Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 1, Randomized, Double Blind, Placebo Controlled, Dose Escalation, and Bioavailability Study Evaluating the Safety and Pharmacokinetics of VX-659 in Healthy Subjects and in Subjects With Cystic Fibrosis
Brief Summary: Evaluate the safety and tolerability of VX-659 in healthy subjects


Options:
A: Inclusion Criteria:

* Homozygous for F508del-CFTR gene
* Sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis
* Body weight ≥ 40 kg
* FEV1 ≥ 40% predicted
* Oxygen saturation ≥ 90% breathing ambient air
* Hematology and clinical chemistry of blood and urine results with no clinically significant abnormalities that would interfere with the study assessments
* Negative pregnancy test for women of child bearing potential
* Sexually active subjects of child bearing potential willing to follow contraception requirements

Exclusion Criteria:

* Previous enrollment in another cohort for this study.
* Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment within 4 weeks of Study Day 1.
* Any change in chronic therapies for CF lung disease within 4 weeks of Study Day 1.
* Blood hemoglobin \<10 g/dL at screening.
* Serum albumin \<2.5 g/dL at screening.
* Abnormal liver function defined as ≥ 3 x upper limit of normal (ULN) in three or more of the following: AST, ALT, GGT, ALP, total bilirubin at screening.
* History of abnormal renal function (creatinine clearance \< 50 mL/min using Cockcroft-Gault equation) within a year at screening.
* History, including the screening assessment, of ventricular tachycardia or other ventricular arrhythmias.
* History, including the screening assessment, of prolonged QT and/or QTcF interval (\> 450 msec).
* History of solid organ or hematological transplantation.
* Intranasal medication changes within 14 days prior to Study Day 1
* Required Use of continuous (24 hr/d) or nocturnal supplemental oxygen.
* Concomitant use of any inhibitors or inducers of CYP3A4.
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: Inclusion Criteria:

Healthy Volunteers: PARTS A, B, and C

* Males and Females of non-childbearing potential.
* Between the ages of 18 and 60 years inclusive
* Healthy, as defined per protocol.
* Body mass index (BMI) of 18.0 to 32.0 kg/m2 inclusive
* Body weight \>50 kg

CF Patients: PART D

* Body weight ≥35 kg.
* Males and Females of non-childbearing potential.
* Sweat chloride value ≥ 60 mmol/L at screening.
* Heterozygous for F508del and a minimal function CFTR mutation
* Forced expiratory volume in 1 second (FEV1) ≥40% and ≤90% of predicted at screening

Exclusion Criteria:

Healthy Volunteers: PARTS A, B, and C

* History of any illness or any clinical condition that in the opinion of the investigator might confound the results of the study or pose additional risk to the subject.
* Any condition possibly affecting drug absorption.
* History of febrile illness within 14 days before the first study drug dose.
* Glucose-6-phosphate dehydrogenase (G6PD) deficiency assessed at Screening.

CF Patients: PART D

* History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk to the subject.
* History of cirrhosis with portal hypertension.
* Risk factors for Torsade de Pointes.
* G6PD deficiency assessed at Screening.
* Abnormal Laboratory Values.
* Lung infection with organisms associated with a more rapid decline in pulmonary status
* History of solid organ or hematological transplantation.
D: Inclusion Criteria:

* Evidence of signed and dated informed consent/assent document(s) indicating that the subject (and/or his parent/legal guardian) has been informed of all pertinent aspects of the trial
* Age \>=6 years.
* Body weight \>=16 kg.
* Sweat chloride \>60 milliequivalent per liter (mEq/L)
* Documentation of the presence of a nonsense mutation in at least 1 allele of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, as determined by genotyping performed at a laboratory certified by the College of American Pathologists (CAP), or under the Clinical Laboratory Improvement Act/Amendment (CLIA), or by an equivalent organization
* Verification that a blood sample has been drawn for sequencing of 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
* Demonstration at Visit 2 of a valid %-predicted FEV1 within 15% of the Screening % predicted FEV1 value
* Resting oxygen saturation (as measured by pulse oximetry) \>=92% on room air.
* Confirmed screening laboratory values within pre-specified ranges
* In subjects 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 60-day follow-up period
* Willingness and ability to comply with all study procedures and assessments, including scheduled visits, drug administration plan, study procedures, laboratory tests, and study restrictions

Exclusion Criteria:

* Known hypersensitivity to any of the ingredients or excipients of the study drug
* Previous participation in the Phase 3 trial of ataluren (PTC124-GD-009-CF).
* Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or re-initiation) in a chronic treatment/prophylaxis regimen for Cystic Fibrosis (CF) or for CF-related conditions within 4 weeks prior to screening
* Chronic use of inhaled aminoglycosides (eg, tobramycin) or use of inhaled aminoglycosides within 4 weeks prior to screening.
* Exposure to another investigational drug within 4 weeks prior to screening
* Ongoing participation in any other therapeutic clinical trial
* Evidence of pulmonary exacerbation or acute upper or lower respiratory tract infection (including viral illnesses) within 3 weeks prior to screening
* Treatment with intravenous antibiotics within 3 weeks prior to screening
* Ongoing immunosuppressive therapy (other than corticosteroids)
* Ongoing warfarin, phenytoin, or tolbutamide therapy
* History of solid organ or hematological transplantation
* Major complications of lung disease (including massive hemoptysis, pneumothorax, or pleural effusion) within 8 weeks prior to screening
* 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 x number of years smoked).
* Prior or ongoing medical condition (eg, concomitant illness, alcoholism, drug abuse, psychiatric condition), medical history, physical findings, electrocardiogram (ECG) findings, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject, makes it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results

Answer: C