Clinical Trials Register

Summary
EudraCT Number:	2020-005995-37
Sponsor's Protocol Code Number:	COAV101A12306
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-06-21
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

France - ANSM

A.2

EudraCT number

2020-005995-37

A.3

Full title of the trial

A Phase lllb, open-label, single-arm, single-dose, multicenter study to evaluate the safety, tolerability and efficacy of gene replacement therapy with intravenous OAV101 (AVXS-101) in pediatric patients with spinal muscular atrophy (SMA)

Etude de phase IIIb, multicentrique, en ouvert, à un seul bras, évaluant la sécurité d’emploi, la tolérance, et l’efficacité d’une dose unique de thérapie génique par OAV101 (AVXS-101), administrée par voie intraveineuse, chez des patients pédiatriques atteints d’amyotrophie spinale

A.3.1

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

Safety and Efficacy of Intravenous OAV101 (AVXS-101) in Pediatric Patients With Spinal Muscular Atrophy (SMA) (SMART)

Sécurité et efficacité d'OAV101 (AVXS-101) administrée par voie intraveineuse, chez des patients pédiatriques atteints d’amyotrophie spinale (SMART)

A.3.2

Name or abbreviated title of the trial where available

SMART

A.4.1

Sponsor's protocol code number

COAV101A12306

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04851873

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	Novartis Pharma AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma SAS
B.5.2	Functional name of contact point	Information&Communication Médicales
B.5.3	Address:
B.5.3.1	Street Address	8/10 rue Henri Sainte-Claire Deville
B.5.3.2	Town/ city	Rueil Malmaison Cedex
B.5.3.3	Post code	92500
B.5.3.4	Country	France
B.5.4	Telephone number	+33 1 5547 6600
B.5.5	Fax number	+33 15547 6100
B.5.6	E-mail	icm.phfr@novartis.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	Zolgensma
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Gene Therapies EU Limited
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	EMA/OD/028/15
D.3 Description of the IMP
D.3.1	Product name	OAV101
D.3.2	Product code	AVXS-101
D.3.4	Pharmaceutical form	Solution for 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	OAV101
D.3.9.3	Other descriptive name	previously termed sc.AAV9.CB.SMN and AVXS-101
D.3.9.4	EV Substance Code	SUB193254
D.3.10	Strength
D.3.10.1	Concentration unit	vector genomes (vg)/mL
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	20000000000000
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)	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	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

Spinal Muscular Atrophy

Amyotrophie spinale

E.1.1.1

Medical condition in easily understood language

Spinal Muscular Atrophy

Amyotrophie spinale

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	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

To assess the safety and tolerability of IV OAV101 over a 12-month period in participants with SMA weighing ≥ 8.5 kg and ≤ 21 kg

Evaluer pendant une période de 12 mois la sécurité d’emploi et la tolérance d’OAV101 administré par voie IV chez des patients atteints d’amyotrophie spinale pesant entre ≥ 8,5 kg et ≤ 21 kg

E.2.2

Secondary objectives of the trial

To determine the efficacy of IV OAV101 at 6 and 12 months post dose in participants with SMA weighing ≥ 8.5 kg and ≤ 21 kg as measured by change from baseline in:
· Developmental motor milestone achievement as assessed by World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) and Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III) criteria
· Hammersmith Functional Motor Scale - Expanded (HFMSE)
· Revised Upper Limb Module (RULM), as appropriate according to participant age

Evaluer l’efficacité d’OAV101, 6 et 12 mois après son administration chez des patients atteints d’amyotrophie spinale pesant entre ≥ 8,5 kg et ≤ 21 kg
· Atteinte des étapes de développement moteur selon les critères MGRS de l’Organisation mondiale de la Santé [OMS] (WHO-MGRS, World Health Organization-Multicentre Growth Reference Study) et les critères de la troisième édition de l’échelle de Bayley pour le développement des nourrissons et des enfants (Bayley-III)
• Variation par rapport à la Baseline de l’échelle étendue de la fonction motrice d’Hammersmith (HFMSE, Hammersmith Functional Motor Scale-Expanded)
• Variation par rapport à la Baseline du score du module révisé des membres supérieurs (RULM, Revised Upper Limb Module), le cas échéant, en fonction de l’âge des patients

