- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03005184
Mechanism(s) Underlying Cardiovascular Effects of ARB/NEP Inhibition - Aim 2
Study Overview
Status
Intervention / Treatment
Detailed Description
Study Type
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Tennessee
-
Nashville, Tennessee, United States, 37232
- Vanderbilt University Medical Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Stable patients with a reduced EF
- EF less than or equal to 40% (confirmed by echocardiogram within the last six months), and
- history of symptoms of New York Heart Association class I, II or III HF
- stable clinical symptoms including no hospitalizations for the last six months
- treatment with a stable dose of an ACEi or ARB and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks
- treatment with a stable dose of an 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
Exclusion Criteria:
- History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, 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 decompensated HF within the last six 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 SBP<100 mmHg at screening or <90 mmHg during the study
- Serum potassium >5.2 mmol/L at screening or >5.4 mmol/L during the study
- 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 within six months
- 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 LV dilatation
- Presence of other hemodynamically significant obstructive lesions of the left ventricular outflow tract, including aortic and subaortic stenosis
- Type 1 diabetes
- Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c >9%
- Hematocrit <35%
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/1.73m2)=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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: S/V+Pla, S/V+I, Enal+Pla, Enal+I
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: S/V+Pla, Enal+I, S/V+I, Enal+Pla
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: S/V+Pla, Enal+Pla, Enal+I, S/V+I
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: S/V+I, S/V+Pla, Enal+I, Enal+P
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: S/V+I, Enal+Pla, S/V+Pla, Enal+I
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: S/V+I, Enal+I, Enal+Pla, S/V+Pla
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: Enal+Pla, S/V+Pla, S/V+I, Enal+I
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: Enal+Pla, S/V+I, Enal+I, S/V+Pla
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: Enal+Pla, Enal+I, S/V+Pla, S/V+I
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: Enal+I, S/V+Pla, Enal+Pla, S/V+I
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: Enal+I, S/V+I, S/V+Pla, Enal+Pla
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
Experimental: Enal+I, Enal+Pla, S/V+I, S/V+Pla
Enal indicated Enalapril 10 mg bid for seven days, and S/V indicates Sacubitril-Valsartan 200 mg bid for seven days.
Pla indicates intravenous placebo given on the seventh day of treatment, whereas I indicates intravenous icatibant given on the seventh day of treatment.
Each treatment period is separated by a three-week washout during which patients receive Valsartan 80 mg bid.
|
oral medication during run-in and washout period
oral medication
oral medication
intravenous medication
intravenous medication
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
change in systolic blood pressure
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
change in plasma cGMP
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
heart rate
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
renal plasma flow
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
glomerular filtration rate
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
change in diastolic blood pressure
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
fractional excretion of sodium
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
urine albumin-to-creatinine ratio
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
brain natriuretic peptide (BNP) to N-terminal pro-BNP ratio
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
plasminogen activator inhibitor-1
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
tissue plasminogen activator
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
aldosterone
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
urine cGMP
Time Frame: 7-hour period after 7-day intervention
|
7-hour period after 7-day intervention
|
Collaborators and Investigators
Study record dates
Study Major Dates
Study Start (Anticipated)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Heart Diseases
- Cardiovascular Diseases
- Heart Failure
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Peripheral Nervous System Agents
- Enzyme Inhibitors
- Analgesics
- Sensory System Agents
- Anti-Inflammatory Agents, Non-Steroidal
- Analgesics, Non-Narcotic
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Protease Inhibitors
- Angiotensin II Type 1 Receptor Blockers
- Angiotensin Receptor Antagonists
- Angiotensin-Converting Enzyme Inhibitors
- Complement Inactivating Agents
- Bradykinin B2 Receptor Antagonists
- Bradykinin Receptor Antagonists
- Valsartan
- Enalapril
- Sacubitril and valsartan sodium hydrate drug combination
- Icatibant
Other Study ID Numbers
- IRB#161306
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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