Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 3

NCT04649229 | Completed Phase 4 DMC FDA Drug

• 1 other identifier: 2000028712
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 1

Brief Summary

This is a double-blind, randomized, two x two crossover (aprepitant vs placebo) during both initiation of Entresto, LCZ696, (50 mg dose) and at steady-state of Entresto (200 mg bid dose or the highest tolerated dose).

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (2)

• Mean arterial pressure (MAP)

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

  Over six hours on each of the four study days

• Urine sodium excretion

  Urine sodium excretion will be measured for six hours following administration of 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

  Over six hours on each of four study days

Study Arms (4)

placebo, aprepitant, placebo, aprepitant

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 aprepitant. 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 aprepitant, respectively.

Drug: LCZ 696; Drug: Placebo; Drug: Para-aminohippurate; Drug: Iohexol; Drug: Aprepitant

placebo, aprepitant, aprepitant, 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 aprepitant. 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 aprepitant and placebo, respectively.

Drug: LCZ 696; Drug: Placebo; Drug: Para-aminohippurate; Drug: Iohexol; Drug: Aprepitant

aprepitant, placebo, placebo, aprepitant

EXPERIMENTAL

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. 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 aprepitant, respectively.

Drug: LCZ 696; Drug: Placebo; Drug: Para-aminohippurate; Drug: Iohexol; Drug: Aprepitant

aprepitant, placebo, aprepitant, placebo

EXPERIMENTAL

After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. 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 aprepitant and placebo, respectively.

Drug: LCZ 696; Drug: Placebo; Drug: Para-aminohippurate; Drug: Iohexol; Drug: Aprepitant

Interventions

Placebo DRUG

Placebo or aprepitant 120 mg will be given orally on study days 1 and 2 and again on study days 3 and 4

aprepitant, placebo, aprepitant, placebo; aprepitant, placebo, placebo, aprepitant; placebo, aprepitant, aprepitant, placebo; placebo, aprepitant, placebo, aprepitant

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

aprepitant, placebo, aprepitant, placebo; aprepitant, placebo, placebo, aprepitant; placebo, aprepitant, aprepitant, placebo; placebo, aprepitant, placebo, aprepitant

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.

aprepitant, placebo, aprepitant, placebo; aprepitant, placebo, placebo, aprepitant; placebo, aprepitant, aprepitant, placebo; placebo, aprepitant, placebo, aprepitant

Iohexol DRUG

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

aprepitant, placebo, aprepitant, placebo; aprepitant, placebo, placebo, aprepitant; placebo, aprepitant, aprepitant, placebo; placebo, aprepitant, placebo, aprepitant

Aprepitant DRUG

Placebo or aprepitant 120 mg will be given orally on study days 1 and 2 and again on study days 3 and 4

aprepitant, placebo, aprepitant, placebo; aprepitant, placebo, placebo, aprepitant; placebo, aprepitant, aprepitant, placebo; placebo, aprepitant, placebo, aprepitant

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 ≤55%, 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 three months, or one month if hospitalized only once for initial diagnosis of HF
• 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 and EF ≤35%, treatment with a stable dose of an mineralocorticoid receptor (MR) antagonist for at least four weeks, unless not possible due to renal function or adverse reaction
• For female subjects, the following conditions must be met:
• postmenopausal status for at least one year
• status post-surgical sterilization
• or if childbearing potential, utilization of barrier methods of birth control or an oral contraceptive and willingness to undergo urine β-HCG testing on every study day
• Age 18 years of age or older

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 3 months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization) or one month if hospitalized only once for initial diagnosis of HF
• 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 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:
• a. 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 with clinically significant residual deficits
• 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 ventricular (LV) dilatation
• Presence of other hemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic stenosis

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Yale New Haven Hospital

New Haven, Connecticut, 06520, 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; p-Aminohippuric Acid; Iohexol; Aprepitant

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; Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Nancy J. Brown, MD

  Yale University

  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 of Internal Medicine

Study Record Dates

• First Submitted: November 12, 2020
• First Posted: December 2, 2020
• Study Start: May 27, 2021
• Primary Completion: May 22, 2025
• Study Completion: May 22, 2025
• Last Updated: March 17, 2026

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)