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Trial record 2 of 10 for:    lcz696 mri

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

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ClinicalTrials.gov Identifier: NCT04687111
Recruitment Status : Active, not recruiting
First Posted : December 29, 2020
Last Update Posted : May 11, 2021
Sponsor:
Collaborator:
The Heartbeat Trust
Information provided by (Responsible Party):
Mark Ledwidge, St Vincent's University Hospital, Ireland

Tracking Information
First Submitted Date  ICMJE July 25, 2018
First Posted Date  ICMJE December 29, 2020
Last Update Posted Date May 11, 2021
Actual Study Start Date  ICMJE December 16, 2015
Estimated Primary Completion Date June 11, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 29, 2021)
Change in Left Atrial Volume Index (LAV/BSA*) [ Time Frame: Baseline-18 months ]
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).
Original Primary Outcome Measures  ICMJE
 (submitted: December 22, 2020)
Change in Left Atrial Volume Index (LAVI) [ Time Frame: Baseline-18 months ]
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 (CMRI)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 29, 2021)
  • Change in left ventricular function (E/e') [ Time Frame: Baseline -18 months ]
    Measured average E/e' using Doppler-echocardiography
  • Change in left atrial volume index (LAV/BSA*) [ Time Frame: Baseline - 9 months ]
    Measured using Doppler Echocardiography between baseline and 9 months. (*BSA calculated using the DuBois formula)
  • Change in left atrial function measured as total left atrial ejection fraction (LAEF) [ Time Frame: Baseline -18 months ]
    Measured as total LAEF ((LAVmax - LAVmin)/LAVmax, by cardiac MRI
  • Change in left atrial function measured as left atrial stroke volume index [ Time Frame: Baseline -18 months ]
    Measured as left atrial stroke volume index (LAVmax - LAVmin)/BSA (measured using Du Bois formula), or LAVimax-LAVimin by cardiac MRI
  • Change in left ventricular structure measured as LVMi [ Time Frame: Baseline -18 months ]
    Measured using left ventricular mass index (LVMi), indexed to BSA (calculated using the DuBois formula) using cardiac MRI
  • Change in left ventricular function (LVEF) [ Time Frame: Baseline -18 months ]
    Measured as left ventricular ejection fraction (LVEF) using cardiac MRI
  • Change in measures of vascular compliance (pulse pressure) [ Time Frame: Baseline -18 months ]
    Measured using pulse pressure calculated from 24 hour ABPM measurements
  • Change in natriuretic peptide biomarker profile [ Time Frame: Baseline -18 months ]
    Defined as log-transformed NT-proBNP
  • Time to first all cardiovascular death and major adverse cardiac events (MACE) requiring hospitalisation over 18 months [ Time Frame: Baseline - 18 months ]
    MACE includes arrythmia (including atrial fibrillation/flutter), transient ischaemic attack, stroke, valvular heart disease, myocardial infarction, peripheral or pulmonary thrombosis/embolus or heart failure
  • Change in Left Atrial Volume Index (LAVi) analysed per protocol. [ Time Frame: Baseline - 18 months ]
    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)
Original Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2020)
  • Change in Left Atrial Volume Index (LAVI) [ Time Frame: Baseline -18 months ]
    Measured as left atrial volume indexed to body surface area (DuBois formula) using Echocardiography
  • Change in Left Atrial Volume Index (LAVI) [ Time Frame: Baseline -9 months ]
    Measured as left atrial volume indexed to body surface area (DuBois formula) using Echocardiography
  • Change in CMRI left atrial function [ Time Frame: Baseline -18 months ]
    Measured as total LAEF (LAVImax-LAVImin)/LAVImax by cMRI.
  • Change in CMRI left atrial strain [ Time Frame: Baseline -18 months ]
    Measured using feature tracking by cMRI
  • Change in left atrial function by Doppler Echocardiography [ Time Frame: Baseline - 18 months ]
    Doppler Echocardiography measured E/A ratio
  • Change in left atrial function by Doppler Echocardiography [ Time Frame: Baseline - 9 months ]
    Doppler Echocardiography measured E/A ratio
  • Change in CMRI parameters of left ventricular structure [ Time Frame: Baseline -18 months ]
