Conditions: Relapsing-Remitting Multiple Sclerosis (RRMS)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 193
Healthy volunteers: no

Brief summary:
The primary objective of this study is to investigate whether Peg-IFN beta-1a improves the satisfaction of Relapsing-Remitting Multiple Sclerosis (RRMS) participants unsatisfied with injectable subcutaneous Interferons, as measured by the Abbreviated Treatment Satisfaction Questionnaire to Medication (TSQM-9), at 12 weeks. The secondary objectives of this study are to evaluate in this study population: effects of Peg-IFN beta-1a treatment on participants' satisfaction at 24 weeks; effects of Peg-IFN beta-1a treatment on short-term participants' adherence; effects of Peg-IFN beta-1a treatment on participants' fatigue; effects of Peg-IFN beta-1a on disease activity and physical disability; impact of Peg-IFN beta-1a treatment on participant-reported health-related quality of life; impact of Peg-IFN beta-1a treatment on participants' injection-system satisfaction; Evaluate the relationship between participants' satisfaction and adherence; Evaluate the relationship between participants' satisfaction and social-demographic factors (age, sex, employment working, level of education, etc) and clinical characteristics (annualized relapse rate \[ARR\], disability, etc.) and to evaluate the treatment safety and tolerability.

Detailed description:

Arms:
arm 1: 125 μg administered subcutaneously (SC) every 2 weeks

Interventions: intervention 1: peginterferon beta-1a
Intervention descriptions: intervention 1: 125 mcg administered subcutaneously (SC) every 2 weeks.

Protocol document:
Prot_001.pdf: 




  
    
  
 
  
 
 
  
  
  
 
 
 
 
   
 
 
 
  
  
 
 
  
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
   
 
  
 
   
 
  
  
  
  
  
  
  
  
 
 
  
 
    
   
   
 
 
   
   
 
 
 
   
 
  
 
   
 
 
 
 
   
 
 
 
  
   
 
  
 
  
          
 
 
 
 
   
  
      
   
 
 
 
  
 
  
   
  
   
 
  
  
 
 
 
     
        
   
   
 
 
  
  
   
   
  
 
 
  
      
 
  
  
  
  
  
   
 
 
 
  
 
  
   
  
   
 
 
 
  
   
  
 
   
 
 
 
  
 
 
   
   
 
  
 
  
  
   
 
 
   
 
 
 
 
   
  
   
 
 
 
 
  
   
 
 
 
 
 
   
 
  
  
  
  
  
    
  
    
  
  
  
  
 
 
  
 
 


  
     
  
 
  
  
  
 
 
 
 
  
    
 
 
 
 
 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
   
 
 
  
   
 
 
      
  
 
   
  
   
  
 
 
 
  
  
 
    
  
  
  
  
  
   
 
  
  
  
 
  
  
  
 
  
 
 
 
  
 
   
   
 
   
  
  
  
  
  
  
 
 
 
  
  
 
 
  
  
  
  
 
 
  
  
 
 
   
 
 
  
  
 
 
   
  
 
 
     
   
  
 
 
   
 
 
  
 
 
  
 
  
 
  
 
  
 
 
  
 
  
  
  
  
  
 
  
   
       
    
  
  
  
 
    
   
  
   
 
  
 
  
   
  
  
 
   
 
   
   
 
 
  
  
 
   
   
     
  
 
  
   
    
  
  
 
 
  
  
 
   
 
 
    
   
 
 
   
 
  
  
  
  
  
    
  
 
 
  
  
  
  
 
 
  
 
 


  
     
  
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
  
 
 
 
 
  
 
 
 
  
 
 
  
    
  
  
  
 
 
 
 
  
  
 
   
 
 
  
   
  
  
  
 
  
 
  
  
 
 
 
  
  
  
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
  
  
  
 
 
  
  
  
 
 
 
  
  
  
 
 
 
  
  
  
 
    
 
 
  
 
  
  
 
  
  
 
 
 
 
 
  
  
  
 
 
 
  
  
 
 
  
 
  
 
  
  
  
 
   
  
 
 
 
  
   
            
  
 
 
  
  
   
  
  
 
 
 
   
 
 
 
 
 
  
  
  
 
 
  
 
      
  
  
 
  
  
 
   
     
   
  
  
 
   
   
  
   
 
  
  
  
  
  
    
  
 
 
  
  
  
  
 
 
  
 
 


  
     
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
 
 
 
   
 
 
  
  
 
 
  
 
 
 
  
 
 
  
  
  
  
 
  
  
 
  
 
 
  
 
  
  
 
  
 
  
 
  
  
 
 
  
  
 
 
    
  
 
 
  
  
  
  
 
  
   
  
  
  
     
  
  
  
  
  
  
  
 
     
  
  
 
 
  
    
 
  
 
 
  
 
  
  
  
 
  
  
  
  
  
 
  
  
  
 
 
  
 
  
  
  
  
  
 
 
 
  
  
  
 
  
 
 
  
  
  
 
 
  
  
    
  
  
  
  
 
 
  
 
 




  
      
  
 
  
  
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
  
 
 
  
  
 
 
 
 
 
  
  
 
 
  
  
 
 
  
 
 
 
  
  
 
 
  
  
 
 
  
  
  
 
 
 
 
 
  
   
 
  
  
 
 
  
  
 
 
 
 
  
  
 
 
  
   
 
 
 
 
  
  
  
 
 
  
   
 
  
  
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
  
  
 
 
 
  
 
  
 
 
 
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
  
  
 
 
  
 
    
 
 
  
  
 
 
  
  
  
  
  
    
  
 
 
  
  
  
  
 
 
  
 
 


  
      
  
 
 
 
      
  
 
      
  
  
  
  
  
  
 
 
  
 
  
 
  
 
  
 
 
 
  
 
  
 
 
 
 
  
  
  
 
 
 
  
  
  
  
  
 
 
 
  
  
  
 
 
 
  
  
    
  
 
 
  
 
  
  
  
 
  
 
 
 
 
  
 
 
  
  
  
 
  
  
 
 
 
  
  
  
  
  
  
 
  
  
  
  
  
 
 
  
 
  
  
  
 
 
 
 
  
  
 
    
  
 
 
  
  
 
  
  
  
  
  
  
  
 
  
  
 
  
  
    
  
 
 
  
  
 
  
  
 
 
 
 
 
 
  
  
    
 
 
  
 
  
 
  
  
    
  
   
  
  
  
  
  
 
 
  
 
  
  
  
  
  
 
  
 
 
  
  
  
 
  
  
  
  
  
 
 
  
  
  
 
 
  
  
 
 
  
  
 
  
  
  
   
  
  
 
 
 
 
  
  
    
  
  
 
  
  
  
 
 
 
 
  
  
  
 
  
 
  
  
  
  
  
  
    
  
 
 
  
  
  
  
  
    
  
 
 
  
  
  
  
 
 
  
 
 


  
      
  
 
  
  
 
 
  
  
  
 
 
  
 
 
  
  
  
  
 
  
 
 
 
  
  
 
 
  
  
  
  
 
  
    
  
  
    
 
  
  
  
  
 
 
 
 
  
  
 
  
 
 
    
  
  
 
  
  
  
 
 
  
  
 
 
  
  
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
  
  
  
  
 
      
 
  
 
 
  
  
 
 
  
  
 
  
 
 
 
 
   
 
  
 
 
 
  
 
 
  
    
    
 
 
  
 
 
  
    
    
 
  
 
  
 
 
  
    
  
   
 
  
 
 
  
  
 
  
 
 
 
  
  
 
  
 
  
  
  
 
 
  
 
 
  
  
  
 
  
  
  
 
 
 
  
  
  
  
  
 
 
 
  
  
   
 
 
 
  
  
  
  
  
    
  
 
 
  
  
  
  
 
 
  
 
 


  
    
  
 
  
 
  
  
  
 
 
  
  
  
 
 
  
 
 
  
 
 
      
 
  
  
  
  
  
    
   
 
  
  
 
 
 
 
  
 
 
  
  
  
  
  
 
 
  
  
 
    
 
 
  
 
  
  
  
 
 
  
 
 
  
 
  
 
  
    
 
 
  
 
  
  
  
    
  
 
 
  
 
  
 
 
 
  
   
 
 
  
 
  
  
  
  
  
  
  
 
 
  
  
  
    
 
 
 
  
  
  
 
 
  
  
  
 
  
  
  
  
    
    
 
  
 
 
  
  
 
 
      
  
  
 
 
  
  
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
  
 
 
 
  
    
  
  
 
  
 
  
 
  
  
  
    
 
 
 
 
 
  
    
 
 
 
 
  
  
  
    
  
 
 
 
   
  
  
  
  
  
  
 
  
  
  
  
  
  
   
 
  
  
    
    
  
 
  
  
  
  
  
  
 
 
 
  
  
  
  
 
 
  
  
  
 
  
  
  
  
  
 
 
  
 
 
  
  
  
  
  
    
  
    
  
  
  
  
 
 
  
 
 


  
      
  
 
  
  
  
 
 
  
  
  
  
  
  
  
 
 
  
  
  
  
  
 
  
 
  
  
  
 
 
  
 
  
 
 
 
  
  
  
  
  
  
 
 
  
 
 
  
 
  
  
   
  
 
 
  
  
  
  
   
  
  
  
  
  
    
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
   
    
  
 
 
  
  
  
  
  
 
 
    
  
  
  
  
 
  
 
 
  
  
 
 
  
  
  
 
 
 
 
  
 
  
 
  
  
 
 
  
  
 
 
  
  
  
 
  
  
  
 
  
  
 
 
  
  
  
  
  
  
 
 
  
 
  
  
  
  
  
  
  
  
 
  
  
    
  
  
  
  
 
 
 
  
  
  
  
  
 
 
  
  
  
  
  
    
  
 
 
  
  
  
  
 
 
  
 
 


  
    
  
 
  
  
  
 
  
 
  
 
 
 
  
 
  
 
  
 
  
  
  
 
 
 
      
  
 
 
  
  
  
  
  
  
 
 
      
 
 
 
 
   
  
    
  
  
  
  
   
  
  
  
  
  
 
  
 
 
 
    
   
 
 
  
 
  
  
  
  
  
  
  
 
  
  
 
  
 
  
  
    
    
  
  
  
  
 
  
  
  
 
  
  
  
  
  
 
 
    
 
 
    
  
    
    
  
  
 
 
 
  
  
  
    
  
  
  
 
  
  
 
  
    
  
 
  
  
 
 
  
   
   
  
 
  
 
  
 
  
  
    
    
  
    
 
  
  
    
  
  
 
 
  
 
  
    
      
   
 
    
  
 
  
 
  
  
  
    
    
  
 
  
  
  
  
    
  
 
   
  
 
 
 
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
 
 
 
  
  
  
    
  
 
  
  
  
  
  
  
  
  
  
 
  
 
 
  
  
  
  
  
  
  
 
 
 
  
    
  
    
  
 
 
 
 
 
  
  
  
  
  
    
  
    
  
  
  
  
 
 
  
 
 


  
 
  
 
  
 
  
  
  
 
 
 
 
 
  
  
  
  
 
 
 
 
 
  
  
  
  
  
  
  
 
 
  
  
  
  
 
  
 
    
 
 
  
 
 
 
 
  
  
 
  
 
 
  
  
 
 
  
 
  
 
  
  
 
 
  
 
 
  
 
  
  
  
  
  
  
 
  
 
 
 
 
 
    
  
  
  
 
  
  
  
  
  
 
  
  
 
  
  
 
    
  
  
 
 
  
 
 
 
  
  
 
 
 
  
  
  
 
   
  
  
 
  
  
  
 
  
 
 
  
   
  
  
  
  
  
  
 
 
 
 
  
    
    
    
  
  
  
  
 
  
    
 
  
 
   
 
    
  
  
 
 
 
  
  
  
  
  
 
 
 
    
  
 
 
 
  
  
 
 
 
 
  
      
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
    
  
    
  
  
  
  
 
 
  
 
 


  
      
  
 
 
 
  
 
  
 
  
 
 
  
  
 
 
 
 
  
  
  
  
 
    
  
  
  
  
 
 
  
   
    
 
 
 
  
  
 
  
  
  
 
  
  
  
 
  
  
 
 
  
 
 
 
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
    
 
  
  
  
  
  
  
  
 
 
  
    
 
  
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
  
  
 
  
    
  
  
  
  
 
  
  
  
  
  
  
  
  
 
 
 
 
   
    
 
 
 
  
  
    
  
  
 
 
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
    
  
  
  
  
 
 
  
  
 
   
  
  
    
  
  
 
  
  
  
 
  
  
  
    
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
 
 
  
 
 
  
  
  
  
 
  
 
 
  
 
 
  
 
 
    
 
 
 
  
  
  
  
   
 
 
    
    
 
   
    
  
 
  
  
 
 
  
  
  
 
 
 
   
  
  
   
  
  
 
  
 
 
    
    
  
        
  
  
 
  
  
    
    
    
 
 
 
 
 
 
  
  
  
  
 
 
  
 
 
  
  
  
  
 
 
  
 
 


  
    
  
 
 
  
  
  
 
  
  
  
  
  
    
  
 
 
  
  
  
  
 
 
  
 
 




  
 
  
 
 
 
 
 
  
  
 
  
 
  
 
  
  
  
 
  
  
  
  
  
  
  
  
 
 
  
 
  
 
  
 
 
  
  
 
  
 
  
  
  
 
 
  
 
 
  
 
 
 
  
  
 
 
 
  
 
 
 
 
  
  
  
 
 
 
  
  
 
 
 
  
  
 
  
  
 
  
  
  
  
 
 
 
 
 
 
  
  
    
 
 
    
    
  
     
 
  
  
  
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
    
  
    
  
  
  
  
 
 
  
 
 


   
 
  
 
  
 
 
 
  
  
  
 
  
      
 
  
 
  
 
 
  
  
 
 
 
 
  
 
  
  
  
  
  
 
  
  
  
   
  
    
  
  
  
 
 
 
  
  
  
 
  
  
  
  
 
 
 
  
    
  
 
    
  
  
  
  
    
  
  
  
 
  
 
  
  
 
  
  
 
  
  
  
  
  
  
 
  
 
 
  
  
  
    
    
    
  
 
 
      
      
     
    
  
 
 
  
 
 
  
    
    
  
  
  
 
  
  
 
 
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
 
 
  
  
 
 
  
  
  
  
  
 
 
  
  
  
 
 
  
  
  
  
  
  
 
  
 
 
  
  
  
  
    
 
 
    
    
    
 
 
 
  
  
 
 
  
    
  
  
  
        
   
  
   
      
  
  
 
 
 
      
  
 
 
 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
 
 
 
  
  
  
  
      
  
  
  
  
 
  
 
  
  
      
  
 
  
  
  
  
  
  
 
      
  
  
  
  
  
  
  
   
    
  
    
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
    
  
  
  
 
  
  
  
  
    
  
 
  
  
  
  
  
  
 
 
 
 
 
  
  
    
    
    
    
 
  
  
      
  
    
  
  
  
  
  
 
 
 
  
  
  
  
  
  
  
  
  
 
 
 
  
   
  
  
  
  
  
   
  
  
   
    
  
  
  
 
  
      
  
  
  
  
  
  
 
  
  
 
    
  
 
   
  
 
 
  
 
 
  
  
  
 
  
 
 
  
  
  
  
  
  
  
 
  
 
  
  
  
  
      
  
  
  
  
  
 
  
 
    
 
 


  
 
  
 
    
  
 
  
 
 
  
 
  
  
  
 
  
 
  
  
    
  
  
  
   
  
  
 
 
    
  
    
 
   
  
  
 
  
  
  
  
 
  
    
 
  
  
    
    
  
    
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
    
 
  
      
  
  
  
    
 
  
 
  
  
  
      
  
  
  
  
  
  
 
  
     
 
  
  
 
 
  
  
  
    
  
 
  
  
 
  
  
  
    
  
    
  
  
 
 
      
 
 
 
  
  
  
  
  
 
  
    
  
  
  
  
 
 
  
  
  
    
  
 
  
  
  
 
       
          
  
  
    
    
  
 
  
  
  
  
  
 
  
 
 
  
  
 
  
 
    
 
 
  
  
 
  
  
 
 
  
  
  
 
 
  
  
  
  
  
 
  
  
 
     
 
 
  
  
    
  
  
  
  
  
 
 
  
  
  
  
  
    
  
  
 
 
  
 
  
  
 
  
    
    
  
  
  
  
   
  
  
  
  
  
  
  
 
 
    
  
  
  
  
 
 
  
  
    
  
  
 
 
  
  
  
  
 
   
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


  
 
  
 
  
  
  
 
 
 
  
    
 
  
  
  
  
  
  
 
 
 
  
  
    
  
  
  
  
  
  
  
 
 
  
 
    
  
   
  
  
  
 
  
 
 
  
 
  
  
  
 
 
  
  
 
  
  
 
 
  
 
  
   
 
  
  
  
  
    
  
  
  
  
  
 
  
  
 
 
    
  
 
 
    
  
  
  
 
 
  
    
  
  
  
  
 
  
  
  
    
 
  
  
    
  
  
  
 
 
 
   
  
  
 
 
 
    
 
   
   
  
    
    
  
  
  
 
 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
 
  
  
