Clinical Trials Register

Summary
EudraCT Number:	2015-001985-25
Sponsor's Protocol Code Number:	250-201
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2016-01-13
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

2015-001985-25

A.3

Full title of the trial

A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular BMN 250 in Patients with Mucopolysaccharidosis Type IIIB (MPS IIIB, Sanfilippo Syndrome Type B)

Estudio abierto con aumento de la dosis en fase 1/2 para evaluar la seguridad, tolerabilidad, farmacocinética y eficacia del BMN 250 intracerebroventricular en pacientes con mucopolisacaridosis tipo IIIB (MPS IIIB, Síndrome de Sanfilippo tipo B)

A.3.1

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

Phase 1/2 Study to Evaluate the Safety and Efficacy of BMN 250 in Patients with MPS IIIB

Estudio fase 1/2 para evaluar la seguridad y eficacia de BMN 250 en pacientes con MPS IIIB.

A.4.1

Sponsor's protocol code number

250-201

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	BioMarin Pharmaceutical 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	BioMarin Pharmaceutical 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	BioMarin Pharmaceutical Inc.
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	105 Digital Drive
B.5.3.2	Town/ city	Novato
B.5.3.3	Post code	94949
B.5.3.4	Country	United States
B.5.6	E-mail	clinicaltrials@bmrn.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	EMA/OD/213/14
D.3 Description of the IMP
D.3.1	Product name	N/A
D.3.2	Product code	BMN 250
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	Intraventricular use (Noncurrent)
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	BMN 250
D.3.9.3	Other descriptive name	RHNAGLU-IGF2
D.3.9.4	EV Substance Code	SUB177868
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	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	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	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 IIIB (Sanfilippo Syndrome Type B, MPS IIIB)

Mucopolisacaridosis tipo IIIB (MPS IIIB, Síndrome de Sanfilippo tipo B)

E.1.1.1

Medical condition in easily understood language

NAGLU deficiency

Deficiencia NAGLU

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	18.1
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	18.1
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 the safety and tolerability of BMN 250 administered to subjects with MPS IIIB by an implanted intracerebroventricular (ICV) reservoir and catheter.

To evaluate the impact of BMN 250 on cognitive function in patients with MPS IIIB as assessed by development quotient (DQ).

Evaluar la seguridad y tolerabilidad del BMN 250 administrado a pacientes con MPS IIIB mediante un depósito implantado y un catéter ICV.

Evaluar el impacto de BMN 250 en la función cognitiva de pacientes con MPS IIIB, evaluado por el coeficiente de desarrollo (DQ).

E.2.2

Secondary objectives of the trial

To characterize single- and repeated-dose pharmacokinetics (PK) of BMN 250 in cerebrospinal fluid (CSF) and plasma.

To characterize immunogenicity of BMN 250 in CSF and serum.

To evaluate the impact of BMN 250 treatment on CSF, serum, and urine GAGs.

To evaluate the impact of BMN 250 treatment on brain structure assessed by MRI.

Caracterizar la farmacocinética (FC) de dosis únicas y repetidas de BMN 250 en el líquido cefalorraquídeo (LCR) y el plasma.

Caracterizar la inmunogenicidad del BMN 250 en el LCR y el suero.

Evaluar el impacto del tratamiento con BMN 250 en los GAG en el LCR, el suero y la orina.

Evaluar el impacto del tratamiento con BMN 250 en la estructura cerebral, evaluado por resonancia magnética (RM).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Part 1: Dose Escalation Period:

Has deficient NAGLU enzyme activity at screening.

Is between 1 and 10 years of age.

Has presented with signs/symptoms consistent with MPS IIIB; for individuals who have not presented with signs/symptoms of the disease (e.g., siblings of known patients), the determination of eligibility will be at the discretion of the BioMarin medical monitor in conjunction with the site investigator.

Written informed consent from parent or legal guardian and assent from subject, if required.

Has the ability to comply with protocol requirements, in the opinion of the investigator.

Part 2: Stable Dose Period:

Participated in and met protocol requirements for transitioning from Study 250-901 or participated in Part 1 of Study 250-201

Written informed consent from parent or legal guardian and assent from subject, if required

Parte 1: Período de aumento de la dosis:

Tener actividad deficiente de la enzima NAGLU en el momento de la selección.

Tener entre 1 y 10 años de edad

Haber presentado signos/síntomas compatibles con MPS IIIB; en el caso de los pacientes que no hayan presentado signos/síntomas de enfermedad (p. ej., hermanos de pacientes conocidos), la determinación de la idoneidad quedará a criterio del monitor médico de BioMarin en conjunción con el investigador del centro.

Consentimiento informado por escrito de los padres o del tutor legal y asentimiento del paciente, si se requiere.

Según la opinión del investigador, es capaz de cumplir los requisitos del protocolo

Parte 2: Período de dosis estable:

Haber participado y cumplido los requisitos del protocolo para pasar del estudio 250-901 o haber participado en la parte 1 del estudio 250-201.

Consentimiento informado por escrito de los padres o del tutor legal y asentimiento del paciente, si se requiere.

E.4

Principal exclusion criteria

Part 1: Dose Escalation Phase:

Has received stem cell, gene therapy, or enzyme replacement therapy for MPS IIIB.

Has contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities).

Has contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, or aneurysm clip in the brain).

Has a history of poorly controlled seizure disorder.

Is prone to complications from intraventricular drug administration, including patients with hydrocephalus or ventricular shunts.

Has received any investigational medication within 30 days prior to the Baseline visit or is scheduled to receive any investigational drug during the course of the study.

Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with protocol requirements, the subject's well-being or safety, or the interpretability of the subject's clinical data.

Is pregnant at any time during the study

Part 2: Stable Dose Period:
Has received stem cell, gene therapy or ERT for MPS IIIB

Has contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities)

Has contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, or aneurysm clip in the brain)

Is prone to complications from intraventricular drug administration, including patients with hydrocephalus or ventricular shunts

Has received any investigational medication within 30 days prior to the Baseline visit or is scheduled to receive any investigational drug during the course of the study

Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject´s ability to comply with protocol requirements, the subject´s well-being or safety, or the interpretability of the subject´s clinical data.

Is pregnant at any time during the study

Parte 1: Período de aumento de la dosis
Haber recibido células madre, terapia génica o tratamiento enzimático sustitutivo (TES) para la MPS IIIB.

Tener contraindicaciones para la neurocirugía (p. ej. cardiopatía congénita, trastorno respiratorio grave o alteraciones de la coagulación).

Tener contraindicaciones para las exploraciones por RM (p. ej., marcapasos cardíaco, fragmento metálico o chip en el ojo o un clip para aneurisma en el cerebro).

Tener antecedentes de trastorno convulsivo mal controlado.

Ser propenso a tener complicaciones por la administración intraventricular de medicamentos, incluidos pacientes con hidrocefalia o derivaciones ventriculares.

Haber recibido algún medicamento en fase de investigación en los 30 días anteriores a la visita inicial o tener programada la administración de algún medicamento en fase de investigación durante el transcurso del estudio.

Tener un problema médico o circunstancias atenuantes que, en opinión del investigador, podrían afectar a la capacidad del paciente para cumplir los requisitos del protocolo, el bienestar o la seguridad del paciente o la interpretación de los datos clínicos del paciente.

Estar embarazada en cualquier momento durante el estudio.

Parte 2: Período de dosis estable:
Haber recibido células madre, terapia génica o tratamiento enzimático sustitutivo (TES) para la MPS IIIB.

Tener contraindicaciones para la neurocirugía (p. ej. cardiopatía congénita, trastorno respiratorio grave o alteraciones de la coagulación).

Tener contraindicaciones para las exploraciones por RM (p. ej., marcapasos cardíaco, fragmento metálico o chip en el ojo o un clip para aneurisma en el cerebro).

Ser propenso a tener complicaciones por la administración intraventricular de medicamentos, incluidos pacientes con hidrocefalia o derivaciones ventriculares.

Haber recibido algún medicamento en fase de investigación en los 30 días anteriores a la visita inicial o tener programada la administración de algún medicamento en fase de investigación durante el transcurso del estudio.

Tener un problema médico o circunstancias atenuantes que, en opinión del investigador,podrían afectar a la capacidad del paciente para cumplir los requisitos del protocolo, el bienestar o la seguridad del paciente o la interpretación de los datos clínicos del paciente.

Estar embarazada en cualquier momento durante el estudio.

E.5 End points

E.5.1

Primary end point(s)

E.5.1.1

Timepoint(s) of evaluation of this end point

Safety and tolerability reviews include: continuous monitoring of AEs and concomitant medications; clinical lab assessments at Screening, prior to/day after first dose at each dose level and Q4W until next dose escalation in Part1, and Screening, prior to/day after first dose and Q4W thereafter in Part2;CSF for cell count, protein, glucose collected prior to weekly infusions; pre/post-dose blood samples for serial PK analysis monitored for glucose level; complete physical exam at Screening, Baseline and dose escalation visits in Part1 and Baseline and Weeks 24 and 48 in Part2; brief physical exams at weekly dosing visits when complete exams not performed; ECG and EEG at Screening and end of study.

