Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis Who Are Heterozygous for the F508del Mutation and a Minimal Function Mutation (F/MF)
Brief Summary: This study will evaluate the efficacy of VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are heterozygous for F508del and a minimal function mutation (F/MF subjects).


Options:
A: 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.
B: Inclusion Criteria:

1. Age 8 - 17 years old
2. Diagnosed with type 1 diabetes for at least one year
3. HbA1c \<10% for 6 month prior to start of trial

Exclusion Criteria:

1. Subjects with another chronic medical condition that could affect gut microbiota (examples: Crohn's disease, cystic fibrosis, irritable bowel syndrome, etc.)
2. Subjects taking medications or supplements that could affect gut microbiota (examples: antibiotics, probiotics, prebiotics, laxatives, etc.)
3. Subjects with a positive celiac disease screen
C: Inclusion Criteria:

* Male or female with a confirmed diagnosis of cystic fibrosis defined by:

  * Clinical features consistent with the diagnosis of CF; AND
  * Sweat chloride ≥60 mmol/L by pilocarpine iontophoresis; OR
  * Genotypic confirmation of CFTR mutation
* Aged 18 years or older
* Ability to provide sputum samples for microbiological evaluation throughout the study either spontaneously or induced.
* Chronic colonization with Burkholderia spp. defined as at least two positive microbiological cultures in expectorated sputum within the last 12 months from Visit 1.
* Use of inhaled aztreonam three times daily in a 4 weeks on/off cycle treatment regimen or a continuous intake regimen for at least 4 weeks before screening visit. For on/off cycles, screening visit should take place in the off phase. Randomization visit should take place the first day "on" to harmonize the aztreonam inhalation period with the IMP intake period.
* Willingness to stop treatment with other inhaled antibiotics.
* At Screening no clinical or laboratory findings suggestive of significant pulmonary illness, other than CF, which in the opinion of the investigator would preclude participation in the study.
* FEV1 greater than 25% of the predicted normal value following adjustment for age, gender, and height according to the Global Lung Initiative
* Female subjects of child bearing potential and male subjects participating in the study who are sexually active must use acceptable contraception. Female subjects documented as being of non-child-bearing potential are exempt from the contraceptive requirements.
* Provision of written informed consent.

Exclusion Criteria:

* Changes in underlying therapy within the 14 days prior to Day 0. Subjects must be willing to remain on the same underlying stable therapy regimens for the duration of the study until the final follow-up visit at Day 98.
* Changes in physiotherapy technique or schedule within 14 days prior to Day 0.
* Prohibited medications within 7 days prior to Day 0. Concomitant administration of inhaled mannitol or hypertonic saline within 7 days prior to Day 0.
* Concomitant use of inhaled antibiotics other than aztreonam.
* Pulmonary exacerbation within 28 days of Screening.
* Lactose intolerance/milk allergy.
* On-going acute illness. Subjects must not have needed an outpatient visit, hospitalization or required any change in therapy for other pulmonary disease between Screening and Day 0.
* History of, or planned organ transplantation.
* Active allergic bronchopulmonary aspergillosis (ABPA) in the last 12 months prior to Screening, defined as having received treatment for ABPA.
* Inability or unwillingness to provide sputum samples for microbiological evaluation throughout the study either spontaneously or induced by means of using inhaled hypertonic saline.
* Clinically significant abnormal findings on haematology or clinical chemistry. In addition, any value ≥ 3 x the upper limit of normal will exclude the subject from participating in the study.
* Subjects unable to perform pulmonary function tests according to the ATS/ERS criteria.
* Pregnant or breast-feeding women. A negative urine pregnancy test must be demonstrated in females of child-bearing potential at Screening.
* Subjects who have participated in any interventional clinical trial within the 28 days prior to Day 0.
* Subjects with documented or suspected, clinically significant, alcohol or drug abuse, as determined by the Investigator.
* Current malignant disease (with the exception of basal cell carcinoma; BCC).
* Any serious or active medical or psychiatric illness, which in the opinion of the Investigator, would interfere with subject treatment, assessment, or compliance with the protocol.
* Patients not willing/able to follow the study instructions.
* Resistance to aztreonam, or intolerance to aztreonam or any of its excipients.
D: Key Inclusion Criteria:

* Heterozygous for the F508del mutation (F/MF)
* 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

Answer: D