Clinical Trials Register

Summary
EudraCT Number:	2007-003111-31
Sponsor's Protocol Code Number:	2007-1-18-20-6
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2008-05-16
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 - PEI

A.2

EudraCT number

2007-003111-31

A.3

Full title of the trial

Influence of postoperative influenza vaccination versus GM-CSF in immune-compromised patients undergoing pancreatic or esophageal resection on the course of immunosuppression and the postoperative infection rate.

A.3.1

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

Influence of postoperative vaccination (Mutagrip) versus and intravenous infusion of a leucocyte multiplying hormone (GM-CSF) in immune-compromised patients undergoing pancreatic or esophageal operation on the course of immunosuppression and the postoperative infection rate.

A.3.2

Name or abbreviated title of the trial where available

ART VI

A.4.1

Sponsor's protocol code number

2007-1-18-20-6

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN27114642

A.5.4

Other Identifiers

Name:

ARTVI

Number:

ARTVI

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	Charité - Universitaetsmedizin Berlin
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	Charité - Universitaetsmedizin Berlin
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	Charité - Universitaetsmedizin Berlin, Department of Anaesthesiology and Intensive Care Medicine, CVK, CCM
B.5.2	Functional name of contact point	Univ. - Prof. Dr. Claudia Spies
B.5.3	Address:
B.5.3.1	Street Address	Augustenburger Platz 1
B.5.3.2	Town/ city	Berlin
B.5.3.3	Post code	13353
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4930551102
B.5.5	Fax number	+4930551909
B.5.6	E-mail	claudia.spies@charite.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	Mutagrip
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Pasteur MSD 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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Mutagrip
D.3.4	Pharmaceutical form	Solution for 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.3.9.3	Other descriptive name	INFLUENZA VACCINE (SPLIT VIRION, INACTIVATED)
D.3.10	Strength
D.3.10.1	Concentration unit	AgU antigen unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	45
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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)	Yes
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	Leukine
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer HealthCare Pharmaceuticals Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Leukine
D.3.2	Product code	Sargramostim
D.3.4	Pharmaceutical form	Powder 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	SARGRAMOSTIM
D.3.9.1	CAS number	123774721
D.3.10	Strength
D.3.10.1	Concentration unit	µg/m2 microgram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	250
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	ANTINEOPLASTIC AND IMMUNOSTIMULATING AGENT; a recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) that is produced by recombinant DNA technology in a yeast.

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 injection
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Post-operative immunological stimulation in severe immune suppression. The study population is made up of adult, which are able to give their inform consent by their own. The patients are undergoing elective esophageal resection or pancreas resection. Both men and women should enrolled in the clinical trial. The participants included in the clinical trial will not be selected with regard to their sex. The clinical trial is a pilot study.

E.1.1.1

Medical condition in easily understood language

Post-operative immunological activation in weakened immune system

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

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

A postoperative vaccination with influenza-vaccine or postoperative treatment with sargramostim within the phase of severe immunsuppression, leads to (compared to placebo) an improvement of immunoreactivity by absence of an immuno paralysis (measured by the normalisation of the HLA-DR expression of monocytes, > 10.000 antigens/monocyte).

E.2.2

Secondary objectives of the trial

- postoperative infection rate
- incidence of postoperative delirium (CAM-ICU, NuDESC, DDS)
- postoperative ventilation time (hours), ICU length of stay, Charité length of stay, APACHE-II-Score, SAPS-II-Score, SOFA-Score, TISS-28-Score
- The first 33 included patients will be analysed in regard to the following parameters:
1. Parameters of immune system function
- levels of different cytokines
- Th1/Th2 ratio,
- Th17/Treg ratio,
2. quantitative expression of transcription factors (T-bet, Eomesodermin, GATA-3, Foxp3, RORγt, PU.1) and proteins (SOCS-3, SOCS-1, TGF-ß, IL-17) as well as the synthesis of associated effector proteins

