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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
  Purpose
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.

Condition Intervention Phase
Heart Failure With Preserved Ejection Fraction
Drug: LCZ696
Drug: Valsartan
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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.


Estimated Enrollment: 4600
Study Start Date: July 2014
Estimated Study Completion Date: March 2019
Estimated Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: LCZ696
LCZ696 50mg, 100mg and 200 mg dosage strengths will be available for dose adjustments.
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.
Drug: Valsartan
Valsartan 40mg, 80mg and 160mg dosage strengths will be available for dose adjustments.

  Eligibility

Ages Eligible for Study:   50 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01920711

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

  Show 800 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01920711     History of Changes
Other Study ID Numbers: CLCZ696D2301  2013-001747-31 
Study First Received: August 8, 2013
Last Updated: June 12, 2016
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Health Products Regulatory Agency
European Union: European Medicines Agency
Japan: Pharmaceuticals and Medical Device Agency
France: National Agency for the Safety and Health Product
Germany: Federal Institute for Drug and Medicinal Devices
Hungary: National Institute of Pharmacy and Nutrition
Italy: Spanish Agency for Medicines and Health Product
China: Food and Drug Administration
Canada: Health Canada
India: Director General of Health Services, Ministry of Health and Family Welfare, Government of India

Keywords provided by Novartis:
Heart failure, preserved ejection fraction, diastolic heart failure

Additional relevant MeSH terms:
Heart Failure
Heart Diseases
Cardiovascular Diseases
Valsartan
LCZ 696
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2016