Clinical Trials Register

Summary
EudraCT Number:	2014-002098-12
Sponsor's Protocol Code Number:	232SM201
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-04-09
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

Germany - BfArM

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

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

A.3.2

Name or abbreviated title of the trial where available

NURTURE

A.4.1

Sponsor's protocol code number

232SM201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02386553

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/251/2016

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	Medical Director
B.5.3	Address:
B.5.3.1	Street Address	Building 5, Foundation Park, Roxborough Way
B.5.3.2	Town/ city	Maidenhead, Berkshire
B.5.3.3	Post code	SL6 3UD
B.5.3.4	Country	United Kingdom
B.5.6	E-mail	clinicaltrials@biogen.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	Spinraza
D.2.1.1.2	Name of the Marketing Authorisation holder	Biogen Idec 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	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	Nusinersen
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)

E.1.1.1

Medical condition in easily understood language

Spinal Muscular Atrophy (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	20.1
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 Nusinersen administered intrathecally in preventing or delaying the need for respiratory intervention or death in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA).

E.2.2

Secondary objectives of the trial

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

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).
- Ulnar 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.

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 the first dosing (Day1) 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.

Note: Other protocol defined Inclusion/Exclusion criteria may apply

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to Day 2891

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 Hammersmith Functional Motor Scale -
Expanded (HFMSE)
7 Change from Baseline in weight for age/length
8 Change from Baseline in head circumference
9 Change from Baseline in chest circumference ratio
10 Change from Baseline in head to chest circumference ratio
11 Change from Baseline in arm circumference ratio
12 Incidence of adverse events (AEs) and/or serious adverse events
(SAEs).
13 Change from Baseline in clinical laboratory parameters
14 Change from Baseline in electrocardiograms (ECGs)
15 Change from Baseline in vital signs
16 Change from Baseline in nerological examinations
17 Cerebrospinal fluid (CSF) and plasma Nusinersen concentrations

E.5.2.1

Timepoint(s) of evaluation of this end point

Points 1 and 3 will be measured at 13 and 24 months of age
Points 2 will be measured at 13 months, and 2, 3, 4, 5, 6, 7 and 8 years of age
Point 4 to 16 inclusive will be measured up to Day 2891
Point 17 will be measured up to Day 2801

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

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Qatar

Taiwan

Australia

Canada

United States

Germany

Italy

Türkiye

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

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)

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. Written informed consent from the parent(s) or legal guardian(s) is required. If required by country regulations, assent forms will be available for subjects who reach 6 years of age to 8 years of age.

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

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

2015-05-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-08-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-12-17

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