Heart FailurePhase 4NCT04113109
Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 2
A Phase 4 study testing LCZ 696, Icatibant and Para-aminohippurate in people with Heart Failure, run by Vanderbilt University Medical Center at 1 site in United States.
Trial 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… 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, Icatibant and Para-aminohippurate
- Type of treatment
- 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
- 1 Nov 2019to 30 Jul 2025
- Phase
- Phase 4
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 ≤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
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- 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
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 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
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- 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
- 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 [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >3.0 x upper limit of normal range]
- 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 chronic systemic glucocorticoid therapy within the last year
- 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
Vanderbilt University Medical Center
Nashville, Tennessee, 37232
About this study
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.
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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
- Being tested
- LCZ 696, Icatibant, placebo, Para-aminohippurate, Iohexol
- 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).
IcatibantDrug
Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day.
placeboDrug
Placebo (vehicle) will be given at the same rate as icatibant.
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: LCZ 696; Drug: Icatibant; Drug: placebo; Drug: Para-aminohippurate; Drug: Iohexol |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean Arterial Pressure
Mean arterial pressure (MAP) will be measured before and after administration of LCZ696 on each of the four study days.
Measured: Eight hours
Urine Sodium Excretion
Urine sodium excretion will be measured for six hours following study 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: 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.
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.
Measured: 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.
Measured: Over six hours on each of four study days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Oct 2019
- Study start1 Nov 2019
- Primary completion1 Apr 2025
- Study completion30 Jul 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 (4)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 Vanderbilt University Medical CenterThe 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
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Nancy J. Brown, MD, Vanderbilt University Medical Center
- Investigators
- Nancy J. Brown, M.D., Principal investigator, Vanderbilt University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04113109
- Sponsor's protocol ID
- #191228
- Status last verified
- Aug 2026
- First submitted
- 26 Sep 2019
- Last updated
- 11 Aug 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 27170530Gupta DK, Stevenson LW, Garner EM, Maulion C, Nian H, Wright PR, Turcu AF, Wei S, Brown NJ. Modest Contribution of Bradykinin to Blood Pressure Reduction by Sacubitril/Valsartan in Chronic Heart Failure. Circ Heart Fail. 2026 Jun;19(6):e014117. doi: 10.1161/CIRCHEARTFAILURE.125.014117. Epub 2026 Apr 24.
PubMed 42028604