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Heart Failure with Mid-range Ejection FractionPhase 3SPIRIT-HFNCT04727073

Spironolactone in the Treatment of Heart Failure

A Phase 3 study testing Experimental: Spironolactone in people with Heart Failure with Mid-range Ejection Fraction and Heart Failure with Preserved Ejection Fraction, run by Charite University, Berlin, Germany at 69 sites in 5 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial 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. Read more about this study

Who is it for?
Ages 50 to 100 years
What is being tested?
Experimental: Spironolactone
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
743 participants
Where
69 sitesin 5 countries
Study dates
1 Nov 2018to 1 Oct 2024
Phase
Phase 3

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 to 100 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients eligible for inclusion in this study have to fulfill all of the following criteria:
  • 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
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  • 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

Who cannot join

  • 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.
  • 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.
Show all 34Show fewer
  • 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.
  • Presence of significant (i.e., more than moderate) valvular heart disease expected to lead to surgery during the trial in the investigators opinion.
  • Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within the 3 months prior to VR.
  • 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.
  • Patients with prior major organ transplant or intent to transplant (on transplant list) or with current ventricular assist device (VAD) therapy.
  • 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.
  • Evidence of present bilateral renal artery stenosis
  • 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.
  • 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)
  • 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.
  • Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives before enrollment, whichever is longer.
  • 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).
  • History or presence of any other disease (i.e. including malignancies) with a life expectancy of < 1 years.
  • History of non-compliance to medical regimens and patients who are considered potentially unreliable.
  • Subjects who are legally detained in an official institution.
  • Subjects who may be dependent on the sponsor, the investigator or the trial sites, have to be excluded from the trial.
  • 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.
  • 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.

Trial locations and contacts

69 sites in 5 countries.

69 sites in 5 countries

Germany38 sites

  • Kardiologische Praxis Dr. Wolfgang Jungmair

    Bad Homburg, 61348

  • Kerckhoff Heart and Thorax Center

    Bad Nauheim, 61231

  • Herz- und Diabeteszentrum NRW, Bad Oeynhausen

    Bad Oeynhausen, 32545

  • Charité University of Medicine Berlin, CCM

    Berlin, 10117

  • Klinische Forschung Berlin GbR

    Berlin, 10787

  • Studienzentrum Rankestraße

    Berlin, 10789

  • Charité University of Medicine, CBF

    Berlin, 12200

  • Caritas-Klinik Maria Heimsuchung

    Berlin, 13187

  • Charité University of Medicine (CVK)

    Berlin, 13353

  • German Heart Center Berlin, Clinic for Internal Medicine - Cardiology

    Berlin, 13353

  • Helios Klinikum Emil von Behring GmBH

    Berlin, 14165

  • Städtisches Klinikum Brandenburg GmbH

    Brandenburg an der Havel, 14770

  • Stiftung Bremer Herzen (BIHKF)

    Bremen, 28277

  • Zentrum für klinische Studien Dresden

    Dresden, 01099

  • Heart Center Dresden, Technical University of Dresden

    Dresden

  • Zentrum für klinische Studien Südbrandenburg

    Elsterwerda, 04910

  • University Hospital of Giessen

    Giessen, 35392

  • University of Goettingen

    Goettigen, 37075

  • University Medicine Greifswald

    Greifswald, 17475

  • Universitätsklinikum Halle (Saale)

    Halle, 6120

  • University Heart Center Hamburg

    Hamburg, 20246

  • University of Heidelberg

    Heidelberg, 69120

  • University Hospital Jena

    Jena, 07743

  • University Medical Center of Schleswig-Holstein, Campus Kiel

    Kiel, 24105

  • Universitätsklinikum Leipzig

    Leipzig, 04103

  • Heart Center Leipzig-University Hospital

    Leipzig, 04289

  • University Hospital Schleswig-Holstein, University Heart Centre Lübeck

    Lübeck, 23538

  • University Hospital Mainz

    Mainz, 55131

  • University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University

    Mannheim, 68167

  • Kliniken Maria Hilf GmbH

    Mönchengladbach, 41063

  • German Heart Center Munich

    Munich, 80636

  • University Hospital Klinikum rechts der Isar (TUM)

