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)

February 17, 2023 updated by: Novartis Pharmaceuticals

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)

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.

Study Overview

Detailed 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

Study Type

Interventional

Enrollment (Actual)

465

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Quebec, Canada, G1R 2J6
        • Novartis Investigative Site
    • British Columbia
      • Victoria, British Columbia, Canada, V8R4R2
        • Novartis Investigative Site
    • Manitoba
      • Winnipeg, Manitoba, Canada, R2H 2A6
        • Novartis Investigative Site
    • Ontario
      • Hamilton, Ontario, Canada, L8L 2X2
        • Novartis Investigative Site
    • Quebec
      • Montreal, Quebec, Canada, H1T 1C8
        • Novartis Investigative Site
      • Montreal, Quebec, Canada, H3G 1A4
        • Novartis Investigative Site
      • Montreal, Quebec, Canada, H2X 0A9
        • Novartis Investigative Site
      • Saguenay, Quebec, Canada, G7H 5H6
        • Novartis Investigative Site
      • Sherbrooke, Quebec, Canada, J1H 5N4
        • Novartis Investigative Site
      • Terrebonne, Quebec, Canada, J6V 2H2
        • Novartis Investigative Site
    • California
      • Long Beach, California, United States, 90806
        • Novartis Investigative Site
      • Los Angeles, California, United States, 90033-4605
        • Novartis Investigative Site
      • Orange, California, United States, 92868
        • Novartis Investigative Site
      • San Diego, California, United States, 92123
        • Novartis Investigative Site
      • San Francisco, California, United States, 94110
        • Novartis Investigative Site
      • San Pablo, California, United States, 94806
        • Novartis Investigative Site
      • Santa Ana, California, United States, 92704
        • Novartis Investigative Site
    • Colorado
      • Colorado Springs, Colorado, United States, 80923
        • Novartis Investigative Site
      • Lakewood, Colorado, United States, 80228
        • Novartis Investigative Site
      • Littleton, Colorado, United States, 80120
        • Novartis Investigative Site
    • Connecticut
      • West Hartford, Connecticut, United States, 06109
        • Novartis Investigative Site
      • West Haven, Connecticut, United States, 06516
        • Novartis Investigative Site
    • Delaware
      • Newark, Delaware, United States, 19713
        • Novartis Investigative Site
    • Florida
      • Gainesville, Florida, United States, 32610
        • Novartis Investigative Site
      • Hialeah, Florida, United States, 33016
        • Novartis Investigative Site
      • Jacksonville, Florida, United States, 32209
        • Novartis Investigative Site
      • Sarasota, Florida, United States, 34239
        • Novartis Investigative Site
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Novartis Investigative Site
      • Atlanta, Georgia, United States, 30310
        • Novartis Investigative Site
      • Augusta, Georgia, United States, 30901
        • Novartis Investigative Site
    • Idaho
      • Boise, Idaho, United States, 83702
        • Novartis Investigative Site
    • Illinois
      • Chicago, Illinois, United States, 60637
        • Novartis Investigative Site
      • Elk Grove Village, Illinois, United States, 60007
        • Novartis Investigative Site
      • Oakbrook Terrace, Illinois, United States, 60181
        • Novartis Investigative Site
      • Park Ridge, Illinois, United States, 60068
        • Novartis Investigative Site
      • Peoria, Illinois, United States, 61614
        • Novartis Investigative Site
      • Peoria, Illinois, United States, 61606
        • Novartis Investigative Site
      • Winfield, Illinois, United States, 60190
        • Novartis Investigative Site
    • Indiana
      • Elkhart, Indiana, United States, 46514
        • Novartis Investigative Site
      • Indianapolis, Indiana, United States, 46202
        • Novartis Investigative Site
      • Indianapolis, Indiana, United States, 46237
        • Novartis Investigative Site
      • Muncie, Indiana, United States, 47303
        • Novartis Investigative Site
      • Richmond, Indiana, United States, 47374
        • Novartis Investigative Site
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • Novartis Investigative Site
    • Louisiana
      • Alexandria, Louisiana, United States, 71301
        • Novartis Investigative Site
      • Baton Rouge, Louisiana, United States, 70808
        • Novartis Investigative Site
    • Maine
      • Bangor, Maine, United States, 04401
        • Novartis Investigative Site
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Novartis Investigative Site
      • Salisbury, Maryland, United States, 21804
        • Novartis Investigative Site
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Novartis Investigative Site
      • Boston, Massachusetts, United States, 02215
        • Novartis Investigative Site
      • Boston, Massachusetts, United States, 02118
        • Novartis Investigative Site
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • Novartis Investigative Site
      • Detroit, Michigan, United States, 48202
        • Novartis Investigative Site
      • Detroit, Michigan, United States, 48201
        • Novartis Investigative Site
      • Ypsilanti, Michigan, United States, 48197
        • Novartis Investigative Site
    • Minnesota
      • Saint Paul, Minnesota, United States, 55101
        • Novartis Investigative Site
    • Mississippi
      • Jackson, Mississippi, United States, 39216
        • Novartis Investigative Site
    • Nebraska
      • Lincoln, Nebraska, United States, 68510
        • Novartis Investigative Site
      • Omaha, Nebraska, United States, 68198
        • Novartis Investigative Site
    • Nevada
      • Las Vegas, Nevada, United States, 89201
        • Novartis Investigative Site
      • Reno, Nevada, United States, 89502
        • Novartis Investigative Site
    • New Jersey
      • Elmer, New Jersey, United States, 08318
        • Novartis Investigative Site
      • Haddon Heights, New Jersey, United States, 08035
        • Novartis Investigative Site
      • Newark, New Jersey, United States, 07102
        • Novartis Investigative Site
    • New Mexico
      • Albuquerque, New Mexico, United States, 87106
        • Novartis Investigative Site
    • New York
      • Albany, New York, United States, 12205
        • Novartis Investigative Site
      • Bronx, New York, United States, 10461
        • Novartis Investigative Site
      • Flushing, New York, United States, 11355
        • Novartis Investigative Site
      • Johnson City, New York, United States, 13790
        • Novartis Investigative Site
      • Manhasset, New York, United States, 11030
        • Novartis Investigative Site
      • New York, New York, United States, 10029
        • Novartis Investigative Site
      • Poughkeepsie, New York, United States, 12601
        • Novartis Investigative Site
      • Roslyn, New York, United States, 11576
        • Novartis Investigative Site
      • Staten Island, New York, United States, 10310
        • Novartis Investigative Site
      • Stony Brook, New York, United States, 11794
        • Novartis Investigative Site
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599-7075
        • Novartis Investigative Site
      • Durham, North Carolina, United States, 27710
        • Novartis Investigative Site
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Novartis Investigative Site
      • Toledo, Ohio, United States, 43608
        • Novartis Investigative Site
    • Oklahoma
      • Bartlesville, Oklahoma, United States, 74006
        • Novartis Investigative Site
      • Tulsa, Oklahoma, United States, 74104
        • Novartis Investigative Site
    • Pennsylvania
      • Abington, Pennsylvania, United States, 19001
        • Novartis Investigative Site
      • Camp Hill, Pennsylvania, United States, 17011
        • Novartis Investigative Site
      • Natrona Heights, Pennsylvania, United States, 15065
        • Novartis Investigative Site
      • Philadelphia, Pennsylvania, United States, 19107
        • Novartis Investigative Site
    • South Dakota
      • Rapid City, South Dakota, United States, 57701
        • Novartis Investigative Site
      • Sioux Falls, South Dakota, United States, 57105
        • Novartis Investigative Site
    • Tennessee
      • Nashville, Tennessee, United States, 37212
        • Novartis Investigative Site
    • Texas
      • Amarillo, Texas, United States, 79106
        • Novartis Investigative Site
      • Dallas, Texas, United States, 75246
        • Novartis Investigative Site
      • Galveston, Texas, United States, 77555-1062
        • Novartis Investigative Site
    • Vermont
      • Burlington, Vermont, United States, 05401
        • Novartis Investigative Site
    • Virginia
      • Lynchburg, Virginia, United States, 24501
        • Novartis Investigative Site
    • Washington
      • Seattle, Washington, United States, 98122
        • Novartis Investigative Site
    • Wisconsin
      • Madison, Wisconsin, United States, 53792-1615
        • Novartis Investigative Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 99 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: sacubitril/valsartan

