A Phase 3 Extension Study of Ataluren (PTC124®) in Subjects With Nonsense-Mutation-Mediated Cystic Fibrosis
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- PTC Therapeutics
- Enrollment
- 191
- Locations
- 31
- Primary Endpoint
- Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
Study Overview
Brief Summary
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 extension trial that will evaluate the long-term safety of ataluren in adult and pediatric participants with nonsense mutation CF (nmCF), as determined by adverse events and laboratory abnormalities. The study will also assess changes in pulmonary function, CF pulmonary exacerbations, health-related quality of life, antibiotic use for CF-related infections, CF-related disruptions to daily living, body weight, and CF pathophysiology. Funding source for this study is the FDA OOPD.
Detailed Description
This Phase 3, open-label, safety and efficacy study will be performed at sites in North America, Europe, and Israel. The study will enroll up to approximately 208 participants with nmCF who participated in a previous Phase 3 study of ataluren (PTC124-GD-009-CF [Study 009], NCT00803205). Participants will receive study drug 3 times per day (TID) (at breakfast, lunch, and dinner) for approximately 48 weeks (approximately 1 year). Study assessments will be performed at clinic visits every 8 weeks.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Masking Description
This extension study was not blinded. The investigators and participants remained blinded to the Study 009 treatment assignments throughout participation in Study PTC124-GD-009e-CF.
Eligibility Criteria
- Ages
- 6 Years to — (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Completion of blinded study drug treatment in the previous Phase 3 study (PTC124-GD-009-CF).
- •Ability to provide written informed consent (parental/guardian consent if applicable)/assent (if <18 years of age).
- •In participants who are sexually active, willingness to abstain from sexual intercourse or employ a barrier or medical method of contraception during ataluren administration and the 4-week follow up period.
- •Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions.
Exclusion Criteria
- •Known hypersensitivity to any of the ingredients or excipients of the study drug (list provided at study sites).
- •Current pregnancy or lactating, or pregnancy or lactating during the previous Phase 3 study.
- •Ongoing participation in any other therapeutic clinical trial.
- •Prior or ongoing medical condition (for example, concomitant illness, psychiatric condition, behavioral disorder, alcoholism, drug abuse), medical history, physical findings, 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.
Arms & Interventions
Ataluren/Ataluren
Participants who received double-blind ataluren during Study 009 will continue to receive open-label ataluren 3 times per day TID: 10 milligram (mg)/kilogram (kg) of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total dose 40 mg/kg/day), for up to 96 weeks. Participants will be followed for 4 weeks after treatment.
Intervention: Ataluren (Drug)
Placebo/Ataluren
Participants who received double-blind placebo during Study 009 will receive open-label ataluren TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total dose 40 mg/kg/day), for up to 96 weeks. Participants will be followed for 4 weeks after treatment.
Intervention: Ataluren (Drug)
Outcomes
Primary Outcomes
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time Frame: Baseline (Week 1 [Total Study Week 48]) up to 4 Weeks Post-Treatment (Week 100 [Total Study Week 148]) or Premature Discontinuation (PD) (whichever occurred first)
A TEAE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship that occurred or worsened in the period extending from the first dose of study drug to 6 weeks after the last dose of study drug. A serious adverse event (SAE) was an adverse event (AE) resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. AE severity was graded as follows: Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening; Grade 5: fatal. A TEAE was considered related if in the opinion of the Investigator it was possibly or probably caused by the study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the Adverse Events module.
Number of Participants With Any Treatment-Emergent Laboratory Abnormality (TELA)
Time Frame: Baseline (Week 1 [Total Study Week 48]) up to 4 Weeks Post-Treatment (Week 100 [Total Study Week 148]) or PD (whichever occurred first)
A TELA is any abnormal laboratory value that started or worsened after administration of study drug. Abnormal values were defined as values outside normal range. Values considered abnormal included -Hepatic: Serum total bilirubin ≥1.5\*upper limit of normal (ULN); serum gamma glutamyl transferase \>2.5\*ULN; serum alanine aminotransferase increase of \>150 units/liter (U/L) without increased creatine kinase; -Adrenal: plasma adrenocorticotropic hormone \>ULN (normal cortisol); -Renal: serum cystatin C \>1.33 milligrams (mg)/L; serum creatinine \>ULN-1.5\*ULN for age; serum blood urea nitrogen ≥1.5\*ULN; urine protein:creatinine \>0.40 mg/deciliter (dL):mg/dL; urine protein:osmolality \>0.30 mg/L:milliosmoles/kilogram; urine blood 2+; - Serum Electrolytes: serum sodium \>150 millimoles (mmol)/L, \<130 mmol/L; serum potassium \>5.5, \<3.0 mmol/L; serum magnesium \>1.23 mmol/L, \<0.5 mmol/L; total serum calcium \>2.9 mmol/L, \<2.0 mmol/L; serum phosphorous \<0.8 mmol/L; serum biocarbonate- \<16 mmol/L.
Secondary Outcomes
- Percentage Change From Baseline in Percent-Predicted of FEV1 at Weeks 48 and 96(Week 48 (Total Study Week 96), End of Treatment (EOT) (Week 96 [Total Study Week 144]))
- Total Lung Computed Tomography (CT) Score at Weeks 48 and 96(Week 48 (Total Study Week 96) and EOT (Week 96 [Total Study Week 144]))
- Percent-Predicted of Forced Vital Capacity (FVC) at Baseline(Baseline (Week 1 [Total Study Week 48]))
- Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks(Baseline (Week 1 [Total Study Week 48]) up to Week 48 (Total Study Week 96))
- Number of Participants With Severe Pulmonary Exacerbations as Defined by Modified Fuch's Criteria(Weeks 43 up to 48 and Weeks 91 up to 96 (Total Study Weeks 91 up to 96 and Weeks 139 up to 144))
- Change From Baseline for the Respiratory Domain Score of the Cystic Fibrosis (CF) Questionnaire-Revised (CFQ-R) at Weeks 48 and 96(Baseline (Week 1 [Total Study Week 48]), Week 48 (Total Study Week 96), EOT (Week 96 [Total Study Week 144]))
- Rate of Study Drug Compliance(Baseline (Week 1 [Total Study Week 48]) up to EOT (Week 96 [Total Study Week 144]))
- Predose Concentration of Ataluren(Predose at Weeks 1, 16, 32, 48, 64, 80 and EOT (Week 96) (Total Study Weeks 48, 64, 80 96, 112, 128, and 144, respectively))
- Number of Participants Who Required Interventions for Pulmonary Symptoms(Baseline (Week 1 [Total Study Week 48]) up to EOT (Week 96 [Total Study Week 144]))
- Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in 1 Second (FEV1) at Baseline(Baseline (Week 1 [Total Study Week 48]))
- Percentage Change From Baseline in Percent-Predicted of FVC at Weeks 48 and 96(Week 48 (Total Study Week 96), EOT (Week 96 [Total Study Week 144]))
- Change From Baseline in the Concentration of Sweat Chloride at Week 48(Baseline (Week 1 [Total Study Week 48]), Week 48 (Total Study Week 96))
- Percent-Predicted of Forced Expiratory Flow Between 25% and 75% of Expiration (FEF25-75) at Baseline(Baseline (Week 1 [Total Study Week 48]))
- Percentage Change From Baseline in Percent-Predicted of FEF25-75 at Weeks 48 and 96(Week 48 (Total Study Week 96), EOT (Week 96 [Total Study Week 144]))
- Number of Participants With Pulmonary Exacerbations as Defined by Modified Fuch's Criteria(Baseline (Week 1 [Total Study Week 48]) up to Week 48 and EOT (Week 96) (Total Study Weeks 96 and 144))
- Duration of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria(Weeks 43 up to 48 and Weeks 91 up to 96 (Total Study Weeks 91 up to 96 and Weeks 139 up to 144))
- Number of Participants With Disruptions in Activities of Daily Living Because of Pulmonary Symptoms(Baseline (Week 1 [Total Study Week 48]) up to EOT (Week 96 [Total Study Week 144]))
- Duration of Disruptions in Activities of Daily Living Because of Pulmonary Symptoms(Baseline (Week 1 [Total Study Week 48]) up to EOT (Week 96 [Total Study Week 144]))
- Change From Baseline in Body Weight at Weeks 48 and 96(Baseline (Week 1 [Total Study Week 48]), Week 48 (Total Study Week 96), EOT (Week 96 [Total Study Week 144]))
- Change From Baseline in Body Mass Index (BMI) at Weeks 48 and 96(Baseline (Week 1 [Total Study Week 48]), Week 48 (Total Study Week 96), EOT (Week 96 [Total Study Week 144]))
- Change From Baseline in the Nasal Transepithelial Potential Difference (TEPD) at Week 48(Baseline (Week 1 [Total Study Week 48]) and Week 48 (Total Study Week 96))