  
  
  
  
  
 
 
  
  
  
  
  
   
  
  
    
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
    
 
 
  
    
  
  
  
 
  
  
  
    
 
 
  
    
  
    
      
 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
 
 
 
  
  
  
 
  
  
  
  
  
 
    
  
  
  
 
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


  
     
  
 
  
  
  
 
  
  
  
  
  
    
  
  
  
  
      
       
  
  
  
  
     
 
  
  
  
  
  
  
  
  
  
 
     
 
 
  
  
  
  
  
  
  
  
    
  
 
 
 
  
  
  
  
  
  
    
  
  
  
    
  
  
  
  
  
  
 
  
  
 
 
    
  
  
  
 
 
  
   
 
  
  
  
  
  
  
 
   
  
  
  
  
 
  
  
  
   
 
  
  
 
  
  
  
    
 
    
  
  
  
  
  
  
  
  
 
  
  
 
 
  
  
  
  
    
    
  
  
  
  
  
  
      
  
  
  
  
  
 
 
  
  
  
    
  
  
  
  
  
  
  
    
 
    
  
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
 
  
  
    
  
 
  
  
  
  
  
  
 
      
  
  
  
  
  
  
  
   
    
  
   
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
    
  
  
  
    
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
 
 
 
 
  
    
  
  
 
  
 
    
  
  
    
 
 
  
    
  
 
  
  
  
  
  
  
 
 
 
  
  
  
  
 
  
  
  
  
  
  
 
 
  
  
    
  
 
  
  
  
 
 
  
  
    
  
 
 
  
  
  
 
  
  
 
  
  
    
  
  
  
  
  
 
  
  
  
  
 
 
  
  
  
 
  
  
  
 
 
      
  
  
 
  
 
   
  
 
  
 
  
  
  
  
 
 
 
 
  
  
    
 
 
    
  
    
 
  
  
  
   
    
  
 
    
  
   
  
 
 
  
  
  
  
  
 
 
  
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
 
 
  
  
 
  
  
  
  
   
 
 
  
 
  
 
 
  
 
 
 
  
 
  
  
  
 
 
  
  
 
  
  
  
  
  
 
 
  
    
 
 
  
  
 
    
  
 
    
  
  
  
  
  
  
  
 
 


  
     
  
 
  
  
  
 
 
  
  
  
    
 
 
  
  
  
  
  
 
  
  
  
    
 
 
 
 
 
  
  
   
  
  
  
  
    
  
  
  
  
  
 
  
    
  
  
  
  
  
  
  
  
  
 
  
 
 
  
  
  
  
  
  
 
 
  
  
  
  
  
 
      
 
 
 
 
 
  
    
    
  
 
  
  
    
  
  
  
  
 
 
  
  
 
  
  
   
  
  
  
  
    
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 
 
  
 
 


  
 
  
 
 
 
  
 
 
 
 
 
  
 
  
  
  
 
  
  
 
 
  
 
 
  
  
  
  
  
  
 
 
 
  
  
   
  
 
  
 
 
   
 
  
  
 
    
  
   
 
 
 
  
 
  
  
 
 
  
  
    
    
  
  
 
  
 
 
 
 
    
  
      
 
  
 
 
 
 
    
  
  
 
  
 
 
  
  
    
  
 
  
 
 
  
    
  
  
  
  
 
  
 
 
  
  
   
 
  
  
 
  
 
 
 
 
    
 
  
 
  
  
  
  
  
  
  
  
 
  
  
 
  
  
 
  
 
  
 
  
  
 
  
  
 
 
  
  
  
 
 
  
  
 
  
  
  
  
  
  
 
 
 
 
  
 
  
  
    
  
 
 
  
  
  
   
 
 
 
  
 
  
  
  
    
  
 
   
 
 
      
 
  
  
  
    
  
    
  
  
   
 
    
 
  
  
  
    
  
 
 
  
  
   
 
    
 
  
  
  
  
  
  
 
 
  
  
  
 
 
   
 
    
 
  
  
  
  
  
 
 
  
 
  
 
 
 
 
   
 
    
 
 


  
 
  
 
  
  
  
 
  
  
  
    
  
  
  
 
 
  
  
   
  
 
  
  
  
 
 
  
  
  
  
  
  
  
  
   
    
  
  
 
 
    
  
 
 


  
 
  
 
 
  
 
  
  
 
  
  
  
 
       
  
 
 
  
 
  
   
  
   
 
  
  
    
  
  
    
 
 
    
  
 
 
  
    
    
  
  
  
  
 
  
  
  
  
  
    
    
  
 
 
  
 
 
  
  
    
    
  
    
  
  
  
  
 
 
 
  
  
  
  
  
 
  
  
 
 
  
    
    
  
    
 
  
  
  
  
  
  
 
 
    
 
  
  
   
  
  
  
    
  
  
  
  
  
 
 
  
  
  
  
  
 
  
  
  
 
      
  
 
  
      
  
  
 
 
 
  
    
  
  
  
  
    
    
  
  
 
  
  
  
  
  
  
  
  
  
  
 
   
 
 
  
  
  
  
  
 
 
  
  
  
  
  
 
  
  
  
    
  
  
 
  
 
 
  
    
 
 
  
 
  
  
    
  
  
 
  
  
  
 
  
 
 
  
    
  
    
   
 
  
 
  
  
  
  
      
    
  
  
  
  
  
    
  
 
  
 
 
  
  
  
  
 
  
  
  
  
   
   
  
 
 
  
  
  
  
 
 
 
  
  
  
  
  
    
    
  
 
 
 
  
  
  
  
    
  
  
  
  
    
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
   
 
 
 
 
  
  
  
 
   
  
  
  
  
  
    
  
  
  
 
 
 
    
    
  
  
    
  
  
  
    
  
    
 
 


  
 
  
 
  
 
 
 
  
  
  
 
  
 
 
  
    
  
 
 
  
  
  
  
  
  
  
 
 
  
 
  
 
 
  
  
 
 
  
 
 


  
 
  
 
 
 
 
 
  
 
  
  
  
 
  
  
    
    
  
  
  
  
  
  
  
  
   
 
 
  
    
  
  
  
  
 
 
  
  
  
  
  
  
 
  
  
 
    
  
  
  
  
    
 
  
  
  
  
  
  
 
 
  
 
 
    
  
  
    
  
 
 
  
 
  
  
  
  
  
  
  
    
  
  
 
  
  
  
  
  
  
  
  
    
 
 
  
  
 
  
  
  
   
 
  
 
 
  
 
 
 
 
 
 
  
  
  
 
   
    
  
  
  
  
 
 
  
  
 
  
    
    
  
  
  
  
 
 
 
  
  
    
 
 
    
  
  
  
  
  
  
   
 
 
  
 
  
  
  
  
  
  
 
 
 
 
  
  
  
  
   
 
 
 
   
 
 
    
  
  
 
 
    
    
  
  
 
 
 
  
 
  
  
 
    
  
 
 
 
    
  
 
 
 
 
 


  
 
  
 
 
 
 
  
  
  
 
  
 
  
  
  
  
 
  
  
  
  
    
 
  
  
  
  
   
      
 
 
  
  
 
  
  
  
  
  
  
  
    
  
 
  
  
  
 
 
  
  
 
 
  
  
  
  
 
  
 
  
  
    
    
  
   
  
  
  
    
  
 
   
  
  
  
  
  
  
  
  
 
 
 
    
  
 
  
  
    
  
  
 
 
 
 
 
 
  
      
  
  
  
  
 
 
  
  
  
  
 
 
  
   
  
  
 
   
  
  
    
  
  
 
 




  
 
  
 
 
  
 
  
  
  
 
  
  
  
  
  
  
   
  
  
  
  
  
 
  
  
  
  
  
 
 
 
 
  
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
   
    
   
 
 
 
 
 
 
 
 
  
   
    
  
  
 
 
  
  
  
  
 
  
 
 
 
  
  
  
  
  
  
  
    
  
  
  
  
  
 
 
  
  
  
  
  
 
 
  
  
  
 
  
  
 
  
    
  
  
  
  
  
    
  
  
 
 
 
  
  
    
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
  
   
  
  
 
 
  
 
  
    
  
  
  
 
    
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
 
 
 
 


  
 
  
 
 
 
 
 
  
  
  
 
  
  
  
  
  
    
  
 
  
  
  
 
 
 
 
 
  
  
  
  
 
  
  
  
 
 
 
  
  
  
    
      
   
  
  
 
  
        
  
    
  
    
  
 
  
  
    
    
 
  
  
  
  
  
  
  
 
  
  
  
    
  
  
  
 
 
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
 
 
  
 
 
  
 
  
  
  
  
  
  
  
    
  
  
  
  
  
 
    
  
  
 
  
  
 
 
  
  
 
 
 
 
 
  
      
  
  
  
  
  
   
  
 
  
  
 
 
  
 
  
 
 
   
 
 
 
  
  
 
 
  
 
 
 
  
  
 
    
  
 
  
 
 
 
   
  
  
  
  
  
  
 
  
 
 
 
   
  
  
  
  
  
  
 
  
 
 
   
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
 
  
  
  
  
  
  
  
  
  
  
    
 
  
  
 
 
  
    
    
    
  
  
  
  
    
 
 
 
  
    
    
  
    
  
  
    
  
    
    
  
  
  
 
  
 
  
    
  
 
  
    
    
    
      
  
  
  
  
  
 
  
  
  
  
    
    
  
    
  
    
  
  
    
 
  
    
    
  
  
  
  
  
  
  
    
 
 
    
  
  
    
  
 
 
        
  
  
  
 
 
      
 
  
  
  
  
    
  
    
  
  
    
    
 
 
  
  
  
    
  
  
 
 
    
 
 
  
 
 
  
  
  
    
  
    
  
  
 
 
  
 
  
  
  
  
  
  
  
  
  
 
 
 
 


  
 
  
 
  
  
  
 
  
  
  
    
 
 
  
 
 
  
  
 
 
  
  
 
 
 
 
 
 
 
  
  
  
  
  
  
 
  
  
  
 
 
  
 
    
  
 
 
  
  
  
  
  
  
 
 
 
  
  
  
    
  
 
  
  
 
 
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
 
  
 
  
  
  
  
  
  
 
 
  
  
  
 
  
 
 
  
  
  
  
 
    
  
  
 
 
 


  
 
  
 
    
  
 
 
  
  
 
  
  
 
 
 
  
  
  
 
  
 
 
  
  
  
  
  
 
 
  
  
 
  
  
  
  
 
  
  
  
  
 
  
  
  
    
  
  
  
  
 
 
 
  
 
  
  
  
 
 
  
  
  
  
 
  
  
  
 
 
  
 
 
  
 
 
  
    
  
 
  
  
 
  
  
  
  
    
    
  
  
 
  
  
  
  
  
  
 
    
  
  
 
  
  
  
   
 
  
  
  
  
  
  
  
  
   
    
  
  
  
 
  
  
  
  
  
  
    
  
 
 
  
  
  
  
  
 
 
 
  
  
  
 
  
  
  
  
 
 
 
 
  
  
 
  
    
  
  
  
  
  
  
 
 
  
  
 
  
  
  
  
 
  
  
  
    
  
  
  
  
 
  
  
  
  
 
 
  
  
    
 
 
  
  
  
  
  
  
  
  
  
  
    
    
  
 
 
 


       
    
 
 
 
 
 
  
  
  
 
 
 
  
  
 
  
 
 
 
 
  
  
  
  
  
  
  
  
 
  
    
  
  
  
    
  
  
  
  
 
 
    
 
 
 
  
  
  
 
 
  
  
  
  
 
  
 
 
  
  
    
 
 
 
  
  
 
  
  
 
  
  
 
    
 
  
 
 
 
 
  
  
  
  
 
  
  
 
  
  
 
  
 
  
 
  
  
  
  
  
 
 
   
  
 
 
  
    
    
 
  
 
 
  
  
  
   
    
  
  
 
 
    
 
 
 
  
  
  
 
  
  
 
    
  
 
  
  
  
      
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
  
  
  
 
 
 
  
  
 
  
  
  
  
  
  
  
 
 
  
  
  
 
  
 
      
  
  
  
  
  
      
  
 
  
  
      
 
  
  
  
   
  
 
 
  
 
 
  
  
  
  
  
    
 
 
 
  
  
  
  
  
    
   
  
  
 
 
 
 
 
  
  
  
  
  
  
 
 
 
 
  
  
  
  
  
  
  
  
  
      
  
 
  
 
  
  
    
  
 
 
  
  
 
 
  
  
  
  
  
  
  
  
  
    
 
 
 
 
 
 
 
  
 
  
  
  
 
  
 
  
      
  
  
 
  
    
  
  
  
 
  
  
  
  
  
    
    
  
  
 
  
 
  
  
  
  
  
  
    
  
  
  
  
  
 
 
  
    
  
  
    
  
  
  
  
  
  
  
  
 
    
  
  
  
  
    
 
 


  
   
  
 
 
  
  
  
 
  
  
  
 
  
 
  
 
 
 
  
 
  
  
  
  
 
  
 
 
   
 
 
  
 
  
  
  
  
 
 
  
 
 
  
  
  
  
  
  
 
 
  
  
  
    
  
  
 
 
  
 
  
  
 
  
  
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
    
 
 
  
  
  
 
 
   
  
    
  
 
  
  
        
 
 
 
  
    
  
  
 
 
    
  
 
  
  
  
  
 
  
 
      
  
  
  
  
   
  
 
 
  
  
  
  
  
  
  
  
  
  
 
 
  
 
  
  
  
 
      
 
  
 
  
  
  
  
 
 
  
  
  
 
  
  
  
  
    
 
 
  
  
        
   
  
  
 
 
 
 
 
  
 
   
    
 
 
 
    
 
 
  
  
 
 
 
 
  
 
 
  
    
  
  
  
      
 
 
 
 
    
  
 
  
    
  
  
  
    
    
  
  
 
 
  
  
  
 
 
 


  
 
  
 
 
 
 
  
  
 
 
  
  
  
 
  
  
 
  
  
 
 
  
  
  
    
  
  
  
 
  
 
  
 
 
 
  
 
 
  
  
  
  
  
  
  
  
 
  
 
 
  
  
  
  
 
 
  
  
  
 
  
  
  
 
 
  
 
 
  
  
 
  
    
    
    
  
  
 
 
  
 
  
 
 
  
 
 
  
 
  
  
  
  
  
  
  
    
  
    
   
  
  
  
 
 
  
  
  
    
 
 
 
 
  
  
 
 
 
  
 
  
  
 
  
  
  
  
  
 
  
 
 
  
 
  
  
  
  
  
  
    
    
  
  
 
 
  
 
  
      
  
  
  
   
    
  
 
    
  
  
  
  
 
 
 
 
   
  
 
 
  
    
  
  
  
 
  
  
  
 
  
    
 
  
    
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
 


  
 
  
 
  
  
  
 
 
 
 
  
 
 
  
  
 
 
  
  
  
  
    
    
  
    
  
 
  
  
  
  
  
  
    
  
  
 
 
  
 
 
  
  
 
  
    
 
  
  
 
 
  
  
  
  
    
  
  
  
  
  
 
 
  
 
    
  
  
  
 
 
 
 
 
 
  
 
  
 
  
    
  
  
  
  
  
  
  
  
  
  
 
  
  
    
  
  
  
  
  
  
  
  
  
  
  
 
 
 
  
 
 
  
 
 
    
  
  
  
      
    
 
  
 
 
 
  
  
  
  
  
  
  
    
  
  
  
  
 
 
  
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
   
 
 
  
    
  
  
  
 
  
 
 
  
  
 
 
    
  
  
  
  
    
  
 
  
    
 
 
 
  
 
 
 
  
  
  
  
  
  
 
 
  
 
  
  
  
  
  
  
    
  
  
    
     
  
  
  
  
  
  
 
  
  
 
   
 
 
 
 
  
    
    
 
   
  
      
 
  
 
  
  
  
    
  
  
  
  
  
    
  
 
 
 
  
 
  
  
    
  
  
    
  
 
 
  
  
  
    
 
  
 
 
 
  
  
  
  
 
  
 
  
  
  
  
    
   
    
  
    
  
   
 
 
  
  
  
    
  
  
  
  
  
  
  
    
 
  
    
  
  
  
 
 


      
 
  
 
 
 
  
  
  
 
 
  
 
  
  
  
 
  
 
  
 
 
 
  
  
  
  
  
  
  
  
  
 
 
 
  
      
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
    
  
  
  
  
  
    
 
 
  
  
 
 
  
 
 
  
  
  
  
 
 
  
 
 
 
  
  
  
  
  
  
 
 
  
 
 
  
  
  
  
 
 
  
      
  
 
 
  
  
 
 
  
 
 
  
 
 
 
   
  
 
  
 
 
 
  
  
  
  
 
 
  
  
  
  
 
 
 
  
     
  
  
  
  
  
 
 
  
 
 
  
 
 
 
    
  
 
  
  
  
 
 
 
 
 
  
  
  
  
 
 
  
  
 
 
  
  
  
  
 
 
  
      
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
   
  
  
  
  
  
 
 
  
 
 
  
 
 
 
    
 
 
 
  
  
  
  
  
  
  
 
 
  
  
  
  
  
 
 
 
 
  
  
  
  
  
  
 
 
    
  
 
  
  
  
  
  
  
  
    
  
  
  
  
 
 
 
  
 
  
  
    
  
 
  
    
    
  
 
  
  
 
  
  
    
    
  
  
 
 
 
  
  
  
  
  
    
    
    
 
    
  
  
 
 
  
    
  
    
    
  
 
  
  
 
 
  
    
    
  
 
 
  
 
 
  
  
 
  
    
    
  
  
  
  
  
  
    
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
 
 
 
 
  
      
 
 
    
  
  
  
  
 
 
  
  
  
  
  
 
 
 




  
 
  
 
 
 
   
  
 
  
  
  
 
  
 
 
  
  
    
  
  
  
  
 
 
 
  
  
 
  
    
  
  
  
  
  
  
    
  
  
 
  
 
  
  
  
  
  
  
  
  
 
 
  
 
 
 
  
  
 
 
 
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
 
 
  
  
  
 
   
  
  
 
  
  
  
  
 
 
 
  
  
    
  
  
  
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
 
  
 
   
  
  
  
 
 
 
  
  
  
  
    
 
  
 
 
  
  
 
  
 
  
  
 
    
  
  
  
  
  
  
  
  
  
     
 
   
  
  
  
  
  
 
  
 
 
 
  
  
  
    
  
  
  
  
 
 
  
  
 
 
 
 
 
  
  
 
 
    
  
  
  
 
  
  
 
 
    
 
  
  
  
  
  
  
 
 
  
  
    
  
 
 
 
 
 
 
 
 
   
  
 
 
  
 
 
 
 
 
  
  
  
 
 
 
 
  
  
  
  
   
 
  
  
  
  
  
 
    
  
   
  
  
  
  
  
  
 
 
  
  
  
  
 
  
  
    
  
  
 
 
 
 
 
 
    
  
  
  
  
  
  
  
  
  
  
  
   
  
  
  
  
 
 
  
  
  
  
  
  
  
   
  
  
 
  
  
 
  
 
 
  
  
 
 
  
  
 
  
  
  
  
  
  
  
  
  
 
 






  
     
  
 
  
  
  
 
  
    
  
  
  
  
  
  
  
    
  
    
    
  
 
  
  
  
  
    
 
 
  
  
  
  
  
 
 
  
 
  
  
  
  
  
  
  
  
  
  
 
  
    
  
  
  
  
  
  
  
  
 
 
  
  
  
 
  
 
 
  
  
  
    
  
 
  
    
  
  
  
  
  
  
 
    
  
  
 
 
  
  
    
  
  
    
    
  
 
  
  
 
 
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
 
  
  
 
 
 
 
  
 
  
  
  
  
  
  
  
 
  
  
  
  
    
  
  
  
  
  
 
 
 
 
    
    
  
  
  
  
  
 
 


  
     
  
 
  
  
  
 
 
 
  
 
  
  
 
 
 
 
 
  
  
 
  
  
  
  
  
  
    
   
 
  
  
  
 
  
  
 
 
  
      
  
  
 
 
  
 
 
 
  
  
  
  
 
  
    
   
 
  
  
 
    
  
   
 
 
  
  
      
  
  
  
  
    
  
 
 
  
 
 
  
 
 
 
  
  
  
 
  
  
  
 
  
  
  
  
 
 
  
    
    
  
      
 
  
  
  
  
 
 
 
 
    
  
  
 
  
  
  
  
 
 
 
 
    
  
 
  
  
  
  
 
 
  
    
  
  
  
  
 
  
  
  
  
 
 
  
  
   
 
  
 
 
 
  
  
  
  
 
 
 
 
  
  
 
 
 
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
 
  
 
  
 
  
  
 
 
  
  
  
 
 
  
  
 
  
  
  
  
  
  
  
 
  
    
  
  
  
  
  
  
  
  
  
    
 
  
  
  
    
  
 
   
  
      
 
  
  
  
    
  
    
  
  
   
 
 
 
 
  
  
  
    
  
 
 
  
  
   
 
    
 
  
  
  
    
  
 
 
  
  
  
 
 
   
 
    
 
 


  
    
  
 
  
  
  
 
  
  
  
    
  
 
 
  
 
  
 
 
 
 
   
 
    
 
  
  
  
    
  
  
  
 
  
  
   
  
 
  
  
  
 
 
  
  
  
  
  
  
  
  
   
    
  
  
 
 
    
  
 
 
  
  
  
 
 
  
  
  
  
   
    
  
  
  
  
 
  
 
  
  
  
  
  
  
 
  
  
 
  
   
    
  
  
 
 
  
 
 
  
 
  
  
  
  
  
  
 
   
  
  
  
    
  
 
 
 
  
  
 
 
  
 
 
 
  
  
  
  
  
  
  
  
    
   
  
  
 
  
  
    
    
  
  
      
  
  
  
 
 
 
  
  
  
    
  
  
 
 
  
 
    
   
 
 
    
  
  
 
  
 
    
    
    
    
    
  
  
  
  
  
  
  
 
    
  
  
 
  
  
  
  
  
    
 
  
 
  
 
 
   
  
  
      
  
  
  
  
 
  
  
  
  
  
  
    
  
  
 
 
  
  
 
  
 
    
  
    
  
  
  
  
  
  
 
    
    
  
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
   
      
  
 
 
  
  
   
  
  
  
  
    
 
 
  
  
  
   
  
      
  
    
 
  
  
  
  
  
 
 
  
  
  
  
 
  
    
  
  
  
  
  
    
    
      
   
  
  
  
 
 
  
  
 
  
  
  
 
 
 
  
    
  
  
    
  
   
   
  
 
 
  
  
  
  
  
  
  
  
 
  
  
  
 
 


  
 
  
 
 
  
  
 
  
  
  
 
  
  
  
  
  
  
  
    
  
  
 
  
 
  
    
 
   
  
  
  
 
  
  
  
  
  
  
  
 
  
  
  
 
  
  
 
 
  
  
  
 
  
  
  
 
  
  
  
  
  
 
  
    
 
  
  
 
 
  
 
  
    
  
  
  
  
  
 
 
  
  
  
  
   
  
  
 
 
  
 
 
 
 
 
  
 
  
  
    
  
  
  
  
  
  
  
  
  
 
  
 
   
  
    
  
  
  
  
 
   
  
  
   
 
  
  
 
  
  
  
  
  
  
  
    
  
    
  
 
 
  
    
    
  
  
  
  
 
 
  
 
  
 
  
    
 
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
 
  
    
  
  
  
  
  
  
    
 
 
 
  
 
  
    
 
   
    
  
  
  
  
  
   
 
 
    
    
 
   
    
  
 
  
  
 
 
  
  
 
 
  
 
   
  
  
  
  
  
  
  
  
  
 
  
  
    
  
      
  
  
  
  
  
    
    
 
  
 
 
  
 
 


  
     
 
 
 
 
 
  
  
  
 
  
  
  
 
  
  
  
  
 
  
  
  
   
  
  
  
 
  
  
 
  
  
  
  
 
  
  
  
  
  
  
  
    
  
 
 
 
 
 
 
  
  
  
  
  
    
  
  
  
  
  
  
 
 
  
  
  
 
  
  
 
  
  
  
  
  
  
 
 
  
  
  
  
  
  
 
  
    
  
  
 
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
    
    
  
  
     
 
 
  
  
  
    
    
 
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
 
  
  
  
 
    
 
 
 
  
 
    
  
    
 
 
  
 
  
    
  
  
 
  
 
  
  
  
    
 
  
  
  
  
  
 
  
  
  
  
  
  
  
    
  
 
 
  
  
 
  
    
  
  
 
  
  
  
 
  
  
  
    
    
  
  
    
  
  
  
  
  
 
 
  
  
    
 
 
  
  
 
  
  
  
    
  
   
  
  
  
  
  
 
 
 
  
  
 
    
  
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
    
  
  
  
   
  
  
 
 
 
    
  
  
  
  
 
  
  
  
  
    
  
  
  
 
      
 
  
    
  
 
  
 
 
  
  
  
  
  
  
  
  
 
 
  
  
  
 
 
    
  
  
  
  
    
    
  
  
  
  
   
  
  
    
  
    
    
  
 
  
 
 
  
  
  
  
  
  
  
  
    
    
  
 
 
  
  
  
  
  
  
 
    
  
  
  
  
    
 
  
  
  
  
  
  
  
 
 
 


  
 
  
 
  
  
  
 
  
  
  
  
   
  
  
  
 
  
  
 
    
  
  
  
  
 
  
 
    
  
  
 
 
  
  
  
  
    
  
  
  
  
 
 
  
  
 
    
  
  
  
  
  
  
  
  
 
  
  
 
  
   
  
 
 
  
 
   
  
  
    
  
  
    
  
      
  
  
  
  
  
  
 
  
  
  
  
  
  
  
    
  
  
  
  
 
  
  
  
  
  
  
  
  
 
 
  
  
  
  
   
    
  
  
  
  
  
 
 
 
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
  
 
 
 
 
  
  
  
  
   
 
 
    
  
  
    
 
  
  
  
  
  
  
  
    
    
    
  
 
 
 
 
  
  
 
 
  
 
  
  
  
  
  
  
  
  
  
  
 
 
  
    
 
  
    
  
  
  
  
  
  
 
 


  
 
  
 
 
 
 
  
  
  
 
  
  
  
 
 
  
  
  
  
  
  
    
 
   
  
  
  
 
 
  
 
 
  
  
  
  
  
    
  
 
 
  
  
 
  
 
  
  
 
  
  
  
 
 
  
  
  
  
  
 
 
  
    
 
  
  
  
    
  
  
  
 
  
 
 
   
  
  
  
  
    
  
  
 
  
  
  
   
 
 
 
 
  
 
  
 
  
  
 
  
 
 
  
  
   
  
  
    
  
  
  
 
  
  
  
  
  
 
    
  
  
  
  
 
 
  
 
  
  
  
  
  
   
 
  
  
  
  
  
 
  
    
  
  
    
  
  
 
    
  
    
 
  
    
    
  
  
  
  
  
 
  
  
 
   
  
  
  
      
  
  
  
  
 
 
  
 
  
  
  
  
  
  
    
  
  
  
  
  
   
  
  
  
 
 
  
  
 
  
  
  
 
  
  
  
 
 
 
  
  
    
 
  
  
 
  
  
    
  
 
 
  
  
    
  
  
  
  
  
  
 
    
  
  
  
  
  
 
  
  
  
  
 
 
 
  
  
    
  
  
  
  
  
  
 
 




  
 
  
 
 
 
 
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
    
  
   
 
  
  
  
 
    
  
    
  
    
  
 
 
 
  
 
  
  
  
   
    
  
  
  
 
  
  
   
    
  
  
  
  
  
 
  
  
 
  
 
 
  
    
  
 
  
  
  
  
    
     
  
    
 
 
  
  
  
  
  
 
 
  
  
 
  
  
  
  
 
 
 
  
 
 
   
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
    
  
  
  
 
  
    
 
    
 
 
 
  
  
  
      
  
  
     
    
  
 
 


       
      
 
 
 
 
  
  
  
 
 
  
    
  
  
        
  
  
  
  
  
 
  
  
 
 
 
  
  
  
  
  
  
  
 
  
 
  
 
  
  
  
  
  
  
  
  
 
 
  
  
 
 
 
  
  
  
  
  
  
  
  
    
 
 
 
    
  
  
 
 
  
    
    
        
  
  
  
  
    
 
  
    
   
  
    
  
 
 
  
  
    
  
  
     
 
  
 
 
  
  
  
  
    
  
  
  
  
  
   
  
  
    
  
  
 
 
  
    
    
        
  
  
 
   
  
   
 
    
  
  
  
 
 
  
    
 
 
        
  
  
  
  
 
 
    
    
 
 
  
  
  
  
  
    
  
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
 
  
   
  
  
  
  
    
  
  
  
  
  
 
 
    
  
    
  
    
  
    
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
 
 
 
  
  
 
 
 
  
  
 
   
  
   
  
  
  
  
  
 
 
  
  
  
    
  
    
  
  
  
 
    
  
 
  
  
  
 
 
 
 
  
    
  
  
   
  
  
  
  
  
  
  
  
  
 
  
  
  
    
  
  
  
  
  
  
  
  
  
  
 
  
  
 
 
 
  
  
 
 
  
  
 
   
    
  
  
 
 
  
  
  
  
  
  
  
 
 
  
    
  
    
  
    
  
    
  
  
  
 
  
  
  
 
  
  
  
  
  
    
  
  
    
 
  
      
  
  
  
  
 
 
  
  
  
  
  
 
 
 


  
 
  
 
  
  
  
 
  
  
  
  
  
   
 
 
  
  
  
  
  
  
 
  
    
    
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
 


  
     
  
 
       
  
 
 
 
  
  
  
 
 
  
  
  
  
  
 
 
  
 
 
  
  
  
 
 
  
 
 
  
  
  
  
    
  
 
 
  
  
  
  
  
 
 
 
 
  
  
    
  
  
  
    
  
  
  
  
  
 
  
  
  
  
    
    
  
  
    
  
 
 
  
 
 
 
  
  
 
  
 
 
  
  
 
 
  
  
 
 
  
  
  
  
  
    
  
    
  
  
  
  
 
 
  
 
 


  
 
  
 
 
 
    
  
  
  
  
 
  
  
  
 
    
 
  
  
 
    
 
   
  
  
 
    
  
  
  
  
 
 
  
  
  
  
 
  
 
 
 
 
    
  
  
  
 
    
  
  
  
  
 
 
  
  
  
  
  
    
  
    
  
  
  
  
 
 
  
 
 





















































SAP_000.pdf: 
Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
Pag. 1 di 18 
SAP PLATINUM final version 1.0 - 03 May 2018 
1
STATISTICAL ANALYSIS PLAN 
PLATINUM STUDY  
Multicenter interventional Phase IV study for the assessment of the effects on patient’s 
satisfaction of Plegridy (pre-filled pen) in subjects with relapsing-remitting multiple 
sclerosis unsatisfied with other injectable subcutaneous Interferons.   
Promotore: 
Biogen Italia Srl 
Via G. Spadolini 5 
Centro Leoni A 
20141 Milan Italy 
Study Identification Number (SIN) : 
Progetto n. BIIT0215/NCT02587065 
PLATINUM STUDY 
Data Management: 
 
 
 
Version: 
Final 1.0 
Date: 
03/05/2018 






Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 3 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
3
 
 
SUMMARY 
 
SIGNATURE ....................................................................................................................................... 2 
SUMMARY ........................................................................................................................................ 3 
LIST OF ABBRAVIATIONS .................................................................................................................... 4 
1. 
Objective of  Sap ...................................................................................................................... 5 
2. 
Sudy design ............................................................................................................................. 5 
3. 
Study objectives ....................................................................................................................... 6 
4. 
Inclusion/exclusion criteria ....................................................................................................... 6 
5. 
Study population ...................................................................................................................... 7 
6. 
Sample size .............................................................................................................................. 7 
7. 
Software .................................................................................................................................. 7 
8. 
Variables for analysis ............................................................................................................... 8 
9. 
Missing data .......................................................................................................................... 12 
10. 
Statistical analysis .................................................................................................................. 12 
11. 
Efficacy data .......................................................................................................................... 12 
a. 
Primary Endpoint Analysis ...................................................................................................... 12 
b. 
Secondary Endpoints Analysis ................................................................................................. 13 
12. 
Safety Data ............................................................................................................................ 13 
a. 
Adverse events ....................................................................................................................... 13 
b. 
Clinical Laboratory Tests ......................................................................................................... 13 
13. 
Tables ................................................................................................................................... 15 
 
 
 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 4 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
4
 
LIST OF ABBRAVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis Of Variance 
APTS 
All Patients Treated Set 
ARR 
Annualized Relapse Rate 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DMT 
Disease Modifying Treatments 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Scale 
ET 
Early Termination 
FPI 
First Patient In 
FSS 
Fatigue Severity Scale 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl-Transferase 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IFN 
Interferon 
IWRS 
Interactive Web Response System 
LPI 
Last Patient In 
LPLV 
Last Patient Last Visit 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MSTCQ 
Adapted Sclerosis Treatment Concerns Questionnaire 
MusiQol 
Multiple Sclerosis International Quality of Life questionnaire 
PHI 
Protected Health Information 
RBC 
Red Blood Cell 
RRMS 
Relapsing-Remitting Multiple Sclerosis 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard deviation 
SMPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TSQM 
Treatment Satisfaction Questionnaire to Medication 
WBC 
White Blood Cell  
 
 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 5 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
5
1.  Objective of Sap 
This document outlines the statistical methods to be implemented in the analysis of the clinical data 
of PLATINUM study. The purpose of this plan is to provide general guidelines from which the analysis 
will proceed, containing a details of the outcomes of the analysis described in the protocol.  
Results from this planned analysis will be used for publication. 
 
