Clinical Trials Register

Summary
EudraCT Number:	2017-004087-35
Sponsor's Protocol Code Number:	AVXS-101-CL-304
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:	2018-04-20
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

2017-004087-35

A.3

Full title of the trial

A Global Study of a Single, One-Time Dose of AVXS-101 Delivered to Infants with Genetically Diagnosed and Pre-symptomatic Spinal Muscular Atrophy with Multiple Copies of SMN2

Estudio global de una única dosis y en una sola administración de AVXS-101 en lactantes con atrofia muscular espinal presintomática diagnosticada genéticamente y con múltiples copias del gen SMN2.

A.3.1

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

Single dose gene replacement therapy clinical trial for infants with genetically diagnosed and pre-symptomatic Spinal Muscular Atrophy

Ensayo clinic de una sola dosis de terapia génica en lactantes con atrofia muscular espinal geneticamente diagnosticada y prseintomatica.

A.3.2

Name or abbreviated title of the trial where available

SPR1NT

A.4.1

Sponsor's protocol code number

AVXS-101-CL-304

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	AveXis, 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	AveXis, 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	AveXis, Inc.
B.5.2	Functional name of contact point	Sr. Global Trial Operations Manager
B.5.3	Address:
B.5.3.1	Street Address	2275 Half Day Road, Suite 200
B.5.3.2	Town/ city	Bannockburn IL
B.5.3.3	Post code	60015
B.5.3.4	Country	United States
B.5.4	Telephone number	12245002097

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/3/15/1509
D.3 Description of the IMP
D.3.1	Product name	AVXS-101 (previously known as scAAV9.CB.SMN)
D.3.2	Product code	AVXS-101
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	Yes
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	onasemnogene abeparvovec
D.3.9.1	CAS number	1922968-73-7
D.3.9.2	Current sponsor code	AVXS-101
D.3.10	Strength
D.3.10.1	Concentration unit	vector genomes (vg)/mL
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20000000000000 to 60000000000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
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	Yes
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

Spinal Muscular Atrophy

Atrofia Muscular Espinal

E.1.1.1

Medical condition in easily understood language

Spinal Muscular Atrophy

Atrofia Muscular Espinal

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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

Safety
•Evaluate the safety of AVXS-101 through incidence of adverse events (AEs) and/or serious adverse events (SAEs)
•Evaluate the safety of AVXS-101 based on the change from baseline in clinical laboratory parameters

Efficacy objectives will be assessed independently for each cohort.
Eff. for patients with bi-allelic SMN1 deletions and 2 copies of SMN2:
•Assess the efficacy of AVXS-101 by demonstrating functional independent sitting for at least 30 seconds up to 18 months of age
Efficacy for patients with 3 copies of SMN2:
•Assess the efficacy of AVXS-101 based on the proportion of patients achieving the ability to stand without support for at least three seconds up to 24 months of age
Efficacy for patients with 4 copies of SMN2:
•Ass. the efficacy of AVXS-101 by demonstrating the ability to achieve a scaled score on Bayley V.3 Gross and Fine Motor Subtests within 1.5 standard deviations of chronological development reference standard as assessed at 36 months of age

Seguridad:
•Ev. seg. de AVXS-101 a través de la incidencia de acont. adv. (AA) y de aconte. adv. graves (AAG).
•Ev. seg. de AVXS-101 basándose en el cambio con respecto al valor basal en los result. de los aná. clínics.
Los objs. de la efic. se eva. de manera indepen. en cada cohorte.
Efic. en pacien. con 2 copias del gen SMN2:
•Ev. la efic. de AVXS-101 mostrando la cap. de sedestación indep. funcional durante un mín.: 30 seg - 18 meses de edad.
Efic. en pacien. con 3 copias del gen SMN2:
•Ev.la efic. de AVXS-101 basándose en la proporción de pacien. que consiguen quedarse de pie sin ayuda durante un mín. de: 3 segs. - 24 meses de edad.
Efic. en pacien. con 4 copias del gen SMN2:
•Ev. la efi. de AVXS-101 mostrando la capacidad para lograr una puntuación transformada en las subescalas de motricidad fina y general de las Esc. Bayley de desarrollo infantil-III dentro de 1,5 desviaciones estándar de un patrón de desarrollo cronológico de ref. evaluado a los 36 meses de edad.

