Brief Summary
The purpose of this study was 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.
Brief Title
Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction
Detailed Description
This was a multicenter, randomized, double-blind, parallel group, active-controlled, study to evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan, on morbidity and mortality in heart failure patients (NYHA Class II-IV) with preserved ejection fraction. Specifically, the study evaluated the effect of sacubitril/valsartan compared to the active comparator valsartan in the reduction of the rate of CV death and total HF hospitalizations in patients with HFpEF. The trial consisted of two periods: (1) a single-blind treatment run-in epoch that lasted from 3 to 8 weeks, in which patients received valsartan 80 mg bid, followed by sacubitril/valsartan 100 mg bid and (2) a double-blind randomized treatment epoch (sacubitril/valsartan 200 mg bid or valsartan 160 mg bid). In this study, investigators were responsible for assessing and submitting all events which could potentially fulfill the criteria for the primary, secondary, or other clinical endpoints to a Clinical Endpoint Committee (CEC). Investigator reported events were assessed by the CEC for adjudication.
For angioedema or angioedema-like events, investigators completed an Adjudication Questionnaire for an Angioedema-like Event form. All angioedema reports were forwarded to an Angioedema Adjudication Committee (AAC) by Novartis for assessment.
For angioedema or angioedema-like events, investigators completed an Adjudication Questionnaire for an Angioedema-like Event form. All angioedema reports were forwarded to an Angioedema Adjudication Committee (AAC) by Novartis for assessment.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Heart Failure With Preserved Ejection Fraction
Eligibility 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 (NYHA class II-IV)
* 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.
* 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 (NYHA class II-IV)
* 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.
Inclusion 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 (NYHA class II-IV)
* Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.
* Elevated NT-proBNP
inclusion/
* 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 (NYHA class II-IV)
* Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.
* Elevated NT-proBNP
inclusion/
Gender
All
Gender Based
false
Keywords
Heart failure
preserved ejection fraction
diastolic heart failure
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
50 Years
NCT Id
NCT01920711
Org Class
Industry
Org Full Name
Novartis
Org Study Id
CLCZ696D2301
Overall Status
Completed
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
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 (PARAGON-HF)
Primary Outcomes
Outcome Description
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.
Outcome Measure
Cumulative Number of Primary Composite Events of Cardiovascular (CV) Death and Total (First and Recurrent) HF Hospitalizations.
Outcome Time Frame
Total follow up time (up to 57 months)
Secondary Ids
Secondary Id
2013-001747-31
Secondary Outcomes
Outcome Description
The KCCQ is a validated instrument for self-assessment of quality of life and health status in heart failure (HF) patients. The clinical summary score, which is derived from the physical limitations and heart failure (HF) symptoms domains of the KCCQ is a valid measure for assessing the patient's health aspects that may be influenced by CV medications. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. 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.
Outcome Time Frame
Baseline, 8 months
Outcome Measure
Change in the Clinical Summary Score From Baseline to Month 8 by Kansas City Cardiomyopathy Questionnaire (KCCQ)
Outcome Description
Evaluation of change from baseline to Month 8 in NYHA functional class, a well established grading scale used to classify a heart failure's (HF) patients' level of functionality based on the signs and symptoms of HF exhibited by the patient.
Outcome Time Frame
Baseline, 8 months
Outcome Measure
Change From Baseline to Month 8 in New York Heart Association (NYHA) Functional Class
Outcome Description
Analyis of composite renal endpoint defined as renal death, or reaching ESRD, or ≥50% decline in eGFR relative to baseline, using Cox's proportional hazards model.
Outcome Time Frame
Randomization to total follow-up time (up to 57 months)
Outcome Measure
Participants With First Occurrence of a Composite Renal Endpoint
Outcome Description
Analysis for all-cause mortality using Cox's proportional hazards model.
Outcome Time Frame
Randomization to total follow up time (up to 57 months)
Outcome Measure
All-cause Mortality
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
50
Investigators
Investigator Type
Principal Investigator
Investigator Name
Sandhya Murthy
Investigator Email
smurthy@montefiore.org
Investigator Phone
718-904-3507
Categories Mesh Debug
Heart/Cardiovascular --- HEART FAILURE
Brain, Spinal Cord & Nervous System --- HEART DISEASES
Heart/Cardiovascular --- HEART DISEASES
Blood Disorders --- CARDIOVASCULAR DISEASES
Blood & Bone Marrow Cancers --- CARDIOVASCULAR DISEASES
Heart/Cardiovascular --- CARDIOVASCULAR DISEASES
MeSH Terms
HEART FAILURE
HEART FAILURE, DIASTOLIC
HEART DISEASES
CARDIOVASCULAR DISEASES
SACUBITRIL AND VALSARTAN SODIUM HYDRATE DRUG COMBINATION
VALSARTAN
TETRAZOLES
AZOLES
HETEROCYCLIC COMPOUNDS, 1-RING
HETEROCYCLIC COMPOUNDS
VALINE
AMINO ACIDS, BRANCHED-CHAIN
AMINO ACIDS
AMINO ACIDS, PEPTIDES, AND PROTEINS
AMINO ACIDS, ESSENTIAL