Clinical trial NCT04043806
Conditions: Cystic Fibrosis
Sponsor: Vertex Pharmaceuticals Incorporated
Start date: 2019-08-09; Completion date: 2022-12-14
Enrollment: 458 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study evaluated the long-term safety and tolerability of elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA) triple combination (TC) treatment in participants with cystic fibrosis (CF).

Detailed description:

Arms: arm 1: Part A: Participants received ELX 200 milligram (mg) once daily (qd),TEZ 100 mg qd, and IVA 150 mg every 12 hours (q12h) in the treatment period for 96 weeks.

Part B: Participants from certain countries participated in Part B and continued to received ELX 200 mg qd /TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 48 weeks.
Interventions: intervention 1: ELX/TEZ/IVA intervention 2: IVA
Intervention descriptions: intervention 1: Fixed-dose combination (FDC) tablet for oral administration. intervention 2: Tablet for oral administration.

Protocol documents:
Prot_000.pdf: 


 
  
  
  
 
    
 
 
 
 
 
 
 
  
 
  
  
  
  
  
   
  
  
  
 
  
  
  
  
   
 
 
  
  
  
  
 
  
  
  
  
  
   
  
  
  
 
  
  
   
  
 
  
 
  
  
 
  
 
  
    
  
  
  
  
  
  
   
 
  
  
  
  
  
 
  
 
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
  
 
 
  
 
  
 
 
  
 
  
  
  
  
   
 
  
  
 
 


 
  
  
  
 
    
 
 
 
 
 
 
 
 
 
    
   
  
  
  
  
  
  
  
 
   
  
  
  
  
 
 
  
 
  
  
  
  
  
   
  
  
 
  
  
 
  
 
  
  
   
  
  
 
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
   
  
  
 
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
  
 
  
  
 
  
  
  
  
   
   
  
 
  
 
 
  
  
  
  
  
  
  
  
  
  
   
   
  
 
  
  
  
  
  
 
  
 
 
  
  
  
  
  
 
  
  
 
  
 
    
  
  
  
 
   
  
  
    
  
  
   
  
 
   
  
  
  
  
  
  
  
 
  
  
    
  
  
    
  
  
  
    
 
  
  
  
 
  
  
  
  
  
  
  
 
  
 
  
  
  
 
  
  
  
  
  
  
 
  
  
  
 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
   
  
  
  
  
   
  
  
  
  
  
   
  
  
 
  
  


 
  
  
  
 
    
 
 
 
 
 
 
  
  
    
   
  
  
  
  
   
  
   
  
  
 
 
  
  
  
  
 
  
  
  
  
  
  
  
   
  
  
  
  
  
   
  
  
   
  
 
  
  
 
 
 
  
  
  
 
  
  
  
  
  
  
 
  
   
  
   
 
   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
 
  
  
  
  
  
  
 
  
 
  
  
 
 
  
  
  
 
  
  
   
 
  
  
   
  
   
  
  
  
  
  
  
  
 
  
 
 
  
  
   
  
   
  
   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
   
  
   
  
  
 
  
  
   
   
   
  
   
  
  
  
  
  
 
 
  
 
  
 
 
  
  
  
  
   
  
  
  
  
   
  
   
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
   
   
  
  
 


 
  
  
  
 
    
 
 
 
 
 
 
 
  
 
 
  
   
   
   
  
  
  
  
 
  
  
  
 
   
   
  
  
  
 
  
   
  
  
  
  
 
  
   
   
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
 
 








 
  
  
  
 
    
 
 
 
 
 
 
 
  
 
 
 
  
 
  
   
  
 
  
 
  
 
  
 
  
  
 
 
  
 
  
  
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
 
  
  
  
 
 
 
 
   
  
   
  
 
 
 
 
 
  
  
 
 
 
 
  
  
  
 
 
 
 
  
  
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
  
  
  
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
   
 
 
 
 
   
 
 
 


 
  
  
  
 
  
   
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
  
   
   
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
 
 
 
 
  
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
  
  
  
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 


 
  
  
  
 
  
   
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
  
  
  
 
 
 
 
  
 
 
 
 
  
  
  
  
 
 
 
 
  
  
  
 
 
 
 
 
 
  
  
  
  
  
 
  
  
  
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
  
  
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
    
  
 
 
 
 
  
 
   
  
  
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
  
 
 
 
 
   
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
  
  
  
  
 
 
 
 
   
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
  
  
  
  
  
  
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
  
  
 
 
 


 
  
  
  
 
  
   
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
 
 
 
 
 
  
  
  
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 


 
  
  
  
 
  
   
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
  
 
 
 
  
  
  
 
 
 
  
  
  
 
 
  
  
 
 
  
  
 
 
 
  
  
  
  
 
 
  
 
 
 
 
  
  
 
 
  
   
 
 
  
 
 
  
  
  
 
  
  
   
  
 
   
  
   
  
  
 
 
  
  
 
 
 
 
 
 
  
  
 
  
 
 
  
  
    
 
 
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
  
 
  
 
 
  
 
 
  
  
 
 
  
  
 
 
 
  
  
  
 
 
  
  
 
 
  
  
 
  
 
 
  
  
 
 
  
  
 
 
 
 
 
 
  
 
 
  
  
  
  
 
 
  
 
 
  
 
 
   
 


 
  
  
  
 
  
   
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
  
  
  
  
    
 
 
  
  
 
 
  
 
 
 
  
 
 
  
 
 
  
  
  
  
  
 
 
  
   
  
  
 
 
 
 
  
 
 
  
  
 
 
  
  
 
  
  
 
 
  
  
  
    
  
   
  
 
 
  
  
 
 
  
  
 
 
  
 
 
  
 
  
   
 
 
  
  
 
 
  
 
 
  
 
 
 
 
  
  
 
 
 
 
  
   
 
 
  
 
 


 
  
  
  
 
  
   
 
 
 
 
 
 
 
 
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
 
  
 
 
  
 
  
   
 
  
  
  
  
  
  
  
  
   
  
 
 
  
  
  
  
  
  
  
 
  
   
  
  
  
  
 
   
  
  
 
  
  
  
  
 
  
  
 
 
 
  
  
   
  
  
  
   
  
 
   
  
  
  
  
  
  
  
  
  
  
 
   
  
  
  
 
    
  
  
  
 
  
  
 
  
 
 
  
   
   
   
 
  
  
  
  
  
   
  
  
  
   
 
  
  
  
   
  
  
  
 
  
  
   
  
  
 
 
  
  
  
  
   
  
  
 
  
   
  
  
 
 
 
 
  
  
  
 
  
  
   
 
  
 
   
 
 
 
  
  
  
  
 
  
  
 
 
  
  
  
  
   
 
  
  
  
 
   
   
   
  
  
   
  
  
  
  
 
  
  
  
  
   
 
  
   
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
   
  
   
  
  
  
  
 
  
  
 
  
  
  
   
  
 
  
  
   
  
  
  
  
  
  
  
 
 
  
  
 
 
  
   
  
  
 
 
 
  
  
  
  
  
 
   
   
  
  
 
  
 
  
  
  
   
 
  
  
 
  
  
  
  
  
  
  
  
  
 
 
 
  
  
   
  
  
 
  
  
  
  
   
  
  
  
  
  
 
  
   
 
  
  
 
 
  
  
   
  
  
  
   
  
 
  
  
   
  
   
  
  
  
  
  
  
  
 
 
  
  
  
 
  
  
 
  
 
  
  
 
  
 
  
  
 
  
  
  
  
 
 
  
  
  
  
  
  
  
 
  
 
 
  
 
 
  
  
  


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
   
 
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
    
  
  
  
  
  
  
   
  
 
  
  
   
  
  
  
  
  
 
  
  
 
 
  
 
  
  
  
  
 
 
 
  
  
 
  
 
  
  
  
  
  
 
 
 
 
  
  
 
  
  
   
  
  
 
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
 
  
 
 
 
 
  
 
  
  
  
 
 
 
  
  
  
 
  
  
  
 
  
 
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
 
 
   
  
  
  
  
 
 
  
   
  
 
 
  
  
  
  
  
  
  
 
  
  
 
  
  
  
   
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
 
  
  
   
  
  
  
   
   
  
 
 
  
  
  
  
   
  
 
   
  
  
  
  
   
   
 
 
  
  
  
  
   
  
 
   
  
  
  
  
   
   
 
 
  
  
  
 
   
  
  
  
  
 
  
  
  
  
  
 
  
  
 
  
   
  
   
 
  
  
 
  
   
  
  
 
   
 
 




 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
  
  
  
  
 
  
  
 
   
  
 
   
  
  
  
  
   
  
  
  
  
 
  
  
   
  
  
  
  
 
  
  
   
  
  
 
  
  
  
  
  
 
  
   
  
  
 
  
 
  
   
  
  
  
 
 
  
  
  
   
   
 
 
   
  
 
  
  
   
  
 
  
  
  
  
 
  
   
  
  
  
  
  
   
 
 
  
  
  
  
  
  
 
  
  
  
  
   
  
   
  
  
   
  
 
 
  
  
  
    
  
  
  
 
  
 
  
   
 
 
  
  
   
  
  
  
 
  
  
 
  
   
   
  
 
  
   
 
 
  
  
 
  
 
  
  
  
 
  
  
  
 
  
  
   
   
  
 
  
  
   
  
 
  
  
  
  
 
  
  
  
  
  
 
  
 
 
 
 
   
  
  
  
  
  
 
  
  
  
 
  
  
   
  
 
  
   
  
 
 
  
  
  
   
   
  
 
  
  
   
  
  
 
  
  
 
  
 
  
  
  
  
   
  
  
  
  
  
 
 
 
 
  
   
  
   
  
  
  
   
 
  
  
    
  
   
 
 
 
  
  
  
 
 
 
  
   
 
  
   
  
  
  
 
  
 
  
  
 
 
  
 
  
  
  
  
 
  
  
  
  
  
  
 
 
  
  
   
  
   
  
  
 
  
  
  
  
  
   
 
  
 
  
 
  
  
  
  
  
  
   
  
  
  
  
 
  
  
  
   
   
 
  
 
 
 
  
  
 
  
  
   
   
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
 
  
 
 
  
  
 
  
  
  
 
  
  
  
  
  
  
 
  
    
  
  
  
 
   
 
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
 
  
 
 
   
 
 
  
  
  
   
 
 
  
  
 
  
   
   
 
  
  
  
  
   
  
 
  
  
 
  
  
 
  
  
  
  
   
 
  
  
  
   
  
   
  
   
   
  
   
   
  
   
  
  
 
  
 
  
   
  
  
 
  
   
   
  
  
 
  
  
  
   
  
  
  
   
   
   
  
 
  
  
 
 
 
  
  
 
  
 
 
  
  
  
  
  
  
  
 
  
  
   
  
  
  
  
  
  
  
 
  
  
  
   
  
  
  
 
  
  
 
  
  
  
  
  
  
  
  
 
  
  
 
  
  
   
   
 
  
  
 
  
  
 
  
  
 
  
  
  
 
   
  
  
 
  
  
 
  
 
    
  
  
  
  
  
  
 
  
  
  
 
 
  
   
  
  
  
  
  
   
  
  
  
  
 
  
  
  
  
  
  
  
 
 
  
  
   
  
 
 
   
  
 
  
 
 
  
   
  
  
  
 
 
 
 
 
  
  
   
 
  
  
   
  
 
  
  
  
  
  
 
  
  
  
   
  
  
  
  
   
   
  
 
   
  
 
  
  
  
  
 
 
   
  
  
   
  
 
 
 
   
  
  
  
  
  
 
 
  
  
 
  
  
 
  
  
   
 
  
  
 
 
  
 
 
  
  
  
 
  
 
   
  
  
  
 
  
  
 
  
  
  
  
  
  
 
  
 
   
   
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
 
 
 
  
 
 
  
 
  
 
  
  
 
  
 
  
 
  
  
 
  
  
 
   
  
 
  
 
 
  
 
 
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
  
 
   
  
   
  
 
 
 
 
  
  
 
  
 
 
 
  
 
  
  
 
  
  
 
   
  
 
  
 
 
  
 
 
  
 
  
  
  
 
  
  
 
 
  
 
  
  
  
  
 
 
  
  
  
 
  
   
 
 
  
 
  
  
 
  
  
  
 
  
  
  
  
  
   
 
 
  
 
 
  
  
 
  
  
  
  
 
  
  
 
  
 
  
  
 
  
  
  
 
  
  
  
  
  
   
 
 
  
  
  
  
 
  
   
   
  
  
 
  
  
   
    
  
  
 
  
  
   
  
  
  
  
  
  
 
  
  
 
 
 
  
  
  
  
 
  
 
 
  
 
  
  
  
  
  
 
 
  
   
  
  
 
 
  
  
  
 
  
  
  
 
  
  
   
  
   
 
  
  
   
 
   
   
  
 
  
  
  
 
   
  
  
 
  
 
  
  
  
 
  
  
  
   
  
  
  
  
 
 
  
  
  
  
  
 
   
 
  
  
  
   
 
  
  
  
  
  
  
  
  
  
  
  
 
 
   
  
  
   
 
  
  
 
  
  
 
   
  
  
  
  
  
 
  
  
 
 
  
 
  
  
  
  
   
  
  
   
  
 
  
  
   
 
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
   
  
  
 
  
 
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
   
  
  
 
  
  
 
 
  
  
 
  
    
  
  
  
 
   
  
  
 
  
   
  
  
 
  
  
   
  
  
 
   
  
  
  
  
  
  
  
   
 
   
  
   
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
 
  
  
 
  
  
  
 
  
  
 
  
  
  
  
 
  
  
  
 
 
  
 
  
  
 
  
  
 
  
  
 
  
  
 
  
 
  
  
 
 
  
  
  
   
  
  
 
 
  
  
 
 
  
  
  
   
  
    
  
 
   
    
  
 
 
  
  
 
  
 
  
  
 
  
  
  
 
 
  
   
 
  
  
  
 
 
    
  
  
 
  
 
  
  
  
    
  
  
  
  
  
  
  
   
 
  
 
  
  
 
  
  
 
   
  
  
 
  
  
  
   
 
  
  
  
  
  
  
 
  
 
 
  
  
  
   
 
  
  
 
  
  
   
 
  
 
  
 
 
  
  
  
   
 
  
  
  
 
  
  
  
 
  
 
 
  
  
  
  
  
   
 
  
  
   
  
  
 
 
   
   
 
  
  
  
  
  
  
   
 
  
   
 
  
  
  
  
   
 
  
  
 
  
  
   
  
  
  
  
   
 
  
   
   
 
  
 
  
  
  
  
   
 
  
  
  
 
  
 
 
  
  
  
  
   
 
  
  
  
 
  
 
  
 
  
  
  
   
 
  
   
 
  
  
   
 
  
  
 
  
   
  
 
  
   
  
 
  
  
  
 
 
 
  
  
  
  
  
  
  
  
   
   
  
 
  
 
 
  
 
 
  
  
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
 
   
  
  
    
  
  
 
  
  
  
 
 
 
  
 
  
  
  
  
 
  
   
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
 
  
 
 
 
  
  
 
  
 
  
  
  
  
 
  
  
   
  
 
  
  
  
 
  
 
  
  
  
 
  
  
  
   
 
  
  
 
  
   
 
  
  
  
  
  
  
  
 
  
  
  
  
  
 
  
   
  
   
 
  
  
 
   
   
  
  
  
 
  
  
   
  
 
  
  
  
 
  
  
   
   
  
  
 
 
  
  
  
  
   
  
   
  
  
  
 
  
  
  
 
  
 
  
 
  
  
   
   
  
  
  
  
 
  
  
 
  
   
  
   
  
  
  
 
  
  
  
 
  
 
  
  
 
  
  
  
  
  
  
  
  
 
  
  
  
 
 
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
 
  
 
 
  
 
  
  
  
 
  
   
  
  
   
 
  
  
  
  
  
  
  
 
  
 
  
  
 
  
  
  
 
  
  
  
  
  
  
 
  
  
 
  
  
 
  
  
 
  
  
  
  
   
 
  
  
 
  
  
 
  
  
 
  
  
  
  
  
  
  
   
 
  
  
 
  
   
  
 
  
  
  
   
  
  
 
  
  
  
  
 
  
  
  
   
 
  
  
  
  
  
  
 
 
  
  
  
 
  
  
  
   
  
  
  
  
  
 
 
  
  
  
  
   
  
  
  
  
   
  
 
 
  
  
  
  
  
 
  
  
  
 
  
   
  
 
  
  
  
  
 
 
  
  
   
 
  
  
  
 
  
  
  
  
 
  
  
   
 
  
  
 
  
  
   
  
   
  
  
  
  
  
   
 
 
  
  
  
  
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
 
  
   
  
   
   
  
   
 
  
 
   
  
 
  
  
  
 
  
  
 
 
  
  
  
 
  
  
  
  
  
  
  
  
 
   
  
  
  
  
   
  
 
   
  
  
  
  
 
 
  
   
  
  
 
  
 
  
  
  
 
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
   
   
  
  
 
   
  
 
  
 
  
 
 
  
  
  
  
  
  
  
  
 
  
 
  
   
  
   
 
  
   
  
   
 
  
  
 
  
 
  
   
  
   
   
  
  
  
  
   
  
  
 
 
  
 
   
  
  
 
  
  
 
  
  
 
 
  
 
  
 
 
  
  
   
  
 
   
  
  
  
  
  
  
  
  
  
 
  
  
   
  
  
 
  
  
  
  
  
  
  
   
  
   
 
  
 
  
 
 
  
  
  
   
 
 
  
   
  
  
 
  
  
  
  
 
  
 
  
  
 
  
  
  
  
 
  
  
 
  
  
   
  
   
 
  
  
 
 
  
   
  
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
   
  
 
 
  
  
  
  
  
  
   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
   
  
   
  
  
 
   
 
  
  
  
 
  
  
   
   
 
  
  
   
  
 
  
  
  
 
  
  
 
 
  
   
 
  
  
  
  
  
 
  
   
  
  
  
  
 
  
  
  
 
  
 
  
 
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
 
  
  
   
  
  
 
  
  
  
  
  
  
 
  
    
  
   
  
   
    
    
  
  
   
  
  
  
  
  
  
  
 
  
  
  
  
  
  
   
   
  
   
    
  
  
   
 


 
  
  
  
 
  
   
 
 
 
 
 
 
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
 
   
 
  
 
  
 
  
  
  
  
  
 
  
   
  
   
  
  
  
  
 
 
  
  
  
  
   
  
  
  
  
  
   
 
  
  
 
  
  
  
  
  
  
  
   
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
 
  
  
  
  
 
   
  
  
  
 
   
  
  
  
  
 
  
   
 
 
   
 
  
  
  
 
  
   
  
  
  
 
  
  
  
 
  
 
  
  
  
 
  
  
 
 
 
  
  
  
 
  
  
 
 
  
  
  
  
 
  
   
  
  
  
  
   
  
  
  
  
 
  
 
 
  
  
  
   
 
 
  
 
  
  
  
 
 
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
 
  
  
 
  
  
  
  
 
  
  
  
  
 
 
  
  
  
   
  
 
  
 
  
  
  
 
  
  
 
  
 
  
  
  
  
  
  
  
  
   
 
   
  
  
 
  
   
 
  
  
   
  
  
 
 
  
   
  
  
  
  
  
  
  
  
   
  
 
  
   
   
  
  
 
  
  
   
  
 
 
  
   
  
  
  
 
  
  
  
  
 
  
 
 
 
  
  
  
  
  
  
  
   
 
  
   
 
  
  
  
  
  
  
 
  
   
 
  
 
   
   
  
 
 
  
  
  
  
  
  
  
 
  
  
  
 
 
  
 
  
  
  
  
  
  
 
 
  
  
  
  
  
 
 
  
 
  
  
  
  
  
   
 
    
  
   
 
 
 
  
  
 
 
  
  
   
 
 
   
  
  
  
 
  
  
  
  
 
 
  
 
  
  
  
  
 
  
  
  
  
 
  
 
 
  
  
   
 
  
 
  
 
  
  
  
  
  
 
  
  
  
  
  
  
 
 
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
 
  
 
 
  
  
  
  
  
 
  
  
 
 
  
  
 
  
  
  
 
  
  
  
  
  
 
  
  
 
 
  
  
  
 
  
  
  
 
  
  
  
 
  
   
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
  
  
  
 
  
 
  
   
  
  
  
  
   
 
   
  
  
   
  
  
  
  
 
  
    
  
  
  
   
  
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
   
  
  
  
  
 
 
  
  
    
  
  
 
  
  
  
   
  
 
  
 
 
  
  
  
 
  
  
  
 
 
  
 
 
  
 
  
   
 
  
 
  
  
  
  
 
 
  
  
  
  
 
  
 
  
  
  
 
 
 
  
 
 
  
 
 
  
 
  
  
 
  
 
  
 
  
  
  
  
 
  
 
 
  
   
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
 
 
 
  
  
  
 
  
   
 
  
  
  
  
 
  
 
  
  
  
  
  
  
  
   
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
    
  
   
  
 
 
  
  
  
  
  
  
 
  
   
  
 
  
  
 
  
  
  
 
  
  
  
  
  
  
 
 
 
 
 
   
  
  
  
  
  
  
 
   
  
 
  
   
   
  
 
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
 
  
 
  
  
 
  
  
  
   
  
  
  
 
  
  
 
 
  
  
 
  
  
  
  
  
 
  
  
  
  
  
 
 
 
  
   
  
  
 
  
  
 
  
  
  
  
  
 
  
  
  
 
  
 
 
  
  
  
  
  
 
  
   
  
  
 
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
   
  
 
  
  
  
  
 
  
   
  
  
 
  
  
 
 
  
 
  
  
  
  
 
   
 
  
 
   
  
  
  
  
 
 
  
  
  
 
 
  
  
 
  
   
  
  
 
 
  
 
 
  
  
  
   
   
  
 
  
  
 
  
 
  
  
 
  
   
 
 
   
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
 
   
  
  
  
  
  
 
 
  
  
  
 
  
 
  
   
   
   
  
  
  
  
  
  
  
 
 
  
  
 
  
 
  
 
  
  
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
 
 
 
  
 
  
  
 
  
 
  
  
  
   
 
 
  
   
  
   
  
  
  
  
 
  
  
 
  
  
 
  
 
  
  
   
  
  
  
  
 
  
  
 
  
  
  
  
  
  
 
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
  
   
  
  
  
  
  
  
 
 
 
   
   
  
 
  
 
  
 
 
 
  
  
  
  
 
  
    
  
  
 
  
  
  
 
  
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
   
  
 
  
   
  
 
 
  
  
 
  
  
  
  
   
  
 
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
 
  
   
  
 
  
  
  
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
  
 
 
  
 
 
  
  
 
 
 
 
  
  
  
 
 
 
 
  
 
  
  
 
  
  
  
 
  
 
 
  
 
 
  
 
 
  
  
  
 
  
 
  
  
  
  
  
  
  
  
   
  
  
  
  
  
  
  
  
  
   
  
  
  
  
 
  
  
  
  
 
  
  
  
 
  
  
  
 
 
   
  
  
  
  
 
  
  
  
 
  
 
 
  
 
  
 
 
  
  
 
  
 
  
 
  
   
 
  
  
 
  
  
   
  
  
  
  
 
  
   
  
  
 
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
 
 
  
 
   
  
  
  
  
  
  
 
  
    
  
  
 
  
   
 
  
 
 
  
  
    
  
  
  
  
 
 
  
  
 
  
  
  
  
  
 
  
  
   
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
 
 
  
  
  
  
 
  
  
 
  
   
 
  
 
 
  
  
   
 
  
   
  
 
  
  
  
  
 
 
 
 
  
   
 
 
 
  
 
  
 
 
  
  
  
  
  
 
  
   
 
   
  
  
  
 
 
  
   
  
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
 
  
  
  
  
  
 
 
 
   
  
  
    
  
  
  
   
  
  
  
  
  
   
 
  
 
 
  
  
   
  
  
 
  
  
  
  
  
  
     
  
   
  
  
  
  
  
  
 
  
  
  
  
 
 
  
  
 
  
  
  
 
 
  
  
  
 
  
 
  
  
  
 
 
 
 
  
  
  
  
  
  
  
 
  
   
  
  
 
  
 
  
  
 
  
  
 
  
  
  
 
 
  
  
  
  
  
   
  
 
  
 
  
   
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
 
  
 
  
  
  
  
 
  
 
  
  
  
 
  
  
  
  
  
   
  
 
  
   
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
   
 
   
   
  
  
  
 
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
   
  
 
  
  
  
  
  
  
 
  
  
  
  
   
  
  
 
  
   
  
  
 
   
  
  
  
  
  
 
  
 
 
  
  
  
 
  
  
  
  
  
  
  
  
  
   
 
 
   
  
 
  
    
  
   
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
 
 
  
  
   
   
  
  
  
  
  
  
   
  
 
  
  
  
 
  
  
   
  
  
  
  
 
   
  
  
  
  
  
  
  
 
  
   
 
  
   
  
  
  
  
  
  
  
  
  
 
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
 
  
   
 
   
 
  
  
  
 
  
 
  
  
  
 
  
  
  
  
 
  
  
  
 
  
  
  
  
  
   
  
  
  
  
 
 
 
  
  
 
 
  
  
  
  
  
 
  
 
  
 
  
  
 
  
  
  
   
 
  
 
  
   
  
  
  
  
  
   
  
  
  
  
  
  
  
  
 
  
  
   
 
  
  
  
 
  
 
  
  
  
  
  
  
   
  
 
  
  
  
   
  
  
 
 
 
     
  
   
 
  
 
   
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
 
   
  
   
  
  
 
  
   
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
 
  
 
  
 
  
   
  
 
  
   
  
  
  
 
  
 
 
 
  
 
  
  
 
  
  
  
  
  
   
 
 
  
   
  
  
  
  
   
  
  
  
  
  
 
  
  
   
  
   
  
  
 
 
  
 
 
  
 
  
 
   
 
   
  
  
 
  
 
  
  
  
  
   
  
  
 
 
  
  
  
  
  
  
  
 
  
  
   
 
 
  
   
  
 
 
  
  
   
  
 
  
   
   
   
 
   
   
  
 
 
  
 
  
  
 
  
  
  
  
  
   
 
  
   
   
   
  
  
  
  
  
 
  
  
  
  
  
   
 
 
