Study of Ataluren (PTC124™) in Cystic Fibrosis

Cystic fibrosis (CF) is a genetic disorder caused by a mutation in the gene that makes the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A specific type of mutation called a nonsense (premature stop codon) mutation is the cause of CF in approximately 10% of patients with the disease. Ataluren is an orally delivered investigational drug that has the potential to overcome the effects of the nonsense mutation. This study is a Phase 3 trial that will evaluate the clinical benefit of ataluren in adult and pediatric participants with CF due to a nonsense mutation. The main goals of the study are to understand whether ataluren can improve pulmonary function and whether the drug can safely be given for a long period of time. The study will also assess the effects of ataluren on CF pulmonary exacerbation frequency, cough frequency, health-related quality of life, antibiotic use for CF-related infections, CF-related disruptions to daily living, body weight, and CF pathophysiology.

This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, efficacy and safety study, designed to document the clinical benefit of ataluren when administered as therapy of participants with CF due to a nonsense mutation (premature stop codon) in the CFTR gene. It is planned that \~208 participants who are ≥6 years of age and have a forced expiratory volume in 1 second (FEV1) ≥40% and ≤90% of predicted will be enrolled. Study participants will be enrolled at sites in North America, Europe, and Israel. They will be randomized in a 1:1 ratio to either ataluren or placebo. Participants will receive study drug 3 times per day (at morning, midday, and evening) for 48 weeks. Participants will be evaluated at clinic visits every 8 weeks. Additional safety laboratory testing, which may be performed at the investigational site or at an accredited local laboratory or clinic, is required every 4 weeks for the first 6 months of study participation. At the completion of blinded treatment, all compliant participants will be eligible to receive open-label ataluren in a separate extension study.

Eligibility Criteria:
Inclusion Criteria:

* Ability to provide written informed consent (parental/guardian consent and participant assent if \<18 years of age)
* Age ≥6 years
* Body weight ≥16 kg
* Abnormal nasal transepithelial potential difference (TEPD) total chloride conductance (a less electrically negative value than -5 millivolts (mV) for total chloride conductance \[Δchloride-free+isoproterenol\])
* Sweat chloride \>40 milliequivalents/liter (mEq/L)
* Documentation of the simultaneous presence of a nonsense mutation in at least 1 allele of the CFTR gene and a CF-causing mutation in the other CFTR allele, as determined by gene sequencing from a laboratory certified by the College of American Pathologists (CAP), under the Clinical Laboratory Improvement Act/Amendment (CLIA), or by an equivalent organization
* Verification that a blood sample has been drawn for confirmation of the presence of a nonsense mutation in the CFTR gene
* Ability to perform a valid, reproducible spirometry test using the study-specific spirometer with demonstration of an FEV1 ≥40% and ≤90% of predicted for age, gender, and height
* Resting oxygen saturation (as measured by pulse oximetry) ≥92% on room air
* Documentation by VivoMetrics that the participant has satisfactorily completed a 24-hour LifeShirt® cough frequency assessment
* Confirmed screening laboratory values within the central laboratory ranges (hepatic, adrenal, renal, serum electrolytes, and reproduction \[women only\] parameters)
* In participants 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
* Willingness and ability to comply with scheduled visits, drug administration plan, study restrictions, and study procedures

Exclusion Criteria:

* Known hypersensitivity to any of the ingredients or excipients of the study drug
* Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or reinitiation) in a chronic treatment/prophylaxis regimen for CF or for CF-related conditions within 4 weeks prior to start of study treatment
* Exposure to another investigational drug within 4 weeks prior to start of study treatment
* Treatment with systemic aminoglycoside antibiotics at the time of the Baseline TEPD assessment
* Treatment with intravenous antibiotics within 3 weeks prior to start of study treatment
* History of solid organ or hematological transplantation
* Ongoing immunosuppressive therapy (other than corticosteroids)
* Ongoing warfarin, phenytoin, or tolbutamide therapy
* Ongoing participation in any other therapeutic clinical trial
* Major complications of lung disease (including massive hemoptysis, pneumothorax, or pleural effusion) within 8 weeks prior to start of study treatment
* Evidence of pulmonary exacerbation or acute upper or lower respiratory tract infection (including viral illnesses) within 3 weeks prior to randomization
* Known portal hypertension
* Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test
* Pregnancy or breast-feeding
* Current smoker or a smoking history of ≥10 pack-years (number of cigarette packs/day \* number of years smoked)
* Prior or ongoing medical condition (for example, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, electrocardiography 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.