E.2.2

Secondary objectives of the trial

Efficacy for patients with 2 copies of SMN2:
• Determine the efficacy of AVXS-101 based on survival, defined as avoidance of death or the requirement of permanent ventilation in the absence of acute illness or perioperatively as assessed at 14 months of age
• Assess efficacy of AVXS-101 by demonstrating the ability to maintain weight at or above the third percentile without need for non-oral/mechanical feeding support at any visit up to 18 months of age

Efficacy for patients with 3 copies of SMN2:
• Assess the efficacy of AVXS-101 by demonstrating the ability to walk alone defined as the ability to take at least five steps independently displaying coordination and balance at any visit up to 24 months of age

Eficacia en los pacientes con 2 copias del gen SMN2:

• Determinar la eficacia de AVXS-101 basándose en la supervivencia, definida como la evitación de la muerte o la necesidad de ventilación mecánica permanente en ausencia de enfermedad aguda o de manera perioperatoria, evaluada a los 14 meses de edad.
• Evaluar la eficacia de AVXS-101 mostrando la capacidad para mantener el peso corporal en el tercer percentil o por encima de este, sin necesidad de alimentación no oral/mecánica en cualquier visita hasta los 18 meses de edad.

Eficacia en los pacientes con 3 copias del gen SMN2:

• Evaluar la eficacia de AVXS-101 mostrando la capacidad para caminar solo, definida como la capacidad para dar un mínimo de cinco pasos de manera autónoma, exhibiendo coordinación y equilibrio, en cualquier visita hasta los 24 meses de edad.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All patients:
• Age ≤6 weeks (≤42 days) at time of dose
• Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test
• Compound muscle action potential (CMAP) ≥2 mV at Baseline
• Gestational age of 35 to 42 weeks
• Genetic diagnosis as described below, obtained from an acceptable newborn or pre-natal screening test method

Patients with 2 copies of SMN2
• Patients with pre-symptomatic SMA Type 1 as determined by the following features:
• Bi-allelic deletion of SMN1
• 2 copies of SMN2

Patients with 3 copies of SMN2
• Patients with pre-symptomatic SMA Type 2 as determined by the following features:
• Bi-allelic deletion of SMN1
• 3 copies of SMN2

Patients with 4 copies of SMN2
• Patients predominantly with pre-symptomatic SMA Type 3 as determined by the following features:
• Bi-allelic deletion of SMN1
• 4 copies of SMN2

Todos los pacientes:
• Edad ≤6 semanas (≤42 días) en el momento de la administración de la dosis.
• Capacidad de tolerar líquidos diluidos, demostrada mediante una prueba de deglución formal de diagnóstico inmediato.
• Potencial de acción muscular compuesto (PAMC) ≥2 mV en la visita basal; se llevará a cabo una revisión centralizada de los datos del PAMC
• Edad gestacional de 35 a 42 semanas
• Diagnóstico genético, tal y como se describe a continuación, obtenido a partir de un método aceptable de cribado prenatal o neonatal.

Pacientes con 2 copias del genSMN2
• Pacientes con AME tipo 1 presintomática determinada por las siguientes características:
- 2 copias del gen SMN2
- Delecion Bialelica de SMN1

Pacientes con 3 copias del genSMN2
• Pacientes con AME tipo 2 presintomática determinada por las siguientes características:
- 3 copias del gen SMN2
- Delecion Bialelica de SMN1

Pacientes con 4 copias del genSMN2:
• Pacientes con AME tipo 3 presintomática determinada por las siguientes características:
- 4 copias del gen SMN2
- Delecion Bialelica de SMN1

