Clinical Trials Register

Summary
EudraCT Number:	2011-001699-20
Sponsor's Protocol Code Number:	042011
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-02-03
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2011-001699-20

A.3

Full title of the trial

International Collaborative Treatment Protocol for Children and Adolescents with Langerhans Cell Histiocytosis

Protocolo internacional colaborativo de tratamiento para niños y adolescentes con histiocitosis de células de Langerhans

A.3.1

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

Treatment Protocol for Children and Adolescents with Langerhans Cell Histiocytosis

Protocolo de tratamiento para niños y adolescentes con histiocitosis de células de Langerhans

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	Helmut Gadner, MD, PhD
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	Inacid D. A. P.
D.2.1.1.2	Name of the Marketing Authorisation holder	Lundbeck Pharmaceuticals Ireland Limited
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Inacid D. A. P.
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	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Mercaptopurina
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen Pharma Trading Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Mercaptopurina
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	Vinblastina
D.2.1.1.2	Name of the Marketing Authorisation holder	Faulding Farmacéutica, S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Vinblastina
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	Prednisona Alonga
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi-Aventis, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Prednisona
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	Ebetrexat
D.2.1.1.2	Name of the Marketing Authorisation holder	Ebewe Pharma
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	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: 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	Leustatin
D.2.1.1.2	Name of the Marketing Authorisation holder	Janssen-Cilag S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Citarabina Pfizer
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer, S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Citarabina
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	20
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	Fludarabina
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva Pharma, SLU
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Fludarabina
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	Lemtrada
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme Therapeutics Ltd
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	Lemtrada
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	Alemtuzumab
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	30
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
D.2.1.1.2	Name of the Marketing Authorisation holder	CSL Behring GmbH
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	Melfalan
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	Spain
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	Melfalan
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.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

Histiocitosis de células de Langerhans

E.1.1.1

Medical condition in easily understood language

Langerhans cell histiocytosis (LCH) is a rare disorder of bone marrow derived histiocytes

La histiocitosis de células de Langerhans (LCH) es una enfermedad rara derivada de los histiocitos de la médula ósea

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

To decrease mortality in MS-LCH by an early switch of patients with risk organ involvement, who do not respond to front-line therapy, to a more intensive treatment (Stratum III or Stratum IV).

Reducir la mortalidad en MS-LCH mediante un cambio precoz de pacientes con afectación de órganos de riesgo, que no responden a terapia de primera línea, a un tratamiento más intensivo (Estrato III o Estrato IV).

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.

- Validar prospectivamente un nuevo sistema de clasificación para la actividad de la enfermedad y la evaluación de la respuesta al tratamiento.
- Investigar la incidencia acumulativa de neurodegeneración radiográfica y clínica en pacientes con lesiones de hueso "riesgo-SNC" y déficits endocrinos.
- Estudiar la historia natural de LCH en pacientes que no necesitan terápica sistémica inicial y las consecuencias a largo plazo y la calidad de vida de todos los pacientes registrados (con y sin terapia sistémica).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

? Definitive diagnosis of Langerhans cell histiocytosis
? Age less 18 years at time of definitive diagnosis
? Met inclusion criteria for the respective stratum
? Signed written informed consent

? Diagnóstico definitivo de histiocitosis de células de Langerhans
? Edad menor a 18 años en el momento del diagnóstico definitivo
? Cumplir los criterios de inclusión para los estratos respectivos
? Consentimiento informado escrito firmado

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

- Estrato I
Embarazo (pacientes en edad fértil deben tener una prueba apropiada antes de la quimioterapia),
Consecuencias permanentes relacionadas con LCH (vértebra plana, colangitis esclerosante, fibrosis pulmonar, etc.) en ausencia de enfermedad activa.
Terapia sistémica previa
- Estrato II
Pacientes con enfermedad progresiva en órganos de riesgo,
Consecuencias permanentes (colangitis esclerosante, fibrosis pulmonar, etc.) sin evidencia de LCH activa en el mismo órgano o en cualquier otra ubicación,
Inexistencia de consentimiento escrito del paciente o de sus padres o tutor legal
- Estrato III
Colangitis esclerosante aislada sin evidencia de LCH activa hepática como única evidencia de afectación de órgano de riesgo,
Función renal inadecuada según creatinina en sangre > 3x normal para la edad
- Estrato IV
Fallo pulmonar (que requiere ventilación mecánica) no debido a LCH activa,
Esclerosis del hígado aislada o fibrosis pulmonar, sin LCH activa,
Infección no controlada activa amenazante para la vida.
Función renal reducida con un GFR de menos de 50ml/1.73m2/min,
Embarazo o lactancia activa,
Inexistencia de consentimiento informado firmado
- Estrato V
Pacientes sin ninguna evidencia de lesiones SNC-LCH tumorales aisladas o lesiones ND-SNC
- Estrato VI
Pacientes con LCH de sistema único que tienen una lesión SNC tumoral aislada (elegible para Estrato V),
Pacientes con lesión SNC-riesgo aislada o lesiones de hueso multifocales (elegible para Estrato I, Grupo 2)
- Estrato VII
Inexistencia de consentimiento para seguimiento a largo plazo

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

?Estrato I
Supervivencia libre de reactivación
?Estrato II
Supervivencia libre de reactivación
?Estrato III
La respuesta después de 2 ciclos de 2-CdA/ARA-C,
?Estrato IV
supervivencia libre de enfermedad y supervivencia global 1 y 3 años después de intensidad reducida que condiciona el trasplante de células madre hematopoyéticas (RIC-HSCT)
?Estrato V
Estudiar el curso de LCH-SNC-neurodegenerativa,
Respuesta de lesiones tumorales aisladas SNC a 2-CdA,
?Estrato VI
Supervivencia libre de reactivación
?Estrato VII
Índice y espectro de consecuencias permanentes

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

?Estrato I, Estrato II
Análisis finales: reclutamiento de 7 años + 5 años mínimo de seguimiento
?Estrato III
medio año después de cierre del estudio
?Estrato IV
después de un año del reclutamiento + tres años de seguimiento

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

?Estrato I
Supervivencia global,
Incidencia de consecuencias permanentes,
Toxicidad del tratamiento,
La proporción de pacientes vivos y libres de enfermedad sin consecuencias permanentes,
Incidencia acumulativa de reactivaciones en órganos de riesgo
?Estrato II
Determinar el índice de respuesta a la combinación de prednisona, vincristina y citarabina,
La proporción de pacientes vivos y libres de enfermedad sin consecuencias permanentes,
Describir toxicidades relacionadas con el tratamiento,
Comparar los índices de reactivación después de la continuación del tratamiento con indometacina vs. 6-MP/MTX.
?Estrato III
Tiempo hasta resolución completa de la enfermedad (enfermedad no activa)
El tipo de terapia subsiguiente utilizada, intensiva y/o de mantenimiento
La mortalidad temprana y tardía
La toxicidad temprana y tardía
?Estrato IV
Determinar la mortalidad relacionada con el trasplante d+100,
Determinar la incidencia de recuperación hematopoyética, y quimerismo donante en d+100 y 1 año post RIC-HSCT,
Determinar la incidencia de grados II-IV y III-IV agudos GVHD,
Determinar la incidencia de GVHD crónica
?Estrato V
Evaluar si la terapia sistémica puede ser beneficiosa para pacientes con manifestación clínica ND-SNC-LCH,
Evaluar el rol de 2-CdA para prevenir ND-SNC-LCH en pacientes con SNC-LCH tumoral aislada,
Estudiar la eficacia de la inmunoglobina intravenosa y citarabina intravenosa en el tratamiento de ND-SNC-LCH,
Evaluar marcadores de neurodegeneración y actividad LCH en el fluido espinal de pacientes con diabetes insípida además de pacientes con signos radiológicos y/o clínicos de SNC-LCH
?Estrato VI
Necesidad de terapia sistémica posteriormente durante el curso de la enfermedad,
Espectro e incidencia acumulativa de consecuencias permanentes
?Estrato VII
Identificar posibles factores de riesgo para PC,
Evaluar el rol del tratamiento sistémico para prevenir PC

E.5.2.1

Timepoint(s) of evaluation of this end point

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

Canada

India

Israel

New Zealand

Norway

Russian Federation

Serbia

Switzerland

Turkey

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.

Cada paciente será seguido después de terminar el tratamiento del estrato específico por cinco años. Estimamos un tiempo reclutamiento de siete años y un seguimiento a largo plazo de cinco años.

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:

1100

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:

300

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

500

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

270

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

Children

Niños

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

800

F.4.2.2

In the whole clinical trial

1100

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

Ninguno

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Austrian Group for Pediatric Hematology / Oncology
G.4.3.4	Network Country	Austria
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	Sociedad Española de Oncología y Hematología Pediátricas (SEHOP
G.4.3.4	Network Country	Spain
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Histiocyte Society
G.4.3.4	Network Country	United States

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-04-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-08

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

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