ARNI in Asymptomatic Patients With Elevated Natriuretic Peptide and Elevated Left Atrial Volume Index eLEvation

Diastolic Dysfunction Clinical Trial

— PARABLE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02682719
• Other study ID #: HBT-GCP-PTCL-01
• Status: Recruiting
• Phase: Phase 2
• First received: February 8, 2016
• Last updated: February 15, 2016
• Start date: December 2015
• Est. completion date: December 2018

Study information

• Verified date: February 2016
• Source: The Heartbeat Trust
• Contact: Kenneth McDonald, MD, FRCPI
• Phone: 0035312713071
• Email: kenneth.mcdonald[@]ucd.ie
• Is FDA regulated: No
• Health authority: Ireland: Health Products Regulatory Authority
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether LCZ696 (valsartan/sacubitril) is safe and has beneficial effects on the heart and blood vessels in patients with high blood pressure and/or diabetes or other risk factors for developing heart failure (elevated levels of natriuretic peptide and elevated left atrial volume index). Patients will be randomized to receive LCZ696 or valsartan (and matching placebo) for 18 months to assess the impact on left ventricular diastolic function.

Description:

The STOP-HF prospective, randomized trial demonstrated that a biomarker driven strategy of natriuretic peptide (NP) based screening and collaborative care with general practice can help target cardiovascular prevention and improve outcome in an at-risk population of patients without heart failure.

However, while successful, the STOP-HF biomarker strategy lacks a specific pharmacological intervention linked to the screening biomarker, NP. The most appropriate therapy to build on STOP-HF is LCZ696 (sacubitril/valsartan), a first in class angiotensin receptor neprilysin inhibitor (ARNI). As neprilysin degrades biologically active NP, LCZ696 increases myocardial cyclic guanosine monophosphate (cGMP) while reducing myocardial stiffness and hypertrophy. 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.

Elevated NP in an at-risk population independently identifies cardiovascular risk, which can be specifically targeted by LCZ696. In a small number of patients (4%) 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 normal systolic function of the left ventricle but who have significant isolated diastolic dysfunction. These patients have asymptomatic left ventricular diastolic dysfunction (ALVDD) and are at heightened risk for heart failure and other cardiovascular events. The Investigators and others, have shown that cardiac inflammation, fibrosis and hypertrophy drive the pathophysiology. Importantly, there is currently no specific therapy for these patients, beyond conventional risk factor control.

Interrupting this pathophysiological process at an early stage before the development of ventricular dysfunction, may prevent/slow development to heart failure and also have an impact on the development of other cardiovascular events driven by this pathophysiological process. This represents a novel way to modify risks at an earlier stage in the natural course of cardiovascular disease, in a targeted and individualized manner. It is known that suppressing the RAAS will reduce the pro-fibrotic impact of angiotensin II. Addition of neprilysin inhibitor sacubitril in LCZ696, will reduce degradation of endogenous, cardio-protective, biologically active NPs and cGMP and will augment the beneficial impact on fibro-inflammation beyond conventional RAAS modifying therapy.

There are a number of emerging biochemical and imaging surrogates of left ventricular dysfunction, which can be evaluated in a relatively small population over a short time frame in a prospective, phase II study design. Of these, one of the most reliable, continuous markers of diastolic function in the heart is LAVI. There was a dramatic impact of LCZ696 on LAVI in comparison with valsartan in the PARAMOUNT study. Furthermore, this endpoint can be precisely defined using cardiac magnetic resonance imaging (cMRI) in a phase II design. In this study, doppler Echocardiographic images will be collected to correlate with cMRI images. Doppler Echocardiography will be more feasible in follow on studies with larger populations.

In summary, it has been demonstrated that asymptomatic patients with elevated NP levels are at higher risk of heart failure and other cardiovascular events. Elevated NP in this setting represents a protective, endogenous response to fibro-inflammation. The predominant cardiac abnormality in these patients is ALVDD, which can be tracked using LAVI. The hypothesis is that augmenting this protective fibro-inflammatory response with LCZ696 could demonstrate superiority over the current state of art therapy in patients with hypertension or diabetes and elevated NP in a phase II study design and, in doing so, PARABLE may deliver a major clinical innovation in the prevention of cardiovascular disease.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: December 2018
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

1. Age > 40yrs

2. Cardiovascular risk factor(s) including at least one of:

• History of hypertension (medicated for greater than one month);

• History of diabetes;

3. Elevated NP: BNP>50pg/ml or NT-proBNP >250 pg/ml

4. LAVI > 28 mL/m2 obtained during Doppler Echocardiography within 6 months prior to screening

5. 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. A history of asymptomatic left ventricular systolic dysfunction defined as LVEF reading <50%, at any time.

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

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

• Hypersensitivity to gadolinium containing contrast agents

• Brain aneurysm clip

• Implanted neural stimulator

• Implanted cardiac pacemaker or defibrillator

• Cochlear implant

• Ocular foreign body (e.g. metal shavings)

• Other implanted medical devices: (e.g. Swan-Ganz catheter)

• Insulin pump

• 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:

• History of major gastrointestinal tract surgery including gastrectomy, gastroenterostomy, or bowel resection.

