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)

Heart Failure With Preserved Ejection Fraction (HFpEF) Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03988634
• Other study ID #: CLCZ696DUS01
• Status: Completed
• Phase: Phase 3
• Start date: June 27, 2019
• Est. completion date: December 14, 2022

Study information

• Verified date: February 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 have been stabilized and initiated at the time of or within 30 days post-decompensation.

Description:

The purpose of this study is to assess 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 have been stabilized and initiated at the time of or within 30 days post-decompensation

Recruitment information / eligibility

• Status: Completed
• Enrollment: 465
• Est. completion date: December 14, 2022
• Est. primary completion date: December 14, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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 will be 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 will have been 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):

a. 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 b. Patients recruited in-hospital will be randomized based on the qualifying local lab value in-hospital NT-proBNP or BNP value. c. 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.

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction (HFpEF)

Intervention

Drug:
• sacubitril/valsartan
Sacubitril/valsartan (LCZ696) is available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily, for the double-blind period. Valsartan matching placebo is available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily, for the double-blind period.
• valsartan
Valsartan is available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily, for the double-blind period. Sacubitril/valsartan (LCZ696) matching placebo is available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily, for the double-blind period.

Locations

Country	Name	City	State
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	Quebec
Canada	Novartis Investigative Site	Saguenay	Quebec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	Terrebonne	Quebec
Canada	Novartis Investigative Site	Victoria	British Columbia
Canada	Novartis Investigative Site	Winnipeg	Manitoba
United States	Novartis Investigative Site	Abington	Pennsylvania
United States	Novartis Investigative Site	Albany	New York
United States	Novartis Investigative Site	Albuquerque	New Mexico
United States	Novartis Investigative Site	Alexandria	Louisiana
United States	Novartis Investigative Site	Amarillo	Texas
United States	Novartis Investigative Site	Ann Arbor	Michigan
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Augusta	Georgia
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Bangor	Maine
United States	Novartis Investigative Site	Bartlesville	Oklahoma
United States	Novartis Investigative Site	Baton Rouge	Louisiana
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	Boston	Massachusetts
United States	Novartis Investigative Site	Bronx	New York
United States	Novartis Investigative Site	Burlington	Vermont
United States	Novartis Investigative Site	Camp Hill	Pennsylvania
United States	Novartis Investigative Site	Chapel Hill	North Carolina
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Colorado Springs	Colorado
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Durham	North Carolina
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	Flushing	New York
United States	Novartis Investigative Site	Gainesville	Florida
United States	Novartis Investigative Site	Galveston	Texas
United States	Novartis Investigative Site	Haddon Heights	New Jersey
United States	Novartis Investigative Site	Hialeah	Florida
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	Johnson City	New York
United States	Novartis Investigative Site	Kansas City	Kansas
United States	Novartis Investigative Site	Lakewood	Colorado
United States	Novartis Investigative Site	Las Vegas	Nevada
United States	Novartis Investigative Site	Lincoln	Nebraska
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	Lynchburg	Virginia
United States	Novartis Investigative Site	Madison	Wisconsin
United States	Novartis Investigative Site	Manhasset	New York
United States	Novartis Investigative Site	Muncie	Indiana
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	Newark	New Jersey
United States	Novartis Investigative Site	Newark	Delaware
United States	Novartis Investigative Site	Oakbrook Terrace	Illinois
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	Peoria	Illinois
United States	Novartis Investigative Site	Peoria	Illinois
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Poughkeepsie	New York
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	Roslyn	New York
United States	Novartis Investigative Site	Saint Paul	Minnesota
United States	Novartis Investigative Site	Salisbury	Maryland
United States	Novartis Investigative Site	San Diego	California
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	San Pablo	California
United States	Novartis Investigative Site	Santa Ana	California
United States	Novartis Investigative Site	Sarasota	Florida
United States	Novartis Investigative Site	Seattle	Washington
United States	Novartis Investigative Site	Sioux Falls	South Dakota
United States	Novartis Investigative Site	Staten Island	New York
United States	Novartis Investigative Site	Stony Brook	New York
United States	Novartis Investigative Site	Toledo	Ohio
United States	Novartis Investigative Site	Tulsa	Oklahoma
United States	Novartis Investigative Site	West Hartford	Connecticut
United States	Novartis Investigative Site	West Haven	Connecticut
United States	Novartis Investigative Site	Winfield	Illinois
United States	Novartis Investigative Site	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportional change in NT-proBNP from baseline to the average of weeks 4 and 8	To demonstrate the effect of sacubitril/valsartan vs. valsartan on time-averaged proportional change in NT-proBNP from baseline to Weeks 4 and 8 in HFpEF patients with a WHF event (HFpEF decompensation) who have been stabilized for and initiated at the time of or within 30 days post-decompensation	Baseline to weeks 4 and 8
Secondary	Composite hierarchical outcome	The effect of sacubitril/valsartan vs. valsartan on composite hierarchical outcome consisting of: a) time to CV death, b) total HF hospitalizations, c) total urgent HF visits, and d) time-averaged proportional change in NT-proBNP (from baseline to Weeks 4 and 8) using win ratio methodology	Baseline, Weeks 4, Weeks 8, and Overtime Up to 84 Weeks
Secondary	Cumulative number of recurrent composite events overtime	To assess the effect of sacubitril/valsartan vs. valsartan on total composite events based on CV death, HF hospitalizations, and urgent HF visits	Overtime up to Week 84
Secondary	Incidences of a composite endpoint of worsening renal function	To assess the effect of sacubitril/valsartan vs. valsartan on the incidences of a composite endpoint of worsening renal function (renal death, reaching ESRD, or decline in eGFR >/= 50%)	Overtime up to Week 84
Secondary	Proportional change in NT-proBNP from baseline to Week 8	To assess the effect of sacubitril/valsartan vs. valsartan on change in NT-proBNP from baseline to Week 8	Baseline to week 8
Secondary	Proportional change from baseline in hs-Troponin (high sensitivity) at Weeks 4 and 8	To assess the effect of sacubitril/valsartan vs. valsartan on change from baseline in hs-Troponin (high sensitivity) at Weeks 4 and 8	Baseline, Week 4 and Week 8