HypertensionPhase 4NCT03738878

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

A Phase 4 study testing Valsartan, LCZ696 and Bradykinin in people with Hypertension, run by Vanderbilt University Medical Center at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

Who is it for?: Ages 18 to 60 years
Conditions the study is for: Hypertension
What is being tested?: Valsartan, LCZ696 and Bradykinin
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 4 participants
Where: 1 siteUnited States
Study dates: 15 Nov 2018to 1 Dec 2024
Phase: Phase 4
Are there results?: Yes, posted in the registrySummary in the doctors' view

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 to 60 years
All sexes
No healthy volunteers
Adult

Who may be able to join

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.

Who cannot join

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)

Show all 29Show fewer

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)
Use of hormone-replacement therapy
Breast feeding and pregnancy
History or presence of immunological or hematological disorders
History of malignancy other than non-melanoma skin cancer
Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
Clinically significant gastrointestinal impairment that could interfere with drug absorption
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, 37205

Other trials in United States

About this study

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.

Read the detailed description

After informed consent is obtained, subjects will undergo a screening history and physical exam, and anti-hypertensive medications will be withdrawn. During this period, blood pressure (BP) will be measured every one to three days.

After subjects have been off anti-hypertensive medications for three weeks (four for spironolactone), they will be randomized to four-week treatment with valsartan 160 mg bid (80 mg bid for one week, then 160 mg bid) or LCZ696 200 bid (100 mg bid for one week, then 200 mg bid) in a double-blind fashion. On the morning of the 28th day of study drug, subjects will report to the Vanderbilt Clinical Research Center (CRC) after an overnight fast. Subjects will be studied in the supine position in a temperature-controlled room. They will be instrumented for intra-arterial infusions. Subjects will be given their last dose of study drug. One hour after drug administration, we will measure forearm blood flow (FBF) and give bradykinin, substance P, or BNP. Each peptide will be infused in three graded doses for five minutes. After administration of all three peptides, subjects will be allowed to rest for an hour. Then they will be given a single oral dose of sitagliptin 200 mg and be allowed to rest for 90 minutes. We will repeat baseline measurements and the peptide infusions with an intervening rest period. The four-week study treatment and protocol will be repeated after a three-week washout, until participants complete both arms.

Conditions: Hypertension
Being tested: Valsartan, LCZ696, Bradykinin, Substance P, BNP
Medical subject headings: Hypertension

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

ValsartanDrug
oral valsartan
LCZ696Drug
Also called Entresto
oral LCZ696
BradykininDrug
Intra-arterial bradykinin at three graded doses
Substance PDrug
Intra-arterial substance P at three graded doses
BNPDrug
Also called Nesiritide
Intra-arterial BNP at three graded doses
SitagliptinDrug
Also called Januvia
oral sitagliptin

Study groups in NCT03738878
Study group	Role	What they receive
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. Receives: 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. Receives: Drug: Valsartan; Drug: LCZ696; Drug: Bradykinin; Drug: Substance P; Drug: BNP; Drug: Sitagliptin

What is being measured

The primary outcome is the main question the study is designed to answer.

Forearm Blood Flow
Forearm blood flow measured by strain gauge plethysmography before and after intra-arterial peptide infusion
Measured: After four-week treatment with each crossover drug

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

15 Nov 20181 Dec 2024

First posted13 Nov 2018
Study start15 Nov 2018
Primary completion1 Dec 2024
Study completion1 Dec 2024

Why it stopped: An alternative study was developed to replace this study.

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.
Other trials for HypertensionStudies 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: 4 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03738878
Sponsor's protocol ID: IRB#170762
Status last verified: Jul 2025
First submitted: 8 Nov 2018
Last updated: 3 Aug 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 3 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Mechanism(s) Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 1
ClinicalTrials.gov ID: NCT03738878
Acronym / sponsor ID: IRB#170762
Conditions: Hypertension
Phase: Phase 4
Study type: Interventional
Recruitment status: TerminatedReason stopped: An alternative study was developed to replace this study.
Enrolment: 4 participants (actual)
Lead sponsor: Vanderbilt University Medical CenterUniversity, hospital or other
Study start: 15 Nov 2018 (actual)
Primary completion: 1 Dec 2024 (actual)
Study completion: 1 Dec 2024 (actual)
First posted: 13 Nov 2018 (actual)
Results: Posted 3 Aug 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Basic science
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
valsartan then LCZ696	Active comparator	Drug: Valsartan, Drug: LCZ696, Drug: Bradykinin, Drug: Substance P, Drug: BNP, Drug: SitagliptinAfter 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.
LCZ696 then valsartan	Active comparator	Drug: Valsartan, Drug: LCZ696, Drug: Bradykinin, Drug: Substance P, Drug: BNP, Drug: SitagliptinAfter 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.

Who may qualify

Ages: 18 to 60 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult

Key inclusion criteria (8 listed)

Patients with essential hypertension defined as having
For female subjects, the following conditions must be met:

Key exclusion criteria (29 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Valsartanoral valsartan	Drug	LCZ696 then valsartan, valsartan then LCZ696
LCZ696Also: Entrestooral LCZ696	Drug	LCZ696 then valsartan, valsartan then LCZ696
BradykininIntra-arterial bradykinin at three graded doses	Drug	LCZ696 then valsartan, valsartan then LCZ696
Substance PIntra-arterial substance P at three graded doses	Drug	LCZ696 then valsartan, valsartan then LCZ696
BNPAlso: NesiritideIntra-arterial BNP at three graded doses	Drug	LCZ696 then valsartan, valsartan then LCZ696
SitagliptinAlso: Januviaoral sitagliptin	Drug	LCZ696 then valsartan, valsartan then LCZ696

Primary outcome

Forearm Blood Flow
Time frame: After four-week treatment with each crossover drug
Forearm blood flow measured by strain gauge plethysmography before and after intra-arterial peptide infusion

Results and safety

Results posted to the registry on 3 Aug 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Valsartan Then LCZ696	0	0
LCZ696 Then Valsartan	1	1

Primary outcome: Forearm Blood Flow

Time frame: After four-week treatment with each crossover drug. Mean (Full Range). Unit: mL/min/100mL

Measure	LCZ696 n = 1	Valsartan n = 1
Value	2.46 (2.46 to 2.46)	2.99 (2.99 to 2.99)

Population analysed: Because the study was terminated data from only one participant are included and no statistical analyses were performed.

Adverse events

Time frame: Adverse event data were collected over the full duration of the study - approximately 12 weeks.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
LCZ966	0 of 1 (0%)	1 of 1 (100%)	0 of 1
Valsartan	0 of 1 (0%)	0 of 1 (0%)	0 of 1

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 3 Aug 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: No

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Chronic Kidney Disease, Hypertension (HTN)
Recruiting
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An Open-Label Extension Study to Evaluate Inhaled Treprostinil SMI in Participants With Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease (PH-COPD)
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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Valsartan, LCZ696 and Bradykinin in people with Hypertension, run by Vanderbilt University Medical Center at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 3 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 3 Aug 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Forearm Blood Flow (time frame: After four-week treatment with each crossover drug). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03738878.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Aug 2025.