E.4

Principal exclusion criteria

• Weight at screening visit <2 kg
• Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or respiratory support) at the screening visit
• Any clinical signs or symptoms at screening or immediately prior to dosing that are, in the opinion of the Investigator, strongly suggestive of SMA (e.g., tongue fasciculation, hypotonia, areflexia)
• Tracheostomy or current prophylactic use or requirement of non invasive ventilatory support at any time and for any duration prior to screening or during the screening period
• Patients with signs of aspiration/inability to tolerate non thickened liquids based on a formal swallowing test performed as part of screening or patients receiving any non-oral feeding method
• Treatment with an investigational or commercial product, including nusinersen, given for the treatment of SMA. This includes any history of gene therapy, prior antisense oligonucleotide treatment, or cell transplantation.
• Patients whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards
• Serious non respiratory tract illness requiring systemic treatment and/or hospitalization within 2 weeks prior to screening
• Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 weeks prior to dosing
• Previous, planned or expected major surgical procedure including scoliosis repair surgery/procedure during the study assessment period
• Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 4 weeks prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab)
• Anti AAV9 antibody titer >1:50 as determined by Enzyme linked Immunosorbent Assay (ELISA) binding immunoassay

• Peso corporal en la visita de selección <2 kg.
• Hipoxemia (saturación de oxígeno <96 % durante el sueño o la vigilia sin oxígeno suplementario ni ventilación mecánica) en la visita de selección.
• Cualquier signo o síntoma clínico en la selección o inmediatamente antes de la administración que, en opinión del investigador, sea muy sugestivo de AME (p. ej., fasciculaciones linguales, hipotonía, arreflexia)
• Traqueotomía o uso profiláctico en curso o necesidad de ventilación mecánica no invasiva en cualquier momento y de cualquier duración antes de la selección o durante el período de selección.
• Pacientes con signos de aspiración/incapacidad para tolerar líquidos no espesos, sobre la base de una prueba de deglución formal realizada como parte de la selección, o pacientes que estén recibiendo alimentación no oral por cualquier método.
• Tratamiento para la AME con un producto en investigación o comercializado, por ejemplo, nusinersén. Entre los tratamientos para la AME se incluyen los antecedentes de terapia génica, tratamiento previo con oligonucleótidos antisentido o trasplante de células.
• Pacientes cuyo peso para la edad esté por debajo del tercer percentil según los patrones de crecimiento infantil de la Organización Mundial de la Salud (OMS)
• Enfermedad grave no respiratoria que requiera tratamiento sistémico u hospitalización en las 2 semanas previas a la selección.
• Infección de las vías respiratorias altas o bajas que precise atención médica, intervención médica o aumento del tratamiento complementario de cualquier manera en las 4 semanas anteriores a la administración.
• Intervención quirúrgica mayor previa, programada o prevista, incluida la corrección quirúrgica de la escoliosis, durante el período de evaluación del studio.
• Uso concomitante de cualquiera de los siguientes: fármacos para el tratamiento de miopatías o neuropatías, fármacos para tratar la diabetes mellitus o tratamiento inmunodepresor en curso, plasmaféresis, inmunomoduladores como adalimumab, tratamiento inmunodepresor en las 4 semanas previas a la terapia génica (p. ej., corticoesteroides, ciclosporina, tacrolimús, metotrexato, ciclofosfamida, inmunoglobulina i.v., rituximab).
• Título de anticuerpos anti-AAV9 >1:50 determinado por enzimoinmunoanálisis de adsorción (ELISA).

E.5 End points

E.5.1

Primary end point(s)

Criteria for Evaluation:
Safety:
Primary:
• Incidence of adverse events (AEs) and/or serious adverse events (SAEs)
• Change from baseline in clinical laboratory parameters

Efficacy objectives will be assessed independently for each cohort.

Efficacy for patients with 2 copies of SMN2:
Primary:
• Proportion of patients achieving the development milestone of functional independent sitting at any visit up to 18 months of age

Efficacy for patients with 3 copies of SMN2:
Primary:
• Proportion of patients achieving the ability to stand without support for at least three seconds at any visit up to 24 months of age

Efficacy for patients with 4 copies of SMN2:
Primary:
• Proportion of patients demonstrating the ability to achieve a scaled score on Bayley V.3 Gross and Fine Motor Subtests within 1.5 standard deviations of chronological development reference standard as assessed at 36 months of age

Criterios de evaluación:
Seguridad:
Principal:
• Incidencia de acontecimientos adversos (AA) y acontecimientos adversos graves (AAG).
• Cambio con respecto al valor basal en los resultados de los análisis clínicos.
Los objetivos de la eficacia se evaluarán de manera independiente en cada cohort

Eficacia en los pacientes con 2 copias del gen SMN2:
Principal:
• Proporción de pacientes que alcanzan el hito de desarrollo de sedestación independiente funcional en cualquier visita hasta los 18 meses de edad.

