A Study of Ataluren in Pediatric Participants With Cystic Fibrosis
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis
Study type: Interventional
Phase: Phase 2

Summary: 
      In some participants with cystic fibrosis (CF), the disease is caused by a nonsense mutation
      (premature stop codon) in the gene that makes the cystic fibrosis transmembrane regulator
      (CFTR) protein. Ataluren has been shown to partially restore CFTR production in animals with
      CF due to a nonsense mutation. The main purpose of this study is to understand whether
      ataluren can safely increase functional CFTR protein in the cells of participants with CF due
      to a nonsense mutation.
    

Detailed description: 
      In this study, participants with CF due to a nonsense mutation will be treated with a new
      investigational drug called ataluren. Evaluation procedures (history, physical examination,
      blood and urine tests to assess organ function, electrocardiogram [ECG], chest x-ray, and
      CF-specific tests) to determine if a participant qualifies for the study will be performed
      within 21 days prior to the start of treatment. Eligible participants with
      nonsense-mutation-mediated CF will receive 2 repeated 28-day cycles, each comprising of 14
      days on therapy and 14 days off therapy. In a crossover design, participants will be
      randomized to receive ataluren treatment in Cycle 1 by either of the following regimens:

        -  Ataluren, given 3 times per day (TID) with a regimen of 4 milligrams/kilograms (mg/kg)
           at breakfast, 4 mg/kg at lunch, and 8 mg/kg at dinner, or

        -  Ataluren, given 3 TID with a regimen of 10 mg/kg at breakfast, 10 mg/kg at lunch and 20
           mg/kg at dinner.

      In Cycle 2, participants will then receive the drug according to the regimen opposite from
      that given in Cycle 1.

      There will be a 2-night stay at the clinical research center at the beginning and at the end
      of each 14 days of ataluren treatment, which means that there will be four 2-night stays at
      the clinical research center during the study. During the study, ataluren efficacy, safety,
      and pharmacokinetics (PK) will be evaluated periodically with measurements of transepithelial
      potential difference (TEPD), nasal mucosal brushing to assess for cellular CFTR messenger
      ribonucleic acid (mRNA) and protein, medical history, physical examinations, blood tests,
      sputum test, urinalysis, ECGs, chest x-ray, and pulmonary function tests.

      The measurement of TEPD, also known as nasal potential difference, provides a sensitive
      evaluation of sodium and chloride transport directly in secretory epithelial cells. TEPD
      assessments are made on the nasal epithelium cells lining the inferior turbinate because
      these cells are easier to access than the respiratory epithelial cells lining the lower
      airways and have been shown to have the same ion transport characteristics. As an endpoint,
      TEPD has the advantage that it can detect chloride transport changes that are a quantitative
      integration of the presence, functional activity, and apical location of the CFTR in airway
      cells. Furthermore, it is a direct measure of CFTR activity that is not likely to be affected
      by supportive or palliative treatments for CF (with the possible exception of systemically
      administered aminoglycoside antibiotics).
    

Intervention name(s): Ataluren
Intervention type(s): Drug
Intervention description(s): Ataluren will be provided as a vanilla-flavored powder to be mixed with water, milk, or apple juice. Participants are to receive a total of 42 doses of ataluren during each cycle, for a total of 84 doses of ataluren in both cycles.
Other intervention name(s): PTC124
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cystic fibrosis; Nonsense mutation; Premature stop codon