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CompletedNCT03988634PARAGLIDE-HFUpdated Mar 6, 2025Results posted

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)

A Phase 3 interventional study of sacubitril/valsartan and valsartan in Heart Failure With Preserved Ejection Fraction (HFpEF), sponsored by Novartis Pharmaceuticals. Completed at 97 sites in 2 countries. Open to participants aged 18 Years to 99 Years. Per ClinicalTrials.gov, last updated 2025-03-06.

Sponsored by Novartis Pharmaceuticals · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
467
Allocation
Randomized
Ages
18 Years to 99 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Heart Failure With Preserved Ejection Fraction (HFpEF)

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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
03

In context

Heart Failure

5,701 studies on the registry are indexed under Heart Failure; 1,220 are open to participants now.

This study's enrollment of 467 is above the median of 72 across 3,736 interventional studies indexed under Heart Failure.

Browse Heart Failure studies →

Lead sponsor

Novartis Pharmaceuticals is the lead sponsor of 2,673 studies on the registry; 228 are open to participants now.

Of its 576 completed or terminated interventional studies of FDA-regulated products, 431 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 99 Years
Sexes eligible
All
Accepts healthy volunteers
No

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).

  1. Has not taken an ACEi for 36 hours prior to randomization

Exclusion criteria

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.
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
467 participants (actual)

Study arms

  • Experimental
    sacubitril/valsartan (LCZ696)

    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)

    Drug: sacubitril/valsartan · Drug: valsartan matching placebo

  • Active comparator
    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)

    Drug: valsartan · Drug: sacubitril/valsartan matching placebo

Interventions

  • Drugsacubitril/valsartan

    Sacubitril/valsartan (LCZ696) was available as 24/26 mg, 49/51 mg, and 97/103 mg in tablet form to be taken orally, twice daily

    Also known as: LCZ696

  • Drugvalsartan

    Valsartan was available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily

  • Drugsacubitril/valsartan matching placebo

    Sacubitril/valsartan (LCZ696) matching placebo was available as tablet form to be taken orally, twice daily

  • Drugvalsartan matching placebo

    Valsartan matching placebo was available as tablet form to be taken orally, twice daily

06

What researchers measure

Primary outcomes

  1. Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 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.

    Time frame: Baseline, Average of Week 4 and Week 8

Secondary outcomes

  1. Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome

    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.

    Time frame: Up to 84 weeks

  2. EAC Adjudicated Recurrent Composite Events

    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.

    Time frame: Up to Week 84

  3. Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function

    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.

    Time frame: Up to Week 84

  4. Proportional Change in NT-proBNP From Baseline to 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.

    Time frame: Baseline and Week 8

  5. Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 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.

    Time frame: Baseline, Week 4 and Week 8

  6. Dosing Levels and Discontinuations

    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

    Time frame: Randomization, Week 8, Week 24

  7. Incidence of Adverse Events of Special Interest (AESI) During Treatment

    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%)

    Time frame: Up to week 84

07

Results

Posted Jul 29, 2024
Limitations and caveats
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.

Participant flow

Of 586 patients screened for the study, 467 patients were randomized to receive treatment, and 466 randomized patients were treated. The study had 90 sites in the US and 10 sites in Canada

Double-Blind
Participant flow — Double-Blind
MilestoneDouble-blind Phase Sacubitril+ Valsartan (LCZ696)Double-blind Phase ValsartanOpen-label Phase Sacubitril+ Valsartan
Started2342330
Treated patients2332330
Completed1731820
Not completed61510
Withdrew: Adverse event400
Withdrew: Death18260
Withdrew: Lost to follow-up670
Withdrew: Physician decision950
Withdrew: Subject decision24130
Open-Label
Participant flow — Open-Label
MilestoneDouble-blind Phase Sacubitril+ Valsartan (LCZ696)Double-blind Phase ValsartanOpen-label Phase Sacubitril+ Valsartan
Started0050
Completed0041
Not completed009
Withdrew: Adverse event007
Withdrew: Physician decision001
Withdrew: Technical problems001

Outcome measures

PrimaryTime-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 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.

