Clinical Trials Register

Summary
EudraCT Number:	2013-002287-11
Sponsor's Protocol Code Number:	BAY1021189/15371
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-09-24
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2013-002287-11

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 reduced ejection fraction.

Studio di Fase II, di dose finding, multicentrico, in doppio cieco, controllato con placebo, a gruppi paralleli, per valutare gli effetti farmacodinamici, la sicurezza, la tollerabilità e la farmacocinetica di quattro regimi posologici dello stimolatore orale di sGC BAY 1021189 per 12 settimane in pazienti con peggioramento dell’insufficienza cardiaca e con frazione di eiezione ridotta (HFrEF)

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 reduced ejection fraction

Studio di Fase IIb sulla sicurezza ed efficacia di quattro regimi posologici di BAY 1021189 in pazienti con HfrEF affetti da insufficienza cardiaca cronica in via di peggioramento (SOCRATES-REDUCED)

A.3.2

Name or abbreviated title of the trial where available

SOCRATES-REDUCED

A.4.1

Sponsor's protocol code number

BAY1021189/15371

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

Insufficienza Cardiaca

E.1.1.1

Medical condition in easily understood language

Heart failure

Insufficienza Cardiaca

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	16.0
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 the primary endpoint change in NT-proBNP at 12 weeks in patients with worsening chronic heart failure with reduced ejection fraction.

Individuare la dose ottimale dello stimolatore orale solubile della guanilato-ciclasi (sGC) BAY 1021189 per la Fase III che possa essere somministrato in aggiunta alla terapia standard per l’insufficienza cardiaca con ridotta frazione di eiezione, caratterizzandone la sicurezza, la tollerabilità, gli effetti farmacodinamici e la farmacocinetica, e per identificare un rapporto dose-risposta significativo per l’endpoint primario, cioè la variazione del N-terminal pro-brain natriuretic peptide (NT-proBNP) a 12 settimane in pazienti con peggioramento dell’insufficienza cardiaca cronica con frazione di eiezione ridotta (HFrEF)

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 ≥1000 or BNP ≥300 pg/mL in sinus rhythm, or NT-proBNP ≥1600 or BNP ≥500 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, and resting HR ≥50 and <100 bpm at randomization

- LVEF <45% by echocardiography at randomization

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.

Insufficienza cardiaca cronica in via di peggioramento (WCHF) che richieda l’ospedalizzazione (o il trattamento diuretico endovenoso [IV] per l’insufficienza cardiaca senza ricovero in ospedale) con inizio del trattamento del farmaco in studio dopo stabilizzazione clinica
1. Anamnesi di insufficienza cardiaca cronica di classe NYHA II-IV e terapia standard per l’insufficienza cardiaca >30 giorni prima dell’ospedalizzazione1
2. Peggioramento dell’insufficienza cardiaca al momento dell’ospedalizzazione1
a. N-terminal pro-brain natriuretic peptide (NT-proBNP) >1000 o brain natriuretic peptide(BNP) >300 in ritmo sinusale oppure NT-proBNP >1600 o BNP >500pg/mL nella fibrillazione atriale dosati di routine presso il laboratorio locale , e
b. Sintomi e segni di congestione (segni clinici o radiografici nelle radiografie del torace di routine che dimostrino un versamento pleurico, congestione polmonare o cardiomegalia)
3. Stabilizzazione clinica definita come:
a. nessun vasodilatatore e.v. per >24h e nessun diuretico e.v. per >12h prima della randomizzazione e
b. Pressione arteriosa sistolica (SBP) >110 e <160, e frequenza cardiaca a riposo (HR) >50 e <100 battiti al minuto (bpm) alla randomizzazione
4. Frazione di eiezione del ventricolo sinistro (LVEF) <45% all’ ecocardiografia alla randomizzazione

1 o trattamento diuretico e.v. per insufficienza cardiaca senza ospedalizzazione

E.4

Principal exclusion criteria

1. Legal lower age limitations for adults (country specific)
2. IV inotropes at any time after hospitalization
3. Concurrent of anticipated nitrate use (all routes, incl. prn) for the treatment of ischemic heart disease or HF, including:
- subjects tolerant of and treated with isosorbide dinitrate/hydralazine therapy for chronic HFrEF according to guideline recommendations
- subjects requiring nitrates as anti-anginal therapy in addition or alternatively to beta-blockers
4. Cardiac comorbidity (either of the following):
- 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
- Symptomatic carotid stenosis, or transient ischemic attack or stroke within 30 days prior to randomization
- New initiation of cardiac resynchronization therapy within 60 days prior to randomization
- Listing for heart transplantation and/or anticipated/implanted ventricular assist device
- Complex congenital heart disease
5. 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
6. Concomitant Treatment with a PDE5 inhibitor or sGC stimulator
7. Participation in another clinical study or treatment with another investigational product ≤30 days prior to randomization

