Spironolactone In The Treatment of Heart Failure (SPIRIT-HF)

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure With Preserved Ejection Fraction; Heart Failure With Mid-range Ejection Fraction
• Intervention / Treatment: Drug: Experimental: Spironolactone; Drug: Placebo Comparator

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.

• Study Type: Interventional
• Enrollment (Anticipated): 1300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Andrea Deichl, MD; Phone Number: +4930450665374; Email: spirit-hf@charite.de
• Study Contact Backup: Name: Christina Gaulhofer, M.Sc.; Phone Number: +4930450553782; Email: spirit-hf@charite.de

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; 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; 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 Comparator: Arm B; 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; Placebo of Spironolactone in tablet form taken daily with dosage escalation rules in accordance with dosage of the study drug Spironolactone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)].	Time Frame: Total follow up time (up to 48 months)

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: Ludwig-Maximilians - University of Munich; University Medicine Greifswald; University of Göttingen; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK); Echo Core Lab Berlin; Institute for Cardiovascular Computer-assisted Medicine, Charité; Coordinating Centre for Clinical Trials, Charité
• Investigators: Principal Investigator: Burkert Pieske, Prof. MD, Charite University of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2018
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: January 28, 2019
• First Submitted That Met QC Criteria: January 26, 2021
• First Posted (Actual): January 27, 2021

Study Record Updates

• Last Update Posted (Actual): January 29, 2021
• Last Update Submitted That Met QC Criteria: January 28, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: heart failure; diastolic dysfunction; Spironolactone; preserved ejection fraction; mid-range ejection fraction; Mineralcorticoid Receptor Antagonist
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Mineralocorticoid Receptor Antagonists; Diuretics, Potassium Sparing; Spironolactone
• Other Study ID Numbers: SPIRIT-HF DZHK08; SPIRIT-HF DZHK8 (Other Grant/Funding Number: Deutsches Zentrum für Herzkreislaufforschung)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No