 
  
  
  
  
  
  
 
  
  
  
  
 
    
 
  
  
 
  
  
 
 
  
  
  
  
  
  
 
  
   
 
  
 
  
 
  
  
  
  
  
  
 
 
  
 
   
  
 
  
  
  
  
  
 
 
 
 
  
  
  
 
  
  
 
  
   
 
 
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
   
 
  
  
  
 
  
 
  
  
  
  
  
  
 
  
   
  
  
  
 
  
  
  
  
  
  
 
 
  
  
  
    
  
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
  
  
 
 
  
 
  
  
  
 
  
 
  
 
  
  
 
 
  
   
  
  
  
 
  
  
  
  
   
 
  
 
  
  
  
  
  
 
  
  
  
    
  
    
 
  
 
  
  
   
  
  
  
   
 
 
  
  
  
  
   
  
  
  
  
 
  
 
   
  
  
 
  
 
 
  
   
   
  
  
  
 
  
  
 
 
  
  
  
    
  
 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
  
 
  
  
  
  
  
  
  
 
  
  
 
  
   
  
  
  
  
  
 
  
  
   
 
 
  
 
  
   
  
  
 
    
  
   
   
 
  
  
  
  
  
  
  
 
  
  
 
  
 
   
  
  
  
    
  
  
 
   
 
  
  
  
 
  
 
  
 
  
   
  
 
 
  
  
  
 
  
  
  
   
   
  
  
 
 
 
 
   
  
  
  
  
   
  
  
 
 
  
  
  
 
 
  
 
 
 
   
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
  
  
  
  
 
 
   
  
  
  
 
  
  
 
  
  
   
   
  
  
  
 
   
  
  
  
 
   
  
  
  
   
 
 
  
  
 
 
  
  
 
  
  
   
  
  
 
  
  
  
  
  
  
 
  
  
   
  
  
 
 
  
  
  
  
  
   
  
  
 
  
  
  
 
  
   
  
  


 
  
  
  
 
  
   
 
 
 
 
 
 
  
 
  
  
 
 
  
  
  
 
 
 
 
  
  
 
  
 
 
 
  
   
   
  
 
   
  
 
  
 
  
  
 
 
 
  
  
  
  
  
  
   
  
 
 
 
   
  
  
   
 
 
 
 
  
 
  
   
 
  
   
  
  
 
 
 
  
  
  
  
  
   
 
  
  
  
  
  
   
  
 
 
 
  
  
   
  
 
   
  
  
   
    
 
  
  
  
   
 
 
 
 
   
  
  
  
 
  
  
   
  
  
   
   
  
 
  
 
  
  
 
  
  
  
 
  
  
 
  
 
  
 
 
 
 
  
  
  
  
   
 
 
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
 
  
  
   
 
  
  
  
  
 
  
  
   
  
 
  
  
  
  
  
   
  
 
  
  
  
 
  
  
  
  
  
 
  
  
 
  
  
   
  
 
  
  
  
  
   
  
   
  
 
  
  
  
  
 
  
  
  
 
  
   
 
  
  
 
  
  
   
  
  
 
  
   
  
  
   
  
 
  
 
  
  
 
 
 
  
  
  
 
  
  
   
  
   
  
  
  
 
  
 
  
 
  
   
 
  
   
  
  
  
  
  
 
  
 
 
  
  
 
  
  
   
  
 
   
  
  
  
  
  
 
  
  
  
 
  
 
 
  
  
  
  
 
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
 
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
   
  
   
  
    
 
   
   
  
 
 
  
  
  
  
   
  
 
  
  
 
  
  
  
 
 
  
  
 
 
 
   
  
 
  
  
  
  
   
   
  
  
 
 
   
  
  
 
  
  
  
  
  
  
 
  
  


 
  
  
  
 
  
   
 
 
 
 
 
 
  
 
 
  
  
 
  
  
 
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
   
  
 
  
   
 
  
  
  
  
  
  
  
 
  
    
  
 
  
  
 
   
  
  
 
 
  
  
  
  
 
   
  
  
  
  
  
 
  
  
 
  
  
  
   
  
  
 
 
  
  
 
      
  
  
  
 
  
  
  
  
   
 
 
  
   
  
  
  
  
  
  
  
  
 
  
  
   
 
 
  
  
 
   
 
  
  
 
  
  
 
  
   
 
 
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
   
 
  
  
  
 
  
 
  
  
 
  
 
  
  
   
  
  
  
 
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
 
  
  
 
 
  
  
   
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
   
  
  
  
  
  
  
  
  
 
  
   
   
  
  
  
  
 
  
  
  
  
  
   
  
  
  
  
 
  
  
  
  
  
  
   
   
  
 
  
 
  
  
 
  
   
 
  
   
  
 
  
  
 
 
  
  
   
  
  
  
  
  
  
   
  
  
 
 
  
  
   
  
  
  
 
  
 
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
   
   
   
  
   
 
  
  
  
  
 
  
 
 
  
  
  
  
  
 
  
  
 
  
 
 
  
 
 
  
  
 
  
  
  
  
 
  
   
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
 
  
  
  
  
 
  
  
 
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
    
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
  
  
   
  
  
  
  
 
  
 
 
  
  
 
  
 
 
  
  
  
  
  
  
  
 
 
    
  
 
  
  
  
  
  
 
 
  
  
  
  
 
 
  
 
  
 
  
  
  
  
 
  
  
  
   
  
  
  
  
   
   
 
  
 
 
  
  
  
   
  
 
  
  
  
  
  
 
  
  
  
   
 
 
 
  
  
   
  
  
  
 
  
  
 
  
  
  
  
   
  
  
  
  
 
  
  
   
  
   
  
   
 
  
   
  
  
   
  
  
  
  
 
  
 
 
  
 
 
  
  
 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
   
 
  
  
  
 
  
  
  
 
  
  
  
 
 
 
  
  
 
  
 
 
 
  
  
 
 
 
 
  
  
 
  
 
 
 
  
  
  
 
 
  
  
  
  
  
  
 
  
 
 
 
  
  
  
  
  
 
  
  
 
  
 
  
 
 
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
    
  
 
  
  
 
  
 
  
  
  
  
  
  
 
 
 
 
  
 
   
  
 
 
 
  
 
  
  
 
  
  
 
  
  
 
   
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
 
  
  
  
  
 
  
 
 
  
  
 
 
  
   
  
   
  
 
 
 
  
  
   
  
  
 
 
  
 
  
  
 
 
 
  
  
   
  
  
 
  
  
 
  
  
 
  
  
  
 
  
    
  
   
  
   
  
  
  
  
 
  
  
  
 
  
 
  
 
    
  
   
   
  
 
  
   
  
    
 
  
  
   
  
  
  
  
  
  
 
  
 
 
  
   
  
   
  
 
  
   
 
   
 
  
  
   
   
 
  
 
 
 
  
  
  
  
  
 
  
 
 
  
 
  
 
 
  
  
 
  
  
 
  
  
  
 
  
  
  
 
   
  
  
  
 
 
  
  
  
 
  
 
 
  
  
   
  
  
   
 
  
  
   
  
  
 
 
  
  
   
  
   
  
  
 
  
 
   
  
   
  
  
   
   
  
 
 
  
  
  
 
  
  
  
 
 
  
  
  
  
 
 
 
  
     
  
   
   
  
  
   
  
  
   
  
  
   
   
  
   
  
  
 
   
  
 
  
  
  
   
  
  
 
  
  
 
  
  
   
  
   
  
  
  
 
  
  
  
 
 
 
  
  
  
 
  
   
 
  
  
   
  
   
  
  
  
   
  
   
  
   
  
   
  
  
  
 
 
   
   
  
  
   
 
  
  
 
  
  
 
 
  
  
  
  
    
  
  
  
  
 
 
  
   
  
  
  
   
  
  
  
   
 
  
   
  
  
 
  
 
  
   
  
  
 
  
  
  
 
  
  
 
  
  
  
  
  
  
  
 
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
 
 
 
  
   
  
 
  
 
 
  
  
 
  
  
  
  
   
  
 
 
  
   
  
  
 
  
  
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
 
  
  
 
 
 
  
  
  
 
  
   
  
  
  
  
   
  
  
  
  
 
  
 
  
  
 
  
  
  
 
 
  
   
  
  
  
 
  
   
 
 
  
 
  
  
  
  
 
  
  
   
  
  
 
 
   
  
 
  
 
  
  
  
  
   
   
   
  
   
 
  
  
  
   
  
  
 
  
   
  
 
 
  
  
  
  
  
  
   
   
   
 
  
 
 
  
   
  
 
  
  
  
   
  
  
   
  
  
  
  
 
  
  
 
   
  
  
  
  
 
  
  
 
  
   
 
  
  
  
 
  
 
  
  
  
  
  
 
  
 
  
  
 
  
 
  
  
  
  
 
  
  
 
  
  
   
 
 
  
  
   
 
 
  
  
 
  
  
   
 
  
   
  
   
 
  
  
  
 
  
 
  
 
  
  
  
 
  
  
  
  
  
 
  
  
  
   
  
 
  
  
 
 
  
  
 
   
  
 
  
  
  
  
  
  
  
  
   
  
  
 
  
  
  
 
  
  
  
  
 
  
  
 
  
  
 
  
  
  
  
 
  
 
 
  
 
 
  
  
  
  
 
  
   
   
  
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
 
 
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
 
 
  
  
 
  
   
 
  
  
 
  
  
  
  
 
  
  
   
 
 
 
 
 
  
 
 
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
   
 
  
  
 
 
  
   
  
 
  
  
  
   
  
   
 
  
  
  
  
 
 
  
   
  
  
 
 
  
  
  
  
  
  
  
 
  
  
  
 
  
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
 
   
  
  
  
  
 
  
   
  
  
  
  
  
   
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
 
  
 
 
 
  
 
   
   
  
  
  
  
 
  
  
 
  
   
  
  
  
 
 
  
   
  
 
 
 
  
  
  
  
 
 
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
   
  
   
   
  
  
  
 
 
  
   
  
  
 
 
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
 
   
  
 
 
 
  
  
 
 
  
  
  
  
  
 
  
  
 
  
   
  
  
  
 
 
  
   
  
  
 
  
  
  
  
 
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
   
  
   
   
  
  
  
 
 
  
   
  
  
 
 
  
  
  
  
  
 
  
  
  
 
  
  
  
  
 
  
  
  
 
   
  
 
 
 
  
  
 
   
   
  
  
 
  
  
  
  
 
  
   
  
  
  
 
 
  
   
 
 
 
  
   
  
 
  
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
 
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
   
  
  
 
 
  
  
 
 
 
  
 
 
 
  
 
  
 
  
  
 
  
 
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
 
   
  
  
 
   
  
  
  
 
  
  
  
 
   
  
 
   
  
  
  
  
  
 
  
  
  
 
  
  
 
  
 
 
  
 
  
  
 
  
  
  
  
   
  
  
 
  
  
  
  
  
  
  
  
 
 
  
 
  
  
  
  
  
  
  
  
   
  
   
  
 
  
 
  
  
 
  
  
  
  
 
  
    
 
  
  
  
  
 
  
  
 
  
  
   
   
 
 
  
  
 
  
 
 
 
  
  
  
  
  
  
 
  
 
  
 
 
  
  
 
  
 
 
  
  
 
  
   
   
  
  
  
    
  
 
  
 
  
 
  
  
  
   
  
  
 
  
  
  
  
  
 
  
   
    
  
  
  
  
  
  
  
 
  
   
  
  
   
  
    
 
  
   
  
  
  
 
 
 
  
  
  
  
  
  
  
  
  
  
 
  
  
 
  
   
  
  
  
  
  
  
 
  
  
 
  
  
   
  
 
  
  
  
  
 
  
  
  
 
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
    
 
  
  
  
  
  
 
  
  
  
  
  
   
   
 
 
  
  
  
   
  
  
  
  
  
 
   
  
  
 
 
  
   
  
  
  
  
  
 
  
  
  
  
 
 
 
  
  
  
   
  
  
  
 
  
 
  
   
  
 
  
   
  
  
   
  
  
 
  
  
  
  
  
  
  
  
 
   
 
 
  
  
 
  
  
  
 
  
 
 
 
 
  
  
  
   
   
  
 
 
 
  
   
 
  
  
 
 
 
  
  
  
  
  
  
  
  
 
  
 
  
  
 
  
  
 
  
  
 
  
 
  
   
  
 
  
  
  
 
   
   
  
 
  
  
 
  
  
  
  
  
 
  
   
   
 
  
  
  
  
   
  
  
  
 
  
  
  
  
   
  
  
 
  
  
  
 
  
  
  
  
 
  
  
  
  
  
 
  
 
  
  
 
  
  
  
 
 
   
  
 
  
   
  
  
  
   
 
  
 
  
  
  
  
   
  
  
  
  
  
  
  
 
  
   
  
  
 
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
 
  
 
 
  
  
  
 
  
  
  
  
 
  
 
  
  
   
  
   
   
 
  
  
  
 
 
  
  
  
    
  
 
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
 
   
  
  
  
  
  
  
  
 
 
  
  
  
   
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
   
  
  
 
 
  
  
  
   
  
  
  
  
  
  
  
 
  
   
  
   
  
  
  
  
  
  
 
  
  
  
   
  
  
  
  
 
 
  
  
  
  
  
  
  
  
   
  
   
  
  
  
   
  
  
  
 
  
  
  
 
  
  
 
  
 
 
  
   
 
  
  
  
   
  
 
  
  
  
 
  
  
 
  
   
  
 
  
 
  
  
  
 
 
 
 
  
  
  
  
  
  
  
 
  
 
  
   
  
  
  
  
  
  
   
 
 
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
 
  
   
 
  
  
 
  
 
  
  
  
  
  
  
  
 
   
 
  
  
  
  
    
  
  
  
  
  
 
  
  
  
  
  
  
  
   
  
 
  
   
  
  
  
   
  
 
  
  
  
   
  
  
   
 
  
  
  
  
  
 
   
  
  
 
  
  
  
  
 
  
   
  
  
  
  
  
 
  
  
  
 
  
  
 
  
   
  
  
  
 
  
  
 
   
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
   
  
  
  
 
  
  
  
  
  
  
  
  
  
 
 
 
  
  
  
  
  
  
  
   
  
  
 
  
 
  
  
  
   
  
  
 
 
  
  
 
  
   
  
  
  
 
  
  
 
  
 
   
  
  
 
  
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
   
  
 
 
  
  
  
  
  
  
  
  
 
  
   
 
   
  
    
  
   
 
  
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
 
  
  
 
  
  
 
  
  
  
  
  
 
  
  
 
  
  
 
  
  
  
  
   
  
 
  
 
  
  
  
  
 
 
 
  
  
  
  
 
  
  
   
 
  
 
 
  
  
  
  
  
   
 
 
 
 
 
  
 
  
 
  
  
  
  
   
 
 
 
  
  
   
  
  
 
  
  
  
    
  
 
   
  
 
 
  
  
   
  
  
   
  
   
 
  
  
 
  
  
 
  
  
  
  
  
   
   
  
  
  
  
 
  
  
  
  
   
  
   
 
  
  
 
  
  
  
  
  
 
 
  
  
   
   
  
  
  
 
  
  
  
  
  
  
  
  
   
 
  
   
 
  
  
 
  
   
  
   
 
 
  
 
  
  
  
 
  
 
   
  
  
 
  
   
  
  
  
  
  
  
  
 
  
  
  
   
  
  
  
  
  
  
   
 
  
  
   
   
   
  
  
  
  
  
 
 
  
  
 
  
  
   
  
   
  
 
  
  
  
  
  
 
  
  
 
  
   
 
  
   
    
 
    
  
   
  
  
  
 
  
  
   
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
   
  
  
   
  
   
   
  
 
  
  
   
 
  
  
  
  
 
  
    
  
   
  
  
   
  
  
 
 
  
   
  
 
  
 
  
  
 
  
  
 
 
   
  
  
 
  
  
  
 
  
 
 
   
  
  
 
  
  


 
  
  
  
 
  
   
 
 
 
 
 
 
 
  
  
 
  
  
 
 
   
  
  
  
 
  
  
  
   
  
  
   
 
  
  
 
  
 
  
  
  
 
 
  
   
  
  
  
 
 
   
 
  
 
  
 
  
  
 
  
  
  
  
  
  
 
  
 
  
  
  
   
  
   
 
  
  
    
 
    
  
   
  
  
  
  
  
  
  
 
 
  
  
  
 
  
    
  
  
   
 
  
 
 
  
   
 
 
  
   
  
  
  
   
 
  
  
  
  
   
    
  
   
  
  
 
  
    
 
  
  
  
  
  
  
  
  
 
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
  
   
  
 
  
 
 
  
  
  
  
 
  
  
   
 
  
  
  
  
 
  
 
  
  
 
  
  
   
  
  
 
  
   
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
 
  
 
  
  
   
   
  
  
 
  
  
  
 
 
  
   
 
  
   
    
  
   
  
  
   
 
  
  
  
  
  
   
  
  
 
 
  
  
 
 
  
  
  
  
   
 
  
  
  
 
 
  
  
  
  
  
  
  
  
 
  
  
   
  
 
 
  
 
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
   
  
  
   
  
  
  
 
 
  
  
 
  
 
 
  
 
  
  
 
  
 
  
  
  
 
 
  
  
  
   
  
  
 
  
 
   
  
  
  
   
  
  
  
  
  
  
 
  
  
 
  
  
 
  
   
  
  
  
  
  
  
 
 
  
  
  
  
  
   
 
  
   
  
  
  
  
  
 
  
   
   
 
  
   
  
 
 
  
   
  
 
  
  
 
  
  
  
 
  
  
 
   
  
   
 
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
 
   
  
  
  
  
  
  
 
  
   
  
   
  
  
 
  
 
 
  
  
  
   
  
  


 
  
  
  
 
  
   
 
 
 
 
 
 
  
 
  
  
   
   
  
 
  
  
  
 
  
  
  
  
  
  
   
  
 
  
 
 
  
 
 
  
  
 
  
   
  
 
  
  
  
  
  
 
 
  
 
  
  
  
  
  
   
  
   
 
  
  
  
  
  
  
  
  
  
 
  
  
 
   
 
  
  
  
  
  
  
  
  
  
 
 
  
   
  
  
  
  
  
  
  
  
 
 
  
  
 
 
  
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
   
 
  
 
  
  
  
 
 
  
   
   
 
  
 
  
  
  
 
  
 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
 
  
  
 
 
   
 
   
 
  
  
  
  
 
  
  
 
 
 
  
  
  
 
  
  
   
  
 
 
 
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
 
  
   
 
  
   
 
 
  
 
 
 
  
  
  
 
  
  
 
  
   
 
  
  
 
  
  
  
  
 
  
  
  
 
  
  
 
 
 
  
  
  
  
  
  
 
  
  
  
  
 
 
  
  
 
 
   
   
 
  
 
  
   
  
  
  
  
 
  
 
  
 
  
  
 
 
  
 
  
  
  
  
 
  
  
  
 
  
  
  
  
   
 
  
  
   
   
  
 
 
  
  
 
 
   
  
  
  
  
 
  
  
 
  
  
  
  
 
  
    
  
  
  
  
 
  
 
  
  
  
 
  
  
  
  
   
  
   
  
 
 
  
 
  
  
 
  
  
   
  
  
  
 
  
  
  
  
  
 
  
 
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
   
  
  
  
 
  
   
  
  
  
  
 
  
  
 
  
   
  
  
  
  
  
  
 
  
  
 
  
  
  
  
 
  
  
  
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
 
  
  
  
  
  
   
  
  
   
 
  
 
  
  
  
  
 
  
  
  
  
  
 
  
   
 
  
 
  
  
  
  
  
  
   
 
  
   
 
 
  
  
  
  
  
 
 
  
  
  
 
  
   
 
 
  
   
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
   
 
 
 
  
  
  
  
  
  
  
  
  
  
 
 
  
 
  
  
  
  
  
   
  
 
  
  
  
  
 
  
  
  
  
  
 
  
  
 
  
 
  
 
 
  
  
  
  
 
 
  
 
  
  
  
 
  
  
  
  
  
 
  
  
  
 
  
 
  
 
  
 
  
  
   
  
  
  
 
  
  
  
 
 
 
  
   
  
  
 
  
 
  
  
  
  
  
  
  
 
  
  
  
   
  
 
  
  
  
  
 
  
  
 
  
  
 
  
 
 
  
  
  
 
  
  
  
   
  
  
  
 
  
  
 
  
   
   
  
  
 
  
  
  
  
  
  
 
   
 
  
 
  
  
 
  
    
  
   
 
 
  
  
 
 
  
 
  
 
 
  
  
  
  
  
  
  
  
  
   
  
  
  
   
 
  
   
 
  
  
  
 
 
   
  
  
 
 
  
   
  
 
  
  
  
   
  
  
  
  
  
  
 
  
  
 
 
  
   
 
 
 
  
  
 
  
   
   
  
 
  
   
  
  
  
 
  
 
  
   
  
 
  
   
  
 
  
 
  
 
 
  
  
  
  
  
 
  
  
  
 
  
 
 
  
  
  
   
 
   
 
  
 
  
   
   
  
  
  
  
 
  
  
  
  
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
 
 
  
  
 
  
  
   
  
  
   
 
 
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
 
 
  
   
   
  
  
  
  
  
  
  
 
   
 
  
  
  
  
  
  
  
 
  
  
  
 
 
  
  
  
  
 
  
  
   
 
  
  
  
  
   
 
  
  
  
  
  
  
  
  
  
  
 
   
  
  
  
  
  
  
   
  
  
  
  
 
  
  
 
  
 
 
  
  
   
  
  
 
  
  
  
  
  
  
  
  
 
  
 
  
  
 
  
  
 
  
 
  
  
  
  
   
 
  
  
 
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
  
  
  
  
  
 
 
 
  
  
 
  
 
  
  
  
  
  
 
  
 
  
 
  
  
   
   
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
 
   
  
  
  
  
  
  
 
 
  
  
 
  
  
  
  
  
  
   
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
   
  
 
 
  
  
 
   
  
  
  
   
   
  
  
  
 
 
 
 
  
  
 
  
  
  
  
 
  
 
  
  
  
  
   
 
 
  
 
  
 
  
  
  
  
  
  
  
  
 
  
 
  
 
  
  
  
  
 
  
  
  
  
  
 
  
 
  
  
  
   
  
  
  
 
 
  
  
 
  
   
 
  
  
 
  
   
   
  
 
   
  
  
  
  
  
  
 
  
 
  
  
 
  
  
  
   
 
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
   
   
 
  
  
  
 
 
  
 
 
 
  
   
  
  
  
 
  
  
  
 
  
  
   
  
  
  
  
 
 
  
    
  
   
  
  
  
 
  
  
 
 
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
 
 
  
 
  
  
  
  
  
  
 
  
   
 
   
  
 
  
 
  
  
  
  
   
  
 
  
  
  
  
   
  
  
  
  
 
  
  
  
  
  
   
  
 
  
  
  
   
  
  
  
 
 
  
   
  
  
 
  
   
    
  
   
  
 
  
   
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
   
 
  
  
  
  
  
 
  
  
 
  
 
 
  
   
 
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
 
  
   
  
 
 
  
  
  
  
  
  
  
  
 
  
  
 
  
   
   
  
 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
 
  
  
 
  
  
 
 
   
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
 
  
 
  
  
 
   
   
 
  
  
  
  
  
  
    
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
 
  
 
  
 
  
  
  
  
  
   
   
  
  
  
   
  
 
  
  
 
 
 
 
 
  
  
  
  
   
  
   
  
  
 
  
  
  
 
  
 
 
  
   
 
  
 
   
  
  
  
   
   
  
 
   
  
  
  
  
   
   
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
 
  
  
  
   
  
  
  
 
 
  
   
   
  
  
  
 
 
  
  
 
 
  
  
  
  
     
   
  
  
   
  
  
 
  
  
 
  
  
  
  
 
  
 
  
   
  
 
   
  
   
  
   
   
  
  
 
  
  
 
  
  
  
  
  
  
  
  
  
 
   
  
   
 
  
  
 
  
  
  
 
  
   
  
  
  
  
 
 
  
  
  
    
  
  
 
   
  
 
   
  
  


 
  
  
  
 
  
   
 
 
 
 
 
 
  
 
  
 
   
  
  
  
  
  
  
 
 
   
 
 
  
  
 
  
  
 
  
  
  
  
  
  
  
  
   
   
 
 
  
  
  
  
  
  
  
   
  
 
  
 
  
  
 
  
   
  
 
  
 


 
  
  
  
 
  
   
 
 
 
 
 
 
  
 
   
  
  
  
   
  
  
 
 
  
 
  
  
 
   
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
   
  
  
   
  
  
  
  
  
  
 
 
   
  
 
  
  
  
  
  
  
  
 
 
  
 
  
  
 
  
  
  
  
  
 
  
  
  
 
  
 
 
  
 
  
  
 
  
  
  
  
  
 
  
  
  
 
  
 
  
 
  
  
  
  
 
  
  
  
  
 
 
  
 
  
  
  
 
  
  
  
  
 
  
  
 
  
 
 
  
  
  
  
  
  
   
  
  
  
  
 
 
   
  
 
  
  
   
   
  
  
  
 
  
  
 
 
  
  
  
  
  
   
  
  
  
  
 
   
  
  
  
  
  
  
  
 
 
  
 
  
  
  
 
 
  
 
  
  
 
   
  
  
   
 
  
   
 
  
 
  
 
   
  
  
  
 
   
  
  
   
  
  
 
  
  
  
  
  
 
 
  
 
  
 
 
  
  
  
 
  
  
  
  
 
  
  
  
 
   
  
  
  
  
  
 
 
 
 
  
  
  
  
  
 
 
  
  
   
  
  
  
 
 
 
  
  
  
  
   
  
   
  
 
 
 
  
  
   
 
 




 
  
  
  
 
  
   
 
 
 
 
 
 
  
  
  
 
    
  
  
  
  
   
  
  
  
  
 
  
   
   
  
  
 
  
  
   
 
  
   
  
  
  
  
 
 
  
  
  
 
  
  
  
  
  
   
 
  
  
 
 
  
   
  
 
  
  
  
  
  
  
  
  
 
  
  
 
  
 
 
  
  
 
 
 
  
 
  
 
 
   
 
 
 




  
  
  
  
  
  
  
  
