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

NCT02556450 | Completed Phase 2 DMC

• 1 other identifier: Homage
• Study Type: interventional
• Target: 528
• Locations: 6 countries
• Sites: 9

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.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (1)

• Changes in serum concentrations of PIIINP

  mmol/l

  9 months

Secondary Outcomes (10)

• changes in serum plasma levels of Biomarkers

  9 months

• Cardiac remodelling 1

  9 months

• Cardiac remodelling 2

  9 months

• Cardiac remodelling 3

  9 months

• Cardiorespiratory performance during exercise

  baseline, 9 months

Study Arms (2)

Spironolacton Group

EXPERIMENTAL

Spironolacton Sandoz given 25mg daily oral use

Drug: Spironolacton

Control group

NO INTERVENTION

Only background treatment

Interventions

Spironolacton DRUG

Administration of Spironolacton 25 mg per day

Also known as: Spironolacton Sandoz

Spironolacton Group

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent will be obtained prior to any study procedure;
• Age \>60 years
• Clinical risk factors for developing heart failure, either:
• Coronary artery disease (h/o myocardial infarction, angioplasty or coronary artery bypass) Or
• 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)

You may not qualify if:

• 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.
• . 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.

Sponsors & Collaborators

• ACS Biomarker: lead
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator
• London School of Hygiene and Tropical Medicine: collaborator

Study Sites (9)

Hopital Sud Francilien

Corbeil-Essonnes, 91106, France

Location

CHU de Nancy

Nancy, 54500, France

Location

Charite Universitatsmedizin Berlin, Kardiologie

Berlin, D-13353, Germany

Location

St, Michaels Hospital

Dublin, Ireland

Location

Santa Margherita Hospital

Cortona, 52044, Italy

Location

Maastricht University Medical Center

Maastricht, 6202AZ, Netherlands

Location

Queen Elizabeth University Hospital

Glasgow, G51 4TF, United Kingdom

Location

Castle Hill Hospital

Hull, HU16 5JQ, United Kingdom

Location

Central Manchester University Hospitals NHS

Manchester, M13 9WL, United Kingdom

Location

Related Publications (7)

• Yu YL, Siwy J, An DW, Gonzalez A, Hansen T, Latosinska A, Pellicori P, Ravassa S, Mariottoni B, Verdonschot JA, Ahmed F, Petutschnigg J, Rossignol P, Heymans S, Cuthbert JJ, Girerd N, Clark AL, Verhamme P, Nawrot TS, Janssens S, Cleland JG, Zannad F, Diez J, Mischak H, Ferreira JP, Staessen JA; HOMAGE investigators. Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial. Heart. 2024 Sep 16;110(19):1180-1187. doi: 10.1136/heartjnl-2023-323796.

  PMID: 38729636 DERIVED

• 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.

  PMID: 36065795 DERIVED

• Verdonschot JAJ, Ferreira JP, Pizard A, Pellicori P, Brunner La Rocca HP, Clark AL, Cosmi F, Cuthbert J, Girerd N, Waring OJ, Henkens MHTM, Mariottoni B, Petutschnigg J, Rossignol P, Hazebroek MR, Cleland JGF, Zannad F, Heymans SRB; HOMAGE "Heart Omics in AGEing" Consortium. The Effect of Spironolactone in Patients With Obesity at Risk for Heart Failure: Proteomic Insights from the HOMAGE Trial. J Card Fail. 2022 May;28(5):778-786. doi: 10.1016/j.cardfail.2021.12.005. Epub 2021 Dec 18.

  PMID: 34933097 DERIVED

• 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.

  PMID: 34372849 DERIVED

• 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.

  PMID: 33549556 DERIVED

• 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.

  PMID: 31950604 DERIVED

• 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.

  PMID: 31104495 DERIVED

MeSH Terms

Conditions

Heart Failure

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Officials

• John Cleland, PhD

  Imperial College London

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 8, 2015
• First Posted: September 22, 2015
• Study Start: January 1, 2016
• Primary Completion: September 30, 2018
• Study Completion: January 31, 2019
• Last Updated: March 8, 2022

Record last verified: 2022-03

Locations

IE (1); IT (1); NL (1); DE (1); GB (3); FR (2)