Clinical Trials Register

Summary
EudraCT Number:	2013-002288-25
Sponsor's Protocol Code Number:	BAY1021189/15829
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-02-10
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2013-002288-25

A.3

Full title of the trial

A randomized parallel-group, placebo-controlled, double-blind, multi-center dose finding phase II trial exploring the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the oral sGC stimulator BAY 1021189 over 12 weeks in patients with worsening heart failure and preserved ejection fraction.

Randomizált, párhuzamos csoportos, placebo kontrollos, kettős-vak, multicentrikus, dózis kereső, II fázisú vizsgálat a BAY 1021189 orális sGC stimulátor négyféle dózisának 12 hétig tartó adagolásával a farmakodinamikai hatások, biztonságosság és tolerálhatóság, valamint a farmakokinetika vizsgálata súlyosbodó szívelégtelenségben szenvedő, csökkent ejekciós frakcióval rendelkező betegeknél

A.3.1

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

Study to research BAY 1021189 in patients with worsening heart failure with preserved ejection fraction

A négy különböző adagolási séma szerint alkalmazott BAY 1021189 IIb. fázisú biztonságossági és hatásossági vizsgálata csökkent ejekciós frakcióval járó súlyosbodó szívelégtelenségben szenvedő betegeknél (SOCRATES-REDUCED)

A.3.2

Name or abbreviated title of the trial where available

SOCRATES-PRESERVED

A.4.1

Sponsor's protocol code number

BAY1021189/15829

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	Bayer HealthCare AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bayer HealthCare AG
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	Bayer HealthCare AG
B.5.2	Functional name of contact point	Bayer Clinical Trials Contact
B.5.3	Address:
B.5.3.1	Street Address	CTP Team/ RE:"EU CTR"/ Bayer Pharma AG
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13342
B.5.3.4	Country	Germany
B.5.6	E-mail	clinical-trials-contact@bayerhealthcare.com

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	No
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	BAY 1021189 1.25 mg coated tablet
D.3.2	Product code	BAY 1021189
D.3.4	Pharmaceutical form	Coated 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.3.9.2	Current sponsor code	BAY102189
D.3.9.3	Other descriptive name	BAY 1021189
D.3.9.4	EV Substance Code	SUB32031
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	1.25
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.IMP: 2
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	No
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	BAY 1021189 tablet 5 mg
D.3.2	Product code	BAY 1021189
D.3.4	Pharmaceutical form	Coated 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.3.9.2	Current sponsor code	BAY 1021189
D.3.9.3	Other descriptive name	BAY 1021189
D.3.9.4	EV Substance Code	SUB32031
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	5
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	Coated 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

Szívelégtelenség

E.1.1.1

Medical condition in easily understood language

Heart failure

Szívelégtelenség

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10008908
E.1.2	Term	Chronic heart failure
E.1.2	System Organ Class	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 find the optimal dose of BAY 1021189 for Phase III that can be given in addition to standard diuretic and comorbidity treatment by characterizing the safety, tolerability, pharmacodynamic effects, and pharmacokinetics, and detecting a significant dose-response relationship in at least one of the two primary endpoints change in NT-proBNP and change of left atrial volume at 12 weeks in patients with worsening chronic heart failure with preserved ejection fraction.

E.2.2

Secondary objectives of the trial

N/A

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent signed before any study-specific procedure
2. Ability to understand and follow study-related instructions
3. Worsening chronic heart failure requiring hospitalization (or IV diuretic treatment for HF without hospitalization) with initiation of study treatment after clinical stabilization:

Diagnostic methods:
- History of chronic HF: NYHA class II-IV ≥30 days before hospitalization (or before IV diuretic treatment for HF without hospitalization)
- Worsening HF at hospitalization (or at the time of IV diuretic treatment for HF without hospitalization)
- NT-proBNP ≥300 or BNP ≥100 pg/mL in sinus rhythm, or NT-proBNP ≥600 or BNP ≥200 pg/mL in A. fib. in local routine labs, and
- Symptoms and signs of congestion (clinical or radiographic signs in routine chest x-ray demonstrating pleural effusion, pulmonary congestion (redistribution, interstitial or alveolar edema), or cardiomegaly

- Clinical stabilization defined by
- no IV vasodilator for >24h and no IV diuretic for >12h before randomization and
- SBP ≥110 and <160, DBP ≥40 and <100 mmHg, and resting HR ≥50 and <100 bpm at randomization

- Diagnostic criteria of HFpEF by echocardiography at randomization
- LVEF ≥45% and
- Enlarged LA indicated by one of the following parameters: Left atrial volume (LAV) index ≥28 ml/m2, or LAV >58 mL in male and >52 mL in female patients, or LA area >20 cm2, or LA diameter >40 mm in male and >38 mm in female patients.

