Clinical Trials Register

Summary
EudraCT Number:	2014-002098-12
Sponsor's Protocol Code Number:	232SM201
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:	2015-03-24
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

2014-002098-12

A.3

Full title of the trial

An Open-Label Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Subjects With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

Studio in aperto volto alla valutazione dell’efficacia, la sicurezza, la tollerabilità e la farmacocinetica di ISIS 396443 somministrato in dosi multiple per via intratecale in soggetti con diagnosi genetica di atrofia muscolare spinale in fase presintomatica.

A.3.1

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

A Study of Multiple Doses of ISIS ISIS 396443 Delivered to Infants with
Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

Uno studio di dosi multiple di ISIS 396443 somministrato a neonati con atrofia muscolare spinale in fase presintomatica geneticamente diagnosticata

A.3.2

Name or abbreviated title of the trial where available

NURTURE

A.4.1

Sponsor's protocol code number

232SM201

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	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
B.5.2	Functional name of contact point	Medical Director
B.5.3	Address:
B.5.3.1	Street Address	Innovation House, 70 Norden Road
B.5.3.2	Town/ city	Maidenhead
B.5.3.3	Post code	SL6 4AY
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	clinicaltrials@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	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/3/12/976
D.3 Description of the IMP
D.3.1	Product name	Survival of Motor Neuron 2 (SMN2) Splicing Modulator Antisense Oligonucleotide
D.3.2	Product code	ISIS 396443 (BIIB058)
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	ISIS 396443
D.3.9.1	CAS number	1258984-36-9
D.3.9.2	Current sponsor code	ISIS 396443 (BIIB058)
D.3.9.3	Other descriptive name	ISIS 396443 (BIIB058)
D.3.9.4	EV Substance Code	SUB130563
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	2.4
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	2 - MOE Antisense Oligonucleotide

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

Spinal Muscular Atrophy (SMA)

Atrofia Muscolare Spinale (SMA)

E.1.1.1

Medical condition in easily understood language

Spinal Muscular Atrophy (SMA)

Atrofia Muscolare Spinale (SMA)

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

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	10041582
E.1.2	Term	Spinal muscular atrophy
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

The primary objective of the study is to examine the efficacy of multiple doses of ISIS 396443 administered intrathecally in preventing or delaying the need for respiratory intervention or death in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA).

L’obiettivo primario dello studio è quello di esaminare l’efficacia di ISIS 396443 somministrato in dosi multiple per via intratecale nel prevenire o ritardare il bisogno di intervento respiratorio o decesso nei bambini con diagnosi genetica di SMA in fase presintomatica

E.2.2

Secondary objectives of the trial

Secondary objectives of this study are to examine the effects of ISIS 396443 in infants with genetically diagnosed and presymptomatic SMA.

Gli obiettivi secondari di questo studio sono quelli di esaminare gli effetti di ISIS 396443 nei bambini con diagnosi genetica di SMA presintomatica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age ≤ 6 weeks at first dose
- Genetic documentation of 5q SMA homozygous gene deletion or mutation or compound heterozygous mutation.
- Genetic documentation of 2 or 3 copies of survival motor neuron 2 (SMN2).
- Compound muscle action potential (CMAP) ≥ 1 mV at Baseline.
- Gestational age of 37 to 42 weeks for singleton births; gestational age of 34 to 42 weeks for twins.
- Meet additional study related criteria.

- età ≤6 settimane alla prima dose
- documentazione genetica di mutazione o delezione omozigote del gene 5q della SMA o mutazione eterozigote composto
- documentazione genetica di 2 o 3 copie del gene di sopravvivenza dei motoneuroni 2(SMN2)
-Potenziale di azione muscolare compopsto (CMAP) ≥1 mV al Basale
- Età gestazionale da 37 a 42 settimane per le nascite di neonato unico; età gestazionale
di 34 a 42 settimane per i gemelli
- Soddisfare i criteri addizionali relativi allo studio.

E.4

Principal exclusion criteria

- Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or respiratory support).
- Any clinical signs or symptoms at Screening or immediately prior to dosing that are, in the opinion of the Investigator, strongly suggestive of SMA.
- Clinically significant abnormalities in hematology or clinical chemistry parameters.
- Treatment with an investigational drug given for the treatment of SMA biological agent, or device. Any history of gene therapy, prior antisense oligonucleotide (ASO) treatment, or cell transplantation.
- Meet additional study related criteria.

