LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00887588
First received: April 22, 2009
Last updated: August 12, 2015
Last verified: August 2015
  Purpose

The study will assess the effects of 36 weeks of treatment with LCZ696 compared to valsartan on N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) in patients with chronic heart failure and preserved left-ventricular ejection fraction.


Condition Intervention Phase
Chronic Heart Failure
Drug: LCZ696
Drug: Valsartan
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A 36-week, Randomized, Double-blind, Multi-center, Parallel Group, Active Controlled Study to Evaluate the Efficacy, Safety and Tolerability of LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) [ Time Frame: Baseline, 12 weeks ] [ Designated as safety issue: No ]
    Evaluation of NT-proBNP was performed by a central laboratory. Change from baseline in NT-proBNP was presented as a ratio where the ratio was calculated as the NT-proBNP value at 12 weeks over the NT-proBNP value at baseline. A ratio < 1 indicates improvement.


Secondary Outcome Measures:
  • Change From Baseline in NT-proBNP and Brain Natriuretic Peptide (BNP) [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    Evaluation of NT-proBNP and BNP was performed by a central laboratory. Change from baseline in NT-proBNP and in BNP was presented as a ratio where the ratio for NT-proBNP was calculated as the NT-proBNP value at 36 weeks over the NT-proBNP value at baseline, and the ratio for BNP was calculated as the BNP value at 36 weeks over the BNP value at baseline. A ratio < 1 indicates improvement.

  • Change From Baseline in Plasma Cyclic Guanine Monophosphate (cGMP) [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    Evaluation of cGMP was performed by a central laboratory. Change from baseline in cGMP was presented as a ratio where the ratio was calculated as the cGMP value at 36 weeks over the cGMP value at baseline. A ratio < 1 indicates improvement.

  • Change From Baseline in Echocardiography (ECHO) Parameters: Left Ventricular End (LVE) Diastolic Diameter, LVE Systolic Diameter, Septal End Diastolic Thickness, Posterior LV Wall End Diastolic Thickness, Relative Wall Thickness, Left Atrial Dimension [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

  • Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

  • Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

  • Change From Baseline in Echocardiography Parameters: Left Ventricular Mass [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

  • Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

  • Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

  • Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

  • Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A ratio < 1 indicates improvement.

  • Change in Echocardiography Parameters: Isovolumic Relaxation Time [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

  • Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity [ Time Frame: Baseline, 36 weeks ] [ Designated as safety issue: No ]
    A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.

  • Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    The KCCQ is a self-administered questionnaire. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and quality of life, each with different Likert scale wording, including limitations, frequency, bother, change in condition, understanding, levels of enjoyment and satisfaction. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. A positive change from baseline indicates improvement.

  • Percentage of Participants With Clinical Composite Assessment of Improved, Unchanged or Worsened [ Time Frame: 36 weeks ] [ Designated as safety issue: No ]
    The clinical composite assessment is defined as follows: Improved = a) participant improved (markedly or moderately) in the global assessment of disease activity with no worsening of NYHA functional class and no major adverse cardiovascular event or b) participant improved in NYHA functional class with no worsening (markedly or moderately) in the global assessment of disease activity and no major adverse cardiovascular event. Worsened = participant worsened (markedly or moderately) in the global assessment of disease activity or in NYHA functional class or experienced a major adverse cardiovascular event. Unchanged = participant does not meet the definition for improved or worsened.

  • Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    The NYHA Functional Classification classifies patients' heart failure according to the severity of their symptoms. The classification is as follows: Class I: no limitation of physical activity, ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath); Class II: slight limitation to physical activity, comfortable at rest, ordinary physical activity results in fatigue, palpitation or dyspnea; Class III: marked limitation of physical activity, comfortable at rest, less than ordinary activity causes fatigue, palpitation or dyspnea; Class IV: unable to carry on any physical activity without discomfort, symptoms of heart failure at rest, if any physical activity is undertaken, discomfort increases.

  • Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    eGFR was calculated from the serum creatinine concentration determined by central laboratory assessment. A positive change from baseline indicates improvement.

  • Change From Baseline in Serum Creatinine [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    Evaluation of serum creatinine was performed by central laboratory. A negative change from baseline indicates improvement.

  • Change From Baseline in Albumin/Creatinine Ratio [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    Evaluation of albumin/creatinine was performed by central laboratory. A ratio < 1 indicates improvement.

  • Change From Baseline in Arterial Stiffness Parameters: Brachial Systolic Blood Pressure (SBP), Brachial Diastolic Blood Pressure (DBP), Central Augmentation Pressure, Central Pressure at T1-DP, Central SBP, Central DBP, Central Mean Pressure [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement.

  • Change From Baseline in Arterial Stiffness Parameters: Heart Rate Correct Cen Aug/Pulse Ht [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement.

  • Change From Baseline in Arterial Stiffness Parameters: Heart Rate [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement.

  • Change From Baseline in Arterial Stiffness Parameters: Pulse Wave Velocity [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    A vascular arterial stiffness sub-study was conducted in a subset of participants. Noninvasive arterial tonometry was assessed using the Sphygmor device. Participants had arterial stiffness, pulse wave velocity and central pressures measured. A negative change from baseline indicates improvement.

  • Change From Baseline in Sitting SBP, Sitting DBP and Sitting Pulse Pressure (PP) [ Time Frame: baseline, 36 weeks ] [ Designated as safety issue: No ]
    Sitting blood pressure and sitting pulse pressure were assessed. A negative change from baseline indicates improvement.


