Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 933
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare LY900014 to insulin lispro, both in combination with insulin glargine or insulin degludec, in participants with type 2 diabetes (T2D).

Detailed description:

Arms:
arm 1: LY900014 given subcutaneously (SC) with each meal with either 100 U/mL (U-100) basal insulin glargine given SC once or twice daily or U-100 or 200 U/mL (U-200) insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. arm 2: Insulin lispro given SC with each meal with either U-100 basal insulin glargine given SC once or twice daily or U-100 or U-200 insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. arm 3: LY900014 given subcutaneously (SC) with each meal with either U-100 basal insulin glargine given SC once or twice daily or U-100 or U-200 insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets. arm 4: Insulin lispro given SC with each meal with either U-100 basal insulin glargine given SC once or twice daily or U-100 or U-200 insulin degludec given SC once daily. Prandial insulin doses were individualized and titrated according to protocol-defined targets.

Interventions: intervention 1: LY900014 intervention 2: Insulin Lispro intervention 3: Insulin Glargine intervention 4: Insulin Degludec intervention 5: Metformin intervention 6: SGLT2 inhibitor
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC intervention 3: Administered SC intervention 4: Administered SC intervention 5: Administered orally. intervention 6: Administered orally.

Protocol document:
Prot_000.pdf: 
 
   
 
  
  
  
  
   
   
  
    
    
  
   
  
   
       
 
 
 
 
 
  
 
 
 


  
 
 
  
 
 
 
 
 
  
   
  
 
  
 
  
 
   
  
   
 
 
  
  
 
 
  
  
     
   
     
      
 
      
        
    
   
    
    
   
   
    
  
  
  
  
   
   
  
        
   
  
   
 
     
    
  
  
   
 
  
  
  
    
  
      
  
  
  
 
       
  
 
  
  
    
   
   
   
   
 
         
   
 
  
   
 
        
   
 
    
   
  
  
  
 
  
  
  
 
  
   
      
  
   
  
  
  
    
  
  
  
 
 
 
 
 
  
   
 
  
 
  
   
  
 
  
  
 
  
  
  
    
 


  
 
 
  
  
 
 
  
 
 
  
   
 
  
  
 
  
   
 
  
 
 
 
 
 
 
  
  
  
 
   
 
  
   
  
  
  
   
   
 
  
 
  
 
  
  
 
   
  
  
 
 
 


  
 
 
 
 
  
 
 
 
  
   
  
 
  
  
 
 
  
  
 
  
 
    
 
 
 
 
  
 
 
   
  
 
  
  
  
  
  
 
  
  
 
  
  
 
 
  
  
 
  
  
 
 
  
 
 
  
 
  
 
  
   
 
 
  
  
 
  
  
  
 
  
 
  
 
  
 
 
  
 
 
 
  
 


  
 
 
  
  
  
  
 
   
   
 
  
  
 
 
 
  
  
  
 
  
  
   
  
  
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
  
   
 
  
    
 
 
 
 
 
 
 
 


  
 
 
  
  
 
  
  
   
   
 
  
 
 
   
  
  
 
  
 
  
  
  
 
  
  
 
  
  
  
 
   
  
  
 
  
 
 
   
  
    
  
  
 


  
 
 
  
     
   
  
 
     
   
  
 


  
 
 
  
 
  
   
  
 
   
  
 
   
  
    
 
   
  
  
  
  
   
    
  
  
  
 
  
   
 
   
  
  
  
 
   
  
 
  
   
 
  
  
   
   
 
 
   
    
  
   
  
 
  
 
 
  


  
 
 
   
 
  
  
  
  
   
   
  
     
   
  
   
  
   
      
 
  
  
    
  
  
  
  
  
  
  
   
   
  
  
  
   
  
  
  
  
 
  
     
      
             
  
  
  
  
   
  
   
      
   
  
  
 
  
   
   
  
  
  
 
  
  
  
    
     
  
   
   
     
     
 
  
  
  
  
   
   
  
  
     
    
  
  
  
  
  
   
    
  
  
   
  
   
 
  
    
   
    
  
    
  
 
  
  
         
    
  
   
  
  
   
  
  
   
  
   
   
    
   
    
   
 
 
 
  
    
  
   
  
   
      
  
  
 
  
   
  
   
  
   
  
 
  
  
  
 
  
   
 
 
    
   
  
 
  
      
  
      
  
  
  
  
  
  
 
  
 
   
    
   
   
 
    
   
  
 
  
  
   
  
 
  
 
   
   
 
  
  
 
  
 
    
    
  
 
  
       
   
  
  
  
  
    
  
   
  
    
   
  
 
  
  
   
  
   
    
   
 
  
  
 
  
 
    
    
  
 
  
   
    
   
  
  
  
  
    
    
 


  
 
 
    
   
  
 
  
  
   
  
  
 
    
   
 
  
  
 
  
 
   
    
   
   
  
 
  
 
  
  
   
      
  
 
 
  
   
 
  
    
  
 
  
  
   
  
   
    
     
 
  
 
 
  
 
     
  
 
  
        
   
 
  
  
  
 
   
   
        
 
  
 
  
  
   
  
   
    
    
 
 
  
 
     
  
 
  
        
   
 
 
  
   
  
  
 
  
  
   
  
 
  
  
 
    
  
  
  
  
  
 
  
  
   
   
  
  
  
 
 
    
  
  
  
  
 
  
  
   
  
   
     
   
  
 
    
       
  
  
   
  
 
  
  
 
  
 
  
  
   
   
  
  
  
    
  
  
 
 
    
  
  
 
   
  
  
 
   
 
  
  
   
  
   
    
   
  
 
 
  
   
 
  
    
   
 
   
  
  
 
   
   
  
  
  
  
 
 
 
   
      
  
      
  
        
  
  
   
  
      
  


  
 
 
  
 
  
  
  
  
 
  
  
    
  
 
  
      
    
  
      
   
  
  
    
  
  
 
    
  
  
    
  
  
  
  
  
 
  
   
  
  
 
  
      
  
  
 
      
   
  
  
  
     
   
   
  
  
  
  
  
    
   
  
   
    
   
   
  
    
  
 
  
 
  
  
     
  
  
  
   
  
    
    
  
  
    
   
  
  
  
   
   
  
  
    
    
  
 
 
  
     
 
  
  
  
    
  
 
  
  
  
   
   
  
    
  
    
  
   
  
   
   
    
 
   
  
    
  
   
  
  
  
   
    
     
  
  
  
    
    
  
   
   
  
     
  
 
  
   
    
   
 
  
     
 
    
  
    
   
  
  
  
   
    
    
  
    
       
   
   
  
     
 
 
   
  
  
 
   
   
  
   
  
  
 
   
   
  
   
  
  
  
  
 
   
     
  
    
   
 
  
   
 
  
  
   
  
  
       
  
   
  
 
   
  
     
  
  
     
      
   
  
  
    
  
  
   
   
    
    
 
     
  
     
  
  
    
    
  
       
   
  
  
    
    
  
 
   
  
     
   
 
   
    
  
   
     
  
 
  
    
   
   
   
 
    
  
 
     
  
   
  
   
    
 
   
  
 


  
 
 
        
  
   
    
  
   
  
       
  
   
  
  
  
   
    
   
   
 
 
   
  
      
    
   
  
  
 
   
  
  
    
    
  
 
   
  
   
  
      
  
  
  
 
   
    
   
  
 
  
     
  
     
 
    
  
   
  
 
  
  
  
   
      
   
    
  
 
     
   
   
  
   
   
  
  
  
    
   
 
    
  
  
  
    
  
   
  
    
    
  
    
  
  
      
    
    
   
  
  
  
  
   
  
    
        
  
   
    
     
     
    
     
       
  
  
  
    
   
  
       
  
   
    
  
          
   
  
    
    
  
 
  
   
  
    
  
   
    
   
  
    
   
    
    
   
    
 
    
  
 
    
      
  
   
  
   
  
  
      
  
 
     
  
  
 
  
   
   
  
   
   
     
   
    
 
     
   
   
 
  
   
    
    
 
  
 
 
   
   
 
    
  
 
  
  
  
    
  
     
   
  
    
    
  
 
 
      
   
             
  
  
  
    
  
        
  
  
  
     
 
          
  
   
   
  
  
   
 
      
 
  
  
   
  
    
     
  
  
  
    
   
  
    
  
  
  
  
    
    
  
    
   
  
   
  
  
          
       
     
 
 
     
    
   
 
      
       
  
 
   
  
    
    
     
  
  
  
  
 
  
  
       
  
  
  
  
    
    
     
    
  
  
   
  
    
  
  
       
  
      
  
  
  
  
  
  
  
    
  
  
  
  
  
  
  
 
  
  
   
  
   
  
  
  
 
  
    
    
  
  


  
 
 
   
   
   
   
   
   
  
   
 
  
    
  
  
   
      
     
   
   
 
  
  
    
   
  
   
 
  
    
   
  
   
 
    
   
  
 
  
  
  
  
   
  
 


  
 
 
  
 
 
 
  
  
 
 
 
   
   
 
 
   
 
   
 
  
   
   
   
   
 
  
  
  
   
  
   
   
  
   
   
  
   
  
   
   
   
   
  
   
  
  
  
  
   
  
   
  
  
   
  
   
   
  
   
   
  
   
  
   
   
   
   
  
  
 
   
  
         
       
  
    
    
  
  
  
   
  
  
  
   
 
   
  
 
  
   
 
  
  
 
 
   
  
         
              
    
  
  
  
   
  
  
  
  
   
  
         
              
    
  
  
  
   
  
 
  
  
     
     
  
  
  
  
   
  
  
 
 
  
  
     
     
  
  
  
  
   
  
  
 
   
 
   
 
   
     
 


  
 
 
 
 
 
  
  
 
 
 
   
   
 
 
   
 
   
 
  
   
   
   
   
 
  
  
  
   
  
   
   
  
   
   
  
   
  
   
   
   
   
  
   
  
  
  
  
   
  
   
  
  
   
  
   
   
  
   
   
  
   
  
   
   
   
   
  
   
  
 
 
  
         
              
    
  
  
  
  
 
  
         
  
  
  
           
    
 
  
  
  
 
   
 
   
 
  
     
  
  
  
  
  
  
   
 
   
  
  
  
 
  
  
 
         
       
       
    
  
  
  
   
  
  
  
 
 
  
  
 
  
  
 
  
 
   
 
         
       
       
    
  
  
  
  
  
  
  
  
   
 
  
     
 
   
  
  
  
  
  
 
  
  
  
  
  


  
 
 
 
 
 
  
  
 
 
 
   
   
 
 
   
 
   
 
  
   
   
   
   
 
  
  
  
   
  
   
   
  
   
   
  
   
  
   
   
   
   
  
   
  
  
  
  
   
  
   
  
  
   
  
   
   
  
   
   
  
   
  
   
   
   
   
  
 
    
 
 
  
 
 
  
 
 
  
  
 
   
  
 
 
 
  
  
 
  
  
 
  
  
  
  
 


  
 
 
  
     
  
    
  
    
  
   
  
  
  
  
   
 
 
  
     
  
   
  
      
   
     
  
  
  
 
 
  
  
  
   
  
  
 
  
   
 
  
  
  
   
  
 
  
   
  
  
  
   
  
   
  
  
  
 
  
   
   
  
   
  
 
 
  
 
   
 
  
  
  
 
      
  
      
  
  
   
   
  
  
  
 
  
  
  
  
  
   
  
  
 
      
    
   
    
    
    
  
   
  
      
   
 
  
   
   
 
  
  
   
  
     
 
    
   
    
   
  
    
    
  
   
  
   
     
   
  
  
  
  
  
  
        
  
  
    
   
 
    
  
   
   
  
   
    
  
   
       
    
       
     
  
  
  
   
   
       
    
  
     
  
 
  
       
  
     
   
  
   
  
   
  
   
  
 
   
    
    
  
       
           
         
  
 
  
    
     
   
     
  
    
   
  
   
  
   
  
       
  
  
   
  
   
   
   
  
   
   
  
 
  
   
        
  
   
    
   
 
  
  
  
   
     
     
    
  
  
   
  
 
  
  
  
  
  
  
   
  
  
    
   
  
  
     
      
  
   
            
     
      
  
   
   
 
  
  
     
     
  
   
  
 
  
  
  
   
  
  
   
   
   
   
  
  
  
  
  
   
 
  
  
       
  
   
  
   
  
  
       
   
  
 
  
  
   
  
     
   
 
  
      
    
      
  
  
   
  
  
  
     
    
 
    
      
  
  
   
   
 
  
  
     
   
 
    
  
  
  


  
 
 
   
   
   
  
  
    
    
     
   
  
   
  
  
  
   
   
         
  
  
  
   
 
     
  
  
    
  
  
  
  
  
  
  
 
   
   
 
  
  
    
     
  
 
   
     
   
 
  
   
   
    
  
  
  
   
  
    
  
  
   
 
   
 
   
 
  
  
  
  
  
    
     
   
  
  
   
  
       
  
   
   
           
  
  
  
      
   
   
  
      
   
  
   
   
     
   
  
           
  
  
  
     
  
  
  
 
  
  
   
   
    
     
 
  
      
       
  
 
   
         
     
 
    
  
  
 
       
   
 
  
    
     
    
    
 
 
  
  
  
  
           
   
  
  
  
  
   
 
  
  
  
  
   
   
   
  
  
 
  
    
 
  
 
         
  
  
 
   
  
  
     
   
      
     
   
  
  
  
  
 
  
     
      
  
  
 
 
 
    
        
    
   
  
    
  
  
         
  
   
   
 
 
   
  
  
   


  
 
 
 
  
  
 
  
  
  
 
 
  
  
 
   
   
   
  
  
  
  
  
  
  
  
 
  
  
  
  
  
 
 
  
    
    
 
  
  
  
  
  
 
  
    
  
  
  
 
  
   
  
  
 
     
 
  
  
 
 
     
 
  
  
 
 
 
  
  
          
  
   
  
 
   
  
   
   
  
   
  
 
   
  
   
   
  
  
  
   
  
  
 
 
 
   
    
  
  
  
      
 
  
  
  
  
  
  
  
  
 
  
  
    
  
  
  
  
   
   
    
  
   
  
   
  
  
  
  
    
  
  
  
   
   
  
   
  
  
   
  
  
  
   
   
  
   
   
  
  
     
   
 
  
  
  
 
    
    
    
  
   
  
 
   
   
  
   
  
   
   
 
 
   
    
   
  
 
 
  
  
   
  
   
  
   
 
    
  
   
  
 
     
   
 
   
 
 
  
 
  
  
  
  
   
     
  
 
 
        
  
 
  
 
 
       
 
 
  
  
 
 
  
  
    
  
      
  
  
 
  
  
    
  
 
  
  
  
  
 
    
 
   
  
  
  
  
   
  
  
  
  
    
  
   
  
  
 
  
  
    
   
   
   
  
  
 
  
   
   
 
  
  
  
       
 
   
  
  
  
      
  
  
  
 
    
  
  
  
  
  
     
   
 
  
  
  
  
   
  
   
  
  
  
  
  
  
    
  
   
    
  
  
   
  
 
  
  
  
     
  
  
  
  
 


  
 
 
  
 
  
  
  
   
     
 
 
 
  
      
  
  
  
   
  
 
 
  
  
   
   
  
   
   
   
 
  
  
  
    
   
  
  
  
   
 
  
     
 
   
 
  
 
   
 
   
 
  
   
    
   
  
 
  
   
  
    
 
 
  
      
  
  
  
  
   
 
  
  
 
  
  
   
  
     
 
     
  
  
    
     
      
  
   
   
  
 
  
  
    
  
 
  
  
  
      
  
   
  
 
  
  
 
    
  
    
  
  
  
   
  
  
  
  
  
  
  
 
 
  
  
   
  
    
  
 
  
  
   
  
  
  
   
  
  
 
   
  
  
   
  
  
   
   
   
 
   
 
  
  
  
   
 
  
   
  
  
  
  
   
 
  
 
  
   
 
  
  
  
  
  
 
 
 
  
 
   
    
  
  
  
  
  
  
   
  
  
   
  
 
  
     
   
  
   
  
   
  
  
 
  
    
     
   
   
 
  
 
  
   
  
  
  
  
   
    
  
 
    
   
  
   
   
  
  
 
     
   
    
  
   
   
 
  
  
  
 
     
 
  
   
  
  
   
    
  
  
  
   
 
  
 
  
   
  
  
 
  
  
   
  
  
  
   
  
   
  
      
  
  
  
    
      
 
   
  
   
   
  
  
  
  
   
   
  
   
  
   
  
     
    
  
   
    
 
  
  
  
     
  
   
  
 
   
 
   
   
  
  
   
 
  
     
  
   
  
 


  
 
 
 
    
 
  
  
 
  
  
  
  
  
 
  
   
 
  
     
  
  
 
  
  
  
 
  
   
   
  
  
 
  
  
  
   
   
  
  
   
  
 
 
  
   
  
  
 
  
  
  
  
 
  
   
   
 
   
   
 
   
 
  
  
  
 
   
  
 
   
  
  
   
   
  
 
     
  
  
  
 
  
  
   
  
    
  
  
 
   
  
  
    
 
  
  
  
  
  
  
  
  
  
   
   
   
   
   
  
   
  
    
  
 
    
   
  
  
  
 
 
  
 
   
    
    
   
   
    
   
  
  
  
  
  
  
   
   
  
    
  
  
  
 
   
  
  
     


  
 
 
 
 
   
   
   
 
 
 
 
    
   
  
   
  
   
 
  
   
   
 
      
   
 
    
  
    
  
      
  
  
  
   
  
 
  
 
   
    
   
   
 
    
   
 
   
  
   
  
 
  
    
   
 
  
  
   
 
    
    
  
 
  
       
   
  
  
  
  
   
  
 
    
   
 
   
  
   
  
 
  
  
  
   
 
  
  
   
 
    
    
  
 
  
   
    
   
  
  
  
  
    
    
 
    
   
 
   
  
   
 
  
  
    
 
  
 
  
 
  
 
   
    
   
   
  
 
  
 
  
  
   
      
  
 
 
  
   
 
  
    
  
 
  
  
   
  
   
    
     
 
  
 
 
  
 
     
  
 
  
        
   
 
  
  
  
  
   
   
        
 
  
 
  
  
   
  
   
    
     
 
 
 
  
 
     
  
 
  
 
      
   
 
 
  
   
  
  
 
  
  
   
  
   
  
    
  
  
  
  
  
   
  
   
   
 
    
  
  
  
 
  
 


  
 
 
  
  
 
  
  
   
  
   
     
   
  
 
    
       
 
  
  
 
  
  
 
  
  
   
  
   
   
  
  
  
   
    
  
  
 
   
  
  
 
   
 
  
  
   
  
   
    
   
  
 
 
  
   
 
  
   
  
   
 
 
  
   
  
  
 
  
    
 
 
  
 
  
   
  
  
  
  
  
  
 
 
  
 
  
  
 
  
 
  
  
   
   
     
   
    
   
 
  
  
    
   
  
     
 
  
  
   
  
   
    
   
    
      
  
  
  
   
    
   
 
  
 
  
 
  
 
  
  
   
   
    
    
   
    
 
  
 
  
  
   
    
   
  
 
    
  
 
  
   
 
     
 
 
          
  
 
  
  
   
  
   
   
  
 
   
 
  
    
 
   
   
  
 
   
  
  
   
  
  
   
  
 
  
  
  
  
   
    
   
  
  
 
   
  
 
 
   
  
 
  
  
  
   
  
  
    
   
  
   
 
   
  
  
  
 


  
 
 
 
 
    
   
  
  
  
 
  
  
  
 
  
  
   
 
 
  
  
 
 
  
   
  
  
   
  
 
  
  
    
 
       
  
  
 
  
  
 
   
  
  
 
  
 