    CMRI measured LVMI, LVESVi, LVEDVi
  • Change in CMRI parameters of left ventricular function [ Time Frame: Baseline -18 months ]
    CMRI measured LVEF, SV, CI, CMR e', myocardial strain measured using feature tracking
  • Change in Doppler Echocardiography parameters of left ventricular structure [ Time Frame: Baseline - 18 months ]
    Doppler Echocardiography measured LVMI, LVESVi, LVEDVi.
  • Change in Doppler Echocardiography parameters of left ventricular structure [ Time Frame: Baseline - 9 months ]
    Doppler Echocardiography measured LVMI, LVESVi, LVEDVi.
  • Change in Doppler Echocardiography parameters of left ventricular function [ Time Frame: Baseline - 18 months ]
    Doppler Echocardiography measured LVEF, SV, CI, Lateral/medial e' and lateral/medial/average E/e'
  • Change in Doppler Echocardiography parameters of left ventricular function [ Time Frame: Baseline - 9 months ]
    Doppler Echocardiography measured LVEF, SV, CI, Lateral/medial e' and lateral/medial/average E/e'
  • Impact of sacubitril/valsartan on endpoints in subset of patients with or without baseline atrial cardiomyopathy, using EHRA/HRS/APHRS/SOLAECE 2016 consensus definition. [ Time Frame: Baseline - 18 months ]
    Defined as a complex of electrophysiological (e.g. atrial fibrillation, atrial flutter), structural/architectural (e.g. LAVI >34ml/m2) or contractile (e.g. LAEF, elevated E/A ratio) on cMRI / Doppler Echocardiography
  • Impact of sacubitril/valsartan on endpoints in subset of patients with or without baseline atrial cardiomyopathy, using EHRA/HRS/APHRS/SOLAECE 2016 consensus definition. [ Time Frame: Baseline - 9 months ]
    Defined as a complex of electrophysiological (e.g. atrial fibrillation, atrial flutter), structural/architectural (e.g. LAVI >34ml/m2) or contractile (e.g. LAEF, elevated E/A ratio) on cMRI / Doppler Echocardiography
  • Impact of sacubitril/valsartan on prevalent and new onset atrial cardiomyopathy using EHRA/HRS/APHRS/SOLAECE 2016 consensus definition. [ Time Frame: Baseline - 18 months ]
    Defined as a complex of electrophysiological (e.g. atrial fibrillation, atrial flutter), structural/architectural (e.g. LAVI >34ml/m2) or contractile (e.g. LAEF, elevated E/A ratio) on cMRI / Doppler Echocardiography
  • Impact of sacubitril/valsartan on prevalent and new onset atrial cardiomyopathy using EHRA/HRS/APHRS/SOLAECE 2016 consensus definition. [ Time Frame: Baseline - 9 months ]
    Defined as a complex of electrophysiological (e.g. atrial fibrillation, atrial flutter), structural/architectural (e.g. LAVI >34ml/m2) or contractile (e.g. LAEF, elevated E/A ratio) on cMRI / Doppler Echocardiography
  • Impact of sacubitril/valsartan on primary and secondary endpoints dependent on baseline natriuretic peptide. [ Time Frame: Baseline - 18 months ]
    Subset analyses dependent on whether patients are above or below BNP 50 pg/mL, median BNP, median NTproBNP and median NTproBNP/BNP ratio at baseline.
  • Impact of sacubitril/valsartan on primary and secondary endpoints dependent on baseline natriuretic peptide levels. [ Time Frame: Baseline - 9 months ]
    Subset analyses dependent on whether patients are above or below BNP 50 pg/mL, median BNP, median NTproBNP and median NTproBNP/BNP ratio at baseline.
  • Correlation between Doppler Echocardiography and cMRI measures of left atrial structure and function [ Time Frame: Baseline and 18 months ]
    CMRI and Doppler Echocardiography measured LAVI, LAEF
  • Correlation between Doppler Echocardiography and cMRI measures of left ventricular structure and function [ Time Frame: Baseline and 18 months ]
    CMRI and Doppler Echocardiography LVMI, LVEF, e'
  • Correlation of cardiac MRI-e' with Left Atrial and Left Ventricular Feature Tracking Analysis [ Time Frame: Baseline and 18 months ]
    CMRI measured e' and strain measures using feature tracking
  • Change in the numbers of patients with progression of left ventricular dysfunction. [ Time Frame: Baseline - 18 months ]
    Defined using Doppler Echocardiography as: ejection fraction <50% with change of >5%; and/or lateral E/e' >13 or average E/e' >14 (with change >2); and/or lateral e'<9, with reduction >2 over 9 and 18 months.
  • Change in the numbers of patients with progression of left ventricular dysfunction. [ Time Frame: Baseline - 9 months ]
