Clinical trial NCT00887588: LCZ696 Compared to Valsartan in Patients With Chronic Heart Failure and Preserved Left-ventricular Ejection Fraction
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Heart Failure
Keywords: Chronic heart failure
preserved ejection fraction
cardiovascular disease
NT-proBNP
biomarkers
Heart failure with preserved left-ventricular ejection
fraction
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-04-24
Enrollment: 307
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility 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

Primary outcomes:
measure: Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
timeFrame: Baseline, 12 weeks
Secondary outcomes:
measure: Change From Baseline in NT-proBNP and Brain Natriuretic Peptide (BNP)
timeFrame: baseline, 36 weeks
measure: Change From Baseline in Plasma Cyclic Guanine Monophosphate (cGMP)
timeFrame: baseline, 36 weeks
measure: 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
timeFrame: Baseline, 36 weeks
measure: Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume
timeFrame: Baseline, 36 weeks
measure: Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction
timeFrame: Baseline, 36 weeks
measure: Change From Baseline in Echocardiography Parameters: Left Ventricular Mass
timeFrame: Baseline, 36 weeks
measure: Change From Baseline in Echocardiography Parameters: Left Ventricular Mass Index
timeFrame: Baseline, 36 weeks
measure: Change From Baseline in Echocardiography Parameters: Left Atrial Volume Index
timeFrame: Baseline, 36 weeks
measure: Change From Baseline in Echocardiography Parameters: Ewave Velocity, A Wave Velocity, e' at Septal Mitral Annulus, e' at Lateral Mitral Annulus
timeFrame: Baseline, 36 weeks
measure: Change From Baseline in Echocardiography Parameters: Ratio of E to A Velocity, E/e' Ratio
timeFrame: Baseline, 36 weeks
measure: Change in Echocardiography Parameters: Isovolumic Relaxation Time
timeFrame: Baseline, 36 weeks
measure: Change From Baseline in Echocardiography Parameters: Tricuspid Regurgitation Velocity
timeFrame: Baseline, 36 weeks
measure: Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score and Individual Domain Summary Scores
timeFrame: baseline, 36 weeks
measure: Percentage of Participants With Clinical Composite Assessment of Improved, Unchanged or Worsened
timeFrame: 36 weeks
measure: Percentage of Participants With New York Heart Association (NYHA) Class I, II, II or IV
timeFrame: baseline, 36 weeks
measure: Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
timeFrame: baseline, 36 weeks
measure: Change From Baseline in Serum Creatinine
timeFrame: baseline, 36 weeks
measure: Change From Baseline in Albumin/Creatinine Ratio
timeFrame: baseline, 36 weeks
measure: 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
timeFrame: baseline, 36 weeks
measure: Change From Baseline in Arterial Stiffness Parameters: Heart Rate Correct Cen Aug/Pulse Ht
timeFrame: baseline, 36 weeks
measure: Change From Baseline in Arterial Stiffness Parameters: Heart Rate
timeFrame: baseline, 36 weeks
measure: Change From Baseline in Arterial Stiffness Parameters: Pulse Wave Velocity
timeFrame: baseline, 36 weeks
measure: Change From Baseline in Sitting SBP, Sitting DBP and Sitting Pulse Pressure (PP)
timeFrame: baseline, 36 weeks
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Novartis Investigative Site
state: Arkansas
city: Chicago
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Detroit
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Grand Island
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Lincoln
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Oklahoma City
country: United States
facility: Novartis Investigative Site
state: Oklahoma
city: Tulsa
country: United States
facility: Novartis Investigative Site
state: Oklahoma
city: Hillsboro
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Wyomissing
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ciudad Autonoma de Bs As
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Ramos Mejia
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: San Martin
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: San Miguel de Tucuman
country: Argentina
facility: Novartis Investigative Site
state: Tucuman
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Corrientes
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Santa Fe
country: Argentina
facility: Novartis Investigative Site
city: Goiania
country: Brazil
facility: Novartis Investigative Site
state: GO
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Sao Jose do Rio Preto
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Brampton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Göttingen
country: Germany
facility: Novartis Investigative Site
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Andhra Pradesh, INDIA
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Andhra Pradesh
city: New Delhi
country: India