    Munich, 80992

  • University Hospital Munich, Ludwig-Maximilians University

    Munich, 81377

  • University Hospital rechts der Isar

    Munich, 81675

  • Kardiologische Praxis Am Park Sanssoucci

    Potsdam, 14471

  • Praxis Dr. Markus Knapp/Daniela Breuninger

    Schwäbisch Hall, 74523

  • MVZ Schwering West GmbH

    Schwerin, 19057

  • Universitätsklinikum Ulm

    Ulm, 89081

Other trials in Germany

France10 sites

  • Besançon University Hospital

    Besançon, 25030

  • Centre Hospitalier de Beziers

    Béziers, 34500

  • CHU Clermont-Ferrand

    Clermont-Ferrand, 6300

  • Groupe Hospitalier de la Rochelle-Ré-Aunis

    La Rochelle, 17019

  • CHU Grenoble Alpes Hopital Michallon

    La Tronche, 38700

  • CHU Arnaud de villeneuve

    Montpellier, 34295

  • CHRU Nancy Brabois

    Nancy, 54500

  • CHU Haut Lévêque Cardiologie

    Pessac, 33604

  • Hôpital Sainte Musse

    Toulon, 83100

  • CHU Toulouse - Hôpital Rangueil

    Toulouse, 31059

Other trials in France

Serbia9 sites

  • Institute for Rehabilitation

    Belgrade, 11000

  • Clinical Hospital Center B. Kosa

    Belgrade

  • Clinical Hospital Center Dr. Dragisa Misovic

    Belgrade

  • Clinical Hospital Center Zvezdara

    Belgrade

  • Dedinje Cardiovascular Institute

    Belgrade

  • Insitute of Cardiovascular Diseases of Vojvodina

    Kamenitz

  • Nis Clinical Center

    Niš

  • General Hospital Uzice

    Užice

  • General Hospital Vršac

    Vršac

Other trials in Serbia

Netherlands7 sites

  • Meander Medisch Centrum

    Amersfoort, 3813 TZ

  • Ziekenhuis Amstelland

    Amstelveen, 1186 AM

  • OLVG locatie Oost

    Amsterdam, 1091 AC

  • Van Weel-Bethesda Ziekenhuis

    Dirksland, 3240 AD

  • St. Jansdal Ziekenhuis

    Harderwijk, 3844 DG

  • Elkerliek Ziekenhuis

    Helmond, 5707 HA

  • Gelre Ziekenhuizen

    Zutphen, 7207 AE

Other trials in Netherlands

Austria5 sites

  • Medical University of Graz

    Graz, 8010

  • Medical University Innsbruck

    Innsbruck, 6020

  • Clinic Klagenfurt Wörthersee

    Klagenfurt, 9020

  • University Hospital St. Pölten

    Pölten, 3100

  • Medical University of Vienna

    Vienna, 1090

Other trials in Austria

About this study

Official title: 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

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.

Read the 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.

Being tested
Experimental: Spironolactone, Placebo Comparator
Keywords
heart failure, mid-range ejection fraction, preserved ejection fraction, diastolic dysfunction, Spironolactone, Mineralcorticoid Receptor Antagonist
Medical subject headings
Heart Failure

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Experimental: SpironolactoneDrug

    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.

  • Placebo ComparatorDrug

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

Study groups in NCT04727073
Study groupRoleWhat they receive
Arm AExperimentalExperimental: 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.
Receives: Drug: Experimental: Spironolactone
Arm BPlacebo comparatorPlacebo Comparator: Placebo Placebo of Spironolactone in tablet form taken daily with dosage escalation rules in accordance with dosage of the study drug Spironolactone.
Receives: Drug: Placebo Comparator

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (1)

  1. Secondary Objective: Comparison of spironolactone to placebo in reducing the rate of hospitalisations and deaths

    • To compare Spironolactone to placebo in reducing the recurrent rate of heart failure Hospitalizations [Time Frame: Follow-up time up to 48month.]
    • 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, whichever occurred first) [Time Frame: Total follow up time (up to 48 months)].
    • To compare Spironolactone to placebo in reducing the recurrent rate of hospitalizations from any cause [Time Frame: Total follow up time (up to 48 months)].
    • To compare Spironolactone to placebo in reducing the rate of death from cardiovascular (CV) cause [Time Frame: Total follow up time (up to 48 months)].
    • To compare Spironolactone to placebo in reducing the rate of death from any cause [Time Frame: Total follow up time (up to 48 months)].

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jan 2021
  2. Study start1 Nov 2018
  3. Primary completion1 Oct 2024
  4. Study completion1 Oct 2024

Why it stopped: No extension of study funding by the DZHK following COVID-19 pandemic-induced prolongation of the recruitment period, also requiring manufacturing of further study drug batches

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
743 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04727073
Sponsor's protocol ID
SPIRIT-HF DZHK08
Other IDs
SPIRIT-HF DZHK8
Acronym
SPIRIT-HF
Status last verified
Mar 2025
First submitted
28 Jan 2019
Last updated
28 Mar 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

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