Clinical Trials Register

Summary
EudraCT Number:	2011-002254-31
Sponsor's Protocol Code Number:	THR-PS-03
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2011-11-30
Trial 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

Finland - Fimea

A.2

EudraCT number

2011-002254-31

A.3

Full title of the trial

Double-blinded, randomized trial in severe pneumonia patients with severe sepsis investigating the safety and efficacy of co-administration of iloprost and ascending doses of eptifibatide compared to low-molecular-weight heparin.

A.3.1

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

Treatment with Iloprost and Integrilin compared to standard care in severe pneumonia patients with severe sepsis.

A.4.1

Sponsor's protocol code number

THR-PS-03

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	Rigshospitalet, ITA 4131, Department of Intensive care
B.1.3.4	Country	Denmark
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	Thrombologic ApS
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Rigshospitalet, ITA 4131, Department of Intensive care
B.5.2	Functional name of contact point	principal Investigator
B.5.3	Address:
B.5.3.1	Street Address	Blegdamsvej 9
B.5.3.2	Town/ city	Copenhagen Ø
B.5.3.3	Post code	2100
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004535348388
B.5.5	Fax number	004535452736

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	INTEGRILIN 0,75 mg/ml solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Ltd
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.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous drip use (Noncurrent) Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EPTIFIBATIDE
D.3.9.1	CAS number	188627-80-7
D.3.9.2	Current sponsor code	NAP
D.3.9.3	Other descriptive name	NAP
D.3.9.4	EV Substance Code	SUB12498MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2
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	Yes
D.2.1.1.1	Trade name	Ilomedin, Concentrate for infusion
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous 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	0
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB14185MIG
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	27
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	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	Klexane Cum Conservans 100mg/ml, injection
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis Oy
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	Klexane Cum Conservans
D.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ENOXAPARIN SODIUM
D.3.9.1	CAS number	01/08/9041
D.3.9.4	EV Substance Code	SUB11933MIG
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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Severe pneumonia with Sepsis and Septic Shock

E.1.1.1

Medical condition in easily understood language

Severe pneumonia and Blood poisoning

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10040070
E.1.2	Term	Septic shock
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluating the safety and efficacy of co-administration of Eptifibatide and Iloprost as compared to placebo in addition standard care in severe pneumonia patients with severe sepsis or septic chock.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. At least 18 years of age AND

2. Suspected or proven bacterial pneumonia requiring administration of antibiotics:

• Clinical diagnosis of pneumonia, (i.e. new or increased cough, production of purulent sputum or a change in the character of sputum in subjects who normally have purulent sputum, typical auscultatory findings of pneumonia on chest examination) and:

• chest radiograph or CT within the last 24 hr showing a pulmonary infiltrate

3. Dyspnea and/or tachypnea (>20 breaths/minute) or mechanical ventilation

4. Two or more systemic inflammatory response syndrome (SIRS) criteria within the last 24 hours:

-Temperature </= 36˚ C or >/= 38˚C
-Heart rate >/= 90 beats per minute
-Mechanical ventilation for acute respiratory process or respiratory rate >/= 20 breaths per minute or PaC02 < 4.2 kPa
-WBC >/= 12,000/mm³ OR </= 4,000/mm³ OR > 10% bands

5. At least one organ failure beyond respiratory failure (cerebral, cardiovascular, hepatic, renal or coagulation within the last 24 hours (> 2 in SOFA score for the specific organ system) AND

6. Can be randomized into trial and dosed < 48 h after severe sepsis diagnosis AND

7. Consent is obtainable

E.4

Principal exclusion criteria

1. Patient is pregnant or breast-feeding

2. Patient weighs more than 125 kg

3. Patients with known allergy towards any of the investigational products or contraindications which should be excluded according to the investigational product specifications

4. Investigators clinical decision deeming study participation not favourable for the patient

5. Patients in whom the clinician finds antithrombotic therapy contraindicated – prophylaxis included

6. Patients at increased risk of bleeding: Surgery in the previous 12 h, expected surgery within 72 h, epidural or spinal puncture in the previous 12 h, platelet count less than 30,000/mm3 in the previous 24 h, INR above 2.0 in the previous 24 h, need of blood products for bleeding in the previous 24 h, treatment with any antithrombotics within 12 h (profylaxis excepted), current or previous intracranial bleeding or traumatic brain or spinal injury within the last month.