E.4 Criteri di esclusione principali(elencare i più importanti):
- Ipossiemia (saturazione di ossigeno <96% sveglio o addormentato senza
ossigeno supplementare o supporto respiratorio).
- Eventuali segni o sintomi clinici allo screening o immediatamente prima
della somministrazione della dose che sono, a giudizio dello sperimentatore, fortemente suggestivi di SMA.
- Alterazioni clinicamente significative nei parametri di ematologia o chimica clinica
- Il trattamento con un farmaco sperimentale proposta per il trattamento della SMA,
agente biologico, o dispositivo. Ogni storia di terapia genica, precedente trattamento con oligonucleotide antisenso (ASO) trattamento, o trapianto di cellule.
- Soddisfare i criteri addizionali relativi allo studio.

E.5 End points

E.5.1

Primary end point(s)

Time to death or respiratory intervention. The time will be the age of the participant at the first occurrence of either a respiratory intervention or death. Respiratory intervention is defined as invasive or noninvasive ventilation for ≥6 hours/day continuously for 7 or more days OR tracheostomy.

Tempo al decesso o all’intervento respiratorio. Il tempo sarà l’età del soggetto alla prima ricorrenza di intervento respiratorio o di decesso. L’intervento respiratorio è definito come ventilazione invasiva o non invasiva per ≥6 ore/giorno in modo continuativo per 7 giorni o più O tracheostomia.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to Day 868

Fino al giorno 868

E.5.2

Secondary end point(s)

1 Percentage of participants developing clinically manifested spinal muscular trophy(SMA)
2 Percentage of participants alive
3 Percentage of participants who attained motor milestones assessed as part of the Hammersmith Infant Neurological Examination (HINE)
4 Percentage of participants who attained motor milestones as assessed by World Health Organization (WHO) criteria
5 Change from Baseline in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale
6 Change from Baseline in weight for age/length
7 Change from Baseline in head chest and arm circumference
8 Change from Baseline in head to chest circumference ratio
9 Incidence of adverse events (AEs) and/or serious adverse events (SAEs).
10 Change from Baseline in clinical laboratory parameters, electrocardiograms (ECGs), and vital signs
11 Cerebrospinal fluid (CSF) and plasma ISIS 396443 concentrations

1. Percentuale di soggetti che sviluppano una atrofia muscolare spinale (SMA) clinicamente manifestata
2. Percentuale di soggetti vivi
3. Percentuale di soggetti che hanno raggiunto acquisizioni motorie secondo i criteri dell’HINE (Hammersmith Infant Neurological Examination)
4. Verrà presentata la proporzione di soggetti che hanno raggiunto acquisizioni motorie secondo i criteri dell’OMS
5. I cambiamenti dal valore basale nei parametri della scala di valutazione della funzionalità motoria Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND).

6. Variazione rispetto al basale nel peso/ lunghezza per età
7. Variazione rispetto al basale nella circonferenza della testa, del petto e del braccio
8. Cambiamento dal basale nel rapporto di circonferenza testa/torace
9. L'incidenza di eventi avversi (EA) e / o eventi avversi gravi
(SAE).
10. Variazione rispetto al basale dei parametri clinici di laboratorio,
elettrocardiogramma (ECG), e segni vitali
11. Concentrazioni di ISIS 396.443 nel liquido cerebrospinale (CSF) e plasma

E.5.2.1

Timepoint(s) of evaluation of this end point

Points 1-8 inclusive will be measured at 13 and 24 months of age
Points 9 and 10 inclusive will be measured up to 868 days
Point 11 will be measured up to 778 days

I punti dall’1-8 inclusi saranno misurati a 13 e 24 mesi di età
I punti 9 e 10 inclusi verranno misurati fino a 868 giorni
Il punto 11 sarà misurato fino a 778 giorni

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

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

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity assessments

Valutazioni di immunogenicità

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

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

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

Australia

Germany

Israel

Italy

Qatar

Taiwan

Turkey

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

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

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)

Yes

F.1.1.2.1

Number of subjects for this age range:

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

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)

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 trial will enrol babies 6 weeks old or less who are unable to provide
informed consent. Before a subject's participation in the trial, the
Investigator will be required to obtain written informed consent from
the parent(s) or legal guardian(s)

Verranno arruolati bambini con meno di 6 settimane di vita, non in grado di fornire il consenso informato. Prima della partecipazione di un soggetto,lo Sperimentatore dovrà ottenere il consenso informato scritto dai genitori o dai tutorei legali

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)

Please see protocol section 11.6

Si prega di fare riferimento al protocollo, sezione 11.6

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

2015-05-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-04-01

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

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