Clinical Trials Register

Summary
EudraCT Number:	2017-002430-23
Sponsor's Protocol Code Number:	TigetT10_MPS1H
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:	2020-03-09
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

2017-002430-23

A.3

Full title of the trial

A phase I/II study evaluating safety and efficacy of autologous hematopoietic stem and progenitor cells genetically modified with IDUA lentiviral vector encoding for the human α-L-iduronidase gene for the treatment of patients affected by Mucopolysaccharidosis Type I, Hurler variant

Studio clinico di fase I/II per valutare la sicurezza ed efficacia del trapianto di cellule staminali ematopoietiche autologhe geneticamente modificate con un vettore lentivirale IDUA codificante per il gene della α-L-iduronidasi umana per il trattamento di pazienti affetti da Mucopolisaccaridosi di tipo I Hurler.

A.3.1

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

Gene therapy study with autologous hemapoietic stem cells for patients affected by MPSIH

Studio di terapia genica con cellule staminali ematopoietiche autologhe per pazienti affetti da MPSIH

A.3.2

Name or abbreviated title of the trial where available

TigetT10_MPS1H

A.4.1

Sponsor's protocol code number

TigetT10_MPS1H

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 SAN RAFFAELE
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fondazione Telethon
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	OSPEDALE SAN RAFFAELE
B.5.2	Functional name of contact point	SR-TIGET Clinical Trial Office (TCT
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	0039 02 2643 6321
B.5.5	Fax number	0039 02 2643 6545
B.5.6	E-mail	tcto@hsr.postecert.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	No
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	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	Cellule CD34+ autologhe trasdotte con IDUA LV codificante per il cDNA dell'alfa-L-iduronidasi
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
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	BUSILVEX - 6 MG/ML - CONCENTRATO PER SOLUZIONE PER INFUSIONE - USO ENDOVENOSO - FLACONCINO - 10 ML 8 FLACONCINI
D.2.1.1.2	Name of the Marketing Authorisation holder	PIERRE FABRE MEDICAMENT
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BUSULFANO
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	BUSULFANO
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	80
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 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	FLUDARABINA ACCORD - "25 MG/ML CONCENTRATO PER SOLUZIONE INIETTABILE O PER INFUSIONE" 5 FLACONCINI IN VETRO DA 2 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ACCORD HEALTHCARE LIMITED
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	FLUDARABINA FOSFATO
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	FLUDARABINA FOSFATO
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	160
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 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	MABTHERA - 2 FIALE 100 MG 10 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION LIMITED
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	RITUXIMAB
D.3.10	Strength
D.3.10.1	Concentration unit	mg/m2 milligram(s)/square meter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	375
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 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	MYELOSTIM - 34 1 FLACONCINO LIOFILIZZATO 33.6 MIU + SIRINGA PRERIEMPITA SOLVENTE 1 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	CHUGAI SANOFI AVENTIS
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	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LENOGRASTIM
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	LENOGRASTIM
D.3.10	Strength
D.3.10.1	Concentration unit	IU/ml international unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	34
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 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	MOZOBIL - 20 MG/ML - SOLUZIONE INIETTABILE - USO SOTTOCUTANEO - FLACONCINO (VETRO) - 24 MG/1.2 ML 1 FLACONCINO
D.2.1.1.2	Name of the Marketing Authorisation holder	GENZYME EUROPE B.V.
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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PLERIXAFOR
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	PLERIXAFOR
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.24
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.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

Mucopolysaccharidosis type I Hurler

Mucopolisaccaridosi di tipo I Hulrer

E.1.1.1

Medical condition in easily understood language

Rare hereditary lysosomal storage disorder characterized by a lack/reduced activity of the IDUA, present in all tissues and particularly important in connective tissue, bone and in the nervous system

Rara malattia genetica ereditaria caratterizzata da mancata/ridotta attività dell’IDUA, presente in tutti i tessuti e particolarmente importante nel tessuto connettivo e osseo e nel sistema nervoso

E.1.1.2

Therapeutic area

Body processes [G] - Genetic Phenomena [G05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10056886
E.1.2	Term	Mucopolysaccharidosis I
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic 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 safety and tolerability of autologous CD34+ cell enriched fraction that contains HSC transduced with LV encoding the IDUA gene in pediatric patients with MPS IH following a myeloablative conditioning regimen

Valutare la sicurezza e la tollerabilità dell’infusione di cellule staminali ematopoietiche (HSC) CD34+ autologhe trasdotte con un vettore lentivirale codificante il gene IDUA umano (LV-IDUA) in pazienti pediatrici affetti da MPS IH dopo terapia di condizionamento mieloablativa.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of autologous CD34+ cell enriched fraction that contains HSC transduced with LV encoding the IDUA gene in pediatric patients with MPS IH following a myeloablative conditioning regimen

Valutare l’efficacia dell’infusione di cellule staminali ematopoietiche (HSC) CD34+ autologhe trasdotte con un vettore lentivirale codificante il gene IDUA umano (LV-IDUA) in pazienti pediatrici affetti da MPS IH dopo terapia di condizionamento mieloablativa.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent by parent/legal guardian
2. Sex: Males or Females
3. Age: ≥ 28 days and ≤ 11 years old
4. Biochemically and molecularly proven MPS IH
5. Lansky Index > 80 %
6. Indication to HSCT
7. Lack of a non-heterozygous (for mutated IDUA) HLA-matched sibling donor or a ≥7/8 (4 digits high-resolution typing) HLA-matched cord blood donor with a cellularity ≥5 x 107 Total Nucleated Cells (TNC)/Kg after 1-month search
8. Adequate cardiac, renal, hepatic and pulmonary functions

