Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode.

Acute Heart Failure Clinical Trial

— PIONEER-HF  

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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02554890
• Other study ID #: CLCZ696BUS01
• Status: Completed
• Phase: Phase 4
• Start date: April 29, 2016
• Est. completion date: July 24, 2018

Study information

• Verified date: September 2020
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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%).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 887
• Est. completion date: July 24, 2018
• Est. primary completion date: June 29, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Heart Failure
• Heart Failure

Intervention

Drug:
• sacubitril/valsartan (LCZ696)
sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.
• Enalapril
Enalapril tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.
• sacubitril/valsartan (LCZ696) matching placebo
matching placebo of sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.
• enalapril matching placebo
enalapril matching placebo tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.

Locations

Country	Name	City	State
United States	Novartis Investigative Site	Abington	Pennsylvania
United States	Novartis Investigative Site	Alexandria	Louisiana
United States	Novartis Investigative Site	Ann Arbor	Michigan
United States	Novartis Investigative Site	Annapolis	Maryland
United States	Novartis Investigative Site	Atlantis	Florida
United States	Novartis Investigative Site	Augusta	Georgia
United States	Novartis Investigative Site	Aurora	Illinois
United States	Novartis Investigative Site	Bakersfield	California
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Bangor	Maine
United States	Novartis Investigative Site	Baton Rouge	Louisiana
United States	Novartis Investigative Site	Bay City	Michigan
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Boise	Idaho
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Bridgeport	Connecticut
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Brooklyn	New York
United States	Novartis Investigative Site	Buffalo	New York
United States	Novartis Investigative Site	Camden	New Jersey
United States	Novartis Investigative Site	Camp Hill	Pennsylvania
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Charleston	South Carolina
United States	Novartis Investigative Site	Charlottesville	Virginia
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Clarksburg	West Virginia
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Daytona Beach	Florida
United States	Novartis Investigative Site	Denver	Colorado
United States	Novartis Investigative Site	Des Moines	Iowa
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Elk Grove Village	Illinois
United States	Novartis Investigative Site	Elkhart	Indiana
United States	Novartis Investigative Site	Elmer	New Jersey
United States	Novartis Investigative Site	Fort Lauderdale	Florida
United States	Novartis Investigative Site	Fort Smith	Arkansas
United States	Novartis Investigative Site	Fresno	California
United States	Novartis Investigative Site	Gainesville	Florida
United States	Novartis Investigative Site	Gainesville	Florida
United States	Novartis Investigative Site	Grand Forks	North Dakota
United States	Novartis Investigative Site	Greenville	North Carolina
United States	Novartis Investigative Site	Greenville	South Carolina
United States	Novartis Investigative Site	Haddon Heights	New Jersey
United States	Novartis Investigative Site	Hartford	Connecticut
United States	Novartis Investigative Site	Hartford	Connecticut
United States	Novartis Investigative Site	Hattiesburg	Mississippi
United States	Novartis Investigative Site	Hollywood	Florida
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Jackson	Mississippi
United States	Novartis Investigative Site	Jacksonville	Florida
United States	Novartis Investigative Site	Jacksonville	Florida
United States	Novartis Investigative Site	Johnson City	New York
United States	Novartis Investigative Site	Kansas City	Missouri
United States	Novartis Investigative Site	Kansas City	Kansas
United States	Novartis Investigative Site	Lakeland	Florida
United States	Novartis Investigative Site	Little Rock	Arkansas
United States	Novartis Investigative Site	Littleton	Colorado
United States	Novartis Investigative Site	Long Beach	California
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Louisville	Kentucky
United States	Novartis Investigative Site	Louisville	Kentucky
United States	Novartis Investigative Site	Lynchburg	Virginia
United States	Novartis Investigative Site	Macon	Georgia
United States	Novartis Investigative Site	Madison	Wisconsin
United States	Novartis Investigative Site	Manhasset	New York
United States	Novartis Investigative Site	Maplewood	Minnesota
United States	Novartis Investigative Site	Marietta	Georgia
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	Muncie	Indiana
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	Natrona Heights	Pennsylvania
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	Newark	New Jersey
United States	Novartis Investigative Site	Oakbrook Terrace	Illinois
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Orange	California
United States	Novartis Investigative Site	Park Ridge	Illinois
United States	Novartis Investigative Site	Pasadena	California
United States	Novartis Investigative Site	Peoria	Illinois
United States	Novartis Investigative Site	Peoria	Illinois
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Plano	Texas
United States	Novartis Investigative Site	Poughkeepsie	New York
United States	Novartis Investigative Site	Providence	Rhode Island
United States	Novartis Investigative Site	Rapid City	South Dakota
United States	Novartis Investigative Site	Reno	Nevada
United States	Novartis Investigative Site	Richmond	Indiana
United States	Novartis Investigative Site	Richmond	Virginia
United States	Novartis Investigative Site	Rochester	New York
United States	Novartis Investigative Site	Sacramento	California
United States	Novartis Investigative Site	Saint Paul	Minnesota
United States	Novartis Investigative Site	Saint Paul	Minnesota
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	San Marino	California
United States	Novartis Investigative Site	San Pablo	California
United States	Novartis Investigative Site	Sarasota	Florida
United States	Novartis Investigative Site	Slidell	Louisiana
United States	Novartis Investigative Site	Stanford	California
United States	Novartis Investigative Site	Staten Island	New York
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Toledo	Ohio
United States	Novartis Investigative Site	Tulsa	Oklahoma
United States	Novartis Investigative Site	Vero Beach	Florida
United States	Novartis Investigative Site	Virginia Beach	Virginia
United States	Novartis Investigative Site	Washington	District of Columbia
United States	Novartis Investigative Site	Wausau	Wisconsin
United States	Novartis Investigative Site	West Haven	Connecticut
United States	Novartis Investigative Site	White River Junction	Vermont
United States	Novartis Investigative Site	Winfield	Illinois
United States	Novartis Investigative Site	Winston-Salem	North Carolina
United States	Novartis Investigative Site	Winter Haven	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (4)

