Clinical Trials Register

Summary
EudraCT Number:	2012-003151-11
Sponsor's Protocol Code Number:	ECD-TCZ-1-03/2012
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:	2012-09-21
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

2012-003151-11

A.3

Full title of the trial

An open-label, single-arm, phase II, prospective, pilot study of tocilizumab in patients with Erdheim-Chester disease.

Trial clinico pilota di fase II, in aperto, prospettico, a braccio singolo con tocilizumab in pazienti con malattia di Erdheim-Chester.

A.3.1

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

Tocilizumab administration in patients affected by Erdheim-Chester patology.

Somministrazione di tocilizumab in pazienti affetti da malattia di Erdheim-Chester.

A.4.1

Sponsor's protocol code number

ECD-TCZ-1-03/2012

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	OSPEDALE S. RAFFAELE DI MILANO
B.1.3.4	Country	Italy
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	finanziamento dal Ministero della Salute Bando Giovani Ricercatori 2009
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS Ospedale San Raffaele
B.5.2	Functional name of contact point	Medicina ind. immunologico clinico
B.5.3	Address:
B.5.3.1	Street Address	via Olgettina, 60
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20132
B.5.3.4	Country	Italy
B.5.4	Telephone number	0226433872
B.5.5	Fax number	0226433737
B.5.6	E-mail	lorenzo.dagna@unisr.it

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	ROACTEMRA*INF FL 4ML 20MG/ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	TOCILIZUMAB
D.3.9.1	CAS number	375823-41-9
D.3.9.4	EV Substance Code	SUB20313
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	20
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.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

Erdheim Chester patology

malattia di Erdheim Chester

E.1.1.1

Medical condition in easily understood language

not Langerhans histiocytosis

istiocitosi non Langerhans

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	HLT
E.1.2	Classification code	10020118
E.1.2	Term	Histiocytoses
E.1.2	System Organ Class	10005329 - Blood and lymphatic system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

to evaluate the efficacy and safety of Tocilizumab in the treatment of the disease Erdheim-Chester extrascheletrica.

valutare l'efficacia e la sicurezza di Tocilizumab nel trattamento della malattia di Erdheim-Chester extrascheletrica.

E.2.2

Secondary objectives of the trial

evaluate the efficacy and safety of Tocilizumab in the treatment of the disease Erdheim-Chester extrascheletrica.

valutare l'efficacia e la sicurezza di Tocilizumab nel trattamento della malattia di Erdheim-Chester extrascheletrica.

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

PHARMACOGENETIC:
Vers:1
Date:2012/03/01
Title:immunophenotyping and transcriptional fingerprinting pag. 9-10 of the core protocol to correlate individual profiles with disease characteristics.
Objectives:-determination of serum and plasma level of cytokines / chemokines and other relevant plasma markers and , if possible,evaluation of their production by cells derived from the site of the lesion and their changes during treatment with Tocilizumab - functional studies on monocytes of patients at various stages of treatment -analysis of sampling of plasma / serum, nucleic acids (RNA / DNA) and from peripheral blood mononuclear cells (PBMCs)t

FARMACOGENETICA:
Vers:1
Data:2012/03/01
Titolo:STUDI IN VITRO - IMMUNOFENOTIPIZZAZIONE e FINGERPRINTING TRASCRIZIONALE (pag. 9-10 del protocollo principale)
Obiettivi:-determinazione dei livelli serici e plasmatici di citochine/chemiochine rilevanti ed altri marcatori plasmatici e valutazione , quando possibile della loro produzione da parte di cellule derivanti dal sito della lesione e la loro variazione in corso di trattmento con Tocilizumab - studi funzionali sui monociti di pazienti nelle diverse fasi del trattamento -campionamento di plasma/siero,acidi nucleici (RNA/DNA) e cellule mononucleate da sangue periferico (PBMC) per correlare profili individuali con caratteristiche della malattia.

E.3

Principal inclusion criteria

-Patients aged > = 18 years able to understand and sign an informed consent--diagnosis of ECD histologically documented ; -advanced disease limited to the skeleton, with at least one measurable lesion; -disease progression in the course of now most commonly used therapies (eg corticosteroids, interferon-alpha, methotrexate) or a location (such as cardiac or CNS) known to be unresponsive to any of the treatments currently available; -if women of childbearing age are necessary: a negative pregnancy test and the ability to exclude securely the beginning of a pregnancy for the duration of the study.

