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

Study Description

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Brief Summary:

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 or disease	Intervention/treatment	Phase
Heart Failure With Preserved Ejection Fraction	Drug: LCZ696; Drug: Valsartan	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	4822 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, 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
Actual Study Start Date :	July 18, 2014
Estimated Primary Completion Date :	March 15, 2019
Estimated Study Completion Date :	March 15, 2019

Arms and Interventions

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Arm	Intervention/treatment
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.

Outcome Measures

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Primary Outcome Measures :

1. 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) ]
   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 :

1. Change in the clinical summary score from baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ) [ Time Frame: Baseline, 8 months ]
   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.
2. Change from baseline to Month 8 in New York Heart Association (NYHA) functional class [ Time Frame: Baseline, 8 months ]
   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.
3. Time to first occurance of a composite renal endpoint [ Time Frame: Total follow up time (up to 57 months) ]

   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
4. Time to all-cause mortality [ Time Frame: Total follow up time (up to 57 months) ]
   Evaluation of the time to all cause death.

Eligibility Criteria

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Ages Eligible for Study:	50 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
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

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Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Mütze T, Glimm E, Schmidli H, Friede T. Group sequential designs with robust semiparametric recurrent event models. Stat Methods Med Res. 2018 Jan 1:962280218780538. doi: 10.1177/0962280218780538. [Epub ahead of print]

Solomon SD, Rizkala AR, Gong J, Wang W, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, Van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Shi VC, Lefkowitz MP, McMurray JJV. Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction: Rationale and Design of the PARAGON-HF Trial. JACC Heart Fail. 2017 Jul;5(7):471-482. doi: 10.1016/j.jchf.2017.04.013. Epub 2017 Jun 26. Review.

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 ( EudraCT Number )
First Posted:	August 12, 2013
Last Update Posted:	June 4, 2018
Last Verified:	May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided
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

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

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