Spironolactone In The Treatment of Heart Failure

Spironolactone In The Treatment of Heart Failure- A Double-blind, Randomized, Placebo-controlled, Parallel Group Interventional Phase III Study to Determine Efficacy and Safety of Spironolactone on the Composite Endpoint of Recurrent Heart Failure Hospitalizations and Cardiovascular Death in Patients With Heart Failure With Mid-range or Preserved Ejection Fraction

Sponsors

Lead Sponsor: Charite University, Berlin, Germany

Collaborator: Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Echo Core Lab Berlin
University of Göttingen
University Medicine Greifswald
Ludwig-Maximilians - University of Munich
Institute for Cardiovascular Computer-assisted Medicine, Charité
Coordinating Centre for Clinical Trials, Charité

Source Charite University, Berlin, Germany
Brief Summary

The purpose of this study is to determine whether the treatment of patients with HFmrEF and HFpEF at high risk of cardiovascular events with the mineralocorticoid receptor antagonist (MRA) spironolactone reduces a composite of recurrent heart failure hospitalizations and cardiovascular mortality.

Detailed Description

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. The efficacy and safety of mineralocorticoid receptor antagonist (MRA) in reducing the risk of death and hospitalizations has been proven with two separate substances (Spironolactone; RALES 1999 and Eplerenone; EMPHASIS 2011) in symptomatic heart failure patients with reduced left- ventricular ejection fraction (HFrEF). In 2013 the TOPCAT investigators tried to proof similar efficacy in patients with heart failure and preserved ejection fraction (≥ 45%). Because of regional variations in the enrollment process and difficulties regarding drug adherence the trial revealed neutral findings but the substance spironolactone was still able to show its potential benefit in the American cohort. Hence, the investigators see a strong rationale for testing a mineralocorticoid receptor blocker in patients suffering from heart failure with mid-range or preserved left ventricular ejection fraction. Intervention: Mineralocorticoid receptor blocker Spironolactone in tablet form taken daily. Starting dosage will be 25 mg OD with dosage escalation to 50 mg OD within 4 weeks if kidney function at VR was > 30 mL/min/m2 and potassium < 4.5 mmol/L. Spironolactone is not approved for the treatment of HFmrEF and HFpEF. Matching placebo in tablet form taken daily with dosage escalation rules in accordance with dosage of the study drug Spironolactone. Visits: Screening (VScr), Visit of Randomization (VR), V1 Safety Visit (1 week), V2 (4 weeks), V2S Safety Visit (5 week), V3 (4 months), V4 (8 months), V5 (12 months), V6 (18 months), V7 (24 months), V8 (30 months), V9 (36 months), V10 (42 months), V11/EOT (48 months); VXS (1 week after Visit X). Individual intervention duration with spironolactone or placebo will be continued until the overall expected event rate is reached or until withdrawal of informed consent. Based on previous HF trials the investigators calculate a mean follow-up duration of 3 years (range 2-4 years) depending on the individual inclusion date. Duration of follow-up will be event-rate based, with an expected overall study duration of 60 months. With an anticipated recruitment phase of 24 months; this will result in a maximum follow-up of 48 months and an average follow-up per patient of 36 months assuming a constant recruitment rate.

Overall Status Recruiting
Start Date 2018-11-01
Completion Date 2024-12-31
Primary Completion Date 2024-12-31
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Primary Objective: Cumulative number of primary composite events of cardiovascular (CV) death and total HF hospitalizations Time Frame: Total follow up time (up to 48 months)
Secondary Outcome
Measure Time Frame
Secondary Objective: Comparison of spironolactone to placebo in reducing the rate of hospitalisations and deaths Time Frame: Total follow up time (up to 48 months)
Enrollment 1300
Condition
Intervention

Intervention Type: Drug

Intervention Name: Experimental: Spironolactone

Description: Spironolactone (an aldosterone antagonist) in tablet form taken daily. The initial study drug dose is 25 mg/day (one tablet) and may be titrated up to 50 mg/day (two tablets) within 4 weeks if kidney function at VR was > 30 mL/min/m2 and potassium < 4.5 mmol/L.

Arm Group Label: Arm A

Intervention Type: Drug

Intervention Name: Placebo Comparator

Description: Placebo of Spironolactone in tablet form taken daily with dosage escalation rules in accordance with dosage of the study drug Spironolactone.

Arm Group Label: Arm B

Eligibility

Criteria:

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) during VR 4. Symptom(s) of HF ≥ 30 days prior to VR 5. HF Hospitalization or treatment with intravenous (IV) diuretics for worsening HF within 12 months prior to VR 6. Left ventricular ejection fraction ≥ 40 % at screening measured by echocardiography and evidence of structural/ functional abnormalities (at least one of the following criteria): LAVI > 34 ml/m2// E/émean ≥ 13// Mean e' (septal and lateral) < 9 cm/s 7. NT-proBNP > 300 pg/ml (SR) or > 900 pg/ml (AF) on the Visit 1 ECG; only if NT-proBNP is NOT available: BNP > 80/ 250 pg/ml (SR/AF) 8. Controlled systolic BP: defined as a target systolic BP < 140 mm Hg. Subjects with BP up to and including 160 mm Hg are eligible for enrollment if on 3 or more medications to control BP (Patients with uncontrolled BP should be considered for Re-Screening after optimization of antihypertensive therapy has been established) 9. Serum potassium < 5.0 mmol/L prior to randomization Exclusion Criteria: Patients fulfilling any of the following criteria are not eligible for inclusion in this study. The investigator may apply no additional exclusion criteria, in order to ensure that the study population will be representative of all eligible patients. 1. Hyperkalemia (potassium level ≥ 5.5 mmol/L) within the past two weeks before VR 2. Hyponatraemia (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 Modification in Diet in Renal Disease (MDRD) formula at Visit 1 or serum creatinine level ≥ 1,8 mg/dl (> 160 μmol/ml) 4. History of anuria or acute renal failure (as defined by the RIFLE 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 Modification in Diet in Renal Disease (MDRD) 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 RIFLE criteria for AKI; see Appendix XVIII.3) within the past two weeks prior to randomization 5. Acute coronary syndrome (including MI) and elective PCI within 30 days prior to VR. 6. Cardiac surgery, other major CV surgery, or urgent percutaneous coronary intervention (PCI) within the 3 months prior to VR 7. 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. 8. 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), anemia or obesity. Specifically, patients with the following are not eligible for randomization: - Severe pulmonary disease including chronic obstructive pulmonary disease (COPD) or severe asthma bronchiale ( (ie requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy) or - anemia (hemoglobin < 10 g/dL males and < 9.5 g/dL females), or - body mass index (BMI) > 40 kg/m2 9. Evidence of right sided HF in the absence of left-sided structural heart disease. 10. Specific etiologies such as infiltrative, genetic hypertrophic cardiomyopathy, pericardial constriction, sarcoidosis, amyloidosis and any other storage diseases. 11. Clinically significant congenital heart disease underlying heart failure. 12. 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. 13. Presence of significant (i.e., more than moderate) valvular heart disease expected to lead to surgery during the trial in the investigators opinion. 14. Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within the 3 months prior to VR. 15. Coronary or carotid artery disease or valvular heart disease likely to require surgical or percutaneous intervention within the 6 months after VR in the investigators opinion. 16. Patients with prior major organ transplant or intent to transplant (on transplant list) or with current ventricular assist device (VAD) therapy. 17. Evidence of hepatic disease as determined by any one of the following: SGOT (AST) or SGPT (ALT) values exceeding 3x the upper limit of normal (ULN), bilirubin >1.5 mg/dl at VR. 18. Evidence of present bilateral renal artery stenosis 19. Known intolerance or history of hypersensitivity to the active substance (Spironolactone) or to any of the excipients of the Investigational Medicinal Product (IMP) or placebo. 20. Present use of any aldosterone antagonist, potassium supplements or potassium sparing diuretics at the time of enrollment. (Consider stopping these potassium sparing drugs if clinically possible and upon discussion with the patient) 21. Required treatment with prohibited Co-medications according to the summary of product characteristics with the exception of ACE inhibitors or angiotensin receptor blockers (as described in the protocol in IV.2). , careful monitoring of plasma lithium and dose adjustment are required. 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 (e.g. history of non-compliance to medical regimens, patients who are considered potentially unreliable, patients with a history of addiction). 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 are legally detained in an official institution. 27. Subjects who may be dependent on the sponsor, the investigator or the trial sites, have to be excluded from the trial. 28. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test. 29. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during study participation and until 2 months after the last dose off study drug.

Gender:

All

Minimum Age:

50 Years

Maximum Age:

100 Years

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Burkert Pieske, Prof. MD Principal Investigator Charité University of Medicine
Overall Contact

Last Name: Andrea Deichl, MD

Phone: +4930450665374

Email: [email protected]

Location
Facility: Status:
Medical University of Graz | Graz, 8010, Austria Recruiting
Medical University Innsbruck | Innsbruck, 6020, Austria Not yet recruiting
Clinic Klagenfurt Wörthersee | Klagenfurt, 9020, Austria Recruiting
University Hospital St. Pölten | Pölten, 3100, Austria Recruiting
Medical University of Vienna | Vienna, 1090, Austria Recruiting
Besançon University Hospital | Besançon, 25030, France Not yet recruiting
Centre Hospitalier de Beziers | Béziers, 34500, France Recruiting
CHU Clermont-Ferrand | Clermont-Ferrand, 6300, France Recruiting
Groupe Hospitalier de la Rochelle-Ré-Aunis | La Rochelle, 17019, France Recruiting
CHU Grenoble Alpes Hopital Michallon | La Tronche, 38700, France Recruiting
CHU Arnaud de villeneuve | Montpellier, 34295, France Recruiting
CHRU Nancy Brabois | Nancy, 54500, France Recruiting
CHU Haut Lévêque Cardiologie | Pessac, 33604, France Recruiting
Hôpital Sainte Musse | Toulon, 83100, France Recruiting
CHU Toulouse - Hôpital Rangueil | Toulouse, 31059, France Recruiting
Kardiologische Praxis Dr. Wolfgang Jungmair | Bad Homburg, 61348, Germany Recruiting
Kerckhoff Heart and Thorax Center | Bad Nauheim, 61231, Germany Recruiting
Herz- und Diabeteszentrum NRW, Bad Oeynhausen | Bad Oeynhausen, 32545, Germany Recruiting
Charité University of Medicine Berlin, CCM | Berlin, 10117, Germany Recruiting
Klinische Forschung Berlin GbR | Berlin, 10787, Germany Recruiting
Studienzentrum Rankestraße | Berlin, 10789, Germany Recruiting
Charité University of Medicine, CBF | Berlin, 12200, Germany Recruiting
Caritas-Klinik Maria Heimsuchung | Berlin, 13187, Germany Not yet recruiting
Charité University of Medicine (CVK) | Berlin, 13353, Germany Recruiting
German Heart Center Berlin, Clinic for Internal Medicine - Cardiology | Berlin, 13353, Germany Recruiting
Helios Klinikum Emil von Behring GmBH | Berlin, 14165, Germany Not yet recruiting
Städtisches Klinikum Brandenburg GmbH | Brandenburg an der Havel, 14770, Germany Recruiting
Stiftung Bremer Herzen (BIHKF) | Bremen, 28277, Germany Recruiting
Zentrum für klinische Studien Dresden | Dresden, 01099, Germany Recruiting
Heart Center Dresden, Technical University of Dresden | Dresden, Germany Recruiting
Zentrum für klinische Studien Südbrandenburg | Elsterwerda, 04910, Germany Recruiting
University Hospital of Giessen | Gießen, 35392, Germany Recruiting
University of Goettingen | Goettigen, 37075, Germany Recruiting
University Medicine Greifswald | Greifswald, 17475, Germany Recruiting
Universitätsklinikum Halle (Saale) | Halle (Saale), 6120, Germany Recruiting
University Heart Center Hamburg | Hamburg, 20246, Germany Recruiting
University of Heidelberg | Heidelberg, 69120, Germany Recruiting
University Hospital Jena | Jena, 07743, Germany Recruiting
University Medical Center of Schleswig-Holstein, Campus Kiel | Kiel, 24105, Germany Recruiting
Universitätsklinikum Leipzig | Leipzig, 04103, Germany Recruiting
