Clinical Trials Register

Summary
EudraCT Number:	2018-001762-42
Sponsor's Protocol Code Number:	4658-402
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-12-13
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

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2018-001762-42

A.3

Full title of the trial

A Randomized, Double-Blind, Dose Finding and Comparison Study of the Safety and Efficacy of a High Dose of Eteplirsen, Preceded by an Open-Label Dose Escalation, in Patients with Duchenne Muscular Dystrophy With Deletion Mutations Amenable to Exon 51 Skipping

Randomizált, kettős-vak, dóziskereső és dózis-összehasonlító vizsgálat az eteplirszen nagy adagjának biztonságosságának és hatásosságának értékelésére, amelyet nyílt elrendezésű dóziseszkaláció előz meg, Duchenne-féle izomdystrophiában szenvedő, az 51-esexon átugrásával kezelhető deléciós mutációval rendelkező betegeknél

A.3.1

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

A research study to compare different doses of a new investigational medicinal product for treatment of certain patients with Duchenne muscular dystrophy

A.4.1

Sponsor's protocol code number

4658-402

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	PPD
B.5.2	Functional name of contact point	Liana Baker
B.5.3	Address:
B.5.3.1	Street Address	929 North Front Street
B.5.3.2	Town/ city	Wilmington, NC
B.5.3.3	Post code	28401
B.5.3.4	Country	United States
B.5.4	Telephone number	+1215591 6631
B.5.6	E-mail	Liana.Baker@ppdi.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/3/08/586
D.3 Description of the IMP
D.3.1	Product name	Eteplirsen
D.3.2	Product code	AVI-4658
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	ETEPLIRSEN
D.3.9.1	CAS number	1173755-55-9
D.3.9.2	Current sponsor code	AVI-4658
D.3.9.4	EV Substance Code	SUB129287
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	20.0
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

Open-Label Dose Escalation
Evaluate the safety and tolerability of weekly IV doses of 100 and 200 mg/kg of eteplirsen.

Double-blind Dose Finding and Dose Comparison Part:
• To investigate the effect of a selected high dose of eteplirsen (100 mg/kg or 200 mg/kg) as compared with 30 mg/kg, administered weekly IV, on motor function in ambulant DMD patients with confirmed deletion genotypes amenable to Exon 51 skipping
• To select a single higher dose of eteplirsen for dose comparison

E.2.2

Secondary objectives of the trial

Double-Blind Dose Finding and Dose Comparison Part :
• To evaluate the effect of a selected high dose as compared with 30 mg/kg of eteplirsen, administered weekly IV, on
o Ambulatory performance
o Pulmonary function
o Dystrophin expression
• To evaluate the PK and PD of doses higher than 30 mg/kg of eteplirsen
• To evaluate safety and tolerability of doses higher than 30 mg/kg of eteplirsen administered weekly IV

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

A patient must meet all of the following criteria to be eligible to participate in this study.
1. Be a male with an established clinical diagnosis of DMD and an out-of-frame deletion mutation of the DMD gene amenable to exon 51 skipping (for example, deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, and 52-63).
2. Be aged 4 to 13 years, inclusive
3. Ambulatory patient, able to perform TTRISE in 10 seconds or less at the time of screening visit.
4. Able to walk independently without assistive devices.
5. Has intact right and left biceps muscles (the preferred biopsy site) or an alternative upper arm muscle group that will allow for sufficiently sized (1 cm3) muscle biopsies to be obtained prior to and on treatment (for patients in the double-blind part of the study).
6. Has been on a stable dose or dose equivalent of oral corticosteroids for at least 12 weeks prior to randomization, and the dose is expected to remain constant (except for modifications to accommodate changes in weight and stress-related needs as per recently published guidelines throughout the study).
7. For ages 7 years and older, has stable pulmonary function (forced vital capacity ≥50% of predicted and no requirement for nocturnal ventilation) that, in the Investigator’s opinion, is unlikely to decompensate significantly over the duration of the study.
For ages 4 to 6 years , does not require support from ventilator or non-invasive ventilation at time of screening.
8. If sexually active, agree to use a male condom during such activity for the entire duration of the study and for 90 days after the last dose. The sexual partner must also use a medically acceptable form of contraceptive (ie, female oral contraceptives) during this timeframe. Acceptable methods of contraception include combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intra-uterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence; or condom in combination with either cap, diaphragm, or sponge with spermicide (double-barrier contraception).
9. Has (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the study requirements.
10. Is willing to provide informed assent (if applicable) and has (a) parent(s) or legal guardian(s) who is (are) willing to provide informed consent for the patient to participate in the study.

E.4

Principal exclusion criteria

A patient who meets any of the following criteria will be excluded from this study:
1. Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks prior to randomization that may have an effect on muscle strength or function. Growth hormone for short stature and testosterone for delayed puberty are permitted if physician has documented the diagnosis and medical necessity of treatment and if the patient has been on a stable dose for at least 24 weeks prior to randomization.
2. Current or previous treatment with any other experimental pharmacologic treatment for DMD or any prior exposure to antisense oligonucleotide, gene therapy or gene editing; except the following:
Ezutromid in the last 12 weeks prior to first dose.
Drisapersen in the last 36 weeks prior to first dose
Suvodirsen in the last 12 weeks prior to first dose.
Vamorolone in the last 12 weeks prior to first dose.
Eteplirsen (previous or current use)
3. Major surgery within 3 months prior to randomization or planned surgery for any time during this study, except for allowed protocol-specified surgery, as applicable.
4. Presence of any significant neuromuscular or genetic disease other than DMD (eg, dwarfism).
5. Gamma-glutamyl transpeptidase (GGT) > 3 × the upper limit of normal (ULN) or serum bilirubin > ULN unexplained by Gilbert’s Syndrome.
6. Any known impairment of renal function (eg, estimated glomerular filtration rate [eGFR] ≤ 60 mL/min as assessed by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation), or dipstick protein result +2, or persistent and unexplained dipstick protein result +1
7. Platelet count < the lower limit of normal.
8. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease or malignancy.
9. Has evidence of cardiomyopathy, as defined by left ventricular ejection fraction <50% on the screening ECHO or the Fridericia’s correction formula (QTcF) ≥450 milliseconds based on the screening ECGs.
10. Prior or ongoing medical condition that could, in the Investigator’s opinion, adversely affect the safety of the patient, make it unlikely that the course of treatment would be completed, or impair the assessment of study results.
11. Known hypersensitivity to eteplirsen or any excipients of eteplirsen.
12. Is, in the Investigator’s opinion, unable or unwilling to comply with the study procedures.

E.5 End points

E.5.1

Primary end point(s)

Open-Label Dose Escalation:
Incidence of AEs, Incidence of adverse events of special interest (AESIs), Abnormal changes from Baseline or worsening of vitals or physical examination findings, Incidence of SAEs, Safety laboratory assessments, Electrocardiograms (ECGs) and Echocardiograms (ECHO).

Double-Blind Dose Finding and Dose Comparison Part:
-Change from Baseline at Week 72 in NSAA total score (for conditional efficacy interim analysis)
-Change from Baseline at Week 96 in NSAA total score (for efficacy interim analysis)
-Change from Baseline at Week 144 in NSAA total score (for final analysis)

E.5.1.1

Timepoint(s) of evaluation of this end point

Open-label Dose Escalation
week 1- 8 safety and tolerability data will be assessed to determine if the if the dose 100mg/kg and escalation dose 200mg/kg are safe.

Double-blind Dose Finding and Dose Comparison
on baseline all patients undergo muscle biopsy pre-dose
One additional muscle biopsy at either 12, 24, or 48 weeks
Dose selection analyses will be performed on muscle biopsy data from Week 24. Additionally, an efficacy interim analysis will be performed (See Section 13.5 for details).
AE assessment at baseline and continuous throughout the study. ECG
at screening, week 1, 4, 8, and 12, and every 12 weeks thereafter.
ECHO at screening, week 48, 96, and 144.
Change from baseline at Week 144

E.5.2

Secondary end point(s)

• Change from Baseline at Week 144 in
o TTRISE from floor
o 10-meter walk/run time
o 6MWT
o Timed 4-step stair ascend test
o Forced vital capacity percent predicted (FVC%p)
• Time to LOA through Week 144
• Change from Baseline at either Week 24, Week 48 or Week 144 in skeletal muscle dystrophin expression by:
o Western blot (quantitation)
o IHC fiber intensity
o Exon skipping quantitation by ddPCR
• PK parameters (plasma and sparse muscle biopsy)
• Incidence of AEs
• Incidence of AESIs
• Incidence of SAEs
• Safety laboratory assessments
• ECGs
• ECHO
• Abnormal changes from Baseline or worsening of vital signs and physical examination findings

E.5.2.1

Timepoint(s) of evaluation of this end point

Change from baseline at Week 144
Change from baseline at either Week 12, Week 24, or Week 48
6MWT, 10 meter walk/run timer and Time to rise from floor will be assesses on screening visit and week 12

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

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

The open-label period of the study evaluates the tolerability of the higher dose eteplirsen in DMD patients

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

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Open-label Dose Escalation followed by a Double-blind Dose Finding and Dose Comparison part

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

different dosage of the same product

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

Australia

Colombia

Mexico

Serbia

Turkey

Canada

Czechia

Denmark

Germany

Greece

Hungary

Ireland

Italy

Korea, Republic of

Netherlands

New Zealand

Norway

Poland

Romania

Russian Federation

Slovenia

Spain

Sweden

Switzerland

Taiwan

Ukraine

United Kingdom

United States

France

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

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:

154

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:

136

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

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

a male 7-13 years old with an established clinical diagnosis of DMD and an out-of-frame deletion mutation of
the DMD gene amenable to exon 51 skipping

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

154

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 trial the patients will get back to their normal treatment of that condition under their physician

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

2022-03-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-22

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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