Cystic Fibrosis
Conditions
Keywords
Cystic fibrosis, Nonsense mutation, Premature stop codon, PTC124, Ataluren, PTC Therapeutics
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 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.
Detailed description
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.
Interventions
DRUGAtaluren
Ataluren will be provided as a vanilla-flavored powder to be mixed with water.
DRUGPlacebo
Placebo matching to ataluren will be provided.
Sponsors
Cystic Fibrosis Foundation
PTC Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in One Second (FEV1) at Baseline | Baseline (Week 1) | Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FEV1 (the amount of air that can be exhaled in 1 second). Spirometry was assessed by using current guidelines of the American Thoracic Society (ATS) and European Respiratory Society (ERS). Baseline was the average of percent-predicted FEV1 at screening and randomization. |
| Percentage Change From Baseline in Percent-Predicted of FEV1 at Week 48 | End of Treatment (EOT) (Week 48) | Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FEV1 (the amount of air that can be exhaled in 1 second). Spirometry was assessed by using current guidelines of the American Thoracic Society (ATS) and European Respiratory Society (ERS). The percentage of change in percent-predicted of FEV1 was calculated as follows: (\[percent-predicted FEV1-Baseline percent-predicted FEV1\]/Baseline percent-predicted FEV1)\*100. Baseline was the average of percent-predicted FEV1 at screening and randomization. A negative change from Baseline indicates that percent-predicted of FEV1 decreased. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Percent-Predicted of FVC at Week 48 | EOT (Week 48) | Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FVC (the amount of air that can be exhaled after taking a deep breath). Spirometry was assessed by using current guidelines of the ATS and ERS. The percentage of change in percent-predicted of FVC was calculated as follows: ((percent-predicted FVC-Baseline percent-predicted FVC)/Baseline percent-predicted FVC)\*100. Baseline was the average of percent-predicted FVC at screening and randomization. A negative change from Baseline indicates that percent-predicted of FVC decreased. |
| Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks | Baseline to EOT (Week 48) | A Respiratory Event Form, which collected data on various signs, symptoms, and effects for each event, was completed by the Investigator when informed by the participant of a respiratory event. Pulmonary exacerbations were assessed by using the modified Fuchs' criteria, which defines an exacerbation as a respiratory event requiring treatment with parenteral antibiotics for any 4 of the following 12 symptoms, with or without intravenous 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% or more from a previously recorded value; or radiographic changes indicative of pulmonary function. The 48-week exacerbation rate was determined by adding the weekly rates for each arm and dividing the sum by 48. |
| Change From Baseline in Awake Cough Hourly Rate at Week 48 | Baseline, EOT (Week 48) | The frequency of awake cough was measured using the LifeShirt, which incorporates motion-sensing transducers, electrodes, a microphone, and a 3-axis accelerometer into a lightweight vest. The rate was determined by dividing the total number of coughs by 24 (the number of hours of the observation period). Baseline was the latest, valid assessment prior to the treatment. A negative change from Baseline indicates that coughing decreased. |
| Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48 | Baseline, EOT (Week 48) | The CFQ-R consists of 44 items, including generic scales of physical functioning, role functioning, vitality, health perceptions, emotional functioning, and social functioning, and CF-specific scales of respiratory and digestive symptoms, body image, eating disturbances, and treatment burden. Each domain score ranges from 1 to 4. Scores were linearly transformed to a 0 to 100 scale, with higher scores indicating better health. Domain scores were calculated by using the following formula: 100 \* (sum of responses - minimum possible sum)/ (maximum possible sum - minimum possible sum). The minimum possible sum = number of questions \* 1; the maximum possible = the number of questions \* 4. Baseline was the latest, valid assessment prior to the treatment. A negative change from Baseline indicates that health has worsened. Participants may have switched age groups during the study. |
| Percent-Predicted of Forced Vital Capacity (FVC) at Baseline | Baseline (Week 1) | Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FVC (the amount of air that can be exhaled after taking a deep breath). Spirometry was assessed by using current guidelines of the ATS and ERS. Baseline was the average of percent-predicted FVC at screening and randomization. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Rate of Disruptions in Activities of Daily Living Because of Pulmonary Symptoms | Baseline up to EOT (Week 48) | During treatment, any disruption in the activities of daily living, such as missed school or work, was documented if it was due to an exacerbation-like episode. Participants and caregivers recorded all disruptions in an electronic diary. The rate of disruptions was defined as the total days with disruptions to daily living divided by the total study duration. |
