Clinical Trials Register

Summary
EudraCT Number:	2020-005768-74
Sponsor's Protocol Code Number:	ImmunoSep
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:	2022-02-03
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

Germany - BfArM

A.2

EudraCT number

2020-005768-74

A.3

Full title of the trial

PERSONALIZED IMMUNOTHERAPY IN SEPSIS: A MULTICENTRE AND MULTINATIONAL, DOUBLE-BLIND, DOUBLE-DUMMY RANDOMIZED CLINICAL TRIAL (THE IMMUNOSEP TRIAL)

A.3.1

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

Administration of immunotherapy according to the function of immune system in sepsis

A.3.2

Name or abbreviated title of the trial where available

ImmunoSep

A.4.1

Sponsor's protocol code number

ImmunoSep

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	Hellenic Institute for the Study of Sepsis
B.1.3.4	Country	Greece
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	Hellenic Institute for the Study of Sepsis
B.4.2	Country	Greece
B.4.1	Name of organisation providing support	European Union Horizon 2020
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hellenic Institute for the Study of Sepsis
B.5.2	Functional name of contact point	President of the Board
B.5.3	Address:
B.5.3.1	Street Address	88 Michalakopoulou str.
B.5.3.2	Town/ city	Athens
B.5.3.3	Post code	11528
B.5.3.4	Country	Greece
B.5.4	Telephone number	00302107480662
B.5.5	Fax number	00302107480662
B.5.6	E-mail	insepsis@otenet.gr

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	Kineret
D.2.1.1.2	Name of the Marketing Authorisation holder	Swedish Orphan Biovitrum
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	Anakinra
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
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	Anakinra
D.3.9.1	CAS number	143090-92-0
D.3.9.4	EV Substance Code	SUB05500MIG
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	100
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	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	Imukin
D.2.1.1.2	Name of the Marketing Authorisation holder	Clinigen Healthcare B.V.
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	Recombinant human interferon gamma-1b
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.3.8	INN - Proposed INN	recombinant human interferon gamma-1b
D.3.9.1	CAS number	98059-61-1
D.3.9.3	Other descriptive name	INTERFERON GAMMA-1B
D.3.9.4	EV Substance Code	SUB12076MIG
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	0.1
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	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	Injection
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
D.8.3	Pharmaceutical form of the placebo	Injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Sepsis

E.1.1.1

Medical condition in easily understood language

Severe infections that cause organ failure

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10040053
E.1.2	Term	Sepsis secondary
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Our aim is to conduct one RCT in sepsis to assess whether personalized adjunctive immunotherapy directed against a state of either fulminant hyper-inflammation or immunoparalysis is able to change sepsis outcomes. Patients will be selected by a panel of biomarkers and laboratory findings and will be allocated to placebo or immunotherapy treatment according to their needs. The study enrolment will be competitive between the participating study sites.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age equal to or above 18 years.
• Both genders.
• In case of women, unwillingness to become pregnant during the study period.
• Written informed consent provided by the patient or by one first degree relative/spouse in case of patients unable to consent.
• Community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) or primary bacteremia (BSI).
• Sepsis defined by the Sepsis-3 definitions. More precisely, sepsis is defined as the presence of total SOFA (sequential organ failure assessment score) equal to 2 or more for Patients who are admitted with infection at the emergency department OR as any increase of admission SOFA by 2 or more points for patients already hospitalized.
• Patients with signs of fulminant hyper-inflammation or sepsis associated immunoparalysis. Since the state of hyperinflammation is considered more life-threatening than the state of immunoparalysis, patients with lab findings of both immune states are allocated to treatment targeting hyper-inflammation. It is explicitly stated that patients diagnosed with COVID-19 infection may participate only in the fulminant hyper-inflammation arm.
• Time from classification into sepsis by the Sepsis-3 definitions and start of blind intervention less than 72 hours.

E.4

Principal exclusion criteria

• Age below 18 years.
• Denial for written informed consent.
• Acute pyelonephritis or intraabdominal infection, meningitis or skin infection.
• Any stage IV malignancy.
• Neutropenia defined as an absolute neutrophil count lower than 1,500/mm3.
• Any 'do not resuscitate' decision in the hospital.
• In the case of BSI, patients with blood cultures growing coagulasenegative staphylococci or skin commensals or catheter-related infections cannot be enrolled.
• Active tuberculosis (TB) as defined by the co-administration of drugs for the treatment of TB.
• Infection by the human immunodeficiency virus (HIV).
• Any primary immunodeficiency.
• Oral or intravenous intake of corticosteroids at a daily dose equal or greater than 0.4 mg/kg prednisone or greater the last 15 days.
• Any anti-cytokine biological treatment the last one month.
• Medical history of systemic lupus erythematosus.
• Medical history of multiple sclerosis or any other demyelinating disorder.
• Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy study endpoint will be the comparative difference in the mean total SOFA (Sequential Organ Failure Assessment) score until day 9 after randomization. At least 1.4 points decrease of the mean total SOFA score in the immunotherapy arm compared to the standard-of-care arm on day 9 of follow-up must be achieved. For patients dying before day 9, their mean SOFA score until the day of death will be used for this comparison.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 9

E.5.2

Secondary end point(s)

• 28-day mortality
• 90-day mortality
• The change of mean total SOFA score on day 15 of the end of treatment.
• The impact of personalized immunotherapy on the reversal of hyperinflammation or immunoparalysis. This endpoint applies on day 15 of the end of treatment and it is defined as follows: a) for patients with fulminant hyper-inflammation as any at least 15% decrease of the baseline serum ferritin; and b) for patients with sepsis-associated
immunoparalysis as restoration of Quantibrite to above 8,000 AB/C with serum ferritin below 4,420 ng/mL.

E.5.2.1

Timepoint(s) of evaluation of this end point

Days 15, 28 and 90

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

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Switzerland

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

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

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.1.1.1

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:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

180

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Some of patients may be sedated under mechanical ventilation in the Intensive Care Unit. This condition makes impossible that they consent and consent needs to be asked by the legal representative.

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

280

F.4.2.2

In the whole clinical trial

280

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

2022-05-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-04-27

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