Spironolactone in the Treatment of Heart Failure

NCT04727073 | Terminated Phase 3 DMC

• 2 other identifiers: SPIRIT-HF DZHK08SPIRIT-HF DZHK8
• Study Type: interventional
• Target: 743
• Locations: 5 countries
• Sites: 69

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.

Conditions

Heart Failure with Mid-range Ejection Fraction; Heart Failure with Preserved Ejection Fraction

Keywords

heart failure; mid-range ejection fraction; preserved ejection fraction; diastolic dysfunction; Spironolactone; Mineralcorticoid Receptor Antagonist

Outcome Measures

Primary Outcomes (1)

• Primary Objective: Cumulative number of primary composite events of cardiovascular (CV) death and total HF hospitalizations

  Cumulative number of primary composite events of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations in symptomatic HF patients (NYHA II-IV) with mid-range (LVEF 40- 49 %) or preserved (LVEF ≥ 50 %) ejection fraction.

  Time Frame: Total follow up time (up to 48 months)

Secondary Outcomes (1)

• 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)

Study Arms (2)

Arm A

EXPERIMENTAL

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.

Drug: Experimental: Spironolactone

Arm B

PLACEBO COMPARATOR

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

Drug: Placebo Comparator

Interventions

Experimental: Spironolactone DRUG

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 A

Placebo Comparator DRUG

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

Arm B

Eligibility Criteria

• Age: 50 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent.
• Male or female, age ≥ 50 years
• Current symptoms of Heart Failure (NYHA ≥ II) during VR
• Symptom(s) of HF ≥ 30 days prior to VR
• HF Hospitalization or treatment with intravenous (IV) diuretics for worsening HF within 12 months prior to VR
• 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
• 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)
• 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)
• Serum potassium \< 5.0 mmol/L prior to randomization

You may not qualify if:

• Hyperkalemia (potassium level ≥ 5.5 mmol/L) within the past two weeks before VR
• Hyponatraemia (sodium level \< 135 mmol/L) prior to randomization
• 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)
• 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
• Acute coronary syndrome (including MI) and elective PCI within 30 days prior to VR.
• Cardiac surgery, other major CV surgery, or urgent percutaneous coronary intervention (PCI) within the 3 months prior to VR
• 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.
• 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
• Evidence of right sided HF in the absence of left-sided structural heart disease.
• Specific etiologies such as infiltrative, genetic hypertrophic cardiomyopathy, pericardial constriction, sarcoidosis, amyloidosis and any other storage diseases.
• Clinically significant congenital heart disease underlying heart failure.
• 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.

Sponsors & Collaborators

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

Study Sites (69)

Medical University of Graz

Graz, 8010, Austria

Location

Medical University Innsbruck

Innsbruck, 6020, Austria

Location

Clinic Klagenfurt Wörthersee

Klagenfurt, 9020, Austria

Location

University Hospital St. Pölten

Pölten, 3100, Austria

Location

Medical University of Vienna

Vienna, 1090, Austria

Location

Besançon University Hospital

Besançon, 25030, France

Location

Centre Hospitalier de Beziers

Béziers, 34500, France

Location

CHU Clermont-Ferrand

Clermont-Ferrand, 6300, France

Location

Groupe Hospitalier de la Rochelle-Ré-Aunis

La Rochelle, 17019, France

Location

CHU Grenoble Alpes Hopital Michallon

La Tronche, 38700, France

Location

CHU Arnaud de villeneuve

Montpellier, 34295, France

Location

CHRU Nancy Brabois

Nancy, 54500, France

Location

CHU Haut Lévêque Cardiologie

Pessac, 33604, France

Location

Hôpital Sainte Musse

Toulon, 83100, France

Location

CHU Toulouse - Hôpital Rangueil

Toulouse, 31059, France

Location

Kardiologische Praxis Dr. Wolfgang Jungmair

Bad Homburg, 61348, Germany

Location

Kerckhoff Heart and Thorax Center

Bad Nauheim, 61231, Germany

Location

Herz- und Diabeteszentrum NRW, Bad Oeynhausen

Bad Oeynhausen, 32545, Germany

Location

Charité University of Medicine Berlin, CCM

Berlin, 10117, Germany

Location

Klinische Forschung Berlin GbR

Berlin, 10787, Germany

Location

Studienzentrum Rankestraße

Berlin, 10789, Germany

Location

Charité University of Medicine, CBF

Berlin, 12200, Germany

Location

Caritas-Klinik Maria Heimsuchung

Berlin, 13187, Germany

Location

Charité University of Medicine (CVK)

