Clinical Trials Register

Summary
EudraCT Number:	2012-005082-13
Sponsor's Protocol Code Number:	101MS328
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-02-18
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2012-005082-13

A.3

Full title of the trial

A Phase 1, Multicenter, Open-Label, Single-Arm, Multiple Dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Natalizumab in Pediatric Subjects with Relapsing Remitting Multiple Sclerosis

Studio di fase I, multicentrico, in aperto, a braccio singolo, a dose multipla per valutare la farmacocinetica e la farmacodinamica di natalizumab in soggetti pediatrici con sclerosi multipla recidivante remittente

A.3.1

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

A.4.1

Sponsor's protocol code number

101MS328

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/252/2012

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Biogen Idec Research Limited
B.1.3.4	Country	United Kingdom
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	Biogen Idec Research Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Biogen Idec Research Limited
B.5.2	Functional name of contact point	not available
B.5.3	Address:
B.5.3.1	Street Address	Innovation House, 70 Norden Road
B.5.3.2	Town/ city	Maidenhead Berkshire
B.5.3.3	Post code	SL6 4AY
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	441628501000
B.5.5	Fax number	441628501010
B.5.6	E-mail	cta.submissions@biogenidec.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	Yes
D.2.1.1.1	Trade name	TYSABRI
D.2.1.1.2	Name of the Marketing Authorisation holder	Elan Pharma International 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.3.2	Product code	AN100226, BG00002
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	NATALIZUMAB
D.3.9.1	CAS number	189261-10-7
D.3.9.4	EV Substance Code	SUB22282
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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

Relapsing Remitting Multiple Sclerosis

Sclerosi Multipla Recidivante Remittente

E.1.1.1

Medical condition in easily understood language

Multiple Sclerosis

Sclerosi Multipla

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10063399
E.1.2	Term	Relapsing-remitting multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is to determine the PK profile of multiple doses of natalizumab in pediatric subjects with RRMS.

L’obiettivo primario dello studio è di determinare il profilo PK di dosi multiple di natalizumab nei soggetti pediatrici affetti da SMRR

E.2.2

Secondary objectives of the trial

The secondary objectives of this study in this study population are as follows:
• To characterize the PD profile of natalizumab (as defined by α4 integrin binding).
• To determine the safety and tolerability of multiple doses of natalizumab.

Gli obiettivi secondari di questo studio in questa popolazione dello studio sono i seguenti: • Caratterizzare il profilo PD di natalizumab (definito dal legame con integrina α4). • Determinare la sicurezza e la tollerabilità di dosi multiple di natalizumab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

To be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of enrollment or at the timepoint specified in the individual eligibility criterion listed:
1. Ability of parents or legal guardians to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations. Subjects may provide assent in addition to the parental or guardian consent, if appropriate.
2. Aged from 10 to less than 18 years old at the time of informed consent or assent.
3. Diagnosis of RRMS according to Krupp [Krupp 2007] on behalf of the International Pediatric MS Study Group and Polman [Polman 2011] at Screening. RRMS diagnosis must be confirmed by a brain MRI scan performed within the 12 months prior to Screening or at Screening.
4. It has been determined by the treating physician that natalizumab treatment is appropriate for this subject based on their disease status.
5. Subjects of childbearing potential, who are sexually active, must practice effective contraception during the study and be willing and able to continue contraception for 3 months after their last infusion of study treatment. For further details of contraceptive requirements for this study, please refer to Section 15.5.3.

Per essere idonei a partecipare a questo studio, i candidati devono soddisfare i seguenti criteri di idoneità al momento dell'arruolamento o al momento specificato nel criterio di inclusione individuale elencato: 1. Capacità dei genitori o tutori legali di capire lo scopo e rischi dello studio e fornire il consenso informato firmato e datato e l'autorizzazione ad utilizzare le informazioni sanitarie protette, in conformità con le normative nazionali e locali in materia di privacy. I soggetti possono fornire un assenso in aggiunta al consenso dei genitori o del tutore, se appropriato. 2. Devono avre un’età da maggiore o uguale di 10 anni a meno di 18 anni al momento del consenso informato o dell’assenso. 3. Diagnosi di SMRR secondo Krupp [Krupp 2007] a nome del gruppo di studio internazionale sulla SM pediatrica e secondo Polman [Polman 2011] allo Screening. La diagnosi di SMRR deve essere confermata da una scansione RMI del cervello eseguita entro i 12 mesi precedenti allo screening o allo Screening. 4. È stato determinato dal medico curante che il trattamento con natalizumab è appropriato per questo soggetto in base allo stato della malattia. 5. Soggetti in età fertile, che sono sessualmente attive, deve utilizzare un metodo contraccettivo efficace durante lo studio ed essere disposti e in grado di continuare la contraccezione per 3 mesi dopo la loro ultima infusione del trattamento in studio. Per ulteriori dettagli circa la necessità di utilizzare contraccettivi di questo studio, si prega di fare riferimento alla Sezione 15.5.3 del protocollo.

