Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 2

STATUS

Recruiting
End date

May 14, 2024
participants needed

80
sponsor

Vanderbilt University Medical Center

Send

Updated on 14 June 2022

See if I qualify

ejection fraction

heart failure

enzyme inhibitors

potassium

beta blockers

nt-probnp

nesiritide

b-type natriuretic peptide

ace inhibitor

natriuretic peptide

vasodilator

angiotensin

beta-adrenergic blocking agents

enalapril

valsartan

angiotensin converting enzyme

angiotensin ii receptor antagonists

n-terminal pro-bnp

Summary

LCZ696, a molecular complex of the angiotensin receptor blocker (ARB) valsartan with an inhibitor of neprilysin (NEP, neutral endopeptidase-24.11) sacubitril improved mortality compared to enalapril in patients with heart failure (HF), reduced ejection fraction (EF), and increased brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) in the PARADIGM-HF trial.1 The PIONEER-HF study demonstrated the efficacy of LCZ696 in preventing rehospitalization in patients with acutely decompensated HF.2

LCZ696 has been underutilized in heart failure, in part due to concerns about hypotension. NEP degrades several vasodilator peptides including bradykinin, substance P and brain-type natriuretic peptide. Decreased degradation of endogenous bradykinin could contribute to hypotension at initiation of LCZ696 through vasodilation or through increased natriuresis and diuresis. Inhibition of the bradykinin B2 receptor using icatibant would be expected to prevent this effect.

Objectives

The main objectives of this mechanistic randomized, double-blind, crossover-design study are:

The primary objective is to test the hypothesis that endogenous bradykinin contributes to effects of ARB/NEP inhibition on blood pressure, natriuresis, and diuresis at initiation.
The secondary objective is to test the hypothesis endogenous bradykinin contributes to effects of ARB/NEP inhibition on blood pressure, natriuresis, and diuresis after up-titration.

Eighty (80) subjects with stable heart failure who meet all inclusion/exclusion criteria will be enrolled. Subjects who qualify will collect their urine for 24 hours before each study day for measurement of volume, sodium and potassium. At the start of the study, they will stop their regular angiotensin-converting enzyme (ACE) inhibitor or ARB. After a 48-hour washout, they will undergo a study day in which they are given a single dose of 50 mg LCZ696. They will also receive either the bradykinin B2 receptor antagonist icatibant or placebo vehicle in random order (double-blind). After a 96-hour washout, they will repeat the study day and receive a single dose of 50 mg LCZ696 and the opposite study drug (icatibant or placebo). After completion of the two acute study days, subjects will take LCZ696 50 mg bid for two weeks, followed by LCZ696 100 mg bid for three weeks, and then LCZ696 200 mg bid, following the conservative up-titration protocol from the TITRATION study.3 Criteria for continuing up-titration appear in the full study protocol. On the 7th and 10th day of the 200 mg bid or highest tolerated dose, subjects will again undergo two more study days three days apart in which they are randomized to receive either icatibant or vehicle.

Details

Condition	Heart Failure
Treatment	Placebo, Iohexol, Para-Aminohippurate, LCZ 696, Icatibant
Clinical Study Identifier	NCT04113109
Sponsor	Vanderbilt University Medical Center
Last Modified on	14 June 2022

How understandable was the trial content above?

Hard to understand

Easy to understand

Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Black and white men and women
	Stable patients with a reduced ejection fraction (EF)
	EF ≤40%, and
	history of symptoms of New York Heart Association (NYHA) class I, II, or III heart failure (HF)
	stable clinical symptoms including no hospitalizations for the last six months
	who are not already taking LCZ696
	treatment with a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or
	for patients with NYHA Class II or III HF, treatment with a stable dose of an mineralocorticoid receptor (MR) antagonist for at least four weeks, unless not possible due to renal function or serum potassium
	angiotensin receptor blocker (ARB) and with a beta blocker (unless
	For female subjects, the following conditions must be met
	contraindicated or not tolerated) for at least four weeks
	postmenopausal status for at least one year, or
	status post-surgical sterilization
	or if of childbearing potential, utilization of barrier methods of birth control or an oral contraceptive and willingness to undergo urine β- human chorionic gonadotropin (HCG) testing on every study day
Exclusion Criteria
	History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEi, ARBs, or neutral endopeptidase inhibitor (NEPi), as well as known or suspected contraindications to the study drugs
	History of angioedema
	History of decompensated HF within the last three 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 systolic blood pressure (SBP)<100 mmHg at screening or <95 mmHg during the study
	Serum potassium >5.2 mmol/L at screening or >5.4 mmol/L during the study
	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/1.73 m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742
	if female)
	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
	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 left ventricle (LV) dilatation
	Presence of other hemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic stenosis
	Type 1 diabetes
	Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c >9%
	In T2DM, dipeptidyl peptidase-4 inhibitor use for one month prior to enrollment will be excluded due to possible interaction with LCZ696
	Hematocrit <35%
	Breast feeding and pregnancy
	History or presence of immunological or hematological disorders
	History of malignancy not felt to be cured, except non-melanoma skin cancer
	Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
	History of hypersensitivity reaction to contrast
	Clinically significant gastrointestinal impairment that could interfere with drug absorption
	History of pancreatitis or known pancreatic lesions
	Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >3.0 x upper limit of normal range]
	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
	Treatment with chronic systemic glucocorticoid therapy within the last year
	Treatment with lithium salts
	History of alcohol or drug abuse
	Treatment with any investigational drug in the one month preceding the study
	Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
	Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

How to participate?

Step 1 Connect with a study center

Select a site
Send a message

You have contacted , on

Your message has been sent to the study team at ,

A copy of the message has been sent to your email

What happens next?

You can expect the study team to contact you via email or phone in the next few days.
Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Primary Contact

By sending a message, I agree that my data will be sent to a representative for the selected site and processed in accordance with this website's Privacy Policy (see link in footer).

Step 2 Get screened

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

Step 3 Enroll in the clinical study

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Step 4 Get your study results

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Browse trials for

b-type natriuretic peptide

beta-adrenergic blocking agents

enalapril

valsartan

angiotensin converting enzyme

angiotensin ii receptor antagonists

n-terminal pro-bnp

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Edit Delete

Added by •

•

Private

Edit Delete

Reply by • • Private

Edit Delete

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

Enter the passcode

The passcode will expire in None.

Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 2