Eficacia en los pacientes con 3 copias del gen SMN2:
Principal:
• Proporción de pacientes que consiguen quedarse de pie sin ayuda durante un mínimo de tres segundos en cualquier visita hasta los 24 meses de edad

Eficacia en los pacientes con 4 copias del gen SMN2:
Principal:
• Proporción de pacientes con la capacidad para lograr una puntuación transformada en las subescalas de motricidad fina y general de las Escalas Bayley de desarrollo infantil-III dentro de 1,5 desviaciones estándar de un patrón de desarrollo cronológico de referencia evaluado a los 36 meses de edad.

E.5.1.1

Timepoint(s) of evaluation of this end point

Patients with 2 copies of SMN2:
18 months of age
Patients with 3 copies of SMN2:
24 months of age
Patients with 4 copies of SMN2:
36 months of age

Pacientes con 2 copias de SMN2:
18 meses de edad
Pacientes con 3 copias de SMN2:
24 meses de edad
Pacientes con 4 copias de SMN2:
36 meses de edad

E.5.2

Secondary end point(s)

Patients with 2 copies of SMN2:
• Proportion of patients that have survived and have not required permanent ventilation in the absence of acute illness or perioperatively assessed at 14 months of age
• Proportion of patients that have achieved the ability to maintain weight at or above the third percentile without need for non-oral/mechanical feeding support at any visit up to 18 months of age

Patients with 3 copies of SMN2:
• Proportion of patients demonstrating the ability to walk alone defined as the ability to take at least five steps independently displaying coordination and balance at any visit up to 24 months of age

Patients with 4 copies of SMN2:
Not Applicable

Pacientes con 2 copias de SMN2:
• Proporción de pacientes que han sobrevivido y no han necesitado ventilación mecánica permanente en ausencia de enfermedad aguda o de forma perioperatoria a los 14 meses de edad.
• Proporción de pacientes que logran mantener el peso corporal en el tercer percentil o por encima de este, sin necesidad de alimentación no oral/mecánica en cualquier visita hasta los 18 meses de edad

Pacientes con 3 copias de SMN2:
• Proporción de pacientes que logran la capacidad de caminar solos, definida como la capacidad para dar un mínimo de cinco pasos de manera autónoma, exhibiendo coordinación y equilibrio, en cualquier visita hasta los 24 meses de edad.

Pacientes con 4 copias de SMN2:

No aplica.

E.5.2.1

Timepoint(s) of evaluation of this end point

Patients with 2 copies of SMN2:
• Proportion of patients that have survived and have not required permanent ventilation assessed at 14 months of age
• Proportion of patients that have achieved the ability to maintain weight at or above the third percentile without need for non-oral/mechanical feeding support at any visit up to 18 months of age

Patients with 3 copies of SMN2:
• 24 months of age

Patients with 4 copies of SMN2:
Not Applicable

Pacientes con 2 copias de SMN2:
• Proporción de pacientes que han sobrevivido y no han necesitado ventilación mecánica permanente en ausencia de enfermedad aguda o de forma perioperatoria a los 14 meses de edad.
• Proporción de pacientes que logran mantener el peso corporal en el tercer percentil o por encima de este, sin necesidad de alimentación no oral/mecánica en cualquier visita hasta los 18 meses de edad.

Pacientes con 3 copias de SMN2:
• 24 meses de edad.

Pacientes con 4 copias de SMN2:

No aplica.

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

E.6.7

Pharmacodynamic

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)

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.7.1

Other trial design description

Open-label, single-arm, single-dose

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.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

Australia

Belgium

Canada

Germany

Israel

Italy

Japan

Korea, Democratic People's Republic of

Netherlands

Spain

Taiwan

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

Ultima visita ultimo paciente

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)

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

F.3.3.1

Women of childbearing potential not using contraception