Clinical Trials Register

Summary
EudraCT Number:	2011-001699-20
Sponsor's Protocol Code Number:	042011
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2015-12-30
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

Czechia - SUKL

A.2

EudraCT number

2011-001699-20

A.3

Full title of the trial

LCH-IV
International Collaborative Treatment Protocol for Children and Adolescents with LANGERHANS CELL HISTIOCYTOSIS

LCH-IV
IV. mezinárodní multicentrická studie histiocytózy z Langerhansových buněk pro děti a adolescenty

A.3.1

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

LCH-IV
Treatment Protocol for Children and Adolescents with
LANGERHANS CELL HISTIOCYTOSIS

A.3.2

Name or abbreviated title of the trial where available

LCH-IV

A.4.1

Sponsor's protocol code number

042011

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	St. Anna Kinderkrebsforschung
B.1.3.4	Country	Austria
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	Histiocytosis Association of America
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	St. Anna Kinderkrebsforschung
B.5.2	Functional name of contact point	S2IRP, LCH Study Center
B.5.3	Address:
B.5.3.1	Street Address	Zimmermannplatz 10
B.5.3.2	Town/ city	Vienna
B.5.3.3	Post code	1090
B.5.3.4	Country	Austria
B.5.4	Telephone number	+43(0)140 4704760
B.5.5	Fax number	+43(0)140 4707430
B.5.6	E-mail	LCH@ccri.at

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	‘Indocid’ Capsules 25 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen Pharma Trading Limited
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Indocid
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INDOMETACIN
D.3.9.1	CAS number	53-86-1
D.3.9.4	EV Substance Code	SUB08180MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	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	Puri-Nethol
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen Pharma Trading Limited, 12/13 Exchange Place, Dublin, Irsko
D.2.1.2	Country which granted the Marketing Authorisation	Ireland
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	Puri-Nethol
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MERCAPTOPURINE
D.3.9.1	CAS number	50-44-2
D.3.9.4	EV Substance Code	SUB12149MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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: 3
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	Vinblastin Teva 1 mg/ml, injekční roztok
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharmaceuticals CR, s.r.o. Praha, Česká republika
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Vinblastinsulfat
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	VINBLASTINE SULFATE
D.3.9.1	CAS number	143-67-9
D.3.9.4	EV Substance Code	SUB05098MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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: 4
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	Prednison 5 Léčiva
D.2.1.1.2	Name of the Marketing Authorisation holder	Zentiva, k. s., Praha, Česká republika
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Prednisolon
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PREDNISOLONE
D.3.9.1	CAS number	50-24-8
D.3.9.4	EV Substance Code	SUB10018MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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: 5
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	Methotrexat Ebewe 10 mg tablety
D.2.1.1.2	Name of the Marketing Authorisation holder	Ebewe Pharma Ges.m.b.H. Nfg KG 4866 Unterach, Rakousko
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Ebetrexat
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METHOTREXATE
D.3.9.1	CAS number	59-05-2
D.3.9.4	EV Substance Code	SUB08856MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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: 6
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	LITAK 2 mg/ml injekční roztok
D.2.1.1.2	Name of the Marketing Authorisation holder	Lipomed GmbH Hegenheimer Strasse 2 D-79576 Weil/Rhein N ě mecko
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	Leustatin
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	CLADRIBINE
D.3.9.1	CAS number	4291-63-8
D.3.9.4	EV Substance Code	SUB06635MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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: 7
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	ALEXAN 50mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Ebewe Pharma Ges. m.b.H.Nfg.KG, A-4866 Unterach, Rakousko
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Cytarabin
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	CYTARABINE
D.3.9.1	CAS number	147-94-4
D.3.9.4	EV Substance Code	SUB06880MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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: 8
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	Fludarabin Ebewe 25 mg/ml koncentrát pro přípravu injekčního nebo infuzního roztoku
D.2.1.1.2	Name of the Marketing Authorisation holder	EBEWE Pharma Ges.m.b.H. Nfg. KG Mondseestr. 11 4866 Unterach RAKOUSKO
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Fludarabin
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	FLUDARABINE
D.3.9.1	CAS number	21679-14-1
D.3.9.4	EV Substance Code	SUB07678MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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: 9
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	Thymoglobuline 5 mg/ml, prášek pro infuzní roztok
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme Europe B.V. Gooimeer 10 1411 DD Naarden Nizozemsko
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Thymoglobuline
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	Thymoglobuline
D.3.9.1	CAS number	216503-57-0
D.3.9.4	EV Substance Code	SUB12459MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	5
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: 10
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 100 mg/ml infuzní roztok
D.2.1.1.2	Name of the Marketing Authorisation holder	CSL Behring s.r.o., Česká republika
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Immunglobulin
D.3.9.1	CAS number	8000012-66-0
D.3.9.3	Other descriptive name	IMMUNGLOBULIN
D.3.9.4	EV Substance Code	SUB14187MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
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: 11
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	Alkeran
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen Pharma Trading Limited 12/13 Exchange Place, I.F.S.C, Dublin 1, Irsko
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	Alkeran
D.3.4	Pharmaceutical form	Powder and solvent 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	MELPHALAN
D.3.9.1	CAS number	148-82-3
D.3.9.4	EV Substance Code	SUB08728MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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: 12
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	Vincristine Teva 1 mg/ml, injekční roztok
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharmaceuticals CR, s.r.o., Radlická 3185/1C, Praha, 150 00, Česká Republika
D.2.1.2	Country which granted the Marketing Authorisation	Czech Republic
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	vincristini sulfas
D.3.4	Pharmaceutical form	Solution for injection/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.3.9.3	Other descriptive name	VINCRISTINE SULFATE
D.3.9.4	EV Substance Code	SUB05101MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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