2. Sudy design 
This is a 6 month, phase IV, open-label, single-arm, interventional, multicentric study, based on self-
administered questionnaires and aimed at evaluating patient-reported effects on user’s satisfaction 
of Peg-IFN beta-1a therapy on patients unsatisfied with other injectable, subcutaneous Interferons. 
The relevant evaluations will be performed at baseline, week 12 and week 24. 
Informed consent will be obtained at baseline prior to study enrolment and before collection of all 
relevant clinical information (i.e., relapses, EDSS).  
Clinical evaluation and questionnaire administration will be performed at baseline (within 2 weeks 
before Peg-IFN beta-1a therapy onset) and after 12 and 24 weeks. 
Subjects may elect to discontinue from study treatment at any time, due to medical reasons 
(contraindications, medical conditions that necessitate drug discontinuation according to the 
Investigator) or at personal and/or Investigator’s discretion. In all cases, reasons for discontinuation 
from investigational treatment or withdrawal from the study will be recorded in the subject’s CRF. 
All relevant and required information about any adverse event (serious and non-serious), including 
laboratory abnormalities and about pregnancy and cases of overdose occurring during the study will 
be collected and registered in the subject’s CRF.  
In case of SAE, pregnancy, or cases of overdose, the Investigator will have to notify Biogen Italia Srl’s 
Drug Safety Unit immediately and no later than 24 hours from its occurrence, by fax or e-mail. Any 
event follow-up will have to be notified to Biogen Italia’s Drug Safety Unit within 24 hours from its 
recording. 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 6 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
6
 
3. Study objectives 
 Primary objective 
The primary objective of this study is to investigate whether Peg-IFN beta-1a improves the 
satisfaction of RRMS patients unsatisfied with injectable subcutaneous Interferons, as measured by 
the Abbreviated Treatment Satisfaction Questionnaire to Medication (TSQM-9), at 12 weeks. 
 Secondary objective 
The secondary objectives of this study are to evaluate in this study population: 
• 
effects of Peg-IFN beta-1a treatment on patients’ satisfaction at 24 weeks; 
• 
effects of Peg-IFN beta-1a treatment on short-term patients’ adherence; 
• 
effects of Peg-IFN beta-1a  treatment on patients’ fatigue; 
• 
effects of Peg-IFN beta-1a on disease activity and physical disability; 
• 
impact of Peg-IFN beta-1a  treatment on patient-reported health-related quality of life; 
• 
impact of Peg-IFN beta-1a  treatment on patients’ injection-system satisfaction; 
• 
evaluate the relationship between patients’ satisfaction and adherence; 
• 
evaluate the relationship between patients’ satisfaction and social-demographic factors  (age, 
sex, employment working, level of education, etc) and clinical characteristics  
(ARR, disability, 
etc.) 
• 
 evaluate the treatment safety and tolerability. 
 
4. Inclusion/exclusion criteria 
Inclusion Criteria 
 Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI) in accordance 
with national and local subject privacy regulations.   
 Aged between 18 and 65 years old inclusive, at the time of informed consent. 
 Subjects diagnosed with Relapsing Remitting MS according to 2010 McDonald criteria. 
 Subjects with EDSS score between 0.0 and 5.0 at baseline. 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 7 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
7
 Treatment with injectable subcutaneous Interferons with score < 58 in the “convenience 
satisfaction” domain of TSQM-9. 
 Period of stability from last relapse of at least 30 days before the baseline visit. 
 Treatment with intravenous corticosteroids completed at least 30 days before the baseline visit 
(assumption of oral cortisone allowed as long as within 4 mg per day for no longer than 3 
days). 
Exclusion Criteria 
 Pregnancy or breast-feeding. 
 Depression or other psychiatric disorders. 
 Unwillingness or inability to comply with the requirements of the protocol. 
 Have any contra-indications to treatment with Peg-IFN-beta 1a according to the Summary of 
Product Characteristics 
 
5. Study population 
Full Analysis Set (FAS) consisting of all enrolled patients who took at least one dose of the study 
medication. 
 
6. Sample size 
Data for estimating the sample size were derived from studies reporting the distribution (mean value 
and standard deviation) of the TSQM-9 in MS patients treated with IFN (9). Assuming an average 
value of the overall convenience domain at baseline of 55 (SD=16) (9), with 250 subjects we have a 
power of 90% to detect a change of 3 points on the overall convenience domain (from 55 to 58) 
under the conservative hypothesis of a SD=16 (9) for the difference between baseline and week 12. 
However, by assuming a drop-out rate up to 10% during the study, we consider it appropriate to 
enrol a total of 275 patients. 
 
7. Software  
The analysis will be performed using the  software Stata version 14.0. 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 8 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
8
 
8. Variables for analysis 
This section contains definitions and conventions that will be used for the analysis. 
 
Demographic and baseline characteristics 
 
Demographic (age, gender, education and employment) and medical information (disease duration, 
previous treatments, comorbidities and concomitant therapies, EDSS score and number of relapses in 
the previous 12 months) will be obtained at baseline.  
 
Efficacy 
 
Being this a health outcomes research study, the term efficacy refers to the assessment of the following 
patients’ reported parameters, corresponding to the primary and secondary objectives of the study, and 
to the measurement of the related endpoints:  
 overall treatment satisfaction;  
 injection system satisfaction; 
 adherence to treatment; 
 health-related quality of life;  
 fatigue.  
All the endpoint-related questionnaires, described below, will be administered at baseline and after 12 
and 24 weeks of treatment.  
 
Primary variables 
 
a) Patients’ Satisfaction assessment 
- 
Abbreviated Treatment Satisfaction Questionnaire to Medication (TSQM-9) 
 
The TSQM Version 1.4 is a 14-item psychometrically robust and validated instrument consisting of four 
scales. The four scales of the TSQM include the effectiveness scale (questions 1 to 3), the side effects 
scale (questions 4 to 8), the convenience scale (questions 9 to 11) and the global satisfaction scale 
(questions 12 to 14). In the TSQM-9, the five items related to side effects of medication were not 
included, which creates a need to psychometrically assess the performance of the abbreviated 
instrument.  
 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 9 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
9
TSQM Scale scores computed by adding the items loading on each factor.  The lowest possible score is 
subtracted from this composite score and divided by the greatest possible score minus the lowest 
possible score. This provided a transformed score between 0 and 1 that should be multiplied by 100.  
(see below) [Note that only one item may be missing from each scale before the subscale should be 
considered invalid for that respondent] 
 
EFFECTIVENESS 
([(Item 1 + Item 2 + Item 3) – 3] divided by 18) * 100 
If one item is missing 
([(Sum(Item 1? + Item 2? + Item 3?)) – 2] divided by 12) * 100 
 
CONVENIENCE 
([Sum(Item 9 to Item 11) – 3] divided by 18) * 100 
If one item is missing 
([(Sum(Item9? to Item11?)) – 2] divided by 12) * 100 
 
GLOBAL SATISFACTION 
([Sum(Item 12 to Item 14) – 3] divided by 14) * 100 
If either Item 12 or 13 is missing 
([(Sum(Item12? to Item14?)) – 2] divided by 10) * 100 
If Item 14 is missing 
([(Sum(Item12 and Item13)) – 2] divided by 8) * 100 
 
The TSQM-9 domain scores range from 0 to 100 with higher scores representing higher satisfaction on 
that domain. 
 
 
Secondary variables 
 
b) Patients’ adherence assessment 
 
A questionnaire assessing adherence and the reasons for not taking drug at the recommended 
frequency of administration. 
 
c) Patients’ Injection-System Satisfaction 
- 
Adapted Sclerosis Treatment Concerns Questionnaire (MSTCQ) 
 
The MSTCQ is a validated patient questionnaire developed to address patient concerns with IFN-beta 
treatment that are not related to efficacy. It has two domains: injection-system satisfaction and side 
effects. The side-effects domain comprises 3 subscales: ISRs, global side effects, and FLS. All questions in 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 10 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
10
the MSTCQ have a 5-point response choice, with lower total scores indicating better outcomes. A 
version adapted for Plegridy will be used. 
In scoring of MSTCQ you have a referance to the Scoring manual For Version 3 May 2014. 
 
 
d) Health Related Quality of Life  
- 
Multiple Sclerosis International Quality of Life questionnaire (MusiQoL) 
 
MusiQoL version 5.2 (Multiple Sclerosis International Quality of Life) is a multi-dimensional self-
administered questionnaire consisting of 31 items describing nine dimensions of health-related quality 
of life. The nine dimensions assess many aspect of QoL that are specific to MS patients (activities of 
daily living, psychological wellbeing, symptoms, relationship with friends, relationship with family, 
sentimental and sexual life, coping rejection, relationship with healthcare system). Items listed in the 
MusiQoL questionnaire have responses describing frequency/extent of an event on a five-point scale 
ranging from never/not at all (option 1) to always/very much (option 5). For some items the scores must 
be reversed. 
To obtain a total score for the entire MusiQoL questionnaire, all nine dimensions must be completed to 
an extent that is meaningful. 
Sometimes a patient may not complete every item on the MusiQoL questionnaire. If this happens, there 
are simple rules to follow: 
 If <50% of the items within a dimension have been answered, the remaining answers are voided 
and no scoring is possible for that dimension, or for the MusiQoL questionnaire as a whole (i.e. 
the global index score cannot be calculated). 
 If ≥50% of the items within a dimension have been answered, the mean value of these answered 
items will apply to the entire dimension. 
 Some dimensions may still provide valid scores and useful information, as long as the criteria 
above have been met. 
All of the 9 dimensions and the global index are linearly transformed and standardized on a 0-100 scale.  
Higher scores indicate a better level of health-related QoL for each dimension and for the global index 
score.  
 
e) Patients’ Fatigue 
- 
Fatigue Severity Scale (FSS) 




Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 12 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
12
9. Missing data 
For missing data in TSQM-9, MSTCQ and  MusiQol see paragraph Variable of analysis. 
For the other variables no imputation technique will be apply. 
 
