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 Homozygous for the F508del Mutation (F/F)

INTERVENTION: During the TEZ/IVA Run‐in Period, study drug refers to TEZ/IVA and IVA. During the Treatment Period, study drug refers to VX‐445/TEZ/IVA and matching placebo, TEZ/IVA and matching placebo, and IVA. Active study drugs will be orally administered as fixed‐dose combination (FDC) film‐coated tablets (2 VX‐445/TEZ/IVA tablets or 1 TEZ/IVA tablet) in the morning and as 1 film‐coated IVA tablet in the evening. Active substance: VX‐445, TEZ (tezacaftor; VX‐661), and IVA (ivacaftor, VX‐770) Activity: CFTR corrector, CFTR corrector, and CFTR potentiator (increased Cl* secretion) Strength: 100‐mg VX‐445/50‐mg TEZ/75‐mg IVA FDC tablet Active substance: TEZ (tezacaftor; VX‐661) and IVA (ivacaftor; VX‐770) Activity: CFTR corrector and CFTR potentiator (increased Cl* secretion) Strength: 100‐mg TEZ/150‐mg IVA FDC tablet Active substance: IVA (ivacaftor; VX‐770) Activity: CFTR potentiator (increased Cl* secretion) Strength: 150‐mg tablet CONDITION: ; Cystic fibrosis 10010613 PRIMARY OUTCOME: Primary Endpoint: ; Absolute change in percent predicted forced expiratory volume in 1 second ; (ppFEV1) from baseline at Week 4; SECONDARY OUTCOME: Key Secondary Endpoints: ; * Absolute change in sweat chloride (SwCl) from baseline at Week 4 ; * Absolute change in CF Questionnaire‐Revised (CFQ‐R) respiratory domain score ; from baseline at Week 4 ; Other Secondary Endpoints ; * Safety and tolerability assessments based on adverse events (AEs), clinical ; laboratory values, ECGs, vital signs, and pulse oximetry ; * PK parameters of VX‐445, TEZ, M1‐TEZ, and IVA ; INCLUSION CRITERIA: 1. Subject (or his or her legally appointed and authorized representative) will sign and date an informed consent form (ICF), and, when appropriate, an assent form. 2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures. 3. Age 12 years or older, on the date of informed consent. 4. Confirmed diagnosis of CF as determined by the investigator. 5. Subject has the F/F genotype. Note: If the screening CFTR genotype result is not received before Day ‐28, a previous CFTR genotype laboratory report may be used to establish eligibility. Subjects who have been enrolled and whose screening genotype is not confirmed to be F/F must be discontinued from the study (Section 9.9). 6. Forced expiratory volume in 1 second (FEV1) value *40% and *90% of predicted mean for age, sex, and height (equations of the Global Lung Function Initiative [GLI])9 at the Scre