Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event (HFpEF Decompensation) Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation (PARAGLIDE-HF)
NCT ID: NCT03988634
Last Updated: 2025-03-06
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
467 participants
INTERVENTIONAL
2019-06-29
2022-12-14
Brief Summary
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Detailed Description
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Randomized patients were deemed hemodynamically stabilized and needed to meet all inclusion and none of the exclusion criteria. Patients were randomized 1:1 to LCZ696 or valsartan. Initial dose at randomization was determined based on the patient's previous dose of or lack of ACEi/angiotensin receptor blocker (ARB) immediately prior to current worsening heart failure (WHF) event (heart failure with preserved ejection fraction \[HFpEF\]) decompensation, or at the time of post-decompensation randomization.
LCZ696 dose or valsartan dose levels may have been increased to the targeted desired dose of 97/103 mg \[200 mg\] BID or valsartan 160 mg BID on an every 2-week basis or earlier based on clinical need and investigator judgment. Every effort was made to titrate to and maintain patients on the target dose level, as tolerated by the patient.
To maintain the blinding, patients were required to take their assigned active treatment tablet along with placebo matching the opposite treatment BID.
The protocol had 4 amendments. Protocol Version 00 (Original Protocol) included a double-blind phase through Week 8 followed by an open-label phase during Weeks 8 to 12. Protocol Amendment 01 omitted the open-label phase and followed patients for a maximum of 20 months in a double-blinded treatment phase. Throughout all protocol versions, the primary endpoint remained the time-averaged proportional change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from Baseline to Weeks 4 and 8. The most recent protocol amendment (Amendment 04) reduced the sample size to approximately 450 patients (from 800) with 85% power for the primary endpoint, deemphasizing the statistical power for key secondary clinical endpoints; however, clinical events were still assessed as secondary endpoints.
No efficacy analyses include "OPEN LABEL' data. After Protocol Amendment 01, the open-label option was removed from the study, only the 233 patients randomized in the Double-blind Phase Sacubitril+ Valsartan (LCZ696) and the 233 patients randomized in the Double-blind Phase Valsartan arms were included in the efficacy analysis.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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sacubitril/valsartan (LCZ696)
Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg twice daily (Dose Level 3).
Patients were required to take a total of two tablets twice daily (one tablet of active sacubitril and valsartan , and one tablet of valsartan matching placebo)
sacubitril/valsartan
Sacubitril/valsartan (LCZ696) was available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily
valsartan matching placebo
Valsartan matching placebo was available as tablet form to be taken orally, twice daily
valsartan
Study treatment was titrated to the target dose of valsartan 160 mg twice daily (Dose Level 3).
Patients were required to take a total of two tablets twice daily (one tablet of active valsartan, and one tablet of sacubitril and valsartan matching placebo)
valsartan
Valsartan was available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily
sacubitril/valsartan matching placebo
Sacubitril/valsartan (LCZ696) matching placebo was available as tablet form to be taken orally, twice daily
Interventions
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sacubitril/valsartan
Sacubitril/valsartan (LCZ696) was available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily
valsartan
Valsartan was available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily
sacubitril/valsartan matching placebo
Sacubitril/valsartan (LCZ696) matching placebo was available as tablet form to be taken orally, twice daily
valsartan matching placebo
Valsartan matching placebo was available as tablet form to be taken orally, twice daily
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Patients \>=18 years of age, male or female
3. Current hospitalization for Worsening Heart Failure (WHF) (HFpEF decompensation), or within 30 days of discharge following a WHF event (defined as hospitalization, emergency department (ED) visit or out-of-hospital urgent HF visit, all requiring IV diuretics). 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). Eligible patients were randomized after IV diuresis for HFpEF is given (and no earlier than 36 hours from their last ACEi dose if applicable) and within 30 days post-decompensation after presentation with acute HFpEF decompensation and meeting the following definitions of hemodynamic stability:
Randomized patients were hemodynamically stable defined in this study as:
1. SBP \>=100mmHg for the preceding 6 hours prior to randomization; no symptomatic hypotension
2. No increase (intensification) in IV diuretic dose within last 6 hours prior to randomization
3. No IV inotropic drugs for 24 hours prior to randomization
4. No IV vasodilators including nitrates within last 6 hours prior to randomization
4. HFpEF with most recent LVEF \> 40% (within past 3 months)
5. Elevated NT-proBNP or BNP at the time of acute HFpEF decompensation or post-decompensation screening (and within 72 hours for out-of-hospital randomization, if applicable):
1. Patients not in Atrial Fibrillation(AF) at the time of biomarker assessment: NT-proBNP \>= 500pg/mL or BNP \>= 150 pg/mL; patients in AF at the time of biomarker assessment: NT-proBNP \>= 1000pg/mL or BNP \>= 300 pg/mL
2. Patients recruited in-hospital were randomized based on the qualifying local lab value in-hospital NT-proBNP or BNP value.
3. Patients enrolled post-decompensation can be randomized based on their NT-proBNP or BNP value in the following way:
i. if enrolling in post-decompensation setting then need eligible screening/local NTproBNP/BNP within 72 hours of randomization. The test value could be from recent hospitalization if within 72 hours or ii. would require (re)drawing NT-proBNP or BNP labs in post-decompensation setting if the lab value is not already available within the last 72 hours).
6\) Has not taken an ACEi for 36 hours prior to randomization
Exclusion Criteria
2. Entresto™ (sacubitril/valsartan) usage within the past 60 days
3. eGFR \< 20ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at most recent assessment prior to randomization and within 24 hours prior to inpatient randomization or 72 hours prior to outpatient randomization
4. Serum potassium \> 5.2 mEq/L at most recent assessment prior to randomization and within 24 hours prior to inpatient randomization or 72 hours prior to outpatient randomization
5. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within 30 days prior to randomization
6. Probable alternative diagnoses that in the opinion of the investigator could account for the patient's HF symptoms (i.e. dyspnea, fatigue) such as significant pulmonary disease (including primary pulmonary HTN), anemia or obesity.
7. Isolated right HF in the absence of left-sided structural heart disease
8. History of hypersensitivity (i.e. including angioedema), known or suspected contraindications, or intolerance to any of the study drugs including ARNIs (i.e. sacubitril/valsartan), and/or ARBs
9. Patients with a known history of angioedema due to any etiology
10. Patients with a history of heart transplant or LVAD, currently on the transplant list, or with planned intent to implant LVAD or CRT device within the initial three months of enrollment during the trial
11. A cardiac or non-cardiac medical condition other than HF with an estimated life expectancy of \< 6 months
12. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy including suspected or confirmed amyloid heart disease (amyloidosis)
13. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate \> 110 bpm
14. Clinically significant congenital heart disease felt to be the cause of the patient's symptoms and signs of HF
15. Coronary or carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention within the duration of the trial
16. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study
17. 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
18. Participation in any other clinical trial involving investigational agents or devices within the past 30 days
19. Current confirmed COVID19 infection
20. Past COVID19 infection with persistent symptom burden suspected due to COVID19 (further defined in Section 5.2).
21. 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.
22. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of investigational drug and for 7 days off of study drug. Highly effective contraception methods are defined in protocol.
18 Years
99 Years
ALL
No
Sponsors
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Novartis Pharmaceuticals
INDUSTRY
Responsible Party
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Principal Investigators
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Novartis Pharmaceuticals
Role: STUDY_DIRECTOR
Novartis Pharmaceuticals
Locations
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University of Calif Irvine Med Cntr
Irvine, California, United States
Memorial Care Health System Memorialcare Long Beach
Long Beach, California, United States
University Of Southern California .
Los Angeles, California, United States
University Of Southern California
Los Angeles, California, United States
San Diego Cardiac Center
San Diego, California, United States
Zuckerberg General W84 Research .
San Francisco, California, United States
Sutter Health Network .
San Pablo, California, United States
Helping Hands Medical Associates INC
Santa Ana, California, United States
St Francis Medical Center
Colorado Springs, Colorado, United States
Colorado Heart and Vascular .
Lakewood, Colorado, United States
South Denver Cardiology Associates PC
Littleton, Colorado, United States
Hartford Healthcare Headache Center
West Hartford, Connecticut, United States
VA Connecticut Healthcare System
West Haven, Connecticut, United States
Cardiology Physicians PA .
Newark, Delaware, United States
University of Florida Health .
