Study of VX-661 Alone and in Combination With VX-770 in Subjects Homozygous to the F508del-CFTR Mutation

• Safety and tolerability of active drug vs placebo [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  Measured by incidence of treatment-emergent adverse events
  
  
• Safety and tolerability of active drug vs placebo [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  Measured by clinical laboratory values (serum chemistry, hematology, coagulation studies, and urinalysis)
  
  
• Safety and tolerability of active drug vs placebo [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  Measured by 12-lead ECG outcomes
  
  
• Safety and tolerability of active drug vs placebo [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  Measured by vital signs
  
  
• Absolute change in sweat chloride [ Time Frame: From baseline across all visits through Day 28 ] [ Designated as safety issue: No ]
  

• Change in sweat chloride [ Time Frame: From baseline to each visit up to Day 28 ] [ Designated as safety issue: No ]
  
• Change in percent predicted forced expiratory volume in 1 second [ Time Frame: From baseline through Day 28 ] [ Designated as safety issue: No ]
  
• Change in forced expiratory volume in 1 second [ Time Frame: From baseline to each visit and from baseline through Day 28 ] [ Designated as safety issue: No ]
  
• Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score [ Time Frame: From baseline to each visit up to Day 28 ] [ Designated as safety issue: No ]
  
• Maximum plasma concentration (Cmax) of VX-661, VX-770, and their respective metabolites in plasma when VX-661 is administered alone and when the 2 drugs are administered together. [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  PK blood samples will be drawn on Days 1, 7, 14, 21, 28, 35, 42, and at the follow-up visit.
  
  
• Minimum plasma concentration (Cmin) of VX-661, VX-770, and their respective metabolites in plasma when VX-661 is administered alone and when the 2 drugs are administered together. [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  PK blood samples will be drawn on Days 1, 7, 14, 21, 28, 35, 42, and at the follow-up visit.
  
  
• Average plasma concentration (Cavg) of VX-661, VX-770, and their respective metabolites in plasma when VX-661 is administered alone and when the 2 drugs are administered together. [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  PK blood samples will be drawn on Days 1, 7, 14, 21, 28, 35, 42, and at the follow-up visit.
  
  
• Area under the plasma concentration versus time curve (AUC) of VX-661, VX-770, and their respective metabolites in plasma when VX-661 is administered alone and when the 2 drugs are administered together. [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  PK blood samples will be drawn on Days 1, 7, 14, 21, 28, 35, 42, and at the follow-up visit.
  
  
• Time to attain maximum plasma concentration (tmax) of VX-661, VX-770, and their respective metabolites in plasma when VX-661 is administered alone and when the 2 drugs are administered together. [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  PK blood samples will be drawn on Days 1, 7, 14, 21, 28, 35, 42, and at the follow-up visit.
  
  
• Apparent clearance after oral administration (CL/F) of VX-661, VX-770, and their respective metabolites in plasma when VX-661 is administered alone and when the 2 drugs are administered together. [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  PK blood samples will be drawn on Days 1, 7, 14, 21, 28, 35, 42, and at the follow-up visit.
  
  
• Apparent volume of distribution (V/F) of VX-661, VX-770, and their respective metabolites in plasma when VX-661 is administered alone and when the 2 drugs are administered together. [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  PK blood samples will be drawn on Days 1, 7, 14, 21, 28, 35, 42, and at the follow-up visit.
  
  
• Apparent terminal elimination half-life (t1/2z) of VX-661, VX-770, and their respective metabolites in plasma when VX-661 is administered alone and when the 2 drugs are administered together. [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  PK blood samples will be drawn on Days 1, 7, 14, 21, 28, 35, 42, and at the follow-up visit.
  
  
• Accumulation and metabolic ratio of VX-661, VX-770, and their respective metabolites in plasma when VX-661 is administered alone and when the 2 drugs are administered together. [ Time Frame: Through Day 56 ] [ Designated as safety issue: No ]
  PK blood samples will be drawn on Days 1, 7, 14, 21, 28, 35, 42, and at the follow-up visit.
  
  

This is a Phase 2, randomized, multicenter, double-blinded, placebo-controlled, 3-part study of VX 661 monotherapy, VX 770 monotherapy, and VX 661/VX 770 cotherapy in subjects with CF homozygous for the F508del CFTR mutation.

This study will be separated into three parts: Part A, Part B, or Part C. Subjects may only participate in one part of the study. Part A will enroll 120 subjects. Part B will enroll 80 subjects. Part C will enroll 4-8 subjects.

Initiation of Parts B and C will depend on results from PK, PD, and safety data from Part A.