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

NCT04113109 | Completed Phase 4 DMC FDA Drug

• 1 other identifier: #191228
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (2)

• mean arterial pressure

  Mean arterial pressure (MAP) will be measured before and after administration of LCZ696 on each of the four study days.

  Eight hours

• Urine sodium excretion

  Urine sodium excretion will be measured for six hours following study LCZ696 on each of the four study days.

  Total urine output from drug administration to six hours following drug administration

Secondary Outcomes (5)

• Heart rate

  Over six hours on each of four study days

• Urine volume

  Over six hours on each of four study days

• Renal plasma flow

  Over six hours on each of four study days

• Glomerular filtration rate

  Over six hours on each of four study days

• Urine albumin-to-creatinine ratio

  Through study completion, an average of 49 days

Study Arms (4)

placebo, icatibant, placebo, icatibant

EXPERIMENTAL

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and icatibant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and icatibant, respectively.

Drug: LCZ 696; Drug: Icatibant; Drug: placebo; Drug: Para-aminohippurate; Drug: Iohexol

placebo, icatibant, icatibant, placebo

EXPERIMENTAL

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and icatibant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive icatibant and placebo, respectively.

Drug: LCZ 696; Drug: Icatibant; Drug: placebo; Drug: Para-aminohippurate; Drug: Iohexol

icatibant, placebo, placebo, icatibant

EXPERIMENTAL

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and icatibant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and icatibant, respectively.

Drug: LCZ 696; Drug: Icatibant; Drug: placebo; Drug: Para-aminohippurate; Drug: Iohexol

icatibant, placebo, icatibant placebo

EXPERIMENTAL

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and icatibant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive icatibant and placebo, respectively.

Drug: LCZ 696; Drug: Icatibant; Drug: placebo; Drug: Para-aminohippurate; Drug: Iohexol

Interventions

LCZ 696 DRUG

Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose).

Also known as: Entresto

icatibant, placebo, icatibant placebo; icatibant, placebo, placebo, icatibant; placebo, icatibant, icatibant, placebo; placebo, icatibant, placebo, icatibant

Icatibant DRUG

Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day.

icatibant, placebo, icatibant placebo; icatibant, placebo, placebo, icatibant; placebo, icatibant, icatibant, placebo; placebo, icatibant, placebo, icatibant

placebo DRUG

Placebo (vehicle) will be given at the same rate as icatibant.

icatibant, placebo, icatibant placebo; icatibant, placebo, placebo, icatibant; placebo, icatibant, icatibant, placebo; placebo, icatibant, placebo, icatibant

Para-aminohippurate DRUG

Para-aminohippurate (PAH) will be given at a dose of 8 mg/kg loading dose followed by a 12 mg/min steady-state infusion during each study day.

icatibant, placebo, icatibant placebo; icatibant, placebo, placebo, icatibant; placebo, icatibant, icatibant, placebo; placebo, icatibant, placebo, icatibant

Iohexol DRUG

Iohexol will be given as 5 mL of iohexol solution (3.235 g iohexol) intravenously on each study day.

icatibant, placebo, icatibant placebo; icatibant, placebo, placebo, icatibant; placebo, icatibant, icatibant, placebo; placebo, icatibant, placebo, icatibant

Eligibility Criteria

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

You may qualify if:

• 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 angiotensin receptor blocker (ARB) and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks
• 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.
• For female subjects, the following conditions must be met:
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Related Publications (3)

• McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.

  PMID: 25176015 BACKGROUND

• Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7;380(6):539-548. doi: 10.1056/NEJMoa1812851. Epub 2018 Nov 11.

  PMID: 30415601 BACKGROUND

• Senni M, McMurray JJ, Wachter R, McIntyre HF, Reyes A, Majercak I, Andreka P, Shehova-Yankova N, Anand I, Yilmaz MB, Gogia H, Martinez-Selles M, Fischer S, Zilahi Z, Cosmi F, Gelev V, Galve E, Gomez-Doblas JJ, Nociar J, Radomska M, Sokolova B, Volterrani M, Sarkar A, Reimund B, Chen F, Charney A. Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens. Eur J Heart Fail. 2016 Sep;18(9):1193-202. doi: 10.1002/ejhf.548. Epub 2016 May 12.

  PMID: 27170530 BACKGROUND

MeSH Terms

Conditions

Heart Failure

Interventions

sacubitril and valsartan sodium hydrate drug combination; icatibant; p-Aminohippuric Acid; Iohexol

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Aminohippuric Acids; Hippurates; Benzamides; Amides; Organic Chemicals; para-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Keto Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Triiodobenzoic Acids; Iodobenzoates

Study Officials

• Nancy J. Brown, M.D.

  Vanderbilt University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• 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: Professor

Study Record Dates

• First Submitted: September 26, 2019
• First Posted: October 2, 2019
• Study Start: November 1, 2019
• Primary Completion: April 1, 2025
• Study Completion: July 30, 2025
• Last Updated: August 24, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)