Personalised Prospective Comparison of ARni With ArB in Patients With Natriuretic Peptide eLEvation

NCT04687111 | Unknown Phase 2 DMC

• 2 other identifiers: HBT-PTCL-01, SVUH-2015-0022015-002928-53
• Study Type: interventional
• Target: 250
• Locations: 1 country
• Sites: 2

Brief Summary

Sacubitril-valsartan, an Angiotensin Receptor Blocker-Neprilysin Inhibitor (ARNI), currently marketed for the management of heart failure, has been shown to reduce cardiovascular morbidity and mortality in stage C heart failure with reduced ejection fraction. In stage C HFpEF, sacubitril-valsartan has also been shown to reduce left atrial volume index measured using echocardiography over a 9 month timeframe. The PARABLE study investigates the hypothesis that sacubitril-valsartan can provide benefits in terms of left atrial structure and function as well as left ventricular structure and function in asymptomatic (stage A/B HFpEF) patients. This is a prospective, randomised, double-blind, double-dummy, phase II study design. The patient population will have hypertension and/or diabetes together with preserved ejection fraction, elevated natriuretic peptide (NP) and abnormal left atrial volume index (LAVI, \> 28 mL/m2).

Conditions

Atrial Remodeling; Myocardial Dysfunction; Left Ventricular Remodeling; Left Ventricular Diastolic Dysfunction; Hypertension; Cardiovascular Morbidity; Fibrosis Myocardial; Inflammatory Myopathy; Atrial Arrhythmia

Keywords

Natriuretic peptide; Atrial remodelling; Atrial cardiomyopathy; Asymptomatic left ventricular diastolic dysfunction; Preserved ejection fraction; Myocardial fibrosis; Myocardial inflammation; Ventricular dysfunction

Outcome Measures

Primary Outcomes (1)

• Change in Left Atrial Volume Index (LAV/BSA*)

  Measured as left atrial volume (Simpson's method, using a stack of short axis slices across the entire left atrium) indexed to body surface area (\*DuBois formula) using Cardiac Magnetic Resonance Imaging (cardiac MRI).

  Baseline-18 months

Secondary Outcomes (10)

• Change in left ventricular function (E/e')

  Baseline -18 months

• Change in left atrial volume index (LAV/BSA*)

  Baseline - 9 months

• Change in left atrial function measured as total left atrial ejection fraction (LAEF)

  Baseline -18 months

• Change in left atrial function measured as left atrial stroke volume index

  Baseline -18 months

• Change in left ventricular structure measured as LVMi

  Baseline -18 months

Study Arms (2)

Control

ACTIVE COMPARATOR

Valsartan 40mg bid titrated to maximum dose of 160mg bid

Drug: Valsartan

Intervention

EXPERIMENTAL

Sacubitril/Valsartan 50mg bid titrated to maximum dose of 200mg bid

Drug: Sacubitril-Valsartan

Interventions

Sacubitril-Valsartan DRUG

Sacubitril-Valsartan is an Angiotensin Receptor blocker and Neprilysin Inhibitor

Also known as: LCZ696, Entresto

Intervention

Valsartan DRUG

Valsartan is an Angiotensin Receptor Blocker

Control

Eligibility Criteria

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

You may qualify if:

• Age \> 40yrs with cardiovascular risk factor(s) including at least one of:
• History of hypertension (medicated for greater than one month);
• History of diabetes;
• Elevated NP: Elevated NP: BNP between 20 and 280pg/ml or NT-proBNP values between 100 pg/ml and 1,000 pg/ml within 6 months prior to screening or at screening
• LAVI \> 28 mL/m2 obtained during Doppler Echocardiography within 6 months prior to screening or at screening
• Subjects must give written informed consent to participate in the study and before any study related assessments are performed.

You may not qualify if:

• A history of heart failure.
• Asymptomatic left ventricular systolic dysfunction defined as LVEF \<50% on most recent measurement.
• Systolic blood pressure \<100mmHg
• Persistent atrial fibrillation.
• History of hypersensitivity, allergy or intolerance to LCZ696, ARB or neprilysin therapy or to any of the excipients or other contraindication to their use.
• Previous history of intolerance to recommended target doses for ARBs
• Subjects who require treatment with both an ACE inhibitor and an ARB
• Presence of haemodynamically significant mitral and /or aortic valve disease.
• Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis.
• Conditions that are expected to compromise survival over the study period.
• Serum potassium level \> 5.2 mmol/L at screening.
• Severe renal insufficiency (eGFR \<30 mL per minute per 1.73 m2).
• Hepatic dysfunction (Any LFT \> 3 times the upper limit of normal (ULN))
• Concomitant use of aliskiren
• History of angioedema.

Sponsors & Collaborators

• Mark Ledwidge: lead
• The Heartbeat Trust: collaborator

Study Sites (2)

The STOP-HF Service, St Michael's Hosptial

Dún Laoghaire, Co Dublin, Ireland

Location

St Vincents University Hospital

Dublin, Dublin 4, Ireland

Location

Related Publications (17)

• Ledwidge M, Gallagher J, Conlon C, Tallon E, O'Connell E, Dawkins I, Watson C, O'Hanlon R, Bermingham M, Patle A, Badabhagni MR, Murtagh G, Voon V, Tilson L, Barry M, McDonald L, Maurer B, McDonald K. Natriuretic peptide-based screening and collaborative care for heart failure: the STOP-HF randomized trial. JAMA. 2013 Jul 3;310(1):66-74. doi: 10.1001/jama.2013.7588.

  PMID: 23821090 BACKGROUND

• Huelsmann M, Neuhold S, Resl M, Strunk G, Brath H, Francesconi C, Adlbrecht C, Prager R, Luger A, Pacher R, Clodi M. PONTIAC (NT-proBNP selected prevention of cardiac events in a population of diabetic patients without a history of cardiac disease): a prospective randomized controlled trial. J Am Coll Cardiol. 2013 Oct 8;62(15):1365-72. doi: 10.1016/j.jacc.2013.05.069. Epub 2013 Jun 27.

  PMID: 23810874 BACKGROUND

• Phelan D, Watson C, Martos R, Collier P, Patle A, Donnelly S, Ledwidge M, Baugh J, McDonald K. Modest elevation in BNP in asymptomatic hypertensive patients reflects sub-clinical cardiac remodeling, inflammation and extracellular matrix changes. PLoS One. 2012;7(11):e49259. doi: 10.1371/journal.pone.0049259. Epub 2012 Nov 12.

  PMID: 23152884 BACKGROUND

• Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006 Feb;27(1):47-72. doi: 10.1210/er.2005-0014. Epub 2005 Nov 16.

  PMID: 16291870 BACKGROUND

• Gardner DG, Chen S, Glenn DJ, Grigsby CL. Molecular biology of the natriuretic peptide system: implications for physiology and hypertension. Hypertension. 2007 Mar;49(3):419-26. doi: 10.1161/01.HYP.0000258532.07418.fa. Epub 2007 Feb 5. No abstract available.

  PMID: 17283251 BACKGROUND

• Hogg K, Swedberg K, McMurray J. Heart failure with preserved left ventricular systolic function; epidemiology, clinical characteristics, and prognosis. J Am Coll Cardiol. 2004 Feb 4;43(3):317-27. doi: 10.1016/j.jacc.2003.07.046.

  PMID: 15013109 BACKGROUND

• Querejeta R, Lopez B, Gonzalez A, Sanchez E, Larman M, Martinez Ubago JL, Diez J. Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation. 2004 Sep 7;110(10):1263-8. doi: 10.1161/01.CIR.0000140973.60992.9A. Epub 2004 Aug 16.

  PMID: 15313958 BACKGROUND

• Martos R, Baugh J, Ledwidge M, O'Loughlin C, Conlon C, Patle A, Donnelly SC, McDonald K. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation. 2007 Feb 20;115(7):888-95. doi: 10.1161/CIRCULATIONAHA.106.638569. Epub 2007 Feb 5.