Morrow DA, Velazquez EJ, DeVore AD, Desai AS, Duffy CI, Ambrosy AP, Gurmu Y, McCague K, Rocha R, Braunwald E. Clinical Outcomes in Patients With Acute Decompensated Heart Failure Randomly Assigned to Sacubitril/Valsartan or Enalapril in the PIONEER-HF Trial. Circulation. 2019 May 7;139(19):2285-2288. doi: 10.1161/CIRCULATIONAHA.118.039331. — View Citation

Morrow DA, Velazquez EJ, DeVore AD, Prescott MF, Duffy CI, Gurmu Y, McCague K, Rocha R, Braunwald E. Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEER-HF trial. Eur Heart J. 2019 Oct 21;40(40):3345-3352. doi: 10.1093/eurheartj/ehz240. — View Citation

Velazquez EJ, Morrow DA, DeVore AD, Ambrosy AP, Duffy CI, McCague K, Hernandez AF, Rocha RA, Braunwald E. Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial. Am Heart J. 2018 Apr;198:145-151. doi: 10.1016/j.ahj.2018.01.004. Epub 2018 Jan 10. — View Citation

Velazquez EJ, Morrow DA, DeVore AD, Duffy CI, Ambrosy AP, McCague K, Rocha R, Braunwald E; PIONEER-HF Investigators. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure. N Engl J Med. 2019 Feb 7;380(6):539-548. doi: 10.1056/NEJMoa1812851. Epub 2018 Nov 11. Erratum in: N Engl J Med. 2019 Mar 14;380(11):1090. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline	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.	Baseline, Week 4 and Week 8
Secondary	Number of Patients With Incidences of Symptomatic Hypotension	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.	8 weeks of treatment
Secondary	Number of Patients With Incidences of Hyperkalemia	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.	8 weeks of treatment
Secondary	Number of Patients With Incidences of Angioedema	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.	8 weeks of treatment
Secondary	Change From Baseline in High Sensitivity Troponin (Hs-Troponin)	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.	Baseline, Week 4/Week 8
Secondary	Change From Baseline in Urinary cGMP	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)	Baseline, Week 4 and Week 8
Secondary	Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio	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).	Baseline, Week 4 and Week 8
Secondary	Change From Baseline in BNP to NTproBNP Ratio	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.	baseline, Week 4 and Week 8
Secondary	N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8	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.	Baseline, Week 8

External Links

•   A Plain Language Trial Summary is available on novartisclinicatrials.com