Neurocognitive tests at Baseline in Part1, and Baseline, Weeks 12, 24, 36, 48 in Part2.

Las evaluaciones de seguridad y tolerabilidad incluyen: monitorización continua de AA y medicación concomitante; evaluaciones de lab clínico en S, antes de/ día tras primera dosis en cada nivel de dosis y C4S hasta próx aumento de dosis en P1, y selección, antes de/ día tras primera dosis y C4S en P2; LCR para conteo de células, proteínas, glucosa recolectada antes de infusiones semanales; muestras de sangre pre/ post dosis para análisis PK serie monitorizado para nivel de glucosa; examen físico completo en visitas de selección, basal y escalada de dosis en P1 y basal y en S24 y 48 en P2; exámenes físicos breves en visitas semanales de dosificación cuando no se han hecho completos; ECG y EEG en selección y final del estudio.
Pruebas neurocognitivas en basal P1 y B, S 12, 24, 36, 48 en P2.

E.5.2

Secondary end point(s)

The secondary objectives of this study are:
*to characterize single- and repeated-dose pharmacokinetics (PK) of BMN 250 in cerebrospinal fluid (CSF) and plasma
*to characterize immunogenicity of BMN 250 in CSF and serum
*to evaluate the impact of BMN 250 treatment on CSF, serum and urine GAGs
*to evaluate the impact of BMN 250 treatment on brain structure assessed by magnetic resonance imaging (MRI)

Los objetivos secundarios de este estudio son:
-Caracterizar la farmacocinética (FC) de dosis únicas y repetidas de BMN 250 en el líquido cefalorraquídeo (LCR) y el plasma.
- Caracterizar la inmunogenicidad del BMN 250 en el LCR y el suero.
- Evaluar el impacto del tratamiento con BMN 250 en los GAG en el LCR, el suero y la orina.
- Evaluar el impacto del tratamiento con BMN 250 en la estructura cerebral, evaluado por resonancia magnética (RM).

E.5.2.1

Timepoint(s) of evaluation of this end point

Sampling of CSF and blood (plasma) for serial PK and GAG analyses will be following the first dose and subsequent dose escalations in Part 1 and for the doses administered at Baseline, and Weeks 5, 12 and 36 in Part 2. CSF and blood (plasma) samples will also be used for trough PK performed Q4W in Part 2.

CSF and serum will be drawn throughout the study to analyze immunogenicity.

Urine will be collected for GAGs/creatinine analysis prior to initial dosing at each dose level and Q4W until the next dose escalation in Part 1, and Baseline and Q4W thereafter in Part 2.

Brain structure will be evaluated by MRI during both Part 1 and Part 2 Baseline visits and at Weeks 24 and 48 in Part 2.

Muestras de LCR y sangre (plasma) para análisis de PC serial y GAG seguirán la primera dosis y escaladas de dosis posteriores en parte 1 y para dosis administradas en Basal, y semanas 5, 12 y 36 en la Parte 2. LCR y smuestras de sangre (plasma) se utilizarán también para PKC realizada C4S en Parte 2.

LCR y suero se extraerán durante todo el estudio para analizar la inmunogenicidad.

La orina se recogerá para su análisis GAG / creatinina antes de la primera dosis en cada nivel de dosis y C4S hasta el próximo aumento de la dosis en la parte 1, y la línea de base y C4S a partir de entonces en la parte 2.

La estructura del cerebro será evaluado por RM tanto en Parte 1 y Parte 2 durante las visitas Basales, y en semanas 24 y 48 en la parte 2.

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

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)

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

Yes

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

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Baseline Control

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

Baseline Control

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

Australia

Brazil

Colombia

Germany

Spain

Taiwan

Turkey

United Kingdom

E.8.7

Trial has a data monitoring committee

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

UVUP

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

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The subjects included in this trial are between 1 to 10 years of age. Therefore before any study-related procedures are performed, parents or legal guardians of the subjects must provide informed consent, and if required, subjects must assent.

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)

Expected normal treatment for the condition

Tratamiento normal esperado para la condición

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-03-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-02-02

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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IMP with orphan designation in the indication
Orphan Designation Number:
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