Time frame:
Baseline, Average of Week 4 and Week 8
Reported as:
Geometric mean · Geometric Mean Ratio
Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 8
Geometric Mean RatioSacubitril/Valsartan (LCZ696)Valsartan
Time-averaged Proportional Change in NT proBNP From Baseline to Weeks 4 and 80.7200 (0.6430 to 0.8062)0.8425 (0.7561 to 0.9387)
Statistical analysis
  • Sacubitril/Valsartan (LCZ696) vs Valsartan · ANCOVA · p = 0.0492 · Geometric mean ratio: 0.8546 · 95% CI 0.7307 to 0.9994Geometric Mean Ratio: sac/val vs valsartan
SecondaryNumber of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome

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.

Time frame:
Up to 84 weeks
Reported as:
Number · Pairwise comparisons
Number of Pairwise Comparisons With Wins or Ties in the Endpoint Adjudication Committee (EAC)-Adjudicated Composite Hierarchical Outcome
Pairwise comparisonsSacubitril/Valsartan (LCZ696)ValsartanOpen-label Phase Sacubitril+ Valsartan
Time to CV death wins21701536—
Time to CV death ties5058350583—
Number and times of HF hospitalizations during follow-up wins69636357—
Number and times of HF hospitalizations during follow-up ties3726337263—
Number and times of urgent HF visits during follow-up wins930572—
Number and times of urgent HF visits during follow-up ties3576135761—
Time-averaged proportional change in NT-proBNP wins99878343—
Time-averaged proportional change in NT-proBNP ties1743117431—
Overall wins2005016808—
Overall ties1743117431—
Statistical analysis
  • Sacubitril/Valsartan (LCZ696) vs Valsartan · unmatched pairwise win-ratio · p = 0.1578 · Win ratio: 1.193 · 95% CI 0.934 to 1.524A win ratio greater than 1 was in favor of sacubitril/valsartan arm
SecondaryEAC Adjudicated Recurrent Composite Events

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.

Time frame:
Up to Week 84
Reported as:
Number · events per 100 subject years
EAC Adjudicated Recurrent Composite Events
events per 100 subject yearsSacubitril/Valsartan (LCZ696)ValsartanOpen-label Phase Sacubitril+ Valsartan
EAC Adjudicated Recurrent Composite Events63.519 (51.330 to 77.732)76.189 (63.010 to 91.310)—
Statistical analysis
  • Sacubitril/Valsartan (LCZ696) vs Valsartan · LWYY model · p = 0.3563 · Rate ratio: 0.8346 · 95% CI 0.5684 to 1.2255A rate ratio \< 1 indicates an effect in favor of LCZ696
SecondaryTotal Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function

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.

Time frame:
Up to Week 84
Reported as:
Number · events of worsening renal function
Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function
events of worsening renal functionSacubitril/Valsartan (LCZ696)ValsartanOpen-label Phase Sacubitril+ Valsartan
Total Number of Confirmed Incidences of a Composite Endpoint of Worsening Renal Function3446—
Statistical analysis
  • Sacubitril/Valsartan (LCZ696) vs Valsartan · negative binomial regression model · p = 0.3155 · Rate ratio: 0.6249 · 95% CI 0.2496 to 1.5649
SecondaryProportional Change in NT-proBNP From Baseline to 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.

Time frame:
Baseline and Week 8
Reported as:
Geometric mean · Geometric mean ratio
Proportional Change in NT-proBNP From Baseline to Week 8
Geometric mean ratioSacubitril/Valsartan (LCZ696)Valsartan
Proportional Change in NT-proBNP From Baseline to Week 80.6778 (0.5882 to 0.7810)0.7275 (0.6359 to 0.8323)
Statistical analysis
  • Sacubitril/Valsartan (LCZ696) vs Valsartan · ANCOVA · p = 0.4766 · Ratio of the change: 0.9316 · 95% CI 0.7661 to 1.1329
SecondaryProportional Change From Baseline in Hs-Troponin at Weeks 4 and 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.

Time frame:
Baseline, Week 4 and Week 8
Reported as:
Geometric mean · Geometric mean ratio
Proportional Change From Baseline in Hs-Troponin at Weeks 4 and 8
Geometric mean ratioSacubitril/Valsartan (LCZ696)Valsartan
Week 40.8124 (0.76 to 0.87)0.9826 (0.92 to 1.05)
Week 80.7545 (0.70 to 0.81)0.9310 (0.87 to 1.00)
Statistical analysis
  • Sacubitril/Valsartan (LCZ696) vs Valsartan · ANCOVA · p = <.0001 · Ratio of the change: 0.8268 · 95% CI 0.76 to 0.91
  • Sacubitril/Valsartan (LCZ696) vs Valsartan · ANCOVA · p = <.0001 · Ratio of the change: 0.8103 · 95% CI 0.74 to 0.89
SecondaryDosing Levels and Discontinuations

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

Time frame:
Randomization, Week 8, Week 24
Reported as:
Count of participants · Participants
Dosing Levels and Discontinuations
ParticipantsSacubitril/Valsartan (LCZ696)ValsartanOpen-label Phase Sacubitril+ Valsartan
Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) — Dose Level 1133130—
Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) — Dose Level 22932—
Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) — Dose Level 300—
Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) — No Treatment00—
Participants Randomized In-Hospital ; Timepoint: Randomization (initial dose) — Off Treatment00—
Participants Randomized In-Hospital ; Timepoint: Week 8 — Dose Level 12940—
Participants Randomized In-Hospital ; Timepoint: Week 8 — Dose Level 22223—
Participants Randomized In-Hospital ; Timepoint: Week 8 — Dose Level 34848—
Participants Randomized In-Hospital ; Timepoint: Week 8 — No Treatment2718—
Participants Randomized In-Hospital ; Timepoint: Week 8 — Off Treatment105—
Participants Randomized In-Hospital ; Timepoint: Week 24 — Dose Level 11218—
Participants Randomized In-Hospital ; Timepoint: Week 24 — Dose Level 2516—
Participants Randomized In-Hospital ; Timepoint: Week 24 — Dose Level 33232—
Participants Randomized In-Hospital ; Timepoint: Week 24 — No Treatment1911—
Participants Randomized In-Hospital ; Timepoint: Week 24 — Off Treatment31—
Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) — Dose Level 16260—
Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) — Dose Level 2911—
Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) — Dose Level 300—
Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) — No Treatment00—
Participants Randomized Out-of-hospital; Timepoint: Randomization (Initial Dose) — Off Treatment00—
Participants Randomized Out-of-hospital; Timepoint: Week 8 — Dose Level 11821—
Participants Randomized Out-of-hospital; Timepoint: Week 8 — Dose Level 21512—
Participants Randomized Out-of-hospital; Timepoint: Week 8 — Dose Level 32220—
Participants Randomized Out-of-hospital; Timepoint: Week 8 — No Treatment35—
Participants Randomized Out-of-hospital; Timepoint: Week 8 — Off Treatment21—
Participants Randomized Out-of-hospital; Timepoint: Week 24 — Dose Level 11011—
Participants Randomized Out-of-hospital; Timepoint: Week 24 — Dose Level 2810—
Participants Randomized Out-of-hospital; Timepoint: Week 24 — Dose Level 31615—
Participants Randomized Out-of-hospital; Timepoint: Week 24 — No Treatment39—
Participants Randomized Out-of-hospital; Timepoint: Week 24 — Off Treatment14—
SecondaryIncidence of Adverse Events of Special Interest (AESI) During Treatment

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%)

Time frame:
Up to week 84
Reported as:
Count of participants · Participants
Incidence of Adverse Events of Special Interest (AESI) During Treatment
ParticipantsSacubitril/Valsartan (LCZ696)ValsartanOpen-label Phase Sacubitril+ Valsartan
Symptomatic hypotension5636—
Hyperkalemia4543—
Angioedema01—
Worsening renal function5072—

