Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure

NCT ID: NCT02556450

Last Updated: 2022-03-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 528 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-31
• Study Completion Date: 2019-01-31

Brief Summary

Despite advances in care, prognosis remains poor once overt Heart Failure (HF) has developed. Prevention is most efficient when directed toward patients at risk and when mechanistically targeted to patients most likely to respond. An increase in myocardial and possibly vascular collagen content (fibrosis) may be a major determinant of the transition to HF. In patients with hypertension and diabetes, two important risk-factors for HF, changes in blood markers of fibrosis occur before clinically overt HF develops. These markers are also related to prognosis.

In the general population, Galectin-3 (Gal-3), a potential marker of fibrosis, is associated with cardiovascular (CV) risk factors, and predicts development of HF. In animal models, Gal-3 is a key mediator of aldosterone-induced CV and renal fibrosis and dysfunction.

The investigators hypothesize that the mineralocorticoid receptor antagonist (MRA), spironolactone, may prevent HF by acting on extracellular matrix remodelling, especially in patients with active fibrogenesis, identified by high Gal-3 levels. The benefit/risk ratio of spironolactone might be superior in patients with a higher compared to lower plasma concentrations of Gal-3.

Main objective is to investigate whether spironolactone can favourably alter extra-cellular matrix remodelling, assessed by changes in the fibrosis biomarker Procollagen Type III N-Terminal Peptide (PIIINP), in patients at increased risk of developing heart failure and whether this effect is greater in patients with increased plasma concentrations of Gal-3.

Detailed Description

The investigators hypothesize that the mineralocorticoid receptor antagonist (MRA), spironolactone, may prevent HF by acting on extracellular matrix remodelling, especially in patients with active fibrogenesis, identified by high Gal-3 levels. The benefit/risk ratio of spironolactone might be superior in patients with a higher compared to lower plasma concentrations of Gal-3.

Conditions

Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: SINGLE

Study Groups

Spironolacton Group

Spironolacton Sandoz given 25mg daily oral use

Group Type: EXPERIMENTAL

Spironolacton

Intervention Type: DRUG

Administration of Spironolacton 25 mg per day

Control group

Only background treatment

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Spironolacton

Administration of Spironolacton 25 mg per day

Intervention Type: DRUG

Other Intervention Names

Spironolacton Sandoz

Eligibility Criteria

Inclusion Criteria

• Written informed consent will be obtained prior to any study procedure;
• Age >60 years
• Clinical risk factors for developing heart failure, either:

1. Coronary artery disease (h/o myocardial infarction, angioplasty or coronary artery bypass) Or

2. At least two of the following:

• Diabetes Mellitus requiring Hypoglycaemic Pharmacotherapy
• Receiving pharmacological treatment for Hypertension
• Microalbuminuria
• Abnormal ECG (left ventricular hypertrophy, QRS >120msec, abnormal Q-waves)
• Biological risk: NT-pro-BNP values between 125 and 1,000 ng/L or BNP values between 35 and 280 pg/ml (consistent with ESC guidelines indicating risk of HF but helping to rule out prevalent HF or atrial fibrillation which are associated with marked increases in NT-proBNP/BNP and should be investigated)

Exclusion Criteria

• Recent wound healing/inflammation:
• Surgical procedure, coronary, cerebral or peripheral vascular events or infection in the prior 3 months
• Cancer
• Autoimmune disease
• Hepatic Disease
• Pre-existing diagnosis of clinical HF
• Moderate/severe LV systolic ventricular dysfunction, i.e. LVEF <45%
• Moderate or severe valve disease (investigators opinion)
• eGFR< 30ml/min
• Serum potassium >5.0 mmol/L
• Treatment with an MRA or a loop diuretic (furosemide, bumetanide, ethacrynic acid or torasemide) in the previous three months
• Potassium supplements or potassium-sparing diuretic at time of enrolment.
• Atrial fibrillation within one month prior to inclusion (AF lasting <60 seconds on ambulatory ECG monitoring is permitted)

•. History of hypersensitivity to spironolactone.

