Clinical Trials Register

Summary
EudraCT Number:	2018-000102-33
Sponsor's Protocol Code Number:	69HCL16_0079
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Not Authorised
Date on which this record was first entered in the EudraCT database:	2018-01-23
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

France - ANSM

A.2

EudraCT number

2018-000102-33

A.3

Full title of the trial

Effectiveness of Intravenous Immunoglobulins (IVIG) in Toxic Shock Syndromes in children: a multicenter European randomized controlled trial

Efficacité des immunoglobulines humaines normales (IGHN) dans les chocs toxiques (staphylococciques et streptococciques) chez l’enfant : un essai clinique randomisé multicentrique européen

A.3.1

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

Effectiveness of Intravenous Immunoglobulins (IVIG) in Toxic Shock Syndromes in children.

Efficacité des immunoglobulines humaines normales (IGHN) dans les chocs toxiques (staphylococciques et streptococciques) chez l’enfant

A.3.2

Name or abbreviated title of the trial where available

IGHN2

A.4.1

Sponsor's protocol code number

69HCL16_0079

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	Hospices Civils de Lyon
B.1.3.4	Country	France
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	CSL Behring
B.4.2	Country	France
B.4.1	Name of organisation providing support	Ministry of Health
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hospices Civils de Lyon
B.5.2	Functional name of contact point	Valérie Plattner
B.5.3	Address:
B.5.3.1	Street Address	3 Quai des Célestins
B.5.3.2	Town/ city	Lyon
B.5.3.3	Post code	69002
B.5.3.4	Country	France
B.5.4	Telephone number	472406840+33
B.5.5	Fax number	472115190+33
B.5.6	E-mail	drci_promo@chu-lyon.fr

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	Privigen
D.2.1.1.2	Name of the Marketing Authorisation holder	CSL Behring 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	Privigen
D.3.4	Pharmaceutical form	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	Immunoglobulin
D.3.9.3	Other descriptive name	HUMAN NORMAL IMMUNOGLOBULIN
D.3.9.4	EV Substance Code	SUB14196MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2000
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	Yes
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	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	Vialebex
D.2.1.1.2	Name of the Marketing Authorisation holder	LFB-BIOMEDICAMENTS
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Vialebex
D.3.4	Pharmaceutical form	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	Albumin
D.3.9.3	Other descriptive name	HUMAN ALBUMIN SOLUTION
D.3.9.4	EV Substance Code	SUB12026MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	4
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	Yes
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

toxic shock syndrome

choc toxique

E.1.1.1

Medical condition in easily understood language

toxic shock

choc toxique

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	20.1
E.1.2	Level	PT
E.1.2	Classification code	10044248
E.1.2	Term	Toxic shock syndrome
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

To assess the efficacy on organ dysfunctions of IVIG treatment in the acute phase of streptococcal or staphylococcal toxic shock syndrome in children.

Evaluer l'efficacité, sur les dysfonctions d’organes, du traitement par IGHN en phase aiguë du choc toxique streptococcique ou staphylococcique chez les enfants.

E.2.2

Secondary objectives of the trial

• to estimate the efficacy of IVIG on global mortality during the year of follow-up
• to estimate the impact of IVIG on the outcome in terms of disability and impairment one year after recruitment
• to assess the efficacy of IVIG on the time course of organ dysfunctions over the first 5 days in PICU and at PICU discharge
• to assess the safety of IVIG use

Objectives of the biological ancillary study:
• to evaluate T lymphocytes Vß kinetics of expansion, due to staphylococcal and streptococcal toxins superantigen activation (Vß specific signature of toxins), and show the impact of the IVIG treatment on this kinetics
• to look for Mendelian genetic predisposition to those severe infections, leading to innate immunity dysfunction

• évaluer l'efficacité des IGHN sur la mortalité globale au cours de l'année de suivi
• évaluer l'impact des IGHN sur l’évolution du patient en termes d'incapacité et de déficience un an après le recrutement
• évaluer l'efficacité des IGHN sur l'évolution des dysfonctions d’organes au cours des 5 premiers jours en réanimation et à la sortie de réanimation
• évaluer la sécurité d’utilisation des IGHN

Objectifs de l’étude ancillaire biologique:
• évaluer la cinétique d'expansion des Vß des lymphocytes T, en réponse à l'activation du superantigène par les toxines staphylococciques et streptococciques (signature Vß spécifique des toxines), et montrer l'impact du traitement par IGHN sur cette cinétique
• rechercher la prédisposition génétique mendélienne à ces infections sévères, conduisant à un dysfonctionnement immunitaire inné

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

● To estimate the efficacy of IVIG on superantigens
● To improve in vivo knowledges of IGHN mechanisms

● Evaluer l'efficacité des IGHN sur les superantigènes
● Améliorer les connaissances in vivo des mécanismes des IGHN

E.3

Principal inclusion criteria

• 1 month ≥ Age < 18 years
• Admitted to PICU with a strong suspicion of staphylococcal or streptococcal infection, at least one of the following criteria:
- TSS as defined by Centre for Disease Control criteria (see appendix)
- Or group A Streptococcus necrotizing fasciitis (positive streptest)
- Or varicella with infected lesions and rash or positive streptest
- Or erythrodermic rash in menstrual period
- Or pleuropneumonia with erythrodermic rash or positive streptest in pleural fluid
- Or erythrodermic rash and biological fluid positive to Streptococcus A or Staphylococcus (articular, pericardial, bronchopulmonary, pharynx ...)
• And with shock resistant to fluid resuscitation, defined as the existence, despite 40 ml/kg of fluid bolus (patients < 12 yo) or 30 ml/kg of fluid bolus (patients ≥ 12 yo), within the last 3 hours, of:
- Hypotension (<5th percentile)
- Or systolic blood pressure < 2 SD regarding age
- or need for vasoactive drugs in order to maintain blood pressure at a normal level (dopamine > 5µg/kg/min or dobutamine, adrenaline, noradrenaline, milrinone whatever the dose)
- or 2 signs of hypo perfusion among:
*metabolic acidosis with base deficit> 5
*lactate x 2 normal laboratory value
*diuresis < 0,5 ml/kg/h
*capillary refill time > 5 sec
*Skin/central temperature difference > 3 ° C
• And with informed consent signed by at least one parent and oral approval of the other parent before any procedures or treatments related to the study.

• 1 mois ≥ Age < 18 ans
• Admis en réanimation pédiatrique, avec forte suspicion d’infection staphylococcique ou streptococcique (au moins un des critères suivants) :
- Critères de définition des chocs toxiniques du CDC (voir en annexe)
- Ou Fasciite nécrosante à streptocoque A (streptest positif)
- Ou Varicelle avec lésions infectées et erythrodermie ou streptest positif
- Ou Erythrodermie dans un contexte menstruel
- Ou Pleuropneumopathie avec erythrodermie ou streptest positif dans le liquide pleural
- Ou Erythrodermie et liquide biologique positif au streptocoque A ou staphylocoque (articulaire, péricardique, broncho-pulmonaire, pharynx…)
• Et choc réfractaire au remplissage défini par l’existence, malgré 40 ml/kg de remplissage (patients < 12 ans) ou 30 ml/kg de remplissage (patients ≥ 12 ans) dans les 3 heures précédentes de :
- Hypotension (<5ème percentile)
- Ou pression artérielle systolique < 2 DS par rapport à l’âge
- ou besoin de drogues vaso-actives pour maintenir la PA à la valeur normale (dopamine > 5μg/kg/min ou dobutamine, adrénaline, noradrénaline, milrinone quelle que soit la dose)
- ou 2 signes d’hypoperfusion parmi :
*acidose métabolique avec déficit de base > 5
*lactate x 2 la valeur normale du laboratoire
*diurèse < 0,5 ml/kg/h
*TRC > 5 sec
*différence température cutanée/centrale > 3°C
• Et consentement éclairé écrit obtenu par au moins un des titulaires de l’autorité parentale (et a minima l’accord oral du second titulaire) avant toute procédure et traitement liés à l’étude.

E.4

Principal exclusion criteria

- First signs of shock appeared more than 24h ago
- Known hypersensitivity to one of the components (IVIG or albumin)
- Hypersensitivity to homologous immunoglobulins, specifically in very rare cases of Ig A deficit, when the patient has antiIgA antibodies
- Known hyperprolinemia
- Immunodeficiency (constitutive or acquired),
- Ongoing immunosuppressive therapy
- Kawasaki disease
- No national health cover

- Premiers signes de choc apparus depuis plus de 24 heures
- Hypersensibilité connue à l’un des composants des traitements,
- Hypersensibilité aux immunoglobulines homologues, particulièrement dans les très rares cas de déficit en IgA, lorsque le patient présente des anticorps anti-IgA.
- Hyperprolinémie connue,
- Déficit immunitaire constitutif ou acquis,
- Traitement par immunosuppresseur,
- Maladie de Kawasaki,
- Absence de couverture par un régime de sécurité sociale.

E.5 End points

E.5.1

Primary end point(s)

Average variation in PELOD-2 score between day of admission and day 3, compared between IVIG and albumin arms.

Variation moyenne du score PELOD-2 entre le jour de l’admission (J1) et le jour 3 (comparaison entre le bras IGHN et le bras albumine).

E.5.1.1

Timepoint(s) of evaluation of this end point

D1 (admission), D3

J1 (admission), J3

E.5.2

Secondary end point(s)

- Day 60 and Year 1 survival rate (comparison between the two groups).
- Patients’ outcome in terms of disability and impairment: Pediatric Version of the Glasgow Outcome Scale-Extended (GOS-E Peds) at Year 1 (comparison between the two groups).
- Time course of organ dysfunction (PELOD2 score and New or Progressive Multiorgan Dysfunctions criteria (NP-MODS)) over the first five days in PICU and at PICU discharge (comparison between the two groups).
- AEs and SAEs collected during patients’ participation (comparison between the two groups).

- Taux de survie des patients à J60 et 1 an (comparaison entre les deux bras).
- Evolution des patients en termes d’incapacité et de déficiences : Pediatric Version of the Glasgow Outcome Scale-Extended (GOS-E Peds) à 1 an (comparaison entre les deux bras).
- Evolution au cours du temps des dysfonctions d’organes (PELOD2 et new or progressive multiorgan dysfunctions criteria (NP-MODS)) pendant les 5 premiers jours en réanimation et à la sortie de réanimation (comparaison entre les deux bras).
- Evénements indésirables et événements indésirables graves recueillis pendant toute la participation des patients à la recherche (comparaison entre les deux bras).

E.5.2.1

Timepoint(s) of evaluation of this end point

D1, D2 to D5, discharge, D60, M12

J1, J2 à J5, sortie, J60, M12

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Vialebex (Albumin 4%)

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

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 months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

166

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

minors

mineurs

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

166

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

Aucun

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

2018-03-22

Ethics Committee Opinion of the trial application

Not-Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-02

P. End of Trial
P.	End of Trial Status	Not Authorised

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