Clinical Trials Register

Summary
EudraCT Number:	2019-000601-77
Sponsor's Protocol Code Number:	5051-201
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2019-11-25
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

Netherlands - Competent Authority

A.2

EudraCT number

2019-000601-77

A.3

Full title of the trial

A Phase 2, Two-Part, Multiple-Ascending-Dose Study of SRP-5051 for Dose Determination, then Dose Expansion, in Patients with Duchenne Muscular Dystrophy Amenable to Exon 51-Skipping Treatment

A.3.1

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

A research study of a new investigational medicinal product for the treatment of Duchenne Muscular Dystrophy patients

A.4.1

Sponsor's protocol code number

5051-201

A.5.4

Other Identifiers

Name:

IND

Number:

134648

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	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	1-888-SAREPTA (1-888-727-3782)
B.5.6	E-mail	clinicaltrials@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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Vesleteplirsen
D.3.2	Product code	SRP-5051
D.3.4	Pharmaceutical form	Lyophilisate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
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	Vesleteplirsen
D.3.9.1	CAS number	2101569-97-3
D.3.9.2	Current sponsor code	SRP-5051
D.3.9.3	Other descriptive name	peptide-conjugated phosphorodiamidate morpholino oligomer for exon 51 skipping
D.3.9.4	EV Substance Code	SUB197949
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	50
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

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 is a rare, fatal degenerative neuromuscular disease with an X-linked recessive inheritance caused by mutations in the dystrophin gene

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.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part A:
To evaluate the safety and tolerability of multiple ascending doses of SRP-5051 (4 mg/kg, 10 mg/kg, 20 mg/kg, and 30 mg/kg), administered intravenously (IV) every 4 weeks, and determine the maximum tolerated dose (MTD)

Part B
To evaluate dystrophin protein level in skeletal muscle tissue following SRP-5051 treatment, administered IV every 4 weeks at the doses selected based on data from Part A

E.2.2

Secondary objectives of the trial

Part A
To determine the pharmacokinetics (PK) of SRP-5051 in plasma and urine, and of the major metabolite SRP-5051A in plasma, at each of the aforementioned multiple ascending doses of SRP-5051, administered IV every 4 weeks

Part B
• To evaluate exon-skipping level in skeletal muscle tissue following SRP-5051 treatment, administered IV every 4 weeks at the doses selected based on data from Part A
• To evaluate the ongoing safety and tolerability of SRP-5051 treatment, administered IV every
4 weeks at the doses selected based on data from Part A
• To determine the PK of SRP-5051 in plasma and urine, and of the major metabolite SRP-5051A in plasma
• To evaluate, via immunohistochemistry, percent dystrophin-positive fibers (PDPF) and mean intensity following SRP-5051 treatment, administered IV every 4 weeks at the doses selected based on data from Part A

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion Criteria for Patients Previously Treated with SRP-5051
Patients previously treated with SRP-5051 must meet all of the following criteria to participate in this study:
I 1. Has received prior SRP-5051 treatment in Part A of this study or in Study 5051-102.
I 2. If sexually active, agrees to use a male condom during such activity for the entire duration of the study and for 90 days after the last dose of study drug. The sexual partner must also use a highly effective form of contraceptive (refer to Appendix 1 for guidance on highly effective contraceptive methods) during this timeframe.
I 3. Is willing to provide informed consent or informed assent (if applicable) and has (a) parent(s) or legal guardian(s) who is (are) willing to provide written informed consent for the patient to participate in the study.

Inclusion Criteria for Patients Treatment-Naïve to SRP-5051
Patients who are treatment-naïve to SRP-5051 must meet all of the following criteria to participate in this study:
I 1. Is male.
I 2. Is 7 to 21 years of age, inclusive.
I 3. Has a genetic diagnosis of DMD and an out-of-frame deletion mutation of the DMD gene amenable to exon 51-skipping treatment.
I 4. Has been on a stable dose of oral corticosteroids for at least 12 weeks prior to study drug administration or has not received corticosteroids for at least 12 weeks prior to study drug administration.
I 5. Has stable pulmonary function (FVC ≥ 40% of predicted and no requirement for nocturnal ventilation as a result of the complications of DMD) that, in the Investigator’s opinion, is unlikely to decompensate significantly over the duration of the study. NOTE: patients on nocturnal ventilation because of sleep apnea, obesity, or other conditions caused by corticosteroid use are allowed to participate in the study if FVC % predicted is ≥ 40
I 6. If sexually active, agrees to use a male condom during such activity for the entire duration of the study and for 90 days after the last dose of study drug. The sexual partner must also use a highly effective form of contraceptive (refer to Appendix 1 for guidance on highly effective contraceptive methods) during this timeframe.
I 7. Is willing to provide informed consent or informed assent (if applicable) and has (a) parent(s) or legal guardian(s) who is (are) willing to provide written informed consent for the patient to participate in the study.).

E.4

Principal exclusion criteria

Exclusion Criteria for Patients Previously Treated with SRP-5051:
E 1. Has a current infection, or history of an infection within 12 weeks prior to Day -1 requiring intravenous treatment with an antibiotic, or oral antibiotics that may affect renal or cardiac function.
E 2. Has a known kidney disease (identified by eGFR [calculated using Schwartz 2012 cystatin C equation] of < 90 mL/min/1.73 m2) or had an acute kidney injury within 24 weeks prior to Screening.
E 3. Major surgery within 12 weeks prior to Screening, or planned surgery or procedures that would interfere with the conduct of the study.
E 4. Presence of other clinically significant illness, including cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or infection or malignancy.
E 5. Any other condition that, in the Investigator’s opinion, could interfere with the patient’s participation in the trial, including body weight loss to < 18 kg.
E 6. Inability to comply with the study protocol.
E 7. Is an employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members of the employees or the Investigator.
E 8. Any patient who is taking medications that increase the risk of bleeding, in the Investigator’s opinion
E 9. Platelet count < 150 × 10^3/μL.
E 10. Known hypersensitivity to the study drug (ie, SRP-5051) or to any of its components.
E 11. Has:
a. Hypomagnesemia (< lower limit of normal) at Screening
b. Other abnormal electrolyte values considered clinically significant by the Investigator upon medical review and in consultation with the Medical Monitor at Screening;
c. Serum creatinine > upper limit of normal (ULN) at Screening.
E 12. Has quantitative urinalysis or urine microscopy findings above the ULN for RBCs or WBCs.
E 13. Urine Protein/Creatinine Ratio ≥ 200 mg/g and UACR ≥ 30 mg/g OR 24-hour urine values for protein ≥ 200 mg/24 hr at Screening and albumin ≥ 30 mg/24 hr. (Note that 24-hour urine protein does not need to be performed during screening if the UPCR/UACR criteria are met).
E 14. GGT > 3 × ULN at Screening
E 15. Is being treated with a proton pump inhibitor, loop diuretic, or thiazide diuretic at the time of study initiation.
E 16. Treatment with any exon 51-skipping therapy within 4 weeks prior to Screening, or with any experimental gene therapy for the treatment of DMD at any time.
For other exclusion criteria please refer to Protocol