    Defined using Doppler Echocardiography as: ejection fraction <50% with change of >5%; and/or lateral E/e' >13 or average E/e' >14 (with change >2); and/or lateral e'<9, with reduction >2 over 9 and 18 months.
  • Pharmacogenetic response to therapy (i.e. change in primary and secondary endpoints) dependent on status of common genetic variants (pr proxies in high LD) associated with sacubitril-valsartan and the expression and metabolism of natriuretic peptides [ Time Frame: Baseline - 18 months ]
    Literature defined variants associated with NPPB (e.g. rs6676300, rs198389) NPPA (e.g. rs198358), NPPC (rs4796751), NPRC (e.g. rs1173771, rs2270915, rs976576), MME (e.g. rs9829347, rs3773874), CLCN6 (rs5063), MTHFR (e.g. rs3753584, rs2066462), KLKB1 (e.g. rs4253238, 4253311), FURIN (rs2521501, rs1894401), POC1B (rs11105306), SLC39A8 (e.g. rs13126505, rs13107325), DPP4 (rs12617656) and CES (e.g. rs2244613, rs8192935, rs2244613).
  • Pharmacogenetic response to therapy (i.e. change in primary and secondary endpoints) dependent on status of common genetic variants (pr proxies in high LD) associated with sacubitril-valsartan and the expression and metabolism of natriuretic peptides [ Time Frame: Baseline - 9 months ]
    Literature defined variants associated with NPPB (e.g. rs6676300, rs198389) NPPA (e.g. rs198358), NPPC (rs4796751), NPRC (e.g. rs1173771, rs2270915, rs976576), MME (e.g. rs9829347, rs3773874), CLCN6 (rs5063), MTHFR (e.g. rs3753584, rs2066462), KLKB1 (e.g. rs4253238, 4253311), FURIN (rs2521501, rs1894401), POC1B (rs11105306), SLC39A8 (e.g. rs13126505, rs13107325), DPP4 (rs12617656) and CES (e.g. rs2244613, rs8192935, rs2244613).
  • Change in natriuretic peptide biomarker profile. [ Time Frame: Baseline - 9 and baseline - 18 months ]
    Defined as log-scale in NT-proBNP, BNP, NTproBNP/BNP ratio and other related peptides, ANP, urinary cGMP
  • Change in blood biomarkers of collagen turnover, ECM turnover, myocardial damage, myocardial fibrosis, inflammation and renin angiotensin aldosterone system. [ Time Frame: Baseline - 18 months ]
    Measured as markers of collagen turnover (e.g. Col1A1, PICP, PIIINP), ECM turnover (e.g. MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-4), myocardial damage (hsTroponin), fibrosis (e.g. Galectin-3, sST-2), inflammation (e.g. IL-1R1, IL-R2, IL-2RA, IL-6RA, IL-6, TNF-α, MCP1, CT1, GDF15 and RAAS (e.g. PRA, aldosterone).
  • Change in urinary bio-markers of natriuretic peptide between baseline and 9 months and baseline and 18 months. [ Time Frame: Baseline - 18 months ]
    Measured as urinary cGMP
  • Correlation between Doppler Echocardiography and cMRI measures of left atrial and ventricular structure and function and blood biomarkers. [ Time Frame: Baseline and 18 months ]
    Measured as CMR and Doppler Echocardiography LAVI, LAEF, LVEF, e', E/e' and blood biomarkers of collagen turnover, ECM turnover, myocardial damage, myocardial fibrosis, inflammation and renin angiotensin aldosterone system described above.
  • Incidence of all adverse events (AEs) over 18 months. [ Time Frame: Baseline - 18 months ]
    Defined as clinical tolerability, expected AEs, serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: December 22, 2020)
  • Change in cognitive function: Standardised Mini-Mental State Examination. [ Time Frame: Baseline - 18 months ]
    Measured as the overall summary score and individual domain score of the Standardised Mini-Mental State Examination, which ranges from 0 to 30 with lower scores reflecting worse cognitive function
  • Change in cognitive function: Montreal Cognitive Assessment questionnaires. [ Time Frame: Baseline - 18 months ]
    Measured as the overall summary score and individual domain score of the Montreal Cognitive Assessment (MoCA) questionnaires, which ranges from 0 to 30 with lower scores reflecting worse cognitive function
  • Change in quality of life: measured using the EuroQoL-5D-5L instrument [ Time Frame: Baseline - 9 and baseline - 18 months ]
    Measured as the overall summary score and individual domain score of the EuroQOL-5D-5L instrument, which ranges from 0 to 100 with lower scores reflecting worse health related quality of life.
