Clinical Trials Register

Summary
EudraCT Number:	2014-003960-20
Sponsor's Protocol Code Number:	SHP-610-201
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:	2015-01-26
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

2014-003960-20

A.3

Full title of the trial

A Open-Label Extension of Study HGT-SAN-093 Evaluating the
Safety and Efficacy Study of HGT-1410 (Recombinant Human
Heparan N Sulfatase) Administration via an Intrathecal Drug
Delivery Device in Pediatric Patients with Mucopolysaccharidosis
Type IIIA Disease

Estudio de extensión abierto de HGT-SAN-093 para evaluar la seguridad y la eficacia de la administración de HGT-1410 (heparán N sulfatasa humana recombinante) mediante un dispositivo de administración intratecal de medicación en pacientes pediátricos con mucopolisacaridosis de tipo IIIA

A.3.1

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

An Extension Study to Evaluate the Safety and Efficacy of HGT-1410 Administration in Pediatric Patients with Sanfilippo Syndrome Type A

Estudio de extensión para evaluar la seguridad y la eficacia de la administración de HGT-1410 en pacientes pediátricos con Sindrome de Sanfilipo de tipo A

A.4.1

Sponsor's protocol code number

SHP-610-201

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	Shire human Genetic Therapies, Inc.
B.1.3.4	Country	United States
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	Shire human Genetic Therapies, Inc.
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	Shire Human Genetic Therapies Inc
B.5.2	Functional name of contact point	Kenia Baez
B.5.3	Address:
B.5.3.1	Street Address	300 Shire Way
B.5.3.2	Town/ city	Lexington
B.5.3.3	Post code	MA 02421
B.5.3.4	Country	United States
B.5.4	Telephone number	+34914229372
B.5.5	Fax number	0017814821819
B.5.6	E-mail	InfoShireIberica@shire.com

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	Yes
D.2.5.1	Orphan drug designation number	EU/3/08/582
D.3 Description of the IMP
D.3.1	Product name	Recombinant human heparan N-sulfatase (rhHNS)
D.3.2	Product code	HGT-1410
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	Intrathecal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available
D.3.9.2	Current sponsor code	HGT-1410
D.3.9.3	Other descriptive name	Recombinant human heparan N-sulfatase
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
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	Yes
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	Yes
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	Human protein heparan N-sulfatase produced in a human cell line by genetic engineering technology.

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

Sanfilippo Syndrome Type A or Mucopolysaccharidosis (MPS IIIA)

Síndrome de Sanfilippo de tipo A o mucopolisacaridosis (MPS IIIA)

E.1.1.1

Medical condition in easily understood language

Sanfilippo Syndrome Type A or Mucopolysaccharidosis (MPS IIIA)

Síndrome de Sanfilippo de tipo A o mucopolisacaridosis (MPS IIIA)

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	LLT
E.1.2	Classification code	10056918
E.1.2	Term	Sanfilippo's syndrome
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	PT
E.1.2	Classification code	10056890
E.1.2	Term	Mucopolysaccharidosis III
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 long-term safety in patients with mucopolysaccharidosis type IIIA disease (MPS IIIA or Sanfilippo Type A) who received HGT-1410

Evaluar la seguridad a largo plazo en pacientes con mucopolisacaridosis de tipo IIIA (MPS IIIA o síndrome de Sanfilippo de tipo A) que hayan recibido HGT-1410

E.2.2

Secondary objectives of the trial

To evaluate the following: The long-term cognitive function as measured by the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) or Kaufman Assessment Battery for Children, 2nd Edition (KABC-II), age-equivalent and developmental quotient (DQ) scores in patients with MPS IIIA who received HGT-1410; the long-term adaptive behavioral function, assessed by Vineland Adaptive Behavior Scales, Second Edition (VABS-II) in patients who received HGT-1410; the total cortical grey matter volume, as assessed by volumetric MRI of the
brain, in patients who received HGT-1410.

Evaluar lo siguiente:
La función cognitiva a largo plazo determinada mediante las Escalas de Bayley de desarrollo infantil, tercera edición (BSID-III), o de la Batería de evaluación de Kaufman para niños, segunda edición (KABC-II), las puntuaciones de equivalentes de edad y coeficiente de desarrollo (CD) en pacientes con MPS IIIA que hayan recibido HGT-1410; la conducta adaptativa a largo plazo, evaluada mediante las Escalas de conducta adaptativa de Vineland, segunda edición (VABS-II), en pacientes que hayan recibido HGT-1410; El volumen total de sustancia gris cortical, evaluado mediante RM volumétrica del cerebro, en pacientes que hayan recibido HGT-1410.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients must meet all of the following criteria to be considered eligible for enrollment:
1. Patient has completed through at least the Week 48 visit of Study HGT-SAN-093.
2. The patient?s parent(s) or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board- (IRB-)/Independent Ethics Committee- (IEC-) approved informed consent form after all relevant aspects of the study have been explained and discussed. Consent of the patient?s parent(s) or legally authorized guardian(s) and the patient?s assent, as relevant, must be obtained.

