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Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2016 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01920711
First received: August 8, 2013
Last updated: June 12, 2016
Last verified: June 2016

August 8, 2013
June 12, 2016
July 2014
March 2019   (final data collection date for primary outcome measure)
Cumulative number of primary composite events of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations. [ Time Frame: Total follow up time (up to 57 months) ] [ Designated as safety issue: No ]
The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF patients (New York Heart Association [NYHA] Class II-IV) with preserved ejection fraction (left ventricular ejection fraction [LVEF] ≥45%). The treatment arm with the lower rate of events will be deemed as having a successful response.
Cumulative number of primary composite events of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations. [ Time Frame: Total follow up time (up to 57 months) ] [ Designated as safety issue: No ]
The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF patients (NYHA Class II-IV) with preserved EF (LVEF ≥45%). The treatment arm with the lower rate of events will be deemed as having a successful response.
Complete list of historical versions of study NCT01920711 on ClinicalTrials.gov Archive Site
  • Change in the clinical summary score from baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ) [ Time Frame: Baseline, 8 months ] [ Designated as safety issue: No ]
    Evaluation of change from baseline to month 8 in KCCQ a most sensitive, specific, and responsive health-related quality of life measure for heart failure symptoms and physical limitations.
  • Change from baseline to Month 8 in New York Heart Association (NYHA) functional class [ Time Frame: Baseline, 8 months ] [ Designated as safety issue: No ]
    Evaluation of change from baseline to Month 8 in NYHA functional class, a well established grading scale used to classify a HF patients' level of functionality based on the signs and symptoms of HF exhibited by the patient.
  • Time to first occurance of a composite renal endpoint [ Time Frame: Total follow up time (up to 57 months) ] [ Designated as safety issue: No ]

    Evaluate significance of outcome modifying agents in worsening renal dysfunction.

    Composite renal endpoint defined as follows:

    • renal death, or
    • reaching ESRD, or
    • ≥50% decline in eGFR relative to baseline
  • Time to all-cause mortality [ Time Frame: Total follow up time (up to 57 months) ] [ Designated as safety issue: No ]
    Evaluation of the time to all cause death.
  • Cumulative number of events of the extended composite endpoint of CV death, total HF hospitalizations, total non-fatal strokes, and total non-fatal myocardial infarctions (MIs). [ Time Frame: Total follow up time (up to 57 months) ] [ Designated as safety issue: No ]
    Evaluation of the composite endpoint of CV death, total HF hospitalizations, total strokes, and total MIs. The treatment arm with the lower rate of events will be deemed a successful response.
  • Change from baseline to Month 8 in New York Heart Association (NYHA) functional class [ Time Frame: 8 months ] [ Designated as safety issue: No ]
    Evaluation of change from baseline to Month 8 in NYHA functional class, a well established grading scale used to classify a HF patients' level of functionality based on the signs and symptoms of HF exhibited by the patient
  • Time to new onset of atrial fibrillation (AF) [ Time Frame: Total follow up time (up to 57 months) ] [ Designated as safety issue: No ]
    Evaluation of the time to onset of atrial fibrillation (AF) in patients wtihout prior AF (no prior history of AF and no AF at baseline).
  • Time to all-cause mortality [ Time Frame: Total follow up time (up to 57 months) ] [ Designated as safety issue: No ]
    Evaluation of the time to all cause death.
Not Provided
Not Provided
 
Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction
A Multicenter, Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients (NYHA Class II-IV) With Preserved Ejection Fraction
The purpose of this study is to evaluate the effect of LCZ696 compared to valsartan in the reduction of cardiovascular death and heart failure(HF) hospitalizations in patients with HF with preserved ejection fraction.
Not Provided
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Heart Failure With Preserved Ejection Fraction
  • Drug: LCZ696
    LCZ696 50mg, 100mg and 200 mg dosage strengths will be available for dose adjustments.
  • Drug: Valsartan
    Valsartan 40mg, 80mg and 160mg dosage strengths will be available for dose adjustments.
  • Experimental: LCZ696
    Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of LCZ696 during the double blind period is 200 mg b.i.d.
    Intervention: Drug: LCZ696
  • Active Comparator: Valsartan
    Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of Valsartan during the double blind period is 160 mg b.i.d.
    Intervention: Drug: Valsartan
Rossi A, Gheorghiade M, Triposkiadis F, Solomon SD, Pieske B, Butler J. Left atrium in heart failure with preserved ejection fraction: structure, function, and significance. Circ Heart Fail. 2014 Nov;7(6):1042-9. doi: 10.1161/CIRCHEARTFAILURE.114.001276. Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
4600
March 2019
March 2019   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Left ventricular ejection fraction (LVEF) ≥45% by echo during screening epoch or within 6 months prior to study entry.
  • Symptom(s) of heart failure (HF) and requiring treatment with diuretic(s) for HF at least 30 days prior to study entry.
  • Current symptom(s) of HF
  • Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.
  • Elevated NT-proBNP

Exclusion Criteria:

  • Any prior measurement of LVEF < 40%.
  • Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months , or urgent percutaneous coronary intervention within 3 months or and elective PCI within 30 days prior to entry.
  • Any clinical event within the 6 months prior to entry could have reduced the LVEF (e.g., MI, CABG), unless an echo measurement performed after the event confirms a LVEF ≥45%.
  • Current acute decompensated HF requiring therapy.
  • Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB) or a renin inhibitor.
  • Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dl, or body mass index (BMI) > 40 kg/m2.
  • Systolic blood pressure (SBP) ≥ 180 mmHg at entry, or SBP >150 mmHg and <180 mmHg at entry unless the patient is receiving 3 or more antihypertensive drugs, or SBP < 110 mmHg at entry.

Other protocol-defined inclusion/exclusion criteria may apply.

Both
50 Years and older   (Adult, Senior)
No
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals
United States,   Argentina,   Australia,   Austria,   Belgium,   Brazil,   Bulgaria,   Canada,   China,   Croatia,   Czech Republic,   Denmark,   Finland,   France,   Germany,   Greece,   Guatemala,   Hungary,   India,   Israel,   Italy,   Japan,   Korea, Republic of,   Mexico,   Netherlands,   Norway,   Peru,   Philippines,   Poland,   Romania,   Russian Federation,   Serbia,   Singapore,   Slovakia,   South Africa,   Spain,   Sweden,   Switzerland,   Taiwan,   Turkey,   United Kingdom
Portugal
 
NCT01920711
CLCZ696D2301, 2013-001747-31
Yes
Not Provided
Not Provided
Novartis Pharmaceuticals
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
June 2016

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