Clinical Trials Register

Summary
EudraCT Number:	2021-003474-31
Sponsor's Protocol Code Number:	COAV101B12301
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-09-15
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

Greece - EOF

A.2

EudraCT number

2021-003474-31

A.3

Full title of the trial

A randomized, sham-controlled, double-blind study to evaluate the efficacy and safety of intrathecal (IT) OAV101 in patients with later onset Type 2 spinal muscular atrophy (SMA) who are ≥ 2 to < 18 years of age, treatment naive, sitting, and never ambulatory

Μία τυχαιοποιημένη, διπλά τυφλή μελέτη με ομάδα εικονικής παρέμβασης με σκοπό την αξιολόγηση της αποτελεσματικότητας και της ασφάλειας του ενδορραχιαία (ΕΡ) χορηγούμενου OAV101 σε ασθενείς με όψιμη έναρξη νωτιαίας μυικής ατροφίας τύπου 2, ηλικίας ≥ 2 έως < 18 ετών, οι οποίοι δεν έχουν λάβει θεραπεία, είναι ικανοί να παραμείνουν σε καθιστή θέση και δεν υπήρξαν ποτέ περιπατητικοί

A.3.1

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

Safety and efficacy of Intrathecal OAV101 in Pediatric Patients with Spinal Muscular Atrophy (SMA) (STEER)

A.3.2

Name or abbreviated title of the trial where available

STEER

A.4.1

Sponsor's protocol code number

COAV101B12301

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/015/2022

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 (Hellas) S.A.C.I.
B.5.2	Functional name of contact point	Medical information Desk
B.5.3	Address:
B.5.3.1	Street Address	National Road No 1 (12th km)
B.5.3.2	Town/ city	Metamorphosis, Athens
B.5.3.3	Post code	GR-144 51
B.5.3.4	Country	Greece
B.5.4	Telephone number	+30 2102816415
B.5.5	Fax number	+30 2102850590
B.5.6	E-mail	medinfo.gr@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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Yes
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	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	equal
D.3.10.3	Concentration number	40000000000000
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	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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Okrido 6mg/mL oral solution
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharmapol Arzneimittelvertrieb-GmbH
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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.3.1	Product name	Okrido
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PREDNISOLONE SODIUM PHOSPHATE
D.3.9.1	CAS number	125-02-0
D.3.9.2	Current sponsor code	prednisolone
D.3.9.3	Other descriptive name	PREDNISOLONE SODIUM PHOSPHATE
D.3.9.4	EV Substance Code	SUB04018MIG
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	6
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	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

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

E.1.1.1

Medical condition in easily understood language

Spinal Muscular Atrophy

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 compare the efficacy of OAV101 IT vs. sham control as measured by the change from baseline in Hammersmith Functional Motor Scale- Expanded (HFMSE) total score.

E.2.2

Secondary objectives of the trial

- To compare the efficacy of OAV101 IT vs. sham control in two patient age groups: ≥ 2 to < 5 years (HFMSE, Revised Upper Limb Module (RULM)); ≥ 2 to < 18 years (RULM)
- To evaluate the safety and tolerability of OAV101 IT vs. sham control in patients ≥ 2 to < 18 years)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Diagnostic confirmation during screening period of 5q SMA
- The patient must be treatment naive (historical or current use) for all SMN-targeting therapies (e.g., risdiplam (Evrysdi) and nusinersen (Spinraza)).
- ≥ 2 years and < 18 years of age at screening visit 1
- Onset of clinical signs and symptoms at ≥ 6 months of age
- Patient must have a complete HFMSE assessment with an available total score, as administered by qualified clinical evaluator during the screening period for trial eligibility
- Able to sit independently at screening, but has never had the ability to walk independently.
- Estimated life expectancy > 2 years from screening, in the opinion of the Investigator
- Meets age-appropriate institutional criteria for use of anesthesia/sedation as assessed by the physician responsible for administering anesthesia/sedation

(Full list of inclusion criteria can be found in the clinical protocol Section 5.1)

E.4

Principal exclusion criteria

- Excluding SMA, any medical condition considered clinically significant by the Investigator, including cardiomyopathy, hepatic dysfunction, kidney disorder, endocrine disorder including diabetes
mellitus, gastrointestinal disorders, metabolic disorders, untreated B6 deficiency, severe respiratory compromise and significant brain abnormalities at either Screening or Baseline that, in the opinion of the investigator, would interfere with the overall interpretation of safety or efficacy of the study.
- Anti-AAV9 antibody titers >1:50 at Screening as determined by ligand binding immunoassay. NOTE: A negative anti-AAV9 antibody titer is defined as ≤1:50.
- Clinically significant abnormalities in test results during screening period and/or during baseline period as determined by the Investigator
- Participants will be excluded from the trial for inpatient surgery hospitalization, hospitalization for a pulmonary event, or hospitalization for nutritional support within 2 months prior to Screening and up to Day 1. In addition, patients will not be eligible for the trial if at Screening, inpatient major surgery is planned at any time during the 64-week study. Any other surgeries must not interfere with the ability of the patient to perform the study assessments.
- Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts the participant's ability to perform any of the outcome measure testing required in the protocol and from which the participant has not fully recovered or achieved a stable baseline upon entry into screening period
- Contraindications for lumbar puncture procedure, (including but not limited to cutaneous infection at the treatment site and signs or symptoms of increased intracranial pressure), active administration of any intrathecal therapy, presence of an implanted shunt for the drainage of CSF, presence of an implanted central nervous system (CNS) catheter, or any impediment to CSF access.

(Full list of exclusion criteria can be found in the clinical protocol Section
5.2)

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in HFMSE total score at the end of Follow-up Period 1 (defined in Section 12.4.1 of the clinical protocol) in the overall study population (≥ 2 to < 18 years age group)

E.5.1.1

Timepoint(s) of evaluation of this end point

up to 12 months

E.5.2

Secondary end point(s)

- Change from baseline in HFMSE total score at the end of Follow-up Period 1 in the ≥ 2 to < 5 years age group
- Achievement of at least a 3-point improvement from baseline in HFMSE total score at the end of Follow-up Period 1 in the overall study population
- Achievement of at least a 3-point improvement from baseline in HFMSE total score at the end of Follow-up Period 1 in the ≥ 2 to < 5 years age group
- Change from baseline in RULM at the end of Follow-up Period 1 in the ≥ 2 to < 18 years age group
- Change from baseline in the RULM at the end of Follow-up Period 1 in the ≥ 2 to < 5 years age group
- Incidence of treatment emergent adverse events (TEAEs) and serious TEAEs (SAEs)
- Number of participants with adverse events of special interest (AESIs)
- Evaluation of changes from baseline in vital signs, physical/neurological examinations, laboratories (chemistry, hematology, liver function tests), echocardiogram, ECG, anthropometry, and C-SSRS
- Number (and percentage) of patients with intracardiac thrombi
- Number(and percentage) of patients with low cardiac function
- Evaluation of vector shedding in treated patients.

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 12 months

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

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

E.8.2.3.1

Comparator description

Sham-procedure

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

Brazil

China

Colombia

Egypt

India

Malaysia

Mexico

Saudi Arabia

Singapore

South Africa

Taiwan

Thailand

United Arab Emirates

United States

Viet Nam

Greece

Italy

Denmark

Russian Federation

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.

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:

125

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

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

125

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)

At the end of study all participants will be eligible to enroll in a long-term follow-up study (15 years) to monitor long-term safety and efficacy.

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

2023-01-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-12-15

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

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