Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 2b Extension Study of PTC124 as an Oral Treatment for Nonsense-Mutation-Mediated Cystic Fibrosis
Brief Summary: In some patients with cystic fibrosis (CF), the disease is caused by a nonsense mutation (premature stop codon) in the gene that makes the cystic fibrosis transmembrane regulator (CFTR) protein. PTC124 has been shown to partially restore CFTR production in animals with CF due to a nonsense mutation. In an ongoing Phase 2a study being performed at the Hadassah University Hospital - Mount Scopus in Israel, patients with nonsense-mutation-mediated CF have received PTC124 in two 14-day treatment courses. Preliminary results from that study indicate that PTC124 has pharmacodynamic activity of PTC124 in CF and that PTC124 can be safely administered in this patient population. This Phase 2b extension study is designed to evaluate the activity and safety of 3 months (approximately 84 days) of continuous treatment with PTC124 in the same patients who were enrolled to the Phase 2a study. The main purpose of this study is to understand whether PTC124 can be safely administered and achieve pharmacodynamic activity in patients with CF due to a nonsense mutation.


Options:
A: Inclusion Criteria:

* Heterozygous for F508del-CFTR and a second allele with a CFTR mutation predicted to have residual function
* Forced Expiratory Volume in 1 Second (FEV1) greater than or equal to (≥) 40 percent (%) and less than or equal to (≤) 90% of predicted normal for age, sex, and height during screening
* Sweat chloride value ≥60 millimole per liter (mmol/L) during screening OR as documented in the participant's medical record
* Stable CF disease as judged by the investigator

Exclusion Criteria:

* History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the participant
* An acute upper or lower respiratory infection, pulmonary exacerbation
* History of solid organ or hematological transplantation
* Ongoing or prior participation in an investigational drug study (including studies investigating VX-661, lumacaftor \[VX-809\], and/or ivacaftor) within 30 days of screening
* Pregnant and nursing females
* Sexually active participants of reproductive potential who are not willing to follow the contraception requirements
B: Inclusion Criteria:

* CF as diagnosed by:

  1. Documented sweat chloride greater than or equal to 60 mEq/L by quantitative pilocarpine iontophoresis test; or
  2. Two well-characterized genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene; or
  3. Abnormal nasal potential difference with accompanying symptoms characteristic of CF.
* PA present in expectorated sputum or throat swab culture at Screening.
* Participants must have received three or more courses of TIS within the previous 12 months.
* Participants on chronic azithromycin must have had no change in regimen in the previous 3 months and must have had a need for TIS and/or additional antipseudomonal therapy since initiation of azithromycin.
* Forced expiratory volume in 1 second (FEV1) between (and including) 25% and 75% predicted at Screening.
* Ability to perform reproducible pulmonary function tests.
* Arterial oxygen saturation (SaO2) greater than or equal to 90% on room air at Screening.

Exclusion Criteria:

* Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 mg prednisone every other day.
* History of sputum or throat culture swab yielding Burkholderia cepacia in the past 2 years.
* History of daily continuous oxygen supplementation or requirement for more than 2 liters/minute at night.
* Administration of any investigational drug or device within 28 days of Screening (Visit 1) or within 6 half-lives of the investigational drug (whichever was longer).
* Known local or systemic hypersensitivity to monobactam antibiotics.
* Inability to tolerate inhalation of a short acting Beta-2 agonist.
* Changes in antimicrobial, bronchodilator, anti-inflammatory, or corticosteroid medications within 7 days before Screening or between Screening and the next visit.
* Changes in physiotherapy technique or schedule within 7 days before Screening or between Screening and the next visit.
* History of lung transplantation.
* A chest X-ray indicating abnormal findings at Screening or within the previous 90 days.
* Abnormal renal or hepatic function or serum chemistry at Screening (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\] greater than 5 times the upper limit of normal range; Creatinine greater than 2 times the upper limit of normal range).
* Positive pregnancy test at Screening.
* Female of childbearing potential who was lactating or in the opinion of the investigator was not practicing acceptable birth control.
* Any serious or active medical or psychiatric illness, which in the opinion of the investigator would have interfered with participant treatment, assessment, or compliance with the protocol.
C: Key Inclusion Criteria:

* Homozygous for the F508del mutation (F/F)
* Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤90% of predicted mean for age, sex, and height

Key Exclusion Criteria:

* Clinically significant cirrhosis with or without portal hypertension
* Lung infection with organisms associated with a more rapid decline in pulmonary status
* Solid organ or hematological transplantation

Other protocol defined Inclusion/Exclusion criteria may apply
D: 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.

Answer: D