Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Randomized, Double-Blind, Ivacaftor-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation and a Second CFTR Allele With a Gating Defect That Is Clinically Demonstrated to be Ivacaftor Responsive
Brief Summary: This is a Phase 3, randomized, double-blind, ivacaftor-controlled, parallel-group, multicenter study of tezacaftor in combination with ivacaftor in subjects aged 12 years and older with CF who are heterozygous for the F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive.


Options:
A: Inclusion Criteria:

* Signed informed consent available before any study specific tests or procedures are performed
* Patients must be at least 18 years of age at time of inclusion (i.e. upon signature of informed consent)
* Patient diagnosed with Cystic Fibrosis according to standard criteria (i.e. either elevated sweat chloride content above 60 mmol/ L and/ or genetic testing)
* Patient is homozygous for the deltaF508 mutation
* Patient has a mild-to-moderate stage of lung disease as determined by FEV1 (FEV1 between 40 and 100% predicted)
* Patient has a stable condition of lung disease (no ongoing or recent pulmonary exacerbation and no change in current treatment) within the last 4 weeks prior to screening
* Ability and willingness to understand and follow study procedures for the entire study
* Patients do not smoke. Patients with a history of smoking can be included, if they have refrained from smoking for the last 3 months. If a patients starts smoking during the study participation, he/ she needs to be excluded and considered to be a drop out
* Body mass index (BMI): ≥ 16 kg/ m² (calculated by dividing the patient's weight by the square of his/ her height \[kg/ m2\])

Inclusion criterion valid for study part 1 only:

- Women of childbearing potential must agree to use adequate contraception when sexually active. 'Adequate contraception' is defined as one highly effective form of contraception (intrauterine devices \[IUD\], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method ). If a partner's vasectomy is the chosen method of contraception or if a partner has documented azoospermia, a hormone or barrier method must be used in combination. Adequate contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration

Inclusion criteria valid for study part 2 only:

* Women of childbearing potential must agree to use adequate contraception when sexually active. 'Adequate contraception' is defined as one highly effective form of contraception (intrauterine devices \[IUD\], contraceptive implants or tubal sterilization) or a combination of methods (hormone method with a barrier method). For patients on Orkambi hormonal methods (including hormonal oral contraceptives) cannot be accepted in this study. They need to choose non-hormonal methods. If a partner's vasectomy is the chosen method of contraception or if a partner has documented azoospermia, a hormone or barrier method must be used in combination. Adequate contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration
* Patients receiving Orkambi (Lumcaftor + Ivacaftor) as part of their standard care need to be on stable Orkambi treatment for at least 3 months prior to screening (patients on Lumacaftor and/or Ivacaftor are excluded in part 1)

Exclusion Criteria:

* Patients with Cystic Fibrosis with any background other than homozygous deltaF508 mutation
* Exclusion criterion only valid for study part 1: Patients receiving treatment with Lumacaftor and/ or Ivacaftor
* Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization. Also any history of moderate hemoptysis within the 3 months prior to inclusion
* Any history of pneumothorax, bronchial artery embolization or massive hemoptysis. Massive hemoptysis being defined as acute bleeding \>240 mL in a 24-hour period or recurrent bleeding \>100 mL/ d over several days
* A positive sputum culture for Burkholderia cenocepacia, Burkholderia dolosa, and/ or Mycobacterium abscessus either currently or within the previous year
* Active allergic broncho-pulmonary aspergillosis
* Current pulmonary exacerbation
* Known history of solid organ transplantation
* Known history of any form of pulmonary hypertension
* Clinically relevant deviations of the screened laboratory parameters from reference ranges outside of expected changes for Cystic Fibrosis patients, especially a hemoglobin value below 110 g/L or a creatinine clearance based on the Cockcroft-Gault formula \< 15 ml/ min
B: Inclusion Criteria:

* Male or female with confirmed diagnosis of CF
* All subjects must have an A455E mutation on at least 1 CFTR allele; no more than 10 subjects may have an F508del mutation on 1 CFTR allele.
* Forced expiratory volume in one second (FEV1) ≥30% of predicted and ≤90% of predicted at the Screening Visit, based on the Global Lung Function Initiative (GLI)-2012 multi ethnic all-age reference equations.
* Stable CF disease as judged by the investigator.
* Willing to remain on a stable medication regimen for CF from 4 weeks before Day 1 through the Follow up Visit.

Exclusion Criteria:

* History of any comorbidity reviewed at the Screening Visit 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 subject.
* A G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H mutation on at least one CFTR allele.
* Pregnant or breastfeeding.
* Any abnormal laboratory values at the Screening Visit.
* History of cataract/lens opacity, or evidence of cataract/lens opacity determined to be clinically significant by the ophthalmologist or optometrist during the ophthalmologic examination at the Screening Visit.
* Use of strong inhibitors or strong inducers of CYP3A, including consumption of certain herbal medications and certain fruit and fruit juices, within 14 days before Day 1
* Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements
C: Key Inclusion Criteria:

* Part 1: Heterozygous for F508del and an MF mutation (F/MF)
* Part 2: Homozygous for F508del (F/F)
* FEV1 value ≥40% and ≤90% of the predicted mean for age, sex, and height

Key Exclusion Criteria:

* History of clinically significant cirrhosis with or without portal hypertension
* Lung infection with organisms associated with a more rapid decline in pulmonary status
* History of solid organ or hematological transplantation

Other protocol-defined Inclusion/Exclusion criteria may apply
D: Inclusion Criteria:

* Heterozygous for F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive
* FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height during screening
* 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 subject.
* Pregnant and nursing females (females of childbearing potential must have a negative pregnancy test at Screening and Week -4 Visits).
* Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements

Answer: D