Brief Summary
The purpose of this study was to assess the effect of in-hospital initiation of sacubitril/valsartan (LCZ696) vs. enalapril on time averaged proportional change in NT-proBNP in patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF) and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 40%).
Brief Title
Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Acute Heart Failure
Eligibility Criteria
Key Inclusion Criteria:
1. Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.
2. Currently hospitalized for ADHF. Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x-ray) at time of hospitalization.
3. Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status:
* SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension
* No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization
* No i.v. inotropic drugs for 24 hours prior to randomization
* No i.v. vasodilators including nitrates within last 6 hours prior to randomization
4. LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of \>40%.
5. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.
Key Exclusion Criteria:
1. Currently taking sacubitril/valsartan tablets or any use within the past 30 days.
2. Enrollment in any other clinical trial involving an investigational agent or investigational device.
3. History of hypersensitivity, known or suspected contraindications, or intolerance to any of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor).
4. Patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.
5. Requirement of treatment with both ACE inhibitor and ARB.
6. eGFR \< 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at screening.
7. Serum potassium \> 5.2 mEq/L at screening.
8. Known hepatic impairment (as evidenced by total bilirubin \> 3 mg/dL, or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as varices
9. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within one month prior to Visit 1.
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.
1. Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.
2. Currently hospitalized for ADHF. Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x-ray) at time of hospitalization.
3. Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status:
* SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension
* No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization
* No i.v. inotropic drugs for 24 hours prior to randomization
* No i.v. vasodilators including nitrates within last 6 hours prior to randomization
4. LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of \>40%.
5. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.
Key Exclusion Criteria:
1. Currently taking sacubitril/valsartan tablets or any use within the past 30 days.
2. Enrollment in any other clinical trial involving an investigational agent or investigational device.
3. History of hypersensitivity, known or suspected contraindications, or intolerance to any of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor).
4. Patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.
5. Requirement of treatment with both ACE inhibitor and ARB.
6. eGFR \< 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at screening.
7. Serum potassium \> 5.2 mEq/L at screening.
8. Known hepatic impairment (as evidenced by total bilirubin \> 3 mg/dL, or increased ammonia levels, if performed), or history of cirrhosis with evidence of portal hypertension such as varices
9. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within one month prior to Visit 1.
10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.
Inclusion Criteria
Inclusion Criteria:
1. Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.
2. Currently hospitalized for ADHF. Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x-ray) at time of hospitalization.
3. Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status:
* SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension
* No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization
* No i.v. inotropic drugs for 24 hours prior to randomization
* No i.v. vasodilators including nitrates within last 6 hours prior to randomization
4. LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of \>40%.
5. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.
1. Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.
2. Currently hospitalized for ADHF. Patients with a diagnosis of acute heart failure had to have symptoms and signs of fluid overload (i.e. jugular venous distention, edema or rales on auscultation or pulmonary congestion on chest x-ray) at time of hospitalization.
3. Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status:
* SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension
* No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization
* No i.v. inotropic drugs for 24 hours prior to randomization
* No i.v. vasodilators including nitrates within last 6 hours prior to randomization
4. LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of \>40%.
5. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.
Gender
All
Gender Based
false
Keywords
Acute
Heart Failure
reduced ejection fraction
NTproBNP
Heart failure with reduced ejection fraction (HFREF)
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT02554890
Org Class
Industry
Org Full Name
Novartis
Org Study Id
CLCZ696BUS01
Overall Status
Completed
Phases
Phase 4
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled 8-week Study to Evaluate the Effect of Sacubitril/Valsartan (LCZ696) Versus Enalapril on Changes in NT-proBNP and Safety and Tolerability of In-hospital Initiation of LCZ696 Compared to Enalapril in HFrEF Patients Who Have Been Stabilized Following Hospitalization for Acute Decompensated Heart Failure (ADHF).
Primary Outcomes
Outcome Description
To assess the effect of in-hospital initiation of sacubitril/valsartan vs. enalapril on the time-averaged percentage change of NT-proBNP from baseline in patients who have been stabilized following hospitalization for ADHF and reduced ejection fraction (left ventricular ejection fraction \[LVEF\] ≤ 40%) between week 4 and 8.
Number of patients with both a baseline value and a value at Week 4 or Week 8. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. N-terminal pro b-type natriuretic peptide (NTproBNP) are peptide (small proteins) that are either hormones or part of the peptide that contained the hormone at one time. They are continually produced in small quantities in the heart and released in larger quantities when the heart senses that it needs to work harder, as in heart failure.
