Study of Ataluren (PTC124) in Cystic Fibrosis

Study Overview
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Brief Summary
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The primary objective of this study is to determine the long-term safety and tolerability of ataluren in participants with nonsense mutation cystic fibrosis (nmCF) who completed participation in the double-blind study PTC124-GD-009-CF (NCT00803205), as assessed by adverse events and laboratory abnormalities. The secondary objective of this study includes the assessment of the efficacy of ataluren, as measured by forced expiratory volume in 1 second (FEV1) and pulmonary exacerbation rate, and other safety parameters (for example, 12-lead electrocardiogram [ECG] measurements, vital signs).

Official Title
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An Open-Label Safety and Efficacy Study for Patients With Nonsense Mutation Cystic Fibrosis Previously Treated With Ataluren (PTC124)

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Ataluren


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Ability to provide written informed consent (parental/guardian consent and participant assent if less than [<] 18 years of age). Evidence of completed participation in the double-blind study, PTC124-GD-009-CF (Study 009). Body weight greater than or equal to (≥) 16 kilograms (kg). Performance of a valid, reproducible spirometry test using the study-specific spirometer during the screening period. Confirmed laboratory values within the central laboratory ranges at screening. In male and female 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 60-day follow-up period. Willingness and ability to comply with all study procedures and assessments, including scheduled visits, drug administration plan, laboratory tests, and study restrictions. Key Exclusion Criteria: Chronic use of systemic tobramycin within 4 weeks prior to screening. Evidence of pulmonary exacerbation or acute upper or lower respiratory tract infection (including viral illnesses) within 3 weeks prior to screening or between screening and randomization. Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or re-initiation) in a chronic treatment/prophylaxis regimen for CF or for CF-related conditions within 4 weeks prior to screening and randomization. Known hypersensitivity to any of the ingredients or excipients of the study drug. Exposure to another investigational drug within 4 weeks prior to screening. Treatment with intravenous antibiotics within 3 weeks prior to screening. History of solid organ or hematological transplantation. Ongoing immunosuppressive therapy (other than corticosteroids). Positive hepatitis B surface antigen, hepatitis C antibody test or human immunodeficiency virus (HIV) test. Known portal hypertension. Pregnancy or breast-feeding.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ataluren<br>Participants will receive ataluren suspension orally 3 times a day (TID), 10 milligrams/kilogram (mg/kg) at morning, 10 mg/kg at midday, and 20 mg/kg at evening (total daily dose 40 mg/kg) for 192 weeks. | Drug: Ataluren<br>* Ataluren will be administered per dose and schedule specified in the arm.<br>* Other names: PTC124;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | AE: any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severity of an AE was classified as: mild (does not interfere with usual function), moderate (interferes to some extent with usual function), severe (interferes significantly with usual function), life threatening (results in potential threat to life), and fatal AEs. Drug-related AEs: AEs with a possible or probable relationship to study drug. Serious AEs: death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention. TEAE: AE that occurred or worsened from first dose of study drug to 4 weeks after last dose of study drug. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline (Day 1) up to end of study (Week 196) | 
| Number of Participants With Clinically Significant Laboratory Abnormalities | Laboratory parameters tests included hematology, biochemistry assay (hepatic, renal, and serum electrolyte values), adrenal assays, and urinalysis. Clinical significance was defined as per investigator's judgement. | Baseline (Day 1) up to end of study (Week 196) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at the End of Treatment (Week 192), as Assessed by Spirometry | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Percent of predicted FEV1 = (observed value)/(predicted value) * 100%. Change from baseline in percent predicted FEV1 at the end of treatment was reported. | Baseline, Week 192 | 
| Percentage of Participants With Pulmonary Exacerbation, As Assessed by Modified Fuchs Criteria | The modified Fuchs' criteria defined exacerbation as the presence of at least 4 of the following 12 Fuchs' signs and symptoms without the requirement for treatment with antibiotics: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature greater than (>) 38 degrees celsius (°C); anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary function. | Baseline up to Week 192 | 
| Percentage of Participants With Pulmonary Exacerbation, As Assessed by Expanded Fuchs' Criteria | The expanded Fuchs' criteria defined exacerbation as the presence of at least 4 of the following 12 Fuchs' signs and symptoms requiring any form of antibiotic treatment (inhaled, oral, or intravenous): change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature >38°C; anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary function. | Baseline up to Week 192 | 
| Percentage of Participants With Pulmonary Exacerbation, As Assessed by Classic Fuchs' Criteria | The Classic Fuchs' criteria defined exacerbation as the presence of at least 4 of the following 12 Fuchs' signs and symptoms requiring treatment with parenteral antibiotics: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; fatigue; temperature >38°C; anorexia; sinus pain; change in sinus discharge; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary function. | Baseline up to Week 192 | 
| Change From Baseline in 12-Lead Electrocardiogram (ECG) Parameters at Final Visit (Week 196) | ECG parameters included RR duration, PR duration, QRS duration, QT duration, QTCB (Bazett's correction formula) duration, QTCF (Fridericia's correction formula) duration. | Baseline, Week 196 | 
| Change From Baseline in Heart Rate at Final Visit (Week 196), as Assessed by 12-Lead ECG | Heart rate was measured using 12-lead ECG. | Baseline, Week 196 | 
| Change From Baseline in Vital Signs at Final Visit (Week 196) | Vital Signs included systolic blood pressure (SBP) and diastolic blood pressure (DBP). | Baseline, Week 196 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic fibrosis, Nonsense mutation, Premature stop codon, PTC124, Ataluren