Clinical Trials Register

Summary
EudraCT Number:	2016-004062-26
Sponsor's Protocol Code Number:	BAY1067197/17582
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-03-20
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

Germany - BfArM

A.2

EudraCT number

2016-004062-26

A.3

Full title of the trial

A multicenter, randomized, placebo-controlled, parallel group, double blind, dose-finding Phase II trial to study the efficacy, safety, pharmacokinetic and pharmacodynamic effects of the oral partial adenosine A1 receptor agonist neladenoson bialanate over 20 weeks in patients with chronic heart failure and preserved ejection fraction

A.3.1

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

PANACHE - A phase II trial to study neladenoson bialanate over 20 weeks in patients with chronic heart failure with preserved ejection fraction

A.4.1

Sponsor's protocol code number

BAY1067197/17582

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 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 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 AG
B.5.2	Functional name of contact point	Bayer Clinical Trials Contact
B.5.3	Address:
B.5.3.1	Street Address	.
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13342
B.5.3.4	Country	Germany
B.5.4	Telephone number	4930300139003
B.5.6	E-mail	clinical-trials-contact@bayer.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 1067197 hydrochloride film coated tablet 5 mg
D.3.2	Product code	BAY 1067197 hydrochloride film coated tablet 5 mg
D.3.4	Pharmaceutical form	Film-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.3.8	INN - Proposed INN	neladenoson bialanate
D.3.9.2	Current sponsor code	BAY 1067197
D.3.9.3	Other descriptive name	BAY 1067197
D.3.9.4	EV Substance Code	SUB32032
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.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 1067197 hydrochloride film coated tablet 10 mg
D.3.2	Product code	BAY 1067197 hydrochloride film coated tablet 10 mg
D.3.4	Pharmaceutical form	Film-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.3.8	INN - Proposed INN	neladenoson bialanate
D.3.9.2	Current sponsor code	BAY 1067197
D.3.9.3	Other descriptive name	BAY 1067197
D.3.9.4	EV Substance Code	SUB32032
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	10
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: 3
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 1067197 hydrochloride film coated tablet 20 mg
D.3.2	Product code	BAY 1067197 hydrochloride film coated tablet 20 mg
D.3.4	Pharmaceutical form	Film-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.3.8	INN - Proposed INN	neladenoson bialanate
D.3.9.2	Current sponsor code	BAY 1067197
D.3.9.3	Other descriptive name	BAY 1067197
D.3.9.4	EV Substance Code	SUB32032
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	20
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	Film-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

chronic heart failure with preserved ejection fraction (LVEF equal or above 45%)

E.1.1.1

Medical condition in easily understood language

chronic heart failure with preserved ejection fraction

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	20.0
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

Find the optimal dose of neladenoson bialanate for the Phase III trial by detecting and characterizing a significant dose-response relationship in the primary efficacy endpoint, absolute change from baseline in 6-minute walking distance (6MWD) at 20 weeks, in patients with chronic heart failure with preserved ejection fraction (HFpEF), and by characterizing the safety, tolerability, pharmacokinetic and pharmacodynamic effects of the compound when given in addition to appropriate therapy for specific co-morbidities

E.2.2

Secondary objectives of the trial

An exploratory objective is to further assess pharmacokinetic parameters and blood and urine biomarkers.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Men or women aged 45 years and older
2. Diagnosis of chronic heart failure (CHF), NYHA class II-IV (without evidence of a non-cardiac explanation for dyspnea), LVEF ≥ 45% assessed by any imaging modality (e.g. echocardiography, cardiac magnetic resonance, cine levocardiography) within the previous 6 months with no significant change in clinical status suggesting potential for deterioration in ejection fraction.
3. In the 6 months prior to run-in:
a) Requirement of treatment with a diuretic
AND
b) Elevated natriuretic peptides, defined as one of:
o BNP ≥ 75 pg/mL or NT-proBNP ≥ 300 pg/mL (sinus rhythm)
o BNP ≥ 200 pg/mL or NT-proBNP ≥ 900 pg/mL (atrial fibrillation)
AND
c) At least one of the following:
o LA enlargement (LA diameter ≥ 3.9 cm, LA volume ≥ 55 mL,
LAVI ≥ 29 mL/m2, or LAA ≥ 20 cm2) (assessed by local imaging)
o LV hypertrophy (septal or posterior wall thickness ≥ 1.1 cm) (local imaging)
o Elevated filling pressures (invasive assessment) at rest (PAWP ≥ 20 mmHg or LVEDP ≥ 15 mmHg) or with exercise (PAWP ≥ 25 mmHg) (historical records)
4. 6MWD ≥ 100 m and ≤ 550 m at Visit 2 (baseline)
5. Written informed consent signed before any study-specific procedure

