|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Duchenne Muscular Dystrophy
|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
|Diseases [C] - Musculoskeletal Diseases [C05]
|E.1.2 Medical condition or disease under investigation
|Duchenne muscular dystrophy
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|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 Part:
Selection of a high dose (100 mg/kg vs 200 mg/kg) as compared with 30 mg/kg administered IV once weekly.
Evaluate the PK, PD (exon skipping
quantitation), safety and tolerability of doses higher than 30 mg/kg of eteplirsen, to select a single higher dose of eteplirsen for dose comparison
Double-Blind Dose Comparison:
Comparison of a selected high dose of eteplirsen with 30 mg/kg IV weekly.
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 Duchenne muscular dystrophy (DMD) patients with confirmed deletion genotypes amenable to exon 51 skipping
|Secondary objectives of the trial
|Double-blind Dose Comparison:
Comparison of a selected high dose of eteplirsen with 30 mg/kg IV weekly on:
To evaluate safety and tolerability of a selected high dose as compared with 30 mg/kg of eteplirsen, administered weekly IV
|Trial contains a sub-study
|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 7 to 13 years, inclusive
3. Have achieved a mean 6MWT distance of ≥300 and ≤450 meters (without assistance) at both the Screening and Baseline visits for the double-blind part.
4. Have 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).
5. Have 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).
6. Have 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.
7. 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).
8. Have (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the study requirements.
9. 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.
|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 1 weeks prior to first dose.
Drisapersen in the last 36 weeks prior to first dose
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 (LLN).
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 (LVEF) <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
|Primary end point(s)
|Open-Label Dose Escalation:
Incidence of AEs, adverse events of special interest (AESIs) serious adverse events (SAEs), Safety laboratory assessments, ECGs and ECHO
Double-Blind Dose Finding:
Dystrophin expression in biopsied muscle tissue
Plasma PK parameters of 30, 100, and 200 mg/kg of eteplirsen,
administered IV weekly
Incidence of AEs, AESIs and SAEs
Abnormal changes from baseline or worsening of vitals or physical examination findings
Safety laboratory assessments
ECGs and ECHO
Tissue concentration of eteplirsen from biopsied muscle tissue
Change from baseline at Week 144 in North Star Ambulatory Assessment (NSAA) total score
|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
on baseline all patients undergo muscle biopsy pre-dose
One additional muscle biopsy at either 12, 24, or 48 weeks
Interim analyses will be performed on muscle biopsy data at Weeks 12 to assess dystrophin expression for high dose selection; additional interim analyses will be conducted at Week 24 and, if a high dose is not selected, at Week 48
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
|Secondary end point(s)
|Change from Baseline at Week 144 in
o 6-minute walk test (6MWT)
o 10 meter walk/run time
o Timed 4 step stair ascend test
o Time to rise from floor
Annual decline rate in FVC % predicted
Time to Loss of Ambulation (LOA)
Change in skeletal muscle dystrophin expression by:
o Western blot (quantitation)
o IHC fiber intensity
o Exon skipping quantitation by PCR
Incidence of AEs
Incidence of AESIs
Incidence of SAEs
Safety laboratory assessments
|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
|Scope of the trial
|Other scope of the trial description
|The open-label period of the study evaluates the tolerability of the higher dose eteplirsen in DMD patients
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
|Other trial design description
|Open-label Dose Escalation followed by a Double-blind Dose Finding and Dose Comparison part
| Comparator of controlled trial
|Other medicinal product(s)
| different dosage of the same product
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Korea, Republic of
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days