E.4

Principal exclusion criteria

Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of enrollment or at the timepoint specified in the individual criterion listed:
Medical History
1. Diagnosis of acute disseminated encephalomyelitis, neuromyelitis optica, isolated optic neuritis or transverse myelitis, progressive MS, or any other potential differential diagnosis of pediatric-onset RRMS.
2. History of human immunodeficiency virus.
3. History of hepatitis C virus antibody or current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Subjects with immunity to hepatitis B from previous natural infection (defined asnegative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) are eligible to participate in the study (US Centers for Disease Control and Prevention’s interpretation of the hepatitis B serology panel).
4. History of or current signs and symptoms suggestive of PML.
5. History of inflammatory disorders, metabolic neurogenetic leukodystrophies, toxic leukoencephalopathies, or vascular conditions.
6. History of premalignant or malignant disease.
7. History of severe allergic or anaphylactic reactions, or known drug hypersensitivity.
8. Clinically significant infections or medical illness from 30 days prior to Screening or between Screening and the first infusion of study treatment.
9. Diagnosis of MS relapse within 30 days prior to enrollment.
10. History of, or abnormal laboratory values indicative of, significant medical, neurologic (other than MS), or psychiatric disorders that might preclude participation in the study in the opinion of the Investigator.
11. Abnormal laboratory values at Screening defined at following thresholds:
a. bilirubin level >2 times the upper limit of normal (× ULN)
b. absolute lymphocyte count ≤750/mm3, hemoglobin ≤10 g/dL, or platelet count ≤100,000/mm3
c. serum creatinine >1.5 mg/dL
d. alanine aminotransferase (ALT), OR aspartate aminotransferase (AST), OR gamma-glutamyltransferase (GGT) >2 × ULN
MS Treatment History
12. Prior natalizumab therapy.
13. Prior treatment with total lymphoid irradiation.
14. Prior treatment with cladribine, mitoxantrone, fingolimod, teriflunomide, T cell or T-cell receptor vaccination, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, or any therapeutic monoclonal antibody or other immunosuppressive therapy.
15. Plasmapheresis or cytapheresis within 12 months prior to the first infusion of study treatment.
16. Prior treatment with intravenous immunoglobulin (IVIg) within 4 months prior to the first infusion of study treatment.
17. Treatment with IV or oral corticosteroids (topical corticosteroids are acceptable) or related products within 30 days prior to the first infusion of study treatment.
18. Immunomodulatory treatment, i.e., interferon beta or glatiramer acetate within 2 weeks prior to the first infusion of study treatment.
Miscellaneous
19. Nursing or pregnant female, or female planning to become pregnant during study participation.
20. Participation in any other investigational study that involved treatment with an investigational drug or prior treatment with any experimental agent outside a clinical study.
21. Other unspecified reasons that, in the opinion of the Investigator and/or Biogen Idec, make the subject unsuitable for enrollment.

