Clinical Trials Register

Summary
EudraCT Number:	2016-003168-37
Sponsor's Protocol Code Number:	Thllo
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:	2018-11-29
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

2016-003168-37

A.3

Full title of the trial

Therapeutic Iloprost for the treatment of Acute Respiratory Distress Syndrome (ARDS) (the ThIlo-Trial): a prospective, randomized, multicenter phase II study

A.3.1

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

New therapy for patients suffering Acute Respiratory Distress Syndrome

A.3.2

Name or abbreviated title of the trial where available

Thllo

A.4.1

Sponsor's protocol code number

Thllo

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	University Tuebingen
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Department of Aneshesia and intensive care University Hospital Tuebingen
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	University Department of Anesthesia and intensive care
B.5.2	Functional name of contact point	Intensive Care Unit
B.5.3	Address:
B.5.3.1	Street Address	Hoppe-Seyler-Str. 3
B.5.3.2	Town/ city	Tuebingen
B.5.3.3	Post code	72076
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4970712986622
B.5.5	Fax number	+497071295533
B.5.6	E-mail	peter.rosenberger@med.uni-tuebingen.de

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	Yes
D.2.1.1.1	Trade name	Ventavis
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG, D-13342 Berlin, Deutschland
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ventavis
D.3.4	Pharmaceutical form	Nebulisation 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 TROMETAMOL
D.3.9.1	CAS number	73873-87-7
D.3.9.4	EV Substance Code	SUB14185MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute respiratory distress syndrome requiring mechanical ventilation

E.1.1.1

Medical condition in easily understood language

Patients with pulmonary insufficiency requiring mechanical ventilation

E.1.1.2

Therapeutic area

Diseases [C] - Symptoms and general pathology [C23]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. Improvement of oxygenation (defined as paO2/FiO2 ratio)

E.2.2

Secondary objectives of the trial

2. Overall survival in 90-day follow-up period (90 day all-cause mortality).
3. SOFA Organ failure Scores at day 1-14, 28 and 90
4. duration of mechanical ventilation support
5. ICU length of stay
6. Ventilator associated pneumonia
7. Barotrauma
8. Pulmonary hemorrhage
9. Gastrointestinal hemorrhage
10. Pulmonary embolism
11. Delirium
12. ICU acquired weakness
13. Discharge Location (home, skilled nursing facility, rehabilitation)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. ARDS as defined according to the Berlin Definition10 starting from mild stage with acute onset and
1. PaO2/ FiO2 ≤ 300 at time of ARDS diagnosis
2. Bilateral opacities on frontal chest radiograph, and
3. requirement for positive pressure ventilation via an endotracheal tube or non-invasive ventilation
4. no clinical signs of left atrial hypertension detected via echocardiography, or if measured, a Pulmonary Arterial Wedge Pressure (PAOP) less than or equal to 18 mmHg.
5. The term “acute onset” is defined as following: the duration of the hypoxemia criterion (#i) and the chest radiograph criterion (#ii) must be ≤ 28 days at the time of randomization. Patients must be randomized within 96 hours of diagnosis of ARDS and no later than 7 days from the initiation of mechanical ventilation.
6. Subject’s Age ≥ 18 years

E.4

Principal exclusion criteria

1. Subject’s Age < 18 years
2. More than 7 days since initiation of mechanical ventilation
3. more than 96 hours from ARDS diagnosis to randomization
4. Patient, surrogate or physician not committed to full intensive care support.
5. Positive Pregnancy test at the time of screening.
6. Contraindications for Iloprost: Conditions where the effects of Iloprost on platelets might increase the risk of hemorrhage (e.g. active peptic ulcers, trauma, intracranial hemorrhage), severe coronary heart disease, myocardial infarction (within the last 6 months), decompensated heart failure, severe arrhythmias, unstable angina pectoris, pulmonary arterial hypertension caused by occlusion of pulmonary veins, cerebrovascular events (e.g. transient ischemic attack, stroke) within the last 3 months, congenital or acquired valvular defects with clinically relevant myocardial function disorders not related to pulmonary hypertension, patients taking Direct Thrombin Inhibitors within previous 24hrs. before study randomization.
7. Patients having NO Therapy within the previous 24hrs. before study randomization
8. Patients who received Iloprost treatment for any indication within 48 hours prior to the enrolment into the clinical trial
9. Patients dependent on the sponsor, investigator and their employees, as well as persons dependent on the manufacturer of the investigational drug
10. Subject (male or female) is not willing to use highly effective methods of contraception according to the “Clinical trial fertility group” recommendations (http://www.hma.eu/fileadmin/dateien/Human_Medicines/01About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf) during treatment until the visit at day 28 (adequate: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner1, sexual abstinence2).
1 Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomized partner has received medical assessment of the surgical success2 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

E.5 End points

E.5.1

Primary end point(s)

Improvement of oxygenation (defined as PaO2/FiO2 ratio)

E.5.1.1

Timepoint(s) of evaluation of this end point

during ICU lengh of stay

E.5.2

Secondary end point(s)

Overall survival in 90-day follow-up period (90 day all cause mortality)
SOFA Organ failure scores
duration of mechanical ventilation support
ICU length of stay
Ventilator associated pneumonia
Barotrauma
gastrointestinal hemorrhage
pulmonary embolism
Delirium
ICU aquired weakness
discharge location

E.5.2.1

Timepoint(s) of evaluation of this end point

During ICU length of stay

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

E.6.5

Efficacy

E.6.6

Pharmacokinetic

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

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

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

Standard of Care, Ventilation according to ARDSNet protocol

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

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

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

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Subjects requiring ventilation therapy because of respiratory failure.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

150

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

2019-03-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-11-18

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