Clinical trial NCT02556450: Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure
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 "
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure
Lead sponsor: ACS Biomarker
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
name: London School of Hygiene and Tropical Medicine
First posted: 2015-09-22
Enrollment: 528
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Changes in serum concentrations of PIIINP
timeFrame: 9 months
Secondary outcomes:
measure: changes in serum plasma levels of Biomarkers
timeFrame: 9 months
measure: Cardiac remodelling 1
timeFrame: 9 months
measure: Cardiac remodelling 2
timeFrame: 9 months
measure: Cardiac remodelling 3
timeFrame: 9 months
measure: Cardiorespiratory performance during exercise
timeFrame: baseline, 9 months
measure: Vascular function
timeFrame: screening, baseline, month1, month3, month 6, month 9
measure: heart failure or AF
timeFrame: 9 months
measure: Adverse events
timeFrame: screening, baseline, month1, month3, month 6, month 9
measure: Worsening renal function
timeFrame: screening, baseline, month1, month3, month 6, month 9
measure: Hyperkalemia
timeFrame: screening, baseline, month1, month3, month 6, month 9
Other outcomes:
Locations:
city: Corbeil-Essonnes
country: France
facility: Hopital Sud Francilien
city: Nancy
country: France
facility: CHU de Nancy
city: Berlin
country: Germany
facility: Charite Universitatsmedizin Berlin, Kardiologie
city: Dublin
country: Ireland
facility: St, Michaels Hospital
city: Cortona
country: Italy
facility: Santa Margherita Hospital
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Hull
country: United Kingdom
facility: Castle Hill Hospital
city: Manchester
country: United Kingdom
facility: Central Manchester University Hospitals NHS
Study officials:
affiliation: Imperial College London
name: John Cleland, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.