Clinical Trials Register

Summary
EudraCT Number:	2007-002402-21
Sponsor's Protocol Code Number:	SIOPEL6
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-12
Trial results	View 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

2007-002402-21

A.3

Full title of the trial

SIOPEL 6
A multi-centre open label randomised phase III trial of the efficacy of
Sodium Thiosulphate in reducing ototoxicity in patients receiving
Cisplatin chemotherapy for
STANDARD RISK HEPATOBLASTOMA

Ensayo multicéntrico, abierto, aleatorizado, de fase III sobre la eficacia de tiosulfato sódico en la reducción de la ototoxicidad en pacientes que reciben quimioterapia con cisplatino para

HEPATOBLASTOMA DE RIESGO ESTÁNDAR

A.3.1

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

Trial for treating hepatoblastomas (liver tumour) in children with a drug
(sodium thiosulfate) to reduce ototoxicity of chemotherapy (cisplatin)

Tratamiento de los hepatoblastomas (tumores hepáticos) en niños con un fármaco (tiosulfato sódico) para reducir el daño auditivo por quimioterapia (cisplatino)

A.3.2

Name or abbreviated title of the trial where available

SIOPEL 6

A.4.1

Sponsor's protocol code number

SIOPEL6

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	Sociedad Española de Hematología-Oncología Pediátrica
B.1.3.4	Country	Spain
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	SEHOP
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	SEHOP
B.5.2	Functional name of contact point	national trial coordination
B.5.3	Address:
B.5.3.1	Street Address	av. Menendez Pidal s/n
B.5.3.2	Town/ city	Cordoba
B.5.3.3	Post code	14005
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034957010497
B.5.5	Fax number	0034957010017
B.5.6	E-mail	mariae.mateos.sspa@juntadeandalucia.es

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.3.1	Product name	Tiosulfato sódico
D.3.2	Product code	ADH300001
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tiosulfato sodico
D.3.9.1	CAS number	10102-17-7
D.3.9.2	Current sponsor code	SEHOP
D.3.9.3	Other descriptive name	tiosulfato pentahidrato disódico
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
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	Yes
D.3.11.13.1	Other medicinal product type	this is an inorganic salt, thiol compound (compuesto del tiol)

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

standard risk hepatoblastoma

hepatoblastoma estándar

E.1.1.1

Medical condition in easily understood language

liver tumour typical of children

tumor hepático típico de la edad infantil

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	HLT
E.1.2	Classification code	10019825
E.1.2	Term	Hepatoblastomas
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10019824
E.1.2	Term	Hepatoblastoma resectable
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of STS to reduce the hearing impairment caused
by Cisplatin chemotherapy

Evaluar la eficacia de STS para reducir la deficiencia auditiva provocada por la quimioterapia con cisplatino

E.2.2

Secondary objectives of the trial

To carefully monitor any potential impact of STS on response to Cisplatin
and survival.
To assess the short- and long-term tolerability of the combination of STS
and Cisplatin.
To prospectively evaluate and validate biological, radiological and
pathological features of standard risk hepatoblastoma for future risk
adapted management.
To investigate the effect of STS on the formation of Cisplatin-DNA
adducts.
To prospectively collect patient DNA specifically for the analysis of
possible genetic factors that may contribute to the development of
treatment related ototoxicity and nephrotoxicity

Controlar exhaustivamente cualquier impacto potencial de STS en la respuesta a cisplatino y la supervivencia.
Evaluar la tolerabilidad a corto y largo plazo de la combinación de STS y cisplatino.
Evaluar y validar de manera prospectiva características biológicas, radiológicas y patológicas del hepatoblastoma de riesgo estándar para el tratamiento futuro adaptado al riesgo.
Investigar el efecto de STS en la formación de complejos cisplatino-ADN.
Recoger de manera prospectiva ADN de los pacientes específicamente para el análisis de posibles factores genéticos que podrían contribuir al desarrollo de ototoxicidad y nefrotoxicidad relacionadas con el tratamiento

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Histologically confirmed newly diagnosed hepatoblastoma
Standard risk hepatoblastoma (defined in section 10.1)
Age ≤ 18 years and > 1 month
Written informed consent and national/local ethics committee and
regulatory approval
Centre/country willing and able to organise audiometry at the minimum
required quality standard and to provide the contact details of the
Consultant Audiologist or Ear Nose and Throat Surgeon who will take the
responsibility for seeing that this is done (see Section 15.9)
Ability to comply with requirements for submission of material for
central review
For females of child-bearing potential, a negative pregnancy test prior to
study treatment is required.
Any patient who is of reproductive age should agree to use adequate
contraception for the duration of the trial.