Berlin, 13353, Germany

Location

German Heart Center Berlin, Clinic for Internal Medicine - Cardiology

Berlin, 13353, Germany

Location

Helios Klinikum Emil von Behring GmBH

Berlin, 14165, Germany

Location

Städtisches Klinikum Brandenburg GmbH

Brandenburg, 14770, Germany

Location

Stiftung Bremer Herzen (BIHKF)

Bremen, 28277, Germany

Location

Zentrum für klinische Studien Dresden

Dresden, 01099, Germany

Location

Heart Center Dresden, Technical University of Dresden

Dresden, Germany

Location

Zentrum für klinische Studien Südbrandenburg

Elsterwerda, 04910, Germany

Location

University Hospital of Giessen

Giessen, 35392, Germany

Location

University of Goettingen

Goettigen, 37075, Germany

Location

University Medicine Greifswald

Greifswald, 17475, Germany

Location

Universitätsklinikum Halle (Saale)

Halle, 6120, Germany

Location

University Heart Center Hamburg

Hamburg, 20246, Germany

Location

University of Heidelberg

Heidelberg, 69120, Germany

Location

University Hospital Jena

Jena, 07743, Germany

Location

University Medical Center of Schleswig-Holstein, Campus Kiel

Kiel, 24105, Germany

Location

Universitätsklinikum Leipzig

Leipzig, 04103, Germany

Location

Heart Center Leipzig-University Hospital

Leipzig, 04289, Germany

Location

University Hospital Schleswig-Holstein, University Heart Centre Lübeck

Lübeck, 23538, Germany

Location

University Hospital Mainz

Mainz, 55131, Germany

Location

University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University

Mannheim, 68167, Germany

Location

Kliniken Maria Hilf GmbH

Mönchengladbach, 41063, Germany

Location

German Heart Center Munich

Munich, 80636, Germany

Location

University Hospital Klinikum rechts der Isar (TUM)

Munich, 80992, Germany

Location

University Hospital Munich, Ludwig-Maximilians University

Munich, 81377, Germany

Location

University Hospital rechts der Isar

Munich, 81675, Germany

Location

Kardiologische Praxis Am Park Sanssoucci

Potsdam, 14471, Germany

Location

Praxis Dr. Markus Knapp/Daniela Breuninger

Schwäbisch Hall, 74523, Germany

Location

MVZ Schwering West GmbH

Schwerin, 19057, Germany

Location

Universitätsklinikum Ulm

Ulm, 89081, Germany

Location

Meander Medisch Centrum

Amersfoort, 3813 TZ, Netherlands

Location

Ziekenhuis Amstelland

Amstelveen, 1186 AM, Netherlands

Location

OLVG locatie Oost

Amsterdam, 1091 AC, Netherlands

Location

Van Weel-Bethesda Ziekenhuis

Dirksland, 3240 AD, Netherlands

Location

St. Jansdal Ziekenhuis

Harderwijk, 3844 DG, Netherlands

Location

Elkerliek Ziekenhuis

Helmond, 5707 HA, Netherlands

Location

Gelre Ziekenhuizen

Zutphen, 7207 AE, Netherlands

Location

Institute for Rehabilitation

Belgrade, 11000, Serbia

Location

Clinical Hospital Center B. Kosa

Belgrade, Serbia

Location

Clinical Hospital Center Dr. Dragisa Misovic

Belgrade, Serbia

Location

Clinical Hospital Center Zvezdara

Belgrade, Serbia

Location

Dedinje Cardiovascular Institute

Belgrade, Serbia

Location

Insitute of Cardiovascular Diseases of Vojvodina

Kamenitz, Serbia

Location

Nis Clinical Center

Niš, Serbia

Location

General Hospital Uzice

Užice, Serbia

Location

General Hospital Vršac

Vršac, Serbia

Location

MeSH Terms

Conditions

Heart Failure

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Officials

• Burkert Pieske, Prof. MD

  Charité University of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Univ. Prof. Dr. med. Frank Edelmann

Study Record Dates

• First Submitted: January 28, 2019
• First Posted: January 27, 2021
• Study Start: November 1, 2018
• Primary Completion: October 1, 2024
• Study Completion: October 1, 2024
• Last Updated: March 28, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

NL (7); SE (9); AU (5); FR (10); DE (38)