  • Difference between groups in terms of CD14+, CD16+/- profile and monocyte RNA expression profile [ Time Frame: Baseline - 9 and baseline - 18 months ]
    Determined using flow-cytometry and transcriptome analysis of isolated monocytes in a subset of patients at baseline and follow up
  • Impact of sacubitril/valsartan on biomarkers of angiogenesis, hypoxia, cardiac remodelling, cell adhesion, platelet activation, coagulation, chemotaxis, catabolic stress, inflammation and fibrosis [ Time Frame: Baseline - 18 months ]
    Biomarkers will be measured as normalised protein expression (log transformed) using Olink CVIII panel proximity-extension-assay. The measured biomarkers are AP-N, AZU1, BLM hydroxylase, CCL15/16/24, CXCL16, CDH5, CPA1, CPB1, CASP3, CTSD, CTSZ, ALCAM, CHI3L1, CHIT1, COL1A1, CD93, CNTN1, CSTB, SELE, PI3, EPHB4, FABP4, Gal3/4, GRN, GDF15, IFGBP1/2/7, ITGB2, ICAM2, IL1RT1/2, IL17RA, IL18BP, IL2RA, IL6RA, JAM-1, KLK6, LRLreceptor, LTBR, MEME, MMP2/3/9, TIMP4, MCP1, PRTN3, MPO, MB, NTproBNP, Notch3, OPN, OPG, SELP, PON3, PGLYRP1, PLC, PAI, PECAM1, GP6, PDGFsubunitA, PCSK9, DLK1, PSP-D, RETN, RARRES2, CD163, SCGB3A2, SPON1, ST2, TR-AP, TFPI, t-PA, Transferrin Receptor protein1, TFF3, TLT-2, TNFSF13B, TNF-R1/2, TNFRSF10C, TNFRSF14, FAS, AXL, SHPS-1, U-PAR, uPA, vWF.
  • Difference between treatment groups in terms of the incidence of atrial fibrillation/flutter [ Time Frame: Between 9 and 18 months ]
    Measured non-invasively over 5-7 days using continuous electrocardiogram monitoring in a subgroup of patients
  • Difference between treatment groups in terms of the incidence of paroxysmal supraventricular tachycardia [ Time Frame: Between 9 and 18 months ]
    Measured non-invasively over 5-7 days using continuous electrocardiogram monitoring in a subgroup of patients
  • Incidence of emergency (unplanned) hospitalisations for major adverse cardiovascular events [ Time Frame: Baseline - 18 months ]
    Major adverse cardiac events defined as per Ledwidge et al JAMA 2013, including arrhythmia (including atrial fibrillation/flutter), transient ischaemic attack, stroke, valvular heart disease, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure
  • Incidence of any of adverse cardiovascular events (with or without hospitalisation) [ Time Frame: Baseline - 18 months ]
    Adverse cardiac events as above include arrhythmia (including atrial fibrillation/flutter), transient ischaemic attack, stroke, valvular heart disease, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure
  • Incidence of all cardiovascular AEs requiring hospital admission [ Time Frame: Baseline - 18 months ]
    Using pharmacovigilance and adverse event reporting system
  • Incidence of emergency and non-emergency non-cardiovascular AEs requiring hospital admission [ Time Frame: Baseline - 18 months ]
    Using pharmacovigilance and adverse event reporting system
  • Incidence of all-cause AEs requiring hospital admission [ Time Frame: Baseline - 18 months ]
    Using pharmacovigilance and adverse event reporting system
  • Pharmacogenetic responses to therapy dependent on polygenic risk score of blood pressure, atrial fibrillation, atrial dilatation associated gene variants, and established pharmacogenetic gene variants of natriuretic peptide pathway and sacubitril [ Time Frame: Baseline - 18 months ]
    Using above and below median polygenic risk scores from from GWAS and specific genes associated with natriuretic peptide / sacubritril valsartan metabolism (NPPB, NPPA, NPRC (NPR3), MME, FURIN, CLCN, DPP4, KLKB1, CES1 gene variants)
  • Subgroup analyses on primary outcome in addition to secondary endpoints [ Time Frame: Baseline - 18 months ]
    Pre-specified subgroups include above and below median age, BMI, eGFR; gender, obesity, vascular disease, hypertension, diabetes, atrial fibrillation/flutter
  • Use of circulating metabolomic profile to identify responders to sacubitril-valsartan [ Time Frame: Baseline - 18 months ]
    Evaluation of responders based on minimum LAVI change of -3.5 ml/m2
  • Extension analysis following end of treatment with blinded, double-dummy investigational medicinal product. [ Time Frame: 18 months to 27 months ]
    Evaluation of secondary and exploratory endpoints 9 months after completing therapy with sacubitril-valsartan versus valsartan
 
