The Effect of Neprilysin (LCZ696) on Exercise Tolerance in Patients With Heart Failure


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Verified June 2017 by University of Sao Paulo General Hospital

Sponsor:

Information provided by (Responsible Party):

University of Sao Paulo General Hospital

ClinicalTrials.gov Identifier:

NCT03190304

First received: June 14, 2017

Last updated: June 14, 2017

Last verified: June 2017

Studies with new drugs in the treatment of heart failure (HF), such as the combination of valsartan/sacubitril, also known as LCZ696, have demonstrated important clinical impact on the morbidity and mortality outcomes in HF population. However, the effect of LCZ696 on the pathophysiological mechanisms of HF such as exercise tolerance (peak VO2) and peripheral muscle blood flow is not known. Since LCZ696 is a new drug with promising effects on the treatment of HF, the objective of the present study will be to evaluate the effect of LCZ696 in patients with HF on: 1) peak VO2, 2) 6-minute walk test, 3) peripheral muscle blood flow, 4) muscle strength, and 5) body composition.

Heart Failure
Exercise Tolerance
Vasodilation
Body Composition
Muscle Strength
Drug: Neprilysin
Drug: Enalapril
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

double-blind, randomized clinical trial

Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment

Official Title: The Effect of NEPRIlysin (LCZ696) on EXercise TOLerance, Muscle Vasodilatation, Muscle Strength and Body Composition in Patients With Heart Failure – NEPRIExTol-HF Trial

Primary Outcome Measures:

Secondary Outcome Measures:

  • Walking distance [ Time Frame: 6 months ]

    To test the effect of treatments on 6 minutes walking test

  • Muscle vasodilation [ Time Frame: 6 months ]

    To test the effect of treatments on forearm blood flow evaluated by venous occlusion plethysmography

  • Muscle strength [ Time Frame: 6 months ]

    To test the effect of treatments on muscle strength evaluated by handgrip

  • Body composition [ Time Frame: 6 months ]

    To test the effect of treatments on lean muscle mass evaluated by dual energy x-ray absorptiometry

Estimated Enrollment: 52
Actual Study Start Date: June 14, 2017
Estimated Study Completion Date: December 14, 2018
Estimated Primary Completion Date: July 14, 2018 (Final data collection date for primary outcome measure)
Active Comparator: Enalapril

Enalapril at a dose of 10 mg twice daily for 6 months

Drug: Enalapril

To compare the effect of Enalapril and Neprilysin on exercise tolerance in patients with heart failure

Other Name: Angiotensin converting enzyme inhibitor

Experimental: Neprilysin (LCZ696)

LCZ696 at a dose of 200 mg twice daily for 6 months

Drug: Neprilysin

To compare the effect of Enalapril and Neprilysin on exercise tolerance in patients with heart failure

Other Name: LCZ696

Heart failure (HF) with reduced ventricular ejection fraction is a disease that affects around 5.7 million people in the United States, with a mortality rate of approximately 50% within 5 years. HF is characterized by an exacerbation of the renin-angiotensin-aldosterone system (RAAS), which leads to an increase in sympathetic nerve outflow, peripheral vasoconstriction, and reduced functional capacity. Moreover, many clinical trials have been developed for the treatment of HF patients focused on inhibition of RAAS, such as enalapril. Nevertheless, hospitalization and mortality rates in this population are excessive. However, studies with new drugs, such as the combination of valsartan/sacubitril, also known as LCZ696, have demonstrated important clinical impact on the morbidity and mortality outcomes in HF population. However, the effect of LCZ696 on the pathophysiological mechanisms of HF such as exercise tolerance (peak VO2) and peripheral muscle blood flow is not known. Since LCZ696 is a new drug with promising effects on the treatment of HF, the objective of the present study will be to evaluate the effect of LCZ696 in patients with HF on: 1) peak VO2, 2) 6-minute walk test, 3) peripheral muscle blood flow, 4) muscle strength, and 5) body composition.

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Symptomatic patients with heart failure (men and women) aged >18 years,
  2. Functional class II, III or IV by the New York Heart Association (NYHA)
  3. Left ventricular ejection fraction <35%
  4. Ischemic and nonischemic etiology
  5. Type B natriuretic peptide (BNP) >150 pg/ml (or pro-BNP [N-terminal-proBNP] ≥ 600 pg / ml) or if the patient was hospitalized for cardiac decompensation within the preceding 12 months, BNP >100 pg/ml (or N-terminal-proBNP ≥ 400 pg / ml)

Exclusion Criteria:

  1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACE inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), or neprilysin inhibitors, as well as known or suspected contraindications to the study drugs.
  2. Previous history of intolerance to recommended target doses of ACEIs or ARBs.
  3. Known history of angioedema.
  4. Requirement for treatment with both ACEIs and ARBs.
  5. Current acute decompensated heart failure (exacerbation of chronic heart failure manifested by signs and symptoms that may require intravenous therapy).
  6. Symptomatic hypotension.
  7. Estimated glomerular filtration rate (eGFR) <30%.
  8. Serum potassium >5.4 mmol/L.
  9. Acute coronary syndrome, stroke, transient ischaemic attack, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within the 3 months.
  10. Coronary or carotid artery disease likely to require surgical or percutaneous intervention within the 6 months.
  11. Implantation of a cardiac resynchronization therapy (CRT) device within 3 months or intent to implant a CRT.
  12. History of heart transplant or on a transplant list or with left ventricular (LV) assistance device.
  13. History of severe pulmonary disease.
  14. Diagnosis of peripartum- or chemotherapy-induced cardiomyopathy within the 12 months.
  15. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months.
  16. Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker.
  17. Presence of haemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to LV dilatation.
  18. Presence of other haemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic stenosis.
  19. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including, but not limited to, any of the following: History of active inflammatory bowel disease during the 12 months. Active duodenal or gastric ulcers during the 3 months. Evidence of hepatic disease as determined by any one of the following: aspartate aminotransferase or alanine aminotransferase values exceeding 2x upper limit of normal, history of hepatic encephalopathy, history of oesophageal varices, or history of porto-caval shunt. Current treatment with cholestyramine or colestipol resins.
  20. Presence of any other disease with a life expectancy of <5 years.

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03190304

Marcelo Rodrigues dos Santos
São Paulo, SP, Brazil, 05403-900
Contact: Antonio P Barreto, PhD    +55 11 2661-5043    pereira.barreto@incor.usp.br   

University of Sao Paulo General Hospital

Principal Investigator: Antonio P Barretto, PhD Heart Institute (InCor), University of Sao Paulo Medical School

Responsible Party: University of Sao Paulo General Hospital
ClinicalTrials.gov Identifier: NCT03190304     History of Changes
Other Study ID Numbers: NEPRIExTol-HF Trial
Study First Received: June 14, 2017
Last Updated: June 14, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Heart Failure
Heart Diseases
Cardiovascular Diseases
Enalapril
Enalaprilat
Angiotensin-Converting Enzyme Inhibitors
Enzyme Inhibitors
LCZ 696
Protease Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on June 16, 2017