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

Heart Failure Clinical Trial

— Homage  

Official title:

Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure. A Proof of Concept Clinical Trial Within the EU FP 7 (European Union FP7) "HOMAGE" Programme " Heart OMics in AGing "

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02556450
• Other study ID #: Homage
• Status: Completed
• Phase: Phase 2
• Start date: January 2016
• Est. completion date: January 31, 2019

Study information

• Verified date: March 2022
• Source: ACS Biomarker
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 528
• Est. completion date: January 31, 2019
• Est. primary completion date: September 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• Spironolacton
Administration of Spironolacton 25 mg per day

Locations

Country	Name	City	State
France	Hopital Sud Francilien	Corbeil-Essonnes
France	CHU de Nancy	Nancy
Germany	Charite Universitatsmedizin Berlin, Kardiologie	Berlin
Ireland	St, Michaels Hospital	Dublin
Italy	Santa Margherita Hospital	Cortona
Netherlands	Maastricht University Medical Center	Maastricht
United Kingdom	Queen Elizabeth University Hospital	Glasgow
United Kingdom	Castle Hill Hospital	Hull
United Kingdom	Central Manchester University Hospitals NHS	Manchester

Sponsors (3)

Lead Sponsor	Collaborator
ACS Biomarker	Institut National de la Santé Et de la Recherche Médicale, France, London School of Hygiene and Tropical Medicine

Countries where clinical trial is conducted

France,  Germany,  Ireland,  Italy,  Netherlands,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in serum concentrations of PIIINP	mmol/l	9 months
Secondary	changes in serum plasma levels of Biomarkers	PICP (synthesis), ICTP (degradation) and GAL3	9 months
Secondary	Cardiac remodelling 1	NT-proBNP (ELISA, central Lab), from baseline to 9 months (Certified centers and central readings).	9 months
Secondary	Cardiac remodelling 2	Left Ventricular Mass (g/m)	9 months
Secondary	Cardiac remodelling 3	Left Atrial Volume (ml)	9 months
Secondary	Cardiorespiratory performance during exercise	Shuttle walk test: Distance walked in meters	baseline, 9 months
Secondary	Vascular function	non-invasive technologies: BP lab Audicor system	screening, baseline, month1, month3, month 6, month 9
Secondary	heart failure or AF	Rate of the clinical composite of development of heart failure or atrial fibrillation, non-fatal myocardial infarction or stroke or CV death from baseline to 9 months. The HOMAGE blinded clinical event committee will adjudicate all serious adverse events.	9 months
Secondary	Adverse events	All adverse events	screening, baseline, month1, month3, month 6, month 9
Secondary	Worsening renal function	decline in eGFR >20%	screening, baseline, month1, month3, month 6, month 9
Secondary	Hyperkalemia	rise of serum potassium to >5.5 mmol/L	screening, baseline, month1, month3, month 6, month 9