Duchenne Muscular Dystrophy
Conditions
Keywords
DMD
Brief summary
This study is designed to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of AVI-4658 (eteplirsen) in both 50.0 mg/kg and 30.0 mg/kg doses administered over 24 weeks in subjects diagnosed with Duchenne muscular dystrophy (DMD).
Detailed description
For details regarding the roll-over extension study 4658-us-202, please refer to NCT01540409.
Interventions
Treatment group 1 (n=4): 50.0 mg/kg eteplirsen once weekly x 24 weeks via a 60-minute i.v. infusion Treatment group 2 (n=4): 30.0 mg/kg eteplirsen once weekly x 24 weeks via a 60-minute i.v. infusion Treatment group 3 (n=4): matching placebo once weekly x 24 weeks via a 60-minute i.v. infusion; treatment group 3a will match two placebo subjects to 50.0 mg/kg eteplirsen; treatment group 3b will match two placebo subjects to 30.0 mg/kg eteplirsen
OTHERPlacebo
sterile, isotonic, clear, colorless phosphate buffered saline solution of eteplirsen at a concentration of 100 mg/mL in single-use vials containing a nominal volume of 1.0 mL without preservatives.
Sponsors
Sarepta Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
7 Years to 13 Years
Healthy volunteers
No
Inclusion criteria
Major Inclusion and
Exclusion criteria
Inclusion Criteria: A subject must meet all of the following criteria to be eligible for this study. * Be a male with DMD and have an out-of-frame deletion(s) that may be corrected by skipping exon 51 \[e.g., deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63\], as confirmed in a Clinical Laboratory Improvement Act-accredited laboratory by any of the peer-reviewed and published methodology that evaluates all exons (including, but not limited to, multiplex ligation-dependent probe, comparative genomic hybridization, and single condition amplification/internal primer analysis). * Be between the ages of 7 and 13 years, inclusive. * Have stable cardiac function and stable pulmonary function (forced vital capacity \[FVC\] ≥50% of predicted and not require supplemental oxygen) that, in the Investigator's opinion, is unlikely to decompensate over the duration of the study. * Be receiving treatment with oral corticosteroids and have been on a stable dose for at least 24 weeks before study entry. Subjects may be allowed to take other (non-RNA antisense or gene therapy) medication (including angiotensin-converting enzyme \[ACE\] inhibitors, β blockers, losartan potassium, and coenzyme Q) as long as they have been on a stable dose of the medication for 24 weeks before the screening visit (Visit 1) and the dose will remain constant throughout the study. * Have intact right and left biceps muscles or an alternative upper arm muscle group. * Achieve an average distance within 200m and 400m ±10% (i.e. within 180m and 440m) while walking independently over six minutes. * Have a left ventricular ejection fraction (LVEF) of \>40% based on the ECHO that is obtained at the screening visit (Visit 1). A subject who has abnormal ECHO findings but who has an LVEF of \>40% may be enrolled in the study at the Investigator's discretion; however, the subject must have been receiving stable doses of ACE inhibitors or β blockers for at least 24 weeks before study entry. * Have a parent(s) or legal guardian(s) who is able to understand and comply with the all of the study procedure requirements. * 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 subject to participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Number (%) of Dystrophin Positive Fibers | After 12 weeks for 4 patients who received 50 mg/kg and 2 patients who received placebo. After 24 weeks for 4 patients who received 30 mg/kg and 2 patients who received placebo. | The primary efficacy endpoint will be based on the pre-treatment and post-treatment change in the number (%) of dystrophin positive fibers as measured in the muscle biopsy tissue on immunohistochemistry (IHC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline: 6 Minute Walk Test (6MWT) - Intent to Treat Population (ITT) | 24 weeks | A key secondary efficacy endpoint will be based on the pre-treatment and post-treatment Change from baseline: 6 Minute Walk Test (6MWT) - Intent to Treat population (ITT) |
| Change From Baseline: 6 Minute Walk Test (6MWT) - Modified Intent to Treat Population (mITT) | 24 weeks | A key secondary efficacy endpoint will be based on the pre-treatment and post-treatment of the 6-MWT distance. Change from baseline: 6 Minute Walk Test (6MWT) - modified Intent-to-Treat population (mITT). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AVI-4658 (Eteplirsen) 30 mg/kg 30 mg/kg eteplirsen for 24 weeks | 4 |
| AVI-4658 (Eteplirsen) 50 mg/kg 50 mg/kg eteplirsen for 24 weeks | 4 |
| Placebo Placebo: phosphate buffered saline solution identical in appearance to eteplirsen for 24 weeks | 4 |
| Total | 12 |
Baseline characteristics
| Characteristic | AVI-4658 (Eteplirsen) 50 mg/kg | Placebo | AVI-4658 (Eteplirsen) 30 mg/kg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 8.5 years STANDARD_DEVIATION 1.29 | 8.5 years STANDARD_DEVIATION 1.73 | 9.3 years STANDARD_DEVIATION 0.5 | 8.8 years STANDARD_DEVIATION 1.22 |
| Region of Enrollment United States | 4 participants | 4 participants | 4 participants | 12 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 4 |
Outcome results
Primary
Change in the Number (%) of Dystrophin Positive Fibers
The primary efficacy endpoint will be based on the pre-treatment and post-treatment change in the number (%) of dystrophin positive fibers as measured in the muscle biopsy tissue on immunohistochemistry (IHC).
Time frame: After 12 weeks for 4 patients who received 50 mg/kg and 2 patients who received placebo. After 24 weeks for 4 patients who received 30 mg/kg and 2 patients who received placebo.
Population: The sample size for the study was selected based on Proof of Principal approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AVI-4658 (Eteplirsen) 30 mg/kg | Change in the Number (%) of Dystrophin Positive Fibers | 23 percentage of dystrophin Pos. fibers |
| Placebo - Week 24 Biopsy | Change in the Number (%) of Dystrophin Positive Fibers | -7.48 percentage of dystrophin Pos. fibers |
| AVI-4658 (Eteplirsen) 50 mg/kg | Change in the Number (%) of Dystrophin Positive Fibers | 0.79 percentage of dystrophin Pos. fibers |
| Placebo - Week 12 Biopsy | Change in the Number (%) of Dystrophin Positive Fibers | -0.63 percentage of dystrophin Pos. fibers |
Secondary
Change From Baseline: 6 Minute Walk Test (6MWT) - Intent to Treat Population (ITT)
A key secondary efficacy endpoint will be based on the pre-treatment and post-treatment Change from baseline: 6 Minute Walk Test (6MWT) - Intent to Treat population (ITT)
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AVI-4658 (Eteplirsen) 30 mg/kg | Change From Baseline: 6 Minute Walk Test (6MWT) - Intent to Treat Population (ITT) | -134.8 Meters | Standard Error 72.36 |
| Placebo - Week 24 Biopsy | Change From Baseline: 6 Minute Walk Test (6MWT) - Intent to Treat Population (ITT) | -2.3 Meters | Standard Error 14.95 |
| AVI-4658 (Eteplirsen) 50 mg/kg | Change From Baseline: 6 Minute Walk Test (6MWT) - Intent to Treat Population (ITT) | -17.3 Meters | Standard Error 14.03 |
Secondary
Change From Baseline: 6 Minute Walk Test (6MWT) - Modified Intent to Treat Population (mITT)
A key secondary efficacy endpoint will be based on the pre-treatment and post-treatment of the 6-MWT distance. Change from baseline: 6 Minute Walk Test (6MWT) - modified Intent-to-Treat population (mITT).
Time frame: 24 weeks
Population: The mITT population excludes 2 patients in the 30mg/kg arm who showed rapid disease progression within weeks of enrollment, and were unable to complete assessments that required ambulation at or beyond Week 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AVI-4658 (Eteplirsen) 30 mg/kg | Change From Baseline: 6 Minute Walk Test (6MWT) - Modified Intent to Treat Population (mITT) | -12.5 Meters | Standard Error 1.5 |
| Placebo - Week 24 Biopsy | Change From Baseline: 6 Minute Walk Test (6MWT) - Modified Intent to Treat Population (mITT) | -2.3 Meters | Standard Error 14.95 |
| AVI-4658 (Eteplirsen) 50 mg/kg | Change From Baseline: 6 Minute Walk Test (6MWT) - Modified Intent to Treat Population (mITT) | -17.3 Meters | Standard Error 14.03 |
Post Hoc
Adverse Events >30%
Adverse events that occurred in \>30% of the overall patient population across treatment arms.
Time frame: 24 Weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AVI-4658 (Eteplirsen) 30 mg/kg | Adverse Events >30% | Cough | 1 Number of patients |
| AVI-4658 (Eteplirsen) 30 mg/kg | Adverse Events >30% | Hypokalemia (a known side effect of steroids) | 2 Number of patients |
| AVI-4658 (Eteplirsen) 30 mg/kg | Adverse Events >30% | Procedural Pain | 1 Number of patients |
| AVI-4658 (Eteplirsen) 30 mg/kg | Adverse Events >30% | Oropharyngeal Pain | 3 Number of patients |
| AVI-4658 (Eteplirsen) 30 mg/kg | Adverse Events >30% | Extremity Pain | 0 Number of patients |
| Placebo - Week 24 Biopsy | Adverse Events >30% | Hypokalemia (a known side effect of steroids) | 2 Number of patients |
| Placebo - Week 24 Biopsy | Adverse Events >30% | Procedural Pain | 3 Number of patients |
| Placebo - Week 24 Biopsy | Adverse Events >30% | Oropharyngeal Pain | 0 Number of patients |
| Placebo - Week 24 Biopsy | Adverse Events >30% | Cough | 1 Number of patients |
| Placebo - Week 24 Biopsy | Adverse Events >30% | Extremity Pain | 1 Number of patients |
| AVI-4658 (Eteplirsen) 50 mg/kg | Adverse Events >30% | Extremity Pain | 3 Number of patients |
| AVI-4658 (Eteplirsen) 50 mg/kg | Adverse Events >30% | Cough | 2 Number of patients |
| AVI-4658 (Eteplirsen) 50 mg/kg | Adverse Events >30% | Procedural Pain | 3 Number of patients |
| AVI-4658 (Eteplirsen) 50 mg/kg | Adverse Events >30% | Hypokalemia (a known side effect of steroids) | 2 Number of patients |
| AVI-4658 (Eteplirsen) 50 mg/kg | Adverse Events >30% | Oropharyngeal Pain | 3 Number of patients |
Post Hoc
Frequency of AEs Related to Eteplirsen
Frequency of AEs that the study physician considered to be any of the following: Related; Possibly related; or Probably related to eteplirsen.
Time frame: 24 Weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AVI-4658 (Eteplirsen) 30 mg/kg | Frequency of AEs Related to Eteplirsen | Intermittent Nausea (mild) | 0 Number of patients |
| AVI-4658 (Eteplirsen) 30 mg/kg | Frequency of AEs Related to Eteplirsen | Other AEs related to eteplirsen | 0 Number of patients |
| Placebo - Week 24 Biopsy | Frequency of AEs Related to Eteplirsen | Intermittent Nausea (mild) | 0 Number of patients |
| Placebo - Week 24 Biopsy | Frequency of AEs Related to Eteplirsen | Other AEs related to eteplirsen | 0 Number of patients |
| AVI-4658 (Eteplirsen) 50 mg/kg | Frequency of AEs Related to Eteplirsen | Intermittent Nausea (mild) | 1 Number of patients |
| AVI-4658 (Eteplirsen) 50 mg/kg | Frequency of AEs Related to Eteplirsen | Other AEs related to eteplirsen | 0 Number of patients |