Adverse events

Collected over Adverse events of the double-blind phase were reported from first dose of study treatment until end of study treatment plus 1 month post treatment, up to a maximum duration of 21 months. For those patients enrolled during the original version (00) of the protocol, where the open-label phase existed, adverse events were reported during the 4 week Open-Label period, and 1 month post treatment, for a maximum of 2 months.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Double-blind Phase Sacubitril+ Valsartan (LCZ696)18/233 (7.7%)119/233 (51.1%)161/233 (69.1%)
Double-blind Phase Valsartan26/233 (11.2%)117/233 (50.2%)165/233 (70.8%)
Open-label Phase Sacubitril+ Valsartan0/50 (0%)3/50 (6%)14/50 (28%)
Most frequent serious events
Showing 10 of 228
Most frequent serious events
EventDouble-blind Phase Sacubitril+ Valsartan (LCZ696)Double-blind Phase ValsartanOpen-label Phase Sacubitril+ Valsartan
Cardiac failureCardiac disorders22/23320/2330/50
Acute kidney injuryRenal and urinary disorders21/23315/2330/50
Cardiac failure congestiveCardiac disorders14/23319/2330/50
HypotensionVascular disorders15/23313/2330/50
Cardiac failure acuteCardiac disorders11/23314/2330/50
PneumoniaInfections and infestations7/23314/2330/50
Atrial fibrillationCardiac disorders10/23313/2330/50
SyncopeNervous system disorders10/2339/2330/50
Acute respiratory failureRespiratory, thoracic and mediastinal disorders9/2338/2330/50
Acute myocardial infarctionCardiac disorders2/2338/2330/50
Most frequent other events
Showing 10 of 20
Most frequent other events
EventDouble-blind Phase Sacubitril+ Valsartan (LCZ696)Double-blind Phase ValsartanOpen-label Phase Sacubitril+ Valsartan
SARS-CoV-2 test negativeInvestigations58/23373/2330/50
HypotensionVascular disorders58/23340/2331/50
Acute kidney injuryRenal and urinary disorders35/23347/2330/50
HyperkalaemiaMetabolism and nutrition disorders38/23343/2333/50
Blood creatinine increasedInvestigations23/23327/2333/50
SARS-CoV-2 test positiveInvestigations23/23318/2330/50
HypokalaemiaMetabolism and nutrition disorders19/23322/2331/50
Urinary tract infectionInfections and infestations19/23321/2332/50
DizzinessNervous system disorders21/23318/2331/50
Renal impairmentRenal and urinary disorders11/23320/2331/50

Baseline characteristics

Demographic and baseline characteristics are based on the full analysis set (FAS), as primary and secondary analysis are based on the FAS. The FAS consisted of all patients to whom study treatment was assigned by randomization and at least 1 dose of study treatment received.

Age, Continuous
Age, Continuous(years)Sacubitril/Valsartan (LCZ696)ValsartanTotal
Mean69.2 ± 11.9570.5 ± 11.5669.8 ± 11.76
Sex: Female, Male
Sex: Female, Male(Participants)Sacubitril/Valsartan (LCZ696)ValsartanTotal
Female121121242
Male112112224
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Sacubitril/Valsartan (LCZ696)ValsartanTotal
White176176352
Black5052102
Asian336
Native Hawaiian or Other Pacific Islander112
American Indian or Alaska Native314
08

