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Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode. (PIONEER-HF)

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ClinicalTrials.gov Identifier: NCT02554890
Recruitment Status : Completed
First Posted : September 18, 2015
Results First Posted : September 24, 2019
Last Update Posted : September 24, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this study was to assess the effect of in-hospital initiation of sacubitril/valsartan (LCZ696) vs. enalapril on time averaged proportional change in NT-proBNP in patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF) and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 40%).

Condition or disease Intervention/treatment Phase
Acute Heart Failure Drug: sacubitril/valsartan (LCZ696) Drug: Enalapril Drug: sacubitril/valsartan (LCZ696) matching placebo Drug: enalapril matching placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 887 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
Official Title: A Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled 8-week Study to Evaluate the Effect of Sacubitril/Valsartan (LCZ696) Versus Enalapril on Changes in NT-proBNP and Safety and Tolerability of In-hospital Initiation of LCZ696 Compared to Enalapril in HFrEF Patients Who Have Been Stabilized Following Hospitalization for Acute Decompensated Heart Failure (ADHF).
Actual Study Start Date : April 29, 2016
Actual Primary Completion Date : June 29, 2018
Actual Study Completion Date : July 24, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: sacubitril/valsartan (LCZ696)

Initial dose for patients randomized to sacubitril/valsartan (LCZ696) was determined by the blood pressure at the time of randomization. Study treatment was titrated to the target dose of sacubitril/valsartan (LCZ696) 97/103 mg bid (Dose Level 3). Titration was based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement.

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

Drug: sacubitril/valsartan (LCZ696)
sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.
Other Name: LCZ696

Drug: enalapril matching placebo
enalapril matching placebo tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.

Active Comparator: Enalapril

Initial dose for patients randomized to enalapril were determined by the blood pressure at the time of randomization. Study treatment were titrated to the target dose of enalapril 10 mg bid. Titration were based on blood pressure at the time of the visit. Dose adjustments were only allowed if indicated per protocol defined safety and tolerability criteria and investigator judgement.

Patients were required to take a total of two tablets twice daily (one tablet of active enalapril, second from sacubitril and valsartan matching placebo pack)

Drug: Enalapril
Enalapril tablet with minimum dose 2.5 mg, maximum dose 10 mg twice daily administered orally.

Drug: sacubitril/valsartan (LCZ696) matching placebo
matching placebo of sacubitril/valsartan (LCZ696) tablet with minimum dose 24/26 mg, maximum dose 97/103 mg twice daily administered orally.




Primary Outcome Measures :
  1. N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Time-averaged Change From Baseline [ Time Frame: Baseline, Week 4 and Week 8 ]

    To assess the effect of in-hospital initiation of sacubitril/valsartan vs. enalapril on the time-averaged percentage change of NT-proBNP from baseline in patients who have been stabilized following hospitalization for ADHF and reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 40%) between week 4 and 8.

    Number of patients with both a baseline value and a value at Week 4 or Week 8. Plasma NT-proBNP (pg/mL) values were averaged from Week 4 and Week 8 visits. N-terminal pro b-type natriuretic peptide (NTproBNP) are peptide (small proteins) that are either hormones or part of the peptide that contained the hormone at one time. They are continually produced in small quantities in the heart and released in larger quantities when the heart senses that it needs to work harder, as in heart failure.



Secondary Outcome Measures :
  1. Number of Patients With Incidences of Symptomatic Hypotension [ Time Frame: 8 weeks of treatment ]
    Examine the effect of LCZ696 vs. enalapril on incidence of symptomatic hypotension during 8 weeks of treatment Hypotension is low blood pressure. Patients with hypotension may experience symptoms when their blood pressure drops, compared to the patient's normal values. Symptoms of hypotension can include dizziness, lightheadedness, blurred vision, weakness, fatigue, nausea, palpitations, and headache.

  2. Number of Patients With Incidences of Hyperkalemia [ Time Frame: 8 weeks of treatment ]
    Hyperkalemia is defined as Potassium level >5.5 mEq/L. Hyperkalemia is the medical term that describes a potassium level in your blood that's higher than normal. Potassium is a chemical that is critical to the function of nerve and muscle cells, including those in your heart.

  3. Number of Patients With Incidences of Angioedema [ Time Frame: 8 weeks of treatment ]
    Angioedema is a type of abrupt swelling that occurs under the skin and/or mucous membranes and is often localized to the head, neck, throat, and/or tongue, but may occur elsewhere, including the genitalia and intestines. Severe cases may be associated with difficulty in breathing.

  4. Change From Baseline in High Sensitivity Troponin (Hs-Troponin) [ Time Frame: Baseline, Week 4/Week 8 ]
    time-averaged (Weeks 4 and 8) change from baseline in hs-troponin T. hs-Troponin-T is a biomarker that is released from the heart under stress or injury conditions.

  5. Change From Baseline in Urinary cGMP [ Time Frame: Baseline, Week 4 and Week 8 ]
    Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP. Urinary Cyclic GMP (cGMP) is a biomarker measured in the urine that reflects the activity of biomarkers such as BNP (Brain Natriuretic Peptide)

  6. Change From Baseline in Urinary cGMP to Urinary Creatinine Ratio [ Time Frame: Baseline, Week 4 and Week 8 ]

    Time-averaged (Weeks 4 and 8) change from baseline in urinary cGMP to urinary creatinine ratio.

    Urinary cGMP to urinary creatinine ratio is how much urinary cGMP (which reflects natriuretic peptide activity) compared to a compound in the urine called creatinine (which helps your doctor evaluate how well your kidneys are functioning).


  7. Change From Baseline in BNP to NTproBNP Ratio [ Time Frame: baseline, Week 4 and Week 8 ]
    Time-averaged (Weeks 4 and 8) change from baseline in BNP to NT-proBNP ratio. BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure.

  8. N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Values and Change From Baseline at Week 8 [ Time Frame: Baseline, Week 8 ]

    BNP and NT-proBNP are small proteins produced in large amounts when the heart senses it needs to work harder, such as in heart failure. The test measuring BNP to NT-proBNP is measuring how much of each of these biomarkers are present in order to evaluate heart failure.

    Plasma NT-proBNP (pg/mL) values were Week 8 visit.




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  1. Possess the capacity to provide written informed consent which must be obtained before any assessment is performed.
  2. Currently hospitalized for ADHF. 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) at time of hospitalization.
  3. Eligible patients will be randomized no earlier than 24 hours and up to ten days after presentation while still hospitalized as long as meet the following definition of stable status:

    • SBP ≥100mm Hg for the preceding 6 hours prior to randomization; no symptomatic hypotension
    • No increase (intensification) in i.v. diuretic dose within last 6 hours prior to randomization
    • No i.v. inotropic drugs for 24 hours prior to randomization
    • No i.v. vasodilators including nitrates within last 6 hours prior to randomization
  4. LVEF ≤40% within the past 6 months (including current hospitalization) using echocardiography, multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography, provided no subsequent study documented an EF of >40%.
  5. Elevated NT-proBNP ≥ 1600pg/mL OR BNP ≥400 pg/mL during current hospitalization.

Key Exclusion Criteria:

  1. Currently taking sacubitril/valsartan tablets or any use within the past 30 days.
  2. Enrollment in any other clinical trial involving an investigational agent or investigational device.
  3. History of hypersensitivity, known or suspected contraindications, or intolerance to any of the study drugs, including ACEIs, ARBs, or Sacubitril (NEP inhibitor).
  4. Patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy.
  5. Requirement of treatment with both ACE inhibitor and ARB.
  6. eGFR < 30 ml/min/1.73 m2 as measured by the simplified Modification of Diet in Renal Disease (MDRD) formula at screening.
  7. Serum potassium > 5.2 mEq/L at screening.
  8. 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
  9. Acute coronary syndrome, stroke, transient ischemic attack; cardiac, carotid or other major CV surgery; percutaneous coronary intervention (PCI) or carotid angioplasty, within one month prior to Visit 1.
  10. 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.
  11. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02554890


  Show 127 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] October 5, 2017
Statistical Analysis Plan  [PDF] August 20, 2018


Publications:
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02554890     History of Changes
Other Study ID Numbers: CLCZ696BUS01
First Posted: September 18, 2015    Key Record Dates
Results First Posted: September 24, 2019
Last Update Posted: September 24, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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 patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Acute
Heart Failure
reduced ejection fraction
NTproBNP
Heart failure with reduced ejection fraction (HFREF)
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Valsartan
Enalapril
Enalaprilat
LCZ 696
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors