Clinical Trials Register

Summary
EudraCT Number:	2016-002019-16
Sponsor's Protocol Code Number:	U-2015-030
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-07-25
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

Sweden - MPA

A.2

EudraCT number

2016-002019-16

A.3

Full title of the trial

Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction

A.3.1

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

Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction

A.3.2

Name or abbreviated title of the trial where available

SPIRRIT-HFPEF

A.4.1

Sponsor's protocol code number

U-2015-030

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	Uppsala Clinical Research center
B.1.3.4	Country	Sweden
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	Hjärt-lungfonden
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Uppsala Clinical Reseach center
B.5.2	Functional name of contact point	Mirjam Goedkoop Project manager
B.5.3	Address:
B.5.3.1	Street Address	Dag Hammarskjölds väg 38
B.5.3.2	Town/ city	Uppsala
B.5.3.3	Post code	75185
B.5.3.4	Country	Sweden
B.5.4	Telephone number	4601861100009509
B.5.6	E-mail	mirjam.goedkoop@ucr.uu.se

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	Spironolaktion Pfizer Spironolakton Orion Spironolakton Takeda Spironolakton Accord Eplerenone Sandoz Eplerenone Accord Eplerenone Bluefish Eplerenone Teva Eplerenone Krka Eplerenon Medical Valley Eplerenone STADA
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer, Orion, Takeda, Accord, Sandoz, Accord, Bleufish, Teva, STADA, Krka, Medical Valley Invest AB
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
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, Eplerenone
D.3.2	Product code	SUB10631MIG, SUB06574MIG
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.3.9.3	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	equal
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	EPLERENONE
D.3.9.4	EV Substance Code	SUB06574MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart Failure with Preserved Ejection Fraction, HFPEF

E.1.1.1

Medical condition in easily understood language

Heart failure with preserved pump function

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10076396
E.1.2	Term	Heart failure with preserved ejection fraction
E.1.2	System Organ Class	100000004849

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 is to assess whether the initiation of spironolactone or eplerenone plus standard of care compared to standard of care alone reduces the incidence rate for total heart failure (HF) hospitalizations or cardiovascular (CV) death in HFpEF, studied with the pragmatic Registry-based Randomized Clinical Trial (RRCT) methodology.

E.2.2

Secondary objectives of the trial

The secondary efficacy objectives are to evaluate:
1. Time to CV death or first HF hospitalization
2. Time to CV death
3. Incidence rate for total HF hospitalizations
4. Time to HF hospitalization
5. Time to all-cause mortality
6. Incidence rate for total all-cause hospitalizations
7. Time to all-cause hospitalization
8. Incidence rate for all-cause hospitalization or all-cause mortality

Exploratory efficacy objectives are to evaluate:
1. Time to sudden death or aborted cardiac arrest
2. Time to acute coronary syndrome/acute myocardial infarction
3. Time to stroke
4. Time to hospitalization for hypokalemia
5. Time to new-onset atrial fibrillation (Sweden only)
6. Time to new-onset diabetes mellitus (Sweden only)

Safety objectives are to evaluate changes in potassium and renal function

Adherence will be evaluated by assessing time to cross-over (from spironolactone/ eplerenone to control and from control to spironolactone/ eplerenone)

New secondary exploratory objectives
7. Incidence rate for total HF events, HF hospitalizations, or CV death
8. Incidence rate for unplanned non-hospitalized heart failure events
9. Time to unplanned non-hospitalized heart failure event
10. Incidence rate for total escalation of loop diuretic therapy, HF events, HF hospitalizations, or CV death
11. Incidence rate for escalation of loop diuretic therapy
12. Time to escalation of loop diuretic therapy

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

SUBSTUDY TITLE: Echocardiography and biomarkers in the Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction

Substudy Protocol version 2, 2019

Primary Outcome Measures:
1. Net increase compared to controls in LA reservoir strain at 12-month follow-up.
2. Net reduction compared to controls of NT-proBNP at 12-month follow-up

Secondary Outcomes
1. Reverse LA remodelling (LAVi) at 12-month follow-up
2. Improvement in doppler-based Stroke Volume Index (SVi) at 12-month follow-up
3. Improvement in RV-pulmonary arterial (PA) coupling (TAPSE/PA systolic pressure) at
12-month follow up
4. Changes in the OLINK cardiovascular, inflammatory and metabolic proteomic panels
5. Changes in single biomarkers reflecting inflammation, renal dysfunction,
neurohormonal activation, endothelial function

