Duchenne Muscular Dystrophy
Conditions
Brief summary
This study is designed to evaluate the ability of ataluren to increase dystrophin protein levels in muscle cells of participants with nmDMD. The study will evaluate the levels of dystrophin before and after 40 weeks of ataluren therapy using muscle biopsies and 2 validated assay methods, electrochemiluminescence (ECL) and immunohistochemistry.
Interventions
DRUGAtaluren
Ataluren will be administered as per the dose and schedule specified in the arm.
Sponsors
PTC Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
2 Years to 7 Years
Healthy volunteers
No
Inclusion criteria
* Evidence of signed and dated informed consent/assent document(s) indicating that the participant (and/or his parent/legal guardian) has been informed of all pertinent aspects of the trial. * Phenotypic evidence of duchenne muscular dystrophy (DMD) based on the onset of characteristic clinical symptoms or signs (for example, proximal muscle weakness, waddling gait, and Gowers' maneuver) and an elevated serum creatine kinase (CK). Medical documentation of phenotypic evidence of DMD needs to be provided upon request by the Sponsor's medical monitor. * Documentation of the presence of a nonsense point mutation in the dystrophin gene as determined by gene sequencing. Review and approval of documentation by sponsor or designee is required prior to enrollment. * Willing to undergo muscle biopsy.
Exclusion criteria
* Ongoing intravenous (IV) aminoglycoside or IV vancomycin therapy. * Known contra-indication to muscle biopsy (such as bleeding or clotting disorders). * Prior or ongoing therapy with ataluren. * Known hypersensitivity to any of the ingredients or excipients of the study drug (for example, refined polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, colloidal silica, magnesium stearate). * Exposure to another investigational drug within 2 months prior to start of study treatment, or ongoing participation in any interventional clinical trial. * Requirement for daytime ventilator assistance or any use of invasive mechanical ventilation via tracheostomy. Evening non-invasive mechanical ventilation such as use of bilevel positive airway pressure (Bi-PAP) therapy is allowed. * Elevated serum creatinine or cystatin C levels at screening. * Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder), medical history, physical findings or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Dystrophin Level at Week 40, as Measured by ECL | Baseline, Week 40 | The percent change in dystrophin level from baseline in ambulatory nonsense mutation duchenne muscular dystrophy (nmDMD) participants after treatment with ataluren for 40 weeks was analyzed using quantitative assay (ECL).The least square (LS) mean and 90% confidence interval (CI) were analyzed from a mixed-model repeated measures (MMRM) with factors of muscle locations and visits as fixed effects, and participants as a random effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Dystrophin Level at Week 40, as Determined by Immunohistochemistry (IHC) Membrane Stain Density | Baseline, Week 40 | The percent change in dystrophin level from baseline in ambulatory nmDMD participants after 40 weeks of ataluren therapy was determined by IHC membrane stain density. The LS mean and 90% CI were analyzed from an MMRM with factors of muscle locations and visits as fixed effects, and participants as a random effect. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ataluren Participants received ataluren oral suspension 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening each day for 40 weeks. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Ataluren |
|---|---|
| Age, Continuous | 4.8 years STANDARD_DEVIATION 1.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 20 |
| other Total, other adverse events | 18 / 20 |
| serious Total, serious adverse events | 2 / 20 |
Outcome results
Primary
Percent Change From Baseline in Dystrophin Level at Week 40, as Measured by ECL
The percent change in dystrophin level from baseline in ambulatory nonsense mutation duchenne muscular dystrophy (nmDMD) participants after treatment with ataluren for 40 weeks was analyzed using quantitative assay (ECL).The least square (LS) mean and 90% confidence interval (CI) were analyzed from a mixed-model repeated measures (MMRM) with factors of muscle locations and visits as fixed effects, and participants as a random effect.
Time frame: Baseline, Week 40
Population: ITT population included all enrolled participants with a valid assessment of dystrophin level at baseline, as measured by ECL.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ataluren | Percent Change From Baseline in Dystrophin Level at Week 40, as Measured by ECL | 6.559 percent change |
Secondary
Percent Change From Baseline in Dystrophin Level at Week 40, as Determined by Immunohistochemistry (IHC) Membrane Stain Density
The percent change in dystrophin level from baseline in ambulatory nmDMD participants after 40 weeks of ataluren therapy was determined by IHC membrane stain density. The LS mean and 90% CI were analyzed from an MMRM with factors of muscle locations and visits as fixed effects, and participants as a random effect.
Time frame: Baseline, Week 40
Population: ITT population included all enrolled participants with a valid assessment of dystrophin level at baseline, as measured by ECL.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ataluren | Percent Change From Baseline in Dystrophin Level at Week 40, as Determined by Immunohistochemistry (IHC) Membrane Stain Density | 4.914 percent change |