1. Inotropi e.v. in qualsiasi momento dopo l’ospedalizzazione
2. Utilizzo di nitrati in passato o previsto (qualsiasi somministrazione compresa la percutanea)per il trattamento di cardiopatia ischemica o HFrEF
3. Cardiopatie concomitanti
o Eziologie specifiche dell’insufficienza cardica, compresa la cardiomiopatia ipertrofica con ostruzione del deflusso del ventricolo sinistro (LV); patologia pericardica; patologia infiltrativa o infiammatoria del miocardio; valvulopatia con grave rigurgito aortico o mitralico, stenosi aortica moderata o severa, stenosi mitralica che richieda intervento chirurgico o endocardite in fase attiva; oppure
Sindrome coronarica acuta (ACS), compresa l’angina instabile, infarto miocardico senza sopra livellamento del tratto ST (NSTEMI) o infarto miocardico con sopra livellamento del tratto ST (STEMI) o bypass dell’arteria coronarica (CABG) entro 60 giorni precedenti la randomizzazione o indicazione all’angioplastica percutanea o al bypass (PCI o CABG); oppure
o Ischemia cardiaca significativa alla prova da sforzo condotta entro 1 anno prima dell’arruolamento non seguita da rivascolarizzazione oppure
o Stenosi carotidea sintomatica o attacco ischemico transitorio (TIA) o ictus entro 30 giorni prima della randomizzazione; oppure
o Nuovo inizio di trattamento di resincronizzazione cardiaca (CRT) entro 60 giorni prima della randomizzazione oppure
o In lista per trapianto al cuore e/o previsto impianto/impianto in corso di dispositivo ventricolare di assistenza
o Cardiopatia congenita complessa
4. Patologie concomitanti non-cardiache al momento della randomizzazione
Velocità di filtrazione glomerulare <30 mL/min/1,73 m2 calcolata mediante MDRD; oppure
o Insufficienza epatica Child-Pugh B o C; oppure
o Indice di massa corporea (BMI) >40 kg/m²; oppure
o Neoplasia maligna o altra affezione non-cardiaca che limiti l’aspettativa di vita a <1 anno; oppure
o Grave pneumopatia con necessità di ossigenoterapia continua a domicilio oppure recente embolizzazione dell’arteria bronchiale per emottisi massiva
5. Partecipazione ad un altro studio clinico o trattamento con un altro prodotto sperimentale ≤30 giorni prima della randomizzazione

E.5 End points

E.5.1

Primary end point(s)

1. Change from baseline to week 12 in log-transformed NT-proBNP

Variazione del log NTproBNP alla settimana 12 rispetto al basale

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12 of treatment.

12° settimana di trattamento

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
10. Incidence of ICD / CRT-D interventions

1)Variazioni nella struttura/funzione cardiaca misurata tramite ecocardiografia
2)Variazioni nei biomarcatori
3)Variazioni di pressione/frequenza cardiaca
4)Variazioni nella qualità della vita
5)Ospedalizzazione e morte per cause cardiovascolari
6)Variazione classe NYHA
7) Incidenza di fibrillazione atriale
8) Variazioni della terapia per insufficienza cardiaca
9) Variazione del Composite Congestion Score
10) Incidenza di interventi ICD/CRT-D

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
10. From baseline to 12 weeks

1)dal basale alle 12 settimane
2) dal basale alle 12 settimane
3) dal basale alle 12 settimane
4) dal basale alle 12 settimane
5) dal basale alle 12 settimane
6) dal basale alle 12 settimane
7) dal basale alle 12 settimane
8) dal basale alle 12 settimane
9) dal basale alle 12 settimane
10) dal basale alle 12 settimane

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:

328

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

320

F.4.2.2

In the whole clinical trial

410

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

N.A.

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

2013-09-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-09

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IMP with orphan designation in the indication
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