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

NCT00887588 | Completed Phase 2 Results DMC

• 2 other identifiers: CLCZ696B22142009-010208-27
• Study Type: interventional
• Target: 307
• Locations: 14 countries
• Sites: 81

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.

Conditions

Chronic Heart Failure

Keywords

Chronic heart failure; preserved ejection fraction; cardiovascular disease; NT-proBNP; biomarkers; Heart failure with preserved left-ventricular ejection; fraction

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (23)

• Change From Baseline in NT-proBNP and Brain Natriuretic Peptide (BNP)

  baseline, 36 weeks

• Change From Baseline in Plasma Cyclic Guanine Monophosphate (cGMP)

  baseline, 36 weeks

• 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

  Baseline, 36 weeks

• Change From Baseline in Echocardiography Parameters: LVE Diastolic Volume, LVE Systolic Volume, Left Ventricular Stroke Volume, Left Atrial Volume

  Baseline, 36 weeks

• Change From Baseline in Echocardiography Parameters: Left Ventricular Ejection Fraction

  Baseline, 36 weeks

Study Arms (2)

LCZ696

EXPERIMENTAL

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; Drug: Placebo

Valsartan

ACTIVE COMPARATOR

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; Drug: Placebo

Interventions

LCZ696 DRUG

50 mg, 100 mg and 200 mg tablets

LCZ696

Valsartan DRUG

40 mg, 80 mg and 160 mg tablets

Valsartan

Placebo DRUG

matching placebo to LCZ696 and Valsartan

LCZ696; Valsartan

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (81)

Novartis Investigative Site

Little Rock, Arkansas, 72205, United States

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Chicago, Illinois, 60657, United States

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Detroit, Michigan, 48201, United States

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Grand Island, Nebraska, 68803, United States

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Lincoln, Nebraska, 68506, United States

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Oklahoma City, Oklahoma, 73120, United States

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Tulsa, Oklahoma, 74133, United States

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Hillsboro, Oregon, 97123, United States

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Wyomissing, Pennsylvania, 19610, United States

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Nashville, Tennessee, 37203, United States

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Houston, Texas, 77025, United States

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Caba, Buenos Aires, C1408INH, Argentina

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Ciudad Autonoma de Bs As, Buenos Aires, C1119ACN, Argentina

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Ramos Mejía, Buenos Aires, B1704ETD, Argentina

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San Martín, Buenos Aires, B1650CSQ, Argentina

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Corrientes, Corrientes Province, W3400, Argentina

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Córdoba, Córdoba Province, X5000EPU, Argentina

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Córdoba, Córdoba Province, X5000EVQ, Argentina

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Rosario, Santa Fe Province, S200CVD, Argentina

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Santa Fe, Santa Fe Province, 3000, Argentina

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Santa Fe, Santa Fe Province, S3000FWO, Argentina

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San Miguel de Tucumán, Tucumán Province, T4000EBR, Argentina

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Goiânia, Goiás, 74605-050, Brazil

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Porto Alegre, Rio Grande do Sul, 90610-000, Brazil

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São José do Rio Preto, São Paulo, 15015-750, Brazil

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São Paulo, São Paulo, 05403-000, Brazil

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Brampton, Ontario, L6Z 4N5, Canada

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Montreal, Quebec, H3A 1A1, Canada

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Montreal, Quebec, H3G 1A4, Canada

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Göttingen, D-37075, Germany

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Hyderabad, Andhra Pradesh, 500012, India

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Hyderabad, Andhra Pradesh, India, 500034, India

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Mangalore, Karnataka, 575002, India

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Manipal, Karnataka, 576104, India

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Mumbai, Maharashtra, 400 022, India

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Nagpur, Maharashtra, 44000033, India

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Nagpur, Maharashtra, 440012, India

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New Delhi, National Capital Territory of Delhi, 110060, India

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Jaipur, Rajasthan, 302001, India

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Jaipur, Rajasthan, 302004, India

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Hyderabad, 500 063, India

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Bergamo, BG, 24128, Italy

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Cosenza, CS, 87100, Italy

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Pisa, PI, 56124, Italy

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Casorate Primo, PV, 27022, Italy

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Sarzana, SP, 19038, Italy

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San Daniele del Friuli, UD, 33038, Italy

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Somma Lombardo, VA, 21019, Italy

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Ede, Netherlands, 6716 RP, Netherlands

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Amsterdam, 1105 AZ, Netherlands

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Delft, NL 2625 AD, Netherlands

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Goes, 4462 RA, Netherlands

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Groningen, 9713 GZ, Netherlands

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Heerenveen, 8441 PW, Netherlands

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Heerlen, 6419 PC, Netherlands

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Hengelo, 7555 DL, Netherlands

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Warszawa/Anin, Poland, 04-761, Poland

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Piotrkow Trybunalski, 97-300, Poland

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Sieradz, 98-200, Poland

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Wroclaw, 50-981, Poland

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Wroclaw, 51-124, Poland

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Craiova, Jud. Dolj, 200147, Romania

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Craiova, Jud.Dolj, 200235, Romania

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Baia Mare, 430031, Romania

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Piteşti, 110114, Romania

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Moscow, 117292, Russia

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Moscow, 121552, Russia

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S.-Petersburg, 196247, Russia

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Saint Petersburg, 194044, Russia

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Saint Petersburg, 197341, Russia

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Singapore, Singapore, 119074, Singapore

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Singapore, Singapore, 169609, Singapore

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Seville, Andalusia, 41009, Spain

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L'Hospitalet de Llobregat, Barcelona, 08907, Spain

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A Coruña, Galicia, 15006, Spain

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Santiago de Compostela, Galicia, 15706, Spain

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Novartis Investigative Site

Madrid, Madrid, 28034, Spain

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Madrid, Madrid, 28046, Spain

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Novartis Investigative Site

Alicante, Valencia, 03004, Spain

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Novartis Investigative Site

Caracas, Distrito Federal, 1010, Venezuela

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Novartis Investigative Site

Maracaibo, Zulia, 4011, Venezuela

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Related Publications (9)

• 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.

  PMID: 22932717 BACKGROUND

• Myhre PL, Liu Y, Kulac IJ, Claggett BL, Prescott MF, Felker GM, Butler J, Pina IL, Rouleau JL, Zile MR, McMurray JJV, Ward JH, Solomon SD, Januzzi JL. Changes in mid-regional pro-adrenomedullin during treatment with sacubitril/valsartan. Eur J Heart Fail. 2023 Aug;25(8):1396-1405. doi: 10.1002/ejhf.2957. Epub 2023 Jul 11.

  PMID: 37401523 DERIVED

• Biering-Sorensen T, Lassen MCH, Shah A, Claggett B, Zile M, Pieske B, Pieske-Kraigher E, Voors A, Shi V, Lefkowitz M, Packer M, McMurray JJV, Solomon SD; PARAMOUNT Investigators. The Effect of Sacubitril/Valsartan on Left Ventricular Myocardial Deformation in Heart Failure with Preserved Ejection Fraction (PARAMOUNT trial). J Card Fail. 2023 Jun;29(6):968-973. doi: 10.1016/j.cardfail.2023.03.019. Epub 2023 Apr 7.

  PMID: 37031887 DERIVED

• 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.

  PMID: 30354399 DERIVED

• 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.

  PMID: 26754625 DERIVED

• 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.

  PMID: 26280447 DERIVED

• 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.

  PMID: 25277997 DERIVED

• 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.

  PMID: 25138249 DERIVED

• 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.

  PMID: 24184245 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases

Interventions

sacubitril and valsartan sodium hydrate drug combination; Valsartan

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Valine; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

• Novartis

  Novartis

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2009
• First Posted: April 24, 2009
• Study Start: November 1, 2009
• Primary Completion: December 1, 2011
• Study Completion: December 1, 2011
• Last Updated: August 25, 2015
• Results First Posted: August 13, 2015

Record last verified: 2015-08

Locations

ES (7); BR (4); RU (5); VE (2); NL (8); CA (3); AR (11); IN (11); IT (7); US (11); DE (1); PL (5); RO (4); SG (2)