  
 
    
 
 
 
 
 
 
  
 
  
  
  
  
 
 
   
  
  
  
  
  
  
  
 
 
  
  
  
  
   
  
 
  
   
  
  
  
 
  
  
  
  
  
   
  
  
  
  
 
  
 
   
  
  
 
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
 
  
  
   
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
 
   
  
  
   
  
  
  
    
   
 
  
  
   
  
  
  
   
  
  
  
 
 
  
  
 
  
 
  
  
  
  
  
 
 
   
  
  
  
  
  
 
  
   
 
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
 
  
   
  
  
  
 
 
  
  
  
  
  
   
  
  
  
  
 
 
 
  
  
   
  
  
 
  
  
  
  
  
  
 
 
  
  
  
   
  
  
   
  
  
  
  
 
  
 
  
  
  
  
  
  
   
  
  
  
 
 
 
   
 
  
   
   
  
  
  
 
 
 
  
  
  
  
  
   
 
  
 
  
  
  
 
  
  
  
   
  
  
 
  
 
  
  
  
  
 
  
  
 
  
 
  
  
  
 
  
  
  
 
 













SAP_001.pdf: 
Statistical Analysis Plan (Methods) - DMC 
Page 1 of 31 
Protocol Number: VX18-445-113 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
 
 
VERTEX PHARMACEUTICALS INCORPORATED  
Statistical Analysis Plan 
(Methods) 
Protocol Number VX18-445-113 Version 1.0 
 
 
 
A Phase 3, Open-label Study Evaluating the Long-term Safety of VX-
445 Combination Therapy in Subjects With Cystic Fibrosis 
 
Authors of SAP:  
 
 
Version: 1.0 
Version Date of SAP: July 12, 2021 
 
Vertex Pharmaceuticals Incorporated 
50 Northern Avenue 
Boston, Massachusetts 02210-1862 
 
CONFIDENTIAL 
This document contains confidential information.  Any use, distribution, or disclosure without the prior written 
consent of Vertex Pharmaceuticals Incorporated is strictly prohibited except to the extent required under 
applicable laws or regulations.  Persons to whom the information is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 


Statistical Analysis Plan (Methods)  
Page 2 of 31 
Protocol Number: VX18-445-113 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
1 
TABLE OF CONTENTS 
 
1 
Table of Contents ................................................................................................................... 2 
3 
Introduction ............................................................................................................................ 5 
4 
Study Objectives .................................................................................................................... 5 
4.1 
Primary Objective ............................................................................................................. 5 
5 
Study Endpoints ..................................................................................................................... 5 
5.1 
Primary Endpoint .............................................................................................................. 5 
5.2 
Other Endpoint ................................................................................................................. 5 
6 
Study Design ........................................................................................................................... 5 
6.1 
Overall Design .................................................................................................................. 5 
6.2 
Sample Size and Power .................................................................................................... 6 
6.3 
Randomization .................................................................................................................. 7 
6.4 
Blinding and Unblinding .................................................................................................. 7 
7 
Analysis Sets ........................................................................................................................... 7 
8 
Statistical Analysis ................................................................................................................. 7 
8.1 
General Considerations .................................................................................................... 7 
8.2 
Background Characteristics .............................................................................................. 8 
8.2.1 
Subject Disposition ................................................................................................... 8 
8.2.2 
Demographics and Baseline Characteristics ............................................................. 9 
8.2.3 
Medical History ...................................................................................................... 10 
8.2.4 
Prior and Concomitant Medications ....................................................................... 10 
8.2.5 
Study Drug Exposure .............................................................................................. 11 
8.2.6 
Study Drug Compliance ......................................................................................... 11 
8.2.7 
Important Protocol Deviations ................................................................................ 11 
8.3 
Efficacy Analysis ............................................................................................................ 12 
8.4 
Safety Analysis ............................................................................................................... 12 
8.4.1 
Adverse Events ....................................................................................................... 12 
8.4.2 
Clinical Laboratory Assessments ........................................................................... 14 
8.4.3 
Electrocardiogram .................................................................................................. 15 
8.4.4 
Vital Signs .............................................................................................................. 15 
8.4.5 
Pulse Oximetry ....................................................................................................... 15 
8.4.6 
Physical Examination ............................................................................................. 15 
8.4.7 
Ophthalmology Examination .................................................................................. 15 
8.4.8 
Spirometry .............................................................................................................. 16 
8.6 
Other Analyses ............................................................................................................... 16 
8.6.1 
Sweat Chloride ....................................................................................................... 16 


Statistical Analysis Plan (Methods)  
Page 3 of 31 
Protocol Number: VX18-445-113 
 
 
Vertex Pharmaceuticals Incorporated 
Confidential Information 
9 
Interim and DMC Analyses ................................................................................................ 17 
9.1 
Interim Analysis ............................................................................................................. 17 
9.2 
IDMC Analysis ............................................................................................................... 17 
10 References ............................................................................................................................. 18 
11 Appendices ............................................................................................................................ 19 
Appendix A: Analysis Visit Windows for Safety Assessments............................................... 19 
Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates ................. 22 
Appendix C: Imputation Rules for Missing AE dates ............................................................. 23 
Appendix D: Criteria for Threshold Analysis .......................................................................... 24 
Appendix E: Adverse Events of Special Interest ..................................................................... 30 
Appendix F: Details of GLI Equations for Calculating ppFEV1 ............................................. 31 
 
 


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3 
INTRODUCTION 
This statistical analysis plan (SAP) for the final analysis is based on the most recent approved 
clinical study protocol (CSP), the most recent approved electronic case report form (eCRF), and 
the most recent approved eCRF completion guidelines.  
This SAP (Methods) documents the planned statistical analyses of safety and other endpoints. 
The SAP (Methods) will be finalized and approved prior to the clinical database lock for the final 
analysis. Analyses will be performed separately for Part A and B, unless otherwise specified. 
Any revisions to the approved SAP will be documented and approved in an amendment to the 
SAP prior to the clinical database lock for the final analysis. Any changes made to the SAP 
Methods after the clinical database lock has occurred will be documented in the clinical study 
report for this study.  
The Vertex Biometrics Department will perform the statistical analysis described in this 
document. SAS (Version 9.4 or higher) will be used to generate all statistical outputs (tables, 
figures, listings, and datasets).  
4 
STUDY OBJECTIVES  
4.1 
Primary Objective 
To evaluate the long-term safety and tolerability of VX-445 (ELX)/ tezacaftor (TEZ)/ ivacaftor 
(IVA) 
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoint 
Safety and tolerability of long-term treatment with ELX/TEZ/IVA based on adverse events 
(AEs), clinical laboratory values, ECGs, vital signs, pulse oximetry, and spirometry. 
5.2 
Other Endpoint 
Sweat chloride.  
6 
STUDY DESIGN  
6.1 
Overall Design  
This is a Phase 3, multicenter, open-label study for subjects who transferred from Study 659-105, 
a Phase 3 Vertex study investigating VX-659/ TEZ/IVA, who meet eligibility criteria (Section 8 
in CSP).  
Two separated regional amendments were developed in March 2021. The regional protocol for 
US and UK was amended to add optional home collected sweat chloride at unscheduled home 
visit. The study design kept intact as the original one-part design. The regional protocol for  
Australia, Canada, Spain and Poland was amended to add a Part B, so that subjects in these 
countries without commercially-available ELX/TEZ/IVA who complete Part A would have the 
opportunity to participate in Part B for an additional 48 weeks.  


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A schematic of the study design for the regional amendment of Australia, Canada, Spain and 
Poland is shown in Figure 6-1. The schematic of the study design for other countries contains 
only Part A of the Figure 6-1.  
All subjects in Parts A and B will receive a TC of ELX/TEZ/IVA at the same dose level as that 
evaluated in the ELX Phase 3 pivotal trials (ELX 200 mg once daily [qd], TEZ 100 mg once 
daily [qd], and IVA 150 mg every 12 hours [q12h]). Study drug administration is described in 
Section 9.6 in CSP.  
Study visits and assessments to be conducted for Parts A and B are shown in Table 3-1 and table 
3-2, of the CSP respectively. All visits will occur within the windows specified.  
 
Figure 6-1 
VX18-445-113 Study Design 
 
 
 
 
 
 
 
 
 
ELX: elexacaftor; IVA: ivacaftor; q12h: every 12 hours; qd: once daily; TEZ: tezacaftor 
Note: Figure is not drawn to scale. 
a 
All subjects will receive ELX 200 mg qd, TEZ 100 mg qd, and IVA 150 mg q12h. 
b 
Subjects whose Part B Day 1 Visit is on the same day as the Part A Week 96 Visit do NOT have to repeat 
any Part B Day 1 assessments that were specified to be performed at the Part A Week 96 Visit. Subjects 
whose Part B Day 1 and Part A Week 96 Visits do not coincide must complete all assessments specified 
for the Part A Week 96 and Part B Day 1 Visits. 
For treatment continuity, in countries where ELX/TEZ/IVA is not commercially available (i.e. 
Australia, Canada, Spain and Poland), an option to return to this study will be offered to subjects 
who depart this study to enroll in another 
Vertex study of investigational CFTR modulators (hereafter referred to as “another qualified 
Vertex study”) based on the following: 
• Subjects receive open-label ELX/TEZ/IVA during the other study's Run-in Period but do 
not qualify to receive study drug in the Treatment Period of the other study 
• Meet all eligibility criteria for this study (Section 8 in CSP) at their Returning Visit. 
Subjects who resume participation in this study will resume treatment with study drug after 
completion of a Returning Visit. Resumption of participation in this study following departure to 
another qualified Vertex study will be permitted once. 
6.2 
Sample Size and Power 
Part A Treatment Period 
ELX/TEZ/IVA
a 
Part A Safety 
Follow-up 
Study  
659-105 
Part A Week 96
b 
Part A Day 1 
Part B Treatment Period  
ELX/TEZ/IVA
a 
Part B Safety 
Follow-up 
Part B Week 48 
Part B Day 1
b 


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The primary objective of the study is the evaluation of the long-term safety and tolerability of 
ELX/TEZ/IVA. This is an open-label study that enrolled subjects previously enrolled in Study 
659-105 and met the Study 445-113 eligibility criteria.  
Over 400 subjects were enrolled. With this number of subjects exposed to ELX/TEZ/IVA 
treatment, AEs by Preferred Term (PT) that occur with a frequency of >1% will be ruled out with 
95% confidence, when 0 events are observed in that PT. 
6.3 
Randomization 
Randomization is not required because all subjects will be treated identically in a single cohort. 
6.4 
Blinding and Unblinding 
This is an open-label study. Refer to the CSP section 10.7 for details. 
7 
ANALYSIS SETS 
The following analysis sets are defined: All Subjects Set and Safety Set.  
The All Subjects Set for Parts A and B are defined as all subjects who were enrolled (defined as 
subject having data in the clinical database) in Part A or Part B of this study, respectively. This 
analysis set will be used for individual subject data listings and disposition summary tables 
unless otherwise specified. 
The Safety Sets for Part A and B are defined as all subjects who have received at least 1 dose of 
study drug in Part A or Part B of this study, respectively. The Safety Set will be used for all 
safety analyses unless otherwise specified. 
8 
STATISTICAL ANALYSIS 
8.1 
General Considerations 
In general, data will be summarized by the treatment group in this study.  
The precision standards for reporting safety variables are provided in an internal Biometrics 
document that specifies the programming rules including the precision for derived variables.  
Continuous variables will be summarized using the following descriptive summary statistics: 
the number of subjects (n), mean, standard deviation (SD), median, minimum value (min), and 
maximum value (max).  
Categorical variables will be summarized using counts and percentages. Percentages will be 
presented to 1 decimal place. 
Baseline value, unless otherwise specified, for the long-term safety analysis is defined as the 
most recent non-missing measurement (scheduled or unscheduled) collected before the first dose 
of ELX/TEZ/IVA in Part A of this study.  
Baseline of sweat chloride is defined as the most recent non-missing sweat chloride (scheduled 
or unscheduled) collected before the first dose of VX-659 in VX17-659-102 or VX17-659-103 
studies.  
Absolute change from baseline will be calculated as post-baseline value - baseline value. 