E.4

Principal exclusion criteria

1. Acute decompensated heart failure (defined as acute exacerbation of HF that may require IV therapy with diuretics, vasodilators or inotropic drugs and / or mechanical support) within the past 4 weeks
2. Initiation or dose modification of cardiovascular pharmacological therapy within the past 2 weeks (dose modification of pre-existing diuretic / anticoagulant medication is allowed based on patient-specific needs)
3. Inability to exercise: wheelchair / scooter / walker dependent; dependent on supplemental oxygen
4. HF is not the primary factor limiting activity as indicated by the patient affirming #1, #2 or #3 of the following questionnaire:
My ability to be active is most limited by:
#1 - Joint, foot, leg, hip or back pain
#2 - Unsteadiness or dizziness impairing daily mobility
#3 - Lifestyle, weather, or I just don’t like to be active
5. Previous diagnosis of HFrEF (LVEF < 40%)
6. Known clinically significant persistent coronary ischemia (based on medical history, a preexisting or a recent clinical stress test)
7. Occurrence of any of the following within 3 months:
o Clinically evident myocardial infarction
o Hospitalization for unstable angina
o Stroke or transient ischemic attack
o Coronary artery bypass graft (CABG)
o Percutaneous coronary intervention (PCI)
o Implantation of a cardiac resynchronization therapy device (CRTD)
o Major surgery (that could interfere with patients’ ability to exercise)
8. PCI, CABG or implantation of a CRTD planned between randomization and end of study
9. Sustained systolic blood pressure ≤ 90 mmHg and / or signs and symptoms of hypotension prior to randomization
10. Sustained systolic blood pressure ≥ 160 mmHg prior to randomization
11. Sustained bradycardia with heart rate < 50 beats/minute or tachycardia with heart rate > 100 beats/minute prior to randomization
12. Known clinically relevant ventricular arrhythmias (sustained ventricular tachycardia, ventricular flutter or fibrillation) within 3 months prior to randomization based on either medical history or device generated data (if applicable)
13. Clinically relevant permanent or intermittent AV-block > grade II in patients without a permanent pacemaker or ICD / CRTD
14. Severe uncorrected valvular heart disease
15. Listing for heart transplantation and / or anticipated implantation of a ventricular assist device
16. Severe pulmonary disease with any of the following:
o Requirement of continuous (home) oxygen or
o History of chronic obstructive pulmonary disease ≥ GOLD III
o Use of systemic corticosteroids
17. Asthma bronchiale with any of the following:
o Symptoms not well-controlled within the past 6 months or
o Ever intubated or in an intensive care unit for asthma
18. Anemia with hemoglobin < 10 g/dL within 3 months prior to randomization. If several values are available the latest result should be used.
19. Body mass index (BMI) > 40 kg/m2 at randomization (German Specific)
20. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 calculated by Modification of Diet in Renal Disease (MDRD) formula within 3 months prior to randomization (see Appendix 16.1). If several values are available the latest result should be used.
21. Hepatic insufficiency classified as Child-Pugh B or C (see Appendix 16.2), or any of the following:
o Primary biliary cirrhosis (PBC)
o Primary sclerosing cholangitis
o PBC-autoimmune hepatitis overlap syndrome
22. Concomitant use of any of the following therapy that cannot be discontinued:
o Moderate or strong CYP3A4 inhibitors (Of note: grapefruit is a strong CYP3A4 inhibitor)
o CYP3A4 inducers
o Strong CYP2C8 inhibitors (Of note: clopidogrel is a strong CYP2C8 inhibitor)
o Theophylline
o Drugs having significant pre-systemic clearance via UGT1A1 in the intestine
Respective substances must be stopped at least 7 days before randomization.
30. Otherwise vulnerable patients. The patient is in custody by order of an authority or a court of law (German specific)

E.5 End points

E.5.1

Primary end point(s)

Absolute change from baseline in 6MWD after 20 weeks of treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

at the end of the study, no formal interim analysis is planned

E.5.2

Secondary end point(s)

• Activity (e.g. duration, intensity) reported values and absolute change from baseline at 20 weeks
• NT-proBNP (pg/mL), measured values (log transformed) and absolute / relative change from baseline at 20 weeks to assess elevated filling pressures
• High sensitivity troponin T (hs-TNT; ng/L), measured values (log transformed) and absolute / relative change from baseline at 20 weeks as a biomarker of myocardial injury
• KCCQ, as described in protocol Section 9.4.6.1, measured values and absolute / relative change from baseline

E.5.2.1

Timepoint(s) of evaluation of this end point

at the end of the study, no formal interim analysis is planned

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

Yes

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

biomarkers

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

Bulgaria

Germany

Greece

Israel

Italy

Japan

Poland

Portugal

Spain

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

The end of the study as a whole will be reached as soon as the last visit of the last patient has occurred in all centers in all participating countries (EU and non EU)

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:

230

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

219

F.4.2.2

In the whole clinical trial

288

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

2017-04-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-06-20

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