Conditions: Influenza
Keywords: Tamiflu® Influenza Oseltamivir Flu S-033188
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2184
Healthy volunteers: no

Brief summary:
The primary objective of this study is to evaluate the efficacy of a single, oral dose of baloxavir marboxil compared with placebo by measuring the time to improvement of influenza symptoms in patients with influenza presenting within 48 hours of symptom onset.

Detailed description:

Arms:
arm 1: Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of \< 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. arm 2: Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1. arm 3: Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.

Interventions: intervention 1: Baloxavir Marboxil intervention 2: Placebo to Baloxavir Marboxil intervention 3: Oseltamivir intervention 4: Placebo to Oseltamivir
Intervention descriptions: intervention 1: Tablets taken orally intervention 2: Matching tablets taken orally intervention 3: Capsules taken orally intervention 4: Matching placebo capsules taken orally

Protocol document:
Prot_002.pdf: 
 
Shionogi Study Title:  
A Phase 3, Multicenter, Randomized, Double-blind 
Study of a Single Dose of S-033188 Compared with 
Placebo or Oseltamivir 75 mg Twice Daily for 5 Days in 
Patients with Influenza at High Risk of Influenza 
Complications 
Shionogi Study Number: 
1602T0832 
ClinicalTrials.gov 
Registration No. 
NCT02949011  
Study Document 
Protocol Version 3 (Amendment 2) 
 
History of Protocol Amendments 
Version 1 (Original) 
05 August 2016 
This version of the protocol was not used to conduct the study 
Version 2 
16 September 2016 
This version of the protocol was not used to conduct the study 
Version 3 
31 October 2016 
 




 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
  
 
 
   
 
  
   
   
   
  
   
   
   
  
   
    
  
               
  
  
   
     
  
    
    
  
    
       
 
  
     
    
 
    
    
  
 
  
 
  
      
  
  
    
  
  
 
    
    
   
    
  
 
      
      
    
        
   
  
         
  
  
    
 
  
      
  
          
    
     
  
  
      
  
    
     
 
  
    
  
    
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
 
  
 
 
   
  
  
  
    
     
 
    
    
      
  
        
   
        
 
 
  
 
 
  
  
  
  
 
    
    
     
       
  
    
 
  
       
   
  
   
   
 
  
  
 
    
    
     
       
  
   
      
    
         
      
   
  
   
    
 
    
    
     
       
  
    
 
  
    
  
   
    
 
    
    
     
       
  
   
               
    
  
  
    
 
  
  
 
    
    
   
  
    
  
  
  
  
          
   
   
    
  
 
    
    
    
    
     
    
  
    
    
    
    
     
   
             
    
    
   
  
   
    
    
 
   
    
                 
 
  
 
    
   
     
     
    
 
  
    
    
 
  
  
  
  
 
    
      
  
    
     
 
       
  
  
  
  
     
  
    
            
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
  
 
    
  
  
 
  
   
  
  
 
    
  
    
 
  
         
   
       
  
 
             
  
    
        
    
 
      
    
    
        
    
      
      
  
    
  
       
  
  
  
 
    
    
    
    
   
 
  
  
  
  
 
  
   
  
     
     
     
     
 
     
      
  
  
  
  
  
 
     
      
  
  
  
  
  
 
  
 
  
  
  
  
 
       
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
  
 
      
  
  
  
  
  
 
 
  
  
  
  
 
  
   
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
  
 
      
  
  
  
  
  
 
           
   
   
            
  
  
   
    
      
       
 
  
 
   
  
            
   
   
      
  
  
  
  
    
   
    
   
       
    
    
  
    
  
  
  
 
   
  
  
  
    
    
 
 
 
    
        
  
      
     
 
  
        
    
  
  
  
  
     
     
  
    
  
  
 
   
  
  
    
   
   
  
    
    
      
  
              
    
 
  
  
  
     
   
  
  
         
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
  
      
  
    
  
      
   
   
       
 
            
  
    
  
  
 
  
  
        
    
        
     
  
   
     
   
  
 
  
  
  
  
    
  
       
  
 
  
  
  
    
     
 
      
  
       
      
  
 
     
          
   
   
 
  
        
     
    
         
    
 
  
  
    
  
        
    
 
 
     
   
  
  
      
  
  
  
     
           
   
   
  
    
  
 
  
  
      
     
   
  
      
          
  
  
 
  
    
    
  
   
  
  
 
    
  
 
  
  
  
  
  
 
  
   
    
    
  
 
  
  
  
  
  
  
 
 
  
       
    
    
  
  
 
  
 
    
  
       
 
    
  
       
 
 
   
  
  
  
    
  
    
  
    
    
  
  
 
  
  
  
  
    
    
 
  
  
  
   
    
  
    
   
  
  
  
  
  
     
  
 
  
         
  
  
    
  
 
  
  
  
   
    
  
  
  
     
  
  
    
 
 
  
  
  
    
     
  
      
   
  
        
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
   
       
      
  
  
 
 
         
  
      
      
 
  
    
  
    
  
  
  
  
  
    
  
   
  
  
 
  
   
  
    
  
  
      
  
  
  
  
  
       
  
        
    
    
        
  
  
  
  
      
  
       
  
      
  
    
  
  
     
  
      
         
   
       
 
 
 
  
  
   
   
  
  
   
          
    
  
   
  
      
  
    
  
 
 
    
 
  
    
  
     
  
  
  
 
  
  
  
      
  
    
  
  
  
    
  
         
  
    
  
  
    
    
    
    
       
 
   
        
  
 
   
  
  
      
  
  
  
  
       
    
     
  
 
  
  
      
  
  
  
  
 
  
    
  
           
 
  
  
      
   
  
  
      
         
  
    
  
  
     
      
   
  
  
       
     
  
    
   
   
  
  
 
    
  
  
  
    
  
 
  
   
    
  
   
   
        
        
    
   
         
        
     
    
  
         
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
  
    
  
    
  
 
 
   
    
   
   
         
      
   
   
  
     
        
    
   
  
     
        
  
  
   
    
  
   
   
  
    
        
     
   
  
     
        
     
    
  
         
   
 
    
  
  
 
       
  
   
  
    
  
  
      
                        
 
  
  
  
  
  
  
      
    
    
  
    
  
  
 
 
    
  
 
 
  
  
 
  
  
    
 
  
    
 
 
  
  
  
   
  
  
    
   
    
 
  
 
  
 
   
      
   
   
  
     
  
       
   
  
      
    
                
   
  
  
      
   
  
  
      
 
  
 
 
 
  
  
  
           
   
  
 
  
    
  
  
  
 
 
   
  
          
   
  
   
        
 
    
            
     
    
 
 
 
  
    
            
      
 
 
   
     
            
 
 
   
  
  
      
        
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
 
   
    
  
    
  
    
 
   
  
          
 
 
   
      
  
  
 
 
 
    
 
 
   
      
  
  
    
 
 
  
 
 
   
    
 
   
  
  
  
        
 
  
        
 
   
     
  
 
 
   
   
  
  
 
 
    
  
    
  
   
 
 
 
  
  
 
  
  
 
 
  
    
  
  
 
 
  
      
   
 
 
 
  
  
   
 
   
  
    
        
 
  
   
    
   
 
  
  
 
  
 
 
  
 
  
 
   
  
  
  
       
  
 
 
  
    
  
   
  
 
    
   
  
 
  
  
      
 
  
               
  
  
        
 
      
  
           
              
  
 
 
  
  
  
   
  
    
     
    
  
  
  
     
    
    
   
     
    
  
    
  
  
      
 
    
  
        
  
  
  
  
  
 
  
  
  
      
      
  
      
   
  
    
  
    
     
  
  
      
  
  
   
 
    
  
   
    
   
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
     
    
  
      
      
  
     
 
   
   
        
  
     
      
           
    
  
  
  
  
    
  
 
  
   
  
  
      
      
    
  
    
  
  
    
  
     
  
         
  
  
  
      
 
  
    
      
    
  
     
  
   
     
    
  
   
         
      
  
  
   
  
 
  
  
  
 
  
  
  
      
     
  
  
 
  
  
  
    
    
  
   
   
      
  
    
  
 
     
      
   
    
   
        
      
  
    
  
    
   
        
    
  
 
    
        
  
  
  
  
   
  
  
  
  
  
 
  
    
    
             
   
  
  
       
  
    
  
   
      
     
             
  
  
  
  
   
  
     
  
  
      
 
 
   
    
   
   
 
    
    
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
 
 
  
    
 
  
    
  
 
  
    
  
 
  
   
  
 
    
 
  
 
 
  
 
  
 
  
 
 
  
 
 
  
 
  
 
  
 
  
 
    
  
  
 
  
 
 
    
  
  
  
  
   
 
  
  
  
  
  
  
    
 
  
  
    
  
  
    
 
  
  
  
 
  
 
  
    
  
 
 
 
  
 
   
  
 
  
  
    
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
    
  
 
  
 
 
 
  
 
  
  
 
  
 
  
  
 
  
 
  
  
 
  
 
  
 
  
 
  
 
  
 
  
  
  
  
 
  
 
  
 
  
 
  
  
     
  
 
    
  
    
    
  
  
  
 
  
  
 
  
 
  
       
 
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
  
 
  
 
  
   
  
 
  
 
  
  
      
 
  
 
  
  
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
 
 
  
 
   
 
  
 
   
  
 
 
  
 
  
 
  
 
     
 
  
 
    
          
 
  
 
   
  
   
  
 
 
 
 
 
 
 
 
    
 
  
 
   
 
  
 
  
  
   
   
  
 
  
 
  
 
 
 
 
 
  
 
  
 
  
  
    
 
  
 
  
  
 
  
 
  
 
  
 
  
 
  
 
  
 
 
  
 
 
  
  
   
 
  
 
  
 
  
 
  
  
    
  
 
  
 
  
  
    
 
  
 
 
 
 
 
     
    
  
   
  
 
  
 
  
 
  
  
 
  
 
  
  
 
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
   
   
  
 
  
 
   
 
  
 
 
  
 
   
  
 
  
   
  
 
  
 
  
 
  
 
  
 
  
 
  
 
   
 
  
 
 
  
 
  
 
  
 
  
 
  
 
  
   
  
 
   
  
 
    
  
 
  
  
    
 
  
 
  
  
 
  
 
  
  
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
  
 
  
  
   
  
    
 
 
 
  
 
  
  
 
  
 
  
  
 
  
 
  
   
  
  
   
 
 
 
 
 
 
  
 
  
 
  
 
  
  
     
  
 
   
  
    
    
 
  
  
      
 
  
 
  
  
 
  
 
 
  
 
  
  
 
 
 
 
    
      
    
  
 
 
 
 
  
      
 
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
  
 
  
 
  
  
 
  
 
  
  
 
  
 
 
  
 
  
 
  
 
   
 
  
 
    
 
  
 
  
 
  
 
  
     
   
  
 
 
  
 
  
 
 
 
  
 
   
   
  
 
  
 
  
 
   
   
  
 
  
 
  
 
    
 
 
  
 
   
    
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
  
  
 
  
 
  
  
 
  
 
   
  
 
  
 
   
 
  
 
   
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
  
 
  
 
 
  
 
  
 
  
 
  
 
  
 
  
  
   
  
 
   
  
    
  
    
  
 
  
  
      
 
  
 
  
  
 
  
 




 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
 
 
 
   
 
  
 
 
  
   
  
  
   
 
 
 
 
 
  
   
    
  
  
   
  
 
  
 
 
  
   
    
  
  
 
 
 
 
 
  
 
  
 
 
  
   
  
 
 
    
      
   
 
 
 
  
 
 
    
    
  
  
   
 
   
   
  
  
 
 
  
   
  
  
   
 
 
 
 
    
  
 
 
 
  
 
  
 
 
     
   
  
   
 
   
          
    
  
 
  
       
   
 
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
 
    
 
  
  
    
     
  
 
 
  
 
 
 
 
 
 
 
  
   
 
 
  
  
 
 
 
 
  
    
 
  
 
   
  
    
 
  
  
     
   
  
   
  
    
 
  
         
       
  
    
  
 
 
 
  
  
  
  
 
 
  
 
 
 
    
 
 
       
 
 
    
 
 
  
    
  
 
 
   
  
    
  
 
  
 
 
  
 
 
  
  
 
  
  
  
  
 
 
  
 
 
  
  
 
 
  
 
 
 
    
 
 
    
  
  
  
  
 
 
 
  
    
   
 
   
 
 
  
  
 
 
 
 
 
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
     
 
 
  
 
 
  
      
             
  
  
 
 
  
 
 
  
  
 
 
 
  
 
 
 
  
 
 
  
    
  
   
 
 
  
  
  
   
   
 
  
  
  
 
 
 
   
  
  
  
   
  
  
 
 
  
  
 
 
      
 
  
   
 
  
  
 
 
  
  
  
 
 
 
  
  
 
  
 
 
  
 
  
    
  
  
 
 
  
 
  
   
  
      
  
 
  
  
  
 
  
  
    
  
 
 
    
 
   
  
  
 
 
 
 
  
 
   
  
  
  
   
  
  
  
 
  
  
  
  
 
 
  
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
 
 
 
 
 
 
  
 
   
  
  
  
          
  
 
  
  
  
    
  
  
  
  
  
  
 
  
    
 
  
  
 
 
  
   
 
  
 
  
    
 
 
  
  
  
  
  
 
 
  
  
  
 
 
 
  
  
  
   
  
  
  
  
 
 
 
 
     
 
 
  
 
 
  
  
 
  
  
    
 
   
  
  
    
 
  
   
  
 
 
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
 
       
  
  
      
  
  
  
 
  
  
  
    
     
    
  
     
  
  
  
  
       
 
           
      
  
     
 
     
    
           
  
  
  
   
      
  
     
         
  
 
    
  
   
  
  
      
   
       
  
         
 
   
         
   
       
  
   
  
    
  
         
       
 
  
  
   
  
  
  
  
   
      
    
 
  
  
    
    
  
    
 
        
  
  
      
  
 
     
    
  
  
  
   
  
  
     
  
   
    
  
    
    
  
    
  
    
 
       
      
    
    
   
           
   
  
     
      
 
  
    
  
    
          
    
  
   
    
    
   
  
  
 
    
   
  
    
  
    
      
   
    
  
        
       
   
    
  
     
  
      
    
 
  
        
  
  
  
     
     
         
            
   
   
  
  
    
    
  
     
    
        
        
  
  
      
  
        
  
      
 
    
  
    
    
     
  
 
  
  
  
  
  
  
  
 
  
        
 
    
  
  
  
   
    
  
  
  
     
   
    
      
  
        
    
 
    
  
  
  
    
   
  
  
  
    
      
    
     
   
    
     
  
    
       
  
   
  
   
  
        
    
  
    
  
   
    
     
         
  
   
   
  
 
















 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
  
 
  
  
  
    
 
 
  
 
  
   
  
  
      
  
 
  
     
  
   
       
             
       
  
   
  
   
  
  
     
   
 
    
  
  
  
  
    
 
     
  
   
    
    
  
 
  
 
  
  
    
   
  
    
    
  
    
   
   
  
  
    
  
  
 
  
   
        
        
   
   
   
  
   
   
    
  
        
    
   
  
   
  
      
  
  
  
  
        
     
  
  
  
    
   
  
  
 
  
 
  
  
  
      
  
 
   
   
    
  
   
    
  
 
   
    
  
      
        
 
  
    
  
      
  
  
    
    
   
   
      
  
  
  
  
 
      
      
   
  
  
  
 
    
    
    
  
         
     
   
   
    
        
  
  
 
      
  
  
  
  
    
 
  
     
  
    
     
  
    
 
        
     
  
    
        
  
 
    
  
  
        
      
   
  
     
   
            
   
  
  
  
        
  
    
     
  
    
  
  
  
  
 
  
  
  
    
  
  
 
 
      
  
 
  
   
 
  
  
    
     
  
    
    
 
  
  
  
    
  
  
  
  
 
  
    
  
    
  
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
  
  
  
 
  
 
 
  
    
  
  
  
  
 
  
  
     
  
  
  
 
  
  
  
      
    
  
  
 
  
 
 
  
  
 
  
  
  
  
  
 
  
 
  
  
  
  
 
  
   
  
    
    
 
  
  
    
  
     
      
     
 
 
  
  
  
  
  
  
      
   
           
  
      
       
 
       
  
  
    
   
   
  
  
    
  
  
  
 
  
    
  
  
    
  
  
 
  
     
  
  
  
    
  
  
    
  
  
  
  
    
 
   
  
    
  
  
  
   
        
    
  
       
    
  
    
    
 
  
 
  
         
  
   
   
 
                      
          
                     
  
       
  
  
    
  
 
         
    
     
  
 
      
      
    
      
   
   
  
   
    
      
    
            
 
    
    
  
  
  
    
  
  
   
  
  
  
  
   
  
 
  
    
          
  
  
   
    
 
  
  
  
 
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
 
 
   
  
  
 
  
  
     
   
 
  
    
     
       
  
    
 
  
       
   
  
   
   
 
 
  
  
  
 
  
  
     
   
 
  
    
     
       
  
   
               
       
  
  
   
    
 
    
    
     
       
  
    
 
  
    
  
   
    
 
    
    
     
       
  
   
               
    
  
  
    
 
 
   
  
  
 
    
  
     
   
   
    
   
  
    
  
  
  
  
          
   
   
   
 
  
  
 
    
    
    
    
     
    
  
 
  
    
    
    
     
   
             
    
    
   
  
   
    
    
 
   
    
                 
 
 
 
  
 
    
     
   
 
  
         
     
    
   
 
  
    
 
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
  
  
  
 
    
      
  
    
   
       
   
   
  
     
  
    
 
             
 
 








 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
  
  
  
   
  
  
     
 
   
  
  
  
   
    
    
    
     
      
  
 
  
     
  
       
  
  
   
     
  
   
  
  
     
  
  
   
       
  
             
    
     
    
  
  
      
    
  
     
   
     
  
  
   
    
  
    
        
 
   
  
    
  
  
 
  
  
    
  
  
  
       
 
       
    
    
         
 
    
  
    
  
    
  
  
  
  
        
  
    
        
     
  
    
   
      
     
    
  
   
      
  
      
   
  
  
  
   
   
    
 
      
    
    
       
      
 
  
   
        
  
    
 
  
  
      
     
   
    
   
   
  
     
   
  
     
    
    
  
  
      
       
 
 
  
      
       
      
   
  
  
     
       
    
 
  
     
  
   
  
   
  
     
      
    
  
  
      
  
    
  
  
    
    
  
    
  
  
  
  
     
  
  
    
  
  
  
      
   
        
  
  
    
   
  
  
  
   
   
  
            
 
  
      
     
          
 
    
    
          
   
 
    
  
    
   
  
      
   
    
  
  
  
       
  
      
 
   
  
    
  
    
   
 




 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
 
 
 
  
  
 
          
  
    
         
  
     
  
           
  
 
    
  
    
  
   
  
   
      
     
       
  
  
    
      
  
        
 
    
    
       
    
    
 
  
      
  
  
  
 
    
        
  
      
     
 
 
        
    
  
  
  
  
     
     
  
    
  
  
 
   
  
  
    
   
   
  
    
    
      
  
              
    
 
  
  
  
     
   
  
  
         
 
  
      
  
    
  
    
     
 
   
    
 
            
  
    
  
  
 
  
  
        
    
        
     
  
   
     
   
  
 
  
  
  
  
    
  
       
  
 
  
  
  
    
     
 
      
  
       
      
  
 
     
          
   
   
 
  
        
     
    
         
    
 
  
  
    
  
        
    
 
 
     
   
  
  
  
      
  
 
   
     
           
  
    
  
    
  
 
  
  
      
     
   
  
      
          
  
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
    
  
   
  
  
 
 
    
  
 
  
  
  
  
  
 
  
   
    
    
  
 
  
  
  
  
  
  
 
 
  
       
    
    
  
  
 
  
 
    
  
       
    
  
       
 
 
   
  
  
  
    
  
    
  
    
    
  
  
 
  
  
  
  
    
    
 
  
  
  
   
    
  
    
   
  
  
  
  
  
     
  
 
  
          
  
  
    
  
 
  
  
  
   
    
  
  
  
     
  
  
    
 
 
  
  
  
    
  
     
  
      
   
  
        
 
   
       
    
    
  
    
  
  
  
 
 
  
 
           
  
      
      
 
 
    
  
    
  
  
  
  
  
    
  
   
  
  
  
   
  
    
  
  
      
  
  
  
  
  
       
  
        
    
    
        
  
  
  
  
      
  
       
  
      
  
    
  
  
     
  
      
         
   
       
 
 
 
  
  
   
   
  
  
   
          
    
  
   
  
      
  
    
  
 
   
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
  
     
  
  
  
 
 
  
  
      
  
    
  
  
  
    
  
         
  
    
 
  
    
    
    
    
       
 
   
        
  
 
   
  
  
      
  
  
  
  
       
    
     
  
 
  
  
      
  
  
  
  
 
  
    
  
           
 
  
  
      
   
  
  
      
         
  
    
        
      
   
  
  
       
     
  
    
   
   
  
  
 
    
  
 
  
  
 
  
    
   
    
   
     
     
 
 
    
    
  
     
  
    
  
    
  
 
    
  
  
  
    
  
 
   
  
  
         
  
      
      
  
  
    
    
  
      
    
   
        
    
     
  
    
  
  
 
      
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
 
 
 
    
 
  
  
 
 
  
  
  
     
 
  
  
 
  
        
  
    
       
 
  
 
  
  
  
  
     
 
  
 
  
  
    
  
  
    
  
   
 
  
  
  
  
  
    
  
  
 
 
  
  
 
  
  
  
  
  
  
  
  
 
 
  
     
 
      
          
  
        
     
  
  
   
     
  
 
    
  
   
   
   
  
   
    
          
  
  
   
  
     
  
    
  
  
    
         
  
  
    
      
         
  
     
     
          
    
  
 
       
  
  
       
      
       
    
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
 
 
  
 
    
    
    
    
   
 
  
  
  
  
 
  
   
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
     
      
  
  
  
  
  
 
  
 
  
  
  
  
 
       
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
  
 
      
  
  
  
  
  
 
 
  
  
  
  
 
  
   
  
     
     
     
     
 
  
 
      
  
  
  
  
  
 
  
 
      
  
  
  
  
  
 
           
   
   
            
  
  
   
    
      
       
 
   
    
    
    
  
 
      
  
      
  
      
  
 
   
            
    
  
        
  
  
   
      
    
        
    
        
    
       
    
 
  
         
    
       
 
   
    
  
    
  
 
  
     
         
      
   
 
   
       
    
    
  
  
 
       
  
   
    
  
    
    
 
   
        
 
  
    
 
  
   
  
  
           
    
 
  
      
          
  
  
  
   
      
     
    
    
      
    
  
   
  
  
  
  
 
  
 
    
               
  
  
    
 
  
   
 
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
 
  
      
    
 
  
    
  
 
 
    
   
  
    
    
 
        
  
 
    
    
  
   
    
  
   
  
    
   
   
  
  
  
    
        
  
      
    
    
    
  
     
      
     
  
  
    
   
 
  
        
          
   
 
  
  
      
  
    
  
  
 
  
      
  
        
  
  
 
      
  
  
  
  
  
  
  
      
  
    
     
  
  
       
     
 
     
     
  
       
    
   
 
  
  
   
    
  
   
      
  
 
  
  
      
  
     
  
  
    
    
   
  
        
  
   
       
  
     
  
     
   
     
  
    
      
    
   
    
      
  
  
    
  
    
  
    
    
    
  
       
    
          
  
    
    
    
 
  
      
    
     
      
 
    
  
    
  
      
    
 
  
  
  
  
  
  
     
     
     
  
  
  
  
   
    
    
  
      
   
     
        
   
  
   
    
 
  
  
      
   
    
   
  
 
 
      
  
  
      
  
     
  
     
    
        
      
 
  
  
  
  
      
  
    
  
     
  
  
     
    
       
      
     
          
     
  
   
            
            
    
  
   
  
  
   
      
 
  
  
   
  
  
  
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
 
  
        
     
  
     
   
   
       
        
  
  
    
  
   
  
    
    
    
      
 
    
    
   
      
  
   
   
  
  
      
         
  
      
  
     
      
  
  
   
    
  
  
      
 
  
    
      
  
       
       
  
     
          
     
      
   
     
  
      
  
     
    
      
  
    
     
   
    
     
     
     
  
      
 
                
        
  
  
  
 
    
    
    
    
  
  
  
  
  
  
    
   
         
    
  
        
        
   
 
   
  
        
    
  
  
 
      
    
    
      
      
 
   
        
    
   
  
     
       
  
  
          
   
  
    
  
     
    
  
 
  
 
  
 
  
  
    
           
  
   
   
  
   
  
         
      
 
    
  
    
      
  
  
  
      
  
        
       
                   
  
    
     
    
       
     
    
  
   
    
     
      
  
   
      
 
     
    
      
  
  
  
   
    
  
    
      
  
    
  
  
  
     
  
        
     
    
     
        
    
   
      
   
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
 
  
  
 
  
    
   
             
   
 
     
  
  
 
  
  
 
    
  
     
  
           
   
 
      
     
      
    
   
    
     
  
   
    
      
  
  
  
    
 
  
    
   
  
        
   
 
   
  
    
    
  
   
  
  
  
 
  
  
  
   
    
    
  
                       
  
  
           
 
  
  
 
  
   
  
  
     
 
 
  
 
       
  
   
  
    
  
  
      
                        
  
  
  
  
  
      
    
    
  
    
  
  
 
 
    
  
 
 
  
  
 
  
  
    
 
  
    
 
 
  
  
  
   
  
  
    
   
    
 
  
 
  
 
   
      
   
   
  
     
  
       
   
  
      
    
                
   
  
  
      
   
  
  
      
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
 
  
 
 
  
      
  
    
        
     
  
  
  
  
  
                 
    
         
          
     
                
   
  
   
  
    
    
    
    
   
     
  
              
   
    
 
    
    
      
      
    
            
     
  
   
     
    
   
  
      
 
  
  
  
      
        
   
 
  
  
 
 
 
 
   
  
  
  
        
  
 
  
   
   
      
  
   
  
      
     
  
  
       
  
  
   
   
  
  
    
  
  
  
 
    
   
 
   
  
 
  
 
 
  
  
  
    
    
 
   
  
 
  
 
  
  
  
 
  
  
  
    
 
 
    
 
 
  
 
  
  
  
   
  
  
     
  
    
  
  
    
  
     
 
      
    
   
  
        
   
     
     
        
     
     
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
 
  
  
   
 
      
  
   
   
    
  
  
 
  
  
      
    
     
    
 
 
 
  
      
  
  
 
  
  
 
  
  
  
  
 
  
  
   
     
    
    
     
 
       
     
  
        
    
 
  
  
      
     
    
    
  
 
        
      
  
  
      
   
  
   
  
    
    
    
    
    
     
  
  
  
  
   
    
      
  
 
      
    
     
  
  
    
   
      
        
      
    
 
        
     
  
   
  
  
 
    
  
  
  
      
    
     
    
 
 
  
  
   
          
  
  
    
   
  
 
  
 
  
      
    
   
  
  
   
  
    
     
  
  
       
   
     
     
  
  
      
  
    
 
  
     
    
 
  
   
    
 
    
          
  
        
    
 
 
  
      
     
   
 
 
    
    
  
 
       
      
  
  
      
   
 
  
     
   
  
    
       
 
  
  
    
    
    
  
  
   
  
 
    
  
 
  
  
  
  
      
          
     
  
    
     
  
    
  
  
     
         
   
  
  
    
    
  
  
  
    
 
  
  
  
  
 
    
  
 
  
  
  
    
  
    
   
 
  
       
    
   
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
  
    
 
   
      
     
  
      
    
 
    
  
    
 
  
     
     
        
   
    
    
  
    
   
     
  
  
  
            
    
     
  
    
  
      
     
   
   
  
         
     
     
  
     
       
  
     
     
      
      
            
    
   
    
   
     
      
      
  
   
  
      
    
      
     
  
      
   
    
    
        
  
     
      
      
         
     
   
      
       
           
 
 
  
 
  
  
    
  
        
  
  
 
   
  
    
  
    
    
 
              
      
     
  
  
      
    
  
  
 
   
   
     
  
    
  
 
 
  
    
    
  
  
 
      
  
        
        
 
        
  
     
   
    
 
    
     
      
   
     
    
 
      
    
    
     
   
    
  
 
 
   
  
  
 
 
   
    
  
  
    
   
     
  
    
    
  
    
  
    
      
      
 
  
  
 
     
  
    
  
  
  
  
     
    
      
      
  
 
             
              
   
   
  
     
  
           
      
 
    
    
           
     
  
  
   
            
         
     
 
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
     
       
         
 
  
 
    
    
       
    
  
   
    
  
    
     
  
    
  
     
  
     
    
  
   
 
 
 
    
  
    
    
  
  
   
 
    
      
     
    
    
   
     
  
    
  
            
   
  
  
    
         
    
   
                  
    
    
   
      
           
     
  
   
  
    
  
  
 
         
 
        
  
    
  
       
     
  
     
     
     
  
       
      
   
    
    
  
    
 
 
    
 
  
  
  
       
  
    
    
 
  
 
 
     
 
     
 
  
     
 
  
 
 
  
 
  
    
    
  
 
  
    
   
  
    
  
    
 
 
  
  
   
  
         
    
  
      
   
   
   
  
  
    
    
     
  
  
  
  
 
       
  
  
      
    
    
  
  
    
    
             
 
             
      
   
    
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
   
     
 
 
 
    
  
 
  
  
  
       
  
    
    
 
  
 
 
  
      
 
  
 
 
    
 
  
    
        
          
  
  
    
 
    
        
    
      
  
 
               
        
    
     
   
    
  
    
  
   
     
 
 
  
 
  
  
  
       
  
    
     
 
  
 
   
     
  
      
  
      
  
   
    
     
      
   
 
 
 
  
      
     
  
    
      
   
     
  
  
  
   
 
  
 
  
      
  
 
  
  
           
    
  
     
  
  
  
    
      
  
  
                 
                
 
              
                      
                     
  
      
 
  
  
      
  
   
  
  
  
  
  
    
  
    
    
    
 
               
   
     
 
    
  
  
     
  
      
 
  
          
     
      
    
 
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
  
 
 
   
    
      
  
          
   
      
   
  
  
    
  
    
 
  
    
      
           
   
   
 
            
      
  
    
   
 
  
      
     
   
   
 
    
 
 
 
    
   
  
 
  
  
      
 
 
                
  
  
       
  
    
        
      
           
                  
  
       
  
  
         
    
   
  
     
  
    
  
  
      
     
 
   
  
    
   
  
    
  
     
   
   
  
  
      
  
  
   
     
  
    
    
  
  
 
    
      
     
  
 
    
  
  
  
 
 
  
 
 
   
  
      
                
     
  
     
  
        
  
      
          
  
   
 
  
  
      
            
    
                
           
               
        
     
 
  
  
    
    
           
   
   
      
   
      
    
    
  
    
     
  
    
   
  
 
 
  
  
    
  
    
    
     
      
      
   
                
       
                
        
                       
  
       
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
        
      
    
    
  
    
   
  
  
  
    
  
    
  
   
  
            
  
    
  
  
 
  
  
        
    
      
    
  
 
 
        
      
    
   
       
                   
      
    
    
   
  
  
  
    
  
       
    
 
  
  
        
  
    
  
   
  
    
           
  
   
       
          
  
           
 
      
     
  
  
  
  
 
 
  
 
      
    
  
        
  
      
 
                       
  
      
 
    
  
    
    
    
  
  
  
  
 
  
  
  
    
  
  
  
  
     
      
       
  
    
  
  
 
 
  
  
  
    
 
   
   
  
   
     
     
  
 
     
 
 
 
  
    
 
   
 
 
  
  
 
  
  
  
    
  
  
       
     
  
    
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
  
 
 
  
 
 
   
  
  
  
  
  
  
 
    
  
  
    
  
   
  
  
  
  
  
  
 
  
  
  
 
  
 
 
 
  
  
 
 
    
  
  
  
  
  
 
  
  
  
  
  
  
 
 
  
  
    
  
 
      
    
    
   
      
  
    
  
 
 
 
  
  
  
    
  
 
  
  
    
  
    
  
   
  
            
  
    
  
  
 
  
 
      
  
  
  
  
     
  
  
 
    
     
  
    
    
     
  
  
 
        
    
  
 
     
  
  
   
  
  
   
  
     
  
  
  
     
  
   
 
      
  
          
  
   
  
  
 
  
 
   
  
  
   
    
  
  
   
 
        
    
  
           
  
    
  
 
      
    
 
    
     
    
                
             
   
  
  
    
 
      
   
  
 
  
 
   
  
   
  
           
   
  
      
  
  
  
    
   
  
      
   
         
  
   
  
  
  
  
  
  
       
  
   
  
    
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
        
  
  
    
  
    
   
 
     
      
  
  
  
    
  
  
    
   
      
      
  
   
  
  
    
     
    
  
  
   
  
  
      
  
  
     
    
      
   
  
      
  
  
     
 
   
  
 
 
  
  
  
 
 
     
      
  
  
    
  
  
 
  
 
  
  
    
    
 
        
      
    
    
   
  
  
  
    
  
  
        
 
  
  
     
  
    
 
  
  
  
  
    
     
    
  
 
  
     
        
        
     
  
 
  
  
     
     
            
      
   
     
    
     
    
   
   
          
      
    
 
      
      
  
  
  
  
  
    
   
  
  
  
    
    
     
    
             
   
    
   
  
  
    
  
   
  
  
  
 
  
  
  
      
   
    
     
        
    
   
  
     
         
  
  
  
   
    
      
     
    
   
  
              
    
  
    
   
  
  
     
  
  
      
    
  
   
       
          
 
  
 
      
         
  
  
          
 
        
    
  
    
   
   
                     
           
    
  
    
  
  
        
    
   
  
 
        
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
    
   
        
    
 
   
  
  
     
  
     
  
 
 
  
      
      
      
  
 
     
  
 
  
      
      
  
    
 
    
    
 
  
    
  
  
    
  
  
 
 
  
  
   
  
  
 
  
    
    
  
      
 
 
    
   
  
  
  
 
  
 
  
   
 
  
  
  
 
  
    
  
    
  
  
     
  
  
    
   
  
    
 
 
    
   
  
     
  
    
  
    
    
  
 
      
  
 
  
      
      
  
  
    
 
  
  
          
    
 
  
  
  
    
   
      
      
    
  
 
 
  
     
     
        
      
  
 
     
  
 
  
            
  
    
    
     
      
   
  
      
  
   
       
    
   
         
    
        
    
  
   
    
   
  
    
 
 
     
     
   
  
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
  
  
   
    
  
 
 
 
     
  
  
 
    
  
  
  
  
    
  
     
 
         
  
  
   
     
 
  
  
   
  
 
    
  
    
  
 
 
  
    
  
  
  
    
    
   
     
  
  
    
  
     
  
    
  
    
  
   
    
  
  
  
    
    
   
 
    
  
      
      
   
    
 
  
    
     
    
  
     
  
    
    
  
      
     
     
  
      
  
      
        
  
  
   
    
    
 
    
  
  
      
    
  
        
  
  
    
    
     
  
  
  
 
 
  
  
          
  
     
         
  
 
  
  
      
   
    
   
     
 
  
  
      
    
     
 
  
  
  
  
  
  
      
  
 
  
  
  
    
   
  
    
   
    
   
  
 
 
  
  
      
  
    
   
  
   
  
  
  
  
    
   
  
   
  
  
    
     
  
  
  
 
  
  
 
 
 
     
    
  
       
        
         
  
 
  
 
 
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
 
    
   
 
 
 
   
 
 
  
  
  
 
  
  
  
  
 
 
  
  
        
   
   
    
 
      
      
  
    
  
 
      
    
      
  
  
  
      
  
     
  
     
  
 
  
 
  
  
  
     
      
  
  
    
        
   
 
   
  
     
      
    
  
 
  
    
         
        
  
 
  
    
 
         
     
  
      
      
    
  
     
  
      
 
        
              
      
   
   
    
  
  
  
       
       
     
 
     
     
 
 
    
  
  
    
  
   
       
     
  
    
  
  
  
  
  
 
  
  
  
  
      
  
  
   
 
      
      
    
           
 
  
    
  
     
     
  
    
 
    
         
   
  
      
  
 
    
    
        
    
    
     
  
   
  
     
     
        
    
       
  
  
  
           
      
  
  
  
    
  
  
    
  
  
  
  
   
        
  
      
     
  
    
       
    
  
    
  
     
      
  
    
    
            
   
  
      
        
    
   
    
   
    
   
  
 
 
 
 




 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
   
  
  
    
  
 
  
  
   
             
  
   
 
         
    
  
  
         
     
  
  
         
     
 
    
     
    
    
      
     
  
   
    
  
  
      
 
  
   
    
  
    
  
 
  
   
    
      
  
   
   
   
       
  
   
    
  
      
 
  
      
       
  
  
       
       
  
   
    
  
     
  
  
  
  
      
  
   
  
 
 
 
 
   
  
  
  
  
    
    
   
 
  
     
    
  
    
    
 
    
    
   
    
   
 
  
      
  
     
  
    
 
  
    
   
     
  
  
     
         
   
  
  
  
    
                 
    
 
      
     
     
    
     
   
  
  
     
      
  
      
 
    
         
  
  
    
 
    
  
        
            
 
  
      
     
    
     
 
    
          
      
  
  
     
     
    
      
      
     
   
     
      
    
     
    
  
      
              
    
  
  
 
  
  
    
         
  
  
 
 
   
  
  
  
   
 
      
  
                  
      
  
   
  
  
  
  
    
  
  
        
     
  
 




 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
  
    
    
  
 
  
    
  
  
  
   
         
 
   
    
      
    
    
   
  
    
     
     
  
  
    
   
                
   
     
  
 
    
    
    
      
  
      
 
    
  
      
    
  
     
      
 
    
      
 
    
  
      
  
    
  
    
 
    
  
      
  
    
  
     
   
  
    
    
   
 
    
    
  
    
    
  
    
 
    
  
  
   
    
      
    
 
           
    
           
 
    
      
     
     
      
 
     
    
    
  
    
   
  
      
  
    
   
 
    
     
  
   
 
    
    
 
    
    
  
  
  
     
  
     
  
     
      
  
  
    
  
  
 
   
  
    
  
  
  
    
    
  
    
  
  
  
    
    
  
      
      
    
  
    
 
  
  
    
     
    
  
      
  
  
  
  
     
 
  
        
     
  
     
  
      
  
  
     
    
   
  
        
    
  
      
    
 
  
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
 
   
  
  
 
 
   
   
   
        
  
  
  
  
    
  
    
  
   
  
          
       
    
     
      
     
    
    
  
 
   
      
    
  
    
  
 
  
    
    
      
  
  
 
      
       
    
    
    
 
  
   
      
      
     
  
  
    
          
  
      
    
    
    
    
  
     
    
           
      
    
  
 
   
      
      
  
   
  
  
     
  
  
    
    
  
  
  
  
  
 
  
    
     
       
    
   
    
  
   
  
  
    
  
 
   
    
   
  
       
  
  
     
  
    
  
  
  
  
     
     
            
  
 
  
  
  
    
     
  
    
 
        
    
  
          
 
    
    
    
  
     
   
 
    
      
   
       
      
 
  
  
  
    
    
      
   
    
    
 
       
   
         
    
  
    
    
   
        
    
  
  
  
  
  
    
  
  
  
    
  
      
  
  
   
 
    
  
    
    
  
  
  
 
  
    
   
        
    
      
   
  
  
      
     
       
 
  
  
   
  
  
  
  
   
  
    
  
   
  
    
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
      
  
   
         
    
 
 
  
   
  
  
    
 
  
  
 
  
       
      
  
 
   
    
    
    
  
   
  
 
 
       
   
    
  
  
     
  
     
  
  
  
  
 
      
  
     
   
   
     
 
  
           
    
      
 
  
      
   
   
  
  
   
  
   
   
      
  
      
 
         
  
       
      
  
          
    
    
    
   
  
  
     
   
  
 
 
  
 
  
 
 
        
     
          
  
   
  
  
      
      
 
  
  
    
  
      
      
  
      
      
        
  
      
      
        
  
      
       
      
        
      
        
  
 
     
     
   
    
  
  
      
   
   
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
  
  
    
  
  
 
  
    
  
 
 
 
  
  
  
  
 
  
  
   
  
   
 
 
 
         
    
  
   
     
  
       
      
      
      
        
        
       
   
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
 
  
  
    
      
   
   
    
   
  
      
  
 
        
            
    
    
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
 
  
 
  
 
 
  
  
      
      
      
    
 
 
  
  
  
      
    
  
   
      
    
     
     
  
   
 
      
     
    
    
      
 
    
           
            
       
  
  
  
  
  
  
  
  
      
    
    
  
  
  
  
  
  
  
  
   
  
   
  
  
  
      
   
    
  
      
   
     
   
 
  
  
        
       
    
  
   
  
  
  
    
  
        
  
   
    
  
    
  
  
  
      
 
  
   
  
    
  
      
  
 
  
      
    
  
      
  
 
  
     
    
  
   
          
     
  
  
      
  
    
  
       
   
   
    
      
    
  
 
  
        
    
      
    
   
      
    
    
  
      
    
 
 
   
  
  
    
   
  
  
      
  
  
  
  
 
    
      
  
    
     
             
  
  
 
  
    
      
  
      
   
   
  
   
       
    
   
  
 
  
  
      
   
      
  
  
   
 
      
  
   
  
  
        
   
  
    
 
    
  
    
  
  
  
         
   
    
  
   
  
        
    
     
  
  
    
 
     
  
    
      
            
   
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
     
  
  
     
      
    
   
  
     
  
        
  
    
  
   
     
  
  
    
      
  
    
      
  
           
  
 
     
  
            
  
  
        
  
      
     
   
     
  
 
    
  
     
  
  
  
  
       
     
    
      
  
    
    
 
     
    
     
  
    
     
  
  
   
  
     
      
  
   
    
    
      
     
     
 
  
  
    
  
      
  
      
 
  
    
         
       
  
   
      
  
    
  
      
  
     
    
  
  
  
      
    
  
      
 
    
  
  
      
     
  
  
     
  
      
  
          
 
     
     
   
  
  
   
  
      
  
   
       
     
 
   
  
      
          
  
    
     
 
        
    
  
        
    
 
    
    
    
       
   
     
  
             
     
  
   
      
     
  
    
  
  
  
    
    
    
  
      
  
 
    
   
        
      
    
 
   
  
    
  
      
  
  
  
 
   
     
   
  
  
    
  
    
  
  
   
 
  
   
   
 
 
 
  
    
 
  
    
 
  
  
   
  
    
 
 
  
    
 
 
  
    
 
 
  
    
 
 
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
 
 
  
  
  
      
      
  
    
 
 
    
 
 
  
  
  
    
    
   
       
  
   
  
  
  
    
      
      
   
    
 
    
  
     
   
    
    
  
  
  
  
    
  
    
        
  
      
      
  
     
   
  
  
  
  
      
   
    
   
  
 
    
  
    
  
      
    
  
                
  
 
  
      
  
    
  
 
  
    
  
  
 
  
    
  
 
   
  
  
    
    
        
          
    
  
   
   
            
  
  
    
  
  
    
          
  
  
    
            
  
   
        
    
     
    
   
    
  
 
          
      
  
   
  
   
   
      
    
  
  
 
    
  
     
  
    
    
  
 
  
          
    
   
    
 
      
      
    
  
   
  
 
    
      
      
  
  
  
    
   
      
  
  
     
 
      
        
  
  
    
 
 
    
  
        
      
 
 
  
    
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
    
    
  
 
        
  
  
    
  
    
      
   
    
    
     
    
     
     
  
      
    
  
      
  
 
    
  
  
  
  
 
  
    
      
  
    
  
  
  
 
 
       
      
  
    
   
 
            
    
  
    
   
  
 
    
        
  
    
    
      
 
    
  
  
 
  
 
  
    
      
      
    
    
 
      
  
    
   
     
        
    
  
    
   
  
 
  
  
        
  
    
  
 
      
      
  
  
  
  
 
          
  
    
  
             
 
  
  
  
  
  
 
  
  
  
           
   
  
 
  
    
  
  
  
  
    
  
    
      
    
  
      
      
     
   
   
  
  
    
    
  
  
 
   
  
     
 
  
    
      
 
  
        
 
  
    
      
 
  
        
  
  
  
  
        
        
    
  
      
       
   
 
     
    
   
    
  
    
   
    
       
   
  
     
  
  
  
    
  
    
      
    
  
      
      
       
   
 
    
  
        
  
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
  
    
 
 
    
 
  
    
 
      
   
      
 
  
  
  
        
 
  
   
    
 
  
        
 
  
        
 
       
  
  
    
  
    
  
  
    
      
      
     
     
  
    
   
  
   
  
  
 
  
  
  
  
    
  
  
  
   
  
          
   
  
   
        
     
   
  
            
     
  
    
            
   
 
  
      
  
    
  
  
  
    
            
     
    
   
     
    
           
    
  
  
     
  
  
   
        
 
  
    
    
    
    
            
      
 
   
  
         
    
   
    
 
           
    
     
     
 
     
      
  
  
     
     
            
 
       
    
     
  
       
            
     
        
   
     
  
        
        
   
  
    
  
  
  
   
  
  
      
        
     
   
  
  
  
    
   
  
     
  
     
  
        
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
     
    
  
    
  
    
 
   
  
          
 
       
    
     
  
     
   
  
    
   
  
  
       
      
  
      
     
    
    
     
  
     
     
  
    
   
 
     
      
  
  
  
   
  
      
 
       
    
     
  
     
      
  
    
  
    
   
  
  
  
     
      
  
  
    
   
  
 
       
    
     
  
     
      
  
    
  
    
 
    
  
  
     
    
       
    
     
  
     
   
    
       
       
   
  
  
  
        
     
   
        
  
  
   
  
  
  
        
     
   
  
  
  
       
  
     
  
     
  
  
    
        
   
  
  
  
     
     
  
 
       
    
     
  
     
     
  
    
    
   
   
    
    
   
    
    
     
   
      
    
   
  
     
   
  
  
 
      
   
    
  
  
  
   
 
  
      
  
    
          
 
  
   
  
  
   
        
     
  
          
       
  
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
  
    
  
   
 
 
     
   
  
    
  
  
  
  
  
 
  
  
 
    
    
  
  
 
     
   
     
  
    
 
 
  
 
  
  
    
 
   
  
     
  
     
       
   
  
  
    
 
      
   
    
  
    
 
    
  
   
    
  
 
   
    
  
 
  
 
 
  
  
  
        
     
  
   
 
  
  
  
  
           
   
  
  
      
  
  
 
  
 
   
    
    
  
    
  
    
           
     
  
  
 
  
 
    
  
    
     
  
         
 
 
    
  
    
  
      
  
  
    
      
   
  
      
  
   
     
    
  
  
          
      
  
  
    
  
 
    
           
     
  
  
  
  
 
  
   
  
  
      
      
      
 
   
     
  
              
  
    
         
     
  
  
   
    
  
 
  
   
  
    
        
   
 
   
        
  
  
    
  
            
    
      
     
    
         
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
      
   
                 
   
   
    
    
  
 
   
    
  
          
    
  
  
      
  
  
 
  
  
   
  
  
  
    
           
       
  
     
  
  
    
  
            
    
      
     
      
         
         
    
   
  
 
  
           
    
  
  
 
  
  
  
 
  
  
      
 
  
  
  
  
      
           
  
  
    
    
            
      
 
  
  
    
  
            
    
      
     
       
  
   
    
           
       
  
            
  
      
    
 
  
     
     
            
 
  
  
    
  
            
    
      
     
      
     
 
      
  
  
   
  
  
      
        
    
    
   
  
    
     
  
   
  
    
        
  
   
    
 
    
     
  
      
  
     
      
  
  
  
   
  
      
 
    
     
  
      
  
     
      
  
  
    
   
  
 
    
     
  
      
  
     
    
    
     
  
      
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
   
  
  
  
        
 
                
   
    
             
    
   
    
  
   
    
  
       
    
    
  
  
      
  
  
 
  
  
   
  
  
    
        
  
                
    
    
 
                 
    
 
  
   
  
  
  
    
    
    
  
  
      
  
 
 
  
  
         
  
     
     
  
 
    
     
  
      
  
  
 
   
    
    
   
   
   
      
     
    
      
   
  
      
  
     
   
  
  
 
    
     
  
      
  
  
    
  
    
  
   
 
 
  
        
    
  
           
 
  
   
      
  
    
  
 
  
  
  
  
   
  
  
  
  
 
  
  
 
    
   
  
 
  
        
  
             
   
  
  
   
  
  
  
 
  
  
          
  
  
 
  
 
  
      
    
  
      
      
 
    
  
  
    
        
   
      
     
  
            
  
  
  
   
    
        
    
     
   
      
      
  
    
     
        
    
   
  
    
    
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
      
        
 
   
   
       
     
  
  
  
    
   
    
      
  
  
 
  
    
          
      
  
   
    
   
  
  
  
      
      
   
  
              
    
       
  
  
  
      
  
  
  
 
         
  
  
   
      
   
      
    
  
      
    
  
  
         
  
    
     
  
  
   
  
  
 
     
    
  
   
      
   
      
    
  
      
    
  
  
         
  
    
     
  
  
  
       
     
          
 
     
      
           
   
  
      
  
  
 
 
      
   
    
     
   
  
  
    
     
      
       
    
    
    
      
      
   
  
 
 
  
 
  
  
        
  
    
  
    
      
  
  
  
    
  
   
       
  
  
      
    
      
  
 
    
  
  
  
  
     
   
  
  
    
     
  
 
  
    
   
    
  
  
  
 
  
      
     
       
  
    
 
 
 
  
  
    
  
        
 
 
  
  
     
    
  
      
      
    
    
  
    
    
    
 
      
  
      
   
     
    
  
      
       
        
  
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
      
       
    
  
     
   
  
   
    
  
          
 
 
    
  
    
   
    
 
    
  
    
    
        
        
   
  
  
  
  
 
  
  
  
  
 
 
  
    
                      
      
      
      
    
  
   
   
                 
      
    
      
    
  
        
  
     
  
  
        
      
  
      
 
    
  
  
    
  
        
     
  
  
   
  
  
 
   
    
 
  
      
      
     
    
  
   
 
  
      
       
   
 
  
      
 
  
      
      
    
  
      
    
  
   
  
  
 
 
 
 
  
    
      
      
   
  
     
  
    
        
  
      
    
        
   
 
 
 
  
    
  
      
       
  
  
  
 
  
     
      
  
      
      
 
      
  
  
 
  
  
   
      
     
  
  
   
 
 
  
    
  
      
  
 








 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
      
 
  
      
   
      
  
  
 
 
  
  
      
          
   
 
  
    
    
  
  
  
      
 
      
     
   
  
   
  
    
 
  
    
    
  
        
    
   
   
     
  
  
      
     
      
  
    
      
      
 
              
  
  
      
   
    
    
      
  
  
      
   
     
     
  
    
      
    
     
      
  
  
      
    
  
    
  
  
  
  
    
    
  
  
  
 
  
    
  
     
     
   
  
   
    
    
      
  
    
   
     
    
   
    
  
  
    
     
      
  
  
  
   
 
  
 
      
       
      
    
   
 
       
    
        
    
 
    
          
          
    
  
  
 
 
    
  
  
    
   
    
     
      
  
  
    
      
 
    
   
    
    
      
 
    
        
    
     
   
    
  
  
     
  
    
    
      
      
        
  
    
 
      
          
  
  
     
 
      
      
    
      
   
    
    
  
   
   
     
    
  
  
   
    
 
  
    
        
  
  
   
   
  
      
  
    
  
    
  
          
    
  
      
        
      
  
    
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
      
      
    
  
    
   
  
   
      
    
       
  
  
  
  
 
  
    
    
       
      
   
  
 
      
      
    
  
     
     
     
    
  
  
  
 
   
    
    
 
  
  
  
 
        
    
    
      
  
    
 
    
  
   
  
  
   
  
   
  
    
   
  
      
    
  
   
  
    
  
  
   
  
  
    
  
 
   
  
  
 
 
    
  
    
      
  
      
   
  
    
    
    
      
     
    
      
    
      
       
    
  
      
  
     
   
   
  
  
  
  
    
    
      
   
  
 
      
      
  
    
    
  
         
    
  
    
     
  
  
    
     
   
  
        
    
      
  
      
  
  
    
    
     
      
   
  
  
    
        
  
    
       
  
       
  
      
       
           
     
       
   
       
  
 
    
    
    
       
  
    
    
 
      
   
            
        
 
      
       
     
  
      
  
   
  
    
  
 
 
  
    
    
  
    
 
         
  
        
   
  
 
    
  
  
    
        
  
      
 
  
    
  
         
    
  
 
  
  
  
  
           
    
  
    
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
      
       
     
   
 
    
  
 
   
  
 
  
   
 
 
  
    
  
  
     
  
   
  
  
    
  
  
      
  
 
    
    
        
  
    
   
   
  
  
  
     
      
 
    
 
     
      
  
    
      
      
   
    
   
    
 
  
    
     
  
      
      
     
     
  
    
     
  
    
  
      
   
  
    
  
  
  
  
 
  
        
   
  
      
  
  
 
    
  
  
   
  
 
   
  
 
  
   
    
  
   
  
   
  
 
  
  
   
 
 
 
  
  
  
  
  
 
 
  
      
      
  
      
 
     
    
      
    
 
  
  
  
    
      
 
   
    
      
  
 
 
    
  
    
              
  
  
  
  
         
     
  
    
  
 
   
  
    
     
   
  
    
   
     
  
  
   
 
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
   
  
   
    
    
  
   
 
  
  
  
  
  
   
  
    
    
  
     
  
  
  
  
    
  
    
    
   
    
      
    
  
 
  
    
  
    
    
     
  
   
     
       
    
  
    
  
 
    
   
     
  
    
   
  
  
    
    
   
  
    
    
 
    
  
       
  
  
     
    
 
      
      
  
    
   
  
   
    
  
 
  
  
    
  
    
  
    
 
    
     
  
  
  
 
    
 
  
    
       
      
  
     
   
            
  
  
    
  
      
  
  
       
     
  
     
    
  
    
    
  
  
    
   
   
    
 
     
  
  
  
  
  
    
      
   
  
     
  
      
    
   
    
   
    
  
     
    
  
   
  
     
      
            
 
        
  
  
    
    
  
   
      
    
   
  
     
  
   
  
  
  
      
   
   
  
  
    
    
    
    
   
  
   
   
  
   
    
      
        
  
  
  
  
  
 
 
  
    
      
      
    
  
 
   
    
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
    
 
  
  
      
   
            
   
 
  
  
    
      
  
   
   
  
    
  
     
  
    
   
 
    
  
          
 
  
  
           
   
  
      
      
   
      
  
  
  
    
     
             
    
       
   
 
          
       
    
     
  
    
   
      
    
      
  
  
  
      
    
    
  
  
 
    
    
  
   
    
  
  
  
    
 
  
    
    
    
  
  
    
 
 
    
  
  
  
   
      
 
  
        
  
    
   
     
    
    
  
  
  
  
      
   
      
     
   
      
  
   
             
   
  
  
  
  
  
    
  
  
      
     
     
  
  
       
      
  
  
    
  
 
  
  
  
  
      
     
  
   
    
  
       
   
 
  
               
  
  
      
   
         
   
    
    
    
 
    
    
  
      
          
   
   
        
   
  
   
  
  
   
   
  
  
    
  
         
  
  
     
      
     
  
  
  
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
 
  
    
  
    
      
    
 
 
    
      
  
 


 
 
 
  
  
 
  
   
 
 
 
 
 
 
      
 
  
 
  
    
    
  
   
   
  
   
 
    
   
  
  
 
  
   
  
  
  
    
  
   
   
  
  
    
   
    
    
   
     
  
  
  
    
   
  
  
    
  
    
    
  
   
  
       
    
      
  
   
     
  
  
    
  
  
 
  
  
    
  
    
  
        
 
 
 
 
  
    
    
       
    
      
  
  
   
  
  
   
 
    
 
  
  
    
    
     
  
    
   
  
   
    
  
  
   
  
 
     
  
    
    
       
  
   
   
      
   
    
  
 
  
    
    
  
  
  
    
    
   
    
   
    
 
  
   
    
  
  
   
  
  
   
   
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
    
  
 
 
  
  
  
  
  
    
  
    
 
    
  
   
    
      
  
                 
  
      
   
   
  
     
  
   
  
  
  
  
   
  
  
   
    
   
    
  
    
  
   
   
  
  
  
     
  
    
     
  
 


 
 
 
  
  
 
  
   
 
 
 
 
 
 
      
  
    
   
      
  
  
 
   
  
  
    
 
  
    
  
    
 
  
  
  
   
 
  
    
    
   
  
    
 
 
  
  
    
    
  
 
 
  
  
  
  
   
  
    
 
  
  
   
   
  
     
    
    
   
    
       
   
   
   
  
    
   
  
 
  
   
  
  
   
    
    
    
         
  
  
  
  
        
  
  
    
  
  
    
   
  
 


 
 
 
  
  
 
  
   
 
  
 
  
     
    
    
  
 
 
  
 
  
 
  
   
   
   
   
    
    
  
  
  
  
 
 
 
  
  
    
  
  
  
    
  
  
  
       
 
  
  
 
   
   
    
   
    
   
   
   
   
   
   
   
   
   
   
  
 
   
  
        
              
  
  
  
  
  
             
  
  
  
        
              
  
  
  
  
  
             
 
  
        
              
  
  
  
  
  
             
  
 
 
        
              
  
  
  
  
  
             
  
  
     
 
        
              
  
  
  
  
  
             
 
  
        
              
  
  
  
  
  
             
    
  
  
        
              
  
  
  
  
  
             
   
  
  
   
   
  
          
  
  
  
  
  
             
 
 
  
 
 
 
  
  
 
 
 
   
 
   
  
  
 
 
  
 
 
 
   
 
 
 
  
 
 
 
   
  
 
  
 
  
 
   
   
  
  
 
  
                          
  
  
  
  
      
     
 
 
 
  
  
  
  
 
  
  
 
  
  
 
  
   
   
  
   
           
  
                   
   
 
  
  
 
   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
  
  
  
  
      
  
  
  
  
  
  
  
 
  
 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
   
 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
  
    
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
   
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
    
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
     
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
    
 
  
   
 
  
  
   
           
  
                 
  
  
 
 


 
 
 
  
  
 
  
   
 
  
 
  
     
    
 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
 
  
                          
  
  
  
  
      
  
 
  
  
  
 
    
  
  
      
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
  
  
      
  
  
  
  
  
  
  
 
     
       
   
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 
  
  
   
 
 
  
  
      
              
  
  
  
  
  
  
  
 
     
   
  
 
       
  
  
        
   
   
  
 
     
 
   
   
     
  
   
  
        
   
     
      
 
   
  
    
   
    
     
  
    
       
  
  
    
              
    
          
   
      
            
   
  
      
   
               
               
      
    
                
 
           
  
      
           
   
       
   
   
            
         
       
  
  
   
  
     
  
   
        
      
     
  
    
   
  
        
      
        
  
 
  
  
       
     
  
      
    
  
       
  
      
    
     
   
  
      
      
   
   
       
               
  
  
       
  
    
        
      
                              
 
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 






 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
    
 
 
 
 
  
 
  
   
 
 
 
    
 
 
  
   
   
    
   
  
    
 
       
  
  
    
      
   
   
  
  
    
  
    
  
   
  
 
 
 
    
  
                            
 
  
   
 
       
  
  
      
  
         
 
  
   
       
       
  
  
      
  
            
  
  
     
  
    
  
    
 
  
  
   
   
 
       
  
  
      
  
         
 
           
  
    
      
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
    
  
 
 
 
 
 
 
 
 
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
   
  
    
  
  
 
 
  
    
  
  
        
   
 
 
    
    
  
    
    
  
 
  
  
  
  
  
  
  
  
    
  
 
  
  
    
  
  
  
   
  
  
      
  
 
            
                 
  
        
     
   
 
                   
  
    
   
    
  
  
    
  
     
  
  
    
     
  
      
   
 
    
    
  
       
  
   
    
 
  
      
   
  
  
  
 
  
    
  
  
  
  
  
    
      
  
     
  
    
   
    
  
   
  
  
  
  
  
  
  
    
       
  
     
     
    
  
  
  
    
  
  
   
   
    
  
     
  
  
  
  
      
     
      
         
  
   
      
      
  
  
  
  
     
      
   
  
  
  
    
  
  
  
  
  
 
   
  
    
           
     
  
  
 
 
        
    
  
        
  
  
 
  
     
  
    
     
  
  
 
  
  
  
 
  
  
 
  
        
 
  
   
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
  
  
    
  
  
     
  
 
 
 
 
 
 
  
  
 
  
  
 
  
  
  
 
  
     
 
  
   
  
    
    
     
 
  
 
  
    
  
     
 
 
    
 
  
    
  
    
 
    
           
  
  
  
   
 
  
  
  
    
   
    
 
 
  
  
  
  
 
        
    
  
    
   
  
  
                   
 
  
    
  
  
  
  
                  
      
    
   
     
       
     
    
     
  
  
     
  
    
  
    
   
  
        
    
    
   
    
 
  
    
  
      
  
  
     
  
  
 
  
        
    
  
        
   
  
          
  
  
  
  
  
   
  
  
  
    
   
    
  
     
  
  
  
 
  
      
  
  
  
 
      
      
   
  
 
           
  
    
  
    
  
  
    
  
  
   
  
    
 
  
 
 


 
 
 
  
  
  
  
   
 
 
 
 
 
 
      
           
    
         
    
 
 
      
  
    
   
   
  
  
    
  
      
  
  
 
    
  
  
                 
         
     
  
  
    
  
    
  
  
    
  
  
   
  
    
 
  
 
                   
  
    
   
    
  
  
    
  
     
  
  
      
  
  
    
 
    
  
  
   
    
  
 
                 
  
    
    
 
 




 
 
 
     
 
 
 
  
  
 
  
  
  
  
   
  
  
  
    
     
 
    
   
      
  
        
   
        
 
 
  
  
  
 
  
   
  
    
   
 
 
 
 
  
 
 
  
  
  
    
   
  
        
     
 
 
 
   
  
    
  
   
  
  
 
  
 
  
 
  
 
 
 


Signature Page 
Document Information 
Short Title :  
 
 
Name : 
 
 
 
Object ID : 
 
 
 
 
 
 
Signature 
 
Date : 
 
 
(GMT) 
Signed by : 
 
(Name and ID) 
Justification : 
 
 
 
 
 
Electronic signature page generated by MIND 
 
E_PC_T0832_Ph3 DBT-HR_Ed03_Approved
Approved as 
Clinical Study Protocol: T0832, Phase 3 HR study-Amendment 02
Oct 31, 2016 05:34:00
PPO
PPO
CPI

SAP_001.pdf: 
 
Shionogi Study Title:  
A Phase 3, Multicenter, Randomized, Double-blind 
Study of a Single Dose of S-033188 Compared with 
Placebo or Oseltamivir 75 mg Twice Daily for 5 Days in 
Patients with Influenza at High Risk of Influenza 
Complications 
Shionogi Study Number: 
1602T0832 
ClinicalTrials.gov 
Registration No. 
NCT02949011  
Study Document 
Statistical Analysis Plan Version 2     19 June 2019 
 
History of Statistical Analysis Plan Amendments 
Version 1 (Original) 
06 April 2018 
Version 2 
19 June 2018 
Revisions  to Version  1 are document within Version 2 
 


STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 3, Multicenter, Randomized, Double-blind 
Study of a Single Dose of S-033188 Compared with 
Placebo or Oseltamivir 75 mg Twice Daily for 5 Days 
in Patients with Influenza at High Risk of Influenza 
Complications 
Study Number: 
1602T0832 
Study Phase: 
3 
Product Name: 
S-033188 
Sponsor: 
Shionogi & Co., Ltd./Shionogi Inc. 
 
Issue Date: 
 
Version 2.0  
19 June 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi. This Confidential Material 
should only be viewed by those individuals or companies that have been given prior 
written authorization to do so by Shionogi (“Authorized Users”). This Confidential 
Material should not be made available in any form to any person or company, other 
than the Authorized Users and their respective employees or associates on a 
need-to-know basis, without the written consent from Shionogi. 
 
 


PPD


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 3 of 53 
RECORDS ON REVISIONS 
Version 
Date 
Author 
Remarks 
Version 1.0 
06 April 2018 
 
First version 
Collaborators: 
 
Version 2.0 
19 June 2018 
 
 Definition of ITTI population 
in Section 5.1 was updated. 
 Allowance for EQ-5D-5L in 
Section 6.3 was updated. 
 Definition of baseline for 
efficacy in Section 6.5.2 was 
updated. 
 Supplemental analyses for 
efficacy assessment were 
added in Section 9.8. 
 Section 10.1 2) was updated. 
 Section 10.2 5) was added. 
 Supplemental analyses for 
safety assessment were added 
in Section 10.6. 
PPD
PPD
PPD


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 4 of 53 
TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................... 2 
RECORDS ON REVISIONS ............................................................................................. 3 
TABLE OF CONTENTS .................................................................................................... 4 
LIST OF IN-TEXT TABLES .............................................................................................. 6 
1. 
INTRODUCTION ...................................................................................................... 7 
2. 
OVERVIEW ................................................................................................................ 7 
3. 
STUDY OBJECTIVES ............................................................................................... 7 
3.1 
Primary Objective ........................................................................................................ 7 
3.2 
Secondary Objectives .................................................................................................. 7 
3.3 
Other Efficacy Objective ............................................................................................. 8 
3.4 
Safety Objectives ......................................................................................................... 8 
3.5 
Pharmacokinetic Objective .......................................................................................... 8 
3.6 
Health Economic Outcomes Research Objective ........................................................ 8 
4. 
OUTLINE OF STUDY DESIGN ............................................................................... 8 
4.1 
Study Blinding ............................................................................................................. 8 
4.2 
Allocation Procedure ................................................................................................... 8 
4.3 
Target Sample Size ...................................................................................................... 8 
5. 
ANALYSIS POPULATIONS ................................................................................... 10 
5.1 
Efficacy and Safety Populations ................................................................................ 10 
6. 
HANDLING OF DATA IN ANALYSES .................................................................. 11 
6.1 
Statistical Analysis ..................................................................................................... 11 
6.2 
Statistical Tests .......................................................................................................... 11 
6.3 
Acceptable Time Windows for Investigations, Observations, and Examinations ..... 11 
6.4 
Handling of Missing Data .......................................................................................... 14 
 
Handling of Virology Test Data in Consideration of the Stability 
6.4.1
Window ................................................................................................. 16 
6.5 
Definition ................................................................................................................... 16 
 
Display of Days of Study ...................................................................... 16 
6.5.1
 
Baseline ................................................................................................. 16 
6.5.2
7. 
DEMOGRAPHIC VARIABLES AND OTHER BASELINE 
CHARACTERISTICS .............................................................................................. 17 
7.1 
Subject Disposition .................................................................................................... 17 
7.2 
Demographic and Baseline Characteristics ............................................................... 17 
8. 
STUDY CONDUCT ................................................................................................. 18 
8.1 
Treatment Exposure and Compliance ........................................................................ 18 
8.2 
Medical History ......................................................................................................... 19 
8.3 
Prior and Concomitant Medications .......................................................................... 19 
9. 
EFFICACY ANALYSIS ........................................................................................... 19 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 5 of 53 
9.1 
Primary Endpoint ....................................................................................................... 21 
 
Analyses of Primary Endpoint .............................................................. 22 
9.1.1
9.1.1.1 
Primary Analysis ................................................................................... 22 
9.1.1.2 
Other Analysis ....................................................................................... 23 
9.1.1.3 
Sensitivity Analysis ............................................................................... 23 
9.2 
Secondary Endpoints ................................................................................................. 24 
9.3 
Other Endpoints ......................................................................................................... 30 
9.4 
Analyses of the Secondary Endpoints ........................................................................ 32 
9.5 
Analyses of the Other Endpoints ............................................................................... 35 
9.6 
Subgroup Analyses for Primary and Secondary Endpoint ......................................... 37 
9.7 
Analyses for Health Technology Assessment ............................................................ 41 
 
Comparison of Treatment Groups ......................................................... 41 
9.7.1
 
Summary of Specific Conditions .......................................................... 41 
9.7.2
9.8 
Supplemental Analyses .............................................................................................. 42 
10. SAFETY EVALUATION .......................................................................................... 42 
10.1 
Adverse Events .......................................................................................................... 42 
10.2 
Clinical Laboratory .................................................................................................... 43 
10.3 
Vital Signs.................................................................................................................. 45 
10.4 
Electrocardiography ................................................................................................... 45 
10.5 
Subgroup Analyses for Safety Endpoint .................................................................... 45 
10.6 
Supplemental Analyses .............................................................................................. 46 
11. INTERIM ANALYSES ............................................................................................. 46 
12. PROGRAMMING SPECIFICATIONS .................................................................... 46 
13. BLINDED REVIEW ................................................................................................ 50 
14. SUMMARY OF CHANGES FROM PROTOCOL SPECIFIED ANALYSIS ......... 50 
15. REFERENCES ......................................................................................................... 51 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 6 of 53 
LIST OF IN-TEXT TABLES 
Table 1 
Statistical Power to Compare between S-033188 and Oseltamivir .. 10 
Table 2-1 
Acceptable Time Windows for Parameters of the Patient Diary ...... 12 
Table 2-2 
Acceptable Time Windows for Parameters Other than Data from 
the Patient Diary ............................................................................... 13 
Table 3 
Statistical Methods Used to Analyze Each Endpoint ........................ 20 
Table 4 
Priority of Categories ........................................................................ 43 
Table 5 
Prespecified Criteria .......................................................................... 45 
Table 6 
Summary of the Number of Digits Displayed for Endpoints ........... 47 
Table 7 
Summary of the Number of Digits Displayed .................................. 48 
Table 8 
Category of Variable ......................................................................... 49 
 
 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 7 of 53 
1. INTRODUCTION 
This document describes the statistical methods to be used in the summary and analysis 
of data from Protocol 1602T0832. All decisions regarding final analysis, as defined in 
this statistical analysis plan (SAP), have been made prior to unblinding/database lock of 
the study data. Table, listing, and figure (TLF) mock-ups are described in the TLF shell 
document prepared separately. Details of the analyses of pharmacokinetics and 
pharmacokinetics/pharmacodynamics will also be described in a separate document. 
All the analyses described in the SAP will be performed in the Biometrics Department, 
Shionogi Inc. or Biostatistics Department, Shionogi & Co., Ltd. 
The analyses of ‘Polymorphic and treatment-emergent amino acid substitutions in the PA 
gene of evaluable virus’ and ‘Drug susceptibility in patients with evaluable virus’ in 
Section 9.3 will be reported in a separate document from the clinical study report (CSR). 
2. OVERVIEW 
This is a randomized, double-blind, multicenter, parallel-group, placebo- and 
active-controlled study enrolling 2157 patients diagnosed with influenza. Patients are 
randomly assigned in a ratio of 1:1:1 to receive a single dose of 40 or 80 mg of S-033188 
according to their weight category, 75 mg twice daily (BID) of oseltamivir for 5 days, or 
placebo. With the aim to achieve a broadly comparable exposure, patients who weigh 
< 80 kg at Screening will receive 40 mg of S-033188, and patients who weigh ≥ 80 kg at 
Screening will receive 80 mg of S-033188. 
For the schedule of this study, see Appendix 1. 
3. STUDY OBJECTIVES 
3.1 
Primary Objective 
 To evaluate the efficacy of a single, oral dose of S-033188 compared with placebo 
by measuring the time to improvement of influenza symptoms in patients with 
influenza 
3.2 
Secondary Objectives 
 To evaluate the efficacy of a single, oral dose of S-033188 compared with 
oseltamivir 75 mg BID for 5 days by measuring the time to improvement of 
influenza symptoms in patients with influenza 
 To evaluate the efficacy of a single, oral dose of S-033188 compared with placebo 
by measuring the secondary endpoints in patients with influenza 
 To evaluate the efficacy of a single, oral dose of S-033188 compared with 
oseltamivir 75 mg BID for 5 days by measuring the secondary endpoints in 
patients with influenza 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 8 of 53 
3.3 
Other Efficacy Objective 
 To evaluate the polymorphic and treatment-emergent amino acid substitutions in 
the polymerase acidic protein (PA) gene and drug susceptibility in patients with 
evaluable virus 
3.4 
Safety Objectives 
 To compare the safety and tolerability of a single dose of S-033188 with placebo 
 To compare the safety and tolerability of a single dose of S-033188 with 
oseltamivir 75 mg BID for 5 days 
 To compare the frequency of adverse events (AEs) in patients with influenza of a 
single dose of S-033188 with oseltamivir 75 mg BID for 5 days and with placebo 
3.5 
Pharmacokinetic Objective 
 To determine the pharmacokinetics (PK) of the active form of S-033188, ie, 
S-033447, in patients with uncomplicated influenza virus infection 
3.6 
Health Economic Outcomes Research Objective 
 To compare the total quality-of-life change by measuring the EuroQol–5 
Dimensions–5 Levels (EQ-5D-5L) and a work productivity (WP) questionnaire in 
patients treated with S-033188 compared with oseltamivir 75 mg BID for 5 days 
and placebo 
4. OUTLINE OF STUDY DESIGN 
4.1 
Study Blinding 
The study will be conducted in a double-blind, double-dummy fashion by using placebo 
matching S-033188 and oseltamivir in appearance, labeling, and packaging.  
4.2 
Allocation Procedure 
Patients are randomized on a 1:1:1 basis to S-033188 group, oseltamivir group or placebo 
group. An interactive response technology (IRT) is used to assign patients to numbers for 
which treatment is randomly assigned. The randomization is stratified by region (Asia, 
North America/Europe, Southern Hemisphere), body weight (< 80 kg, ≥ 80 kg), baseline 
composite symptom score (≤ 14, ≥ 15), and preexisting and worsened symptom (Yes, No: 
if a patient has at least 1 of 3 symptoms [namely cough, muscle or joint pain, or fatigue] 
that is preexisting and worsened, the patient will be assigned to the ‘Yes’ category, 
otherwise ‘No’). 
4.3 
Target Sample Size 
The required sample size of the Intention-to-treat Infected (ITTI) Population will be 1185 
(395 patients for each treatment group). 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 9 of 53 
It is assumed that the reverse transcription polymerase chain reaction (RT-PCR) positive 
rate for influenza A or B virus will be 55%. Therefore, 2157 patients (719 patients for 
each treatment group) will be randomized to ensure an adequate number of patents in the 
ITTI Population. The number of randomized patients may change based on the 
percentage of patients who are RT-PCR positive during the study. 
The primary analysis of the time to improvement of influenza symptoms is to compare 
between the S-033188 group and placebo group. 
The median of the time to alleviation of symptoms in the placebo-controlled clinical trial 
of oseltamivir for high risk patients was estimated to be 161.0 hours (95% confidence 
interval [CI]: 117.3, 215.5) in the placebo group. Based on this result and the fact that the 
proposed study will use a modified primary endpoint, it was assumed that the median 
time to improvement of influenza symptoms in the placebo group will be 150 hours. 
In the Japanese Phase 2 clinical trial in otherwise healthy patients, the median of the time 
to alleviation of symptoms was 49.5 hours (95% CI: 44.5, 64.4) in the 40-mg group 
versus 77. 7 hours (95% CI: 67. 6, 88.7) in the placebo group. Assuming the ratio of 0.64 
(49.5/77.7) for the median time to alleviation of symptoms in the S-033188 group versus 
the placebo group is not different between otherwise healthy patients and high risk 
patients, it can further be assumed that the difference between the S-033188 and placebo 
groups is 54 hours (96 hours in the S-033188 group, 150 hours in the placebo group). In 
the past, placebo-controlled clinical trials of oseltamivir for the otherwise healthy and 
high risk patients, have demonstrated that the difference in the median time to alleviation 
of symptoms between the placebo group and the oseltamivir group for the otherwise 
healthy patients was larger than that in the studies of high risk patients. Therefore, it is 
speculated that the difference between the S-033188 group and the placebo group will be 
< 54 hours. 
The required sample size will therefore be calculated based on the conservative 
assumption of a 36-hour difference (assuming that the median time to improvement of 
influenza symptoms in the placebo group and the S-033188 group was 150 and 114 hours, 
respectively) in the median time to improvement of influenza symptoms between the 
S-033188 group and the placebo group to ensure at least 90% power in the efficacy 
evaluation of S-033188. 
Patients will be randomized on a 1:1 basis to either S-033188 or placebo and a follow-up 
period will be 336 hours (14 days). Assuming that the time follows an exponential 
distribution, the study will require 790 patients in the ITTI Population in order for the 
generalized Wilcoxon test to have 90% or more power with a 2-sided significance level 
of 5% (395 patients in the S-033188 group and placebo group, respectively). 
Using a 1:1 randomization ratio between the S-033188 group and the oseltamivir group, 
the ITTI population of oseltamivir will be 395 patients. Table 1 shows the statistical 
power to compare between the S-033188 group and the oseltamivir group under several 
sets of assumed time to improvement of influenza symptoms. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 10 of 53 
Table 1 
Statistical Power to Compare between S-033188 and 
Oseltamivir 
Median time to alleviation of symptoms 
(S-033188 group, oseltamivir group) 
Statistical power for comparison between 
the S-033188 group and the oseltamivir group 
by stratified generalized Wilcoxon test 
(114 hours, 126 hours) 
22.3% 
(108 hours, 126 hours) 
45.3% 
(102 hours, 126 hours) 
71.5% 
(96 hours, 126 hours) 
90.2% 
 
5. ANALYSIS POPULATIONS 
5.1 
Efficacy and Safety Populations 
The definitions of the Intention-to-treat-Infected (ITTI) Population and the Per-protocol 
Set (PPS) as efficacy populations, and Safety Population are provided below. In this study, 
the ITTI Population is the primary analysis population. The PPS is the secondary analysis 
population, and data from the PPS will be used to perform a sensitivity analysis for the 
primary analysis. 
The following analysis populations will be analyzed for this study. The analysis 
populations will be determined before unblinding. 
1) Intention-to-treat-Infected Population 
This population includes all patients who receive the study drug with a confirmed 
diagnosis of influenza virus infection and are enrolled at sites with good clinical 
practice (GCP) compliance. Confirmation of influenza virus infection will be 
based on the results of RT-PCR on Day 1. The population will be analyzed 
according to the treatment to which the patients are randomized.  
2) Per-protocol Set  
This population includes all subjects included in the ITTI Population and did not 
meet any of the following conditions: 
 Ineligible patients 
 Patients with noncompliance of treatment 
– Treatment compliance rate is less than 60%. The definition of treatment 
compliance rate shown in Section 8.1 will be used. 
 Patients with inadequate Follow-up 
– Subjects have no symptom data after initial treatment 
 Patients with prohibited medications 
 Patients with incorrect treatment allocation 
 Patients with severe protocol deviation 
3) Safety population  
This population includes all randomized patients who receive at least 1 dose of 
the study drug. The population will be analyzed according to the initial treatment 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 11 of 53 
that the patients actually received. If a subject takes S-033188 and oseltamivir as 
the initial treatment, the subject belongs to the S-033188 group. 
6. HANDLING OF DATA IN ANALYSES 
6.1 
Statistical Analysis 
Unless otherwise noted, continuous variables will be summarized by using the number of 
nonmissing observations, arithmetic mean, standard deviation, median, minimum, and 
maximum values as summary statistics; categorical variables will be summarized by 
using the frequency count and the percentage of subjects in each category as summary 
statistics. 
Subject study data, including data not appearing in tables, will be presented in by-subject 
data listings. In general, all tables will be presented by treatment group. Individual 
subject data and any derived data will be presented by treatment and subject. All analyses 
and tabulations will be performed using SAS® Version 9.2 or higher. 
6.2 
Statistical Tests 
All statistical tests will be performed at the 0.05 significance level using 2-sided tests, 
unless otherwise noted. 
The primary endpoint will first be compared between the S-033188 and placebo groups 
(primary analysis). Together with the primary efficacy analysis, the comparison between 
the S-033188 and the oseltamivir groups (secondary analysis) will be conducted. For the 
submission to countries other than Japan the secondary analysis will only be performed if 
a statistically significant difference is observed in the primary analysis, in order to 
maintain control of overall type I error. 
6.3 
Acceptable Time Windows for Investigations, Observations, and 
Examinations 
The acceptable time windows shown in Table 2-1 will be used to collect data from the 
patient diary. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 12 of 53 
Table 2-1 
Acceptable Time Windows for Parameters of the Patient 
Diary 
Time Point 
Specified Assessment Time 
Point 
Acceptable Time Window 
12 hours postdose 
Time of first dosing + 12 hours 
Between ≥ 6 and < 18 hours after first dosing 
24 hours postdose 
Time of first dosing + 24 hours 
Between ≥ 18 and < 30 hours after first dosing 
36 hours postdose 
Time of first dosing + 36 hours 
Between ≥ 30 and < 42 hours after first dosing 
48 hours postdose 
Time of first dosing + 48 hours 
Between ≥ 42 and < 54 hours after first dosing 
60 hours postdose  
Time of first dosing + 60 hours 
Between ≥ 54 and < 66 hours after first dosing 
72 hours postdose 
Time of first dosing + 72 hours 
Between ≥ 66 and < 78 hours after first dosing 
84 hours postdose 
Time of first dosing + 84 hours 
Between ≥ 78 and < 90 hours after first dosing 
96 hours postdose 
Time of first dosing + 96 hours 
Between ≥ 90 and < 102 hours after first dosing 
108 hours postdose 
Time of first dosing + 108 hours 
Between ≥ 102 and < 114 hours after first dosing 
120 hours postdose 
Time of first dosing + 120 hours 
Between ≥ 114 and < 126 hours after first dosing 
132 hours postdose 
Time of first dosing + 132 hours 
Between ≥ 126 and < 138 hours after first dosing 
144 hours postdose 
Time of first dosing + 144 hours 
Between ≥ 138 and < 150 hours after first dosing 
156 hours postdose 
Time of first dosing + 156 hours 
Between ≥ 150 and < 162 hours after first dosing 
168 hours postdose 
Time of first dosing + 168 hours 
Between ≥ 162 and < 174 hours after first dosing 
180 hours postdose 
Time of first dosing + 180 hours 
Between ≥ 174 and < 186 hours after first dosing 
192 hours postdose 
Time of first dosing + 192 hours 
Between ≥ 186 and < 198 hours after first dosing 
204 hours postdose 
Time of first dosing + 204 hours 
Between ≥ 198 and < 210 hours after first dosing 
216 hours postdose 
Time of first dosing + 216 hours 
Between ≥ 210 and < 222 hours after first dosing 
240 hours postdose 
Time of first dosing + 240 hours 
Between ≥ 228 and < 252 hours after first dosing 
264 hours postdose 
Time of first dosing + 264 hours 
Between ≥ 252 and < 276 hours after first dosing 
288 hours postdose 
Time of first dosing + 288 hours 
Between ≥ 276 and < 300 hours after first dosing 
312 hours postdose 
Time of first dosing + 312 hours 
Between ≥ 300 and < 324 hours after first dosing 
336 hours postdose 
Time of first dosing + 336 hours 
Between ≥ 324 and < 348 hours after first dosing 
360 hours postdose 
Time of first dosing + 360 hours 
Between ≥ 348 and < 372 hours after first dosing 
384 hours postdose 
Time of first dosing + 384 hours 
Between ≥ 372 and < 396 hours after first dosing 
408 hours postdose 
Time of first dosing + 408 hours 
Between ≥ 396 and < 420 hours after first dosing 
432 hours postdose 
Time of first dosing + 432 hours 
Between ≥ 420 and < 444 hours after first dosing 
456 hours postdose 
Time of first dosing + 456 hours 
Between ≥ 444 and < 468 hours after first dosing 
480 hours postdose 
Time of first dosing + 480 hours 
Between ≥ 468 and < 492 hours after first dosing 
504 hours postdose 
Time of first dosing + 504 hours 
Between ≥ 492 and < 516 hours after first dosing 
528 hours postdose 
Time of first dosing + 528 hours 
Between ≥ 516 and < 600 hours after first dosing 
 
Time points for EuroQol–5 Dimensions–5 Levels (EQ-5D-5L) and a visual analogue 
scale included in EQ-5D-5L will be not assigned separately. 
 
The acceptable time windows shown in Table 2-2 will be used for the assessment of 
items other than data from the patient diary. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 13 of 53 
Table 2-2 
Acceptable Time Windows for Parameters Other than 
Data from the Patient Diary 
Time Point 
Acceptable Time Window 
Predose at Visit 1 (Day 1: Day -2 to Day1) 
Predose from Day -2 to Day 1 for safety 
assessment 
Predose at Visit 1(Day 1) 
Predose on Visit 1 for efficacy assessment 
Postdose at Visit 1 (Day 1) 
QOL assessment with EQ-5D-5L 
questionnaire: 
by 0.5 hour post-dose on Day 1 
Other measurements: 
0.5 to 4 hours post-dose on Day 1 
Visit 2 (Day 2) 
Day 2 
Visit 3 (Day 3) 
Between Days 3 and 4 
Optional Visit 1 (Day 4) 
Day 4 
Visit 4 (Day 5) 
Between Days 5 and 6 
Optional Visit 2 (Day 6) 
Day 6 
Visit 5 (Day 9) 
Between Days 7 and 11 
Visit 6 (Day 15) 
Between Days 12 and 18 
Visit 7 (Day 22) 
Between Days 19 and 25 
Early Termination 
Date of Early Termination + 3 days 
 
Measurements collected within the acceptable time window for each scheduled 
assessment time point, including data obtained at the time of withdrawal, will be used for 
the analyses of all endpoints at each assessment time point. For all patients with multiple 
measurements within a visit window, the measurement obtained closest to the target time 
point will be used, except for EQ-5D-5L at 528 hours. If 2 measurements collected with 
the same time deviation exist before and after the target time point, the measurement 
obtained before the target time point will be adopted for analysis. Only for the assessment 
of EQ-5D-5L at 528 hours, data entered at the site is prioritized if multiple measurements 
collected within the window. The assessment time point having no measurements within 
the corresponding acceptable time window will be considered as missing. 
In the patient diary, if there are multiple measurements which may be adopted for a 
scheduled assessment, even though the above rules have been strictly followed, the 
measurements of the earlier assessment date or the earlier assessment time of day will be 
adopted (with the priority given to morning, followed by afternoon, evening, and bedtime, 
in this order). If multiple measurements collected at the same time (date and time) for 
body temperature, the highest measurement will be adopted. 
In the assessment of items from other than the patient diary, if there are multiple 
measurements that may be adopted for a scheduled assessment time point (even though 
the above rules have been strictly followed), the below rules will be applied: 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 14 of 53 
1. The measurements at the time point entered in the case report form (CRF) will be 
adopted. 
2. The measurements with the smallest specimen ID will be adopted if there are still 
more than one measurement after rule 1 is applied. 
6.4 
Handling of Missing Data 
If the time of first dosing is missing and the dates of first dosing and assessment of 
influenza symptom before randomization are same, the time of assessment of influenza 
symptom before randomization will be imputed. 
Other missing data will not be imputed.  
-
 Patients who do not experience improvement of symptoms will be censored at the 
last observation time point, except for sensitivity analysis for the primary 
analysis. 
– If all symptoms were missing after baseline, the time to improvement of 
symptoms, the time to improvement of symptoms excluding cough, the time 
to improvement of the 4 systemic symptoms, the time to improvement of the 
3 respiratory symptoms, and the time to improvement of individual symptoms 
will be handled as missing. 
-
 The following rules will be applied to the assessment of the primary endpoint. 
 
If at least 1 of 7 influenza symptom scores except for the preexisting 
symptoms judged as ‘not worsened’ and ‘severe’ at baseline is missing but the 
date and time of assessment are not missing, the missing values will 
conservatively be treated as failures at the corresponding date and time of 
assessment. 
 
If influenza symptom scores are missing for the preexisting symptoms judged 
as ‘not worsened’ and ‘severe’ at baseline, these symptoms will not be 
evaluated for assessment of the primary endpoint. 
-
 The following rule will be applied to the assessment of ‘Time to alleviation of 
symptoms’. 
 
If at least 1 of the 7 influenza symptom scores is missing but the date and time 
of assessment are recorded, this missing assessment will conservatively be 
treated as a moderate or severe symptom (as failures) at the corresponding 
date and time of assessment. 
-
 The following rules will be applied to the assessment of ‘Time to improvement of 
the 4 systemic symptoms’. 
 
If at least 1 of 4 systemic symptom scores except for the preexisting 
symptoms judged as ‘not worsened’ and ‘severe’ at baseline is missing but the 
date and time of assessment are not missing, the missing values will 
conservatively be treated as having a moderate or severe symptom (as 
failures) at the corresponding date and time of assessment. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 15 of 53 
 
If influenza symptom scores are missing for the preexisting symptoms judged 
as ‘not worsened’ and ‘severe’ at baseline, these will not be evaluated for 
assessment. 
-
 The following rules will be applied to the assessment of ‘Time to improvement of 
the 3 respiratory symptoms’. 
 If at least 1 of 3 respiratory symptom scores except for the preexisting 
symptoms judged as ‘not worsened’ and ‘severe’ at baseline is missing but the 
date and time of assessment are not missing, the missing values will 
conservatively be treated as having a moderate or severe symptom (as 
failures) at the corresponding date and time of assessment.  
 If influenza symptom scores are missing for the preexisting symptoms judged 
as ‘not worsened’ and ‘severe’ at baseline, these will not be evaluated for 
assessment. 
-
 The following rule will be applied to the assessment of ‘Time to improvement of 
individual symptoms’. 
 
If the symptom score is missing but the date and time of assessment are 
recorded, the missing assessment will conservatively be treated as not 
improved (as failures). 
-
 The following rule will be applied to the assessment of ‘Time to resolution of 
fever’. 
 If the value of body temperature is missing but the date and time of 
assessment are recorded, the missing assessment will conservatively be treated 
as more than 37ºC (as failures). 
-
 The following rule will be applied to the assessment of ‘Time to return to 
preinfluenza health status’. 
 If the score of health status is missing but the date and time of assessment are 
recorded, the missing assessment will conservatively be treated as having less 
than the score of the preinfluenza health status. 
-
 For the sensitivity analysis for the primary endpoint, the patients who do not 
experience improvement of symptoms will be treated as follows. 
– For patients who discontinue from the study and still have influenza 
symptoms, the time to improvement of symptoms will be censored as 336 
hours. 
– In consideration of treatment duration of the oseltamivir group. 
 For patients who discontinue up to Day 5 and still have influenza, the time 
to improvement of symptoms will be censored at the last observation time 
point. 
 If patients who discontinue after Day 5 and still have influenza, the time to 
improvement of symptoms will be censored as 336 hours. 
– In consideration of the reason of the discontinuation. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 16 of 53 
 For patients who discontinue due to AE or lack of efficacy, the time to 
improvement of symptoms will be censored as 336 hours. 
 
For patients who discontinue due to other reason, the time to improvement 
of symptoms of will be censored at the last observation time point. 
 
Handling of Virology Test Data in Consideration of the Stability 
6.4.1
Window 
Sample processing time is defined as the time between the time of sample collecting and 
the time of sample aliquotting recorded in the shipment manifest from Eurofins. Any 
quantitative influenza virus titer and quantitative PCR samples processed within 96 hour 
as sample processing time will be included for analysis. The qualitative PCR before 
initial dosing is excluded from the 96 hour turn-around requirement. All qualitative PCRs 
before initial dosing will be considered evaluable regardless of sampling and aliquotting 
time. If the time of sample aliquotting is not recorded at Eurofins, sample processing time 
will be treated as missing and the sample will not be used for analysis. 
6.5 
Definition 
 
Display of Days of Study 
6.5.1
The date of the first dose and the day before the first dose of the treatment will be 
designated as Day 1 and Day -1, respectively. 
 
Baseline 
6.5.2
For influenza symptom scores, the measurement entered in the CRF is defined as baseline. 
If there are influenza symptom scores entered in the e-Diary prior to the initial dosing, 
these measurements will not be used for analysis. 
For body temperature, the measurement entered in the CRF as baseline is defined as 
baseline.  
For assessment of health and EQ-5D-5L1, the measurement with the following 2 
conditions is defined as baseline. If there are multiple measurements that may be adopted, 
the measurement obtained at the earliest time will be used, otherwise measurements prior 
to the initial dosing will not be used for analysis. 
 Data observed when e-Diary is set up 
 Data observed on the same date as the date of the first administration 
For assessment of health prior to influenza symptoms, the measurement with the 
following condition is defined as health status prior to influenza symptoms. If there are 
                                                 
1 Baseline time point for EQ-5D-5L and a visual analogue scale included in EQ-5D-5L 
will be not assigned separately. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 17 of 53 
multiple measurements that may be adopted, the measurement obtained at the earliest 
time will be used.  
 Data observed on the same date as the date of the first administration 
For efficacy assessments other than above, baseline is defined as the measurement 
obtained at Visit 1 (predose). 
For safety assessments other than above, baseline is defined as the last measurement 
obtained before the first administration. 
7. DEMOGRAPHIC VARIABLES AND OTHER BASELINE 
CHARACTERISTICS 
7.1 
Subject Disposition 
1) Among all randomized subjects, the numbers of subjects who complete the study 
and subjects who discontinue the study will be tabulated by treatment group. For 
subjects who discontinue the study, reasons for withdrawal will also be tabulated 
by treatment group. 
2) The number and percentage of subjects included in each of the ITTI and the PPS 
Populations among all randomized subjects will be calculated by treatment group. 
For the subjects excluded from each population, the reason for exclusion will be 
summarized. Fisher’s exact test will be performed with a 2-sided significance 
level of 0.15 to check differences between the S-033188 group and the placebo or 
the oseltamivir group regarding the distribution of subjects in the ITTI and the 
PPS Populations. 
3) The number and percentage of subjects included in the Safety population among 
all randomized subjects will be calculated by treatment group. For the subjects 
excluded from the Safety population, the reason for exclusion will be summarized. 
Patients who take at least 1 dose of the study drug will be included in the 
treatment group of the drug that they received. Patients who do not take any doses 
of study drug will be included in the treatment group that they were randomized 
to. 
7.2 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics among the ITTI and Safety 
Populations will be summarized using descriptive statistics for the S-033188 group, 
oseltamivir group and placebo group. For quantitative data, the descriptive statistics will 
be calculated. For qualitative data, the frequency of each category and the percentage of 
subjects in each category among all subjects included in the analysis population will be 
presented.  


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 18 of 53 
-
 Continuous variables 
Age, height, body weight, body mass index (BMI), composite symptom scores of 
influenza symptoms body temperature, influenza virus titer at baseline, amount of 
virus RNA at baseline 
-
 Categorical variables 
Age, body weight, sex, region, race, ethnicity, prior drug, prior therapy, medical 
history, smoking habits, presence or absence of meal before initial study treatment, 
presence or absence of meal after initial study treatment, duration between meal 
and administration (hours) (definition: absolute value of “time of dosing on Day 1” 
minus “time of meal obtained closest to the time of dosing on Day 1”), composite 
symptom scores, time to treatment from flu onset, influenza virus subtype based 
on Rapid Influenza Diagnostic Test (RIDT), influenza virus subtype based on 
RT-PCR, presence or absence of flu vaccination. 
If the mealtime before/after initial study treatment and the time of initial study treatment 
are not chronological, it will be assumed that the date is before/after the date of initial 
study treatment. 
High risk factors (see Table 8) among the ITTI and Safety Populations will also be 
summarized by treatment groups. 
The preexisting and worsened symptoms of ‘cough’, ‘muscle or joint pain’, and ‘fatigue’ 
will also be summarized by treatment groups for the ITTI Population. The categories for 
the summarization are ‘preexisting and worsened’, ‘preexisting and not worsened’ and 
‘absent’. The percentage of patients with ‘preexisting and worsened’ will be calculated 
by treatment groups for the ITTI population also. 
8. STUDY CONDUCT 
8.1 
Treatment Exposure and Compliance 
The duration of treatment exposure will be summarized with descriptive statistics by the 
S-033188 group and oseltamivir group for the safety population. 
The duration of treatment exposure [day] in the oseltamivir group is defined as the dosing 
period during which a subject takes medication as follows: 
{(final dose date) – (initial dose date) + 1} 
For the S-033188 group, duration of exposure is defined as 1 day if actual S-033188 
tablets are dosed on Day 1. 
The treatment compliance rate will be summarized with descriptive statistics by the 
treatment group for the Safety population. In addition, the frequency of each category 
(shown in Table 8) and the percentage of subjects in each category among all subjects 
included in the analysis population will be presented. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 19 of 53 
The treatment compliance rate [%] in the oseltamivir group is defined as: 
100×{(actual frequency of treatment exposure) / (expected frequency of treatment exposure by 
early discontinuation of treatment)}  
For S-033188 group, treatment compliance is defined as 100% if actual S-033188 tablets 
are dosed on Day 1. 
8.2 
Medical History 
Prior and concomitant medical histories will be coded using the MedDRA Version 19.1. 
Medical history (concurrent and previous disease) will be presented by treatment groups 
for the Safety population. 
8.3 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary. Medication consists of drug and therapy. Prior medication is 
defined as all medications taken before Day 1 of study administration. Concomitant 
medication is defined as all medications taken on Day 1 or later. The drug and therapy 
can also be classified as both prior and concomitant if the medication starts before study 
administration and is still ongoing after study administration. 
For Safety population, the number of subjects who took prior medication and 
concomitant medication, and corresponding proportion will be summarized by WHO 
class and Preferred Term for each treatment group. For Safety population, the number of 
subjects who had prior therapy and concomitant therapy, and corresponding proportion 
will be summarized for each treatment group. 
For ITTI Population, the frequency of acetaminophen use collected in the eDiary will be 
summarized by treatment groups. If the date or time of acetaminophen use is missing, but 
the record is available, the record is counted as the information that the patient uses 
acetaminophen. The Wilcoxon rank sum test will be used to compare the frequencies 
between the S-033188 group and the placebo or the oseltamivir group. The 2-sided 
significance level will be set at 0.15 in these analyses. 
9. EFFICACY ANALYSIS 
In the ITTI Population that is the primary analysis population, the primary endpoint and 
all secondary endpoints will be analyzed. For the PPS that is a secondary analysis 
population, only the primary endpoint will be analyzed. Table 3 summarizes the primary 
endpoint, secondary endpoints, other endpoints and statistical methods used to analyze 
these endpoints. The detailed statistical methods are described in later sections. 
The analysis of each efficacy endpoint will consist of comparison between the S-033188 
group (40 mg and 80 mg combined) and the placebo group, and comparison between the 
S-033188 group (40 mg and 80 mg combined) and the oseltamivir group. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 20 of 53 
Table 3 
Statistical Methods Used to Analyze Each Endpoint 
Endpoint Analysis 
Statistical 
Method 
Primary Endpoint 
Time to improvement of symptoms 
1, 2, 9, 10, 11 
Secondary 
Endpoints 
Proportion of patients positive for influenza virus titer 
3, 13 
Proportion of patients positive by RT-PCR 
3, 13 
Change from baseline in influenza virus titer 
4, 12 
Change from baseline in the amount of virus RNA 
(RT-PCR) 
4, 12 
Area under the curve adjusted by baseline in influenza virus 
titer 
4, 12 
Area under the curve adjusted by baseline in the amount of 
virus RNA (RT-PCR) 
4, 12 
Time to cessation of viral shedding by influenza virus titer 
1, 9, 10, 11 
Time to cessation of viral shedding by RT-PCR 
1, 9, 10, 11 
Proportion of patients whose symptoms has been improved 
3, 13 
Time to alleviation of symptoms 
1, 9, 10, 11* 
Time to improvement in the 4 systemic symptoms 
1, 9, 10, 11* 
Time to improvement in the 3 respiratory symptoms 
1, 9, 10, 11* 
Time to resolution of fever 
1, 9, 10, 11 
Proportion of patients reporting normal temperature 
3, 13 
Body temperature 
6, 12 
Time to improvement of individual symptoms 
1, 9, 10, 11* 
Time to return to preinfluenza health status 
1, 9, 10, 11* 
Requirement for systemic antibiotics for infections 
secondary to influenza infection 
5, 13 
Incidence of influenza-related complications 
5, 13 
Other Endpoints 
Serum influenza antibody titer 
7, 13, 14 
Polymorphic and treatment-emergent amino acid 
substitutions in the PA gene of evaluable virus 
13 
Drug susceptibility in patients with evaluable virus 
12 
EQ-5D-5L and EQ VAS 
12 
Work productivity questionnaire 
12 
Intrahousehold infection rate 
8 
EQ-5D-5L = EuroQol–5 Dimensions–5 Levels; EQ VAS = Euro Qol visual analog scale 
* 
Confidence interval of difference in median time between treatment groups will not be calculated. 
[Statistical test methods] 
1. Stratified Peto-Prentice’s generalized Wilcoxon test 
2. Stratified log rank test 
3. Mantel-Haenszel test 
4. van Elteren test 
5. Fisher’s exact test 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 21 of 53 
6. Analysis of covariance (ANCOVA) 
7. Wilcoxon rank sum test 
8. Poisson regression model 
[Summarization methods] 
9. Kaplan-Meier curve 
10. Median time and its 95% confidence interval 
11. Treatment group difference in median time and its 95% confidence interval (Bootstrap method) 
12. Summary statistics (continuous variables) 
13. Summary statistics (categorical variables) 
14. Geometric mean 
9.1 
Primary Endpoint 
The primary efficacy endpoint will be the time to improvement of influenza symptoms 
(with modification for preexisting symptoms): 
 Preexisting symptoms (i.e., cough, fatigue, or muscle/joint pain that existed prior 
to developing influenza) that were judged by the patient to be worse at baseline 
(i.e., the predose examinations) must improve from baseline severity 
o Improvement in baseline severity is as follows: 
 Severe moderate, mild, or absent 
 Moderate mild or absent 
 Mild mild or absent 
 Absent mild or absent 
o Note: At baseline (i.e., the predose examinations), patients will only be asked 
if preexisting symptoms existed (within the last 30 days) and if they were 
worsened by influenza. Patients will be asked to rate the severity at baseline 
that needs to improve. To avoid recall bias, patients will not be asked to rate 
the severity of preexisting symptoms prior to influenza. 
 Preexisting symptoms (i.e., cough, fatigue, or muscle/joint pain that existed prior 
to developing influenza) that were judged by the patient to NOT be worse at 
baseline (i.e., the predose examinations) must have their baseline severity 
maintained 
o Maintenance of baseline severity is as follows: 
 Severe severe or less than severe 
 Moderate moderate or less than moderate 
 Mild mild or absent 
 Absent mild or absent 
 For new symptoms at baseline (i.e., the predose examinations), alleviation of 
symptoms assessment must be achieved 
o Alleviation of symptoms is as follows: 
 Severe mild or absent 
 Moderate mild or absent 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 22 of 53 
 Mild mild or absent 
 Absent mild or absent 
Time to improvement of influenza symptoms is defined as the time from the initiation of 
the study treatment to the improvement of influenza symptoms. Once all of a patient’s 
influenza symptoms are alleviated, maintained, or improved (hereafter all will be called 
‘improvement’) as defined above, the endpoint for that patient will be reached, for a 
duration of at least 21.5 hours (24 hours −10%). 
Patients who do not experience improvement of symptoms will be censored at the last 
observation time point.  
 
Analyses of Primary Endpoint 
9.1.1
9.1.1.1 
Primary Analysis 
The time to improvement of influenza symptoms will be compared between the S-033188 
group and the placebo group or the oseltamivir group using the stratified Peto-Prentice’s 
generalized Wilcoxon test with composite symptom score, i.e, sum of 7 influenza 
symptoms, at baseline (≤ 14 or ≥ 15), preexisting and worsened symptom (Yes or No: if a 
patient has at least 1 of 3 symptoms [namely cough, muscle or joint pain, or fatigue] that 
is preexisting and worsened, the patient will be assigned to the ‘Yes’ category , otherwise 
‘No’), and region (Asia, North America/Europe, Southern Hemisphere) as stratification 
factors.  
[Comparison between the S-033188 group and the placebo group] 
proc lifetest data = analysisdata; 
where TRTP in ("S-033188", "Placebo"); 
time TIME * CENSOR (0); 
 strata SCOREC PREEX REGION / group = TRTP test = PETO ; 
run;quit; 
-
 TRTP: Treatment group 
-
 TIME: Time to alleviation of symptoms 
-
 SCOREC: Category of baseline composite symptom score (≤ 14 or ≥ 15) 
-
 PREEX: Category of preexisting and worsened (Yes or No) 
-
 REGION: Category of region (Asia, North America/Europe, Southern 
Hemisphere) 
The same analysis in PPS will be performed as a sensitivity analysis. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 23 of 53 
9.1.1.2 
Other Analysis 
The Kaplan-Meier survival curve will be plotted for each treatment group, and the 
median time to improvement of influenza symptoms and its 95% CI will be calculated. 
The Greenwood method will be used in the calculation of the CIs. In addition, the 
treatment group difference in median time and its 95% CI will be estimated.  
The 95% CI of treatment group difference in median time will be obtained by the 
bootstrap percentile method. The 10,000 bootstrap samples will be generated using the 
following SAS code. A random seed of 16010831 and 16010832 will be used for 
comparison between the S-033188 and the placebo or the oseltamivir, respectively. Then, 
the treatment group difference in median time will be calculated in each bootstrapped 
sample and its 95% CI will be constructed using percentiles of the bootstrap distribution. 
proc surveyselect data = analysisdata seed = 16010831 out = bootstap method = urs  
rate = 1.0 rep = 10000 outhits; 
 strata TRTP; 
run;quit; 
-
 TRTP: Treatment group 
The same analysis in PPS will be performed as a sensitivity analysis. 
9.1.1.3 
Sensitivity Analysis 
1) Time to improvement of influenza symptoms will be compared between the 
S-033188 group and the placebo group using the stratified log-rank test with 
composite symptom score at baseline (≤ 14 or ≥ 15), preexisting and worsened 
symptom (Yes or No), and region (Asia, North America/Europe, Southern 
Hemisphere) as stratification factors. Patients who do not experience 
improvement of influenza symptoms will be censored at the last observation time 
point. The same analysis will be applied to compare the S-033188 group with the 
oseltamivir group. 
2) Patients who discontinue from the study and still do not achieve the improvement 
of influenza symptoms will be treated as follows in the similar analysis described 
in Sections 9.1.1.1, 9.1.1.2 and 9.1.1.3 (excluding analyses of PPS population and 
95% CI for the treatment group difference in the median time). 
-
 If a patient discontinues from the study and still does not achieve 
improvement of influenza symptoms, the time to improvement of influenza 
symptoms will be treated as censored at 336 hours. 
-
 In consideration of treatment duration of the oseltamivir group. 
 For patients who discontinue up to Day 5 and still do not achieve 
improvement of influenza symptoms, the time to improvement of 
influenza symptoms will be treated as censored at the last observation time 
point. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 24 of 53 
 For patients who discontinue after Day 5 and still do not achieve the 
improvement of influenza symptoms, the time to improvement of 
influenza symptoms will be treated as censored at 336 hours. 
-
 In consideration of the reason of the discontinuation. 
 If a patient discontinues due to an AE or lack of efficacy, the time to 
improvement of influenza symptoms will be treated as censored at 336 
hours. 
 If a patient discontinues due to other reasons, the time to improvement of 
influenza symptoms of the patients will be censored at the last observation 
time point. 
3) Time to improvement of symptoms excluding the cough symptom will be 
compared between the S-033188 group and the placebo group using the same 
analysis method as that for the sensitivity analysis in Section 9.1.1.3 2). The same 
analysis will be applied to compare the S-033188 group with the oseltamivir 
group. 
9.2 
Secondary Endpoints 
1) Proportion of patients positive for influenza virus titer (unit: %) 
Proportion of patients positive for influenza virus titer is defined as the percentage 
of patients whose influenza virus titer is not less than the lower limit of 
quantification (0.7 log10TCID50/mL) or positive among those assessed for 
influenza virus titer on Days 2, 3, 4, 5, 6, and 9. Patients with a positive influenza 
virus titer on Day 1 will be included in this analysis. 
2) Proportion of patients positive by RT-PCR (unit: %) 
Proportion of patients positive by RT-PCR is defined as the percentage of patients 
with detectable virus RNA (2.05 for flu A and 2.83 for flu B log10 vp/mL) among 
those assessed by RT-PCR on Days 2, 3, 4, 5, 6, and 9.  
Patients with a positive by RT-PCR on Day 1 will be included in this analysis. 
3) Change from baseline in influenza virus titer (unit: log10TCID50/mL) 
Change from baseline in influenza virus titer is defined as the change from 
baseline in influenza virus titer on Days 2, 3, 4, 5, 6, and 9. If influenza virus titer 
is less than the lower limit of quantification, the virus titer will be imputed 0.7 
(log10TCID50/mL).  
Patients with a positive virus titer on Day 1 will be included in this analysis. 
4) Change from baseline in the amount of virus RNA (RT-PCR) (unit: log10 virus 
particles/mL) 
Change from baseline in the amount of virus RNA is defined as the change from 
baseline in the amount of virus RNA on Days 2, 3, 4, 5, 6, and 9. If the amount of 
virus RNA is less than the lower limit of quantification and greater than or equal 
to the lower limit of detection, the amount of virus RNA will be imputed 2.18 for 
flu A and 2.93 for flu B (log10 virus particles/mL). If the amount of virus RNA is 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 25 of 53 
less than the lower limit of detection, the amount of virus RNA will be imputed 
2.05 for flu A and 2.83 for flu B (log10 vp/mL). If the result is reported as ‘POS’ 
but the amount of virus RNA is not reported, the record will not be used for 
analysis. If a patient is infected with 1 virus type, the amount of virus RNA for 
infected virus type will be used for analysis. If a patient is infected with multiple 
virus types, the sum of those amounts of virus RNA 
[






B
flu 
for 
amount 
log
A
flu 
for 
amount 
log
10
10
10
10
10
log

] will be used for analysis. If the 
amount of virus RNA is missing for at least 1 of the multiple infected virus types 
collected on the same date, the amount of multiple virus RNA will be handled as 
missing at the corresponding date of assessment.  
Patients with a positive by RT-PCR on Day 1 will be included in this analysis. 
5) Area under the curve adjusted by baseline in influenza virus titer  
(unit: log10TCID50/mL×hours) 
This endpoint is defined as AUC of change from baseline in influenza virus titer 
from Day 1 to Day 9. Area under the curve is calculated using the trapezoidal 
method. Area under the curve of change from time 0 (t0) to time K (tK) is given by 
the formula 
 










K
k
k
k
k
k
t
t
y
y
y
1
1
0
1
2
2
 
where tk (hours) represents the time of the kth viral titer assessment (k = 0, ..., K) 
and yk represents the log10 value of the kth viral titer assessment (log10TCID50/mL). 
The lower limit is defined as 0.7 (log10TCID50/mL). One day is equal to 24-hours.  
Patients with a positive influenza virus titer on Day 1 and available sample on 
Day 9 will be included in this analysis.  
All measurements collected within acceptable time windows from Day 1 to Day 9 
will be used to calculate the endpoint. If more than one measurement is collected 
on the same date, the measurement with smallest specimen ID will be used. 
6) Area under the curve adjusted by baseline in the amount of virus RNA (RT-PCR) 
(unit: log10 virus particles/mL × hours) 
This endpoint is defined as AUC of change from baseline in the amount of virus 
RNA (RT-PCR) from Day 1 to Day 9. The AUC is calculated using the same 
formula described in ‘Area under the curve adjusted by baseline in influenza virus 
titer’. The lower limit of quantification and greater than or equal to the lower limit 
of detection is defined as 2.18 for flu A and 2.93 for flu B (log10 virus 
particles/mL). The amount of virus RNA is less than the lower limit of detection, 
the amount of virus RNA will be imputed 2.05 for flu A and 2.83 for flu B (log10 
vp/mL). If a patient is infected with one virus type, the amount of virus RNA for 
infected virus type will be used for analysis. If a patient is infected with multiple 
virus types, the sum of those amounts of virus RNA will be used for analysis. If 
the amount of virus RNA is missing for at least one of the multiple infected virus 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 26 of 53 
types collected on the same date, the amount of multiple virus RNA will be 
handled as missing at the corresponding date of assessment.  
Patients with a positive by RT-PCR on Day 1 and available sample on Day 9 will 
be included in this analysis. 
All measurements collected within acceptable time windows from Day 1 to Day 9 
will be used to calculate the endpoint. If more than one measurement is collected 
on the same date, the measurement with smallest specimen ID will be used. 
7) Time to cessation of viral shedding by influenza virus titer (unit: hours) 
This endpoint is defined as the time between the initiation of the study treatment 
and first time when the influenza virus titer is below the limit of detection 
(0.7 log10TCID50/mL) or negative. Patients whose virus titers have not reached 
the limit by the last observation time point will be treated as censored at that time 
point. One day is converted into 24 hours. 
Patients with a positive virus titer on Day 1 will be included in this analysis.  
8) Time to cessation of viral shedding by RT-PCR (unit: hours) 
This endpoint is defined as the time between the initiation of the study treatment 
and first time when the virus RNA by RT-PCR is below the limit of detection. 
Patients whose virus RNA have not reached the limit by the last observation time 
point will be treated as censored at that time point. For the patients with multiple 
virus types, this endpoint is defined as the time between the initiation of the study 
treatment and first time when the virus RNA by RT-PCR is below the limit of 
detection for all virus types. One day is converted into 24 hours. 
Patients with a positive virus RNA on Day 1 will be included in this analysis. 
9) Proportion of patients whose symptoms have been improved (unit: %) 
This endpoint is defined as the percentage of patients whose symptoms have been 
improved at 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the 
initial of study treatment. The improvement of influenza symptom is defined in 
the Section 9.1. 
10) Time to alleviation of symptoms (unit: hours) 
This endpoint is defined as the time between the initiation of the study treatment 
and the alleviation of influenza symptoms. The alleviation of symptoms is defined 
as the time when all of 7 influenza symptoms (cough, sore throat, headache, nasal 
congestion, feverishness or chills, muscle or joint pain, and fatigue) have been 
assessed by the patient as 0 (None) or 1 (Mild) in the patient eDiary, for a 
duration of at least 21.5 hours (24 hours −10%). Patients, who do not experience 
alleviation of symptoms, will be censored at the last observation time point.  
11) Time to improvement of the 4 systemic symptoms (unit: hours) 
The endpoint is defined as the time between the initiation of the study treatment 
and the improvement of the all 4 systemic symptoms (headache, feverishness or 
chills, muscle or joint pain, and fatigue). The improvement of influenza symptom 
is defined in the Section 9.1. Once all 4 of a patient’s influenza symptoms are 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 27 of 53 
alleviated, maintained, or improved as defined, the endpoint for that patient will 
be reached, for a duration of at least 21.5 hours (24 hours −10%). 
Patients who do not experience improvement of 4 systemic symptoms will be 
censored at the last observation time point. 
12) Time to improvement of the 3 respiratory symptoms (unit: hours) 
The endpoint is defined as the time between the initiation of the study treatment 
and the improvement of the all 3 respiratory symptoms (cough, sore throat, and 
nasal congestion). The improvement of influenza symptom is defined in the 
Section 9.1. Once all 3 of a patient’s influenza symptoms are alleviated, 
maintained, or improved as defined, the endpoint for that patient will be reached, 
for a duration of at least 21.5 hours (24 hours −10%). 
Patients who do not experience improvement of 3 respiratory symptoms will be 
censored at the last observation time point.  
13) Time to resolution of fever (unit: hours) 
Time to resolution of fever is defined as the time between the initiation of the 
study treatment and the resolution of fever. The resolution of fever is defined as 
the time when the patient’s self-measured axillary temperature becomes less than 
37ºC and is maintained at less than 37ºC for at least 12 hours. Patients who do not 
experience resolution of fever by the last observation time point will be censored 
at that time point. Patients whose body temperatures at baseline are less than 37ºC 
or not collected will be excluded from the analysis. Body temperature obtained 
when e-diary is set up after initial dosing will not be used for analysis. Because 
these data may be observed due to e-dairy system’s incorrect setting. 
14) Proportion of patients reporting normal temperature (unit: %) 
Proportion of patients reporting normal temperature is defined as the percentage 
of patients whose axillary body temperature drops to less than 37ºC after the 
initiation of the study treatment at 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 
216 hours. Body temperature obtained when e-diary is set up after initial dosing 
will not be used for analysis. 
Patients whose body temperatures at baseline are less than 37ºC or not collected 
will be excluded from the analysis. 
15) Body temperature (unit: degree) 
Body temperature is defined as measured axillary body temperature at 12, 24, 36, 
48, 72, 96, and 120 hours. Body temperature obtained when e-diary is set up after 
initial dosing will not be used for analysis. 
Patients whose body temperatures at baseline are not collected will be excluded 
from the analysis. 
16) Time to improvement of individual symptoms (unit: hours) 
Time to improvement of cough symptom is defined as the time between the 
initiation of the study treatment and the improvement of cough. The improvement 
cough is defined as a patient’s cough symptom is improved as defined in the 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 28 of 53 
section 9.1, the endpoint for that patient will be reached, for a duration of at least 
21.5 hours (24 hours −10%). 
Patients who do not experience the improvement of cough symptom by the last 
observation time point will be censored at that time point.  
Patients, whose symptoms at baseline are assessed as 0 (None), 1 (Mild), 2 
(Moderate) but preexisting and not worsened, or 3 (Severe) but preexisting and 
not worsened, will be excluded from the analysis. 
The following endpoints are defined in a similar way. 
-
 Time to improvement of sore throat symptom 
-
 Time to improvement of headache symptom 
-
 Time to improvement of nasal congestion symptom 
-
 Time to improvement of feeling feverish or having chills symptom 
-
 Time to improvement of aches and pains of the muscle or joints symptom 
-
 Time to improvement of fatigue symptom 
For analyses of ‘sore throat’, ‘headache’, ‘nasal congestin’ and ‘feeling feverish 
or having chills’, patiens , whose symptoms at baseline are assessed as 0 (None), 
1 (Mild), will be excluded from the analysis population. 
17) Time to return to preinfluenza health status (unit: hours) 
Time to return to preinfluenza health status is defined as the time from the 
initiation of the study treatment to the first time when health status score is equal 
to or higher than the preinfluenza health status score. Patients who have the 
smaller score than the score as preinfluenza health status by the last observation 
time point will be censored at that time point.  
Patients whose health status scores at baseline are equal to or higher than the 
score as preinfluenza health status will be excluded from the analysis. The health 
status score obtained when e-diary is set up after initial dosing will not be used for 
analysis. 
18) Requirement for systemic antibiotics for infections secondary to influenza 
infection (unit: %) 
This endpoint is defined as the percentage of patients who take antibiotics for any  
of the predefined complications (sinusitis, otitis media, bronchitis and pneumonia). 
The records will be identified with the following criteria, which is an example for 
sinusitis, in the form of ‘Incidence of influenza-related complication’. 
 ‘Did these symptoms start after the influenza treatment was given on Day 1?’ 
is ‘Yes’. 
 And ‘Have antibiotics been given to treat the sinusitis?’ is ‘Yes’ 
19) Incidence of influenza-related complications (unit: %) 
This endpoint is defined as the percentage of patients who experience each 
influenza-related complication (any influenza-related complications, 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 29 of 53 
hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically 
confirmed pneumonia). The complications of hospitalization and death will be 
identified from the information of the serious AEs captured in the eCRF. Other 
complications will be identified from the information of specific complication 
eCRFs with the following diagnostic criteria. 
-
 Sinusitis 
 ‘Sinusitis’ in the ‘Form Incidence of influenza-related complications’ is 
‘Yes’ 
 And  ‘Did these symptoms start after the influenza treatment was given 
on Day 1?’ in the ’Form Sinusitis’ is ‘Yes’ 
 And  ‘Does the patient have a purulent nasal discharge?’ in the ’Form 
Sinusitis’ is ‘Yes’ 
 And  ‘Does the patient have facial pain, pressure sensation, or sensation 
of fullness?’ in the ’Form Sinusitis’ is ‘Yes’ 
 And  ‘Does the patient have nasal obstruction, congestion or stuffiness?’ 
in the ’Form Sinusitis’ is ‘Yes’ 
-
 Otitis media 
 ‘Otitis media’ in the ‘Form Incidence of influenza-related complications’ 
is ‘Yes’ 
 And  ‘Did these symptoms start after the influenza treatment was given 
on Day 1?’ in the ’Form Otitis Media’ is ‘Yes’ 
 And  ‘Does the patient have pain or fullness in one or more ears?’ in 
the ’Form Otitis Media’ is ‘Yes’ 
 And  ‘Does the patient have tympanic membrane bulging or fullness on 
otoscopy?’ in the ’Form Otitis Media’ is ‘Yes’ 
-
 Bronchitis  
 ‘Bronchitis’ in the ‘Form Incidence of influenza-related complications’ is 
‘Yes’ 
 And  ‘Did these symptoms start after the influenza treatment was given 
on Day 1?’ in the ’Form Bronchitis’ is ‘Yes’ 
 And  ‘Does the subject have a productive cough that has got worse after 
Day 1?’ in the ’Form Bronchitis’ is ‘Yes’ 
-
 Pneumonia 
 ‘Pneumonia’ in the ‘Form Incidence of influenza-related complications’ is 
‘Yes’ 
 And  ‘Did these symptoms start after the influenza treatment was given 
on Day 1?’ in the ’Form Pneumonia’ is ‘Yes’ 
 And  ‘Does a Chest X Ray confirm pneumonia i.e. consolidation?’ in 
the ’Form Pneumonia’ is ‘Yes’ 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 30 of 53 
9.3 
Other Endpoints 
1) Serum influenza antibody titer 
This endpoint is defined as the ratio of value on Day 22 to that on Day 1. 
2) Polymorphic and treatment-emergent amino acid substitutions in the PA gene of 
evaluable virus 
This endpoint is defined as follows: 
– The percentage of samples which have polymorphic amino acid substitutions 
on Day 1 compared to the reference sequence 
– The percentage of samples which have treatment-emergent amino acid 
substitutions between Day 1 and the RT-PCR positive time point 
For treatment-emergent amino acid substitutions in the PA gene, sequencing data 
obtained at the baseline (Day 1) and the last RT-PCR positive time point will be 
compared for treatment-emergent amino acid substitutions in the PA gene in the 
S-033188 group and placebo group, respectively.  
For polymorphic amino acid substitutions in the PA gene, sequencing data 
obtained at the baseline (Day 1) will be compared to that of the reference 
sequence in the S-033188 group and the placebo group, respectively. 
The patients who have sequencing data will be included in this analysis. 
3) Drug susceptibility in patients with evaluable virus (unit: EC50 nM, IC50 nM) 
This endpoint is defined as follows: 
– EC50 for S-033447 at baseline 
– IC50 for oseltamivir at baseline 
– The ratio of EC50 for S-033447 relative to EC50 for reference stain 
– The ratio of IC50 for oseltamivir relative to IC50 for reference stain 
If the EC50 is less than the lower limit, the EC50 will be imputed as the lower limit 
value (0.03 nM). If the EC50 is greater than upper limit, the EC50 will be imputed 
as the value of upper limit (1000 nM). 
If the IC50 is less than the detection limit, the IC50 will be imputed as detection 
limit value (0.01 nM). If the IC50 is greater than upper limit, the IC50 will be 
imputed as the value of upper limit (10000 nM). 
The patients with a detected value at baseline will be included in this analysis. 
However, the patients infected with multiple virus types will be excluded from the 
analysis. 
4) EQ-5D-5L and EQ VAS 
These endpoints consist of the change from baseline in the index value calculated 
from the EQ-5D-5L questionnaire and that in EQ VAS score at 12, 24, 36, 48, 60, 
72, 84, 96, 108, 120, 132, 144,156, 168, 180, 192, 204, 216, 240, 264, 288, 312, 
336, 360, 384, 408, 432, 456, 480, 504, and 528 hours. A conversion table 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 31 of 53 
proposed by Ikeda et al. [1] will be used to convert EQ-5D-5L status to index 
value. 
The EQ-5D-5L and EQ VAS data obtained when e-diary is set up after initial 
administration will not be used for analysis. Because these data may be observed 
due to e-dairy system’s incorrect setting. 
5) Work productivity questionnaire 
The WP questionnaire consists of 4 questions regarding employment, hours 
worked, productivity while at work, and requirement for personal assistance. The 
following 2 endpoints are derived from Q1 to Q3 questions. If a subject reported 
the Q1 as 0, the ‘percentage of absenteeism due to influenza illness’ and 
‘percentage of work productivity loss due to influenza illness’ will not be 
calculated. 
The percentage of absenteeism due to influenza illness is defined as follows; 
100 × (duration unable to work due to influenza illness: Q2) / (duration of 
working per 21 days: Q1 × 21 days / 7 days) (unit: %) 
The patients whose Q1 and Q2 were observed with the same unit will be included 
in this analysis. 
The percentage of work productivity loss due to influenza illness is defined as 
follows; 
100 × {(duration unable to work due to influenza illness: Q2) + (duration of 
working below normal standard: Q3)}/ (duration of working per 21 days: Q1 × 21 
days / 7 days) (unit: %) 
The patients whose Q1, Q2 and Q3 were observed with the same unit will be 
included in this analysis. 
6) Intrahousehold infection rate (for Japan site only) 
Intrahousehold infection rate in each patient is defined as follows; 
100 × (the number of household members infected between Day 1 and Day 15) 
/ {(the number of household members, excluding the patient himself/herself) – 
(the number of household members infected by Day 1)} (unit: %). 
The patients who have no household members or whose all household members 
have already been infected by Day 1 will be excluded from the analysis 
population.  
When a part of the date of influenza diagnosis is observed for a household 
member, he/she is defined as an influenza case in household. If any part of the 
date of his/her influenza diagnosis is missing, it will be assumed that he/she is 
diagnosed on Day 1. 
For each of the following time periods, definition of this endpoint will be defined 
as below. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 32 of 53 
-
 100 × (the number of household members infected between Day 1 and Day 3) 
/ {(the number of household members, excluding the patient him/herself) – 
(the number of household members infected by Day 1)} (unit: %) 
-
 100 × (the number of household members infected between Day 1 and Day 4) 
/ {(the number of household members, excluding the patient him/herself) – 
(the number of household members infected by Day 1)} (unit: %) 
-
 100 × (the number of household members infected between Day 1 and Day 6) 
/ {(the number of household members, excluding the patient him/herself) – 
(the number of household members infected by Day 1)} (unit: %) 
-
 100 × (the number of household members infected between Day 1 and Day 
11) / {(the number of household members, excluding the patient him/herself) 
– (the number of household members infected by Day 1)} (unit: %) 
9.4 
Analyses of the Secondary Endpoints 
The analysis population for the following analyses will be the ITTI Population unless 
otherwise specified.  
1) Proportion of patients positive for influenza virus titer and virus RNA by RT-PCR 
 The proportion of patients positive for influenza virus titer/virus RNA 
(RT-PCR) at each scheduled time point will be calculated. The corresponding 
95% CIs will be calculated by the Clopper-Pearson method. 
 The Mantel-Haenszel test with baseline composite symptom score (≤14 or 
≥ 15), preexisting and worsened symptom (Yes or No) and region (Asia, North 
America/Europe, Southern Hemisphere) as stratification factors will be used 
to compare these endpoints between two groups at each scheduled time point. 
2) Change from baseline in influenza virus titer and in the amount of virus RNA 
(RT-PCR) 
 The summary statistics for the change from baseline in influenza virus titer 
and in the amount of virus RNA (RT-PCR) will be presented by treatment 
group at each scheduled time point. 
 The van Elteren test with baseline composite symptom score (≤14 or ≥15), 
preexisting and worsened symptom (Yes or No) and region (Asia, North 
America/Europe, Southern Hemisphere) as stratification factors will be used 
to compare these endpoints between two groups at each scheduled time point. 
The p-value for the van Elteren test is derived using the below SAS code and 
identified as the p-value for “Row Mean Scores Differ” in the “Alternative 
Hypothesis of Cochran-Mantel-Haenszel Statistics” on the output window. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 33 of 53 
[Example: Comparison between the S-033188 group and the placebo group] 
proc freq data= analysisdata; 
table PRE*REGION*SCOREC*TRTP*VARIABLE / cmh2 scores=modridit 
noprint; 
where TRTP in ("S-033188", "Placebo"); 
run; 
-
 PRE: Preexisting and worsened symptom 
-
 REGION: Region 
-
 SCOREC: Category of Baseline composite symptom score 
-
 TRTP: Treatment group 
-
 VARIABLE: Response variable 
3) Area under the curve adjusted by baseline in influenza virus titer and in the 
amount of virus RNA (RT-PCR) 
 The same analysis methods as for ‘the change from baseline in influenza virus 
titer and the amount of virus RNA’ will be applied. 
4) Time to cessation of viral shedding by influenza virus titer/by virus RNA 
 This endpoint will be compared between the S-033188 group and the placebo 
group or the Oseltamivir group using the stratified Peto-Prentice’s generalized 
Wilcoxon test with composite symptom score (≤ 14 or ≥ 15), preexisting and 
worsened symptom (Yes, No), and region (Asia, North America/Europe, 
Southern Hemisphere) as stratification factors. 
 The Kaplan-Meier survival curve will be plotted for each treatment group, and 
the median time to improvement of influenza symptoms and its 95% CI will 
be calculated. In addition, the treatment group difference in median time and 
its 95% CI will be estimated. The 95% CI of difference of median time will be 
obtained using the method described in the Section 9.1.1.2. Random seeds 
will be set as 16010833 and 16010834 for comparison between the S-033188 
and the placebo or the oseltamivir for influenza virus titer, 16010835 and 
16010836 for comparison between the S-033188 and the placebo or the 
oseltamivir for virus RNA. 
5) Proportion of patients whose symptoms has been improved 
 The same analysis methods as for the ‘proportion of patients positive for 
influenza virus titer’ will be applied. 
6) Time to alleviation of symptoms 
 This endpoint will be compared between the S-033188 group and the placebo 
group or the oseltamivir group using the stratified Peto-Prentice’s generalized 
Wilcoxon test with composite symptom score (≤ 14 or ≥ 15), preexisting and 
worsened symptom (Yes or No), and region (Asia, North America/Europe, 
Southern Hemisphere) as stratification factors. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 34 of 53 
 The Kaplan-Meier survival curve will be plotted for each treatment group, and 
the median time and its 95% CI will be calculated. In addition, the treatment 
group difference in median time will be estimated. 
7) Time to improvement of the 4 systemic symptoms/3 respiratory symptoms 
 The same analysis methods as for the ‘time to alleviation of symptoms’ will 
be applied. 
8) Time to resolution of fever  
 The same analysis methods as for the ‘time to cessation of viral shedding by 
influenza virus titer/by virus RNA’ will be applied. Random seeds will be set 
as 16010837 and 16010838 for comparison between the S-033188 and the 
Placebo or the oseltamivir, respectively. 
9) Proportion of patients reporting normal temperature 
 The same analysis methods as for the ‘proportion of patients positive for 
influenza virus titer’ will be applied. 
10) Body temperature 
 The summary statistics for the body temperature will be presented by 
treatment group at each scheduled time point. 
 Analysis of covariance (ANCOVA) with baseline composite symptom score, 
preexisting and worsened symptom (Yes or No), region (Asia, North 
America/Europe, Southern Hemisphere) and body temperature at baseline as 
covariates will be used to compare the endpoint between 2 groups and 
calculate least squares means, the corresponding standard errors and the 
corresponding 95% CI.  
[Example: Comparison between the S-033188 group and the placebo group] 
proc mixed data= analysisdata; 
 class REGION TRTP PRE; 
 model VARIABLE = TRTP PRE REGION bSCORE BASE /cl; 
 lsmeans TRTP; 
 estimate "S-033188 vs Placebo" TRTP 1 -1 0/cl; 
 estimate "S-033188 vs Oseltamivir" TRTP 1 0 -1/cl; 
run; 
-
 PRE: Preexisting and worsened symptom 
-
 REGION: Region 
-
 bSCORE: Baseline composite symptom score 
-
 BASE: Body temperature at baseline 
-
 TRTP: Treatment group 
-
 VARIABLE: Response variable 
11) Time to improvement of individual symptoms 
 The same analysis methods as for the ‘time to alleviation of symptoms’ will 
be applied. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 35 of 53 
12) Time to return to preinfluenza health status 
 The same analysis methods as for the ‘time to alleviation of symptoms’ will 
be applied. 
13) Requirement for systemic antibiotics for infections secondary to influenza 
infection 
 The proportion and the corresponding 95% CI will be calculated by treatment 
group. The 95% CIs will be calculated by the Clopper-Pearson method. 
 The Fisher’s exact test will be used will be used to compare the proportion 
between the S-033188 and both the Placebo and oseltamivir groups. 
14) Incidence of influenza-related complications 
 The same analysis method as for the ‘requirement for systemic antibiotics for 
infections secondary to influenza infection’ will be applied. 
9.5 
Analyses of the Other Endpoints 
1) Serum influenza antibody titer 
 Serum antibody titers measured on Day 1 and Day 22 will be categorized, and 
the frequency of each category and the corresponding percentage will be 
summarized by influenza virus subtype based on RT-PCR and treatment 
group.  
 The ratio of value at Day 22 to that at Day 1 will be categorized, and the 
frequency of each category and the corresponding percentage will be tabulated 
by influenza virus subtype based on RT-PCR and treatment group.  
If serum antibody titer is observed as < 10 and > 1280, the ratio of value at 
Day 22 to that at Day 1 will be calculated using 10 and 1280, respectively. 
 The categorized serum antibody titer at Day 1 and at Day 22 will be 
cross-tabulated.  
 The geometric mean value of the ratio of value at Day 22 to that at Day 1 will 
be calculated, and the Wilcoxon rank sum test will be used to compare the 
ratio between the S-033188 and the placebo or the oseltamivir. 
If serum antibody titer is observed as < 40 due to haemolytic serum sample, the 
observation will be handled as missing data for the above analyses. 
2) Polymorphic and treatment-emergent amino acid substitutions in the PA gene of 
evaluable virus 
The patients who have sequencing performed will be included in the following 
analysis. 
 For the S-033188 group and the placebo group, amino acid substitutions data 
at the Day 1 and at the last RT-PCR positive time point will be cross-tabulated 
by each amino acid position in PA, influenza virus type and subtype of 
sequence sample and treatment group, in consideration of the reference 
sequence. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 36 of 53 
3) Drug susceptibility of evaluable virus 
 The summary statistics for EC50 and IC50 at baseline will be presented by 
influenza virus type and subtype based on RT-PCR and treatment group 
(including overall group).  
 The summary statistics for the ratio of EC50 at baseline relative to EC50 for 
reference stain and the ratio of IC50 at baseline relative to IC50 for reference 
stain will be presented by influenza virus type and subtype based on RT-PCR 
and treatment group (including overall group). For the patients infected with 
influenza A virus (A/H1N1pdm or A/H3), EC50 of reference strain 
A/Victoria/361/2011 and IC50 of reference strain A/PuertoRico/8/34 will be 
used. For the patients infected with influenza B virus, EC50 of reference stain 
B/Wisconsin/1/2010 and IC50 of reference strain B/Lee/40 will be used.  
4) Change in EQ-5D-5L and EQ VAS 
 The summary statistics for change in the index value and change in visual 
analog scale (VAS) score will be presented by treatment group at each 
scheduled time point. As a reference, the summary statistics at baseline will 
also be presented. 
5) Work productivity questionnaire 
 The summary statistics for the percentage of absenteeism due to influenza 
illness and the percentage of work productivity loss due to influenza illness 
will be presented by treatment group.  
 For Question 4 in Work Productivity (WP) Questionnaire, the summary 
statistics for the number of days required for personal assistance will be 
presented by treatment group. One day is equal to 24 hours. 
6) Intrahousehold infection rate 
Let K be the total number of patients included in this analysis, yk be the 
number of kth patient’s household members infected between Day 1 and Day 
15, and nk be the number of kth patient’s household members uninfected by 
Day 1 (k = 1, ..., K). Under the assumption that yk is distributed according to 
Poisson distribution with mean μk, the following Poisson regression model 
will be applied;  




k
k
k
x
n
1
0
log
log






 


k
ky


Var
 (: dispersion parameter) 
In the model, ݔ௞ is a group indicator variable for the kth patient, i.e., ݔ௞ൌ
1 for the S-033188 group, ݔ௞ൌ0 for the control group (the placebo group or 
the oseltamivir group). The
0
is an intercept parameter, 
1
is a regression 
parameter. Intrahousehold infection rates for the S-033188 group and the 
control group are given by 
)
exp(
1
0


and 
)
exp(
0

, respectively.  


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 37 of 53 
The dispersion parameter  will be estimated as Pearson’s chi-square 
divided by its degrees of freedom. 
Estimate and 95% CI of intrahousehold infection rate of each treatment group 
and comparison between two treatment groups will be carried out using the 
following SAS code. In addition, a risk ratio of the S-033188 group to the 
control group and the corresponding 95% CI will be estimated by the above 
Poisson regression model. 
Data analysisdata; 
 set analysisdata; 
 lnum=log(NUM); 
run; 
 [Comparison between the S-033188 group and the placebo group or 
oseltamivir group] 
proc genmod data = analysisdata; 
 class TRTP; 
 model RES = TRTP / dist = poisson link = log offset = lnum scale = pearson; 
 lsmeans TRTP / cl exp; 
 estimate "S-033188 vs Placebo"    TRTP 1 -1 0/ exp; 
 estimate "S-033188 vs Oseltamivir" TRTP 1 0 -1/ exp; 
run; 
-
 NUM: Number of household members uninfected by Day 1 
-
 TRTP: Treatment group (1:S-033188, 2:Placebo, 3: Oseltamivir) 
-
 RES: Number of household members infected between Day 1 and Day 15 
The similar Poisson regression model will be applied using the number of 
household members yk infected during each of the following time periods as a 
response variable;  
-
 From Day1 to Day 3 
-
 From Day 1 to Day 4 
-
 From Day1 to Day 6 
-
 From Day 1 to Day 11 
9.6 
Subgroup Analyses for Primary and Secondary Endpoint 
Time to improvement of symptoms 
Analyses of time to improvement of symptoms (Kaplan-Meier curve, the median time 
and its 95% CI, deference in median times and stratified Peto-Prentice’s generalized 
Wilcoxon test described in Section 9.1.1.1, 9.1.1.2) will be presented for the following 
subgroup 1), 2), 3), 4), 5), 6), 7) and 8). 
Subgroup analyses will be performed for the ITTI Population in the following subgroups. 
No multiplicity adjustment will be applied. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 38 of 53 
1) Total score of influenza symptoms at baseline 
 ≤ 14 points 
 ≥ 15 points 
The stratified Peto-Prentice’s generalized Wilcoxon test with preexisting and 
worsened symptom (Yes or No) and region as stratification factors will be 
applied. 
2) Region 
 Asia 
 North America/Europe 
 Southern hemisphere 
Stratified Peto-Prentice’s generalized Wilcoxon test with composite symptom 
score at baseline (≤ 14 or ≥ 15) and preexisting and worsened symptom (Yes or 
No) as stratification factors will be applied. 
3) Preexisting and worsened symptom 
 Yes 
 No 
Stratified Peto-Prentice’s generalized Wilcoxon test with composite symptom 
score at baseline (≤ 14 or ≥ 15) and region as stratification factors will be applied. 
4) Individual high risk categories grouped as follows (12 factors: Categories = Yes or 
No) 
 Asthma or chronic lung disease, Endocrine disorders, Residents of long-term 
care facilities, Compromised immune system, Neurological and 
neurodevelopmental disorders, Heart disease, Adults ≥ 65 years of age, 
American Indians and Alaskan Natives, Blood disorders, Metabolic disorders, 
Morbid obesity (BMI ≥ 40), Women who are within 2 weeks postpartum and 
are not breastfeeding 
This analysis will only be assessed for subgroups representing more than or equal 
to 10% of the whole population. 
5) Age ≥ 65 years and other high risk factors 
 Age factor (≥ 65 years) and other high risk factors 
 Only age factor (≥ 65 years) 
 Other 
If a patient is equal to or greater than 65 years and suffered from other high risk 
factors, the patient is categorized in ‘Age factor (≥ 65 years) and other high risk 
factors’.  
If a patient is equal to or greater than 65 years and suffered from no other factors, 
the patient is categorized in ‘Only age factor (≥ 65 years)’. 
If a patient is less than 65 years, the patient is categorized in ‘Other’. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 39 of 53 
6) Body weight 
 < 80 kg  
 ≥ 80 kg  
7) Influenza virus type based on RT-PCR 
 A/H1pdm 
 A/H3 
 B 
8) Time to treatment from flu onset 
 0 hours ≤ to ≤ 12 hours 
 12 hours ≤ to ≤ 24 hours 
 24 hours < to ≤ 36 hours 
 36 hours < to ≤ 48 hours 
Analyses of time to improvement of symptoms (the median time and its 95% CI, 
deference in median times and stratified generalized Wilcoxon test described in 
Section 9.1.1.1, 9.1.1.2) will be presented for the following subgroup 9 and 10.  
9) Meals before and after dosing 
 Dosing > 4 hours before or > 4 hours after food intake 
 Dosing within 2 to 4 hours before or 2 to 4 hours after food intake  
 Dosing < 2 hours before or < 2 after food intake 
If a subject has had meals both before and after dosing, the priority will be given 
to a category closer to the time of dosing. If multiple applicable categories exist 
even under this condition, data obtained before dosing will be adopted. 
10) Age 
 < 18 years  
 18 years ≤ 64 years 
 65 years ≤ 74 years  
 ≥ 75 years 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 40 of 53 
Time to improvement of the three respiratory symptoms 
Analysis of this endpoint will be presented for the subgroup 4) ‘Individual high risk 
categories’, but the Kaplan-Meier curve will not be created. Only for subgroups of which 
percentage is more than or equal to 10% of the whole population will be analyzed.  
Time to improvement of cough symptom 
Analysis of this endpoint will be presented for the subgroup 4) ‘Individual high risk 
categories’, but the Kaplan-Meier curve will not be created. Only for subgroups of which 
percentage is more than or equal to 10% of the whole population will be analyzed. 
Complications 
Analysis of complications will be presented for the subgroup 4) ‘Individual high risk 
categories’. Only for subgroups of which percentage is more than or equal to 10% of the 
whole population will be analyzed. 
Time cessation of viral shedding by virus to titer/RT-PCR 
Analysis of the time cessation of viral shedding by virus to titer/RT-PCR will be 
presented for the subgroup 4 ‘Individual high risk categories’, but the Kaplan-Meier 
curve will not be created. The analysis results only for subgroups of which percentage is 
more than or equal to 10% of the whole population will be shown. 
For these endpoints, the subgroup analysis for the subgroup 7) ‘Influenza virus type 
based on RT-PCR’ will also be performed (the Kaplan-Meier curve will be created). 
Proportion of patients positive for influenza virus titer/RT-PCR 
For these endpoints, the subgroup analysis for the subgroup 7) ‘Influenza virus type 
based on RT-PCR’ will also be performed. Only for the proportion of patients positive for 
influenza virus titer, the subgroup analysis for ‘8) Time to treatment from flu onset’ will 
be performed. 
Change from baseline in influenza virus titer/amount of virus RNA (RT-PCR) 
For these endpoints, the subgroup analysis for the subgroup 7) ‘Influenza virus type 
based on RT-PCR’ will also be performed. Only for the change from baseline in influenza 
virus titer, the subgroup analysis for ‘8) Time to treatment from flu onset’ will be 
performed. 
Area under the curve adjusted by baseline in influenza virus titer/RT-PCR 
For these endpoints, the subgroup analysis for the subgroup 7) ‘Influenza virus type 
based on RT-PCR’ will also be performed. 
Intrahousehold infection rate 
For these endpoints, the subgroup analysis for the subgroup 7) ‘Influenza virus type 
based on RT-PCR’ will also be performed. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 41 of 53 
9.7 
Analyses for Health Technology Assessment 
 
Comparison of Treatment Groups 
9.7.1
For health technology assessment, the primary endpoint and the change from baseline in 
influenza virus titer will be analyzed for specific subgroups. 
 
Vaccination = Yes 
 
Vaccination = No 
For analysis of the health technology assessment endpoint, the analysis methods 
described in Sections 9.1.1.1 and 9.1.1.2 will be applied. 
For analysis of the change from baseline in influenza virus titer, the analysis method 
described in Section 9.4 2) will be applied. 
 
Summary of Specific Conditions 
9.7.2
For health technology assessment, summary statistics (the number of nonmissing 
observations, arithmetic mean, and standard deviation) for the EQ-5D-5L index will be 
calculated at each evaluation time point by 4 specific conditions in the Japanese 
population. Similarly, the summary statistics for the absenteeism and work productivity 
loss due to influenza illness and the time required for personal assistance at the end of 
follow-up time will be calculated by 4 specific conditions in the Japanese population. 
Note that these analyses are not for comparison of treatment arms. The definitions of 
4 specific conditions are shown below. 
Conditions 
Improvement of 
influenza symptoms 
[a] 
Any influenza-related complications 
(death, hospitalization, sinusitis, 
otitis media, bronchitis, and 
radiologically confirmed 
pneumonia) 
Any 
treatment-related 
AEs 
With flu symptoms, 
no complications, 
no treatment-related AE 
No 
No 
No 
Without flu symptoms, 
no complications, 
no treatment-related AE 
Yes 
No 
No 
With flu symptoms, 
no complications, 
with treatment-related AE 
No 
No 
Yes 
Without flu symptoms, 
no complications, 
with treatment-related AE 
Yes 
No 
Yes 
AE = adverse event; flu = influenza 
[a] The patients whose time to improvement of influenza symptoms is censored or who have no observations of 
influenza symptom score after the start of treatment will be considered as 'No' at all evaluation time points. The 
patients whose all influenza symptoms at baseline are mild or absent will be considered as ‘Yes’ at all evaluation 
time points. 
 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 42 of 53 
9.8 
Supplemental Analyses 
As supplemental analyses, the primary endpoint (time to improvement of influenza 
symptoms) and the time to cessation of viral shedding by influenza virus titer will be 
conducted including the subjects enrolled in Site 
 and 
 with a confirmed diagnosis 
of influenza virus infection. 
 
10. SAFETY EVALUATION 
The following analyses will be performed in the safety population. 
10.1 Adverse Events 
Adverse events will be classified by system organ class and preferred term using Medical 
Dictionary for Regulatory Activities (MedDRA) Version 19.1. Adverse events reported 
after the initial dose of study drug will be used for safety analyses. 
1) The number and proportion of patients who experienced at least 1 AE will be 
tabulated by treatment group. Their 95 % CIs will also be calculated with the 
Clopper-Pearson method. In addition, the proportion in the S-033188 group will 
be compared with the value in the placebo group or the oseltamivir group using 
the Fisher’s exact test. The number of events will also be tabulated. Death, other 
serious AEs, AEs leading to withdrawal of the study drug, and treatment-related 
AEs will be summarized in the same manner as the overall summary of AEs. The 
definitions of death, other serious AEs, AEs leading to withdrawal, 
treatment-related AEs are shown below. 
Term 
Definition 
Death 
AEs with “Fatal” in terms of outcome. 
Other serious AEs 
(Serious AEs excluding death) 
AEs with “Serious” in terms of seriousness excluding 
death 
AEs leading to withdrawal of the 
study drug 
AEs with “Drug withdrawn” in terms of the action taken 
for study drug. 
Treatment-related AEs 
AEs with “Related” in terms of the causal relationship 
with study drug. 
AEs = adverse events 
2) The number and proportion of patients who experienced AEs will be tabulated by 
System Organ Class (SOC) and Preferred Term (PT) for each treatment group. 
For these summaries, patients with multiple AEs will be counted only once within 
the SOC and PT. Serious AEs excluding death, AEs leading to withdrawal of the 
study drug, treatment-related AEs, serious treatment-related AEs excluding death, 
and treatment-related AEs leading to withdrawal of the study drug will be 
summarized in a similar manner. In addition, the AEs, of which proportions are 
equal to or higher than 2% in any treatment groups, will be tabulated by SOC and 
PPD
PPD


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 43 of 53 
PT. 
3) The number and proportion of patients who experienced AEs in each category of 
the severity, the outcome, and the time-of-onset will be tabulated by SOC and PT 
in each treatment group.  
Regarding summarization of the severity and the outcome, a patient with multiple 
AEs will be counted only once in the highest priority of the categories shown in 
Table 4, if the SOCs or PTs are same.  
The time-of-onset is categorized into Week 1 (1 to 7 days postdose), Week 2 (8 to 
14 days postdose), and Week ≥ 3 (≥15 days postdose). Each AE will be classified 
into a time-of-onset category based on the number of days that is calculated as 
(Date of AE onset – Date of dosing + 1). If a patient experiences multiple AEs of 
the same SOC or PT in different categories, the patient will be counted once in 
each category. 
Treatment-related AEs will be summarized in a similar manner. 
Table 4 
Priority of Categories 
 
Category 
Priority 
Severity 
Outcome 
1 
Grade 5 
Fatal 
2 
Grade 4 
Recovered/Resolved with sequelae 
3 
Grade 3 
Not recovered/Not resolved 
4 
Grade 2 
Recovering/Resolving 
5 
Grade 1 
Recovered/Resolved 
6 
 
Unknown 
4) Adverse events related to hepatic disorders (SMQ code = 20000006) and 
neuropsychiatric disorders (SOC = psychiatric disorders or nervous system 
disorders) will be listed.  
10.2 Clinical Laboratory 
If reported values include inequality signs (> or <), the values without inequality sings 
will be used for summarizing the results. 
1) For each of the hematological and biochemical test parameter, summary statistics 
of observed values and changes from baseline at each time point will be presented 
by treatment group at each scheduled time point.  
2) For each urinalysis parameter, the frequency of each category will be summarized 
by treatment group at each scheduled time point.  
3) Each observed value will be classified into 3 categories: “within the normal range,” 
“higher than normal,” and “lower than normal.” The frequency of each category 
will be summarized by treatment group at each scheduled time point. 
4) The number and proportion of patients who meet the prespecified criteria shown 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 44 of 53 
in Table 5 will be presented by treatment group during the study (after first 
dosing). If a patient meet multiple criterion in all observed time points, the patient 
will be counted only once within the worst category.  
5) The number and proportion of patients, whose each parameter is categorized into 
Grade 3 and 4 based on the Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events Version 2.1, will be summarised by treatment 
group at each scheduled time point. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 45 of 53 
Table 5 
Prespecified Criteria 
Term 
Criteria 
ALT (U/L) 
≤ 3 × ULN 
 
> 3 to ≤ 5 × ULN 
 
> 5 to ≤ 20 × ULN 
 
>20 × ULN 
AST (U/L) 
≤ 3 × ULN 
 
> 3 to ≤ 5 × ULN 
 
> 5 to ≤ 20 × ULN 
 
> 20 × ULN 
Total bilirubin (mg/dL) 
≤ 1.5 × ULN 
 
> 1.5 to ≤ 3 × ULN 
 
> 3 to ≤ 10 × ULN 
 
> 10 × ULN 
AST (U/L) or ALT (U/L) 
≤ 3 × ULN 
 
> 3 to ≤ 5 × ULN 
 
> 5 to ≤ 20 × ULN 
 
> 20 × ULN 
AST (U/L) or ALT (U/L) and Total bilirubin (mg/dL) 
Meet all of the following criteria at 
the same time point: 
 
AST > 3 × ULN or ALT > 3 × 
ULN 
 
Total bilirubin value > 2 × ULN 
ULN = upper limit of normal. 
10.3 Vital Signs 
For each of the vital signs (diastolic blood pressure, systolic blood pressure, respiratory 
rate, and pulse rate), summary statistics of observation and the change from baseline will 
be presented by treatment group at each scheduled time point.  
10.4 Electrocardiography  
The frequency of each electrocardiography (ECG) finding will be summarized by 
treatment group at each scheduled time point. Each ECG finding will be classified into 3 
categories: “normal,” “abnormal-not clinically significant,” and “abnormal-clinically 
significant.” 
10.5 Subgroup Analyses for Safety Endpoint 
Analyses of AEs Sections 10.1 1 and 2, except proportion of patients who experienced 
AEs of 2% or higher, will be presented for the following subgroups. 
Subgroup analyses will be performed for the Safety population. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 46 of 53 
1) Body weight 
 < 80 kg  
 ≥ 80 kg  
2) Age 
 < 18 years  
 18 years ≤ 64 years 
 65 years ≤ 74 years 
 ≥ 75 years 
3) High risk factors (12 factors: Categories = Yes or No) 
 Asthma or chronic lung disease, Endocrine disorders, Residents of long-term 
care facilities, Compromised immune system, Neurological and 
neurodevelopmental disorders, Heart disease, Adults aged ≥ 65 years, 
American Indians and Alaskan Natives, Blood disorders, Metabolic disorders, 
Morbid obesity (BMI ≥ 40), Women who are within 2 weeks postpartum and 
are not breastfeeding 
10.6 Supplemental Analyses 
As supplemental analyses, the number and proportion of patients who experienced AEs, 
AEs of which proportions are equal to or higher than 2% in any treatment groups and 
treatment-related AEs will be tabulated by SOC and PT for each treatment group with 
patients enrolled excluding site 
 which had repeated deviations in protocol required 
procedures, will be performed. 
11. INTERIM ANALYSES 
No interim analysis for efficacy assessment is planned in this study. 
12. PROGRAMMING SPECIFICATIONS 
Unless otherwise specified, the following conventions will be used when the analysis 
TLFs are prepared: 
 Every summary table and figure will clearly specify the analysis population being 
summarized. Listings will be prepared for all patients randomized. 
 Treatment group of the S-033188 in the listings will be reported as following 
rules. 
-
 S-033188 40 mg: Kit number (1) was assigned and the S-033188 was 
administered 
-
 S-033188 80 mg: Both kit number (1) and (2) were assigned and the S-033188 
was administered 
 Number of digits to be displayed for calculated values 
PPD


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 47 of 53 
For the following endpoints, data will be rounded off to 8 decimal places, and the 
rounded values will be used for analysis. The digit displayed in analysis tables for each 
endpoint is shown in Table 6. 
Table 6 
Summary of the Number of Digits Displayed for 
Endpoints 
 
Number of digits displayed 
(after the decimal point) 
Endpoint 
Minimum 
Maximum 
Mean 
Median 
SD 
CI 
 
Time to improvement of symptoms 
 
Time to cessation of viral shedding by influenza virus 
titer/RT-PCR 
 
Time to improvement of the 4 systemic symptoms 
 
Time to improvement of the 3 respiratory symptoms 
 
Time to alleviation of symptoms 
 
Time to resolution of fever 
 
Time to improvement of individual symptoms 
 
Time to return to preinfluenza health status 
 
Area under the curve adjusted by baseline in influenza 
virus titer 
 
Area under the curve adjusted by baseline in the amount 
of virus RNA (RT-PCR) 
 
Time required for personal assistance due to influenza 
illness 
1 
1 
1 
Index value 
Percentage of absenteeism due to influenza illness 
Percentage of work productivity loss due to influenza illness 
3 
3 
3 
 
Change from baseline in influenza virus titer 
 
Change from baseline in amount of virus RNA 
 
Drug susceptibility in patients with evaluable virus: the 
ratio of EC50/IC50 at baseline relative to EC50/IC50 for 
reference 
2 
2 
2 
Treatment compliance rate 
1 
2 
2 
CI = confidence interval; SD = standard deviation 
Summary statistics will be displayed to the number of digits as shown in Table 7. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 48 of 53 
Table 7 
Summary of the Number of Digits Displayed 
 
No. of digits displayed 
p-value 
Round off to 4 decimal places 
However, p value of < 0.0001 will be displayed as “< .0001” 
Number of subjects 
Display as a whole number 
Mean, SD, median, adjusted mean, 
SE, 95% CI 
One decimal place beyond the number of decimal places 
with which the original endpoint is presented 
Minimum, maximum 
Same number of digits of the observed data 
Percentage (%) 
Round off to 1 decimal place 
CI = confidence interval; SD = standard deviation; SE = standard error 
 Categories used for summarization 
Basically, categories described in CRFs will be used. If data need to be categorized, the 
data will be categorized according to Table 8 below.  


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 49 of 53 
Table 8 
Category of Variable 
Variable 
Category 
Age 
12-19 years, 20-29 years, 30-39 years, 40-49 years, 
50-59 years, 60-64 years 
Body weight 
< 80 kg, ≥ 80 kg 
Timing of meal before and after dosing 
< 2 hours, 2- 4 hours, > 4 hours 
Time of onset of influenza symptoms 
0-12 hours, 12-24 hours, 24-36 hours, 36-48 hours 
Influenza virus subtype based on RIDT 
A, B, A and B, Negative, Unknown 
Influenza virus subtype based on 
RT-PCR 
A/H1N1pdm: A/H1N1pdm 
A/H3: A/H3 
B:B 
Mixed infection: A/H1N1pdm and B, A/H3 and B, 
A/Unknown and B, A/ND and B, A/H1N1pdm and A/H3 
and B, A/H1N1pdm and A/H3 
Other: A/Unknown, A/ND, Unknown 
Negative: 
Not done: 
 
The above virus subtype classification is derived from 
the following specification: 
-
 
A/H1N1pdm: H1_2009 
-
 
A/H3: H3 
-
 
A/H1N1pdm and A/H3: H1_2009/H3 
-
 
A/ND: ND 
-
 
A/Unknown: UNKNOWN 
Virus subtype classification used for 
subgroup analysis 
A/H1N1pdm, A/H3, B 
Serum influenza antibody titer 
(Day 1, Day 22) 
< 10, ≥ 10 to < 20, ≥ 20 to < 40, ≥ 40 to < 80, ≥ 80 to 
<160, ≥160 
Serum influenza antibody titer 
(Ratio of Day 22 relative to Day 1) 
<4, ≥ 4 to < 8, ≥ 8 to < 16, ≥ 16 to < 32, ≥ 32 to < 64, ≥ 
64 to < 128, ≥ 128 to < 256, ≥ 256 
Composite symptom score at baseline 
≤ 14, ≥ 15 
Treatment compliance rate 
< 80, ≥ 80 
Acetaminophen use 
0, 1-2, 3-4, ≥ 5 
Time of onset of AE 
Week 1 (≥ 1 to < 8 days), Week 2 (≥ 8 to < 15 days), 
Week ≥ 3 (≥ 15 days) 
Urine protein 
-, 1+, 2+, 3+, 4+, Unknown 
Urine glucose 
-, 1+, 2+, 3+, 4+, Unknown 
Urobilinogen 
-, 1+, 2+, 3+, 4+, Unknown 
Urine occult blood 
-, 1+, 2+, 3+, 4+, Unknown 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 50 of 53 
Variable 
Category 
High risk factor 
Asthma or chronic lung disease, Endocrine disorders, 
Residents of long-term care facilities, Compromised 
immune system, Neurological and neurodevelopmental 
disorders, Heart disease, Adults >= 65 years of age, 
American Indians and Alaskan natives, Blood disorders, 
Metabolic disorders, Morbid obesity (BMI >= 40), 
Women who are within 2 weeks postpartum and are not 
breastfeeding 
13. BLINDED REVIEW 
The PCR positive rate at baseline will be estimated during the study. 
14. SUMMARY OF CHANGES FROM PROTOCOL SPECIFIED 
ANALYSIS 
 The definition of the Safety population was updated. The patients enrolled at sites 
with GCP noncompliance were not included in the population, originally. These 
patients will be included based on the updated definition. 
 An additional condition for the viral samples was described in the Section 6.4.1. 
 It was planned in Section 9.11.1 that the summary for action taken with the study 
drug will be presented by system organ class and preferred term. Due to single 
dose of S-033188, this analysis is not performed.  
 The frequency of each pair of laboratory tests at baseline and scheduled time 
points, which were described in Section 9.11.3 in the protocol, were not 
presented. 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _____________________________________________________________________________________  
 
Confidential 
Page 51 of 53 
15. REFERENCES 
[1] Ikeda S., et al. Developing a Japanese version of the EQ-5D-5L value set, J. Natl. Inst. 
Public Health, 64 (1): 2015 p.47-55  
 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _______________________________________________________________________________________________________________________________  
 
Confidential 
Page 52 of 53 
Appendix 1 
Time and Events Schedule 
 
Treatment Period 
Follow-up Period 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D11 
D12 
D13 
D14 
D15 
D22/ 
ET 
V1 
V2 
V3 
OpV1 
V4 
OpV2 
 
 
V5 
 
 
 
 
 
V6 
V7 
Visit Window (days) 
- 
- 
+ 1 
- 
+ 1 
- 
 
 
± 2 
 
 
 
 
 
± 3 
± 3 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historya 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rapid Influenza Diagnostic Test  
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Dispensation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient 
eDiaryc 
Body Temperature 
Measurement 
Xd 
4 Times Daily 
Twice Daily 
 
 
Assessment of Severity of 
Influenza Symptoms 
Xd 
Twice Daily 
Once Daily 
 
 
EQ-5D-5L 
Xd 
Twice Daily 
Once Daily 
Assessment of Health 
Xd 
Once Daily 
 
 
Assessment of Health Prior 
to Influenza Symptoms 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WP Questionnaire 
 
X (the earliest visit following the resolution of symptoms, at Day 22, or ET)
Assessment of Influenza-related 
Complications (sinusitis, bronchitis, 
otitis media, pneumonia) 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
Full Physical Examination 
Xe, f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe
Symptom-focused Physical 
Examination 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
Concomitant Therapies 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
Study Drug Accountability 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test (WOCBP)g 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Immunological Tests 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Routine Laboratory Tests (hematology 
and blood chemistry) 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Influenza Antibody Titer Test 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Nasopharyngeal (preferred)/pharyngeal 
(if nasopharyngeal cannot be collected) 
Swabs (Virology Test) 
Xh 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
Xi 
Xi, j 


S-033188 
Shionogi 
Clinical Study Protocol: 1602T0832 
19 June 2018 
 _______________________________________________________________________________________________________________________________  
 
Confidential 
Page 53 of 53 
Vital Sign Measurements 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
Electrocardiography 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacokinetic Blood Samples 
Xk 
X 
Xk 
 
X 
 
 
 
 
 
 
 
 
 
Xk 
 
Adverse Event Assessments 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
X 
Record if Meal Eaten and Time 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intrahousehold Infection Interview (for 
Japan only) 
X 
X 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
D = day; eDiary = electronic diary; EuroQol–5 Dimensions–5 Levels; ET = early termination; OpV= optional visit; V = visit; WOCBP = women of childbearing potential; 
WP = work productivity 
a 
Include a review of prior therapies.  
b 
Not necessary if a site has performed a Rapid Influenza Diagnostic Test (RIDT) prior to consideration for the study. 
c 
The patient will measure or assess and record in the patient eDiary, body temperature 4 times daily (morning, noon, evening, and bedtime) from Days 1 to 3 and twice daily 
(morning and evening) from Days 4 to 14; assessment of health once daily (evening) from Days 1 to 14; the severity of influenza symptoms twice daily (morning and 
evening) from Days 1 to 9 and once daily (evening) from Days 10 to 14; and the EQ-5D-5L twice daily (morning and evening) from Days 1 to 9 and once daily (evening) 
from Days 10 to 22. The WP questionnaire will be assessed at the earliest visit following the resolution of symptoms, at Day 22, or ET.  
d 
Predose; if the study treatment is initiated at 18:00 or later on Day 1, the patient will not need to perform the Day 1 evening assessments.  
e 
Including measurement of body weight.  
f 
Height and body mass index will be measured at the predose examinations only.  
g 
Urine pregnancy test will be performed only for females who are not diagnosed as postmenopausal. 
h 
Predose.  
i 
To be collected if the investigator determines that flu symptoms are persisting.  
j 
If the investigator determines that flu symptoms are persisting at ET.  
k 
Blood samples will be collected for the measurement of plasma drug concentrations once each at Visits 2 (Day 2) and 4 (Day 5). If circumstances permit, samples also will be 
collected postdose at Visit 1 (Day 1) within the period from 0.5 to 4 hours after the initial dose, at Visit 3 (Day 3), and at Visit 6 (Day 15).