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Icatibant / Iohexol / LCZ 696 · Phase 4 Trial
ClinicalTrials.gov · August 11, 2026
Early or partial results. Treat as a signal, not a conclusion.
This is a completed Phase 4 mechanistic crossover trial designed to test whether endogenous bradykinin contributes to the hypotensive and natriuretic effects of LCZ696 (ARB/NEP inhibition) in stable heart failure patients. The study enrolled 46 participants (fewer than the planned 80) and assessed mean arterial pressure and urine sodium excretion after acute dosing and after up-titration, comparing LCZ696 with and without bradykinin B2 receptor antagonism; however, results are not reported in this registry record.
Phase 4, Interventional, Randomized, Crossover, Quadruple masking, Basic Science purpose. Heart Failure; age from 18 Years. Intervention: placebo, icatibant, placebo, icatibant; placebo, icatibant, icatibant, placebo; icatibant, placebo, placebo, icatibant; icatibant, placebo, icatibant placebo. Compared with: Placebo (vehicle); crossover design used each participant as their own control. n = 46. 1 site: United States.
This is a completed Phase 4 mechanistic crossover trial designed to test whether endogenous bradykinin contributes to the hypotensive and natriuretic effects of LCZ696 (ARB/NEP inhibition) in stable heart failure patients. The study enrolled 46 participants (fewer than the planned 80) and assessed mean arterial pressure and urine sodium excretion after acute dosing and after up-titration, comparing LCZ696 with and without bradykinin B2 receptor antagonism; however, results are not reported in this registry record.
This is a registry record with no results reported; no efficacy or safety outcomes are available for evaluation.
If results support the hypothesis that bradykinin mediates LCZ696-induced hypotension, this could inform strategies to mitigate early blood pressure drops and enable wider adoption of this mortality-beneficial therapy in heart failure. Until results are published, no clinical recommendation can be made.
This is a completed mechanistic Phase 4 crossover study testing a hypothesis about bradykinin's role in ARB/NEP inhibitor hypotension in heart failure; no results are reported in this registry record.
As stated by the source record.
Quoted from the source exactly as published.
If results support the hypothesis that bradykinin mediates LCZ696-induced hypotension, this could inform strategies to mitigate early blood pressure drops and enable wider adoption of this mortality-beneficial therapy in heart failure. Until results are published, no clinical recommendation can be made.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no key findings. That is a gap in the analysis, not a judgement about the study.
Registry record from ClinicalTrials.gov (NCT04113109). This is a study registration, not published results. Lead sponsor: Vanderbilt University Medical Center. Recruitment status: COMPLETED. Phase: PHASE4. Study type: INTERVENTIONAL. Enrollment: 46 participants (ACTUAL). Conditions: Heart Failure. Interventions: DRUG: LCZ 696; DRUG: Icatibant; DRUG: placebo; DRUG: Para-aminohippurate; DRUG: Iohexol. Primary outcome measures: Mean Arterial Pressure , Eight hours; Urine Sodium Excretion , Total urine output from drug administration to six hours following drug administration. Brief 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.
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