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

Primary Purpose

Heart Failure

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Spironolacton
Sponsored by
ACS Biomarker
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Heart Failure

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Hopital Sud Francilien
  • CHU de Nancy
  • Charite Universitatsmedizin Berlin, Kardiologie
  • St, Michaels Hospital
  • Santa Margherita Hospital
  • Maastricht University Medical Center
  • Queen Elizabeth University Hospital
  • Castle Hill Hospital
  • Central Manchester University Hospitals NHS

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Spironolacton Group

Control group

Arm Description

Spironolacton Sandoz given 25mg daily oral use

Only background treatment

Outcomes

Primary Outcome Measures

Changes in serum concentrations of PIIINP
mmol/l

Secondary Outcome Measures

changes in serum plasma levels of Biomarkers
PICP (synthesis), ICTP (degradation) and GAL3
Cardiac remodelling 1
NT-proBNP (ELISA, central Lab), from baseline to 9 months (Certified centers and central readings).
Cardiac remodelling 2
Left Ventricular Mass (g/m)
Cardiac remodelling 3
Left Atrial Volume (ml)
Cardiorespiratory performance during exercise
Shuttle walk test: Distance walked in meters
Vascular function
non-invasive technologies: BP lab Audicor system
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.
Adverse events
All adverse events
Worsening renal function
decline in eGFR >20%
Hyperkalemia
rise of serum potassium to >5.5 mmol/L

Full Information

First Posted
September 8, 2015
Last Updated
March 7, 2022
Sponsor
ACS Biomarker
Collaborators
Institut National de la Santé Et de la Recherche Médicale, France, London School of Hygiene and Tropical Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT02556450
Brief Title
Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure
Acronym
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 "
Study Type
Interventional

2. Study Status

Record Verification Date
March 2022
Overall Recruitment Status
Completed
Study Start Date
January 2016 (undefined)
Primary Completion Date
September 30, 2018 (Actual)
Study Completion Date
January 31, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ACS Biomarker
Collaborators
Institut National de la Santé Et de la Recherche Médicale, France, London School of Hygiene and Tropical Medicine

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
528 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Spironolacton Group
Arm Type
Experimental
Arm Description
Spironolacton Sandoz given 25mg daily oral use
Arm Title
Control group
Arm Type
No Intervention
Arm Description
Only background treatment
Intervention Type
Drug
Intervention Name(s)
Spironolacton
Other Intervention Name(s)
Spironolacton Sandoz
Intervention Description
Administration of Spironolacton 25 mg per day
Primary Outcome Measure Information:
Title
Changes in serum concentrations of PIIINP
Description
mmol/l
Time Frame
9 months
Secondary Outcome Measure Information:
Title
changes in serum plasma levels of Biomarkers
Description
PICP (synthesis), ICTP (degradation) and GAL3
Time Frame
9 months
Title
Cardiac remodelling 1
Description
NT-proBNP (ELISA, central Lab), from baseline to 9 months (Certified centers and central readings).
Time Frame
9 months
Title
Cardiac remodelling 2
Description
Left Ventricular Mass (g/m)
Time Frame
9 months
Title
Cardiac remodelling 3
Description
Left Atrial Volume (ml)
Time Frame
9 months
Title
Cardiorespiratory performance during exercise
Description
Shuttle walk test: Distance walked in meters
Time Frame
baseline, 9 months
Title
Vascular function
Description
non-invasive technologies: BP lab Audicor system
Time Frame
screening, baseline, month1, month3, month 6, month 9
Title
heart failure or AF
Description
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.
Time Frame
9 months
Title
Adverse events
Description
All adverse events
Time Frame
screening, baseline, month1, month3, month 6, month 9
Title
Worsening renal function
Description
decline in eGFR >20%
Time Frame
screening, baseline, month1, month3, month 6, month 9
Title
Hyperkalemia
Description
rise of serum potassium to >5.5 mmol/L
Time Frame
screening, baseline, month1, month3, month 6, month 9

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
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: 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) 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John Cleland, PhD
Organizational Affiliation
Imperial College London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hopital Sud Francilien
City
Corbeil-Essonnes
ZIP/Postal Code
91106
Country
France
Facility Name
CHU de Nancy
City
Nancy
ZIP/Postal Code
54500
Country
France
Facility Name
Charite Universitatsmedizin Berlin, Kardiologie
City
Berlin
ZIP/Postal Code
D-13353
Country
Germany
Facility Name
St, Michaels Hospital
City
Dublin
Country
Ireland
Facility Name
Santa Margherita Hospital
City
Cortona
ZIP/Postal Code
52044
Country
Italy
Facility Name
Maastricht University Medical Center
City
Maastricht
ZIP/Postal Code
6202AZ
Country
Netherlands
Facility Name
Queen Elizabeth University Hospital
City
Glasgow
ZIP/Postal Code
G51 4TF
Country
United Kingdom
Facility Name
Castle Hill Hospital
City
Hull
ZIP/Postal Code
HU16 5JQ
Country
United Kingdom
Facility Name
Central Manchester University Hospitals NHS
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
34933097
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.
Results Reference
derived
PubMed Identifier
34372849
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.
Results Reference
derived
PubMed Identifier
33549556
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.
Results Reference
derived
PubMed Identifier
31950604
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.
Results Reference
derived
PubMed Identifier
31104495
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.
Results Reference
derived

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

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