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- HLA-DR expression on monozytes ≤ 10.000 antigens/monocyte on the first postoperative day
- elective pancreas resection or esophagus resection,
- male or female subjects, aged ≥18,
- Written informed consent,
- negative pregnancy test (ßHCG in urine),
- women of childbearing age with highly effective contraception (PEARL-Index < 1%) or > 2 years postmenopausal,
- no participation in another investigational drug trial during the present clinical trial;

E.4

Principal exclusion criteria

- HLA-DR expression on monocytes > 10.000 antigens/monocyte on the first postoperative day
- missing informed consent,
- aged <18,
- missing willingness for storage and transfer of pseudonymised medical data related to the clinical trial,
- persons who are detained officially or legally to an official institution,
- participation in another investigational drug trial,
- employee of Charité
- pregnancy (positive for ßHCG in blood)
- lactation
- female patients with reproductive potential without highly effective contraception
- congenital or acquired blood disease
- chemo- or radiotherapy within last 28 days
- leukemia
- emergency operations
- detected infections within last 7 days before operation
- positive for hepatitis B/C
- positive for HIV
- patients reacting allergic or sensitive to active pharmaceutical ingredients, to other components or to possible contaminations of the investigational new drug (or known specific allergic reaction)
- autoimmune diseases
- taking of immunosuppressives
- untreated arrhythmia
- instable angina pectoris
- symptomatic congenital heart defect
- thrombosis and thrombembolic events in clinical anamnesis
- Laboratory parameters:
- platelets ≤ 100.000/µl
- neutrophiles ≤ 1.500/µl
- hemoglobin ≤ 8g/dl
- bilirubin > 2g/dl
- creatinin > 1,5g/dl
- AST/ALT > 90U/l

E.5 End points

E.5.1

Primary end point(s)

HLA-DR expression of monocytes
A postoperative vaccination with influenza-vaccine or postoperative treatment with sargramostim within the phase of severe immunsuppression, leads to (compared to placebo) an improvement of immunoreactivity by absence of an immuno paralysis (measured by the normalisation of the HLA-DR expression of monocytes, > 10.000 antigens/monocyte).

E.5.1.1

Timepoint(s) of evaluation of this end point

HLA-DR expression of monocytes
on the first 5 post-operative days

E.5.2

Secondary end point(s)

For all 60 study patients:
1.1. Post-operative infection rate
1.2. Post-operative incidence of delir (CAM-ICU, NuDesc, DDS)
1.3. Ventilation time, intensive care unit (ICU) stay, length of stay, APACHE II score, SAPS II score, SOFA score, TISS-28 score
For the first 33 study patients:
2.1. Cytokines in serum, Th1/ Th2-ratio, Th17/ Treg-ratio, further parameters of immune function
2.2. Quantitative expression of transcription factors (T-bet, Eomesodermin, Gata-3, Foxp3, ROR-gamma t, PU.1, STAT-1, STAT-3, STAT-5, NF kappa B) and proteins (SOCS-3, SOCS-1, SOCS-5, TGF-beta, IL-17, IL-6, IL-10, IFN-y, TNF-a, IL-23, IL-10) as well as the synthesis of the corresponding effector proteins

E.5.2.1

Timepoint(s) of evaluation of this end point

For all 60 study patients on the first 9 post-operative days:
1.1. Post-operative infection rate
1.2. Post-operative incidence of delir (CAM-ICU, NuDesc, DDS)
1.3. Ventilation time, intensive care unit (ICU) stay, length of stay, APACHE II score, SAPS II score, SOFA score, TISS-28 score
For the first 33 study patients on the first 5 post-operative days:
2.1. Cytokines in serum, Th1/ Th2-ratio, Th17/ Treg-ratio, further parameters of immune function
2.2. Quantitative expression of transcription factors (T-bet, Eomesodermin, Gata-3, Foxp3, ROR-gamma t, PU.1, STAT-1, STAT-3, STAT-5, NF kappa B) and proteins (SOCS-3, SOCS-1, SOCS-5, TGF-beta, IL-17, IL-6, IL-10, IFN-y, TNF-a, IL-23, IL-10) as well as the synthesis of the corresponding effector proteins

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.7.1

Other trial design description

double-dummy

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

Last visit of the last subject

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