Clinical Trials Register

Summary
EudraCT Number:	2014-002008-25
Sponsor's Protocol Code Number:	4053-101
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-09-10
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2014-002008-25

A.3

Full title of the trial

A 2-Part, Randomized, Double-Blind, Placebo-Controlled, Dose Titration, Safety, Tolerability, and Pharmacokinetics Study (Part 1) Followed by an Open-Label Efficacy and Safety Evaluation (Part 2) of SRP-4053 in Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping

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.3.2

Name or abbreviated title of the trial where available

N/A

A.4.1

Sponsor's protocol code number

4053-101

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	Voisin Consulting
B.5.2	Functional name of contact point	Clinical Trial Operations
B.5.3	Address:
B.5.3.1	Street Address	3 rue des Longs Prés
B.5.3.2	Town/ city	Boulogne-Billancourt
B.5.3.3	Post code	92100
B.5.3.4	Country	France
B.5.6	E-mail	clinicaltrialinformation@voisinconsulting.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	SRP-4053
D.3.2	Product code	SRP-4053
D.3.4	Pharmaceutical form	Concentrate 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	Not Available
D.3.9.1	CAS number	1422959-91-8
D.3.9.2	Current sponsor code	SRP-4053
D.3.9.3	Other descriptive name	Phosphorodiamidate morpholino oligomer for exon 53 skipping
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
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

Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping

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	17.0
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

PART 1 : To evaluate the safety and tolerability of four escalating doses of SRP-4053 administered once weekly for at least 2 weeks per dose level compared to placebo

PART 2 :
- To assess the effect of SRP-4053 administered weekly on ambulation, endurance, and muscle function as measured by change from Baseline to Week 48 on the 6-Minute Walk Test (6MWT) compared to untreated control patients
- To assess the biological activity (dystrophin expression) compared to pre-treatment.

E.2.2

Secondary objectives of the trial

PART 1 : To determine the pharmacokinetics of four escalating doses of SRP-4053 administered once weekly for at least 2 weeks per dose level compared to placebo

PART 2 :
- To assess the safety, tolerability, and pharmacokinetics of SRP-4053 administered weekly compared to untreated control patients
- To assess the effect of SRP-4053 on respiratory muscle strength as measured by change from Baseline to Week 48 in maximal inspiratory and expiratory pressure % predicted as compared to untreated control patients

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male aged 6 to 15, inclusive.
2. For treated patients (all patients in Part 1 + 12 additional treated patients in Part 2), established clinical diagnosis of DMD amenable to exon 53 skipping (e.g. deletions of exons such as 42-52, 45-52, 47-52, 48-52, 49-52, 50-52, 52, or 54-58) as documented by a genetic report from an accredited laboratory confirming deletion endpoints by multiplex ligation-dependent probe amplification (MLPA) or sequencing.
3. For Part 2 untreated control patients, established clinical diagnosis of DMD with confirmed genomic deletion of exon(s) not amenable to exon 53 skipping as documented by an accredited laboratory and genomic methodology.
4. Have intact right and left biceps muscles or an alternative upper arm muscle group.
5. Have stable cardiac and pulmonary function that, in the Investigator’s opinion, is unlikely to decompensate over the duration of the study.
6. Achieve a mean distance of two separate assessments on two consecutive days at screening and again at baseline (prior to investigational drug product administration) ≥250 meters on the 6MWT with the two means being ±15% of each other. (Personal assistance or use of any assistive devices for ambulation is not permitted during the 6MWT.)
7. Patients must meet one of the following two criteria:
• NSAA (North Star Ambulatory Assessment) total score >17; or
• Rise (Gowers) time < 7 seconds
8. Have been on a stable dose of oral corticosteroids for at least 24 weeks prior to Week 1 and the dose is expected to remain constant throughout the study. Note: patients may be allowed to take other (non-RNA antisense or gene therapy) medication including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), β blockers, and potassium provided they have been on a stable dose for 12 weeks prior to Week 1 and the dose is expected to remain constant throughout the study.
9. Have a parent(s) or legal guardian(s) who is able to understand and comply with the study procedure requirements.
10. Be willing to provide informed assent and have a parent(s) or legal guardian(s) who is willing to provide written informed consent for the patient to participate in the study.

