Clinical Trials Register

Summary
EudraCT Number:	2020-002372-13
Sponsor's Protocol Code Number:	SRP-9001-303
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2022-10-11
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2020-002372-13

A.3

Full title of the trial

A Phase 3, Multinational, Randomized, Double-Blind, Placebo-Controlled Systemic Gene Transfer Therapy Study to Evaluate the Safety and Efficacy of SRP-9001 in Non-Ambulatory and Ambulatory Subjects With Duchenne Muscular Dystrophy (ENVISION)

A.3.1

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

Study to evaluate the Safety and Efficacy of SRP-9001 in non ambulatory and ambulatory Subjects with Duchenne Muscular Dystrophy

A.3.2

Name or abbreviated title of the trial where available

ENVISION

A.4.1

Sponsor's protocol code number

SRP-9001-303

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT05881408

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/052/2022

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Sarepta Therapeutics, 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	Sarepta Therapeutics, 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	Sarepta Therapeutics, Inc.
B.5.2	Functional name of contact point	Patient Recruitment
B.5.3	Address:
B.5.3.1	Street Address	215 First Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02142
B.5.3.4	Country	United States
B.5.4	Telephone number	+1888 727 3782
B.5.6	E-mail	SareptaAlly@sarepta.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/3/20/2250
D.3 Description of the IMP
D.3.2	Product code	SRP-9001
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	Delandistrogene moxeparvovec
D.3.9.1	CAS number	2305040-16-6
D.3.9.2	Current sponsor code	SRP-9001
D.3.9.3	Other descriptive name	adeno-associated virus serotype rh74 containing the human micro-dystrophin gene
D.3.9.4	EV Substance Code	SUB197789
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	1.33 x 10^13
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Duchenne Muscular Dystrophy

E.1.1.1

Medical condition in easily understood language

Duchenne Muscular Dystrophy

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	10052655
E.1.2	Term	Duchenne muscular dystrophy gene carrier
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10013801
E.1.2	Term	Duchenne muscular dystrophy
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 evaluate the effect of SRP-9001 on physical function in Part 1 as assessed by the Performance Upper Limb (PUL) (Version 2.0 [V2.0])

E.2.2

Secondary objectives of the trial

To evaluate the effect of SRP-9001 on respiratory function in Part 1 as assessed by:
o Forced vital capacity (FVC) percent predicted
o Peak expiratory flow (PEF) percent predicted

To evaluate micro-dystrophin expression from SRP-9001 at 12 weeks (Part 1) as measured by western blot of biopsied muscle tissue

To evaluate subject and parent/caregiver proxy reported Upper Extremity Function, using the Patient-Reported Outcomes Measurement Information System (PROMIS®) tool

To evaluate the safety of SRP-9001

For Cohort 2 only: To evaluate the effect of SRP-9001 on physical function as assessed by the North Star Ambulatory assessment (NSAA) score

To evaluate cardiac strain over time by cardiac magnetic resonance imaging (cMRI)

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Select sites will participate in a musculoskeletal sub-study to undergo musculoskeletal imaging
assessments at the time points indicated in Section 3.3. A musculoskeletal MRI will be
performed to evaluate the structure and function of skeletal muscles as well as lean body mass.

A subset of subjects will have a muscle biopsy performed at Week 12.
The biopsy will be of the biceps muscle, preferably on the left arm. If the biceps muscle is not viable, prior approval from the Sponsor is required for using an alternate muscle of the upper extremity.

A subset of parents/caregivers will be invited to participate in a qualitative interview sub-study
which will involve a pre-interview questionnaire and a 60-minute telephone interview after the
Part 1 Week 72 (or early termination from Part 1) visit to provide a better understanding of
individuals’ experiences with DMD and the study drug and identify potential improvements with
the study drug. Participants must be willing and able to participate in qualitative semi-structured
interviews. The interviews will be conducted by trained interviewers from RTI Health Solutions
or their qualitative research partner following a semi structured interview guide

E.3

Principal inclusion criteria

A subject must meet the following criteria to be eligible to participate in this study:

1. Is male at birth and has a definitive diagnosis of DMD prior to Screening based on documentation of clinical findings and prior confirmatory genetic testing using a clinical diagnostic genetic test. Genetic report must describe a frameshift deletion, frameshift duplication, premature stop (“nonsense”), canonical splice mutation, or other pathogenic variant in the DMD gene fully contained between exons 18 to 79 (inclusive) that is expected to lead to complete absence of dystrophin protein.
• Mutations fully or partially contained within exons 1-17 (inclusive) are not eligible.

2. Cohort 1 only (non-ambulatory):
a. Has been non-ambulatory for a minimum of 6 months with onset of non-ambulatory status defined as participant- or caregiver-reported age at continuous wheelchair use, approximated to the nearest month, with an NSAA walk score of "0" and inability to perform the 10MWR at the Screening visit.
b. Has a PUL entry item score ≥ 2 at the Screening visit.
c. Has a total PUL score of ≥ 20 and ≤ 40 at the Screening visit.

3. Cohort 2 only (ambulatory ≥ 8 years to < 18 years of age):
a. ≥ 8 to < 18 years of age at the time of Screening.
b. Has a PUL entry item score > 3 and < 6 at the Screening visit.
c. Has a total PUL score of ≥ 20 and ≤ 40 at the Screening visit.
d. Has an NSAA score ≥ 12 and ≤ 26 at the Screening visit.

4. Able to cooperate with motor assessment testing.

5. Has been on a stable dose of oral corticosteroids for at least 12 weeks before Screening and the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study. Note that no use of corticosteroids is considered a stable dose (ie, 0 mg).

