Conditions: Essential Tremor
Keywords: SAGE-324
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 97
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the long-term safety and tolerability of SAGE-324 in participants with essential tremor (ET).

Detailed description:

Arms:
arm 1: Participants will receive SAGE-324 15 milligrams (mg) from Day 1 to Day 14, followed by up-titration to 30 mg from Day 15 to Day 28, then to 45 mg from Day 29 to Day 42, and then 60 mg starting on Day 43, orally, once daily.

Interventions: intervention 1: SAGE-324
Intervention descriptions: intervention 1: SAGE-324 oral tablets

Protocol document:
Prot_000.pdf: 


  
  
 
  
  
 
 
  
 
  
  
 
 
 
  
  
 
 
  
  
  
 
 
  
 
  
  
 
 
  
 
  
 
 
  
  
 
 
  
  
 
 
  
  
 
   
  
  
 
  
  
 
   
  
  
   
  
 
   
  
  
   
  
 
     


 
  
 
 
 
 
  
 
  
 
 
  
 
 
  
 
 
  
 
  
 
  
 
 
  
  
 
 
  
 
  
  
 
  
 
  
 
 
 
 
 
  
 
 
  
  
 
  
 
 
 
 
 
 
 
 
  
  
 
  
  
  
 
  
 
 
 
   
  
 
   
 
 
   
 
 
   
 
 
  
  
 
  
  
 
  
  
 
  
  
 
  
 
  
  
   
  
   
   
  
  
   
 
  
 
  
  
  
  
 
  
  
  
 
  
 
  
  
   
  
  
  
  
  
  
  
  
 
  
  
  
   
  
  
 
  
  
 
 
 
     


  
  
 
 
 
 
  
  
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
    
 
    
 
    
 
    
 
 
 
 
 
  
  
    
  
    
    
      
    
 
  
    
  
  
  
  
  
  
  
 
  
 
  
  
    
  
  
  
  
  
  
  
  
 
  
  
  
    
  
  
 
  
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
  
  
  
  
 
  
 
  
   
  
 
 
 
  
  
   
 
  
   
   
   
 
 
  
 
  
   
   
  
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
     


  
 
 
  
 
  
  
 
 
 
 
  
 
 
 
  
  
 
 
   
 
 
  
  
  
 
  
  
  
  
 
 
  
 
  
 
 
 
  
  
 
 
  
  
 
 
 
 
 
  
  
  
 
  
 
  
  
   
  
  
 
  
  
 
 
 
 
 
  
 
  
  
  
 
  
 
 
 
 
 
 
  
  
 
 
 
  
  
  
 
 
 
 
 
 
 
     




  
 
 
  
 
  
  
 
 
 
 
 
  
  
  
   
  
  
  
  
  
   
  
  
  
  
  
  
  
  
  
  
  
   
  
 
  
  
  
  
  
  
  
  
  
  
  
   
  
 
 
  
  
   
   
 
  
   
  
 
 
 
  
  
   
  
  
  
  
   
  
  
  
  
 
 
  
  
   
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
   
  
   
  
   
  
  
  
  
  
 
  
  
  
  
  
   
   
    
 
  
 
 
 
  
  
  
  
  
  
  
  
   
  
  
  
  
  
 
  
  
  
  
  
  
 
   
   
  
 
  
  
 
  
     


  
 
 
  
 
  
  
 
 
 
  
  
   
 
  
  
  
  
   
  
 
  
 
  
   
  
  
  
  
   
  
 
  
 
  
 
  
  
  
  
 
  
   
  
 
 
 
  
  
   
  
   
 
  
   
  
  
  
  
   
   
   
  
   
   
  
 
  
 
  
  
  
 
  
  
  
  
  
  
  
  
   
  
  
  
  
 
   
   
   
   
  
    
  
  
  
  
 
  
 
  
   
  
  
  
  
   
  
  
  
   
 
  
  
 
  
 
  
  
   
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
   
  
   
  
  
  
  
  
  
  
  
  
  
 
  
    
  
 
  
  
   
   
   
  
  
  
  
  
  
 
   
  
  
  
  
  
  
   
  
  
 
  
  
  
  
  
  
  
   
   
  
  
 
  
  
 
  
   
  
  
  
  
  
  
  
  
   
 
  
  
  
  
  
  
  
 
  
  
  
  
 
   
   
  
  
  
 
   
  
 
  
  
 
  
   
 
  
  
  
  
 
  
 
 
  
  
  
  
  
  
  
 
  
  
  
  
   
 
   
   
   
 
  
   
  
   
  
  
  
  
  
   
  
  
 
 
   
  
   
  
  
  
  
  
   
  
  
 
 
  
   
  
  
 
  
  
  
  
  
  
   
  
 
   
  
  
  
  
   
  
  
  
  
  
  
  
 
 
  
  
  
  
   
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
 
  
  
     
  
  
  
   
 
  
  
  
  
    
  
 
  
  
  
 
  
 
  
  
  
   
  
   
  
  
 
  
   
 
 
  
  
 
  
  
  
 
  
  
  
  
 
  
  
  
  
   
  
  
   
  
  
  
  
 
 
  
  
 
  
  
  
 
  
  
  
 
 
   
  
  
  
  
   
  
   
  
  
  
 
  
 
 
    
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
   
   
  
   
 
  
  
 
 
 
  
  
   
  
  
  
     


  
 
 
  
 
  
  
 
 
 
 
  
  
  
   
   
  
  
  
  
 
 
  
    
   
 
  
   
  
  
  
   
  
 
  
  
 
  
  
  
  
   
   
 
  
 
  
   
   
  
   
  
  
  
  
 
  
  
 
  
  
  
  
  
  
 
  
  
  
  
  
   
  
  
  
  
 
  
 
  
  
  
  
  
   
  
  
 
 
  
  
   
   
  
  
   
  
 
  
   
  
  
  
   
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
 
  
 
  
   
  
 
 
  
  
  
  
 
  
  
  
  
 
  
   
  
  
 
 
  
  
 
   
  
  
   
  
  
  
   
   
  
 
  
  
 
  
  
   
 
  
  
   
 
  
  
 
   
  
  
  
 
  
  
  
  
  
  
   
  
  
  
 
  
  
  
   
  
  
  
   
   
  
 
   
 
  
  
   
  
  
 
  
   
   
  
  
  
  
  
  
   
  
  
 
 
  
  
  
  
  
  
   
  
 
 
   
   
  
   
    
  
  
  
  
  
   
  
  
  
 
  
   
   
  
   
   
  
  
  
  
  
  
   
   
 
 
  
   
  
   
   
 
 
  
  
  
  
  
  
  
  
    
   
  
 
  
   
 
  
  
  
  
  
  
 
  
  
   
  
  
  
  
 
  
  
  
  
  
 
 
  
   
  
 
   
  
  
  
 
   
   
  
   
   
  
  
  
 
  
 
  
  
  
  
  
   
   
  
  
  
 
 
  
  
   
  
  
  
 
  
  
  
   
  
   
   
  
  
  
 
  
 
  
  
   
 
 
   
  
  
   
  
  
   
   
 
  
  
  
   
  
  
   
 
 
  
 
  
   
  
   
   
   
  
  
 
  
  
  
   
  
  
  
  
  
  
  
 
  
  
  
   
  
     


  
 
 
  
 
  
  
 
 
 
 
  
 
  
  
  
  
   
  
  
   
 
   
  
   
  
  
  
  
   
  
  
   
 
 
 
  
  
   
  
  
  
  
   
  
  
  
  
  
   
   
   
 
  
 
  
  
 
  
  
  
  
  
  
  
  
  
 
  
   
  
   
   
  
  
 
  
  
   
  
  
   
  
   
 
 
  
  
  
   
 
  
   
  
 
  
  
  
   
  
 
  
  
   
  
   
  
   
  
 
  
  
   
  
 
 
  
   
   
  
  
   
   
  
   
  
   
  
  
   
    
     
   
   
   
  
 
  
 
 
 
  
  
  
  
 
 
  
  
  
   
  
   
  
   
  
  
 
   
  
  
  
  
   
   
   
  
 
 
   
   
   
  
  
  
  
  
  
 
 
  
  
  
  
  
   
 
  
  
  
  
 
  
 
  
    
  
   
  
   
    
 
  
  
  
  
  
  
  
   
  
  
 
 
  
  
   
   
   
   
  
  
  
  
  
 
  
  
   
  
   
  
  
  
  
  
 
 
  
 
  
  
  
    
   
  
  
  
 
  
   
  
  
   
  
  
  
  
  
  
  
 
  
 
 
  
  
  
   
  
  
  
  
   
  
   
  
   
   
  
  
 
  
 
 
  
  
 
  
    
  
 
  
 
  
 
   
 
 
  
 
  
 
   
  
  
  
 
  
  
  
 
  
  
  
   
  
  
   
  
  
  
  
  
  
  
  
 
  
 
  
  
   
 
  
  
  
  
  
  
  
  
  
  
  
   
  
  
  
  
  
  
  
 
  
  
 
 
  
     
  
  
  
   
  
  
 
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
    
  
  
 
     


  
 
 
  
 
  
  
 
 
 
  
  
  
  
  
  
  
  
   
  
   
  
  
  
 
   
  
  
  
  
 
  
  
  
  
   
  
 
 
 
  
  
  
  
 
  
  
  
   
 
  
  
 
  
   
  
  
 
 
  
  
 
  
  
  
  
  
  
  
  
 
  
  
   
  
  
  
  
  
 
  
   
  
 
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
 
  
  
  
 
  
  
 
 
 
 
   
  
 
  
  
  
  
  
  
  
  
  
  
   
 
   
  
  
  
  
   
  
  
  
  
 
  
  
 
  
  
   
  
  
 
  
 
  
  
  
  
 
  
  
  
   
  
  
  
  
  
  
  
  
 
  
 
  
  
 
  
  
  
  
  
  
  
 
 
  
 
  
  
 
 
  
     


  
 
 
  
 
  
  
 
 
 
  
  
  
   
  
  
 
 
 
 
  
 
  
 
     
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
  
  
 
 
  
 
  
 
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
  
 
  
 
     
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
  
 
 
 
  
  
 
 
 
 
  
   
 
 
  
  
 
 
 
 
  
   
  
  
  
  
  
  
  
  
  
   
  
  
 
   
  
  
   
  
  
  
   
  
  
 
  
  
  
   
  
 
 
 
  
   
   
  
 
  
  
  
   
  
  
  
   
  
 
  
  
  
  
  
  
  
 
 
 
 
  
  
  
  
  
  
 
  
  
  
 
  
   
  
   
 
  
  
  
  
  
  
  
 
  
 
  
   
  
   
 
  
  
     


  
 
 
  
 
  
  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
   
   
  
   
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
     
   
  
  
  
 
   
   
  
  
  
  
   
  
  
  
  
 
  
  
  
 
  
   
   
 
  
  
  
  
  
  
  
  
   
  
  
  
   
   
  
 
  
   
  
   
  
  
  
  
  
  
  
  
  
 
  
   
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
    
  
  
   
   
  
  
  
  
  
  
   
  
  
  
  
  
  
  
  
  
  
 
   
  
   
  
   
  
   
  
   
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
 
  
   
  
  
  
  
   
  
  
  
  
  
  
  
  
  
 
  
   
  
  
  
  
  
 
  
   
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
  
 
  
  
   
 
 
  
  
  
  
  
  
  
   
  
 
 
   
  
   
  
 
  
    
  
 
  
 
  
 
   
  
 
  
 
  
 
   
  
  
  
  
   
 
 
  
  
    
  
  
  
  
  
   
  
   
  
  
 
  
  
  
  
   
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
 
  
     
  
  
  
   
  
  
  
 
  
 
  
 
 
  
  
   
  
   
  
  
   
  
  
  
  
   
   
   
 
 
  
   
  
  
  
  
 
  
  
  
  
  
  
 
  
  
   
  
  
  
  
  
  
   
   
    
  
 
 
  
  
  
  
  
  
   
 
 
  
  
  
  
  
 
  
   
  
  
  
  
  
  
 
 
 
 
     


  
 
 
  
 
  
  
 
 
 
  
  
  
  
  
 
   
  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
 
  
 
  
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
  
  
 
  
   
  
  
  
  
  
  
  
  
  
   
  
  
 
  
  
  
   
  
 
 
 
  
   
  
  
 
  
   
   
  
 
  
  
  
   
  
  
  
   
  
   
  
  
  
  
  
 
  
 
 
 
 
     


  
 
 
  
 
  
  
 
 
 
  
  
  
  
  
  
 
  
  
  
 
  
 
  
  
  
 
  
  
  
  
  
 
  
 
  
   
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
   
   
  
   
 
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
   
  
  
  
   
   
  
  
  
 
   
   
  
  
 
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
    
  
  
  
  
   
  
 
  
 
  
  
   
  
  
  
  
  
  
  
  
  
  
 
   
  
   
  
   
  
   
  
   
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
 
  
   
 
  
  
  
 
 
 
 
  
   
  
  
   
  
  
  
  
  
  
  
  
 
  
  
  
  
   
 
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
 
  
  
     
  
  
  
   
  
 
  
 
  
 
 
 
  
  
   
  
   
  
  
   
  
  
  
  
   
   
   
  
 
  
   
  
  
  
 
 
 
     


  
 
 
  
 
  
  
 
 
 
  
  
  
    
  
 
 
  
 
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
   
  
 
 
  
 
 
  
  
 
  
  
 
  
 
 
  
  
 
  
  
 
  
  
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
  
 
 
  
 
  
 
  
  
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     


  
 
 
  
 
  
  
 
 
 
 
  
 
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
   
  
 
 
  
 
 
  
  
 
  
  
 
  
 
 
  
  
 
  
  
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
 
  
  
 
  
   
  
  
  
  
  
  
  
  
  
   
   
  
   
 
 
   
  
  
   
  
 
 
 
  
   
  
  
  
  
   
  
  
 
 
  
   
   
  
 
  
  
  
   
  
  
  
   
  
   
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
  
  
  
 
  
  
  
 
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
   
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
   
   
  
   
 
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
   
  
  
  
   
   
  
  
  
 
   
   
  
  
 
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
    
  
  
  
  
   
  
 
  
  
  
  
   
  
  
  
  
  
  
  
  
  
  
 
   
  
   
  
   
  
   
  
   
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
 
  
   
  
  
  
 
 
 
 
  
   
  
  
   
  
  
  
  
  
  
  
  
 
  
  
  
  
   
 
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
 
  
  
     
  
  
  
   
  
 
  
 
  
 
 
 
  
  
   
  
   
  
  
   
  
  
  
  
   
   
   
  
 
  
   
  
  
  
 
     


  
 
 
  
 
  
  
 
 
 
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
 
  
  
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
  
  
  
  
  
  
  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
   
  
 
 
 
  
 
  
 
 
 
  
  
 
 
 
  
  
 
 
 
  
 
 
 
  
 
  
  
   
  
 
 
 
  
 
 
 
 
   
  
 
 
 
   
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
  
 
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
  
  
  
 
 
 
  
 
 
 
  
  
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
  
  
  
 
 
 
  
  
 
 
 
  
  
 
 
 
  
 
 
 
 
  
 
  
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
  
  
 
 
 
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
  
  
  
 
 
 
  
  
 
 
 
  
  
 
 
 
  
 
 
 
  
  
  
  
 
 
 
  
  
 
 
 
  
  
  
  
 
 
 
  
  
 
 
 
   
  
  
  
 
  
 
 
 
  
  
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
   
  
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
  
  
 
 
 
  
  
  
  
  
  
 
 
 
  
  
  
 
 
 
  
 
 
 
  
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
  
  
   
  
  
  
 
 
 
  
  
  
 
 
 
 
 
 
 
  
 
 
 
  
  
  
 
 
 
  
  
 
 
 
  
 
 
 
 
  
 
 
 
 
   
 
 
 
   
 
 
 
  
 
 
 
  
 
 
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
  
 
 
 
  
  
  
   
  
  
  
 
 
  
  
  
  
  
 
   
  
 
 
  
  
  
    
  
 
 
 
 
  
  
  
  
 
 
  
   
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
 
 
  
 
  
  
 
  
  
  
  
  
 
 
 
  
 
 
 
 
  
  
 
 
  
 
 
  
  
 
 
  
  
  
 
 
 
 
  
  
  
 
 
   
 
 
   
 
 
  
  
 
 
  
 
 
  
  
  
  
 
  
  
 
 
  
  
 
 
  
  
 
 
 
 
 
  
  
 
 
  
 
 
  
  
  
 
  
  
 
 
  
  
 
 
 
 
 
 
 
 
  
  
  
 
 
  
  
   
  
 
 
  
  
  
 
  
  
 
 
  
  
  
  
  
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
  
  
  
  
  
 
 
   
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
    
  
  
   
 
  
  
 
  
  
 
  
  
   
 
  
  
  
 
   
  
  
 
  
  
  
 
  
  
  
 
  
  
  
  
 
  
   
   
  
  
   
  
  
   
   
 
   
 
  
  
  
 
  
   
    
 
  
  
 
  
  
  
   
  
 
   
  
  
 
  
  
  
 
 
  
  
  
    
  
  
   
  
 
  
  
  
  
  
  
  
  
  
  
   
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
 
 
  
  
  
   
  
 
    
  
 
  
  
  
  
 
  
 
  
   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
 
  
  
  
  
  
 
  
  
  
 
   
  
  
  
  
  
 
  
   
 
  
  
  
  
  
  
 
  
  
  
   
  
 
  
  
 
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
   
  
  
  
 
   
  
  
 
  
  
 
    
 
  
 
  
 
  
  
  
  
  
   
  
   
  
 
  
  
   
  
  
  
  
  
  
  
  
  
 
  
 
 
  
  
  
  
 
 
  
   
  
  
  
  
   
   
   
  
 
  
 
   
   
 
  
  
   
  
   
  
 
  
  
  
  
  
  
  
  
 
 
  
 
 
   
  
  
  
  
  
 
  
   
  
 
  
  
 
 
  
   
  
 
  
  
   
  
  
  
  
  
  
 
   
  
   
  
  
  
  
  
 
  
  
 
  
  
   
   
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
   
 
  
  
  
    
  
  
   
  
  
 
  
  
 
 
  
 
  
 
  
 
 
 
 
 
 
  
   
  
 
 
  
  
  
   
 
  
  
  
  
  
  
  
  
   
  
 
  
  
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
   
 
  
   
  
  
  
  
 
  
  
   
  
  
  
   
  
  
  
 
 
  
  
  
  
 
  
  
  
  
   
  
  
  
 
  
  
  
  
  
  
  
  
   
   
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
   
  
  
  
 
  
 
 
  
 
 
  
  
 
    
  
  
   
 
  
  
 
   
 
  
  
  
 
  
  
 
 
  
  
  
 
  
   
  
 
  
 
  
  
 
  
  
  
   
   
 
  
 
  
   
  
  
  
  
 
 
   
  
  
  
  
  
  
  
  
  
    
  
 
  
  
  
  
  
   
  
  
  
 
  
  
 
  
   
 
  
  
  
   
  
  
  
   
 
  
  
  
 
  
   
  
  
  
  
  
 
  
  
    
  
  
   
   
  
  
  
  
   
 
  
  
  
  
  
  
  
  
 
  
 
  
 
  
  
 
 
  
  
   
  
  
  
  
 
 
 
 
  
  
  
  
   
  
 
  
 
  
  
  
   
 
 
  
 
 
 
 
  
 
  
   
  
  
 
   
   
  
  
  
  
  
  
  
 
  
  
  
 
  
 
 
 
  
   
   
  
 
  
   
  
  
 
  
   
  
  
  
  
  
  
  
  
 
  
   
  
   
   
 
 
  
 
   
 
  
  
 
  
  
  
  
  
 
 
  
 
  
  
  
  
  
  
   
    
  
  
 
  
  
  
 
  
   
 
  
  
  
 
  
  
  
  
  
  
  
 
   
 
 
  
  
  
 
  
  
  
   
  
 
  
  
   
  
  
  
  
  
  
 
  
  
   
  
  
  
   
 
  
  
 
   
 
  
  
  
  
  
   
    
  
 
  
  
 
  
 
  
  
  
  
  
   
  
  
  
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
   
  
  
  
   
  
  
   
  
  
 
   
  
  
  
  
  
  
  
  
  
 
 
 
  
   
  
  
  
  
  
   
 
 
 
  
  
  
  
   
  
 
  
 
  
  
 
 
   
 
 
  
  
 
  
  
  
  
  
  
 
  
 
  
  
  
  
 
 
 
 
  
    
   
   
   
 
  
  
  
  
  
   
  
  
  
  
 
  
  
  
  
 
 
  
  
   
  
  
 
  
   
  
 
  
  
 
  
 
     




  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
  
  
 
  
  
  
   
 
  
  
  
  
   
  
  
  
  
  
  
 
  
  
   
  
  
  
  
 
  
  
  
  
 
  
  
  
   
  
  
  
  
  
   
   
 
 
   
  
 
 
  
  
   
  
  
  
  
   
  
  
  
 
  
 
 
  
   
  
  
 
  
 
 
 
 
  
 
  
 
  
  
  
  
  
   
  
   
  
  
  
 
  
  
  
  
  
  
  
   
  
    
  
  
 
 
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
   
  
 
  
  
 
 
 
  
  
  
  
  
  
  
   
 
  
  
 
  
   
  
 
  
  
   
  
 
  
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
  
  
 
  
   
  
 
 
 
  
  
   
  
  
  
  
  
  
  
  
  
   
   
   
  
   
  
  
  
  
 
  
  
  
 
  
  
 
  
  
  
  
  
  
  
  
 
  
  
 
   
   
   
   
  
    
  
  
 
  
  
  
 
  
   
  
 
 
  
   
 
 
  
  
  
  
  
 
  
 
 
  
   
  
 
  
  
   
 
  
  
  
 
  
  
  
  
  
 
  
  
   
  
   
  
  
 
   
  
  
  
  
  
  
   
   
  
  
  
  
   
   
   
  
  
 
  
  
  
  
   
  
  
  
  
  
 
   
  
  
 
  
  
 
  
  
  
  
   
  
  
  
  
  
  
 
  
   
  
  
  
  
  
 
  
  
   
  
  
  
  
  
  
 
  
 
  
  
  
  
 
   
  
  
  
  
 
   
  
 
  
  
 
  
   
 
  
  
  
  
 
  
 
 
  
  
  
  
  
  
 
 
  
  
  
  
   
 
   
 
  
  
  
  
  
  
   
  
  
 
  
  
   
 
  
  
 
  
  
   
  
  
  
  
  
  
 
  
 
 
  
   
  
  
   
  
  
 
  
  
   
  
 
  
 
   
  
 
  
  
  
 
  
   
  
 
  
  
  
  
  
  
 
  
   
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
  
  
  
  
  
  
  
   
  
   
  
   
  
  
  
  
  
 
 
   
 
  
    
 
 
  
 
  
 
  
 
 
  
 
  
 
   
 
  
  
 
  
  
  
 
  
  
 
  
 
  
 
   
  
  
   
  
  
 
  
  
  
 
  
 
 
  
  
  
  
 
  
  
  
 
  
  
  
 
  
  
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
  
  
  
  
 
  
  
  
  
 
  
 
 
  
 
     
  
 
  
  
  
  
 
 
 
  
 
 
 
  
  
  
  
   
  
  
  
   
  
 
  
 
  
 
  
   
   
  
  
 
  
  
  
 
  
  
  
   
  
  
 
 
  
  
  
  
 
 
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
 
  
  
 
  
  
  
  
   
  
 
  
  
  
   
  
  
  
  
  
  
  
  
  
  
  
   
   
  
 
  
   
  
  
  
  
 
 
  
  
   
 
  
   
  
   
  
   
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
  
 
 
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
 
  
  
  
 
  
 
  
 
  
   
  
  
  
  
   
  
  
  
  
 
   
 
  
    
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
   
  
  
   
 
 
 
 
  
 
  
  
   
  
  
  
  
  
  
  
  
   
  
 
 
 
  
 
  
    
   
 
  
   
  
  
  
   
  
 
  
 
 
  
  
  
  
   
   
 
 
  
 
  
   
   
  
   
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
 
  
  
   
  
  
  
  
 
  
 
  
 
  
  
  
   
  
  
 
  
  
  
   
   
  
  
   
  
 
  
   
  
  
  
  
  
  
 
 
  
  
 
  
 
   
  
  
  
  
 
  
 
  
   
 
  
 
  
  
  
  
 
  
  
 
  
  
  
   
  
  
 
 
  
  
 
   
  
  
   
  
 
  
   
   
  
  
  
  
  
  
  
   
 
  
  
   
 
 
 
 
  
  
  
 
 
  
  
  
 
  
  
   
  
  
 
  
  
  
  
   
  
  
  
   
   
 
  
   
 
 
  
   
  
  
  
  
   
   
  
  
  
 
 
  
  
  
 
 
 
  
  
  
 
  
  
   
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
   
   
  
   
    
  
  
 
  
  
   
  
 
 
  
  
   
   
  
   
   
  
 
  
  
  
  
   
   
 
 
  
   
  
   
   
  
  
   
  
  
  
  
  
  
    
   
  
 
  
  
 
  
  
  
  
  
  
 
  
  
   
  
  
  
 
 
  
  
  
  
  
  
   
   
  
 
   
  
  
  
 
   
   
  
   
   
  
  
  
 
 
  
  
 
 
  
  
 
  
   
  
  
  
  
 
  
  
  
   
  
  
  
  
  
  
  
   
  
   
  
  
  
  
 
  
  
 
  
   
 
  
   
  
  
   
 
  
   
   
   
  
 
 
  
  
  
   
 
 
 
 
  
  
   
  
   
   
   
  
  
 
  
  
  
   
  
  
 
  
  
  
  
 
  
  
  
   
  
  
  
 
  
  
  
  
   
  
  
  
 
  
  
   
  
  
  
  
   
 
  
  
 
 
  
  
  
   
  
  
  
  
   
  
  
  
 
  
   
   
   
 
  
   
  
 
  
  
  
  
  
  
  
  
 
  
 
  
  
   
  
   
   
  
  
  
  
  
   
  
  
   
  
   
 
  
  
  
  
   
 
  
   
  
 
  
  
  
  
  
 
  
  
   
  
  
  
   
 
 
 
  
  
  
 
  
  
   
   
  
  
   
   
  
  
     
 
  
   
    
     
   
  
  
  
  
 
 
  
  
  
  
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
  
  
  
   
  
  
  
  
  
  
 
   
  
 
  
  
   
   
  
  
 
  
   
   
   
  
  
  
  
  
  
 
  
  
  
  
  
  
   
  
  
  
  
 
  
  
 
  
    
  
   
  
   
   
  
  
  
  
  
  
  
  
   
 
  
  
 
  
  
   
   
   
   
  
  
 
  
   
 
 
  
   
  
   
  
  
 
  
  
 
  
  
  
  
  
  
    
   
  
  
 
  
  
   
  
  
   
  
 
  
  
 
  
 
  
   
  
  
   
  
  
  
  
 
  
   
  
  
  
 
  
 
  
  
  
   
 
   
  
  
  
 
  
  
 
  
  
  
 
  
  
  
  
 
 
  
 
  
  
   
  
 
 
  
 
 
  
  
  
  
 
  
   
  
   
  
  
 
  
  
 
  
  
  
   
  
  
  
  
  
 
 
  
 
  
  
  
 
  
 
 
 
  
 
  
 
  
  
 
  
  
 
 
  
  
  
 
 
  
  
  
 
  
  
  
  
 
  
  
  
 
  
  
 
  
  
  
   
  
 
  
  
 
  
  
 
  
   
  
 
  
  
   
  
 
  
 
 
  
   
 
 
  
  
 
   
 
  
  
  
  
  
 
  
  
 
   
  
 
 
  
  
  
  
 
 
  
 
 
 
  
  
 
 
  
  
  
  
 
  
  
  
  
 
 
    
   
 
 
  
  
  
 
  
   
  
 
  
  
  
 
  
   
  
  
  
  
  
   
   
 
   
  
  
 
  
  
  
  
  
   
  
  
 
  
  
  
 
  
  
  
  
  
  
  
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
   
 
  
  
 
  
  
   
  
   
  
  
 
 
 
  
 
 
 
 
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
  
 
 
  
  
  
   
  
  
  
 
 
  
   
  
  
  
 
 
   
  
 
  
    
  
  
  
  
 
 
 
   
  
  
  
  
 
  
 
   
  
  
   
 
   
  
  
  
  
 
 
  
  
  
 
  
  
  
 
 
  
  
  
 
  
 
   
  
  
  
  
 
 
  
  
  
 
  
 
  
 
 
  
  
  
  
 
  
  
  
  
  
 
 
  
  
  
 
  
  
  
 
 
 
 
  
 
 
 
  
  
 
 
  
 
 
  
  
  
  
  
  
  
  
  
 
 
  
  
 
  
  
 
  
  
   
 
  
  
  
 
  
   
 
   
  
  
  
 
 
  
 
  
   
 
  
  
  
  
  
 
  
  
 
  
   
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
  
  
  
  
  
  
 
 
  
 
 
 
  
 
  
  
  
  
  
   
  
  
 
  
   
  
   
  
  
  
 
  
  
 
 
  
 
  
 
  
  
 
 
  
  
  
 
  
   
  
  
  
   
  
  
 
  
 
   
   
  
   
  
  
  
 
 
 
   
  
  
 
   
   
  
   
  
 
  
  
  
 
  
 
 
  
   
  
  
  
  
  
  
 
   
   
  
 
  
  
 
 
 
 
 
 
  
  
  
   
 
 
  
  
  
  
   
  
  
   
 
  
   
   
 
  
 
  
   
  
   
  
  
 
  
   
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
  
  
  
   
 
  
   
  
 
  
 
   
  
  
 
  
  
   
  
  
  
 
  
 
  
 
  
  
 
  
  
  
 
  
 
  
  
  
 
  
  
 
  
  
 
 
  
  
  
  
  
 
  
 
  
  
  
  
  
  
   
  
  
  
  
 
  
  
 
  
    
  
   
  
 
 
   
 
  
  
   
   
   
   
  
  
 
  
 
 
  
   
  
   
  
  
 
  
  
 
  
 
  
 
 
  
 
  
   
  
 
  
  
  
  
  
 
 
 
 
  
  
  
 
  
  
  
  
  
  
 
 
  
   
   
  
 
 
  
  
  
  
  
  
  
   
  
   
  
  
 
   
  
  
  
  
  
  
   
   
  
  
  
  
   
   
   
  
 
  
  
  
  
  
   
  
  
  
  
 
  
   
  
  
 
  
  
  
  
  
  
 
   
   
  
  
  
  
  
 
  
   
  
  
 
  
  
  
  
  
   
  
  
  
  
 
  
  
  
 
  
  
  
  
   
  
  
 
  
  
  
   
  
  
  
  
   
 
  
  
   
  
 
  
   
   
   
 
  
 
 
  
  
  
  
  
  
  
  
 
  
  
  
  
   
  
  
  
 
  
  
   
   
   
   
  
  
  
  
 
 
 
   
  
  
   
 
  
    
  
  
 
  
  
   
  
  
 
  
 
   
   
  
   
   
  
 
  
  
  
  
   
   
 
 
  
   
  
   
   
 
 
  
   
  
  
  
  
  
  
    
   
  
 
  
  
  
  
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
  
  
  
  
 
  
  
   
  
  
 
  
 
  
  
  
  
 
  
   
  
  
  
 
  
   
  
  
   
 
  
  
   
   
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
 
  
  
   
  
  
 
  
  
  
  
 
 
 
 
  
 
 
  
  
 
  
 
  
  
  
  
 
  
  
   
   
 
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
 
  
  
 
  
 
  
   
  
  
 
 
  
  
 
  
  
 
   
  
  
  
  
  
  
 
  
  
 
  
 
  
  
  
   
 
  
  
 
   
 
  
  
  
  
  
  
   
   
  
 
   
  
  
 
  
  
  
  
  
  
  
 
  
 
 
  
   
  
 
  
  
  
   
  
   
  
  
 
  
  
  
  
  
  
   
  
  
  
  
  
  
 
   
  
  
 
  
  
 
 
  
  
  
  
   
  
 
  
  
  
   
 
  
  
  
 
  
 
  
  
  
 
 
  
   
 
 
  
 
 
 
  
 
  
  
  
   
  
  
  
   
   
  
 
  
 
  
  
  
  
 
 
  
  
 
  
  
  
 
  
  
  
  
 
 
 
  
   
   
  
   
 
  
  
  
  
  
  
  
  
  
 
 
  
  
  
    
  
  
  
 
 
  
  
 
  
 
  
  
  
  
  
 
  
   
  
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
 
  
 
  
  
   
   
 
  
  
   
  
  
   
  
  
   
  
  
  
  
   
  
  
  
 
  
   
  
  
  
  
  
   
  
 
  
  
  
   
  
  
 
 
  
 
  
  
  
 
  
  
  
  
 
  
  
  
 
 
  
 
  
 
  
  
 
  
 
  
   
   
  
  
 
  
  
  
  
  
  
  
   
 
   
  
  
  
 
  
  
  
  
   
   
   
  
   
  
  
  
 
  
  
 
  
  
 
  
  
   
  
  
 
  
 
  
  
  
  
 
  
 
 
  
 
  
 
 
  
 
  
  
 
  
 
  
   
 
  
  
  
   
 
  
 
   
 
   
  
  
  
  
  
  
   
  
  
    
  
  
  
  
 
  
  
 
  
  
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
  
 
  
  
 
 
  
  
  
   
  
  
  
 
 
  
   
  
  
  
  
   
   
  
 
 
  
   
  
  
  
 
 
  
  
  
  
 
  
 
  
   
  
 
  
  
  
  
 
 
  
  
  
  
  
  
  
   
  
  
 
 
 
  
  
  
  
  
 
  
 
 
 
  
 
  
  
 
  
  
 
 
  
  
  
  
   
  
  
 
  
  
 
  
   
  
 
 
  
 
 
  
 
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
 
  
  
 
  
 
  
  
  
  
 
 
  
  
 
  
   
 
  
 
  
 
  
  
 
  
 
   
  
  
 
  
 
 
  
  
 
  
  
 
  
 
  
  
  
  
  
  
 
  
   
  
 
  
 
  
  
  
 
 
  
  
  
  
 
  
 
 
  
  
  
  
  
  
 
  
 
  
 
 
  
 
 
 
  
 
   
  
 
  
   
 
 
  
  
  
 
   
  
 
 
  
 
 
  
  
  
 
 
 
  
  
  
  
  
   
   
  
  
   
  
  
  
  
 
  
 
  
  
  
 
  
  
 
 
  
  
  
   
  
  
 
 
  
  
  
  
 
  
  
  
  
  
  
 
 
  
  
  
  
  
  
   
  
  
 
 
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
   
  
 
  
  
 
  
  
 
  
   
  
  
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
  
 
  
  
  
  
  
 
  
 
 
  
   
   
 
  
  
  
 
  
  
  
 
 
 
  
 
 
  
  
  
   
  
  
  
 
  
 
 
  
   
  
  
 
  
 
 
  
 
  
 
  
   
  
  
 
  
 
 
  
  
 
  
  
   
   
 
  
 
 
 
 
 
  
  
   
  
  
  
 
  
 
  
   
 
  
 
  
   
  
 
 
  
   
  
  
 
  
 
  
  
  
  
  
   
  
 
  
  
  
 
  
 
  
  
  
 
  
 
  
  
   
  
 
 
  
 
  
 
 
 
  
  
  
  
   
   
  
  
  
   
  
 
   
  
 
  
  
  
 
  
 
  
 
  
  
  
  
  
   
  
  
  
 
  
   
  
  
  
   
  
 
 
 
  
  
   
  
   
 
  
 
 
  
  
  
  
  
 
  
  
  
  
 
 
  
  
  
  
  
 
  
 
  
   
 
 
  
  
  
  
 
  
  
  
  
  
 
 
 
  
 
 
  
  
   
  
  
   
  
  
  
 
  
  
  
  
  
  
 
   
  
 
  
  
  
    
  
  
    
 
  
 
 
  
   
  
  
  
  
  
  
  
    
  
 
  
 
  
    
  
  
  
  
  
  
 
  
 
 
 
  
  
  
 
 
  
  
  
   
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
   
  
  
 
  
  
  
  
  
  
 
  
  
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
  
 
  
  
  
  
  
  
   
  
  
 
 
  
   
 
  
  
  
   
  
  
  
 
  
  
  
  
 
  
 
 
  
   
  
  
  
  
  
  
   
  
 
 
  
  
  
 
 
  
  
  
  
  
   
  
  
  
 
 
 
  
  
  
 
  
  
  
 
  
  
 
  
  
  
  
 
 
  
 
 
  
  
 
 
  
 
  
  
 
 
  
 
  
 
  
 
  
   
  
   
  
 
 
  
 
 
  
  
   
  
  
 
   
  
  
 
 
  
  
  
  
 
  
 
  
  
 
  
  
  
   
  
  
  
  
  
  
 
  
 
  
  
  
  
   
   
  
  
  
  
 
  
 
  
  
  
  
 
  
 
 
   
  
   
 
  
  
 
 
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
 
  
  
  
  
 
   
 
  
  
  
 
  
  
  
  
  
  
  
  
 
 
  
 
  
  
  
  
  
  
 
   
   
  
  
 
 
   
   
  
  
 
  
   
  
  
  
  
  
  
  
  
 
  
   
   
 
  
  
  
  
 
  
  
  
  
  
  
 
   
 
  
  
  
  
   
  
   
  
  
  
  
  
 
 
  
  
 
  
   
  
   
  
  
 
  
 
 
  
   
  
  
 
   
  
 
 
  
  
  
  
 
  
  
  
  
  
  
   
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
  
   
   
  
 
  
 
  
  
  
 
 
  
  
  
  
  
 
  
  
 
  
  
  
  
    
  
 
   
 
  
  
  
 
  
  
 
 
  
   
  
  
 
 
  
  
  
  
 
  
  
  
 
  
  
  
   
 
  
  
 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
 
  
  
  
  
 
  
  
  
  
 
  
  
 
 
  
  
  
   
   
  
 
  
 
 
   
  
   
 
  
  
  
 
  
  
   
  
 
  
  
 
  
   
 
 
  
   
  
 
 
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
 
  
  
 
 
  
  
  
  
  
  
  
 
  
 
  
 
  
  
  
  
  
  
 
  
 
  
  
  
  
 
  
  
  
 
  
  
  
 
 
  
 
  
  
  
  
  
 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
   
  
  
  
  
  
 
   
 
 
  
  
  
  
  
  
 
  
 
  
  
 
  
  
  
  
  
  
 
   
  
   
  
   
 
   
  
  
  
 
  
   
  
  
  
  
  
   
  
  
 
  
  
 
 
  
  
  
  
  
 
  
  
  
 
  
 
 
 
   
  
   
 
   
  
 
  
  
  
  
 
  
   
  
   
  
 
  
   
  
  
 
 
  
 
  
 
  
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
   
  
  
 
  
  
 
  
   
  
   
 
  
 
 
  
 
 
 
  
  
 
 
  
  
  
  
  
 
  
 
  
   
  
  
 
  
  
 
  
  
  
  
 
  
 
 
  
  
   
   
 
  
  
 
  
 
 
  
   
  
  
  
 
  
  
 
  
  
  
  
 
  
 
  
  
 
  
  
 
  
  
  
  
  
 
    
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
  
 
  
  
 
  
   
 
  
  
   
   
  
 
  
   
   
  
    
   
 
  
  
  
 
  
  
  
 
  
   
  
  
  
 
 
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
 
 
  
  
  
   
   
  
 
 
 
 
  
  
  
  
  
  
   
 
 
  
  
  
  
 
  
  
  
  
  
   
 
  
 
 
  
  
  
    
  
   
  
  
  
 
  
 
 
 
  
  
  
 
  
 
  
  
   
 
  
  
   
 
   
  
  
  
  
   
 
 
 
  
  
 
  
 
   
    
  
    
 
  
  
  
  
 
  
   
 
 
  
   
  
 
  
  
  
   
 
  
  
  
  
  
    
  
 
 
  
  
  
 
   
 
   
  
  
  
   
 
   
  
  
  
    
 
  
  
  
  
  
 
  
  
  
  
  
  
   
   
  
  
  
  
  
 
 
 
  
  
  
  
  
  
  
  
  
 
  
  
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
  
  
  
  
  
 
  
  
  
 
  
   
   
  
  
  
  
 
 
  
   
  
  
 
  
 
   
  
 
   
 
  
  
  
  
 
 
  
 
  
   
 
  
  
 
  
 
  
   
 
  
  
 
  
  
  
  
  
   
   
  
 
  
  
  
  
 
  
  
  
   
  
  
 
  
   
 
  
  
 
   
  
  
 
  
  
 
  
  
  
 
  
  
 
  
 
  
   
 
  
  
 
  
 
  
   
 
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
 
  
  
  
 
  
 
  
  
  
  
    
   
 
  
 
  
  
  
  
  
  
  
  
   
  
 
  
  
 
  
  
  
 
  
  
  
  
  
  
 
 
  
  
  
   
  
  
  
 
  
   
 
  
  
   
  
  
  
 
 
 
  
  
 
  
  
  
 
  
  
  
  
   
 
  
  
   
  
  
  
  
  
  
  
 
 
  
   
  
  
  
  
  
 
  
  
   
  
   
 
 
  
  
  
 
  
  
  
  
 
  
  
  
 
 
  
  
 
   
    
 
    
  
  
 
  
  
  
  
   
  
  
  
 
  
  
 
  
  
  
   
   
  
  
  
  
 
  
  
  
  
 
  
   
  
  
  
  
  
  
  
 
  
  
 
  
 
 
  
  
 
  
 
 
  
  
  
 
  
  
  
  
   
  
 
 
  
 
  
  
   
  
   
  
  
  
  
  
 
  
  
   
  
  
  
  
  
 
   
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
  
  
  
  
  
 
  
 
  
  
  
  
 
 
  
  
  
   
  
 
  
  
  
  
 
  
   
 
 
  
  
 
 
  
  
  
  
  
 
  
 
  
  
 
  
   
  
  
  
  
 
 
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
 
  
  
 
  
 
   
  
  
  
  
  
  
   
  
  
  
  
 
 
 
  
   
  
  
 
 
  
  
  
 
 
 
  
  
  
   
  
 
  
  
  
  
  
 
  
  
  
  
  
  
   
  
 
  
   
 
  
 
  
   
  
   
  
  
  
 
  
  
  
 
  
  
  
   
    
  
  
  
  
 
  
  
  
  
 
  
   
 
 
  
   
   
  
   
 
  
    
  
   
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
 
 
  
 
  
   
  
  
  
   
   
  
 
  
  
   
  
  
  
 
  
  
 
  
  
  
   
  
   
  
 
  
  
 
 
 
 
  
  
  
  
  
  
 
  
 
  
  
  
 
  
  
 
  
   
  
 
  
  
  
  
 
  
 
 
  
  
  
 
 
  
 
 
  
  
   
  
 
  
  
  
 
  
  
  
 
  
 
 
  
  
 
  
  
  
  
 
   
  
   
 
  
  
    
   
  
 
 
   
  
   
  
  
  
  
 
  
 
 
  
  
  
  
  
  
  
  
 
  
  
 
  
 
   
  
   
  
  
  
 
 
 
   
 
  
  
  
   
 
  
 
   
  
  
 
  
  
  
 
 
   
  
   
  
 
  
  
  
  
  
  
  
   
  
  
  
 
  
 
  
  
   
  
  
  
  
 
  
  
   
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
  
 
  
  
  
 
 
   
   
  
  
  
  
  
 
  
  
  
  
 
  
  
  
 
  
   
 
  
  
 
  
  
  
  
  
 
  
  
  
   
  
   
  
   
   
   
 
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
   
  
  
 
   
 
  
  
  
  
  
   
  
 
  
  
  
  
  
  
   
  
    
  
 
  
  
  
  
 
  
  
  
 
  
  
   
  
   
  
   
    
 
  
  
  
  
  
  
  
 
  
  
  
 
 
  
  
  
  
  
  
 
  
  
  
  
   
 
   
  
  
  
 
   
  
  
 
  
   
  
  
   
  
  
 
  
 
   
  
   
  
  
  
  
 
  
  
  
    
   
  
 
  
  
 
 
   
  
  
  
 
  
  
  
  
  
  
   
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
   
 
  
    
  
  
  
  
   
  
   
 
   
  
 
  
   
  
   
  
  
   
   
  
 
  
  
  
 
  
  
   
 
   
 
  
   
  
 
  
  
 
  
  
  
  
 
  
   
  
  
  
  
  
 
  
  
  
 
  
  
  
   
  
  
  
  
  
 
 
  
  
  
 
 
 
  
   
  
   
  
 
 
  
 
  
 
  
  
 
  
  
  
 
  
  
  
  
  
  
  
 
 
 
  
  
  
  
  
   
  
  
 
  
  
  
  
 
  
 
  
  
  
 
  
   
    
  
   
 
  
 
  
   
  
  
  
  
 
  
  
  
   
 
  
  
 
  
  
 
  
 
  
 
  
   
  
  
  
 
 
  
  
  
 
   
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
  
 
 
  
 
 
  
  
   
  
  
  
  
 
 
  
   
 
  
  
 
  
  
 
  
  
 
  
 
  
  
  
 
  
   
  
  
  
 
 
  
  
 
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
 
 
  
  
   
   
 
  
 
  
 
    
  
 
  
 
  
 
  
  
  
  
  
 
  
  
  
  
   
   
  
  
  
 
  
  
  
  
   
  
  
  
 
  
 
  
   
  
  
  
    
  
   
  
 
 
   
  
   
  
   
   
   
 
 
  
  
 
  
 
  
  
  
  
  
  
  
 
  
  
 
 
  
  
  
  
  
  
  
  
 
  
 
  
  
 
  
  
  
 
  
   
   
  
  
  
  
  
  
    
   
 
  
   
 
 
  
  
  
  
   
   
  
 
  
  
  
  
  
 
 
  
  
  
 
  
   
  
  
  
  
  
 
  
 
  
 
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
 
  
 
 
  
  
 
 
  
  
  
  
 
 
  
  
 
  
   
 
  
  
  
  
  
  
   
   
  
 
 
  
   
  
 
  
 
  
   
 
   
  
  
  
  
  
  
 
  
 
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
 
  
  
 
  
 
 
  
  
 
  
   
  
 
  
  
  
  
  
  
  
  
  
 
  
 
  
 
   
   
 
  
 
  
  
  
   
 
   
  
 
 
   
 
  
  
  
  
 
  
   
  
 
  
  
 
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
 
 
  
  
  
  
   
 
  
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
   
  
  
  
 
  
 
  
  
  
  
 
  
  
  
 
 
  
  
  
  
   
  
  
  
 
  
   
  
  
  
  
 
  
  
 
  
 
  
 
  
  
   
  
  
 
  
  
 
  
   
 
  
 
  
 
  
   
 
  
  
  
  
  
  
  
  
   
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
   
  
  
 
  
  
  
  
  
  
  
 
  
  
  
 
  
 
  
  
  
 
  
  
  
  
  
 
  
 
  
 
  
  
  
 
  
  
  
  
  
 
  
  
  
  
   
  
  
  
  
   
 
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
 
  
 
  
 
  
  
  
  
  
 
 
  
   
  
  
 
  
  
 
  
  
 
  
   
  
  
  
 
  
  
  
  
  
  
 
  
 
  
  
     
  
 
 
  
  
  
  
   
  
 
  
  
   
  
 
   
   
   
 
 
  
 
   
   
  
  
  
  
  
    
  
  
 
 
  
 
  
 
 
   
  
  
 
  
 
  
  
  
 
  
 
  
  
  
  
 
  
  
  
 
  
 
  
 
  
  
  
 
  
  
  
  
 
  
  
  
 
  
 
  
 
  
  
  
 
 
  
  
  
   
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
   
  
  
 
 
  
   
 
  
  
  
  
  
  
  
   
 
  
 
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
   
 
  
   
  
  
 
  
  
  
   
 
  
  
 
  
  
 
 
  
  
   
  
 
  
  
 
  
  
  
  
 
  
  
   
  
  
  
  
   
  
  
 
 
  
   
 
  
  
  
  
  
  
 
  
 
  
  
 
  
  
  
  
  
  
  
   
  
 
  
  
  
   
 
  
   
  
  
 
  
  
  
   
 
  
  
 
  
  
 
 
  
   
  
  
  
    
   
 
   
  
  
 
 
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
 
 
  
  
 
  
  
 
  
 
 
  
 
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
   
 
  
  
 
  
  
  
  
  
  
  
 
 
  
 
  
   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
 
  
   
  
  
 
  
  
  
  
   
  
 
  
  
 
 
  
  
   
  
  
  
  
  
   
  
  
 
   
  
  
 
  
   
  
  
  
 
 
   
  
  
  
  
 
  
 
 
  
 
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
    
  
  
  
  
   
 
 
   
  
  
 
  
  
  
   
   
  
 
  
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
  
  
  
  
 
 
  
  
  
  
 
  
  
 
  
  
  
  
  
  
 
  
  
  
  
   
  
 
 
  
  
  
  
  
  
 
  
   
  
 
  
  
 
  
  
  
 
  
  
  
  
 
  
  
 
 
  
  
 
 
 
 
 
   
  
 
  
  
 
  
   
  
  
  
  
  
 
  
  
  
 
  
 
  
  
  
 
  
  
  
 
  
  
  
 
  
   
  
  
  
  
 
 
 
  
  
  
 
  
  
  
  
  
 
  
  
  
  
 
 
  
  
 
  
  
  
  
  
  
  
  
 
  
  
   
  
  
  
  
  
 
  
   
 
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
   
 
  
  
  
 
  
   
  
  
  
  
 
 
  
 
  
  
 
 
  
  
   
  
  
  
  
  
 
  
   
 
  
  
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
 
  
  
 
  
  
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
  
  
 
  
  
   
  
  
 
  
 
  
  
 
  
 
  
   
  
  
  
  
  
  
  
  
  
 
 
  
  
 
 
  
  
  
  
  
  
 
  
 
 
  
  
  
  
  
 
  
 
  
  
  
 
  
  
 
 
  
  
 
  
  
 
 
 
  
  
  
  
 
  
  
  
  
 
  
   
   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
  
   
  
  
   
  
 
  
 
 
  
  
  
  
  
   
  
  
 
  
 
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
   
   
  
 
  
  
  
 
  
  
 
 
  
  
  
  
  
  
  
  
   
  
 
  
  
  
  
 
  
  
  
 
  
  
  
  
 
 
   
  
  
   
  
  
  
  
  
  
  
 
 
  
   
  
  
  
 
  
  
  
 
  
 
  
 
  
  
  
  
  
   
   
  
 
  
 
  
  
  
  
 
  
 
  
  
  
 
  
 
  
 
  
  
  
   
  
  
 
 
  
    
  
  
  
 
  
  
  
 
  
 
 
 
  
  
 
  
  
   
  
  
  
  
  
  
  
 
  
 
  
 
  
  
  
  
  
 
  
 
  
  
  
  
 
 
  
 
  
  
  
   
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
  
 
  
  
  
  
  
  
 
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
 
  
 
  
  
  
  
 
  
 
  
  
  
 
  
  
 
 
 
  
 
  
   
  
  
  
 
  
  
  
 
  
  
  
 
 
  
  
  
   
  
  
  
  
 
  
  
   
  
  
 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
 
  
  
  
  
 
  
 
   
  
  
  
  
  
   
 
  
  
 
 
 
  
 
  
  
 
  
  
   
  
 
  
  
  
  
   
  
 
  
  
    
  
  
 
  
  
 
   
 
  
  
 
  
   
  
  
  
  
 
  
 
  
  
  
  
 
  
  
 
  
  
  
  
 
  
  
 
 
  
   
  
 
  
  
 
  
  
 
 
  
  
  
 
 
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
   
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
  
  
   
   
  
  
  
  
  
  
  
  
  
   
  
 
  
  
   
 
  
 
  
 
 
  
  
 
 
  
 
  
  
  
 
  
  
 
 
  
  
  
  
 
  
  
  
 
 
  
  
  
 
 
 
 
  
 
  
 
  
  
 
  
    
  
 
  
  
  
 
 
 
 
  
   
  
  
  
  
  
  
  
  
 
 
  
 
 
  
 
  
  
  
  
  
 
 
  
  
  
  
  
 
  
  
 
 
  
   
  
  
  
  
 
  
 
  
  
  
  
  
  
  
 
 
  
 
  
 
 
  
  
  
  
  
  
   
  
  
  
  
  
 
  
  
  
  
  
   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
   
 
 
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
   
 
  
  
  
  
  
  
 
 
  
  
  
  
  
   
  
 
  
  
 
  
  
  
  
 
   
  
  
 
   
 
  
  
 
 
 
   
 
   
 
   
  
 
 
  
 
  
 
  
   
  
  
  
  
  
  
 
 
  
    
 
  
    
  
  
   
  
 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
 
 
 
  
  
  
  
 
  
  
 
   
  
   
  
 
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
  
  
 
 
  
  
 
 
  
  
  
  
  
 
  
  
 
 
  
  
  
  
   
  
  
 
  
  
  
 
  
  
 
 
  
 
 
 
  
  
  
 
  
  
  
  
  
  
  
 
 
 
 
  
  
  
  
 
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
  
  
 
 
  
  
  
  
 
 
  
  
 
  
 
 
  
   
  
  
  
  
  
  
  
  
  
 
  
 
  
 
  
  
 
  
  
  
  
  
  
  
   
  
 
  
  
    
  
  
 
  
  
  
  
  
 
 
  
  
   
 
  
 
  
  
 
  
  
  
  
   
 
  
   
  
  
  
 
    
    
  
  
  
  
  
   
 
 
  
  
  
  
 
  
  
  
  
 
  
  
 
 
  
   
 
  
  
  
   
   
 
  
 
 
  
  
  
  
  
  
  
  
 
  
 
 
  
   
  
   
   
 
  
  
  
 
 
  
  
 
  
   
   
   
 
  
  
 
  
  
  
  
   
 
  
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
  
  
  
  
  
  
  
  
 
 
  
 
  
  
  
  
  
   
  
 
 
  
  
  
  
 
  
  
  
  
 
  
   
 
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
  
  
 
  
  
  
  
 
  
  
  
  
  
 
  
   
  
 
  
   
  
 
 
  
   
  
 
  
  
 
  
  
  
  
 
   
  
  
  
  
  
 
  
 
  
 
  
  
  
  
  
  
  
  
  
  
   
   
 
 
  
   
  
  
  
   
  
  
  
  
 
 
  
  
   
 
  
 
  
   
   
  
  
 
   
  
  
 
   
 
  
   
  
  
 
 
  
   
  
 
 
  
 
  
  
 
  
 
 
 
   
  
  
   
  
  
   
  
  
 
  
  
   
  
 
  
 
  
 
  
  
  
   
 
  
  
  
  
  
  
  
  
  
  
 
 
  
 
  
  
  
  
  
  
 
 
  
  
  
   
  
  
  
  
 
  
  
  
 
  
  
   
  
  
  
   
 
  
  
  
 
 
  
  
  
   
  
  
  
 
  
  
  
 
  
 
  
   
  
  
  
  
   
  
  
 
 
  
  
 
  
  
  
  
 
  
  
 
  
   
  
  
  
  
  
  
  
  
 
   
  
 
  
  
  
  
  
  
   
  
 
  
   
  
 
 
  
  
  
 
   
   
  
 
 
  
  
  
 
  
   
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
   
  
  
  
  
 
  
  
  
 
  
   
  
 
 
   
  
 
  
  
 
  
 
  
   
  
  
  
 
   
 
  
  
 
 
  
  
   
  
  
 
  
 
 
  
 
   
  
 
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
   
  
  
  
  
 
  
  
  
   
  
  
   
  
 
 
 
  
  
  
 
  
   
  
  
  
  
  
  
  
  
   
  
  
  
  
  
   
  
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
  
  
  
  
  
  
 
  
  
  
 
 
 
  
  
 
 
  
 
  
   
  
 
 
  
  
  
 
   
  
 
  
  
  
  
  
 
  
  
 
  
   
  
  
  
  
 
  
  
 
  
 
 
 
  
  
  
 
  
  
  
  
 
  
  
 
  
  
 
  
  
  
  
  
  
  
 
  
 
 
  
   
  
  
  
  
  
  
  
   
 
  
 
  
  
  
  
  
 
  
   
  
 
 
  
  
  
   
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
 
 
  
  
  
   
  
  
  
 
 
 
 
  
  
  
  
 
  
  
  
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
 
  
 
 
 
   
 
 
  
 
 
 
  
   
  
 
 
 
 
  
  
  
 
 
  
   
  
  
  
  
 
 
  
   
 
  
 
  
 
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
 
  
   
  
 
  
  
 
   
  
  
  
   
  
  
  
  
 
  
  
  
  
  
  
  
 
 
  
 
 
  
 
   
 
  
  
  
  
 
 
  
  
  
 
  
  
 
  
  
  
  
   
    
  
 
  
  
  
 
  
  
  
 
 
  
  
  
  
  
  
 
    
   
  
  
  
 
  
 
   
 
 
 
  
  
   
   
 
 
    
  
  
 
  
  
  
  
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
  
 
  
  
  
   
  
  
  
  
 
  
 
   
 
  
  
  
   
  
  
  
   
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
   
   
  
  
 
  
  
   
 
   
  
  
  
  
 
  
 
 
 
     


  
 
 
  
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
   
 
  
  
   
  
  
  
  
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
  
  
  
  
 
 
  
  
 
  
  
 
 
  
  
  
  
  
  
  
 
  
   
    
 
 
   
   
  
 
 
  
  
 
  
 
  
  
   
  
   
  
 
  
 
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
  
  
   
  
  
  
  
  
 
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
 
  
 
 
  
  
  
  
  
  
  
  
  
   
 
  
  
  
  
   
  
 
  
  
  
  
 
 
  
 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
   
 
 
  
  
  
 
  
  
 
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
   
 
 
  
  
 
  
  
   
  
   
  
  
  
 
 
 
 
   
  
  
  
  
  
  
  
 
  
 
 
 
  
  
 
  
  
 
  
  
 
 
  
 
  
 
  
  
   
  
   
  
  
  
 
  
 
  
  
  
  
   
 
 
     


  
  
 
 
  
  
 
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
  
 
     


  
  
   
 
 
 
  
  
   
 
 
 
 
  
 
 
   
 
  
   
  
 
 
  
   
  
  
  
  
   
  
  
  
  
 
  
   
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
    
 
  
 
  
  
 
  
 
  
  
 
  
    
  
  
  
  
  
  
  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
   
  
 
  
 
  
 
  
  
 
  
 
  
 
  
  
  
 
  
   
  
  
  
 
 
  
  
  
  
  
 
 
  
  
  
 
   
 
  
  
  
 
 
  
 
  
  
  
 
  
 
  
 
  
  
 
  
  
  
 
  
 
  
  
  
 
  
  
 
  
  
 
 
  
  
  
  
  
 
  
   
  
   
  
 
  
  
  
  
  
  
  
 
 
  
   


  
  
   
 
 
 
  
  
   
 
 
 
  
  
  
  
  
  
  
 
  
  
  
 
 
  
  
  
   
  
  
  
 
  
  
   
  
  
  
  
  
  
   
  
  
 
  
  
 
 
  
  
  
   
  
 
  
  
 
  
 
 
  
  
  
 
  
  
 
  
  
  
  
  
  
   
  
  
  
  
  
  
 
  
  
  
 
  
   


  
  
   
 
 
 
  
  
   
 
 
 
 
  
 
 
  
 
  
  
 
 
  
  
  
 
  
  
 
  
 
 
 
  
 
  
 
  
  
 
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
 
  
  
  
  
  
 
  
  
  
  
   
  
  
  
  
  
  
 
  
  
  
   
  
   
  
  
  
  
 
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
   
  
 
  
  
  
  
 
  
  
  
  
  
  
   
  
  
 
  
  
  
  
  
 
  
  
   
  
  
  
 
  
  
  
 
  
  
  
   
  
  
 
  
   
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
   
 
  
  
 
 
 
  
  
 
  
  
  
  
  
  
   
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
 
  
 
  
  
  
 
 
  
  
  
  
   
  
 
  
 
  
  
   
  
  
  
  
   
 
  
 
   
  
  
  
 
  
  
  
  
  
  
 
  
  
 
  
   
  
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
 
 
  
  
  
 
 
 
  
  
   
 
  
  
  
  
 
 
 
  
   



SAP_001.pdf: 


Cli nical St u d y Re p ort  
 
3 2 4 -E T D -3 0 3  
1 6. 1 St u d y I nf or mati o n  
 
 
 
1  
 
 
  
 
9.       
S T A TI S TI C A L M E T H O D S I N T E RI M A N A L Y SI S P L A N  
T he f oll o wi n g statistical a nal ysis pla n is pr o vi de d:  
Sa ge _ 3 2 4 -E T D -3 0 3 _sa p _ v 1 0 _ 2 0 2 4 1 0 2 2  
P a g e  1  of  6 0






St atisti c al   A n al ysis  Pl a n   M et h o ds   V ers i o n  1. 0  2 2  O ct 2 0 2 4
S a g e  T h er a p e uti cs, I n c.
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3)
C  O  N FI  D E  N TI  A L
3
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
  P h  D
S a g e  T h er a p e uti cs, I n c
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
D at e
P a g e  4  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
4  
 
T  A  B  L  E   O F   C  O  N  T  E  N  T S 
1.  
LI S T   O F   A  B  B  R E  VI  A TI  O  N S...................................................................  6  
2.  
I  N T  R  O  D  U  C TI  O  N ....................................................................................  7 
3.  
S T  U  D  Y   O  BJ E  C TI  V E S ............................................................................  8  
3. 1.  
Pri  m ar y   O bj e cti v e .....................................................................................  8  
3. 2.  
S e c o n d ar y   O bj e cti v e .................................................................................  8  
 
  8 
4.  
S T  U  D  Y  E  N  D P  OI  N T S ..............................................................................  9  
4. 1.  
Pri  m ar y  E n d p oi nt ......................................................................................  9  
4. 2.  
S e c o n d ar y  E n d p oi nts ................................................................................  9  
 
  9 
5.  
S T  U  D  Y   D E SI  G  N ...................................................................................  1 0  
5. 1.  
O v er all   D esi g n ........................................................................................  1 0  
5. 2.  
S a  m pl e  Si z e  a n d  P o  w er ..........................................................................  1 1  
5. 3.  
R a n d o  mi z ati o n ........................................................................................  1 1  
5. 4.  
Bli n di n g  a n d   U n bli n di n g ........................................................................  1 1  
6.  
M  O  DI FI  C  A TI  O  N S .................................................................................  1 2  
6. 1.  
M o difi c ati o ns fr o  m t h e   A p pr o v e   d   Cli ni c al  St u d y  Pr ot o c ol ....................  1 2  
6. 2.  
M o difi c ati o ns fr o  m t h e   A p pr o v e d  St atisti c al   A n al ysis  Pl a n ..................  1 2  
6. 3.  
M o difi c ati o ns fr o  m t h e   A p pr o v e d   D  M  C   C h art er ...................................  1 2  
7.  
A  N  A L  Y SI S  S E T S ..................................................................................  1 3  
7. 1.  
All  P arti ci p a nts  S et .................................................................................  1 3  
7. 2.  
S af et y  S et ................................................................................................  1 3  
 
  1 3 
 
  1 3 
8.  
S T  A TI S TI  C  A L   A  N  A L  Y SI S ..................................................................  1 4  
8. 1.  
G e n er al   C o nsi d er ati o ns ...........................................................................  1 4  
8. 2.  
B a c k gr o u n d   C h ar a ct eristi cs ....................................................................  1 4  
8. 2. 1.  
P arti ci p a nt   Dis p ositi o n ............................................................................  1 4  
8. 2. 2.  
Pr ot o c ol   D e vi ati o ns ................................................................................  1 5  
8. 2. 3.  
D e  m o gr a p hi cs  a n d   B as eli n e   C h ar a ct eristi cs ...........................................  1 5  
P a g e  5  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
5  
 
8. 2. 4.  
M e di c al/ S ur gi c al   Hist or y ........................................................................  1 6  
8. 2. 5.  
Pri or  a n d   C o n c o  mit a nt   M e di c ati o ns .......................................................  1 6  
8. 2. 6.  
I n v esti g ati o n al  Pr o d u ct  E x p os ur e ...........................................................  1 7 
8. 2. 7.  
I n v esti g ati o n al  Pr o d u ct   A d h er e n c e .........................................................  1 8 
 
  1 8 
 
  1 8 
 
  1 8 
 
  1 8 
 
  1 9 
 
  1 9 
 
  2 1 
8. 4.  
S af et y   A n al ysis .......................................................................................  2 3  
8. 4. 1.  
A d v ers e  E v e nts .......................................................................................  2 3  
8. 4. 2.  
Cli ni c al  L a b or at or y .................................................................................  2 4  
8. 4. 3.  
El e ctr o c ar di o gr a  m ...................................................................................  2 7  
8. 4. 4.  
Vit al  Si g ns ..............................................................................................  2 8  
8. 4. 5.  
P h ysi c al  E x a  mi n ati o n .............................................................................  2 9  
8. 4. 6.  
C ol u  m bi a  S ui ci d e  S e v erit y   R ati n g  S c al e (  C- S S  R S) ...............................  2 9  
8. 4. 7.  
P h ysi ci a n    Wit h dr a  w al   C h e c klist ( P   W  C- 2 0) ...........................................  3 0  
8. 4. 8.  
E p  w ort h  Sl e e pi n ess  S c al e ( E S S) ............................................................  3 1  
8. 4. 9.  
Ot h er  S af et y   A n al ysis .............................................................................  3 1  
 
  3 1 
8. 6.  
Ot h er   A n al ysis ........................................................................................  3 1  
9.  
S  U  M  M  A  R  Y   O F I  N T E  RI  M   A  N  D   D  M  C   A  N  A L  Y S E S ..........................  3 2  
9. 1.  
I nt eri  m   A n al ysis ......................................................................................  3 2 
9. 2.  
D  M  C   A n al ysis ........................................................................................  3 2  
1 0.  
R E F E  R E  N  C E S .......................................................................................  3 3  
1 1.  
LI S T   O F   A P P E  N  DI  C E S.........................................................................  3 5  
A P P E  N  DI  X   A.  S  C  H E  D  U L E   O F   A S S E S S  M E  N T S ...............................................  3 6  
A P P E  N  DI  X   B.  H  A  N  D LI  N  G   O F   MI S SI  N  G   D  A T E S .............................................  4 5  
A P P E  N  DI  X   C.  LI S T   O F   DI S P L  A  Y S .....................................................................  4 7  
P a g e  6  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
6  
 
1.       
LI S  T   O F   A  B  B  R  E  VI  A  TI  O  N S 
T h e f oll o  wi n g  a b br e vi ati o ns  a n d s p e ci alist t er  ms  ar e  us e d i n t his st atisti c al  a n al ysis  pl a n 
( S  A P).  
T a bl e  1:        
A b b r e vi ati o ns  a n d  S p e ci alist   T e r  ms 
A b b r e vi ati o n      D efi niti o n 
A E 
a d v ers e  e v e nt 
 
 
B  MI      
b o d y   m ass i n d e x 
C  O  VI  D- 1 9      
C or o n a vir us  dis e as e  2 0 1 9 
C- S S  R S      
C ol u  m bi a- S ui ci d e  S e v erit y   R ati n g  S c al e 
E  C  G      
el e ctr o c ar di o gr a  m 
e  C  R F      
el e ctr o ni c  c as e r e p ort f or  m 
E  O S      
E n d  of  St u d y 
E  O T      
E n d  of  Tr e at  m e nt 
E S S 
E p  w ort h  Sl e e pi n ess  S c al e 
E T 
ess e nti al tr e  m or 
I P 
i n v esti g ati o n al  pr o d u ct 
M e d  D  R  A      
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es 
 
 
 
 
P   W  C- 2 0      
2 0-it e  m  P h ysi ci a n    Wit h dr a  w al   C h e c klist 
Q T c F      
Q T  c orr e ct e d  a c c or di n g t o  Fri d eri ci a’s f or  m ul a   
S  A E      
s eri o us  a d v ers e  e v e nt 
S  A P      
st atisti c al  a n al ysis  pl a n 
S  D 
st a n d ar d  d e vi ati o n 
S  O  C      
S yst e  m   Or g a n   Cl ass 
T E  A E      
tr e at  m e nt- e  m er g e nt  a d v ers e  e v e nt 
 
 
W  H  O-  D  D      
W orl d   H e alt h   Or g a ni z ati o n   Dr u g   Di cti o n ar y 
P a g e  7  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
7  
 
2.       
I  N  T  R  O  D  U  C  TI  O  N 
T his st atisti c al  a n al ysis  pl a n ( S  A P) is f or  t h e fi n al  a n al ysis  of  St u d y  3 2 4- E T  D- 3 0 3  a n d is 
b as e d  o n t h e  a p pr o v e d  cli ni c al st u d y  pr ot o c ol  d at e d  0 2   N o v  2 0 2 3,   V ersi o n  4. 0. 
T his  S  A P  a d dr ess es t h e  o bj e cti v es  of t h e st u d y  a n d  d es cri b es t h e  pl a n n e d st atisti c al  a n al ys es 
a n d  d at a  pr es e nt ati o ns.   All  a n al ys es  a n d  d at a  pr es e nt ati o ns   will  b e  g e n er at e d  usi n g  S  A S ®  
V ersi o n  9. 4  or  hi g h er s oft  w ar e ( S  A S I nstit ut e,   C ar y,   N ort h   C ar oli n a,   U S  A).  T his  S  A P   will  b e 
fi n ali z e d  a n d  a p pr o v e d  b ef or e t h e  cli ni c al  d at a b as e l o c k.   A n y  c h a n g es   m a d e t o t h e  S  A P  aft er 
t h e  cli ni c al  d at a b as e l o c k  h as  o c c urr e d   will b e  d o c u  m e nt e d  a n d  dis c uss e d i n t h e  cli ni c al st u d y 
r e p ort f or t his st u d y. 
 
P a g e  8  of  6 0










St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
1 2  
 
6.       
M  O  DI FI  C  A  TI  O  N S  
6. 1.       M o difi c ati o ns f r o  m t h e   A p p r o v e d   Cli ni c al  St u d y  P r ot o c ol 
T h er e  ar e  n o   m o difi c ati o ns i n  a n al ysis s p e cif i e d i n t h e  cli ni c al st u d y  pr ot o c ol ( v ersi o n  4. 0, 
d at e d  0 2   N o v  2 0 2 3). 
6. 2.       M o difi c ati o ns f r o  m t h e   A p p r o v e d  St atisti c al   A n al ysis  Pl a n 
T his is t h e first  v ersi o n  of t h e  S  A P f or t h e fi n al  a n al ysis. 
6. 3.       M o difi c ati o ns f r o  m t h e   A p p r o v e d   D   M  C   C h a rt e r 
N ot   A p pli c a bl e. 
P a g e  1 3  of  6 0




St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
1 4  
 
8.       
S  T  A  TI S  TI  C  A  L   A  N  A  L  Y SI S 
8. 1.       G e n e r al   C o nsi d e r ati o ns 
All  p arti ci p a nt  d at a, i n cl u di n g t h os e t h at  ar e  d e  ri v e d, t h at s u p p ort t h e t a bl es  a n d fi g ur es   will 
b e  pr es e nt e d i n t h e  p arti ci p a nt  d at a listi n gs.  S o m e  d at a   m a y  b e  pr es e nt e d  o nl y i n  p arti ci p a nt 
d at a listi n gs, s o  m e   m a y  b e  pr es e nt e d   wit h  a  c orr es p o n di n g t a bl e  or fi g ur e; t h es e   will  b e 
i n di c at e d i n r el e v a nt s e cti o ns  b el o  w. 
F or  all s af et y       
  a n al ys es   w h er e  a p pli c a bl e,  b as eli n e is  d efi n e d  as t h e l ast 
n o n-  missi n g   m e as ur e  m e nt  pri or t o t h e first  d os e  of I P.   F or s c or es t h at  ar e   m a d e  u p  of it e  m 
s c or es,  all it e  m s c or es   m ust  c o  m e fr o  m t h e s a m e  visit t o  b e  c o nsi d er e d  as  b as eli n e f or t h e 
o v er all s c or e. 
C o nti n u o us  e n d p oi nts   will  b e s u  m  m ari z e d   w  it h  n,   m e a n, st a n d ar d  d e vi ati o n ( S  D),   m e di a n, 
first  a n d t hir d  q u artil es (  Q 1,   Q 3),   mi ni  m u  m (  mi n),  a n d   m a xi  m u  m (  m a x).  T h e   mi ni  m u  m  a n d 
m a xi  m u  m   will  b e r e p ort e d   wit h t h e s a  m e  n u  m b er  of  d e ci  m al  pl a c es  as t h e s o ur c e (r a  w)  d at a. 
M e a n  a n d   m e di a n   will  b e r e p ort e d t o  1  d e ci  m al  pl a c e   m or e t h a n t h e s o ur c e (r a  w)  d at a  a n d 
st a n d ar d  d e vi ati o n   will  b e r e p ort e d t o  2  d e ci  m al  pl a c es   m or e t h a n t h e s o ur c e (r a  w)  d at a.   A n y 
v al u es t h at r e q uir e tr a nsf or  m ati o n t o st a n d ar d  u n its (  m etri c  or  SI)   will  b e  c o n v ert e d   wit h t h e 
a p pr o pri at e  c orr es p o n di n g  pr e cisi o n. I n  a d diti o n,  c h a n g e fr o  m  b as eli n e  v al u es   will  b e 
c al c ul at e d  at  e a c h ti  m e  p oi nt  a n d s u  m  m ari z e d  d es cri pti v el y. 
C at e g ori c al  e n d p oi nts ( e g, i n ci d e n c e  of  a n  a d v ers e   e v e nt)   will  b e s u  m  m ari z e d  usi n g  c o u nts 
a n d  p er c e nt a g es.  P er c e nt a g es   will  b e  pr es e nt e d t o   1  d e ci  m al  pl a c e  u nl ess  ot h er  wis e s p e cifi e d.   
P arti ci p a nts   will  b e s u  m  m ari z e d  a c c or di n g t o tr e at  m e nt r e c ei v e d.  “  B y -visit ” s u  m  m ari es  ar e 
b as e d  o n t h e l ast  d os e r e c ei v e d  b ef or e t h e s p e c ifi c  e v al u ati o n.   A d v ers e  e v e nts s u  m  m ari es  ar e 
b as e d  o n t h e l ast  d os e r e c ei v e d  b ef or e t h e st art  of t h e   A E.   N ot e t h at it is  p ossi bl e f or  a 
p arti ci p a nt t o  b e  c o u nt e d  u n d er   m or e t h a n  o n e  d os e i n s u  m  m ari es.  Si n c e  b as eli n e is  b y 
d efi niti o n  b ef or e t h e first  d os e  of I P,  b as eli n e  v al u es i n listi n g   will  h a v e  n o  d os e  d esi g n ati o n, 
a n d i n s u  m  m ari es it   will  b e  pr es e nt e d  u n d er  “ S a g e- 3 2 4  O v er all ”  .   F or  dis pl a ys f or   w hi c h  n o 
s u c h  d at e  a p pli es,  e. g.  d e  m o gr a p hi cs,  dis e as e  hist or y,  et c., t h e  pr es e nt ati o n   will  n ot  b e  b y 
d os e  gr o u p,  b ut   will  b e  b y  a g gr e g at e  S  A  G E- 3 2 4  gr o u p. 
8. 2.       B a c k g r o u n d   C h a r a ct e risti cs  
8. 2. 1.       P a rti ci p a nt   Dis p ositi o n 
T h e s u  m  m ar y  of  dis p ositi o n   will  us e t h e   A ll  P arti ci p a nts  S et  a n d i n cl u d e  n u  m b er  of 
p arti ci p a nts   w h o   w er e s cr e e n e d, s cr e e n f ail e d, s u c c essf ull y s cr e e n e d  b ut  di d  n ot  d os e,  a n d 
s u c c essf ull y s cr e e n e d  a n d  d os e d ( o v er all  a n d  b y  pr e vi o us st u d y  p arti ci p ati o n),  a n d,  usi n g t h e 
n u  m b er  of  p arti ci p a nts   w h o s u c c essf ull y s cr e e n e d  a n d  d os e d  as t h e  d e n o  mi n at or, t h e  n u  m b er 
a n d  p er c e nt a g e  of  p arti ci p a nts   w h o  c o  m pl et e d tr e at  m e nt,   w h o  dis c o nti n u e d tr e at  m e nt 
( o v er all,  b y  d os e l e v el,  a n d  b y  pri  m ar y r e as o n f or  dis c o nti n ui n g tr e at  m e nt),   w h o  c o  m pl et e d 
t h e st u d y,  a n d   w h o  dis c o nti n u e d t h e st u d y ( o v er all  a n d  b y  pri  m ar y r e as o n).  
 
P a g e  1 5  of  6 0




St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
1 6  
 
8. 2. 4.       M e di c al/ S u r gi c al   Hist o r y  
M e di c al/s ur gi c al  hist or y   will  b e  c o d e d t o   M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es 
(  M e d  D  R  A) t er  ms,  usi n g   V ersi o n  2 5,  or  hi g h er.  T h e   M e d  D  R  A  v ersi o n   will  b e i n cl u d e d i n t h e 
f o ot n ot es  of r el at e d  o ut p uts.   M e di c al/s ur gi c al hist or y   will  b e s u  m  m ari z e d  usi n g  dis cr et e 
s u  m  m ar y st atisti cs f or  e a c h   M e d  D  R  A  S yst e  m  Or g a n   Cl ass ( S  O  C)  a n d  Pr ef err e d  T er  m ( P T) 
usi n g t h e  S af et y  S et.  
A g e  at  E T  di a g n osis ( y e ars),  a g e  p arti ci p a nt t hi n ks  E T st art e d ( y e ars),  y e ars   wit h  E T 
di a g n osis ( a g e  at  b as eli n e   mi n us  a g e  at  E T  di a g n osis),  y e ars si n c e  p arti ci p a nt t hi n ks  E T 
st art e d ( a g e  at  b as eli n e   mi n us  a g e   w h e n  p arti ci p a nt t hi n ks  E T st art e d), tr e  m or r es p o nsi v e t o 
al c o h ol,  p ast tr e at  m e nts f or  E T,  a n d r es p o ns e t o   p ast tr e at  m e nt f or  E T   will  b e s u  m  m ari z e d 
usi n g t h e  S af et y  S et.  T h e  d at a listi n g   will  als o i n cl u d e r e as o n f or  dis c o nti n u ati o n fr o  m t h e 
p ast tr e at  m e nt.   
T h e  dis e as e  hist or y   will  b e s u  m  m ar i z e d f or t h e f oll o  wi n g  c at e g ori es: 
    A g e  at  E T  di a g n osis ( < 4 0  y e ars,  4 0 t o  6 0  y e ars,  > 6 0  y e ars) 
    A g e  p arti ci p a nt t hi n ks  E T st art e d ( < 2 0  y  e ars,  2 0 t o  4 0  y e ars,  > 4 0 t o  6 0  y e ars, 
> 6 0  y e ars) 
    Y e ars   wit h  E T  di a g n osis ( 3 t o  < 6  y e ars,  6 t o  1 0  y e ars,  > 1 0  y e ars) 
      Y e ars si n c e  p arti ci p a nt t hi n ks  E T st art e d ( 3 t o  < 6  y e ars,  6 t o  1 0  y e ars,  > 1 0  y e ars) 
    Tr e  m or r es p o nsi v e t o  al c o h ol:   Y es (I nt er  m e di at e,    W or k e d    W ell),   N o (  N o,  a littl e), 
N  A 
    P ast tr e at  m e nt f or  E T (  Y es,   N o) 
    R es p o ns e t o  p ast tr e at  m e nt f or  E T:   Y es   (I nt er  m e di at e,    W or k e d    W ell),   N o (  N o,  a 
littl e),   Y es  a n d   N o ( d e n o  mi n at or f or  p er c e nt a g es   will  b e  p arti ci p a nts  h a vi n g  p ast 
tr e at  m e nt f or  E T) 
8. 2. 5.       P ri o r  a n d   C o n c o  mit a nt    M e di c ati o ns  
M e di c ati o ns   will  b e r e c or d e d  at  e a c h st u d y    visit  a n d  c o d e d i nt o  dr u g  cl ass ( a n at o  mi c al 
t h er a p e uti c  c h e  mi c al [  A T  C]  L e v el  2)  a n d  P T  usi n g    W orl d   H e alt h   Or g a ni z ati o n-  Dr u g 
di cti o n ar y (   W  H  O-  D  D)   Gl o b al   B 3   M ar c h  2 0 2 2,  or l at er.  
All   m e di c ati o ns t a k e n   wit hi n  3 0  d a ys  pri or   t o i nf or  m e d  c o ns e nt t hr o u g h t h e  d ur ati o n  of t h e 
st u d y (i n cl u di n g st art  a n d  e n d  d at es, r o ut e, d os e/ u nits, fr e q u e n c y,  a n d i n di c ati o n)   will  b e 
r e c or d e d  o n t h e  el e ctr o ni c  c as e r e p ort f or  m ( e  C  R F).  
T h os e   m e di c ati o ns t a k e n  pri or t o t h e i niti ati o n  of t h e I P  will  b e  d e n ot e d  “ Pri or ”.  T h os e 
m e di c ati o ns t a k e n  pri or t o t h e i niti ati o n  of t h e   I P  a n d  c o nti n ui n g  b e y o n d t h e i niti ati o n  of t h e 
I P  or t h os e   m e di c ati o ns st art e d  at t h e s a  m e ti  m e or  aft er t h e i niti ati o n  of t h e I P   will  b e 
d e n ot e d  “  C o n c o  mit a nt ”.  N ot e t h at   m e di c ati o n t a k e n  b ef or e   t h e i niti al  d osi n g  of I P  a n d 
c o nti n u e d  aft er t h e i niti al  d osi n g  will  b e  c at e g ori z e d  as  a  pri or   m e di c ati o n  a n d s e p ar at el y  as  a 
c o n c o  mit a nt   m e di c ati o n. 
P a g e  1 7  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
1 7  
 
M e di c ati o ns   will  b e fl a g g e d i n t h e list   i n g  a c c or di n g t o   w h et h er t h e y  ar e  “ Pri or ”  or 
“  C o n c o  mit a nt ”  as  d efi n e d  a b o v e.  I n t h e  e v e nt  of  a   missi n g st art  or st o p  d at e  ass o ci at e d   wit h  a 
m e di c ati o n,  o nl y t h e  cl assifi c ati o n ( pri or  a n d/  or  c o n c o  mit a nt)   will  b e i  m p ut e d  usi n g t h e 
al g orit h  m  d es cri b e d i n    A p p e n di x   B.   D at es   will  n ot  b e i  m p ut e d. 
Pri or  a n d  c o n c o  mit a nt   m e di c ati o ns   will  b e s u  m  m ari z e d s e p ar at el y  usi n g t h e  S af et y  S et  as t h e 
n u  m b er  a n d  p er c e nt a g e  of  p arti ci p a nts   wit h  e a c h   m e di c ati o n  at  b ot h t h e   A T  C  a n d  P T l e v els. 
C o n c o  mit a nt  pr o c e d ur es   will  b e list e d     wit h  S  O  C/ P T,  b ut  n ot s u  m  m ari z e d. 
8. 2. 6.       I n v esti g ati o n al  P r o d u ct   E x p os u r e  
T ot al i n v esti g ati o n al  pr o d u ct  e x p os ur e (i n   m g) is   d efi n e d  as t h e t ot al   m g  of  S  A  G E- 3 2 4 t h at 
w as t a k e n  d uri n g t h e st u d y. If  a  p arti ci p a nt s ki ps  a  d os e  o n  a n y  of t h e  d a ys, t h e  d os e t a k e n is 
0   m g.   
T ot al  e x p os ur e  d ur ati o n t o  S  A  G E- 3 2 4 (i n  d a ys) is  d efi n e d  as ( d at e  of l ast  d os e  –   d at e  of first 
d os e  +  1).   N ot e t h at t his  d o es  n ot  e x cl u d e  d a ys   w h e n t h e  d os e  h as  b e e n   mi ss e d. 
Pl a n n e d  e x p os ur e f or  p arti ci p a nts   wit h  n o  u ns c h e d ul e d  d os e r e d u cti o ns/i n cr e as es is  d efi n e d 
as t h e s u  m  of:  
    1 4  d a ys  of tr e at  m e nt (  D a y  1 t hr o u g h   D a y  1 4) ti  m es  1 5   m g 
    1 4  d a ys  of tr e at  m e nt (  D a y  1 5 t hr o u g h   D a y  2 8) ti  m es  3 0   m g 
    1 4  d a ys  of tr e at  m e nt (  D a y  2 9 t hr o u g h   D a y  4 2) ti  m es  4 5   m g 
    N u  m b er  of  d a ys fr o  m   D a y  4 3 t o  e n d  of tr e at  m e nt, i n cl usi v e, ti  m es  6 0   m g 
If  a  p arti ci p a nt  h as  a n  u ns c h e d ul e d  d os e r e d u cti o n/i n cr e as e,  or  d os e r e d u cti o ns/i n cr e as es, 
pl a n n e d  e x p os ur e   will  b e  as i n di c at e d  u ntil t h e  p oi nt  of t h e first  u ns c h e d ul e d 
r e d u cti o n/i n cr e as e.  Pl a n n e d  e x p os ur e fr o  m t h e  p oi nt  of t h e first  u ns c h e d ul e d 
r e d u cti o n/i n cr e as e   will  b e t h e  assi g n e d  d os e tim es t h e  n u  m b er  of  d a ys fr o  m t h e  d at e  of t h e 
r e d u cti o n/i n cr e as e (i n cl usi v e) t o t h e  d at e  of t he  n e xt r e d u cti o n/i n cr e as e ( e x cl usi v e)  or t h e 
d at e  of  e n d  of tr e at  m e nt (i n cl usi v e).  Pl a n n e d  e x p os ur e f or   a n y  a d diti o n al  u ns c h e d ul e d 
r e d u cti o ns/i n cr e as es   will  b e  h a n dl e d i n  a si  mil ar   m a n n er  as t h e  assi g n e d  d os e ti  m es t h e 
n u  m b er  of  d a ys fr o  m t h e  d at e  of t h e r e d u cti o n/i n cr e as e (i n cl usi v e) t o t h e  d at e  of t h e  n e xt 
r e d u cti o n/i n cr e as e ( e x cl usi v e)  or t h e  d at e  of  e n d  of tr e at  m e nt (i n cl usi v e). 
P er c e nt  of t h e  pl a n n e d  e x p os ur e r e c ei v e d is  d efi n e d  as t h e t ot al i n v esti g ati o n al  pr o d u ct 
e x p os ur e,  di vi d e d  b y  pl a n n e d  e x p os ur e, ti  m es  1 0 0. 
T ot al i n v esti g ati o n al  pr o d u ct  e x p os ur e, t ot al  e x p os ur e  d ur ati o n,  a n d  p er c e nt  of  pl a n n e d 
e x p os ur e r e c ei v e d   will  b e s u  m m ari z e d  usi n g t h e  S af e  t y  S et.  T h e  n u  m b er  a n d  p er c e nt a g e  of 
p arti ci p a nts   wit h  p er c e nt  of  pl a n n e d  e x p os ur e r e c ei v e d  < 8 0  %,  8 0  % t o  < 1 0 0  %,  a n d  ≥ 1 0 0  % 
will  b e s u  m  m ari z e d.  T ot al  e x p os ur e  d ur ati o n ( o v e  r  all  d os es t a k e n)   will  als o  b e s u  m  m ari z e d 
b y  d os e  at ti  m e  of tr e at  m e nt  dis c o nt i n u ati o n  usi n g t h e  S af et y  S et. 
P a g e  1 8  of  6 0




St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
1 9  
 
P a g e  2 0  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
2 0  
 
P a g e  2 1  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
2 1  
 
P a g e  2 2  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
2 2  
 
P a g e  2 3  of  6 0




St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
2 4  
 
    T E  A E l e a di n g t o  d os e i nt err u pti o n 
    T E  A E l e a di n g t o  d os e r e d u cti o n 
    T E  A E r el at e d t o I P 
    T E  A E l e a di n g t o I P  dis c o nti n u ati o n 
    T E  A E l e a di n g t o st u d y  dis c o nti n u ati o n 
    S eri o us  T E  A E 
    S eri o us  T E  A E r el at e d t o I P 
    S eri o us  T E  A E l e a di n g t o I P  dis c o nti n u ati o n 
    S eri o us  T E  A E l e a di n g t o st u d y  dis c o nti n u ati o n 
    T E  A E r es ulti n g i n  d e at h 
T h e i n ci d e n c e  of  T E  A Es   will  b e s u  m  m ari z e d  b y  S yst e  m   Or g a n   Cl ass ( S  O  C)  a n d  Pr ef err e d 
T er  m ( P T). I n  a d diti o n, s u  m  m ari es   will  b e  pr o vi d e d  b y   m a xi  m u  m s e v erit y (  mil d  <   m o d er at e 
< s e v er e)  a n d  b y   m a xi  m u  m r el ati o ns hi p (r el at e d  >  n ot r el at e d) t o I P.   A n y  T E  A Es l e a di n g t o 
I P  dis c o nti n u ati o n,  a n y  T E  A E l e a di n g t o st u d y  dis c o nti n u ati o n,  a n d  an y tr e at  m e nt- e  m er g e nt 
S  A Es   will  als o  b e s u  m  m ari z e d, s ort e d  b y  d es c e n di n g fr e q u e n c y i n  S  O  C  a n d  P T.  
P arti ci p a nts   will  b e  c o u nt e d  o nl y  o n c e   wit hi n  e a c h  S  O  C  a n d  P T  at t h e   m a xi  m u  m s e v erit y i n 
t h e f oll o  wi n g  or d er: s e v er e,   m o d er at e,  a n d   mil d.  P arti ci p a nts   will  b e  c o u nt e d  o nl y  o n c e 
wit hi n  e a c h  S  O  C  a n d  P T  at t h e str o n g est r el ati o ns hi p t o I P i n t h e f oll o  wi n g  or d er: r el at e d,  n ot 
r el at e d t o I P.   A n   A E   wit h   missi n g s e v erit y   will  b e  c o nsi d er e d  as ‘ s e v er e’,  a n d   wit h   missi n g 
r el ati o ns hi p t o I P will  b e  c o nsi d er e d  as ‘r el at e d’ f or t h e  p ur p os es  of s u  m  m ari zi n g t h es e  d at a.   
T h e i n ci d e n c e  of  T E  A Es  a n d tr e at  m e nt- e  m er g e nt  S  A Es   will  als o  b e  pr es e nt e d i n  or d er  of 
d e cr e asi n g fr e q u e n c y  b y  P T. 
All   A Es (i n cl u di n g t h os e   wit h  o ns et  b ef or e t h e st art  of I P) t hr o u g h t h e  e n d  of t h e st u d y   will 
b e list e d. I n  a d diti o n, s e p ar at e listi n gs  c o nt ai ni n g i n di vi d u al  p arti ci p a nt   A E  d at a f or  all 
d e at hs,  S  A Es,   A Es l e a di n g t o I P  dis c o nti n u a ti o n,  a n d   A Es l e a di n g t o st u d y  dis c o nti n u ati o n 
will  b e  pr o vi d e d. 
8. 4. 2.       Cli ni c al   L a b o r at o r y 
All st atisti c al  a n al ys es  of l a b or at or y  v al u es   w  ill  b e  p erf or  m e d  usi n g  SI  u nits.  T h e f oll o  wi n g 
p ar a  m et ers  ar e   m e nti o n e d i n t h e  pr ot o c ol,  h e n c e   will  b e s u  m  m ari z e d;  a n y  ot h er  p ar a  m et ers 
f or   w hi c h  d at a  ar e r e p ort e d   will  b e list e d  b ut  n ot s u  m  m ari z e d. 
Bi o c h e  mistr y: 
    R e n al  P a n el:  gl u c os e,  c al ci u  m,  p h os p h or us,  bl o o d  ur e a  nitr o g e n,  cr e ati ni n e, s o di u  m, 
p ot assi u  m,  c hl ori d e, t ot al  c ar b o n  di o xi d e  c o nt e nt  
    H e p ati c  P a n el:  al b u  mi n,  al a ni n e tr a ns a  mi n a  s e (  A L T),  as p art at e tr a ns a  mi n as e (  A S T), 
t ot al  bilir u bi n,  dir e ct  bilir u bi n, i n dir e ct bilir u bi n,  al k ali n e  p h os p h at as e, t ot al  pr ot ei n, 
l a ct at e  d e h y dr o g e n as e,  g a  m  m a  gl ut a  m yl tr a nsfer as e,  cr e ati n e  ki n as e (  M  B  a n d   M  M)  
P a g e  2 5  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
2 5  
 
    Ot h er: t ot al li pi d  pr ofil e,  cr e ati n e  p h os p h o ki n as e, t h yr oi d sti  m ul ati n g  h or  m o n e ( T S  H), 
al c o h ol l e v el,   H b  A 1 c  
C o a g ul ati o n: 
    A cti v at e d  p arti al t hr o  m b o pl asti n ti  m e,    pr ot hr o  m bi n ti  m e,  a n d i nt er n ati o n al 
n or  m ali z e d r ati o  
H e  m at ol o g y: 
    R e d  bl o o d  c ell (  R  B  C)  c o u nt,  h e  m o gl o bi n,  h e  m at o crit,   w hit e  bl o o d  c ell  c o u nt   wit h 
diff er e nti al,  pl at el et  c o u nt,  a n d if   R  B  C i n di c es  ar e  a b n or  m al, r efl e x   R  B  C   m or p h ol o g y 
is i n di c at e d  
Uri n al ysis: 
    Pr ot ei n,  gl u c os e,  p  H,  bl o o d, l e u k o c yt es, l e u k o c yt e  est er as e,  ur o bili n o g e n,  bilir u bi n, 
k et o n es,  nitrit e,   m y o gl o bi n 
S o  m e  n u  m eri c l a b  v al u es   m a y  b e r e p ort e d  as ‘ < n. n’  or ‘ > n. n’; t h es e   will  b e  a n al y z e d i n t h e 
s u  m  m ar y st atisti cs  as  n. n/ 2  a n d  n. n, r es p e cti v e l y.  F or  e x a  m pl e, tri gl y c eri d es r e c or d e d  as 
“ < 0. 5 0 ”    m  m ol/ L   w o ul d  b e  a n al y z e d  as  0. 2 5   m  m ol/ L  a n d  p ot assi u  m r e c or d e d  as 
“ > 6. 0   m  m ol/ L ”    w o ul d  b e  a n al y z e d  as  6. 0   m  m ol/ L. 
All  b y- visit l a b or at or y s u  m  m ar y t a b  l es   will  pr es e nt r es ults f or t h e  S af et y  S et  p arti ci p a nts 
o v er all,  a n d  b y  d os e l e v el r e c ei v e d  pri or t o  t h e  gi v e n  e v al u ati o n.  F or s u  m  m ari z ati o n  of 
i n ci d e n c e  d at a  a n y ti  m e  p ost- b as eli n e,  p arti ci pa nt  d at a   will  b e s u  m  m ari z e d  a c c or di n g t o t h e 
l ast  d os e r e c ei v e d   w h e n  a  p arti c ul ar  crit eri o n w as   m et (t h us,  a  p arti ci p a nt   m a y  c o ntri b ut e  d at a 
u n d er   m or e t h a n  o n e  d os e if  a  crit eri o n   w as   m et  p ost- b as eli n e   w hil e t a ki n g  diff er e nt  d os es). 
C o nti n u o us  h e  m at ol o g y,  c h e  mistr y,  c o a g ul ati o n,  a n d  uri n al ysis r es ults (r a  w  a n d  c h a n g e fr o  m 
b as eli n e)   will  b e s u  m  m ari z e d  at  e a c h s c h e d ul e d  ti  m e  p oi nt.   C at e g ori c al  uri n al ysis r es ults   will 
b e s u  m  m ari z e d  b y fr e q u e n ci es  a n d  p er c e nt a g es  at  e a c h s c h e d ul e d ti  m e  p oi nt.  T h e  n u  m b er 
a n d  p er c e nt a g e  of  p arti ci p a nts   wit h s hift fr o  m  b as eli n e  b as e d  o n t h e l a b or at or y  n or  m al r a n g es 
pr o vi d e d  b y t h e l a b or at or y   will  b e t a b ul at e d  at  e a c h s c h e d ul e d  visit. 
A n y l a b or at or y  v al u e  c o nsi d er e d  cli ni c all y si g nifi  c a nt  b y t h e i n v esti g at or is  c a pt ur e d  as  a n 
a d v ers e  e v e nt. 
T h e  n u  m b er  a n d  p er c e nt a g e  of  p arti ci p a nts   wi t h  p ot e nti all y  cli ni c all y si g nifi c a nt ( P  C S) 
v al u es  at  a n y ti  m e  aft er I P  a d mi nistr ati o n (i n cl u di n g  u ns c h e d ul e d  visits)   will  b e s u  m  m ari z e d 
f or t h e  h e  m at ol o g y,  c h e  mistr y,  a n d  c o a g ul ati o n  p ar a  m et ers  d efi n e d i n T a bl e  5 , T a bl e  6 ,  a n d 
T a bl e  7 , r es p e cti v el y.  P  C S  v al u es f or  e a c h s c h e d ul e d  visit  a n d  e n d- of-tr e at  m e nt  a n d  e n d- of-
st u d y  v al u es   will  als o  b e  pr o vi d e d.  T h es e s u  m m ari es   will  b e  d o n e  usi n g t h e  S af et y  S et, 
o v er all f or  S  A  G E- 3 2 4  as   w ell  as  b y  d os e l e v el. 
Li v er f u n cti o n t ests   will  b e   m o nit or e d  cl os el y;  P  C S  v al u es   (T a bl e  8 )   will  b e s u  m  m ari z e d 
usi n g t h e  S af et y  S et f or i n ci d e n c e  a n y ti  m e  p ost- b as eli n e f or t h es e  P  C S t hr es h ol ds (f or 
c o n diti o ns i n v ol vi n g   m or e t h a n  o n e  p ar a  m et er, t h e r es ults  n e e d t o  b e fr o  m t h e s a  m e 
ti  m e p oi nt). 
P a g e  2 6  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
2 6  
 
C h e  mistr y,  h e  m at ol o g y,  c o a g ul ati o n,  a n d  uri n al ysis  d  at a   will  b e list e d   wit h t h e  v al u es  o utsi d e 
t h e  n or  m al r a n g es  a n d  P  C S  crit eri o n fl a g g ed.   Bl o o d  c ell   m or p h ol o g y  a n d   mi cr os c o p y t est 
r es ults   will  b e list e d   w h e n  a v ail a bl e  b ut n ot s u  m  m ari z e d.   Vir us s er ol o g y,  pr e g n a n c y t ests, 
a n d  uri n e  dr u gs  of  a b us e  d at a   will   b e list e d  b ut  n ot s u  m  m ari z e d. 
T a bl e  5:  P ot e nti all y   Cli ni c all y  Si g nifi c a nt   V al u es f o r   H e  m at ol o g y 
L a b o r at o r y  P a r a  m et e r      S e x      
U nits      
C rit e ri a f o r  P  C S   V al u es (  O bs e r v e d  v al u es) 
 
      
 
Hi g h  
L o  w  
H e  m o gl o bi n                          M al e      
g/ L       
> 1 8 5  
< 1 1 5 
 
F e  m al e      g/ L       
> 1 7 0 
< 1 0 0 
H e  m at o crit    
M al e      
Fr a cti o n  of  1      > 0. 5 5  
< 0. 3 8 5  
 
F e  m al e      Fr a cti o n  of  1      > 0. 4 9 
< 0. 3 4 5 
Pl at el et  c o u nt  
      
1 0 ^ 9/ L       
> 6 0 0 
< 1 2 5 
W hit e  bl o o d  c ell      
      
1 0 ^ 9/ L       
> 1 5  
< 2. 5  
B as o p hils  
      
1 0 ^ 9/ L       
> 0. 5 
N  A 
E osi n o p hils 
      
1 0 ^ 9/ L       
> 1. 5 
N  A 
N e utr o p hils  
      
1 0 ^ 9/ L       
N  A  
< 1. 5  
L y  m p h o c yt es  
      
1 0 ^ 9/ L       
> 6. 0  
< 0. 5  
M o n o c yt es  
      
1 0 ^ 9/ L       
> 1. 4 
N  A 
T a bl e  6:  P ot e nti all y   Cli ni c all y  Si g nifi c a nt   V al u es f o r   C h e  mist r y 
L a b o r at o r y  P a r a  m et e r      
U nits      
C rit e ri a f o r  P  C S   V al u es (  O bs e r v e d  v al u es) 
 
 
Hi g h  
L o  w  
Al b u  mi n  
g/ L       
> 7 0  
< 2 8  
Bl o o d  ur e a  nitr o g e n  
m  m ol/ L      
> 1 0. 7 1 
N  A 
C al ci u  m 
m  m ol/ L      
> 2. 7 5 
< 2. 0 
C hl ori d e 
m  m ol/ L      
> 1 2 0 
< 9 0 
Cr e ati ni n e 
m  m ol/ L      
> 3 x  U L  N  or  > 3 x   B as eli n e       
G a  m  m a   Gl ut a  m yl  Tr a nsf er as e        
> 3 x  U L  N 
 
Gl u c os e 
m  m ol/ L      
> 1 3. 9 
< 2. 8 
S o di u  m  
m  m ol/ L       
> 1 5 0 
< 1 3 2  
P ot assi u  m  
m  m ol/ L       
> 5. 4  
< 3. 3  
Pr ot ei n  
g/ L 
 
< 4 5 
Bi c ar b o n at e  
m  m ol/ L       
> 3 4  
< 1 8  
C hl ori d e  
m  m ol/ L       
> 1 2 0  
< 9 0  
P h os p h or us  
m  m ol/ L      
> 1. 9 4 
< 0. 6 1 
Li v er  F u n cti o n  T ests ( L F T)      
 
 
 
Bilir u bi n  
μ m ol/ L         
> 2 x  U L  N 
 
As p art at e   A  mi n otr a nsf er as e       
U/ L       
> 3 x  U L  N 
 
Al a ni n e   A  mi n otr a nsf er as e       
U/ L       
> 3 x  U L  N 
 
Al k ali n e  P h os p h at as e       
U/ L       
> 1. 5 x  U L  N 
 
T a bl e  7:  P ot e nti all y   Cli ni c all y  Si g nifi c a nt   V al u es f o r   C o a g ul ati o n 
P a r a  m et e r  
P ot e nti all y   Cli ni c all y  Si g nifi c a nt   V al u es  
Pr ot hr o  m bi n ti  m e ( P T)  
> = 1. 1 1  x   U L  N 
A cti v at e d  p arti al t hr o  m b o pl asti n ti  m e ( a P T T)      
> 1. 5  x   U L  N 
P a g e  2 7  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
2 7  
 
T a bl e  8:  P ot e nti all y   Cli ni c all y  Si g nifi c  a nt   V al u es f o r   Li v e r  F u n cti o n   T ests 
P a r a  m et e r  
P ot e nti all y   Cli ni c all y  Si g nifi c a nt   V al u es  
Al a ni n e   A  mi n otr a nsf er as e   
> 3 x  U L  N,  > 5 x  U L  N,  > 1 0 x  U L  N  
As p art at e   A  mi n otr a nsf er as e  
> 3 x  U L  N,  > 5 x  U L  N,  > 1 0 x  U L  N  
Al a ni n e   A  mi n otr a nsf er as e   O  R    
As p art at e   A  mi n otr a nsf er as e  
> 3 x  U L  N,  > 5 x  U L  N,  > 1 0 x  U L  N  
Al k ali n e  P h os p h at as e  
> 1. 5 x  U L  N,  > 2 x  U L  N 
T ot al   Bilir u bi n 
> 1. 5 x  U L  N,  > 2 x  U L  N 
T ot al   Bilir u bi n  >  2 x  U L  N  A  N  D   (  Al a ni n e   A  mi n otr a nsf er as e O  R     As p art at e   A  mi n otr a nsf er as e 
> 3 x  U L  N),  a n y ti  m e  p ost b as eli n e,  d o  n ot  n e e d t o  b e  at t h e s a  m e  visit 
P ot e nti al   H y’s  L a  w : [ T ot al   Bilir u bi n  > = 2 x  U L  N A  N  D     Al k ali n e  P h os p h at as e  < 2 x  U L  N,   m e as ur e d  at 
t h e s a  m e  visit] A  N  D   [(  Al a ni n e   A  mi n otr a nsf er as e O  R   As p art at e   A  mi n otr a nsf er as e  > 3 x  U L  N)   A  N  D 
Al k ali n e  P h os p h at as e  < 2 x  U L  N  ,   m e as ur e d  at t h e s a  m e  visit], t  w o  c o n diti o ns  at  a n y ti  m e 
p ost b as eli n e,  d o  n ot  n e e d t o  b e  at t h e s a  m e  visit 
8. 4. 3.       El e ct r o c a r di o g r a  m 
All  b y- visit  E  C  G s u  m  m ar y t a bl es   will  pr es e nt r e  s ults f or  S af et y  S et  p arti ci p a nts  o v er all,  a n d 
als o  b y  d os e l e v el r e c ei v e d  pri or t o t h e  e v al u ati o n.  F or s u  m  m ari z ati o n  of i n ci d e n c e  a n y ti  m e 
p ost- b as eli n e,  p arti ci p a nt  d at a   wi ll  b e s u  m  m ari z e d  a c c or di n g t o t h e l ast  d os e r e c ei v e d   w h e n  a 
p arti c ul ar  crit eri o n   w as   m et (t h us,  a  p arti ci p a n t   m a y  c o ntri b ut e  d at a  u n d er   m or e t h a n  o n e 
d os e if  a  crit eri o n   w as   m et  p ost- b as eli n e   w h il e t a ki n g  diff er e nt  d os es).  L ast  v al u e  o n 
tr e at  m e nt  a n d l ast  v al u e  o n st u d y   will  b e s um  m ari z e d  u n d er t h e  d os e l e v el l ast r e c ei v e d. 
T h e  a v er a g e  of  a n y   m ulti pl e  v al u es  c oll e ct e d  at   o n e  visit   will  b e  us e d f or s u  m  m ari z ati o n  of 
c o nti n u o us  v ari a bl es, i n cl u di n g  b as eli n e  E  C  G  v al u es.  F or  e a c h  E  C  G   m e as ur e  m e nt ( h e art r at e 
a n d  P  R,   Q  R S,   Q T,  a n d   Q T c F i nt er v als), t h e  o bs er v e d  v al u e  at  e a c h s c h e d ul e d  visit  a n d 
c h a n g e fr o  m  b as eli n e  at  e a c h s c h e d ul e d  visi t   will  b e  pr o vi d e d.  T his s u  m  m ar y   will  als o 
i n cl u d e l ast  v al u es  o n tr e at  m e nt  a n d  o n st u d y.  L ast  v al u e  o n tr e at  m e nt is  d efi n e d  as t h e l ast 
p ost- b as eli n e  v al u e  b et  w e e n first  d os e  of I P  ( e x cl usi v e)  a n d  u p t o l ast  d os e  of I P  +  1  d a y 
(i n cl usi v e).  L ast  v al u e  o n st u d y is  d efi n e d  as t he l ast  p ost- b as eli n e  v al u e  aft er t h e first  d os e  of 
I P. 
I n  a d diti o n, t h e  n u  m b er  a n d  p er c e nt a g e  of  p arti ci p a nts   wit h  P  C S  a n d  p ot e nti all y  cli ni c all y 
si g nifi c a nt  c h a n g e ( P  C S  C)  v al u es   will  b e  s u  m  m ari z e d  b y s c h e d ul e d ti  m e p oi nt  a n d f or  a n y 
ti  m e  p ost- b as eli n e, i n cl u di n g l ast  v al u e  o n tr e at  m e nt  a n d l ast  v al u e  o n st u d y.  I n di vi d u al 
v al u es  of   Q T c F   will  b e  us e d  f or  P  C S  d et er  mi n ati o n r at h er t h a n t h e  a v er a g e  of   m ulti pl e  v al u es 
c oll e ct e d  at  o n e  visit.  P ot e nti all y  cli ni c all y si g nifi c a nt  v al u es   will  b e i d e ntifi e d f or  E  C  G 
p ar a  m et ers  as  o utli n e d i n  T a bl e  9 .  
A s hift t a bl e  of  o v er all  E  C  G i nt er pr et ati o n fr o  m  b as eli n e t o s c h e d ul e d  p ost- b as eli n e  visits 
will  b e  pr es e nt e d f or t h e f oll o  wi n g  c at e g ori es:   ‘  N or  m al’, ‘  A b n or  m al,   N ot   Cli ni c all y 
Si g nifi c a nt’,  a n d ‘  A b n or  m al,  Cli ni c all y  Si g nifi c a nt’.    T h e s hift t a bl e   will  b e  pr es e nt e d  b y  visit 
–   o v er all  a n d  b y  d os e l e v el.  
Cli ni c all y si g nifi c a nt  a b n or  m al fi n di n gs   will  b e r e p ort e d  as  a d v ers e  e v e nts.  T h e  a v er a g e  of 
a n y   m ulti pl e  v al u es  c oll e ct e d  at  o n e  visit  of  e a c h  p ar a  m et er   will  b e i n cl u d e d i n t h e  d at a 
listi n g.  
P a g e  2 8  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
2 8  
 
T a bl e  9:  P ot e nti all y   Cli ni c all y  Si g nifi c a nt   V al u es f o r   Q  T c F 
 
U nits  
C rit e ri a f o r  P  C S   V al u es 
(  O bs e r v e d   V al u es) 
C rit e ri a f o r  P  C S  C   V al u es 
(  C h a n g e f r o  m   B as eli n e) 
      
Hi g h 
L o  w      
I n c r e as e 
D e c r e as e 
ms e c      
> 4 5 0   ms e c  a n d  ≤ 4 8 0  ms e c 
> 4 8 0    ms e c  a n d ≤ 5 0 0 ms e c 
> 5 0 0   ms e c 
N  A      
> 3 0   ms e c  a n d  ≤ 6 0    ms e c 
> 6 0    ms e c 
N  A 
8. 4. 4.       Vit al  Si g ns 
All  b y- visit  vit al si g n s u  m  m ar y t a  bl es   will  pr es e nt r es ults f or  S a f et y  S et  p arti ci p a nts  o v er all, 
a n d  als o  b y  d os e l e v el r e c ei v e d  pri or t o t h e  e v al u ati o n.  F or s u  m  m ari z ati o n  of i n ci d e n c e  at  a n y 
ti  m e  p ost- b as eli n e,  p arti ci p a nt d at a   will  b e s u  m  m ari z e d  a c c or di n g t o t h e l ast  d os e r e c ei v e d 
w h e n  a  p arti c ul ar  crit eri o n   w as   m et (t h us,  a  p arti ci p a nt   m a y  c o ntri b ut e  d at a  u n d er   m or e t h a n 
o n e  d os e if  a  crit eri o n   w as   m et  p ost- b as eli n e   w hil e t a ki n g  diff er e nt  d os es).   
Vit al si g n r es ults (s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur e [  m  m  H g],  p uls e  pr ess ur e (  m  m  H g), 
b o d y t e  m p er at ur e [   C],  h e art r at e [ b e ats  p er   mi n ut e  or  b p  m],  a n d r es pir at or y r at e [ br e at hs  p er 
mi n ut e])  a n d  c h a n g es fr o  m  b as eli n e   w  ill  b e s u  m  m ari z e d  b y s c h e d ul e d  visit –   o v er all  a n d  b y 
d os e l e v el.  P uls e  pr ess ur e is  d efi n e d  as [s yst o li c  bl o o d  pr ess ur e -  di ast oli c  bl o o d  pr ess ur e].  
P ot e nti all y  cli ni c all y si g nifi c a nt  v al u es   will  b e  i d e ntifi e d f or  vit al si g n  p ar a  m et ers  as  o utli n e d 
i n T a bl e  1 0 .  F or  a n y  p ost- b as eli n e  visit,  p ot e nti all y cli ni c all y si g nifi c a nt  v al u es   will  b e 
s u  m  m ari z e d  b y  visit. 
A n y  vit al si g n r es ults  c o nsi d er e d  cli ni c all y si g nifi  c a nt  b y t h e i n v esti g at or   will  b e  c a pt ur e d  as 
a d v ers e  e v e nts. 
 
 
P a g e  2 9  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
2 9  
 
T a bl e  1 0:  P ot e nti all y   Cli ni c all y  Si g nifi c a nt   V al u es f o r   Vit al  Si g n  P a r a  m et e rs 
Vit al  Si g n 
U nits      
C rit e ri a f o r  P  C S   V al u es 
(  O bs e r v e d  v al u es) 
C rit e ri a f o r  P  C S  C 
v al u es (  C h a n g e f r o  m 
B as eli n e  v al u es) 
 
 
Hi g h  
L o  w       
I n cr e as e     D e cr e as e  
H e art r at e 
(s u pi n e  a n d st a n di n g) 
B e ats/  mi n       > 1 2 0  
< 4 0       
      
 
S yst oli c   Bl o o d  Pr ess ur e 
(s u pi n e  a n d st a n di n g)  
m  m  H g       
> 1 8 0 
< 9 0       
≥ 3 0      
≥ 3 0 
Di ast oli c   Bl o o d  pr ess ur e 
(s u pi n e  a n d st a n di n g)  
m  m  H g       
> 1 1 0 
< 5 0       
≥ 2 0      
≥ 2 0  
S u pi n e -  St a n di n g 
S yst oli c   Bl o o d  Pr ess ur e 
m  m  H g      
≥ 2 0 
      
      
 
S u pi n e  –   St a n di n g 
Di ast oli c   Bl o o d  Pr ess ur e 
m  m  H g      
≥ 1 0 
      
      
 
Ort h ost ati c  h y p ot e nsi o n: 
s u pi n e –  st a n di n g  S  B P  a n d 
D  B P   
m  m  H g      
S  B P  ≥ 2 0  a n d 
D  B P   ≥ 1 0 
      
      
 
S  B P  ≥ 2 0  or   D  B P 
≥ 1 0 
      
      
 
8. 4. 5.       P h ysi c al   E x a  mi n ati o n  
T h e  o c c urr e n c e  of  a  p h ysi c al  e x a  mi n ati o n  a n d t h e  d at e  a n d ti  m e,  al o n g   wit h t h e r es ults  of t h e 
m e nt al st at us  e x a  m  a n d t h e  a b br e vi at e d  n e u  r ol o gi c al  e x a  m  ar e  c oll e ct e d.  T h es e   will  b e 
pr es e nt e d i n i n di vi d u al  p arti ci p a nt  d at a listi n gs  o nl y  usi n g t h e  S af et y  S et.   Aft er s cr e e ni n g, 
a n y  cli ni c all y si g nifi c a nt  a b n or  m al fi n di n gs i n  p h ysi c al  e x a  mi n ati o ns   will  b e r e p ort e d  as 
A Es.    
8. 4. 6.       C ol u  m bi a  S ui ci d e  S e v e rit y   R ati n g  S c al e (  C- S S  R S) 
All  b y- visit   C- S S  R S s u  m  m ar y t a bl es   will  pr es e nt   r es ults f or  S af et y  S et  p arti ci p a nts  o v er all, 
a n d  als o  b y  d os e l e v el r e c ei v e d  pri or t o t h e  gi v e n  visit.  F or s u  m  m ari z ati o n  of i n ci d e n c e  d at a 
a n y ti  m e  p ost- b as eli n e,  S a f et y  S et  p arti ci p a nt  d at a   will  b e s u  m  m ari z e d  a c c or di n g t o t h e  d os e 
r e c ei v e d i  m  m e di at el y  pri or t o t h e  e v al u ati o n (t h us,  a  p arti ci p a nt   m a y  c o ntri b ut e  d at a  u n d er 
m or e t h a n  o n e  d os e if  a  crit eri o n   w as   m et  p os  t- b as eli n e   w hil e t a ki n g  diff er e nt  d os es).   
S ui ci d alit y  d at a  c oll e ct e d  o n t h e   C- S S  R S is  c oll e ct e d  d uri n g t h e  cli ni c  visits  at  S cr e e ni n g  a n d 
p ost- b as eli n e  visits.  T h e   C- S S  R S i n cl u d es ‘ y es’  or ‘ n o’ r es p o ns es f or  ass ess  m e nt  of s ui ci d al 
i d e ati o n   wit h  n u  m eri c r ati n g f or t h e s e v erit y (fr o  m  1 t o  5   wit h  5  b ei n g t h e   m ost s e v er e)  a n d 
b e h a vi or (fr o  m  6 t o  1 0   wit h  1 0  b ei n g   m ost s e v er e).  T h e  “  B as eli n e/ S cr e e ni n g ”   C - S S  R S f or  m 
will  b e  c o  m pl et e d  at s cr e e ni n g (lif eti  m e  hist  or y  a n d  p ast  2 4   m o nt hs).  T h e  “ Si n c e  L ast   Visit ” 
C- S S  R S f or  m   will  b e  c o  m pl et e d  at  all s u bs e q u e nt  visits. 
T h e  c at e g ori c al  o ut c o  m es  of   C- S S  R S   wit h  bi n ar y r es p o ns e ( “  Y es ”/  “  N o ”) i n cl u d e: 
S ui ci d al i d e ati o n   wit h  5  b ei n g t h e   w orst: 
    1:   wis h t o  b e  d e a d 
P a g e  3 0  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
3 0  
 
    2:  n o n-s p e cifi c  a cti v e s ui ci d al t h o u g hts 
    3:  a cti v e s ui ci d al i d e ati o n   wit h  a n y   m et h o ds ( n ot  pl a n)   wit h o ut i nt e nt t o  a ct 
    4:  a cti v e s ui ci d al i d e ati o n   wit h s o  m e i nt e nt t o  a ct,   wit h o ut s p e cifi c  pl a n 
    5:  a cti v e s ui ci d al i d e ati o n   wit h s p e cifi c  pl a n  a n d i nt e nt 
S ui ci d al  b e h a vi or   wit h  1 0  b ei n g t h e   w orst: 
    6:  pr e p ar at or y  a cts  or  b e h a vi or 
    7:  a b ort e d  att e  m pt 
    8: i nt err u pt e d  att e  m pt  
    9:  a ct u al  att e  m pt 
    1 0:  c o  m pl et e d s ui ci d e 
S ui ci d al  b e h a vi or is  c o nsi d er e d   w ors e t h a n s ui ci d al i d e ati o n.  T h e  p arti ci p a nt ’s  n o n-s ui ci d al 
s elf-i nj uri o us  b e h a vi or is  als o  ass ess e d s e p ar at el y  as  p art  of   C- S S  R S: 
    1 1: s elf-i nj uri o us  b e h a vi or   wit h o ut s ui ci d al i nt e nt 
B as eli n e f or  e a c h  q u esti o n is  d efi n e d  as t h e   w orst  of t h e  ass ess  m e nts  d o n e  b ef or e t h e first 
d os e  of I P ,  e x cl u di n g t h e lif eti  m e  v ersi o n.  T his   will t y pi c all y i n cl u d e t h e ‘ p ast  2 4-  m o nt h’ 
v ersi o n fr o  m s cr e e ni n g  a n d ‘si n c e l ast  visit’   v ersi o n fr o  m   D a y  1,  as   w ell  as  a n y  u ns c h e d ul e d 
visits  d o n e  b ef or e t h e first  d os e  of I P;  a n y  ‘Y es  ’ r es p o ns e   will   m a k e t h e  b as eli n e  v al u e  as 
‘Y es  ’. 
T h e  n u  m b er  a n d  p er c e nt a g e  of  p arti ci p a nt s   wit h  at l e ast  o n e r es p o ns e  of ‘  Y es’ t o  a n y 
C- S S  R S s ui ci d al i d e ati o n  or s ui ci d al  b e h a vi  or it e  m,  as   w ell  as f or  p arti ci p a nt ’s  n o n-s ui ci d al 
s elf-i nj uri o us  b e h a vi or,   will  b e s u  m  m ari z e d  b y  visit.  
C h a n g e fr o  m  b as eli n e f or   C- S S  R S   will  b e  ass e  ss e d  usi n g s hift t a bl es.  S u  m  m ar y  of s hift fr o  m 
b as eli n e i n   C- S S  R S s ui ci d al i d e ati o n  a n d s u i ci d al  b e h a vi or   will  b e  pr es e nt e d f or t h e 
c at e g ori es  “ n o s ui ci d al i d e ati o n/ b e h a vi or ”,  “ s ui ci d al i d e ati o n”,  a n d  “ s ui ci d al  b e h a vi or ” f or 
e a c h s c h e d ul e d  ass ess  m e nt ti  m e  p oi nt. If t h e  a ns  w er t o  all  5  ass ess  m e nts i n s ui ci d al i d e ati o n 
a n d  all  5  ass ess  m e nts i n s ui ci d al  b e h a vi or is ‘  N o’ , t h e n t h e  c at e g or y f or t h e t a bl e is 
c o nsi d er e d  as ‘  N o s ui ci d al i d e ati o n/ b e h a vi or’. If  a n y  of t h e  a ss ess  m e nts i n s ui ci d al  b e h a vi or 
ar e  ‘Y es  ’, t h e  c at e g or y is  c o nsi d er e d  as ‘ S ui ci d al  b e h a vi or’. If  a n y  of t h e  ass ess  m e nts i n 
s ui ci d al i d e ati o n  ar e  ‘Y es  ’  b ut  all  ass ess  m e nts i n s ui ci d al  b e h a vi or  ar e ‘N o  ’, t h e  c at e g or y is 
c o nsi d er e d  as ‘ S ui ci d al i d e ati o n’.  
I n  a d diti o n,  a s u  m  m ar y  of s hift i n s ui ci d al i d e ati o n fr o  m  b as eli n e   m a xi  m u  m r a n k s c or e f or 
a n y ti  m e  p ost- b as eli n e   m a xi  m u  m r a n k s c or e   will  b e  pr es e nt e d.   M a xi  m u  m s c or e  0 r ef ers t o  all 
‘N o  ’ f or  all  ass ess  m e nts i n t h e  d esir e d  p erio d f or  all  5  q u esti o ns  o n s ui ci d al i d e ati o n. 
8. 4. 7.       P h ysi ci a n    Wit h d r a  w al   C h e c klist ( P   W  C- 2 0)   
T h e  P   W  C- 2 0 is  a s h ort er  v ersi o n  of t h e  P e n n  P h ysi ci a n    Wit h dr a  w al   C h e c kli st  b as e d  o n t h e 
2 0 it e  ms t h at  pr o vi d e d t h e  b est  diff er e nti ati o n fr o  m  pl a c e b o i n  pr e vi o us tri als.  T h e  P   W  C- 2 0 
P a g e  3 1  of  6 0




St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
3 2  
 
9.       
S  U   M   M  A  R  Y   O F I  N  T  E  RI   M   A  N  D   D   M  C   A  N  A  L  Y S  E S 
9. 1.       I nt e ri  m   A n al ysis 
N ot  a p pli c a bl e. 
9. 2.       D   M  C   A n al ysis 
N ot  a p pli c a bl e.  
P a g e  3 3  of  6 0




St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
3 4  
 
Z a p pi a   M,   Al b a n es e   A,   Br u n o  E,  et  al.  Tr e at  m e n t  of  ess e nti al tr e  m or:  a s yst e  m ati c r e vi e  w  of 
e vi d e n c e  a n d r e c o  m  m e n d ati o ns fr o  m t h e It ali a n   M o v e  m e nt   Dis or d ers   Ass o ci ati o n. J   N e ur ol. 
2 0 1 3; 2 6 0( 3): 7 1 4- 4 0.  
P a g e  3 5  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
3 5  
 
1 1.       
LI S  T   O F   A P P  E  N  DI  C  E S 
P a g e  3 6  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4 
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
3 6  
 
A P P  E  N  DI  X   A.     S  C  H  E  D  U  L  E   O F   A S S  E S S   M  E  N  T S 
 
 
 
 
 
 
 
 
 
 
P a g e  3 7  of  6 0
















St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4 
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
4 4  
 
 
 
P a g e  4 5  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
4 5  
 
A P P  E  N  DI  X   B.     H  A  N  D  LI  N  G   O F    MI S SI  N  G   D  A  T  E S 
P arti al  d at es   will  a d h er e t o t h e f oll o  wi n g  c o n v e nti o ns i n  or d er t o  cl assif y  T E  A Es  a n d t o 
cl assif y  pri or  a n d  c o n c o  mit a nt   m e di c ati o ns.  
I n  g e n er al, listi n gs   will  pr es e nt t h e  a ct u al  p arti al  or   missi n g  v al u es r at h er t h a n t h e i  m p ut e d 
v al u es t h at   m a y  b e  us e d i n  d eri v ati o n.  
A d v e rs e   E v e nts 
I n t h e  e v e nt  of  a   missi n g/i n c o  m pl et e st art  or st o p  d at e  ass o ci at e d   wit h  a n  a d v ers e  e v e nt,  o nl y 
t h e tr e at  m e nt- e  m er g e n c e   will  b e i  m p ut e d  usi n g t h e  al g orit h  m  b el o  w.   D at es   will  n ot  b e 
i  m p ut e d.  
I n  g e n er al, if t h e   missi n g/i n c o  m pl et e st art  d at e is  n ot  cl e arl y  pri or t o i niti ati o n  of tr e at  m e nt, 
t h e n t h e   A E   will  b e  c o nsi d er e d  a  T E  A E.   
If t h e   A E  e n d  d at e is  pri or t o t h e i niti ati o n  of tr e at  m e nt, t h e   A E   will  n ot  b e  c o nsi d er e d  a 
T E  A E. 
If t h e   A E  e n d  d at e is  o n  or  aft er t h e i niti ati o n  of tr e at  m e nt: 
    If t h e   A E st art  d at e is  c o  m pl et el y   missi n g  or if t h e  y e ar is   missi n g, t h e n t h e   A E   will 
b e  c o nsi d er e d  a  T E  A E 
    F or  p arti al   A E st art  d at es: 
o    K n o  w n  y e ar,  u n k n o  w n   m o nt h  a n d  d a y ( or  k n o  w n  y e ar  a n d  d a y,  u n k n o  w n 
m o nt h) 
    If t h e  y e ar is t h e s a  m e  as  or l at er t h a n t h e  y e ar  of t h e first  d os e, t h e   A E 
will  b e  c o nsi d er e d  a  T E  A E 
    Ot h er  wis e, t h e   A E   will  n ot  b e  c o nsi d er e d  a  T E  A E 
o    K n o  w n  y e ar  a n d   m o nt h,  u n k n o  w n  d a y 
    If t h e   m o nt h  a n d  y e ar  ar e t h e s a  m e  as  or l at er t h a n t h e   m o nt h  a n d  y e ar 
of t h e first  d os e, t h e   A E   will  b e  c o nsi d er e d  a  T E  A E 
    Ot h er  wis e, t h e   A E   will  n ot  b e  c o nsi d er d  a  T E  A E 
P ri o r  a n d   C o n c o  mit a nt    M e di c ati o ns 
N o i  m p ut ati o n  pr o c ess   will  b e  us e d t o  esti  m at e   missi n g  d at a,  e x c e pt f or t h e  p ur p os es  of 
cl assif yi n g   m e di c ati o ns  as  pri or  a n d/ or  c o n c o  mit a nt.  T h e f oll o  wi n g  al g orit h  ms   will  b e  us e d 
f or  p arti all y   missi n g  d at es. 
F or st art  d at es  of   m e di c ati o n  us es: 
    T h e  d a y  a n d   m o nt h  ar e   missi n g: if t h e  p arti c i p a nt st art e d r e c ei vi n g t h e st u d y  d osi n g i n 
t h e r e p ort e d  y e ar, t h e first  d osi n g  d at e   will  b e  us e d  as t h e st art  d at e;  ot h er  wis e 
’ 0 1 J a n u ar y’   will  b e  us e d  as  t h e st art  d at e. 
P a g e  4 6  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
4 6  
 
    T h e  d a y is   missi n g: if t h e  p arti ci p a nt st art e d r e c ei vi n g t h e st u d y  d osi n g i n t h e r e p ort e d 
m o nt h  a n d  y e ar, t h e first  d osi n g  d at e   will  b e   us e d  as t h e st art  d at e;  ot h er  wis e, t h e first 
d a y  of t h e r e p ort e d   m o nt h  a n d  y e ar   will  b e  us e d  as t h e st art  d at e. 
F or st o p  d at es  of  e v e nts  or   m e di c ati o n  us es: 
    T h e  d a y  a n d   m o nt h  ar e   missi n g: if t h e st u d y  e n d  d at e is i n t h e r e p ort e d  y e ar, t h e st u d y 
e n d  d at e  will  b e  us e d  as t h e st o p  d at e;  ot h er  wis e, ‘ 3 1   D e c e  m b er’   will  b e  us e d  as t h e 
st o p  d at e. 
    T h e  d a y is   missi n g: if t h e st u d y  e n d  d at e  is i n t h e r e p ort e d   m o nt h  a n d  y e ar, t h e st u d y 
e n d  d at e   will  b e  us e d  as t h e st o p  d at e;  ot h er  wis e, t h e  e n d  of t h e r e p ort e d   m o nt h  a n d 
y e ar   will  b e  us e d  as t h e st o p  d at e. 
If  a   m e di c ati o n  h as t h e st o p  d at e  c o  m pl et el y   missi n g  or   missi n g t h e  y e ar, t his   m e di c ati o n   will 
b e  c o nsi d er e d  as  o n g oi n g  a n d  c o n c o  mit a nt. If  a  p arti ci p a nt is   missi n g  a tr e at  m e nt st art  d at e, 
m e di c ati o n   will  n ot  b e  cl assifi e d  as  eit h er  pri or  or  c o n c o  mit a nt. 
P a g e  4 7  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
4 7  
 
A P P  E  N  DI  X   C.     LI S  T   O F   DI S P  L  A  Y S 
 
Dis pl a y   N u  m b er        
Dis pl a y  Titl e   
A n al ysis  S et   Us e d 
T a bl es  
1 4. 1. 1  
Dis p ositi o n  of  P arti ci p a nts   
All  P arti ci p a nts 
1 4. 1. 2  
A n al ysis  S ets   
All  P arti ci p a nts 
1 4. 1. 3. 1  
M aj or  Pr ot o c ol   D e vi ati o ns   
S af et y  S et  
1 4. 1. 3. 2   
Pr ot o c ol   D e vi ati o ns   R el at e d t o   C  O  VI  D- 1 9      S af et y  S et  
1 4. 1. 4. 1  
D e  m o gr a p hi cs  a n d   B as eli n e   C h ar a ct eristi cs      S af et y  S et  
1 4. 1. 4. 2  
D e  m o gr a p hi cs  a n d   B as eli n e   C h ar a ct eristi cs 
- S u b gr o u ps 
S af et y  S et  
1 4. 1. 5  
S u  m  m ar y  of   Dis e as e   Hist or y  
S af et y  S et  
1 4. 1. 6  
M e di c al/ S ur gi c al   Hist or y    
S af et y  S et  
1 4. 1. 7. 1  
Pri or   M e di c ati o ns   
S af et y  S et  
1 4. 1. 7. 2  
C o n c o  mit a nt   M e di c ati o ns   
S af et y  S et  
1 4. 1. 8. 1  
I n v esti g ati o n al  Pr o d u ct  E x p os ur e      
S af et y  S et  
1 4. 1. 8. 2  
T ot al  E x p os ur e   D ur ati o n  b y   D os e  at 
I n v esti g ati o n al  Pr o d u ct   Dis c o nti n u ati o n  
S af et y  S et  
1 4. 1. 8. 3  
I n v esti g ati o n al  Pr o d u ct   A d h er e n c e      
S af et y  S et  
P a g e  4 8  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
4 8  
 
1 4. 3. 1. 1  
S u  m  m ar y  of  Tr e at  m e nt -E  m er g e nt   A d v ers e 
E v e nts  
S af et y  S et  
1 4. 3. 1. 2  
Tr e at  m e nt -E  m er g e nt   A d v ers e  E v e nts  b y 
S yst e  m   Or g a n   Cl ass  a n d  Pr ef err e d  T er  m 
S af et y  S et  
1 4. 3. 1. 3  
Tr e at  m e nt -E  m er g e nt   A d v ers e  E v e nts  b y 
Pr ef err e d  T er  m  
S af et y  S et  
P a g e  4 9  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
4 9  
 
1 4. 3. 1. 4  
S eri o us  Tr e at  m e nt - E  m er g e nt   A d v ers e 
E v e nts  b y  S yst e  m   Or g a n   Cl ass  a n d 
Pr ef err e d  T er  m  
S af et y  S et  
1 4. 3. 1. 5  
Tr e at  m e nt - E  m er g e nt   A d v ers e  E v e nts 
L e a di n g t o I n v esti g ati o n al  Pr o d u ct 
Dis c o nti n u ati o n  b y  S yst e  m   Or g a n   Cl ass 
a n d  Pr ef err e d  T er  m  
S af et y  S et  
1 4. 3. 1. 6  
Tr e at  m e nt - E  m er g e nt   A d v ers e  E v e nts 
L e a di n g t o  St u d y   Dis c o nti n u ati o n  b y 
S yst e  m   Or g a n   Cl ass  a n d  Pr ef err e d  T er  m 
S af et y  S et  
1 4. 3. 1. 7  
Tr e at  m e nt -E  m er g e nt   A d v ers e  E v e nts  b y 
M a xi  m u  m  S e v erit y   
S af et y  S et  
1 4. 3. 1. 8  
Tr e at  m e nt -E  m er g e nt   A d v ers e  E v e nts  b y 
M a xi  m u  m   R el ati o ns hi p t o I n v esti g ati o n al 
Pr o d u ct  
S af et y  S et  
1 4. 3. 1. 9  
S eri o us  Tr e at  m e nt - E  m er g e nt   A d v ers e 
E v e nts  b y  Pr ef err e d  T er  m  
S af et y  S et  
1 4. 3. 4. 1. 1  
S u  m  m ar y  of   Cli ni c al   C h e  mistr y  
S af et y  S et  
1 4. 3. 4. 1. 2  
S hift  of   Cli ni c al   C h e  mistr y  
S af et y  S et  
1 4. 3. 4. 1. 3  
P ot e nti all y   Cli ni c all y  Si g nifi c a nt ( P  C S) 
V al u es i n   Cli ni c al   C h e  mistr y  E x cl u di n g 
Li v er  F u n cti o n  T ests  
S af et y  S et  
1 4. 3. 4. 1. 4  
P ot e nti all y   Cli ni c all y  Si g nifi c a nt ( P  C S) 
V al u es i n  Li v er  F u n cti o n  T ests   A n y  Ti  m e 
P ost - b as eli n e 
S af et y  S et  
1 4. 3. 4. 2. 1  
S u  m  m ar y  of   H e  m at ol o g y  
S af et y  S et  
1 4. 3. 4. 2. 2  
S hift  of   H e  m at ol o g y  
S af et y  S et  
1 4. 3. 4. 2. 3  
P ot e nti all y   Cli ni c all y  Si g nifi c a nt ( P  C S) 
V al u es i n   H e  m at ol o g y   
S af et y  S et  
1 4. 3. 4. 3. 1  
S u  m  m ar y  of   C o a g ul ati o n  
S af et y  S et  
1 4. 3. 4. 3. 2  
S hift  of   C o a g ul ati o n  
S af et y  S et  
P a g e  5 0  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
5 0  
 
1 4. 3. 4. 3. 3  
P ot e nti all y   Cli ni c all y  Si g nifi c a nt ( P  C S) 
V al u es i n   C o a g ul ati o n   
S af et y  S et  
1 4. 3. 4. 4. 1. 1       
S u  m  m ar y  of   Uri n al ysis,   C o nti n u o us 
P ar a  m et ers  
S af et y  S et  
1 4. 3. 4. 4. 1. 2       
S u  m  m ar y  of   Uri n al ysis,   C at e g ori c al 
P ar a  m et ers  
S af et y  S et  
1 4. 3. 4. 4. 2  
S hift  of  Uri n al ysis 
S af et y  S et  
1 4. 3. 4. 5. 1   
S u  m  m ar y  of  1 2 - L e a d  El e ctr o c ar di o gr a  m      S af et y  S et  
1 4. 3. 4. 5. 2  
S hift  of   O v er all  El e ctr o c ar di o gr a  m 
I nt er pr et ati o n 
S af et y  S et  
1 4. 3. 4. 5. 3  
P ot e nti all y   Cli ni c all y  Si g nifi c a nt ( P  C S) 
Q T c F   V al u es   
S af et y  S et  
1 4. 3. 4. 6. 1  
S u  m  m ar y  of   Vit al  Si g ns  
S af et y  S et  
1 4. 3. 4. 6. 2  
P ot e nti all y   Cli ni c all y  Si g nifi c a nt ( P  C S) 
V al u es i n   Vit al  Si g ns   
S af et y  S et  
1 4. 3. 4. 7. 1  
S u  m  m ar y  of   C ol u  m bi a -S ui ci d e  S e v erit y 
R ati n g  S c al e    
S af et y  S et  
1 4. 3. 4. 7. 2  
S hift  Fr o  m   B as eli n e i n  C ol u  m bi a-  S ui ci d e 
S e v erit y   R ati n g  S c al e (  C -S S  R S)  S ui ci d al 
I d e ati o n  a n d  S ui ci d al   B e h a vi or  b y  St u d y 
Visit   
S af et y  S et  
1 4. 3. 4. 7. 3  
S hift  Fr o  m   B as eli n e i n   C ol u  m bi a -S ui ci d e 
S e v erit y   R ati n g  S c al e (  C -S S  R S)   M a xi  m u  m 
S e v erit y  S c or e i n  S ui ci d al I d e ati o n  at   A n y 
Ti  m e  P ost   b as eli n e 
S af et y  S et  
1 4. 3. 4. 8  
S u  m  m ar y  of  P h ysi ci a n    Wit h dr a  w al 
C h e c klist ( P   W  C  - 2 0) 
S af et y  S et  
1 4. 3. 4. 9. 1  
S u  m  m ar y  of  E p  w ort h  Sl e e pi n ess  S c al e  – 
I n di vi d u al It e  ms 
S af et y  S et  
1 4. 3. 4. 9. 2  
S u  m  m ar y  of  E p  w ort h  Sl e e pi n ess  S c al e  – 
T ot al  S c or e  
S af et y  S et  
P a g e  5 1  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
5 1  
 
Listi n gs  
1 6. 2. 1. 1  
P arti ci p a nt   Dis p ositi o n  
All  P arti ci p a nts 
1 6. 2. 1. 2  
S cr e e n  F ail ur es  
S cr e e n  F ail ur e 
P arti ci p a nts  
1 6. 2. 2. 1  
I n cl usi o n/ E x cl usi o n   Crit eri a   Vi ol ati o ns      
All  P arti ci p a nts, 
E x cl u di n g  S cr e e n 
F ail ur es  
1 6. 2. 2. 2  
Pr ot o c ol   D e vi ati o ns  
S af et y  S et  
1 6. 2. 3  
A n al ysis  S ets   
All  P arti ci p a nts 
1 6. 2. 4. 1  
D e  m o gr a p hi cs  a n d I nf or  m e d   C o ns e nt        
S af et y  S et  
1 6. 2. 4. 2  
C hil d  - b e ari n g  P ot e nti al 
S af et y  S et  
1 6. 2. 4. 3. 1  
M e di c al/ S ur gi c al   Hist or y    
S af et y  S et  
1 6. 2. 4. 3. 2  
Ess e nti al  Tr e  m or   Dis e as e   Hist or y       
S af et y  S et  
1 6. 2. 4. 4. 1  
Pri or   M e di c ati o ns  
S af et y  S et  
1 6. 2. 4. 4. 2  
C o n c o  mit a nt   M e di c ati o ns   
S af et y  S et  
1 6. 2. 4. 5  
C o n c o  mit a nt  Pr o c e d ur es   
S af et y  S et  
1 6. 2. 5. 1  
I n v esti g ati o n al  Pr o d u ct   Dis p e ns ati o n  a n d 
R et ur n   
S af et y  S et  
1 6. 2. 5. 2. 1  
I n v esti g ati o n al  Pr o d u ct   A d  mi nistr ati o n – 
D ail y   D osi n g   Di ar y   
S af et y  S et  
1 6. 2. 5. 2. 2  
I n v esti g ati o n al  Pr o d u ct   A d  mi nistr ati o n – 
L o g   R e c or ds  
S af et y  S et  
1 6. 2. 5. 3  
I n v esti g ati o n al  Pr o d u ct  E x p os ur e  a n d 
A d h er e n c e   
S af et y  S et  
P a g e  5 2  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
5 2  
 
1 6. 2. 7. 1  
A d v ers e  E v e nts   
S af et y  S et  
1 6. 2. 7. 2  
S eri o us   A d v ers e  E v e nts  
S af et y  S et  
1 6. 2. 7. 3  
D e at hs   
S af et y  S et  
1 6. 2. 7. 4  
A d v ers e  E v e nts  L e a di n g t o I n v esti g ati o n al 
Pr o d u ct   Dis c o nti n u ati o n  
S af et y  S et  
1 6. 2. 7. 5  
A d v ers e  E v e nts  L e a di n g t o  St u d y 
Dis c o nti n u ati o n   
S af et y  S et  
1 6. 2. 8. 1. 1  
Cli ni c al   C h e  mistr y   
S af et y  S et  
1 6. 2. 8. 1. 2  
Cli ni c al   H e  m at ol o g y   
S af et y  S et  
1 6. 2. 8. 1. 3  
Cli ni c al   C o a g ul ati o n   
S af et y  S et  
1 6. 2. 8. 1. 4  
Uri n al ysis   
S af et y  S et  
1 6. 2. 8. 2. 1  
Pr e g n a n c y  T est  
S af et y  S et  
1 6. 2. 8. 2. 2  
F S  H  T esti n g  
S af et y  S et  
1 6. 2. 8. 2. 3  
L o c al   Dr u g  S cr e e n  
S af et y  S et  
1 6. 2. 8. 2. 4  
L o c al   Al c o h ol  S cr e e n  
S af et y  S et  
P a g e  5 3  of  6 0


St atisti c al   A n al ysis  Pl a n   M et h o ds   V ersi o n  1. 0  2 2  O ct 2 0 2 4       
S a g e  T h er a p e uti cs, I n c. 
Pr ot o c ol   N u  m b er:  3 2 4- E T  D- 3 0 3 (  V ersi o n  4. 0  0 2   N o v  2 0 2 3) 
C  O  N FI  D E  N TI  A L 
 
5 3  
 
1 6. 2. 8. 2. 5  
C e ntr al  L a b or at or y   Dr u g  S cr e e n   
S af et y  S et  
1 6. 2. 8. 3  
1 2 - L e a d  El e ctr o c ar di o gr a  m ( E  C  G)      
S af et y  S et  
1 6. 2. 8. 4  
Vit al  Si g ns   
S af et y  S et  
1 6. 2. 8. 5  
P h ysi c al  E x a  mi n ati o ns  
S af et y  S et  
1 6. 2. 8. 6  
M e nt al  St at us  E x a  mi n ati o n    
S af et y  S et  
1 6. 2. 8. 7  
A b br e vi at e d   N e ur ol o gi c al  E x a  mi n ati o n      
S af et y  S et  
1 6. 2. 8. 1 0  
C ol u  m bi a  -S ui ci d e  S e v erit y   R ati n g  S c al e 
(  C- S S  R S) 
S af et y  S et  
1 6. 2. 8. 1 1  
P h ysi ci a n    Wit h dr a  w al   C h e c klist  
S af et y  S et  
1 6. 2. 8. 1 2  
E p  w ort h  Sl e e pi n ess  S c al e  
S af et y  S et  
 
P a g e  5 4  of  6 0






Si g n er   E v e nt s
Si g n at ur e
Ti  m e st a  m p
El e ctr o ni c   R e c or d  a n d   Si g n at ur e   Di s cl o s ur e: 
        N ot   Off er e d  vi a   D o c u  Si g n
I n   P er s o n   Si g n er   E v e nt s
Si g n at ur e
Ti  m e st a  m p
E dit or   D eli v er y   E v e nt s
St at u s
Ti  m e st a  m p
A g e nt   D eli v er y   E v e nt s
St at u s
Ti  m e st a  m p
I nt er  m e di ar y   D eli v er y   E v e nt s
St at u s
Ti  m e st a  m p
C ertifi e d   D eli v er y   E v e nt s
St at u s
Ti  m e st a  m p
C ar b o n   C o p y   E v e nt s
St at u s
Ti  m e st a  m p
Wit n e s s   E v e nt s
Si g n at ur e
Ti  m e st a  m p
N ot ar y   E v e nt s
Si g n at ur e
Ti  m e st a  m p
E n v el o p e   S u  m  m ar y   E v e nt s
St at u s
Ti  m e st a  m p s
E n v el o p e   S e nt
H a s h e d/  E n cr y pt e d
2 3-  O ct- 2 0 2 4 |  0 9: 3 2
C ertifi e d   D eli v er e d
S e c urit y   C h e c k e d
2 3-  O ct- 2 0 2 4 |  0 9: 5 2
Si g ni n g   C o  m pl et e
S e c urit y   C h e c k e d
2 3-  O ct- 2 0 2 4 |  0 9: 5 4
C o  m pl et e d
S e c urit y   C h e c k e d
2 4-  O ct- 2 0 2 4 |  0 8: 4 5
P a y  m e nt   E v e nt s
St at u s
Ti  m e st a  m p s
El e ctr o ni c   R e c or d  a n d   Si g n at ur e   Di s cl o s ur e
P a g e  5 7  of  6 0


E  L  E  C  T  R  O  NI  C   R  E  C  O  R  D   A  N  D  SI  G  N  A  T  U  R  E   DI S  C  L  O S  U  R  E    
Fr o  m ti  m e t o ti  m e,  S a g e  T h er a p e uti cs -  P art  1 1 (  w e,  us  or   C o  m p a n y)   m a y  b e r e q uir e d  b y l a  w t o 
pr o vi d e t o  y o u  c ert ai n   writt e n  n oti c es  or  dis cl o s ur es.   D es cri b e d  b el o  w  ar e t h e t er  ms  a n d 
c o n diti o ns f or  pr o vi di n g t o  y o u s u c h  n oti c es  a n d  dis cl os ur es  el e ctr o ni c all y t hr o u g h t h e   D o c u Si g n 
s yst e  m.  Pl e as e r e a d t h e i nf or  m ati o n  b el o  w  c ar ef ull y  a n d t h or o u g hl y,  a n d if  y o u  c a n  a c c ess t his 
i nf or  m ati o n  el e ctr o ni c all y t o  y o ur s atisf a cti o n  a n d a gr e e t o t his  El e ctr o ni c   R e c or d  a n d  Si g n at ur e 
Dis cl os ur e ( E  R S  D),  pl e as e  c o nfir  m  y  o ur  a gr e e  m e nt  b y s el e cti n g t h e  c h e c k- b o x  n e xt t o ‘I  a gr e e t o 
us e  el e ctr o ni c r e c or ds  a n d si g n at ur es’  b ef or e  cli c ki n g ‘  C  O  N TI  N  U E’   wit hi n t h e   D o c u Si g n 
s yst e  m. 
 
G etti n g  p a p e r  c o pi es    
At  a n y ti  m e,  y o u   m a y r e q u est fr o  m  us  a  p a p er   c o p y  of  a n y r e c or d  pr o vi d e d  or   m a d e  a v ail a bl e 
el e ctr o ni c all y t o  y o u  b y  us.   Y o u   will  h a v e t h e  a bilit y t o  d o  w nl o a d  a n d  pri nt  d o c u  m e nts   w e s e n d 
t o  y o u t hr o u g h t h e   D o c u Si g n s yst e  m  d uri n g  a n d i  m  m e di at el y  aft er t h e si g ni n g s essi o n  a n d, if  y o u 
el e ct t o  cr e at e  a   D o c u Si g n  a c c o u nt,  y o u   m a y  a c c e ss t h e  d o c u  m e nts f or  a li  mit e d  p eri o d  of ti  m e 
( us u all y  3 0  d a ys)  aft er s u c h  d o c u  m e nts  ar e first s e nt t o  y o u.   Aft er s u c h ti  m e, if  y o u   wis h f or  us t o 
s e n d  y o u  p a p er  c o pi es  of  a n y s u c h  d o c u  m e nts fr o  m  o ur  offi c e t o  y o u,  y o u   will  b e  c h ar g e d  a 
$ 0. 0 0  p er- p a g e f e e.   Y o u   m a y r e q u est  d eli v er y  of s u c h  p a p er  c o pi es fr o  m  us  b y f oll o  wi n g t h e 
pr o c e d ur e  d es cri b e d  b el o  w. 
 
Wit h d r a  wi n g  y o u r  c o ns e nt     
If  y o u  d e ci d e t o r e c ei v e  n oti c es  a n d  dis cl os ur es fr o  m  us  el e ctr o ni c all y,  y o u   m a y  at  a n y ti  m e 
c h a n g e  y o ur   mi n d  a n d t ell  us t h at t h er e aft er  y o u   w a nt t o r e c ei v e r e q uir e d  n oti c es  a n d  dis cl os ur es 
o nl y i n  p a p er f or  m at.   H o  w  y o u   m ust i nf or  m  us  of  y o ur  d e cisi o n t o r e c ei v e f ut ur e  n oti c es  a n d 
dis cl os ur e i n  p a p er f or  m at  a n d   wit h dr a  w  y o ur  c o ns e nt t o r e c ei v e  n oti c es  a n d  dis cl os ur es 
el e ctr o ni c all y is  d es cri b e d  b el o  w. 
 
C o ns e q u e n c es  of  c h a n gi n g  y o u r   mi n d    
If  y o u  el e ct t o r e c ei v e r e q uir e d  n oti c es  a n d  dis cl os ur es  o nl y i n  p a p er f or  m at, it   will sl o  w t h e 
s p e e d  at   w hi c h   w e  c a n  c o  m pl et e  c ert ai n st e ps i n tr a ns a cti o ns   wit h  y o u  a n d  d eli v eri n g s er vi c es t o 
y o u  b e c a us e   w e   will  n e e d first t o s e n d t h e r e q uir e d  n oti c es  or  dis cl os ur es t o  y o u i n  p a p er f or  m at, 
a n d t h e n   w ait  u ntil   w e r e c ei v e  b a c k fr o  m  y o u  y o ur  a c k n o  wl e d g  m e nt  of  y o ur r e c ei pt  of s u c h 
p a p er  n oti c es  or  dis cl os ur es.  F urt h er,  y o u   will  n o l o n g er  b e  a bl e t o  us e t h e   D o c u Si g n s yst e  m t o 
r e c ei v e r e q uir e d  n oti c es  a n d  c o ns e nts  el e ctr o ni c all y fr o  m  us  or t o si g n  el e ctr o ni c all y  d o c u  m e nts 
fr o  m  us. 
 
All  n oti c es  a n d  dis cl os u r es   will  b e s e nt t o  y o u  el e ct r o ni c all y    
P a g e  5 8  of  6 0


U nl ess  y o u t ell  us  ot h er  wis e i n  a c c or d a n c e   wit h   t h e  pr o c e d ur es  d es cri b e d  h er ei n,   w e   will  pr o vi d e 
el e ctr o ni c all y t o  y o u t hr o u g h t h e   D o c u Si g n s yst e  m  all r e q uir e d  n oti c es,  dis cl os ur es, 
a ut h ori z ati o ns,  a c k n o  wl e d g e  m e nts,  a n d  ot h er  d o c u  m e n ts t h at  ar e r e q uir e d t o  b e  pr o vi d e d  or   m a d e 
a v ail a bl e t o  y o u  d uri n g t h e  c o urs e  of  o ur r el ati o ns hi p   wit h  y o u.  T o r e d u c e t h e  c h a n c e  of  y o u 
i n a d v ert e ntl y  n ot r e c ei vi n g  a n y  n oti c e  or  dis cl os ur e,   w e  pr ef er t o  pr o vi d e  all  of t h e r e q uir e d 
n oti c es  a n d  dis cl os ur es t o  y o u  b y t h e s a  m e   m et h o d  a n d t o t h e s a  m e  a d dr ess t h at  y o u  h a v e  gi v e n 
us.  T h us,  y o u  c a n r e c ei v e  all t h e  dis cl os ur es  a n d  n oti c es  el e ctr o ni c all y  or i n  p a p er f or  m at t hr o u g h 
t h e  p a p er   m ail  d eli v er y s yst e  m. If  y o u  d o  n ot  a gr e e   wit h t his  pr o c ess,  pl e as e l et  us  k n o  w  as 
d es cri b e d  b el o  w.  Pl e as e  als o s e e t h e  p a r a gr a p h i  m  m e di at el y  a b o v e t h at  d es cri b es t h e 
c o ns e q u e n c es  of  y o ur  el e cti n g  n ot t o r e c ei v e  d eli v er y  of t h e  n oti c es  a n d  dis cl os ur es 
el e ctr o ni c all y fr o  m  us. 
 
H o  w t o  c o nt a ct  S a g e   T h e r a p e uti cs -  P a rt  1 1:    
Y o u   m a y  c o nt a ct  us t o l et  us  k n o  w  of  y o ur  c h a n g es  as t o  h o  w   w e   m a y  c o nt a ct  y o u  el e ctr o ni c all y, 
t o r e q u est  p a p er  c o pi es  of  c ert ai n i nf or  m ati o n fro  m  us,  a n d t o   wit h dr a  w  y o ur  pri or  c o ns e nt t o 
r e c ei v e  n oti c es  a n d  dis cl os ur es  el e ctr o ni c all y  as f oll o  ws: 
T o  c o nt a ct  us  b y  e  m ail s e n d   m e ss a g es t o: 
 
 
T o  a d vis e  S a g e   T h e r a p e uti cs -  P a rt  1 1  of  y o u r  n e  w  e  m ail  a d d r ess    
T o l et  us  k n o  w  of  a  c h a n g e i n  y o ur  e  m ail  a d dr ess   w h er e   w e s h o ul d s e n d  n oti c es  a n d  dis cl os ur es 
el e ctr o ni c all y t o  y o u,  y o u   m ust s e n d  a n  e  m ail   m ess a g e t o  us  at 
  a n d i n t h e 
b o d y  of s u c h r e q u est  y o u   m ust st at e:  y o ur  pr e vi o us  e  m ail  a d dr ess,  y o ur  n e  w  e  m ail  a d dr ess.     W e 
d o  n ot r e q uir e  a n y  ot h er i nf or  m ati o n fr o  m  y o u t o  c h a n g e  y o ur  e  m ail  a d dr ess.  
If  y o u  cr e at e d  a   D o c u Si g n  a c c o u nt,  y o u   m a y  u p d at e it   wit h  y o ur  n e  w  e  m ail  a d dr ess t hr o u g h  y o ur 
a c c o u nt  pr ef er e n c es.  
 
T o  r e q u est  p a p e r  c o pi es f r o  m    S a g e   T h e r a p e uti cs -  P a rt  1 1  
T o r e q u est  d eli v er y fr o  m  us  of  p a p er  c o pi es  of t h e  n oti c es  a n d  dis cl os ur es  pr e vi o usl y  pr o vi d e d 
b y  us t o  y o u  el e ctr o ni c all y,  y o u   m ust s e n d  us  a n  e  m ail t o 
  a n d i n t h e  b o d y  of 
s u c h r e q u est  y o u   m ust st at e  y o ur  e  m ail  a d dr ess,  f ull  n a  m e,   m aili n g  a d dr ess,  a n d t el e p h o n e 
n u  m b er.    W e   will  bill  y o u f or  a n y f e es  at t h at ti  m e, if  a n y. 
 
T o   wit h d r a  w  y o u r  c o ns e nt   wit h  S a g e   T h e r a p e uti cs -  P a rt  1 1    
T o i nf or  m  us t h at  y o u  n o l o n g er   wis h t o r e c ei v e f ut ur e  n oti c es  a n d  dis cl os ur es i n  el e ctr o ni c 
f or  m at  y o u   m a y: 
P a g e  5 9  of  6 0


i.  d e cli n e t o si g n  a  d o c u  m e nt fr o  m   wit hi n  y o ur si g ni n g s essi o n,  a n d  o n t h e s u bs e q u e nt  p a g e, 
s el e ct t h e  c h e c k- b o x i n di c ati n g  y o u   wis h t o   wit h dr a  w  y o ur  c o ns e nt,  or  y o u   m a y; 
ii. s e n d  us  a n  e  m ail t o 
  a n d i n t h e  b o d y  of s u c h r e q u est  y o u   m ust st at e  y o ur 
e  m ail, f ull  n a  m e,   m aili n g  a d dr ess,  a n d t el e p h o n e  n u  m b er.    W e  d o  n ot  n e e d  a n y  ot h er i nf or  m ati o n 
fr o  m  y o u t o   wit h dr a  w  c o ns e nt..   T h e  c o ns e q u e n c es  of  y o ur   wit h dr a  wi n g  c o ns e nt f or  o nli n e 
d o c u  m e nts   will  b e t h at tr a ns a cti o ns   m a y t a k e  a l o n g er ti  m e t o  pr o c ess.. 
 
R e q ui r e d  h a r d  w a r e  a n d s oft  w a r e    
T h e   mi ni  m u  m s yst e  m r e q uir e  m e nts f or  usi n g t h e   D o c u Si g n s yst e  m   m a y  c h a n g e  o v er ti  m e.  T h e 
c urr e nt s yst e  m r e q uir e  m e nts  ar e f o u n d  h er e:  htt ps://s u p p ort. d o c usi g n. c o  m/ g ui d es/si g n er- g ui d e-
si g ni n g-s yst e  m-r e q uir e  m e nts .  
 
A c k n o  wl e d gi n g  y o u r  a c c ess  a n d  c o ns e nt t o  r e c ei v e  a n d si g n  d o c u  m e nts  el e ct r o ni c all y    
T o  c o nfir  m t o  us t h at  y o u  c a n  a c c ess t his i nf or  m ati o n  el e ctr o ni c all y,   w hi c h   will  b e si  mil ar t o 
ot h er  el e ctr o ni c  n oti c es  a n d  dis cl os ur es t h at   w e   wi ll  pr o vi d e t o  y o u,  pl e as e  c o nfir  m t h at  y o u  h a v e 
r e a d t his  E  R S  D,  a n d (i) t h at  y o u  ar e  a bl e t o  pri nt  o n  p a p er  or  el e ctr o ni c all y s a v e t his  E  R S  D f or 
y o ur f ut ur e r ef er e n c e  a n d  a c c ess;  or (ii) t h at  y o u  ar e  a bl e t o  e  m ail t his  E  R S  D t o  a n  e  m ail  a d dr ess 
w h er e  y o u   will  b e  a bl e t o  pri nt  o n  p a p er  or s a v e it f or  y o ur f ut ur e r ef er e n c e  a n d  a c c ess.  F urt h er, 
if  y o u  c o ns e nt t o r e c ei vi n g  n oti c es  a n d  dis cl os ur es  e x cl usi v el y i n  el e ctr o ni c f or  m at  as  d es cri b e d 
h er ei n, t h e n s el e ct t h e  c h e c k- b o x  n e xt t o ‘I  a gr e e t o  us e  el e ctr o ni c r e c or ds  a n d si g n at ur es’  b ef or e 
cli c ki n g ‘  C  O  N TI  N  U E’   wit hi n t h e   D o c u Si g n s yst e  m.  
B y s el e cti n g t h e  c h e c k-  b o x  n e xt t o ‘I  a gr e e t o  us e  el e ctr o ni c r e c or ds  a n d  si g n at ur es’,  y o u  c o nfir  m 
t h at: 
 
Y o u  c a n  a c c ess  a n d r e a d t his  El e ctr o ni c   R e c or d  a n d  Si g n at ur e   Dis cl os ur e;  a n d 
 
Y o u  c a n  pri nt  o n  p a p er t his  El e ctr o ni c   R e c or d  a n d  Si g n at ur e   Dis cl os ur e,  or s a v e  or s e n d 
t his  El e ctr o ni c   R e c or d  a n d   Dis cl os ur e t o  a l o c ati o n   w h er e  y o u  c a n  pri nt it, f or f ut ur e 
r ef er e n c e  a n d  a c c ess;  a n d 
 
U ntil  or  u nl ess  y o u  n otif y  S a g e  T h er a p e uti cs -  P art  1 1  as  d es cri b e d  a b o v e,  y o u  c o ns e nt t o 
r e c ei v e  e x cl usi v el y t hr o u g h  el e ctr o ni c   m e a ns all  n oti c es,  dis cl os ur es,  a ut h ori z ati o ns, 
a c k n o  wl e d g e  m e nts,  a n d  ot h er  d o c u  m e nts t h at   ar e r e q uir e d t o  b e  pr o vi d e d  or   m a d e 
a v ail a bl e t o  y o u  b y  S a g e  T h er a p e uti cs -  P art  1 1  d uri n g t h e  c o urs e  of  y o ur r el ati o ns hi p 
wit h  S a g e  T h er a p e uti cs -  P art  1 1. 
P a g e  6 0  of  6 0