  PMID: 17283265 BACKGROUND

• Ahmed SH, Clark LL, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, McClure CD, Spinale FG, Zile MR. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation. 2006 May 2;113(17):2089-96. doi: 10.1161/CIRCULATIONAHA.105.573865. Epub 2006 Apr 24.

  PMID: 16636176 BACKGROUND

• Nishikimi T, Maeda N, Matsuoka H. The role of natriuretic peptides in cardioprotection. Cardiovasc Res. 2006 Feb 1;69(2):318-28. doi: 10.1016/j.cardiores.2005.10.001. Epub 2005 Nov 10.

  PMID: 16289003 BACKGROUND

• 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

• Watson CJ, Glezeva N, Horgan S, Gallagher J, Phelan D, McDonald K, Tolan M, Baugh J, Collier P, Ledwidge M. Atrial Tissue Pro-Fibrotic M2 Macrophage Marker CD163+, Gene Expression of Procollagen and B-Type Natriuretic Peptide. J Am Heart Assoc. 2020 Jun 2;9(11):e013416. doi: 10.1161/JAHA.119.013416. Epub 2020 May 20.

  PMID: 32431194 BACKGROUND

• Januzzi JL Jr, Prescott MF, Butler J, Felker GM, Maisel AS, McCague K, Camacho A, Pina IL, Rocha RA, Shah AM, Williamson KM, Solomon SD; PROVE-HF Investigators. Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction. JAMA. 2019 Sep 17;322(11):1085-1095. doi: 10.1001/jama.2019.12821.

  PMID: 31475295 BACKGROUND

• Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Dungen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP; PARAGON-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620. doi: 10.1056/NEJMoa1908655. Epub 2019 Sep 1.

  PMID: 31475794 BACKGROUND

• Ibrahim NE, McCarthy CP, Shrestha S, Gaggin HK, Mukai R, Szymonifka J, Apple FS, Burnett JC Jr, Iyer S, Januzzi JL Jr. Effect of Neprilysin Inhibition on Various Natriuretic Peptide Assays. J Am Coll Cardiol. 2019 Mar 26;73(11):1273-1284. doi: 10.1016/j.jacc.2018.12.063.

  PMID: 30898202 BACKGROUND

• Shah SJ, Katz DH, Selvaraj S, Burke MA, Yancy CW, Gheorghiade M, Bonow RO, Huang CC, Deo RC. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015 Jan 20;131(3):269-79. doi: 10.1161/CIRCULATIONAHA.114.010637. Epub 2014 Nov 14.

  PMID: 25398313 BACKGROUND

• Ledwidge M, Dodd JD, Ryan F, Sweeney C, McDonald K, Fox R, Shorten E, Zhou S, Watson C, Gallagher J, McVeigh N, Murphy DJ, McDonald K. Effect of Sacubitril/Valsartan vs Valsartan on Left Atrial Volume in Patients With Pre-Heart Failure With Preserved Ejection Fraction: The PARABLE Randomized Clinical Trial. JAMA Cardiol. 2023 Apr 1;8(4):366-375. doi: 10.1001/jamacardio.2023.0065.

  PMID: 36884247 DERIVED

MeSH Terms

Conditions

Atrial Remodeling; Ventricular Remodeling; Ventricular Dysfunction, Left; Hypertension; Myositis; Myocarditis; Ventricular Dysfunction

Interventions

sacubitril and valsartan sodium hydrate drug combination; Valsartan

Condition Hierarchy (Ancestors)

Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Cardiomyopathies

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

Study Officials

• Fiona Ryan, Co-Investigator, PhD

  Heartbeat Trust, 3 Crofton Terrace, Dun Laoghaire, Co Dublin

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Double-blind, double-dummy.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Research Director, STOP-HF Unit

Model Details: Randomised, prospective, active comparator, double blind, double dummy, controlled trial.

Study Record Dates

• First Submitted: July 25, 2018
• First Posted: December 29, 2020
• Study Start: December 16, 2015
• Primary Completion: June 11, 2021
• Study Completion: June 11, 2021
• Last Updated: May 11, 2021

Record last verified: 2021-05

Locations

IE (2)