Study locations

97 sites
  • University of Calif Irvine Med Cntr
    Irvine, California 92660, United States
  • Memorial Care Health System Memorialcare Long Beach
    Long Beach, California 90806, United States
  • University Of Southern California .
    Los Angeles, California 90033-4605, United States
  • University Of Southern California
    Los Angeles, California 90033-4605, United States
  • San Diego Cardiac Center
    San Diego, California 92123, United States
  • Zuckerberg General W84 Research .
    San Francisco, California 94110, United States
  • Sutter Health Network .
    San Pablo, California 94806, United States
  • Helping Hands Medical Associates INC
    Santa Ana, California 92704, United States
  • St Francis Medical Center
    Colorado Springs, Colorado 80923, United States
  • Colorado Heart and Vascular .
    Lakewood, Colorado 80228, United States
  • South Denver Cardiology Associates PC
    Littleton, Colorado 80120, United States
  • Hartford Healthcare Headache Center
    West Hartford, Connecticut 06109, United States
  • VA Connecticut Healthcare System
    West Haven, Connecticut 06516, United States
  • Cardiology Physicians PA .
    Newark, Delaware 19713, United States
  • University of Florida Health .
    Gainesville, Florida 32610, United States
  • New Generation of Medical Research Avera Health N Central Heart
    Hialeah, Florida 33016, United States
  • University of Florida Health Science Center
    Jacksonville, Florida 32209, United States
  • Intercoastal Medical Group
    Sarasota, Florida 34239, United States
  • Morehouse School Of Medicine
    Atlanta, Georgia 30310, United States
  • Emory University School of Medicine/Winship Cancer Institute
    Atlanta, Georgia 30322, United States
  • University Cardiology Associates
    Augusta, Georgia 30901, United States
  • St Lukes Idaho Cardiology Associates CLCZ696BUS13
    Boise, Idaho 83702, United States
  • University of Chicago .
    Chicago, Illinois 60637, United States
  • Amita Health
    Elk Grove Village, Illinois 60007, United States
  • Midwest Cardiovascular Institute .
    Oakbrook Terrace, Illinois 60181, United States
  • Advocate Medical Group .
    Park Ridge, Illinois 60068, United States
  • Unity Point Health Methodist
    Peoria, Illinois 61606, United States
  • OSF HealthCare
    Peoria, Illinois 61614, United States
  • Northwestern Medicine Northwestern University
    Winfield, Illinois 60190, United States
  • Midwest Cardiovascular Research and Education Foundation .
    Elkhart, Indiana 46514, United States
  • Indiana University Health
    Indianapolis, Indiana 46202, United States
  • Franciscan Health Services Research Center .
    Indianapolis, Indiana 46237, United States
  • Indiana University Health
    Muncie, Indiana 47303, United States
  • Reid Hosp And Hlth Care Services
    Richmond, Indiana 47374, United States
  • The Uni of Kansas Medical Center
    Kansas City, Kansas 66160, United States
  • Alexandria Cardiology Clinic
    Alexandria, Louisiana 71301, United States
  • The Franciscan Missionaries
    Baton Rouge, Louisiana 70808, United States
  • Northern Light Easter Maine Medical Center .
    Bangor, Maine 04401, United States
  • Johns Hopkins Univ School of Med
    Baltimore, Maryland 21287, United States
  • Tidal Health Peninsula Regional Inc .
    Salisbury, Maryland 21804, United States
  • Massachusetts General Hospital
    Boston, Massachusetts 02114, United States
  • Boston Univeristy Medical Center .
    Boston, Massachusetts 02118, United States
  • Beth Israel Deaconess Med Ctr CLCZ696D2301
    Boston, Massachusetts 02215, United States
  • University of Michigan Hs
    Ann Arbor, Michigan 48109, United States
  • Detroit Medical Center Cardiovascular Clinical Trial .
    Detroit, Michigan 48201, United States
  • Henry Ford Hospital Cardiovascular Medicine
    Detroit, Michigan 48202, United States
  • Trinity Health Michigan Heart .
    Ypsilanti, Michigan 48197, United States
  • Novartis Investigative Site
    Saint Paul, Minnesota 55101, United States
  • Jackson Heart Clinic
    Jackson, Mississippi 39216, United States
  • Nebraska Heart Institute CHI Health Nebraska
    Lincoln, Nebraska 68510, United States
  • University of Nebraska Medical Center
    Omaha, Nebraska 68198, United States
