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)
- Conditions
- Heart Failure With Preserved Ejection Fraction (HFpEF)
- Interventions
- Registration Number
- NCT03988634
- Lead Sponsor
- Novartis Pharmaceuticals
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 467
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description sacubitril/valsartan (LCZ696) valsartan matching placebo 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) valsartan sacubitril/valsartan matching placebo 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 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) sacubitril/valsartan (LCZ696) sacubitril/valsartan 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)
- Primary Outcome Measures
Name Time Method Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 8 Baseline, Average of Week 4 and Week 8 To demonstrate the effect of sacubitril/valsartan vs. valsartan on time-averaged proportional change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to weeks 4 and 8 in heart failure with preserved ejection fraction (HFpEF) patients with a worsening heart failure event (HFpEF decompensation) who have been stabilized for and initiated at the time of or within 30 days post-decompensation.
Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. The change from baseline to average of Week 4 and Week 8 was expressed as the geometric mean of the ratio: Week - 8/Baseline.
NT-proBNP is a protein produced in large amounts by the heart when it is not working properly, as in heart failure.
Baseline value was the last non-missing assessment of plasma NT-proBNP before the first administration of study drug.
- Secondary Outcome Measures
Name Time Method Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome Up to 84 weeks This hierarchical composite endpoint consists of 4 ordered components: 1. Time to CV death, 2. Number and times of HF hospitalizations during follow-up, 3. Number and times of urgent HF visits during follow-up, 4. Time averaged proportional change in NT-proBNP from baseline to Weeks 4 and 8. This endpoint was analyzed estimating the unmatched win ratio by comparing every participant in the sacubitril/valsartan arm to every participant in the valsartan arm to determine a winner (unmatched pairing method). For every pair, a patient is labelled a 'winner' (i.e. achieve a better clinical outcome) or a 'loser'. Otherwise they are considered tied. The reported unit is the total "wins" or "ties" for each treatment group from performing such a hierarchical comparison.
Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function Up to Week 84 This endpoint calculated the incidences of a composite endpoint of worsening renal function defined as:
* renal death (from adverse events data)
* reaching end-stage renal disease (ESRD) (Sustained eGFR \<15mL/min/m2, chronic dialysis, or renal transplant)
* ≥ 50% decline in estimated glomerular filtration rate (eGFR) relative to baseline \[using central laboratory measurements (scheduled or unscheduled visits)\]
The Investigator-reported AE and central laboratory data was used to identified event of interest in this secondary endpoint.
Events that occurred in the randomized double-blind treatment phase were included in the analysis.Proportional Change in NT-proBNP From Baseline to Week 8 Baseline and Week 8 This endpoint intended to assess the effect of sacubitril/valsartan vs. valsartan on change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to Week 8.
NT-proBNP is a protein produced in large amounts by the heart when it is not working properly, as in heart failure.
The change from baseline to Week 8 was expressed as the geometric mean of the ratio: Week 8/Baseline.Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8 Baseline, Week 4 and Week 8 This endpoint intended to assess the effect of sacubitril/valsartan vs. valsartan on change from baseline in high sensitivity (hs)-Troponin at Weeks 4 and 8. Analysis was repeated for both the visits, Week 4 and Week 8 separately.
Hs-Troponin-T is a biomarker that is released from the heart under stress or injury conditions.
The change from baseline to Week 4 and Week 8 was expressed as the geometric mean of the ratio: Week 4 or Week 8/Baseline.EAC Adjudicated Recurrent Composite Events Up to Week 84 This endpoint calculated the cumulative number of the following composite events over time:
* CV death
* recurrent HF hospitalizations
* recurrent urgent HF visits The time to these recurrent events was analyzed using the semi-parametric proportional rates model (abbreviated as LWYY model).
The exposure-adjusted rate per 100 subject years (EAR) was calculated diving the total number of events by 100 subject years (total exposure up to event/censoring).
The role of the Endpoint Adjudication Committee (EAC) was to ensure that all treatment outcomes were judged uniformly, using standard criteria and processes.
Events that occurred in the double-blind treatment phase are included in the analysis.Incidence of Adverse Events of Special Interest (AESI) During Treatment Up to week 84 This endpoint intended to calculate the incidence of the following adverse events of special interest (AESI) during treatment:
Symptomatic hypotension, Hyperkalemia (potassium \> 5.5 mEq/L), Angioedema and worsening renal function (defined as an increase in serum creatinine of ≥ 0.5 mg/dL and worsening of the eGFR by at least 25%)Dosing Levels and Discontinuations Randomization, Week 8, Week 24 The dosing level has been summarized by treatment group and in-/out-of-hospital randomization status. The dose levels used were:
Dose Level 1: 40 mg valsartan or 24/26 mg \[50 mg\] LCZ696, BID; Dose Level 2: 80 mg valsartan or 49/51 mg \[100 mg\] LCZ696, BID; Dose Level 3: 160 mg valsartan or 97/103 mg \[200 mg\] LCZ696, BID
Patients counted as "Off Treatment" are those who prematurely permanently discontinued study treatment but continued with visits.
Patients counted as "No Treatment" are those who permanently discontinued with both study treatment and study visits
Trial Locations
- Locations (86)
Boston Univeristy Medical Center .
🇺🇸Boston, Massachusetts, United States
Colorado Heart and Vascular .
🇺🇸Lakewood, Colorado, United States
Swedish Medical Ctr Cardiovascular Re
🇺🇸Seattle, Washington, United States
Indiana University Health
🇺🇸Muncie, Indiana, United States
University Of Southern California
🇺🇸Los Angeles, California, United States
Morehouse School Of Medicine
🇺🇸Atlanta, Georgia, United States
Thomas Jefferson Univ Hospital .
