Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3 Efficacy and Safety Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis
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.


Options:
A: Inclusion Criteria: Participants must meet all of the following conditions to be eligible for enrollment into the study:

1. Diagnosis of CF based on conclusively abnormal sweat test (sweat chloride \>35 milliequivalents \[mEq\]/liter).
2. Abnormal nasal epithelial TEPD total chloride conductance (a more electrically negative value than 5 mV for Δchloride-free+isoproterenol).
3. Presence of a mutation in both alleles.
4. Documentation that a blood sample has been drawn for reconfirmation of the presence of a nonsense mutation in the CFTR gene.
5. Age ≥6 years.
6. Body weight ≥25 kg.
7. FEV1 ≥40% of predicted for age, gender, and height.
8. Oxygen saturation ≥92% on room air.
9. Willingness of male and female participants, if not surgically sterile, to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and follow-up periods.
10. Negative pregnancy test (for females of childbearing potential).
11. Willingness and ability to comply with scheduled visits, drug administration plan, study procedures (including TEPD measurements, clinical laboratory tests, pulmonary function tests, and PK sampling), and study restrictions.
12. Ability to provide written informed consent and/or assent.
13. Evidence of signed and dated informed consent document (by the participant or a legal guardian) indicating that the participant and/or the legal guardian has been informed of all pertinent aspects of the trial.

Exclusion Criteria: The presence of any of the following conditions will exclude a participant from enrollment in the study:

1. Prior exposure to ataluren.
2. Prior or ongoing medical condition (for example, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, ECG findings, or laboratory abnormality that, in the Investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
3. Ongoing acute illness including acute upper or lower respiratory infections within 2 weeks before start of study treatment.
4. History of major complications of lung disease (including recent massive hemoptysis or pneumothorax) within 2 months prior to start of study treatment.
5. Abnormalities on screening chest x-ray suggesting clinically significant active pulmonary disease other than CF, or new, significant abnormalities such as atelectasis or pleural effusion which may be indicative of clinically significant active pulmonary involvement secondary to CF.
6. Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test.
7. Hemoglobin \<10 grams/deciliter (g/dL).
8. Serum albumin \<2.5 g/dL.
9. Abnormal liver function (serum total bilirubin \> the upper limit of normal, or serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or gamma-glutamyl transferase (GGT) \>2.0 times the upper limit of normal).
10. Abnormal renal function (serum creatinine \>1.5 times upper limit of normal).
11. Pregnancy or breast-feeding.
12. History of solid organ or hematological transplantation.
13. Exposure to another investigational drug within 14 days prior to start of study treatment.
14. Ongoing participation in any other therapeutic clinical trial.
15. Ongoing use of thiazolidinedione peroxisome proliferator-activated receptor gamma (PPAR γ) agonists, for example, rosiglitazone (Avandia® or equivalent) or pioglitazone (Actos® or equivalent).
16. Change in intranasal medications (including use of corticosteroids, cromolyn, ipratropium bromide, phenylephrine, or oxymetazoline) within 14 days prior to start of study treatment.
17. Change in treatment with systemic or inhaled corticosteroids within 14 days prior to start of study treatment.
18. Use of or requirement for inhaled gentamicin or amikacin within 14 days prior to start of study treatment or during study treatment.
19. Requirement for systemic aminoglycoside antibiotics within 14 days prior to start of study treatment.
B: Inclusion Criteria:

Patients must meet all of the following conditions to be eligible for enrollment into the study:

* Completion of ≥ 1 cycle of PTC124 treatment in the previous Phase 2a study protocol (Protocol Number PTC124-GD-005-CF).
* Abnormal nasal epithelial TEPD total chloride conductance (a more electrically negative value than -5 mV for Δchloride-free+isoproterenol).
* FEV1 ≥ 40% of predicted for age, gender, and height.
* Oxygen saturation (as measured by pulse oximetry) ≥92% on room air.
* Willingness of male and female patients, if not surgically sterile, to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and follow-up periods.
* Negative pregnancy test (for females of childbearing potential).
* Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, and study restrictions.
* Ability to provide written informed consent.
* Evidence of signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial.

Exclusion Criteria:

The presence of any of the following conditions will exclude a patient from enrollment in the study:

* Prior or ongoing medical condition, medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the patient, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
* Ongoing acute illness including acute upper or lower respiratory infections within 2 weeks before start of study treatment in this study.
* History of major complications of lung disease (including recent massive hemoptysis or pneumothorax) within 2 months prior to start of study treatment in this study.
* Abnormalities on screening chest x-ray suggesting clinically significant active pulmonary disease other than CF, or new, significant abnormalities such as atelectasis or pleural effusion which may be indicative of clinically significant active pulmonary involvement secondary to CF.
* Hemoglobin \<10 g/dL.
* Serum albumin \<2.5 g/dL.
* Abnormal liver function (serum total bilirubin \> the upper limit of normal, or serum ALT, AST, or GGT \>2.0 times the upper limit of normal). Abnormal renal function (serum creatinine \>1.5 times upper limit of normal).
* Pregnancy or breast-feeding.
* History of solid organ or hematological transplantation.
* Exposure to another investigational drug within 14 days prior to start of study treatment in this study.
* Ongoing participation in any other therapeutic clinical trial.
* Ongoing use of thiazolidinedione peroxisome proliferator-activated receptor gamma (PPAR γ) agonists, eg, rosiglitazone (Avandia® or equivalent) or pioglitazone (Actos® or equivalent).
* Change in intranasal medications (including use of corticosteroids, cromolyn, ipratropium bromide, phenylephrine, or oxymetazoline) within 7 days prior to start of study treatment in this study.
* Change in treatment with systemic or inhaled corticosteroids within 7 days prior to start of study treatment in this study.
* Use of or requirement for inhaled gentamicin or amikacin within 14 days prior to start of study treatment in this study or during study treatment.
* Requirement for systemic aminoglycoside antibiotics within 14 days prior to start of study treatment in this study.
C: Inclusion Criteria:

* Diagnosis of CF based on documented evidence of a conclusively abnormal sweat test (sweat chloride \>60 milliequivalents/litre \[mEq/liter\]).
* Abnormal chloride secretion as measured by TEPD (a less than -5 mV TEPD assessment of chloride secretion with chloride-free amiloride and isoproterenol).
* Presence of a nonsense mutation in one of the alleles of the CFTR gene.
* Age ≥18 years.
* Body weight ≥40 kg.
* Forced expiratory volume in 1 second (FEV1) ≥40% of predicted for age, gender, and height (Knudson standards).
* Oxygen saturation (as measured by pulse oximetry) ≥92% on room air.
* Willingness of male and female participants, if not surgically sterile, to abstain from sexual intercourse or employ a barrier or medical method of contraception during the study drug administration and follow-up periods.
* Negative pregnancy test (for females of childbearing potential).
* Willingness and ability to comply with scheduled visits, drug administration plan, study procedures, and study restrictions.
* Ability to provide written informed consent.

Exclusion Criteria:

* Prior or ongoing medical condition, medical history, physical findings, ECG findings, or laboratory abnormality that, in the Investigator's opinion, could adversely affect the safety of the participant, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results.
* Ongoing acute illness including acute upper or lower respiratory infections within 2 weeks before start of study treatment.
* History of major complications of lung disease within 2 months prior to start of study treatment.
* Abnormalities on screening chest x-ray suggesting clinically significant active pulmonary disease other than CF, or new, significant abnormalities that may be indicative of clinically significant active pulmonary involvement secondary to CF.
* Positive hepatitis B surface antigen, hepatitis C antibody test, or human immunodeficiency virus (HIV) test.
* Hemoglobin \<10 grams per deciliter (g/dL).
* Serum albumin \<2.5 g/dL.
* Abnormal liver function (serum alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], gamma-glutamyl transferase \[GGT\], alkaline phosphatase, lactate dehydrogenase \[LDH\], or total bilirubin \> upper limit of normal).
* Abnormal renal function (serum creatinine \>1.5 times upper limit of normal).
* Pregnancy or breast-feeding.
* History of solid organ or hematological transplantation.
* Exposure to another investigational drug within 14 days prior to start of study treatment.
* Ongoing participation in any other therapeutic clinical trial.
* Ongoing use of thiazolidinedione peroxisome proliferator-activated receptor gamma (PPAR γ) agonists, eg, rosiglitazone (Avandia® or equivalent) or pioglitazone (Actos® or equivalent)
* Change in intranasal medications (including use of corticosteroids, cromolyn, ipratropium bromide, phenylephrine, or oxymetazoline) within 14 days prior to start of study treatment.
* Change in treatment with systemic or inhaled corticosteroids within 14 days prior to start of study treatment.
* Use or requirement for inhaled gentamicin or amikacin within 14 days prior to start of study treatment or during study treatment.
* Requirement for systemic aminoglycoside antibiotics within 14 days prior to start of study treatment.
D: 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.

Answer: D