6. Has rAAVrh74 antibody titers < 1:400 (ie, not elevated) as determined by an ELISA.

7. Subjects who are sexually active must agree to use, for the entire duration of the study, a condom and the female sexual partner must also use a medically acceptable form of birth control (eg, oral contraceptive). Refer to Appendix 1 for guidance on highly effective contraceptive methods.

8. Has (a) parent(s) or legal caregiver(s) or is a subject who is ≥ 18 years of age who is (are) able to understand and comply with the study visit schedule and all other protocol requirements.

9. Is willing to provide informed assent or consent (if applicable) and has (a) parent(s) or legal guardian(s) or is a subject ≥18 years of age who is (are) willing to provide informed consent for the subject to participate in the study.

E.4

Principal exclusion criteria

A subject who meets any of the following criteria will be excluded from this study:

1. Has left ventricular ejection fraction < 40% on the Screening ECHO or clinical signs and/or symptoms of cardiomyopathy.

2. Forced vital capacity < 40% of predicted value at Screening.

3. Major surgery within 3 months prior to Day 1 or planned surgery or procedure that would interfere with the conduct of the study for any time during this study.

4. Presence of any other clinically significant illness, including cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or infection or malignancy or concomitant illness or requirement for chronic drug treatment that in the opinion of the Investigator creates unnecessary risks for gene transfer therapy or a medical condition or extenuating circumstance that, in the opinion of the Investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability.

5. Has serological evidence of current, chronic, or active human immunodeficiency virus, hepatitis C, or hepatitis B infection.

6. Has a symptomatic infection (eg, upper respiratory tract infection, pneumonia, pyelonephritis, meningitis) within 4 weeks prior to Day 1.

7. Demonstrates cognitive delay or impairment that could confound motor development in the opinion of the Investigator.

8. Treatment with any of the following therapies according to the time frames specified:
• Any time:
− Gene therapy
− Cell based therapy (eg, stem cell transplantation)
− CRISPR/Cas9, or any other form of gene editing
• Within 12 weeks of Day 1 and anytime during the study:
− Use of human growth factor or vamorolone
• Within 6 months of Day 1 and anytime during the study:
− Any investigational medication
− Any treatment designed to increase dystrophin expression (eg, Translarna™, EXONDYS 51™, VILTEPSO™)

9. Has received a live virus vaccine within 4 weeks or inactive vaccine within 2 weeks of the Day 1 visit or expects to receive a vaccination during the first 3 months after Day 1.

10. Has abnormal laboratory values considered clinically significant including but not limited
to:
• Gamma-glutamyl transferase (GGT) > 2 × ULN
• Glutamate dehydrogenase (GLDH) >15 U/L
• Total bilirubin > ULN. Note that elevations in total bilirubin confirmed to be due toGilbert's syndrome are not exclusionary.
• White blood cell count > 18,500 per µL
• Platelets ≤ 150,000 per µL

11. Has a known hypersensitivity to SRP-9001 or its excipients

12. Subject or family does not want to disclose subject’s study participation with general practitioner/primary care physician and other medical providers.

13. In the opinion of the Investigator, the subject is not likely to be compliant with the study protocol.

E.5 End points

E.5.1

Primary end point(s)

Change in PUL (V2.0) total score

E.5.1.1

Timepoint(s) of evaluation of this end point

From Baseline to Week 72 (Part 1)

E.5.2

Secondary end point(s)

•Change in PEF% predicted from Baseline to Week 72 (Part 1)
•Change in FVC% predicted from Baseline to Week 72 (Part 1)
•The quantity of micro-dystrophin protein expression at Week 12 (Part 1) as measured by western blot
•Change in PROMIS score per domain from Baseline to 72 weeks (Part 1)
For Cohort 2 only •Change in the NSAA score from Baseline to
Week 72 (Part 1) and Week 52 (Part 2)
•Incidence of treatment-emergent adverse events (TEAEs)
•Incidence of adverse events of special interest (AESIs)
•Clinically significant changes in vital signs and physical examination findings
•Incidence of serious adverse events (SAEs)
•Clinically significant changes in safety laboratory assessments, electrocardiograms (ECGs), echocardiograms (ECHOs)
•Change in global circumferential strain from baseline to Week 72 (Part 1).

E.5.2.1

Timepoint(s) of evaluation of this end point

•Change in PEF% predicted from Baseline to Week 72 (Part 1)
•Change in FVC% predicted from Baseline to Week 72 (Part 1)
•Quantity of micro-dystrophin protein expression at Week 12 (Part 1) as measured by western blot
•Change in PROMIS score per domain from Baseline to 72 weeks (Part 1)
For Cohort 2 only •Change in the NSAA score from Baseline to Week 72 (Part 1)
•Incidence of treatment-emergent adverse events
•Incidence of adverse events of special interest
•Clinically significant changes in vital signs and physical examination findings
•Incidence of serious adverse events
•Clinically significant changes in safety laboratory assessments, electrocardiograms (ECGs), echocardiograms (ECHOs)
•Change in global circumferential strain from baseline to Week 72 (Part 1).

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

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

E.8.1.6

Cross over

Yes

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

Yes

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.8.5

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

Israel

Japan

United Kingdom

United States

Belgium

France

Germany

Italy

Spain

Sweden

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

Last Patient Last Visit

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:

111

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)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

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

Patients who are ≥ 8 to < 18 years of age at the time of randomization.

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

148

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)

After completion of the Part 2 Week 52 assessments, subjects will be eligible to enroll into an extension study to assess long-term safety and efficacy. All subjects will be followed for long-term safety and efficacy in the extension study for at least 5 years after SRP-9001 infusion.

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

2023-09-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2023-02-09

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

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