Descriptive Information
Brief Title  ICMJE Personalised Prospective Comparison of ARni With ArB in Patients With Natriuretic Peptide eLEvation
Official Title  ICMJE A Randomised, Controlled, Double-blind, Double-dummy, Clinical Trial Comparing Sacubitril-Valsartan Versus Valsartan in Asymptomatic, Stage A/B HFpEF Patients With Elevated Natriuretic Peptide and Abnormal LAVI. (Previously NCT02682719)
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).
Detailed Description

Background.

An effective prevention strategy is critical if the established epidemic of heart failure and cardiovascular disease is to be curbed. This is particularly important in the context of increasing community prevalence of stage B HFpEF and left ventricular diastolic abnormalities associated with hypertension and diabetes and requires community diagnostics and targeted preventative therapies. Individualising risk beyond the presence of established risk factors can be achieved with NP assessment. Elevated NP in a population with established cardiovascular disease defines a group more prone to cardiac dysfunction, heart failure and other cardiovascular events. This can be used to risk stratify asymptomatic populations, targeting those most likely to need intensive intervention and follow-up.

In the prospective, randomised, pragmatic St Vincent's Screening TO Prevent Heart Failure (STOP-HF) trial [Ledwidge 2013], NP-based screening and collaborative care with general practice provided a multi-faceted intervention for patients with risk factors for heart failure. This involved community NP screening, improved use of RAAS modifying therapy, collaborative care with general practice as well as cardiovascular coaching for patients with mild elevations of BNP (>50 pg/mL).The intervention reduced stage B and C heart failure, most of which was preserved ejection fraction, as well as major adverse cardiovascular events requiring hospitalisation. This first of type study, along with a second study in diabetes [Huelsmann 2013], indicates that a biomarker driven strategy based on NP screening amongst stage AB heart failure patients is feasible and has an impact on heart failure and other cardiovascular diseases. These studies have been incorporated into 2017 American Heart Association/American College of Cardiology guidelines as well as other international guideline recommendations in heart failure.

However, while successful, the STOP-HF biomarker strategy lacks a specific pharmacological intervention linked to the screening biomarker, NP. An analysis of the STOP-HF follow-up study, supports other work showing that the minor C allele of genetic variant rs198389 of the NPPB gene (in the promoter region) is associated with sustained, elevated circulating levels of BNP and reduced incidence of left ventricular dysfunction over a five-year follow up period. These data support the hypothesis that use of LCZ696 to pharmacologically raise NP could provide cardioprotection in stage A/B heart failure patients. As neprilysin degrades biologically active NP, LCZ696 increases myocardial cyclic guanosine monophosphate (cGMP) which reduces vascular and myocardial stiffness as well as hypertrophy. This could improve cardiac structure and performance. NPs also stimulate natriuresis, diuresis, vasodilation and have been shown to have anti-fibrotic and anti-sympathetic benefits, which could augment the STOP-HF preventative strategy with a specific pharmacological intervention. [Ledwidge 2103, Phelan 2012, Potter 2006, Gardiner 2007]. Atrial tissue gene expression of BNP in patients with stage B HFpEF is associated with atrial fibrosis, procollagen expression and presence of M2 monocyte-derived-macrophage marker CD163 [Watson 2020]. Further analyses of the STOP-HF follow-up study shows that BNP strongly associates with the presence of atrial cardiomyopathy, an independent predictor of new onset major adverse cardiovascular events.

Taken together, these data could support a role for sacubitril-valsartan versus valsartan alone in favourably modulating vascular compliance, cardiac structure, cardiac function as well as progression of left atrial structural and functional abnormalities amongst patients with stage B HFpEF. If left atrial structure and function is also associated with new onset major adverse cardiovascular events, the intervention could also modulate cardiovascular events. Finally, new CMRI imaging measures of cardiac function, such as CMR e' have been developed and will allow full characterisation of the cardiovascular impact of the intervention, including in subsets of patients with established atrial cardiomyopathy.

Rationale for the study

Elevated NP in an at-risk population independently identifies cardiovascular risk, which can be specifically targeted by LCZ696. In a small proportion of patients (<5%) with cardiovascular risk factors and elevated NP, significant asymptomatic LV systolic dysfunction will be present and for these RAAS modifying therapy is mandated. However, there is a larger group of patients with elevated NP who have stage B HFpEF, with or without diastolic dysfunction. These patients may have preclinical, or asymptomatic, left ventricular diastolic dysfunction (ALVDD), atrial cardiomyopathy (AC) or both and are at heightened risk for heart failure and other cardiovascular events [Watson 2020].

The increase in NP in stage B HFpEF, ALVDD and AC is likely a fibro-inflammatory signal, which in-turn contributes to tissue remodelling, vascular disease, myocardial stiffening and left ventricular dysfunction. For example, hypertension, a common risk factor for ALVDD, is associated with an adverse accumulation of fibrous tissue and studies have demonstrated a strong relationship between ventricular stiffness, myocardial collagen content and plasma levels of myocardial collagen turnover markers [Hogg 2004, Querejeta 2004]. Cardiac inflammation, fibrosis and hypertrophy drive the pathophysiology [Gardiner 2007, Martos 2007] associated with vascular disease, myocardial stiffening, and left atrial as well as left ventricular dysfunction. [Phelan 2012, Jannuzzi 2019] Interrupting this pathophysiological process at an early stage before the development of ventricular dysfunction may prevent or slow development to heart failure and also have an impact on the development of other cardiovascular events driven by this pathophysiological process. This may be particularly important for prevention of the development of a sub-type of stage C HFpEF characterised by older age, elevated LAVI, atrial fibrillation and chronic kidney disease, which puts patients at very high risk adverse outcome [Shah 2015]. Importantly, there is currently no specific disease modifying therapy for these patients, beyond conventional risk factor control.

