Clinical Trials Register

Summary
EudraCT Number:	2013-002783-12
Sponsor's Protocol Code Number:	BAYq6256/16483
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-18
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

2013-002783-12

A.3

Full title of the trial

A multi-center, open-label, randomized cross-over study to compare the acute tolerability and pharmacokinetics of BAY Q 6256 (iloprost; Ventavis) inhalation using the I-Neb nebulizer and the FOX nebulizer in patients with pulmonary arterial hypertension

A.3.1

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

Offene und multizentrische Studie bei Patienten mit Lungenhochdruck zum Überkreuzvergleich (Cross-over) von Verträglichkeit und Blutspiegeln von Iloprost (Ventavis) nach Inhalation von Ventavis mit dem Fox-Vernebler und dem I-Neb-Vernebler

A.3.2

Name or abbreviated title of the trial where available

Administration von Iloprost aerosol comparing two nebulizers: Fox and I-Neb

A.4.1

Sponsor's protocol code number

BAYq6256/16483

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 Trial Contact
B.5.3	Address:
B.5.3.1	Street Address	CTP Team/Ref: "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@bayer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	Ventavis 10
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	ORPHA131352
D.3 Description of the IMP
D.3.1	Product name	Ventavis 10
D.3.2	Product code	Bay Q 6256
D.3.4	Pharmaceutical form	Nebuliser solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ILOPROST
D.3.9.1	CAS number	78919-13-8
D.3.9.2	Current sponsor code	Bay q 6256
D.3.9.4	EV Substance Code	SUB08136MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
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	Yes
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	Yes
D.2.1.1.1	Trade name	Ilomedin 20 [20 µg / ml]
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Vital GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	ORPHA13370
D.3 Description of the IMP
D.3.1	Product name	Ilomedin 20
D.3.2	Product code	Bay q 6256
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ILOPROST
D.3.9.1	CAS number	78919-13-8
D.3.9.2	Current sponsor code	Bay q 6256
D.3.9.4	EV Substance Code	SUB08136MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/ml microgram(s)/millilitre
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	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with Pulmonary arterial hypertension, WHO class III, who have been on therpay with Ventavis 10 for at least 4 weeks

E.1.1.1

Medical condition in easily understood language

Patienten mit Lungenbluthochdruck im Schweregrad WHO III, die seit mindestens 4 Wochen eine Inhalationstherapie mit Ventavis 10 durchführen

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10036727
E.1.2	Term	Primary pulmonary hypertension
E.1.2	System Organ Class	100000004855

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 primary objective of this study is to assess, in subjects with pulmonary arterial hypertension, the acute tolerability of 5 µg iloprost inhaled as Ventavis 20 µg/mL solution through a FOX nebulizer with that of 5 µg iloprost inhaled as Ventavis 10 µg/mL solution through the I Neb nebulizer.

E.2.2

Secondary objectives of the trial

The secondary objective is to compare the pharmacokinetics of iloprost as administered by these two methods

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female aged ≥ 18 years.
2. Written informed consent given. [This consent must have been given before any study-specific procedures are conducted. A single informed consent form will cover both the main study, Parts 1–3, and the extension, Part 4.]
3. Current diagnosis of pulmonary hypertension (updated Dana Point Classification 1).
4. Current inhalative therapy with 5 µg iloprost using the I Neb nebulizer.
5. WHO functional class III at the time of the patient's commencement of inhalative therapy with iloprost.
6. Hemodynamic diagnosis of PAH showing mean pulmonary arterial pressure (mPAP) > 25 mmHg, pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) < 15 mmHg and pulmonary vascular resistance (PVR) > 320 dyn•s•cm–5.
7. Ability to understand and follow study-related instructions.
8. If non-specific types of chronic treatment for PAH are being administered: Stable dosage of these for at least the 4 weeks up to screening.
9. If PAH-specific drug treatments (such as endothelin receptor antagonist (ERA) or phosphodiesterase-5 (PDE5) inhibitors) are being administered: Stable dosage of these for at least the 3 months up to screening.

