Study of Ataluren (PTC124) in Nonambulatory Participants With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy (nmDMD/BMD)
Study of Ataluren (PTC124) in Nonambulatory Participants With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy (nmDMD/BMD)
Duchenne/Becker muscular dystrophy (DMD/BMD) is a genetic disorder that develops in boys. It
 is caused by a mutation in the gene for dystrophin, a protein that is important for
 maintaining normal muscle structure and function. Loss of dystrophin causes muscle fragility
 that leads to weakness and loss of walking ability during childhood and teenage years. A
 specific type of mutation, called a nonsense (premature stop codon) mutation is the cause of
 DMD/BMD in approximately 10-15% of boys with the disease. Ataluren (PTC124) is an orally
 delivered, investigational drug that has the potential to overcome the effects of the
 nonsense mutation. This study is a Phase 2a trial that enrolled boys with nonsense mutation
 DMD/BMD who have lost independent mobility due to the disease. This study evaluated the
 safety and tolerability of ataluren (PTC124) and also evaluated efficacy outcomes in this
 participant population.
It was planned that this Phase 2a, open-label, safety and efficacy study to be performed at 5
 sites in the US and 1 site in the United Kingdom.

 The study was to enroll ~30 boys with nonsense mutation DMD/BMD (nmDBMD) who have been
 nonambulatory for at least 1 year. Enrollment was to be stratified to ensure evaluation of
 ~15 participants who were receiving chronic corticosteroid therapy and of ~15 participants
 who were not receiving chronic corticosteroid therapy. Participants were to take ataluren 3
 times per day (at breakfast, lunch, and dinner) for 48 weeks (~1 year). Study assessments
 were to be performed at clinic visits during screening, every 6 weeks for 2 visits and then
 every 12 weeks until the end of the study. Additional safety laboratory testing was to be
 required 4 times during the course of the study; this could have been performed at the
 investigational site, at an accredited local laboratory or clinic, or in the participant's
 home using a nursing service. When the blind for a similar study (PTC124-GD-007-DMD;
 NCT00592553) was revealed, the results indicated lack of efficacy for the high dose.
 Therefore, even though an independent data monitoring committee (DMC) agreed that both
 ataluren dose levels were well tolerated by the participants, the DMC recommended
 discontinuing ongoing studies with participants with nmDBMD receiving high-dose ataluren.
Inclusion Criteria:

 -  Diagnosis of DMD or BMD

 -  Presence of a nonsense mutation in the dystrophin gene

 -  Unable to ambulate independently for ≥1 year due to DMD/BMD

 -  Presence of sufficient shoulder and elbow function to perform study-related functional
 procedures (for example, 9-hole peg test)

 -  Adequate hepatic, renal, and adrenal function

 -  Ability to provide evaluable pretreatment echocardiogram and lung function assessments

 -  Willingness and ability to comply with scheduled visits, drug administration plan,
 study procedures, laboratory tests, and study restrictions

 -  Ability to provide written informed consent (parental/guardian consent if
 applicable)/assent (if <18 years of age)

 Exclusion Criteria:

 -  Initiation of systemic corticosteroid therapy within 6 months prior to start of study
 treatment or use of systemic aminoglycoside antibiotic within 3 months prior to start
 of study treatment

 -  Use of any intermittent systemic corticosteroid therapy regimen (for example, 10 days
 on followed by 10 days off, weekend dosing, every-other-day dosing); note that
 participants must have either been receiving a daily dosing regimen of prednisone,
 prednisolone, or deflazacort at the time of enrollment into the study or must have not
 been receiving any systemic corticosteroids

 -  Any change in treatment for congestive heart failure within 3 months prior to start of
 study treatment

 -  Ongoing warfarin or phenytoin therapy

 -  Prior therapy with ataluren

 -  Known hypersensitivity to any of the ingredients or excipients of ataluren (Litesse®
 UltraTM [refined polydextrose], polyethylene glycol 3350, Lutrol® micro F127
 [poloxamer 407], mannitol 25C, crospovidone XL10, hydroxyethyl cellulose, vanilla, Cab
 O Sil® M5P [colloidal silica], magnesium stearate).

 -  Exposure to another investigational drug within 2 months prior to start of study
 treatment

 -  History of major surgical procedure within 1 month prior to start of study treatment
 or expectation of major surgical procedure (for example, scoliosis surgery) during the
 48-week treatment period of the study

 -  Ongoing immunosuppressive therapy (other than corticosteroids)

 -  Ongoing participation in any other clinical trial

 -  Requirement for daytime ventilator assistance

 -  Uncontrolled clinical symptoms and signs of congestive heart failure

 -  Prior or ongoing medical condition (for example, concomitant illness, psychiatric
 condition, behavioral disorder, alcoholism, drug abuse), medical history, physical
 findings, electrocardiogram (ECG) 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