7. Patients requiring any form of antithrombotics (beyond profylaxis) in therapeutic doses or prothrombotics in any dose, including;

Unfractionated heparin within 8 hours before the infusion (prophylactic heparin up to 15,000 U/day permitted).

Low-molecular-weight heparin within 12 hours (prophylactic doses permitted).

Having received Warfarin within 3 days before the infusion as well as if INR exceeded the upper limit of normal.

Acetylsalicylic acid more than 650 mg/day within 3 days before the study.
Thrombolytic therapy within 3 days before the study (catheter clearance doses permitted).

Glycoprotein IIb-IIIa antagonists within 7 days before the study.

Antithrombin III with dose greater than 10,000 U within 12 hours before the study.

Protein C within 24 hours of the study.

8. Previous diagnosed condition that might mimic or complicate the course and
evaluation of the infectious disease process (severe bronchiectasis, lung abcess or empyema, aspiration pneumonia, active tuberculosis, pulmonary malignancy, cystic fibrosis, severe chronic interstitial pneumonia, COPD or other forms of chronic lung disease requiring home oxygen treatment or resulting in chronic CO2 retention, , etc.)

9. Patient not expected to survive more than 30 days because of uncorrectable medical
or surgical condition other than sepsis

10.Patient with acute or chronic renal failure requiring dialysis (renal failure without need for dialysis permitted).

11. Patient with hematological malignancies of any kind

12. Patients who have undergone transplantation of bone marrow, liver, pancreas, heart,
lung, or bowel (kidney transplant permitted)

13. Patient has known hypercoagulable condition:
APC resistance
Hereditary protein C, protein S, or antithrombin III deficiency
Anticardiolipin or antiphospholipid antibody
Lupus anticoagulant
Homocysteinemia
Recent or highly suspected pulmonary embolism or deep venous thrombosis (within 3
mo)

14. Patients with known congenital hypocoagulable diseases

15. Patient with known AIDS

16. Patient with known primary pulmonary hypertension

E.5 End points

E.5.1

Primary end point(s)

Change in platelet count from baseline to 72 hours post treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary end point is evaluated throughout the 72 hour treatment period and after 28 and 90 days

E.5.2

Secondary end point(s)

•Severe bleeding (intracranial or clinical bleeding with the use of 3 RBC units or more) (KyperSept trial)
•Any bleeding
•Endothelial activation (changes in markers): sE-selectin, ICAM-1, HMGB-1, vWF, sTM, sCD40L Syndecan-1, IL-6, Protein C, sFlt-1, sVCAM-1
•Difference in day 7, 28 and 90 day mortality between patients receiving Eptifibatide and Iloprost and placebo
•Changes in SOFA score from baseline to 72 h and day 5 and 7 post randomisation
•Days of vasopressor, ventilator and renal replacement therapy and use of blood product (in ICU) after randomisation
•Occurrence of deep venous thrombosis at compression ultrasound at day 3 and 7 after randomisation
•DIC score changes from baseline to Day 1, 3 and 7

E.5.2.1

Timepoint(s) of evaluation of this end point

The secondary endpoint are evaluated througout the 72 hour treatment period and after 7, 28 and 90 days

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

E.6.7

Pharmacodynamic

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

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

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

All patients who withdraw from the trial for any reason and at any time should have an end of trial examination. Patients will be examined for any status changes that require further follow-up. All withdrawn patients will be followed-up as the remaining patients in the trial. If consent is withdrawn, the person making the withdrawal will be asked for permission to follow up for 90 days after randomisation.

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

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

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

Patients are unable to consent because of acute illness, so next of kin will be asked to consent on behalf of the patient. The Investigator must as soon as possible obtain consent from the patient as soon as he/she is able.

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)

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

2011-12-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-08

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

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