-Pazienti di età >= 18 anni di età in grado di comprendere e di firmare un consenso informato; -diagnosi di ECD documentata istologicamente; -stadio avanzato della malattia limitata allo scheletro, con almeno una lesione misurabile; -progressione della malattia in corso di terapie ad oggi maggiormente utilizzate (es. corticosteroidi, interferone-alfa, methotrexate) o con una localizzazione (SNC o cardiaca ad esempio) nota per essere non responsiva ad alcuno dei trattamenti ad oggi disponibili; -se donne in età fertile, e' necessario un test di gravidanza negativo e la possibilità di escludere in modo certo l’inizio di una gravidanza per tutta la durata dello studio.

E.4

Principal exclusion criteria

-history of hypersensitivity to tocilizumab or to any of the excipients;-serious infections requiring hospitalization or antibiotic therapy within 30 days before enrollment in the study;-active tuberculosis, listeriosis, histoplasmosis, sepsis, abscesses, opportunistic infections, active HBV or HCV-previous history of tuberculosis (as documented by a positive PPD skin test and / or a positive QuantiFERON test and / or chest radiography), in the absence of documented and appropriate administration of a specific treatment for tuberculosis latent-history of infection with HIV-past history (<5 years before enrollment) of a lymphoproliferative disorder or a solid tumor (excluding treated basal cell or squamous cell carcinoma of the skin);-moderate or severe heart failure (class NYHAIII / IV), uncontrolled diabetes mellitus or other diseases that, in the opinion of the physician responsible for the protocol can be detrimental to the patient if he / she would enroll in the study, history of alcohol-and / or drug abuse - previous treatment with alkylating agents (chlorambucil, cyclophosphamide);-serum creatinine> 1.6 mg / dL in women or> 1.9 mg / dl in male patients, AST and / or ALT ≥ 3 x ULN, platelets <100.000/fL; hemoglobin <8.5 g / dl, WBC <1000 / fL; lymphocytes <500/fL, total bilirubin> 2.0 mg / dL

-storia di ipersensibilità a tocilizumab o ad uno qualsiasi degli eccipienti; -infezioni gravi che richiedano ospedalizzazione o terapia antibiotica nei 30 giorni precedenti l'arruolamento nello studio; -tubercolosi attiva, listeriosi, istoplasmosi, sepsi, ascessi, infezioni opportunistiche; attiva da HBV o da HCV; -storia pregressa di tubercolosi (come documentato da un test cutaneo PPD positivo e/o una prova QuantiFERON positiva e/o un radiogramma del torace), in assenza di un'amministrazione documentato e appropriato di un trattamento specifico per la tubercolosi latente; -storia di infezione da HIV; -storia passata (<5 anni prima dell’arruolamento) di una malattia linfoproliferativa o di un tumore solido (esclusi curato cellule basali o carcinoma a cellule squamose della pelle); -insufficienza cardiaca moderata o grave (classe NYHAIII/IV), diabete mellito non controllato o di altre malattie che, a giudizio del medico responsabile del protocollo può essere di danno al paziente, se lui / lei sarebbe iscriversi nello studio; -storia di alcool e / o abuso di droghe; - un precedente trattamento con farmaci alchilanti (clorambucile, ciclofosfamide); -creatinina sierica> 1.6 mg / dL nelle donne o > 1.9 mg / dl nei pazienti maschi, AST e / o ALT ≥ 3 x ULN, piastrine <100.000/fL; emoglobina <8,5 g / dl; WBC <1000 / fL; linfociti <500/fL; bilirubina totale> 2,0 mg / dL

E.5 End points

E.5.1

Primary end point(s)

efficacy and safety of Tocilizumab

efficacia/sicurezza di Tocilizumab

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months after the beginning of the treatment

6 mesi post inizio del trattamento

E.5.2

Secondary end point(s)

efficacy and safety of Tocilizumab

efficacia/sicurezza di Tocilizumab

E.5.2.1

Timepoint(s) of evaluation of this end point

4 weeks after the last administration

4 settimane dall'ultima somministrazione

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

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

studio pilota

pilot study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1

Number of subjects for this age range:

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

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

for responder patients the treatment will go on; no reponder patients will be treated according to normal clinical practise.

qualora la risposta al trattamento risulti positiva, questo verra' continuato. Qualora il paziente non risponda alla terapia, verra' seguito secondo quanto previsto dalla normale pratica clinica.

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

2012-09-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-13

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

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