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Symptomatic SMA diagnosis based on gene mutation analysis with bi-allelic survival motor neuron 1 (SMN1) mutations (deletion or point mutations) and any copy of the survival motor neuron 2 (SMN2) gene.
Weight ≥ 8.5 kg and ≤ 21 kg at the time of Screening Visit 2
Naive to treatment or have discontinued an approved drug/therapy

other protocol-defined inclusion criteria may apply

Patient atteint d’amyotrophie spinale symptomatique diagnostiquée par l’analyse de mutations génétiques : les deux allèles du gène SMN1 doivent être porteurs de mutations (ponctuelles ou délétions), quel que soit le nombre de copies du gène SMN2
Patient ayant un poids compris entre ≥ 8,5 kg et ≤ 21 kg au moment de la Visite de Sélection
Patient naïf de tout traitement de l’amyotrophie spinale ou ayant arrêté un médicament/traitement autorisé

d'autres critères d'inclusion définis par le protocole peuvent s'appliquer

E.4

Principal exclusion criteria

Previous OAV101 use or previous use of any AAV9 gene therapy
Body Mass Index (BMI) < 3rd percentile based on World Health Organization (WHO) Child Growth Standard
Participant with history of aspiration pneumonia or signs of aspiration (eg, coughing or sputtering of food) within 4 weeks prior to screening
Anti-Adeno-associated virus serotype 9 (AAV9) antibody titer > 1:50 as determined by ligand binding immunoassay at the time of screening
History of gene therapy, hematopoietic transplantation, or solid organ transplantation

other protocol-defined exclusion criteria may apply

Utilisation antérieure d’OAV101 ou de toute autre thérapie génique basée sur AAV9
Indice de masse corporelle < 3ème percentile selon les normes de croissance de l’enfant de l’Organisation mondiale de la Santé
Antécédents de pneumonie d’inhalation ou signes d’inhalation (par ex. toux ou crachats de nourriture) au cours des 4 semaines précédant la Sélection
Titre d’anticorps anti-AAV9 > 1:50, déterminé au moment de la Sélection à l’aide d’un test immunologique de liaison de ligand
Antécédent de thérapie génique, de greffe de moelle osseuse ou de transplantation d’organe

d'autres critères d'exclusion définis par le protocole peuvent s'appliquer

E.5 End points

E.5.1

Primary end point(s)

Number of participants with treatment emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.

Number of participants with important identified and important potential risks (Adverse Events of Special Interest (AESI)) The following are important identified and important potential risks (AESI) associated with OAV101: Hepatotoxicity, Thrombocytopenia, Cardiac adverse events, Sensory abnormalities suggestive of ganglionopathy, and Thrombotic microangiopathy. These will be assessed by the investigator.

Change from baseline in vital signs measurements - systolic and diastolic blood pressure (mmHg)

Change from baseline in vital signs measurements - respiratory rate (breaths per minute)

Change from baseline in vital signs measurements - pulse (beats per minute)

Change from baseline in vital signs measurements - temperature (degrees Celsius)

Change from baseline in vital signs measurements - oxygen saturation level (%)

Nombre de participants ayant un évènements indésirables graves et non graves survenant sous traitement. Un évènements indésirables est tout événement médical (par exemple, tout signe défavorable et involontaire [y compris les résultats de laboratoire anormaux], symptôme ou maladie) chez un participant à un essai clinique après avoir fourni un consentement éclairé écrit pour la participation à l'étude.

Nombre de participants présentant des risques importants identifiés et potentiels importants (Evénements indésirables d'intérêt particulier (AESI)). Les éléments suivants sont des risques importants identifiés et potentiels importants (AESI) avec OAV101:
Hépatotoxicité, thrombocytopénie, événement indésirable cardiaques, anomalies sensorielles évocatrices d'une ganglionopathie et microangiopathie thrombotique. Ils seront évalués par l'investigateur.

Changement dans les mesures des signes vitaux - pression artérielle systolique et diastolique (mmHg)

Changement par rapport à la ligne de base dans les mesures des signes vitaux - fréquence respiratoire (respirations par minute)

Changement dans les mesures des signes vitaux - pouls (battements par minute)

Changement dans les mesures des signes vitaux - température (degrés Celsius)

Changement dans les mesures des signes vitaux - niveau de saturation en oxygène (%)

E.5.1.1

Timepoint(s) of evaluation of this end point

up to 12 months

jusqu'à 12 mois

E.5.2

Secondary end point(s)

Achievement of development motor milestones according to the Bayley Scale of Infant and Toddler Development.
Developmental motor milestones are assessed via the developmental milestone checklist, formed of 10 yes/no questions with optional video documentation. The developmental milestones are: head control, sitting with support, sitting without support, sitting without support for 30 seconds, hands-and-knees crawling, pulls to stand, standing with assistance, walking with assistance, standing alone and walking alone. A yes response indicates that the patient reached a particular development milestone.