• Inflammatory bowel disease during the 12 months prior to Visit 1.

• Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase.

• 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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diastolic Dysfunction

Intervention

Drug:
• LCZ696

• Valsartan

Other:
• Placebo to LCZ696

• Placebo to Valsartan

Locations

Country	Name	City	State
Ireland	The STOP-HF Service, St Michael's Hosptial	Dun Laoghaire	Dublin

Sponsors (2)

Lead Sponsor	Collaborator
The Heartbeat Trust	Novartis Ireland Ltd

Country where clinical trial is conducted

Ireland, 

References & Publications (5)

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. Epub 2007 Feb 5. Review. — View Citation

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. — View Citation

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. Epub 2007 Feb 5. — View Citation

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of treatment-related adverse events		18 months	Yes
Other	Change from baseline to 18 months in overall summary score and individual domain score for health related quality of life	This will be assessed through the administration of the EuroQoL-5D-5L instrument which is designed to assess the current health status of subjects. It consists of five domains and one visual analogue scale. This instrument assesses morbidity, self-care, usual activity, pain and anxiety and depression of subjects.	18 months	Yes
Other	Change from baseline to 18 months in overall summary score and individual domain score of the standardised MMSE to assess cognitive function.	This will be assessed through the administration of the Standardized Mini-Mental State Examination which is a 30 point test designed to measure various domains of cognitive function including orientation to time and place; registration; concentration; short-term recall; naming familiar items; repeating a common expression; and the ability to read and follow written instructions, write a sentence, construct a diagram, and follow a three-step verbal command	18 months	Yes
Other	Change from baseline to 18 months in overall summary score and individual domain score of the MoCA to assess cognitive function.	This will be assessed through the administration of the Montreal Cognitive Assessment which is a a 30 point test designed to assess several cognitive domains including short-term memory recall, visuospatial abilities, executive functions, attention, concentration and working memory, language, orientation and place	18 months	Yes
Other	Number of cardiovascular adverse events	Cardiovascular adverse events are defined as emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure.	18 months	Yes
Primary	Change in left atrial volume index (LAVI)	LAVI will be measured by cardiac MRI	18 months	No
Secondary	Change in left atrial volume index (LAVI)	LAVI will be measured by cardiac MRI	9 months	No
Secondary	Change in cardiac MRI parameters of left ventricular structure and function		9 months	No
Secondary	Change in cardiac MRI parameters of left ventricular structure and function		18 months	No
Secondary	Change in LAVI measured by doppler echocardiography		9 months	No
Secondary	Change in LAVI measured by doppler echocardiography		18 months	No
Secondary	Correlation between doppler echocardiography measured LAVI and cardiac MRI measured LAVI		18 months	No
Secondary	Change in doppler echocardiographic parameters of left ventricular structure and function		9 months	No
Secondary	Change in doppler echocardiographic parameters of left ventricular structure and function		18 months	No
Secondary	Change in log-scale in NT-proBNP		9 months	No
Secondary	Change in log-scale in NT-proBNP		18 months	No
Secondary	Change in log-scale urinary cGMP		9 months	No
Secondary	Change in log-scale urinary cGMP		18 months	No
Secondary	Change in markers of collagen turnover (PICP)		9 months	No
Secondary	Change in markers of collagen turnover (PICP)		18 months	No
Secondary	Change in markers of collagen turnover (PIIINP)		9 months	No
Secondary	Change in markers of collagen turnover (PIIINP)		18 months	No
Secondary	Change in markers of ECM turnover (MMP-2)		9 months	No
Secondary	Change in markers of ECM turnover (MMP-2)		18 months	No
Secondary	Change in markers of ECM turnover (MMP-9)		9 months	No
Secondary	Change in markers of ECM turnover (MMP-9)		18 months	No
Secondary	Change in markers of ECM turnover (TIMP-1)		9 months	No
Secondary	Change in markers of ECM turnover (TIMP-1)		18 months	No
Secondary	Change in markers of myocardial damage (hsTroponinT)		9 months	No
Secondary	Change in markers of myocardial damage (hsTroponinT)		18 months	No
Secondary	Change in markers of fibrosis (sST-2)		9 months	No
Secondary	Change in markers of fibrosis (sST-2)		18 months	No
Secondary	Change in markers of inflammation (IL-6)		9 months	No
Secondary	Change in markers of inflammation (IL-6)		18 months	No
Secondary	Change in markers of inflammation (TNF-a)		9 months	No
Secondary	Change in markers of inflammation (TNF-a)		18 months	No
Secondary	Change in markers of inflammation (MCP1)		9 months	No
Secondary	Change in markers of inflammation (MCP1)		18 months	No
Secondary	Change in markers of inflammation (GDF15)		9 months	No
Secondary	Change in markers of inflammation (GDF15)		18 months	No
Secondary	Change in markers of inflammation (CT1)		9 months	No
Secondary	Change in markers of inflammation (CT1)		18 months	No
Secondary	Change in markers of renal function (creatinine clearance)	Creatinine clearance will be measured using the estimated glomerular filtration rate (eGFR)	18 months	Yes