Clinical trial NCT03988634: 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)
Official title: A Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled Study to Evaluate the Effect of Sacubitril/Valsartan (LCZ696) Versus Valsartan on 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure With Preserved Ejection Fraction (HFpEF)
Keywords: Heart failure with preserved ejection fraction (HFpEF)
Heart failure hospitalization
NYHA
NT-proBNP
Acute decompensated heart failure
Sacubitril/valsartan
Global evaluation of treatment effectiveness (GETE)
Worsening Heart Failure
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-06-17
Enrollment: 467
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The effect of sacubitril/valsartan vs. valsartan on changes in NT-proBNP, safety, and tolerability in HFpEF patients with a WHF event (HFpEF decompensation) who had been stabilized and initiated at the time of or within 30 days post-decompensation.

Detailed description: This study used a randomized, double-blind, double-dummy, active-controlled, parallel group design conducted across 100 centers in the US and Canada. The study duration was a maximum of 20 months (minimum follow up was 8 weeks).

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.

Eligibility criteria: INCLUSION CRITERIA:

1. Signed informed consent must be obtained prior to participation in the study
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:

1. Any clinical event within the 90 days prior to randomization that could have reduced the LVEF (i.e., myocardial infarction (MI), coronary artery bypass graft (CABG), unless an echo measurement was performed after the event confirming the LVEF to be \> 40%
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.