10. Statistical analysis 
The primary and secondary endpoints will be evaluated using a repeated measures ANOVA. The 
repeated measures ANOVA is used to compare group means on a dependent variable across repeated 
measurements of time. This statistical method is used for making simultaneous comparisons between 
two or more means of two or more related, not independent, groups. 
However, in addition, it could be useful to apply a general linear mixed model that models for group 
means as fixed effects while simultaneously modeling for individual subject variables as random effects 
(12). This kind of model is a subject-specific model and is a choice for analysing longitudinal data. Unlike 
the repeated measures ANOVA, which requires a complete balanced array of data, the mixed model can 
accommodate a dataset with a large portion missing. Although the repeated measures ANOVA requires 
a fixed time schedule among all individual units, the mixed model can accommodate flexible time 
schedules. Furthermore, rather than treating time as a categorical variable, as in the repeated measures 
ANOVA, the mixed model is capable of treating time as either a continuous variable or a categorical 
variable or both. 
Spearman's correlation coefficient measures the strength of association between two ranked variables. 
Differences will be considered statistically significant if the p-value will be less or equal to a type I error 
=0.05 (two-sided test).  
 
11. Efficacy data 
a. Primary Endpoint Analysis 
The primary endpoint is to evaluate the changes from baseline in the score of convenience satisfaction 
domain of TSQM-9 at 12 weeks. (Stata instruction: anova var1  time, repeated(time) 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 13 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
13
 
b. Secondary Endpoints Analysis 
• Changes from baseline in the score of all domains of TSQM-9 at 24 weeks; 
• Changes from baseline in patient adherence to study treatment survey at 12 and 24 weeks; 
• Changes from baseline in the score of FSS (Fatigue Status Scale) at 12 and 24 weeks; 
• Changes from baseline in the score of Adapted Sclerosis Treatment Concerns Questionnaire (MSTCQ) 
at 12 and 24 weeks; 
• Changes from baseline in the score of Multiple Sclerosis International Quality of Life questionnaire 
(MusiQoL) at 12 and 24 weeks; 
• Changes from baseline in clinical measures (ARR, percentage of relapse-free patients), measures at 24 
weeks. 
 
All the above primary and secondary endpoints will be analysed by a repeated measures analysis of 
variance adjusted for baseline factors (age, sex, disease duration, previous treatment duration, EDSS) 
(Stata instruction: anova var1 var2 …. time, repeated(time)). 
Correlations between variables will be assessed by a Spearman rank correlation coefficient (Stata 
instruction: spearman var1 var2)). 
To evaluate the relationship between patients’ satisfaction and social-demographic factors (age, sex, 
employment working, level of education, etc.) and clinical characteristics (ARR, disability, etc.) 
generalized linear mixed models for repeated measurements will be performed (Stata instruction: mixed 
var1 var2|| patient:). 
 
12. Safety Data 
a. Adverse events 
All events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Type and 
incidence of all AEs will be tabulated. Severity and drug relatedness of all reported AEs will be tabulated.  
 
b. Clinical Laboratory Tests 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 14 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
14
For the clinical laboratory data, descriptive statistics will be generated for all tests performed. 
Laboratory abnormalities will be determined in accordance with the normal ranges of the clinical 
laboratory. Laboratory abnormalities will be tabulated. 
 
 
 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 15 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
15
 
13. Tables 
The following tables will be repeated for each visit, if applicable. 
 
P1. 
Number and percentage of patients enrolled per center 
P2. 
Number and percentage of patients stratified by gender; mean and median age, range and 
interquartile range; 
P3. 
Number and percentage of patients stratified by race; 
P4. 
Number and percentage of patients stratified by educational level; 
P5. 
Number and percentage of patients stratified by working status; 
P6. 
Mean and median age, range and interquartile range of time since diagnosis of SM; 
P7. 
Number and percentage of patients undergoing pharmacological treatment for MS by active 
substance; mean and median, interquartile range and range of the dose and distribution of 
the frequency of treatment administration; 
P8. 
Number and percentage of patients undergoing concomitant pharmacological treatment  by 
active substance; mean and median, interquartile range and range of the duration; 
P9. 
Mean and median, range and interquartile range of the total number of relapses from the 
diagnosis; 
P10. Mean and median, interquartile range and range of the total number of relapses in the last 
year; 
P11. Number and percentage of patients stratified for relevant previous and / or concomitant 
diseases; if previous, mean and median, range and interquartile range of duration; if 
ongoing, number and percentage of the diseases being treated; 
P12. Number and percentage of patients stratified by outcome (not performed / normal / 
abnormal) to physical examination in relation to: 
a) General appearence; 
b) Skin; 
c) Head, neck, thyroid;  
d) Ear, nose, throat; 
e) Muscolo-skeletal; 
f) Respiratory; 


Statistical Analysis Plan 
Protocol N. BIIT0215– Platinum 
 
 
Pag. 16 di 18 
 
SAP PLATINUM final version 1.0 - 03 May 2018 
16
g) Heart; 
h) Peripheral vascular; 
i) Gastrointestinal 
j)  Abdomen, liver; 
k) Renal and genitourinary 
l) Endocrine / Metabolic 
m) Neurologic; 
n) Mental status; 
o) Other; 
P13. Mean and median, interquartile range and range of height, weight and bmi value 
P14. Mean and median, interquartile range and range of temperature, respiration rate, heart 
rate, maximum and minimum blood pressure; 
P15. Mean and median, range and interquartile range of the number of episodes of acute 
exacerbation since the last visit; 
P16. Mean and median, interquartile range and range of EDSS score; 
P17. Mean and median, interquartile range and range of TSQM-9, all domains: effectiveness,  
convenience and global satisfaction; 
P18. Change from baseline in the score of convenience satisfaction domain of TSQM-9 at 12 
weeks; 
P19. Change from baseline in the score of all domains of the TSQM-9 at 24 weeks; 
P20. Adjusted repeated measures analysis of variance for change of convenience satisfaction 
domain of TSQM-9 at 12 and 24 weeks; 
P21. Number and percentage of patient who have correctly taken the prescribed doses of 
treatment within the last 28 days; if don’t, mean and median, interquartile range and range 
of injections have not been performed during the last 28 days; 
P22. Number and percentage of patients per reasons to non correctly taken the treatment: 
a) Anxiety for injection 
b) Skin reaction 
c) Forgot to take the dose 
d) Pain at the injection site 


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e) Depression  
f) Headhache 
g) Fatigue 
h) Flu-like symptoms 
i) “I did not want to” 
j) “I am not sure of the benefits” 
k) “I am tired of injections” 
l) No one available for injection 
m) Uncomfortable dosing 
n) “I am pregnant / I have planned a pregnancy” 
o) Other 
P23. Mean and median, interquartile range and range of injections expected from the therapy 
taken in the last 28 days; 
P24. Mean and median, interquartile range and range of MSTCQ; 
P25. Change from baseline in the score of the MSTCQ at 12 and 24 weeks; 
P26. Adjusted repeated measures analysis of variance for change of the MSTCQ at 12 and 24 
weeks; 
P27. Mean and median, interquartile range and range of MusiQol; 
P28. Change from baseline in the score of the MusiQol at 12 and 24 weeks; 
P29. Adjusted repeated measures analysis of variance for change of the MusiQol at 12 and 24 
weeks; 
P30. Mean and median, interquartile range and range of FSS; 
P31. Change from baseline in the score of the FSS at 12 and 24 weeks; 
P32. Adjusted repeated measures analysis of variance for change of the FSS at 12 and 24 weeks; 
P33. Mean and median, interquartile range and range of EDSS; 
P34. Change from baseline in the score of the EDSS at 12 and 24 weeks; 
P35. ARR, Annualized Relapse Rate 
P36. Number and percentage of abnormalities in laboratory values per each test; 
P37. List of  all laboratory abnormalities; 
P38. Number and percentage of adverse events stratified by severity;