Clinical Trials Register

Summary
EudraCT Number:	2020-005768-74
Sponsor's Protocol Code Number:	ImmunoSep
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-11-18
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

Italy - Italian Medicines Agency

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)

IMMUNOTERAPIA PERSONALIZZATA NELLA SEPSI: UNO STUDIO CLINICO RANDOMIZZATO, MULTICENTRICO E MULTINAZIONALE, IN DOPPIO CIECO E DOUBLE-DUMMY (LO STUDIO IMMUNOSEP)

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.

Somministrazione dell’immunoterapia in base al funzionamento del sistema immunitario in corso di sepsi.

A.3.2

Name or abbreviated title of the trial where available

ImmunoSep

A.4.1

Sponsor's protocol code number

ImmunoSep

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04990232

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	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	Mediolanum Cardio Research
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	Via G. Carducci 19
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20123
B.5.3.4	Country	Italy
B.5.4	Telephone number	0039026125141
B.5.5	Fax number	00390292853602
B.5.6	E-mail	jori@mcr-med.com

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	Sweden
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	Injection
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.3.9.1	CAS number	143090-92-0
D.3.9.2	Current sponsor code	NA
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	600
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Immukin
D.2.1.1.2	Name of the Marketing Authorisation holder	Clinigen Healthcare Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	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.3.9.1	CAS number	98059-61-1
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	recombinant human interferon-y
D.3.9.4	EV Substance Code	SUB02706MIG
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	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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Sepsi

E.1.1.1

Medical condition in easily understood language

Severe infections that cause organ failure

grave infezione che causa danni agli organi

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.

verificare l'effetto di una strategia di immunoterapia personalizzata sulla morbidità dei pazienti con sepsi o shock settico e iperinfiammazione associata a sepsi o immunoparalisi.

E.2.2

Secondary objectives of the trial

Not applicable

Non applicabile

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.
Patients with signs of fulminant hyper-inflammation or sepsis associated immunoparalysis. 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.

Età pari o superiore a 18 anni
Sesso maschile o femminile
Se donna, non intenzionata a iniziare una gravidanza durante il periodo di studio.
Consenso informato scritto da parte del paziente o del suo rappresentante legale in caso di pazienti non in grado di dare il proprio consenso.
Polmonite acquisita in comunità (CAP) o polmonite acquisita in ospedale (HAP) o polmonite associata al ventilatore (VAP) o batteriemia primaria (BSI)
Sepsi definita secondo le definizioni di Sepsis-3
Pazienti con segni di iper-infiammazione fulminante o immunoparalisi associata a sepsi; i pazienti con diagnosi di COVID-19 possono partecipare solo al braccio di iper-infiammazione fulminante.
Tempo intercorso tra la classificazione in sepsi secondo le definizioni di Sepsis-3 e l'inizio dell'intervento in cieco inferiore a 72 ore.

E.4

Principal exclusion criteria

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.

Pielonefrite acuta o infezione intra-addominale, meningite o infezione cutanea.
Qualsiasi neoplasia al IV stadio.
Neutropenia definita come conta assoluta dei neutrofili inferiore a 1.500/mm3.
Qualsiasi decisione di "non rianimare" in ospedale.
In caso di BSI (bloodstream infection – infezioni ematiche), non possono essere arruolati pazienti con emocolture in cui sono presenti stafilococchi coagulasi-negativi o commensali della pelle o infezioni correlate al catetere.
Tubercolosi (TB) attiva, definita dalla co-somministrazione di farmaci per il trattamento della TB.
Infezione da virus dell'immunodeficienza umana (HIV).
Qualsiasi immunodeficienza primaria.
Assunzione orale o endovenosa di corticosteroidi a una dose giornaliera pari o superiore a 0,4 mg/kg di prednisone o superiore negli ultimi 15 giorni.
Qualsiasi trattamento biologico anticitochine nell'ultimo mese.
Anamnesi di lupus eritematoso sistemico.
Anamnesi di sclerosi multipla o di qualsiasi altro disturbo demielinizzante.
Gravidanza o allattamento. Le donne in età fertile eseguiranno un test di gravidanza sulle urine prima dell'inclusione nello studio

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.

L'endpoint primario dello studio di efficacia sarà la differenza comparativa del punteggio medio totale SOFA (Sequential Organ Failure Assessment) fino al giorno 9 dopo la randomizzazione. Deve essere ottenuta una riduzione di almeno 1,4 punti del punteggio medio totale SOFA nel braccio immunoterapia rispetto al braccio standard di cura al giorno 9 del follow-up. Per i pazienti che muoiono prima del giorno 9, sarà utilizzato per questo confronto il punteggio medio SOFA fino al giorno del decesso.

E.5.1.1

Timepoint(s) of evaluation of this end point

day 9

9 giorni

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

• Mortalità a 28 giorni.
• Mortalità a 90 giorni.
• La variazione del punteggio medio totale SOFA al giorno 15 della fine del trattamento.
• L'impatto dell'immunoterapia personalizzata sull'inversione dell'iper-infiammazione o dell'immunoparalisi.
Questo endpoint è definiti come segue: a) per i pazienti con iperinfiammazione fulminante, qualsiasi diminuzione di almeno il 15% della ferritina sierica basale; e b) per i pazienti con immunoparalisi associata a sepsi, il ripristino del Quantibrite a più di 8.000 ABC (antigen binding capacity) con ferritina sierica inferiore a 4.420 ng/ml.
• L'impatto dell'immunoterapia personalizzata sulla risoluzione dell'infezione che ha portato all'arruolamento nello studio.
• Lo sviluppo di biomarcatori genomici, epigenomici, proteomici, metabolomici e microbiomici surrogati per gli endpoint primari e secondari. Questo deriverà dall’analisi del materiale genomico e proteomico che sarà analizzato dai partner del progetto ImmunoSep.

E.5.2.1

Timepoint(s) of evaluation of this end point

day 15, 28 and 90

15, 28 e 90 giorni

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

Yes

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.8.4.1

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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

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.

alcuni pazienti potrebbero essere sedati e sotto ventilazione meccanica in Terapia Intensiva. In questi casi il consenso sarà richiesto al legale rappresentante.

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

270

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)

not applicable

non applicabile

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

2023-02-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-02-09

P. End of Trial
P.	End of Trial Status	Ongoing

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