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Safety and Tolerability of In-hospital Initiation of LCZ696 Compared to Valsartan in HFpEF Patients With Acute Decompensated Heart Failure (ADHF) Who Have Been Stabilized During Hospitalization (PARAGLIDE-HF)

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ClinicalTrials.gov Identifier: NCT03988634
Recruitment Status : Not yet recruiting
First Posted : June 17, 2019
Last Update Posted : June 17, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE June 13, 2019
First Posted Date  ICMJE June 17, 2019
Last Update Posted Date June 17, 2019
Estimated Study Start Date  ICMJE June 19, 2019
Estimated Primary Completion Date February 11, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2019)
Proportional change in NT-proBNP from baseline to the average of weeks 4 and 8 [ Time Frame: Baseline to weeks 4 and 8 ]
To assess the effect of in-hospital initiation of sacubitril/valsartan vs. valsartan on the time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8 in patients with HFpEF who have been stabilized during hospitalization for acute decompensated heart failure.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 13, 2019)
  • Cumulative number of heart failure re-hospitalizations, for a given patient [ Time Frame: Over 8 weeks ]
    To determine the effect of sacubitril/valsartan vs. valsartan on reducing the rate of total heart failure re-hospitalizations at 8 weeks.
  • Proportional change in NT-proBNP [ Time Frame: Baseline to week 8 ]
    To determine the effect of sacubitril/valsartan vs. valsartan on change in NT-ProBNP from baseline to week 8.
  • Proportional change from baseline at 4 and 8 weeks in the following biomarkers: hs-Troponin (high sensitivity), ST2, and urinary cGMP [ Time Frame: From baseline at 4 and 8 weeks ]
    To determine the effect of sacubitril/valsartan vs. valsartan on change from baseline in biomarkers: hs-Troponin (high sensitivity), ST2, and urinary cGMP at 4 and 8 weeks
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Tolerability of In-hospital Initiation of LCZ696 Compared to Valsartan in HFpEF Patients With Acute Decompensated Heart Failure (ADHF) Who Have Been Stabilized During Hospitalization (PARAGLIDE-HF)
Official Title  ICMJE A Multicenter, Randomized, Double-blind, Double-dummy, Parallel Group, Active Controlled 8-week Study to Evaluate the Effect of Sacubitril/Valsartan (LCZ696) Versus Valsartan on Changes in NT-proBNP and Safety and Tolerability of In-hospital Initiation of LCZ696 Compared to Valsartan in HFpEF Patients With Acute Decompensated Heart Failure (ADHF) Who Have Been Stabilized During Hospitalization (PARAGLIDE-HF)
Brief Summary The purpose of this study is to assess the effect of in-hospital initiation of sacubitril/valsartan (LCZ696) vs. valsartan on time averaged proportional change in NT-proBNP in patients with HFpEF (left ventricular ejection fraction (LVEF) > 40%) who have been stabilized during hospitalization for acute decompensated heart failure.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure With Preserved Ejection Fraction (HFpEF)
Intervention  ICMJE
  • Drug: sacubitril/valsartan

    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 8 week 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 8 week double-blind period.

    Sponsor-provided sacubitril/valsartan tablets will be administered orally twice a day for all patients during the 4 week open label extension.

    Other Name: LCZ696
  • Drug: valsartan

    Valsartan is available as 40 mg, 80 mg, and 160 mg in tablet form to be taken orally, twice daily, for the 8 week 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 8 week double-blind period.

    Sponsor-provided sacubitril/valsartan tablets will be administered orally twice a day for all patients during the 4 week open label extension.

Study Arms  ICMJE
  • Experimental: sacubitril/valsartan

    randomized in a 1:1 ratio: sacubitril/valsartan to valsartan for the 8 week treatment period.

    Initial dose for patients randomized to sacubitril/valsartan (LCZ696) will be determined by patient's previous dose of ACEi/ARB immediately prior to hospital admission for acute decompensated heart failure. 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).

    Intervention: Drug: sacubitril/valsartan
  • Active Comparator: valsartan

    randomized in a 1:1 ratio: sacubitril/valsartan to valsartan for the 8 week treatment period.

    Initial dose for patients randomized to valsartan will be determined by patient's previous dose of ACEi/ARB immediately prior to hospital admission for acute decompensated heart failure. 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).

    Intervention: Drug: valsartan
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 13, 2019)
616
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 11, 2021
Estimated Primary Completion Date February 11, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Currently hospitalized with acute decompensated HFpEF. 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 no earlier than 36 hours and up to ten days after diagnosis of acute decompensation while still hospitalized as long as they meet the following definition of hemodynamic stability:

    • SBP ≥100 mm 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
  2. HFpEF with most recent LVEF >40% (within past 3 months)
  3. Elevated NT-proBNP or BNP during current hospitalization (patients not in AF: NT-proBNP ≥ 800pg/mL or BNP ≥ 250 pg/mL; patients in AF: NT- proBNP ≥ 1600pg/mL or BNP ≥ 500 pg/mL)
  4. 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., MI, CABG), unless an echo measurement was performed after the event confirming the LVEF to be >40%
  2. Currently taking Entresto™ (sacubitril/valsartan) or any prior use
  3. eGFR < 30ml/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 of randomization
  4. Serum potassium > 5.2 mEq/L at most recent assessment prior to randomization and within 24 hours of 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 of 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. Specifically, patients with the following are excluded:

    1. Severe pulmonary disease including chronic obstructive pulmonary disease (COPD) (i.e. requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy) or
    2. Hemoglobin (Hgb) < 10 g/dL males and < 9.5 g/dL females or
    3. Body mass index (BMI) > 50 kg/m2 at randomization
  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 intent to implant LVAD or CRT device within the 12 week duration of the trial
  11. A cardiac or non-cardiac medical condition other than HF with an estimated life expectancy of < 3 months
  12. Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy including 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 12 week 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. Pregnant or nursing women; women of childbearing potential that are not using a highly effective method of contraception until 1 week following last dose

Other protocol-defined inclusion/exclusion criteria may apply

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03988634
Other Study ID Numbers  ICMJE CLCZ696DUS01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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 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
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP