Clinical Trials Register

Summary
EudraCT Number:	2017-000697-11
Sponsor's Protocol Code Number:	SPIRIT-HF
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-08-01
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

France - ANSM

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	4930450565400
B.5.5	Fax number	4930450565900
B.5.6	E-mail	burkert.pieske@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 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

6. Patients with at least 1 of the following:
HF hospitalization (defined as HF listed as the major reason for hospitalization) within 12 months prior to Visit of Screening and NT-proBNP >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. 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

E.4

Principal exclusion criteria

1.hyperkalemia (potassium level ≥ 5.5 mmol/L) within the past two weeks before VR
2.Hyponatriaemia (Na < 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 VScr/VR or serum creatinine level ≥ 1,8 mg/dl (> 160 μmol/ml)
4. History of anuria or acute RF (defined by RIFLE crit. for AKI;3) within past 2 wk before VR
5. Acute CS (including MI) and elective PCI within 30 days prior to VR.
6.Cardiac surgery, other maj CV surgery, or urgent percutaneous PCI within the 3 months prior to VR
7 Current acute decompens. 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 randomized:
•Severe pulmonary disease including COPD or severe asthma bronchiale as requiring continuous corticotherapy or OLD,
•anemia (hemoglobin < 10 g/d ), 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 HF.
12. Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and uncontrolled persistent or permanent 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 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. Presence of bilateral renal artery stenosis.
19. Known intolerance or history of hypersensitivity to the active substance (Spironolactone) or to any of the excipients of the 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. Concomitant use not recommended:
• other potassium-sparing diuretics (alone or combined) (amiloride, potassium canrenoate, triamterene): risk of potentially fatal hyperkalemia, particularly in renal insufficiency (additive hyperkalemic effects).
• potassium chloride
• cyclosporine, tacrolimus
• lithium: Increased plasma lithium with signs of overdose, as with a salt-free diet (decreased urinary lithium excretion). However, if the use of diuretics is necessary, 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.
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. WOCBP, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 7 days off study drug.

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

Serbia

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

120

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

2019-09-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-09-17

P. End of Trial
P.	End of Trial Status	Ongoing

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