Langerhans cell histiocytosis

E.1.1.1

Medical condition in easily understood language

Langerhans cell histiocytosis (LCH) is a rare disorder of bone marrow derived histiocytes.
For unknown reasons in LCH these cells accumulate in different organs and cause signs and symptoms.

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

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

•Reduction of mortality in multi-system (ms)-LCH by early switch to salvage treatment of pat. with risk organ involvement and without response to 1st-line therapy
•Randomized investigation of prolongation or intensification of continuation therapy to reduce reactivationsa and late sequelae in ms-LCH,
•Randomized investigation to reduce reactivation rate, late sequelae by prolongation of continuation therapy (6 vs. 12 m) in single-system (ss)-LCH with isolated “CNS-Risk” lesion or multifocal bone (mfb) lesions.
•Investigation to achieve disease resolution, prevent reactivations, late sequelae in non-risk organ involvement pati. with 2nd-line treatment (PRED/ARA-C/VCR for 24 weeks, followed by 24m of continuation therapy: Indomethacin vs. 6-MP/MTX) in non-responders to 1st-line treatment or in patients with reactivations

E.2.2

Secondary objectives of the trial

• To validate prospectively a new scoring system for disease activity and treatment response assessment.
• To investigate the cumulative incidence of radiographic and clinical neurodegeneration in patients with “CNS-Risk” bone lesions and endocrine deficits.
• To study the natural history of LCH in patients not needing upfront systemic therapy and the long-term consequences and quality of life of all registered (with and without systemic therapy) patients

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Stratum I:
Patients must be less than 18 years of age at the time of diagnosis,
Patients must have histological verification of the diagnosis of Langerhans cell histiocytosis,
No prior systemic therapy for LCH,
Signed informed consent ,
•Stratum II
Patients of Stratum I who have proressive disease (AD worse) in non-risk organs after Initial Course 1,
AD intermediate or worse in non-risk organs or AD better in risk organs after Initial Course 2,
Disease progression (AD worse) in non-risk organs at any time during continuation treatment,
Active disease at the end of Stratum I treatment,
Disease reactivation in non-risk organs at any time after completion of Stratum I treatment,
Signed informed consent,
•Stratum III
Patients from Stratum I who fulfill the following criteria:
AD worse in risk organs after after Initial Course 1, or AD worse or AD intermediate in risk organs after Initial Course 2,
Presence of unequivocally severe organ dysfunction (hematological dysfunction, liver dysfunction, or both of them),
Signed informed consent,
•Stratium IV
Patients from Stratum I or Stratum III who fulfill the following criteria:
AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after after Initial Course 2 of Stratum I, or
AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD intermediate after the 4th 2-CdA/Ara-C course of Stratum III, and
Presence of unequivocally severe organ dysfunction,
Informed consent available,
Adequate organ function
•Stratum V
All patients with verified diagnosis of LCH and MRI findings consistent with neurodegenerative (ND) CNS-LCH irrespective of previous treatments,
Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion in the hypothalamus-pituitary axis),
Signed informed consent
•Stratum VI
Patients with newly diagnosed single-system LCH (other than mfb, isolated tumorous CNS-LCH, or isolated CNS-risk lesion,
Signed informed consent,
•Stratum VII
All patients registered in LCH IV as long as consent for long-term follow-up has not been witheld