Change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE), as appropriate according to participant age
The HFMSE was devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE is formed of 33 assessments rated from 0 (unable to perform functional task) to 2 (able to perform functional task unassisted). Higher scores indicated higher levels of motor ability.

Change from baseline in Revised Upper Limb Module (RULM), as appropriate according to participant age.
The RULM assesses motor performance in the upper limbs from childhood through adulthood in ambulatory and non-ambulatory individuals with SMA. 'The scale consists of an entry item to establish functional levels and 19 items covering distal to proximal movements. The entry item is a modified version of the Brooke scale, including activities ranging from no functional use of hands (score 0) to full bilateral shoulder abduction (score 6). The entry item does not contribute to the total score but serves as a functional classification of overall upper limb functional ability. Of the remaining 19 items, 18 are scored on a 3 point scoring system and 1 item is scored on a 2 point scoring system. The test is performed unilaterally using the limb preferred by the participant. The total score ranges from 0, if all the items cannot be performed, to 37, if all the activities are achieved fully without any compensation. ' Higher scores indicate higher levels of motor ability.

Atteinte des jalons du développement moteur selon l'échelle de Bayley pour le développement du nourrisson et du tout-petit. Les jalons moteurs du développement sont évalués via une liste composée de 10 questions oui/non avec une documentation vidéo facultative. Les jalons du développement sont : tenir la tête droite, s’asseoir avec un léger soutien, se tenir assis sans soutien, s’asseoir sans soutien 30 secondes, se déplacer à quatre pattes, se mettre debout, se tenir debout avec l’aide de quelqu’un, marcher avec l’aide de quelqu’un, se tenir debout seul et marcher seul(e). Une réponse oui indique que le patient a atteint une étape de développement particulière.

Changement de l'échelle de motricité fonctionnelle Hammersmith - Étendue (HFMSE), selon l'âge des participants. Le HFMSE a été conçu pour être utilisé chez les enfants atteints d’amyotrophie spinale afin de fournir des informations objectives sur la capacité motrice et la progression clinique. Le HFMSE est composé de 33 évaluations notées de 0 (incapable d'effectuer une tâche fonctionnelle) à 2 (capable d'effectuer une tâche fonctionnelle sans assistance). Des scores plus élevés indiquent des niveaux plus élevés de capacité motrice.

Changement dans le module révisé des membres supérieurs (RULM), le cas échéant en fonction de l'âge des participants.
Le RULM évalue les performances motrices des membres supérieurs de l'enfance à l'âge adulte chez les personnes ambulatoires et non ambulatoires atteintes d'amyotrophie spinale. «L'échelle se compose d'un élément d'entrée pour établir les niveaux fonctionnels et de 19 éléments couvrant les mouvements distaux à proximaux. L'item d'entrée est une version modifiée de l'échelle de Brooke, comprenant des activités allant de l'absence d'utilisation fonctionnelle des mains (score 0) à l'abduction bilatérale complète de l'épaule (score 6). L'élément d'entrée ne contribue pas au score total mais sert de classification fonctionnelle de la capacité fonctionnelle globale des membres supérieurs. Sur les 19 éléments restants, 18 sont notés sur un système de notation à 3 points et 1 élément est noté sur un système de notation à 2 points. Le test est effectué unilatéralement en utilisant le membre préféré du participant. Le score total va de 0, si tous les éléments ne peuvent pas être exécutés, à 37, si toutes les activités sont réalisées pleinement sans aucune compensation. Des scores plus élevés indiquent des niveaux plus élevés de capacité motrice

E.5.2.1

Timepoint(s) of evaluation of this end point

up to 12 months

jusqu'à 12 mois

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

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

Tolérance

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

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

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

Canada

Taiwan

United States

Belgium

France

Germany

Italy

Portugal

Spain

Switzerland

United Kingdom

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

Study completion is defined as when the last participant finishes their Study Completion visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision.

La fin de l'étude est atteinte lorsque le dernier participant termine sa dernière visite de l'étude et que toutes les évaluations associées à cette visite ont été documentées et suivies de manière appropriée par l'investigateur ou dans le cas d'une décision d'arrêt précoce de l'étude, la date de cette décision .

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)

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

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

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)

None

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

2021-08-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-07-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-06-13

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