A Phase 4 interventional study of LCZ 696 and Placebo in Heart Failure, sponsored by Yale University. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-03-17.
Sponsored by Yale University · Phase 4, Interventional, and Basic science
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).
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.
5,701 studies on the registry are indexed under Heart Failure; 1,219 are open to participants now.
This study's enrollment of 46 is below the median of 72 across 3,733 interventional studies indexed under Heart Failure.
Browse Heart Failure studies →Yale University is the lead sponsor of 1,724 studies on the registry; 298 are open to participants now.
Of its 210 completed or terminated interventional studies of FDA-regulated products, 126 (60%) have results posted.
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Stable patients with a reduced ejection fraction (EF)
For female subjects, the following conditions must be met:
Exclusion Criteria:
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)
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
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
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
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
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
Placebo or aprepitant 120 mg will be given orally on study days 1 and 2 and again on study days 3 and 4
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.
Iohexol will be given as 5 mL of iohexol solution (3.235 g iohexol) intravenously on each study day.
Placebo or aprepitant 120 mg will be given orally on study days 1 and 2 and again on study days 3 and 4
Mean arterial pressure (MAP)
Mean arterial pressure (MAP) will be measured before and after administration of LCZ696 on each of the four study days
Time frame: 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.
Time frame: Total urine output from drug administration to six hours following drug administration
Heart rate
Heart rate (HR) will be measured before and after LCZ696 on each of the four study days
Time frame: Over six hours on each of four study days
Urine volume
Urine volume will be measured for six hours following LCZ696 on each of the four study days.
Time frame: 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.
Time frame: Over six hours on each of four study days
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
Time frame: Over six hours on each of four study days
Urine albumin-to-creatinine ratio
Urine albumin-to-creatinine ratio (UACR) will be calculated before and after LCZ696 on each of the four study days.
Time frame: Over six hours on each of four study days
Plan to share: No
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Yale University