Gainesville, Florida, United States
New Generation of Medical Research Avera Health N Central Heart
Hialeah, Florida, United States
University of Florida Health Science Center
Jacksonville, Florida, United States
Intercoastal Medical Group
Sarasota, Florida, United States
Morehouse School Of Medicine
Atlanta, Georgia, United States
Emory University School of Medicine/Winship Cancer Institute
Atlanta, Georgia, United States
University Cardiology Associates
Augusta, Georgia, United States
St Lukes Idaho Cardiology Associates CLCZ696BUS13
Boise, Idaho, United States
University of Chicago .
Chicago, Illinois, United States
Amita Health
Elk Grove Village, Illinois, United States
Midwest Cardiovascular Institute .
Oakbrook Terrace, Illinois, United States
Advocate Medical Group .
Park Ridge, Illinois, United States
Unity Point Health Methodist
Peoria, Illinois, United States
OSF HealthCare
Peoria, Illinois, United States
Northwestern Medicine Northwestern University
Winfield, Illinois, United States
Midwest Cardiovascular Research and Education Foundation .
Elkhart, Indiana, United States
Indiana University Health
Indianapolis, Indiana, United States
Franciscan Health Services Research Center .
Indianapolis, Indiana, United States
Indiana University Health
Muncie, Indiana, United States
Reid Hosp And Hlth Care Services
Richmond, Indiana, United States
The Uni of Kansas Medical Center
Kansas City, Kansas, United States
Alexandria Cardiology Clinic
Alexandria, Louisiana, United States
The Franciscan Missionaries
Baton Rouge, Louisiana, United States
Northern Light Easter Maine Medical Center .
Bangor, Maine, United States
Johns Hopkins Univ School of Med
Baltimore, Maryland, United States
Tidal Health Peninsula Regional Inc .
Salisbury, Maryland, United States
Massachusetts General Hospital
Boston, Massachusetts, United States
Boston Univeristy Medical Center .
Boston, Massachusetts, United States
Beth Israel Deaconess Med Ctr CLCZ696D2301
Boston, Massachusetts, United States
University of Michigan Hs
Ann Arbor, Michigan, United States
Detroit Medical Center Cardiovascular Clinical Trial .
Detroit, Michigan, United States
Henry Ford Hospital Cardiovascular Medicine
Detroit, Michigan, United States
Trinity Health Michigan Heart .
Ypsilanti, Michigan, United States
Novartis Investigative Site
Saint Paul, Minnesota, United States
Jackson Heart Clinic
Jackson, Mississippi, United States
Nebraska Heart Institute CHI Health Nebraska
Lincoln, Nebraska, United States
University of Nebraska Medical Center
Omaha, Nebraska, United States
Univ Medical Center Las Vegas
Las Vegas, Nevada, United States
R Ins For Heart And Vascular Health
Reno, Nevada, United States
Inspira Health Network
Elmer, New Jersey, United States
Cooper University Health Care
Haddon Heights, New Jersey, United States
Saint Michael Medical Center
Newark, New Jersey, United States
Cedar Multi-Specialty Clinic
Albuquerque, New Mexico, United States
Albany Associates In Cardiology
Albany, New York, United States
New York Presbyterian Queens .
Flushing, New York, United States
United Health Services Office Of Clinical Trails CLCZ696BUS01
Johnson, New York, United States
Northwell Health .
Manhasset, New York, United States
Mount Sinai Hospital .
New York, New York, United States
HealthQuest
Poughkeepsie, New York, United States
Catholic Hlth Svcs of Long Island
Roslyn, New York, United States
Mount Sinai Health System
Staten Island, New York, United States
Stony Brook University Medical Center CLCZ696G2301
Stony Brook, New York, United States
Montefiore Medical Center .
The Bronx, New York, United States
University Of North Carolina At Chapel Hill CRLX030A2209
Chapel Hill, North Carolina, United States
Duke Health
Durham, North Carolina, United States
Cleveland Clinic Foundation .
Cleveland, Ohio, United States
St. Vincent Mercy Medical Center
Toledo, Ohio, United States
St John Health System
Bartlesville, Oklahoma, United States
Regional Medical Labaratory
Tulsa, Oklahoma, United States
Jefferson Abington .
Abington, Pennsylvania, United States
Allegheny Valley Hospital .
Natrona Heights, Pennsylvania, United States
Capital Area Research LLC CACZ885M2301
Newport, Pennsylvania, United States
Thomas Jefferson Univ Hospital .
Philadelphia, Pennsylvania, United States
Regional Health Clinic Research .
Rapid City, South Dakota, United States
North Central Heart .
Sioux Falls, South Dakota, United States
VA Tennessee Valley Healthcare System
Nashville, Tennessee, United States
Pharma Tex Research .
Amarillo, Texas, United States
Baylor University Medical Center .
Dallas, Texas, United States
The University of Texas Medical Branch
Galveston, Texas, United States
The University of Vermont Medical Center CRLX030A2301
Burlington, Vermont, United States
Centra Health
Lynchburg, Virginia, United States
Swedish Medical Ctr Cardiovascular Re
Seattle, Washington, United States
University of Wisconsin School of Medicine and Public Health CLCZ696BUS01
Madison, Wisconsin, United States
Novartis Investigative Site
Victoria, British Columbia, Canada
Novartis Investigative Site
Winnipeg, Manitoba, Canada
Novartis Investigative Site
Hamilton, Ontario, Canada
Novartis Investigative Site
Montreal, Quebec, Canada
Novartis Investigative Site
Montreal, Quebec, Canada
Novartis Investigative Site
Montreal, Quebec, Canada
Novartis Investigative Site
Québec, Quebec, Canada
Novartis Investigative Site
Saguenay, Quebec, Canada
Novartis Investigative Site
Sherbrooke, Quebec, Canada
Novartis Investigative Site
Terrebonne, Quebec, Canada
Countries
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References
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Peters AE, Li S, Cyr D, Williamson KM, Zieroth S, Fudim M, Ward JH, Mentz RJ. Influence of ejection fraction on outcomes with sacubitril/valsartan in patients with worsening heart failure with EF>40%: The PARAGLIDE-HF Trial. Am Heart J. 2025 Nov;289:158-167. doi: 10.1016/j.ahj.2025.04.023. Epub 2025 Apr 21.
Rambarat P, Erickson T, Cyr D, Ward J, Hernandez A, Morrow D, Starling R, Velazquez E, Zieroth S, Williamson K, Solomon S, Mentz R. Effects of angiotensin-neprilysin inhibition in women vs men: Insights from PARAGLIDE-HF. Am Heart J. 2025 Oct;288:41-51. doi: 10.1016/j.ahj.2025.03.017. Epub 2025 Mar 31.
Shoji S, Cyr DD, Hernandez AF, Velazquez EJ, Ward JH, Williamson KM, Sarwat S, Starling RC, Desai AS, Zieroth S, Solomon SD, Mentz RJ. Win Ratio Analyses Using a Modified Hierarchical Composite Outcome: Insights From PARAGLIDE-HF. Am Heart J. 2025 Feb;280:70-78. doi: 10.1016/j.ahj.2024.10.020. Epub 2024 Nov 4.
Fudim M, Cyr DD, Ward JH, Hernandez AF, Lepage S, Morrow DA, Sharma K, Claggett BL, Starling RC, Velazquez EJ, Williamson KM, Desai AS, Zieroth S, Solomon SD, Braunwald E, Mentz RJ; PARAGLIDE-HF investigators. Association of Sacubitril/Valsartan vs Valsartan With Blood Pressure Changes and Symptomatic Hypotension: the PARAGLIDE-HF Trial. J Card Fail. 2024 Dec;30(12):1568-1577. doi: 10.1016/j.cardfail.2024.04.030. Epub 2024 May 26.
Morrow DA, Velazquez EJ, Desai AS, DeVore AD, Lepage S, Park JG, Sharma K, Solomon SD, Starling RC, Ward JH, Williamson KM, Zieroth S, Hernandez AF, Mentz RJ, Braunwald E. Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure. J Am Coll Cardiol. 2024 Mar 26;83(12):1123-1132. doi: 10.1016/j.jacc.2024.01.027.
Mentz RJ, Ward JH, Hernandez AF, Lepage S, Morrow DA, Sarwat S, Sharma K, Starling RC, Velazquez EJ, Williamson KM, Desai AS, Zieroth S, Solomon SD, Braunwald E; PARAGLIDE-HF Investigators. Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure. J Am Coll Cardiol. 2023 Jul 4;82(1):1-12. doi: 10.1016/j.jacc.2023.04.019. Epub 2023 May 21.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Related Links
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A Plain Language Trial Summary is available at www.novctrd.com
Other Identifiers
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CLCZ696DUS01
Identifier Type: -
Identifier Source: org_study_id
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