  • Univ Medical Center Las Vegas
    Las Vegas, Nevada 89201, United States
  • R Ins For Heart And Vascular Health
    Reno, Nevada 89502, United States
  • Inspira Health Network
    Elmer, New Jersey 08318, United States
  • Cooper University Health Care
    Haddon Heights, New Jersey 08035, United States
  • Saint Michael Medical Center
    Newark, New Jersey 07102, United States
  • Cedar Multi-Specialty Clinic
    Albuquerque, New Mexico 87106, United States
  • Albany Associates In Cardiology
    Albany, New York 12205, United States
  • Montefiore Medical Center .
    Bronx, New York 10461, United States
  • New York Presbyterian Queens .
    Flushing, New York 11355, United States
  • United Health Services Office Of Clinical Trails CLCZ696BUS01
    Johnson, New York 13790, United States
  • Northwell Health .
    Manhasset, New York 11030, United States
  • Mount Sinai Hospital .
    New York, New York 10029, United States
  • HealthQuest
    Poughkeepsie, New York 12601, United States
  • Catholic Hlth Svcs of Long Island
    Roslyn, New York 11576, United States
  • Mount Sinai Health System
    Staten Island, New York 10310, United States
  • Stony Brook University Medical Center CLCZ696G2301
    Stony Brook, New York 11794, United States
  • University Of North Carolina At Chapel Hill CRLX030A2209
    Chapel Hill, North Carolina 27599-7075, United States
  • Duke Health
    Durham, North Carolina 27710, United States
  • Cleveland Clinic Foundation .
    Cleveland, Ohio 44195, United States
  • St. Vincent Mercy Medical Center
    Toledo, Ohio 43608, United States
  • St John Health System
    Bartlesville, Oklahoma 74006, United States
  • Regional Medical Labaratory
    Tulsa, Oklahoma 74104, United States
  • Jefferson Abington .
    Abington, Pennsylvania 19001, United States
  • Allegheny Valley Hospital .
    Natrona Heights, Pennsylvania 15065, United States
  • Capital Area Research LLC CACZ885M2301
    Newport, Pennsylvania 17074, United States
  • Thomas Jefferson Univ Hospital .
    Philadelphia, Pennsylvania 19107, United States
  • Regional Health Clinic Research .
    Rapid City, South Dakota 57701, United States
  • North Central Heart .
    Sioux Falls, South Dakota 57105, United States
  • VA Tennessee Valley Healthcare System
    Nashville, Tennessee 37212, United States
  • Pharma Tex Research .
    Amarillo, Texas 79106, United States
  • Baylor University Medical Center .
    Dallas, Texas 75246, United States
  • The University of Texas Medical Branch
    Galveston, Texas 77555-1062, United States
  • The University of Vermont Medical Center CRLX030A2301
    Burlington, Vermont 05401, United States
  • Centra Health
    Lynchburg, Virginia 24501, United States
  • Swedish Medical Ctr Cardiovascular Re
    Seattle, Washington 98122, United States
  • University of Wisconsin School of Medicine and Public Health CLCZ696BUS01
    Madison, Wisconsin 53792-1615, United States
  • Novartis Investigative Site
    Victoria, British Columbia V8R4R2, Canada
  • Novartis Investigative Site
    Winnipeg, Manitoba R2H 2A6, Canada
  • Novartis Investigative Site
    Hamilton, Ontario L8L 2X2, Canada
  • Novartis Investigative Site
    Montreal, Quebec H1T 1C8, Canada
  • Novartis Investigative Site
    Montreal, Quebec H2X 0A9, Canada
  • Novartis Investigative Site
    Montreal, Quebec H3G 1A4, Canada
  • Novartis Investigative Site
    Saguenay, Quebec G7H 5H6, Canada
  • Novartis Investigative Site
    Sherbrooke, Quebec J1H 5N4, Canada
  • Novartis Investigative Site
    Terrebonne, Quebec J6V 2H2, Canada
  • Novartis Investigative Site
    Quebec, G1R 2J6, Canada
09

References and documents

Study documents

  • Study protocol · Dec 8, 2021
  • Statistical analysis plan · Feb 21, 2023

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 6, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT03988634
Lead sponsor
Novartis Pharmaceuticals
Responsible party
Sponsor
First posted
Jun 17, 2019
Start date
Jun 29, 2019
Primary completion
Dec 14, 2022
Completion
Dec 14, 2022
Results posted
Jul 29, 2024
Last update
Mar 6, 2025

Study contacts

Novartis Pharmaceuticals
study director · Novartis Pharmaceuticals

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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