Exclusion Criteria for Patients Treatment-Naïve to SRP-5051:
E 1. History of hypomagnesemia within 12 weeks prior to Screening.
For TN Cohort patients entering the study in Part B
E 2. Has body weight < 18 kg.
E 3. Has a diagnosis of diabetes (any type).
E 4. Initiation or change of dosing (except for modifications to accommodate changes in weight or changes in standard of care) within 12 weeks prior to Screening for any of the following: angiotensin-converting enzyme inhibitors, angiotensin receptor-blocking agents, β-blockers, or potassium.
E 5. Requires anti-arrhythmic and/or diuretic therapy for heart failure.
E 6. Has a current infection, or history of an infection within 12 weeks prior to Day -1 requiring intravenous treatment with an antibiotic, or oral antibiotics that may affect renal or cardiac function.
E 7. Has a known kidney disease (identified by eGFR [calculated using Schwartz cystatin C equation] of < 90 mL/min/1.73 m2) or had an acute kidney injury within 24 weeks prior to Screening.
E 8. Major surgery within 12 weeks prior to Screening, or planned surgery or procedures that would interfere with the conduct of the study.
E 9. Presence of other clinically significant illness, including cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or infection or malignancy.
E 10. Any other condition that, in the Investigator’s opinion, could interfere with the patient’s participation in the trial.
E 11. Inability to comply with the study protocol.
E 12. Is an employee of the Investigator or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members of the employees or the Investigator.
E 13. Any patient who is taking medications that increase the risk of bleeding, in the Investigator’s opinion
E 14. Platelet count < 150 × 10^3/μL
E 15. Known sensitivity to the study drug (ie, SRP-5051) or to any of its components
E 16. Has:
a. Hypomagnesemia (< lower limit of normal) at Screening
b. Other abnormal electrolyte values considered clinically significant by the Investigator upon medical review and in consultation with the Medical Monitor at Screening;
c. Serum creatinine > upper limit of normal (ULN) at Screening
E 17. Has quantitative urinalysis or urine microscopy findings above the ULN for RBCs or WBCs
For other exclusion criteria please refer to Protocol

E.5 End points

E.5.1

Primary end point(s)

Part A
• Incidence of adverse events (AEs)
• Clinically significant laboratory abnormalities (eg, hematology, chemistry [including
electrolytes], coagulation, urinalysis)

Part B
Change from Baseline in dystrophin protein level (as measured by Western blot) at 28 weeks

E.5.1.1

Timepoint(s) of evaluation of this end point

Part A

All AEs will be reported from the time of providing signed informed consent/assent through the last follow-up visit.

All the routine clinical laboratory tests will be performed during clinic visits at the time points specified in the Schedule of Events for Part A as stated in the Table 1 of the protocol

Part B

Muscle and skin biopsies will be collected at the time points specified in the Schedule of Events in Table 2 of the protocol.

E.5.2

Secondary end point(s)

Part A
PK parameters of SRP-5051 in plasma and urine, and of its major metabolite SRP-5051A in plasma, at each dose level

Part B
• Change from Baseline in exon-skipping level (as measured by ddPCR) at 28 weeks
• Incidence of AEs
• Incidence, severity, and reversibility of hypomagnesemia
• Clinically significant laboratory abnormalities (eg, hematology, chemistry [including electrolytes], coagulation, urinalysis)
• PK parameters of SRP-5051 in plasma and urine, and of the major metabolite SRP-5051A in plasma
• Change from Baseline in PDPF and mean intensity, as measured by immunofluorescence assay

E.5.2.1

Timepoint(s) of evaluation of this end point

Part A

- PK assessments will be collected at the time points specified in the Schedule of Events in Table 1 of the protocol.

Part B

- PK, muscle and skin biopsy, routine laboratory assessments and functional assessments will be collected at the time points specified in the Schedule of Events in Table 1 and Table 2 of the protocol.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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 and Circulating Biomarker. Multiple-Ascending-Dose Study for Dose Determination, then Dose Expansion

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

Yes

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

Multiple-Ascending-Dose Study for Dose Determination, then Dose Expansion

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.8.5

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

Canada

United Kingdom

United States

Belgium

Germany

Italy

Netherlands

Spain

E.8.7

Trial has a data monitoring committee

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)

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

This study will be conducted in both ambulatory and nonambulatory patients, aged 7 to 21 years, inclusive, with DMD amenable to exon 51-skipping treatment.

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)

Sponsor will assess the need for a potential long-term extension study of SRP-5051 at the conclusion of this trial.

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

2019-08-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-10

P. End of Trial
P.	End of Trial Status	Restarted

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