E.4

Principal exclusion criteria

1. Use of any pharmacologic treatment, other than corticosteroids, that might have an effect on muscle strength or function within 12 weeks prior to study entry (e.g., growth hormone, anabolic steroids).
2. Previous treatment with the experimental agents BMN-195 (SMT C1100) or PRO053.
3. Previous or current treatment with any other experimental treatments within 12 weeks prior to study entry or participation in any other clinical trial within 6 months prior to study entry.
4. Have a left ventricular ejection fraction (LVEF) of <50% (or equivalent fractional shortening) based on the screening ECHO and QTc (Fredericia’s correction) >450 msec.
5. Have a forced vital capacity [FVC] <50% of predicted value or require nocturnal ventilation.
6. Major surgery within 3 months prior to Week 1 or planned orthopedic surgery for any time during this study which would interfere with the ability to perform outcome measures.
7. Use of any aminoglycoside antibiotic or statin within 12 weeks of Week 1 or need for use of an aminoglycoside antibiotic or statin during the study.
8. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, behavioral disease or malignancy.
9. Loss ≥30 degrees of plantar flexion from the normal range of movement at the ankle joint due to contracture (i.e. fixed loss of >10 degrees plantar flexion from plantagrade assuming normal range of dorsiflexion of 20 degrees).
10. Change in contracture treatment such as serial casting, contracture control devices, night splints, stretching exercises (passive, active, self) within 3 months prior to enrollment, or expected need for such intervention during the study.
11. Prior or ongoing medical condition that, in the Investigator’s opinion, could interfere with the patient’s participation in the study.

E.5 End points

E.5.1

Primary end point(s)

PART 1:
• Incidence of adverse events (AEs)
• Incidence of clinical laboratory abnormalities (hematology, chemistry, coagulation, urinalysis)
• Incidence of abnormalities in vital signs and physical examinations
• Incidence of abnormalities on electrocardiograms (ECGs) and echocardiograms (ECHO)

PART 2:
- Functional efficacy endpoint:
change from Baseline to Week 48 in the 6-Minute Walk Test (6MWT)
- Biological endpoint:
change from Baseline at Week 48 in the percentage of dystrophin-positive fibers as determined by immunohistochemistry (IHC)

E.5.1.1

Timepoint(s) of evaluation of this end point

PART 1:
• Continuous evaluation of the AEs.
• laboratory abnormalities: Screening (-6 to -4), Baseline (-2 to -1), weekly from week 1 to 9, week 12
• vital signs : every week from screening to week 12
• physical examinations : Screening (D1814), week 1, week 4, week 8, week 12
• ECG: Screening , Baseline, week 7 and 12
• ECHO: Screening, week 12

PART 2:
- Functional efficacy endpoint:
• 6-Minute Walk Test (6MWT): Screening (-6 to -4) (only new patients), Baseline (-2 to -1), Week 12 (only control arm), Week 24, Week 36, Week 48, Week 60
- Biological endpoint:
• IHC: Baseline (-2 to -1), Week 60

E.5.2

Secondary end point(s)

PART 1 and PART 2:

- Pharmacokinetic:
• Maximum plasma concentration (Cmax)
• Time to maximum plasma concentration (tmax)
• Area under the plasma concentration-curve (AUC)
• Apparent volume of distribution at steady state (Vss)
• Elimination half-life (t½)
• Total clearance (CL)
• Mean residence time (MRT)
• Urinary clearance (CLR)

PART2:
- Functional efficacy endpoint:
change from Baseline to Week 48 for the following:
• Pulmonary function tests (PFT): maximum expiratory pressure % predicted (MEP % predicted) and maximum inspiratory pressure % predicted (MIP % predicted)

- Biological endpoint:
change from Baseline at Week 48 for the following:
• Dystrophin intensity levels determined by IHC
• Dystrophin protein levels determined by Western blot (WB)
• Exon 53 skipping determined by reverse transcription-polymerase chain reaction (RT-PCR)

- Safety:
• Incidence of adverse events
• Incidence of clinical laboratory abnormalities (hematology, chemistry, coagulation, urinalysis)
• Incidence of abnormalities in vital signs and physical examinations
• Incidence of abnormalities on electrocardiograms (ECGs) and echocardiograms (ECHO)

E.5.2.1

Timepoint(s) of evaluation of this end point

PART 1 & 2:
- Pharmacokinetic:
Part 1 : Week 1, 3, 5, 7 & 12;
Part 2: Week 13, 36 & 60

PART 2 :
- Efficacy: Screening (-6 to -4) (only new patients), Baseline (-2 to -1), Week 12 (Only control arm), 24, 36,48,60

- Biological: Baseline, Week 60

- Safety:
• Continuous evaluation of the AEs
• laboratory abnormalities: Screening (new patients only), Baseline, weekly from week 13 to 16, week 20, 24, 28, 32, 36, 48 (excluded control arm), 60 & follow-up
• vital signs: every week from screening (new patients only) and baseline to follow-up
• physical examinations: Screening (new patients only), week 13, 16, 20, 24, 28, 32,36,48,60 & follow-up
• ECG: Screening, Baseline, week 24, 36, 48 & 60
• ECHO: Screening, week 36 & 60

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

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)

Yes

E.7.1.1

First administration to humans

Yes

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

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

Yes

E.8.1.7.1

Other trial design description

Study Part 1 : Double blind - Study Part 2 : Open

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

Yes

E.8.2.3.1

Comparator description

Study Part 1 : Placebo ; Study Part 2 : Untreated control group

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

E.8.6.2

Trial being conducted completely outside of the EEA

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:

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

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