| Change From Baseline in Body Weight at Week 48 | Baseline, EOT (Week 48) | Participants were weighed, and the weight was recorded at Baseline and then every 8 weeks during the treatment period. Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that weight increased. |
| Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48 | Baseline, EOT (Week 48) | Expression of IL-8 was measured in serum and in sputum. Sputum was spontaneously produced and tested by using standardized procedures developed by the Cystic Fibrosis Foundation Therapeutics, Inc. Therapeutics Development Network (CFFT-TDN). Baseline was the latest valid assessment prior to the treatment. A negative change from Baseline indicates that the concentration of IL-8 decreased. |
| Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48 | Baseline, EOT (Week 48) | Expression of neutrophil elastase was measured in sputum. Sputum was spontaneously produced and tested by using standardized procedures developed by the CFFT-TDN. Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that the concentration of neutrophil elastase increased. |
| Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48 | Baseline, EOT (Week 48) | Expression of CRP was measured in serum. Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that CRP concentration increased. |
| Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48 | Baseline, EOT (Week 48) | Lungs were imaged by using non-contrast, spiral CT. The total lung score for each CT scan was established by the sum of 5 characteristics from the Brody scoring system, with scores ranging from 0 to 40.5, with lower scores indicating better lung function. The characteristics scored were bronchiectasis (score range 0 - 12), mucus plugging (score range 0- 6), peribronchial thickening (score range 0 - 9), parenchyma (score range 0 - 9), and hyperinflation (score range 0 - 4.5). Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that lung function worsened. |
| Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48 | Baseline, EOT (Week 48) | TEPD was assessed in each nostril using standardized equipment, techniques, and solutions. Assessments were made on the nasal epithelium cells lining the inferior turbinate. Warmed solutions of Ringer's solution, amiloride, chloride-free gluconate, isoproterenol, and adenosine triphosphate (ATP) were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol - amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. Baseline was the latest, valid assessment prior to the treatment. A positive change from Baseline indicates that nasal chloride transport increased. |
| Change From Baseline in Sweat Chloride Concentration at Week 48 | Baseline, EOT (Week 48) | Sweat was collected, from each arm, by using pilocarpine iontophoresis. The chloride concentration in the sweat was quantified for each arm by using standard laboratory methods. Tests were also considered valid if the sweat collection time was ≤35 minutes; tests with longer collection times were also considered valid if extra time was needed to obtain sufficient volume (≥15uL) for analysis. For analysis purposes, the average of the values from each arm were computed. If the assessment was valid and/or available in only 1 arm, this value was used as if it were the average of both arms. The method used was consistent with the CFFT-TDN guidelines. Baseline was the latest, valid assessment prior to the treatment. A negative change from Baseline indicates that sweat chloride concentration decreased. |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Baseline up to 4 Weeks Post-Treatment (Week 52) or Premature Discontinuation (PD) | 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 first dose of study drug to 4 weeks after the last dose of study drug. A serious adverse event (SAE) was an 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. |
| Rate of Study Drug Compliance by Drug Accountability | Baseline up to EOT (Week 48) | Study drug compliance was assessed by using a Pharmacy Subject Study Drug Accountability Log (completed by the investigational site personnel). The rate of compliance was defined as 100 \* (number of sachets taken/number of planned sachets) during the study. All calculations were based on the records of the first dose date to the last dose date. To differentiate dose strengths while maintaining the blind, each kit had a unique kit number and had prominent lettering A and B. Each kit contained 65 packets of 1 of the dose strengths (125, 250, or 1000 mg or matching placebo). Labeling for active drug and placebo was identical. |
| Rate of Study Drug Compliance by Patient-Reported Data | Baseline up to EOT (Week 48) | Patient-reported data were obtained from the participant's electronic daily diary, which was completed by the participant or the caregiver. During study treatment, the electronic daily diary was to be completed by the participant or caregiver each day for each dose. For each participant, compliance is described in terms of the percentage of study drug actually taken. All calculations were based on the records of the first dose date to the last dose date. To differentiate dose strengths while maintaining the blind, each kit had a unique kit number and had prominent lettering A and B. Each kit contained 65 packets of 1 of the dose strengths (125, 250, or 1000 mg or matching placebo). Labeling for active drug and placebo was identical. |
| Concentration of Ataluren | Predose and 2 Hours Postdose at Week 1, Week 16, Week 32, EOT (Week 48) | Blood samples were drawn immediately before administration of the first daily dose (dose taken with breakfast) of study drug and 2 hours after the first daily dose. Whenever possible, the pre-dose sample was to be obtained within 15 minutes of drug administration. Participants in the Placebo arm did not receive Ataluren and are not included in this Outcome Measure. |
| Rate of Interventions for Respiratory Symptoms | Baseline up to EOT (Week 48) | During treatment, any intervention including hospitalization or use of oral, inhaled, or intravenous antibiotics was documented if it was due to an exacerbation-like episode. Participants and caregivers recorded interventions in an electronic diary. The rate of interventions was defined as the total days with interventions divided by the total study duration. |
Countries
Belgium, Canada, France, Germany, Israel, Italy, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
A total of 299 male and female participants with nonsense-mutation-mediated cystic fibrosis (nmCF) aged ≥6 years signed the informed consent form and were screened for eligibility, of which 61 did not meet entry criteria to participate in the study.
Pre-assignment details
A total of 238 participants were randomized in a 1:1 ratio to either ataluren or placebo. Six participants (4 in the ataluren arm; 2 in the placebo arm) were excluded from the Intent-to-Treat (ITT) population because they did not have at least 1 post-Baseline forced expiratory volume (FEV1) assessment by Week 8.
Participants by arm
| Arm | Count |
|---|---|
| Ataluren Participants received ataluren TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks. | 120 |
| Placebo Participants received placebo TID: 10 mg/kg of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment continued for 48 weeks, after which participants were followed for 4 weeks. | 118 |
| Total | 238 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Acquired a Lung Infection | 0 | 1 |
| Overall Study | Adverse Event | 7 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Medical Monitor Decision | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 9 | 9 |
Baseline characteristics
| Characteristic | Ataluren | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 23.0 years STANDARD_DEVIATION 10.06 | 23.2 years STANDARD_DEVIATION 9.24 | 23.1 years STANDARD_DEVIATION 9.64 |
| Sex: Female, Male Female | 58 Participants | 59 Participants | 117 Participants |
| Sex: Female, Male Male | 62 Participants | 59 Participants | 121 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 118 / 120 | 115 / 118 |
| serious Total, serious adverse events | 46 / 120 | 50 / 118 |
Outcome results
Primary
Percentage Change From Baseline in Percent-Predicted of FEV1 at Week 48
Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FEV1 (the amount of air that can be exhaled in 1 second). Spirometry was assessed by using current guidelines of the American Thoracic Society (ATS) and European Respiratory Society (ERS). The percentage of change in percent-predicted of FEV1 was calculated as follows: (\[percent-predicted FEV1-Baseline percent-predicted FEV1\]/Baseline percent-predicted FEV1)\*100. Baseline was the average of percent-predicted FEV1 at screening and randomization. A negative change from Baseline indicates that percent-predicted of FEV1 decreased.
Time frame: End of Treatment (EOT) (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataluren | Percentage Change From Baseline in Percent-Predicted of FEV1 at Week 48 | -2.534 percent change | Standard Deviation 13.2452 |
| Placebo | Percentage Change From Baseline in Percent-Predicted of FEV1 at Week 48 | -5.500 percent change | Standard Deviation 12.5595 |
Comparison: Least squares (LS) mean estimates based on mixed model for repeated measures (Weeks 8, 16, 24, 32, 40 and 48) of relative change in percent-predicted FEV1 as the dependent variable; independent variables including Baseline percent-predicted FEV1, treatment, visit, interactions between treatment and visit and between Baseline percent-predicted FEV1 and visit; and stratification factors of Baseline age, Baseline inhaled antibiotics, and Baseline percent-predicted FEV1.p-value: 0.123595% CI: [-0.756, 6.264]Mixed Models Analysis
Primary
Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in One Second (FEV1) at Baseline
Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FEV1 (the amount of air that can be exhaled in 1 second). Spirometry was assessed by using current guidelines of the American Thoracic Society (ATS) and European Respiratory Society (ERS). Baseline was the average of percent-predicted FEV1 at screening and randomization.