randomized in a 1:1 ratio: sacubitril/valsartan to valsartan for up to approximately 20 months of double-blind treatment.

Initial dose at randomization will be determined based on the patient's previous dose of or lack of ACEi/ARB immediately prior to current WHF event (HFpEF decompensation), or at the time of post-decompensation randomization.

Study treatment will be titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg twice daily (Dose Level 3).

Patients will be required to take a total of two tablets twice daily (one tablet of active sacubitril/valsartan and one tablet of valsartan matching placebo pack).

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.

Other Names:
  • LCZ696
Active Comparator: valsartan

randomized in a 1:1 ratio: sacubitril/valsartan to valsartan for up to approximately 20 months of double-blind treatment.

Initial dose at randomization will be determined based on the patient's previous dose of or lack of ACEi/ARB immediately prior to current WHF event (HFpEF decompensation), or at the time of post-decompensation randomization.

Study treatment will be titrated to the target dose of valsartan 160 mg twice daily (Dose Level 3).

Patients will be required to take a total of two tablets twice daily (one tablet of active valsartan and one tablet of sacubitril/valsartan (LCZ696) matching placebo pack).

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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportional change in NT-proBNP from baseline to the average of weeks 4 and 8
Time Frame: Baseline to 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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Composite hierarchical outcome
Time Frame: Baseline, Weeks 4, Weeks 8, and Overtime Up to 84 Weeks
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
Cumulative number of recurrent composite events overtime
Time Frame: Overtime up to Week 84
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
Incidences of a composite endpoint of worsening renal function
Time Frame: Overtime up to Week 84
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
Proportional change in NT-proBNP from baseline to Week 8
Time Frame: 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
Proportional change from baseline in hs-Troponin (high sensitivity) at Weeks 4 and 8
Time Frame: Baseline, Week 4 and Week 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 27, 2019

Primary Completion (Actual)

December 14, 2022

Study Completion (Actual)

December 14, 2022

Study Registration Dates

First Submitted

June 13, 2019

First Submitted That Met QC Criteria

June 13, 2019

First Posted (Actual)

June 17, 2019

Study Record Updates

Last Update Posted (Estimate)

February 20, 2023

Last Update Submitted That Met QC Criteria

February 17, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of the patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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