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Relative change from baseline will be calculated as 100% × (post-baseline value – baseline 
value)/baseline value.  
Treatment-emergent (TE) Period for Part A will include the time from the first dose of study 
drug in Part A to 28 days after the last dose date of the study drug in Part A or to the completion 
date of study participation in Part A (Section 9.1.5 of the CSP), whichever occurs first.  
Treatment-emergent (TE) Period for Part B will include the time from the first dose of study 
drug in Part B to 28 days after the last dose date of the study drug in Part B or to the completion 
date of study participation in Part B (Section 9.1.5 of the CSP), whichever occurs first.  
The completion date of study participation will be obtained from the end of study page of the 
eCRF for each part respectively. 
For subjects who participate in another qualified Vertex study before completing Study VX18-
445-113 and resume participation in Study VX18-445-113, the TE Period for either Part A or B 
will exclude the time spent in the other study. 
Unscheduled visits: Unscheduled visit measurements will be included in analysis as follows: 
1) In scheduled visit windows per specified visit windowing rules 
2) In the derivation of baseline  and last on-treatment measurements 
3) In the derivation of maximum and minimum values during TE period of either Part A or 
Part B, and maximum and minimum change from baseline values during corresponding 
TE period for the long-term safety analyses 
4) In individual subject data listings as appropriate 
Visit windowing rules: The analysis visit windows for protocol-defined visits are provided in 
Appendix A. 
Incomplete/missing data will not be imputed, unless specified otherwise.  
Outliers: No formal statistical analyses will be performed to detect or remedy the presence of 
statistical outliers, unless specified otherwise. 
Multiplicity: There will be no multiplicity adjustment as no hypothesis test is planned for safety 
analysis, unless specified otherwise. 
8.2 
Background Characteristics  
8.2.1 
Subject Disposition 
Part A and Part B 
Subject disposition will be summarized for the All Subjects Set for corresponding part. 
Number of subjects in the following categories will be summarized:  
• All Subjects Set 
• Safety Set 
• Never dosed 
The number and percentage (based on the Safety Set) of subjects in each of the following 
disposition categories will be summarized: 
• Completed Treatment 


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• Prematurely discontinued treatment and the reasons for discontinuation 
• Completed study 
• Prematurely discontinued the study and the reasons for discontinuation 
• Departed Study VX18-445-113 to participate in another qualified Vertex study 
• Departed Study VX18-445-113 to participate in another qualified Vertex study and returned 
to VX18-445-113  
• Subjects rolled over to Part B (for Part A only).  
A listing will be provided by part, for subjects who discontinued treatment or who discontinued 
study with reasons for discontinuation. A separated listing will be provided by part for subjects 
who departure from the study. 
8.2.2 
Demographics and Baseline Characteristics 
Part A and Part B 
Demographics and baseline characteristics will be summarized based on the Safety Set for 
corresponding part.  
Demographic data will include the following: 
• Age at baseline (in years) 
• Sex (female and male) 
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, and not collected per local regulations) 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, Not Collected per Local Regulations and Other) 
• Geographic region (North America, Europe [including Israel and Australia]) 
Baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• BMI (kg/m2) 
Disease characteristics will include the following: 
• ppFEV1 at baseline (<40, ≥ 40 to <70, ≥70 to ≤90, and >90) 
• ppFEV1 at baseline (continuous)  
• Prior use of dornase alfa (Yes, No) 
• Prior use of azithromycin (Yes, No) 
• Prior use of inhaled antibiotic (Yes, No) 
• Prior use of any bronchodilator (Yes, No)  
• Prior use of any inhaled bronchodilator (Yes, No)  


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• Prior use of any inhaled hypertonic saline (Yes, No) 
•  Infection with Pseudomonas aeruginosa within 2 years prior to screening visit of VX-659 in 
VX17-659-102 or  VX17-659-103 (Positive, Negative) 
In addition, data listings will also be provided for: 
• Informed consent; 
• Inclusion/Exclusion criteria violation for subjects with any such violations. 
8.2.3 
Medical History 
Medical history will be summarized separately for Parts A and B based on the Safety Set. 
Part A and Part B 
Medical history will be coded by using the Medical Dictionary for Regulatory Activities 
(MedDRA).  
Medical history will be summarized descriptively by System Organ Class (SOC) and Preferred 
Term (PT) based on the Safety Set for the corresponding part. The corresponding data listing will 
also be provided. 
8.2.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be summarized separately for Parts A and B based on the 
Safety Set. 
Part A and Part B 
Medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
and categorized as follows: 
• Prior medication: any medication that was administered during the 56 days before the first 
dose of study drug in the corresponding part. For subjects who enroll in another qualified 
Vertex study before completing this study and resume participation in this study, any new or 
changed medication administered after the Departing Visit and prior to the first dose of this 
study’s study drug after resuming participation will also be considered prior medication. 
• Concomitant medication: medication continued or newly received during the TE Period in 
the corresponding part.  
• Post-treatment medication: medication continued or newly received after the TE Period in 
the corresponding part. 
 A given medication may be classified as a prior medication, a concomitant medication, or a 
post-treatment medication; both prior and concomitant; both concomitant and post-treatment; or 
prior, concomitant, and post-treatment.  
If a medication has completely missing or partially missing start/stop date and if it cannot be 
determined whether it was taken before the first dose date, concomitantly during the TE Period, 
or after the TE Period, it will be considered in all 3 categories of prior, concomitant, and 
post-treatment medication. Details for imputing missing or partial start and/or stop dates of 
medication are described in Appendix B. 
Prior medications and concomitant medications will be summarized descriptively using 
frequency tables based on the Safety Set by: 1) preferred name (PN); and 2) Anatomical 


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Therapeutic Chemical (ATC) level 1, ATC level 2, and PN. All medications will be listed for 
each subject.   
8.2.5 
Study Drug Exposure  
Exposure summaries will be separated for Parts A and B based on the Safety Set. 
Part A and Part B 
Duration of study drug exposure (in days) will be calculated as: last dose date of study drug in 
the corresponding part – first dose date of study drug in the corresponding part + 1, regardless of 
study drug interruption.  
For subjects who enroll in another qualified Vertex study before completing this study and 
resume participation in this study, time spent in the other study will be excluded.  
Study drug exposure (in weeks) will be summarized descriptively by the number of subjects (n), 
mean, SD, median, min, and max. It will also be summarized into the following categories: <=24 
weeks, >24-<=48 weeks, >48-<=72 weeks, >72-<=96 weeks, >96 weeks for Part A; <=24 
weeks, >24-<=48 weeks, >48 weeks for Part B .  
Additionally, the total study drug exposure, defined as the sum of the study drug exposure across 
all subjects (in patient-weeks and patient-years), will be provided. 
8.2.6 
Study Drug Compliance  
Study drug compliance will be summarized separately for Parts A and B based on the Safety Set.  
Part A and Part B 
Study drug compliance will be calculated as: 100 × [1 – (total number of days of study drug 
interruption) / (duration of study drug exposure in days)]. A study drug interruption on a given 
day is defined as an interruption of any study drug on that day. For subjects who participate in 
another qualified Vertex study before completing Study VX18-445-113 and resume participation 
in Study VX18-445-113, time spent in the other study will be excluded.  
Study drug compliance will be summarized descriptively by the number of subjects (n), mean, 
SD, median, min, and max. It will also be summarized in categories: <80% and ≥80% using 
frequency tables. 
In addition, percentage of tablets taken will be calculated as 100 × [(total number of tablets 
dispensed) – (total number of tablets returned)] / (total number of tablets planned to be taken per 
day × duration of study drug exposure in days). A summary similar to that for study drug 
compliance will be produced. 
8.2.7 
Important Protocol Deviations 
Important protocol deviation (IPD) will be summarized separately for Parts A and B based on the 
Safety Set.  
Part A and Part B 
An IPD is a deviation that may significantly affect the completeness, accuracy, or reliability of 
the study data or that may significantly affect a subject’s rights, safety, or well-being. A protocol 
deviation review team will categorize IPDs according to the protocol deviation plan during the 
study.  


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Protocol deviations that should be considered as potential IPDs include, but are not limited to: 
• Subject was enrolled in the study despite not satisfying one or more inclusion/exclusion 
criterion 
• Subject was less than 80% compliant with study drug for non-safety reasons 
• Subject received prohibited concomitant medications 
• Subject received the wrong treatment or incorrect doses. 
IPDs will be summarized descriptively based on Safety Set for Part A and Part B separately. 
Additionally, IPDs will be provided in an individual subject data listing based on Safety Set for 
Part A and Part B separately.  
 
8.3 
Efficacy Analysis  
Not applicable.  
8.4 
Safety Analysis 
The primary objective of the study is the evaluation of the long-term safety and tolerability of 
ELX/TEZ/IVA. Safety analysis will be summarized separately for Parts A and B. Part A safety 
analyses will be based on the TE Period for Part A for subjects in the Safety Set for Part A. Part 
B safety analyses will be based on the TE Period for Part B for subjects in the Safety Set for Part 
B. The overall long-term safety profile of study drug will be assessed in terms of the following 
safety and tolerability endpoints: 
• Treatment-emergent adverse events (TEAEs) 
• Clinical laboratory values (i.e., serum chemistry, hematology, coagulation, and urinalysis) 
• ECGs 
• Vital signs including body weight and BMI 
• Pulse oximetry 
• Spirometry 
Only descriptive analysis of safety will be performed, and no statistical testing will be 
performed. 
8.4.1 
Adverse Events 
Summaries of TEAEs will be provided separately for Parts A and B based on the Safety Set.  
For analysis purposes, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs for the corresponding part, defined as follows:  
• Pretreatment AE: any AE that occurred before the first dose date of study drug in the 
TE Period in the corresponding part. For subjects who enroll in another qualified Vertex 
study before completing this study and resume participation in this study, AEs that started 
during participation in another qualified Vertex study and are ongoing at the time of 
Returning Visit will be flagged as pre-treatment AE. 


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• TEAE: any AE that worsened (either in severity or seriousness) or newly developed at or 
after the first dose date of study drug in the TE Period in the corresponding part. 
• Post-treatment AE: any AE that worsened (either in severity or seriousness) or that was 
newly developed after the TE period in this study in the corresponding part.  
For AEs with completely missing or partially missing start dates, if there is no clear evidence 
that the AEs are pre-treatment or post-treatment, the AEs will be classified as TEAEs. 
Details for imputing missing or partial start dates of adverse events are described in Appendix C. 
An overview of all TEAEs will be provided with the following categories separately for Parts A 
and B: 
• Number of TEAEs (total number of TEAEs only) 
• Subjects with any TEAEs  
• Subjects with TEAEs by strongest relationship 
• Subjects with TEAEs by maximum severity 
• Subjects with TEAEs leading to study drug discontinuation (discontinuation of any study 
drugs) 
• Subjects with TEAEs leading to study drug interruption (discontinuation of any study drugs) 
• Subjects with Grade 3/4 TEAEs 
• Subjects with related TEAEs 
• Subjects with serious TEAEs 
• Subjects with related serious TEAEs 
• Subjects with TEAE leading to death  
The frequency counts and percentages as well as the exposure adjusted event rate will be 
presented for the above overview table. The exposure adjusted rate will not be presented for 
strongest relationship and maximum severity categories. 
The following summary tables of TEAEs will be presented separately for Parts A and B: 
• All TEAEs 
• Grade 3/4 TEAEs 
• TEAEs by strongest relationship 
• TEAEs by maximum severity 
• TEAEs leading to treatment discontinuation 
• TEAEs leading to treatment interruption 
• Related TEAEs 
• Serious TEAEs 
• Related serious TEAEs 


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• TEAEs leading to death 
Summaries will be presented separately for Parts A and B by MedDRA SOC and PT using 
frequency counts and percentages (i.e., number and percentage of subjects with an event) and the 
exposure adjusted event rate (except for summary by strongest relationship and maximum 
severity). When summarizing the number and percentages of subjects, subjects with multiple 
occurrences of the same adverse event or a continuing adverse event will be counted once, and 
only the maximum severity level will be presented in the severity summaries, and the strongest 
relationship level in the relationship summaries.  
Additional summary tables separately for Parts A and B will be presented for TEAEs showing 
number, percentage of subjects, and the exposure adjusted event rate 
• All TEAEs by PT 
All AEs, including pretreatment AEs, TEAEs, and post-treatment AEs, will be presented in an 
individual subject data listing based on the All Subjects Set separately for Parts A and B. In 
addition, a listing containing individual subject adverse event data for TEAEs leading to 
treatment discontinuation, TEAEs leading to treatment interruption, Grade 3/4 TEAEs, SAEs and 
all deaths will be provided, with a flag indicating the TEAE status for SAEs and deaths for Parts 
A and B separately. 
8.4.2 
 Clinical Laboratory Assessments 
Summaries of laboratory values will be provided separately for Parts A and B based on the 
Safety Set.  
For the treatment-emergent laboratory assessments, the observed values and change from 
baseline values of the continuous hematology, coagulation and chemistry results will be 
summarized in SI units at each visit during the TE period of the corresponding part separately for 
Parts A and B.  
The number and percentage of subjects with selected test values meeting at least 1 threshold 
analysis criterion event during the TE period of the corresponding part will be summarized 
separately for Parts A and B. The threshold analysis criterion shift from baseline will also be 
summarized for selected laboratory test values separately for Parts A and B. The threshold 
analysis criteria are provided in Appendix D.  
For selected LFT laboratory test (alanine transaminase [ALT], aspartate transaminase [AST], 
alkaline phosphatase [ALP], and total bilirubin), a scatter plot of the maximum treatment-
emergent value versus the baseline value corresponding to ×ULN (upper limit of normal) will be 
presented for the each part. Furthermore, a scatter plot of the maximum treatment-emergent 
value of ALT and AST, separately, versus the maximum treatment-emergent value of total 
bilirubin corresponding to ×ULN will also be presented for the each part.  
Results of positive urine/serum pregnancy test will be listed in individual subject data listings 
only separately for Parts A and B. For positive serum pregnancy listing, subjects with serum 
HCG which are abnormally high will be selected separately for Parts A and B. 
In addition, a listing containing individual subject hematology, chemistry, coagulation and 
urinalysis values will be provided separately for Parts A and B. This listing will include data 
from both scheduled and unscheduled visits. 


