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

Chronic Heart Failure Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00887588
• Other study ID #: CLCZ696B2214
• Secondary ID: 2009-010208-27
• Status: Completed
• Phase: Phase 2
• First received: April 22, 2009
• Last updated: August 12, 2015
• Start date: November 2009
• Est. completion date: December 2011

Study information

• Verified date: August 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Ministry of HealthBrazil: Ministry of HealthCanada: Health CanadaIndia: Ministry of HealthItaly: Ministry of HealthNetherlands: Medicines Evaluation Board (MEB)Poland: Ministry of HealthRomania: Ministry of Public HealthRussia: Pharmacological Committee, Ministry of HealthSingapore: Health Sciences AuthoritySpain: Ministry of HealthVenezuela: Ministry of Health and Social DevelopmentGermany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 307
• Est. completion date: December 2011
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Heart Failure
• Heart Failure

Intervention

Drug:
• LCZ696
50 mg, 100 mg and 200 mg tablets
• Valsartan
40 mg, 80 mg and 160 mg tablets
• Placebo
matching placebo to LCZ696 and Valsartan

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad Autonoma de Bs As	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	Ramos Mejia	Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	San Martin	Buenos Aires
Argentina	Novartis Investigative Site	San Miguel de Tucuman	Tucuman
Argentina	Novartis Investigative Site	Santa Fe
Argentina	Novartis Investigative Site	Santa Fe
Brazil	Novartis Investigative Site	Goiania	GO
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Sao Jose do Rio Preto	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Brampton	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Germany	Novartis Investigative Site	Göttingen
India	Novartis Investigative Site	Hyderabad	Andhra Pradesh, INDIA
India	Novartis Investigative Site	Hyderabad	Andhra Pradesh
India	Novartis Investigative Site	Hyderabad
India	Novartis Investigative Site	Jaipur	Rajasthan
India	Novartis Investigative Site	Jaipur	Rajasthan
India	Novartis Investigative Site	Mangalore	Karnataka
India	Novartis Investigative Site	Manipal	Karnataka
India	Novartis Investigative Site	Mumbai	Maharashtra
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	Nagpur	Maharashtra
India	Novartis Investigative Site	New Delhi	Delhi
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Casorate Primo	PV
Italy	Novartis Investigative Site	Cosenza	CS
Italy	Novartis Investigative Site	Pisa	PI
Italy	Novartis Investigative Site	San Daniele Del Friuli	UD
Italy	Novartis Investigative Site	Sarzana	SP
Italy	Novartis Investigative Site	Somma Lombardo	VA
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Delft
Netherlands	Novartis Investigative Site	Ede
Netherlands	Novartis Investigative Site	Goes
Netherlands	Novartis Investigative Site	Groningen
Netherlands	Novartis Investigative Site	Heerenveen
Netherlands	Novartis Investigative Site	Heerlen
Netherlands	Novartis Investigative Site	Hengelo
Poland	Novartis Investigative Site	Piotrkow Trybunalski
Poland	Novartis Investigative Site	Sieradz
Poland	Novartis Investigative Site	Warszawa/Anin
Poland	Novartis Investigative Site	Wroclaw
Poland	Novartis Investigative Site	Wroclaw
Romania	Novartis Investigative Site	Baia Mare
Romania	Novartis Investigative Site	Craiova	Jud. Dolj
Romania	Novartis Investigative Site	Craiova	Jud.Dolj
Romania	Novartis Investigative Site	Pitesti
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	S.-Petersburg
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Singapore	Novartis Investigative Site	Singapore
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	A Coruna	Galicia
Spain	Novartis Investigative Site	Alicante	Comunidad Valenciana
Spain	Novartis Investigative Site	Hospitalet de Llobregat	Barcelona
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Sevilla	Andalucia
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Detroit	Michigan
United States	Novartis Investigative Site	Grand Island	Nebraska
United States	Novartis Investigative Site	Hillsboro	Oregon
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Lincoln	Nebraska
United States	Novartis Investigative Site	Little Rock	Arkansas
United States	Novartis Investigative Site	Nashville	Tennessee
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Novartis Investigative Site	Tulsa	Oklahoma
United States	Novartis Investigative Site	Wyomissing	Pennsylvania
Venezuela	Novartis Investigative Site	Caracas	Distrito Capital
Venezuela	Novartis Investigative Site	Maracaibo	Estado Zulia

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Venezuela,  Argentina,  Brazil,  Canada,  Germany,  India,  Italy,  Netherlands,  Poland,  Romania,  Russian Federation,  Singapore,  Spain, 

References & Publications (1)

Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ; Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012 Oct 20;380(9851):1387-95. doi: 10.1016/S0140-6736(12)61227-6. Epub 2012 Aug 26. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)	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.	Baseline, 12 weeks	No
Secondary	Change From Baseline in NT-proBNP and Brain Natriuretic Peptide (BNP)	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.	baseline, 36 weeks	No
Secondary	Change From Baseline in Plasma Cyclic Guanine Monophosphate (cGMP)	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.	baseline, 36 weeks	No
Secondary	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	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.	Baseline, 36 weeks	No
Secondary	Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.	Baseline, 36 weeks	No
Secondary	Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.	Baseline, 36 weeks	No
Secondary	Change From Baseline in Echocardiography Parameters: Left Ventricular Mass	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.	Baseline, 36 weeks	No
Secondary	Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.	Baseline, 36 weeks	No
Secondary	Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.	Baseline, 36 weeks	No
Secondary	Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.	Baseline, 36 weeks	No
Secondary	Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A ratio < 1 indicates improvement.	Baseline, 36 weeks	No
Secondary	Change in Echocardiography Parameters: Isovolumic Relaxation Time	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.	Baseline, 36 weeks	No
Secondary	Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity	A limited two-dimensional and Doppler ECHO examination was done to assess ECHO parameters. A negative change from baseline indicates improvement.	Baseline, 36 weeks	No
Secondary	Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores	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.	baseline, 36 weeks	No
Secondary	Percentage of Participants With Clinical Composite Assessment of Improved, Unchanged or Worsened	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.	36 weeks	No
Secondary	Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV	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.	baseline, 36 weeks	No
Secondary	Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)	eGFR was calculated from the serum creatinine concentration determined by central laboratory assessment. A positive change from baseline indicates improvement.	baseline, 36 weeks	No
Secondary	Change From Baseline in Serum Creatinine	Evaluation of serum creatinine was performed by central laboratory. A negative change from baseline indicates improvement.	baseline, 36 weeks	No
Secondary	Change From Baseline in Albumin/Creatinine Ratio	Evaluation of albumin/creatinine was performed by central laboratory. A ratio < 1 indicates improvement.	baseline, 36 weeks	No
Secondary	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	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.	baseline, 36 weeks	No
Secondary	Change From Baseline in Arterial Stiffness Parameters: Heart Rate Correct Cen Aug/Pulse Ht	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.	baseline, 36 weeks	No
Secondary	Change From Baseline in Arterial Stiffness Parameters: Heart Rate	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.	baseline, 36 weeks	No
Secondary	Change From Baseline in Arterial Stiffness Parameters: Pulse Wave Velocity	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.	baseline, 36 weeks	No
Secondary	Change From Baseline in Sitting SBP, Sitting DBP and Sitting Pulse Pressure (PP)	Sitting blood pressure and sitting pulse pressure were assessed. A negative change from baseline indicates improvement.	baseline, 36 weeks	No