Genetic Disorders – Duchenne Muscular Dystrophy

Primary Objective The primary objective of this study is to determine the effect of ataluren on ambulation and endurance as assessed by the 6-minute walk test (6MWT). Secondary Objectives The secondary objectives of this study are to:  Determine the effects of ataluren on ambulation and burst activity as assessed by timed function tests  Determine the effects of ataluren on lower-limb muscle function as assessed by the North Star Ambulatory Assessment (NSAA)  Assess the safety profile of ataluren Exploratory Objectives The exploratory objectives of this study are to:  Determine the effects of ataluren on upper-limb muscle function strength as assessed by the Performance of Upper Limb (PUL) and by the DMD Upper Limb PROM (in subjects ≥7 years old at baseline)  Determine the effects of ataluren on muscle strength as assessed by myometry (in subjects <7 years old at baseline)  Determine the effects of ataluren on skeletal muscle integrity as assessed by magnetic resonance imaging (MRI) (at pre-qualified sites only)  Determine the effects of ataluren on subject- and parent/caregiver-reported health-related quality of life (HRQL) as assessed by questionnaire and at-home diary  Determine the effects of ataluren on pulmonary function as assessed by forced vital capacity (FVC)

Ataluren (PTC124)

Ataluren (PTC124)

oral

125mg, 250mg or 1000mg

Primary Endpoint
The primary endpoint of this study is slope of change in 6-minute walk distance (6MWD)
over 72 weeks.

Secondary Endpoints
 Change from baseline to Week 72 in 6MWD
 Composite of average change in times to run/walk 10 meters, climb 4 stairs, and descend 4 stairs at Week 72
 Change from baseline to Week 72 in time to run/walk 10 meters
 Change from baseline to Week 72 in time to climb 4 stairs
 Change from baseline to Week 72 in time to descend 4 stairs
 Change from baseline to Week 72 in NSAA total score
 Time to loss of ambulation over 72 weeks
 Time to loss of stair-climbing over 72 weeks
 Time to loss of stair-descending over 72 weeks
 Risk of loss of NSAA items over 72 weeks
 Ataluren safety profile characterized by type, frequency, severity, and relationship to
study drug of any adverse events (AEs), or of abnormalities of laboratory tests, vital signs,
physical examinations, or electrocardiograms (ECGs)

Exploratory Endpoints
 Changes from baseline to Week 72 in PUL total score and domain subscores (in subjects ≥7 years old at baseline)
 Change from baseline to Week 72 in DMD Upper Limb PROM total score (in subjects ≥7 years old at baseline)
 Risk of loss of DMD Upper Limb PROM items over 72 weeks (in subjects ≥7 years old at baseline)
 Change from baseline to Week 72 in myometry parameters (in subjects <7 years old at baseline)
 Change from baseline to Week 72 in muscle fat fraction as assessed by MRI (at prequalified sites only)
 Changes from baseline to Week 72 in HRQL as assessed by questionnaire and at-home diary
 Change from baseline to Week 72 in FVC

1. Evidence of signed and dated informed consent/assent document(s) indicating that the
subject (and/or his parent/legal guardian) has been informed of all pertinent aspects of the
trial. Note: If the study candidate is considered a child under local regulation, a parent
or legal guardian must provide written consent prior to initiation of study screening
procedures and the study candidate may be required to provide written assent. The
rules of the responsible institutional review board/ethics committee (IRB/EC)
regarding whether one or both parents must provide consent and the appropriate ages
for obtaining consent and assent from the subject should be followed.
2. Male sex.
3. Age ≥5 years.
4. Phenotypic evidence of DMD based on the onset of characteristic clinical symptoms or
signs (eg, proximal muscle weakness, waddling gait, and Gowers’ maneuver) by 6 years
of age and an elevated serum creatine kinase (CK). Medical documentation of
phenotypic evidence of DMD needs to be provided upon request by the PTC
Therapeutics medical monitor.
5. Documentation of the presence of a nonsense point mutation in the dystrophin gene as
determined by gene sequencing. Note: Review and approval of documentation by
sponsor or designee is required prior to enrollment.
Use of systemic corticosteroids (prednisone/prednisolone or deflazacort) for a minimum
of 12 months immediately prior to start of study treatment, with no significant change in
dosage or dosing regimen for a minimum of 3 months immediately prior to start of study
treatment and a reasonable expectation that dosage and dosing regimen will not change
significantly for the duration of the study. Note: Daily, every other day, high-dose
weekend, and intermittent regimens at doses recommended by the DMD Care
Considerations Working Group [Bushby 2010a], as shown in Table 1, permitted only.
Increases in corticosteroid dose to adjust for increases in body weight will not exclude a
subject from participation.
6. 6MWD ≥150 meters at screening, baseline Day 1, and baseline Day 2. Note: Personal
assistance or use of assistive devices for ambulation (eg, short leg braces, long leg
braces, or walkers) will not be permitted during the 6MWT.
7. Results of the two Baseline 6MWD results must be determined as valid and results of the
Day 2 Baseline 6MWD must be within 20% of the Day 1 Baseline 6MWD.
8. Baseline 6MWD (maximum of valid Day 1 and Day 2 values) must be no more than a
20% reduction from the valid Screening 6MWD.
9. Ability to perform timed function tests (run/walk 10 meters, climb 4 stairs, descend 4
stairs, stand from supine) within 30 seconds at screening and baseline.
10. In subjects who are sexually active, willingness to abstain from sexual intercourse or
employ a barrier or medical method of contraception during the study drug administration
and 4-week follow-up period.
11. Willingness and ability to comply with scheduled visits, drug administration plan, study
procedures, laboratory tests, and study restrictions. Note: Psychological, social, familial,
or geographical factors that might preclude adequate study participation (in particular,
the ability to satisfactorily perform the 6MWT) should be considered.

1. Any change (initiation, change in type of drug, dose modification, schedule modification,
interruption, discontinuation, or reinitiation) in prophylaxis/treatment for cardiomyopathy
within 1 month prior to start of study treatment.
2. Ongoing intravenous (IV) aminoglycoside or IV vancomycin therapy.
3. Prior or ongoing therapy with ataluren.
4. Known hypersensitivity to any of the ingredients or excipients of the study drug [eg,
refined polydextrose, polyethylene glycol 3350, poloxamer 407, mannitol 25C,
crospovidone XL10, hydroxyethyl cellulose, colloidal silica, magnesium stearate].
5. Exposure to another investigational drug within 6 months prior to start of study treatment,
or ongoing participation in any interventional clinical trial. Note: This does not apply to
patients receiving deflazacort through an expanded access program.
6. History of major surgical procedure within 12 weeks prior to start of study treatment, or
expectation of major surgical procedure (eg, scoliosis surgery) during the 72-week
placebo-controlled treatment period.
7. Ongoing immunosuppressive therapy (other than corticosteroids).
8. Requirement for daytime ventilator assistance or any use of invasive mechanical
ventilation via tracheostomy. Note: Evening non-invasive mechanical ventilation such
as use of bi-level positive airway pressure (Bi-PAP) therapy is allowed.
9. Uncontrolled clinical symptoms and signs of congestive heart failure (American College
of Cardiology/American Heart Association Stage C or Stage D) [Hunt 2001].
10. Elevated serum creatinine or cystatin C at screening. Note: If the initial test result is
abnormal, it is permissible to re-test serum creatinine or cystatin C and randomize the
subject if the re-test result is normal.
11. Positive for hepatitis B core antibody or hepatitis C antibody at screening.
12. Prior or ongoing medical condition (eg, concomitant illness, psychiatric condition,
behavioral disorder, alcoholism, drug abuse), medical history, physical findings (eg,
lower-limb injury that may affect 6MWT performance), ECG findings, or laboratory
abnormality that, in the investigator’s opinion, could adversely affect the safety of the
subject, makes it unlikely that the course of treatment or follow-up would be completed,
or could impair the assessment of study results.