Heart Center Leipzig-University Hospital | Leipzig, 04289, Germany Recruiting
University Hospital Schleswig-Holstein, University Heart Centre Lübeck | Lübeck, 23538, Germany Recruiting
University Hospital Mainz | Mainz, 55131, Germany Recruiting
University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University | Mannheim, 68167, Germany Recruiting
German Heart Center Munich | Munich, 80636, Germany Recruiting
University Hospital Klinikum rechts der Isar (TUM) | Munich, 80992, Germany Recruiting
University Hospital Munich, Ludwig-Maximilians University | Munich, 81377, Germany Recruiting
University Hospital rechts der Isar | Munich, 81675, Germany Recruiting
Kliniken Maria Hilf GmbH | Mönchengladbach, 41063, Germany Recruiting
Kardiologische Praxis Am Park Sanssoucci | Potsdam, 14471, Germany Recruiting
MVZ Schwering West GmbH | Schwerin, 19057, Germany Recruiting
Praxis Dr. Markus Knapp/Daniela Breuninger | Schwäbisch Hall, 74523, Germany Recruiting
Universitätsklinikum Ulm | Ulm, 89081, Germany Recruiting
Meander Medisch Centrum | Amersfoort, 3813 TZ, Netherlands Recruiting
Ziekenhuis Amstelland | Amstelveen, 1186 AM, Netherlands Recruiting
OLVG locatie Oost | Amsterdam, 1091 AC, Netherlands Recruiting
Van Weel-Bethesda Ziekenhuis | Dirksland, 3240 AD, Netherlands Recruiting
St. Jansdal Ziekenhuis | Harderwijk, 3844 DG, Netherlands Recruiting
Elkerliek Ziekenhuis | Helmond, 5707 HA, Netherlands Recruiting
Gelre Ziekenhuizen | Zutphen, 7207 AE, Netherlands Recruiting
Institute for Rehabilitation | Belgrade, 11000, Serbia Recruiting
Clinical Hospital Center B. Kosa | Belgrade, Serbia Not yet recruiting
Clinical Hospital Center Dr. Dragisa Misovic | Belgrade, Serbia Not yet recruiting
Clinical Hospital Center Zvezdara | Belgrade, Serbia Not yet recruiting
Dedinje Cardiovascular Institute | Belgrade, Serbia Not yet recruiting
Nis Clinical Center | Niš, Serbia Not yet recruiting
Insitute of Cardiovascular Diseases of Vojvodina | Sremska Kamenica, Serbia Not yet recruiting
General Hospital Uzice | Užice, Serbia Not yet recruiting
General Hospital Vršac | Vršac, Serbia Not yet recruiting
Location Countries

Austria

France

Germany

Netherlands

Serbia

Verification Date

2021-01-01

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Charite University, Berlin, Germany

Investigator Full Name: Burkert Pieske

Investigator Title: Univ. Prof. Dr. med. Burkert Pieske

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Arm A

Type: Experimental

Description: Experimental: Spironolactone Spironolactone (an aldosterone antagonist) in tablet form taken daily. The initial study drug dose is 25 mg/day (one tablet) and may be titrated up to 50 mg/day (two tablets) within 4 weeks if kidney function at VR was > 30 mL/min/m2 and potassium < 4.5 mmol/L.

Label: Arm B

Type: Placebo Comparator

Description: Placebo Comparator: Placebo Placebo of Spironolactone in tablet form taken daily with dosage escalation rules in accordance with dosage of the study drug Spironolactone.

Acronym SPIRIT-HF
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Double (Participant, Investigator)

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