Primary outcomes:
measure: Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 8
timeFrame: Baseline, Average of Week 4 and Week 8
Secondary outcomes:
measure: Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome
timeFrame: Up to 84 weeks
measure: EAC Adjudicated Recurrent Composite Events
timeFrame: Up to Week 84
measure: Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function
timeFrame: Up to Week 84
measure: Proportional Change in NT-proBNP From Baseline to Week 8
timeFrame: Baseline and Week 8
measure: Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8
timeFrame: Baseline, Week 4 and Week 8
measure: Dosing Levels and Discontinuations
timeFrame: Randomization, Week 8, Week 24
measure: Incidence of Adverse Events of Special Interest (AESI) During Treatment
timeFrame: Up to week 84
Other outcomes:
Locations:
city: Irvine
country: United States
facility: University of Calif Irvine Med Cntr
state: California
city: Long Beach
country: United States
facility: Memorial Care Health System Memorialcare Long Beach
state: California
city: Los Angeles
country: United States
facility: University Of Southern California .
state: California
city: Los Angeles
country: United States
facility: University Of Southern California
state: California
city: San Diego
country: United States
facility: San Diego Cardiac Center
state: California
city: San Francisco
country: United States
facility: Zuckerberg General W84 Research .
state: California
city: San Pablo
country: United States
facility: Sutter Health Network .
state: California
city: Santa Ana
country: United States
facility: Helping Hands Medical Associates INC
state: California
city: Colorado Springs
country: United States
facility: St Francis Medical Center
state: Colorado
city: Lakewood
country: United States
facility: Colorado Heart and Vascular .
state: Colorado
city: Littleton
country: United States
facility: South Denver Cardiology Associates PC
state: Colorado
city: West Hartford
country: United States
facility: Hartford Healthcare Headache Center
state: Connecticut
city: West Haven
country: United States
facility: VA Connecticut Healthcare System
state: Connecticut
city: Newark
country: United States
facility: Cardiology Physicians PA .
state: Delaware
city: Gainesville
country: United States
facility: University of Florida Health .
state: Florida
city: Hialeah
country: United States
facility: New Generation of Medical Research Avera Health N Central Heart
state: Florida
city: Jacksonville
country: United States
facility: University of Florida Health Science Center
state: Florida
city: Sarasota
country: United States
facility: Intercoastal Medical Group
state: Florida
city: Atlanta
country: United States
facility: Morehouse School Of Medicine
state: Georgia
city: Atlanta
country: United States
facility: Emory University School of Medicine/Winship Cancer Institute
state: Georgia
city: Augusta
country: United States
facility: University Cardiology Associates
state: Georgia
city: Boise
country: United States
facility: St Lukes Idaho Cardiology Associates CLCZ696BUS13
state: Idaho
city: Chicago
country: United States
facility: University of Chicago .
state: Illinois
city: Elk Grove Village
country: United States
facility: Amita Health
state: Illinois
city: Oakbrook Terrace
country: United States
facility: Midwest Cardiovascular Institute .
state: Illinois
city: Park Ridge
country: United States
facility: Advocate Medical Group .
state: Illinois
city: Peoria
country: United States
facility: Unity Point Health Methodist
state: Illinois
city: Peoria
country: United States
facility: OSF HealthCare
state: Illinois
city: Winfield
country: United States
facility: Northwestern Medicine Northwestern University
state: Illinois
city: Elkhart
country: United States
facility: Midwest Cardiovascular Research and Education Foundation .
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Health
state: Indiana
city: Indianapolis
country: United States
facility: Franciscan Health Services Research Center .
state: Indiana
city: Muncie
country: United States
facility: Indiana University Health
state: Indiana
city: Richmond
country: United States
facility: Reid Hosp And Hlth Care Services
state: Indiana
city: Kansas City
country: United States
facility: The Uni of Kansas Medical Center
state: Kansas
city: Alexandria
country: United States
facility: Alexandria Cardiology Clinic
state: Louisiana
city: Baton Rouge
country: United States
facility: The Franciscan Missionaries
state: Louisiana
city: Bangor
country: United States
facility: Northern Light Easter Maine Medical Center .
state: Maine
city: Baltimore
country: United States
facility: Johns Hopkins Univ School of Med
state: Maryland
city: Salisbury
country: United States
facility: Tidal Health Peninsula Regional Inc .
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Univeristy Medical Center .
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med Ctr CLCZ696D2301
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hs
state: Michigan
city: Detroit
country: United States
facility: Detroit Medical Center Cardiovascular Clinical Trial .
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital Cardiovascular Medicine
state: Michigan
city: Ypsilanti
country: United States
facility: Trinity Health Michigan Heart .
state: Michigan
city: Saint Paul
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Jackson
country: United States
facility: Jackson Heart Clinic
state: Mississippi
city: Lincoln
country: United States
facility: Nebraska Heart Institute CHI Health Nebraska
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: Univ Medical Center Las Vegas
state: Nevada
city: Reno
country: United States
facility: R Ins For Heart And Vascular Health
state: Nevada
city: Elmer
country: United States
facility: Inspira Health Network
state: New Jersey
city: Haddon Heights
country: United States
facility: Cooper University Health Care
state: New Jersey
city: Newark
country: United States
facility: Saint Michael Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: Cedar Multi-Specialty Clinic
state: New Mexico
city: Albany
country: United States
facility: Albany Associates In Cardiology
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center .
state: New York
city: Flushing
country: United States
facility: New York Presbyterian Queens .
state: New York
city: Johnson
country: United States
facility: United Health Services Office Of Clinical Trails CLCZ696BUS01
state: New York
city: Manhasset
country: United States
facility: Northwell Health .
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital .
state: New York
city: Poughkeepsie
country: United States
facility: HealthQuest
state: New York
city: Roslyn
country: United States
facility: Catholic Hlth Svcs of Long Island
state: New York
city: Staten Island
country: United States
facility: Mount Sinai Health System
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Medical Center CLCZ696G2301
state: New York
city: Chapel Hill
country: United States
facility: University Of North Carolina At Chapel Hill CRLX030A2209
state: North Carolina
city: Durham
country: United States
facility: Duke Health
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation .
state: Ohio
city: Toledo
country: United States
facility: St. Vincent Mercy Medical Center
state: Ohio
city: Bartlesville
country: United States
facility: St John Health System
state: Oklahoma
city: Tulsa
country: United States
facility: Regional Medical Labaratory
state: Oklahoma
city: Abington
country: United States
facility: Jefferson Abington .
state: Pennsylvania
city: Natrona Heights
country: United States
facility: Allegheny Valley Hospital .
state: Pennsylvania
city: Newport
country: United States
facility: Capital Area Research LLC CACZ885M2301
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson Univ Hospital .
state: Pennsylvania
city: Rapid City
country: United States
facility: Regional Health Clinic Research .
state: South Dakota
city: Sioux Falls
country: United States
facility: North Central Heart .
state: South Dakota
city: Nashville
country: United States
facility: VA Tennessee Valley Healthcare System
state: Tennessee
city: Amarillo
country: United States
facility: Pharma Tex Research .
state: Texas
city: Dallas
country: United States
facility: Baylor University Medical Center .
state: Texas
city: Galveston
country: United States
facility: The University of Texas Medical Branch
state: Texas
city: Burlington
country: United States
facility: The University of Vermont Medical Center CRLX030A2301
state: Vermont
city: Lynchburg
country: United States
facility: Centra Health
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Ctr Cardiovascular Re
state: Washington
city: Madison
country: United States
facility: University of Wisconsin School of Medicine and Public Health CLCZ696BUS01
state: Wisconsin
city: Victoria
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Winnipeg
country: Canada
facility: Novartis Investigative Site
state: Manitoba
city: Hamilton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Saguenay
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Sherbrooke
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Terrebonne
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Quebec
country: Canada
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: