Study of Ataluren (PTC124™) in Cystic Fibrosis

• Sponsor: PTC Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00803205
• Collaborator: Cystic Fibrosis Foundation (Other)
• Enrollment: 238
• Locations: 38
• Arms: 2
• Actual Duration (Months): 26.1
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: Ataluren; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 238 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Efficacy and Safety Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis
• Actual Study Start Date: Sep 8, 2009
• Actual Primary Completion Date: Nov 12, 2011
• Actual Study Completion Date: Nov 12, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ataluren Participants will receive ataluren 3 times per day (TID): 10 milligrams (mg)/kilogram (kg) of body weight with breakfast, 10 mg/kg with lunch, and 20 mg/kg with dinner (total daily dose 40 mg/kg). Treatment will continue for 48 weeks, after which participants will be followed for 4 weeks.	Drug: Ataluren; Ataluren will be provided as a vanilla-flavored powder to be mixed with water.; Other Names: PTC124
Placebo Comparator: Placebo Participants will receive 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 will continue for 48 weeks, after which participants will be followed for 4 weeks.	Drug: Placebo; Placebo matching to ataluren will be provided.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Other Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama-Birmingham	Birmingham	Alabama	United States	35233
2	Miller Children's Hospital Long Beach	Long Beach	California	United States	90806
3	Lucile Packard Children's Hospital	Palo Alto	California	United States	94304
4	Stanford	Palo Alto	California	United States	94304
5	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
6	The Children's Hospital	Aurora	Colorado	United States	80045
7	University of Miami	Miami	Florida	United States	33136
8	Miami Children's Hospital	Miami	Florida	United States	33155
9	Emory University Cystic Fibrosis Center	Atlanta	Georgia	United States	30322
10	Children's Memorial Hospital	Chicago	Illinois	United States	60614
11	University of Iowa	Iowa City	Iowa	United States	52242
12	Johns Hopkins Children's Center	Baltimore	Maryland	United States	21287
13	Children's Hospital Boston	Boston	Massachusetts	United States	02115
14	Washington University	Saint Louis	Missouri	United States	63110
15	Beth Israel Medical Center	New York	New York	United States	10011
16	New York Medical College	Valhalla	New York	United States	10595
17	University of North Carolina	Chapel Hill	North Carolina	United States	27599
18	Rainbow Babies & Children's Hospital	Cleveland	Ohio	United States	44106
19	Childrens Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
20	University of Texas	Tyler	Texas	United States	75708
21	University of Washington	Seattle	Washington	United States	98195
22	Hôpital Erasme	Brussels		Belgium
23	Hôpital Universitaire des Enfants Reine Fabiola	Brussels		Belgium
24	University Hospital Brussels	Brussels		Belgium
25	University Hospital Leuven	Leuven		Belgium
26	University of Toronto	Toronto		Canada
27	Hôpital Cochin	Paris		France
28	Hôpital Necker - Enfants Malades	Paris		France
29	Hôpital des Enfants	Toulouse		France	31059
30	Klinikum der Universität Köln	Köln		Germany
31	Hadassah University Hospital - Mount Scopus	Jerusalem		Israel	91240
32	Università La Sapienza	Rome		Italy
33	Azienda Ospedaliera di Verona	Verona		Italy
34	Universitair Medisch Centrum Utrecht	Utrecht		Netherlands
35	Hospital Universitario La Paz	Madrid		Spain
36	Karolinska University Hospital, Huddinge	Stockholm		Sweden
37	Belfast City Hospital	Belfast		United Kingdom
38	Alder Hey Children's Hospital	Liverpool		United Kingdom

Sponsors and Collaborators

• PTC Therapeutics
• Cystic Fibrosis Foundation

Investigators

• Study Director: Temitayo Ajayi, MD, PTC Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: PTC Therapeutics
• ClinicalTrials.gov Identifier: NCT00803205
• Other Study ID Numbers: PTC124-GD-009-CF; Orphan Product Grant #FD003715; 2008-003924-52
• First Posted: Dec 5, 2008
• Last Update Posted: May 14, 2020
• Last Verified: May 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by PTC Therapeutics: Cystic fibrosis; Nonsense mutation; Premature stop codon; PTC124; Ataluren; PTC Therapeutics
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis

Study Results

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 Detail	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.

Arm/Group Title	Ataluren	Placebo
Arm/Group Description	Participants received ataluren 3 times daily (TID): 10 milligrams/kilogram (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.	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.
Period Title: Overall Study
STARTED	120	118
Completed Week 16	107	113
Completed Week 24	103	110
As-Treated Population*	120	118
ITT Population	116	116
Per Protocol Population	100	103
COMPLETED	100	104
NOT COMPLETED	20	14

Baseline Characteristics

Arm/Group Title	Ataluren	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	120	118	238
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	23.0 (10.06)	23.2 (9.24)	23.1 (9.64)
Sex: Female, Male (Count of Participants)
Female	58 48.3%	59 50%	117 49.2%
Male	62 51.7%	59 50%	121 50.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Predicted Function (Percent-Predicted) of Forced Expiratory Volume in One Second (FEV1) at Baseline
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Mean (Standard Deviation) [percentage of predicted FEV1]	62.092 (13.6159)	60.232 (15.1437)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ataluren, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3264
	Comments
	Method	ANOVA
	Comments

2. Primary Outcome

Title	Percentage Change From Baseline in Percent-Predicted of FEV1 at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Mean (Standard Deviation) [percent change]	-2.534 (13.2452)	-5.500 (12.5595)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ataluren, Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1235
	Comments	The p-value is the LS-mean for the comparison between active treatment and placebo. The level of significance was 0.04998.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.7540
	Confidence Interval	(2-Sided) 95%; -0.7560 to 6.2640
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.78124
	Estimation Comments

3. Secondary Outcome

Title	Rate of Pulmonary Exacerbations as Defined by Modified Fuch's Criteria Over 48 Weeks
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Mean (95% Confidence Interval) [exacerbations]	1.42	1.78

4. Secondary Outcome

Title	Change From Baseline in Awake Cough Hourly Rate at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Baseline	28.218 (20.2726)	24.472 (16.7828)
Change From Baseline	-0.595 (18.3221)	0.882 (14.3936)

5. Secondary Outcome

Title	Change From Baseline in the Respiratory Domain Score of the Revised Cystic Fibrosis Questionnaire (CFQ-R) at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Aged 6-13 years, Baseline	77.78 (11.070)	79.49 (16.879)
Aged 6-13 years, Change From Baseline	-0.69 (12.028)	-3.57 (21.973)
Age ≥14 years , Baseline	70.06 (15.678)	65.95 (16.771)
Age ≥14 years, Change From Baseline	-2.81 (18.365)	-3.32 (16.245)

6. Secondary Outcome

Title	Percent-Predicted of Forced Vital Capacity (FVC) at Baseline
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Mean (Standard Deviation) [percentage of predicted FVC]	78.332 (13.1825)	76.609 (13.3711)

7. Secondary Outcome

Title	Percentage Change From Baseline in Percent-Predicted of FVC at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Mean (Standard Deviation) [percent change]	-2.139 (10.0463)	-3.484 (9.9304)

8. Other Pre-specified Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (TEAE)
Description	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)

Outcome Measure Data

Analysis Population Description

The As-Treated Population: all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	120	118
At least 1 TEAE	98.3 81.9%	97.5 82.6%
Grade 1 TEAE	15.0 12.5%	16.9 14.3%
Grade 2 TEAE	67.5 56.3%	55.1 46.7%
Grade 3 TEAE	15.8 13.2%	25.4 21.5%
Grade 4 TEAE	0 0%	0 0%
Grade 5 TEAE	0 0%	0 0%
Unrelated TEAE	25.0 20.8%	35.6 30.2%
Unlikely related TEAE	32.5 27.1%	26.3 22.3%
Possibly related TEAE	28.3 23.6%	29.7 25.2%
Probably related TEAE	12.5 10.4%	5.9 5%
Discontinuation due to TEAE	6.7 5.6%	2.5 2.1%
Serious TEAE	37.5 31.3%	40.7 34.5%

9. Other Pre-specified Outcome

Title	Rate of Study Drug Compliance by Drug Accountability
Description	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)

Outcome Measure Data

Analysis Population Description

The As-Treated Population: all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	120	118
Drug Kit A	90.149	85.119
Drug Kit B	90.830	86.614

10. Other Pre-specified Outcome

Title	Rate of Study Drug Compliance by Patient-Reported Data
Description	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)

Outcome Measure Data

Analysis Population Description

The As-Treated Population: all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	120	118
Median (Full Range) [percent of doses taken]	71.48	69.27

11. Other Pre-specified Outcome

Title	Concentration of Ataluren
Description	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)

Outcome Measure Data

Analysis Population Description

The As-Treated Population: all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Ataluren
Arm/Group Description	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.
Measure Participants	120
Week 1 Predose	0
Week 1 Postdose	14.100
Week 16 Predose	4.350
Week 16 Postdose	11.900
Week 32 Predose	4.630
Week 32 Postdose	13.400
Week 48 Predose	3.970
Week 48 Postdose	10.500

12. Other Pre-specified Outcome

Title	Rate of Interventions for Respiratory Symptoms
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Hospitalization	0.010 (0.0222)	0.021 (0.0469)
Use of Antibiotics	0.220 (0.2284)	0.245 (0.2380)

13. Other Pre-specified Outcome

Title	Rate of Disruptions in Activities of Daily Living Because of Pulmonary Symptoms
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Mean (Standard Deviation) [days with disruptions per study]	0.037 (0.0550)	0.047 (0.0755)

14. Other Pre-specified Outcome

Title	Change From Baseline in Body Weight at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Baseline	53.46 (13.941)	56.01 (13.149)
Change From Baseline	0.87 (3.342)	0.83 (3.101)

15. Other Pre-specified Outcome

Title	Change From Baseline in the Concentration of Interleukin-8 (IL-8) in Serum and Sputum at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Serum, Baseline	39.537 (14.1697)	55.845 (131.8505)
Serum, Change From Baseline	-2.334 (13.2141)	-16.197 (138.3108)
Sputum, Baseline	267629.93 (259089.569)	250170.95 (180581.976)
Sputum, Change From Baseline	28882.79 (199160.845)	9957.24 (166348.660)

16. Other Pre-specified Outcome

Title	Change From Baseline in the Concentration of Neutrophil Elastase in Sputum at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	94	94
Baseline	183.64 (221.901)	227.35 (227.881)
Change From Baseline	5.45 (232.824)	-8.67 (296.105)

17. Other Pre-specified Outcome

Title	Change From Baseline in the Concentration of C-Reactive Protein (CRP) in Serum at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Baseline	6.899 (11.5869)	7.037 (8.4411)
Change From Baseline	2.420 (10.5162)	2.031 (10.1202)

18. Other Pre-specified Outcome

Title	Change From Baseline in the Total Lung Score as Assessed by Computed Tomography (CT) at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	105	106
Baseline	9.531 (3.7526)	9.619 (3.4244)
Change From Baseline	0.282 (1.3441)	0.560 (1.5602)

19. Other Pre-specified Outcome

Title	Change From Baseline in Total Nasal Chloride Transport as Assessed by Transepithelial Potential Difference (TEPD) at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	116	116
Baseline	1.578 (3.8786)	1.950 (3.5462)
Change From Baseline	0.312 (5.0574)	0.139 (5.8139)

20. Other Pre-specified Outcome

Title	Change From Baseline in Sweat Chloride Concentration at Week 48
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Ataluren	Placebo
Arm/Group Description	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.	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.
Measure Participants	114	111
Baseline	100.140 (14.2170)	96.586 (15.9279)
Change From Baseline	-1.325 (8.9431)	-0.619 (10.2657)

Adverse Events

Time Frame	Baseline up to 4 Weeks Post-Treatment (Week 52) or Premature Discontinuation (PD)
Adverse Event Reporting Description	The As-Treated Population: all randomized participants who received at least 1 dose of study drug.
Arm/Group Title	Ataluren		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Ataluren		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ataluren		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/120 (38.3%)		50/118 (42.4%)
Gastrointestinal disorders
Haematemesis	1/120 (0.8%)	1	0/118 (0%)	0
Intussusception	1/120 (0.8%)	1	0/118 (0%)	0
Pancreatitis	1/120 (0.8%)	1	1/118 (0.8%)	1
Abdominal pain	0/120 (0%)	0	1/118 (0.8%)	1
Constipation	0/120 (0%)	0	1/118 (0.8%)	1
Gastrointestinal obstruction	0/120 (0%)	0	1/118 (0.8%)	1
General disorders
Pyrexia	1/120 (0.8%)	1	0/118 (0%)	0
Drug withdrawal syndrome	0/120 (0%)	0	1/118 (0.8%)	1
Hepatobiliary disorders
Biliary colic	1/120 (0.8%)	1	0/118 (0%)	0
Cholelithiasis	1/120 (0.8%)	1	0/118 (0%)	0
Immune system disorders
Drug hypersensitivity	1/120 (0.8%)	1	1/118 (0.8%)	1
Infections and infestations
Pneumonia	2/120 (1.7%)	2	0/118 (0%)	0
Appendicitis	1/120 (0.8%)	1	0/118 (0%)	0
Pneumonia mycoplasmal	1/120 (0.8%)	2	0/118 (0%)	0
Urinary tract infection	1/120 (0.8%)	1	0/118 (0%)	0
Bronchopulmonary aspergillosis allergic	0/120 (0%)	0	1/118 (0.8%)	1
Gastroenteritis	0/120 (0%)	0	1/118 (0.8%)	1
Influenza	0/120 (0%)	0	1/118 (0.8%)	1
Mycobacterium abscessus infection	0/120 (0%)	0	2/118 (1.7%)	2
Injury, poisoning and procedural complications
Post procedural haemorrhage	1/120 (0.8%)	1	0/118 (0%)	0
Joint injury	0/120 (0%)	0	1/118 (0.8%)	1
Metabolism and nutrition disorders
Dehydration	1/120 (0.8%)	1	1/118 (0.8%)	1
Anorexia	0/120 (0%)	0	1/118 (0.8%)	1
Musculoskeletal and connective tissue disorders
Hypercreatinaemia	1/120 (0.8%)	1	0/118 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant melanoma	0/120 (0%)	0	1/118 (0.8%)	1
Psychiatric disorders
Depression	0/120 (0%)	0	1/118 (0.8%)	1
Renal and urinary disorders
Renal failure	3/120 (2.5%)	3	0/118 (0%)	0
Renal failure acute	3/120 (2.5%)	3	0/118 (0%)	0
Renal colic	1/120 (0.8%)	1	0/118 (0%)	0
Urinary retention	1/120 (0.8%)	1	0/118 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cystic fibrosis long	34/120 (28.3%)	47	41/118 (34.7%)	66
Haemoptysis	2/120 (1.7%)	2	3/118 (2.5%)	3
Nasal polyps	0/120 (0%)	0	1/118 (0.8%)	1
Vascular disorders
Thrombosis	0/120 (0%)	0	1/118 (0.8%)	1
Other (Not Including Serious) Adverse Events
	Ataluren		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	118/120 (98.3%)		115/118 (97.5%)
Gastrointestinal disorders
Abdominal pain	20/120 (16.7%)		14/118 (11.9%)
Vomiting	14/120 (11.7%)		11/118 (9.3%)
Diarrhoea	13/120 (10.8%)		21/118 (17.8%)
Abdominal pain upper	11/120 (9.2%)		7/118 (5.9%)
Nausea	11/120 (9.2%)		13/118 (11%)
Constipation	7/120 (5.8%)		9/118 (7.6%)
General disorders
Pyrexia	17/120 (14.2%)		22/118 (18.6%)
Fatigue	11/120 (9.2%)		11/118 (9.3%)
Infections and infestations
Viral upper respiratory tract infection	21/120 (17.5%)		32/118 (27.1%)
Sinusitis	15/120 (12.5%)		14/118 (11.9%)
Rhinitis	12/120 (10%)		13/118 (11%)
Nasopharyngitis	10/120 (8.3%)		8/118 (6.8%)
Pharyngitis	7/120 (5.8%)		4/118 (3.4%)
Upper respiratory tract infection	5/120 (4.2%)		12/118 (10.2%)
Metabolism and nutrition disorders
Abnormal loss of weight	10/120 (8.3%)		5/118 (4.2%)
Musculoskeletal and connective tissue disorders
Back pain	8/120 (6.7%)		6/118 (5.1%)
Hypercreatinaemia	8/120 (6.7%)		1/118 (0.8%)
Nervous system disorders
Headache	20/120 (16.7%)		14/118 (11.9%)
Renal and urinary disorders
Nephrolithiasis	8/120 (6.7%)		4/118 (3.4%)
Dysuria	7/120 (5.8%)		1/118 (0.8%)
Respiratory, thoracic and mediastinal disorders
Cystic fibrosis lung	85/120 (70.8%)		82/118 (69.5%)
Cough	28/120 (23.3%)		35/118 (29.7%)
Productive cough	12/120 (10%)		11/118 (9.3%)
Haemoptysis	9/120 (7.5%)		16/118 (13.6%)
Rales	6/120 (5%)		6/118 (5.1%)
Respiratory tract congestion	5/120 (4.2%)		8/118 (6.8%)
Oropharyngeal pain	4/120 (3.3%)		14/118 (11.9%)
Bronchospasm	1/120 (0.8%)		6/118 (5.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor can review results and/or communications prior to public release and can embargo communications regarding trial results for a period that is up to 180 days from the time submitted to the sponsor for review. The sponsor may consult with the PI to require changes to the communication or extend the embargo.