Hepatoblastoma diagnosticado recientemente confirmado histológicamente
Hepatoblastoma de riesgo estándar:
PRETEXT I, II o III
Alfafetoproteína sérica (AFP) > 100 µg//l
Ningún criterio de PRETEXT adicional
Edad 18 años y > 1 mes
Consentimiento informado por escrito y aprobación por parte de los organismos reguladores y del comité ético nacional/local
Centro/país dispuesto y capaz de organizar una audiometría
Posibilidad de cumplir los requisitos para el envío de material para la revisión central (radiología, patología y audiología)
Para mujeres en edad fértil, es necesario obtener una prueba de embarazo negativa antes de iniciar el tratamiento en estudio
Cualquier paciente en edad fértil debe acceder a utilizar un método anticonceptivo apropiado mientras dure el ensayo

E.4

Principal exclusion criteria

High risk hepatoblastoma
Hepatocellular carcinoma
Treatment starting more than 15 days from written biopsy report
Abnormal renal function
Any previous chemotherapy
Identificador del archivo XML: EnC0NadSa9z49p98r3buLEOnYCI=
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Recurrent disease
Previous hypersensitivity to STS
Patient unable to follow the protocol for any reason

Hepatoblastoma de alto riesgo:
Alfafetoproteína sérica (AFP) 100 µg//l
Afectación tumoral en las 4 secciones hepáticas (PRETEXT IV)
Criterios de PRETEXT adicionales:
Enfermedad abdominal extrahepática
Hemorragia intraperitoneal o ruptura tumoral
Metástasis distantes, en cualquier lugar
Metástasis en ganglios linfáticos
Afectación de la vena portal principal
Afectación de las tres venas hepáticas y/o la Vena Cava Inferior
Carcinoma hepatocelular
Inicio del tratamiento más de 15 días después del informe escrito de la biopsia
Función renal anormal definida como TFG calculada < 75% del límite inferior de la normalidad para la edad en el momento del diagnóstico, que por encima de los 2 años de edad es < 60 ml/min/1,73 m2
Cualquier quimioterapia previa
Enfermedad recurrente
Hipersensibilidad previa a STS
Paciente incapaz de seguir el protocolo por cualquier motivo

E.5 End points

E.5.1

Primary end point(s)

Rate of Brock grade 1 hearing loss determined after end of trial
treatment or at an age of at least 3.5 years, whichever is later

Variables primarias
Tasa de pérdida auditiva de grado 1 de Brock determinada una vez finalizado el tratamiento en ensayo o a una edad de al menos 3,5 años, lo que ocurra más tarde.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint will be reached when the last patient has
completed his/her audiological testing or reached 3.5 years of age,
whichever is later. Patients will then be followed up for the secondary
endpoints according to national guidelines

La variable primaria se alcanzará cuando el último paciente haya finalizado las pruebas audiológicas o haya alcanzado los 3,5 años de edad, lo que suceda más tarde. Luego se realizará el seguimiento de los pacientes para las variables secundarias según las directrices nacionales.

E.5.2

Secondary end point(s)

Response to preoperative chemotherapy
Complete resection
Complete remission
Event free survival (EFS)
Overall survival (OS)
Toxicity as graded by CTCAE v 3.0
Long-term renal clearance
Feasibility of central audiology review

Respuesta a la quimioterapia preoperatoria
Resección completa
Remisión completa
Supervivencia libre de eventos (SLE)
Supervivencia global (SG)
Toxicidad según la escala CTCAE v 3.0
Aclaramiento renal a largo plazo
Viabilidad de la revisión central de la audición

E.5.2.1

Timepoint(s) of evaluation of this end point

Expected duration of recruitment period: 3.8 years

Duración prevista del periodo de inclusión: 3,8 años

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

no treatment

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

Australia

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

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:

115

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

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

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

115

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)

no treatment after completion of trial
normal care for patients with this pathology

no tratamiento tras finalizar Ensayo
controles habituales segun patologia de base tras finalizar Ensayo

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-11-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-07-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-05-08

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