Number of patients with both a baseline value and a value at Week 4 or Week 8. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. N-terminal pro b-type natriuretic peptide (NTproBNP) are peptide (small proteins) that are either hormones or part of the peptide that contained the hormone at one time. They are continually produced in small quantities in the heart and released in larger quantities when the heart senses that it needs to work harder, as in heart failure.
Outcome Measure
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline
Outcome Time Frame
Baseline, Week 4 and Week 8
Secondary Outcomes
Outcome Description
Examine the effect of LCZ696 vs. enalapril on incidence of symptomatic hypotension during 8 weeks of treatment Hypotension is low blood pressure. Patients with hypotension may experience symptoms when their blood pressure drops, compared to the patient's normal values. Symptoms of hypotension can include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache.
Outcome Time Frame
8 weeks of treatment
Outcome Measure
Number of Patients With Incidences of Symptomatic Hypotension
Outcome Description
Hyperkalemia is defined as Potassium level \>5.5 mEq/L. Hyperkalemia is the medical term that describes a potassium level in your blood that's higher than normal. Potassium is a chemical that is critical to the function of nerve and muscle cells, including those in your heart.
Outcome Time Frame
8 weeks of treatment
Outcome Measure
Number of Patients With Incidences of Hyperkalemia
Outcome Description
Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, including the genitalia and intestines. Severe cases may be associated with difficulty in breathing.
Outcome Time Frame
8 weeks of treatment
Outcome Measure
Number of Patients With Incidences of Angioedema
Outcome Description
time-averaged (Weeks 4 and 8) change from baseline in hs-troponin T. hs-Troponin-T is a biomarker that is released from the heart under stress or injury conditions.
Outcome Time Frame
Baseline, Week 4/Week 8
Outcome Measure
Change From Baseline in High Sensitivity Troponin (Hs-Troponin)
Outcome Description
Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP. Urinary Cyclic GMP (cGMP) is a biomarker measured in the urine that reflects the activity of biomarkers such as BNP (Brain Natriuretic Peptide)
Outcome Time Frame
Baseline, Week 4 and Week 8
Outcome Measure
Change From Baseline in Urinary cGMP
Outcome Description
Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP to urinary creatinine ratio.
Urinary cGMP to urinary creatinine ratio is how much urinary cGMP (which reflects natriuretic peptide activity) compared to a compound in the urine called creatinine (which helps your doctor evaluate how well your kidneys are functioning).
Urinary cGMP to urinary creatinine ratio is how much urinary cGMP (which reflects natriuretic peptide activity) compared to a compound in the urine called creatinine (which helps your doctor evaluate how well your kidneys are functioning).
Outcome Time Frame
Baseline, Week 4 and Week 8
Outcome Measure
Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio
Outcome Description
Time-averaged (Weeks 4 and 8) change from baseline in BNP to NT-proBNP ratio. BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure.
Outcome Time Frame
baseline, Week 4 and Week 8
Outcome Measure
Change From Baseline in BNP to NTproBNP Ratio
Outcome Description
BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure.
Plasma NT-proBNP (pg/mL) values were Week 8 visit.
Plasma NT-proBNP (pg/mL) values were Week 8 visit.
Outcome Time Frame
Baseline, Week 8
Outcome Measure
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
James Tauras
Investigator Email
jtauras@montefiore.org
Investigator Phone
Categories Mesh Debug
Heart/Cardiovascular --- HEART FAILURE
Brain, Spinal Cord & Nervous System --- HEART DISEASES
Heart/Cardiovascular --- HEART DISEASES
Blood Disorders --- CARDIOVASCULAR DISEASES
Blood & Bone Marrow Cancers --- CARDIOVASCULAR DISEASES
Heart/Cardiovascular --- CARDIOVASCULAR DISEASES
MeSH Terms
HEART FAILURE
HEART DISEASES
CARDIOVASCULAR DISEASES
SACUBITRIL
VALSARTAN
SACUBITRIL AND VALSARTAN SODIUM HYDRATE DRUG COMBINATION
ENALAPRIL
TETRAZOLES
AZOLES
HETEROCYCLIC COMPOUNDS, 1-RING
HETEROCYCLIC COMPOUNDS
VALINE
AMINO ACIDS, BRANCHED-CHAIN
AMINO ACIDS
AMINO ACIDS, PEPTIDES, AND PROTEINS
AMINO ACIDS, ESSENTIAL
DIPEPTIDES
OLIGOPEPTIDES
PEPTIDES