Los pacientes deberán cumplir todos los criterios siguientes para poder ser incluidos en el estudio:
1. El paciente ha llegado hasta, como mínimo, la visita 48 del estudio HGT-SAN-093.
2. Los padres o tutores legales del paciente deberán haber firmado voluntariamente un documento de consentimiento informado, aprobado por el comité ético de investigación clínica, una vez explicados y comentados todos los aspectos pertinentes del estudio. Será obligatorio obtener el consentimiento de los padres o tutores legales y el asentimiento del paciente, cuando proceda.

E.4

Principal exclusion criteria

Patients will be excluded from the study if any of the following criteria are met:
1. The patient, if randomized to treatment in Study HGT-SAN-093, has experienced a decline of more than 20 points in the BSID-III cognitive DQ score between Baseline and the Week 48 visit in Study HGT-SAN-093, AND, upon individual evaluation by the Investigator, has been deemed a treatment failure*.
2. The patient has experienced, in the opinion of the Investigator, a safety or medical issue that contraindicates treatment with HGT-1410, including but not limited to clinically relevant intracranial hypertension, severe infusion-related reactions after treatment with HGT-1410, uncontrollable seizure disorder.
3. The patient has a known hypersensitivity to any of the components of HGT-1410.
4. The patient is enrolled in another clinical study, other than HGT-SAN-093, that involves clinical investigations or use of any investigational product (drug or [intrathecal/spinal] device) within 30 days prior to study enrollment or at any time during the study.
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at an unacceptably high risk for anesthesia due to airway compromise or other conditions.
6. The patient has a condition that is contraindicated as described in the SOPH-APORT ® Mini S IDDD Instructions for Use, including:
a.- The patient has had, or may have, an allergic reaction to the materials of construction of the SOPH-A-PORT ® Mini S device
b.- The patient?s body size is too small to support the size of the SOPH-A-PORT ® Mini S Access Port, as judged by the Investigator
c.- The patient?s drug therapy requires substances known to be incompatible with the materials of construction
d.- The patient has a known or suspected local or general infection
e.- The patient is at risk of abnormal bleeding due to a medical condition or therapy
f.- The patient has one or more spinal abnormalities that could complicate safe implantation or fixation
g.- The patient has a functioning CSF shunt device
h.- The patient has shown an intolerance to an implanted device
7. The patient is unable to comply with the protocol (eg, is unable to return for safety evaluations, or is otherwise unlikely to complete the study) as determined by the Investigator.
*All treated patients in Study HGT-SAN-093 will have their cognitive development assessed at the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 20 points or less in the BSID-III DQ score is observed, then the patient may proceed into
the Study SHP-610-201 without further evaluation. If a decline from Baseline of more than 20 points in DQ score is observed, then an
individual evaluation by the Investigator will occur to determine if the patient is a treatment failure. This individual evaluation will
take into account the DQ scores, VABS-II score, physical status, and any other information available for that patient at that time. If the Investigator deems the patient to
be a treatment failure, then the patient may not enter the Study SHP-610-201.

Se excluirá del estudio a los pacientes que cumplan alguno de los criterios siguientes:
1. El paciente, si se le asignó un tratamiento en el estudio HGT-SAN-093, ha presentado un descenso de más de 20 puntos en el CD cognitivo de la escala BSID-III entre la visita basal y la semana 48 en el estudio HGT-SAN-093 Y, según la evaluación individual realizada por el investigador, se ha considerado que representa un fracaso del tratamiento*.
2. El paciente ha experimentado, en opinión del investigador, un problema médico o de seguridad que contraindica el tratamiento con HGT-1410, por ejemplo, hipertensión intracraneal de importancia clínica, una reacción grave a la infusión después del tratamiento con HGT-1410 o un trastorno comicial no controlable.
3. El paciente tiene hipersensibilidad conocida a alguno de los componentes de HGT- 1410.
4. El paciente participa en otro estudio clínico, aparte de HGT-SAN-093, que suponga investigaciones clínicas o el uso de un producto en investigación (fármaco o dispositivo [intratecal/vertebral]) en los 30 días previos a la inclusión en este estudio o en algún momento durante el mismo.
5. El paciente tiene hipersensibilidad confirmada o supuesta a los anestésicos o se considera que existe un riesgo inaceptablemente alto para la anestesia debido a un deterioro de las vías respiratorias u otras enfermedades.
6. El paciente presenta alguna de las contraindicaciones que se detallan en las instrucciones de uso del sistema de administración de medicación por vía intratecal (SAMI) SOPH-A-PORT® Mini S, como por ejemplo:
a. El paciente ha sufrido o podría sufrir una reacción alérgica a los materiales empleados en la fabricación del dispositivo SOPH-A-PORT® Mini S.
b. El paciente tiene un tamaño corporal demasiado pequeño para soportar el tamaño del puerto de acceso SOPH-A-PORT® Mini S, según el criterio del investigador.
c. El paciente necesita tratamiento farmacológico con sustancias incompatibles con los materiales de fabricación.
d. El paciente sufre una infección local o general confirmada o supuesta.
e. El paciente corre riesgo de sufrir una hemorragia anormal debida a una enfermedad o tratamiento.
f. El paciente tiene una o varias anomalías vertebrales que podrían complicar la implantación o la fijación de forma segura.
g. El paciente lleva un dispositivo de derivación del líquido cefalorraquídeo (LCR) en funcionamiento.
h. El paciente ha demostrado intolerancia a un dispositivo implantado.
7. El paciente no puede cumplir el protocolo (p. ej., no puede acudir a las evaluaciones de la seguridad o es improbable que finalice el estudio por otros motivos), en opinión del investigador.
*Se hará una evaluación del desarrollo cognitivo a todos los pacientes tratados en el estudio HGT-SAN-093 en la visita de la semana 48 del estudio HGT-SAN-093. Si se observa un descenso de 20 puntos o menos en la puntuación del CD de la BSID-III con respecto al valor basal, el paciente podrá incorporarse al estudio SHP-610-201 sin necesidad de más evaluaciones. Si se observa un descenso de más de 20 puntos de la puntuación del CD con respecto al valor basal, el investigador realizará una evaluación individual para determinar si el paciente representa un fracaso del tratamiento. Esta evaluación individual tendrá en cuenta las puntuaciones del CD, la puntuación de las escalas VABS-II, el estado físico y todos los demás datos del paciente disponibles en ese momento. Si el investigador considera que el paciente representa un fracaso del tratamiento, el paciente no podrá incorporarse al estudio SHP-610-201.

E.5 End points

E.5.1

Primary end point(s)

Safety is the primary objective of the study and will be assessed during the study by the following:
- collection of adverse events (by type, severity, and relationship to treatment [HGT-1410, the IDDD, device surgical procedure, or IT administration process])
- changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)
- physical examination
- vital signs
- 12-lead electrocardiogram (ECG) recordings
- CSF laboratory parameters (including chemistries, cell counts)
- anti-rhHNS antibodies in CSF and serum, including determination of antibodies having enzyme neutralizing activity

La seguridad es el objetivo primario del estudio y se evaluará mediante las determinaciones siguientes:
- recopilación de los acontecimientos adversos (por tipo, intensidad y relación con el tratamiento [HGT-1410, SAMI, implantación quirúrgica del dispositivo o proceso de administración IT])
- alteraciones en los análisis clínicos (bioquímica sérica, hematología, análisis de orina)
- exploración física
- constantes vitales
- electrocardiogramas (ECG) de 12 derivaciones
- parámetros de análisis del LCR (bioquímica, recuentos celulares)
- anticuerpos anti-rhHNS en el LCR y el suero, incluida la determinación de anticuerpos con actividad neutralizante enzimática

E.5.1.1

Timepoint(s) of evaluation of this end point

120 weeks

120 semanas

E.5.2

Secondary end point(s)

- The change from Baseline in BSID-III or KABC-II age-equivalent, DQ, and developmental delay scores
- The change from Baseline in adaptive behavioral function domains, assessed by VABS II, using raw scores, age-equivalent scores, and DQ scores
- The change from Baseline in total cortical grey matter volume, as assessed by MRI

- La variación con respecto a los valores basales de las Escalas de Bayley (BSID-III) o en la Batería de evaluación de Kaufman para niños (KABC-II), las puntuaciones de equivalentes de edad, coeficiente de desarrollo (CD) y escalas de retraso de desarrollo.
- La variación con respecto a los valores basales de la conducta adaptativa, evaluada mediante las Escalas de conducta adaptativa de Vineland (VABS-II), las puntuaciones de equivalentes de edad y coeficiente de desarrollo (CD).
- La variación con respecto a los valores basales del volumen total de sustancia gris cortical, evaluado mediante resonancia magnética (RM) volumétrica del cerebro

E.5.2.1

Timepoint(s) of evaluation of this end point

120 weeks

120 semanas

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of Life and Health Economics

Calidad de vida y valoración de economía sanitaria.

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

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

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

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.8.5

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

France

Germany

Italy

Netherlands

Spain

United Kingdom

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

Last visit of the last patient in the clinical study

Última visita del último paciente en el ensayo clínico

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

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)

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

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Children between 24 and 60 months

Niños entre 24 y 60 meses

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

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)

None

Ninguno

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

2015-02-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-30

P. End of Trial
P.	End of Trial Status	Completed

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IMP with orphan designation in the indication
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