E.4

Principal exclusion criteria

•Stratum I
Pregancy (patients of child-bearing age must be appropriately tested before chemotherapy),
LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis, lung fibrosis, etc.) in the absence of active disease,
Prior systemic therapy
•Stratum II
Patients with progressive disease in risk organs,
Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without evidence of active LCH in the same organ or in any other locations,
No written consent of the patient or his/her parents or legal guardian
•Stratum III
Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of risk organ involvement,
Inadequate renal function as defined by serum creatinine > 3x normal for age
•Stratum IV
Pulmonary failure (requiring mechanical ventilation) not due to active LCH,
Isolated liver sclerosis or pulmonary fibrosis, without active LCH,
Uncontrolled active life-threatening infection.
Decreased renal function with a GFR of less than 50ml/1.73m2/min,
Pregnancy or active breast feeding,
Failure to provide signed informed consent
•Stratum V
Patients without any evidence of isolated tumorous CNS-LCH lesions or ND-CNS lesions
•Stratum VI
Patients with single-system LCH who have an isolated tumorous CNS lesion (eligible for Stratum V),
Patients with isolated CNS-risk or mfb lesion (eligible for Stratum I, Group 2)
•Stratum VII
no consent for long-term follow up available

E.5 End points

E.5.1

Primary end point(s)

•Stratum I
Reactivation-free survival
•Stratum II
Reactivation-free survival
•Stratum III
The response after 2 cycles of 2-CdA/ARA-C,
•Stratum IV
overall and disease free survival at 1 and 3 years after reduced intensity conditioning hematopoietic stem cell transplantation (RIC-HSCT)
•Stratum V
To study the course of Neurodegenerative-CNS-LCH,
Response of isolated tumorous CNS lesions to 2-CdA,
•Stratum VI
Reactivation free survival
•Stratum VII
Rate and spectrum of permanent consequences

E.5.1.1

Timepoint(s) of evaluation of this end point

•Stratum I, Stratum II
Final analyses: seven year recruitment + 5 years minimum follow up
•Stratum III
half a year after study closure
•Stratum IV
after year recruitment + three years follow up

E.5.2

Secondary end point(s)

•Stratum I
Overall survival,
Incidence of permanent consequences,
Toxicity of treatment,
The proportion of patients alive and free of disease without permanent consequences,
Cumulative incidence of reactivations in risk organs
•Stratum II
To determine the response rate to the combination of prednisone, vincristine and cytarabine,
The proportion of patients alive and free of disease without permanent consequences,
To describe treatment-related toxicities,
To compare reactivation rates after continuation treatment with Indomethacin vs. 6-MP/MTX.
•Stratum III
Time to complete disease resolution (Non-Active Disease)
The type of subsequent intensive and/or maintenance therapy utilized
The early and late mortality
The early and late toxicity
•Stratum IV
To determine d+100 transplant related mortality,
To determine the incidence of hematopoietic recovery, and donor chimerism at d+100 and 1 year post RIC-HSCT,
To determine the incidence of grades II-IV and III-IV acute GVHD,
To determine the incidence of chronic GVHD
•Stratum V
To assess whether systemic therapy can be beneficial for patients with clinically manifest ND-CNS-LCH,
To assess the role of 2-CdA in preventing ND-CNS-LCH in patients with isolated tumorous CNS-LCH,
To study the efficacy of intravenous immunoglobulin and intravenous cytarabine in the treatment of ND-CNS-LCH,
To assess markers of neurodegeneration and LCH activity in the spinal fluid of patients who have diabetes insipidus as well as patients with radiologic and/or clinical signs of CNS-LCH
•Stratum VI
Need for systemic therapy later during disease course,
Spectrum and cumulative incidence of permanent consequences
•Stratum VII
Identify possible risk factors for PC,
Assess the role of systemic treatment in preventing PC

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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

Yes

E.8.2.2

Placebo

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

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

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

Argentina

Australia

Belarus

Brazil

Canada

Korea, Republic of

New Zealand

Norway

Poland

Russian Federation

Serbia

Switzerland

United States

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

Each patient will be followed after end of specific Stratum treatment for another five years. We estimate a recruitment time of seven years and a long term follow up time of five years.

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

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:

1400

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)

Yes

F.1.1.3.1

Number of subjects for this age range:

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

400

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

650

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

300

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

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

Mentally handicaped children

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

700

F.4.2.2

In the whole clinical trial

1400

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)

long term follow up

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

2016-03-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-06

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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