Investigating blood pressure responses in heart failure treatment

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

This study is testing how a new heart failure treatment called LCZ696 affects blood pressure in patients while also looking at the role of a substance called substance P.

Quick facts

• Phase: Phase 4
• Study type: Interventional
• Enrollment: 80 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Yale University (Academic / other)
• Drugs / interventions: prednisone
• Locations: 1 site (New Haven, Connecticut)
• Trial ID: NCT04649229 on ClinicalTrials.gov

What this trial studies

This interventional study aims to explore the mechanisms behind blood pressure responses in patients with heart failure when treated with LCZ696, a combination of an angiotensin receptor blocker and neprilysin inhibitor. It employs a double-blind, randomized, two x two crossover design, comparing the effects of aprepitant versus placebo during the initiation and steady-state phases of LCZ696 treatment. The study will involve 80 stable heart failure patients with reduced ejection fraction, assessing how endogenous substance P influences blood pressure, natriuresis, and diuresis. The findings could provide insights into optimizing heart failure management and minimizing hypotensive effects.

Who should consider this trial

Good fit: Ideal candidates include stable heart failure patients with reduced ejection fraction and a history of symptoms classified as NYHA class I, II, or III.

Not a fit: Patients who are not stable or those already taking LCZ696 may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved management strategies for heart failure patients, reducing the risk of hypotension during treatment.

How similar studies have performed: Previous studies have shown the efficacy of LCZ696 in heart failure management, but this specific mechanistic approach is novel.

Eligibility criteria

Inclusion 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

Exclusion Criteria:

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:

   a. eGFR (mL/min/1.73 m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742 if female)
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

Where this trial is running

New Haven, Connecticut

• Yale New Haven Hospital — New Haven, Connecticut, United States (Recruiting)

Study contacts

• Principal investigator: Nancy J. Brown, MD — Yale University
• Study coordinator: Christopher Maulion, MD

Conditions Heart Failure