• Requiring treatment with prohibited medication according to SmPC with exception of ACE inhibitors or angiotensin receptor blockers
• Patients unable to give written informed consent.
• Participation in another interventional trial in the preceding month
• Ability to walk is, in the investigators opinion, clearly limited by joint disease or other locomotor problems rather than by cardiorespiratory fitness

• Minimum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Institut National de la Santé Et de la Recherche Médicale, France

OTHER_GOV

Sponsor Role: collaborator

London School of Hygiene and Tropical Medicine

OTHER

Sponsor Role: collaborator

ACS Biomarker

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John Cleland, PhD

Role: PRINCIPAL_INVESTIGATOR

Imperial College London

Locations

Hopital Sud Francilien

Corbeil-Essonnes, , France

CHU de Nancy

Nancy, , France

Charite Universitatsmedizin Berlin, Kardiologie

Berlin, , Germany

St, Michaels Hospital

Dublin, , Ireland

Santa Margherita Hospital

Cortona, , Italy

Maastricht University Medical Center

Maastricht, , Netherlands

Queen Elizabeth University Hospital

Glasgow, , United Kingdom

Castle Hill Hospital

Hull, , United Kingdom

Central Manchester University Hospitals NHS

Manchester, , United Kingdom

Countries

France; Germany; Ireland; Italy; Netherlands; United Kingdom

References

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Reference Type: DERIVED

PMID: 38729636 (View on PubMed)

Monzo L, Ferreira JP, Cleland JGF, Pellicori P, Mariottoni B, Verdonschot JAJ, Hazebroek MR, Collier TJ, Cuthbert JJ, Pieske B, Edelmann F, Petutschnigg J, Khan J, Ahmed FZ, Girerd N, Bozec E, Diez J, Gonzalez A, Clark AL, Cosmi F, Staessen JA, Heymans S, Rossignol P, Zannad F. Dyskalemia in people at increased risk for heart failure: findings from the heart 'OMics' in AGEing (HOMAGE) trial. ESC Heart Fail. 2022 Dec;9(6):4352-4357. doi: 10.1002/ehf2.14086. Epub 2022 Sep 6.

Reference Type: DERIVED

PMID: 36065795 (View on PubMed)

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Reference Type: DERIVED

PMID: 34933097 (View on PubMed)

Verdonschot JAJ, Ferreira JP, Pellicori P, Brunner-La Rocca HP, Clark AL, Cosmi F, Cuthbert J, Girerd N, Mariottoni B, Petutschnigg J, Rossignol P, Cleland JGF, Zannad F, Heymans SRB; HOMAGE "Heart Omics in AGEing" consortium. Proteomic mechanistic profile of patients with diabetes at risk of developing heart failure: insights from the HOMAGE trial. Cardiovasc Diabetol. 2021 Aug 9;20(1):163. doi: 10.1186/s12933-021-01357-9.

Reference Type: DERIVED

PMID: 34372849 (View on PubMed)

Ferreira JP, Verdonschot J, Wang P, Pizard A, Collier T, Ahmed FZ, Brunner-La-Rocca HP, Clark AL, Cosmi F, Cuthbert J, Diez J, Edelmann F, Girerd N, Gonzalez A, Grojean S, Hazebroek M, Khan J, Latini R, Mamas MA, Mariottoni B, Mujaj B, Pellicori P, Petutschnigg J, Pieske B, Rossignol P, Rouet P, Staessen JA, Cleland JGF, Heymans S, Zannad F; HOMAGE (Heart Omics in AGEing) Consortium. Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF. JACC Heart Fail. 2021 Apr;9(4):268-277. doi: 10.1016/j.jchf.2020.11.010. Epub 2021 Feb 3.

Reference Type: DERIVED

PMID: 33549556 (View on PubMed)

Pellicori P, Ferreira JP, Mariottoni B, Brunner-La Rocca HP, Ahmed FZ, Verdonschot J, Collier T, Cuthbert JJ, Petutschnigg J, Mujaj B, Girerd N, Gonzalez A, Clark AL, Cosmi F, Staessen JA, Heymans S, Latini R, Rossignol P, Zannad F, Cleland JGF. Effects of spironolactone on serum markers of fibrosis in people at high risk of developing heart failure: rationale, design and baseline characteristics of a proof-of-concept, randomised, precision-medicine, prevention trial. The Heart OMics in AGing (HOMAGE) trial. Eur J Heart Fail. 2020 Sep;22(9):1711-1723. doi: 10.1002/ejhf.1716. Epub 2020 Jan 16.

Reference Type: DERIVED

PMID: 31950604 (View on PubMed)

Ferreira JP, Verdonschot J, Collier T, Wang P, Pizard A, Bar C, Bjorkman J, Boccanelli A, Butler J, Clark A, Cleland JG, Delles C, Diez J, Girerd N, Gonzalez A, Hazebroek M, Huby AC, Jukema W, Latini R, Leenders J, Levy D, Mebazaa A, Mischak H, Pinet F, Rossignol P, Sattar N, Sever P, Staessen JA, Thum T, Vodovar N, Zhang ZY, Heymans S, Zannad F. Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure. Circ Heart Fail. 2019 May;12(5):e005897. doi: 10.1161/CIRCHEARTFAILURE.118.005897.

Reference Type: DERIVED

PMID: 31104495 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

Homage

Identifier Type: -

Identifier Source: org_study_id