Time frame: Baseline (Week 1)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataluren | Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in One Second (FEV1) at Baseline | 62.092 percentage of predicted FEV1 | Standard Deviation 13.6159 |
| Placebo | Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in One Second (FEV1) at Baseline | 60.232 percentage of predicted FEV1 | Standard Deviation 15.1437 |
p-value: 0.3264ANOVA
Secondary
Change From Baseline in Awake Cough Hourly Rate at Week 48
The frequency of awake cough was measured using the LifeShirt, which incorporates motion-sensing transducers, electrodes, a microphone, and a 3-axis accelerometer into a lightweight vest. The rate was determined by dividing the total number of coughs by 24 (the number of hours of the observation period). Baseline was the latest, valid assessment prior to the treatment. A negative change from Baseline indicates that coughing decreased.
Time frame: Baseline, EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Awake Cough Hourly Rate at Week 48 | Baseline | 28.218 coughs/hour | Standard Deviation 20.2726 |
| Ataluren | Change From Baseline in Awake Cough Hourly Rate at Week 48 | Change From Baseline | -0.595 coughs/hour | Standard Deviation 18.3221 |
| Placebo | Change From Baseline in Awake Cough Hourly Rate at Week 48 | Baseline | 24.472 coughs/hour | Standard Deviation 16.7828 |
| Placebo | Change From Baseline in Awake Cough Hourly Rate at Week 48 | Change From Baseline | 0.882 coughs/hour | Standard Deviation 14.3936 |
Secondary
Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48
The CFQ-R consists of 44 items, including generic scales of physical functioning, role functioning, vitality, health perceptions, emotional functioning, and social functioning, and CF-specific scales of respiratory and digestive symptoms, body image, eating disturbances, and treatment burden. Each domain score ranges from 1 to 4. Scores were linearly transformed to a 0 to 100 scale, with higher scores indicating better health. Domain scores were calculated by using the following formula: 100 \* (sum of responses - minimum possible sum)/ (maximum possible sum - minimum possible sum). The minimum possible sum = number of questions \* 1; the maximum possible = the number of questions \* 4. Baseline was the latest, valid assessment prior to the treatment. A negative change from Baseline indicates that health has worsened. Participants may have switched age groups during the study.
Time frame: Baseline, EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48 | Aged 6-13 years, Baseline | 77.78 units on a scale | Standard Deviation 11.07 |
| Ataluren | Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48 | Age ≥14 years , Baseline | 70.06 units on a scale | Standard Deviation 15.678 |
| Ataluren | Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48 | Aged 6-13 years, Change From Baseline | -0.69 units on a scale | Standard Deviation 12.028 |
| Ataluren | Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48 | Age ≥14 years, Change From Baseline | -2.81 units on a scale | Standard Deviation 18.365 |
| Placebo | Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48 | Aged 6-13 years, Change From Baseline | -3.57 units on a scale | Standard Deviation 21.973 |
| Placebo | Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48 | Aged 6-13 years, Baseline | 79.49 units on a scale | Standard Deviation 16.879 |
| Placebo | Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48 | Age ≥14 years, Change From Baseline | -3.32 units on a scale | Standard Deviation 16.245 |
| Placebo | Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48 | Age ≥14 years , Baseline | 65.95 units on a scale | Standard Deviation 16.771 |
Secondary
Percentage Change From Baseline in Percent-Predicted of FVC at Week 48
Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FVC (the amount of air that can be exhaled after taking a deep breath). Spirometry was assessed by using current guidelines of the ATS and ERS. The percentage of change in percent-predicted of FVC was calculated as follows: ((percent-predicted FVC-Baseline percent-predicted FVC)/Baseline percent-predicted FVC)\*100. Baseline was the average of percent-predicted FVC at screening and randomization. A negative change from Baseline indicates that percent-predicted of FVC decreased.
Time frame: EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed 'signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataluren | Percentage Change From Baseline in Percent-Predicted of FVC at Week 48 | -2.139 percent change | Standard Deviation 10.0463 |
| Placebo | Percentage Change From Baseline in Percent-Predicted of FVC at Week 48 | -3.484 percent change | Standard Deviation 9.9304 |
Secondary
Percent-Predicted of Forced Vital Capacity (FVC) at Baseline
Spirometry was used to assess pulmonary function by measuring the percentage of predicted function, which was determined on the basis of the height value obtained at the same study visit, for FVC (the amount of air that can be exhaled after taking a deep breath). Spirometry was assessed by using current guidelines of the ATS and ERS. Baseline was the average of percent-predicted FVC at screening and randomization.
Time frame: Baseline (Week 1)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed 'signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataluren | Percent-Predicted of Forced Vital Capacity (FVC) at Baseline | 78.332 percentage of predicted FVC | Standard Deviation 13.1825 |
| Placebo | Percent-Predicted of Forced Vital Capacity (FVC) at Baseline | 76.609 percentage of predicted FVC | Standard Deviation 13.3711 |
Secondary
Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks
A Respiratory Event Form, which collected data on various signs, symptoms, and effects for each event, was completed by the Investigator when informed by the participant of a respiratory event. Pulmonary exacerbations were assessed by using the modified Fuchs' criteria, which defines an exacerbation as a respiratory event requiring treatment with parenteral antibiotics for any 4 of the following 12 symptoms, with or without intravenous 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% or more from a previously recorded value; or radiographic changes indicative of pulmonary function. The 48-week exacerbation rate was determined by adding the weekly rates for each arm and dividing the sum by 48.
Time frame: Baseline to EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ataluren | Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks | 1.42 exacerbations |
| Placebo | Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks | 1.78 exacerbations |
Other Pre-specified
Change From Baseline in Body Weight at Week 48
Participants were weighed, and the weight was recorded at Baseline and then every 8 weeks during the treatment period. Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that weight increased.
Time frame: Baseline, EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Body Weight at Week 48 | Baseline | 53.46 kg | Standard Deviation 13.941 |
| Ataluren | Change From Baseline in Body Weight at Week 48 | Change From Baseline | 0.87 kg | Standard Deviation 3.342 |
| Placebo | Change From Baseline in Body Weight at Week 48 | Baseline | 56.01 kg | Standard Deviation 13.149 |
| Placebo | Change From Baseline in Body Weight at Week 48 | Change From Baseline | 0.83 kg | Standard Deviation 3.101 |
Other Pre-specified
Change From Baseline in Sweat Chloride Concentration at Week 48
Sweat was collected, from each arm, by using pilocarpine iontophoresis. The chloride concentration in the sweat was quantified for each arm by using standard laboratory methods. Tests were also considered valid if the sweat collection time was ≤35 minutes; tests with longer collection times were also considered valid if extra time was needed to obtain sufficient volume (≥15uL) for analysis. For analysis purposes, the average of the values from each arm were computed. If the assessment was valid and/or available in only 1 arm, this value was used as if it were the average of both arms. The method used was consistent with the CFFT-TDN guidelines. Baseline was the latest, valid assessment prior to the treatment. A negative change from Baseline indicates that sweat chloride concentration decreased.
Time frame: Baseline, EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure. Two and 5 participants in the ataluren and placebo groups, respectively, were not evaluable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Sweat Chloride Concentration at Week 48 | Baseline | 100.140 millimoles/L | Standard Deviation 14.217 |
| Ataluren | Change From Baseline in Sweat Chloride Concentration at Week 48 | Change From Baseline | -1.325 millimoles/L | Standard Deviation 8.9431 |
| Placebo | Change From Baseline in Sweat Chloride Concentration at Week 48 | Change From Baseline | -0.619 millimoles/L | Standard Deviation 10.2657 |
| Placebo | Change From Baseline in Sweat Chloride Concentration at Week 48 | Baseline | 96.586 millimoles/L | Standard Deviation 15.9279 |
Other Pre-specified
Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48
Expression of CRP was measured in serum. Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that CRP concentration increased.
Time frame: Baseline, EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48 | Baseline | 6.899 mg/liter (L) | Standard Deviation 11.5869 |
| Ataluren | Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48 | Change From Baseline | 2.420 mg/liter (L) | Standard Deviation 10.5162 |
| Placebo | Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48 | Baseline | 7.037 mg/liter (L) | Standard Deviation 8.4411 |
| Placebo | Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48 | Change From Baseline | 2.031 mg/liter (L) | Standard Deviation 10.1202 |
Other Pre-specified
Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48
Expression of IL-8 was measured in serum and in sputum. Sputum was spontaneously produced and tested by using standardized procedures developed by the Cystic Fibrosis Foundation Therapeutics, Inc. Therapeutics Development Network (CFFT-TDN). Baseline was the latest valid assessment prior to the treatment. A negative change from Baseline indicates that the concentration of IL-8 decreased.
Time frame: Baseline, EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48 | Serum, Baseline | 39.537 picograms/mL | Standard Deviation 14.1697 |
| Ataluren | Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48 | Serum, Change From Baseline | -2.334 picograms/mL | Standard Deviation 13.2141 |
| Ataluren | Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48 | Sputum, Baseline | 267629.93 picograms/mL | Standard Deviation 259089.569 |
| Ataluren | Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48 | Sputum, Change From Baseline | 28882.79 picograms/mL | Standard Deviation 199160.845 |
| Placebo | Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48 | Sputum, Change From Baseline | 9957.24 picograms/mL | Standard Deviation 166348.66 |
| Placebo | Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48 | Serum, Baseline | 55.845 picograms/mL | Standard Deviation 131.8505 |
| Placebo | Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48 | Sputum, Baseline | 250170.95 picograms/mL | Standard Deviation 180581.976 |
| Placebo | Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48 | Serum, Change From Baseline | -16.197 picograms/mL | Standard Deviation 138.3108 |
Other Pre-specified
Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48
Expression of neutrophil elastase was measured in sputum. Sputum was spontaneously produced and tested by using standardized procedures developed by the CFFT-TDN. Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that the concentration of neutrophil elastase increased.
Time frame: Baseline, EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure. Twenty-two participants each in the ataluren and placebo groups were not evaluable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48 | Baseline | 183.64 ug/mL | Standard Deviation 221.901 |
| Ataluren | Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48 | Change From Baseline | 5.45 ug/mL | Standard Deviation 232.824 |
| Placebo | Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48 | Baseline | 227.35 ug/mL | Standard Deviation 227.881 |
| Placebo | Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48 | Change From Baseline | -8.67 ug/mL | Standard Deviation 296.105 |
Other Pre-specified
Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48
Lungs were imaged by using non-contrast, spiral CT. The total lung score for each CT scan was established by the sum of 5 characteristics from the Brody scoring system, with scores ranging from 0 to 40.5, with lower scores indicating better lung function. The characteristics scored were bronchiectasis (score range 0 - 12), mucus plugging (score range 0- 6), peribronchial thickening (score range 0 - 9), parenchyma (score range 0 - 9), and hyperinflation (score range 0 - 4.5). Baseline was the latest valid assessment prior to the treatment. A positive change from Baseline indicates that lung function worsened.
Time frame: Baseline, EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure. Eleven and 10 participants in the ataluren and placebo groups, respectively, were not evaluable.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48 | Baseline | 9.531 units on a scale | Standard Deviation 3.7526 |
| Ataluren | Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48 | Change From Baseline | 0.282 units on a scale | Standard Deviation 1.3441 |
| Placebo | Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48 | Baseline | 9.619 units on a scale | Standard Deviation 3.4244 |
| Placebo | Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48 | Change From Baseline | 0.560 units on a scale | Standard Deviation 1.5602 |
Other Pre-specified
Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48
TEPD was assessed in each nostril using standardized equipment, techniques, and solutions. Assessments were made on the nasal epithelium cells lining the inferior turbinate. Warmed solutions of Ringer's solution, amiloride, chloride-free gluconate, isoproterenol, and adenosine triphosphate (ATP) were perfused for ≥3-minute sequentially through a nasal catheter while a voltage tracing was recorded. Total chloride transport was computed for each nostril. The total chloride transport values were calculated by subtracting the voltages at the end of a perfusion from the voltage at the end of an earlier perfusion (isoproterenol - amiloride). The average of the values for each nostril was computed. If the assessment was available in only 1 nostril, this value was used as if it were the average of both nostrils. Baseline was the latest, valid assessment prior to the treatment. A positive change from Baseline indicates that nasal chloride transport increased.
Time frame: Baseline, EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48 | Baseline | 1.578 millivolts | Standard Deviation 3.8786 |
| Ataluren | Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48 | Change From Baseline | 0.312 millivolts | Standard Deviation 5.0574 |
| Placebo | Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48 | Baseline | 1.950 millivolts | Standard Deviation 3.5462 |
| Placebo | Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48 | Change From Baseline | 0.139 millivolts | Standard Deviation 5.8139 |
Other Pre-specified
Concentration of Ataluren
Blood samples were drawn immediately before administration of the first daily dose (dose taken with breakfast) of study drug and 2 hours after the first daily dose. Whenever possible, the pre-dose sample was to be obtained within 15 minutes of drug administration. Participants in the Placebo arm did not receive Ataluren and are not included in this Outcome Measure.
Time frame: Predose and 2 Hours Postdose at Week 1, Week 16, Week 32, EOT (Week 48)
Population: The As-Treated Population: all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ataluren | Concentration of Ataluren | Week 1 Predose | 0 micrograms/milliliter (ug/mL) |
| Ataluren | Concentration of Ataluren | Week 1 Postdose | 14.100 micrograms/milliliter (ug/mL) |
| Ataluren | Concentration of Ataluren | Week 16 Predose | 4.350 micrograms/milliliter (ug/mL) |
| Ataluren | Concentration of Ataluren | Week 16 Postdose | 11.900 micrograms/milliliter (ug/mL) |
| Ataluren | Concentration of Ataluren | Week 32 Predose | 4.630 micrograms/milliliter (ug/mL) |
| Ataluren | Concentration of Ataluren | Week 32 Postdose | 13.400 micrograms/milliliter (ug/mL) |
| Ataluren | Concentration of Ataluren | Week 48 Predose | 3.970 micrograms/milliliter (ug/mL) |
| Ataluren | Concentration of Ataluren | Week 48 Postdose | 10.500 micrograms/milliliter (ug/mL) |
Other Pre-specified
Percentage of Participants With Treatment-Emergent Adverse Events (TEAE)
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 first dose of study drug to 4 weeks after the last dose of study drug. A serious adverse event (SAE) was an 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.
Time frame: Baseline up to 4 Weeks Post-Treatment (Week 52) or Premature Discontinuation (PD)
Population: The As-Treated Population: all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | At least 1 TEAE | 98.3 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 1 TEAE | 15.0 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 2 TEAE | 67.5 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 3 TEAE | 15.8 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 4 TEAE | 0 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 5 TEAE | 0 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Unrelated TEAE | 25.0 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Unlikely related TEAE | 32.5 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Possibly related TEAE | 28.3 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Probably related TEAE | 12.5 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Discontinuation due to TEAE | 6.7 percent of participants |
| Ataluren | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE | 37.5 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Discontinuation due to TEAE | 2.5 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | At least 1 TEAE | 97.5 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Unrelated TEAE | 35.6 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 1 TEAE | 16.9 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Probably related TEAE | 5.9 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 2 TEAE | 55.1 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Unlikely related TEAE | 26.3 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 3 TEAE | 25.4 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Serious TEAE | 40.7 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 4 TEAE | 0 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Possibly related TEAE | 29.7 percent of participants |
| Placebo | Percentage of Participants With Treatment-Emergent Adverse Events (TEAE) | Grade 5 TEAE | 0 percent of participants |
Other Pre-specified
Rate of Disruptions in Activities of Daily Living Because of Pulmonary Symptoms
During treatment, any disruption in the activities of daily living, such as missed school or work, was documented if it was due to an exacerbation-like episode. Participants and caregivers recorded all disruptions in an electronic diary. The rate of disruptions was defined as the total days with disruptions to daily living divided by the total study duration.
