NCT04113109

Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 2

• Status: Completed
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 46 (actual)
• Sponsor: Vanderbilt University Medical Center · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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 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. 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

Interventions

Type	Name	Description
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).
DRUG	Icatibant	Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day.
DRUG	placebo	Placebo (vehicle) will be given at the same rate as icatibant.
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.

Timeline

• Start date: 2019-11-01
• Primary completion: 2025-04-01
• Completion: 2025-07-30
• First posted: 2019-10-02
• Last updated: 2025-08-24

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study