Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 1

NCT03738878 | Terminated Phase 4 Results DMC FDA Drug

• 1 other identifier: IRB#170762
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to test the hypothesis that combined angiotensin receptor blockade (ARB)/neprilysin (NEP) inhibition potentiates the effects of exogenous bradykinin, substance P, and brain natriuretic peptide (BNP) on forearm blood flow or endothelial tissue-type plasminogen activator (t-PA) release compared to ARB alone. A secondary goal is to determine if there is an interactive effect of ARB/NEP inhibition and dipeptidyl peptidase 4 (DPP4) inhibition on responses to these peptides.

Conditions

Hypertension

Outcome Measures

Primary Outcomes (1)

• Forearm Blood Flow

  Forearm blood flow measured by strain gauge plethysmography before and after intra-arterial peptide infusion

  After four-week treatment with each crossover drug

Study Arms (2)

valsartan then LCZ696

ACTIVE COMPARATOR

After four-week treatment with valsartan, participants will receive intra-arterial infusions of bradykinin, substance P, and BNP in the presence and absence of sitagliptin. Then, after three-week washout and four week therapy with LCZ696, participants will receive intra-arterial infusions of bradykinin, substance P, and BNP in the presence and absence of sitagliptin.

Drug: Valsartan; Drug: LCZ696; Drug: Bradykinin; Drug: Substance P; Drug: BNP; Drug: Sitagliptin

LCZ696 then valsartan

ACTIVE COMPARATOR

After four-week treatment with LCZ696, participants will receive intra-arterial infusions of bradykinin, substance P, and BNP in the presence and absence of sitagliptin. Then, after three-week washout and four week therapy with valsartan, participants will receive intra-arterial infusions of bradykinin, substance P, and BNP in the presence and absence of sitagliptin.

Drug: Valsartan; Drug: LCZ696; Drug: Bradykinin; Drug: Substance P; Drug: BNP; Drug: Sitagliptin

Interventions

Valsartan DRUG

oral valsartan

LCZ696 then valsartan; valsartan then LCZ696

LCZ696 DRUG

oral LCZ696

Also known as: Entresto

LCZ696 then valsartan; valsartan then LCZ696

Bradykinin DRUG

Intra-arterial bradykinin at three graded doses

LCZ696 then valsartan; valsartan then LCZ696

Substance P DRUG

Intra-arterial substance P at three graded doses

LCZ696 then valsartan; valsartan then LCZ696

BNP DRUG

Intra-arterial BNP at three graded doses

Also known as: Nesiritide

LCZ696 then valsartan; valsartan then LCZ696

Sitagliptin DRUG

oral sitagliptin

Also known as: Januvia

LCZ696 then valsartan; valsartan then LCZ696

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Patients with essential hypertension defined as having
• untreated, seated systolic blood pressure (SBP) of 130 mmHg or greater on three separate occasions, or
• untreated, seated diastolic BP (DBP) of 80 or greater on three separate occasions, or
• taken anti-hypertensive agent(s) for a minimum of six months.
• 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 adequate birth control and willingness to undergo urine beta-human chorionic gonadotropin (hCG) testing prior to drug treatment and on every study day.

You may not qualify if:

• Presence of secondary form of hypertension
• Symptomatic hypertension and/or SBP\>170 mmHg or DBP\>110 mmHg, relevant to the washout period
• History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, angiotensin-converting enzyme inhibitor (ACEi), ARBs, or NEPi, as well as known or suspected contraindications to the study drugs
• History of angioedema
• History of pancreatitis or known pancreatic lesions
• History of significant cardiovascular disease (other than essential hypertension and left ventricular hypertrophy)
• Symptomatic hypotension and/or a 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
• Individuals using oral contraceptives and smokers in order to reduce the risk of thrombosis following arterial line placement
• History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack within six months
• Presence of significant pulmonary disorders
• Type 1 diabetes
• Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c \>9%
• Hematocrit \<35%
• Impaired renal function \[estimated glomerular filtration rate (eGFR) of \<30 mL/min/1.73 m2\] 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/1.73m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742 if female)

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37205, United States

Location

MeSH Terms

Conditions

Hypertension

Interventions

Valsartan; sacubitril and valsartan sodium hydrate drug combination; Bradykinin; Substance P; Natriuretic Peptide, Brain; Sitagliptin Phosphate

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential; Kinins; Intercellular Signaling Peptides and Proteins; Peptides; Neuropeptides; Oligopeptides; Proteins; Nerve Tissue Proteins; Autacoids; Inflammation Mediators; Biological Factors; Tachykinins; Natriuretic Peptides; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Triazoles; Pyrazines

Results Point of Contact

• Title: Nancy J. Brown
• Organization: Yale University

nancy.j.brown@yale.edu

2037854672

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Ajunct professor

Study Record Dates

• First Submitted: November 8, 2018
• First Posted: November 13, 2018
• Study Start: November 15, 2018
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: August 3, 2025
• Results First Posted: August 3, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)