Clinical Trials Register

Summary
EudraCT Number:	2014-003702-33
Sponsor's Protocol Code Number:	RG_14-150
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-07-02
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

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2014-003702-33

A.3

Full title of the trial

IMPRESS-AF: IMproved exercise tolerance in patients with PReserved Ejection fraction by Spironolactone on myocardial fibrosiS in Atrial Fibrillation

A.3.1

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

Effect of spironolactone on ability to exercise and heart stiffness in people with irregular heart beats (atrial fibrillation) and normal pumping capacity of the heart

A.3.2

Name or abbreviated title of the trial where available

IMPRESS-AF trial, version 1.0

A.4.1

Sponsor's protocol code number

RG_14-150

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University of Birmingham
B.1.3.4	Country	United Kingdom
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	National Institute for Health Research
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University of Birmingham
B.5.2	Functional name of contact point	Eduard Shantsila
B.5.3	Address:
B.5.3.1	Street Address	University of Birmingham Centre for Cardiovascular Sciences, City Hospital
B.5.3.2	Town/ city	Birmingham
B.5.3.3	Post code	B18 7QH
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01215075086
B.5.6	E-mail	e.shantsila@bham.ac.uk

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	Spironolactone
D.2.1.1.2	Name of the Marketing Authorisation holder	Actavis
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.2	Product code	0025-1001
D.3.4	Pharmaceutical form	Capsule
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.3.9.4	EV Substance Code	AS1
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 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	Capsule
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

Atrial fibrillation with preserved left ventricular systolic function and normal levels of the brain natriuretic peptide.

E.1.1.1

Medical condition in easily understood language

Irregular heart beats in people in normal heart pumping capacity, but reduced heart relaxation.

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10003658
E.1.2	Term	Atrial fibrillation
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10069211
E.1.2	Term	Diastolic heart failure
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10008908
E.1.2	Term	Chronic heart failure
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

People with an irregular heartbeat can find it difficult to exercise and may experience shortness of breath or tiredness because the heart cannot relax properly. This research is trying to find out whether taking a small dose of a drug called Spironolactone can improve the ability to exercise. Spironolactone works as a mild water tablet and is a well-known drug that seems to improve heart function.

E.2.2

Secondary objectives of the trial

The study also aims to find out if the treatment with spironolactone can improve the capacity of the heart to relax better, improve quality of life and to reduce needs for hospital admissions.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Eligible study patients will be
• Age 50 years old or over
• Permanent AF as defined by the European Society of Cardiology (ESC) criteria
• Normal BNP levels (<100 pg/mL)
• Ability to understand and complete questionnaires (with or without use of a
translater/translated materials).

E.4

Principal exclusion criteria

• Severe systemic illness with life expectancy of less than 2 years from
screening
• Left ventricular ejection fraction (LVEF) <50% (echocardiography)
• Severe chronic obstructive pulmonary disease (COPD) (e.g., requiring home
oxygen or chronic oral steroid therapy)
• Severe mitral/aortal valve stenosis/regurgitation
• Significant renal dysfunction (serum creatinine 220 µmol/L or above)
• Increase in potassium level to > 5mmol/L)
• Recent coronary artery bypass graft surgery (within 3 months)
• Use of aldosterone antagonist within 14 days before randomisation
• Use of or potassium sparing diuretic within 14 days before randomisation
• Systolic blood pressure >160 mm Hg
• Any participant characteristic that may interfere with adherence to the
trial protocol

E.5 End points

E.5.1

Primary end point(s)

Improvement in exercise tolerance at 2 years. This will be assessed by difference between the study groups in peak VO2 on CPET.

E.5.1.1

Timepoint(s) of evaluation of this end point

End of 2 years of treatment with spironolactone or placebo.

E.5.2

Secondary end point(s)

• Improvement in exercise tolerance measured by 6-minute walking test (a simple and readily available in clinical practice tool for assessment of exercise performance);
• Improvement in health-related quality of life assessed using the validated Minnesota Living with Heart Failure (MLWHF) and [EQ-5D] questionnaires self-completed by patients;
• Improvement in LV diastolic dysfunction (E/E’ ratio);
• Rate of all-cause hospitalisations (which will include HF-related hospitalisations).
• Rate of spontaneous cardioversion to the sinus rhythm

Additionally we will record any cases of major adverse clinical events, such as death from any causes, death from cardiac causes, hospitalization for cardiac causes, a change in the NYHA class, stroke or systemic thromboembolism. However, we include all cause hospital admissions (which will include HF-related hospitalisations) as a secondary outcome given that such admissions are common in the study population (about 20% per year in the published literature). This information as well as data on cases of death or strokes would be used as pilot data for future studies focused on these hard clinical outcomes and adequately powered for this purpose (the current study is not powered to reliably assess the hard clinical outcomes, although we have included a pre-specific clinical composite outcome as a secondary endpoint).

Safety outcomes The following safety outcomes will be recorded for analysis: (i) development of hyperkalaemia (>5.0 mmol/L) and creatinine rise, (ii) development of gynecomastia, and (iii) development of side effects requiring withdrawal of the study treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

End of 2 years of treatment with spironolactone or placebo.

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

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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.8.4.1

Number of sites anticipated in 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

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1