E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart Failure (i.e. Heart Failure with mid-range/ moderately reduced ejection fraction (LVEF 40- 49 %) or with preserved ejection fraction (LVEF ≥ 50 %) with evidence of impaired left ventricular filling capabilities)/ HFmrEF and HFpEF |
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E.1.1.1 | Medical condition in easily understood language |
Heart Failure (i.e. Heart Failure with mid-range/ moderately reduced ejection fraction or with preserved ejection fraction with evidence of impaired left ventricular filling capabilities) |
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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 |
The primary objective of the SPIRIT-HF study is to compare Spironolactone to Placebo in reducing the rate of the composite endpoint of recurrent heart failure hospitalizations and cardiovascular (CV) death in symptomatic HF patients (NYHA II-IV) with mid-range (LVEF 40- 49 %) or preserved (LVEF ≥ 50 %) ejection fraction. |
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E.2.2 | Secondary objectives of the trial |
• To compare Spironolactone to placebo in reducing the recurrent rate of heart failure hospitalizations from any cause • To compare Spironolactone to placebo in reducing the rate of recurrent non-fatal hospitalizations from cardiovascular (CV) cause (i.e. hospitalization for non-fatal MI, non-fatal stroke, or the management of heart failure) • To compare Spironolactone to placebo in reducing the recurrent rate of hospitalizations from any cause • To compare Spironolactone to placebo in reducing the rate of death from cardiovascular (CV) cause • To compare Spironolactone to placebo in reducing the rate of death from any cause
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 1. Written informed consent 2. Male or female, age ≥ 50 years 3. Current symptoms of Heart Failure (NYHA ≥ II) on diuretic treatment (any) during VR 4. Symptom(s) of HF ≥ 30 days prior to VR 5. Left ventricular ejection fraction ≥ 40 % at screening measured by echocardiography or MRI and evidence of structural/ functional abnormalities (at least one of the following criteria): o LAVI > 34 ml/m2 o E/e’mean ≥ 13 o Mean e’ (septal and lateral) < 9 cm/s o Left ventricular mass index (LVMI) ≥ 115 g/m² (m) and ≥95 g/m² (f) o Septal or posterior left ventricular wall thickness ≥ 1.1 cm o Elevated left ventricular end-diastolic pressure (LVEDP) ≥16 mmHg as determined by invasive measurement o Elevated pulmonary capillary wedge pressure ≥15 mmHg (resting) or ≥25 mmHg (exercise) as determined by invasive measurement 6. Patients with at least 1 of the following: a) HF hospitalization (defined as HF listed as the major reason for hospitalization) within 12 months prior to Visit of Screening and NTproBNP >200 pg/ml for patients in SR or >600 pg/ml for patients in AF on screening visit ECG (only if NT‐proBNP is not available: BNP > 50/160 pg/ml), OR b) NT‐proBNP >300 pg/ml for patients in SR or >900 pg/ml for patients in AF on the screening visit ECG (only if NT‐proBNP is not available: BNP > 80/ 250 pg/ml) (for entering the study a historical measurement of natriuretic peptides within the last 6 months is acceptable) 7. Serum potassium < 5.2 mmol/L prior to randomization
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E.4 | Principal exclusion criteria |
1. History of hyperkalemia (potassium level ≥ 5.5 mmol/L) within the past two weeks before VR 2. Hyponatremia (sodium level < 135 mmol/L) prior to randomization 3. Severe renal dysfunction, defined as an estimated glomerular filtration rate of less than 30 mL/min/1.73m2) as calculated by the CKD EPI 2009 formula at VScr/VR or serum creatinine level ≥ 1,8 mg/dl (> 160 μmol/ml) 4. History of anuria or acute renal failure (as defined by the KDIGO 2012 criteria for AKI; see Appendix XVIII.3) within the past two weeks before VRenal dysfunction, defined as an estimated glomerular filtration rate of less than 30 mL/min/1.73m2) as calculated by the CKD EPI 2009 formula at VScr/VR or serum creatinine level ≥ 1,8 mg/dl (> 160 μmol/ml)History of anuria or acute renal failure (as defined by the KDIGO 2012 criteria for AKI; see Appendix XVIII.3) within the past two weeks prior to randomization 5. Systolic blood pressure(SBP) ≥160 mmHg if not on treatment with ≥3 blood pressure lowering medications or ≥180 mmHg irrespective of treatments, on 3 consecutive measurements at least 2-minute apart, at screening or at randomization 6. Acute coronary syndrome (including MI), urgent and elective percutaneous coronary intervention (PCI) within 30 days prior to VR. This does not include atrial or ventricular ablations, implantations of pacemakers or event recorders and peripheral percutaneous interventions due to peripheral artery disease. 7. Cardiac surgery or other major CV surgery within 3 months prior to VR. This includes percutaneous interventions, such as TAVR, mitral and tricuspid valve clipping or percutaneous reconstruction. 8. Current acute decompensated HF requiring augmented therapy with i.v. diuretics, i.v. vasodilators and/or i.v. inotropic drugs. Patients are eligible after initial stabilization. 