E.4

Principal exclusion criteria

Related to pulmonary disease / PAH
1. PAH related to any etiology other than those specified in the inclusion criteria, especially pulmonary veno-occlusive disease (PVOD)
2. Documented evidence of thromboembolic disease (probability for pulmonary embolism) using methodology such as pulmonary angiogram, ventilation perfusion scan, or chest computed tomography (CT) scan within the 3 years before the screening visit
3. Clinically relevant obstructive lung disease (e.g. asthma or chronic obstructive pulmonary disease, COPD)
4. Receipt of atrial septostomy within the six months before the screening visit
Related to cardiovascular disease
5. Severe coronary heart disease or unstable angina
6. Myocardial infarction within the six months before the screening visit
7. Decompensated cardiac failure if not under close medical supervision
8. Severe arrhythmias
9. Congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension
10. Cerebrovascular events (e.g. transient ischemic attack or stroke) within 3 months before Screening Visit
11. Uncontrolled systemic hypertension as evidenced by systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg on repeated measurement
12. Systemic hypotension with systolic blood pressure < 85 mmHg
Related to other conditions
13. Hypersensitivity to the active substance or to any of the excipients
14. Conditions where the effects of Ventavis on platelets might increase the risk of hemorrhage (e.g. active peptic ulcers, trauma, intracranial hemorrhage)
15. Hepatic impairment (such as acute hepatitis, chronic active hepatitis, or liver cirrhosis Child-Pugh B, C)
16. Chronic renal insufficiency as defined by a creatinine of > 2.5 mg/dL and/or the requirement for dialysis
17. Clinically relevant bleeding disorder or active bleeding
18. Psychiatric, addictive, or other disorder that compromises the ability to give informed consent for participating in this study
19. Clinically relevant abnormal conditions (including laboratory values) at Screening Visit that, in the opinion of the investigator, would compromise the evaluation of the study drug
Related to prior and concomitant medication
20. Addition or dose change of PAH specific drug treatments such as ERA or PDE5 inhibitors within 3 months before Screening Visit
21. Addition or dose change of non-specific type of chronic treatments for PAH such as calcium channel blockers, nitrates, digitalis, or diuretics within 4 weeks before Screening Visit
22. Treatment with an investigational drug or device which has not received regulatory approval within 4 weeks before Screening Visit or during study
23. Any kind of prostanoid other than those mentioned in inclusion criteria no. 9 within a period shorter than 5 half-lives before treatment
Others
24. Pregnant or breastfeeding women
25. Woman of child-bearing potential who does not agree to use an adequate method of contraception, i.e. a combination of two effective methods of birth control, for example a combination of condoms with a safe and highly effective contraception method (prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device) or a double barrier method is used throughout the study
26. Investigators, study staff, or their immediate families
27. Criteria which in the opinion of the investigator preclude participation for scientific reasons, for reasons of compliance, or for reasons of the subject’s safety

E.5 End points

E.5.1

Primary end point(s)

The primary analysis in this study is of safety.
The primary safety variable is:
– The proportion of patients with a meaningful maximum increase (i.e. 25%) in heart rate AND/OR a meaningful maximum decrease (i.e. 20%) in systolic blood pressure within the 30 minutes after the start of inhalation.

E.5.1.1

Timepoint(s) of evaluation of this end point

within 30 minutes after start of inhalation

E.5.2

Secondary end point(s)

The secondary safety variables are:
– Maximum change in systolic, diastolic and mean arterial blood pressure,
– Maximum change in heart rate within the 30 minutes following inhalation,
– Maximum change in oxygen saturation within the 30 minutes following inhalation.

- Pharmacokinetics of Iloprost as administered by two inhalers (Fox and I-Neb)

E.5.2.1

Timepoint(s) of evaluation of this end point

up to 2 hours after start of each inhalation

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

E.6.4

Safety

Yes

E.6.5

Efficacy

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pk profiles until 60 min following inhalation of Ventavis 10 and Ventavis 20 will be established

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Ventavis 10 or Ilomedin 20µg/ml will be administered with the I-Neb and the Fox nebulizer

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.8.5

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

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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 the date when the last subject completed Visit 4 (30 day follow-up period). All subjects will be offered to enter a long term extension Phase of up to 30 months until approval and commercial availability of Ventavis 20 and the FOX nebulizer.

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

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:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

F.4.2.2

In the whole clinical trial

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)

The subjects may:
- return to using Ventavis 10 with the I-Neb nebulizer as they did before prior to entering the study
- continue the long term extension part with ventavis 20 and the FOX nebulizer and thereafter return to using Ventavis 10 with the I-Neb nebulizer
- continue the long term extension part with ventavis 20 and the FOX nebulizer and thereafter, if market authorisation has been granted, continue with Ventavis 20 and the FOX nebulizer in clinical routine.

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

2013-12-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-09-29

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