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8.4.3 
 Electrocardiogram 
Summaries of ECG values will be provided separately for Parts A and B based on the Safety Set.  
For the following ECG interval measurements during the TE period of the corresponding part, a 
summary of observed values and change from baseline values (in msec) will be provided at each 
visit separately for Parts A and B: RR interval, PR interval, QT interval, and QT corrected for 
HR (QTcF), QRS duration, and HR (beats per minute).  
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period of the corresponding part will be summarized separately for Parts A and B. The 
threshold analysis criteria are provided in Appendix D.  
In addition, a listing containing individual subject ECG values will be provided separately for 
Parts A and B. This listing will include data from both scheduled and unscheduled visits. 
8.4.4 
Vital Signs 
Summaries of vital sign values will be provided separately for Parts A and B based on the Safety 
Set.  
For the vital sign measurements during the TE period for the Safety Set for the corresponding 
part, the observed values and change from baseline values will be summarized at each visit 
separately for Parts A and B. The following vital signs parameters will be summarized: BMI 
(kg/m2), weight (kg), systolic and diastolic blood pressure (mm Hg), body temperature (°C), 
pulse rate (beats per minute), and respiratory rate (breaths per minute).  
The number and percentage of subjects meeting at least 1 threshold analysis criterion during the 
TE period for the corresponding part will be summarized separately for Parts A and B. The 
threshold analysis criteria are provided in Appendix D. 
In addition, a listing containing individual subject vital sign values will be provided separately 
for Parts A and B. This listing will include data from both scheduled and unscheduled visits. 
8.4.5 
Pulse Oximetry 
Summaries of pulse oximetry values will be provided separately for Parts A and B based on the 
Safety Set.  
For the percent of oxygen saturation measurements using pulse oximetry during the TE period 
for the Safety Set for the corresponding part, a summary of observed values and change from 
baseline values will be provided at each visit separately for Parts A and B.  
The number and percentage of subjects with shift changes from baseline (normal/missing and 
low according to the reference range) to the lowest percent of oxygen saturation during the TE 
Period for the corresponding part will be summarized separately for Parts A and B. The reference 
range for normal oxygen saturation is specified as >95%, and <=95% for low oxygen saturation. 
8.4.6 
Physical Examination  
No tables/figures/listings will be provided for PE data.  
8.4.7 
Ophthalmology Examination  
Ophthalmology examination results will be provided in a data listing separately for Parts A and 
B, as applicable. 


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8.4.8 
Spirometry  
Summaries of spirometry will be provided separately for Parts A and B based on the Safety Set.  
Summary statistics for raw values of the following spirometry measurements i.e. FEV1 (L), 
percent predicted FEV1 (percentage points), FVC (L), percent predicted FVC (percentage 
points), FEF25-75% (L/sec), percent predicted FEF25-75% (percentage points), FEV1/FVC, percent 
predicted FEV1/FVC (percentage points), will be presented at each visit for Part A and Part B 
separately. 
Percent predicted FEV1 (ppFEV1): the ppFEV1 value is the ratio of FEV1 (L) and predicted FEV1 
(L), expressed as a percentage. See Appendix F for more details. 
8.6 
Other Analyses  
8.6.1 
Sweat Chloride 
Sweat chloride (SwCl): the SwCl value for a given visit will be calculated as the mean of the 
non-missing sweat chloride measurements obtained on the left and right arms at that visit. If one 
of the two arm measurements at a time point is missing, the other will be used as the mean. A 
volume ≥15 µL is required for an accurate determination of sweat chloride. Any results reported 
as having volume <15 µL will be considered missing for analysis purposes. Any sweat chloride 


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values reported as <10 mmol/L or >160 mmol/L will be considered missing for analysis 
purposes. 
Clinic collected Sweat Chloride data 
Clinic collected SwCl values and change from SwCl baseline will be summarized using 
descriptive statistics by genotype (i.e. F/MF and F/F) at each visit for Part A and B respectively 
based on the Safety Set. 
Home collected Sweat chloride data 
Home collected SwCl values will be summarized using descriptive statistics for subjects with 
valid home collected SwCl values (a subset of approximately 50 subjects). Average will be taken 
for a subject if the subject has more than 1 valid home collected SwCl values collected at 
different unscheduled visits.  In addition, the clinic collected sweat chloride at the scheduled 
visits will also be summarized for the same subset of subjects.  
9 
INTERIM AND DMC ANALYSES 
9.1 
Interim Analysis 
IA may take place at any time during the study at the discretion of the sponsor. 
9.2 
IDMC Analysis 
The IDMC’s objectives and operational details will be defined in a separate document (IDMC 
Charter) which was finalized before the first subject first visit. The IDMC’s planned safety 
reviews of study data are outlined in the IDMC Charter and IDMC Statistical Analysis Plan. 
 


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10 
REFERENCES 
1. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall G, Culver BH, et al. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012;40(6):1324-43. 
 
 


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11 
APPENDICES 
Appendix A: Analysis Visit Windows for Safety Assessments 
Table 11-1 
Analysis Visit Windows for Safety Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
Part A  
Spirometry 
Serum Chemistry 
Hematology 
Vital Signs3 
Pulse Oximetry 
Baseline  
Day 15 
 
Week 4 
Week 8 
Week 16 
Week 24 
Week 36 
Week 48 
Week 60 
Week 72 
Week 84 
Week 96 
Safety Follow-up4 
1 
15 
 
29 
57 
113 
169 
253 
337 
421 
505 
589 
673 
Not applicable 
defined in section 8.1 
[1, 22] where day 1 is post-
dose measurement 
(22, 43] 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 687] 
Use nominal visit 
Standard 12-lead ECG  
Baseline  
Day 15 
 
Week 8 
Week 24 
Week 48 
Week 72 
Week 96 
Safety Follow-up4 
1 
15 
 
57 
169 
337 
505 
673 
Not applicable 
defined in section 8.1  
[1, 36] where day 1 is post-
dose measurement 
(36, 113] 
(113, 253] 
(253, 421] 
(421, 589] 
(589, 687] 
Use nominal visit 
Coagulation 
Baseline  
Week 24 
 
Week 48 
Week 72 
Week 96 
Safety Follow-up4 
1 
169 
 
337 
505 
673 
Not applicable 
defined in section 8.1 
[1, 253] where day 1 is post-
dose measurement 
(253, 421] 
(421, 589] 
(589, 687] 
Use nominal visit 


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Table 11-1 
Analysis Visit Windows for Safety Assessments 
Assessment 
Visit1 
Target Study Day 
Analysis Visit Window 
(in study days)2 
Weight, Height and BMI  
Baseline  
Week 4 
 
Week 8 
Week 16 
Week 24 
Week 36 
Week 48 
Week 60 
Week 72 
Week 84 
Week 96 
Safety Follow-up4 
1 
29 
 
57 
113 
169 
253 
337 
421 
505 
589 
673 
Not applicable 
defined in section 8.1 
[1, 43] where day 1 is post-
dose measurement 
(43, 85] 
(85, 141] 
(141, 211] 
(211, 295] 
(295, 379] 
(379, 463] 
(463, 547] 
(547, 631] 
(631, 687] 
Use nominal visit 
Sweat Chloride (Clinic 
collected only) 
Baseline 
Week 24 
 
Week 96 
-- 
169 
 
673 
defined in section 8.1 
[1, 421] where day 1 is post-
dose measurement  
(421, 687] 
Sweat Chloride (collected at 
unscheduled home visits) 
 
Home SwCl collection 
visit 1 
Not applicable 
Use nominal visit5 
Home SwCl collection 
visit 2 
Not applicable 
Use nominal visit5 
Part B 
Spirometry 
Serum Chemistry 
Hematology 
Vital Signs3 
Weight, Height and BMI 
Pulse Oximetry 
Baseline 
Part B Week 12 
 
Part B Week 24 
Part B Week 36 
Part B Week 48 
Part B Safety Follow-up4 
-- 
85 
 
169 
253 
337 
Not applicable 
defined in section 8.1 
[1, 127] where day 1 is post-
dose measurement 
(127, 211] 
(211, 295] 
(295, 351] 
Use nominal visit 
Standard 12-lead ECG  
Baseline 
Part B Week 12 
 
Part B Week 24 
Part B Week 48 
Part B Safety Follow-up4 
-- 
85 
 
169 
337 
Not applicable 
defined in section 8.1 
[1, 127] where day 1 is post-
dose measurement 
(127, 253] 
(253, 351] 
Use nominal visit 
Coagulation 
Baseline 
Part B Week 24 
 
Part B Week 48 
Part B Safety Follow-up4 
-- 
169 
 
337 
Not applicable 
defined in section 8.1  
[1, 253] where day 1 is post-
dose measurement 
(253, 351] 
Use nominal visit 
Sweat Chloride5 
Baseline 
Part B Week 24 
 
Part B Week 48 
-- 
169 
 
337 
Defined in section 8.1 
[1, 253] where day 1 is post-
dose measurement 
(253, 351] 


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Notes: 
1 Visit name for analysis purpose is used to report data in tables and figures. 
 
 
2 The analysis visit windows will be applied using the following rules for both scheduled and unscheduled visits 
except for SwCl collected at unscheduled home visits: 
1. If no numerical measurement is available within a visit window, the measurement will be considered missing 
for the visit. 
2. If there is more than 1 numerical measurement available within a visit window, use the following rules:  
i. The measurement closest to the target day will be used; or  
ii. If there are multiple measurements with the same distance from the target day, the latest measurement 
will be used. If the latest measurement cannot be determined, then unscheduled visit will be selected. 
 
3 For measurement collected on the date of first dose of study drug in Treatment Period, if it cannot be determined 
whether the measurement is before or after the first dose: 
1. Scheduled measurement will be treated as pre-dose observation. 
2. Unscheduled measurement will be treated as post-dose observation. 
 
4 For safety Assessment, Safety Follow-up analysis visit will be based on nominal Safety Follow-up visit. If a 
subject doesn’t have a nominal Safety Follow-up visit but has an ETT visit with study day >687 for Part A or >351 
for Part B, then the ETT visit will be mapped into Safety Follow-up analysis visit for the corresponding part.  
 
5 If one subject has multiple home collected SwCl samples at different unscheduled visits, the assignment of the 
visits will be based on chronological order.  
 
Derived Variables for each part: 
1. Age (in years) at first dose date and post-baseline visit (for demographics, listing and the calculation of 
[percent] predicted spirometry variables): 
Obtain the age at informed consent in “yy, mm” format (e.g., 24 years, 6 months) from the Vital Signs (VS) 
page at the Day 1 Visit and add 0.5 month to convert to days. 
Obtain the informed consent date. 
Then age (in years) at first dose or post-baseline visit = [(first dose date or post-baseline visit date – informed 
consent date) in days + age at informed consent (in days)]/365.25. 
2. Missing first dose date or last dose date 
If the first dose date is missing, use Day 1 visit date. 
If the last dose date of study drug is not available and there is no data to indicate that the subject discontinued 
treatment, the data cutoff date will be used instead.  
If the subject discontinued treatment and the last dose date is missing or partial date is reported, the last dose 
date will be imputed based on, in descending order priority, the Early Treatment Termination (ETT) visit date, 
last visit date before the Safety Follow-up, or the last study drug administration date from EX SDTM domain, 
as appropriate. The imputation algorithm will ensure the imputed last dose date does not exceed the data cutoff 
date. 
3. Electrocardiogram: 
Baseline is defined in Section 8.1. If multiple ECG measurements are obtained on the same calendar day during 
the TE period, 
o 
For summary purpose, the average value will be used as the ECG on that day; 
o 
For threshold analysis purpose, all ECG values will be used 
 


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Appendix B: Imputation Rules for Missing Prior/Concomitant Medication Dates 
Imputation rules for missing or partial medication start/stop dates are defined below: 
1. Missing or partial medication start date: 
a. If only DAY is missing, use the first day of the month.  
b. If DAY and Month are both missing, use the first day of the year.  
c. If DAY, Month and Year are all missing, use a date before the first dose date (to 
impute in practical, use the informed consent date). 
2. Missing or partial medication stop date: 
a. If only DAY is missing, use the last day of the month. 
b. If DAY and Month are both missing, use the last day of the year. 
c. If DAY, Month and year are all missing, assign ‘continuing’ status to stop date (to 
impute in practical, use the End of Study Date to impute). 
In summary, the prior, concomitant, or post categorization of a medication is described below. 
Table 11-2 
Prior, Concomitant, and Post Categorization of a Medication for Part A or B 
Medication Start Date 
Medication Stop Date 
< First Dose Date of 
Study Drug in the 
Corresponding Part  
≥ First Dose Date and  
≤ End Date of TE Period 
in the Corresponding 
Part  
> End Date of TE Period 
in the Corresponding 
Part  
< First dose date of study drug in one 
part 
P 
PC 
PCA 
≥ First dose date and  
≤ End date of TE period in one part 
- 
C 
CA 
> End date of TE period in one part 
- 
- 
A 
P: Prior; C: Concomitant; A: Post 
Same imputation rule will be implemented for missing and/or partial dates of non-
pharmacological treatment/procedure. 
 


