ACTIVE_NOT_RECRUITING

Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 3

Conditions

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

This is a double-blind, randomized, two x two crossover (aprepitant vs placebo) during both initiation of Entresto, LCZ696, (50 mg dose) and at steady-state of Entresto (200 mg bid dose or the highest tolerated dose).

Official Title

Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 3

Quick Facts

Study Start:2021-05-27

Study Completion:2025-10-31

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:ACTIVE_NOT_RECRUITING

Study ID

NCT04649229

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Black and white men and women 2. Stable patients with a reduced ejection fraction (EF) 1. EF ≤55%, and 2. history of symptoms of New York Heart Association (NYHA) class I, II, or III heart failure (HF) 3. stable clinical symptoms including no hospitalizations for the last three months, or one month if hospitalized only once for initial diagnosis of HF 4. who are not already taking LCZ696 3. treatment with a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks 4. for patients with NYHA Class II or III HF and EF ≤35%, treatment with a stable dose of an mineralocorticoid receptor (MR) antagonist for at least four weeks, unless not possible due to renal function or adverse reaction 5. For female subjects, the following conditions must be met: 1. postmenopausal status for at least one year 2. status post-surgical sterilization 3. or if childbearing potential, utilization of barrier methods of birth control or an oral contraceptive and willingness to undergo urine β-HCG testing on every study day 6. Age 18 years of age or older	1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEi, ARBs, or neutral endopeptidase inhibitor (NEPi), as well as known or suspected contraindications to the study drugs 2. History of angioedema 3. History of decompensated HF within the last 3 months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization) or one month if hospitalized only once for initial diagnosis of HF 4. History of heart transplant or on a transplant list or with left ventricular assistance device 5. Symptomatic hypotension and/or a systolic blood pressure (SBP)\<100 mmHg at screening or \<95 mmHg during the study 6. Serum potassium \>5.2 mmol/L at screening or during the study 7. 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: 8. Acute coronary syndrome, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within six months prior to screening 9. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening 10. History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack with clinically significant residual deficits 11. History of ventricular arrhythmia with syncopal episodes 12. Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker 13. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular (LV) dilatation 14. Presence of other hemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic stenosis 15. Type 1 diabetes 16. Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c \>9% 17. In T2DM, dipeptidyl peptidase-4 inhibitor use for one month prior to enrollment will be excluded due to possible interaction with LCZ696 18. Hematocrit \<35% 19. Breast feeding and pregnancy 20. History or presence of immunological or hematological disorders 21. History of malignancy not felt to be cured, except non-melanoma skin cancer 22. Diagnosis of asthma requiring use of inhaled beta agonist more than once a week 23. History of hypersensitivity reaction to contrast 24. Clinically significant gastrointestinal impairment that could interfere with drug absorption 25. History of pancreatitis or known pancreatic lesions 26. Impaired hepatic function with evidence of advanced fibrosis or cirrhosis \[stable aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) trend if \>3.0 x upper limit of normal range as deemed of minimal clinical relevance by the investigators\] 27. 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 28. Treatment with greater than 5 mg of prednisone or equivalent dose of chronic systemic glucocorticoid therapy within the last year or recent (within 6 weeks of first study day) treatment with burst dosed glucocorticoid therapy 29. Treatment with lithium salts 30. History of alcohol or drug abuse 31. Treatment with any investigational drug in the one month preceding the study 32. Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study 33. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Inclusion Criteria

Exclusion Criteria

1. Black and white men and women
2. Stable patients with a reduced ejection fraction (EF)
1. EF ≤55%, and
2. history of symptoms of New York Heart Association (NYHA) class I, II, or III heart failure (HF)
3. stable clinical symptoms including no hospitalizations for the last three months, or one month if hospitalized only once for initial diagnosis of HF
4. who are not already taking LCZ696
3. treatment with a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks
4. for patients with NYHA Class II or III HF and EF ≤35%, treatment with a stable dose of an mineralocorticoid receptor (MR) antagonist for at least four weeks, unless not possible due to renal function or adverse reaction
5. For female subjects, the following conditions must be met:
1. postmenopausal status for at least one year
2. status post-surgical sterilization
3. or if childbearing potential, utilization of barrier methods of birth control or an oral contraceptive and willingness to undergo urine β-HCG testing on every study day
6. Age 18 years of age or older

1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEi, ARBs, or neutral endopeptidase inhibitor (NEPi), as well as known or suspected contraindications to the study drugs
2. History of angioedema
3. History of decompensated HF within the last 3 months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization) or one month if hospitalized only once for initial diagnosis of HF
4. History of heart transplant or on a transplant list or with left ventricular assistance device
5. Symptomatic hypotension and/or a systolic blood pressure (SBP)\<100 mmHg at screening or \<95 mmHg during the study
6. Serum potassium \>5.2 mmol/L at screening or during the study
7. 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:
8. Acute coronary syndrome, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within six months prior to screening
9. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening
10. History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack with clinically significant residual deficits
11. History of ventricular arrhythmia with syncopal episodes
12. Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker
13. Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular (LV) dilatation
14. Presence of other hemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic stenosis
15. Type 1 diabetes
16. Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c \>9%
17. In T2DM, dipeptidyl peptidase-4 inhibitor use for one month prior to enrollment will be excluded due to possible interaction with LCZ696
18. Hematocrit \<35%
19. Breast feeding and pregnancy
20. History or presence of immunological or hematological disorders
21. History of malignancy not felt to be cured, except non-melanoma skin cancer
22. Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
23. History of hypersensitivity reaction to contrast
24. Clinically significant gastrointestinal impairment that could interfere with drug absorption
25. History of pancreatitis or known pancreatic lesions
26. Impaired hepatic function with evidence of advanced fibrosis or cirrhosis \[stable aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) trend if \>3.0 x upper limit of normal range as deemed of minimal clinical relevance by the investigators\]
27. 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
28. Treatment with greater than 5 mg of prednisone or equivalent dose of chronic systemic glucocorticoid therapy within the last year or recent (within 6 weeks of first study day) treatment with burst dosed glucocorticoid therapy
29. Treatment with lithium salts
30. History of alcohol or drug abuse
31. Treatment with any investigational drug in the one month preceding the study
32. Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
33. Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study

Contacts and Locations

Principal Investigator

Nancy J. Brown, MD

PRINCIPAL_INVESTIGATOR

Yale University

Study Locations (Sites)

Yale New Haven Hospital

New Haven, Connecticut, 06520

United States

Collaborators and Investigators

Sponsor: Yale University

Nancy J. Brown, MD, PRINCIPAL_INVESTIGATOR, Yale University

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2021-05-27

Study Completion Date2025-10-31

Study Record Updates

Study Start Date2021-05-27

Study Completion Date2025-10-31

Terms related to this study

Additional Relevant MeSH Terms

Heart Failure