4. Ability to understand and follow study-related instructions
5. Men or confirmed postmenopausal women or women without childbearing potential based on surgical treatment such as bilateral tubal ligation, bilateral ovarectomy, or hysterectomy. Men enrolled in this study must agree to use adequate barrier birth control measures during the treatment period of the study.

E.4

Principal exclusion criteria

1. Legal lower age limitations for adults (country specific)
2. IV inotropes at any time after hospitalization
3. Cardiac comorbidity (any of the following):
- Chronic atrial fibrillation: after enrollment of approximately 141 patients with chronic atrial fibrillation (30% of population), chronic atrial fibrillation will be considered an exclusion criterion
- History of reduced ejection fraction (EF <45%)
- Specific HF etiologies, including:
- Hypertrophic cardiomyopathy with LV outflow tract obstruction; or
- Pericardial disease, such as constrictive pericarditis; or
- Infiltrative or inflammatory myocardial disease such as acute myocarditis, amyloidosis, sarcoidosis; or
- Valvular heart disease: (severe aortic or mitral regurgitation, moderate or severe aortic stenosis, any mitral stenosis requiring surgical repair, active endocarditis)
- Acute coronary syndrome, including unstable angina, NSTEMI or STEMI, or CABG within 60 days prior to randomization, or indication for PCI or CABG
- Significant cardiac ischemia in a stress test within a year of enrollment without revascularization since
- Requirement for nitrates as anti-anginal therapy in addition or alternatively to beta-blockers
- Symptomatic carotid stenosis, or TIA or stroke within 30 days prior to randomization
- Complex congenital heart disease
4. Non-cardiac comorbidity, indicated by either of the following at the time of randomization
- Glomerular filtration rate <30 ml/min/1.73 m2 calculated by Modification of Diet in Renal Disease [MDRD] formula
- Hepatic insufficiency classified as Child-Pugh B or C
- Morbid obesity with a BMI >40 kg/m²
- Malignancy or other non-cardiac condition limiting life expectancy to <1 year, per physician judgment
- Severe pulmonary disease with either requirement of continuous home oxygen or recent bronchial artery embolization for massive hemoptysis
- Subjects with allergies, intolerance or hypersensitivity to investigational drug or any of the excipients
- Medical condition or history thereof that in the opinion of the investigator would impair the ability to complete the planned study procedures
5. Concomitant Treatment with a PDE5 inhibitor or sGC stimulator
6. Participation in another clinical study or treatment with another investigational product ≤30 days prior to randomization

E.5 End points

E.5.1

Primary end point(s)

1. Change from baseline to week 12 in left atrial volume (LAV)
2. Change from baseline to week 12 in log-transformed NT-proBNP

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12 of treatment.

E.5.2

Secondary end point(s)

1. Changes in heart structure/function as measured by echocardiography
2. Changes in biomarkers
3. Changes to blood pressure & heart rate
4. Changes in health-related quality of life
5. Hospitalisations and death from cardiovascular causes
6. Change in NYHA function class
7. Incidence (new or recurrence) of atrial fibrillation
8. Changes in background heart failure therapies
9. Change in Composite Congestion Score

E.5.2.1

Timepoint(s) of evaluation of this end point

1. From baseline to 12 weeks
2. From baseline to 12 weeks
3. From baseline to 12 weeks
4. From baseline to 12 weeks
5. From baseline to 16 weeks
6. From baseline to 12 weeks
7. From baseline to 16 weeks
8. From baseline to 12 weeks
9. From baseline to 12 weeks

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

Belgium

Canada

China

Czech Republic

Denmark

France

Germany

Hungary

Israel

Italy

Japan

Netherlands

Poland

Singapore

Spain

Sweden

Switzerland

Taiwan

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

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.1.1.1

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:

376

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

350

F.4.2.2

In the whole clinical trial

470

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

2014-02-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-09-16

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