Enrollment: 307
Study Start Date: November 2009
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LCZ696
During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 50 mg LCZ696 for 1- 2 weeks, then uptitrated to 100 mg bid for 1 -2 weeks, and thereafter, uptitrated to 200 mg bid.
Drug: LCZ696
50 mg, 100 mg and 200 mg tablets
Drug: Placebo
matching placebo to LCZ696 and Valsartan
Active Comparator: Valsartan
During a single blind, run-in period, participants received placebo. Then at randomization (double blind treatment period), participants started with 40 mg Valsartan twice daily (bid) for 1 - 2 weeks, then were uptitrated to 80 mg bid for 1 -2 weeks, and thereafter, uptitrated to 160 mg bid.
Drug: Valsartan
40 mg, 80 mg and 160 mg tablets
Drug: Placebo
matching placebo to LCZ696 and Valsartan

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with documented stable chronic heart failure (NYHA II-IV):

    • LVEF ≥ 45% (local measurement, assessed by echocardiography, MUGA, CT scan, MRI or ventricular angiography)
    • the ejection fraction must have been obtained within 6 months prior to randomization or after any MI or other event that would affect ejection fraction.
  • Plasma NT-proBNP > 500 pg/ml at Visit 1.
  • Patients with documented stable chronic heart failure (NYHA II-IV).
  • Patients receiving ACE inhibitors (ACEi), an angiotensin receptor blockers (ARB) and/or a beta blockers must be on a stable dose of these medications stable for the 1 month period prior to Visit 1.
  • Patients must be on diuretic therapy prior to Visit 1 (flexible dosing is permitted).
  • Patients with a controlled systolic BP, defined as a target systolic BP less than 140 mm Hg; participants with BP up to and including 160 mm Hg are eligible for enrollment if they are on three or more medications to control BP at randomization (Visit 2).
  • Patients with at least one of the following symptoms at the time of screening (Visit 1):

    • Dyspnea on exertion
    • Orthopnea
    • Paroxysmal nocturnal dyspnea
    • Peripheral edema
  • Patients must have an eGFR ≥ 30 ml/min/1.73 m2 at Visit 1 (calculated by the Modification of Diet in Renal Disease formula).
  • Patients with a potassium ≤5.2 mmol/l at Visit 1.

Exclusion Criteria:

  • Patients with a prior LVEF reading <45%, at any time.
  • Patients who require treatment with both an ACE inhibitor and an ARB.
  • Isolated right heart failure due to pulmonary disease.
  • Dyspnea and/or edema from non-cardiac causes, such as lung disease, anemia, or severe obesity.
  • Presence of hemodynamically significant mitral and /or aortic valve disease.
  • Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis.
  • Presence of hypertrophic obstructive cardiomyopathy.
  • 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: NCT00887588

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Locations
United States, Arkansas
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Little Rock, Arkansas, United States, 72205
United States, Illinois
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Chicago, Illinois, United States, 60657
United States, Michigan
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Detroit, Michigan, United States, 48201
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Grand Island, Nebraska, United States, 68803
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Lincoln, Nebraska, United States, 68506
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Oklahoma City, Oklahoma, United States, 73120
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Tulsa, Oklahoma, United States, 74133
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Hillsboro, Oregon, United States, 97123
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Wyomissing, Pennsylvania, United States, 19610
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Nashville, Tennessee, United States, 37203
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Houston, Texas, United States, 77025
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Caba, Buenos Aires, Argentina, C1408INH
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Göttingen, Germany, D-37075
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Hyderabad, Andhra Pradesh, INDIA, India, 500034
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Hyderabad, India, 500 063
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Bergamo, BG, Italy, 24128
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Cosenza, CS, Italy, 87100
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Amsterdam, Netherlands, 1105 AZ
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Delft, Netherlands, NL 2625 AD
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Ede, Netherlands, 6716 RP
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Groningen, Netherlands, 9713 GZ
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Hengelo, Netherlands, 7555 DL
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Piotrkow Trybunalski, Poland, 97-300
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Sieradz, Poland, 98-200
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Craiova, Jud. Dolj, Romania, 200147
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Craiova, Jud.Dolj, Romania, 200235
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Baia Mare, Romania, 430031
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Pitesti, Romania, 110114
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Moscow, Russian Federation, 117292
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Moscow, Russian Federation, 121552
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S.-Petersburg, Russian Federation, 196247
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Saint-Petersburg, Russian Federation, 194044
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Saint-Petersburg, Russian Federation, 197341
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Singapore, Singapore, 169609
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Singapore, Singapore, 119074
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Sevilla, Andalucia, Spain, 41009
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Hospitalet de Llobregat, Barcelona, Spain, 08907
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Alicante, Comunidad Valenciana, Spain, 03004
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A Coruna, Galicia, Spain, 15006
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Santiago de Compostela, Galicia, Spain, 15706
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Madrid, Spain, 28034
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Madrid, Spain, 28046
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Caracas, Distrito Capital, Venezuela, 1010
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Maracaibo, Estado Zulia, Venezuela, 4011
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Study Director: Novartis Novartis
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00887588     History of Changes
Other Study ID Numbers: CLCZ696B2214, 2009-010208-27
Study First Received: April 22, 2009
Results First Received: July 16, 2015
Last Updated: August 12, 2015
Health Authority: United States: Food and Drug Administration
Argentina: Ministry of Health
Brazil: Ministry of Health
Canada: Health Canada
India: Ministry of Health
Italy: Ministry of Health
Netherlands: Medicines Evaluation Board (MEB)
Poland: Ministry of Health
Romania: Ministry of Public Health
Russia: Pharmacological Committee, Ministry of Health
Singapore: Health Sciences Authority
Spain: Ministry of Health
Venezuela: Ministry of Health and Social Development
Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Novartis:
Chronic heart failure
preserved ejection fraction
cardiovascular disease
NT-proBNP
biomarkers
Heart failure with preserved left-ventricular ejection
fraction

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

ClinicalTrials.gov processed this record on August 27, 2015