Accordingly, suppressing the RAAS will reduce the pro-fibrotic impact of angiotensin II. Addition of sacubitril, which reduces degradation of endogenous, cardio-protective NPs, could reduce pulse pressure, myocardial stiffness and augment the beneficial anti-inflammatory and anti-fibrotic effects of NPs beyond conventional RAAS modifying therapy. The latter may be mediated through impacts on the innate immune system, fibro-inflammation and monocyte-derived-macrophages in the myocardium [Watson 2020].

Several studies have shown that the interplay between the myocardium and extracellular matrix (ECM) can now be evaluated via analysis of serum samples of markers of collagen turnover. [Martos 2007, Querejeta 2007] Altered serum levels of collagen markers (e.g. Collagen 1A1) and matrix metalloproteinase (e.g. MMP-2 and MMP-9) suggest increased collagen turnover associated with fibrosis in diastolic heart failure. [Martos, 2007, Ahmed 2006, Nikishimi 2006] Other biomarkers of cardiac structure and function of relevance in ALVDD/AC include Galectin 3 and ST-2, biomarkers of cardiac remodelling and tissue fibrosis. Finally, cGMP, which blunts activation pathways and diminishes hypertrophy, fibrosis, cellular toxicity, and maladaptive remodelling in the myocardium, may also be modulated by sacubitril-valsartan, not only through inhibition of breakdown of BNP, but also ANP and other vasoactive peptides [Ibrahim 2019].

In high risk patients with preserved ejection fraction, elevated LAVI reflects increased left ventricular filling pressures, fibro-inflammation and is a strong, continuous marker of diastolic dysfunction as well as future cardiovascular events. Interventions that could improve myocardial performance and reduce progression of LAVI and other structural abnormalities might also help prevent cardiac morbidity and progression to stage B/C HFpEF. Sacubitril-valsartan has been shown to modulate NP activity and reduce LAVI in comparison with valsartan in the PARAMOUNT study [Solomon 2012]. The reduction of 2.6 mL/m2 with LCZ696 compared with an increase of 0.3 mL/m2 with valsartan (p=0.007 for difference) from a baseline of 36 mL/m2 over 36 weeks appears to be clinically significant in these patients with preserved ejection fraction. However, further work is required to understand the implications of this result in stage A/B HFpEF, especially using more precisely defined myocardial structure and function with cardiac magnetic resonance imaging (cMRI). Furthermore, in the PARAGON-HF study (Solomon 2019), there was no significant benefit of sacubitril-valsartan in patients with HFpEF with respect to the primary composite outcome of hospitalisation and death. The differential effect of sacubitril-valsartan versus valsartan in relation to left ventricular ejection fraction as well as stage B versus C HFpEF requires further evaluation. No study has evaluated sacubitril-valsartan in patients with stage A/B HFpEF, elevated natriuretic peptides and abnormal LAVI.

Aim

The main aim of the PARABLE trial is to assess the impact of sacubitril-valsartan versus valsartan alone on structural, functional and biochemical abnormalities of the myocardium in an asymptomatic cohort with preserved ejection fraction, cardiovascular risk factors, abnormal LAVI and elevated NP (brain type natriuretic peptide [BNP] and/or N-terminal of the prohormone BNP [NT-proBNP]).

PARABLE tests the hypothesis that sacubitril-valsartan versus valsartan alone would result in beneficial effects on atrial and ventricular structure and function, thereby preventing progression of cardiac abnormalities in stage B HFpEF.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomised, prospective, active comparator, double blind, double dummy, controlled trial.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
Double-blind, double-dummy.
Primary Purpose: Prevention
Condition  ICMJE
  • Atrial Remodeling
  • Myocardial Dysfunction
  • Left Ventricular Remodeling
  • Left Ventricular Diastolic Dysfunction
  • Hypertension
  • Cardiovascular Morbidity
  • Fibrosis Myocardial
  • Inflammatory Myopathy
  • Atrial Arrhythmia
Intervention  ICMJE
  • Drug: Sacubitril-Valsartan
    Sacubitril-Valsartan is an Angiotensin Receptor blocker and Neprilysin Inhibitor
    Other Names:
    • LCZ696
    • Entresto
  • Drug: Valsartan
    Valsartan is an Angiotensin Receptor Blocker
Study Arms  ICMJE
  • Active Comparator: Control
    Valsartan 40mg bid titrated to maximum dose of 160mg bid
    Intervention: Drug: Valsartan
  • Experimental: Intervention
    Sacubitril/Valsartan 50mg bid titrated to maximum dose of 200mg bid
    Intervention: Drug: Sacubitril-Valsartan
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 22, 2020)
250
Original Actual Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 11, 2021
Estimated Primary Completion Date June 11, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age > 40yrs with cardiovascular risk factor(s) including at least one of:

    1. History of hypertension (medicated for greater than one month);
    2. History of diabetes;
  2. 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
  3. LAVI > 28 mL/m2 obtained during Doppler Echocardiography within 6 months prior to screening or at screening
  4. Subjects must give written informed consent to participate in the study and before any study related assessments are performed.

Exclusion Criteria:

  1. A history of heart failure.
  2. Asymptomatic left ventricular systolic dysfunction defined as LVEF <50% on most recent measurement.
  3. Systolic blood pressure <100mmHg
  4. Persistent atrial fibrillation.
  5. History of hypersensitivity, allergy or intolerance to LCZ696, ARB or neprilysin therapy or to any of the excipients or other contraindication to their use.
  6. Previous history of intolerance to recommended target doses for ARBs
  7. Subjects who require treatment with both an ACE inhibitor and an ARB
  8. Presence of haemodynamically significant mitral and /or aortic valve disease.
  9. Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis.
  10. Conditions that are expected to compromise survival over the study period.
  11. Serum potassium level > 5.2 mmol/L at screening.
  12. Severe renal insufficiency (eGFR <30 mL per minute per 1.73 m2).
  13. Hepatic dysfunction (Any LFT > 3 times the upper limit of normal (ULN))
  14. Concomitant use of aliskiren
  15. History of angioedema.
  16. History or evidence of drug or alcohol abuse within the last 12 months
  17. Malignancy or presence of any other disease with a life expectancy of < 2 years
  18. Women who are pregnant, breast-feeding, or women of child bearing potential not using estro-progestative oral or intra-uterine contraception or implants, or women using estro-progestative oral or intra-uterine contraception or implants but who consider stopping it during the planned duration of the study. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. (Contraception must be continued for one week following discontinuation of study drug).
  19. Concomitant participation in other intervention trials
  20. Participation in any investigational drug trial within one month of visit 1.
  21. Refusal to provide informed consent
  22. Subjects with contraindications to MRI

    1. Brain aneurysm clip
    2. Implanted neural stimulator
    3. Implanted cardiac pacemaker or defibrillator
    4. Cochlear implant
    5. Ocular foreign body (e.g. metal shavings)
    6. Other implanted medical devices: (e.g. Swan-Ganz catheter)
    7. Insulin pump
    8. Metal shrapnel or bullet.
  23. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following:

    1. History of major gastrointestinal tract surgery including gastrectomy, gastroenterostomy, or bowel resection.
    2. Inflammatory bowel disease during the 12 months prior to Visit 1.
    3. Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase.
    4. Evidence of hepatic disease as determined by any one of the following: SGOT or SGPT values exceeding 3 x ULN at Visit 1, a history of hepatic encephalopathy, a history of oesophageal varices, or a history of portocaval shunt.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Ireland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04687111
Other Study ID Numbers  ICMJE HBT-PTCL-01, SVUH-2015-002
2015-002928-53 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mark Ledwidge, St Vincent's University Hospital, Ireland
Study Sponsor  ICMJE Mark Ledwidge
Collaborators  ICMJE The Heartbeat Trust
Investigators  ICMJE
Study Director: Fiona Ryan, Co-Investigator, PhD Heartbeat Trust, 3 Crofton Terrace, Dun Laoghaire, Co Dublin
PRS Account St Vincent's University Hospital, Ireland
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP