An Open-Label, Multi-Center, 48-Week Study with a Concurrent Untreated Control Arm to Evaluate the Efficacy and Safety of Eteplirsen in Duchenne Muscular Dystrophy

Principal Investigator: Russell Butterfield
Keywords: Eteplirsen , DUCHENNE MUSCULAR DYSTROPHY , Exon-skipping , investigational drug , muscular dystrophy , DMD , DUCHENNE Department: Pediatric Administration
IRB Number: 00075880 Co Investigator: Nicholas Johnson
Specialty: Neurology
Sub Specialties: Muscular Dystrophy
Recruitment Status: Recruiting

Contact Information

Brianna Jensen

Brief Summary

The primary objective of this study is to evaluate the effect of eteplirsen on ambulation, endurance, and muscle function as measured by change from Baseline to 96 weeks in the 6-minute walk test (6MWT) as compared to an untreated control arm of Duchenne muscular dystrophy (DMD) patients amenable to exon skipping.

The secondary objectives are to evaluate:

  • The effect of eteplirsen on dystrophin expression as measured by the change from pretreatment in dystrophin quantification by Western blot and dystrophin intensity levels determined by immunofluorescence in biopsied muscle tissue

  •  the effect of eteplirsen on respiratory muscle strength as measured by the difference in change from Baseline in forced vital capacity % predicted and in maximal inspiratory and expiratory pressure % predicted between the eteplirsen treated and the untreated control arm of DMD patients amenable to exon skipping

  • the safety and tolerability of eteplirsen

The additional objective is to evaluate the clinical and pharmacodynamic effects of eteplirsen treatment for up to 96 weeks 

Inclusion Criteria

1. Be a male with DMD and meet one of the following criteria:

• Have an out-of-frame deletion that may be treated by exon 51 skipping (e.g. deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63). These patients will be enrolled into the treated group.

• Have an out-of-frame deletion that is not amenable to correction by exon 51 skipping but is amenable to correction by skipping other exons (i.e., whole exon deletions in which the reading frame may be restored by skipping 1 or 2 exons). These patients will be enrolled into the untreated group.

2. Be 7 to 16 years of age, inclusive.

3. Have stable pulmonary function (forced vital capacity % of predicted [FVC %] ≥50% and not require nocturnal ventilation) that, in the Investigator’s opinion, is unlikely to decompensate over the duration of the study.

4. Have intact right and left bicep muscles (the preferred biopsy site) or two alternative upper arm muscle groups.

5. 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 (except for modifications to accommodate changes in weight) 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, potassium, and coenzyme Q, provided they have been on a stable dose for 24 weeks prior to Week 1 and the dose is expected to remain constant throughout the study.

6. Achieve a mean distance of two separate assessments on two consecutive days at the Screening and Baseline visits (prior to Week 1) ≥300 meters on the 6MWT with the two consecutive means being within 15% of each other, and with the Screening and Baseline 6MWT conducted 3 to 5 weeks apart. Personal assistance or use of any assistive devices for ambulation is not permitted during the 6MWT.

7. Male subjects who are in the treated group and are post-pubertal and sexually active must agree to use, for the entire duration of the study and for 90 days post last dose, a male condom and the female sexual partner must also use a medically acceptable form of birth control (e.g. oral contraceptives).

8. Have a parent(s) or legal guardian(s) who is able to understand and comply with all the study requirements.

9. Be willing to provide informed assent (if applicable) 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.

Exclusion Criteria

1. Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks of Week 1 that may have an effect on muscle strength or function (e.g. growth hormone, anabolic steroids).

2. Previous treatment with ezutromid (BMN 195/SMT C1100) at any time.

3. Previous treatment with drisapersen (PRO051) therapy within the last 3 months. To be eligible for the study, patients who were previously treated with disapersen must be free of any of the following prior to Week 1: a) any active skin lesions related to drisapersen injection; b) renal signs/symptoms (including proteinuria or elevated creatinine/cystatin C); c) the presence of anti-platelet antibodies (to be tested at screenign for patients who were previously treated with drisapersen); and d) abnormal platelet count.

4. Previous treatment with any other RNA antisense agent or any gene therapy within the last 6 months, or participation in any other DMD interventional clinical study

within 12 weeks of Week 1, or use of the shock training system or “STS,” or planned use during this
study. Concurrent enrollment in any natural history, observational, or biomarker clinical trial is
permitted, provided the patient’s participation in the other trial does not affect any of the assessments
performed in the 4658-301 clinical study. For patients in the untreated control group only,
continuation in an interventional trial with standard-of-care medication may also be permitted if the
patient’s participation in the standard-of-care interventional trial does not affect any of the
assessments performed in Study 4658-301, and the patient meets all the protocol-required entry

5. Major surgery within 3 months of Week 1, or planned surgery for any time during this study,

except for protocol-specified surgeries, as applicable.

6. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, behavioral disease or malignancy.

7. Use of any aminoglycoside antibiotic within 12 weeks of Week 1 or need for use of an aminoglycoside antibiotic or statin during the study.

8. Have a left ventricular ejection fraction (LVEF) of <50% based on the screening ECHO or QTcF ≥450 msec based on the screening ECG.

9. Loss of ≥30 degrees of plantar flexion from the normal range of movement at the ankle joint due to

contracture (i.e., fixed plantar flexion of 10 degrees or more).

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 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. Additionally, patients who seem unwilling to comply with the study procedures, in the Investigator’s opinion, are to be excluded.