Clinical Trials Register

Summary
EudraCT Number:	2010-018436-41
Sponsor's Protocol Code Number:	Bay 63-2521/14554
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2010-04-22
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

Austria - BASG

A.2

EudraCT number

2010-018436-41

A.3

Full title of the trial

Acute hemoDynamic effects of RIociguat (BAY 63-2521) in patients with puLmonary hypertension Associated with diasTolic heart failurE (DILATE 1): A randomized, double-blind, placebo-controlled, single-dose study in three ascending dose cohorts.

A.3.1

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

Riociguat single -dose study measuring of blood flow in lungs with high blood pressure associated with heart failure.

A.3.2

Name or abbreviated title of the trial where available

DILATE 1

A.4.1

Sponsor's protocol code number

Bay 63-2521/14554

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	NA
B.4.2	Country
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	CTP Team / Ref:"EU CTR"/ S102-R156
B.5.3	Address:
B.5.3.1	Street Address	Müllerstr. 170-178
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	D-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	Riociguat
D.3.2	Product code	BAY 63-2521
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Riociguat
D.3.9.1	CAS number	625115-55-1
D.3.9.2	Current sponsor code	BAY 63-2521
D.3.9.3	Other descriptive name	Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate
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	0. to 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	Riociguat
D.3.2	Product code	BAY 63-2521
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Riociguat
D.3.9.1	CAS number	625115-55-1
D.3.9.2	Current sponsor code	BAY 63-2521
D.3.9.3	Other descriptive name	Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carb
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. to 0
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	Riociguat
D.3.2	Product code	BAY 63-2521
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Riociguat
D.3.9.1	CAS number	625115-55-1
D.3.9.2	Current sponsor code	BAY 63-2521
D.3.9.3	Other descriptive name	Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine-3-yl]-5-pyrimidinyl(methyl)carbamate
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	2. to 0
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

Pulmonary hypertension associated with diastolic heart failure

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	13.1
E.1.2	Level	LLT
E.1.2	Classification code	10037405
E.1.2	Term	Pulmonary hypertension primary
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal 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

The objective of the present study is to evaluate the acute hemodynamic effects, safety, and pharmacokinetics of Riociguat in patients with PH associated with diastolic heart failure.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must fulfill all of the following criteria before being included in the study:
1.Age ≥ 18 years

2.Invasive confirmation of PH associated with DHF documented by right heart catheter measurements of the following parameters:

-PAPmean ≥ 25 mmHg and
- PCWP >15 mmHg
3. Transthoracic echocardiography
- confirming preserved ejection fraction with LVEF>50% and
- evidence for diastolic dysfunction:

either

o in patients with sinus rhythm: either abnormal relaxation (E/A wave ratio <1) or diastolic stiffness (E/A-wave ratio >2)
or
o in patients with atrial fibrillation: E-wave deceleration time <150 ms
4. NYHA class >I
5. Serum NT-proBNP >220 pg/ml

6.Written informed consent

E.4

Principal exclusion criteria

General exclusion criteria:
1.Previous assignment to treatment during this study
2.Participation in another clinical trial during the preceding 30 days.

3.Pregnant women, or breast feeding women, or women with childbearing potential not using a combination of condoms and a safe and highly effective contraception method (hormonal contraception with implants or combined oral contraceptives, certain intrauterine devices [IUDs]).
4.Patients with a medical disorder, condition, or history of such that would impair the patient's ability to participate or complete this study in the opinion of the investigator.
5.Patients with a history of severe allergies or multiple drug allergies.
6.Known hypersensitivity to study drug or any of the excipients
Medication/Treatment exclusion criteria:
1.Pre-Treatment within 30 days before randomization with:
•intravenous (IV) inotropes or IV vasodilators
•endothelin receptor antagonists (ERAs), PDE5 inhibitors or prostanoids.
2.Treatment within 7 days before randomization with NO donors (e.g. nitrates).
3.Requirement of treatment with prohibited drugs (see section 6.9) within 48 h after study drug intake.
Pulmonary diseases exclusion criteria:
1.Bronchial asthma or COPD with Forced Expiratory Volume in one second (FEV1) <60% predicted.
2.Restrictive lung disease with Total Lung Capacity <60% predicted.
3.Severe congenital abnormalities of the lungs, thorax, or diaphragm.
4.O2 therapy
5.Clinical or radiological evidence of Pulmo-Veno-Occlusive Disease (PVOD) or Pulmonary Capillary Hemangiomatosis (PCH).
Exclusion criteria related to abnormalities in blood gases (measured capillary or arterial):
1.SaO2 < 88%
2.PaO2 < 55 mmHg
Cardiovascular exclusion criteria:
1.Pulmonary hypertension of groups other than 2.2 of Dana Point Classification

2.Significant valvular heart disease defined by the requirement for surgical repair apart from tricuspid valvular insufficiency due to PH.

3.Presence of myocardial ischemia as indicated by angina pectoris, stress test, or coronary angiography.

4.Unstable angina or myocardial infarction within the last 3 months.

5. Revascularization procedure (percutaneous coronary intervention [PCI] or coronary artery
bypass graft [CABG]) within the last 3 months.

6. Cardiac surgery within the last 3 months, or transcatheter aortic valve implantation within
30 days, or ongoing prolonged hospitalization after cardiac surgery.

7. Clinical instability with cardiac decompensation or clinical constellation at the time of randomization, characterized by any of the following:

a. Pleural or pericardial effusion requiring pleura- / pericardiocentesis
b. Need for IV diuretic treatment or evidence for volume overload

c. Admission to emergency or intensive care unit

d. Need for non-study procedures including stress testing or contrast media exposure that could confound the results and stress the patient

8. Critical carotid artery stenosis

9. Hypertrophic cardiomyopathy, amyloidosis, or cardiomyopathy associated with storage disease

10. Constrictive pericarditis

11. Resting heart rate while awake <50 bpm or >110 bpm

12. Uncontrolled arterial hypertension (Systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg) or arterial hypertension not optimally managed according to current guidelines and requiring immediate antihypertensive treatment.

Exclusion criteria related to disorders in organ function:
1.Clinically relevant hepatic dysfunction indicated by either:
•Aspartate aminotransferase (AST) >3 times upper limit normal (ULN)
•Child Pugh stage B and C in cirrhotic patients
2.Severe chronic renal insufficiency (glomerular filtration rate [GFR] GFR <30 mL/min calculated by Modification of Diet in Renal Disease [MDRD] formula).

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy variable is the peak decrease from baseline in mean pulmonary arterial pressure (PAPmean).

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

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)

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.8.3

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

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

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

Last patient completed the study

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	No
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.2.1	Number of subjects for this age range:	10
F.1.3	Elderly (>=65 years)	Yes
F.1.3.1	Number of subjects for this age range:	38
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	40
F.4.2	For a multinational trial
F.4.2.1	In the EEA	48
F.4.2.2	In the whole clinical trial	48

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

2010-05-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-05-11

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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