   
  
  
  
   
   
  
   
  
 
    
  
   
 
  
   
    
  
 
  
   
    
  
  
  
   
  
  
   
  
  
  
    
  
  
    
  
  
 
  
 
  
   
  
  
 
  
 
  
 
  
  
  
  
   
    
  
  
 
    
   
   
   
  
  
  
  
    
  
 
    
   
 
  
    
  
  
  
 
    
    
  
 
  
  
 
   
  
  
     
 
       
  
  
  
  
  
  
  
  
  
  
   
  
  
 
   
    
  
  
  
  
   
   
   
  
   
 
  
   
  
  
  
    
  
  
  
 
  
  
   
   
  
 
  
  
   
  
  
   
 
  
   
   
  
 
 
  
  
  
   
  
   
  
        
  
    
  
  
 
   
   
   
  
 
   
  
   
  
  
  
   
 
     
  
   
  
  
  
  
      
  
  
 
  
  
  
  
  
  
  
  
 
  
   
  
        
    
 
  
  
 
   
  
   
  
 
     
  
  
  
 
 
   
   
  
    
  
   
  
  
  
    
  
   
   
 
   
   
  
  
  
  
     
   
   
 
  
  
  
 
  
  
  
  
   
   
         
 
  
  
 
     
     
   
   
 
  
  
    
  
 
   
   
 
  
  
   
  
  
  
   
   


  
 
 
   
   
     
  
  
   
  
 
   
  
 
   
   
 
   
 
     
     
     
  
    
  
  
  
  
  
  
  
    
   
  
       
  
    
  
  
   
  
  
  
   
  
   
    
      
  
  
  
      
   
  
  
   
    
       
   
   
  
  
   
   
      
 
  
    
 
  
  
  
  
  
   
    
   
 
  
        
  
  
      
 
      
   
  
  
  
    
 
 
   
  
   
  
 
  
   
 
   
   
 
  
  
  
   
  


  
 
 
  
    
    
  
  
    
  
  
 
  
  
  
  
   
  
 
  
 
  
    
  
  
  
 
  
  
  
    
   
  
  
  
 
    
    
  
  
 
  
  
  
  
   
   
   
    
   
  
  
  
 
  
  
  
    
   
 
  
 
     
  
  
     
  
  
 
 
  
      
  
  
   
    
  
  
 
  
 
   
   
       
 
  
   
   
 
 
   
  
 
  
   
  
  
 
  
 
  
 
  
  
  
  
   
   
  
 
 
   
   
   
   
  
  
  
  
   
  
    
  
    
  
  
 
  
   
 
  
  
 
  
   
  
   
 
 
   
 
  
  
  
  
   
 
  
    
      
  
  
   
  
 
  
      
  
   
   
 
    
   
  
   
  
   
   
  
  
  
   
    
  
  
   
   
  
  
    
  
   
  
  
  
   
 
  
   
  
    
 
   
  
 
 
    
  
    
  
   
 
  
  
  
  
    
   
  
     
  
  
  
  
  
  
    
 
  
   
  
  
  
  
    
  
 
  
   
  
 
   
 
  
  


  
 
 
  
 
 
     
  
  
 
  
     
 
  
  
  
   
    
  
  
 
   
 
  
  
  
  
   
  
  
  
      
 
 
    
  
   
  
    
  
  
  
  


  
 
 
 
  
   
  
 
 
 
  
 
 
      
   
  
   
    
   
  
    
 
 
  
  
  
  
  
  
   
 
  
   
   
      
  
 
    
 
  
     
 
  
  
 
  
  
   
 
  
   
   
 
 
 
  
  
  
  
       
    
 
  
  
  
  
  
  
  
   
    
  
   
  
   
  
  
  
   
  
  
  
   
  
   
    
   
    
  
  
   
    
    
  
 
   
   
 
   
   
 
  
   
  
   
   
  
 
  
  
  
   
   
 
   
    
  
  
 
  
 
     
  
  
   
  
 
   
  
  
  
    
    
  
 
  
  
  
  
  
  
 
  
         
 
  
   
  
 
   
 
  
  
  
 
   
 
  
  
  
  
  
   
     
 
  
    
  
  
   
  
  
 
  
   
  
  
  
  
   
 
  
   
  
  
        
 
  
  
  
   
 
   
        
  
   
   
 
  


  
 
 
  
  
 
  
  
  
 
   
   
  
 
  
   
  
 
  
   
  
      
   
  
  
    
   
 
   
  
   
  
  
 
  
    
      
  
   
  
  
   
  
 
 
   
    
    
  
   
 
 
   
   
   
  
  
   
  
  
 
   
  
    
 
   
   
  
 
   
 
  
  
   
  
  
  
 
 
  
  
  
  
   
 
  
  
 
  
 
  
 
    
  
 
  
   
   
 
    
  
 
  
 
     
  
  
 
  
 
  
  
  
  
       
 
   
  
  
  
  
 
   
   
   
    
 
   
   
  
 
  
  
 
  
 
  
        
  
 
    
 
   
  
 


  
 
 
  
  
      
   
   
 
   
  
  
 
   
  
 
   
   
   
 
   
  
      
 
  
  
     
  
  
   
 
   
    
  
   
    
 
     
 
  
  
   
   
  
   
  
  
    
  
 
  
    
   
  
    
  
  
    
  
  
 
   
  
  
  
  
 
 
  
   
  
  
  
   
   
 
  
 
  
   
   
    
  
   
  
  
  
  
  
  
 
  
  
  
  
  
   
 
 
   
   
   
  
 
  
 
      
  
  
  
 
 
   
  
 
  
  
  
  
  
   
 
 
  
    
   
    
 
    
  
  
 
 
  
 
  
 
   
   
  
   
   
  
 
  
 
  
   
   
  
          
   
  
  
  
 
  
    
   
  
 
  
 
  
 
  
   
  
    
   
   
 
  
  
  
  
   
    
   
 
 
 


  
 
 
 
 
   
   
  
  
 
     
  
  
 
 
    
  
  
 
   
  
  
 
  
  
  
   
   
  
  
  
 
  
  
   
  
  
  
  
  
  
   
    
  
  
  
   
  
  
   
  
 
  
  
 
  
    
 
  
       
  
  
 
 
  
   
 
  
   
  
  
  
   
  
  
  
  
  
  
  
  
  
  
   
  
  
  
 
  
 
     
  
   
 
   
  
   
  
  
 
  
  
  
  
  
  
  
 
 
  
  
     
 
   
  
 
  
 
    
 
    
  
  
  
  
 
  
  
  
  
  
   
 
  
 
 
    
  
   
  
 
  
 
  
  
     
  
     
  
  
 
 
     
  
   
   
 
  
 
   
  
  
  
 
  
 
   
  
  
  
   
  
   
    
  
 


  
 
 
 
  
  
   
    
 
 
  
  
   
    
 
     
   
  
 
 
   
   
  
  
  
 
      
  
 
   
   
      
    
  
  
  
   
    
   
 
 
   
      
   
 
 
  
 
   
    
    
  
    
  
       
  
   
  
 
  
  
 
   
  
  
 
  
  
     
   
 
  
  
  
   
  
 
  
   
 
  
  
  
 
 
  
  
   
  
 
 
 
  
  
  
   
  
 
 
 
 
  
  
  
  
  
  
  
 
  
 
  
  
 
   
  
  
   
  
  
  
 
   
   
  
  
  
   
   
  
  
  
  
  
   
  
  
  
 
  
  
   
  
 
  
  
   
  
   
 
 
   
   
   
  
 
  
  
 
 
 
  
   
  
  
  
 
  
  
 
  
  
      
 
  
  
 
   
   
  
  
     
   
  
 
  


  
 
 
  
    
   
   
     
  
  
  
  
   
    
  
  
  
 
 
  
  
   
     
 
  
  
 
  
  
 
  
  
      
 
  
  
  
   
 
  
   
  
  
 
   
  
 
 
  
   
  
   
    
  
  
  
  
  
   
 
    
   
  
  
  
  
 
   
  
    
  
 
  
  
  
   
  
  
   
  
 
    
    
   
   
 
 
  
   
    
  
   
  
  
   
  
  
   
   
  
  
   
  
   
  
 
   
 
   
  
 
 
   
   
   
    
  
  
 
  
 
   
      
  
     
  
    
  
 
 


  
 
 
 
  
  
   
  
  
  
  
 
 
   
 
   
   
 
  
   
 
 
 
 
  
 
  
 
  
   
  
 
   
  
 
  
    
  
 
   
  
   
  
   
   
   
       
  
   
  
  
   
   
   
 
  
  
   
  
      
  
  
   
    
    
 
   
  
 
  
   
  
     
 
  
   
    
 
 
 
  
 
   
     
   
    
 
  
   
  
  
   
  
 
   
    
  
   
 
  
   
  
  
  
 
  
 
   
   
  
    
  
 
  
  
  
 
 
  
   
    
  
  
  
 
   
  
  
   
  
   
  
  
 
   
  
  
  
 
  
 
  
  
  
      
   
  
   
  
 
 
 
 
  
 


  
 
 
   
 
 
 
   
   
 
   
   
  
  
    
   
  
 
   
   
 
  
   
  
  
  
   
 
   
    
   
  
   
  
  
  
  
   
  
  
  
  
  
   
 
    
  
  
 
  
  
  
     
  
   
  
  
  
 
  
   
   
   
  
   
   
 
  
  
 
  
   
    
   
  
  
  
  
  
  
   
 
  
   
  
 
  
  
   
 
     
  
  
  
  
 
  
  
 
  
   
  
 
   
   
  
  
    
 
   
 
  
  
  
  
   
   
 
  
  
  
      
  
    
   
    
    
  
   
 
 
 
   
  
  
   
  
  
  
 
  
   
    
   
   
  
   
  
 
  
  
 
  
   
 
   
  
  
 
 
  
  
  
  
 
   
 
    
   
  
  
 
    
   
  
  
 
    
    
 
  
   
 
   
   
   
 
 
 
    
   
 
  
 
     
 
   
   
  
 
  
   
      
  
   
 
      
  
        
  
  
 
  
 
 
   
  
  
    
  
  
   
    
   
    
 
  
 
  
  
  
  
  
  
  
   
 
 
     
  
  
     
  
 
   
   


  
 
 
  
 
  
    
  
  
 
 
   
  
  
 
  
 
 
   
  
     
  
  
    
   
   
 
  
 
 
  
 
  
       
    
  
  
 
 
  
 
  
   
      
    
 
 
   
     
  
   
 
  
    
 
   
    
  
  
   
  
  
     
    
  
  
      
    
  
  
   
  
   
    
   
  
     
   
  
    
    
   
    
  
  
   
 
  
  
 
      
  
  
  
   
  
   
   
  
 
  
  
   
  
 
 
  
  
 
   
  
  
    
 
  
  
   
   
   
     
   
   
 
   
  
 
   
   
  
  
    
 
  
  
     
 
 
   
  
  
   
     
   
   
   
  
  
  
  
   
   
  
  
  
   
  
     
 
   
  
 
  
  
   
  
  
    
 
 
   
   
  
  
  
  
  
  
   
 
  
  
  
   
  
   
  
   
 
  
     
   
  
  
  
  
    
 
  
  
  
  
 
   
   
 
  
      
 
  
   
   
  
  
  
  
  
   
  
  
 
    
  
  
  
 
  
 
   
   
   
  
  
  
      
 
 
   
  
    
  
   
  
  
  
   
  
  
   
  
   
 
   
   
 
   
   
   
  
  
  
  
 
      
 
   
  
  
 
 
   
   
    
 
 
  
  
 
    
  
  
   
  
  
   
   
 
  
 
 
   
  
 
  
  
     
  
   


  
 
 
 
  
 
 
  
    
 
  
  
 
   
  
  
  
  
    
 
    
   
    
     
 
   
 
        
 
  
  
    
 
   
    
  
  
 
     
     
  
 
  
  
 
     
   
 
  
 
 
   
  
 
  
 
 
  
  
  
  
    
 
   
  
   
  
 
 
     
  
 
  
 
 
 
  
 
 
   
  
 
 
   
 
 
   
  
 
 
   
      
  
 
      
    
    
  
   
       
   
  
   
    
   
    
          
  
  
 
     
  
 
   
    
    
   
  
  
  
  
    
  
 
  
  
  
  
  
  
    
   
  
   
   
   
  
 
 
   
  
  
  
  
  
  
    
  
  
 
     
  
   
    
 
 
   
  
 
   
  
  
    
    
    
    
 
 
  
 
  
   
      
  
  
  
 
 
 
 
 
  
   
  
    
  
  
   
  
 
   
  
  
  
  
 
 
  
  
  
   
   
     
  
  
   
  
  
  
 
   
  
 
    
  
   
  
 
  
  
 
  
 
  
 


  
 
 
 
 
   
  
   
   
  
   
   
  
 
 
 
   
     
  
 
  
 
  
   
   
  
  
 
 
   
  
   
  
   
     
  
 
     
 
   
   
  
   
  
  
  
 
 
  
  
  
  
  
  
 
  
 
 
   
    
  
 
   
   
  
 
   
   
   
    
   
   
 
      
 
  
 
  
   
 
   
 
    
 
  
 
  
   
  
   
  
  
 
   
   
 
   
  
 
  
  
  
  
   
  
  
  
 
   
   
  
  
  
    
  
  
 
   
   
  
  
  
     
     
  
 
  
    
  
    
  
  
   
  
  
       
  
  
 
   
  
 
  
    
  
  
   
 
  
  
   
 
   
   
  
   
   
  
   
    
  
 
   
    
  
  
   
  
  
   
 
  
  
  
     
  
  
 
  
   
  
  
 
  
     
   
  
   
  
  
 
 
   
 
  
  
  
  
     
    
 
 
 
   
  
   
   
  
     
   
   
   
  
  
  
 
   
  
   
   
 
   
 
  
   
   
   
   
  
         
 
  
  
  
   
   
 
  
   
  
 
    
   
 
     
  
    
  
   
 
  
  
    
  
  
   
  
   
  
 
   
  
  
  
  
   
   
   
 
  
   
 
  
 
   
   
  
 
   
  
  
  
     
   
  
 
 
  
    
  
  
   
  
 
   
 
  
 
 


  
 
 
  
 
   
   
  
     
  
 
   
 
  
   
   
   
   
  
    
    
  
  
   
   
 
  
   
  
 
 
  
  
 
 
   
  
    
  
   
  
 
  
    
  
  
   
  
   
   
  
  
 
  
  
 
   
   
 
   
   
  
  
  
   
   
  
 
   
  
  
  
 
  
  
  
  
 
  
   
   
  
  
   
  
  
  
  
  
   
  
   
   
  
  
   
   
   
  
 
  
  
    
  
  
  
  
 
   
   
 
 
   
  
    
    
  
 
  
  
   
 
   
  
    
 
   
 
   
   
  
   
   
  
  
  
  
   
   
   
  
  
 
  
  
  
 
 
  
  
  
 
 
  
   
  
   
  
  
  
   
 
  
  
  
  
 
 
  
  
  
  
 
 
  
  
  
 
   
   
  
 
  
   
  
  
  
  
  
  
    
 
   
 
   
  
    
  
  
  
   
   
    
  
   
  
  
 
  
 
  
  
    
  
 
  
  
 
  
 
  
  
  
 
  
  
 
  
 
   
   
 
   
   
  
 
 
   
   
  
 
 
   
   
   
  
 
  
     
  
   
   
  
    
 
  
  
  
 
  
 
 
      
 
   
   
   
 
   
    
  
 
   
    
   


  
 
 
  
  
  
  
     
 
  
   
  
 
   
   
  
  
  
   
  
  
   
 
  
 
  
   
  
  
 
  
  
 
  
  
  
   
   
  
 
  
   
  
  
  
   
    
 
   
  
   
  
 
  
  
  
  
  
   
    
 
   
  
   
  
 
  
   
  
  
  
 
  
  
  
 
  
 
 
   
  
  
   
 
 
   
         
  
 
  
 
    
   
 
  
 
  
  
 
  
   
  
  
   
   
 
 
  
   
  
   
  
   
  
   
  
 
   
  
   
   
  
  
 
   
  
    
  
 
  
  
 
  
  
   
 
  
 
    
  
  
  
   
   
    
   
  
  
 
   
  
  
   
    
      
   
  
  
  
 
   
  
  
  
 
    
 
   
 
  
   
   
  
  
  
 
   
  
   
  
   
  
      
  
  
    
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
   
  
   
   
   
   
   
  
  
   
  
  
   
   
  
  
   
    
   
   
  
   
   
 
   
  
  
   
   
    
   
 
   
 
  
     
  
   
  
   
  
  
  
  
   
  
  
  
 
  
 
   
   
  
  
  
   
 
  
  
    
     
  
  
   
 
 
   
 


  
 
 
 
  
 
  
   
  
   
   
  
  
 
 
 
  
  
  
    
  
  
   
   
   
  
     
 
  
  
    
   
   
  
  
 
  
 
  
  
  
    
  
  
   
   
 
   
  
   
 
   
 
   
  
 
    
  
    
   
  
  
  
 
   
    
   
  
  
 
 
  
    
   
  
   
 
   
  
  
   
     
   
  
  
  
  
  
  
  
  
   
  
 
   
 
 
  
   
   
  
  
 
   
 
  
   
 
  
  
  
  
 
  
   
 
  
  
    
 
    
    
 
   
  
  
  
   
   
  
   
 
  
   
 
   
  
 
  
  
  
 
   
   
    
   
 
   
 
  
   
      
    
   
  
 
    
    
   
    
   
 
  
   
   
 


  
 
 
 
   
  
   
  
 
 
 
  
 
 
  
  
 
 
  
  
  
 
 
 
   
 
  
  
  
 
   
  
  
  
  
  
 
  
 
   
 
  
   
  
  
   
 
  
  
  
  
   
  
   
   
 
  
  
 
  
  
 
 
 
  
  
   
 
 
 
   
   
   
  
  
 
  
  
 
  
  
   
  
 
  
   
    
    
  
  
  
 
 
   
 
   
  
  
   
   
 
 
   
  
   
  
  
 
  
         
  
   
  
  
  
 
 
   
  
 
  
  
  
 
  
 
   
  
  
  
  
  
  
  
  
 
  
  
 
   
    
    
  
  
   
    
  
  
  
  
   
  
 
   
 
 
    
  
   
  
  
   
   
 
     
   
      
  
  
    
 
  
   
   
   
 
 
   
  
   
 
  
  
  
 
   
    
 
  
 


  
 
 
  
  
   
 
 
    
  
 
  
    
   
   
 
  
   
  
  
   
    
     
 
  
 
 
         
  
   
  
  
 
  
   
  
 
 
   
  
  
    
  
 
   
  
  
    
   
 
  
  
  
 
 
  
  
 
     
 
  
   
   
  
 
 
  
   
  
  
 
 
   
  
  
  
   
  
  
  
 
  
 
  
  
  
  
   
  
  
  
 
  
     
  
 
   
   
  
  
  
  
  
  
 
  
  
   
  
  
 
  
  
   
  
      
  
 


  
 
 
 
  
  
 
   
    
  
  
  
  
   
  
 
   
  
    
   
    
  
  
   
   
 
  
  
  
  
  
  
  
 
   
  
 
   
   
  
 
   
   
    
   
  
    
 
 
    
 
   
   
  
  
  
    
    
   
  
    
  
  
  
  
 
  
 
   
   
  
    
  
   
 
  
   
    
 
  
 
 
      
  
  
 
   
    
   
 
  
 
  
 
  
   
   
  
 
  
  
 
    
        
 
  
 
  
    
 
      
  
  
   
      
  
  
  
  
 
   
    
  
  
    
  
    
    
  
  
  
 
  
 
   
  
   
  
  
   
 
   
  
   
   
    
  
  
 
  
  
  
 
  
  
   
  
    
   
  
  
  
  
 
   
  
 
  
  
  
  
   
  
  
  
   
   
     
   
 
      
 
 
  
   
   
   
  
     
  
    
       
 
 
  
 
 
  
 
         
  
 
     
     
    
 


  
 
 
  
 
   
   
   
  
  
 
 
 
   
  
 
  
  
 
  
  
 
 
  
    
 
 
  
 
   
   
  
  
 
 
 
   
  
 
  
  
 
 
  
  
  
 
   
  
 
  
  
     
   
   
  
  
  
  
   
     
 
  
   
  
  
  
  
   
  
 
  
   
  
    
   
  
  
 
    
     
  
 
 
 
      
   
    
  
  
  
 
  
   
   
  
    
   
 
  
  
 
   
   
  
  
 
      
  
  
 
  
   
    
  
   
    
  
    
 
  
    
   
  
    
  
  
   
 
  
  
  
 
 
  
   
  
  
  
   
    
 
   
  
   
  
  
  
  
  
    
 
 
      
 
  
     
       
  
  
     
   
  
 
  
    
      
   
  
  
    
  
 
  
    
     
  
 
  
  
    
  
 
 
 
    
 
  
 
  
  
   
  
    
  
  
 
    
 
 
  
   
       
  
  
 
  
   
    
  
  


  
 
 
 
  
  
   
  
 
  
  
 
  
 
   
 
  
 
     
 
 
  
  
   
    
      
    
   
 
    
    
    
 
    
   
   
 
  
   
  
 
    
    
 
  
  
 
    
    


  
 
 
 
 
 
   
   
 
     
  
  
  
 
  
  
  
   
 
  
   
   
  
  
    
  
   
  
   
  
 
 
   
  
  
   
   
   
   
  
 
 
  
    
  
   
   
 
  
    
  
  
 
 
  
 
  
  
  
    
 
  
   
   
  
 
  
  
 
 
   
    
  
    
 
  
  
  
   
  
  
   
 
  
   
  
  
  
   
 
  
   
  
  
  
 
    
   
  
 
  
 
    
          
     
      
 
   
 
  
  
 
  
 
  
  
    
   
   
 
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
   
 
 
  
  
  
  
    
  
  
   
 
  
  
  
  
  
  
  
   
   
  
  
 


  
 
 
  
  
   
  
  
    
   
  
   
  
 
  
  
 
  
  
 
   
    
  
    
   
 
  
  
 
  
  
 
  
   
 
  
      
  
  
  
   
  
    
  
  
  
   
  
  
    
  
 
  
    
   
  
  
  
  
     
   
  
  
  
  
    
  
  
  
  
  
    
 
  
   
  
  
    
     
 
  
      
 
    
 
   
  
   
   
  
  
    
   
  
   
  
 
   
  
   
  
 
  
  
 
 
  
        
   
  
  
 
   
   
  
 
  
  
  
  
   
   
  
  
  
   
  
 
 
 
  
    
  
  
  
 
 
   
 
  
  
    
  
  
  
  
  
   
  
  
 
  
  
  
 
 
   
   
  
  
  
    
   
  
  
  
   
 
 
  
  
 
    
  
 
  
   
  
  
   
   
 
  
  
 
   
   
   
     
  
 
  
 
   
    
 
  
 
  
  
  
 
  
  
     
   
  
  
   
   
 
  
  
   
    
  
  
   
  
 
  
 
  
   
   
   
    
  
    
  
  
  
  
    
  
   
 
 
  
   
   
 
  
  
 
  
 
  
  
 
  
  
  
  
  
     
  
  
  
    
  
  
   
  
   
 
  
 
    
  
  
  
    
   
 
   
   
 
   


  
 
 
 
  
 
  
  
  
  
   
   
  
  
  
 
  
  
   
  
      
   
  
  
  
  
 
    
 
  
       
  
  
   
 
  
 
   
 
   
  
   
  
     
   
  
  
  
  
  
   
 
        
  
  
 
  
   
  
   
  
    
  
  
  
  
   
 
     
  
  
   
  
   
  
  
  
 
  
 
   
    
  
   
   
  
 
   
  
   
  
   
   
 
    
   
 
    
    
    
   
  
   
  
  
  
   
  
  
  
    
    
 
  
   
 
 
   
  
  
 
  
  
 
   
    
   
  
         
  
  
  
    
   
 
   
     
 
 
   
    
    
 
  
  
   
 
  
 
        
    
    
  
  
  
 
   
  
    
  
   
  
     
   
  
   
      
 
   
  
  
    
   
 
 
  
  
   
   
 
  
     
   
     
   
    
  
  
   
  
     
   
   
  
  
   
    
  
  
 
  
  
 
  
  
   
   
  
  
   
  
   
  
 
   
 
   
  
   
   
    
  
  
   
  
   
  
  
 
  
  
   
  
 
   
   
   
  
  
      
 
   
    
 
   
  
  
     
 
  
  
  
 
  
   
   
    
  
   
 
   
   
  
   
   
    
  
  
  
  
   
  
 
   
  
   
   
      
 
  
  
    
 
 
  
    
  
  
  
  
  
  
  
  
   
   
   
  
  
   
  


  
 
 
  
  
     
  
   
     
  
 
  
   
  
  
   
  
   
   
 
 
  
  
  
 
  
  
    
   
  
   
  
 
 
 
 
  
  
  
  
  
  
  
 
   
  
  
 
     
  
  
 
  
  
   
 
   
  
  
  
   
   
  
  
  
     
 
 
   
 
 
  
   
   
  
 
   
  
   
    
  
   
  
 
   
 
   
  
    
 
  
  
 
    
 
    
  
 
   
    
 
 
 
   
    
  
   
 
  
   
  
 
  
  
 
   
    
   
  
 
  
  
    
  
  
 
  
 
  
 
  
      
  
  
 
 
   
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
  
   
     
     
   
 
   
   
   
 
   
     
     
 
  
   
  
   
  
  
  
  
 
   
   
 
  
    
  
    
   
 
  
 
  
   
 
  
   
     
 
 
  
   
  
  
  
    
  


  
 
 
  
  
     
 
   
   
   
   
  
  
  
  
   
  
  
 
   
  
 
     
  
   
 
  
    
  
  
 
  
 
  
  
  
  
  
  
   
 
 
   
  
   
   
   
 
 
  
   
  
  
  
  
 
  
 
  
    
    
  
   
    
   
 
  
  
  
   
   
  
     
   
 
   
   
   
   
 
 
  
   
 
   
      
    
   
  
 
    
 
  
   
  
   
  
   
    
  
 
   
  
  
 
  
 
  
  
  
  
 
  
  
  
   
  
   
  
 
  
 
    
   
  
  
  
  
       
 
   
   
  
    
  
   
   
 
  
  
   
  
  
 
  
  
  
   
  
  
  
   
  
         
 
  
  
  
       
  
  
   
    
  
   
  
 
   
  
 
  
   
  
   
 
  
   
 
  
   
   
  
  
 
  
  
 
     
    
  
  
    
    
 
 
 
  
 
  
    
   
  
    
  
  
 
  
    
  
  
    
 
  
   
 
  
  
  
 
  
   
  
        
  
 
  
  
     
    
    
  
  
 
  
  
  
  
   
  
  
  
  
       
   
  
  
   
  
  
    
   
  
  
  
  
  
  
  
   
  
  
    
  
  
  
  
  
   
  
   
   


  
 
 
   
    
    
   
  
   
 
  
   
 
   
   
 
  
  
   
   
  
  
 
  
  
   
  
  
 
 
  
   
      
      
 
   
  
 
  
 
   
   
   
 
  
 
  
    
      
   
 
  
  
   
   
  
   
 
 
   
  
  
    
  
 
   
  
    
 
  
   
 
   
  
  
  
      
  
  
    
  
  
  
   
 
   
  
  
   
   
  
   
  
  
  
    
  
   
  
 
   
  
  
  
    
  
   
   
  
 
  
 
  
  
 
   
  
  
    
    
   
  
 
  
  
  
   
    
    
  
    
  
  
  
    
   
 
 
      
   
  
   
   
 
    
   
  
    
   
   
 
 
    
  
  
  
  
   
 
  
  
 
  
  
  
    
 
  
    
 
 
  
  
   
  
   
  
   
   
  
   
  
  
   
  
   
  
  
 
   
 
    
  
  
  
    
   
 
 
   
   
 
 
 
 
  
  
   
 
 
 
  
  
  
    
  
      
   
   
 
   
 


  
 
 
  
 
   
   
   
  
  
 
    
  
   
  
  
    
  
 
  
  
  
 
  
  
  
  
  
   
  
  
   
 
       
  
   
  
  
   
  
  
 
   
  
  
 
  
  
    
  
 
   
  
  
   
  
  
   
  
  
   
  
   
    
   
  
  
    
 
  
  
    
  
 
 
  
  
  
   
 
  
  
 
   
  
  
   
   
   
  
  
  
    
  
  
 
 
   
   
   
  
   
       
   
     
 
  
  
     
   
 
   
   
  
   
  
    
 
  
   
   
  
  
  
  
   
  
  
    
    
  
  
    
  
  
  
   
   
  
 
 
   
    
  
  
   
  
  
  
  
    
 
    
  
   
  
   
  
    
  
 
   
  
    
  
  
     
 
  
  
 
 
  
  
   
      
  
 
   
 
   
   
  
  
  
 
   
  
  
  
   
  
    
   
  
  
  
  
  
   
  
  
    
 
   
  
     
 
  
  


  
 
 
  
 
   
   
  
  
     
  
 
   
  
    
   
  
    
 
   
  
  
  
     
   
  
 
   
    
   
  
  
  
   
 
   
    
     
   
   
  
   
   
  
 
   
  
   
 
  
  
 
   
  
   
 
 
  
 
    
  
  
  
 
   
   
      
 
 
 
 
    
   
  
  
   
  
    
    
 
 
 
    
  
  
    
 
  
    
  
   
   
 
  
 
    
  
  
 
 
  
    
  
  
     
 
  
 
   
 
  
  
 
    
  
  
   
  
   
 
  
  
     
  
   
    
 
  
   
  
  
   
  
   
 
   
  
   
   
  
 
   
  
  
 
  
  
  
 
    
  
 
   
 
  
  
  
    
    
   
  
  
  
    
 
  
      
 
   
 
  
  
 
    
  
  
 
 
 
 
  
 
  
  
 
    
  
  
  
  
  
  
   
   
   
  
   
   
  
 
     
 
   
  
    
 
  
 
  
  
  
     
 
   
  
  
  
  
 
 
   
   
  
     
   
 
 
 
  
   
  
  
 
   


  
 
 
 
  
    
  
    
   
 
   
 
   
    
  
     
 
    
 
  
 
     
    
   
  
  
 
 
  
  
  
  
  
   
    
  
 
  
    
   
  
  
   
    
  
 
  
   
  
   
  
 
  
     
   
   
  
   
  
   
  
   
  
  
    
 
  
   
  
  
   
  
   
   
  
  
  
  
  
  
 
 
  
 
    
  
   
  
   
  
  
  
  
  
 
 
 
  
  
 
  
   
  
   
  
   
   
  
 
  
  
  
 
  
 
   
    
    
 
  
  
 
   
   
   
    
   
  
 
 
 
   
  
  
  
   
  
   
   
 
   
 
  
 
 
  
 
 
  
   
 
 
  
   
  
  
   
    
   
  
  
  
     
   
   
  
  
    
  
   
 
  
  
   
  
  
 
  
 
  
  
   
  
  
  
 
  
  
      
 
 
 
 


  
 
 
  
  
  
 
  
  
  
    
  
  
   
   
   
  
  
 
  
   
  
  
 
  
 
   
  
  
   
  
  
  
 
     
   
 
  
   
  
  
   
   
  
  
  
      
   
 
   
 
  
  
 
  
  
  
   
   
  
 
  
   
 
  
   
  
   
  
    
 
    
    
   
   
 
   
  
    
  
 
 
 
 
 
 
 
 
 
  
 
  
  
   
 
 
 
 
 
 
 
 
 
 
  


  
 
 
 
 
  
 
  
  
  
 
   
   
  
  
 
  
  
   
   
   
  
 
 
 
 
 
 
 
 
 
 
  
   
  
  
 
  
 
 
  
  
  
   
   
  
  
  
  
   
   
   
  
  
   
    
 
  
   
 
 
 
 
  
  
 
   
  
    
  
  
  
  
 
 
  
 
   
  
  
  
   
 
  
  
  
   
  
  
   
 
    
  
 
   
  
  
  
  
 
    
  
 
   
   
  
  
  
  
 
  
  
   
  
   
   
 
  
  
  
  
  
  
  
  
 
   
   
   
   
 
  
  
  
    
   
 


  
 
 
      
   
  
  
    
 
  
    
  
    
     
  
   
  
     
 
 
   
     
 
  
   
  
  
   
   
 
  
    
  
    
  
  
  
  
  
  
  
 
    
  
    
  
    
   
   
 
 
  
 
 
   
  
  
  
  
  
    
  
 
  
  
  
 
  
   
  
  
 
  
  
  
  
  
  
    
    
 
  
   
   
  
  
   
 
  
  
   
   
    
  
  
  
  
  
  
  
 
    
    
  
  
        
   
 
  
 
 
   
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
 
   
    
   
  
   
   
    
  
   
  
   
  
   
 
 
   
  
  
  
 
   
      
   
  
  
    
     
    
    
 
    
  
  
    
  
   
    
   
  
  
 
 
 
  
  
 
 
 
  
  
   
  
  
  
  
  
 
    
  
    
   
  
  
  
  
 
 
  
   
  
 
  
  
  
 
       
 
  
  
   
   
  
  
    
     
 
   
   
  
  
  
  
   
  
  
   
  
   
  
   
  
  
     
  
    
     
  
   
   
  
   
  
  
   
   
  
  
  
  
 
  


  
 
 
 
 
 
   
    
       
  
   
 
   
  
   
 
  
  
    
      
   
  
  
  
   
  
   
   
 
  
   
    
  
 
 
  
  
    
  
   
  
  
      
  
   
  
   
  
 
   
    
  
  
  
 
  
   
  
  
   
   
  
  
   
    
 
  
  
      
   
 
  
  
   
 
 
 
  
    
  
 
  
  
  
  
 
    
 
  
  
 
 
  
   
 
 
 
  
  
   
   
  
  
 
   
  
 
 
  
 
  
  
 
  
         
  
  
    
  
 
  
  
 
   
  
     
       
  
   
        
   
  
  
  
 
  
          
  
 
 
  
    
  
 
    
  
     
  
  
 
    
  
 
  
    
  
 
    
  
    
  
  
 
     
  
  
  
 
  
    
  
  
   
  
  
  
    
        
   
  
 
 
  
 
  
    
     
       
    
  
 
  
  
  
    
 
  
   
  
   
   
  
    
  
    
   
  
  
 
    
    
   
   
 
   
   
  
    
    
  
  
  
   
  
 
   
   
   
 


  
 
 
  
  
     
  
  
  
 
  
 
   
    
  
  
    
  
  
    
    
   
  
  
   
    
  
  
 
  
 
   
 
 
     
  
  
  
  
  
     
 
  
  
   
  
     
  
  
  
    
    
  
    
    
 
  
    
  
   
  
   
   
    
 
    
   
 
  
   
  
 
 
 
   
  
   
 
   
  
  
  
 
   
    
  
   
   
  
  
 
  
  
  
  
  
 
    
 
  
 
  
 
 
  
 
    
  
    
 
  
  
  
 
   
    
 
   
    
   
   
 
  
 
  
  
 
   
 
    
  
 
  
 
   
   
   
   
  
  
 
  
   
  
   
  
  
  
   
  
  
  
   
  
 
   
    
   
  
   
   
     
   
   
  
  
 
     
 
   
    
   
  
   
   
 
  
     
   
  
   
  
   
   
   
  
 
 
   
    
  
  
   
 
    
  
  
  
  
  
 
  
   
  
  
 
   
 
  
 
  
  
   
  
      
 
  
   
 
   
 
     
  
        
   
  
  
  
   
  
  
  
   
     
  
   
  
 
 
   
  
  
  
  
 
 
  
 
 
   
   
  
  
  
    
 
  
   
    
  
  
  
  
    
  
  
   
 
  
   
 
  
  
 
  
   
  
  
  
      
   
  
  
   
    
  
  
    
   
   
  
    
   
   
  
   
  
 
  
 
   
    
    
  
  
 
  
  
  
   
 
 
   
   
 
  
  
      
  
 
  
   
   
     
 
  
   
  
  
 
   
  


  
 
 
 
 
 
 
  
 
  
 
  
  
 
 
 
  
  
   
 
     
 
 
 
  
   
  
  
   
  
  
   
  
  
  
   
  
  
 
 
    
  
  
    
   
  
   
  
  
  
  
      
   
   
  
   
    
   
    
   
  
  
  
  
 
   
 
  
  
  
  
 
  
 
   
   
   
  
   
  
  
  
 
   
   
  
  
  
  
 
  
  
 
  
   
 
   
  
   
    
    
 
  
   
  
  
 
   
  
 
 
   
    
 
  
 
   
  
 
   
  
   
 
   
   
     
  
  
 
   
  
  
 
  
  
  
  
 
  
  
 
  
  
   
      
  
  
  
   
 
  
  
 
  
  
  
 
   
   
  
   
 
   
  
  
  
  
  
  
  
  
 
   
  
  
  
   
  
 
  
  
 
 
 
  
  
   
  
 
   
   
  
 
  
  
  
       
  
 
 
  
  
 
  
   
  
 
   
  
  
 
   
  
 
  
  
  
 
  
    
  
   
  
 
  
  
 
  
  
  
   
   
  
   
 
  
  
   
  
   
  
  
  
 
   
 
  
      
  
    
 
    
  


  
 
 
  
 
  
    
   
 
   
  
 
 
   
    
  
  
  
  
   
 
   
   
 
 
  
  
 
  
   
  
  
  
 
   
  
  
 
 
  
 
 
   
  
   
      
 
   
  
  
 
  
  
    
  
      
  
  
  
   
 
 
   
  
  
  
 
    
   
  
  
 
  
   
  
 
   
   
 
  
  
  
  
   
 
  
  
  
   
  
 
   
   
  
 
   
   
   
   
 
   
 
 
 
  
  
    
      
   
  
  
  
   
  
  
   
   
 
    
 
   
  
 
  
 
    
   
     
    
     
  
  
 
  
    
    
   
  
  
 
   
  
  
 
  
  
 
  
   
  
 
   
  
  
  
 
    
  
  
  
  
 
  
  
  
 
 
  
  
   
   
  
  
 
    
 
  
   
  
      
  
 
  
    
 
  
  
  
 
     
   
  
  
 
   
 
   
  
  
   
  
 
   
  
   
 
  
   
    
  
   
  
   
   
  
  
    
   
  
   
    
  
   
  
    
   
   
   
  
  
  
   
 
  
   
   
 
 
   
  
      
  
 
   
  
  
 
  
   
  
  
 
   
  
  
  
  
   
  
   
   
  
 
  
 
   
 
  
   
  
 
  
 
   
  
 
   
 
    
  
   
  
    
 
   
   
  
   
  


  
 
 
 
  
  
  
  
 
   
  
   
  
  
  
 
    
 
      
  
    
   
  
   
  
  
  
   
  
    
  
    
  
 
   
    
 
   
  
  
 
  
     
 
     
  
    
  
   
   
   
  
 
   
  
 
   
  
  
  
  
  
   
  
   
   
 
 
 
  
  
  
    
 
  
 
   
  
   
 
  
 
  
 
 
 
  
 
   
  
   
  
  
   
  
   
 
  
  
  
 
  
  
   
   
  
  
   
    
 
   
    
  
   
    
   
  
     
 
    
  
    
  
  
   
   
 
    
 
     
   
    
  
  
      
 
   
    
  
 
   
  
  
    
  
   
   
  
     
  
 
 
 
   
  
   
   
  
 
  
   
  
  
 
  
  
 
  
   
 
   
    
 
   
  
 
 
  
  
   
  
 
    
    
  
  
  
    
 
  
   
    
 
     
   
  
   
  
 
    
  
  
  
  
 
     
 
  
    
 
  
 
  
 
   
  
     
 
  
   
    
     
  
 
 
    
 
  
   
 
   
  
  
  
  
  
    
  
     
   
  
 
  
   
   
 
  
   
  
   
  
   
 
 
   
  
   
  
  
 
  
  
 
  
  
   
  
 
  
   
  
   
 
    
  
        
   
  
    
   
  
  
  
   
  
    
 
   
 
  
   
   
 
  
   
    
 
  
   
    
   
 
   
  
   
  
 
   
   
   
  
     
  
 


  
 
 
  
  
  
 
   
      
  
 
  
 
  
 
   
   
     
  
 
  
 
  
 
 
  
    
  
    
 
 
  
 
 
   
    
 
  
    
   
   
   
  
   
 
      
  
   
  
 
   
 
  
   
  
 
   
    
    
   
    
 
  
   
  
 
 
    
 
    
 
 
  
  
    
   
 
  
  
 
  
  
  
 
     
  
   
  
 
  
  
  
  
  
   
     
   
   
  
   
   
   
 
  
   
   
    
 
  
  
 
   
   
 
    
 
 
  
  
 
    
   
  
  
   
 
 
   
   
   
 
  
   
   
  
 
  
  
  
  
 
   
  
  
   
  
  
   
 
  
   
    
 
   
     
  
 
    
  
   
  
  
  
  
  
  
  
    
  
    
 
   
  
    
   
  
  
  
  
  
  
    
   
 
  
  
   
   
  
   
  
  
    
  
  
   
  
  
  
  
  
  
   
  
  
 
    
  
  
  
   
  
  
   
  
  
 
        
  
   
  
 
  
  
   
   
   
 
  
  
  
 
  
  
   
  
  
  
  
   
  
  
   
  
   
 
  
   
  
  
    
    
 
 
   
   
    
  
  
   
 
 
  
    
 
  
     
 
   
  
  
  
   
  
  
   
  
   
  
 
  
  
   
 
  
  
  
    
      
 
 
  
    
  
 
   
   


  
 
 
 
  
 
  
   
 
     
  
  
 
  
   
   
  
  
    
  
 
  
 
     
   
   
 
 
 
   
 
 
  
  
  
  
  
  
  
  
 
  
 
  
   
 
  
  
  
  
 
  
   
  
 
  
  
 
 
  
   
  
  
     
   
 
  
   
  
   
  
   
   
  
  
  
  
   
 
 
   
    
   
 
  
 
    
  
   
  
    
  
  
   
   
    
 
  
 
  
 
 
  
 
  
  
   
   
 
  
   
  
 
  
 
   
   
  
  
  
  
  
   
  
 
  
   
  
  
   
   
 
 
  
   
  
  
  
   
  
  
 
 
   
   
    
         
 
  
  
    
  
     
   
  
 
  
  
   
  
  
 
   
    
   
  
  
  
   
   
  
  
  
  
 
 
  
 
  
 
  
   
  
 
   
  
   
  
  
  
  
  
 
  
  
    
 
   
  
  
    
    
  
    
   
  
    
  
  
 
    
  
  
    
   
     
  
     
  
 
   
 
  
   
  
  
  
  
  
  
  
 
  
 
   
  
   
  
  
  
 
   
  
   
    
  
  
  
  
    
   
     
 
  
  
   
   
  
    
  
  
    
  
  
  
  
   
  
  
  
  
 
  
   
 
 
 
   
   
 
  
  
 
       
  
  
   
 
 
 
  
  
  
   
   
   
  
 
     
  
  
  
  
 
  
    
 
   
  
    
  
  
 


  
 
 
  
   
  
  
  
     
  
 
 
  
         
   
  
   
  
 
   
 
   
   
 
  
   
  
  
   
  
  
 
   
  
  
  
  
  
  
 
   
  
      
  
   
  
  
  
 
   
   
 
  
   
  
  
    
 
    
 
   
  
 
   
  
  
  
  
   
 
  
 
  
  
 
   
  
   
  
   
  
  
  
    
  
  
      
  
   
  
  
   
   
 
  
 
    
     
  
 
  
 
  
  
  
 
  
  
  
 
  
 
   
 
  
   
  
   
   
  
 
 
  
 
  
    
   
  
 
 
  
 
  
   
  
  
 
  
  
  
 
     
  
   
  
  
 
   
  
   
   
 
  
 
   
   
 
  
   
 
   
  
   
 
   
  
    
  
    
  
  
 
  
  
    
   
   
    
   
    
  
  
   
 
   
  
  
   
  
    
  
  
  
   
   
   
  
  
   
  
  
  
  
  
    
  
  
 
     
    
   
 
  
  
 
   


  
 
 
 
  
  
   
    
     
  
  
   
 
  
  
  
   
 
   
   
 
    
   
  


  
 
 
   
   
  
   
   
  
   
 
   
 
   
  
  
  
   
  
  
  
 
   
   
   
 
  
      
  
   
    
  
  
  
 
  
 
  
 
  
 
  
 
  
 
 
  
  
  
   
 
 
  
  
  
 
  
   
 
   
  
  
    
  
  
 
  
  
  
 
 
  
 
  
   
 
  
  
   
  
 
 
 
  
  
  
  
 
   
   
   
   
  
      
  
 
   
  
  
  
   
 
 
   
  
  
  
  
 
  
  
   
   
  
 
 
  
  
 
   
   
   
  
   
  
  
  
   
   
  
   
 
     
  
 
  
  
 
 
  
   
 
  
   
   
   
   
 
  
     
  
    
  
 
  
  
  
   
  
  
  
 
   
   
   
   
   
   
  
  
  
  
  
  
  
  
   
   
  
 
 
   
   
  
   
   
  
 
    
  
  
  
  
  
  
  
 
 
  
   
  
  
 
     
  
 
  
  
  
  
 
 
  
  
 
   
   
   
 
  
 
  
   
 
   
  
 
  
   
  
  
   
   
  
 
  
 
  
  
 
   
   
   
   
    
   
  
  
  
    
   
  
   
 
    
   
 
  
 
  
  
  
   
   
 
  
   
 
 
  
  
  
 
 


  
 
 
  
  
  
  
    
   
  
  
  
  
     
   
   
 
  
  
    
   
 
   
   
 
  
   
  
 
   
 
    
   
  
 
  
  
  
  
  
  
 
 
   
   
  
   
   
  
  
 
    
  
 
  
   
  
  
 
 
  
   
  
  
 
 
   
  
  
  
  
  
  
  
 
  
       
  
  
  
   
  
  
  
   
   
   
 
   
  
   
  
  
  
  
  
  
  
  
 
 
  
   
 
 
  
  
      
  
  
  
 
 
  
  
  
  
   
  
  
  
 
  
  
  
   
 
  
  
   
  
  
  
   
 
  
  
   
 
 
  
   
 
  
  
  
    
  
 
  
  
  
  
 
  
   
  
  
  
  
  
 
  
 
  
     
  
  
  
  
  
  


  
 
 


  
 
 
 
 
 
  
    
  
  
    
   
  
  
 
  
  
  
 
   
     
 
     
   
  
   
    
  
 
  
   
  
  
  
   
  
 
        
 
  
  
    
   
 
 
 
 
  
  
 
 
  
       
   
  
      
   
    
   
  
      
   
    
 
   
  
      
 
  
       
  
   
     
   
 
 
   
    
   
  
    
   
   
 
   
 
 
  
    
  
  
   
   
 
  
    
  
  
  
  
  
  
      
      
  
  
  
  
    
  
    
  
     
   
   
  
  
 
  
  
    
 
 
 
   
  
  
 


  
 
 
  
 
    
   
    
   
 
   
        
      
   
  
   
    
 
   
  
    
   
 
  
  
 
  
  
   
  
  
 
  
  
 
    
  
 
  
  
 
 
  
 
  
  
  
  
      
  
   
  
 
       
    
    
  
  
    
  
 
   
  
   
   
  
     
  
  
  
      
  
   
  
    
 
  
  
   
 
  
  
 
       
   
    
    
  
   
 
   
        
      
      
 
  
  
 
   
  
  
      
   
 
    
  
  
   
   
   
   
  
  
  
     
    
  
  
  
 
   
  
  
 
 


  
 
 
  
   
  
   
 
  
  
 
  
 
 
  
 
 
 
 
 
 
  
 
  
 
  
 
    
    
  
  
  
   
      
  
  
   
    
  
 
 
 
  
 
  
  
  
 
  
  
  
 
  
  
 


  
 
 
  
  
    
  
  
   
  
  
  
  
  
    
  
   
  
   
    
      
        
  
    
    
 
  
 
  
   
  
  
  
 


  
 
 
  
  
 
  
 
 
  
  
 
 
  
 
 
   
 
 
   
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
 
  
 
  
  
 
 
 
  
 
 
 
 
  
 
      
  
   
  
     
  
 
    
    
   
  
 
  
      
   
  
  
  
  
 
  
      
  
   
  
      
   
   
   
      
          
  
  
 
     
  
  
  
    
  
   
   
 
  
     
 
  
      
       
  
 
   
 
       
     
  
    
  
  
 
     
  
      
   
  
 
  
     


  
 
 
  
 
 


  
 
 
 
  
 
  
  
  
 
 
 
  
   
  
  
   
 
   
   
  
 
  
  
   
  
  
  
 
  
 
  
   
  
      
 
   
    
  
  
   
  
   
   
 
  
   
  
    
  
 
   
  
   
   
  
   
     
   
  
  
 
  
    
 
  
 
 
  
   
 
 
  
   
   
   
  
  
 
  
     
 
  
     
    
   
 
   
  
  
  
 
  
    
  
     
 
  
  
 
   
  
    
  
   
    
  
   
 
   
 
  
  
  
  
    
  
   
    
  
    
  
   
   
  
 
  
 
 
  
    
   
 
  
  
  
 
  
  
  
  
 
  
   
  
  
  
 
 
 
 
 
  
    
    
 
   
   


  
 
 
  
 
 
 
   
  
   
 
  
  
  
   
  
 
  
   
    
 
  
  
 
  
  
  
  
 
  
   
  
 
   
 
     
   
  
  
   
  
   
   
  
   
 
  
  
 
 
   
  
 
  
       
 
   
 
  
  
  
 
 
  
  
 
 
  
 
    
  
  
 
   
      
   
  
  
   
   
 
  
  
 
   
   
  
 
  
   
  
 
 
  
  
  
  
 
  
 
  
  
 
  
  
  
 
   
      
   
  
 
   
   
  
 
  
  
 
  
  
  
   
 
 
   
 
   
  
  
    
    
  
  
   
   
   
  
  
 
 
 
  
    
   
    
  
 
  
  
    
 
  
   
  
   
 
   
   
  
  
  
 
   
 
 
    
  
 
   
  
  
 
   
  
   
  
 
   
 
  
  
   
    
 
  
  
  
    
 
  
   
   
      
  
  
  
       
 
   
  
  
 
   
  
  
  
    
  
 
  
  
  
  
 
  
  
   
  
    
   
 
  
   
 


  
 
 
  
  
   
  
 
  
  
   
  
 
  
  
  
 
  
 
  
  
   
    
  
   
   
  
 
  
  
    
  
  
 
  
 
  
  
  
  
  
   
   
  
    
  
  
   
  
    
  
  
  
  
 
   
  
   
  
  
  
   
   
   
      
  
     
  
   
  
 
   
   
  
  
 
     
  
  
   
   
   
  
 
 
 
  
  
  
  
  
  
   
    
   
 
        
 
 
   
   
  
  
 
     
  
 
 
  
   
  
       
 
 
   
   
    
 
  
  
  
    
 
 
   
  
 
   
  
    
  
  
 
  
   
   
 
   
  
   
 
 
 
  
  
  
  
 
   
   
    
  
 
  
 
 
 
 
 
 
   
 
   
 
  
  
   
   
    
 
   
   
  
  
     
  
 
 
    
 
  
 
   
  
    
   
   
   
  
  
  
  
  
 
  
    
  


  
 
 
  
  
  
  
 
 
 
   
    
   
  
  
  
 
  
   
    
   
 
   
   
 
 
  
 
 
 
 
  
 
 
 
   
 
   
 
   
 
   
 
    
 
  
 
   
 
 
   
 
 
 
  
 
  
  
   
 
      
 
     
 
     
 
    
  
   
 
   
 
      
    
   
  
 
  
     
   
   
  
   
 
  
   
  
  
  
 


  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 


  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 


  
 
 
 
  
 
   
  
 
   
   
  
  
   
   
    
  
   
  
  
  
    
  
   
 
    
  
  
  
  
  
     
     
 
  
  
   
   
 
  
  
 
  
    
 
   
 
  
  
 
  
  
  
 
  
    
   
  
     
   
  
 
   
  
    
  
    
  
   
 
  
  
  
  
  
  
  
  
  
   
   
   
   
 
  
    
  
     
  
  
  
  
      
 
 
  
   
  
   
   
 
    


  
 
 
  
  
  
  
 
 


  
 
 
   
  
  
  
  
 
 
 
 
   
  
  
  
 
  
  
  
     
    
  
 
  
  
   
    
  
    
  
  
   
 
  
  
  
  
  
  
   
     
  
   
  
    
   
  
 
 
  
 
  
  
  
  
   
  
  
  
 
  
  
 
  
 
  
  
  
  
  
 
 
       
  
  
    
   
   
  
  
 
  
 
 
    
   
  
  
  
  
 
  
 
 
  
   
  
  
  
      
  
  
 
   
 
 
    
 
   
  
  
      
   
  
 
  
 
    
   
   
 
  
  
   
   
  
   
 
   
  
   
  
  
    
        
  
   
  
   
  
  
  
  
  
 
   
   
  
 
    
  
  
   
  
   
     
 
    
  
  
   
     
  
  
  
  
    
 
   
  
 
  
 
   
   
  
   
  
   
  
  
  
   
 
     
    
  
  
     
 
  
  
 
    
  
  
  
  
   
  
  
  
 
   
     
 
  
 
 
 
  
    
  
   
     
    
   
  
  
  
   
      
  
  
  
 
 
    
    
  
  
  
 


  
 
 
   
  
  
  
 
     
  
  
 
  
  
  
   
  
 
  
  
  
  
   
   
   
  
 
   
  
  
  
   
   
  
 
  
   
  
  
   
  
  
   
  
  
  
    
 
 
   
  
 
    
  
   
     
  
  
     
  
   
      
     
   
  
 
  
    
  
  
  
  
 
   
  
  
  
  
  
  
  
  
  


  
 
 
   
  
  
  
  
  
 
  
 
  
 
  
 
   
 
  
 
 
   
  
     
      
  
 
   
  
     
      
  
 
   
 
  
  
   
 
   
  
   
  
  
   
  
   
  
  
     
  
    
   
 
  
  
 
   
 
    
  
 
   
 
      
 
   
 
 
   
 
 
   
 
 
   
 
  
 
   
  
   
 
   
   
 
  
  
  
   
  
  
  
    
   
 
  
  
   
 
  
  
  
  
     
 
    
      
 
   
 
    
 


  
 
 
 
  
 
  
  
 
 
 
   
   
  
 
  
 
  
  
   
  
 
  
 
 
  
 
  
  
  
  
   
  
  
 
   
    
  
   
  
   
 
 
   
 
 
  
  
 
  
   
  
   
  
   
   
       
  
   
  
  
   
    
  
   
   
   
 
  
   
 
 
  
 
  
 
  
   
   
   
  
  
 
    
  
 
  
      
 
 
 
     
  
  
  
 
 
    
    
  
 
  
   
  
  
  
  
 
  
  
  
  
  
 
 
    
    
    
    
 
  
 
 
  
  
 
 
   
    
  
     
  
  
  
 
  
  
  
  
     
  
 
    
 
  
 
 
 
 
 
 
 
  
  
 
    
   
 
  
  
 
  
  
  


  
 
 
  
 
  
 
 
  
  
  
  
  
 
  
 
  
  
 
 
   
  
  
 
 
   
   
  
 
  
   
  
 
 
 
 
  
  
 
 
  
     
 
  
 
 
  
 
  
   
  
  
 
  
      
  
  
 
      
   
  
  
  
     
   
   
  
  
  
  
  
       
     
 
  
    
    
  
  
  
  
  
  
 
   
   
  
    
  
  
   
  
  
   
    
  
  
 
  
     
 
  
 
      
  
 
  
  
  
   
  
   
  
  
       
  
   
  
 
  
   
  
     
  
  
     
      
   
  
  
    
  
  
   
   
    
    
 
     
  
      
  
  
    
    
  
    
   
  
  
    
    
  
 
   
  
     
  
   
    
   
    
    
  
   
    
   
   
   
     
  
 
     
   
   
  
   
    
  
   
  
 
        
  
   
    
  
   
  
       
  
   
  
  
  
   
    
   
   
 
 
   
  
      
    
   
  
  
 
   
  
  
    
    
  
 
   
  
   
   
      
  
   
    
   
 
 
  
     
  
     
 
    
  
  
  
   
    
   
       
   
    
 


  
 
 
 
     
   
   
  
   
   
  
   
    
   
 
    
  
  
  
    
  
   
  
    
    
  
          
    
    
   
   
  
  
 
   
  
    
        
  
    
    
   
  
     
    
     
         
  
  
  
    
    
  
  
   
  
   
  
      
  
  
  
  
  
   
    
   
 
   
  
     
      
    
  
 
      
 
  
  
    
    
   
   
  
  
  
   
  
 
    
  
   
  
    
        
  
   
  
  
    
    
     
    
    
   
  
    
   
    
  
 
     
   
   
  
   
 
  
  
  
    
    
   
  
  
  
  
  
    
   
  
       
  
   
    
  
          
   
  
    
    
  
 
  
   
   
  
    
  
   
    
   
  
    
   
    
    
   
    
     
  
 
    
      
  
   
  
 
  
 
  
   
  
  
 
  
 
  
 
  
  
  
  
   
    
  
  
 
    
   
   
   
  
  
  
  
     
  
 
 
    
   
 
 
   
  
   
  
 
  
        
  
  
      
  
      
   
  
  
  
 
  
 
  
  
 
  
    
  
  
 
  
   
  
  
 
 
  
   
  
   
 
     
  
  
 
  
  
  
  
 
 
   
 
   
   
  
   
  
  
  
 
 
  
  
  
  
  
  
 
  
   
  
 
  
   
    
  
 
   
   
  
 
  
   
   
    
   
   
 
    
 


  
 
 
  
  
  
   
  
   
 
    
 
   
  
   
  
  
 
   
  
  
 
 
 
 
   
 
   
  
  
   
  
   
 
   
  
     
         
  
 
  
 
    
   
 
  
      
  
 
      
    
   
  
  
 
  
 
       
  
  
 
  
  
 
   
    
  
  
 
  
  
  
 
   
    
    
  
 
   
 
  
   
  
  
  
    
    
 
  
  
    
   
     
  
     
  
 
   
   
 
  
  
  
 
  
  
     
   
  
     
 
  
   
  
  
  
    
   
 
 
  
  
      
 
  
     
   
     
   
    
  
  
   
  
     
   
   
  
  
   
    
  
  
 
  
  
 
  
  
   
   
  
  
   
  
   
  
 
   
 
   
  
   
   
    
  
  
    
 
  
   
  
  
 
  
  
   
  
  
   
   
   
  
  
      
 
   
    
 
   
  
  
     
 
  
  
  
 
     
   
    
  
 
 
 
   
   
  
   
   
   
    
  
   
 
   
   
 
   
   
  
   
   
      
 
  


  
 
 
  
  
  
  
    
  
  
  
 
  
  
 
 
  
 
   
    
  
  
  
  
 
  
    
   
 
  
  
  
    
  
  
  
  
 
  
  
  
  
     
   
  
  
 
    
  
  
  
  
  
    
    
  
  
   
  
  
  
  
   
  
  
 
  
    
 
  
    
   
  
   
  
 
   
  
  
      
   
   
  
  
   
    
   
    
   
   
 
   
  
  
  
  
  
 
   
  
  
  
  
  
 
  
 
  
  
 
 
    
  
  
 
  
     
 
    
   
  
  
 
   
  
  
 
  
  
 
  
   
  
 
   
  
  
  
 
    
  
  
  
  
  
  
  
  
 
 
  
  
   
   
  
  
 
    
 
  
   
  
      
  
 
  
    
 
  
  
  
 
     
   
  
  
 
   
 
   
  
  
   
  
 
   
  
   
 
  
   
    
  
   
  
   
   
 
    
   
  
   
    
  
   
  
    
   
   
   
  
  
  
   
 
  
   
   
 
 
   
  
      
  
 
   
  
  
 
  
   
  
  
 
   
  
  
  
  
   
  
   
   
  
 
  
 
   
 
  
   
  
 
  
 
   
  
 
   
 
    
  
   
  
    
 
   
   
  
   
  
  
    
  
  
  
 
   
  
   
  
  
  
 
    
 
      
  
    
   
  
   
  
  
  
   
  
    
 
    


  
 
 
  
 
   
    
 
   
  
  
 
  
     
 
     
  
    
  
   
   
   
  
 
   
  
 
 
   
  
  
  
  
  
   
  
   
   
 
 
 
  
  
  
    
 
  
 
   
  
   
 
   
  
  
    
    
  
   
 
 
   
    
  
  
  
 
    
  
   
 
 
  
 
   
 
   
 
  
  
 
     
  
  
  
 
   
     
 
  
  
  
  
  
 
   
    
  
  
   
 
   
   
  
   
  
   
 
  
   
  
 
  
  
     
 
    
 
      
  
  
  
 
  
   
   
  
  
  
   
  
 
 
   
  
   
  
    
  
    
  
     
  
 
   
    
 
   
  
  
  
   
   
  
   
   
 
  
  
   
 
  
  
   
  
 
    
  
 
  
  
  
    
 
  
   
    
 
        
 
   
  
 
    
  
  
  
   
 
   
  
  
 
  
  
    
 
  
  
  
 
  
    
  
    
  
   
   
    
     
  
 
  
   
  
  
   
 
   
  
  
  
  
  
    
  
     
   
  
 
  
   
   
 
  
   
  
   
  
  
 
 
   
  
   
  
  
  
 
    
  
    
  
   
   
   
  
 
   
  
 
 
   
 
     
  
   
 
     
   
   
 
 
 
  
  
  
   
  
   
  
   
 


  
 
 
  
 
 
   
  
   
  
  
  
   
  
  
     
  
 
  
  
  
 
   
      
  
 
 
    
 
   
   
     
  
 
  
 
  
 
   
 
   
  
    
 
 
  
 
 
   
     
  
    
   
   
   
  
   
 
      
  
   
  
     
 
  
   
  
 
   
    
   
   
    
 
  
   
  
   
    
 
    
 
 
  
  
    
   
 
   
 
  
   
   
  
 
  
  
  
  
 
   
  
  
   
  
  
   
 
  
   
   
  
 
   
     
  
 
    
  
   
  
  
  
  
  
  
  
    
 
  
    
 
   
  
    
   
  
  
  
  
  
  
 
  
  
 
  
  
    
  
 
     
  
   
  
  
  
 
  
 
   
  
  
  
 
   
  
  
   
  
    
    
 
  
 
 
   
  
  
  
  
   
 
  
  
 
   
  
   
 
    
 
 
    
 
   
 
  
   
  
    
  
  
  
  
   
  
  
  
 
   
     
 
   
 
  
  
    
   
  
  
  
 


  
 
 
  
   
  
  
   
  
  
   
  
  
  
       
 
   
  
   
  
  
  
  
  
 
  
 
  
  
 
 
 
   
  
  
 
  
 
  
  
 
   
  
     
     
  
  
 
   
  
     
     
  
  
 
   
   
 
  
  
   
 
   
 
   
  
   
  
  
   
   
  
   
  
  
     
  
    
   
   
  
 
 
  
  
 
   
   
  
 
    
  
 
   
   
  
 
      
 
   
   
  
 
 
   
   
  
 
 
   
   
  
 
 
   
   
  
 
 
  
 
   
   
  
 
   
   
  
 


  
   
 
  
   
 
  
 
  
 
 
  
   
 
  
 
  
 

SAP_001.pdf: 
Statistical Analysis Plan I8B-MC-ITRN version 3 
 
A Prospective, Randomized, Double-Blind Comparison of LY900014 to Insulin Lispro, Both in 
Combination with Insulin Glargine or Insulin Degludec in Adults with Type 2 Diabetes 
PRONTO-T2D 
 
NCT03214380 
 
Approval Date: 24-Jul-2018 
 


 
 
 
 
 
 
 
 
   
 
 
 
  
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
  
 
  
 
  
 
 
  
   
  
 
 
  
   
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
  
  
 
  
 
   
  
 
 
  
 
   
 
 
   
 
   
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 


I8B-MC-ITRN Statistical Analysis Plan Version 3
Page 2
LY9000014
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan: I8B-MC-ITRN:  A Prospective, 
Randomized, Double-Blind Comparison of LY900014 to Insulin 
Lispro, Both in Combination with Insulin Glargine or Insulin 
Degludec in Adults with Type 2 Diabetes PRONTO-T2D...................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................9
5.
Study Design.....................................................................................................................11
5.1.
Summary of Study Design............................................................................................11
5.2.
Determination of Sample Size ......................................................................................11
5.3.
Method of Assignment to Treatment ............................................................................11
6.
A Priori Statistical Methods ..............................................................................................13
6.1.
General Considerations ................................................................................................13
6.2.
Adjustments for Covariates ..........................................................................................18
6.3.
Handling of Dropouts or Missing Data.........................................................................18
6.4.
Multicenter Studies ......................................................................................................18
6.5.
Multiple Comparisons/Multiplicity...............................................................................19
6.6.
Patient Disposition .......................................................................................................19
6.7.
Patient Characteristics ..................................................................................................20
6.8.
Treatment Compliance .................................................................................................20
6.9.
Important Protocol Deviations......................................................................................20
6.10. Concomitant and Prior Therapy....................................................................................24
6.11. Efficacy Analyses ........................................................................................................25
6.11.1.
Primary Outcome and Methodology.....................................................................25
6.11.2.
Analyses of Multiplicity Adjusted Objectives.......................................................27
6.11.3.
Additional Analyses of the Primary Outcome.......................................................28
6.11.4.
Sensitivity Analyses for Missing Data..................................................................28
6.11.5.
Other Secondary Efficacy Analyses .....................................................................29
6.11.6.
Secondary Health Outcomes Analyses .................................................................30
6.11.7.
Analyses of Exploratory Objectives .....................................................................30
6.12. Safety Analyses............................................................................................................31
6.12.1.
Extent of Exposure...............................................................................................32
6.12.2.
Adverse Events ....................................................................................................32
6.12.3.
Deaths..................................................................................................................34
6.12.4.
Hypoglycemic Events and Other Adverse Events.................................................34


I8B-MC-ITRN Statistical Analysis Plan Version 3
Page 3
LY9000014
6.12.4.1.
Hypoglycemic Events.....................................................................................34
6.12.4.2.
Systemic Hypersensitivity Reaction................................................................36
6.12.4.3.
Injection Site Reaction....................................................................................37
6.12.4.4.
Hepatobiliary Events ......................................................................................37
6.12.4.4.1.
Treatment-Emergent Potential Hepatic Disorder.......................................37
6.12.4.4.2.
Liver Enzyme Lab Values.........................................................................37
6.12.4.4.3.
Treatment-Emergent Elevation of Liver Enzyme Lab 
Values ......................................................................................................38
6.12.5.
Clinical Laboratory Evaluation.............................................................................38
6.12.6.
Vital Signs and Other Physical Findings...............................................................39
6.12.7.
Immunogenicity...................................................................................................40
6.12.7.1.
Treatment Emergent Anti-Insulin Lispro Antibody.........................................40
6.12.7.2.
Anti-Insulin Lispro Antibody Return to Baseline ............................................42
6.12.8.
Patient Narratives.................................................................................................43
6.13. Subgroup Analyses.......................................................................................................43
6.13.1.
Subgroup Analyses for HbA1c.............................................................................43
6.13.2.
Subgroup Analyses for Hypoglycemic Events......................................................44
6.14. Interim Analyses and Data Monitoring.........................................................................44
6.15. Clinical Trial Registry Analyses...................................................................................45
7.
Unblinding Plan................................................................................................................46
8.
References ........................................................................................................................47
9.
Appendices .......................................................................................................................48


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Table of Contents
Table
Page
Table 4.1.
Objectives and Endpoints.......................................................................................9
Table 6.1.
Patient Populations...............................................................................................13
Table 6.2.
Baseline and Post-Baseline Definitions and Patient Population by Study Period and 
Type of Analysis ...............................................................................................................16
Table 6.3.
Description of Important Protocol Deviations.......................................................21
Table 6.4
Additional Exploratory Efficacy Variables...........................................................31
Table 6.5.
Treatment-Emergent Adverse Event Analysis Periods..........................................33
Table 6.6.
Summary of Analyses for Endpoints Related to Hypoglycemia............................35
Table 6.7.
Categorical Criteria for Abnormal Treatment-Emergent Blood Pressure and Pulse 
Measurement, and Categorical Criteria for Weight for Adults............................................40


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Table of Contents
Figure
Page
Figure 5.1.
Illustration of study design. ..................................................................................12
Figure 6.1.
Testing scheme for primary and multiplicity adjusted objectives. .........................28


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Table of Contents
Appendix
Page
Appendix 1.
Empirical Estimation of Relative Event Rate ..................................................49
Appendix 2.
Statistical Analysis for Japan ..........................................................................51
Appendix 3.
Statistical Analysis for Maximum Extended Enrollment (MEE) Addendum ...52


 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
  
 
 
  
   
 
 
 
   
  
   
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
 
 
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
   
  
 
 
 
  
 
 
  
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
   
 
   
 
 
 
   
 
 
 
  
 
 
 
   
 
  
 
  
 
      
   
 
  
 
 
 
 
 
    
  
 
  
 
  
   
  
 
 
  
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
  
 
 
  
 
  
 
  
 
 
 
  
  
 
  
  
  
 
 
 
 
   
 
 
 
   
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
  
  
 
 
   
  
 
 
 
 
  
 
  
 
   
 
 
 
   
 
 
  
 
  


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adding the on IP definition for mixed-meal tolerance test (MMTT) for which the 14-day 
rule is not applicable
removing vital sign analyses except weight analysis for the lead-in period
adding analysis details (for example, defining the pooled country used in the statistical 
modeling and region for subgroup analyses) and removing contradictory statements
clarifying the analysis of important protocol deviations when duplicates occur  


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4.
Study Objectives
Table 4.1 shows the objectives and endpoints of the study. 
Table 4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
1.
(H1) To test the hypothesis that LY900014 is 
noninferior to insulin lispro on glycemic 
control (NIM=0.4% for HbA1c) in patients 
with T2D, when administered as prandial 
insulin (0 to 2 minutes prior to the meal), in 
combination with basal insulin glargine or 
insulin degludec for 26 weeks
1.
Difference between LY900014 and insulin 
lispro in change from baseline to Week 26 in 
HbA1c
Multiplicity Adjusted Objectives
2.
(H2) To test the hypothesis that LY900014 is 
superior to insulin lispro in controlling 1-hour 
PPG excursions, when administered as prandial 
insulin
2.
Difference between LY900014 and insulin 
lispro in the 1-hour PPG excursion (serum 
glucose measured 1 hour after the start of the 
meal minus fasting serum glucose) from an 
MMTT at Week 26
3.
(H3) To test the hypothesis that LY900014 is 
superior to insulin lispro in controlling 2-hour 
PPG excursions when administered as prandial 
insulin
3.
Difference between LY900014 and insulin 
lispro in the 2-hour PPG excursion (serum 
glucose measured 2 hours after the start of the 
meal minus fasting serum glucose) from an 
MMTT test at Week 26
4.
(H4) To test the hypothesis that LY900014 is 
superior to insulin lispro on improving 
glycemic control (HbA1c) when administered 
as prandial insulin
4.
Difference between LY900014 and insulin 
lispro in change from baseline to Week 26 in 
HbA1c
Other Secondary Objectives
5.
To compare LY900014 and insulin lispro with 
respect to the rate of severe hypoglycemic 
events
5.
Rate (events/patient/100 years) of severe 
hypoglycemic events from baseline through 
Week 26
6.
To compare LY900014 and insulin lispro with 
respect to the incidence and rate of documented 
symptomatic postmeal hypoglycemia
6.
Rate (events/patient/year and/or 
events/patient/30 days) and incidence (percent 
of patients with at least 1 event) of documented 
symptomatic postmeal hypoglycemia within 1 
and 2 hours after start of a meal from baseline 
through Week 26
7.
To compare LY900014 and insulin lispro with 
respect to the incidence and rate of documented 
symptomatic hypoglycemia
7.
Rate (events/patient/year and/or 
events/patient/30 days) and incidence (percent 
of patients with at least 1 event) of documented 
symptomatic hypoglycemic events from 
baseline through Week 26
8.
To compare LY900014 and insulin lispro with 
respect to 1,5-AG
8.
Change from baseline 1,5-AG values at 
Week 26
9.
To compare LY900014 and insulin lispro with 
respect to 10-point SMBG profiles
9.
Change from baseline 10-point SMBG values 
at Week 26


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Objectives and Endpoints
Objectives
Endpoints
Other Secondary Objectives (Continued)
10. To compare LY900014 and insulin lispro with 
respect to total, basal, and prandial insulin dose
10. Change from baseline in total, basal and 
prandial insulin dose and prandial/total insulin 
dose ratio at Week 26
11. To compare LY900014 and insulin lispro with 
respect to diabetes treatment satisfaction as 
measured by the ITSQ
11. Change from baseline ITSQ regimen 
inconvenience and lifestyle flexibility domain 
scores at Week 26
12. To compare LY900014 and insulin lispro with 
respect to the proportion of patients achieving 
HbA1c targets
12. The proportion of patients with HbA1c <7% 
and ≤6.5% at Week 26
Tertiary/Exploratory Objectives
13. To compare the safety of LY900014 relative to 
insulin lispro
13. Adverse events, vital signs, chemistry, and 
hematology laboratory measures
14. To compare the incidence of treatment-
emergent anti-insulin lispro antibodies for 
LY900014 and insulin lispro
14. Incidence of treatment-emergent positive anti-
insulin lispro antibodies 
15. To compare LY900014 and insulin lispro with 
respect to quality of life as measured by the 
EQ-5D-5L
15. Change from baseline in EQ-5D-5L 
UK-population based health state index score 
and EQ-VAS score at Week 26
16. To compare LY900014 and insulin lispro with 
respect to the impact that diabetes has on the 
ability to work and perform regular activities as 
measured by the WPAI-GH
16. Change from baseline in WPAI-GH item scores 
at Week 26
17. To compare LY900014 and insulin lispro with 
respect to changes in body weight
17. Change from baseline to Week 26 in weight 
(kg)
18. To compare LY900014 and insulin lispro with 
respect to the proportion of patients achieving 
improvement from baseline HbA1c targets
18. The proportion of patients with shifts in HbA1c 
to <8% and ≤9%, and >9% from baseline to 
Week 26
19. To compare LY900014 and insulin lispro with 
respect to glycemic variability 
19. Within-day and between-day glycemic 
variability measured by the standard deviation 
and the coefficient of variation of 10-point 
SMBG profiles 
Abbreviations:  1,5-AG = 1,5-Anhydroglucitol; EQ-5D-5L = European Quality of Life – 5 Dimensions 5 Level; 
EQ-VAS = EuroQol visual analog scale; HbA1c = hemoglobin A1c; ITSQ = Insulin Treatment Satisfaction 
Questionnaire; MMTT = mixed-meal tolerance test; NIM = noninferiority margin; PPG = postprandial glucose; 
SMBG = self-monitored blood glucose; T2D = type 2 diabetes; WPAI-GH = Work Productivity and Activity 
Impairment Questionnaire General Health.


 
 
 
 
 
 
 
  
 
   
  
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
  
 
  
  
 
 
  
 
 
  
  
 
  
 
  
 
 
   
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
  
   
 
 
 
 
  
  
  
  
 
 
 
 
     
 
 
 
 
  
   
  
 
  
 
 
  
  
 
 
 
 
 
  
 
 
  
  
 
  
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
   
  
  
  
 
   
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
  
 
  
  
  
 
 
  
   
 
 
 
  
 
 
 
 
 
  
    
  
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
   
 
 
 
 
  
   
  
 
 
  
 
 
 
  
 
  
  
  
 
  
 
 
 


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Abbreviations:  T = telephone visit; wk = week.
a At Visit 2, patients treated with insulin aspart, insulin glulisine, regular insulin, or premixed insulin will be 
transferred to insulin lispro.  At Visit 2, patients treated with a basal insulin regimen other than insulin glargine 
U-100 or insulin degludec will be transferred to an allowed study basal regimen of insulin glargine U-100 once or 
twice daily or insulin degludec U-100 or U-200 once daily.  At Visit 8, patients will be randomized to either 
insulin lispro or LY900014 and continue their basal insulin regimen. 
b Titrate basal insulin. 
c Titrate prandial insulin (insulin lispro or LY900014).
d Patients will discontinue study insulins at Week 26.
e Eligible patients will have visits at approximately 3-month intervals for up to 26 weeks after Visit 801 for 
follow-up of insulin lispro antibody levels.
Figure 5.1.
Illustration of study design.


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (hereafter 
Lilly). Any change to the data analysis methods described in the protocol will require an 
amendment ONLY if it changes a principal feature of the protocol. Any other change to the data 
analysis methods described in the protocol, and the justification for making the change, will be 
described in this SAP and/or in the clinical study report (CSR). Additional exploratory analyses 
will be conducted, as deemed appropriate.
Statistical analyses for Japan are described in Appendix 2.  Statistical Analyses for the Maximum 
Extended Enrollment (MEE) Addendum are described in Appendix 3. 
For purposes of analysis, the following populations are defined in Table 6.1:
Table 6.1.
Patient Populations
Population
Description
Entered
All patients who give informed consent.
Enrolled
All patients who receive at least 1 dose of open-label insulin lispro in the 8-week lead-
in period.
Randomized
All patients who are randomly assigned to study treatment at Visit 8.  Treatment group 
will be defined on the basis of the treatment the patients are assigned.
Safety
All randomized patients who receive at least 1 dose of the randomly assigned 
investigational product (IP). Treatment group will be defined on the basis of the 
treatment the patients are assigned.  
Completer
Patients included in the randomized population who have completed Week 26 of study 
treatment without permanent discontinuation of IP. Treatment group will be defined on 
the basis of the treatment the patients are assigned.  
Per Protocol 
Patients included in the randomized population who have completed Week 26 of study 
treatment without permanent discontinuation of IP and without significant protocol 
deviations through Week 26 that would significantly impact the primary objective. 
Treatment group will be defined on the basis of the treatment the patients actually 
receive.
Unless otherwise stated, the efficacy analyses will be conducted on the Randomized Population, 
and the safety analyses will be conducted on the Safety Population.
The primary analysis is for the treatment period through Week 26. 


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Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and CIs will be calculated at 95%, 2-sided. All tests of interactions between treatment 
groups and other factors will be conducted at a 2-sided alpha level of 0.10. 
The definitions of baseline and post-baseline for the efficacy and safety analyses depend on 
which analysis period is being used. The following analysis periods will be used:

Lead-in Period – Visits 2 to 8

26-Week Treatment Period – from randomization to Week 26 prior to 
discontinuation of IP and from randomization to Week 26 (including all data 
regardless of IP use)

26-Week Treatment Period and Safety Follow-Up Visit – from randomization to 
Visit 801 (including all data regardless of IP use)
The data on IP is defined based on the following rules:

For data only measured at an office visit 
o
MMTT postbaseline data will be classified as on IP if the MMTT 
performance date is prior to or on the last IP dose date  
o
Other postbaseline data (for example, vital signs, safety laboratory tests,
and questionnaires) will be considered as on IP if the measurement was 
performed at or prior to the cutoff date defined as 14 days after the last IP 
dose date

For data collected as running records with an exact date stamp such as adverse 
events (AEs) and diary entries where the dates of the measures were not tied with 
the date of an office visit, postbaseline data with dates ≤(last study drug dose date 
+1) will be considered as data on IP.
Table 6.2 describes the rules for determining the patient population, baseline and postbaseline 
observations for the different analysis periods. 
For continuous measures, summary statistics will include sample size, mean, SD, median, 
minimum, and maximum for both the actual and the change from baseline measurements. 
Least-squares (LS) means and standard errors derived from the analysis models will also be 
displayed. Treatment comparisons will be displayed showing the treatment difference LS means 
and the 95% CIs for the treatment differences, along with the p-values for the treatment 
comparisons.
For categorical measures, summary statistics will include sample size, frequency, and 
percentages. Fisher’s exact test or Pearson’s chi-square test will be used for treatment 
comparisons.
For laboratory values, both conventional (CN) and Systeme International (SI) units will be 
presented.  Therefore, both % and mmol/mol will be presented for HbA1c and both mg/dL and 
mmol/L will be presented for glucose measurements.  


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All baseline measures will be analyzed using an analysis of variance (ANOVA) model that has 
treatment as the model term.


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Table 6.2.
Baseline and Post-Baseline Definitions and Patient Population by 
Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline Observations
Lead-In Period
TEAEs
All Enrolled Patients
Prior to first dose of 
open-label insulin 
lispro (or Visit 2 date if 
the dose date is 
missing)
The entire lead-in period after first 
dose of open-label insulin lispro and 
prior to the first dose of IP (or Visit 8 
date if the dose date is missing).
Basal, prandial, and 
total insulin doses, and 
prandial/total insulin 
dose ratios continuous 
analysis
All Randomized 
Patients
Visit 2
Visits 3 to 8 prior to initiation of IP
Weight MMRM and 
ANCOVA
All Randomized 
Patients
Last of Visits 1-2
Visits 3–8
AND
Last of Visits 3-8
26-Week Treatment Period (including Safety Follow-Up Visit where applicable)
HbA1c MMRM and 
ANCOVA (efficacy 
estimand)
All Randomized 
Patients with a 
baseline and at least 1
post-baseline 
observation while on 
IP
Last of Visits 7-8
Visits 11, 13, 15, and 18 prior to 
discontinuation of IP
AND
Last of Visits 9-18 prior to 
discontinuation of IP
HbA1c ANCOVA (ITT 
estimand)
All Randomized 
Patients with a 
baseline and at least 1 
post-baseline 
observation
Last of Visits 7-8
Visit 18 with imputation for patients 
who discontinue study prior to Visit 
18 
HbA1c categorical 
analyses longitudinal 
logistic regression and 
LOCF logistic 
regression
All Randomized 
Patients with a 
baseline and at least 
one post-baseline 
observation while on 
IP
Last of Visits 7-8
Visits 11, 13, 15, and 18 prior to 
discontinuation of IP
AND
Last of Visits 9-18 prior to 
discontinuation of IP
1-hr and 2-hr PPG and 
other MMTT variables
(efficacy estimand)
All Randomized 
Patients with a post-
baseline observation
while on IP
Visit 8 prior to 
initiation of IP
Visit 18 prior to discontinuation of IP
1-hr and 2-hr PPG and 
other MMTT variables 
(ITT estimand)
All Randomized 
Patients with a post-
baseline observation
Visit 8 prior to 
initiation of IP
Visit 18 regardless of IP use
10-point SMBG, basal, 
prandial insulin doses, 
prandial/total insulin 
dose ratios
All Randomized 
Patients with a 
baseline and at least 
one post-baseline 
observation 
Visit 8 prior to 
initiation of IP
Visits 11, 13, 15, and 18 prior to 
discontinuation of IP
AND 
Last of Visits 9-18 prior to 
discontinuation of IP


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Baseline and Post-Baseline Definitions and Patient Population by Study Period and Type of Analysis
Study Period/Analysis
Patient Population
Baseline Observations
Post-Baseline Observations
1,5-AG
All Randomized 
Patients with a 
baseline and at least 
one post-baseline 
observation
Visit 8 prior to 
initiation of IP
Visits 11, 15, and 18 prior to 
discontinuation of IP 
AND 
Last of Visits 9-18 prior to 
discontinuation of IP
Health outcomes:  
ITSQ, EQ-5D-5L, EQ-
VAS, WPAI-GH
All Randomized 
Patients with a 
baseline and a post-
baseline observation
Last of Visits 1-8
Last of Visits 9-18 prior to 
discontinuation of IP
Safety Laboratory Tests 
(chemistry, hematology, 
lipids) – continuous 
analysis
All Patients in the 
Safety Population 
with a baseline and a 
post-baseline 
observation
Last of Visit 1-8
Visit 18 (planned)
AND 
last of Visits 9-18 (planned including 
early discontinuation visits)
regardless of IP use
Safety Laboratory Tests 
(chemistry, hematology, 
lipids) – categorical 
analysis
All Patients in the 
Safety Population 
with a normal 
baseline (with respect 
to the direction being 
analyzed) and a post-
baseline observation
Visits 1-8 (including 
unplanned tests)
Visits 9-18 (including unplanned 
tests) regardless of IP use
TEAEs
All Patients in the 
Safety Population
Prior to first dose of 
randomized IP (or Visit 
8 date if the dose date is 
missing) but after the 
first dose of open-label 
insulin lispro in the 
Lead-in Period
From first dose of randomized IP to 
last dose of randomized IP
AND
From first dose of randomized IP to 
Visit 801 
Hypoglycemia events
Safety Population
All Visits 2-8
All Visits 9-18 prior to 
discontinuation of IP
Weight and vital signs
All Patients in the 
Safety Population 
with a baseline and a 
post-baseline 
observation
Last of Visits 2-8
Visits 9-18 prior to discontinuation of 
IP
AND
Visits 9-801 regardless of IP use
Anti-insulin lispro 
antibodies 
Safety Population
Visit 2
Visits 3-801 regardless of IP use
Abbreviations: 1,5-AG = 1,5-Anhydroglucitol; ANCOVA = analysis of covariance; EQ-5D-5L = European Quality 
of Life – 5 Dimensions 5 Level; EQ-VAS = EuroQol visual analogue scale; HbA1c = hemoglobin A1c; 
IP = investigational product; ITSQ = Insulin Treatment Satisfaction Questionnaire; ITT = intention-to-treat; 
LOCF – last-observation-carried forward; MMTT = mixed meal tolerance test; MMRM = mixed-effect model 
repeated measures; PPG = postprandial glucose; SMBG = self-monitored blood glucose; TEAE = treatment-
emergent adverse event; WPAI-GH = Work Productivity and Activity Impairment General Health.


 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
    
 
 
  
 
 
  
  
  
 
  
 
 
 
 
 
 
  
 
  
  
  
 
   
  
 
 
 
 
 
 
  
 
 
 
   
 
  
   
  
 
  
  
 
  
 
    
  
  
 
  
 
  
 
  
   
 
 
 
   
    
  
 
 
  
  
 
   
 
  
   
   
 
 
 
 
 
  
 
  
  
 
 
  
  
 
 
   
  
 
 
 
  
 
 
 
 
  
 
 
 
  
   
   
 
 
 
 
 
  
 
   
  
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
   
 
 
  
  
  
 
   
  
  
 
 
   
 
   
 
 
 
 
 
   
 
 
 
  
  
   
 
  
 
  
 
  
  
 
 
 
 
 


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6.5.
Multiple Comparisons/Multiplicity
A graphical approach for multiple comparisons will be used to strongly control the overall 
Type I error (2-sided alpha level of 0.05) for testing the treatment effect for the primary and the 
multiplicity adjusted objectives given in Section 4. See Section 6.11.2 for the details of 
graphical testing scheme.
No multiplicity test adjustment will be made for other objectives.
6.6.
Patient Disposition
Patient disposition will be displayed in a flowchart showing the number of patients entered, 
enrolled, randomized, and discontinued across all study periods.
Frequency counts and percentages of all randomized patients completing and discontinuing from 
the study will be presented for each treatment group. Reasons for discontinuation from the study 
and study treatment during the 26-week treatment period will be compared between treatment 
groups using Fisher’s exact test.  Reasons for discontinuation from the study at Visit 801 will be 
summarized by the randomized treatment groups. 
Frequency counts and percentages of all patients entered, enrolled, and discontinued from the 
study during the lead-in period will be summarized. Reasons for discontinuation during 
screening will be summarized for all entered patients. Reasons for discontinuation from the 
study during the lead-in period will be summarized for all enrolled patients.
Time to all-cause discontinuation (discontinuation for any reason) from the study and from study 
treatment will be compared between treatment groups for the 26-week Treatment Period.  The 
Kaplan-Meier product limit method will be used to create survival curves and the log-rank test 
will be used for the treatment comparisons. Time to all-cause discontinuation is defined as the 
total number of days between the randomization date (Visit 8 date) and date of discontinuation 
plus 1.  Patients who complete the treatment period will be treated as censored using the total 
number of days between the randomization date and the Visit 18 date plus 1.  If sufficient 
numbers of patients discontinue the study because of AE, similar analysis will be performed for 
time to discontinuation due to AE. 
A listing of the primary reason for treatment discontinuation (if applicable) and study 
discontinuation will be generated for the Enrolled Population. 
Patient allocation by investigator, grouped by country, will be summarized indicating the number 
of patients who enter the study, the number of patients who participate in the lead-in period, the 
number of patients who are randomized to study treatment, and the number of patients who 
discontinue the study during the 26-Week treatment period.
A listing of the randomization treatment assignment will be generated for all randomized 
patients. 


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6.7.
Patient Characteristics
A summary table will be generated for patient characteristics at study entry using all randomized 
patients. The following variables will be included but not limited to: age, age groups (<40 and 
≥40 years, and <65, ≥65 to <75, ≥75 to <85, ≥85 years), sex, country, ethnicity, race, height, 
weight, body mass index (BMI), BMI groups (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m2). For 
continuous variables, the following statistics will be provided: mean, SD, minimum, maximum, 
and median, and treatment groups will be compared using an analysis of variance (ANOVA) 
model with a term of treatment. For categorical variables, summary statistics will include 
sample size, frequency and percentage, and treatment groups will be compared using Fisher’s 
exact test or Pearson’s chi-square test. A listing of patient characteristics at study entry will be 
provided.
A similar summary of diabetes characteristics will also be generated. The following variables 
will be included but not limited to: duration of diabetes, the type of prandial insulin at study 
entry, the type of basal insulin therapy at study entry (including whether given once daily [QD]
or twice-daily [BID]) and randomization, the type of pre-mix insulin at study entry, number of 
prandial injections at study entry (<3, ≥3), oral antihyperglycemic medication (OAM) use at 
study entry and randomization, prandial insulin dosing plan, HbA1c at study entry and baseline, 
HbA1c stratum (based on measurement at baseline), and fasting serum glucose at Visit 2 and 
baseline (based on mixed-meal tolerance test [MMTT]). 
A listing of patients whose stratification factor value entered into the IWRS (for treatment group 
assignment) is different from the clinical database will also be provided.
For all randomized patients, the number and percentage of patients with historical conditions will 
be summarized by treatment group using Medical Dictionary for Regulatory Activities 
(MedDRA) PT (without regard to SOC), and the number and percentage of patients with 
preexisting conditions will also be summarized by treatment group using MedDRA PT (without 
regard to SOC).  Historical conditions are conditions that end prior to inform consent and 
preexisting conditions are conditions that are still ongoing at inform consent.  Events will be 
ordered by decreasing frequency.  No statistical comparisons between treatment groups will be 
performed.
6.8.
Treatment Compliance
No analysis for treatment compliance is planned for this study.
6.9.
Important Protocol Deviations
Important protocol deviations (IPD) that potentially compromise the data integrity and patients’ 
safety will be summarized by treatment group for all randomized patients.  Patients with more 
than one IPD from the same category, subcategory, and study-specific term (description) will 
only be counted once per patient.
Table 6.3 lists the categories/subcategories of important protocol deviations, source of 
identification, and the method to identify each deviation.


 
 
 
 
 
 
 
  
 
 
  
 
 
  
  
 
  
  
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
  
 
 
  
 
  
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
   
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
   
 
 
  
   
 
 
 
  
 
 
  
 
 
    
 
  
  
  
 


 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
   
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
  
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 


 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
   
    
  
  
  
  
 
 
   
  
  
  
  
 
  
  
  
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
   
 
 
  
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
 
  
 
 
 
  
   
 


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A summary of previous diabetes therapies that were discontinued prior to informed consent will 
be generated for the Enrolled Population. 
Total daily basal and total daily prandial insulin doses for the day prior to Visit 2 will be entered 
into the eCRF.  The daily basal doses and individual prandial insulin doses (that is, morning 
meal, midday meal, evening meal, bedtime/snack/other) will be entered into the electronic 
clinical outcomes assessment (eCOA) device after Visit 2. At a given visit, total daily basal 
insulin dose to be used for analysis will be calculated as the mean of the total daily basal insulin 
doses on the 7 days prior to the visit date (or the days between the previous visit date and the 
current visit date if the number of days between the 2 visit dates is <7). Similarly, the dose for 
each meal will be calculated as the mean of the doses on the 7 days prior to the visit date (or the 
days between the previous visit date and the current visit date, whichever smaller).  Total daily 
prandial insulin dose to be used for analysis will be calculated as the sum of the individual meal 
insulin doses.  If either total daily basal insulin dose or total daily prandial insulin dose is 
missing, total daily insulin dose and prandial/total insulin dose ratio will be set as missing for 
analysis.
Total daily basal insulin dose, total daily prandial insulin dose, total insulin dose, and the ratio of 
prandial insulin dose to total insulin dose during the lead-in period will be summarized by visit
for the Randomized Population. The actual and change from Visit 2 values will be compared 
between treatment groups using an MMRM model including the corresponding dose at Visit 2,
treatment, strata (pooled country, type of basal insulin, the number of prandial doses at study 
entry and HbA1c stratum), visit, treatment-by-visit interaction in the model as fixed factors and 
patient as a random factor. Doses will be summarized in U and U/kg.  Basal insulin dose will be 
summarized independently for glargine and degludec as well as combined. 
Up to 3 OAMs (metformin, dipeptidyl peptidase-4 inhibitor [DPP-4] inhibitor, sodium-glucose 
co-transporter 2 [SGLT2] inhibitor, sulfonylurea, meglitinide and alpha-glucoside inhibitor) are 
allowed prior to the study, and up to 2 OAMs (metformin and SGLT2 inhibitor) are allowed 
during the lead-in and treatment periods. The proportion of patients who were treated with 
OAMs (by class of OAM) at each visit will be summarized and compared between treatment 
groups using Fisher’s exact test. The number of OAMs per patient will also be summarized by 
treatment and by period: lead-in period (Visit 2 to Visit 8) and treatment period (Visit 8 to 
Visit 18).
6.11. Efficacy Analyses
6.11.1. Primary Outcome and Methodology
The primary objective of this study (H1) is to test the hypothesis that LY900014 is noninferior to 
insulin lispro on glycemic control (NIM=0.4% for HbA1c) in patients with T2D, when 
administered as prandial insulin (0 to 2 minutes prior to the meal), in combination with basal 
insulin for 26 weeks.  There will be 2 primary analysis methods, each tested at the full 
significance level of 0.05. 


 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
    
 
  
 
  
 
 
 
 
 
  
   
  
 
 
   
 
 
  
 
   
 
 
 
 
   
  
 
 
 
  
 
  
 
 
 
  
   
 
 
  
 
 
  
   
   
 
 
   
  
 
 
 
 
  
 
 
   
 
  
  
 
  
 
  
 
  
 
   
  
 
  
  
 
  
   
 
  
 
  
 
  
  
  
 
 
 
   
 
 
   
  
 
 
 
   
  
  
 
 
 
  
 
 
  
  
  
   
 
 
 
 
  
  
   
 
 
  
  
   
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
  
  
 
 
 
 
  
 
  
  
 
 
 
  
  
 
 
 
  
 
  
  
  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
   
 
  
 
   
  
 
   
 
 
  
 
 
  
 
 
  
 
  
 
 
 
   
 
  
  
 
  
 
 
  
 
  
   
 
 
  
 
  
 
 
 
  
  
 
 
 
 
 
 
  
   
  
  
   
 
  
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
  
 
 
  
 


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For both primary analysis approaches, LY900014 will be declared noninferior to insulin lispro if 
the upper limit of the 2-sided 95% CI for the LS mean difference in the change from baseline in 
HbA1c for LY900014 minus insulin lispro is below +0.4%.  In addition, the 95% CI for the 
treatment difference will be compared to an alternative NIM of +0.3%.  Both estimands will be 
tested at the full significance level of 0.05. 
6.11.2. Analyses of Multiplicity Adjusted Objectives
A graphical approach for multiple comparisons (Bretz et al. 2011) will be used to strongly 
control the overall Type I error (2-sided alpha level of 0.05) for testing the treatment effect for 
the primary and the following multiplicity adjusted objectives: superiority of LY900014 
compared with insulin lispro for (H2) 1-hour postprandial plasma glucose (PPG) excursion at the 
study primary endpoint, (H3) 2-hour PPG excursion at the study primary endpoint, and (H4) 
change from baseline to the study primary endpoint in HbA1c. Analyses will be performed for 
both the efficacy estimand and ITT estimand.
The graphical testing scheme for this study is displayed in Figure 6.1. All the hypotheses are 
connected by lines with arrowheads indicating the directions of testing paths. The initial 
allocation of study total alpha for each hypothesis is located within the same node of the 
hypothesis. In this study, the study total alpha level (0.05) will be all used for the primary 
objective (H1) in the initial step. Then, the study total alpha level (0.05) will be allocated to 
other objectives according to the values of transition weights shown above the connecting lines 
in the figure once H1 is met. If 1 of the remaining objectives is successfully demonstrated with 
the given alpha level, its alpha will be allocated to the rest of objectives by the transition weights 
in the paths. The iterative test procedure continues until none of the remaining objectives can be 
demonstrated with their preserved alphas or all objectives are demonstrated successful.
An ANCOVA model with strata (pooled country, type of basal insulin, number of prandial doses 
at study entry, and HbA1c stratum) and treatment as fixed effects and baseline as a covariate will 
be used to analyze the 1-hour and 2-hour PPG excursions for both the efficacy (data collected 
prior to discontinuation of IP) and ITT (all data collected regardless of IP use) estimands. 
However, if the percentage of the patients with missing MMTT data at baseline is higher than 
15%, a constrained longitudinal data analysis model (Liu et al. 2009; Lu 2010) will be used 
instead.
The superiority testing on change from baseline to the study primary endpoint in HbA1c will be 
assessed by the same analysis used for the primary objective. The analyses for the ITT and 
efficacy estimands are described in Section 6.11.1. If the p-value is less than the alpha level 
allocated by the graphical approach, the superiority of LY900014 to insulin lispro will be 
achieved.


 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
  
 
    
 
  
 
 
  
 
 
    
 
  
  
 
  
 
 
 
 
   
 
    
  
 
 
 
   
 
 
 
  
  
 
 
   
 
  
  
 
  
 
  
  
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
  
 
  
 
  
 
  
 
 
 
 
 
  
  
 
  
  
 
 
 
  
   
  
 
 
   
  
 
    
 
   
 
   
 
 
  
  
   
 
   
 
    
  
   
 
  
     
 
  
   
 
 
  
 
  
    
 
  
  
 
    
 
 
 
 
  
 
  
  
 
 
 
  
 
  
 
 
 
 
 
  
 
  
 
  
 
   
 
 
  
  
 
  
 
 
   
   
 
 
  
   
 
 
  
   
 
  
 
  
 
 
 
 
   
 
 
 
  
 
    
 


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6.11.5. Other Secondary Efficacy Analyses
The analyses described in Section 6.11.5 to Section 6.11.7 will include data collected from all 
randomized patients prior to permanent discontinuation of IP.  The longitudinal observations of 
actual and change from baseline in HbA1c up to Week 26 will be analyzed using the same 
MMRM model as for the analysis of the primary outcome. For the following secondary efficacy 
endpoints, an MMRM model similar to that for the primary outcome with an additional term of 
HbA1c stratum (≤8%, >8%) will be used:

actual and change from baseline 1,5-AG values

actual and change from baseline 10-point SMBG values (fasting, 1 hour post 
morning meal, 2 hours post morning meal, pre midday meal, 1 hour post midday 
meal, 2 hours post midday meal, pre evening meal, 1 hour post evening meal, 
2 hours post evening meal, and bedtime)

actual and change from baseline in total, basal, and prandial insulin doses and 
prandial/total insulin dose ratios
Three 10-point SMBG profiles are expected to be collected during the 2 weeks prior to specified 
visits.  Valid SMBG profiles will be used for analysis, defined as having non-missing values at 
≥6 time points among the 10 pre-specified time points and being collected during 2 weeks prior 
to a given visit.  For each time point, the average of the corresponding SMBG values from the 
valid SMBG profiles will be used for analysis. The excursion of SMBG for each meal category 
(that is, morning meal, midday meal, and evening meal) calculated using the average values at 
the corresponding time points will be used for analysis.
The following endpoints, collected from the MMTT, will be analyzed using the ANCOVA 
model with strata (pooled country, type of basal insulin, number of prandial doses at study entry, 
and HbA1c stratum) and treatment as fixed effects and baseline as a covariate:

actual and change from baseline in fasting glucose (average of measurements at 
time -15 and 0), and PPG at 15, 30, 60, 120, 180, and 240 minutes after the meal 

PPG excursions at time 15, 30, 180, and 240 minutes after the meal (PPG minus 
fasting glucose)
Sensitivity analysis for PPG excursions may be performed to exclude patients whose PPG 
excursion could be affected by factors including MMTT consumption amount (for example, 
partial MMTT was consumed) and correction bolus insulin usage.  
Treatment comparisons for the proportion of patients with HbA1c <7.0% and ≤6.5% will be
analyzed using a longitudinal logistic regression with repeated measurements conducted by a
generalized linear mixed model including independent variables of treatment, baseline HbA1c
value, visit, baseline HbA1c-by-visit interaction, and treatment-by-visit interaction. An
unstructured covariance structure will be used. As a sensitivity analysis, the proportion of
patients with HbA1c <7.0% and ≤6.5% at Week 26 (Visit 18), imputed using LOCF, will be
compared using a logistic regression model with terms for treatment and baseline HbA1c value.


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6.11.6. Secondary Health Outcomes Analyses
For the Insulin Treatment Satisfaction Questionnaire (ITSQ), the change from baseline to LOCF 
endpoint while on treatment in each domain transformed score (inconvenience, lifestyle, 
hypoglycemic control, glycemic control, delivery system) and overall transformed score will be 
analyzed using the ANCOVA model with strata (pooled country, type of basal insulin, number of 
prandial doses at study entry, and HbA1c stratum), and treatment as fixed effects and baseline as 
a covariate.
6.11.7. Analyses of Exploratory Objectives
Summary statistics, including number of patients and proportion of categorical outcomes 
(5 levels) for the 5 dimensions (mobility, self-care, usual activity, pain/discomfort, and 
anxiety/depression) of the European Quality of Life – 5 Dimensions 5 Level (EQ-5D-5L) will be 
provided by visit and by treatment. The change from baseline to LOCF endpoint (Week 26, 
Visit 18) in the EQ-5D-5L United Kingdom (UK) population-based health state index score and 
EuroQol visual analog scale (EQ-VAS) score will be analyzed using the ANCOVA model with 
terms same as those for ITSQ analysis described in Section 6.11.6.
For the Work Productivity and Activity Impairment Questionnaire General Health (WPAI-GH), 
the change from baseline to LOCF endpoint in each score (absenteeism, presenteeism, work 
productivity loss, and activity impairment) will be analyzed using the ANCOVA model similar 
to ITSQ.
The proportions of patients with HbA1c <8%, ≤8%, <9% and ≤9% at Week 26 will be 
summarized by treatment.
Within-day and between-day glycemic variability measured by the SD and the coefficient of 
variation (CV) of 10-point SMBG profiles will also be analyzed by MMRM model specified in 
Section 6.11.5.  At a given visit, the CV and SD on each day with a valid SMBG profile will be 
calculated using all the glucose values within that day, then the average values of these CVs and 
SDs will be used as the within-day CV and SD at that visit in analysis.  At a given visit, the CV 
and SD at each of the 10 pre-specified SMBG time points will be calculated using the 
corresponding glucose values of the valid SMBG profiles, then the average values of these CVs 
and SDs will be used as the between-day CV and SD at that visit in analysis.  Table 6.4 lists 
additional variables for potential exploratory analyses.


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Table 6.4
Additional Exploratory Efficacy Variables
Variable Description
Derivation
Statistical Method
Incremental areas under the serum 
glucose concentration-time curve 
from 0 to 30 minutes, 0 to 1 hour, 
0 to 2 hours, 0 to 3 hours, and 0 to 
4 hours after the meal in MMTT.
iAUC+:  the total area under the serum glucose 
curve but above the glucose level at time 0 when the 
meal starts for the MMTT within the specific time 
frame.  The area will be calculated by trapezoids 
rule. 
ANCOVA
Area under/above the serum glucose 
concentration time curve from 0 to 
30 minutes, 0 to 1 hour, 0 to 2 hours, 
0 to 3 hours, and 0 to 4 hours after
the meal in MMTT.

AUC: Total area under the serum glucose 
curve calculated by trapezoids area within 
the specific time frame

AUC>180: Total area under the serum 
glucose curve but above the 180 mg/dL 
level within the specific time frame

AOC≤70: Total area above the serum 
glucose curve but below the 70 mg/dL level 
within the specific time frame.
ANCOVA
Glucose variability during MMTT

The CV of all serum glucose values 
collected during the MMTT

The SD of all serum glucose values 
collected during the MMTT.
ANCOVA
1-hour and 2-hour PPG excursions
by 10-point SMBG profile and daily 
average of the 10-point SMBG 
profile

The difference in means between 1-hour 
PPG and fasting PG at the same visit

The difference in means between 2-hour 
PPG and fasting PG at the same visit.

The average of daily mean of the 10-point 
SMBG profile at the same visit
MMRM
Incidence of HbA1c ≤6.5% and 
<7.0% without severe hypoglycemia

Binary indicator with 1 indicating HbA1c 
≤6.5% at Week 26 and no severe 
hypoglycemia during 0-26 weeks of 
treatment

Binary indicator with 1 indicating HbA1c 
<7% at Week 26 and no severe 
hypoglycemia during 0-26 weeks of 
treatment.
Logistic regression
Abbreviations: ANCOVA = analysis of covariance; AOC = area over the curve; AUC =  area under the curve; 
CV = coefficient of variation; iAUC = incremental area under the curve; HbA1c = hemoglobin A1c;
MMTT = mixed-meal tolerance test; MMRM = mixed-effect model repeated measures; PPG = postprandial 
glucose; SD = standard deviation; SMBG = self-monitored blood glucose.
6.12. Safety Analyses
Safety measures will include AEs, hypoglycemia, vital signs and weight, treatment exposure, 
laboratory measures, and antibodies to insulin lispro. Refer to Table 6.1 and Table 6.2 for the 
analysis population and the baseline definition used in the analysis of a safety measurement for a 
specific study period.


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6.12.1. Extent of Exposure
Duration of exposure to study drug will be summarized. The following summary statistics will 
be provided: n, mean, SD, median, minimum, maximum, and sum (that is, total patient-years of 
exposure). The number and proportion of patients falling into the following different exposure 
categories will also be summarized: <1 month (>0 and <30 days), ≥1 and <3 months (≥30 and 
<90 days), ≥3 and <6 months (≥90 days and <180 days) and ≥6 months (≥180 days). 
Patients who complete the study treatment period are required to complete a safety follow-up 
visit without study drug; and patients who discontinue the IP prematurely are encouraged to 
remain in the study without study drug. The days on study after discontinuing IP, and the days 
on study from date of first study drug to the last study visit date up to Visit 801 will also be 
summarized.
6.12.2. Adverse Events
Analyses of AEs will include 2 sets of analyses, unless otherwise specified.  The first set of 
analyses will include data collected prior to permanent discontinuation of IP.  The second set of 
analyses will include all data collected during the course of the entire study including the follow-
up visit, regardless of IP use.
Events that are newly reported after the first dose of prandial insulin provided as study drug (that 
is, open-label insulin lispro used during the lead-in period or IP used during the treatment period)
or reported to worsen in severity from baseline (defined in Table 6.2 for a specific study period)
will be considered TEAEs.  The MedDRA Lowest Level Term (LLT) will be used in the 
treatment-emergent assessment. The maximum severity for each LLT during the baseline period 
will be used as baseline severity. For events occurring on the day of first dose of bolus insulin 
provided by this study, the case report form (CRF)-collected flag will be used to determine
whether the event started or worsened post-treatment. 
In an overview table, the number and percentage of patients who experienced a TEAE, 
experienced serious adverse event (SAE), died due to an AE, discontinued from study due to an
AE, or discontinued IP due to an AE will be summarized by treatment group .
The number and percentage of patients with TEAEs will be summarized by treatment using 
MedDRA PT nested within SOC. Events will be ordered by decreasing frequency within SOC.
As an additional table, the percentages of patients with TEAEs will be summarized by treatment 
using MedDRA PT (without regard to SOC). Events will be ordered by decreasing frequency.
Statistical comparisons will be applied at both the SOC and PT levels. Fisher’s exact test will be 
performed for treatment comparison.
The number and percentage of patients with TEAEs by maximum severity will be summarized
by treatment using MedDRA PT (regardless of SOC) and data collected prior to permanent 
discontinuation of IP. For each patient and TEAE, the maximum severity for the MedDRA PT is 
the maximum postbaseline severity observed from all associated LLTs mapping to the MedDRA 
PT. No statistical comparison between treatment groups will be conducted.


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The number and percentage of patients with common TEAEs (defined as ≥5% before rounding 
for LY900014-treated patients) will be summarized by treatment group using MedDRA PT 
(without regard to SOC). Events will be ordered by decreasing frequency. Treatment will be 
compared by Fisher’s exact test.
The number and percentage of patients who experienced an SAE including deaths and SAEs 
temporally associated or preceding deaths will be summarized by treatment group using 
MedDRA PT regardless of SOC. Events will be ordered by decreasing frequency. A listing of 
all SAEs will also be provided.
The number and percentage of patients who discontinued from study due to an AE will be 
summarized by treatment group using MedDRA (without regard to SOC) using all data 
regardless of IP use.  The number and percentage of patients who discontinued IP due to an AE 
will be also summarized by treatment group using MedDRA PT (without regard to SOC) using 
data prior to permanent discontinuation of IP.  Events will be ordered by decreasing frequency.  
A listing of all AEs as reason for study or IP discontinuation will also be provided.
The number and percentage of patients who experienced other notable TEAEs (potential 
systemic hypersensitivity reaction, injection site reaction, and hepatic disorder) will be 
summarized by treatment group using all TEAEs regardless of IP use.  For events that are 
gender-specific (as defined by MedDRA), the denominator and computation of the percentage 
will include only patients from the given gender.
Table 6.5 summarizes the planned analyses and the requirement of analysis data for different 
analysis periods. A ‘Yes’ in the IP USE column indicates that only data collected prior to 
permanent discontinuation of IP will be included. 
Table 6.5.
Treatment-Emergent Adverse Event Analysis Periods
Analysis Period
Analysis 
Population
Analysis
IP USE
Treatment
Lead-in Period
All enrolled 
patients
AE overview; TEAE by PT; 
SAE, discontinuation due to 
AE
N/A
Open-label insulin 
lispro
Treatment Period 
(0-26 Weeks)
All patients in 
safety population
AE overview; TEAE by 
SOC and by PT; common 
TEAE; TEAEs by maximum 
severity; SAE; IP 
discontinuation due to AE
Yes
LY900014, 
insulin lispro
Week 0 –
Visit 801
All patients in 
safety population
AE overview; TEAE by 
SOC; common TEAE; SAE; 
other notable AEs; study 
discontinuation due to AE
All data 
regardless of 
IP use
LY900014, 
insulin lispro
Abbreviations:  AE = adverse event; IP = investigational product; N/A = not applicable/available; PT = Preferred 
Term; SAE = serious adverse event; SOC = system organ class; TEAE = treatment-emergent adverse event.


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6.12.3. Deaths
The listing of all deaths by patient for all enrolled patients will be provided as part of the SAE 
listing, regardless of the investigator’s or the sponsor’s judgment about causality. Each listing 
will include study ID, investigator ID, patient ID, treatment group, baseline age, sex, associated 
AE, first and last dose date for open label insulin lispro and randomized IP, and the event date.
6.12.4. Hypoglycemic Events and Other Adverse Events
The analysis plans for the following AEs are discussed in Section 6.12.4.1 through 
Section 6.12.4.4:

hypoglycemic events

systemic hypersensitivity reaction

injection site reaction

hepatobiliary events
All these AE analyses will be similar to the TEAE analyses, refer to Table 6.5 for the 
requirement of analysis data for a specific analysis period. 
6.12.4.1. Hypoglycemic Events
Hypoglycemia events that occur during the study outside the MMTT will be captured using an 
eCOA diary starting from Visit 2 through Visit 801. Whenever hypoglycemia is suspected, the 
patient should record the blood glucose value, any associated symptoms, and the treatment 
administered in eCOA. A set of events is counted as 1 event in analysis if it consists of an 
originating event and subsequent continuing events as marked by the patient in eCOA, or the 
duration between adjacent events is ≤30 minutes.  The event with the highest severity will be 
selected for analysis with severity determined in the order of: 1) it is a severe hypoglycemia, 2) 
it has symptoms of hypoglycemia reported, and 3) it has the lowest blood glucose value.  If there 
are multiple events tied in all 3 aspects, the event with the largest number of non-missing 
responses to the questions of nocturnal hypoglycemia and postmeal time frame will be selected.  
If there are still multiple events tied, the latest event (based on data entry time) will be selected.
The following types of hypoglycemia events will be derived in the analysis data sets: 
documented hypoglycemia, severe hypoglycemia, nocturnal hypoglycemia, probable 
symptomatic hypoglycemia, and overall hypoglycemia. Only severe hypoglycemia will be 
collected as AEs and all episodes of severe hypoglycemia will be considered as SAEs.  
Documented hypoglycemia (including documented symptomatic hypoglycemia, documented 
asymptomatic hypoglycemia and documented unspecified hypoglycemia) will be based on blood 
glucose (BG) ≤70 mg/dL.  In addition, documented clinically significant hypoglycemia with 
similar criterion as above documented hypoglycemia except for the threshold of BG <54 mg/dL 
will be summarized.
Table 6.6 provides detailed statistical methods for each endpoint related to hypoglycemia.  For 
these analyses, hypoglycemia events prior to the discontinuation of IP will be summarized.  


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Additional analyses for other types of hypoglycemic events not mentioned in the table and for 
the post-treatment period may be conducted as needed.
The incidence and number of episodes of hypoglycemia during the MMTT will be summarized 
by treatment and time relative to the meal (≤0.5, ≤1, ≤2, ≤4, >1 to ≤2 and >2 to ≤4 hours after 
start of the meal) and analyzed by Fisher’s exact test.
A listing of patients with at least 1 severe hypoglycemia reported (as SAE) after randomization 
will be provided.
A list of MedDRA PTs will be used for the narrow search of potential severe hypoglycemia in 
spontaneously reported AEs. The events identified through the search strategy that are also 
reported as SAEs will be summarized and compared between treatments. Fisher’s exact test will 
be used to assess the treatment difference in the proportion of patients with potential severe 
hypoglycemia.
Table 6.6.
Summary of Analyses for Endpoints Related to Hypoglycemia
Endpoint
Analysis Period
Statistical Method
Rate of hypoglycemic events (per patient 
per 30 days / year)

All Documenteda

Nocturnala

Documented Symptomatica

Overall

Non-Nocturnal (Documented
and occurred between waking 
and bedtime)a

Probable Symptomatic
0-4, 0-12, 0-26, 4-8, 8-12, 
12-26 weeks
Negative binomial regression with 
treatment, and baseline hypoglycemia
event rate with the same category of the
dependent variable as covariates, log
(exposure/30/365.25 days) as the offset in 
the model.
Incidence of hypoglycemic events

All Documenteda

Nocturnala

Documented Symptomatica

Overall

Non-Nocturnal ( Documented
and occurred between waking 
and bedtime)a

Probable Symptomatic
0-4, 0-12, 0-26, 4-8, 8-12, 
12-26 weeks
Logistic regression with treatment, 
baseline hypoglycemia event rate with the 
same category of the dependent variable as
covariates.
Rate of postmeal hypoglycemic events 
(per patient per 30 days / year) for all 
3 main meals

Documented Symptomatica

Documented Asymptomatica
≤0.5, ≤1, ≤2, ≤4, >1 to≤2 
and >2 to ≤4 hours after 
start of a meal within 
0-12,12-26, 0-26 weeks
Negative binomial regression with 
treatment, baseline postmeal hypoglycemia 
event rate with the same category of the 
dependent variable as covariates, log
(exposure/30/365.25 days) as the offset in 
the model.
Incidence of postmeal hypoglycemic 
events for all 3 main meals

Documented Symptomatica

Documented Asymptomatica
≤0.5, ≤1, ≤2, ≤4, >1 to≤2 
and >2 to ≤4 hours after 
start of a meal within 
0-12,12-26, 0-26 weeks
Logistic regression with treatment, 
baseline postmeal hypoglycemia event rate 
with the same category of the dependent 
variable as covariates.


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Summary of Analyses for Endpoints Related to Hypoglycemia
Endpoint
Analysis Period
Statistical Method
Rate of severe hypoglycemic events (per 
patient per year / 100 years)
0-12, 0-26, 12-26 weeks
Exposure adjusted rate per year / 100 years 
(calculated by total number of events 
divided by total exposure for individual 
patients) will be provided and the empirical 
method (see Appendix 1 for details) will be 
used for treatment comparison.
Incidence of severe hypoglycemic events
0-12, 0-26, 12-26 weeks
Proportion of patients with severe 
hypoglycemia will be reported. The
treatment comparison will be based on a
logistic regression model with treatment
and baseline rate as a covariate.
a
All documented hypoglycemia and the subcategories based on the thresholds of blood glucose ≤70 mg/dL and 
blood glucose <54 mg/dL will be analyzed, except for postmeal hypoglycemia for which only the threshold of 
≤70 mg/dL will be applied. 
6.12.4.2. Systemic Hypersensitivity Reaction
The number and proportion of patients experiencing treatment-emergent potential systemic 
hypersensitivity reactions will be summarized and compared by treatment group using Fisher’s
exact test. The following MedDRA SMQ will be used to identify potential systemic 
hypersensitivity reactions from all TEAEs:

Anaphylactic reaction (SMQ). Besides using the narrow and broad terms 
designated within the SMQ, the following search algorithm will also be 
implemented as another approach to determine if a patient had an anaphylactic 
reaction:  if a patient (had at least 1 event in Category A) or (had at least 1 event 
that is in category B and also had at least 1 event that is in category C) or (had at 
least 1 event that is in category D and [also had at least 1 event in category B or at 
least 1 event in category C])

Angioedema (SMQ)

Hypersensitivity (SMQ)
Specifically, need to perform the following: (1) any narrow or algorithmic term from any 1 of
the 3 SMQs indicated above (that is, combined search across narrow and algorithmic portions of
all 3 SMQs); (2) any narrow scope term within each SMQ, separately (that is, narrow SMQ
search); (3) any term within each SMQ, separately (that is, broad SMQ search); (4) narrow scope
term search within each SMQ, report the PT nested within each SMQ.
A similar summary will be provided for the TEAE related to study drug judged by investigator.
Note that an individual patient may contribute multiple events. Also, a single event may satisfy
multiple SMQs, in which case the event contributes to every applicable SMQ.


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6.12.4.3. Injection Site Reaction
The injection site reactions will be searched by MedDRA PTs from all TEAEs. The number and 
percentage of patients experiencing treatment-emergent injection site reaction will be
summarized and compared by treatment group using Fisher’s exact test.
For injection site reactions identified by MedDRA PTs, the presence and severity of erythema, 
induration, pain, pruritus and edema (collected on the eCRF) will be summarized for each 
treatment. There will be no statistical comparison between treatments. 
6.12.4.4. Hepatobiliary Events
6.12.4.4.1.
Treatment-Emergent Potential Hepatic Disorder
The percentages of patients with treatment-emergent drug-related hepatic disorder events will be 
summarized and compared by treatment group using MedDRA PT nested within each SMQ
ordered by decreasing frequency. The following SMQs based on MedDRA will be used to
identify potential hepatic disorders:

broad and narrow terms in the Liver related investigations, signs and symptoms 
SMQ (20000008)

broad and narrow terms in the Cholestasis and jaundice of hepatic origin SMQ 
(20000009)

broad and narrow terms in the Hepatitis non-infections SMQ (20000010)

broad and narrow terms in the Hepatic failure, fibrosis and cirrhosis and other
liver damage SMQ (20000013)

narrow terms in the Liver-related coagulation and bleeding disturbances SMQ
(20000015)
The percentage of patients with any 1 of the terms will be summarized in addition to the 
percentages for each MedDRA PT. The percentages of patients with potentially drug-related
hepatic disorders that led to permanent study treatment discontinuation will be summarized
similarly.
6.12.4.4.2.
Liver Enzyme Lab Values
The liver enzyme measures (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
alkaline phosphatase [ALP], direct bilirubin, total bilirubin) will be summarized by treatment
group. Post-baseline value and the change from baseline (last nonmissing value before 
randomization) to post-baseline value at Week 26 visit (planned test) will be summarized for 
patients who have both a baseline and at least 1 postbaseline result, and compared between 
treatment groups by using ANCOVA model with the term of treatment and baseline value of the 
response variable. All analyses will be provided in both SI and CN units.
The last nonmissing observation at or prior to Week 26 (including early discontinuation visits) 
will also be analyzed by an ANCOVA model with the term of treatment, baseline value of 
response variable. 


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6.12.4.4.3.
Treatment-Emergent Elevation of Liver Enzyme Lab Values
The percentages of patients with the following elevations in hepatic laboratory tests at any time 
during the treatment period (0 to 26 weeks) will be summarized between treatment groups:

The percentages of patients with post-baseline ALT measurement ≥3 times (3X), 
5 times (5X), and 10 times (10X) the Covance upper limit of normal (ULN) will 
be summarized for all patients with a post-baseline value by the following 
baseline categories: ≤1X, >1X to <3X, ≥3X, missing.

The percentages of patients with post-baseline AST measurement greater than or 
equal to 3 3X, 5X, and 10X the Covance ULN will be summarized for all patients 
with a post-baseline value by the following baseline categories: ≤1X, >1X to 
<3X, ≥3X, missing.

The percentages of patients with post-baseline total bilirubin measurement
≥2 times (2X) the Covance ULN will be summarized for all patients with a post-
baseline value by the following baseline categories: ≤1X, >1X to <2X, ≥2X, 
missing.
Baseline will be the maximum observation in the baseline period including the lead-in period. 
The maximum value will be the maximum value from the treatment period. Planned and 
unplanned tests will be included.
Graphical profiles of ALT, AST, total bilirubin, and ALP will be provided for patients with an 
ALT or AST ≥3X ULN or total bilirubin ≥2X ULN during the treatment period. A listing for 
these patients will also be provided, including the actual measurement of ALT, AST, ALP, and 
total bilirubin, the corresponding reference high limits, demographics, disposition, drug exposure 
and AEs. The review for these patients includes an assessment of the proximity of any ALT or 
AST elevation to any total bilirubin elevation, ALP levels, other potential causes, and the 
temporal association with events such as nausea, vomiting, anorexia, abdominal pain, or fatigue.
All patient data, regardless of whether on IP, will be used for the above analyses related to 
hepatobiliary events.
6.12.5. Clinical Laboratory Evaluation
The data from safety laboratory measures will be summarized at Week 26 where the lab test is 
planned to be collected. Postbaseline and change from baseline to postbaseline for laboratory 
tests will be summarized for patients who have both baseline and at least 1 post-baseline result 
and compared between treatment groups by using ANCOVA model with the term of treatment 
and baseline value of the response variable. Analyses will be provided in both SI and CN units.
The last nonmissing observation at or prior to Week 26 (planned tests including early 
termination) will also be analyzed by an ANCOVA model with the term of treatment, baseline 
value of the response variable. 
The percentages of patients with treatment-emergent abnormal, high, or low laboratory results at 
any time during the treatment period (0 to 26 weeks) will be summarized for patients who have 
both baseline and at least 1 post-baseline result and compared between treatment groups using 


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Fisher’s exact tests. A treatment-emergent abnormal result is defined as a change from normal at 
all baseline visits to abnormal at any time during the treatment period. A treatment-emergent 
high result is defined as a change from a value less than or equal to the high limit at all baseline 
visits to a value greater than the high limit at any time during the treatment period. A treatment-
emergent low result is defined as a change from a value greater than or equal to the low limit at 
all baseline visits to a value less than the low limit at any time during the treatment period. 
Planned and unplanned measurements will be included. Covance reference ranges will generally 
be used to define the low and high limits. Only patients who have normal baseline values for the 
analysis being performed will be included in the analysis for treatment-emergence.  
Liver enzymes measures will not be included in the above analyses as different analyses will be 
used as described in Section 6.12.4.4.2 and Section 6.12.4.4.3.
6.12.6. Vital Signs and Other Physical Findings
Post-baseline measurements and change from baseline to post-baseline for vital signs and 
physical characteristics (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse
rate, weight, BMI) at the scheduled visits will be summarized for patients who have both
baseline and at least 1 post-baseline result. 
The measurements during the treatment period (0 to 26 weeks) will be analyzed by an MMRM 
model with treatment, baseline value of the response variable, visit, and visit by treatment 
interaction as fixed factors and patient as the random factor.
The weight measurement during the lead-in period will also be analyzed by an MMRM model 
with Visit 2 value of the response variable, randomized treatment, visit and treatment-by-visit 
interaction as fixed factors, and patient as the random factor.  The analysis will be conducted on 
all randomized patients.
An ANCOVA model will also be used for the analysis of the last nonmissing observation 
(including early discontinuation visit) during the treatment period and during the entire study (up 
to Visit 801). The ANCOVA models are the same as those used for clinical laboratory measures. 
Change from the minimum value during the baseline period to the minimum value during the 
treatment period (0 to 26 weeks) for vital signs and physical characteristics will be summarized 
for patients who have both baseline and at least 1 post-baseline result. Baseline will be the 
minimum of nonmissing observations in the baseline period. The minimum value in the 
treatment period will be analyzed. Similarly, change from the maximum value during the 
baseline period to the maximum value during the treatment period (0 to 26 weeks) for vital signs 
and physical characteristics will be summarized for patients who have both baseline and at least 
1 post-baseline result. Baseline will be the maximum of nonmissing observations in the baseline 
period. The maximum value in the treatment period will be analyzed. 
The percentages of patients with treatment-emergent high or low vital signs and weight at any 
time during the treatment period (0 to 26 weeks) or during the entire study including safety 
follow-up period will be summarized by treatment group for patients who have both baseline and 
at least 1 postbaseline measurement. A treatment-emergent high result is defined as a change 


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from a value less than or equal to the high limit at all baseline visits to a value greater than the 
high limit at any time that meets the specified change criteria during the treatment period or 
during the entire study including safety follow-up period. A treatment-emergent low result is 
defined as a change from a value greater than or equal to the low limit at all baseline visits to a 
value less than the low limit at any time that meets the specified change criteria during the 
treatment period or during the entire study including safety follow-up period. Treatment 
comparison will be based on Fisher’s exact test.  Table 6.7 will be used to define the low and 
high limits and change thresholds. 
Table 6.7.
Categorical Criteria for Abnormal Treatment-Emergent Blood 
Pressure and Pulse Measurement, and Categorical Criteria for
Weight for Adults
Parameter
Low
High
Systolic BP (mm Hg)
(Supine or sitting – forearm 
at heart level)
≤90 and decrease from baseline ≥20
≥140 and increase from baseline ≥20
Diastolic BP (mm Hg)
(Supine or sitting – forearm 
at heart level)
≤50 and decrease from baseline ≥10
≥90 and increase from baseline ≥10
Pulse (bpm)
(Supine or sitting)
<50 and decrease from baseline ≥15
>100 and increase from baseline ≥15
Weight (kg)
(Consistent clothing and
timing in relationship to
meals and voiding)
(Loss) decrease ≥7%
(Gain) increase ≥7%
Abbreviations: BP = blood pressure.
6.12.7. Immunogenicity
Blood samples for immunogenicity testing will be collected to determine antibody production 
against insulin lispro for all enrolled patients since Visit 2 prior to the first dose of study-
provided prandial insulin treatment. Therefore, the blood sample result at Visit 2 will be 
considered as the anti-insulin lispro level at baseline for this study.
Patients who complete the 4-week safety follow-up visit (Visit 801) and have treatment-
emergent anti-insulin lispro antibodies that have not returned to prespecified baseline range 
(Visit 2) will be asked to participate in follow-up to monitor antibody levels. The assessment of 
immunogenicity will include analyses of treatment-emergent anti-insulin lispro antibody up to 
Visit 801 and analyses of anti-insulin lispro antibody return to baseline during the insulin lispro 
antibody safety follow-up period.
6.12.7.1. Treatment Emergent Anti-Insulin Lispro Antibody
The treatment-emergent anti-insulin lispro antibody (denoted as treatment-emergent antidrug 
antibody [TEADA] throughout this SAP) is based on the change from baseline (Visit 2) to post-
baseline (post-Visit 2) in the anti-insulin lispro antibody level (percent binding). Treatment-
emergent antidrug antibody can be sub-classified as either treatment-induced (not detected anti-


 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
   
 
  
   
 
 
 
   
  
 
  
 
   
 
 
 
   
 
 
 
  
  
 
 
 
 
  
 
 
   
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
  
  
 
 
 
 
 
 
  
 
   
  
  
  
  
 
  
  
 
  
  
 
 
 
 
  
  
 
 
 
  
 
 
 
    
 
 
 
  
 
 
  
  
 
 
   
  
 
 
 
 
 
  
 
 
 
 
  
 
  
  
 
 
 
 
 
   
 
 
  
  
 
  
 
 
   
 
 
 
 
 
  
 
  
 
 
   
   
 
 
    
    
  
 
 
 
  
 
 
   
 
 
  
 
 
  
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
   
 
 
  
 
 
  
  
 
 
 
  
 
  
   
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
  
  
 
 
  
 
  
 
  
 
   
 
   
 
 
  
 
 


 
 
 
 
 
 
   
  
 
 
 
  
 
  
 
 
  
 
  
 
  
 
  
 
 
 
 
  
   
 
 
   
 
  
 
  
 
  
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
  
 
  
 
 
 
 
  
 
  
 
 
  
 
  
 
  
 
  
 
 
  
  
 
 
  
  
 
 
 
 
 
  
 
 
  
 
 
 
    
  
   
 
 
 
 
 
  
 
 
 
  
 
  
 
 
  
   
 
  
 
 
 
  
 
 
 
  
  
  
 
 
 
 
 
 
  
 
  
 
  
 
    
 
  
 
 
 
 
  
 
 
  
 
  
  
 
 
 
 
  
 
 
 
  
    
  
 
  
 
  
  
  
 
 
  
  
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
  
  
  
 
 
 
 
  
 
 
 
  
  
 
  
  
 
 
 
  
 
 
 
 
 
 
 
  
   
 
 
   
 
 
  
  
   
  
  
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
  
 
 
  
  
 
 
 
 
 
 
  
 
 
  
  
 
   


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For the patients participating in the insulin antibody follow up, a summary of HbA1c, the insulin 
dose (prandial, basal, and total daily insulin dose), vital signs, body weight, AEs, and 
concomitant medications reported during the immunogenicity follow-up period will be 
summarized by randomized treatment group.  The summary will include descriptive statistics 
and no statistical test will be performed for treatment comparison.
A scatter plot using the antibody percent binding at the last visit in the immunogenicity follow-
up period as X-axis and the HbA1c value at the same visit as Y-axis will be generated.  A similar 
scatter plot with total daily dose as Y-axis will also be generated. 
6.12.8. Patient Narratives
Patient narratives will be provided for all patients in the study who experience any of the
following “notable” events prior to data cutoff for the submission:

deaths

serious adverse events

discontinuations from study (or study drug) due to AEs

pregnancy
A list of patients who meet the criteria for narratives will be provided.
6.13. Subgroup Analyses
6.13.1. Subgroup Analyses for HbA1c
The following subgroups will be analyzed for HbA1c if there are sufficient numbers of patients 
per group (for example, at least 10% in each group):

age (<65 versus ≥65 years and <75 vs. ≥75 years and <65, ≥65 to <75, ≥75 to 
<85, ≥85 years)

hemoglobin A1c stratum (≤8% vs. >8%)

sex (male vs. female)

body mass index (<25 vs. ≥25, and <30 vs. ≥30 kg/m2 and <35 vs. ≥35 kg/m2)

duration of diabetes (using the median as the cut-off)

race

ethnicity

country

region

baseline 1-hour PPG excursion (≤ baseline median, > baseline median)

baseline 1-hour PPG (PPG ≤180 mg/dl, >180 mg/dl)


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
baseline 2-hour PPG excursion (≤ baseline median, > baseline median)

baseline 2-hour PPG (PPG ≤180 mg/dl, >180 mg/dl)

type of basal insulin during the lead-in period (glargine vs. degludec)

prandial insulin dosing plan (carbohydrate counting or pattern adjustment)

number of prandial doses at study entry (<3 vs. ≥3)

sodium-glucose co-transporter 2 inhibitor treatment
Analyses for HbA1c and change from baseline in HbA1c will be performed using an MMRM 
model that includes the same fixed effects given for the primary analysis model plus factors of 
subgroup, 2-way interaction of subgroup and treatment, 2-way interaction of subgroup and visit, 
and 3-way interaction of treatment, visit and subgroup. The interaction of subgroup and 
treatment at the primary endpoint will be evaluated to assess the treatment by subgroup 
interaction. When analyzing HbA1c stratum as a subgroup the baseline HbA1c will be not be 
included as a covariate to avoid confounding. The subgroup interaction effect will be evaluated 
using a significance level of 0.10, unadjusted.
Additional subgroup analyses may also be performed.
6.13.2. Subgroup Analyses for Hypoglycemic Events
For the documented symptomatic hypoglycemia based on the thresholds of blood glucose 
≤70 mg/dL, the following subgroups will be analyzed:

age (<65 vs. ≥65 years and <75 vs. ≥75 years and <65, ≥65 to <75, ≥75 to <85, 
≥85 years)

hemoglobin A1c stratum (≤8% vs. >8%)

region (Europe, North America, Eastern Asia [Japan, Taiwan, Korea], and other 
[India, Mexico, Argentina, Australia])

type of basal insulin during the lead-in period (glargine U-100 vs. degludec 
U-100)

prandial insulin dosing plan (carbohydrate counting or pattern adjustment)
The event rate and incidence will be analyzed using the same model specified in Table 6.6 with 
the addition of factors for subgroup, and 2-way interaction of subgroup and treatment.  The 
2-way interaction will be used to evaluate treatment by subgroup interaction.
6.14. Interim Analyses and Data Monitoring 
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.


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6.15. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset which will be converted to an XML file. Both 
Serious Adverse Events and ‘Other’ Non-Serious Adverse Events are summarized by 
treatment group and MedDRA PT.

An AE is considered ‘Serious’ whether or not it is a TEAE.

An AE is considered in the ‘Other’ category if it is both a TEAE and is not serious.  For 
each Serious AE and ‘Other’ AE, for each term and treatment group, the following are 
provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

For each Serious AE, these additional terms are provided for EudraCT:
o
the total number of occurrences causally related to treatment
o
the total number of deaths
o
the total number of deaths causally related to treatment.  

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may be excluded if a 5% threshold 
is chosen.  Allowable thresholds include 0% (all events), 1%, 2%, 3%, 4%, and 5%.  

Adverse event reporting is consistent with other document disclosures for example, the 
CSR, manuscripts, and so forth. 


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7.
Unblinding Plan
The blinding and unblinding plan will be provided in a separate document stored in the Trial 
Master File. 


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8.
References
Bretz F, Posch M, Glimm E, Klinglmueller F, Maurer W, Rohmeyer K. Graphical approaches for 
multiple comparison procedures using weighted Bonferroni, Simes, or parametric tests. Biom 
J. 2011;53(6):894-913.
Compuational Science Symposium Development of Standard Scripts and Programming Working 
Group. Analyses and Displays Associated with Measures of Central Tendency. Focus on vital 
Sign, Electrocardiogram, and Laboratory Analyte Measuremenets in Phase2-4 clinical Trials 
and Integrated Submission Documents. October 2013. Available at:  
http://www.phusewiki.org/docs/CSS%20White%20Papers%202016/CSS_WhitePaper_Central
Tendency_v1.0.pdf. Accessed March 21, 2018.
Liu GF, Lu K, Mogg R, Mallick M, Mehrotra DV. Should baseline be a covariate or dependent 
variable in analyses of change from baseline in clinical trials? Stat Med. 2009;28(20):2509-
2530.
Lu K. On efficiency of constrained longitudinal data analysis versus longitudinal analysis of 
covariance. Biometrics. 2010;66(3):891-896.
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat. 2013;12(6):337-347.


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9.
Appendices


 
 
 
 
  
  
 
   
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
   
  
 
 
 
 
    
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
    


 
 
 
 
  
  
 
 
 
 
 
 
 
 
 


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Appendix 2.
Statistical Analysis for Japan
Separate analyses will be performed for patients participating in Study ITRN from Japan based 
on 2 databases from:
1) Global database: the global database lock which will occur after all global cohort 
patients have completed Visit 801.
2) Japan database: the database lock which will occur after all Japanese patients who are 
enrolled into both global and MEE cohorts have completed Visit 801.  
The analysis methods will be similar to those described for the main study.  Statistical 
comparisons between treatment groups will be performed.  Analysis models similar to the main 
study will be used without the model term for pooled country. 
The analyses to be included will be documented in a separate list of analyses.