I candidati saranno esclusi dell'ingresso nello studio se uno qualsiasi dei seguenti criteri di esclusione è presente al momento dell'arruolamento o al momento specificato nel singolo criterio elencato:
Storia Medica
1.Diagnosi di encefalomielite acuta disseminata, neuromielite ottica, neurite ottica isolata o mielite trasversale, sclerosi multipla progressiva, o di qualsiasi altra diagnosi potenziale differenziale di SMRR ad insorgenza pediatrica. 2. Storia di virus dell'immunodeficienza umana. 3. Storia di anticorpi contro il virus dell'epatite C o corrente infezione da epatite B (definiti come positivi per l'antigene di superficie dell'epatite B [HBsAg] e / o per l’anticorpo core dell'epatite B [HBcAb]). Soggetti con immunità per epatite B da precedenti infezioni naturali (definito come HBsAg negativo, anticorpo immunoglobulina G di superficie dell’epatite B positivo, e HBcAb positivo) sono idonei a partecipare allo studio (Centri statunitensi per il controllo delle malattie e l'interpretazione del pannello sierologico dell'epatite B per la prevenzione) . 4. Storia di/segni correnti e sintomi indicativi di PML. 5. Storia di malattie infiammatorie, leucodistrofie neurogenetiche metaboliche, leucoencefalopatie tossiche, o condizioni vascolari. 6. Storia di malattia pre-maligna o maligna. 7. Storia di gravi reazioni allergiche o anafilattiche, o ipersensibilità nota al farmaco. 8. Infezioni clinicamente significative o malattia medica da 30 giorni prima dello Screening o tra lo screening e la prima infusione del trattamento in studio. 9. La diagnosi di SM recidiva nei 30 giorni precedenti l'arruolamento. 10. Storia di/Valori di laboratorio anormali indicativi di una disturbi medici significativi, neurologici (diversi da MS), o psichiatrici che possono precludere la partecipazione allo studio a giudizio dello sperimentatore. 11. Valori di laboratorio anormali al momento dello screening definiti alle seguenti soglie: a. livello di bilirubina> 2 volte il limite superiore del valore normale (ULN) b. conta assoluta dei linfociti ≤ 750/mm3, emoglobina ≤ 10 g / dL, o conta piastrinica ≤ 100.000 / mm3 c. creatinina sierica> 1,5 mg / dL d. alanina aminotransferasi (ALT), o aspartato aminotransferasi (AST), o gamma-glutamiltransferasi (GGT)> 2 × ULN
Storia del Trattamento della MS
12. terapia precedente con natalizumab. 13. Precedenti trattamenti con irradiazione linfoide totale. 14. Un precedente trattamento con cladribina, mitoxantrone, fingolimod, teriflunomide, vaccinazione cellule T o recettore T-cellule, ciclofosfamide, ciclosporina, azatioprina, metotressato, micofenolato mofetile, o qualsiasi anticorpo monoclonale terapeutico o altre terapie immunosoppressive. 15. Plasmaferesi o citaferesi nei 12 mesi precedenti la prima infusione del trattamento in studio. 16. Un precedente trattamento con immunoglobuline per via endovenosa (IVIg) entro 4 mesi prima della prima infusione del trattamento in studio. 17. Il trattamento con corticosteroidi per via endovenosa o per via orale (corticosteroidi topici sono accettabili) o prodotti affini entro 30 giorni prima della prima infusione del trattamento in studio. 18. trattamento immunomodulante, vale a dire interferone beta o glatiramer acetato entro 2 settimane prima della prima infusione del trattamento in studio.
Varie 19.Femmina incinta o in allattamento, o lche pianifica una gravidanza durante la partecipazione allo studio. 20. La partecipazione a qualsiasi altro studio sperimentale che ha coinvolto il trattamento con un farmaco sperimentale o un precedente trattamento con qualsiasi agente sperimentale al di fuori di uno studio clinico. 21. Altri motivi non precisati che, a giudizio del ricercatore e / o di Biogen Idec, rendono il soggetto non idoneo all’arruolamento.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoints are as follows: maximum plasma concentration (Cmax) for the 24-hour sampling period, predose (trough) concentrations (Cpredose) from multiple dosing time to maximum plasma concentration (Tmax) for the 24-hour sampling period area under the plasma concentration curve from time of first dose to infinity (AUCinf), apparent clearance (Cl/F), volume of distribution, elimination half-life (t1/2)

Gli end point primari sono i seguenti: Concentrazione plasmatica massima (Cmax) per il periodo di campionamento di 24 ore, Concentrazioni pre-dose (minime) dal dosaggio multiplo (Cpre-dose), Tempo alla concentrazione plasmatica massima (Tmax) per il periodo di campionamento di 24 ore, Area sotto la curva di concentrazione plasmatica dal tempo della prima dose a infinito (AUCinf), Clearance apparente (Cl/F), Volume di distribuzione, Emivita di eliminazione (t1/2).

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

The secondary endpoints are as follows: the average and minimum saturation values of α4 integrin over the dosing interval, incidence of serious adverse events (SAEs), infusion and hypersensitivity reactions, and other AEs, the presence of anti-natalizumab antibodies

Gli end point secondari sono i seguenti: I valori di saturazione medi e minimi di integrina α4 nell’intervallo di dosaggio, L’incidenza di eventi avversi seri (SAE), reazioni all’infusione e di ipersensibilità e altri eventi avversi (EA), La presenza di anticorpi anti-natalizumab.

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

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pediatric Pharmacokinetic Study

Studio Pediatrico di Farmacocinetica

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

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

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

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

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

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

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)

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

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

Ability of parents/legal guardians to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local subject privacy regulations.

Capacità dei genitori/tutori legali di capire lo scopo,i rischi dello studio,fornire il consenso informato firmato,datato e l'autorizzazione all'uso delle informazioni sanitarie protette,in conformità con le normative nazionali sulla privacy

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)

Subjects who complete the PK/PD Study through Week 16 and for whom continued treatment with natalizumab is prescribed by their treating physician may continue uninterrupted treatment with natalizumab in either 1) the Italian National Registry or 2) the Extension Study.

I soggetti che completano lo Studio PK-PD fino alla Settimana 16 e per i quali il medico curante ha prescritto la continuazione del trattamento con natalizumab possono continuare il trattamento ininterrotto con natalizumab nel 1. Registro nazionale italiano o nello 2. Studio di estensione.

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

2013-04-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-02-26

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials