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

INTERVENTION: Product Name: VX‐661/ivacaftor 100mg/150mg Product Code: VX‐661/VX‐770 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: Not yet assigned CAS Number: 1152311‐62‐0 Current Sponsor code: VX‐661 Other descriptive name: VRT‐893661 VRT‐0893661 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ INN or Proposed INN: IVACAFTOR CAS Number: 873054‐44‐5 Current Sponsor code: VX‐770 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 150‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use Trade Name: Kalydeco Product Name: ivacaftor Product Code: VX‐770, VRT‐813077 Pharmaceutical Form: Film‐coated tablet INN or Proposed INN: IVACAFTOR CAS Number: 873054‐44‐5 Current Sponsor code: VX‐770 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 150‐ Pharmaceutical form of the placebo: Film‐coated tablet Route of administration of the placebo: Oral use CONDITION: Cystic Fibrosis ; MedDRA version: 17.1 Level: PT Classification code 10011762 Term: Cystic fibrosis System Organ Class: 10010331 ‐ Congenital, familial and genetic disorders Therapeutic area: Diseases [C] ‐ Respiratory Tract Diseases [C08] PRIMARY OUTCOME: Main Objective: To evaluate the efficacy of VX‐661 in combination with ivacaftor in subjects with CF who are heterozygous for the F508del mutation on the CFTR gene and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive Primary end point(s): Absolute change in percent predicted forced expiratory volume in 1 second (FEV1) from baseline Secondary Objective: To evaluate the safety of VX‐661 in combination with ivacaftor ; ; To investigate the pharmacokinetics (PK) of VX‐661 and its metabolites, M1 and M2 (M1‐661 and M2‐661, respectively) and ivacaftor and its metabolite M1 (M1 ivacaftor); Timepoint(s) of evaluation of this end point: Week 8 SECONDARY OUTCOME: Secondary end point(s): • Relative change in percent predicted FEV1 from baseline through Week 8 ; • Absolute change in sweat chloride from baseline through Week 8 ; • Absolute change in Cystic Fibrosis Questionnaire – Revised (CFQ‐R) respiratory domain score from baseline through Week 8 ; • Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard 12‐lead electrocardiograms (ECGs), vital signs, and pulse oximetry; from screening through 4 weeks after receiving last dose ; • PK parameters of VX‐661, M1‐661, M2‐661, ivacaftor, and M1 ivacaftor through Week 8 Timepoint(s) of evaluation of this end point: Weeks 8 and 12 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. Are the trial subjects under 18? yes Number of subjects for this age range: 100 F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 100 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range