MedPath

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)

Phase 3
Completed
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
Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
sacubitril/valsartan (LCZ696)valsartan matching placeboStudy 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)
valsartansacubitril/valsartan matching placeboStudy 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)
valsartanvalsartanStudy 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/valsartanStudy 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
NameTimeMethod
Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 8Baseline, 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
NameTimeMethod
Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical OutcomeUp 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 FunctionUp 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 8Baseline 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 8Baseline, 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 EventsUp 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 TreatmentUp 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 DiscontinuationsRandomization, 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)

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

Scroll for more (76 remaining)
University of Calif Irvine Med Cntr
🇺🇸Irvine, California, United States

MedPath

Empowering clinical research with data-driven insights and AI-powered tools.

© 2025 MedPath, Inc. All rights reserved.