Clinical Trials Register

Summary
EudraCT Number:	2017-000697-11
Sponsor's Protocol Code Number:	SPIRIT-HF
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2017-12-08
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2017-000697-11

A.3

Full title of the trial

SPIRonolactone In the Treatment of Heart Failure -
A double-blind, randomized, placebo-controlled, parallel group, interventional phase III study to evaluate the efficacy and safety of spironolactone compared to placebo on the composite endpoint of recurrent heart failure hospitalizations and cardiovascular death in patients with heart failure with mid- range or preserved ejection fraction

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

SPIRonolactone In the Treatment of Heart Failure

A.4.1

Sponsor's protocol code number

SPIRIT-HF

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Charité Universitätsmedizin Berlin
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DZHK - Deutsches Zentrum für Herz-Kreislauf-Forschung
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Charité Universitätsmedizin Berlin
B.5.2	Functional name of contact point	Medizinische Klinik m.S Kardiologie
B.5.3	Address:
B.5.3.1	Street Address	Augustenburger Platz 1
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13353
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4930450553731
B.5.5	Fax number	+49304507553731
B.5.6	E-mail	frank.edelmann@dhzc-charite.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Aldactone 25
D.2.1.1.2	Name of the Marketing Authorisation holder	Riemser Pharma GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Spironolactone
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	spironolactone
D.3.9.1	CAS number	52-01-7
D.3.9.3	Other descriptive name	SPIRONOLACTONE
D.3.9.4	EV Substance Code	SUB10631MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	to 25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart Failure (i.e. Heart Failure with mid-range/ moderately reduced ejection fraction (LVEF 40- 49 %) or with preserved ejection fraction (LVEF ≥ 50 %) with evidence of impaired left ventricular filling capabilities)/ HFmrEF and HFpEF

E.1.1.1

Medical condition in easily understood language

Heart Failure (i.e. Heart Failure with mid-range/ moderately reduced ejection fraction or with preserved ejection fraction with evidence of impaired left ventricular filling capabilities)

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

• To compare Spironolactone to placebo in reducing the recurrent rate of heart failure hospitalizations from any cause
• 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)
• To compare Spironolactone to placebo in reducing the recurrent rate of hospitalizations from any cause
• To compare Spironolactone to placebo in reducing the rate of death from cardiovascular (CV) cause
• To compare Spironolactone to placebo in reducing the rate of death from any cause

E.2.3

Trial contains a sub-study

E.3

Principal 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) on diuretic treatment (any) during VR
4. Symptom(s) of HF ≥ 30 days prior to VR
5. Left ventricular ejection fraction ≥ 40 % at screening measured by echocardiography or MRI and evidence of structural/ functional abnormalities (at least one of the following criteria):
o LAVI > 34 ml/m2
o E/e’mean ≥ 13
o Mean e’ (septal and lateral) < 9 cm/s
o Left ventricular mass index (LVMI) ≥ 115 g/m² (m) and ≥95 g/m² (f)
o Septal or posterior left ventricular wall thickness ≥ 1.1 cm
o Elevated left ventricular end-diastolic pressure (LVEDP) ≥16 mmHg as determined by invasive measurement
o Elevated pulmonary capillary wedge pressure ≥15 mmHg (resting) or ≥25 mmHg (exercise) as determined by invasive measurement
6. Patients with at least 1 of the following:
a. HF hospitalization (defined as HF listed as the major reason for hospitalization) within 12 months prior to Visit of Screening and NTproBNP >200 pg/ml for patients in SR or >600 pg/ml for patients in AF on screening visit ECG (only if NT‐proBNP is not available: BNP > 50/160 pg/ml),
OR
b. NT‐proBNP >300 pg/ml for patients in SR or >900 pg/ml for patients in AF on the screening visit ECG (only if NT‐proBNP is not available: BNP > 80/ 250 pg/ml)
(for entering the study a historical measurement of natriuretic peptides within the last 6 months is acceptable)
7. Serum potassium < 5.2 mmol/L prior to randomization

E.4

Principal exclusion criteria

1. History of hyperkalemia (potassium level ≥ 5.5 mmol/L) within the past two weeks before VR
2. Hyponatremia (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 CKD EPI 2009 formula at VScr/VR or serum creatinine level ≥ 1,8 mg/dl (> 160 μmol/ml)
4. History of anuria or acute renal failure (as defined by the KDIGO 2012 criteria for AKI) within the past two weeks before VR
5. Systolic blood pressure(SBP) ≥160 mmHg if not on treatment with ≥3 blood pressure lowering medications or ≥180 mmHg irrespective of treatments, on 3 consecutive measurements at least 2-minute apart, at screening or at randomization
6. Acute coronary syndrome (including MI), urgent and elective percutaneous coronary intervention (PCI) within 30 days prior to VR. This does not include atrial or ventricular ablations, implantations of pacemakers or event recorders and peripheral percutaneous interventions due to peripheral artery disease.
7. Cardiac surgery and other major CV surgery, within the 3 months prior to VR. This includes percutaneous interventions, such as TAVR, mitral and tricuspid valve clipping or percutaneous reconstruction.
8. 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
9. 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) or anemia. Specifically, patients with the following are not eligible for randomization:
10. Evidence of right sided HF in the absence of left-sided structural heart disease
11. Specific etiologies such as infiltrative, genetic hypertrophic cardiomyopathy, pericardial constriction, sarcoidosis, amyloidosis and any other storage diseases
12. Clinically significant congenital heart disease underlying heart failure
13. 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
14. Presence of significant (i.e., more than moderate) coronary and / or valvular heart disease expected to lead to surgery during the following 6 months after randomization in the investigators opinion.
15. Stroke, transient ischemic attack, within 3 months prior to VR
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 present bilateral renal artery stenosis
18. 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
19. Present use of any aldosterone antagonist or potassium sparing diuretics at the time of enrollment. (Consider stopping these potassium sparing drugs if clinically possible and upon discussion with the patient)
20. Required treatment with prohibited Co-medications according to the summary of product characteristics with the exception of ACE inhibitors or angiotensin receptor blockers. Potassium chloride must be used with caution, in the opinion of the investigator, taking into account the current laboratory values and the risk of potentially fatal hyperkalemia. Concomitant use not recommended:
21. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives before enrollment, whichever is longer
22. 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).
23. History or presence of any other disease (i.e. including malignancies) with a life expectancy of < 1 years
24. Subjects who are legally detained in an official institution
25. Subjects who may be dependent on the sponsor, the investigator or the trial sites, have to be excluded from the trial
26. 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
27. 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. Highly effective contraception methods include:
28. Confirmed SARS-CoV-2 infection at the time of randomization

E.5 End points

E.5.1

Primary end point(s)

A composite of death from cardiovascular cause or recurrent heart failure hospitalizations over follow-up time from randomization.

E.5.1.1

Timepoint(s) of evaluation of this end point

death from cardiovascular cause or recurrent heart failure hospitalizations

E.5.2

Secondary end point(s)

• To compare Spironolactone to placebo in reducing the recurrent rate of heart failure hospitalizations
• 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)
• To compare Spironolactone to placebo in reducing the recurrent rate of hospitalizations from any cause
• To compare Spironolactone to placebo in reducing the rate of death from cardiovascular (CV) cause
• To compare Spironolactone to placebo in reducing the rate of death from any cause

exploratory secondary endpoints:
• To compare Spironolactone to placebo in reducing total non-fatal myocardial infarctions (MIs), and total non-fatal strokes
• To compare Spironolactone to placebo in reducing left ventricular hypertrophy (measured by local ECG)
• To compare Spironolactone to placebo on changes in the clinical summary score for HF symptoms, physical limitations and mental dimensions of quality of life (as assessed by the KCCQ, SF-36)
• To compare Spironolactone to placebo in improving NYHA functional classification
• To compare Spironolactone to placebo in increasing the time to develop new onset atrial fibrillation (NOAF) in patients with no history of AF and without AF on ECG during VR
• To compare Spironolactone to placebo in reducing CV deats and total worsening HF events. A subject will be defined as having a CV death or worsening HF event when the subject has:
1. CV death or
2. a hospitalization for HF or
3. receives intravenous (IV) decongestive therapy (IV diuretics, IV neseritide or other natriuretic peptide, IV inotropes, and IV nitroglycerin [NTG]), and does not result in formal inpatient hospital admission, regardless of the setting (i.e. in an emergency room (ER) setting, in the physician’s office, an outpatient treatment facility, etc.).

E.5.2.1

Timepoint(s) of evaluation of this end point

The analysis of the secondary endpoints hospitalization for any cause, for CV reason and for heart failure will follow the same lines. The time to event outcomes among the secondary endpoints will be analyzed using the Cox proportional hazards model. Treatment effects will be reported in terms of hazard ratios with 95% CI and p-values testing the null hypothesis of no effect.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

France

Germany

Netherlands

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLP

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

433

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

866

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

700

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1100

F.4.2.2

In the whole clinical trial

1300

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After completing all the protocol treatment and visits, patients will
continue with regular visits according to usual practice of the clinic.
In the case of premature termination, the reason for withdrawal must
be entered on the appropriate case report form (CRF) page and must
be followed for safety and efficacy until one month after
discontinuation.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-05-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-08-13

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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