Heart FailurePhase 4NCT04649229
Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 3
A Phase 4 study testing LCZ 696, Para-aminohippurate and Iohexol in people with Heart Failure, run by Yale University at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure
- What is being tested?
- LCZ 696, Para-aminohippurate and Iohexol
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 46 participants
- Where
- 1 siteUnited States
- Study dates
- 27 May 2021to 22 May 2025
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 13Show fewer
- 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
Who cannot join
- 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
Show all 34Show fewer
- 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 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
- 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 with evidence of advanced fibrosis or cirrhosis [stable aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) trend if >3.0 x upper limit of normal range as deemed of minimal clinical relevance by the investigators]
- 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 greater than 5 mg of prednisone or equivalent dose of chronic systemic glucocorticoid therapy within the last year or recent (within 6 weeks of first study day) treatment with burst dosed glucocorticoid therapy
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Yale New Haven Hospital
New Haven, Connecticut, 06520
About this study
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).
Read the 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.
- Conditions
- Heart Failure
- Being tested
- LCZ 696, Placebo, Para-aminohippurate, Iohexol, Aprepitant
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
LCZ 696Drug
Also called Entresto
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).
PlaceboDrug
Placebo or aprepitant 120 mg will be given orally on study days 1 and 2 and again on study days 3 and 4
Para-aminohippurateDrug
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.
IohexolDrug
Iohexol will be given as 5 mL of iohexol solution (3.235 g iohexol) intravenously on each study day.
AprepitantDrug
Placebo or aprepitant 120 mg will be given orally on study days 1 and 2 and again on study days 3 and 4
| Study group | Role | What they receive |
|---|---|---|
| placebo, aprepitant, placebo, aprepitant | Experimental | After a 48-hr washout, participants in this arm will be given LCZ696 (sacubitril/valsartan) 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant 120 mg. All participants will then undergo uptitration of LCZ696 (sacubitril/valsartan) 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 120 mg, respectively. Receives: 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 (sacubitril/valsartan) 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant 120 mg. Participants will then undergo uptitration of LCZ696 (sacubitril/valsartan) 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 120 mg and placebo, respectively. Receives: 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 (sacubitril/valsartan) 50 mg and aprepitant 120 mg. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 (sacubitril/valsartan) 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 120 mg, respectively. Receives: 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 (sacubitril/valsartan) 50 mg and aprepitant 120 mg. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 (sacubitril/valsartan) 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 120 mg and placebo, respectively. Receives: Drug: LCZ 696; Drug: Placebo; Drug: Para-aminohippurate; Drug: Iohexol; Drug: Aprepitant |
What is being measured
The primary outcome is the main question the study is designed to answer.
Max Change in Mean Arterial Pressure (MAP)
Mean arterial pressure (MAP) will be measured before and after administration of LCZ696 on each of the four study days
Measured: The maximal change in MAP, as measured by the lowest MAP recorded six hours following drug administration minus the baseline MAP.
Urine Sodium Excretion
Urine sodium excretion will be measured for six hours following administration of LCZ696 on each of the four study days.
Measured: Total urine output from drug administration to six hours following drug administration
Secondary outcomes (4)
Heart Rate
Heart rate (HR) will be measured before and after LCZ696 on each of the four study days
Measured: The maximum change in heart rate as measured by the highest heart rate recorded over six hours after drug administration minus the baseline heart rate.
Urine Volume
Urine volume will be measured for six hours following LCZ696 on each of the four study days.
Measured: Over six hours on each of four study days
Renal Plasma Flow
Renal plasma flow (RPF) will be calculated from para-aminohippurate clearance prior to and following LCZ696 and normalized per body surface area.
Measured: The change in renal plasma flow as measured by the renal plasma flow six hours following administration of the drug minus baseline renal plasma flow.
Glomerular Filtration Rate
Glomerular filtration rate (GFR) will be calculated from the clearance of iohexol prior to and following LCZ66 on each of the four study days and expressed as mL of blood cleared of creatinine per minute.
Measured: The glomerular rate or iohexol clearance calculated based on iohexol concentrations measured serially for six hours after drug administration.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Dec 2020
- Study start27 May 2021
- Primary completion22 May 2025
- Study completion22 May 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 46 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Nancy Brown, Yale University
- Investigators
- Nancy J. Brown, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04649229
- Sponsor's protocol ID
- 2000028712
- Status last verified
- Oct 2026
- First submitted
- 12 Nov 2020
- Last updated
- 27 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 25176015Velazquez 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.
