Clinical Trials Register

Summary
EudraCT Number:	2013-000797-30
Sponsor's Protocol Code Number:	SPI-IIT-002
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-08
Trial results	View 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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2013-000797-30

A.3

Full title of the trial

Inhibition of aldosterone to diminish diffuse myocardial fibrosis in atrial fibrillation

Hæmning af aldosteron for reduktion af diffus fibrose i myokardiet hos patienter med aftrieflimren

A.3.1

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

Suppression of the hormone aldosterone to diminish scar tissue in heart in patients with atrial fibrillation

Hæmning af hormonet aldosteron til reduktion af arvævsdannelse i hjertemuskulaturen hos patienter med forkammerflimren

A.3.2

Name or abbreviated title of the trial where available

INSPIRE-AF

A.4.1

Sponsor's protocol code number

SPI-IIT-002

A.5.4

Other Identifiers

Name:

Amendment 3, protocol 3.0

Number:

SPI-IIT-002

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	Department of Medical Research, Odense University Hospital, Svendborg Hospital
B.1.3.4	Country	Denmark
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	Department of Medical Research, Odense University Hospital, Svendborg Hospital
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Department of Medical Research, Odense University Hospital, Svendborg Hospital
B.5.2	Functional name of contact point	Dragana Rujic
B.5.3	Address:
B.5.3.1	Street Address	Valdemarsgade 53
B.5.3.2	Town/ city	Svendborg
B.5.3.3	Post code	5700
B.5.3.4	Country	Denmark
B.5.4	Telephone number	+4563202402
B.5.5	Fax number	+4563202407
B.5.6	E-mail	dragana.rujic@rsyd.dk

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	Spirix
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Pharma A/S
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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.3.4	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.3.10.3	Concentration number	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

Paroxysmal and persistent atrial fibrillation

Paroksystisk og persisterende atrieflimren

E.1.1.1

Medical condition in easily understood language

Intermittent atrial fibrillation

Anfaldsvis forkammerflimren

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10071667
E.1.2	Term	Persistent atrial fibrillation
E.1.2	System Organ Class	100000004849

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10066664
E.1.2	Term	Recurrent symptomatic atrial fibrillation
E.1.2	System Organ Class	100000004849

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10003661
E.1.2	Term	Atrial fibrillation paroxysmal
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

To investigate whether or not therapy with a mineralocorticoid receptor antagonist (MRA), in this case spironolactone, added to optimal medical treatment in normotensive or hypertensive patients with paroxysmal or persistent atrial fibrillation diminishes diffuse myocardial fibrosis in left atria and ventricle, atrial remodeling and thus improve left atrial function as compared with conventional treatment.

At efterprøve hypotesen, at tillægsbehandling med et mineralocorticoid receptor antagonist, i dette tilfælde spironolacton, hos normotensive eller hypertensive patienter med paroksystisk eller persisterende atrieflimren vil reducere diffus myokardiefibrose i venstre atrium og ventrikel og forbedre venstre atriums funktion sammenlignet med konventionel behandling.

E.2.2

Secondary objectives of the trial

To investigate whether or not add-on therapy with spironolactone reduces recurrent episodes of atrial fibrillation, health economics thus improves quality of life and decreses inflammatory and neurohumoral marksers in blood in patients with paroxysmal or persistent atrial fibrillation compared to usual care.

At undersøge, hvorvidt tillægsbehandling med spironolacton hos patienter med paroksystisk eller persisterende atrieflimren reducerer antal tilbagevendende anfald af atrieflimren, sundhedsmæssige omkostninger følgelig forbedrer livskvalitet og reducerer biomarkører for inflammation og neurohumoral aktivitet sammenlignet med konventionel behandling.

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

Late gadolinium enhancement and modified look locker sequences for quantification of the effect of spironolactone on diffuse atrial and ventricular fibrosis in patients with atrial fibrillation. The CMR sub-study, version 2.0.
The primary study objectives of this sub-study are:
1. To detect and quantify the myocardial ECV as a surrogate for DMF in the left atrium and ventricle by T1 mapping using modified look locker sequences and late gadolinium enhancement technique.
2. To measure volume and volume dynamics of the left atrium.

T1 mapping på venstre atrium og ventrikel for at kvantificere myokardiets ekstracellulære matrix volumen (ECV) som surrogatmarkør for diffus myokardiefibrose ved hjælp af LGE og MOLLI sekvenser, bedømt ud fra CMR skanning.
De primære endepunkter for dette sub-studie er:
1. T1 mapping på venstre atrium og ventrikel ved hjælp af LGE teknik og MOLLI sekvenser.
2. Volumen og ændringer i volumen svarende til venstre forkammer.

E.3

Principal inclusion criteria

Patients ≥ 18 years of age, male or female.
Signed written informed consent.
Paroxysmal atrial fibrillation on one or more occasions, detected on 12-lead ECG or Holter monitoring with each AF-episode lasting ≥ 30 seconds, within the last 12 months prior to the screening visit, or persistent AF on one or more occasions that has been direct current (DC) cardioverted within the last 12 months prior to the screening visit.
Patients with CHA2DS2-VASc score ≥ 1 will be encouraged to start anticoagulant treatment, but will not be excluded if there are reasonable reasons not to, i.e. risk of bleeding. Patients can choose between standard anticoagulation therapies, i.e. warfarin or non vitamin-K oral anticoagulants (NOAC) such as dabigatran, apixaban and rivaroxaban.
Women with childbearing potency must use effective contraception (e.g. implants, hormonal depot injections, combined oral contraceptives, intra-uterine devices or vasectomized partner). Men enrolled in this study must agree to use adequate barrier birth control measures during the treatment period of the study. Reliable contraception should be maintained throughout the study and for 30 days after study drug discontinuation.

Alder > 18 år.
Underskrevet samtykkeerklæring.
Mindst en episodermed EKG- eller Holterdokumenteret paroksystisk atrieflimren af mindst 30 sekunders varighed inden for de sidste 12 måneder eller mindst en episode med EKG- eller Holterdokumenteret persisterende atrieflimren inden for sidste 12 måneder.
Fertile mænd og kvinder i den fødedygtige alder (< 2 år efter sidste menstruation for kvinder) skal anvende sikker antikonception i form af spiral, hormonel antikonception (p-piller, implantat, transdermal depotplaster, vaginalring eller depotinjektion), barrieremetode i kombination med sæddræbende creme eller kirurgisk sterilisation. Kvinder i den fødedygtige alder skal have negativ graviditetstest forud for indgåelse i forsøget.

E.4

Principal exclusion criteria

Chronic atrial fibrillation.
Previous radiofrequency ablation for atrial fibrillation or previous surgical treatment of atrial fibrillation, i.e. MAZE or His-ablation.
Heart failure (New York Heart Association (NYHA) class ≥ II and/or LVEF less than 40%).
Severe coronary artery disease (acute myocardial infarction within 6 months prior to the screening visit, previous coronary artery bypass graft (CABG) or stabile angina pectoris (Canadian Cardiovascular Society (CCS) class ≥II).
Stroke or transient ischemic cerebral attack within 6 months prior to the screening visit.
Pregnant women or women of childbearing potential not on adequate birth control. Only women with a highly effective method of contraception (oral contraception, intra-uterine device or sterile women) can be randomized.
Presence of severe and hemodynamically significant valvular heart disease.
Any disease that limits life expectancy to less than 1 year.
Hepatic insufficiens classified as Child-Pugh B or C.
Participation in another clinical trial, either within the last 30 days or ongoing.
Breastfeeding women.
Ongoing therapy with class IC antiarrhythmics (flecainide, propafenone), amiodarone, dronedarone or sotalol.
Chronic or acute kidney disease (estimated glomerular filtration rate (eGFR) ≤ 45 ml/min/1,73m2 (4-variable MDRD equation)).
Baseline serum potassium > 5,0 mmol/l.
Intolerance or contradictions to spironolactone, i.e. latest product information on Spirix®.
Intolerance or contradictions to dabigatran (Pradaxa®) i.e. latest product information.
Patients who are noncompliant to the medical treatment.
Atrial fibrillation that is associated with an acute reversible condition, i.e. heart surgery, untreated hyperthyroidism etc.

