SPIRIT-HF: Spironolactone In The Treatment of Heart Failure

Sponsor

Charite University, Berlin, Germany (Other)

Overall Status

Recruiting

CT.gov ID

NCT04727073

Collaborator

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

1,300

Enrollment

Locations

Arms

Anticipated Duration (Months)

18.8

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure With Mid-range Ejection Fraction Heart Failure With Preserved Ejection Fraction	Drug: Experimental: Spironolactone Drug: Placebo Comparator	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

1300 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 1, 2018

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

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)]
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.

Secondary Outcome Measures

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)]
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)].

Eligibility Criteria

Criteria

Ages Eligible for Study:

50 Years to 100 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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
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

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.

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.
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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Medical University of Graz	Graz	Austria	8010
2	Medical University Innsbruck	Innsbruck	Austria	6020
3	Clinic Klagenfurt Wörthersee	Klagenfurt	Austria	9020
4	University Hospital St. Pölten	Pölten	Austria	3100
5	Medical University of Vienna	Vienna	Austria	1090
6	Besançon University Hospital	Besançon	France	25030
7	Centre Hospitalier de Beziers	Béziers	France	34500
8	CHU Clermont-Ferrand	Clermont-Ferrand	France	6300
9	Groupe Hospitalier de la Rochelle-Ré-Aunis	La Rochelle	France	17019
10	CHU Grenoble Alpes Hopital Michallon	La Tronche	France	38700
11	CHU Arnaud de villeneuve	Montpellier	France	34295
12	CHRU Nancy Brabois	Nancy	France	54500
13	CHU Haut Lévêque Cardiologie	Pessac	France	33604
14	Hôpital Sainte Musse	Toulon	France	83100
15	CHU Toulouse - Hôpital Rangueil	Toulouse	France	31059
16	Kardiologische Praxis Dr. Wolfgang Jungmair	Bad Homburg	Germany	61348
17	Kerckhoff Heart and Thorax Center	Bad Nauheim	Germany	61231
18	Herz- und Diabeteszentrum NRW, Bad Oeynhausen	Bad Oeynhausen	Germany	32545
19	Charité University of Medicine Berlin, CCM	Berlin	Germany	10117
20	Klinische Forschung Berlin GbR	Berlin	Germany	10787
21	Studienzentrum Rankestraße	Berlin	Germany	10789
22	Charité University of Medicine, CBF	Berlin	Germany	12200
23	Caritas-Klinik Maria Heimsuchung	Berlin	Germany	13187
24	Charité University of Medicine (CVK)	Berlin	Germany	13353
25	German Heart Center Berlin, Clinic for Internal Medicine - Cardiology	Berlin	Germany	13353
26	Helios Klinikum Emil von Behring GmBH	Berlin	Germany	14165
27	Städtisches Klinikum Brandenburg GmbH	Brandenburg an der Havel	Germany	14770
28	Stiftung Bremer Herzen (BIHKF)	Bremen	Germany	28277
29	Zentrum für klinische Studien Dresden	Dresden	Germany	01099
30	Heart Center Dresden, Technical University of Dresden	Dresden	Germany
31	Zentrum für klinische Studien Südbrandenburg	Elsterwerda	Germany	04910
32	University Hospital of Giessen	Gießen	Germany	35392
33	University of Goettingen	Goettigen	Germany	37075
34	University Medicine Greifswald	Greifswald	Germany	17475
35	Universitätsklinikum Halle (Saale)	Halle (Saale)	Germany	6120
36	University Heart Center Hamburg	Hamburg	Germany	20246
37	University of Heidelberg	Heidelberg	Germany	69120
38	University Hospital Jena	Jena	Germany	07743
39	University Medical Center of Schleswig-Holstein, Campus Kiel	Kiel	Germany	24105
40	Universitätsklinikum Leipzig	Leipzig	Germany	04103
41	Heart Center Leipzig-University Hospital	Leipzig	Germany	04289
42	University Hospital Schleswig-Holstein, University Heart Centre Lübeck	Lübeck	Germany	23538
43	University Hospital Mainz	Mainz	Germany	55131
44	University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University	Mannheim	Germany	68167
45	German Heart Center Munich	Munich	Germany	80636
46	University Hospital Klinikum rechts der Isar (TUM)	Munich	Germany	80992
47	University Hospital Munich, Ludwig-Maximilians University	Munich	Germany	81377
48	University Hospital rechts der Isar	Munich	Germany	81675
49	Kliniken Maria Hilf GmbH	Mönchengladbach	Germany	41063
50	Kardiologische Praxis Am Park Sanssoucci	Potsdam	Germany	14471
51	MVZ Schwering West GmbH	Schwerin	Germany	19057
52	Praxis Dr. Markus Knapp/Daniela Breuninger	Schwäbisch Hall	Germany	74523
53	Universitätsklinikum Ulm	Ulm	Germany	89081
54	Meander Medisch Centrum	Amersfoort	Netherlands	3813 TZ
55	Ziekenhuis Amstelland	Amstelveen	Netherlands	1186 AM
56	OLVG locatie Oost	Amsterdam	Netherlands	1091 AC
57	Van Weel-Bethesda Ziekenhuis	Dirksland	Netherlands	3240 AD
58	St. Jansdal Ziekenhuis	Harderwijk	Netherlands	3844 DG
59	Elkerliek Ziekenhuis	Helmond	Netherlands	5707 HA
60	Gelre Ziekenhuizen	Zutphen	Netherlands	7207 AE
61	Institute for Rehabilitation	Belgrade	Serbia	11000
62	Clinical Hospital Center B. Kosa	Belgrade	Serbia
63	Clinical Hospital Center Dr. Dragisa Misovic	Belgrade	Serbia
64	Clinical Hospital Center Zvezdara	Belgrade	Serbia
65	Dedinje Cardiovascular Institute	Belgrade	Serbia
66	Nis Clinical Center	Niš	Serbia
67	Insitute of Cardiovascular Diseases of Vojvodina	Sremska Kamenica	Serbia
68	General Hospital Uzice	Užice	Serbia
69	General Hospital Vršac	Vršac	Serbia