🇺🇸Philadelphia, Pennsylvania, United States
Mount Sinai Hospital .
🇺🇸New York, New York, United States
The University of Texas Medical Branch
🇺🇸Galveston, Texas, United States
Northwestern Medicine Northwestern University
🇺🇸Winfield, Illinois, United States
Regional Medical Labaratory
🇺🇸Tulsa, Oklahoma, United States
VA Tennessee Valley Healthcare System
🇺🇸Nashville, Tennessee, United States
Duke Health
🇺🇸Durham, North Carolina, United States
Henry Ford Hospital Cardiovascular Medicine
🇺🇸Detroit, Michigan, United States
University of Calif Irvine Med Cntr
🇺🇸Irvine, California, United States
San Diego Cardiac Center
🇺🇸San Diego, California, United States
University Of Southern California .
🇺🇸Los Angeles, California, United States
Memorial Care Health System Memorialcare Long Beach
🇺🇸Long Beach, California, United States
Sutter Health Network .
🇺🇸San Pablo, California, United States
Zuckerberg General W84 Research .
🇺🇸San Francisco, California, United States
Helping Hands Medical Associates INC
🇺🇸Santa Ana, California, United States
St Francis Medical Center
🇺🇸Colorado Springs, Colorado, United States
South Denver Cardiology Associates PC
🇺🇸Littleton, Colorado, United States
Cardiology Physicians PA .
🇺🇸Newark, Delaware, 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
Emory University School of Medicine/Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
University of Chicago .
🇺🇸Chicago, Illinois, United States
University Cardiology Associates
🇺🇸Augusta, Georgia, 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
Midwest Cardiovascular Research and Education Foundation .
🇺🇸Elkhart, Indiana, United States
Reid Hosp And Hlth Care Services
🇺🇸Richmond, Indiana, United States
Franciscan Health Services Research Center .
🇺🇸Indianapolis, Indiana, United States
The Uni of Kansas Medical Center
🇺🇸Kansas City, Kansas, United States
Alexandria Cardiology Clinic
🇺🇸Alexandria, Louisiana, United States
Northern Light Easter Maine Medical Center .
🇺🇸Bangor, Maine, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Tidal Health Peninsula Regional Inc .
🇺🇸Salisbury, Maryland, United States
Detroit Medical Center Cardiovascular Clinical Trial .
🇺🇸Detroit, Michigan, United States
Beth Israel Deaconess Med Ctr CLCZ696D2301
🇺🇸Boston, Massachusetts, United States
Nebraska Heart Institute CHI Health Nebraska
🇺🇸Lincoln, Nebraska, United States
Novartis Investigative Site
🇨🇦Quebec, Canada
Univ Medical Center Las Vegas
🇺🇸Las Vegas, Nevada, United States
Inspira Health Network
🇺🇸Elmer, New Jersey, United States
Saint Michael Medical Center
🇺🇸Newark, New Jersey, United States
Cooper University Health Care
🇺🇸Haddon Heights, New Jersey, United States
Albany Associates In Cardiology
🇺🇸Albany, New York, United States
New York Presbyterian Queens .
🇺🇸Flushing, New York, United States
Cedar Multi-Specialty Clinic
🇺🇸Albuquerque, New Mexico, United States
HealthQuest
🇺🇸Poughkeepsie, 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 Health System
🇺🇸Staten Island, New York, United States
Catholic Hlth Svcs of Long Island
🇺🇸Roslyn, New York, United States
Stony Brook University Medical Center CLCZ696G2301
🇺🇸Stony Brook, New York, 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
Jefferson Abington .
🇺🇸Abington, Pennsylvania, United States
Allegheny Valley Hospital .
🇺🇸Natrona Heights, Pennsylvania, United States
Capital Area Research LLC CACZ885M2301
🇺🇸Newport, Pennsylvania, United States
Regional Health Clinic Research .
🇺🇸Rapid City, South Dakota, United States
Pharma Tex Research .
🇺🇸Amarillo, Texas, United States
Baylor University Medical Center .
🇺🇸Dallas, Texas, United States
Centra Health
🇺🇸Lynchburg, Virginia, United States
The University of Vermont Medical Center CRLX030A2301
🇺🇸Burlington, Vermont, United States
Jackson Heart Clinic
🇺🇸Jackson, Mississippi, United States
North Central Heart .
🇺🇸Sioux Falls, South Dakota, United States
R Ins For Heart And Vascular Health
🇺🇸Reno, Nevada, United States
Trinity Health Michigan Heart .
🇺🇸Ypsilanti, Michigan, United States
St Lukes Idaho Cardiology Associates CLCZ696BUS13
🇺🇸Boise, Idaho, United States
The Franciscan Missionaries
🇺🇸Baton Rouge, Louisiana, United States
Hartford Healthcare Headache Center
🇺🇸West Hartford, Connecticut, United States
Johns Hopkins Univ School of Med
🇺🇸Baltimore, Maryland, United States
VA Connecticut Healthcare System
🇺🇸West Haven, Connecticut, United States
University of Michigan Hs
🇺🇸Ann Arbor, Michigan, United States
University of Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
University Of North Carolina At Chapel Hill CRLX030A2209
🇺🇸Chapel Hill, North Carolina, United States
University of Florida Health .
🇺🇸Gainesville, Florida, United States
Montefiore Medical Center .
🇺🇸Bronx, New York, United States
University of Wisconsin School of Medicine and Public Health CLCZ696BUS01
🇺🇸Madison, Wisconsin, United States