 mg bid DRUG

oral medication during run-in and washout period

Enal+I, Enal+Pla, S/V+I, S/V+Pla; Enal+I, S/V+I, S/V+Pla, Enal+Pla; Enal+I, S/V+Pla, Enal+Pla, S/V+I; Enal+Pla, Enal+I, S/V+Pla, S/V+I; Enal+Pla, S/V+I, Enal+I, S/V+Pla; Enal+Pla, S/V+Pla, S/V+I, Enal+I; S/V+I, Enal+I, Enal+Pla, S/V+Pla; S/V+I, Enal+Pla, S/V+Pla, Enal+I; S/V+I, S/V+Pla, Enal+I, Enal+P; S/V+Pla, Enal+I, S/V+I, Enal+Pla; S/V+Pla, Enal+Pla, Enal+I, S/V+I; S/V+Pla, S/V+I, Enal+Pla, Enal+I

Enalapril 10 mg bid DRUG

oral medication

Enal+I, Enal+Pla, S/V+I, S/V+Pla; Enal+I, S/V+I, S/V+Pla, Enal+Pla; Enal+I, S/V+Pla, Enal+Pla, S/V+I; Enal+Pla, Enal+I, S/V+Pla, S/V+I; Enal+Pla, S/V+I, Enal+I, S/V+Pla; Enal+Pla, S/V+Pla, S/V+I, Enal+I; S/V+I, Enal+I, Enal+Pla, S/V+Pla; S/V+I, Enal+Pla, S/V+Pla, Enal+I; S/V+I, S/V+Pla, Enal+I, Enal+P; S/V+Pla, Enal+I, S/V+I, Enal+Pla; S/V+Pla, Enal+Pla, Enal+I, S/V+I; S/V+Pla, S/V+I, Enal+Pla, Enal+I

Sacubitril-Valsartan 200 mg bid DRUG

oral medication

Enal+I, Enal+Pla, S/V+I, S/V+Pla; Enal+I, S/V+I, S/V+Pla, Enal+Pla; Enal+I, S/V+Pla, Enal+Pla, S/V+I; Enal+Pla, Enal+I, S/V+Pla, S/V+I; Enal+Pla, S/V+I, Enal+I, S/V+Pla; Enal+Pla, S/V+Pla, S/V+I, Enal+I; S/V+I, Enal+I, Enal+Pla, S/V+Pla; S/V+I, Enal+Pla, S/V+Pla, Enal+I; S/V+I, S/V+Pla, Enal+I, Enal+P; S/V+Pla, Enal+I, S/V+I, Enal+Pla; S/V+Pla, Enal+Pla, Enal+I, S/V+I; S/V+Pla, S/V+I, Enal+Pla, Enal+I

Icatibant DRUG

intravenous medication

Enal+I, Enal+Pla, S/V+I, S/V+Pla; Enal+I, S/V+I, S/V+Pla, Enal+Pla; Enal+I, S/V+Pla, Enal+Pla, S/V+I; Enal+Pla, Enal+I, S/V+Pla, S/V+I; Enal+Pla, S/V+I, Enal+I, S/V+Pla; Enal+Pla, S/V+Pla, S/V+I, Enal+I; S/V+I, Enal+I, Enal+Pla, S/V+Pla; S/V+I, Enal+Pla, S/V+Pla, Enal+I; S/V+I, S/V+Pla, Enal+I, Enal+P; S/V+Pla, Enal+I, S/V+I, Enal+Pla; S/V+Pla, Enal+Pla, Enal+I, S/V+I; S/V+Pla, S/V+I, Enal+Pla, Enal+I

Placebo DRUG

intravenous medication

Enal+I, Enal+Pla, S/V+I, S/V+Pla; Enal+I, S/V+I, S/V+Pla, Enal+Pla; Enal+I, S/V+Pla, Enal+Pla, S/V+I; Enal+Pla, Enal+I, S/V+Pla, S/V+I; Enal+Pla, S/V+I, Enal+I, S/V+Pla; Enal+Pla, S/V+Pla, S/V+I, Enal+I; S/V+I, Enal+I, Enal+Pla, S/V+Pla; S/V+I, Enal+Pla, S/V+Pla, Enal+I; S/V+I, S/V+Pla, Enal+I, Enal+P; S/V+Pla, Enal+I, S/V+I, Enal+Pla; S/V+Pla, Enal+Pla, Enal+I, S/V+I; S/V+Pla, S/V+I, Enal+Pla, Enal+I

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Stable patients with a reduced EF
• EF less than or equal to 40% (confirmed by echocardiogram within the last six months), and
• history of symptoms of New York Heart Association class I, II or III HF
• stable clinical symptoms including no hospitalizations for the last six months
• 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
• treatment with a stable dose of an MR antagonist for at least four weeks unless not possible due to renal function or serum potassium.
• For female subjects, the following conditions must be met:
• postmenopausal status for at least one year, or
• status post-surgical sterilization

You may not qualify if:

• 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
• History of angioedema
• History of pancreatitis or known pancreatic lesions
• History of decompensated HF within the last six months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization)
• History of heart transplant or on a transplant list or with left ventricular assistance device
• Symptomatic hypotension and/or a SBP\<100 mmHg at screening or \<90 mmHg during the study
• Serum potassium \>5.2 mmol/L at screening or \>5.4 mmol/L during the study
• Acute coronary syndrome, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within six months prior to screening
• Coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening
• History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack within six months
• History of ventricular arrhythmia with syncopal episodes
• Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker
• Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to LV dilatation
• Presence of other hemodynamically significant obstructive lesions of the left ventricular outflow tract, including aortic and subaortic stenosis
• Type 1 diabetes

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

MeSH Terms

Interventions

Valsartan; BID protein, human; Enalapril; sacubitril and valsartan sodium hydrate drug combination; icatibant

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Dipeptides; Oligopeptides; Peptides

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Hugh J. Morgan Professor of Medicine and Pharmacology

Study Record Dates

• First Submitted: December 22, 2016
• First Posted: December 29, 2016
• Study Start: September 1, 2017
• Primary Completion: January 1, 2020
• Study Completion: January 1, 2020
• Last Updated: January 11, 2018

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)