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

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ClinicalTrials.gov Identifier: NCT04649229
Recruitment Status : Recruiting
First Posted : December 2, 2020
Last Update Posted : December 1, 2021
Sponsor:
Information provided by (Responsible Party):
Nancy Brown, Yale University

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).

Condition or disease Intervention/treatment Phase
Heart Failure Drug: LCZ 696 Drug: Placebo Drug: Para-aminohippurate Drug: Iohexol Drug: Aprepitant Phase 4

Detailed Description:

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. The PIONEER-HF study demonstrated the efficacy of LCZ696 in preventing rehospitalization in patients with acutely decompensated HF.

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 substance P could contribute to hypotension at initiation of LCZ696 through vasodilation or through increased natriuresis and diuresis. Antagonism of the NK1 receptor using aprepitant 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 substance P contributes to effects of ARB/NEP inhibition on blood pressure, natriuresis, and diuresis at initiation.

The secondary objective is to test the hypothesis that endogenous substance P 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 NK1 receptor antagonist aprepitant 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 (aprepitant 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. Criteria for continuing up-titration appears 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 aprepitant or placebo.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 3
Actual Study Start Date : May 27, 2021
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : January 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: placebo, aprepitant, placebo, aprepitant
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
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).
Other Name: Entresto

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

Drug: Para-aminohippurate
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.

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

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

Experimental: placebo, aprepitant, aprepitant, placebo
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
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).
Other Name: Entresto

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

Drug: Para-aminohippurate
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.

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

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

Experimental: aprepitant, placebo, placebo, aprepitant
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
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).
Other Name: Entresto

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

Drug: Para-aminohippurate
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.

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

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

Experimental: aprepitant, placebo, aprepitant, placebo
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
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).
Other Name: Entresto

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

Drug: Para-aminohippurate
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.

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

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




Primary Outcome Measures :
  1. Mean arterial pressure (MAP) [ Time Frame: Over six hours on each of the four study days ]
    Mean arterial pressure (MAP) will be measured before and after administration of LCZ696 on each of the four study days

  2. Urine sodium excretion [ Time Frame: Total urine output from drug administration to six hours following drug administration ]
    Urine sodium excretion will be measured for six hours following administration of LCZ696 on each of the four study days.


Secondary Outcome Measures :
  1. Heart rate [ Time Frame: Over six hours on each of four study days ]
    Heart rate (HR) will be measured before and after LCZ696 on each of the four study days

  2. Urine volume [ Time Frame: Over six hours on each of four study days ]
    Urine volume will be measured for six hours following LCZ696 on each of the four study days.

  3. Renal plasma flow [ Time Frame: Over six hours on each of four study days ]
    Renal plasma flow (RPF) will be calculated from para-aminohippurate clearance prior to and following LCZ696.

  4. Glomerular filtration rate [ Time Frame: Over six hours on each of four study days ]
    Glomerular filtration rate (GFR) will be calculated from the clearance of iohexol prior to and following LCZ66 on each of the four study days

  5. Urine albumin-to-creatinine ratio [ Time Frame: Over six hours on each of four study days ]
    Urine albumin-to-creatinine ratio (UACR) will be calculated before and after LCZ696 on each of the four study days.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Black and white men and women
  2. Stable patients with a reduced ejection fraction (EF)

    1. EF ≤55%, and
    2. history of symptoms of New York Heart Association (NYHA) class I, II, or III heart failure (HF)
    3. stable clinical symptoms including no hospitalizations for the last three months, or one month if hospitalized only once for initial diagnosis of HF
    4. who are not already taking LCZ696
  3. 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
  4. 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 adverse reaction
  5. For female subjects, the following conditions must be met:

    1. postmenopausal status for at least one year
    2. status post-surgical sterilization
    3. 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
  6. Age 18 years of age or older

Exclusion Criteria:

  1. 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
  2. History of angioedema
  3. 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
  4. History of heart transplant or on a transplant list or with left ventricular assistance device
  5. Symptomatic hypotension and/or a systolic blood pressure (SBP)<100 mmHg at screening or <95 mmHg during the study
  6. Serum potassium >5.2 mmol/L at screening or during the study
  7. 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)

  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
  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 left ventricular (LV) dilatation
  14. Presence of other hemodynamically significant obstructive lesions of the LV 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. In T2DM, dipeptidyl peptidase-4 inhibitor use for one month prior to enrollment will be excluded due to possible interaction with LCZ696
  18. Hematocrit <35%
  19. Breast feeding and pregnancy
  20. History or presence of immunological or hematological disorders
  21. History of malignancy not felt to be cured, except non-melanoma skin cancer
  22. Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
  23. History of hypersensitivity reaction to contrast
  24. Clinically significant gastrointestinal impairment that could interfere with drug absorption
  25. History of pancreatitis or known pancreatic lesions
  26. Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >3.0 x upper limit of normal range]
  27. 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
  28. Treatment with chronic systemic glucocorticoid therapy within the last year
  29. Treatment with lithium salts
  30. History of alcohol or drug abuse
  31. Treatment with any investigational drug in the one month preceding the study
  32. Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
  33. 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): NCT04649229


Contacts
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Contact: Christopher Maulion, MD 203-583-1874 christopher.maulion@yale.edu

Locations
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United States, Connecticut
Yale New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06520
Contact: Christopher Maulion, MD    203-583-1874    christopher.maulion@yale.edu   
Principal Investigator: Nancy J. Brown, MD         
Sponsors and Collaborators
Yale University
Investigators
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Principal Investigator: Nancy J. Brown, MD Yale University
Publications:
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Responsible Party: Nancy Brown, Professor of Internal Medicine, Yale University
ClinicalTrials.gov Identifier: NCT04649229    
Other Study ID Numbers: 2000028712
First Posted: December 2, 2020    Key Record Dates
Last Update Posted: December 1, 2021
Last Verified: November 2021
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:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Aprepitant
Sacubitril and valsartan sodium hydrate drug combination
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Neurokinin-1 Receptor Antagonists
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Angiotensin Receptor Antagonists