facility: Novartis Investigative Site
state: Delhi
city: Mangalore
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Manipal
country: India
facility: Novartis Investigative Site
state: Karnataka
city: Mumbai
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Nagpur
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Nagpur
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Jaipur
country: India
facility: Novartis Investigative Site
state: Rajasthan
city: Jaipur
country: India
facility: Novartis Investigative Site
state: Rajasthan
city: Hyderabad
country: India
facility: Novartis Investigative Site
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Cosenza
country: Italy
facility: Novartis Investigative Site
state: CS
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Casorate Primo
country: Italy
facility: Novartis Investigative Site
state: PV
city: Sarzana
country: Italy
facility: Novartis Investigative Site
state: SP
city: San Daniele Del Friuli
country: Italy
facility: Novartis Investigative Site
state: UD
city: Somma Lombardo
country: Italy
facility: Novartis Investigative Site
state: VA
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Delft
country: Netherlands
facility: Novartis Investigative Site
city: Ede
country: Netherlands
facility: Novartis Investigative Site
city: Goes
country: Netherlands
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Heerenveen
country: Netherlands
facility: Novartis Investigative Site
city: Heerlen
country: Netherlands
facility: Novartis Investigative Site
city: Hengelo
country: Netherlands
facility: Novartis Investigative Site
city: Piotrkow Trybunalski
country: Poland
facility: Novartis Investigative Site
city: Sieradz
country: Poland
facility: Novartis Investigative Site
city: Warszawa/Anin
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Craiova
country: Romania
facility: Novartis Investigative Site
state: Jud. Dolj
city: Craiova
country: Romania
facility: Novartis Investigative Site
state: Jud.Dolj
city: Baia Mare
country: Romania
facility: Novartis Investigative Site
city: Pitesti
country: Romania
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: S.-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Saint-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Hospitalet de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Alicante
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: A Coruna
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Santiago de Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Caracas
country: Venezuela
facility: Novartis Investigative Site
state: Distrito Capital
city: Maracaibo
country: Venezuela
facility: Novartis Investigative Site
state: Estado Zulia
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
affiliation: Novartis
name: Novartis
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Januzzi JL Jr, Packer M, Claggett B, Liu J, Shah AM, Zile MR, Pieske B, Voors A, Gandhi PU, Prescott MF, Shi V, Lefkowitz MP, McMurray JJV, Solomon SD. IGFBP7 (Insulin-Like Growth Factor-Binding Protein-7) and Neprilysin Inhibition in Patients With Heart Failure. Circ Heart Fail. 2018 Oct;11(10):e005133. doi: 10.1161/CIRCHEARTFAILURE.118.005133.
citation: Zile MR, Jhund PS, Baicu CF, Claggett BL, Pieske B, Voors AA, Prescott MF, Shi V, Lefkowitz M, McMurray JJ, Solomon SD; Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) Investigators. Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction: Data From the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Study. Circ Heart Fail. 2016 Jan;9(1):e002551. doi: 10.1161/CIRCHEARTFAILURE.115.002551.
citation: Andersen MB, Simonsen U, Wehland M, Pietsch J, Grimm D. LCZ696 (Valsartan/Sacubitril)--A Possible New Treatment for Hypertension and Heart Failure. Basic Clin Pharmacol Toxicol. 2016 Jan;118(1):14-22. doi: 10.1111/bcpt.12453. Epub 2015 Sep 4.
citation: Jhund PS, Claggett BL, Voors AA, Zile MR, Packer M, Pieske BM, Kraigher-Krainer E, Shah AM, Prescott MF, Shi V, Lefkowitz M, McMurray JJ, Solomon SD; PARAMOUNT Investigators. Elevation in high-sensitivity troponin T in heart failure and preserved ejection fraction and influence of treatment with the angiotensin receptor neprilysin inhibitor LCZ696. Circ Heart Fail. 2014 Nov;7(6):953-9. doi: 10.1161/CIRCHEARTFAILURE.114.001427. Epub 2014 Oct 2.
citation: Santos AB, Kraigher-Krainer E, Gupta DK, Claggett B, Zile MR, Pieske B, Voors AA, Lefkowitz M, Bransford T, Shi V, Packer M, McMurray JJ, Shah AM, Solomon SD; PARAMOUNT Investigators. Impaired left atrial function in heart failure with preserved ejection fraction. Eur J Heart Fail. 2014 Oct;16(10):1096-103. doi: 10.1002/ejhf.147. Epub 2014 Aug 19.
citation: Kraigher-Krainer E, Shah AM, Gupta DK, Santos A, Claggett B, Pieske B, Zile MR, Voors AA, Lefkowitz MP, Packer M, McMurray JJ, Solomon SD; PARAMOUNT Investigators. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014 Feb 11;63(5):447-56. doi: 10.1016/j.jacc.2013.09.052. Epub 2013 Oct 30.