1. Consenso informato firmato dai genitori o tutori legali
2. Sesso: maschi o femmine
3. Età: ≥ 28 giorni e ≤ 11 anni
4. Diagnosi biochimica e molecolare di MPS IH
5. Indice di Lansky >80%
6. Indicazione al trapianto di cellule staminali ematopoietiche
7. Assenza di donatore non eterozigote (per IDUA) HLA-identico nel nucleo familiare o di donatore di sangue placentare matchato per il sistema HLA ≥ 7/8 (tipizzazione molecolare ad alta risoluzione a 4 cifre) con una cellularità ≥ 5 x107 cellule nucleate totali (TNC) /Kg, ad 1 mese dall’apertura della ricerca.
8. Funzione cardiaca, renale, epatica e polmonare adeguate

E.4

Principal exclusion criteria

1. Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
2. Severe, active viral, bacterial, or fungal infection at eligibility evaluation
3. Patients affected by malignant neoplasia or family history of familial cancer syndromes
4. Cytogenetic alterations associated with high risk of developing hematological malignancies
5. History of uncontrolled seizures
6. Patients with end-organ damage or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study
7. Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA and/or Treponema Pallidum or Mycoplasma active infection
8. Patients with DQ/IQ <70
9. Previous allogeneic HSCT or gene therapy with a different product
10. Controindications to PeIMP (G-CSF, Plerixafor, Busulfan, Fludarabine, Rituximab)

1. Utilizzo di un altro prodotto sperimentale nelle 4 settimane precedenti all’arruolamento nello studio (entro 6 settimane nel caso di prodotti a lunga durata d’azione)
2. Gravi infezioni virali, batteriche o fungine attive al momento della valutazione dell’eleggibilità
3. Pazienti affetti da neoplasie maligne o con storia familiare di sindromi neoplastiche
4. Pazienti con alterazioni citogenetiche associate ad un alto rischio di sviluppare neoplasie ematologiche
5. Storia di convulsioni non controllate
6. Pazienti con insufficienza d’organo o qualsiasi altra malattia grave che, a giudizio dell’investigatore, potrebbe rendere il paziente non candidabile ad essere arruolato nello studio
7. Positività a HIV (sierologia o RNA) e/o positività o infezione attiva da HbsAg e/o HBV e/o HCV e/o Treponema Pallidum e/o Mycoplasma.
8. Pazienti con un DQ/IQ <70
9. Precedente trapianto allogenico di cellule staminali ematopoietiche o terapia genica con un altro prodotto medicinale
10. Controindicazioni ai PeIMP (G-CSF, Plerixafor, Busulfano, Fludarabina, Rituximab)

E.5 End points

E.5.1

Primary end point(s)

Safety
1) Overall survival
2) Achievement of hematological engraftment ≤ day +45 from Advanced Therapy Investigational Medicinal Product (ATIMP) injection. Hematologic engraftment is defined as the first of 3 consecutive days with neutrophil count > 500/mm3 and platelets > 20,000/mm3.
3) Safety of the administration of autologous HSC transduced with LV-IDUA.
4) Overall safety and tolerability measured by AE recording.

Efficacy
1) IDUA activity in blood (DBS) (up to supraphysiologic levels) at 1-year post-treatment

Sicurezza
1) Sopravvivenza globale
2) Ottenimento dell’attecchimento ematologico entro il giorno +45 dall’infusione del prodotto medicinale di terapia avanzata (ATIMP). L’attecchimento ematologico viene definito come il primo di 3 giorni consecutivi con una conta di neutrofili > 500/mm3 e di piastrine > 20,000/mm3.
3) Sicurezza della somministrazione delle HSC autologhe trasdotte con LV-IDUA.
4) Sicurezza generale e tollerabilità; misurata tramite la registrazione degli eventi avversi (AE).

Efficacia
1) Attività IDUA nel sangue (su goccia di sangue essiccata su cartoncino, DBS) (fino a livelli sopra-fisiologici) a 1 anno dal trattamento.

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

Exploratory end-points of efficacy
Polyclonal engraftment evaluated by integration analysis at 6 and 12 months post-treatment

End-point esploratori di efficacia
Attecchimento policlonale; valutato tramite analisi delle integrazioni lentivirali a 6 mesi e a 1 anno dal trattamento

E.5.2.1

Timepoint(s) of evaluation of this end point

Exploratory end-points of efficacy
Polyclonal engraftment evaluated by integration analysis at 6 and 12 months post-treatment

End-point esploratori di efficacia
Attecchimento policlonale; valutato tramite analisi delle integrazioni lentivirali a 6 mesi e a 1 anno dal trattamento

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)

Yes

E.7.1.1

First administration to humans

Yes

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)

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Singolo braccio, in aperto

Single arm, open label

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

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.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Ultima visita dell'ultimo paziente

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Minors

Pazienti minori

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Patients with rare disease

Pazienti affetti da una malattia rara

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Due to the inherent nature of the gene therapy being a once-only treatment, there is no plan to offer further treatment/ doses of the ATIMP following the end of the study. After completion of 1 year follow-up, patients will be asked if they want to be enrolled in a long-term follow-up study and followed-up for at least 8 years after the gene therapy.

Data la natura intrinseca della terapia genica che consiste in una monosomministrazione unica, non vi è alcun piano per offrire ulteriori trattamenti/dosi del ATIMP in studio a seguito della fine dello studio. Al termine dello studio (1 anno di follow-up dopo terapia genica) ai pazienti verrà proposto l'arruolamento in uno studio a lungo-termine per essere seguiti per almeno 8 anni dopo la terapia genica.

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-03-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-12

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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