Time frame: Baseline up to EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for specified categories.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ataluren | Rate of Disruptions in Activities of Daily Living Because of Pulmonary Symptoms | 0.037 days with disruptions per study | Standard Deviation 0.055 |
| Placebo | Rate of Disruptions in Activities of Daily Living Because of Pulmonary Symptoms | 0.047 days with disruptions per study | Standard Deviation 0.0755 |
Other Pre-specified
Rate of Interventions for Respiratory Symptoms
During treatment, any intervention including hospitalization or use of oral, inhaled, or intravenous antibiotics was documented if it was due to an exacerbation-like episode. Participants and caregivers recorded interventions in an electronic diary. The rate of interventions was defined as the total days with interventions divided by the total study duration.
Time frame: Baseline up to EOT (Week 48)
Population: The ITT Population: all randomized participants with data for FEV1 at Baseline and a minimum of 1 post-Baseline assessment before Week 8. Here, 'Number analyzed' signifies participants evaluable for specified categories.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ataluren | Rate of Interventions for Respiratory Symptoms | Hospitalization | 0.010 days with interventions per study | Standard Deviation 0.0222 |
| Ataluren | Rate of Interventions for Respiratory Symptoms | Use of Antibiotics | 0.220 days with interventions per study | Standard Deviation 0.2284 |
| Placebo | Rate of Interventions for Respiratory Symptoms | Hospitalization | 0.021 days with interventions per study | Standard Deviation 0.0469 |
| Placebo | Rate of Interventions for Respiratory Symptoms | Use of Antibiotics | 0.245 days with interventions per study | Standard Deviation 0.238 |
Other Pre-specified
Rate of Study Drug Compliance by Drug Accountability
Study drug compliance was assessed by using a Pharmacy Subject Study Drug Accountability Log (completed by the investigational site personnel). The rate of compliance was defined as 100 \* (number of sachets taken/number of planned sachets) during the study. All calculations were based on the records of the first dose date to the last dose date. To differentiate dose strengths while maintaining the blind, each kit had a unique kit number and had prominent lettering A and B. Each kit contained 65 packets of 1 of the dose strengths (125, 250, or 1000 mg or matching placebo). Labeling for active drug and placebo was identical.
Time frame: Baseline up to EOT (Week 48)
Population: The As-Treated Population: all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ataluren | Rate of Study Drug Compliance by Drug Accountability | Drug Kit A | 90.149 percent of doses taken |
| Ataluren | Rate of Study Drug Compliance by Drug Accountability | Drug Kit B | 90.830 percent of doses taken |
| Placebo | Rate of Study Drug Compliance by Drug Accountability | Drug Kit A | 85.119 percent of doses taken |
| Placebo | Rate of Study Drug Compliance by Drug Accountability | Drug Kit B | 86.614 percent of doses taken |
Other Pre-specified
Rate of Study Drug Compliance by Patient-Reported Data
Patient-reported data were obtained from the participant's electronic daily diary, which was completed by the participant or the caregiver. During study treatment, the electronic daily diary was to be completed by the participant or caregiver each day for each dose. For each participant, compliance is described in terms of the percentage of study drug actually taken. All calculations were based on the records of the first dose date to the last dose date. To differentiate dose strengths while maintaining the blind, each kit had a unique kit number and had prominent lettering A and B. Each kit contained 65 packets of 1 of the dose strengths (125, 250, or 1000 mg or matching placebo). Labeling for active drug and placebo was identical.
Time frame: Baseline up to EOT (Week 48)
Population: The As-Treated Population: all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ataluren | Rate of Study Drug Compliance by Patient-Reported Data | 71.48 percent of doses taken |
| Placebo | Rate of Study Drug Compliance by Patient-Reported Data | 69.27 percent of doses taken |