E.3

Principal inclusion criteria

1. Written informed consent
2. Age ≥50 years
3. Stable heart failure defined by symptoms and signs of heart failure as judged by local Investigator. Patients may be enrolled as an outpatient or at or close to the time of hospital discharge
4. Most recent left ventricular ejection fraction (LVEF) ≥40%
5. Elevated natriuretic peptide levels as defined by any of the following:
a. most recent NT-proBNP >300 ng/L (or BNP >100 pg/mL) in sinus rhythm
(at time of blood sampling); adjustments may be made for BMI according to table 3.
b. most recent NT-proBNP >750 ng/L (or BNP >250 pg/mL) in atrial fibrillation
(at time of blood sampling); adjustments may be made for BMI according to table 3.
c. NT-proBNP >1200 ng/L (or BNP >400 pg/mL) within the last 12 months even if most
recent value is lower
6. Regular use of loop diuretics, defined as daily or most days of the week
7. NYHA Class II-IV

E.4

Principal exclusion criteria

1. Previously enrolled in this study
2. Known EF < 40% ever
3. Current absolute indication or contraindication for MRA in judgement of Investigator. In the absence of absolute indication, patients currently treated with an MRA may have the MRA discontinued and then included in the trial, according to investigator judgement
4. Known chronic liver disease
5. Probable alternative explanations for symptoms such as:
(a) Known primary cardiomyopathy that is hypertrophic with obstruction, constrictive,
restrictive, infiltrative, or congenital (hypertrophic without current obstruction and other
primary cardiomyopathies are allowed)
(b) Primary valve disease (to exclude a patient, the valve disease must be primary AND the
primary cause of the symptoms)
(c) Significant chronic pulmonary disease requiring home O2
(d) Symptomatic anemia (hemoglobin is <10 g/dL (100 g/L) and this is the likely casue of the
symptoms)
(e) Right-sided HF not due to left sided HF

6. Heart transplant or LVAD recipient
7. Systolic blood pressure <90 or >160
8. K >5.0 mmol/L
9. eGFR by MDRD < 30 ml/min/1.73m2
10. Current dialysis
11.Current lithium use
12. Actual or potential for pregnancy
13. Participation in another clinical trial where a mineralcorticoid receptor antagonist is studied. Co-enrollment in trials and observational studies of other medical and device interventions is permitted
14. Not suitable in the opinion of the Investigator due to severe or terminal comorbidity with poor prognosis, or characteristics that may interfere with adherence to trial protocol

E.5 End points

E.5.1

Primary end point(s)

Time to CV death or first HF hospitalization

E.5.1.1

Timepoint(s) of evaluation of this end point

Evaluation of the primary endpoint will be performed at study end

E.5.2

Secondary end point(s)

Secondary
• Time to CV death
• Incidence rate for total HF hospitalizations or cardiovascular death
• Incidence rate for total HF hospitalizations
• Time to HF hospitalization
• Time to all-cause mortality
• Incidence rate for total all-cause hospitalizations
• Time to all-cause hospitalization
• Incidence rate for all-cause hospitalization or all-cause mortality

Exploratory
• Time to sudden death or aborted cardiac arrest
• Time to acute coronary syndrome/acute myocardial infarction
• Time to stroke
• Time to hospitalization for hypokalemia
• Time to new-onset atrial fibrillation (Sweden only)
• Time to new-onset diabetes mellitus (Sweden only)
• Incidence rate for total HF events, HF hospitalizations, or CV death
• Incidence rate for unplanned non-hospitalized heart failure events
• Time to unplanned non-hospitalized heart failure event
• Incidence rate for total escalation of loop diuretic therapy, HF events, HF hospitalizations, or CV death
• Incidence rate for escalation of loop diuretic therapy
• Time to escalation of loop diuretic therapy

Safety
The following changes in potassium and renal function will be assessed by laboratory evaluations and acted upon by local investigators
• Moderate hyperkalemia (K>5.5 mmol/L)
• Severe hyperkalemia (K>6.0 mmol/L)
• Moderate renal impairment: eGFR <30 mL/min/1.73 m2
• Severe renal impairment: eGFR <20 mL/min/1.73 m2
• Doubling of creatinine from baseline
• Increase in K by more than 1.0 mmol/L from baseline
• Levels of eGFR as continuous variable during follow-up
• Levels of K as continuous variable during follow-up

Events listed below will be collected centrally in both Sweden and the US at the end of the study
• Time to hospitalization for hyperkalemia
• Time to new onset hyperkalemia (outpatient encounters will be collected in Sweden only)
• Time to dialysis
• Time to hospitalization for renal failure
• Time to new onset renal failure (outpatient encounters will be collected in Sweden only)

Adherence
• Time to cross-over (from spironolactone to control and from control to spironolactone)

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluation of the secondary endpoints will be performed at study end

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Usual care alone

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

United States

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

LVLS

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 years

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:

2000

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

2000

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

1640

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1640

F.4.2.2

In the whole clinical trial

2000

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)

None

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

2016-09-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-03

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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