PubMed 30415601Senni 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.
PubMed 27170530
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 3
- ClinicalTrials.gov ID
- NCT04649229
- Acronym / sponsor ID
- 2000028712
- Conditions
- Heart Failure
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 46 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Study start
- 27 May 2021 (actual)
- Primary completion
- 22 May 2025 (actual)
- Study completion
- 22 May 2025 (actual)
- First posted
- 2 Dec 2020 (actual)
- Results
- Posted 27 Oct 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| placebo, aprepitant, placebo, aprepitant | Experimental | Drug: LCZ 696, Drug: Placebo, Drug: Para-aminohippurate, Drug: Iohexol, Drug: AprepitantAfter a 48-hr washout, participants in this arm will be given LCZ696 (sacubitril/valsartan) 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant 120 mg. All participants will then undergo uptitration of LCZ696 (sacubitril/valsartan) 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 120 mg, respectively. |
| placebo, aprepitant, aprepitant, placebo | Experimental | Drug: LCZ 696, Drug: Placebo, Drug: Para-aminohippurate, Drug: Iohexol, Drug: AprepitantAfter a 48-hr washout, participants in this arm will be given LCZ696 (sacubitril/valsartan) 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant 120 mg. Participants will then undergo uptitration of LCZ696 (sacubitril/valsartan) 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 120 mg and placebo, respectively. |
| aprepitant, placebo, placebo, aprepitant | Experimental | Drug: LCZ 696, Drug: Placebo, Drug: Para-aminohippurate, Drug: Iohexol, Drug: AprepitantAfter a 48-hr washout, participants in this arm will be given LCZ696 (sacubitril/valsartan) 50 mg and aprepitant 120 mg. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 (sacubitril/valsartan) 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 120 mg, respectively. |
| aprepitant, placebo, aprepitant, placebo | Experimental | Drug: LCZ 696, Drug: Placebo, Drug: Para-aminohippurate, Drug: Iohexol, Drug: AprepitantAfter a 48-hr washout, participants in this arm will be given LCZ696 (sacubitril/valsartan) 50 mg and aprepitant 120 mg. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 (sacubitril/valsartan) 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 120 mg and placebo, respectively. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Black and white men and women
- Stable patients with a reduced ejection fraction (EF)
- 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:
Key exclusion criteria (34 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| LCZ 696Also: EntrestoTreatment 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). | Drug | aprepitant, placebo, aprepitant, placebo, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant |
| PlaceboPlacebo or aprepitant 120 mg will be given orally on study days 1 and 2 and again on study days 3 and 4 | Drug | aprepitant, placebo, aprepitant, placebo, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant |
| Para-aminohippuratePara-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 | aprepitant, placebo, aprepitant, placebo, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant |
| IohexolIohexol will be given as 5 mL of iohexol solution (3.235 g iohexol) intravenously on each study day. | Drug | aprepitant, placebo, aprepitant, placebo, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant |
| AprepitantPlacebo or aprepitant 120 mg will be given orally on study days 1 and 2 and again on study days 3 and 4 | Drug | aprepitant, placebo, aprepitant, placebo, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant, aprepitant, placebo, placebo, aprepitant, placebo, aprepitant |
Primary outcome
Max Change in Mean Arterial Pressure (MAP)
Time frame: The maximal change in MAP, as measured by the lowest MAP recorded six hours following drug administration minus the baseline MAP.
Mean arterial pressure (MAP) will be measured before and after administration of LCZ696 on each of the four study days
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.
4 secondary outcomes
Heart Rate
Time frame: The maximum change in heart rate as measured by the highest heart rate recorded over six hours after drug administration minus the baseline heart rate.
Urine Volume
Time frame: Over six hours on each of four study days
Renal Plasma Flow
Time frame: The change in renal plasma flow as measured by the renal plasma flow six hours following administration of the drug minus baseline renal plasma flow.
Glomerular Filtration Rate
Time frame: The glomerular rate or iohexol clearance calculated based on iohexol concentrations measured serially for six hours after drug administration.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Oct 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 25176015McMurray 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.
- Background: PubMed 30415601Velazquez 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.
- Background: PubMed 27170530Senni 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nancy J. Brown, MD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing LCZ 696, Para-aminohippurate and Iohexol in people with Heart Failure, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 34 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Oct 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Max Change in Mean Arterial Pressure (MAP) (time frame: The maximal change in MAP, as measured by the lowest MAP recorded six hours following drug administration minus the baseline MAP.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04649229, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2026.