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Appendix C: Imputation Rules for Missing AE dates 
Imputation rules for missing or partial AE start date are defined below. If the imputed AE start 
date is before the informed consent/assent date for this study, the AE start date will be imputed 
using the informed consent/assent date.  
• If only Day of AE start date is missing: 
o If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then  
 if AE start year and month are equal to the month and year of first dose date, 
then impute the AE start day as the day of first dose date;  
 else impute the AE start day as 1.  
o else impute the AE start day as 1.  
• If Day and Month of AE start date are missing: 
o If the full (or partial) AE end date is NOT before the first dose date or AE end date is 
missing, then  
 if AE start year is equal to the year of first dose date, then impute the AE start 
month and day as the month and day of first dose date;  
 else impute the AE start month as January and day as 1.  
o else impute the AE start month as January and day as 1.  
• If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site.  
o If the full (or partial) AE end date is NOT before the first dose date of the Treatment 
Period or AE end date is missing, then impute the AE start date as the first dose date.  
o else impute the AE start date as the informed consent date. 
Compare the imputed AE start date with TE period to determine whether the AE is pretreatment 
AE, TEAE or post-treatment AE. 
Imputation rules for partial AE end date are defined below:  
If partial end date, then impute as min (the last day of the month, data cut-off, end of study) if 
day is missing, or min (Dec, data cut-off, end of study) if month is missing. 
 


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Appendix D: Criteria for Threshold Analysis 
Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009.  
AST 
>ULN - ≤3xULN 
>3x - ≤ 5xULN 
>5x - ≤ 8xULN 
>8x - ≤ 20.0xULN 
>20.0xULN 
FDA DILI Guidance Jul 2009. 
ALT or AST 
 (ALT>ULN - ≤  3xULN) or 
(AST>ULN - ≤  3xULN) 
(ALT>3x - ≤  5xULN) or  (AST>3x 
- ≤  5xULN) 
(ALT>5x- ≤  8xULN) or  (AST>5x - 
≤    8xULN) 
(ALT>8x - ≤  20xULN) or (AST>8x 
- ≤ 20xULN) 
ALT>20xULN or AST> 20 xULN 
FDA DILI Guidance 
Alkaline Phosphatase 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2.5 xULN 
>2.5 – ≤ 5.0 x ULN 
>5.0 – ≤ 20.0 x ULN 
>20.0 x ULN 
FDA DILI Guidance Jul 2009.  
Total Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Direct Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
Indirect Bilirubin 
>ULN - ≤ 1.5xULN 
>1.5 – ≤ 2xULN 
>2 – ≤ 3xULN  
>3 – ≤ 10xULN 
>10xULN 
FDA DILI Guidance Jul 2009. 
ALT and Total Bilirubin 
ALT>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 


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Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
AST and Total Bilirubin 
AST>3xULN and TBILI>2xULN 
FDA DILI Guidance Jul 2009.  
 
(ALT or AST) and Total Bilirubin (ALT>3xULN or AST>3xULN) and 
TBILI>2×ULN 
FDA DILI Guidance Jul 2009. 
GGT 
>ULN - ≤ 2.5xULN 
>2.5 –  ≤ 5.0xULN 
>5.0 –  ≤ 20.0xULN  
>20.0xULN 
CTCAE grade 1-4 
Clinical Chemistry (NON-LFT) 
 
Albumin 
<LLN - ≥ 30 g/L 
<30 – ≥ 20 g/L 
<20 g/L 
CTCAE grade 1-3 
Amylase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Creatinine 
>ULN - ≤ 1.5xULN 
>1.5 - ≤ 3.0xULN 
>3.0 - ≤ 6.0xULN 
>6.0xULN 
CTCAE grades 1-4 
Lipase 
>ULN -  ≤  1.5xULN 
>1.5x -  ≤  2xULN 
>2x -  ≤  5xULN 
>5xULN 
Criteria based upon CTCAE 
Total protein 
 
<LLN  
>ULN 
No CTCAE 
Creatine Kinase 
>ULN - ≤ 2.5 x ULN 
>2.5 - ≤ 5 x ULN 
>5 - ≤ 10x ULN  
>10 x ULN 
CTCAE grades 1-4 
 
Hematology 
Hemoglobin 
Hgb decreased (anemia) 
<LLN - ≥ 100 g/L 
<100 – ≥ 80 g/L  
< 80 g/L 
CTCAE grade 1-3 
 
Hgb increased 
>ULN - ≤ 20 g/L above ULN 
>20 g/L above ULN - ≤ 40 g/L 
above ULN 
>40 g/L above ULN 
CTCAE grade 1-3 


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Table 11-3 
Threshold Analysis Criteria for Laboratory Tests (as applicable) 
Parameter 
Threshold Analysis 
Comments 
Platelets 
Platelet decreased 
<LLN - ≥ 75.0 x 10e9 /L 
<75.0 – ≥ 50.0 x 10e9 /L  
<50.0 – ≥ 25.0 x 10e9 /L  
<25.0 x 10e9 /L 
CTCAE grade 1-4 
 
Platelet increased   
>ULN 
No CTCAE available 
 
Reticulocytes/Erythrocytes (%)    <LLN 
>ULN 
No CTCAE 
Coagulation 
 
 
Activated partial thromboplastin 
time  (PTT)  
 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
Prothrombin time (PT) 
International 
Normalized Ratio (INR) 
>ULN - ≤ 1.5 x ULN 
>1.5 – ≤ 2.5 x ULN 
>2.5 x ULN 
CTCAE grade 1-3 
  
Table 11-4 
Threshold Analysis Criteria for Laboratory Tests (for labeling purpose) 
Parameter 
Threshold Analysis 
Comments 
Clinical Chemistry (LFT) 
ALT or AST 
>3xULN 
>5xULN 
>8xULN 
For labeling purpose 
 
Table 11-5 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
HR 
Bradycardia 
 
<50 bpm  
<45 bpm 
Decrease from baseline ≥10 bpm 
Decrease from baseline ≥20 bpm 
<50 bpm and decrease from baseline ≥10 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
 
Per HV grade 2, 3, plus shift change 
 
 


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Table 11-5 
Threshold Analysis Criteria for ECGs 
Parameter 
Threshold Analysis 
Comments 
 
Tachycardia 
 
>100 bpm 
>115 bpm  
>130 bpm  
Increase from baseline ≥10 bpm 
Increase from baseline ≥20 bpm  
>100 bpm and increase from baseline ≥10 bpm 
>100 bpm and increase from baseline ≥20 bpm 
Per HV grade 1, 2, 3, plus shift change 
 
 
PR 
≥240 ms 
≥300 ms 
≥200 ms and increase from baseline ≥40 ms 
≥200 ms and increase from baseline ≥100 ms 
 
QRS 
>110 ms 
>160 ms 
Increase from baseline ≥20 ms 
Increase from baseline ≥40 ms 
 
QTc 
Borderline 
Prolonged* 
Additional 
 
 
>450 ms and <500ms (Male); >470 ms and 
<500ms (Female) 
≥500 ms 
 
Increase from baseline 
Increase from baseline >10 ms 
Increase from baseline >20 ms 
Increase from baseline >40 ms 
Increase from baseline >60 ms 
 
To be applied to any kind of QT correction 
formula.  
 
 
 
 
Note: Based on CPMP 1997 guideline. 
 


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Table 11-6 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
Pulse Rate 
Same as above in ECG category 
 
 
SBP increased 
 
 
>140 mmHg 
>160 mmHg 
>10 mmHg increase from baseline 
>20 mmHg increase from baseline 
 
>140 mmHg & >10 mmHg increase from 
baseline 
>140 mmHg & >20 mmHg increase from 
baseline 
>160 mmHg & >10 mmHg increase from 
baseline 
>160 mmHg & >20 mmHg increase from 
baseline 
 
809/770 analyses 
SBP decrease 
 
 
<90 mmHg 
<80 mmHg 
>10 mmHg decrease from baseline 
>20 mmHg decrease from baseline 
 
<90 mmHg and >10 mmHg decrease from 
baseline 
<90 mmHg and >20 mmHg decrease from 
baseline 
<80 mmHg and >10 mmHg decrease from 
baseline 
<80 mmHg and >20 mmHg decrease from 
baseline 
 
Per HV grade 1, 3, plus shift change 


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Table 11-6 
Threshold Analysis Criteria for Vital Signs 
Parameter 
Threshold Analysis  
Comments 
DBP increased 
 
>90 mmHg 
>100 mmHg 
>5 mmHg increase from baseline 
>10 mmHg increase from baseline 
 
>90 mmHg and >5 mmHg increase from 
baseline 
>90 mmHg and >10 mmHg increase from 
baseline 
>100 mmHg and >5 mmHg increase from 
baseline 
>100 mmHg and >10 mmHg increase from 
baseline 
 
 
DBP decreased 
 
 
<60 mmHg 
<45 mmHg 
>5 mmHg decrease from baseline 
>10 mmHg decrease from baseline 
 
<60 mmHg and >5 mmHg decrease from 
baseline 
<60 mmHg and >10 mmHg decrease from 
baseline 
<45 mmHg and >5 mmHg decrease from 
baseline 
<45 mmHg and >10 mmHg decrease from 
baseline 
 
 
 
 
Weight   
Weight gain  
≥5 % increase from baseline   
≥10 % increase from baseline  
≥ 20% increase from baseline  
 
CTCAE grade 1-3 
 
 
Weight loss  
≥5 % decrease from baseline   
≥10 % decrease from baseline  
≥ 20% decrease from baseline  
 
CTCAE grade 1-3 
 
  
 
 
 


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Appendix E: Adverse Events of Special Interest  
Table 11-7 
MedDRA Preferred Terms for Event of Special Interest 
Adverse event of special interest 
MedDRA preferred terms 
Elevated transaminases 
Alanine aminotransferase abnormal, Alanine aminotransferase 
increased, Aspartate aminotransferase abnormal, Aspartate 
aminotransferase increased, Transaminases abnormal, 
Transaminases increased, Liver function test abnormal, Liver 
function test increased, Hypertransaminasaemia, Hepatic 
enzyme abnormal, Hepatic enzyme increased 
Rash 
Rash, Rash erythematous, Rash macular, Rash maculo-papular, 
Rash maculovesicular, Rash vesicular, Rash pruritic, Rash 
follicular, Rash pustular, Nodular rash, Drug eruption, Fixed 
eruption, Urticaria, Urticaria papular, Urticaria vesiculosa, 
Urticarial dermatitis, Rash morbilliform, Rash papular, Rash 
papulosquamous, Rash rubelliform, Rash scarlatiniform , Drug 
hypersensitivity, Type IV hypersensitivity reaction, Dermatitis, 
Dermatitis atopic, Epidermolysis, Skin toxicity, Dermatitis 
allergic, Dermatitis exfoliative, Dermatitis exfoliative 
generalised, Erythema multiforme, Exfoliative rash, 
Mucocutaneous rash, Acute generalised exanthematous 
pustulosis, Cutaneous vasculitis, Urticarial vasculitis, Dermatitis 
bullous, Drug reaction with eosinophilia and systemic 
symptoms, Epidermal necrosis, Oculomucocutaneous syndrome, 
Skin exfoliation, Skin necrosis, Stevens-Johnson syndrome, 
Toxic epidermal necrolysis, Toxic skin eruption, Perioral 
dermatitis, Vasculitic rash, Immune-mediated dermatitis, Penile 
rash, SJS-TEN overlap, Erythrodermic atopic dermatitis, Scrotal 
rash 
 
 
Note: The preferred terms listed in the table is based on the MedDRA version applicable at the 
time of finalization of the SAP. If the MedDRA version is upgraded at the time of the final 
analysis, the corresponding preferred terms based on the upgraded version, including adding, 
removing and renaming the preferred terms, will be used in the analysis of adverse events of 
special interest. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix F: Details of GLI Equations for Calculating ppFEV1 
Percent predicted values will be calculated for parameters of FEV1, FVC, FEV1/FVC, and 
FEF25%-75% using the Quanjer GLI-2012 Regression Equations and Lookup Tables. Details of the 
derivation of the GLI equation are provided in the article by Quanjer et al. (2012). 
The regression equations and lookup tables required to implement the Quanjer GLI-2012 
predicted values are available in: 
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Quanjer GLI-2012 Regression 
Equation and Lookup Tables (Version 7 April 2013). Global Lung Function Initiative. [online] 
Available at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138978 
[Accessed July 1, 2019]. 
The instructions and tools on how to implement the Quanjer GLI-2012 equations are:   
Philip H. Quanjer, Sanja Stanojevic, Tim J. Cole, Janet Stocks. Implementing GLI-2012 
regression equations (Version 19 July 2015). Global Lung Function Initiative. [online] Available 
at: http://www.ers-education.org/home/browse-all-content.aspx?idParent=138979 [Accessed July 
1, 2019].   
Sanja Stanojevic. GLI-2012 - SAS Macro (Version 2, 7 April 2013). Global Lung Function 
Initiative. [online] Available at: http://www.ers-education.org/home/browse-all-
content.aspx?idParent=138988 [Accessed  July 1, 2019]. 
Data handling rule for spirometry is as follows:  
• Input age with at least 2 decimal place 
• Use height at Day 1 Visit regardless if height is collected at other study visits for subjects 
whose age at informed consent is >21 years. For subjects with age at informed consent is 
<=21 years, height collected at the respective visit should be used; If the height at the 
respective visit is not available, the last non-missing record will be used 
• For race, map CRF black or AA to black, all other races in CRF (except white) are 
mapped to 'other'; multiple checks for race in CRF are also mapped to 'other'; white is a 
reference race in the equations and assumes 0 values for all race coefficients in the       
GLI  equations.