9. Probable alternative diagnoses that in the opinion of the investigator could account for the patient’s HF symptoms (i.e., dyspnea, fatigue) such as significant pulmonary disease (including primary pulmonary HTN) or anemia. Specifically, patients with the following are not eligible for randomization: • Severe pulmonary disease including severe chronic obstructive pulmonary disease (COPD) or severe asthma bronchiale or • anemia (hemoglobin < 10 g/dL males and < 9.5 g/dL females) 10. Evidence of right sided HF in the absence of left-sided structural heart disease 11. Specific etiologies such as infiltrative, genetic hypertrophic cardiomyopathy, pericardial constriction, sarcoidosis, amyloidosis and any other storage diseases 12. Clinically significant congenital heart disease underlying heart failure 13. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and uncontrolled persistent or permanent atrial fibrillation (AF) or flutter (with a heart rate > 100 beats per minute (bpm), RACE II) during VR. If AF with HR > 100/min, the patient may be rescreened after treatment for rate control 14. Presence of significant (i.e., more than moderate) coronary and / or valvular heart disease expected to lead to surgery during the following 6 months after randomization in the investigators opinion. 15. Stroke, transient ischemic attack, within the 3 months prior to VR 16. Patients with prior major organ transplant or intent to transplant (on transplant list) or with current ventricular assist device (VAD) therapy. 17. Presence of bilateral renal artery stenosis. 18. Known intolerance or history of hypersensitivity to the active substance (Spironolactone) or to any of the excipients of the IMP or placebo 20.Present use of any aldosterone antagonist, potassium supplements or potassium sparing diuretics at the time of enrollment. 21. Required treatment with prohibited Co-medications according to the summary of product characteristics with the exception of ACE inhibitors or angiotensin receptor blockers. Concomitant use not recommended 22. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives before enrollment, whichever is longer. 23. Any condition that, in the opinion of the investigator, may prevent the subject from adhering to the study protocol. 24. History or presence of any other disease (i.e. including malignancies) with a life expectancy of < 1 years. 25. History of non-compliance to medical regimens and patients who are considered potentially unreliable. 26. Subjects who may be dependent on the sponsor, the investigator or the trial sites, have to be excluded from the trial. 27, Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, 28. WOCBP, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 7 days off study drug.
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E.5 End points |
E.5.1 | Primary end point(s) |
A composite of death from cardiovascular cause or recurrent heart failure hospitalizations over follow-up time from randomization. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
death from cardiovascular cause or recurrent heart failure hospitalizations |
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E.5.2 | Secondary end point(s) |
• To compare Spironolactone to placebo in reducing the recurrent rate of heart failure hospitalizations • To compare Spironolactone to placebo in reducing the rate of recurrent non-fatal hospitalizations from cardiovascular (CV) cause (i.e. hospitalization for non-fatal MI, non-fatal stroke, or the management of heart failure) • To compare Spironolactone to placebo in reducing the recurrent rate of hospitalizations from any cause • To compare Spironolactone to placebo in reducing the rate of death from cardiovascular (CV) cause • To compare Spironolactone to placebo in reducing the rate of death from any cause
exploratory secondary endpoints: • To compare Spironolactone to placebo in reducing total non-fatal myocardial infarctions (MIs), and total non-fatal strokes • To compare Spironolactone to placebo in reducing left ventricular hypertrophy (measured by local ECG) • To compare Spironolactone to placebo on changes in the clinical summary score for HF symptoms, physical limitations and mental dimensions of quality of life (as assessed by the KCCQ, SF-36) • To compare Spironolactone to placebo in improving NYHA functional classification • To compare Spironolactone to placebo in increasing the time to develop new onset atrial fibrillation (NOAF) in patients with no history of AF and without AF on ECG during VR • To compare Spironolactone to placebo in reducing CV deats and total worsening HF events. A subject will be defined as having a CV death or worsening HF event when the subject has: 1. CV death or 2. a hospitalization for HF or 3. receives intravenous (IV) decongestive therapy (IV diuretics, IV neseritide or other natriuretic peptide, IV inotropes, and IV nitroglycerin [NTG]), and does not result in formal inpatient hospital admission, regardless of the setting (i.e. in an emergency room (ER) setting, in the physician’s office, an outpatient treatment facility, etc.).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The analysis of the secondary endpoints hospitalization for any cause, for CV reason and for heart failure will follow the same lines. The time to event outcomes among the secondary endpoints will be analyzed using the Cox proportional hazards model. Treatment effects will be reported in terms of hazard ratios with 95% CI and p-values testing the null hypothesis of no effect. |
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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 | No |
E.6.11 | Pharmacogenomic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
France |
Germany |
Netherlands |
Serbia |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 85 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 85 |