Permanent (kronisk) atrieflimren.
Patienter med hjerteinsufficiens i NYHA funktionsklasse II-IV og / eller venstre ventrikels uddrivningsfraktion (EF) mindre eller lig med 40 %.
Patienter med atrieflimren, som må betragtes som værende sekundær og dermed reversibel, specielt thyreotoksikose, infektion, kirurgi, akut myokardieinfarkt, alkoholmisbrug, hjerte- eller lungekirurgi.
Aktuel behandling med klasse IC- (flekainid, propafenon) eller klasse III antiarytmika (amiodaron og sotalol) inden for sidste 3 måneder.
Kendte strukturelle hjerteanomalier, herunder hæmodynamisk betydende klapfejl.
Angina pectoris vurderet ved CCS ≥ III.
Ukontrolleret hypertension grad ≥ III til trods for adækvat antihypertensiv behandling.
Patienter, som har fået foretaget radiofrekvensablation for atrieflimren.
Tidligere MAZE-operation eller His-ablation grundet supraventrikulær arytmi.
Patienter, som allerede er i behandling med en aldosteronantagonist, eller som har kontraindikationer mod denne behandling, herunder tendens til hyperkaliæmi (P-Kalium > 5,0 mmol/l).
Nedsat nyrefunktion, herunder akutnyreinsufficiens, anuri, bilateral renal arteriel stenose og nefrotisk syndrom. Kronisk nyreinsufficiens ved eGFR ≤ 45ml/min/1,73 m2 eller P-kreatinin > 220 mikromol/l (beregnet vha. MDRD-formlen).
Baseline P-kalium > 5,0 mmol/l eller P-natrium < 135 mmol/l.
Uacceptable bivirkninger ved behandling med aldosteronantagonist, herunder hyperkaliæmi, gener fra gastrointestinalkanalen og gynækomasti.
Deltagelse i et andet forsøg inden for 30 dage inden inklusion.

E.5 End points

E.5.1

Primary end point(s)

1. Myocardial extracellular volume (ECV) will be quantified as a surrogate for diffuse myocardial fibrosis in left atrium and ventricle by T1 mapping using modified look locker sequences (Siemens) and late gadolinium enhancement technique asserssed by cardiac magnetic resonanse (CMR).
2. Function and volume dynamics of left atrium and ventricle will be assessed with CMR and speckle tracking, strain and strain rate on 2-dimensional (2D) and 3-dimensional (3D) transthoracic echocardiography.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. CMR will be assessed at the time of randomization and at 12 months.
2. Transthoracic echocardiography: both two (2D) and three dimensional (3D) images will be assessed at the time of randomization and at 6 and 12 months.

E.5.2

Secondary end point(s)

1. The burden of atrial fibrillation will be assessed as cumulative burden of atrial fibrillation, registered on 12-lead ECG recordings and serial longterm Holter monitoring, where a recurrent episode of atrial fibrillation is defined as atrial fibrillation ≥ 30 seconds of duration. Burden of atrial fibrillation will also include the total duration of atrial fibrillation, recorded on Holter monitoring.
2. Health economics, including total number of hospitalizations, hospitalizations related to atrial fibrillation and the total duration of hospitalizations in days.
3. Quality of life assessed with Short Form-12 (SF-12) questionnaire.
4. Inflammatory, neurohumoral and potential markers of atrial fibrosis measured in blood. The following efficacy biomarkers will be measured: high-sensitivity C-reactive protein (hs-CRP), Thyroid Stimulation Hormone (TSH), Interleukin-6 (IL6), N-terminal pro-brain natriuretic peptide (NT-proBNP), Atrial (A-type) natriuretic peptide (pro-ANP), renin, Procollagen III N-terminal propeptide and fibulin-1. Blood samples measurements for safety will include measurement of potassium, sodium, creatinine and BUN.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. 7 days Holter monitoring will be performed at the time of randomization and at 6 and 12 months. 12-lead ECG will be performed at the time of randomization, at 1 week and subsequently at 1, 2,3,6,9 and 12 months. The study subjects patents will be encouraged to seek a doctor of choice in case of symptoms that might indicate recurrence of atrial fibrillation to assess a 12-lead ECG.
2. Data will be collected thorughtout 12 months of follow-up period.
3. SF-12 will be performed at baseline and at 12 months.
4. Blood samples: blood samples measurements for biomarkers will be collected at the time of randomization and at 6 and 12 months. Blood samples measurements for safety will be collected at baseline, 1 week and 1, 2,3,6,9 and 12 months.

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

Yes

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

150

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)

The subject will be informed whether or not he or shecould benefit from spironolactone supplementation in treatment of atrial fibrillation.

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

2013-10-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-03-26

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials