E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Elderly patients with Clinical and Biological risk factors for developing heart failure |
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E.1.1.1 | Medical condition in easily understood language |
elderly patients with cardiovascular risks |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
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E.2.2 | Secondary objectives of the trial |
To investigate whether, over nine months. spironolactone can induce favourable changes in: serum or plasma concentrations of other biomarkers of extracellular matrix turnover, in cardiac remodelling, in vascular function , in exercise capacity and To investigate whether spironolactone alters the rate of the clinical composite of development of heart failure or atrial fibrillation, non-fatal myocardial infarction or stroke or CV death; or change pre-specified expected Adverse events
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Written informed consent will be obtained prior to any study procedure;
2. Age >60years
3. Clinical risk factors for developing heart failure, either:
Coronary artery disease (h/o myocardial infarction, angioplasty or coronary artery bypass)
Or
B. At least two of the following:
• Diabetes Mellitus requiring Hypoglycaemic Pharmacotherapy
• Receiving pharmacological treatment for Hypertension
• Microalbuminuria (defined as albumin/creatinine ratio > 3mg/mmol whatever the gender)
• Abnormal ECG (left ventricular hypertrophy, QRS >120msec,
abnormal Q-waves)
4. 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)
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E.4 | Principal exclusion criteria |
1. Recent wound healing/inflammation:
• Surgical procedure, coronary, cerebral or peripheral vascular events or infection in the prior 3 months
• Cancer (life limiting or less than 2 years in remission)
• Autoimmune disease
• Hepatic Disease
2. Pre-existing diagnosis of clinical HF
3. Moderate/severe LV systolic ventricular dysfunction, i.e. LVEF <45%
4. Moderate or severe valve disease (investigators opinion)
5. Corrected eGFR< 30ml/min /1.73m2, using the MDRD four-variable equation
6. Serum potassium >5.0 mmol/L and serum sodium <125 mmol/L (whether ot not associated with hepatic cirrhosis)
7. Treatment with an MRA or a loop diuretic (furosemide, bumetanide, ethacrynic acid or torasemide) in the previous three months
8. Potassium supplements or potassium-sparing diuretic at time of enrolment.
9. Atrial fibrillation within one month prior to inclusion (AF lasting <60 seconds on ambulatory ECG monitoring is permitted)
10. History of hypersensitivity to spironolactone or any of its excipients.
11. Patients who require treatment with prohibited medication according to the summary of product characteristics with the exception of ACE inhibitors or angiotensin receptor blockers – although not their combination
12. Patients unable to give written informed consent.
13. Participation in another interventional trial in the preceding month
14. Ability to walk is, in the investigators opinion, clearly limited by joint disease or other locomotor problems or lung disease rather than by cardiorespiratory fitness
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E.5 End points |
E.5.1 | Primary end point(s) |
Changes in serum concentrations of PIIINP from baseline to nine months. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at 9 months compared to baseline |
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E.5.2 | Secondary end point(s) |
1.Changes in levels of biomarkers of extracellular matrix turnover: PICP (synthesis) and ICTP (degradation).
2.Cardiac remodelling, assessed by echocardiography
3.Distance walked on a shuttle walk-test with assessment of peak heart and respiratory rate if data on shuttle test are available. .
4.Vascular function assessed by non-invasive technologies
5.Rate of the clinical composite of development of heart failure or atrial fibrillation, non-fatal myocardial infarction or stroke or CV death
6.Safety endpoints: Investigator reported adverse events (AEs) will be collected using the ad hoc reporting system. In addition, pre-specified expected AEs will be monitored : Worsening renal function (decline in eGFR >20%), Hyperkalemia (rise of serum potassium to >5.5 mmol/L), Rate of gynaecomastia and/or breast pain, Changes in serum potassium and eGFR, 4.5 Hypotension, falls and fractures
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
at 9 months compared to Baseline and more specifically for safety : at all visits |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open Randomized clinical trial with Blinded Evaluation |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Background treatment only – no additional treatment. |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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All patients will have a final review (by telephone, letter, e-mail or clinic as preferred by the patient) approximately 9 months after the last patient has been enrolled. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |