Clinical Research Studies
Ataluren Phase III Clinical Trial
A Phase 3 Efficacy and Safety Study of Ataluren (PTC124) in Patients with Nonsense Mutation
Craig McDonald, M.D.
Erica Goude, MS, CCRP
Dystrophinopathy is a disease continuum that includes Duchenne muscular dystrophy, which 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. A specific type of mutation, called a nonsense (premature stop codon) mutation is the cause of dystrophinopathy in approximately 10-15% of boys with the disease. Ataluren is an orally delivered, investigational drug that has the potential to overcome the effects of the nonsense mutation. The main goal of this Phase 3 study is to evaluate the effect of ataluren on walking ability. The effect of ataluren on physical function, quality of life, and activities of daily living will be evaluated. This study will also provide additional information on the long-term safety of ataluren.
ataluren 10, 10, 20 mg/kg or placebo for 48 weeks
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- Male sex.
- Age ≥7 and ≤16 years.
- Phenotypic evidence of dystrophinopathy based on the onset of characteristic clinical symptoms or signs (eg, proximal muscle weakness, waddling gait, and Gowers’ maneuver) by 6 years of age, an elevated serum CK, and ongoing difficulty with ambulation.
- Documentation of the presence of a nonsense point mutation in the dystrophin gene as determined by gene sequencing from a laboratory certified by College of American Pathologists (CAP), Clinical Laboratory Improvement Act/Amendment (CLIA), or an equivalent organization.
- Documentation that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the dystrophin gene.
- Use of systemic corticosteroids (prednisone, prednisolone, or deflazacort) for a minimum of 6 months immediately prior to start of study treatment, with no significant change in dosage or dosing regimen (not related to body weight change) 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.
- Valid Screening 6MWD ≥150 meters. Valid Screening 6MWD must be ≤80% of predicted for age and height [Geiger 2007].
- Results of the 2 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.
- Baseline 6MWD (mean of valid Day 1 and Day 2 values) must be no more than a 20% reduction from the valid Screening 6MWD.
- Confirmed screening laboratory values within the central laboratory ranges 12. 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 6-week follow-up period.
- Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions.
- Treatment with systemic aminoglycoside antibiotics within 3 months prior to start of study treatment.
- Initiation of systemic corticosteroid therapy within 6 months prior to start of study treatment.
- Change in systemic corticosteroid therapy (eg, change in type of drug, dose modification not related to body weight change, schedule modification, interruption, or reinitiation) within 3 months prior to start of study treatment.
- Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or reinitiation) in prophylaxis/treatment for congestive heart failure (CHF) within 3 months prior to start of study treatment.
- Ongoing use of coumarin-based anticoagulants (eg. warfarin), phenytoin, tolbutamide, or paclitaxel.
Prior therapy with ataluren.
- 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]
- Exposure to another investigational drug within 3 months prior to start of study treatment.
- History of major surgical procedure within 6 weeks prior to start of study treatment.
- Ongoing immunosuppressive therapy (other than corticosteroids).
- Ongoing participation in any clinical trial (except for studies specifically approved by PTC Therapeutics).
- Expectation of major surgical procedure (eg, scoliosis surgery) during the 12-month treatment period of the study.
- Requirement for daytime ventilator assistance.
- Uncontrolled clinical symptoms and signs of CHF (American College of Cardiology/American Heart Association Stage C or Stage D) [Hunt 2001].
- 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.