Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction - Full Text View

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:

MedlinePlus related topics: Heart Failure

Drug Information available for: Valsartan

U.S. FDA Resources

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.

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

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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):

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.


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 23, 2016

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