Clinical trial NCT02603809
Conditions: Essential Hypertension
Sponsor: Idorsia Pharmaceuticals Ltd.
Start date: 2015-12-14; Completion date: 2017-04-07
Enrollment: 1659 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective will be to evaluate the dose-response of ACT-132577 (aprocitentan) on diastolic blood pressure (DBP) in participants with grade 1 or 2 essential hypertension.

Secondary objectives will be to evaluate the dose-response of ACT-132577 on: systolic blood pressure (SBP); control and response rate of blood pressure; 24-hour ambulatory blood pressure monitoring (ABPM) and to evaluate the safety and tolerability of a once daily oral regimen of 4 doses of ACT-132577.

Detailed description:
Participation in the study is planned to last up to 18 weeks. A single-blind placebo run-in period of 4 to 6 weeks after which participants will be randomized into a double-blind treatment period of 8 weeks and a washout and follow-up period ending with an end-of-study visit approximately 12 weeks after randomization.

Arms: arm 1: After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received placebo orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period. arm 2: After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period. arm 3: After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan 10 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period. arm 4: After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan 25 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period. arm 5: After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received aprocitentan 50 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period. arm 6: After a 4 to 6-week single-blind placebo run-in period, participants will be randomized to received lisinopril 20 mg orally once daily in the morning for 8 weeks during the double-blind treatment period, followed by a 2-week single-blind placebo washout period, followed by a further two-week follow-up period.
Interventions: intervention 1: Aprocitentan 5 mg intervention 2: Aprocitentan 10 mg intervention 3: Aprocitentan 25 mg intervention 4: Aprocitentan 50 mg intervention 5: Lisinopril 20 mg intervention 6: Placebo
Intervention descriptions: intervention 1: One capsule of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril. intervention 2: Two capsules of 5 mg aprocitentan, orally, once daily in the morning for 8 weeks. intervention 3: One capsule of 25 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril. intervention 4: One capsule of 50 mg aprocitentan, orally, once daily in the morning for 8 weeks, along with placebo capsule matching lisinopril. intervention 5: One capsule of 20 mg lisinopril, orally, once daily in the morning for 8 weeks, along with placebo capsule matching aprocitentan intervention 6: One capsule each of placebo matching aprocitentan and placebo matching lisinopril orally, once daily in the morning for 8 weeks.

Protocol documents:
Prot_000.pdf: 
Protocol 
AC-080A201 
Multi-center, double-blind, double-dummy, randomized, placebo- and active-reference, 
parallel group, Phase 2 dose-finding study with ACT-132577 in subjects with essential 
hypertension (grade 1 and 2) 
ClinicalTrials.gov Identifier: NCT02603809 
This study was sponsored by Actelion Pharmaceuticals - study sponsorship was transferred to ldorsia 
Pharmaceuticals Ltd. 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
  
   
  
  
 
    
  
  
 
  
    
   
 
  
 
 
  
 
  
 
  
  
 
  
   
 
  
  
 
  
 
  
  
 
   
   
 
  
 
 
 
 
 
 
  
 
  
  
    
  
  
  
  
    
  
    
  
   
  
  
 
  
      
  
    
    
     
 
  
    
  
  
    
  
  
  
    
  
    
 
    
         
   
   
   
    
   
      
      
    
    
 
  
  
 
  
  
    
  
  
    
  
  
 
  
  
    
  
  
  
  
   
 
 
 








 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
 
  
  
 
 
  
  
   
  
  
 
  
  
  
    
  
  
 
    
 
  
 
  
    
   
  
    
  
  
  
  
    
  
    
    
  
  
 
    
    
   
  
  
   
  
 
  
     
 
  
  
  
  
    
 
  
  
  
 
  
  
  
  
    
  
  
  
  
  
   
   
      
   
   
   
   
   
   
      
 
    
  
 
   
    
  
  
     
  
  
  
      
  
 
  
  
 
  
  
  
  
  
  
 
   
   
   
   
       
   
   
         
    
 
      
    
    
   
   
      
   
   
   
 
   
   
      
   
      
   
        
     
 
      
       
   
   
         
   
   
   
    
   
      
   
   
   
   
   
  
    
  
    
  
    
  
  
  
    
  
  
 
   
      
  
   
    
   
   
   
 
    
    
  
    
 
    
  
  
 
   
   
   
         
      
   
   
      
      
 
      
   
   
   
   
      
      
   
   
    
 
   
   
   
   
         
   
      
  
 
  
  
    
  
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
   
  
 
 
 
 
  
 
    
 
  
  
    
  
 
 
 
  
 
  
 
  
 
  
  
  
  
 
  
 
  
  
 
  
 
 
 
  
  
 
  
  
  
    
  
  
 
  
 
  
 
  
  
    
  
 
    
  
 
  
   
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
 
  
  
  
  
 
  
  
  
 
  
  
  
 
  
 
 
  
 
  
 
  
  
 
  
 
  
 
  
 
 
 
  
  
  
 
  
  
 
  
  
  
 
  
  
 
  
  
  
  
 
  
  
  
  
 
  
  
 
  
  
  
  
 
  
 
  
  
  
  
 
 
  
 
 
  
  
 
  
  
  
  
 
 
 
    
  
 
  
  
  
    
 
    
  
 
  
  
  
 
 
   
  
    
  
 
  
  
 
  
  
 
 
 
  
 
  
  
 
  
  
 
  
  
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
  
 
  
 
 
  
  
 
 
  
  
 
 
  
  
  
 
  
 
  
 
  
 
  
 
  
  
 
 
 
 
 
 
 
    
 
  
 
  
 
 
 
  
 
  
  
 
 
  
  
 
  
  
  
 
      
   
      
   
      
   
      
      
   
  
  
     
 
  
 
    
     
 
      
   
      
   
      
    
 
      
   
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
      
   
      
    
  
 
 
  
  
   
  
 
  
 
 
  
 
 
    
 
 
  
 
  
  
  
 
  
    
    
  
 
  
    
  
  
  
    
  
 
 
 
  
 
 
 
  
 
    
  
 
    
  
 
    
  
 
  
  
    
  
   
  
 
    
  
 
    
  
 
  
  
 
    
  
  
 
  
  
 
    
  
  
 
    
  
  
 
  
  
  
  
 
  
 
 
    
 
    
 
  
  
 
 
 
  
 
  
  
 
  
  
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
  
 
    
  
  
 
 
  
  
 
  
  
 
  
  
 
  
 
  
 
  
 
  
 
    
  
 
  
  
 
    
  
  
  
 
  
  
  
 
    
  
 
  
 
  
 
  
 
    
  
  
  
 
    
  
  
  
 
    
  
  
 
  
 
  
 
  
 
  
  
  
  
 
    
  
 
  
 
  
 
  
  
 
  
  
 
  
  
 
 
 
 
  
 
    
 
 
 
  
  
  
 
  
  
  
 
 
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
    
  
  
 
  
 
    
  
 
 
 
 
  
 
  
  
  
    
 
 
  
  
 
 
 
    
  
  
  
 
 
 
 
  
  
 
 
    
  
  
 
 
    
   
  
  
        
 
  
 
 
  
  
  
  
  
        
  
  
 
 
  
  
  
  
  
  
    
   
  
  
  
 
 
  
  
    
    
  
  
  
  
  
 
    
  
    
  
  
 
 
 
  
  
  
 
 
 
  
  
 
 
 
  
 
   
   
 
 
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
 
 
  
  
 
 
  
  
  
  
 
    
  
  
 
    
  
  
  
  
  
  
  
  
 
  
  
  
 
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
  
 
 
   
  
  
  
 
   
  
 
    
 
 
    
    
 
    
 
 
    
  
  
  
 
  
  
    
 
 
   
  
 
    
  
  
 
   
  
 
   
  
 
 
   
  
 
 
   
  
  
 
   
 
    
  
  
 
   
 
   
  
  
  
 
    
  
  
 
   
  
 
  
 
   
 
   
  
  
 
   
 
   
  
    
 
   
  
    
 
   
  
  
 
    
  
  
 
 
    
  
  
 
    
  
 
   
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
   
  
  
 
   
  
  
 
 
   
  
  
 
   
  
  
  
  
  
 
   
  
  
 
   
  
  
 
   
  
  
 
    
 
 
    
 
  
    
 
    
  
  
 
    
  
  
  
  
 
    
    
 
    
  
  
 
 
   
 
   
  
 
    
 
 
   
 
   
  
 
    
  
 
    
 
 
    
  
  
 
   
  
  
 
   
 
    
  
  
 
    
  
 
    
  
  
  
 
    
  
  
  
 
    
  
  
 
    
  
  
 
    
  
  
 
    
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
   
  
  
  
  
 
    
  
  
 
   
  
  
   
    
 
  
 
    
  
    
  
  
 
   
 
 
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
    
 
 
  
  
    
  
 
  
    
    
 
 
  
  
  
  
    
    
    
  
 
  
  
  
  
  
  
   
  
  
  
   
   
   
   
  
     
    
   
 
  
   
  
   
  
   
   
        
   
   
    
  
  
  
      
  
  
  
  
      
  
  
  
 
  
    
 
    
  
 
  
  
    
      
      
   
      
   
  
  
    
  
 
 
  
  
    
 
  
  
  
      
  
   
  
  
    
  
  
    
  
  
  
      
 
  
  
    
 
  
    
  
    
  
 
  
  
  
    
  
      
  
 
   
    
 
  
    
  
   
   
  
    
  
    
   
    
 
  
  
  
  
  
  
 
  
  
  
  
    
  
    
  
  
      
 
  
 
  
  
    
  
  
   
  
   
   
   
      
    
      
   
   
      
   
    
  
      
  
  
  
  
  
  
  
 
          
  
    
     
   
   
   
 
  
  
  
  
  
  
    
  
  
   
  
   
   
  
  
    
  
    
  
  
    
  
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
   
  
     
  
   
      
   
 
   
    
   
   
   
      
    
   
 
  
  
  
  
  
  
  
  
 
   
   
      
   
    
   
   
    
      
  
 
    
          
   
   
   
    
         
 
  
  
  
  
  
  
  
  
  
 
 
   
   
  
   
       
  
   
   
 
   
    
   
   
   
   
       
 
   
   
  
  
         
   
   
 
    
   
   
   
   
    
   
   
    
 
  
  
  
 
  
  
  
    
  
    
      
    
  
 
   
    
      
    
   
   
      
      
     
   
 
    
  
  
      
  
   
  
   
  
  
    
 
  
  
    
  
 
  
  
  
  
  
  
  
  
  
  
 
      
   
   
    
   
   
   
      
   
 
   
   
   
       
   
    
      
    
       
    
    
  
    
  
  
  
 
  
 
  
  
   
  
   
   
   
    
     
 
   
  
   
   
      
     
 
      
  
  
  
      
  
  
  
  
  
  
   
      
      
   
        
       
      
  
 
   
   
   
   
  
  
     
   
  
  
 
  
  
  
  
  
    
 
  
  
  
 
  
   
   
      
   
   
      
   
   
      
   
 
  
   
   
       
          
   
   
    
    
      
  
    
  
  
  
  
  
  
 
    
    
  
   
  
     
  
   
   
   
         
 
   
    
      
         
   
   
      
   
 
  
  
  
  
  
  
  
    
 
  
  
 
  
 
  
  
  
  
  
    
  
  
 
  
  
    
  
  
  
  
    
  
  
  
   
  
    
      
  
  
  
  
  
  
 
  
  
  
  
    
    
  
  
  
  
  
 
   
   
   
  
     
  
      
   
    


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
    
   
  
    
  
  
   
 
  
  
  
 
 
     
  
   
     
      
   
   
         
 
  
  
  
  
   
   
  
     
   
  
   
   
 
  
  
  
  
  
    
  
  
  
    
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
    
   
  
     
   
   
   
  
  
  
  
   
    
  
  
  
  
  
 
   
    
  
    
  
  
  
   
  
  
 
   
   
     
  
      
       
   
        
   
  
  
  
 
  
    
    
    
  
  
 
   
 
   
    
  
  
  
  
   
    
  
  
  
  
  
   
    
  
  
    
  
  
 
  
  
  
  
 
  
  
  
 
  
  
  
  
    
  
  
 
    
  
 
  
    
  
  
  
  
  
      
  
  
     
   
   
   
   
   
   
      
      
 
  
  
 
  
  
 
    
   
         
   
      
   
      
   
    
 
      
   
   
   
   
    
    
  
   
    
 
  
 
 
  
 
 
  
 
 
 
  
   
 
  
 
 
  
  
 
    
 
   
  
 
 
 
  
 
 
 
  
   
 
  
  
  
 
  
  
  
  


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
      
  
 
  
      
  
 
  
      
  
 
    
    
     
  
  
      
   
  
      
   
  
      
   
  
      
  
 
  
  
 
 
  
  
  
 
 
  
  
 
 
 
  
 
 
  
      
  
  
  
 
    
 
 
 
    
  
  
  
  
  
  
  
  
 
  
  
  
 
    
  
  
  
 
  
   
  
  
   
  
   
    
  
    
  
    
   
   
  
  
  
  
  
 
   
    
    
  
  
  
  
  
  
  
 
  
     
  
  
   
    
   
   
      
 
    
  
  
  
    
  
  
 
      
   
       
    
   
         
    
   
    
   
    
   
   
  
  
    
   
   
 
  
  
  
   
  
  
   
   
   
  
  
  
 
   
   
   
     
     
  
   
   
  
   
 
    
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
    
 
 
 
  
 
  
 
 
  
  
 
    
   
   
  
  
  
  
 
       
     
   
    
  
 
  
    
  
   
 
  
  
  
  
 
   
   
  
  
   
   
 
 
 
    
  
   
 
   
   
     
   
    
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
 
 
  
  
  
 
 
  
   
   
   
    
  
  
 
    
  
  
 
  
    
   
 
  
 
   
  
      
   
      
   
   
 
  
   
  
   
   
   
 
    
  
  
 
  
    
   
  
 
  
 
   
  
 
  
  
  
  
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
  
   
   
   
         
     
  
  
 
      
   
 
  
 
  
  
  
    
  
  
 
   
  
  
 
   
  
  
   
   
 
   
  
  
 
  
 
      
   
    
  
 
  
  
    
  
  
  
    
   
  
   
  
  
    
 
  
  
  
  
  
  
  
  
 
    
  
  
    
        
  
  
 
      
  
  
  
      
 
   
   
  
   
    
   
   
    
  
  
  
  
  
  
        
  
  
  
 
        
  
   
     
   
     
      
   
       
      
   
   
      
   
   
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
    
  
  
    
  
  
  
  
   
   
  
   
      
   
 
    
  
  
  
      
  
    
 
  
  
 
  
 
 
 
  
    
  
  
 
  
  
      
  
      
  
  
  
 
    
  
   
  
     
  
 
   
          
    
   
       
       
    
     
  
     
  
   
   
 
      
         
      
   
      
    
 
    
  
  
    
  
  
  
    
   
   
       
  
   
    
  
  
  
    
      
    
  
  
  
    
 
   
  
  
   
       
     
 
 
 
  
  
  
  
  
  
    
  
 
  
  
    
    
  
    
  
 
   
     
  
  
  
    
    
  
    
    
  
    
  
 
  
  
    
  
    
    
  
 
   
   
  
   
    
   
      
  
 
 
    
  
  
  
  
  
  
    
 
  
  
  
  
    
  
    
  
  
 
         
      
   
      
   
   
 
  
  
  
    
  
    
  
  
  
  
   
   
      
   
    
   
  
 
   
   
   
   
  
  
    
  
 
 
 
  
  
  
  
   
  
   
 
 
    
     
   
   
   
   
   
 
  
  
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
 
 
  
  
      
    
    
  
 
 
  
 
   
 
  
  
    
      
      
  
 
 
   
      
      
      
  
  
 
      
  
  
  
  
      
 
 
  
  
  
  
  
   
  
  
      
 
  
 
 
 
  
  
  
  
  
  
  
  
  
     
 
    
   
  
      
     
 
  
   
    
   
  
 
 
     
   
    
   
     
 
  
    
  
 
  
  
  
 
   
   
    
   
  
   
    
   
   
            
  
    
  
   
 
  
   
    
      
   
    
      
   
 
  
 
    
  
  
  
   
   
   
      
   
   
   
 
  
  
 
  
    
   
  
   
         
 
  
  
  
  
  
    
  
 
    
  
    
  
  
  
  
  
   
    
    
  
  
   
   
   
      
   
   
   
 
  
  


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
 
  
  
       
                   
       
   
        
    
  
  
    
  
  
 
  
  
  
  
  
  
  
  
  
    
    
  
  
     
   
  
  
  
  
    
  
  
    
 
  
  
  
  
  
 
 
    
   
   
   
    
 
   
    
      
  
   
 
   
   
   
   
   
   
   
   
   
 
  
      
  
  
  
  
  
 
      
   
    
   
   
   
      
 
  
 
 
 
 
  
 
   
   
   
   
   
    
 
  
  
    
  
  
  
 
  
  
  
  
  
   
 
  
  
 
  
  
  
 
   
   
   
   
   
   
    
   
 
  
  
  
  
  
    
  
  
  
 
  
  
  
  
    
  
  
  
    
  
 
  
  
  
  
  
  
  
  
 
 
 
  
 
 
  
   
   
   
   
 
   
   
   
   
  
 
 
  
  
  
  
  
  
 
 
  
 
   
  
   
   
   
   
 
   
   
    
     
   
    
   
   
 
    
  
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
   
   
   
   
  
    
 
  
  
  
  
  
 
  
   
   
   
  
 
  
 
  
   
   
   
   
 
   
 
  
  
  
  
  
 
 
  
 
 
   
   
   
      
   
   
   
    
        
   
  
  
       
   
 
  
  
    
      
   
   
 
  
 
  
  
 
   
   
   
   
       
 
  
  
 
  
   
  
      
        
   
  
 
      
  
  
  
  
  
 
  
   
   
   
       
        
   
 
  
     
      
   
  
       
  
 
  
   
   
   
       
        
   
 
  
     
      
   
   
      
  
 
  
  
  
       
        
   
  
 
      
  
  
  
    
 
  
  
   
       
        
   
  
 
      
  
  
  
    
 
  
    
  
  
  
  
    
 
  
  
 
  
  
  
  
    
  
 
  
 
 
  
  
  
  
  
  
   
   
  
   
  
 
 
 
  
 
 
  
  
  
 
 
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
  
 
 
  
   
   
       
        
          
 
  
  
      
  
 
  
   
   
       
    
      
  
 
   
        
 
  
    
    
 
  
 
  
   
   
       
        
     
  
 
  
  
      
  
  
  
  
 
  
  
    
   
 
  
 
    
   
      
 
  
  
 
 
    
  
    
    
  
 
 
 
   
    
      
   
      
   
 
   
  
  
  
    
  
  
  
 
 
  
  
  
    
  
  
  
 
  
       
   
   
       
        
   
 
  
   
  
   
  
   
   
    
   
 
    
   
   
    
      
      
 
  
  
  
   
      
      
    
   
      
   
 
    
  
    
  
  
  
  
  
  
 
   
   
   
   
   
      
   
      
 
  
  
  
  
 
      
    
    
    
 
 
  
  
  
  
  
  
    
     
 
  
  
  
 
  
  
  
       
      
       
             
       
   
 
   
   
      
   
          
 
  
  
  
  
 
       
    
    
      
     
 
    
  
         
    
    
    
      
     
 
    
  
       


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
    
 
    
  
  
 
 
  
  
    
      
  
  
 
   
   
      
  
   
   
    
 
   
   
   
   
   
  
   
 
  
  
    
 
    
    
  
  
 
  
    
  
    
    
  
  
  
    
 
  
    
  
  
  
  
    
 
  
 
  
  
  
    
    
  
 
  
  
    
      
  
  
  
 
      
   
   
    
   
      
    
      
    
  
  
  
    
 
   
        
   
          
 
  
    
  
 
  
  
  
 
  
  
    
  
 
    
  
  
  
  
  
  
 
   
    
   
   
   
   
    
 
      
   
     
    
  
  
    
  
  
  
    
  
    
  
   
   
   
    
      
      
 
  
  
    
   
   
       
        
 
  
  
  
    
  
  
  
   
   
   
   
      
  
   
    
   
     
     
    
    
     
 
   
   
   
   
   
   
      
 
      
      
    
   
   
    
      
 
   
    
    
      
   
  
 
  
  
  
 
  
 
   
   
    
      
      
  
   
    
  
  
  
  
  
  
  
 
   
    
   
    
      
   
   
 
 
  
 
   
    
      
      
   
   
   
 
  
    
  
  
  
 






 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
  
 
    
  
  
      
      
  
  
  
  
  
 
   
  
    
  
    
  
 
  
  
  
  
  
  
    
  
  
    
 
    
 
  
  
  
  
  
  
  
  
  
  
  
  
  
        
  
  
  
  
  
  
  
    
 
  
  
    
    
  
  
    
   
  
  
  
  
    
    
  
  
      
  
  
    
    
    
  
  
   
  
    
 
  
  
    
      
  
    
    
  
      
  
  
  
  
  
  
  
  
   
  
    
  
 
  
  
      
  
 
  
 
  
  
  
  
      
  
  
    
  
      
  
 
  
  
   
  
  
    
  
    
    
 
  
  
  
  
  
  
    
  
  
    
    
  
 
  
  
  
  
  
   
  
    
    
  
    
    
  
 
  
  
 
  
  
  
  
  
  
  
  
  
        
  
  
  
  
  
  
  
  
  
   
 
 
  
  
    
    
  
  
  
  
  
  
  
      
    
  
 
  
    
  
    
 
   
  
  
    
  
    
  
    
  
    
  
  
    
  
  
  
  
    
  
  
      
   
  
 
  
  
  
  
  
  
    
  
  
  
    
  
    
  
  
  
 
  
    
  
  
  
    
    
  
    
    
  
  
      
    
  
  
    
  
  
   
 
    
  
  
    
  
     
  
   
  
    
  
  
  
  
   
  
   
  
    
  
  
   
  
   
  
    
  
  
  
    
 
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
 
 
 
 
  
    
  
  
  
  
  
    
    
 
 
 
  
   
   
      
    
   
     
 
   
      
  
     
     
   
      
   
     
 
  
    
    
      
  
  
  
  
  
   
  
   
   
   
    
  
    
   
 
  
  
  
  
  
  
   
  
    
 
 
   
   
   
   
      
   
 
   
    
  
   
   
  
     
  
   
 
   
       
   
     
      
  
   
  
 
      
   
  
  
  
  
      
      
 
      
   
 
  
      
      
   
      
 
  
    
  
  
      
  
    
  
 
   
   
   
   
      
  
  
  
    
    
 
    
    
   
   
   
       
     
         
 
  
   
   
     
 
 
   
      
    
 
  
  
      
  
  
  
    
  
  
 
 
  
  
  
  
  
  
  
     
      
   
   
 
  
   
   
   
   
   
   
   
 
   
   
   
   
  
   
   
   
 
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
      
  
    
  
 
  
  
  
 
  
  
 
  
  
      
 
  
    
    
 
   
  
  
 
  
    
  
  
  
  
 
  
   
    
   
    
   
   
   
        
 
    
 
  
  
  
  
 
  
         
  
   
  
   
    
  
  
   
      
 
 
   
   
     
  
   
 
 
  
  
  
  
  
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
 
         
   
   
   
  
  
    
  
    
  
 
      
   
    
       
  
  
        
    
  
  
  
    
  
 
  
 
   
   
  
   
      
   
   
   
 
 
  
 
  
 
  
 
 
  
  
  
  
  
 
 
  
  
  
  
  
 
  
  
   
    
  
      
   
   
   
 
  
  
    
  
  
  
  
    
    
 
  
   
   
    
   
      
    
     
    
    
  
   
  
 
  
 
   
  
   
   
   
    
   
   
      
   
 
  
  
 
  
 
  
    
 
  
    
    
  
  
  
  
  
 
    
   
  
   
   
   
   
  
 
   
  
      
      
    
   
 
  
  
  
      
  
  
      
  
    
  
  
    
  
 
    
 
    
  
      
  
 
  
         
  
    
  
   
         
   
     
   
 
  
   
   
   
   
      
          
   
    
   
    
 
   
     
      
   
        
   
 
    
  
    
    
  
    
  
  
  
 
  
     
    
   
   
   
   
   
   
   
   
 
     
   
   
      
    
   
   
  
   
 
  
 
   
    
  
   
 
  
  
   
  
      
  
  
    
  
    
  
    
    
 
  
  
  
  
  
  
    
      
  
 
 
  
  
  
  
  
    
     
  
  
 
   
   
      
   
    
   
     
   
  
   
 
  
    
  
  
  
  
  
  
  
  
  
   
  
 
  
  
  
    
  
  
  
      
   
  
  
   


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
       
   
   
  
   
 
   
    
   
      
    
    
   
  
 
   
   
      
            
   
   
   
      
    
    
 
  
  
   
      
  
   
  
 
   
      
         
   
   
   
   
 
   
    
    
       
   
   
   
    
   
       
      
 
    
   
       
       
 
   
       
  
 
   
       
      
      
  
   
   
   
      
   
 
  
  
  
  
  
  
  
  
  
    
  
 
 
  
    
  
  
    
  
  
  
  
    
  
 
 
  
  
  
      
  
  
  
   
    
   
         
   
   
   
      
     
  
  
   
    
    
   
       
   
    
 
  
   
  
  
 
  
  
  
    
  
  
        
  
  
  
  
 
  
  
        
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
   
  
   
   
    
    
   
   
    
  
   
 
   
   
   
   
    
   
   
         
 
  
  
   
  
  
  
      
    
  
  
 
    
  
     
    
  
  
  
    
  
   
  
  
  
    
  
  
  
  
   
  
    
   
      
   
   
    
 
   
    
    
    
    
   
   
    
    
   
 
   
   
   
    
      
   
    
   
   
    
 
   
      
   
    
   
    
    
    
       
       
 
   
   
      
   
      
    
   
   
   
  
    
 
     
   
   
     
  
   
   
 
 
  
    
  
  
    
  
    
  
  
  
 
   
   
   
      
   
  
       
   
   
 
  
   
     
   
   
   
   
   
 
    
      
   
   
   
      
  
    
 
   
      
   
    
      
   
   
   
   
 
   
   
  
    
   
   
   
   
    
 
   
   
      
   
   
   
   
   
   
   
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
       
   
   
    
   
    
   
   
 
  
    
  
   
   
   
   
   
   
    
   
   
      
   
    
  
 
  
  
  
    
  
 
 
     
  
  
  
  
    
    
   
 
     
  
   
    
  
  
 
  
  
    
 
  
  
  
    
      
    
 
    
    
  
 
   
   
     
     
    
      
      
    
    
   
   
  
   
        
   
   
 
  
  
    
    
 
  
  
    
    
 
     
  
  
    
  
  
  
    
   
   
  
  
    
   
   
      
      
 
   
         
   
       
   
       
       
  
  
  
  
  
 
 
 
  
 
   
   
      
   
         
   
  
      
    
 
  
  
    
  
  
        
 
 
  
  
 
  
  
 
   
  
 
 
  
  
  
  
  
  
  
  
    
 
  
  
  
  
  
  
 
  
  
  
  
  
      
    
  
  
  
      
   
 
  
  
 
  
   
   
   
  
       
 
 
   
 
  
  
  
  
  
   
  
 
 
  
  
  
  
  
 
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
  
  
  
 
 
  
 
 
  
      
    
  
  
 
 
  
 
   
   
   
     
   
 
 
    
  
  
 
  
    
   
   
  
    
      
   
   
   
      
      
     
 
  
  
    
    
  
      
  
  
     
   
  
   
   
  
   
   
  
   
 
    
    
  
  
  
  
    
  
  
   
  
  
    
  
  
  
 
 
  
    
  
  
 
 
    
  
 
      
   
        
      
      
       
 
    
     
  
       
   
   
   
   
   
 
  
  
  
  
 
    
  
  
  
  
 
  
 
   
    
  
  
  
  
    
   
  
  
  
 
  
          
  
  
  
    
  
  
  
  
  
 
  
  
  
  
  
   
        
  
  
  
          
  
    
  
    
   
   
       
      
   
   
      
   
   
    
 
    
  
  
    
  
  
  
 
  
  
      
  
 
  
  
  
    
 
  
  
    
  
  
  
    
   
   
          
      
     
   
     
 
      
    
    
   
   
 
   
     
    
 
  
  
   
  
    
  
    
   
  
     
    
   


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
  
           
  
  
   
         
    
  
    
       
  
  
  
  
    
  
  
  
  
    
      
    
 
    
  
  
  
    
  
  
    
  
  
  
  
  
  
  
  
      
  
  
      
  
  
    
      
    
  
  
 
    
  
  
  
  
  
  
    
    
 
  
  
  
  
  
  
  
  
  
    
  
  
  
  
 
  
    
    
  
    
  
  
  
  
    
  
  
  
 
  
   
  
   
     
  
  
   
    
      
 
    
  
  
  
    
  
  
 
  
  
    
  
    
    
  
    
  
  
 
    
  
  
      
    
   
   
   
       
      
         
  
    
      
    
       
   
   
   
         
      
   
    
  
  
  
  
  
    
  
    
  
  
  
 
  
  
  
  
  
  
    
  
  
  
  
    
  
 
   
  
  
    
  
  
    
    
  
   
  
  
  
    
    
  
  
  
  
  
  
   
   
      
   
  
  
    
   
     
  
    
 
  
    
  
  
  
    
  
  
  
 
  
    
  
  
        
  
 
  
  
  
    
  
  
   


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
    
  
 
 
  
  
  
      
  
 
  
  
  
  
      
  
  
     
  
  
  
    
  
   
   
  
   
  
   
  
    
  
    
 
    
 
 
  
  
  
 
   
      
      
  
        
      
   
      
  
 
      
 
   
    
   
 
  
   
     
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
    
  
  
       
    
  
  
      
   
   
   
    
   
   
      
 
  
  
  
  
   
  
   
    
  
    
  
  
     
  
 
 
   
 
 
    
      
  
  
  
    
    
 
  
  
  
  
  
  
  
  
  
  
      
 
   
  
  
  
  
      
      
   
      
   
    
  
  
  
  
  
  
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
 
 
  
   
    
    
  
   
      
   
 
    
   
   
   
   
   
   
  
 
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
 
  
  
 
  
  
  
  
    
  
 
 
      
  
   
   
  
   
  
  
    
 
  
  
  
  
  
  
  
   
 
  
      
    
  
 
  
  
  
  
    
    
  
  
  
    
 
    
    
  
  
    
  
  
    
    
  
  
    
  
  
  
  
  
  
    
  
  
 
  
      
   
   
     
      
   
 
 
    
    
    
    
 
  
  
    
  
  
  
 
  
 
  
   
 
  
   
      
     
  
   
   
  
       
 
  
 
  
  
 
  
    
  
      
  
  
  
  
    
      
 
 
  
  
    
  
  
  
  
 
  
  
  
  
 
   
  
  
  
    
 
  
 
  
  
  
  
  
  
  
          
 
   
   
  
  
       
   
  
 
 
  
      
  
       
         
    
   
       
 
 
  
 
    
  
    
 
 
 
  
  
    
  
  
  
    
  
    
  
   
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
    
  
    
  
 
 
  
    
  
  
  
  
  
  
        
  
 
  
  
 
  
  
  
 
  
      
    
      
   
    
     
  
  
 
        
    
  
  
  
  
 
 
  
    
   
  
  
  
  
    
  
  
    
 
  
 
 
  
  
  
        
  
  
    
 
 
  
  
  
   
   
   
   
  
   
 
   
  
  
 
    
     
  
      
   
   
   
            
    
 
    
  
  
  
  
 
 
  
   
   
       
  
 
      
 
  
  
    
  
 
 
  
 
  
  
  
  
  
  
    
 
   
   
  
  
  
   
   
   
   
 
 
   
   
   
  
  
   
 
 
    
 
  
  
  
 
  
   
  
  
 
 
  
  
    
 
  
  
  
  
  
  
   
 
  
  
  
    
  
   
 
  
  
  
  
  
  
  
    
  
 
  
   
   
   
   
  
  
    
   
   
   
 
  
  
 
 
  
  
     
  
        
   
 
    
  
   
 
  
  
  
  
 
 
  
  
    
  
        
 
    
      
  
  
  
    
  
  
    
  
      
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
  
  
    
  
  
   
  
  
  
    
 
  
 
  
  
  
 
  
    
  
   
  
    
      
  
 
  
 
  
  
   
  
   
   
   
  
  
    
  
  
  
 
  
    
 
   
 
   
   
  
 
  
  
    
  
  
 
  
  
  
 
  
  
    
  
    
 
  
 
  
 
    
    
  
    
  
  
  
  
     
  
 
  
  
  
    
      
  
  
  
    
  
 
   
  
   
   
   
   
   
    
  
   
  
    
  
  
 
  
 
  
  
  
  
 
 
  
  
  
    
  
  
    
 
 
   
  
  
  
    
  
  
 
    
    
    
    
  
 
  
    
  
  
 
  
  
 
  
      
   
      
      
   
    
     
   
    
 
  
  
      
   
   
         
      
       
  
 
  
 
   
    
    
    
  
  
   
    
  
 
  
   
   
      
   
    
   
    
   
   
   
 
    
      
   
   
      
      
   
    
   
    
  
  
   
     
    
  
  
  
  
 
    
  
 
  
  
    
  
      
 
  
   
   
  
   
   
   
   
   
    
 
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
   
  
 
  
   
  
 
 
    
        
  
  
  
  
    
  
    
 
  
 
  
  
 
  
 
   
 
  
  
  
  
      
 
 
  
  
  
  
  
  
 
 
   
         
    
    
       
    
    
  
  
  
  
  
 
 
  
  
  
    
    
  
  
  
    
  
   
 
  
   
 
  
      
   
   
   
  
    
    
    
    
  
  
  
    
    
  
  
    
    
 
 
    
 
    
    
  
  
  
    
  
  
  
   
  
  
  
    
  
  
  
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
 
  
  
    
  
  
    
    
  
 
 
    
   
  
   
   
   
   
   
  
   
 
  
  
    
  
    
  
  
  
  
  
    
    
    
  
  
  
 
 
  
  
    
 
   
  
   
     
        
  
 
  
  
  
    
    
  
 
  
    
  
 
  
 
  
    
 
 
 
 
  
 
  
  
  
  
  
   
    
  
  
        
 
 
  
  
       
   
  
  
   
       
  
   
   
    
  
  
    
    
  
    
  
  
          
      
   
    
   
   
  
 
  
    
  
  
    
    
  
    
  
 
  
 
  
 
  
  
  
  
 
  
  
   
    
    
        
      
      
 
   
   
      
   
   
   
   
   
   
   
   
    
   
 
    
      
   
   
  
      
  
  
      
   
   
 
  
 
  
   
  
    
    
     
  
  
  
    
 
  
 
   
   
  
     
     
  
       
   
 
  
  
  
  
  
    
      
  
  
  
 
  
  
 
  
    
      
  
  
 
  
  
  
  
  
  
  
 
    
  
    
   
      
   
       
   
  
 
          
             
      
   
   
      
  
 
    
  
    
  
  
    
  
 
  
  
  
 
  
  
  
  
  
  
  
  
    
  
    
   
    
  
  
    
  
      
 
  
  


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
  
  
 
   
   
   
   
   
   
   
         
   
 
  
  
  
  
  
 
    
   
   
   
    
  
      
  
  
   
 
   
   
      
  
  
  
     
      
 
    
  
  
 
  
  
  
  
  
      
      
   
   
     
  
   
    
  
   
 
  
  
  
  
  
  
    
  
  
  
  
  
    
    
  
    
  
  
 
  
 
  
    
   
  
      
  
  
 
 
  
  
  
  
  
  
  
      
  
    
 
 
 
 
  
  
  
  
  
  
 
  
   
   
  
  
   
   
   
   
   
         
 
    
  
 
  
  
  
  
  
 
   
  
  
  
  
    
  
  
 
    
   
   
   
    
   
   
    
    
 
   
   
   
   
      
   
   
      
 
  
      
  
  
  
 
  
  
    
 
  
  
  
  
    
  
  
  
  
  
  
  
  
    
  
 
 
  
 
 
  
     
      
   
    
      
  
  
    
    
    
  
  
  
  
  
  
    
  
  
  
  
  
      
  
  
  
    
    
  
  
 
   
   
   
   
         
   
   
   
      
   
   
 
  
   
   
  
   
   
         
  
    
    
      
   
 
  
  
    
  
      
    
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
 
  
  
    
   
     
  
   
   
   
   
    
 
   
   
   
  
   
  
   
    
   
    
 
  
    
    
  
  
  
  
  
  
  
      
 
  
  
  
  
  
    
  
  
  
      
  
   
        
  
  
  
   
   
        
   
 
    
   
   
    
      
   
   
      
   
 
  
  
  
 
   
  
  
 
  
  
  
    
  
  
    
    
  
  
  
  
 
   
   
         
   
   
    
  
   
    
     
       
   
  
     
   
         
  
  
  
   
  
       
         
       
      
  
  
   
   
  
  
 
  
  
  
 
    
  
  
   
    
  
    
  
    
 
  
  
 
 
    
  
  
   
    
  
 
 
       
    
   
   
          
      
   
    
  
  
  
 
 
       
    
   
   
          
      
   
    
  
  
  
 
  
       
  
   
     
          
     
   
     
 
  
 
 
  
  
   
    
  
    
   
     
     
 
  
  
 
 
  
 
  
  
   
    
   
     
  
   
   
   
   
    
 
   
   
   
  
   
  
   
    
   
    
 
  
    
    
  
  
  
  
  
  
  
      
 
   
    
   
   
    
     
         
     
   
   
      
 
   
    
   
      
    
      
  
   
    
     
  
 
  
  
    
      
  
 
 
  
  
 
  
  
  
  
    
  
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
 
  
  
  
  
  
  
 
  
  
  
 
  
  
  
    
    
  
    
    
  
 
  
  
  
  
    
  
  
 
  
  
 
    
  
  
  
    
    
  
  
 
  
   
  
  
 
  
  
  
 
  
    
  
    
    
  
  
  
  
  
  
  
  
 
    
    
  
  
  
  
  
  
      
  
 
  
  
    
  
  
  
  
  
  
  
    
  
  
 
      
   
     
  
   
   
  
   
   
  
   
  
   
  
     
   
   
   
    
  
  
    
   
      
   
   
  
   
      
   
   
   
 
      
  
   
   
    
     
     
  
 
     
 
       
 
     
 
     
 
    
  
    
    
  
  
 
  
  
 
    
    
  
  
  
  
  
  
    
  
    
 
  
  
  
  
  
  
      
  
 
  
  
    
  
  
  
  
    
 
  
  
  
 
     
  
  
   
   
  
   
  
     
  
  
 
 
  
   
      
         
    
    
   
 
 
  
  
  
  
 
  
 
   
    
   
   
  
  
   
   
  
     
    
 
  
  
  
    
      
  
  
    
      
 
  
  
  
  
  
  
  
  
    
  
  
 
  
    
    
  
   
   
   
   
   
   
   
   
    
    
  
  
    
 
    
  
    
  
  
  
  
    
  
  
  
  
 
   
   
   
   
   
   
    
   
   
   
 
  
  
  
  
  
      
    
  
  
 
   
   
    
   
    
     
   
   
   
    
    
    
  
  
  
  
  
  
  
  
  
    
  
  
  
 
  
  
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
    
  
  
  
  
  
 
  
    
  
 
  
  
  
    
  
  
  
  
 
 
  
  
  
  
  
    
  
    
  
  
 
  
  
  
  
  
  
  
  
  
 
  
    
  
  
    
    
  
  
 
 
 
  
  
  
  
 
  
   
    
       
   
   
   
   
   
   
 
  
    
  
  
  
  
  
  
 
  
  
  
 
     
  
  
   
 
  
  
         
 
   
  
  
  
  
  
  
  
  
  
    
 
  
  
 
  
  
  
   
    
  
  
 
      
    
   
   
   
   
   
    
      
   
 
       
    
    
   
   
  
  
   
 
 
    
      
    
    
  
  
   
    
    
   
      
  
 
  
  
  
  
 
  
  
  
  
  
  
  
  
  
    
  
  
 
   
  
   
      
   
   
    
      
   
      
 
  
    
  
  
 
    
  
  
  
 
   
   
   
   
      
   
   
   
   
   
   
 
  
   
      
   
   
   
   
   
      
 
   
   
      
   
   
    
   
   
    
       
   
         
      
    
      
      
   
   
      
   
 
    
  
  
  
    
    
  
  
  
  
 
 
   
      
  
  
   
   
    
      
   
   
 
    
  
      
  
  
    
    
    
 
    
  
  
 
 
  
    
  
    
    
 
  
  
 
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
 
   
   
  
   
     
   
    
      
 
    
 
  
  
  
  
  
  
  
  
 
  
  
 
 
  
  
  
  
      
  
    
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
 
  
  
  
 
  
    
    
  
  
    
  
  
    
 
  
  
  
 
   
      
      
    
   
   
   
   
   
      
 
    
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
    
      
  
  
  
  
  
 
  
  
  
    
  
  
  
  
  
 
   
    
   
   
   
   
      
   
   
         
   
 
   
   
      
      
     
   
   
  
   
   
 
  
    
  
  
 
  
  
 
 
  
      
  
  
  
  
  
  
    
 
      
   
   
   
      
   
   
      
   
   
  
 
  
    
  
  
    
  
 
  
  
  
  
  
 
  
  
  
  
    
    
  
  
  
  
  
  
  
 
  
  
  
  
    
    
  
  
  
      
 
   
   
  
      
  
   
   
   
  
 
  
  
     
    
  
  
  
  
 
   
   
   
   
   
       
      
   
   
    
   
    
  
  
  
  
  
 
  
  
 
  
  
  
  
  
 
  
  
 
 
   
      
  
  
   
   
   
   
   
 
  
    
    
  
  
    
  
    
  
  
  
 
  
  
  
  
      
    
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
 
  
  
    
  
  
  
    
  
 
  
  
  
    
  
    
  
  
  
  
 
  
    
 
  
  
    
  
  
  
  
  
  
  
  
  
 
    
  
 
  
  
  
 
  
  
    
    
  
  
  
  
    
    
  
 
  
  
  
  
  
  
    
  
  
    
   
  
  
  
    
  
 
  
  
  
    
  
  
  
  
      
  
  
  
 
  
    
      
  
  
 
  
  
  
 
  
  
    
    
  
 
  
  
 
    
      
      
  
   
   
   
   
  
  
      
 
  
 
     
     
  
    
    
  
    
 
   
  
  
  
  
  
  
    
    
 
  
  
  
 
   
   
      
   
   
   
    
   
      
   
   
 
  
  
  
  
  
  
    
    
  
    
 
  
  
    
  
 
   
  
 
    
    
    
  
    
  
    
  
  
  
 
  
  
  
  
  
  
    
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
 
  
    
  
      
  
  
  
    
   
  
  
  
  
  
  
 
  
  
    
 
    
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
      
    
 
    
  
  
 
  
  
  
 
  
 
 
  
  
  
  
  
  
 
   
    
      
   
      
      
  
      
    
   
      
  
      
  
   
 
  
  
  
    
  
  
  
    
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
   
   
   
      
      
   
   
   
   
   
    
 
  
  
  
 
      
   
   
      
      
      
      
    
  
  
  
    
  
 
    
  
  
  
 
    
 
  
  
  
 
  
 
  
    
    
  
 
  
 
    
  
 
  
    
  
  
  
  
    
    
  
  
 
      
  
    
   
   
    
  
      
 
    
  
    
  
  
  
    
  
    
 
  
  
 
   
   
   
   
      
   
   
   
      
   
    
  
  
  
  
      
  
  
  
 
   
  
  
  
  
  
  
  
  
  
  
 
   
   
   
   
   
         
   
         
 
   
   
   
  
    
      
         
   
    
  
 
   
    
      
      
        
   
      
   
 
   
    
     
  
      
   
   
 
   
  
    
   
  
     
      
 
    
 
  
 
  
   
  
      
   
   
   
   
 
  
 
   
    
   
   
   
   
     
   
    
 
   
   
  
    
      
      
        
  
   
   
     
 
  
    
  
    
  
  
  
  
  
   
  
  
  
 
  
  
    
  
  
   
  
  
  
  
  
  
 
  
  
  
  
  
    
  
  
  
  
  
 
   
    
   
   
   
   
   
    
   
    
      
   
   
   
      
    
  
   
   
 
  
  
    
  
    
  
  
  
  
  
  
  
 
  
  
  
   
  
  
  
    
  
  
  
 
    
    
  
  
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
  
 
    
 
    
 
 
 
 
   
   
   
   
   
    
  
     
    
  
  
  
 
  
  
    
    
  
  
 
  
    
  
 
    
      
  
   
  
   
    
   
    
    
      
  
 
    
    
  
    
  
  
  
  
  
 
 
      
   
   
   
  
   
   
   
    
               
   
 
  
        
  
  
  
   
    
 
 
  
  
 
  
  
  
  
  
  
 
    
  
  
  
  
    
  
  
  
  
   
 
  
    
  
  
    
  
  
  
 
  
 
 
 
    
  
 
 
  
  
  
    
    
  
  
 
 
  
  
  
  
      
        
 
      
     
   
   
    
   
   
   
   
   
 
   
    
             
   
    
   
      
  
 
    
  
    
      
  
  
    
  
  
    
  
  
 
  
  
   
 
    
  
  
  
  
 
   
   
   
   
   
   
   
   
    
    
    
   
   
  
  
   
   
   
     
 
    
  
  
 
 
    
  
 
  
  
      
   
     
               
      
 
  
 
 
        
 
 
        
  
  
  
  
    
  
  
 
   
   
   
   
   
   
   
      
    
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
        
  
  
  
    
  
        
 
   
   
   
   
   
   
   
   
    
    
    
   
   
   
  
   
   
   
     
 
    
  
  
 
   
   
   
   
   
  
  
 
   
   
  
   
   
   
      
   
 
  
    
  
  
  
 
   
  
  
   
      
   
   
    
  
    
    
  
  
  
 
   
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
  
  
  
  
 
  
    
  
  
  
 
  
  
  
  
  
  
  
  
 
  
 
 
  
  
    
  
  
  
        
    
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
    
    
  
 
  
   
   
   
   
   
   
   
    
   
 
    
   
   
  
   
   
   
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
 
   
   
     
  
   
    
   
      
  
 
      
    
  
  
 
    
    
        
  
  
  
 
    
    
  
  
        
 
 
  
  
  
 
  
 
  
  
  
  
    
  
    
  
  
 
 
    
  
 
  
  
   
 
    
   
   
      
    
  
    
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
 
  
 
  
 
 
  
    
  
  
  
  
  
  
    
    
  
    
 
  
    
  
  
   
   
     
      
  
   
      
      
   
 
      
   
      
  
         
   
   
    
   
   
 
 
  
  
    
 
  
  
  
  
    
  
   
   
          
   
   
    
          
         
         
 
  
  
  
  
  
      
   
  
   
  
    
  
 
   
        
   
   
  
   
   
   
 
  
  
  
  
   
  
  
    
 
   
   
   
   
    
      
      
   
      
   
   
 
  
   
      
   
      
   
   
      
   
   
    
   
 
   
   
     
       
       
       
   
      
    
   
    
   
   
   
   
   
    
  
   
      
 
 
  
 
  
 
   
   
   
   
   
    
   
   
   
    
  
 
  
  
  
  
  
  
   
      
   
     
      
   
   
 
 
   
      
   
      
    
      
   
   
   
   
 
    
  
  
  
    
  
  
  
    
  
  
  
    
 
  
  
  
  
  
  
  
  
  
 
 
 
  
 
 
  
   
   
   
   
  
   
   
 
   
  
 
  
  
  
  
  
  
  
 
  
  
  
  
   
  
    
  
  
    
  
 
   
  
  


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
  
 
   
   
  
       
  
   
   
    
  
   
 
  
   
    
  
  
    
    
  
  
 
    
    
    
    
  
   
  
 
  
  
  
  
  
  
  
  
  
    
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
 
    
 
  
   
    
 
   
   
   
  
   
   
  
 
 
   
  
   
   
   
   
 
  
 
  
  
  
  
 
 
  
    
    
  
  
  
 
  
  
  
  
    
 
    
   
  
    
 
     
  
  
  
  
  
  
    
  
    
  
  
  
 
    
  
  
    
  
      
  
 
   
  
  
    
  
 
  
  
  
    
  
  
 
  
    
 
 
  
 
 
 
  
 
  
  
 
 
   
   
   
         
  
   
       
       
   
 
  
      
  
  
      
  
  
    
 
  
  
  
 
  
  
  
    
      
  
  
  
      
  
 
  
    
 
  
  
   
   
       
        
  
  
  
     
    
 
  
    
 
  
  
   
   
       
        
  
  
  
     
    
 
  
    
 
  
   
   
       
        
   
  
  
        
  
 
  
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
   
   
  
    
           
  
  
        
  
 
  
    
 
  
    
  
  
  
  
    
 
  
  
  
  
    
      
  
  
  
  
 
 
    
  
      
 
  
    
  
  
  
    
  
      
 
  
  
  
  
    
      
  
    
  
 
 
    
  
    
  
 
 
    
  
  
  
    
  
      
 
  
  
    
    
  
  
  
  
 
  
  
  
    
    
      
  
  
  
      
 
  
  
  
  
    
 
  
  
  
    
      
  
  
  
      
  
  
 
 
  
   
   
       
        
   
  
  
  
      
   
 
  
 
  
    
  
  
  
  
    
 
  
   
   
       
       
   
  
   
    
  
 
  
  
  
    
 
  
   
    
         
          
        
  
   
  
   
  
  
  
  
  
    
 
  
  
    
    
 
  
  
 
 
  
  
 
  
    
 
    
  
 
 
  
 
 
  
  
  
  
 
 
  
 
 
 
  
  
 
 
  
   
   
       
        
             
   
   
       
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
    
    
  
      
  
  
  
     
  
 
  
  
  
 
 
 
   
   
       
        
       
   
  
  
      
  
  
  
 
  
  
  
   
     
  
  
  
  
   
    
  
 
  
 
  
 
 
  
 
 
  
 
   
 
  
   
  
    
      
      
  
  
  
  
 
 
  
 
  
  
 
    
  
    
  
    
      
   
    
  
  
  
 
  
 
 
   
   
   
   
       
   
    
    
   
    
 
  
  
  
  
    
  
  
  
  
  
 
   
   
   
   
    
   
      
      
  
 
  
  
  
  
    
    
  
  
  
  
 
  
  
 
  
 
 
  
 
 
  
  
  
  
  
  
  
  
 
  
    
  
 
   
  
         
   
   
   
   
    
    
   
   
   
   
    
   
   
   
    
      
   
    
 
    
   
      
   
   
   
   
  
      
 
  
 
   
      
   
  
   
      
   
   
 
    
  
    
  
    
  
  
 
 
  
   
      
  
  
   
  
  
 
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
 
 
   
   
   
   
      
   
      
      
   
 
 
   
  
  
  
      
   
  
   
      
   
   
  
 
    
   
   
      
         
         
      
 
  
 
    
  
 
  
    
  
  
 
  
  
  
    
    
  
  
  
  
  
  
  
  
 
   
      
  
   
   
   
       
 
      
   
   
   
      
      
   
   
   
 
  
  
  
    
  
  
    
  
  
  
   
    
      
      
   
   
   
   
   
         
 
  
    
   
   
  
   
   
   
   
  
    
   
     
      
   
   
   
   
    
   
       
   
    
  
  
  
    
  
    
  
  
  
  
  
  
    
    
  
   
  
  
  
  
  
  
  
  
    
    
    
   
  
  
  
 
  
 
  
  
  
  
 
  
  
  
  
  
  
  
  
    
   
  
  
  
    
    
 
  
  
   
  
   
    
  
    
  
    
 
  
  
  
  
  
  
    
  
  
  
   
  
  
   
  
  
 
  
  
    
    
  
        
  
  
  
  
  
 
  
 
 
 
 
  
    
  
 
  
    
    
  
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
 
  
   
    
   
   
   
  
  
  
   
 
      
   
   
   
  
  
  
 
  
  
 
  
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
 
  
  
 
 
  
       
      
      
   
   
   
   
 
  
   
 
  
  
    
    
  
 
   
  
   
   
   
   
    
  
  
    
  
  
 
  
   
   
   
  
  
       
  
      
   
      
   
    
 
 
  
    
    
  
 
    
  
  
  
  
  
 
    
  
  
  
  
  
  
  
  
  
    
  
  
    
    
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
     
   
    
   
  
   
   
      
   
   
 
   
   
   
   
   
   
   
    
      
      
     
  
  
  
  
  
  
  
  
  
    
 
  
   
  
  
 
  
 
  
  
  
 
 
  
  
  
  
    
 
    
  
 
  
    
  
    
  
  
  
  
    
  
  
  
 
  
  
  
    
 
    
  
  
  
  
  
 
   
      
   
   
      
   
  
  
    
  
  
  
  
  
  
  
   
  
 
  
  
  
 
    
   
     
  
  
 
  
      
    
  
    
  
    
  
  
  
 
  
  
  
  
 
 
   
   
   
   
   
   
    
       
        
 
      
  
         
   
   
 
   
   
   
 
    
  
    
  
    
  
  
  
  
  
  
    
  
 
  
    
  
  
  
    
  
  
  
  
  
  
 
  
 
  
  
      
 
 
  
    
 
  
  
  
  
  
    
    
  
  
  
  
  
   


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
  
  
    
      
  
  
    
      
 
    
  
  
  
 
 
    
       
      
   
   
       
   
   
   
 
  
   
   
  
    
  
  
  
   
 
  
 
  
  
  
  
  
  
  
  
  
  
 
 
   
    
      
    
   
        
   
    
   
      
      
 
       
     
  
  
   
      
   
   
   
    
      
 
  
    
  
    
    
  
  
  
  
    
    
  
  
    
  
  
   
  
  
    
  
  
 
  
   
  
    
          
   
   
  
   
  
    
    
   
   
   
   
  
   
    
    
 
  
      
  
  
    
   
  
  
  
  
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
   
  
  
    
  
 
    
  
  
  
    
  
  
  
  
  
  
  
    
  
  
    
      
 
  
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
    
  
  
  
    
  
 
    
  
  
  
    
  
    
  
  
    
    
 
 
  
  
  
  
  
  
    
    
 
  
  
  
 
  
  
  
    
   
  
  
  
  
  
     
  
   
  
   
        
  
    
     
 
  
       
   
    
  
  
  
      
    
  
  
        
 
      
   


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
    
   
 
  
      
      
   
      
  
   
  
  
  
    
  
 
    
  
    
  
  
  
  
  
  
    
  
     
  
  
  
  
  
  
  
   
    
    
   
      
   
    
   
   
 
    
 
       
   
 
  
   
   
      
  
 
  
  
    
    
  
  
  
 
  
 
 
  
  
  
  
    
  
  
 
    
   
 
 
  
  
 
  
 
 
  
  
  
  
  
  
  
  
    
  
  
  
  
  
 
    
    
 
  
  
  
  
   
      
          
   
      
  
   
  
    
      
   
   
      
   
    
   
      
 
   
  
   
  
    
   
  
   
 
  
  
    
  
  
    
  
  
  
  
 
  
  
  
  
    
 
  
    
      
 
  
  
 
   
   
  
  
       
  
   
    
  
  
    
     
   
 
    
 
    
  
  
  
  
  
 
  
    
 
  
 
  
  
  
 
  
    
    
  
  
    
  
    
  
  
  
  
    
    
  
  
  
    
  
  
  
  
 
       
   
   
   
   
   
   
   
   
   
 
  
  
  
  
  
  
  
  
  
   


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
 
  
  
    
      
      
     
  
  
   
 
  
    
  
  
      
  
  
    
  
  
  
 
  
    
    
  
    
  
  
  
  
  
  
    
 
  
  
  
  
    
  
  
  
  
  
  
  
  
  
 
   
   
    
   
   
 
    
      
  
       
   
 
 
  
    
    
  
    
  
 
 
  
  
  
  
  
  
  
  
  
      
  
  
 
    
    
  
    
  
  
    
  
 
   
   
    
     
 
      
   
    
   
   
 
   
  
   
   
   
   
    
   
    
      
      
   
 
    
  
  
    
  
  
  
    
  
  
   
  
  
    
    
  
  
  
   
    
     
   
   
   
    
   
   
    
 
  
 
 
   
   
   
   
   
  
   
          
  
  
  
    
  
  
 
  
    
  
 
  
  
    
  
    
  
    
      
    
   
    
    
 
  
  
  
  
  
  
    
 
   
   
    
  
   
   
   
   
    
   
 
  
  
  
  
  
  
  
   
  
 
   
      
   
   
  
      
   
    
      
      
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
      
  
  
  
    
    
  
    
 
  
    
  
 
 
  
 
  
    
 
  
  
  
  
  
  
  
  
  
  
    
  
   
   
   
  
   
   
   
   
      
 
   
   
   
   
      
   
    
   
 
  
   
  
  
  
  
  
  
    
 
  
    
  
  
  
    
      
  
 
  
  
  
  
      
  
    
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
  
 
  
  
  
    
  
  
 
 
  
  
  
  
   
  
  
  
  
  
    
  
 
    
   
   
      
      
      
  
  
   
   
 
    
   
      
   
      
      
      
   
 
      
   
   
    
   
    
      
   
   
   
 
  
  
  
 
   
   
    
      
      
   
      
   
     
 
  
 
  
  
  
  
  
  
  
  
 
   
    
   
   
    
   
   
  
   
   
    
  
 
   
   
    
      
   
   
      
 
     
    
 
  
  
   
   
   
   
    
   
   
  
    
 
  
  
    
  
  
  
  
  
  
 
   
   
      
    
   
   
   
   
   
 
     
   
      
      
   
  
      
      
    
 
  
    
  
  
  
  
  
 
  
  
 
      
   
  
      
                
      
  
 
  
  
  
    
  
  
  
  
    
  
  
  
     
      
   
   
         
   
   
   
   
   
 
    
    
  
  
    
  
    
  
 
  
   
      
  
   
   
      
      
   
 
    
  
  
    
  
  
    
    
  
    
  
 
    
    
    
  
  
   
   
   
   
   
   
   
   
   
    
  
  
  
  
    
    
  
  
 
  
  
 
   
   
      
   
   
   
   
     
      
   
 
    
   
 
  
  
   
    
  
   
     
   
 
   
  
      
        
  
  
 
   
 
  
    
  
  
  
    
  
 
  
  
    
  
  
      
  
    
    
  
  
 
  
  
  
  
    
    
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
       
      
   
   
      
  
     
   
    
  
  
  
  
    
    
  
  
  
  
    
  
 
  
   
   
  
    
      
   
    
   
      
 
  
 
 
 
  
 
 
  
  
  
  
  
  
  
 
  
  
 
  
 
 
  
  
 
  
  
  
  
  
 
 
  
  
   
  
  
 
  
 
  
  
 
  
  
 
  
  
  
  
  
  
  
  
 
   
  
          
      
  
  
  
  
    
  
   
  
  
  
  
 
    
  
 
 
  
  
  
    
  
    
  
  
  
  
  
 
   
   
  
   
   
   
   
   
   
 
  
  
  
    
  
    
    
  
  
 
  
 
  
 
 
  
  
  
   
  
   
 
 
  
  


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
  
 
  
  
    
  
  
  
    
    
  
  
 
  
  
    
  
  
    
  
  
  
  
    
   
  
  
    
  
  
  
  
    
    
  
  
 
  
  
  
  
      
  
  
    
    
 
  
  
  
  
  
    
  
    
  
  
    
 
 
  
 
  
  
  
  
  
    
  
  
  
  
    
   
    
  
  
          
  
  
    
    
  
 
  
    
  
  
  
    
 
 
  
   
   
    
      
       
    
   
     
   
 
 
    
  
  
    
  
    
  
  
    
  
  
  
    
 
 
  
    
  
 
  
 
 
 
   
   
  
      
   
   
    
      
   
      
    
 
  
  
 
    
  
    
  
  
  
   
    
  
  
  
  
  
  
    
    
  
  
 
    
    
  
  
    
    
  
    
  
  
  
  
  
    
 
  
  
 
   
    
      
      
   
    
   
       
      
    
    
      
  
     
      
  
  
    
   
    
   
 
     
   
      
         
      
   
   
  
      
 
 
 
  
    
  
  
 
  
    
    
 
    
    
  
  
     
   
      
   
       
     
   
   
    
 
 
  
    
  
  
  
  
 
  
   
   
   
   
   
   
   
      
   
  
   
 
  
 
  
      
  
  
  
    
    
 
 
  
    
   
  
    
    
      
  
 
 
  
 
  
  
  
    
  
  
  
 
 
 
   
   
     
    
      
   
  
   
  
  
    


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
   
    
  
   
       
    
      
         
 
    
    
  
  
  
  
  
  
  
  
    
    
  
 
    
      
      
   
       
      
   
   
   
  
      
   
 
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
    
   
   
    
   
    
   
   
    
   
   
   
   
 
  
  
    
  
  
  
  
   
  
  
  
  
 
   
   
      
   
      
   
   
     
   
    
    
 
  
  
  
    
 
  
    
  
  
  
  
 
 
 
 
 
  
    
  
  
 
  
  
 
 
  
  
  
  
  
   
      
 
   
       
    
       
      
  
  
 
  
  
  
  
  
  
  
 
 
  
  
 
  
    
      
  
 
   
 
    
  
    
  
  
  
  
  
 
   
      
   
   
   
   
         
    
 
  
  
    
  
  
  
  
  
  
    
  
  
 
 
    
  
 
      
   
        
      
      
       
 
    
     
  
    
   
   
    
   
   
   
 
  
   
  
  
  
  
  
  
 
   
 
 
  
  
  
  
    
  
  
    
  
  
  
 
  
  
  
  
  
 
  
  
    
    
 
  
  
    
  
  
  
  
  
  
  
  
  
  
  
  
    
  
    
    
  
  
    
  
  
  
  
  
  
  
 
      
   
   
  
    
   
   
   
   
   
 
  
  
      
  
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
  
  
  
  
  
  
  
   
    
  
   
  
   
    
      
      
   
   
   
   
    
      
 
      
   
   
   
    
   
   
    
      
 
    
  
    
  
  
  
  
  
    
    
  
 
    
  
  
  
  
  
  
  
  
  
   
  
  
  
  
  
 
   
   
      
   
   
   
   
    
   
    
    
   
      
   
    
     
   
      
   
  
 
  
    
    
  
  
 
  
  
  
  
  
  
          
  
  
  
    
  
  
  
  
  
 
 
      
   
   
   
      
   
   
   
  
 
  
  
  
  
  
        
  
    
    
     
  
 
  
  
  
  
  
    
  
  
  
 
  
  
  
 
        
  
  
   
  
   
   
    
      
   
   
 
  
  
  
  
  
  
  
  
  
 
  
  
      
  
 
  
  
  
    
 
  
  
      
  
  
     
   
   
        
      
     
   
      
 
    
    
  
  
  
 
  
     
    
  
  
  
   
  
    
    
     
     
    
   
  
      
   
    
  
  
  
  
  
   
  
  
          
  
  
 
  
  
 
  
  
  
      
    
  
  
     
 
   
  
   
   
         
   
   
   
   
   
    
    
  
  
 
 
  
  
  
  
  
  
  
   
            
   
  
   
   
    
   
   
   
 
   
   
      
      
   
   
  
   
   
   
 
  
  
  
  
  
  
    
   


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
 
  
  
  
  
  
 
  
  
  
  
 
 
  
  
  
  
  
  
  
  
    
  
  
  
   
  
  
  
  
  
  
    
 
  
   
    
  
  
   
   
 
      
       
   
  
   
   
     
 
    
 
    
  
  
 
 
  
    
  
    
     
         
   
       
  
 
    
  
 
  
      
   
   
   
    
    
    
 
  
  
  
  
  
  
    
    
  
 
  
    
  
  
    
 
  
   
   
   
   
   
   
     
  
   
   
 
   
  
 
  
  
   
  
  
  
   
   
   
   
   
 
  
   
  
  
   
  
       
      
   
 
  
    
  
  
    
  
  
 
  
  
  
  
 
   
    
   
  
   
   
   
      
   
 
  
  
  
  
  
  
  
  
 
  
  
  
    
 
  
  
  
    
  
 
  
  
  
     
 
   
   
    
   
   
   
    
   
   
   
    
 
  
  
  
    
  
  
  
  
    
  
  
  
  
   
  
   
  
   
   
     
   
  
  
   
 
  
    
  
  
  
  
  
  
  
  
 
  
  
  
    
 
  
   
   
      
   
   
  
      
   
   
  
      
   
 
    
  
    
  
  
    
    
  
 
  
  
  
  
    
  
  
    
  
  
  
    
 
  
    
  
  
  
  
  
    
  
  
  
    
 
  
  
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
   
  
 
  
  
         
    
    
    
  
    
  
  
  
  
  
  
  
    
  
    
  
  
  
  
  
    
  
  
  
    
  
  
    
    
  
 
  
  
 
  
  
  
  
    
  
  
  
    
 
    
  
  
 
  
    
  
  
    
   
 
 
  
  
  
  
 
  
  
  
  
    
 
  
      
   
  
  
    
  
  
  
  
  
 
  
    
    
  
  
    
    
  
      
 
  
  
  
  
  
  
    
    
  
    
   
    
 
  
  
  
  
  
  
  
  
    
  
    
 
  
 
  
  
  
 
  
  
  
  
  
   
  
 
  
    
  
  
 
  
    
    
 
 
 
     
   
   
   
     
    
 
    
 
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
     
  
  
  
  
  
   
  
 
    
  
  
    
  
  
  
  
  
  
  
 
  
  
  
    
  
    
  
 
    
  
    
  
  
  
  
   
   
  
   
    
 
   
  
         
  
   
   
     
  
   
 
  
  
  
  
    
  
  
    
  
  
    
 
       
  
   
    
      
  
      
     
  
 
  
  
    
  
    
  
  
  
    
    
  
  
  
  
  
 
   
   
   
   
       
     
   
   
   
   
   
 
  
  
  
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
    
  
  
  
  
      
   
   
   
   
      
   
  
   
   
   
 
    
  
  
  
  
  
  
  
  
  
  
   
   
      
   
   
   
      
   
   
   
      
   
 
    
  
    
  
  
    
    
  
 
  
      
   
  
  
    
    
        
 
  
  
  
  
  
  
    
    
  
    
   
    
 
  
  
  
  
  
  
  
  
    
  
    
 
  
 
  
  
  
 
 
  
  
  
  
  
  
  
  
    
 
  
    
  
  
 
  
    
    
 
 
 
      
   
   
   
     
     
 
    
 
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
     
  
  
  
  
  
   
  
 
    
  
  
    
  
  
  
  
  
  
  
 
  
  
  
    
  
  
  
  
 
    
  
    
  
  
  
  
   
   
  
   
    
 
   
   
         
  
   
   
     
   
   
 
  
  
  
  
    
  
  
    
  
  
    
 
     
  
   
    
      
          
      
   
 
  
 
    
  
    
  
  
  
    
    
  
  
  
  
  
 
  
   
   
   
   
   
   
   
  
   
   
    
   
  
   
  
   
   
  
      
   
   
 
  
  
  
  
  
  
  
  
    
  
  
  
   
  
  
  
  
  
  
  
    
  
    
  
  
    
   
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
      
      
   
  
    
  
  
    
  
    
  
  
  
  
       
     
   
     
   
      
  
  
 
  
    
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
 
    
    
       
       
  
   
   
       
   
   
  
    
   
 
       
        
           
   
    
      
     
  
   
 
    
 
  
  
  
     
  
  
    
  
    
    
      
  
  
     
     
  
 
  
  
  
  
  
  
  
  
    
  
    
 
  
 
  
  
  
 
  
  
 
 
   
   
 
   
   
   
   
   
   
 
  
  
    
    
    
 
 
  
    
  
  
 
  
    
    
 
  
 
      
   
   
   
     
     
 
    
 
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
  
 
 
  
  
  
  
  
  
  
    
  
   
  
  
 
 
  
  
  
        
  
  
    
  
  
  
  
    
  
  
  
 
    
    
  
    
  
  
  
  
   
  
  
  
   
  
  
  
      
  
  
  
    
  
  
 
  
  
  
  
    
  
  
    
  
  
    
 
     
  
   
    
      
          
      
   
 
  
  


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
      
  
  
  
  
  
  
  
  
  
  
  
  
    
  
  
  
      
  
  
 
  
  
  
  
  
  
  
 
 
  
   
   
     
   
   
   
   
    
   
   
 
  
  
  
  
  
  
    
  
  
 
  
  
    
    
  
  
  
  
 
 
  
  
  
    
     
 
 
    
  
    
  
  
  
  
  
  
  
  
 
 
     
 
    
 
  
  
  
  
  
 
  
    
  
  
 
  
    
    
 
 
  
  
   
   
  
   
  
   
    
         
 
  
 
  
  
    
  
  
  
  
  
  
    
  
  
 
  
  
  
  
  
 
  
  
  
    
 
  
   
   
      
   
   
   
      
   
   
   
      
   
 
    
  
    
  
  
    
    
  
 
  
      
   
  
  
      
       
         
    
   
    
   
   
   
 
    
    
  
    
   
    
 
  
  
  
  
  
  
  
  
    
  
    
 
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
    
 
 
 
  
  
    
    
    
 
 
  
    
  
  
 
  
    
    
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
      
   
   
   
      
     
 
    
 
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
    
  
  
  
  
  
  
  
  
 
  
  
    
  
  
  
  
  
  
  
    
 
  
  
  
  
  
  
  
 
  
   
   
      
   
   
   
      
   
   
   
      
   
 
    
  
    
  
  
    
    
  
 
  
      
   
  
  
      
       
         
    
   
    
   
   
   
 
    
    
  
    
   
    
 
  
  
  
  
  
  
  
  
    
  
    
 
  
 
  
  
  
 
  
  
 
  
  
  
  
  
  
  
  
  
    
 
 
 
  
  
    
    
    
 
 
  
    
  
  
 
  
    
    
 
 
  
      
   
   
   
      
     
 
    
 
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
 
  
  
    
  
  
  
  
  
    
  
  
 
  
  
  
    
  
  
  
  
  
  
  
  
 
  
  
    
  
  
  
  
  
  
    
  
  
 
  
  
  
  
  
 
  
   
   
      
   
   
   
      
   
   
   
      
   
 
    
  
    
  
  
    
    
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
      
    
 
  
    
  
  
    
  
    
  
  
       
       
   
     
  
   
  
  
   
   
    
   
    
 
  
  
  
  
    
 
      
      
  
    
  
  
  
  
  
  
      
   
      
    
    
    
        
  
    
 
  
  
  
  
  
  
  
  
    
  
    
 
  
 
  
  
  
 
  
  
 
  
  
  
  
  
  
  
  
  
    
 
 
 
  
  
    
    
    
 
 
  
    
  
  
 
  
    
    
 
 
  
      
   
   
   
      
     
 
    
 
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
    
  
  
  
  
 
 
  
 
 
  
  
  
  
  
  
 
  
    
  
  
    
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
  
    
    
  
    
  
  
 
 
  
  
  
      
   
     
      
  
    
  
  
  
  
  
      
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
    
 
  
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
  
  
 
  
    
    
 
 
  
  
   
   
  
   
    
   
  
  
   
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
    
  
  
  
  
  
  
    
  
  
 
  
  
  
  
  
 
  
   
   
      
   
   
   
      
   
  
   
      
   
 
    
  
    
  
  
    
    
  
 
  
      
    
  
 
  
  
    
    
        
  
  
  
  
  
  
  
 
  
    
  
    
   
    
 
  
  
  
  
  
  
  
  
    
  
    
 
  
 
  
  
  
 
  
  
 
  
  
  
  
  
  
  
  
  
    
 
  
  
    
    
  
  
  
 
  
    
  
  
 
  
    
    
 
 
  
      
   
   
   
      
     
 
    
 
  
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
 
  
  
  
  
  
    
  
  
  
  
 
  
    
  
  
  
  
  
  
  
  
    
 
    
  
  
  
  
 
  
 
  
  
   
  
  
  
  
  
  
  
  
  
    
   
      
   
   
   
   
      
   
   
   
   
      
   
 
  
  
  
  
  
  
  
 
    
  
  
  
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
      
    
  
    
   
  
  
  
  
  
  
  
  
    
  
 
  
 
  
  
  
 
  
  
 
 
 
  
  
  
  
  
  
  
    
 
 
  
    
    
    
 
 
 
    
  
  
 
  
    
    
 
 
 
      
   
   
   
      
     
 
 
 
  
  
  
  
 
  
  
  
  
 
  
    
  
  
  
  
  
    
  
    
 
 
  
  
  
  
  
 
    
 
  
  
  
  
  
  
 
  
  
  
    
  
  
  
  
    
  
    
  
  
  
    
  
 
  
  
  
 
  
  
   
   
  
   
    
      
      
   
   
   
   
      
  
 
 
  
  
  
    
  
  
  
 
  
  
   
  
 
  
  
  
  
 
  
    
  
 
   
    
      
      
   
   
   
   
      
       
   
    
   
      
      
   
   
      
      
   
    
 
 
 
  
  
   
    
      
      
   
   
   
   
    
      
 
 
  
  
  
  
  
    
  
  
  
  
 
  
    
  
  
    
  
    
  
    
  
  
 
      
      
  
    
      
   
      
   
   
 
  
  
  
    
  
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
  
 
 
   
 
 
  
 
 
  
    
  
    
    
  
    
  
  
  
 
   
  
    
  
  
  
  
  
  
    
    
  
  
  
 
   
    
      
  
  
   
   
         
      
   
    
  
  
  
  
  
  
    
  
    
  
  
  
  
  
  
  
    
  
  
    
  
  
  
  
 
  
  
  
  
  
  
  
  
  
    
    
    
  
  
   
      
      
   
   
      
   
      
   
    
    
  
  
  
  
  
  
    
  
    
  
 
      
      
   
   
   
   
   
      
   
      
 
  
 
  
  
  
  
  
  
 
  
   
  
   
  
  
      
  
     
   
  
 
 
  
    
  
    
    
  
 
     
    
  
  
  
    
  
    
  
    
      
  
  
    
  
  
    
    
  
  
  
  
   
   
  
   
    
    
      
   
   
   
   
 
    
  
  
      
  
  
  
  
  
 
  
  
  
    
    
  
  
    
  
  
  
  
 
    
   
   
   
      
       
      
   
   
   
 
    
    
  
  
  
  
 
  
  
    
    
      
  
    
  
 
 
  
  
  
  
  
  
  
  
  
  
    
 
   
   
   
      
   
  
   
    
      
   
    
   
   
   
   
   
   
        
      
   
 
   
      
      
   
   
      
   
   
    
    
    
   
      
   
   
   
      
  
   
   
   
    
  
  
  
  
  
  
  
  
    
    
  
 
  
  
    
    
  
  
  
  
  
  
  
 
  
    
    
    
  
  
  
  
  
  
  
   
      
      
    
   
  
   
   
   
   
       
   
   
   
   
   
      
      
   
      
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
  
  
  
  
  
    
      
   
 
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
    
  
   
    
  
 
  
  
  
  
  
   
    
  
  
  
 
  
  
  
  
  
  
    
    
 
  
 
   
   
   
   
    
      
   
   
   
   
  
  
 
   
    
   
  
   
   
   
   
 
   
 
    
    
  
  
  
  
  
  
  
    
    
  
 
   
    
   
   
    
   
   
   
   
    
   
 
  
  
  
  
    
  
  
  
  
  
  
 
  
    
  
 
  
 
    
    
  
 
   
   
   
      
   
   
      
   
   
      
 
 
  
  
 
    
  
    
  
    
  
 
      
      
   
      
    
    
   
   
   
 
   
   
   
  
   
      
   
   
   
 
  
  
  
    
 
   
   
      
      
   
      
   
   
   
    
    
    
    
   
   
      
   
   
   
   
 
   
   
   
      
      
  
  
    
   
 
  
    
  
      
    
    
  
  
 
    
    
  
    
  
  
 
   
      
   
   
      
     
    
   
   
 
    
   
   
    
   
   
    
   
   
   
   
 
  
  
    
  
  
    
  
    
 
   
   
   
      
      
     
   
         
   
 
  
  
  
  
  
  
    
  
  
   
  
    
 
  
  
    
  
  
  
    
  
  
 
  
  
  
  
    
  
  
  
  
  
 
 
 
  
  
    
  
 
  
 
  
  
  
  
    
  
  
  
  
  
  
  
 
   
    
    
   
   
  
  
   
   
      
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
    
  
    
  
 
  
  
  
 
  
  
  
  
  
    
    
  
  
  
  
  
 
  
 
  
 
  
 
 
 
 
  
 
  
    
  
 
         
   
   
   
   
   
   
   
   
   
    
   
   
   
     
   
   
         
   
   
 
      
   
  
   
   
      
   
   
    
      
 
    
  
    
    
  
 
  
    
      
    
   
   
    
   
   
      
 
   
   
   
   
     
   
  
      
   
   
 
  
    
      
   
      
   
      
    
  
 
  
  
 
 
      
  
 
  
      
      
         
   
   
       
 
 
  
       
   
   
      
   
   
   
      
   
 
  
    
  
  
  
  
    
  
    
  
 
  
   
   
      
   
      
   
   
    
 
  
  
    
  
  
  
    
  
 
  
 
  
  
    
 
  
  
    
 
      
   
   
   
    
   
   
      
   
    
  
  
  
    
  
 
  
   
  
      
   
      
   
   
 
      
    
    
   
   
      
   
       
   
   
 
    
  
    
    
  
  
    
 
 
  
  
 
  
  
  
    
  
  
  
    
      
  
   
  
  
  
  
    
    
  
  
 
  
 
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
  
 
  
    
  
    
      
  
    
  
  
   
    
    
  
  
    
  
 
  
  
      
  
  
  
  
 
  
  
  
 
  
    
    
  
  
    
  
  
    
    
   
  
  
    
 
  
  
      
  
    
  
  
  
  
  
  
  
 
  
  
  
  
  
  
    
  
    
  
  
  
  
   
  
    
      
    
    
  
  
  
  
    
  
 
  
    
  
    
    
 
  
  
    
  
  
    
 
 
 
   
    
      
      
   
      
      
   
   
   
 
  
  
  
 
 
 
 
 
  
  
  
  
 
 
    
  
  
   
  
  
  
    
 
 
 
   
    
   
   
   
   
   
   
    
   
   
 
   
    
         
      
      
   
   
   
      
    
  
 
  
  
    
  
  
    
  
    
  
  
  
  
 
  
  
    
  
  
      
  
  
  
  
   
     
  
 
   
   
   
   
   
  
   
   
 
 
 
    
  
 
  
  
    
    
  
      
    
  
      
 
    
  
    
  
  
  
  
    
  
   
  
 
    
  
  
  
  
  
  
  
  
  
 
  
      
  
      
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
    
  
   
 
 
  
    
    
    
  
   
  
      
 
  
    
  
       
   
    
  
  
   
     
  
  
  
 
      
  
 
  
    
  
  
   
    
  
 
  
    
  
 
  
  
  
  
  
  
  
    
  
  
        
 
  
  
  
 
  
    
    
  
  
      
 
  
    
  
 
  
  
  
  
  
    
  
  
  
  
 
 
    
    
  
  
    
  
  
  
 
  
  
  
 
  
    
  
  
 
 
  
  
 
   
      
      
  
  
      
    
   
      
   
      
 
  
 
  
 
 
   
         
       
   
   
    
      
      
      
 
    
  
    
  
  
      
  
 
  
  
  
 
  
    
  
  
 
  
  
 
   
    
 
 
  
    
    
  
    
 
  
  
  
  
  
 
  
   
   
      
    
   
   
    
      
 
    
   
    
 
  
  
    
   
   
    
   
   
   
    
   
   
    
   
    
   
    
   
    
      
   
      
   
      
 
  
    
  
  
 
  
  
  
 
  
  
  
  
  
 
 
  
  
  
  
    
  
  
  
 
 
   
   
   
   
   
      
   
   
 
    
  
      
  
    
  
  
  
 
    
   
  
      
   
         
    
   
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
  
  
 
  
  
    
  
  
 
   
  
 
 
  
    
  
  
 
  
  
  
  
  
  
  
    
  
        
  
 
   
  
    
      
          
      
  
   
       
   
   
      
  
   
   
    
   
 
   
  
 
  
    
  
  
 
  
  
  
  
    
  
  
  
    
    
  
 
 
    
  
  
  
    
  
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
   
  
    
      
          
   
   
   
    
         
  
   
      
   
  
     
     
   
       
  
    
  
    
  
  
 
  
 
 
   
    
      
      
   
      
    
   
   
   
 
        
 
  
  
    
  
 
  
  
    
      
  
  
    
  
  
  
 
   
   
   
    
      
   
   
      
      
   
       
    
  
 
  
  
  
    
    
  
  
  
  
  
  
  
 
         
   
  
   
    
   
      
   
       
 
  
  
  
  
  
    
  
    
  
 
   
   
      
   
   
    
   
      
    
 
      
    
  
  
  
  
  
  
  
  
   
  
  
 
  
  
    
      
  
  
  
  
  
      
 
 
      
   
   
      
      
   
   
   
 
 
   
   
   
      
  
         
   
   
 
  
  
    
  
    
  
  
  
 
   
  
  
  
  
    
 
  
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
       
   
   
    
      
   
   
   
    
    
   
   
    
   
   
   
   
   
   
  
    
  
  
  
  
  
  
  
    
  
 
  
    
 
    
  
  
    
  
  
  
  
  
  
 
   
   
      
   
          
   
   
   
 
    
      
    
   
        
  
   
      
 
 
    
      
      
    
   
   
    
      
      
 
  
  
  
  
  
  
  
    
  
  
 
  
      
  
    
  
 
  
    
 
  
  
    
      
  
    
  
    
   
  
  
  
  
 
      
  
  
    
      
   
  
  
  
  
 
      
  
  
  
 
  
    
    
    
   
  
  
  
  
  
  
  
  
    
      
  
   
    
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
      
       
   
   
   
    
  
    
  
  
  
  
  
    
  
  
   
    
  
     
  
   
  
  
  
  
 
    
  
  
   
  
   
   
  
     
   
   
 
   
   
   
   
   
   
  
    
   
   
   
 
  
  
  


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
 
 
  
  
  
    
    
      
  
  
 
 
    
  
  
  
  
  
  
   
         
 
  
  
  
      
  
  
  
 
  
  
 
  
  
  
 
 
  
  
    
  
  
  
  
  
    
  
 
  
  
  
 
  
  
  
  
  
    
  
      
  
  
 
      
    
   
   
  
   
   
   
      
   
 
  
  
  
  
    
  
     
  
  
  
  
 
  
  
 
 
  
 
 
  
  
  
    
  
  
  
  
  
    
  
 
       
         
      
  
  
   
   
    
   
   
    
 
  
  
    
    
  
  
  
  
  
    
 
  
  
  
  
  
  
 
  
  
 
  
  
  
    
  
  
    
  
  
    
  
   
    
  
  
  
    
  
  
  
  
  
 
   
  
 
 
   
  
  
    
  
  
  
  
  
    
  
 
  
  
  
 
  
    
  
  
 
   
   
   
    
      
      
  
  
      
    
  
   
  
  
  
  
  
    
    
 
  
  
  
  
  
    
  
  
  
  
  
 
  
  
    
    
  
  
  
    
    
 
   
    
      
      
   
   
   
   
   
   
 
  
    
  
  
  
  
  
 
  
  
    
    
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
  
  
  
 
   
   
   
      
   
   
   
       
           
 
  
  
    
  
  
  
    
 
  
  
  
 
  
  
  
  
    
  
  
  
 
  
  
  
    
      
  
  
  
  
    
  
 
 
  
   
   
   
       
        
   
   
   
     
    
  
  
      
  
 
  
   
   
   
       
        
   
   
   
     
    
  
  
      
  
 
  
   
   
       
        
   
   
   
   
     
  
 
  
    
 
  
   
   
       
        
   
   
   
        
    
 
  
    
 
  
    
  
  
  
  
    
 
  
  
  
 
  
  
  
 
  
  
  
    
    
  
      
  
  
  
  
   
  
  
  
  
  
    
 
  
  
  
    
      
  
  
  
  
    
  
  
 
 
  
   
   
       
        
   
   
   
         
   
 
  
 
  
    
  
  
  
  
    
 
  
   
  
    
      
   
  
   
    
  
 
  
  
  
    
 
  
   
    
         
          
        
   
   
   
   
  
  
  
  
  
    
 
  
  
 
  
  
 
 
  
  
  
  
  
    
 
    
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
 
 
  
 
 
  
 
 
 
  
  
 
    
    
  
 
  
   
   
       
        
             
   
   
       
  
 
  
  
  
    
    
  
      
  
  
  
     
  
 
  
  
  
 
 
  
   
   
       
        
       
   
   
   
       
  
  
  
 
    
    
  
 
  
  
 
 
  
 
  
  
 
   
 
  
   
  
    
      
      
  
  
  
  
 
 
  
 
  
  
 
    
  
    
  
    
      
   
  
  
  
  
   
  
    
  
 
  
  
  
 
   
   
    
      
         
     
   
          
 
  
  
  
  
  
  
  
  
  
  
 
   
          
   
    
   
    
      
    
   
 
  
   
  
  
    
  
  
    
    
 
    
  
  
   
  
  
    
  
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
  
  
  
 
  
  
  
  
 
  
  
      
    
  
     
  
  
  
  
 
      
    
    
    
 
 
  
  
  
  
  
  
    
      
  
  
  
  
 
 
    
        
    
    
    
      
 
   
    
 
   
   
      
  
          
  
      
   
 
 
       
    
    
      
     
 
    
  
         
    
    
    
      
     
 
    
  
       
   
   
   
        
      
   
       
   
   
 
   
      
  
  
  
  
  
   
  
  
 
  
  
  
    
  
  
  
   
  
 
    
    
   
   
   
   
       
   
    
 
  
 
  
    
  
 
   
    
      
    
   
   
   
   
    
      
 
   
   
   
   
   
    
      
      
      
    
    
    
   
   
   
  
  
      
   
  
 
  
    
  
  
  
  
      
  
  
  
  
 
  
    
  
 
  
  
 
  
  
  
    
    
  
 
  
  
  
    
      
  
  
  
  
    
  
 
    
      
   
   
    
   
  
  
  
  
    
  
  
      
    
  
  
  
    
  
  
   
  
   
      
    
  
    
  
   
   
 
  
  
   
      
   
   
      
     
    
    
       
   
   
    
   
    
      
    
   
   
  
   
   
 
  
  
  
  
  
  
    
    
  
  
   
  
  
  




 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
   
   
   
   
   
       
  
      
      
 
  
  
  
    
  
  
   
  
    
    
 
    
   
  
   
   
    
      
   
   
 
  
    
  
  
     
      
   
  
  
  
 
  
    
  
  
  
  
  
 
  
  
  
  
    
      
      
  
  
 
   
      
   
   
    
   
      
   
   
   
 
    
  
  
    
  
  
  
  
  
  
  
     
  
  
    
  
  
    
  
  
  
  
  
  
 
   
    
    
      
      
   
   
   
  
 
   
   
   
   
   
        
      
      
   
   
    
  
    
    
  
  
  
 
  
  
 
  
  
    
    
  
    
      
  
  
  
 
    
      
   
      
    
   
   
   
   
    
 
  
  
  
  
  
    
    
  
 
  
    
  
  
  
 
  
  
  
    
  
  
  
        
  
  
 
  
  
  
  
  
  
  
    
  
  
  
 
   
   
       
        
   
   
   
   
      
   
 
  
    
  
    
  
  
  
  
  
  
 
   
  
      
    
   
   
   
   
    
 
  
 
  
  
  
    
      
  
  
  
  
  
    
 
    
      
   
      
   
    
    
    
      
 
   
      
      
    
   
   
    
   
   
   
    
      
    
    
  
  
    
  
 
  
  
    
      
  
  
  
  
        
  
 
    
  
    
  
    
  
    
  
  
  
 
      
      
       
    
    
   
   
       
         
   
   
   
  
        
   
   
       
    
      
 
 
      
   
       
       
        
   
   
   
     
    
  
    
  
  
  
  
    
  
  
    
  
 
  
  
    
  
  
  
  
    
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
  
  
  
 
  
  
    
    
  
      
  
  
  
  
    
 
   
   
   
   
    
   
   
   
   
   
   
 
  
    
    
  
  
  
  
 
   
   
       
        
   
   
   
         
   
   
 
    
      
   
       
    
    
      
   
  
    
   
  
    
   
   
    
    
   
   
       
        
 
  
  
  
    
  
  
  
  
    
  
 
      
   
      
       
        
   
   
   
     
    
  
    
  
    
    
  
  
  
  
    
 
   
   
       
        
   
   
   
      
   
 
   
   
   
    
      
      
   
   
   
 
   
  
   
  
  
      
       
        
   
 
   
    
   
    
         
          
        
   
 
  
      
   
   
   
   
    
      
   
   
   
    
 
  
  
  
  
  
 
  
    
  
  
 
   
   
   
   
    
      
         
   
  
  
 
    
  
  
  
  
  
  
  
  
    
    
 
      
    
  
      
    
   
   
   
   
 
  
  
  
 
  
  
    
  
  
  
 
  
      
      
   
    
   
     
   
    
      
    
 
  
  
 
 
  
  
 
 
  
    
  
  
  
  
  
  
      
  
 
      
     
   
  
    
   
   
   
    
 
 
  
  
  
    
  
  
    
 
  
  
  
  
 
  
   
    
    
   
   
   
   
    
   
    
 
  
    
  
    
 
  
      
    
   
   
    
   
   
  
      
   
    
  
 
  
  
  
  
    
    
  
   
  
  
    
  
  


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
   
      
  
      
   
   
   
    
   
    
    
  
   
    
      
         
    
   
   
      
   
 
  
    
  
  
  
  
  
    
 
    
 
  
  
  
  
    
 
  
  
  
    
  
 
  
 
  
 
  
    
  
 
  
  
 
  
  
    
  
  
  
  
    
  
  
 
  
  
  
  
  
    
  
  
  
  
  
 
  
  
  
  
    
    
  
  
  
    
  
 
  
    
  
  
    
    
  
  
  
 
  
    
  
  
 
  
  
  
 
  
  
  
    
  
  
  
    
 
  
 
   
  
      
   
   
   
   
   
   
 
  
  
  
  
  
  
  
  
  
   
   
    
   
   
   
   
   
   
   
   
    
  
  
    
  
  
    
 
  
   
  
    
     
      
   
   
    
   
   
   
   
   
   
    
   
   
   
 
   
      
   
   
   
   
   
      
   
    
    
  
  
  
  
  
  
  
  
    
  
 
  
  
 
 
  
   
   
   
   
   
    
 
  
  
  
 
  
   
    
    
   
   
   
   
   
   
    
 
  
   
  
   
   
   
   
   
 
  
  
  
  
  
 
  
  
 
  
  
  
    
  
 
  
 
 
    
    
  
 




 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
    
  
  
  
  
  
  
    
    
  
  
 
 
   
   
  
   
  
   
    
   
   
 
    
  
    
  
  
  
 
   
   
   
       
   
   
   
   
      
   
   
       
  
    
  
  
    
  
  
    
      
 
  
    
  
  
  
  
    
  
  
  
  
  
  
 
  
  
  
  
    
 
  
  
    
 
   
  
    
      
  
  
  
  
      
 
  
    
 
  
  
  
  
  
    
  
  
     
 
    
      
   
   
   
      
     
  
  
   
 
   
  
  
  
 
     
   
   
 
  
        
 
  
 
 
   
   
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
   
  
 
 
   
  
   
   
  
   
          
   
   
       
 
   
   
  
   
    
   
  
    
   
   
   
   
 
  
  
  
  
 
   
      
   
    
      
   
      
   
      
   
 
  
    
  
  
    
  
  
    
  
  
 
 
 
  
  
  
 
   
  
  
  
  
  
        
  
  
 
 
   
   
   
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
  
    
    
  
   
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
  
  
  
      
  
  
  
      
  
 
  
  
  
 
      
  
  
  
  
  
    
   
  
  
    
  
  
  
  
  
  
  
  
  
 
 
  
  
  
 
  
    
    
  
  
  
  
 
   
   
   
   
    
     
  
   
   
   
   
   
  
 
  
   
    
         
    
   
    
   
 
   
    
   
   
   
  
    
  
   
   
   
 
    
      
  
  
  
    
    
  
    
     
   
   
      
   
      
     
   
   
    
  
    
  
 
  
  
   
   
   
   
   
   
   
   
   
   
    
  
  
  
 
 
    
  
    
  
    
  
    
  
    
  
    
  
    
 
  
  
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
 
    
 
  
  
  
  
  
  
 
 
  
 
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
 
    
 
  
  
  
  
  
  
 
 
  
  
  
  
  
  
 
  
 
  
  
  
  
  
  
 
  
  
 
  
  
  
  
  
  
 
    
 
  
  
  
  
  
  
 
  
  
  
    
  
  
    
  
  
   
    
    
 
 
  
  
  
 
  
    
   
       
    
   
    
    
       
    
    
   
     
   
 
    
  
 
            
   
   
         
   
        
 
 
  
     
    
 
  
  
  
  
  
  
 
    
  
  
  
  
 
    
      
 
  
  
  
  
    
  
    
      
  
  
  
  
 
  
  
  
 
  
    
      
  
    
    
  
  
    
 
    
  
  
  
  
    
  
  
  
  
   
   
      
   
   
   
   
  
      
   
   
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
         
      
   
         
     
      
 
    
    
  
  
  
  
  
  
  
  
     
   
   
      
       
   
   
    
   
   
 
    
  
    
  
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
  
  
    
  
  
   
  
 
  
    
      
  
  
  
  
  
  
  
    
 
   
   
   
   
   
      
         
   
   
   
    
  
  
  
 
  
 
 
 
  
 
  
      
  
   
  
   
  
   
 
      
   
   
       
   
   
      
         
 
    
      
   
  
         
    
   
        
 
  
  
  
  
    
  
  
  
  
 
  
  
  
    
  
  
  
  
  
  
  
  
 
    
  
  
    
  
  
  
  
  
  
 
    
    
  
  
  
  
  
    
  
  
  
  
  
 
   
  
  
    
   
   
   
       
 
  
  
  
    
  
 
  
  
  
  
 
   
   
   
      
   
   
   
      
   
   
    
  
  
  
 
  
  
  
  
  
    
  
    
  
  
  
 
  
  
  
  
  
  
 
   
   
   
   
      
   
   
      
    
    
   
   
      
  
    
   
   
      
   
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
  
  
      
  
  
  
  
  
  
  
   
    
  
 
 
    
 
 
  
    
   
   
   
  
       
    
 
 
   
   
      
   
  
     
  
   
 
   
   
   
    
      
   
      
   
   
    
    
  
  
    
  
  
  
 
  
 
     
  
   
   
         
   
    
 
   
   
   
   
      
  
   
      
   
   
   
 
    
   
   
   
   
   
   
   
   
 
   
      
       
   
    
      
      
   
   
   
 
 
  
 
  
  
  
 
  
  
    
  
    
  
  
  
  
  
    
  
 
 
  
  
  
    
  
  
  
  
  
  
  
 
  
    
  
    
  
  
    
  
  
  
  
   
  
 
  
  
  
  
 
  
    
  
    
  
 
  
 
  
  
  
  
  
    
    
 
      
   
      
      
   
      
   
   
    
    
  
  
  
    
  
  
  
  
  
 
 
    
  
  
    
 
  
  
  
  
  
  
 
      
   
   
   
      
   
   
   
   
      
 
  
 
    
  
  
  
  
    
  
    
   
  
    
  
  
 
  
    
  
  
 
  
  
  
  
  
  
  
 
    
  
  
 
  
  
  
  
    
 
  
  
    
  
   
   
   
         
   
      
   
      
   
   
 
  
  
  
 
    
 
  
  
  
  
  
  
 
  
  
  
  
  
    
  
    
  
 
  
  
  
  
  
  
  
    
 
    
 
  
  
  
  
  
  
  
  
  
  
  
    
 
   
   
  
   
   
   
   
    
   
       
      
      
 
   
    
   
   
      
    
   
   
  
      


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
      
   
   
      
   
    
     
    
         
  
 
 
  
  
  
 
 
 
  
  
  
  
 
  
  
 
  
  
  
  
  
    
    
  
 
 
  
  
  
    
 
    
  
  
  
 
  
  
    
  
    
  
  
    
 
 
  
  
   
  
  
 
   
    
   
   
   
   
   
   
   
   
      
 
 
    
  
  
  
    
  
  
      
 
  
    
   
   
   
    
      
  
  
   
   
   
 
    
      
  
    
  
  
  
  
  
  
 
  
  
  
  
    
 
    
      
   
     
   
   
  
   
      
 
    
   
      
      
      
   
      
   
    
  
  
  
  
  
  
  
  
 
  
    
 
    
  
  
  
    
  
  
 
 
  
  
    
  
    
    
  
  
  
 
    
  
  
  
  
    
      
    
    
 
   
    
      
      
   
  
         
   
    
 
  
  
    
    
    
  
  
  
  
  
  
 
  
  
 
      
  
      
  
      
   
   
 
   
   
   
   
   
   
   
   
   
 
      
   
   
   
  
    
  
    
 
      
   
   
   
   
   
      
      
   
   
       
  
      
  
  
  
  
 
  
  
    
    
  
  
  
 
  
  
     
    
   
  
  
    
  
  
 
  
  
  
 
  
    
    
  
    
 
    
  
    
  
  
  
      
  
  
   
   
   
      
  
   
      
      
   
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
   
   
   
  
    
   
   
   
  
   
  
   
 
  
 
  
  
  
  
  
    
  
  
 
   
  
  
    
  
  
  
  
    
  
  
  
 
    
  
    
  
 
  
    
  
  
  
  
    
    
  
  
  
 
 
  
    
    
  
 
  
  
  
  
  
    
 
    
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
    
  
 
  
  
  
  
  
    
  
  
    
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
   
   
    
    
      
   
   
   
      
   
      
 
 
  
  
  
  
  
    
  
  
  
  
  
  
  
 
   
      
   
   
   
      
   
   
   
   
 
  
   
    
    
  
  
  
  
  
   
 
  
  
    
  
  
  
  
  
    
 
      
    
      
   
         
    
   
   
   
 
      
  
  
    
  
  
    
  
 
  
  
  
    
  
  
  
  
  
 
 
    
  
 
 
   
   
      
      
   
   
   
   
   
 
   
  
   
   
   
   
   
   
   
      
 
  
  
  
  
  
 
 
    
  
    
  
   
  
  
  
  
 
  
 
  
 
 
  
  
  
  
  
    
  
  
  
  
    
 
 
    
      
   
  
   
      
   
  
 
    
    
    
  
    
  
 
      
   
   
   
  
    
   
    
       
      
  
  
 
  
  
  
  
 
   
   
   
   
   
  
  
            
    
  
    
    
  
  
  
  
  
    
   
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
 
  
    
  
  
  
    
  
    
  
  
   
 
  
    
    
  
  
  
  
 
  
 
 
  
  
  
  
    
 
  
    
    
   
   
   
   
   
 
   
   
      
   
       
      
   
   
    
  
     
  
   
  
  
  
  
  
  
  
  
 
   
   
   
   
      
   
  
   
      
 
  
  
  
  
  
  
  
  
 
   
            
   
   
   
   
      
  
  
 
  
  
  
 
  
  
    
    
  
  
    
      
    
  
 
   
   
    
    
   
  
  
  
  
 
  
   
    
    
      
   
   
      
 
  
  
  
  
  
    
  
  
  
         
 
   
  
   
   
   
  
    
       
 
      
   
    
    
  
  
  
  
  
    
 
   
      
      
         
   
       
   
   
    
  
  
  
  
  
  
  
  
  
  
   
   
   
   
     
   
       
   
      
   
    
 
    
    
 
  
  
    
   
  
    
  
  
  
   
    
  
  
  
    
  
  
        
  
  
    
  
   
   
   
   
      
    
   
   
   
   
  
   
 
     
   
   
     
   
   
   
   
   
   
 
  
  
  
  
 
  
  
    
   
  
    
  
  
  
  
 
   
         
   
   
   
      
         
    
   
   
    
   
      
   
   
   
      
      
   
   
         
 
   
      
      
    
    
   
    
      
   
 
  
    
  
  
  
    
 
    
  
 
   
   
   
   
   
   
   
   
   
      
   
 
  
  
  
  
    
    
  
  
  
  
  
 
  
  
  
  
  
  
  
  
    
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
    
  
  
  
  
  
  
    
  
  
    
  
 
    
      
      
   
   
   
   
   
   
   
      
 
  
  
  
  
  
  
  
  
 
  
  
  
 
   
      
   
   
         
         
         
   
  
      
 
  
  
  
  
  
  
  
    
  
  
 
 
  
  
  
  
    
  
  
      
  
  
 
   
    
      
   
   
       
   
      
      
      
   
 
  
  
  
  
  
  
    
  
  
  
  
 
  
 
      
   
      
   
   
   
    
      
   
   
   
 
 
  
  
  
    
  
  
  
  
    
 
  
  
  
  
    
  
  
  
 
  
   
  
  
  
  
    
  
  
    
  
 
  
   
   
  
  
    
   
   
  
         
   
 
  
  
  
    
  
  
  
  
 
   
    
      
   
   
   
   
   
   
   
      
   
 
   
   
      
      
   
   
   
   
   
   
   
 
    
    
    
  
    
  
 
   
   
   
    
    
   
   
   
   
   
   
   
    
    
    
    
  
    
  
  
    
  
  
 
   
   
         
   
     
   
  
   
    
   
   
   
      
  
   
   
  
   
    
 
   
   
   
   
   
   
   
   
   
   
 
    
    
 
  
 
    
  
 
   
          
   
   
  
  
  
  
  
 
  
  
    
  
  
  
  
  
  
    
  
    
 
  
  
  
  
    
  
  
  
    
   
  
  
  
  
  
  
  
 
  
  
   
   
   
  
      
   
      
   
  
  
    
  
  
  
    
  
  
  
  
  
 
  
 
   
      
   
         
      
      
 
   
    
    
   
   
   
    
      
   
    
   
 
  
  
  
    
  
  
  
    
  
  
  
 
   
   
      
    
   
    
      
   
   
   
 
    
  
    
  
  
  
  
    
  
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
      
  
  
  
  
  
  
  
    
  
  
 
  
    
    
  
  
    
  
  
  
 
  
  
  
    
  
  
  
  
  
  
  
    
  
 
   
      
   
   
   
   
        
   
   
   
   
 
   
   
   
    
      
   
      
   
   
      
 
    
 
 
  
  
 
  
  
    
  
    
  
    
  
  
    
  
    
 
 
  
  
  
    
    
  
  
    
    
  
 
  
  
   
  
  
  
    
    
  
  
  
  
  
 
 
  
    
    
  
 
  
  
  
  
    
  
  
  
  
  
  
    
 
  
  
  
  
    
    
  
  
  
  
 
  
  
  
    
  
    
    
  
  
    
  
    
  
 
  
  
    
      
  
 
  
  
  
  
  
  
   
    
    
  
  
    
    
    
  
  
  
  
  
 
  
    
    
  
  
    
  
  
    
 
  
    
  
  
    
  
  
    
  
  
  
  
    
 
  
 
 
  
    
  
      
  
  
  
  
  
  
    
    
   
 
  
 
    
    
    
  
  
   
   
   
   
 
 
  
    
   
  
  
    
  
  
      
 
  
   
      
   
   
  
  
   
 
    
 
  
  
  
  
    
  
    
 
  
  
  
  
    
    
    
    
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
      
 
  
  
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
 
   
   
   
  
   
   
      
       
 
 
  
  
  
    
   
 
    
    
      
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
    
  
  
 
 
  
  
  
  
  
  
  
  
  
  
      
 
  
  
  
  
  
  
 
  
    
  
  
  
 
  
  
    
      
  
  
  
  
    
    
 
 
  
 
  
  
  
    
  
 
   
   
   
   
   
    
      
    
   
   
 
      
   
   
      
   
   
      
   
  
      
 
  
  
  
  
    
 
  
  
  
  
  
  
  
    
  
  
  
  
 
 
  
    
    
  
 
  
    
    
  
  
  
    
   
 
  
  
  
  
  
  
  
  
  
  
  
    
 
  
    
  
  
     
  
  
  
  
   
  
  
      
  
  
     
  
 
  
    
    
  
  
 
  
    
 
  
  
  
    
  
 
  
 
    
  
    
    
  
    
  
 
   
    
  
 
  
    
  
    
  
  
  
  
  
  
 
  
  
  
    
  
      
  
 
  
  
      
         
      
    
      
   
   
 
      
   
      
      
   
      
    
   
  
 
  
  
 
   
      
      
   
      
  
    
   
  
    
  
  
    
    
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
  
 
   
  
    
 
  
  
  
    
    
  
    
  
  
   
 
  
  
    
  
  
   
  
   
  
  
  
 
      
   
   
      
      
   
   
   
 
  
  
  
  
  
  
  
  
  
  
  
   
  
 
  
    
  
  
    
   
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
 
  
  
    
   
   
  
       
 
 
  
  
 
  
  
       
       
      
   
    
    
 
 
  
  
 
 
  
  
    
  
  
  
  
  
  
  
  
 
  
   
  
  
 
 
  
  
  
  
    
    
  
  
  
  
  
     
   
    
    
  
    
       
 
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
 
 
 
  
  
  
  
  
  
    
  
  
    
       
          
    
   
   
   
    
      
 
    
         
   
   
  
    
 
  
    
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
             
   
    
      
   
    
    
      
 
    
   
    
       
    
   
   
   
      
 
 
 
   
    
       
    
    
   
      
      
   
 
    
  
    
  
  
  
  
  
 
   
        
       
   
    
   
    
   
    
    
    
   
    
   
  
   
    
 
  
  
  
  
    
  
  
    
  
  
  
 
   
    
    
    
    
    
        
 
    
    
          
   
    
   
    
   
 
   
   
   
   
  
    
   
 
    
    
       
   
    
    
       
 
 
  
  
   
   
   
    
        
    
    
   
 
    
      
   
   
   
     
  
    
  
  
 
 
  
  
    
    
    
    
  
  
   
       
   
   
    
   
  
  
 
  
    
 
    
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
    
    
  
  
  
  
  
  
  
  
 
     
      
  
   
   
   
   
 
 
   
  
        
       
        
    
    
     
  
  
  
  
  
  
  
    
  
 
 
 
  
  
    
    
    
      
  
    
   
   
  
   
     
   
    
  
  
  
  
 
  
   
   
    
   
    
   
   
    
   
 
     
   
   
   
   
   
   
   
   
 
  
  
  
  
 
  
    
  
    
  
  
  
  
  
  
  
     
  
  
  
  
    
  
    
  
  
  
  
 
  
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
       
  
   
      
  
           
 
 
 
  
 
  
   
  
  
  
  
 
   
    
    
      
   
    
    
    
 
  
  
 
  
 
    
      
   
   
   
 
    
    
       
    
   
    
   
       
  
 
  
  
 
  
  
  
    
  
  
      
    
  
    
        
  
  
   
   
   
   
   
   
 
  
  
  
    
  
  
 
 
   
    
       
        
           
   
      
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
    
 
      
  
  
      
   
   
   
   
 
  
  
 
  
  
   
 
  
  
  
  
    
  
  
    
   
         
  
  
    
    
  
  
  
      
 
  
  
  
  
      
  
    
  
  
 
  
  
    
  
  
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
  
    
    
    
    
    
  
     
  
  
          
      
  
       
 
   
   
    
      
   
      
    
   
    
  
  
    
  
  
    
  
    
 
 
  
    
    
    
    
    
    
   
    
        
 
   
      
      
   
     
    
    
    
 
 
  
  
  
  
  
  
  
   
  
    
 
  
  
  
  
 
 
  
  
    
    
   
   
   
      
   
 
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
   
   
    
  
         
   
    
    
 
 
  
  
    
    
        
        
        
   
    
    
      
   
      
   
   
   
   
   
 
  
  
 
 
 
  
  
    
  
  
  
    
  
   
 
  
 
 
  
  
   
   
      
  
       
   
   
 
 
 
  
  
  
  
  
  
  
  
  
  
    
  
     
      
   
    
      
   
  
 
   
      
   
   
      
      
   
 
  
  
 
    
  
  
  
    
 
    
    
    
   
    
    
   
    
 
 
 
  
  
   
    
       
    
       
   
   
    
   
   
    
   
   
    
   
 
  
  
 
 
  
  
       
    
   
   
   
    
  
   
 
    
  
    
  
  
  
    
 
 
   
    
    
    
        
        
        
       
             
  
   
      
   
   
      
    
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
  
      
  
  
 
  
 
 
  
  
    
   
    
    
    
    
       
    
    
 
        
   
   
      
    
      
      
 
      
      
    
   
      
   
   
 
  
   
    
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
 
      
  
 
 
 
  
  
  
    
  
  
  
  
    
    
  
  
  
 
  
  
  
  
  
  
    
  
  
  
  
  
  
  
 
    
  
  
    
  
  
   
  
  
  
   
   
   
      
   
 
    
   
     
      
   
    
   
    
    
 
   
   
   
      
   
      
      
   
  
 
   
   
   
      
   
        
   
       
      
   
   
   
   
      
   
    
   
    
   
   
      
    
      
    
    
    
   
 
  
  
  
  
  
 
    
    
      
      
                    
      
 
  
  
    
    
  
  
  
  
  
  
  
 
    
    
    
  
    
    
  
  
  
 
 






 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
      
  
  
  
  
  
    
  
  
  
      
  
  
  
  
  
    
 
  
  
    
  
  
  
  
  
  
    
  
 
  
  
      
  
    
  
  
  
  
    
 
 
  
  
  
  
    
  
 
    
  
 
        
 
        
 
    
  
  
  
    
  
  
 
 
 
   
  
  
  
 
  
   
   
   
   
    
   
   
   
   
   
  
 
  
  
  
  
        
  
  
  
    
  
 
  
        
 
  
  
     
    
     
   
   
   
 
    
  
    
  
  
  
  
  
  
  
   
    
        
  
        
 
  
  
  
 
      
 
      
  
  
  
 
  
   
   
    
   
   
   
   
  
  
   
    
  
  
  
  
    
  
  
        
   
        
 
        
 
      
  
  
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
   
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
   
  
  
 
 
    
  
  
    
  
 
 
  
  
  
  
  
 
  
 
  
  
  
  
  
  
  
  
  
 
  
  
  
    
   
 
 
  
  
  
  
 
 
  
  
  
  
    
 
    
  
  
    
 
     
  
  
 
  
  
  
  
  
  
  
  
 
  
   
 
  
  
  
  
  
 
  
  
  
  
  
  
 
 
 
  
  
  
  
  
 
  
  
  
  
 
  
  
  
  
  
 
  
 
  
  
  
  
  
  
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
  
 
 
  
  
  
  
 
 
 
  
  
  
  
 
  
  
  
  
  
 
 
  
 
  
 
  
 
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
 
  
  
 
  
  
 
  
 
 
  
  
 
  
  
  
 
 
  
  
  
  
 
 
  
  
 
 
  
 
  
 
  
 
  
  
  
  
  
  
 
 
  
  
  
  
 
   
   
   
   
     
   
      
   
 
  
 


 
 
 
 
 
  
  
  
  
  
 
 
  
  
 
 
     
  
  
  
  
  
  
  
  
 
  
  
  
 
  
  
  
  
  
 
  
  
 
  
 
 
 
 
 
 
 
 
  
 
  
  
  
  
  
 
  
  
  
  
  
  
  
  
 
  
 
  
 
  
 
  
    
 
  
 
  
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
  
    
  
 
 
 
 
  
  
 

SAP_001.pdf: 
Statistical Analysis Plan 
AC-080A201
Multi-center, double-blind, double-dummy, randomized, placebo- and active-reference, 
parallel group, Phase 2 dose-finding study with ACT-132577 in subjects with essential 
hypertension (grade 1 and 2)
ClinicalTrials.gov Identifier: NCT02603809
This study was sponsored by Actelion Pharmaceuticals - study sponsorship was transferred to Idorsia 
Pharmaceuticals Ltd.


 
 
 
 
STATISTICAL ANALYSIS PLAN 
FOR CLINICAL STUDY REPORT 
 
STUDY AC-080A201 
 
Multi-center, double-blind, double-dummy, randomized, placebo- and active-reference, 
parallel group, Phase 2 dose-finding study with ACT-132577 in subjects with essential 
hypertension (grade 1 and 2) 
 
Purpose of Analysis 
Clinical Study Report 
Investigational Drug 
ACT-132577 
Protocol Number 
AC-080A201 
Actelion Document Number 
D-17.304 
Document Status/Version Number 
Final Version 2.0 
Date 
15 May 2017 
 
 
 
Authors 
, Expert Statistician 
 
, 
 
 
 
Reviewers 
, Medical Science Expert 
 
, Senior Clinical Project 
Scientist 
 
, Senior Expert Statistician 
 
, Head of Biostatistics 
 
, Senior Trial Data Scientist 
 
, Senior Drug Safety Physician 
 
, Global Clinical Project Management 
 
, Senior Clinical 
Pharmacologist 
 
, Global DRA Project Leader 
 
Confidential 
 
May not be used, divulged, published or otherwise disclosed  
without the consent of Actelion Pharmaceuticals Ltd 


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Statistical Analysis Plan 
Doc No D-17.304 
 
TABLE OF CONTENTS 
LIST OF ABBEVIATIONS AND ACRONYMS ...............................................................7
1
INTRODUCTION .........................................................................................................9
2
STUDY DESIGN AND FLOW ....................................................................................9
2.1
Study design ...................................................................................................9
2.2
Study visit and assessment schedule ............................................................10
3
OBJECTIVES .............................................................................................................13
3.1
Primary objective(s) .....................................................................................13
3.2
Secondary objectives ....................................................................................13
3.3
Other objectives ............................................................................................13
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................13
4.1
Changes to the analyses planned in the study protocol ................................13
4.1.1
Analysis sets .....................................................................................13
4.1.2
Analyses of the secondary efficacy variables ...................................13
4.1.3
Safety analysis ..................................................................................15
4.2
Changes in the conduct of the study / data collection ..................................15
5
DEFINITIONS OF VARIABLES ..............................................................................15
5.1
Subjects disposition ......................................................................................15
5.2
Subject characteristics ..................................................................................16
5.2.1
Demographics ...................................................................................16
5.2.2
Baseline disease characteristics ........................................................16
5.2.3
Other baseline characteristics ...........................................................16
5.2.4
Medical history .................................................................................17
5.2.5
Previous and concomitant therapies .................................................17
5.2.6
Other subject characteristics .............................................................18
5.3
Study treatment duration and compliance ....................................................18
5.3.1
Study treatment duration ...................................................................18
5.3.2
Compliance with study treatment .....................................................18
5.3.3
Study treatment discontinuation .......................................................19
5.3.4
Study treatment adjustments or interruptions ...................................19
5.4
Study discontinuation ...................................................................................19
5.5
Efficacy variables .........................................................................................19
5.5.1
Primary efficacy endpoint(s) ............................................................20


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5.5.2
Secondary efficacy endpoints ...........................................................21
5.5.3
Other efficacy endpoints ...................................................................22
5.5.3.1
Illustration of derivation of ABPM endpoints .........................23
5.6
Safety variables .............................................................................................25
5.6.1
Adverse events ..................................................................................25
5.6.1.1
Treatment-emergent adverse events ........................................26
5.6.1.2
Frequency of treatment-emergent adverse events ...................26
5.6.1.3
Intensity of treatment-emergent adverse events ......................26
5.6.1.4
Relationship of treatment-emergent adverse events ................26
5.6.2
Deaths ...............................................................................................26
5.6.3
Serious adverse events ......................................................................27
5.6.4
Adverse events leading to discontinuation of study treatment .........27
5.6.5
Other adverse events .........................................................................27
5.6.6
Physical examination, vital signs and body weight ..........................27
5.6.7
Electrocardiogram .............................................................................27
5.6.7.1
Treatment-emergent ECG abnormalities .................................28
5.6.8
Laboratory .........................................................................................28
5.6.8.1
Treatment-emergent marked laboratory abnormalities ...........29
5.6.9
Other safety variables .......................................................................32
5.7
Quality of life variables ................................................................................32
5.8
Pharmacoeconomic variables .......................................................................32
5.9
Pharmacodynamic variables .........................................................................32
5.10
Pharmacokinetic variables ............................................................................32
6
DEFINITION OF PROTOCOL DEVIATIONS .........................................................32
7
ANALYSIS SETS .......................................................................................................33
7.1
Definitions of analysis sets ...........................................................................33
7.1.1
Screened Set ......................................................................................33
7.1.2
Run-in Set .........................................................................................33
7.1.3
All Randomized Set ..........................................................................33
7.1.4
Full Analysis Set ...............................................................................34
7.1.5
Per-Protocol Set ................................................................................34
7.1.6
Safety Set ..........................................................................................34
7.1.7
Pharmacokinetic Set .........................................................................34
8
DEFINITION OF SUBGROUPS ................................................................................34
9
GENERAL STATISTICAL METHODOLOGY ........................................................34
9.1
Missing data ..................................................................................................35
9.2
Dose-response analysis for the primary endpoint .........................................35


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9.3
Dose-response analyses for continuous data ................................................38
9.4
Dose-response analyses for binary data ........................................................39
10 STATISTICAL ANALYSES ......................................................................................40
10.1
Overall testing strategy .................................................................................40
10.2
General rules for data presentations .............................................................40
10.3
Display of subject disposition, protocol deviations and analysis sets ..........41
10.3.1
Subject disposition ............................................................................41
10.3.2
Protocol deviations ...........................................................................41
10.3.3
Analysis sets .....................................................................................42
10.4
Analyses of subject characteristics ...............................................................42
10.4.1
Demographics ...................................................................................42
10.4.2
Baseline disease characteristics ........................................................42
10.4.3
Other baseline characteristics. ..........................................................42
10.4.4
Medical history .................................................................................42
10.4.5
Previous and concomitant therapies .................................................43
10.4.6
Other subject characteristics .............................................................43
10.5
Analysis of study treatment duration and compliance ..................................44
10.5.1
Study treatment duration ...................................................................44
10.5.2
Compliance with study treatment .....................................................44
10.5.3
Study treatment discontinuation .......................................................44
10.5.4
Study treatment adjustments or interruptions ...................................44
10.5.5
Study withdrawal ..............................................................................44
10.6
Analysis of the primary efficacy variable(s) ................................................44
10.6.1
Hypothesis and statistical model .......................................................45
10.6.2
Handling of missing data ..................................................................45
10.6.3
Main analysis ....................................................................................45
10.6.4
Supportive/sensitivity analyses .........................................................46
10.6.5
Subgroup analyses ............................................................................47
10.7
Analysis of the secondary efficacy variables ...............................................47
10.8
Analysis of other efficacy variables .............................................................48
10.9
Analysis of safety variables ..........................................................................50
10.9.1
Adverse events ..................................................................................50
10.9.2
Deaths, other serious adverse events ................................................51
10.9.2.1
Deaths ......................................................................................51
10.9.2.2
Serious adverse events .............................................................51
10.9.2.3
Adverse events leading to study treatment 
discontinuations .......................................................................52
10.9.2.4
Other adverse events ...............................................................52
10.9.3
Electrocardiography (ECG) ..............................................................52
10.9.4
Laboratory tests .................................................................................52
10.9.4.1
Treatment-emergent marked laboratory abnormalities ...........53


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10.9.5
Physical examination, vital signs and body weight ..........................53
10.9.6
Other safety variables .......................................................................54
10.10
Analysis of quality of life variables (TSQM vII) .........................................54
10.11
Analysis of pharmacoeconomic variables ....................................................54
10.12
Analysis of epidemiological measures and risk-benefit evaluations ............54
10.13
Analysis of pharmacodynamic variables ......................................................54
10.14
Analysis of pharmacokinetic variables .........................................................54
11 GENERAL DEFINITIONS AND DERIVATIONS ...................................................55
11.1
Time windows ..............................................................................................55
11.2
Run-in treatment start date/time ...................................................................56
11.3
Run-in treatment end date/time ....................................................................56
11.4
Randomization date/time ..............................................................................56
11.5
Double-blind treatment start date/time .........................................................56
11.6
Double-blind treatment end date/time ..........................................................57
11.7
Withdrawal period start date/time ................................................................57
11.8
Withdrawal period end date/time .................................................................57
11.9
Study day ......................................................................................................57
11.10
Duration of essential hypertension (years) ...................................................57
11.11
Unit conversion rules ....................................................................................58
11.12
Body Mass Index (BMI) ...............................................................................58
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS ...............58
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES .................................61
13.1
Subject disposition ........................................................................................61
13.2
Protocol deviations .......................................................................................62
13.3
Subject characteristics ..................................................................................63
13.3.1
Demographics ...................................................................................63
13.3.2
Baseline disease characteristics ........................................................63
13.3.3
Other baseline characteristics ...........................................................63
13.3.4
Medical history .................................................................................64
13.3.5
Previous and concomitant therapies .................................................64
13.3.6
Specific previous and concomitant therapies ....................................65
13.3.7
Other subject characteristics .............................................................65
13.4
Study treatment duration and compliance ....................................................65
13.4.1
Study treatment duration ...................................................................65
13.4.2
Compliance with study treatment .....................................................66
13.4.3
Study treatment discontinuation .......................................................66
13.4.4
Study treatment adjustments or interruptions ...................................67
13.5
Study withdrawal ..........................................................................................67


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13.6
Primary efficacy analyses .............................................................................67
13.6.1
Main analysis ....................................................................................67
13.6.2
Supportive/sensitivity analyses .........................................................70
13.6.3
Subgroup analyses ............................................................................74
13.7
Secondary efficacy analyses .........................................................................76
13.8
Other efficacy analyses .................................................................................84
13.9
Safety analyses .............................................................................................87
13.9.1
Adverse events ..................................................................................87
13.9.2
Deaths ...............................................................................................88
13.9.3
Serious adverse events ......................................................................88
13.9.4
Adverse events leading to treatment discontinuation .......................89
13.10
Electrocardiogram (ECG) .............................................................................90
13.11
Laboratory tests ............................................................................................90
13.12
Physical examination, vital signs and body weight ......................................93
13.13
Other safety variables ...................................................................................93
13.14
Other evaluations ..........................................................................................94
13.14.1
PK .....................................................................................................94
13.14.2
PD .....................................................................................................94
14 REFERENCES ............................................................................................................95
15 APPENDICES .............................................................................................................97
 
LIST OF TABLES 
Table 1
Visit and assessment schedule ........................................................................11
Table 2
Thresholds for marked laboratory abnormalities ............................................30
Table 3
Parameterization of models considered in MCP-Mod analyses .....................36
Table 4
Summary of efficacy analyses ........................................................................49
Table 5
Visit time windows .........................................................................................55
 
LIST OF FIGURES 
Figure 1
Example DBP and SBP measured by ABPM .................................................24
Figure 2
Dose-response curves considered in MCP-Mod procedure ............................36
Figure 3
Examples of Emax dose-response relationships ...............................................46
 
LIST OF APPENDICES 
A.
Protocol synopsis ............................................................................................97
B.
Calculation of mean blood pressure measurements based on ABPM ..........105
C.
Calculation of trough-peak ratios based on ABPM ......................................109
D.
Document history ..........................................................................................110


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LIST OF ABBEVIATIONS AND ACRONYMS 
ABPM  
Ambulatory blood pressure monitoring  
AE  
Adverse event  
AIC  
Akaike’s Information Criterion 
ALT  
Alanine aminotransferase  
ANCOVA  
Analysis of covariance  
AP  
Alkaline phosphatase 
AST  
Aspartate aminotransferase  
ATC  
Anatomic therapeutic chemical  
BLQ  
Below the limit of quantification 
BMI  
Body Mass Index 
BOCF  
Baseline observation carried forward 
BP  
Blood pressure  
CI  
Confidence interval  
DB  
Double-blind  
DBP  
Diastolic blood pressure  
ECG  
Electrocardiogram  
eCRF  
Electronic Case Report Form  
Emax  
Maximum effect 
EOS  
End-of-Study  
EOT  
End-of-Treatment  
ET  
Endothelin  
EudraCT  
European Clinical Trials Database 
FAS  
Full Analysis Set  
FDA  
Food and Drug Administration (US) 
HR  
Heart rate  
IVRS  
Interactive Voice Response System 
LOCF  
Last observation carried forward 
LSMeans  
Least Squares Means 
MAR  
Missing at random 
MCP-Mod  
Multiple Comparison Procedure – Modeling  
MCT  
Multiple Contrast Test  
MedDRA  
Medical Dictionary for Regulatory Activities  
o.d.  
Once a day 
OBPM  
(automated) Office blood pressure measurement  
OC  
Observed cases 


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PD  
Protocol deviation 
PK  
Pharmacokinetic  
PPS  
Per-Protocol Set  
PR  
Pulse rate 
RIS  
Run-in Set 
RND  
All Randomized Set 
SAE  
Serious adverse event  
SAF  
Safety Analysis Set 
SAP  
Statistical Analysis Plan  
SAS  
Statistical Analysis Software 
SB  
Single-blind  
SBP  
Systolic blood pressure  
SCR  
Screened Set 
SD  
Standard deviation 
SiDBP  
(Mean trough) sitting diastolic blood pressure  
SiSBP  
(Mean trough) sitting systolic blood pressure  
SOC  
System organ class  
UACR  
Urine albumin-to-creatinine ratio  
ULN  
Upper limit of normal 
WD  
Withdrawal 
WHO  
World Health Organization 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical analyses and data 
presentation for the Clinical Study Report of Study AC-080A201, the Phase 2 
dose-finding trial with ACT-132577 in subjects with essential hypertension (grade 1 
and 2).  
This SAP is based on Version 3 of the protocol dated 30 May 2016 [D-16.063].  
For the layouts of the tables Biostatistics Standards for Analysis Datasets and Outputs 
(Project Code: PR 070; version 3.0) will be used. 
2 
STUDY DESIGN AND FLOW 
2.1 Study design 
Study AC-080A201 is a prospective, multi-center, double-blind, double-dummy, 
randomized, placebo- and active-reference, parallel group, Phase 2 dose-finding study 
with ACT-132577 in subjects with essential hypertension (grade 1 and 2). 
Approximately 1000 subjects are enrolled into the study, in order to have at least 
540 subjects randomized in the 6 following groups using a 1:1:1:1:1:1 ratio: placebo, 
5 mg ACT-132577, 10 mg ACT-132577, 25 mg ACT-132577, 50 mg ACT-132577 and 
lisinopril 20 mg. At least 420 subjects are expected to complete the trial. There are no 
stratification factors. 
The study consists of the following study periods: 
Screening 
The screening period starts with the signature of the “study” informed consent form and 
lasts until Visit 1. During this period study assessments (e.g., laboratory test) are 
performed to determine whether the subject is eligible for the study. 
Run-in period (Period I) 
Period I is a single-blind (SB) placebo period of 4 to 6 weeks starting at Visit 1 and ends 
at Visit 4 / Randomization (after completion of the baseline 24-hour ambulatory blood 
pressure monitoring [ABPM] recording on the last dose of SB study treatment [placebo]). 
The run-in period lasts 4 weeks for anti-hypertensive treatment naïve subjects.  
The run-in period lasts 6 weeks for subjects on anti-hypertensive treatment including a 
2-week wash-out period for anti-hypertensive treatment. The anti-hypertensive treatment 
must be discontinued (according to its label) at Visit 1, if there is no contraindication to 
stop it. 
 


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Treatment period (Period II) 
Period II is a double-blind (DB) treatment period of 8 weeks which starts at Visit 4 with 
the first dose of DB study treatment and ends at Visit 7 at the first dose of SB withdrawal 
treatment. 
Withdrawal period (Period III)  
Period III is a SB placebo period of 2 weeks, which starts at Visit 7 with the first 
administration of first placebo dose (withdrawal [WD] study treatment) and ends at Visit 
8 (WD-End-of-Treatment [EOT]). 
Follow-up period  
The follow-up period, including follow-up telephone call, or follow-up visit only for 
women of childbearing potential to perform the pregnancy test at the site, starts after the 
last dose of SB WD study treatment (placebo) and ends at 30–33 days after the last dose 
of the DB treatment. 
End-of-Study (EOS) 
End-of-Study (EOS) for a single subject is defined as the date of the follow-up telephone 
call or follow-up visit.  
If a subject withdraws consent and does not wish to participate in the study visits, the 
date of consent withdrawal is EOS for this subject. If a subject is declared lost to 
follow-up date of last contact is EOS for this subject. 
In addition, unscheduled visits may take place at any time during the study, in which case 
appropriate assessments may be performed at the discretion of the investigator and must 
be recorded in the electronic Case Report Form (eCRF).  
At the end of the study, the investigator/delegate will explain to the subject what 
treatment(s) / medical care is necessary and available according to local regulations.  
2.2 Study visit and assessment schedule 
Table 1 shows a schematic representation of the assessments during the study. 
 


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Table 1 
Visit and assessment schedule 
PERIODS 
Name / duration 
Period I: Run-in / 4–6 weeks6 
Period II: Double-blind / 8 weeks 
Period III: withdrawal / 2 weeks 
Premature 
EOT 
 
Follow-up 
VISITS 
Number 
Name 
16 
Week –6 
26 
Week –4 
3 
Week –1 
4 
5 
Week 2 
6 
Week 4 
7 
Week 8 
8 
Week 10 
9 
U1, 2, 3, etc.10 
Telephone 
call9or visit11 
 
Name 
Screening**
 
 
Randomization 
 
 
DB-EOT 
WD-EOT 
Within 7 days 
after last study 
treatment 
intake 
Unscheduled 
EOS 
TIME / Week 
 
 
 
Pre- 
 
2 
4 
Part 1 
Part 2 
10 
Day 70 
(± 3 d) 
Any time 
30–33 d after last 
dose of DB treatment 
Day –42 
Day –28 
(± 3 d) 
Day –7 
(± 4 d) Day –1 Day 1
Day 14 
(± 3 d) 
Day 28 
(± 3 d) 
Day 55 
(± 5 d) 
Day 56 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HR*, body weight, height1 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
12-lead ECG* 
X4 
 
 
X9 
 
 
X 
X 
 
X 
X9 
X 
 
Laboratory incl. pregnancy tests*2 
X5 
 
X9 
X9 
 
X 
X 
X 
 
X 
X9 
X 
X 2 
Urinalysis 
 
X7, 9 
 
X9 
 
X 
X 
X 
 
X 
X9 
X 
 
Office BP measurement* 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Home BP device12 
X 
 
 
Ambulatory BP measurement* 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
PK and PD sampling13 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
Compliance with study treatment 
 
X9 
X9 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Study treatment dispensing/return 
X 
X8 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Adverse events3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serious adverse events3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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*Electronically transferred to sponsor.  
** Visit 1 (Screening) can last up to 72 h for obtaining informed consent and performing required assessments.  
1. 
Height is only measured at Visit 1. 
2. 
Serum pregnancy test only for women of childbearing potential. Result is transferred electronically to sponsor. 
3. 
All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after last DB study treatment intake must be reported. 
4. 
Historical ECG is accepted if not older than 6 months.  
5. 
Historical blood laboratory data is accepted to check exclusion criterion 15, if not older than 3 months. In such a case, for women of childbearing potential a 
urine pregnancy test must be performed. If no historical report is available, a blood sample to be taken for laboratory analysis (including pregnancy test for 
women of childbearing potential) by central laboratory. 
6. 
Run-in period is 4 weeks before randomization for anti-hypertensive treatment naïve subjects. Visit 1 is combined with Visit 2. Run-in period is 6 weeks 
before randomization for subjects on anti-hypertensive treatment. Visit 1 and Visit 2 must be performed. 
7. 
Only urine pregnancy test for women of childbearing potential. Result is captured in the eCRF. 
8. 
Only for subjects who were on anti-hypertensive drugs at Visit 1 (i.e., had to perform a Visit 2). 
9. 
If subject discontinued study treatment during run-in period (i.e., between run-in visits) or at an in-person run-in visit (e.g., Visit 3), these tests may not be 
performed 
10. Unscheduled visits may be performed at any time during the study and may include all or some of the indicated assessments, based on the judgment of the 
investigator.  
11. For women of childbearing potential a visit must be organized instead of the telephone call to perform the serum pregnancy test at the site. However, if a 
woman of childbearing potential discontinued study treatment during the run-in period, a telephone call can be made instead of the visit.  
12. Upon investigator’s judgment, a home monitoring device will be dispensed to monitor BP at home, if necessary.  
13. Sample to be taken at trough (i.e., prior to study treatment intake).  
 
AE = adverse event; BP = blood pressure; DB = double-blind; ECG = electrocardiogram; eCRF = electronic Case Report Form; EOS = End-of-Study; EOT = 
End-of-Treatment; HR = heart rate; PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event; WD = withdrawal. 
 


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3 
OBJECTIVES 
3.1 Primary objective(s) 
The primary objective of the study is to explore the dose-response of ACT-132577 on 
diastolic blood pressure (DBP) in subjects with grade 1 or 2 essential hypertension. 
3.2 Secondary objectives 
• Evaluate the dose-response of ACT-132577 on: 
− Systolic blood pressure (SBP)  
− Control and response rate of blood pressure (BP) 
− 24-h ABPM. 
• Evaluate the safety and tolerability of a once a day (o.d.) oral regimen of 4 doses of 
ACT-132577. 
3.3 Other objectives 
• Evaluate steady-state trough plasma concentrations of ACT-132577 
 
in hypertensive subjects.  
• Evaluate steady-state trough endothelin (ET)-1 in hypertensive subjects. 
• Investigate the correlation between ET-1 and ACT-132577 plasma concentrations. 
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
4.1 Changes to the analyses planned in the study protocol 
4.1.1 Analysis sets 
In addition to the analysis sets described in the section 11.1 of the protocol a ‘Run-in Set’ 
(RIS) and an ‘All Randomized Set’ (RND) are defined to be used in summaries of 
disposition and premature study discontinuation [see Section 7.1.2 and Section 7.1.3]. 
4.1.2 Analyses of the secondary efficacy variables 
Where indicated, analyses based on analysis of covariance (ANCOVA) models, mixed 
models or logistic regression models planned in the protocol for the secondary variables, 
were supplemented by a Multiple Comparison Procedure – Modeling (MCP-Mod) 
analysis of the Least Squares Means (LSMeans) obtained from these models. MCP-Mod 
was qualified as an efficient statistical methodology for model-based design and analysis 
of Phase 2 dose finding studies [EMA 2014]. This approach replaces the Dunnett tests 
that were planned in the protocol for these endpoints. 


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In addition, a dose-response analysis was performed for the average change from baseline 
over time (Weeks 2, 4 and 8). 
BP control rates. After completion of the protocol, the Canadian Hypertension Education 
Program (CHEP) issued guidelines proposing cut-offs of 85 mmHg for DBP and 
135 mmHg for SBP, specifically focusing on measurement by automated office blood 
pressure measurement (OBPM) [Leung 2016]. These were added to the secondary 
endpoints. 
Analysis data set for ABPM. ABPM is performed over a 24-h period with the ABPM 
device set to record DBP and SBP at a pre-defined inflation sequence over the 24-h 
period including three measurements per hour during the day and two per hour during the 
night. ABPM data are electronically transferred to 
 and 
subsequently to Actelion. The 
supplements each ABPM reading with an indicator 
of whether the reading satisfied the quality control criteria agreed 
 
 
1. Start time of ABPM is between 06:00 and 11:00 
2. Duration of ABPM is at least 24 hours 
3. Percentage of valid readings in the period of duration is at least 75% 
4. Number of required hours (i.e., hours with at least one reading) is at least 22 
5. Number of exception hours (i.e., hours without a reading) is at most 2 
6. No two consecutive exception hours 
It should be noted that when an ABPM reading does not satisfy all 6 criteria this does not 
necessarily mean that this reading should be excluded from the analysis, as the ABPM 
analysis primarily focuses on the 24 hour means (according to 
report dated 
 For the analysis of 24 hour means, criteria 3 and 6 are considered to be the 
most relevant ones by Actelion. 
For this reason, the ABPM analyses will be based on the subset of subjects from the 
Per-Protocol Set (PPS) with baseline and Week 8 ABPM readings satisfying quality 
criteria 3 and 6 (i.e., ABPM readings having less than 75% valid readings and/or two 
consecutive exception hours will be excluded).  
Trough to peak ratios based on ABPM. In the protocol it was assumed that trough to peak 
ratios of DBP and SBP measured by ABPM would be derived on a subject level. 
However, the definition of subject-specific trough to peak ratios [Omboni 1995] appears 
to be problematic because of individual ABPM variation over time. Based on clinical 
rationale and following the reasoning in recent FDA reviews such as FDA 2007, the 
trough to peak ratios of DBP (and SBP) were re-defined on a treatment group level based 
on the time course of the 24 hours ABPM. As a consequence, the analysis in the protocol 
(which assumed a definition on a subject level) was replaced by descriptive statistics 
[Section 10.7].  


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4.1.3 Safety analysis 
As exploratory analyses, the change from baseline to Week 8 in hemoglobin and weight 
will be analyzed using the MCP-Mod approach [see Sections 10.9.4 and 10.9.5] to 
explore whether there is a dose-response relationship for these variables which are 
associated with the safety of ACT-132577. 
4.2 Changes in the conduct of the study / data collection 
A blinded sample size re-estimation was introduced in Version 3 of the protocol. This 
sample size re-estimation was based on the standard deviation (SD) of the primary 
endpoint, change from baseline to Week 8 in DBP as measured by OBPM in the PPS. As 
a consequence the number of randomized subjects was lowered to 490 (instead of the 
foreseen 540). The lower sample size did not affect the conduct of the study or the 
analysis of the data. 
After database lock but before unblinding, it was noticed that one subject who had a 
Week 8 sitting diastolic blood pressure (SiDBP) outside of the analysis window was, 
however, included in the PPS (after accounting for the protocol deviations [PDs] present 
in the database). The decision was taken by management not to unlock the database and 
to maintain the PPS as it was. The subject remained in the PPS, with a missing value for 
the Week 8 SiDBP. 
5 
DEFINITIONS OF VARIABLES 
Baseline assessments refer to the last available measurement before the start of 
double-blind treatment.  
If date and time of the measurement are collected, baseline is the last one up to the start 
date and time of the double-blind treatment. If only the date is collected, baseline is the 
last one before the start date of the double-blind treatment. For ABPM baseline is the 
period from date/time of last run-in placebo intake up to the date/time of the first 
double-blind treatment intake, i.e., a maximum of 25 hours. 
Screening assessments refer to last available measurement before or on run-in start date 
(Visit 1) before the start of placebo run-in medication. 
5.1 Subjects disposition 
Screened subjects: are all subjects who received a subject number. 
Screening failures: are all subjects with answer ‘NO’ to the question ‘Is the subject 
eligible for the Run-in period?’ in the Eligibility - Run-in Period eCRF).  
Reason for screening failure is collected in the same eCRF form. 
Subjects who failed screening twice will only be counted once (and only the reason for 
the last screening failure will be tabulated). 


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Subjects in Run-in: are all subjects with answer ‘YES’ to the question ‘Is the subject 
eligible for the Run-in period?’ in the Eligibility - Run-in Period eCRF. 
Run-in failures: are all subjects in Run-in with answer ‘NO’ to the question ‘Was the 
subject randomized?’ in the Randomization eCRF. Reason for run-in failure is collected 
in the same eCRF form.  
Randomized subjects: are all subjects who received a randomization number from the 
Interactive Voice Response System (IVRS). 
5.2 Subject characteristics 
5.2.1 Demographics 
Demographic variables are those collected at Screening on the Demographics eCRF 
pages 12–13 (or on page 14 in the event of Re-Screening): 
• Sex 
• Age 
• Race (Black or African American; American Indian or Alaska Native; Native 
Hawaiian or Other Pacific Islander; Asian; White; Other) 
• Ethnicity 
• Country (derived from site number) 
5.2.2 Baseline disease characteristics 
Baseline disease characteristics include: 
• Duration of essential hypertension (years) at Screening [see Section 11.8 for 
definition] 
• Treatment for hypertension ongoing at Screening (Y/N), as collected in the 
Treatment of Hypertension - Summary eCRF. 
• Mean trough sitting diastolic blood pressure (SiDBP) at Screening as measured by 
OBPM 
• Mean trough sitting systolic blood pressure (SiSBP) at Screening as measured by 
OBPM 
5.2.3 Other baseline characteristics 
Other baseline characteristics, recorded on the Height, Body Weight & BMI eCRF 
page 22, at Screening and/or Re-Screening include: 
• Height (cm) at Screening 
• Body weight (kg) at Screening 
• Body Mass Index (BMI; kg/m2) at Screening 


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When necessary, height and body weight are converted into cm and kg, respectively 
[according to conversion rules detailed in Section 11.9]. BMI (kg/m2), derived according 
to the formula in Section 11.10, is collected in the eCRF and will not be (re-) calculated. 
In the event of re-screening, the last available measurement has to be considered in the 
analysis. 
5.2.4 Medical history 
Medical history includes previous and/or concomitant diseases or diagnoses collected on 
the Medical History eCRF page 15. Reported terms are coded using the MedDRA 
dictionary, Version 19.0. 
Any disease or diagnosis is defined as previous if ‘Ongoing at Screening’ is not answered 
with ‘Yes’; all other diseases/diagnoses are considered as concomitant. 
5.2.5 Previous and concomitant therapies 
Therapies are collected in the Previous/Concomitant Medication eCRF, and terms are 
coded using the WHO drug code dictionary and the anatomic therapeutic chemical (ATC) 
class code using the versions available at database lock 
A previous therapy is any treatment for which the end date is prior to the start of study 
(i.e., signing of informed consent). If the end date is missing and the start date of therapy 
is prior to the date of informed consent, then the therapy is considered as previous if 
‘Ongoing at start of treatment?’ is not ticked with ‘Yes’. 
A study-concomitant therapy is any treatment that is ongoing or initiated after signing of 
informed consent, or initiated up to 30 days after the DB study treatment discontinuation 
(Visit 8).  
A double-blind treatment concomitant therapy is any treatment that is either ongoing at 
the start of DB study treatment (i.e., Day 1 – Visit 4 / Randomization) or is initiated 
during the DB treatment period. 
Rules for handling partial or missing dates are detailed in Section 12. 
Forbidden concomitant therapies 
The following concomitant therapies are forbidden from Screening Visit (i.e., Visit 1) 
until the WD-EOT Visit (i.e., Visit 8): 
• Any drug which may affect BP e.g., ophthalmic preparation, sympathomimetics (any 
formulation of decongestants), corticosteroids (intermittent use of topical/nasal 
applications excluded), cyclosporin, tacrolimus, erythropoietin, diet pills, herbal 
supplements, homeopathic compounds, treatment for psychiatric diseases [see 
protocol synopsis Appendix A]. 


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• Endothelin receptor antagonists, and phosphodiesterase type-5 inhibitors. 
• Strong inhibitors or inducers of cytochrome P450 3A4 isoenzyme [see protocol 
synopsis Appendix A]. 
These definitions will be used in the clinical review to identify potential PDs. Forbidden 
medication will not be tabulated as such.  
Specific previous and concomitant therapies  
Not applicable. 
5.2.6 Other subject characteristics 
Not applicable.  
5.3 Study treatment duration and compliance 
5.3.1 Study treatment duration 
Double-blind treatment duration is defined as the number of days between the first dose 
of double-blind study treatment [see definition in Section 11.2] and the last dose of 
double-blind study treatment [see definition in Section 11.4] plus one day, without taking 
into account interruptions. For the purpose of tabulation treatment duration will also be 
expressed in weeks, calculated by dividing the above treatment duration (in days) by 7. 
In addition, run-in treatment duration is defined as the number of days between the first 
dose and last dose of open-label placebo run-in treatment. 
5.3.2 Compliance with study treatment 
Double-blind treatment compliance is based on the Study Drug Dispensing & 
Accountability eCRF. Run-in treatment compliance is based on the same eCRF. 
As per section 5.1.4.2 of the protocol, all subjects had to take 2 capsules o.d. every 
morning from the morning of Visit 4 / Randomization (i.e., Day 1, after completion of the 
baseline 24-hour ABPM recording) to the morning of Visit 7 / Part 1. 
Compliance between Visit 4 and Visit 7 / Part 1 will be then calculated as follows: 
Compliance =  
[(number of capsules dispensed at Visit 4 – number of capsules returned at Visit 6 + 
number of capsules dispensed at Visit 6 – number of capsules returned at Visit 7)/  
(Total number of capsules that should have been taken)] × 100. 
The number of capsules that should have been taken during the double-blind period is the 
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Run-in compliance between Visit 1 and Visit 4 / Part 1 will be calculated similarly.  
Here the expected number of capsules is the run-in treatment duration (in days) as 
defined in Section 5.3.1, multiplied by 2. 
5.3.3 Study treatment discontinuation  
A subject is considered to have prematurely discontinued double-blind study treatment if 
the ‘reason for treatment end’ in the Study drug Log eCRF is ‘PREMATURE 
DISCONTINUATION’ and the ‘Study Period’ is ‘DB TREATMENT’. The reason for 
premature discontinuation will be taken from the Premature Discontinuation of Study 
Treatment eCRF and the study period is ‘DB TREATMENT’. 
Discontinuation from run-in study treatment is defined similarly and the reason will be 
taken from the same eCRF, but with study period = ‘RUN-IN TREATMENT’. 
Discontinuation from withdrawal study treatment (listed only) is defined similarly with 
study period = ‘SB WITHDRAWAL’. In those cases where a subject completed the 
double-blind treatment period, but did not start the withdrawal period, the reason for 
treatment discontinuation will be allocated to the withdrawal period. 
5.3.4 Study treatment adjustments or interruptions 
Study treatment interruptions in the double-blind period are recorded in the Study drug 
Log when ‘Study Period’ is ‘DB TREATMENT’. A subject is considered to have had a 
study treatment interruption if the reason for treatment end is either ‘Temporarily 
interrupted due to an AE’ or ‘Temporarily interrupted not due to an AE’. 
5.4 Study discontinuation 
Subjects who completed the study as per protocol are those with the question “Did the 
subject complete the study?” answered “Yes” in the End-of-Study eCRF. 
On the other hand, a subject is considered to have prematurely discontinued the study if 
the answer to the question ‘Did the subject complete the study?’ in the End-of-Study 
eCRF is ‘No’. The reason for study stop is derived from the same form. Reasons for 
study withdrawal are: Death, Lost to follow up, Subject decision, Physician decision, 
Sponsor decision. 
5.5 Efficacy variables 
All efficacy data are collected electronically and are transferred to Actelion by 
 
. 
OBPM, SiDBP and SiSBP (mmHg) are measured at the study site by the BpTRU® device 
using six measurements per subject / visit. These measurements and their average 
(excluding the first measurement) are uploaded into the 
 database. The data 


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transfer from 
 to Actelion includes the separate measurements as well as the 
average which will be used as the subject’s SiDBP or SiSBP value for that visit. The 
average will not be re-calculated by the sponsor. The sponsor will perform spot checks to 
confirm that the average was been correctly calculated 
 
ABPM is performed over a 24-h period with the ABPM device set to record DBP and 
SBP at a pre-defined inflation sequence over the 24-h period including three 
measurements per hour during the day and two per hour during the night. ABPM data are 
electronically transferred to 
 and subsequently to Actelion. The 
 supplements each ABPM reading with an indicator of whether the reading 
satisfied the quality control criteria agreed between 
 and Actelion 
 
 
1. Start time of ABPM is between 06:00 and 11:00 
2. Duration of ABPM is at least 24 hours 
3. Percentage of valid readings in the period of duration is at least 75% 
4. Number of required hours (i.e., hours with at least one reading) is at least 22 
5. Number of exception hours (i.e., hours without a reading) is at most 2 
6. No two consecutive exception hours 
In addition, there is an indicator (Y/N) for the overall quality of the ABPM reading. This 
is only set to Y if all six criteria are met. 
It should be noted that when an ABPM reading does not satisfy all 6 criteria, this does not 
necessarily mean that this reading should be excluded from the analysis as the ABPM 
analysis primarily focuses on the 24 hour means 
 
. For the analysis of 24 hour means, criteria 3 and 6 are considered to be the 
most relevant ones by Actelion. 
For this reason, the ABPM analyses will be based on the subset of subjects from the PPS 
with baseline and Week 8 ABPM readings satisfying quality criteria 3 and 6 (i.e., ABPM 
readings having less than 75% valid readings and/or two consecutive exception hours will 
be excluded). As this subset is likely to be comprised of < 50% of subjects, formal 
dose-response analyses for the ABPM endpoints will be carried out as needed. 
All assessments (including the unscheduled ones) are considered and re-assigned to the 
most appropriate visit according to the time windows described in Section 11; reference 
to visits are to be intended as references to re-mapped visit, i.e., time window visits. 
5.5.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is the change from baseline to Week 8 of DB treatment 
period (Period II) in mean trough (i.e., 24 hours post-dose) SiDBP, measured by OBPM. 


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Baseline is defined as described in Section 5. Week 8 is the time window of Visit 7 
[Section 11.1].  
SiDBP is retrieved from the SDTM VS domain selecting VSTESTCD=“DIABP” and 
VSSCAT =‘Average’. 
5.5.2 Secondary efficacy endpoints 
• Change from baseline to Week 8 of DB treatment period (Period II) in mean trough 
SiSBP, measured by OBPM and collected as described for SiDBP. 
– SiSBP is retrieved from the SDTM VS domain selecting VSTESTCD=“SYSBP” 
and VSSCAT =‘Average’. 
• Control and response status at Week 8 of DB treatment period (Period II) based on 
trough SiDBP, measured by OBPM; 
– Controlled, if mean SiDBP < 90 mmHg; 
– Responder, if the reduction from baseline in mean SiDBP ≥ 10 mmHg; 
– Controlled according to CHEP guidelines [Leung 2016], if mean SiDBP 
< 85 mmHg. 
• Control and response status at Week 8 of DB treatment period (Period II) based on 
trough SiSBP, measured by OBPM; 
– Controlled, if mean SiSBP < 140 mmHg; 
– Responder, if the reduction from baseline in mean SiSBP ≥ 20 mmHg; 
– Controlled according to CHEP guidelines [Leung 2016], if mean SiSBP 
< 135 mmHg. 
• Change from baseline to Week 8 of DB treatment period (Period II) in 24-hour mean 
DBP, measured by ABPM; 
– ABPM will be measured before start of treatment (Day -1, Visit 4) and after the 
last dose (Day 55, Visit 7). At each visit the 24-hour mean DBP will be derived 
from the area under the DBP-time curve, divided by the time span. [See Figure 1 
for clarification.] Time points later than 25 hours after the first time point will be 
excluded from the calculation. The change from baseline to Week 8 will be 
obtained as the difference in 24-hour mean DBP ABPM between Visit 7 and Visit 
1. 
• Change from baseline to Week 8 of DB treatment period (Period II) in 24-hour mean 
SBP, measured by ABPM; 
– The change from baseline to Week 8 will be obtained as the difference in 24-hour 
mean SBP ABPM between Visit 7 and Visit 1, where the 24-hour mean SBP 
ABPM is calculated similar to the 24-hour mean DBP ABPM. 


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• Trough to peak ratio for DBP based on ABPM. 
– The trough to peak ratio will be derived on treatment group level [FDA 2007] 
based on the time course of ABPM and will be corrected for baseline according to 
the following steps: 
o Patient level: for each visit (Visit 4 / Day -1 and Visit 7 / Part 1) the 
patient’s ABPM-DBP will be averaged by hour after drug intake (0, 1, .., 
24), applying a window of 30 minutes around each hour (lower limit 
excluded; upper limit included).  
o Group level: for each visit (Visit 4 / Day -1 and Visit 7 / Part 1) and hour 
after drug intake (0, 1, .., 24) the ABPM-DBP will be averaged by 
treatment group. 
o Group level: for each hour after drug intake (0, 1, .., 24) and the treatment 
group the difference in mean ABPM-DBP between Week 8 (Visit 7 
Part 1) and baseline (Visit 4 Part 1) will be obtained. 
o Group level: the trough to peak ratio will be calculated as the average of 
the (five) differences at hours 20–24 (expected trough) divided by the 
average of the (five) differences at hours 2–6 (expected peak at 
4 hours ± 2 hours) [See Appendix C for illustration.] 
Baseline is defined as described in Section 5 and Week 8 is the time window of Visit 7 
[Section 11.1].  
In the evaluation of changes from baseline and control/response status, only subjects with 
both the baseline and the time point assessments available will be included. 
5.5.3 Other efficacy endpoints 
• Changes from baseline to time window Visit 5 (Week 2) and time window Visit 6 
(Week 4) of DB treatment period (Period II) in mean trough SiSBP and SiDBP 
(measured by OBPM); 
• Change from baseline to Week 8 of DB treatment period (Period II) in mean daytime 
ABPM; 
– Change from baseline in mean daytime DBP. All ABPM measurements taken 
between 09:00 and 21:00 will be included in this calculation [O’Brien 2013]; 
there may be two parts of the daytime DBP-time curve to be considered for a 
subject at a given visit, one for each calendar day of Visits 4 and 7. At each visit 
the mean daytime DBP will be derived from the area under the DBP-time 
curve(s), divided by the time span(s) [see Appendix B for clarification]. The 
change from baseline to Week 8 will be obtained as the difference in mean 
daytime DBP ABPM between Visit 7 and Visit 4.  
– Change from baseline in mean daytime SBP. Similar to change from baseline in 
mean daytime DBP. 


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• Change from baseline to Week 8 of DB treatment period (Period II) in mean night 
time ABPM; 
– Change from baseline in mean night time DBP. All ABPM measurements taken 
between 01:00 and 06:00 will be included in this calculation [O’Brien 2013]; 
there should be one night time part of the DBP-time curve to be considered for 
each subject at a given visit; in the unlikely event that there are two, only the first 
one will be used). At each visit the mean night time DBP will be derived from the 
area under the DBP-time curve, divided by the time span [see Appendix B for 
further specification]. The change from baseline to Week 8 will be obtained as the 
difference in mean daytime DBP ABPM between Visit 7 and Visit 4. 
– Change from baseline in mean night time SBP. Similar to change from baseline in 
mean night time DBP. 
• Trough to peak ratio for SBP based on ABPM; 
– The trough to peak ratio for SBP will be derived on treatment group level based 
on the time course of ABPM as similar to the trough to peak ratio for DBP. 
• Changes from baseline to time window Visit 8 (Week 10 i.e., Week 2 of withdrawal 
period - Period III) in mean trough SiSBP and SiDBP (measured by OBPM); 
• Changes from Week 8 of Period II to time window Visit 8 (Week 10 i.e., Week 2 of 
withdrawal period - Period III) in mean trough SiSBP and SiDBP (measured by 
OBPM). 
5.5.3.1 Illustration of derivation of ABPM endpoints 
The derivation of the various endpoints based on ABPM is illustrated by means of an 
example. Figure 1 displays the DBP and SBP measured by ABPM in one subject at one 
visit. The data underlying this example figure are included in Appendix B.  
Since ABPM measurements are obtained during 24 hours at two consecutive calendar 
days, the time on the horizontal axis runs from 0–48 hours, clock times 0:00–23:59 
corresponding to the first day and times 24:00–48:00 to the second day The ABPM 
started on 10:29 on the first day and finished on 11:04 on the second day [35:04 in 
Appendix B].  




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88,500 sec gives a 24-hour means of 97.6 and 146.4 mmHg for DBP and SBP, 
respectively.  
– The trapezoidal rule will be applied up to the last measurement within 25 hours. If 
there is another measurement after 25 hours, there will be NO interpolation up to 
25 hours exactly. 
• The mean daytime DBP (SBP) is based on two periods: from 10:29 to 21:00 (limits 
included) on the first day and from 09:00 to 11:04 on the second day (limits included; 
33:00 to 35:04 in Appendix B). The mean daytime DBP and SBP are 99.5 mmHg and 
143.9 mmHg, respectively. 
• The mean night time DBP (SBP) is based on the measurements between 01:00 and 
06:00 on the second day (limits included; 25:00 to 30:00 in Appendix B). The mean 
night time DBP and SBP are 78.4 mmHg and 135.5 mmHg, respectively. 
• Note that measurements between 21:00 on the first day and 01:00 on the second day 
(limits excluded) and between 06:00 and 09:00 on the second day (limits excluded) 
are only included in the calculation of the 24-hour means, but not in the calculation of 
the daytime or night time means. 
5.6 Safety variables 
All assessments are considered and re-assigned to the most appropriate visit according to 
the time windows described in Section 11; reference to visits are to be intended as 
references to re-mapped visit, i.e., time window visits. 
The following safety variables will be evaluated: 
• Treatment-emergent adverse events (AEs); 
• AEs leading to premature discontinuation of study treatment; 
• Treatment-emergent deaths; 
• Treatment-emergent serious adverse events (SAEs); 
• Treatment-emergent electrocardiogram (ECG) abnormalities; 
• Treatment-emergent marked laboratory abnormalities; 
• Changes from baseline to time window Visits 5, 6 and 7 (Weeks 2, 4 and 
8, respectively) of DB treatment period (Period II) in laboratory parameters; 
• Changes from baseline to time window Visits 6 and 7 (Week 4 and Week 8, 
respectively) of DB treatment period (Period II) in ECG parameters (pulse rate [PR], 
QRS, QT, QTcB, QTcF); 
• Changes from baseline to time window Visits 5, 6 and 7 (Weeks 2, 4 and 8, 
respectively) of DB treatment period (Period II) in body weight and PR (BpTRU®). 
5.6.1 Adverse events 
An AE is defined as any term reported by the investigator in the Adverse Event eCRF. 
The original terms used by the investigators to describe AEs are assigned preferred terms 
for classification and tabulation using the MedDRA dictionary, Version 19.0. 


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5.6.1.1 Treatment-emergent adverse events 
Double-blind treatment-emergent AEs are defined as those AEs with onset on or after the 
double-blind treatment start date [see definition in Section 11.2] up to the double-blind 
treatment end date [see definition in Section 11.4] plus 30 days (included). Run-in 
treatment-emergent AEs are AEs with onset dates between the start and end dates of the 
run-in placebo (or the start of double-blind treatment, if applicable; limits included). 
5.6.1.2 Frequency of treatment-emergent adverse events 
Except otherwise specified, the counting of treatment-emergent AEs in the summary 
table is handled as follows: 
• Subjects who experienced the same AE more than once (as qualified by the same 
preferred term[s]) are counted only once. 
• In the event that the reported AE is assigned to several preferred terms, subjects are 
counted for each individual preferred term.  
5.6.1.3 Intensity of treatment-emergent adverse events 
The intensity of an AE is determined by the investigator as ‘mild’, ‘moderate’ or ‘severe’.  
AEs reported more than once (as qualified by the same preferred term) for a subject 
within a specified time period but with different intensities are counted only once, with 
the worst reported intensity in the corresponding analysis. If intensity is missing, the 
event is considered severe. 
5.6.1.4 Relationship of treatment-emergent adverse events 
Relationship to study treatment is determined by the investigator as ‘related’ or ‘not 
related’. An event is considered related if the response to the question ‘Relationship to 
study treatment?’ is answered ‘Related’. 
For AEs reported more than once (as qualified by the same preferred term) for a subject 
within a specified time period, the worst relationship reported is taken. AEs with missing 
relationship are considered in any analysis as ‘Related’. 
5.6.2 Deaths 
Death information is taken from the Death eCRF. The primary cause of death is reported 
on the same form. 
The original terms used by the investigators to describe the primary death cause are 
assigned preferred terms for classification and tabulation using the MedDRA dictionary. 
Double-blind treatment-emergent deaths are those with occurrence on or after the 
double-blind treatment start date [see definition in Section 11.2] up to the double-blind 
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treatment-emergent deaths are deaths that occur between the start and end of the run-in 
placebo (or the start of double-blind treatment, if applicable; limits included). 
5.6.3 Serious adverse events 
An SAE is defined as an AE with “Serious?” = “Yes” on the Adverse Events eCRF.  
Double-blind treatment-emergent SAEs are all SAEs with onset on or after the 
double-blind treatment start date [see definition in Section 11.2] up to the double-blind 
treatment end date [see definition in Section 11.4] plus 30 days (included). Run-in 
treatment-emergent SAEs are SAEs with onset date between the start and end dates of the 
run-in placebo (or the start of double-blind treatment, if applicable; limits included). 
5.6.4 Adverse events leading to discontinuation of study treatment 
These are AEs with ‘Action taken with study drug’ recorded as ‘permanently 
discontinued’ on the Adverse Event eCRF. 
5.6.5 Other adverse events  
Not applicable. 
5.6.6 Physical examination, vital signs and body weight 
Vital signs include PR measured by BpTRU® (simultaneously with BP; the mean is 
provided in the same way, i.e., based on the last 5 of 6 measurements) and body weight 
(DBP and SBP are evaluated as efficacy endpoints). For PR, the value is retrieved from 
the SDTM VS domain by selecting VSTESTCD = “HR” and VSSCAT = ‘Average’. 
All assessments (including the unscheduled ones) are considered and re-assigned to the 
most appropriate visit according to the time windows described in Section 12. 
5.6.7 Electrocardiogram 
A standard 12-lead ECG is performed as defined in the Schedule of Assessments. 
Historical ECG is accepted for Visit 1, if not older than 6 months. Digital 12-lead ECG 
devices will be provided to each site by the central ECG laboratory for the duration of the 
study. All assessments (including the unscheduled ones) are considered and re-assigned 
to the most appropriate visit according to the rules described in Section 11.1. 
The following variables will be evaluated: heart rate (HR; bpm), PR (ms), QRS (ms), QT 
(ms), QTc (ms). In addition, the percentage of subjects with any ECG findings will be 
evaluated. 
QTc (ms) will be calculated according to Fridericia’s formula QTcF = QT/(RR)⅓. 


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ECG data will be electronically transferred from the ECG laboratory database to Actelion 
and will not be (re-)calculated. Note that ECG HR will be evaluated only in the context 
of the ECG. For vital signs, PR will be used based on BpTRU®. 
5.6.7.1 Treatment-emergent ECG abnormalities 
Double-blind treatment-emergent ECG abnormalities are defined as follows: 
• QTcF (Fridericia’s formula) maximum value > 450 ms (H), > 480 ms (HH), or 
> 500 ms (HHH); 
• Maximum increase from baseline in QTcF (Fridericia’s formula) > 30 ms (HH), 
> 60 ms (HHH). 
In addition, each of the six combinations of maximum QTcF and increase in QTcF will 
be considered. 
Note that, in order to allow appropriate interpretation of overall incidence of 
abnormalities > 450 ms, the marked abnormalities are presented cumulatively, e.g., a 
QTc value of 501 ms is reported in > 450 ms (H), > 480 ms (HH) and > 500 ms (HHH) 
categories; the same holds for abnormalities related to changes from baseline (i.e., they 
are presented cumulatively). 
Treatment-emergent ECG abnormalities are defined as those abnormalities with onset on 
or after the double-blind treatment start date [see definition in Section 11.2] up to the 
double-blind treatment end date [see definition in Section 11.4] plus 30 days (included): 
i.e., the highest QTc absolute value and the highest QTc change value at any 
post-baseline time point of assessment up to 30 days after study treatment discontinuation 
are considered in the evaluation of the categories, as defined above. 
5.6.8 Laboratory 
Laboratory data are evaluated in standard international units as provided by the central 
laboratory. The following tests are considered: 
• Hematology: hemoglobin, hematocrit, erythrocyte count, leukocyte count with 
differential counts, platelet count.  
• Chemistry: 
aminotransferases 
(aspartate 
aminotransferase 
[AST] 
/ 
alanine 
aminotransferase [ALT]), alkaline phosphatase [AP], total and direct bilirubin, lactate 
hehydrogenase, creatinine, creatinine clearance, uric acid, glucose, sodium, 
potassium, total protein, albumin, thyroid hormones (triiodothyronine [free T3], 
thyroxine [free T4]) and thyroid-stimulating hormone. 
• Urinalysis: Urine albumin-to-creatinine ratio (UACR). 


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For woman of childbearing potential, urine as well as serum pregnancy tests are 
performed, but these results will not be summarized as part of the laboratory data. 
Positive pregnancy tests (if any) will be reported. 
Results of local laboratory tests (collected on the Local Laboratory eCRF) may be used 
to identify marked abnormalities, but only if no central laboratory test has been 
performed in the same time window. Local laboratory test results will not be used in 
summaries, but will still be listed. 
5.6.8.1 Treatment-emergent marked laboratory abnormalities 
The marked laboratory abnormalities are given in Table 2, copied from appendix 1 of the 
protocol. 


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Table 2 
Thresholds for marked laboratory abnormalities 
 
Parameter 
LL 
LLL 
HH 
HHH 
HHHH 
Hematology 
Hemoglobin  
< 100 g/L 
(< 10 g/dL;  
< 6.2 mmol/L) 
< 80 
(< 8 g/dL;  
< 4.9 mmol/L;) 
Increase in > 20 g/L 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in > 40 g/L 
above ULN or above 
baseline if baseline is 
above ULN 
 
Hematocrit 
< 28% for females  
< 32% for males 
< 20% 
> 60% in men 
> 55% in women 
> 65% 
 
Leukocytes  
< 3.0 × 109/L  
(< 3000/mm3) 
< 2.0 × 109/L 
(< 2000/mm3) 
> 20.0 × 109/L 
(> 20,000/mm3) 
> 100.0 × 109/L 
(> 100,000/mm3) 
 
Platelet count  
< 75 × 109/L 
(< 75,000/mm3) 
< 50 × 109/L  
(< 50,000/mm3) 
> 600× 109/L  
> 999× 109/L 
 
Neutrophils  
< 1.5 109/L  
(< 1500/mm3) 
< 1.0109/L  
(< 1000/mm3) 
NA 
NA 
 
Eosinophils 
NA 
NA 
> 5.0 × 109 or  
> 5% ( > 5000 cells/mm3) 
NA 
 
Lymphocytes 
< 0.8 × 109/L  
(< 800/mm3) 
< 0.5 × 109/L 
(< 500/mm3) 
> 4.0 × 109/L  
(> 4000/mm3) 
> 20 × 109/L  
(> 20,000/mm3) 
 


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Parameter 
LL 
LLL 
HH 
HHH 
HHHH 
Blood Chemistry 
AST (U/L) 
NA 
NA 
> 3 × ULN 
> 5 × ULN 
> 8 × ULN 
ALT (U/L) 
NA 
NA 
> 3 × ULN 
> 5 × ULN 
> 8 × ULN 
AP 
NA 
NA 
> 2.5 × ULN 
> 5 × ULN 
 
Bilirubin Total (µmol/L) 
NA 
NA 
> 2 × ULN 
> 5 × ULN 
 
Creatinine  
NA 
NA 
> 1.5 × ULN or 
> 1.5 × baseline 
> 3 × ULN or 
> 3 × baseline 
 
Creatinine clearance  
< 60 mL/min 
< 30 mL/min 
NA 
NA 
 
Glucose  
< 3.0 mmol /L 
(< 55 mg/dL) 
< 2.2 mmol /L 
(< 40 mg/ dL) 
> 8.9 mmol /L 
(> 160 mg/dL) 
> 13.9 mmol /L 
(> 250 mg/ dL) 
 
Sodium  
 
< 130 mmol/L 
(< 130 mEq/L) 
> 150 mmol/L  
(> 150 mEq/L) 
> 155 mmol/L  
(> 155 mEq/L) 
 
Potassium  
< 3.2(mmol/L) 
< 3.0(mmol/L) 
> 5.5(mmol/L) 
> 6.0(mmol/L) 
 
Uric acid  
NA 
NA 
> 590 (umol/L) 
(> 10 mg/dL) 
> 720 (umol/L) 
(> 12 mg/dL) 
 
Albumin  
< 30 g/L 
(< 3.0 g/dL) 
< 20(g/L 
(< 2.0 g/dL) 
- 
- 
 
ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; NA = not applicable; ULN = upper limit of 
normal. 
 




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4. PD during DB treatment period 
5. PD during withdrawal period and follow-up 
Each PD is classified as important or not. Only important PDs during time periods 3, 4 
and 5 will be summarized by treatment group for the RND set. (All PDs will be listed.) 
Note that an important PD does not necessarily lead to exclusion from the PPS [see 
Section 7.1.6], whereas an unimportant PD may lead to exclusion from the PPS. The 
subset of PDs leading to exclusion from the PPS are: 
1. Double-blind treatment duration less than 49 days: PV_PP.535. 
2. No or no valid Week 8 SiDBP (hence, no primary endpoint): PV_PP.501 and 
PV_MM.501. 
3. Anti-hypertensive treatment still ongoing at randomization: PV_MM.307. 
4. Taking medication during the double-blind treatment interfering with the primary 
efficacy 
parameter 
(SiDBP): 
PV_MM.503, 
PV_MM.504, 
PV_MM.506, 
PV_MM.507, PV_MM.508, PV_MM.509, PV_MM.534. 
5. Compliance with double-blind treatment < 80% or > 120% or treatment not taken 
as per protocol: PV_PP.502 and PV_MM.515. 
Note that exclusion will be done on a subject basis (rather than on subject / visit basis). In 
this particular study this approach is not unreasonable since PDs 1–5 are related to the 8 
week DB treatment period and the primary efficacy endpoint is measured at the end of 
that period. 
The one PD leading to exclusion from the Pharmacokinetic (PK) Set [see Section 7.1.6] 
is that the PK sample for that subject/visit was not taken at trough: PV_MM.512. 
7 
ANALYSIS SETS 
7.1 Definitions of analysis sets 
7.1.1 Screened Set 
The Screened Set (SCR) includes all subjects who received a subject number. 
7.1.2 Run-in Set 
The RIS includes all subjects who received at least one dose of SB placebo in Period I. 
7.1.3 All Randomized Set 
The RND includes all subjects who received a randomization number from the IVRS. 


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7.1.4 Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects in the RND Set who have a baseline 
mean trough SiDBP. Subjects are evaluated according to the study treatment they have 
been assigned to (which may be different from the study treatment they have received). 
7.1.5 Per-Protocol Set 
The PPS includes all subjects from the FAS who have a mean trough SiDBP at Week 8 
of Period II and do not have any important PD as defined in Section 6. Subjects are 
evaluated according to the study treatment they have been assigned to. 
7.1.6 Safety Set 
The Safety Set (SAF) includes all subjects who received at least one dose of study 
treatment in Period II. Subjects are evaluated according to the study treatment they have 
received. 
7.1.7 Pharmacokinetic Set 
The PK Set includes all subjects from the PPS who had at least one evaluable PK trough 
sample. Subjects are evaluated according to the study treatment they have received. 
8 
DEFINITION OF SUBGROUPS 
All subgroup analyses will be performed to investigate the consistency of the treatment 
across subgroups defined by: 
Age 
< 65 versus ≥ 65 years 
 
18–64, 65–84 and ≥ 85 years; for European Clinical Trials (EudraCT) 
Database purposes only 
Sex 
Female, male 
Race 
Black or African American; American Indian or Alaska Native; Native 
Hawaiian or Other Pacific Islander; Asian; White; Other. 
Categories containing less than 5% of randomized subjects will be considered 
in the category ‘Other’ for purpose of analysis. 
Country United States (including Puerto Rico, USA); Canada (CAN); Israel (ISR) 
9 
GENERAL STATISTICAL METHODOLOGY 
This section describes the general statistical methodology, independent of which analysis 
data set is used. These aspects will be addressed in Section 10. SAS and R programming 
statements are provided to specify the details of the analyses. 


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9.1 Missing data 
All analyses based on the PPS will be based on observed cases (OC). It is acknowledged 
that the PPS analyses are based on a selected subset of patients who completed the 
8 weeks of DB treatment with sufficient compliance and who have no missing data at 
Week 8. For the assessment of dose-response reliance on this subset was deemed 
appropriate.  
In analyses based on the FAS missing data will be imputed using last observation carried 
forward (LOCF). This may be justified as a conservative analysis since in this study the 
majority of patients are expected to improve over time [EMA 2010].  
Baseline observation carried forward (BOCF) will be used as a sensitivity analyses for 
missing data imputation. Another sensitivity analysis is provided by a mixed model 
which does not impute the missing data and, in that sense, can be seen as a OC analysis. 
Mixed models are based on the missing at random (MAR) assumption, i.e.: missing data 
can be fully accounted for by baseline covariates and prior measurements. The MAR 
assumption is not unreasonable in the hypertension context, although it cannot be proven.  
9.2 Dose-response analysis for the primary endpoint 
Dose-response data include changes from baseline to Week 8 of DB treatment period in 
mean trough SiDBP (primary endpoint) and mean trough SiSBP (secondary endpoint). 
These data will be analyzed using the MCP-Mod approach [Bretz 2005, Pinheiro 2006]. 
In brief, this methodology consists of two steps: 
1. MCPs step to establish a dose-response signal (i.e., the dose-response curve is not 
flat) using MCPs. 
2. Modeling (Mod) step to estimate the dose-response curve and target doses using 
modeling techniques. 
In this study six models have been pre-specified in the protocol for consideration in all 
MCP-Mod analyses: linear, linear in log (linlog), quadratic, maximum effect (Emax), 
sigmoidal Emax and logistic. See Table 3 for the parameterization of the dose-response 
models and Figure 2 as an illustration of their basic shapes. The initial values for the 
parameters are needed in the MCP step of the procedure. They will be estimated in the 
Mod step based on the actual data.  




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The Lisinopril group will be excluded from all analyses of the dose-response. Note that 
the ‘Model means’ on the vertical axis are plotted on a scale from 0 to -1 for illustrative 
purposes. The actual scale will depend on the endpoint analyzed. 
The null hypothesis of ‘no dose-response’ will be rejected if at least one of the six 
Multiple Contrast Tests (MCTs) has a multiplicity adjusted p-value < 0.05. All 
statistically significant models (i.e., with an adjusted p-value < 0.05) are fitted in the Mod 
step and for each model Akaike’s Information Criterion (AIC) is calculated. The smaller 
the value of AIC (= model deviance + 2 times the number of model parameters), the 
better the fit. The analysis will be performed using the R-package DoseFinding 
[Bornkamp 2016]. The basic R-code is: 
library(DoseFinding) 
doses <- c(0, 5, 10, 25, 50) 
candMod <- Mods(linear = NULL, linlog = NULL, quadratic = -0.005, emax = 50, 
                sigEmax = c(50, 0.5), logistic = c(50, 50), doses = doses, 
                direction=“decreasing”) 
MMfit <- MCPMod(dose=dose, resp=resp, data=DF, addCovars=~base, models = 
candMod, Delta=3) 
 
In the Mods function call the candidate models are specified, together with the assumed 
direction of the effect (decreasing for change from baseline in blood pressure). In the call 
to the MCPMod function, DF is a data frame with objects dose, resp (for response), and 
base (for the baseline value) and Delta is a target difference vs placebo (Delta=3 for 
DBP; Delta=5 for SBP). The object MMfit will be summarized to obtain the MCP test, 
parameter estimates, target dose and AIC. These elements will go in a summary table. 
The object will be plotted to display the fitted dose-response curves. 
Subgroup analyses based on MCP-Mod can be performed by fitting the selected model 
by subgroup using the fitMod function for which the basic R-code is: 
MMfit1 <- fitMod(dose=dose, resp=resp, data=DF[DF$subg==1,], addCovars=~base, 
model=MMfit$selMod) 
MMfit2 <- fitMod(dose=dose, resp=resp, data=DF[DF$subg==2,], addCovars=~base, 
model=MMfit$selMod) 
As a supportive analysis to MCP-Mod, change from baseline to Week 8 in DBP and SBP 
will also be analyzed in an ANCOVA model using the Dunnett test. 
pr oc mi xed dat a=dset ;  
  c l a s s  t r e a t ;  
  mode l  out c ome =t r e a t  ba s e ;  
  l s me a ns  t r e a t /  a dj us t =Dunne t t  di f f =c ont r ol ( ‘ 0’ )  c l ;  
  whe r e  we e k=8 a nd t r e a t  i n ( 0, 1, 2, 3, 4) ;  
r un;  


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9.3 Dose-response analyses for continuous data 
Changes from baseline to Week 8 for other continuous OBPM endpoints will be analyzed 
using the general MCP-Mod approach which consists of two steps.  
First an ANCOVA model is fitted with a factor for treatment group and a covariate for 
the baseline value. The SAS statements (using mock variable names and values) for this 
model are: 
ods out put  l smeans=l sm;  *  expor t  dat a set  l sm as xpt  f i l e;  
pr oc  mi xe d da t a =ds e t ;  
  c l a s s  t r e a t ;  
  mode l  out c ome =t r e a t  ba s e ;  
  l s me a ns  t r e a t /  c ov;  
  whe r e  we e k=8 a nd t r e a t  i n ( 0, 1, 2, 3, 4) ;  
r un;  
Here, treat=0, 1, 2, 3, and 4 for placebo, 5 mg, 10 mg, 25 mg and 50 mg of ACT-132577, 
respectively. Note that the active comparator (treat=5) is excluded from this analysis. 
Then the LSMeans from this model will be analyzed using the general MCP-Mod 
approach. The R statements for this analysis are (Delta=3 for DBP; Delta=5 for SBP): 
# read data frame lsm from xpt file 
est <- lsm$ESTIMATE # LSMeans 
C <- lsm[,c(“COV1”,”COV2”,”COV3”,”COV4”,”COV5”)] # covariance matrix 
doses <- c(0,5,10,25,50) 
MMfit <- MCPMod(type=“general”, dose=doses, resp=est, S=as.matrix(C), 
models=candMod, Delta=3, alpha=0.05) 
Repeated measurements (e.g., changes from baseline to Weeks 2, 4 and 8) will be 
analyzed in two ways: focusing on the last time point (e.g., Week 8 and using Week 2 
and Week 4 only to predict missing data, if needed) and estimating the average effect 
over time. In both cases the general MCP-Mod approach was used. 
Last time point. First a mixed model is fitted with factors for treatment group, time and 
treatment by time interaction and covariates for the baseline value and the interaction 
between baseline and time. An unstructured covariance matrix will be used to account for 
the correlation between repeated measurements from the same subject. The SAS 
statements for this model are: 
ods  out put  l s me a ns =l s m1 ( whe r e =( we e k=8) ) ;  * e xpor t  da t a  s e t  l s m1 a s  xpt  f i l e ;  
pr oc  mi xe d da t a =ds e t  noc l pr i nt =6;  
  c l a s s  t r e a t  we e k s ubj i d;  
  mode l  out c ome =t r e a t  we e k t r e a t *we e k ba s e  ba s e *we e k;  
  r e pe a t e d we e k/  s ubj e c t =s ubj i d t ype =un;  
  l s me a ns  t r e a t *we e k/  c ov;  
  whe r e  t r e a t  i n ( 0, 1, 2, 3, 4) ;  
r un;  


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The LSMeans at Week 8 will then be analyzed using the general MCP-Mod approach. 
The R statements for this analysis are the same as above, except for: 
C <- lsm[,c(“COV3”,”COV6”,”COV9”,”COV12”,”COV15”)] # covariance matrix 
 
Average over time. First the same mixed model is fitted, but without the treatment by 
time interaction. The SAS statements for this model are: 
ods out put  l smeans=l sm2;  *  expor t  dat a set  l sm2 as xpt  f i l e;  
pr oc  mi xe d da t a =ds e t  noc l pr i nt =6;  
  c l a s s  t r e a t  we e k s ubj i d;  
  mode l  out c ome =t r e a t  we e k ba s e  ba s e *we e k;  
  r e pe a t e d we e k/  s ubj e c t =s ubj i d t ype =un;  
  l s me a ns  t r e a t /  c ov;  
  whe r e  t r e a t  i n ( 0, 1, 2, 3, 4) ;  
r un;  
 
Then the LSMeans (averages over time) will be analyzed using the same R statements as 
above with: 
C <- lsm[,c(“COV1”,”COV2”,”COV3”,”COV4”,”COV5”)] # covariance matrix 
 
9.4 Dose-response analyses for binary data 
Binary outcomes include the control and response status for DBP (or SBP) at a fixed time 
point and will also be analyzed using the general MCP-Mod approach. First a logistic 
regression model is fitted with a factor for treatment group and a covariate for the 
baseline value of DBP (or SBP). The SAS statements (using mock variable names and 
values) for this model are: 
ods  out put  l s me a ns =l s m;  * e xpor t  da t a  s e t  l s m a s  xpt  f i l e ;  
pr oc  l ogi s t i c  da t a =ds e t  de s c e ndi ng;  
  c l a s s  t r e a t / pa r a m=gl m;  
  mode l  r e s p=t r e a t  ba s e ;  
  l s me a ns  t r t 01pn/  i l i nk c ov;  
  whe r e  we e k=8 a nd t r e a t  i n ( 0, 1, 2, 3, 4) ;  
r un;  
 
 
Then the estimated differences vs placebo (in data set diff) will be analyzed using the 
general MCP-Mod approach [Pinheiro 2014]. 
# read data frame lsm from xpt file 
est <- lsm$MU #LSMeans 
C <- diag(lsm$STDERRMU^2) 
candMod <- Mods(linear = NULL, linlog = NULL, quadratic = -0.005, emax = 50, 


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                sigEmax = c(50, 0.5), logistic = c(50, 50), doses = doses, 
                direction=“increasing”) 
MMfit 
<- 
MCPMod(type=“general”, 
dose=doses, 
resp=est, 
S=as.matrix(C), 
models=candMod, Delta=0.1, alpha=0.05) 
Since control and response statuses are not expected to change much over time (i.e., from 
Week 2 to 8) a repeated measures analysis of these binary endpoints was omitted. 
10 STATISTICAL ANALYSES 
10.1 Overall testing strategy 
All statistical testing will be performed at a two-sided significance level of 0.05 using 
95% confidence intervals (CIs).  
In the main analysis of the primary endpoint in the PPS the type I error is controlled by 
the MCT part of the MCP-Mod methodology. The primary objective of the trial will be 
evaluated based on this analysis. 
The type I error of the MCP-Mod analysis in the FAS is similarly protected. In the other 
supportive analysis of the primary endpoint Dunnett’s test will be used to correct for 
testing multiple doses vs placebo. The alpha is formally controlled only for the main 
analysis; all other analyses are considered exploratory. 
In all analyses of secondary and other efficacy variables, no correction will be made for 
multiple testing. 
10.2 General rules for data presentations 
This section describes the general rules applied for all data displays. 
SAS version 9.3 is used for the statistical analyses except for the primary endpoint 
(dose-response analysis) that is analyzed by means of the R package. 
Unless otherwise specified in this document: 
• All listings are sorted by randomized treatment, subject number and, when 
appropriate, by visit / date of assessment. If a listing includes non-randomized 
subjects, these will appear after the randomized subjects. All data collected are 
displayed, including unscheduled visits (if any).  
• In summary tables and graphical representations, subjects are grouped by randomized 
treatment group, except for the SAF for which the actual treatment is used.  
• In summary tables based on the RND, FAS, PPS and SAF, the order of the treatment 
groups is: placebo, ACT-132577 5 mg , ACT-132577 10 mg, ACT-132577 25 mg, 
ACT-132577 50 mg and Lisionpril 20 mg, followed by Total (if required). In 
summary tables based on the RIS or SCR, only a total column will be given. 


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• The absolute change from baseline to Visit X is defined as the difference between the 
post-baseline Visit X value and the baseline value. 
• In order to analyze the data at the relevant planned (scheduled) visits, all recorded 
assessments for each subject up to the Week 10 visit are reassigned to the most 
appropriate visit according to the time window for that visit. The windows are 
consecutive (i.e., there are no gaps) and are based on the study day corresponding to 
the date of assessment. Any unscheduled visit is also mapped to a time window. 
Details of the visit mapping are given in Section 11.1. 
• According to section 11.3.2.2 of the protocol, imputation rules for missing data are 
defined for the evaluation of efficacy endpoints at Week 8. Subjects without a value 
in the defined Week 8 time window are included in the analysis according to the rules 
highlighted in Section 9. 
10.3 Display of subject disposition, protocol deviations and analysis sets 
10.3.1 Subject disposition 
Summary tables are provided, on the SCR, RIS and RND sets [see Section 7 for 
terminology], by treatment group (where applicable) and overall, to display the following 
information: 
• Disposition of subjects (screened, entered in run-in, randomized, treated i.e., who 
received at least one dose of study treatment, who completed treatment - see 
Section 5.3.3 for definition, who completed study - see Section 5.4 for details). This 
summary table is also provided by site. 
• Reasons for screening failures [see definition in Section 5.1, overall only].  
• Reasons for run-in failures [see definition in Section 5.1, overall only].  
Percentages are calculated based on screened subjects [see definition in Section 5.1] or 
run-in subjects where appropriate. A listing of screening failures is provided for the SCR 
and a listing of run-in failures for the RIS. Randomization scheme and codes and code 
break or subject unblinding (if any) are provided in separate listings on the RND set. 
10.3.2 Protocol deviations 
All important PDs (as defined by the PD list) will be summarized on the FAS by 
categories, displaying counts and percentages of subjects with at least a PD, by treatment 
group and overall. This summary table is sorted, within each PD temporal category, by 
overall frequency, in descending order; if a tie occurs, the tied characteristics will be 
sorted alphabetically. 
All reported PDs will be reported in a subject listing on the SCR set. Important PDs will 
be flagged accordingly. 


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10.3.3 Analysis sets 
A summary table is provided on the RND set to display the composition of FAS, PPS and 
SAF analysis sets, by treatment group and overall. A listing of subject participation in the 
different analysis sets is also provided. 
A separate summary table is provided on the RND set to display the reasons for exclusion 
from the above analysis sets, by treatment group and overall. In addition, the same table 
is provided by site. 
10.4 Analyses of subject characteristics 
10.4.1 Demographics 
All data [see definition in Section 5.2.1] will be reported in a subject listing based on the 
RND. The listing will include the other baseline characteristics defined in Section 5.2.3. 
Demographic characteristics will be summarized using descriptive statistics by treatment 
group as well as overall for the FAS and PPS.  
Note that age will be summarized as a continuous variable as well as a categorical 
variable (< 65, ≥ 65 years). Age as per EudraCT categories (18–64, 65–84, ≥ 85 years) 
will be tabulated separately based on the FAS. 
10.4.2 Baseline disease characteristics 
All data [see definition in Section 5.2.2] will be reported in a subject listing based on the 
SCR. Baseline disease characteristics will be summarized by treatment group as well as 
overall for the FAS and PPS.  
10.4.3 Other baseline characteristics. 
Other baseline disease characteristics [see definition in Section 5.2.3] will be summarized 
by treatment group and overall using descriptive statistics for the FAS and PPS. 
10.4.4 Medical history 
All previous or ongoing diseases / diagnoses [see definition in Section 5.2.4] will be 
reported in a subject listing. Ongoing diseases / diagnoses will be flagged accordingly. 
Previous and ongoing diseases / diagnoses will be summarized in separate tables. This 
will be done for the FAS and PPS. 
Previous or ongoing diseases / diagnoses will be summarized by treatment group and 
overall, together displaying counts and percentages of subjects having experienced at 
least one disease. Counts and percentages of subjects having experienced at least one 
disease are presented by system organ class (SOC) and individual preferred term within 
each SOC. The summary table is presented in descending order according to the 


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incidence in the highest-dose of active test treatment (e.g., SOC and individual preferred 
term within each SOC with the highest number of occurrences appears first). Equal 
frequency of different SOC / individual preferred terms is sorted in alphabetical order of 
the SOC / individual preferred term. 
The counting of the diseases is handled as follows: 
• Subjects with two or more occurrences of the same disease (as qualified by the same 
preferred term[s]) are counted only once. 
• In the event that the reported disease is assigned to several preferred terms, subjects 
are counted for each individual preferred term.  
10.4.5 Previous and concomitant therapies 
For study reporting purposes, all previous and/or concomitant therapies will be reported 
in a subject listing.  
Counts and percentages of subjects having taken at least one previous, study concomitant 
and double-blind treatment concomitant therapy [see definition in Section 5.2.5] are 
presented by treatment group, by ATC class and individual preferred term within each 
ATC class, separately.  
The summary tables are presented in descending order according to the incidence in the 
highest-dose of active test treatment (e.g., ATC and individual preferred term within each 
ATC with the highest number of occurrences appear first). Equal frequency of different 
ATC / individual preferred terms is sorted in alphabetical order of the ATC / individual 
preferred term. 
The counting of the therapies is handled as follows: 
• Subjects who took the same therapy more than once (as qualified by the same 
preferred term[s]) are counted only once. 
• In the event of the reported medication being assigned to several preferred terms, 
subjects are counted for each individual preferred term. 
For each preferred term the class are allocated using the 3 digits of the ATC code. 
Specific previous and concomitant therapies will be displayed separately as described 
above. 
10.4.6 Other subject characteristics 
Not applicable. 


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10.5 Analysis of study treatment duration and compliance 
10.5.1 Study treatment duration 
The duration of double-blind study treatment [see definition in Section 5.3.1] will be 
summarized on the PPS and SAF using descriptive statistics. Additionally, double-blind 
study treatment will be summarized as categorical variable, presenting the cumulative 
distribution by class interval categorized as 0–2, > 2–4, > 4–8 and > 8 weeks and 
displaying counts and percentages of subjects in each class interval. 
In addition, run-in study treatment duration will be summarized for the RIS. 
10.5.2 Compliance with study treatment 
Double-blind treatment compliance [see definition in Section 5.3.2] will be summarized 
on the FAS and PPS displaying counts and percentages of subjects with compliance 
categorized as: < 80%, 80–120%, and > 120%. Run-in treatment compliance will be 
summarized similarly for the RIS. 
10.5.3 Study treatment discontinuation  
A summary table is provided for the SAF to display counts and percentages of subjects 
who prematurely discontinued double-blind study treatment, as well as the associated 
reasons [see definition in Section 5.3.3], by treatment group and overall. 
Note that premature double-blind study treatment discontinuation does not necessarily 
imply study withdrawal. 
In addition, premature run-in treatment discontinuation will be summarized for the RIS. 
10.5.4 Study treatment adjustments or interruptions 
The number and percentage of subjects with DB study treatment interruptions will be 
provided for the SAF. The associated reasons will be summarized similarly. 
10.5.5 Study withdrawal 
A summary table is provided for the RND to display counts and percentages of subjects 
who prematurely discontinued the study after randomization, as well as the associated 
reasons by treatment group and overall. A listing of discontinued subjects is provided on 
the RND set. A similar table and listing based on the RIS will be provided for premature 
study discontinuation during run-in. 
10.6 Analysis of the primary efficacy variable(s) 
The primary efficacy variable (change from baseline to Week 8 of DB treatment in mean 
trough SiDBP, measured by OBPM) will be analyzed in the PPS and the FAS. The PPS 
analysis is the primary analysis, the analysis in the FAS is supportive. 


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The primary efficacy variable will be summarized by treatment group using descriptive 
statistics for the PPS and FAS. 
10.6.1 Hypothesis and statistical model 
The null hypothesis associated with the primary endpoint is that there is no dose-response 
relationship. 
H0: μ0 = μ1 = μ2 = μ3 = μ4 
Here, μi denotes the mean change from baseline to Week 8 in mean trough SiDBP (µ) for 
ACT-132577 dose (i) (where I = 0 corresponds to placebo). A value of μi < 0 corresponds 
to a decrease in SiDBP. 
The alternative hypothesis is that there is a monotonic dose-response for the primary 
endpoint. 
H1: μ0 ≥ μ1 ≥ μ2 ≥ μ3 ≥ μ4 and μi > μj for at least one i > j or 
μ0 ≤ μ1 ≤ μ2 ≤ μ3 ≤ μ4 and μi < μj for at least one i > j 
Note that larger values of μi – corresponding to less decrease (or more increase) from 
baseline to Week 8 in mean trough SiDBP with increasing dose of ACT-132577 – are 
less favorable. The first part of the alternative hypothesis corresponds to ACT-132577 
being superior to placebo, whereas the second part corresponds to ACT-132577 being 
worse than placebo. 
10.6.2 Handling of missing data 
In the PPS there will be no missing data from the primary endpoint given the definition of 
PPS. For the handling of missing data in the FAS, refer to Section 9.1. 
10.6.3 Main analysis 
The change from baseline to Week 8 of DB treatment period (Period II) in mean trough 
SiDBP will be analyzed using the MCP-Mod approach [Bretz 2005, Pinheiro 2006] 
described in Section 9.1.  
A placebo-corrected mean reduction from baseline of at least 4 mmHg is considered 
clinically relevant.  
Some examples of Emax dose-response relationships are given in Figure 3, where it is 
assumed that the minimum response will be obtained with placebo (mean change from 
baseline -4 mmHg) and the maximum response (change from baseline -8 or -9 mmHg) 
will be reached at the highest dose of ACT-132577 (50 mg).  




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(placebo or active comparator) and a covariate for baseline mean trough SiDBP. In the 
FAS missing data will be imputed by LOCF. 
Sensitivity analysis. As a sensitivity analysis for missing data imputation by LOCF an 
MCP-Mod analysis based on BOCF will be performed in the FAS. 
Also in the FAS, changes from baseline to time window Visit 5 (Week 2), time window 
Visit 4 (Week 4) and Week 8 of DB treatment period (Period II) in mean trough SiDBP 
will also be analyzed using repeated measurements model. A mixed model will be 
applied with factors for treatment group, time (Week 2, 4 or 8), treatment by time 
interaction and a covariate for baseline mean trough SiDBP. An unstructured covariance 
matrix will be used to account for the correlation between repeated measurements from 
the same subject. This can be seen as an OC analysis. The treatment group LSMeans 
obtained from this model will be analyzed using the general MCP-Mod approach 
[Pinheiro 2014].  
Average effect over time. In order to investigate the dose-response on the average 
treatment effect over time, the same mixed model will be used, but without the treatment 
by time interaction. Treatment group LSMeans will be analyzed using the general 
MCP-Mod approach. 
10.6.5 Subgroup analyses 
Subgroup analyses will be performed on the PPS by age (< 65 versus ≥ 65 years), sex, 
race and country.  
In the absence of a published, consolidated approach for subgroup analyses for 
dose-response, subgroup analyses will be performed by fitting the ‘best’ model from the 
overall analysis [see Section 10.6.3] in each of the subgroups. The fitted dose-response 
curves will be compared visually between subgroups. Dose-response by subgroup 
interaction may be investigated in an ad hoc fashion based on AIC. 
10.7 Analysis of the secondary efficacy variables 
Secondary efficacy variables will be analyzed for the PPS at α = 0.05 (two-sided) using 
95% CIs. Additionally, change from baseline to Week 8 in mean trough SiSBP will be 
analyzed for the FAS. No correction for multiple testing will be applied for these 
analyses. 
Change from baseline to Week 8 of DB treatment period (Period II) in mean trough 
SiSBP will be analyzed similarly to the primary endpoint (SiDBP), i.e., MCP-Mod will 
be applied, supplemented by the ANCOVA and the repeated measurements models 
described above. The correlation between the changes from baseline in SiDBP and SiSBP 
will be displayed in a scatter plot for each post-baseline time point. 


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Control (< 90 mmHg and < 85 mmHg, separately) and response (Y/N) at Week 8 of DB 
treatment period (Period II) based on trough SiDBP will be analyzed using a logistic 
regression model with a factor for treatment group and a covariate for baseline mean 
trough SiDBP. Control and response status at Week 8 of Period II based on trough SiSBP 
will be analyzed similarly. 
Change from baseline to Week 8 of DB treatment period (Period II) in 24-hour mean 
DBP based on ABPM will be analyzed using an ANCOVA with a factor for treatment 
group and a covariate for baseline 24-hour mean DBP. Change from baseline to Week 8 
of DB treatment period (Period II) in 24-hour mean SBP based on ABPM will be 
analyzed similarly. 
The baseline and Week 8 average ABPM-DBP curves over time (by hour) will be plotted 
by treatment group [averaging as described in Section 5.5.2]. Additionally, the Week 8 
minus baseline difference will be plotted vs time. Trough to peak ratios for DBP will be 
calculated by treatment group as described in Section 5.5.2.  
10.8 Analysis of other efficacy variables 
Other efficacy analyses will be performed on the PPS. 
Changes from baseline to Week 2 (time window Visit 5) and Week 4 (time window 
Visit 6) of DB treatment period (Period II) in mean trough SiSBP and SiDBP (OBPM) 
will be obtained from the repeated measurements model as described in Section 10.6.4 
under sensitivity analysis. 
Change from baseline to Week 8 of DB treatment period (Period II) in mean daytime 
DBP (SBP) measured by ABPM will be analyzed using an ANCOVA with a factor for 
treatment group and a covariate for baseline mean daytime ABPM. Change from baseline 
to Week 8 of DB treatment period (Period II) in mean night time DBP (SBP) measured 
by ABPM will be analyzed similarly.  
ABPM-SBP curves will be plotted and trough to peak ratios for SBP will be calculated as 
described for DBP based on ABPM. 
Changes from baseline to Week 10 (time window Visit 8; Week 2 of withdrawal period - 
Period III) in mean trough SiSBP and SiDBP (OBPM) will be obtained by extending the 
repeated measurements model described in Section 10.6.4 with an additional time point 
for time window Visit 8 (Week 10 i.e., Week 2 of withdrawal period - Period III).  
Changes from Week 8 of Period II to time Week 10 (time window Visit 8; Week 2 of 
withdrawal period - Period III) in mean trough SiSBP and SiDBP (OBPM) will be 
obtained from the same model using appropriate treatment and time contrasts. 
All efficacy analyses are summarized in Table 4. 


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Table 4 
Summary of efficacy analyses 
Efficacy 
analysis 
Endpoint 
Measure 
Week 
Model 
Dataset(imputation) 
Primary 
SiDBP 
OBPM 
8 
MCP-Mod 
PPS 
 
- Supportive 
SiDBP 
OBPM 
8 
MCP-Mod 
 
FAS 
(LOCF) 
SiDBP 
OBPM 
8 
ANCOVA (Dunnett)  
PPS 
FAS 
(LOCF) 
- Sensitivity 
SiDBP 
OBPM 
8 
MCP-Mod  
 
FAS 
(BOCF) 
 
SiDBP 
OBPM 
8 
MCP-Mod based on 
mixed modela 
 
FAS (OC) 
- Average over 
time 
SiDBP  
OBPM 
2,4,8 
MCP-Mod based on 
mixed modelb 
PPS 
FAS (OC) 
- Subgroup 
SiDBP  
OBPM 
8 
MCP-Mod by subgroup 
PPS 
 
 
 
 
 
 
 
 
Secondary 
SiSBP 
OBPM 
8 
MCP-Mod 
PPS 
FAS 
(LOCF) 
SiSBP 
OBPM 
8 
ANCOVA (Dunnett) 
PPS 
FAS 
(LOCF) 
SiSBP 
OBPM 
8 
MCP-Mod based on 
mixed modela 
 
FAS (OC) 
Average 
SiSBP over 
time   
OBPM 
2,4,8 
MCP-Mod based on 
mixed modelb 
PPS 
FAS (OC) 
Subgroup 
SiSBP  
OBPM 
8 
MCP-Mod 
PPS 
 
Control/ 
response of 
SiDBP 
OBPM 
8 
MCP-Mod based on 
logistic regression 
PPS 
 
Control/ 
response of 
SiSBP 
OBPM 
8 
MCP-Mod based on 
logistic regression 
PPS 
 
24-hour mean 
DBP 
ABPM 
8 
ANCOVA 
PPSc 
 
24-hour mean 
SBP 
ABPM 
8 
ANCOVA 
PPSc 
 
Trough to 
peak ratio 
DBP 
ABPM 
8 
Descriptive statistics 
PPSc 
 
Other 
Mean daytime 
DBP 
ABPM 
8 
ANCOVA 
PPSc 
 


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Efficacy 
analysis 
Endpoint 
Measure 
Week 
Model 
Dataset(imputation) 
Mean night 
time DBP 
ABPM 
8 
ANCOVA 
PPSc 
 
Mean daytime 
SBP 
ABPM 
8 
ANCOVA 
PPSc 
 
Mean night 
time SBP 
ABPM 
8 
ANCOVA 
PPSc 
 
Trough to 
peak ratio SBP 
ABPM 
8 
Descriptive statistics 
PPSc 
 
SiDBP 
OBPM 
8,10 
ANCOVA 
PPS 
 
SiSBP 
OBPM 
8,10 
ANCOVA 
PPS 
 
* If applicable. In the PPS all analyses are based on OC.  
a Also including Week 2 and 4 data, but only to predict missing Week 8 data. 
b Including Week 2, 4 and 8 data to estimate the average effect of time. 
c ABPM analyses are based on the subset of the PPS described in Section 5.5. 
ABPM = ambulatory blood pressure monitoring; ANCOVA = analysis of covariance; BOCF = baseline observation 
carried forward; DBP = diastolic blood pressure; FAS = Full Analysis Set; LOCF = last observation carried forward; 
MCP-Mod = Multiple Comparison Procedure – Modeling; OBPM = automated office blood pressure measurement; 
OC = observed cases; PPS = Per-Protocol Set; SBP = systolic blood pressure; SiDBP = sitting diastolic blood pressure; 
SiSBP = sitting systolic blood pressure. 
MCP-Mod based on mixed model (logistic regression, ANCOVA) implies that first the 
mixed model (logistic regression, ANCOVA) is performed and then the estimated 
differences vs placebo are analyzed using the general MCP-Mod approach 
[Pinheiro 2014]. 
10.9 Analysis of safety variables 
All safety analyses described below will be performed on the SAF. All safety data will be 
listed, with flags for abnormalities, when applicable. 
10.9.1 Adverse events 
All reported AEs will be listed, together with the assigned preferred term/SOC. The 
listings will indicate the period of onset of the AE (run-in, DB treatment or placebo WD). 
Treatment-emergent AEs [see definition in Section 5.6.1.1] will be summarized 
displaying, for each treatment group, counts and percentages of subjects having 
experienced at least one treatment-emergent AE. Counts and percentages of subjects 
having experienced at least one treatment-emergent AE are presented by SOC and 
individual preferred term within each SOC. The summary tables are presented in 
descending order according to the incidence in the highest-dose of active test treatment 
(e.g., SOC and individual preferred term within each SOC with the highest number of 


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occurrences appears first). Equal frequency of different SOC/individual preferred terms is 
sorted in alphabetical order of the SOC/individual preferred term. 
Treatment-emergent AEs related to study treatment, treatment-emergent AEs leading to 
premature discontinuation of study treatment and treatment-emergent AEs with fatal 
outcome will be summarized, separately, by SOC and individual preferred term. 
Treatment-emergent AEs, treatment-emergent AEs leading to premature discontinuation 
of study treatment and treatment-emergent AEs with fatal outcome will be summarized 
also by preferred term only. Treatment-emergent AEs are also summarized by maximum 
intensity. 
For the disclosure of the results to EudraCT and ClinicalTrials.gov (rather than for the 
purpose of the clinical study report), a summary table with an overview of 
treatment-emergent AEs is provided displaying, for each treatment group, counts and 
percentages of subjects having experienced at least a treatment-emergent AE, a severe 
AE, a study-treatment related AE, an AE leading to study treatment discontinuation, a 
non-serious frequent AE, a serious AE, a study-treatment related serious AE, a fatal SAE. 
The occurrence of non-serious, frequent (i.e., the percentage of subjects in at least one of 
the treatment groups equals or exceeds five percent) treatment-emergent AEs will be 
tabulated by SOC and individual preferred term within each SOC. 
10.9.2 Deaths, other serious adverse events 
10.9.2.1 Deaths 
The primary cause of death coded according to MedDRA dictionary [see Section 5.6.2] 
will be summarized displaying, for each treatment group, counts and percentages of 
subjects by class and individual preferred term within each class; the summary table is 
presented in descending order according to the incidence in the highest-dose of active test 
treatment (equal frequencies are sorted in alphabetical order). 
All deaths will be listed. The listings will indicate the period in which the death occurred 
(run-in, DB treatment, placebo WD). 
10.9.2.2 Serious adverse events 
All reported SAEs will be listed and tabulated as described above for AEs.  
The occurrence of treatment-emergent serious AEs will be summarized by SOC and 
individual preferred term within each SOC. The table is presented in descending order 
according to the incidence in the highest-dose of active test treatment (i.e., SOC and 
individual preferred term within each SOC with the highest number of occurrences 
appears first). Ties are sorted in alphabetical order. 


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Treatment-emergent SAEs will also be summarized by preferred term only. 
For the disclosure of the results to EudraCT and ClinicalTrials.gov (rather than for the 
purpose of the clinical study report), treatment-emergent SAEs will be summarized 
displaying, for each treatment group, counts and percentages of subjects with at least a 
treatment-emergent SAE plus the number of events (counted exactly the number of times 
they occurred also within a subject) by SOC and individual preferred term. The summary 
table is presented in descending order according to the incidence in the highest-dose of 
active test treatment (i.e., SOC and individual preferred term within each SOC with the 
highest number of occurrences appears first). Equal frequency of different individual 
preferred terms is sorted in alphabetical order of the individual preferred term. Similarly, 
a separate summary is presented for treatment-emergent SAEs related to study treatment. 
In addition, treatment-emergent SAEs with fatal outcome and treatment-emergent SAEs 
with fatal outcome related to study treatment will be summarized separately, similarly to 
treatment-emergent SAEs.  
10.9.2.3 Adverse events leading to study treatment discontinuations 
A separate subject listing is provided with treatment-emergent AEs leading to study 
treatment discontinuation. Treatment-emergent AEs leading to premature study treatment 
discontinuation will be summarized by SOC and preferred term as well as by preferred 
term only. 
10.9.2.4 Other adverse events 
Not applicable. 
10.9.3 Electrocardiography (ECG) 
Double-blind treatment-emergent ECG abnormalities [see definition in Section 5.6.7.1] 
will be summarized, by treatment group, displaying counts and percentages of subjects 
(and 95% confidence limits according to the Clopper-Pearson method) with at least one 
treatment-emergent ECG abnormality. Values from unscheduled visits are included. 
Subjects may be included in more than one category as the marked abnormality are 
presented cumulatively. 
ECG variables are displayed in a subject listing on the SCR set; a separate listing is 
provided of all ECG variables, restricted to subjects with at least one abnormality [see 
Section 5.6.7 for details]. 
10.9.4 Laboratory tests 
All hematology and chemistry parameters provided by the central and local laboratory are 
displayed in a subject listing. Marked laboratory abnormalities will be flagged 


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accordingly. Laboratory values below the limit of detection (i.e., preceded by ‘<‘) will be 
replaced by half that limit in calculations as well as in determining abnormalities. 
Hematology, chemistry and urine parameters UACR will be summarized by treatment 
group for each time window visit. Changes from baseline in these parameters will be 
summarized for each post-baseline assessment, displaying: 
• observed values at baseline and at the post-baseline visit window 
• absolute change from baseline to post-baseline visit window 
In each evaluation only subjects who had both the assessments at baseline and the 
considered post-baseline time point are included. 
10.9.4.1 Treatment-emergent marked laboratory abnormalities 
For each category (i.e., LL, LLL, HH, HHH, HHHH), treatment-emergent marked 
laboratory abnormalities [see definition in Section 5.6.8.1] will be summarized by 
treatment group, displaying counts and percentages of subjects with at least a 
treatment-emergent marked laboratory abnormality for each parameter for which the 
marked abnormality is defined. Values from unscheduled visits are included. Subjects 
may be included in more than one category for the same parameter. 
In addition, the number of patients with ALT > 3 × upper limit of normal (ULN) and 
bilirubin > 2 × ULN will be tabulated by treatment group and time point (baseline, 
Week 8). 
Percentages are calculated as number of subjects with at least one abnormality for the 
parameter under consideration divided by the number of subjects with any post-baseline 
laboratory measurement. 
The distribution of the changes from baseline in hemoglobin will be plotted for each 
post-baseline visit. As an exploratory analysis, dose trends in the change from baseline to 
Week 8 in hemoglobin will be analyzed using the MCP-Mod approach. The active 
comparator will be excluded from these analyses. 
10.9.5 Physical examination, vital signs and body weight 
Physical examination data performed during the course of the study will be reported in a 
subject listing. Pulse rate and body weight measurements will be reported in a subject 
listing and summarized by time window visit. 
Furthermore, for each post-baseline assessment, average PR (from BpTRU®) and body 
weight will be summarized displaying, for each treatment group, descriptive statistics for: 
• observed values at baseline and at the post-baseline visit window 
• absolute change from baseline to post-baseline visit window 


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In each evaluation only subjects who had both the assessment at baseline and the 
considered post-baseline assessment are included. Only measurements obtained in sitting 
position will be taken into account. 
The density of the changes from baseline in body weight will be plotted for each 
post-baseline visit. As an exploratory analysis, dose trends in the change from baseline to 
Week 8 in body weight ([kg]) will be analyzed using the MCP-Mod approach. The active 
comparator will be excluded from these analyses. 
10.9.6 Other safety variables 
Not applicable. 
10.10 Analysis of quality of life variables (TSQM vII) 
Not applicable. 
10.11 Analysis of pharmacoeconomic variables 
Not applicable.  
10.12 Analysis of epidemiological measures and risk-benefit evaluations 
Not applicable.  
10.13 Analysis of pharmacodynamic variables 
For the analysis of ET-1 the PK set will be used. ET-1 plasma concentrations will be 
summarized by active treatment and visit by arithmetic mean, SD of the mean, minimum, 
maximum, median, coefficient of variation of the arithmetic mean (CV%), and number of 
observations. A subject listing presenting ET-1 data will also be provided. Data 
presentations will follow the general rules as described in Section 10.2.  
10.14 Analysis of pharmacokinetic variables 
ACT-132577 plasma concentrations and, if applicable, 
, will be 
summarized for ACT-132577 treated groups only.  
The data will be summarized by active treatment and visit by arithmetic mean, SD of the 
mean, minimum, maximum, median, coefficient of variation of the arithmetic mean 
(CV%), and number of observations. For mean value calculations, all values below the 
limit of quantification (BLQ values) will be set to zero. If ≤ 50% of the values at a given 
time point are BLQ, these values will be set to zero for calculation of the mean value. If 
≥ 50% of the values at a given time point are BLQ, no mean value will be calculated. 
Additionally, summaries will be created by sex, race and age. 


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A subject listing presenting ACT-132577 data will also be provided. Data presentations 
will follow the general rules as described in Section 10.2.  
11 GENERAL DEFINITIONS AND DERIVATIONS 
11.1 Time windows 
To allow analysis of data at the relevant planned (scheduled) visits, all recorded 
assessments, including unscheduled ones, are re-assigned to the most appropriate visit 
according to the best fitting time window for that visit [see Table 5]. Note that there are 
no ‘gaps’ between the visit windows in order to keep all values in the analysis.  
Table 5 
Visit time windows 
Visit 
Target day* 
Min. day 
Max. day 
1 
–42 
- 
–35 
2 
–28 
–34 
–18 
3 
–7 
–17 
–4 
4 
1 
–3 
1 
5 
14 
1 
21 
6 
28 
22 
42 
7 - I 
55 
43 
EOT*** 
7 - II** 
56 
EOT + 01 m 
EOT + 25 h 
8 
70 
EOT + 25 h 01 m 
No limit 
* Number of days from start of double-blind treatment. 
** Only for ABPM.  
*** For OBPM use EOT + 05 m (for the time of the average SiDBP) 
ABPM = ambulatory blood pressure monitoring; EOT = End-of-Treatment; OBPM = office blood pressure 
measurement; SiDBP = sitting diastolic blood pressure. 
For assessments for which time is collected, please use the following rules: 
• Target day = Target day and time 12:00 
• Min. day = Min. day and time 0:00 
• Max. day = Max. day and time 23:59 


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Visit 4 / Day 1 
• Target day 1 = Start date/time of DB treatment 
• Max. day1 = Start date/time of DB treatment 
Visit 5 / Day 1 
• Min. day 1 = Start date/time of DB treatment + 1 minute 
Visit 7 - I / EOT 
• Max. day = End date/time of DB treatment 
Visit 7 - II / EOT 
• Min. day = End date/time of DB treatment + 1 minute 
In the event that there is more than one value within the same time window, the value 
closest to the planned assessment date will be taken. In the event of equidistant values 
from the planned time point, the last assessment will be considered for the analyses. 
Where multiple assessments fall on the same day the latest is then used. 
11.2 Run-in treatment start date/time 
The run-in treatment start date is the first day of intake of study treatment during the 
run-in period. It is derived from the first treatment start date (in chronological order) in 
the Study Drug Log eCRF where the ‘Study Period’ is ‘ SB RUN-IN’. If the start time of 
the run-in period is missing, it will be set to 00:00. 
11.3 Run-in treatment end date/time 
The run-in treatment end date is the last day of intake of run-in study treatment. It is 
derived from the last DB treatment end date (in chronological order) in the Study Drug 
Log eCRF where the ‘Study Period’ is ‘SB RUN-IN’. If the end time of the run-in period 
is missing, it will be set to the start time of the DB period minus 1 minute, in the event 
that the DB period is missing it will be set to 23:59. 
11.4 Randomization date/time 
The randomization date/time is taken from IVRS. 
11.5  Double-blind treatment start date/time 
It is the first day of intake of study treatment during the double-blind period. It is derived 
from the first treatment start date (in chronological order) in the Study Drug Log eCRF 
where the ‘Study Period’ is ‘DB TREATMENT’.  


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If the date is missing the randomization date (see definition below) is used. If the subject 
is listed as run-in failure [see definition in Section 5.1] the date is set to ‘missing’. If the 
start time of the double-blind treatment is missing and the start date of DB period 
corresponds to the date of Randomization, the Randomization time will be used. In other 
cases the start time of DB will be set to 00:00. 
11.6 Double-blind treatment end date/time 
The double-blind treatment end date is the last day of intake of DB study treatment. It is 
derived from the last DB treatment end date (in chronological order) in the Study Drug 
Log eCRF where the ‘Study Period’ is ‘DB TREATMENT’ and the reason for treatment 
end is ≠ “TEMPORARILY INTERRUPTED DUE TO AN AE” or “TEMPORARILY 
INTERRUPTED NOT DUE TO AN AE”. 
If the study treatment end date is still missing after this derivation, the earliest of the date 
of Visit 7 - Week 8 / EOT /Part 1 and the date of death (if any) is to be imputed. If the 
end date is still missing, the EOS date as defined in the Section 2.1 will be used. If the 
end time of double-blind treatment is missing and DB end date corresponds to the date of 
the first assessment of ABPM at Visit 7, the time of the first ABPM assessment will be 
used, otherwise, it will be set to 23:59. 
11.7 Withdrawal period start date/time 
The withdrawal period start date is the first day of intake of placebo during the 
withdrawal period. It is derived from the first treatment start date (in chronological order) 
in the Study Drug Log eCRF where the ‘Study Period’ is ‘SB WITHDRAWAL’. If the 
time of the WD period is missing the time of last assessment of ABPM at Visit 7 will be 
used, otherwise it will be set to 23:59. 
11.8 Withdrawal period end date/time 
The withdrawal period end date is the date of Visit 8, collected in the Visit Date eCRF. If 
the time is missing it will be set to 23:59. 
11.9 Study day 
The study day is the number of days elapsed since the day of first DB treatment plus 1 
(start of DB treatment is considered Day 1). For dates prior to Day 1, study day is the 
negative number of days between the date under consideration and the date of first DB 
treatment. Therefore, the study day is always different from zero. 
11.10 Duration of essential hypertension (years) 
Duration of essential hypertension (years) = (date of Visit 1 – date of diagnosis)/365.25 
with the date of diagnosis collected in the Essential Hypertension Relevant Disease 
History form of the eCRF. 


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11.11 Unit conversion rules 
Height (cm) = height (in) × 2.54 
Weight (kg) = weight (lbs) × 0.4536 
11.12 Body Mass Index (BMI) 
BMI (kg/m2) = weight (kg) / (height [cm] / 100)2 
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS 
All dates and times used in the analyses are supposed to be complete, apart from the 
types included in the table below. 
The dates in these types that are missing or incomplete are derived as follows: 
1 
Dates are split in 3 parts: year, month and day. Year is the top-level, month is the 
medium level and day is the low level. If a part expected to contain a number is 
numeric but the value is outside a valid range, the complete date is handled as 
missing. For example, if date = 44Nov2000 the whole date is considered to be 
missing. 
2 
If a part is expected to contain a number is not numeric, i.e., contains values, for 
example, ND, NA, --, ??, 2?, it is considered as missing. 
3 
If a part is missing, all lower level parts are considered to be missing. This means 
that a ddmmyy date ‘21ND99’ is considered as ‘----99’. 
4 
Missing parts are changed into acceptable non-missing values in a way depending on 
the type of date to be replaced. 
In the following, ‘lower limit’ and ‘upper limit’ refer to the minimum or maximum, 
respectively, of a possible date. For example, if the day is missing, the lowest limit is the 
first day of the given month and the upper limit is the last day of the given month. If the 
day and month are missing, the lower limit refers to the first day of the given year and the 
upper limit to the last day of the given year. The earliest and the latest of different dates 
refer to the first or last date, respectively, when ordered in sequence.  
Type of date 
Date is incomplete 
Date is missing 
AE resolution 
date 
The upper limit. 
No replacement, the AE is 
considered as ongoing in the 
analysis. 


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Type of date 
Date is incomplete 
Date is missing 
AE onset date 
If the end date of the AE is not before 
the start of double-blind treatment, 
and if the study treatment start falls in 
the range of possible dates, the study 
treatment start date is used. In all the 
other cases the lower limit is used. 
Whichever is the earlier of the 
date of resolution of the AE 
and the study treatment start 
date. 
Medical 
history end 
date 
The upper limit. 
No replacement. 
Medical 
history start 
date 
The lower limit. 
No replacement. 
Concomitant 
medication end 
date 
If the answer to the question 
‘Ongoing at start of treatment?’ in the 
Previous/Concomitant Medication 
eCRF is answered ‘No’ or if the study 
treatment start date-1 falls in the 
range of possible dates, the study 
treatment start date-1 is used. In all 
the other cases the upper limit is used. 
No replacement. If the answer 
to the question ‘Ongoing at 
start of treatment?’ in the 
Previous/Concomitant 
Medication eCRF is answered 
‘Yes’ the therapy is considered 
to have finished after the start 
of treatment. 
Concomitant 
medication 
start date 
If the end date of the medication is 
not before the informed consent 
signature date and if the informed 
consent date falls in the range of 
possible dates, the informed consent 
date is used. 
If the end date of the medication is 
not before the study treatment start 
date and if the study treatment start 
date falls in the range of possible 
dates, the study treatment start date is 
used.  
In all the other cases the lower limit is 
used. 
No 
replacement. 
The 
medication is considered to 
have started before the date of 
consent. 


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Type of date 
Date is incomplete 
Date is missing 
Hospitalization 
discharge date 
The upper limit is used. 
No replacement.  
The hospitalization is 
considered as ongoing in the 
analysis. 
Hospitalization 
admission date 
If the onset date of the AE leading to 
hospitalization falls in the range of 
possible dates, the onset date of the 
AE is used. In all the other cases the 
lower limit is used. 
The onset date of the AE 
leading to hospitalization is 
used. 


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13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES 
The table, listing, and figure naming conventions have three components: Display (T, L, 
F), Name (free text, in general not more than eight characters, but if required to maintain 
uniqueness up to a maximum of ten characters), Suffix (for example, for analysis sets, or 
subgroups, not longer than four characters). Multiple suffixes can be added; 
components/suffixes are separated by ‘_’. Example: T_TEAE _SAF, summary table (T) of 
treatment-emergent adverse events (TEAE) on the SAF.  
The mock layout column refers to the BST standard Outputs Version 3.0 as of March 31, 
2016. 
A number of outputs have been identified as key outputs based on which an initial 
assessment of the dose-response relationship can be made. These are indicated with a 
‘Yes’ in the ‘Key’ columns of the tables below. 
13.1 Subject disposition 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
DISP 
T 
Disposition of 
subjects 
SCR 
Yes 
LAYDISP001 
DISP_SITE 
T 
Disposition of 
subjects by site 
SCR 
 
LAYDISP001 
SCRFAIL 
T 
Reasons for screening 
failure 
SCR 
 
LAYDISP002 
SCRFAIL 
L 
Listing of reasons for 
screening failure 
SCR 
 
LSTCSR011 
RUNFAIL 
T 
Reasons for run-in 
failure 
RIS 
 
LAYDISP002 
RUNFAIL 
L 
Listing of run-in 
failures 
RIS 
 
LSTCSR011 
ANSETOV 
T 
Overview of FAS, 
PPS, SAF and PK 
analysis sets 
RND 
Yes 
LAYDISP001 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
ANSET 
L 
Listing of subject 
participation in the 
different analysis sets  
 
RND 
 
LSTCSR031 
RAND 
L 
Randomization 
scheme and codes 
RND 
 
LSTRAN 
UNBLIND 
L 
Listing of code break 
or subject unblinding 
RND 
 
LSTCSR032 
* T = Summary Table; L = Listing.  
FAS = Full Analysis Set; PK = Pharmacokinetic; PPS = Per-Protocol Set; RIS = Run-in Set; RND = All Randomized 
Set; SAF = Safety Set; SCR = Screened Set. 
13.2 Protocol deviations 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s)** 
Key 
Mock layout 
PRDEVA 
T 
Important protocol 
deviations during the 
double-blind period 
FAS 
 
LAYPD001 
PRDEVI 
T 
Protocol deviations 
leading to exclusion 
from PPS 
FAS 
Yes 
LAYPD002 
PRDEVA 
T 
Important protocol 
deviations during 
run-in period 
RIS 
 
LAYPD001 
PRDEV 
L 
Listing of protocol 
deviations 
SCR 
 
LSTCSR021 
* T = Summary Table; L = Listing.  
FAS = Full Analysis Set; PPS = Per-Protocol Set; RIS = Run-in Set; SCR = Screened Set. 


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13.3 Subject characteristics 
13.3.1 Demographics 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
DEMOG 
T 
Demographic 
characteristics 
FAS, 
PPS, PK 
Yes 
LAYDEM001 
DEMOG 
L 
Listing of 
demographic 
characteristics 
RIS 
 
LSTCSR041 
AGECATEU 
T 
EudraCT age 
categories 
FAS 
 
LAYDEM004 
* T = Summary Table; L = Listing.  
FAS = Full Analysis Set; PK = Pharmacokinetic; PPS = Per-Protocol Set; RIS = Run-in Set.  
 
13.3.2 Baseline disease characteristics 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
BASDC 
T 
Essential hypertension 
at Screening 
FAS, 
PPS 
 
LAYMIX001 
BASDC 
L 
Listing of essential 
hypertension at 
Screening 
SCR 
 
LSTCSR091 
* T = Summary Table; L = Listing.  
FAS = Full Analysis Set; PPS = Per-Protocol Set; SCR = Screened Set. 
13.3.3 Other baseline characteristics 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
OBASDC 
T 
Height at Screening, 
weight and BMI at 
baseline 
FAS, 
PPS, PK 
 
LAYDEM001 
* T = Summary Table; L = Listing.  
BMI = body mass index; FAS = Full Analysis Set; PK = Pharmacokinetic; PPS = Per-Protocol Set; 
 


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13.3.4 Medical history 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
MHSCPR 
T 
Medical history by 
primary system organ 
class (SOC) and 
preferred term 
FAS 
 
LAYMH001 
CDSCPR 
T 
Concomitant disease by 
primary system organ 
class (SOC) and 
preferred term 
FAS 
 
LAYMH001 
PCMHIST 
L 
Listing of subjects with 
previous and 
concomitant medical 
history 
SCR 
 
LSTCSR043 
* T = Summary Table; L = Listing.  
FAS = Full Analysis Set; SCR = Screened Set; SOC = system organ class. 
 
13.3.5 Previous and concomitant therapies 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
PTATCPR 
T 
Previous therapies by 
anatomical 
therapeutic chemical 
(ATC) class and 
preferred term 
FAS 
 
LAYCONMED001 
DBCATCPR 
T 
Double-blind 
treatment concomitant 
therapies by 
anatomical 
therapeutic chemical 
(ATC) class and 
preferred term 
FAS 
 
LAYCONMED001 


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Output 
name 
Display* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
STCATCPR 
T 
Study-concomitant 
therapies by 
anatomical 
therapeutic chemical 
(ATC) class and 
preferred term 
FAS 
 
LAYCONMED001 
PCTHER 
L 
Listing of subjects 
with previous and 
concomitant therapies 
RIS 
 
LSTCSR044 
* T = Summary Table; L = Listing.  
ATC = anatomical therapeutic chemical; FAS = Full Analysis Set; RIS = Run-in Set. 
13.3.6 Specific previous and concomitant therapies 
Not applicable. 
13.3.7 Other subject characteristics 
Not applicable. 
13.4 Study treatment duration and compliance 
13.4.1 Study treatment duration 
Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock 
layout 
TREXP 
T 
Double-blind treatment 
duration 
FAS, 
PPS, SAF 
Yes 
LAYEX001 
TREXP 
T 
Run-in treatment duration 
RIS 
 
LAYEX001 
TREXP 
L 
Listing of run-in and double-
blind treatment duration 
RIS 
 
LSTCSR052 
* T = Summary Table; L = Listing.  
FAS = Full Analysis Set; PPS = Per-Protocol Set; RIS = Run-in Set; SAF = Safety Set. 


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13.4.2 Compliance with study treatment 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
COMPA 
T 
Compliance with double-
blind study treatment 
PPS, 
FAS 
 
LAYCAT001 
COMPA 
T 
Compliance with run-in 
study treatment 
RIS 
 
LAYCAT001 
COMPA 
L 
Listing of compliance with 
double-blind study 
treatment 
SAF 
 
LSTCSR051a 
* T = Summary Table; L = Listing.  
FAS = Full Analysis Set; PPS = Per-Protocol Set; RIS = Run-in Set; SAF = Safety Set. 
 
13.4.3 Study treatment discontinuation 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
PDISCTR 
T 
Reasons for premature 
discontinuation of 
double-blind study treatment 
SAF 
Yes 
LAYDISP003b 
PDISCTR 
T 
Reasons for premature 
discontinuation of run-in 
treatment 
RIS 
 
LAYDISP003b 
PDISCTR 
L 
Listing of subjects who 
discontinued treatment 
RIS 
 
LSTCSR012 
* T = Summary Table; L = Listing.  
RIS = Run-in Set; SAF = Safety Set. 


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13.4.4 Study treatment adjustments or interruptions 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
TREINT 
T 
Reasons for double-blind 
treatment interruptions  
SAF 
 
LAYMIX001 
TREINT 
L 
Listing of subjects with 
double-blind treatment 
interruptions 
SAF 
 
L_TREINT 
 
* T = Summary Table; L = Listing.  
SAF = Safety Set. 
 
13.5 Study withdrawal 
Output 
name 
Display* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
PDISCST 
T 
Reasons for premature study 
discontinuation after 
randomization 
RND 
 
LAYDISP004b 
PDISCST 
T 
Reasons for premature study 
discontinuation before 
randomization  
RIS 
 
LAYDISP004b 
PDISC 
L 
Listing of subjects who 
discontinued the study 
prematurely 
RIS 
 
LSTCSR012 
* T = Summary Table; L = Listing.  
RIS = Run-in Set; RND = All Randomized Set. 
 
13.6 Primary efficacy analyses 
13.6.1 Main analysis 
All outputs for the main analysis will be based on the PPS. Some outputs will also be 
generated for the FAS. These are listed in 13.6.2. 
 
 


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Output name 
Display* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
DBP_VIS 
T 
Mean trough sitting 
diastolic blood pressure 
(SiDBP) as measured 
by OBPM by visit and 
treatment group 
PPS 
 
LAYCON001 
DBP_CHG 
T 
Change from baseline 
to post-baseline visits 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) as measured 
by OBPM by treatment 
group 
PPS 
Yes 
LAYBASE001 
DBP_MCHG 
F 
Mean change from 
baseline to post-
baseline visits in mean 
trough sitting diastolic 
blood pressure 
(SiDBP) as measured 
by OBPM by treatment 
group 
PPS 
Yes 
LAYTIME 
DBP_CHG 
F 
Density of change from 
baseline to post-
baseline visits in mean 
trough sitting diastolic 
blood pressure 
(SiDBP) as measured 
by OBPM by treatment 
group 
PPS 
 
LAYDENS 
DBP_MCPMOD1 
T 
MCP-Mod test for 
dose-response in 
change from baseline 
to Week 8 in mean 
trough sitting diastolic 
blood pressure 
(SiDBP) 
PPS 
Yes 
LAYMCP1 


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Output name 
Display* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
DBP_MCPMOD2 
T 
MCP-Mod estimation 
of dose-response in 
change from baseline 
to Week 8 in mean 
trough sitting diastolic 
blood pressure 
(SiDBP) 
PPS 
Yes 
LAYMCP2 
DBP_MCPMOD 
F 
MCP-Mod estimation 
of dose-response in 
change from baseline 
to Week 8 in mean 
trough sitting diastolic 
blood pressure 
(SiDBP) 
PPS 
 
LAYMCP3 
DBP_MCPMOD_SEL 
F 
MCP-Mod estimation 
of dose-response in 
change from baseline 
to Week 8 in mean 
trough sitting diastolic 
blood pressure 
(SiDBP) - Best fitting 
model 
PPS 
Yes 
LAYMCP4 
DBP_MCPMOD_SEL 
T 
MCP-Mod estimation 
of dose-response in 
change from baseline 
to Week 8 in mean 
trough sitting diastolic 
blood pressure 
(SiDBP) - Best fitting 
model 
PPS 
 
LAYMCP5 
* T = Summary Table; F = Figure.  
 PPS = Per-Protocol Set; MCP-Mod = Multiple Comparison Procedure – Modeling; OBPM = automated office blood 
pressure measurement; SiDBP = sitting diastolic blood pressure. 
 
 
 
 
 
 


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13.6.2 Supportive/sensitivity analyses 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock 
layout 
DBP_VIS 
T 
Mean trough sitting 
diastolic blood pressure 
(SiDBP) as measured by 
OBPM by visit and 
treatment group 
FAS 
 
LAYCON0
01 
DBP_CHG 
T 
Change from baseline to 
post-baseline visits in 
mean trough sitting 
diastolic blood pressure 
(SiDBP) as measured by 
OBPM by treatment 
group 
FAS 
Yes 
LAYBASE0
01 
DBP_MCHG 
F 
Mean change from 
baseline to post-baseline 
visits in mean trough 
sitting diastolic blood 
pressure (SiDBP) as 
measured by OBPM by 
treatment group 
PPS 
Yes 
LAYTIME 
DBP_CHG 
F 
Density of change from 
baseline to post-baseline 
visits in mean trough 
sitting diastolic blood 
pressure (SiDBP) as 
measured by OBPM by 
treatment group 
FAS 
 
LAYDENS 
DBP_MCPMOD
1 
T 
MCP-Mod test for dose-
response in change from 
baseline to Week 8 in 
mean trough sitting 
diastolic blood pressure 
(SiDBP) 
FAS 
Yes 
LAYMCP1 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock 
layout 
DBP_MCPMOD
2 
T 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) 
FAS 
Yes 
LAYMCP2 
DBP_MCPMOD 
F 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) 
FAS 
 
LAYMCP3 
DBP_MCPMOD
_SEL 
F 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) - Best fitting 
model 
FAS 
Yes 
LAYMCP4 
DBP_MCPMOD
_SEL 
T 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) - Best fitting 
model 
FAS 
 
LAYMCP5 
DBP_ANCOVA 
T 
ANCOVA for change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) - ACT-132577 
vs placebo 
PPS, 
FAS 
Yes 
LAYBETW
001 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock 
layout 
DBP_ANCOVA 
F 
ANCOVA for change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) - ACT-132577 
vs placebo 
PPS, 
FAS 
Yes 
LAYFOR 
DBP_ANCOVA
_L 
T 
ANCOVA for change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) - Lisinopril vs 
placebo 
PPS, 
FAS 
Yes 
LAYBETW
001 
 
 
 
 
 
 
DBP_MCPMBO
CF1 
T 
MCP-Mod test for dose-
response in change from 
baseline to Week 8 in 
mean trough sitting 
diastolic blood pressure 
(SiDBP, BOCF) 
FAS 
 
LAYMCP1 
DBP_MCPMBO
CF2 
T 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP, BOCF) 
FAS 
 
LAYMCP2 
DBP_MCPMBO
CF 
F 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP, BOCF) 
FAS 
 
LAYMCP3 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock 
layout 
DBP_MIXED_W
2_W4_W8 
T 
Mixed Model for changes 
from baseline to Weeks 2, 
4 and 8 in mean trough 
sitting diastolic blood 
pressure (SiDBP, OC) - 
ACT-132577 vs placebo  
FAS 
 
LAYBETW
001 
DBP_MIXED_W
2_W4_W8_MCP
1 
 
Mixed Model for changes 
from baseline to Weeks 2, 
4 and 8 in mean trough 
sitting diastolic blood 
pressure (SiDBP, OC) - 
MCP-Mod test for dose-
response at Week 8 
FAS 
 
LAYMCP1 
DBP_MIXED_W
2_W4_W8_MCP
2 
 
Mixed Model for changes 
from baseline to Weeks 2, 
4 and 8 in mean trough 
sitting diastolic blood 
pressure (SiDBP, OC) - 
MCP-Mod estimation of 
dose-response at Week 8 
FAS 
 
LAYMCP2 
DBP_MIXED_W
2_W4_W8_L 
T 
Mixed Model for changes 
from baseline to Weeks 2, 
4 and 8 in mean trough 
sitting diastolic blood 
pressure (SiDBP, OC) - 
Lisinopril vs placebo  
FAS 
 
LAYBETW
001 
 
 
 
 
 
 
DBP_MIXED_A
VER8 
T 
Mixed Model for average 
change from baseline to 
Weeks 2, 4 and 8 in mean 
trough sitting diastolic 
blood pressure (SiDBP, 
OC) - ACT-132577 vs 
placebo  
PPS, 
FAS 
 
LAYBETW
001 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock 
layout 
DBP_MIXED_ 
AVER8_MCP1 
T 
Mixed Model for average 
change from baseline to 
Weeks 2, 4 and 8 in mean 
trough sitting diastolic 
blood pressure (SiDBP, 
OC) - MCP-Mod test for 
dose-response 
PPS, 
FAS 
 
LAYMCP1 
DBP_MIXED_A
VER8_MCP2 
T 
Mixed Model for average 
change from baseline to 
Weeks 2, 4 and 8 in mean 
trough sitting diastolic 
blood pressure (SiDBP, 
OC) - MCP-Mod 
estimation of dose-
response 
PPS, 
FAS 
 
LAYMCP2 
DBP_MIXED_A
VER8_L 
T 
Mixed Model for average 
change from baseline to 
Weeks 2, 4 and 8 in mean 
trough sitting diastolic 
blood pressure (SiDBP, 
OC) - Lisinopril vs 
placebo  
PPS, 
FAS 
 
LAYBETW
001 
* T = Summary Table; L = Listing; F = Figure. 
ANCOVA = analysis of covariance; BOCF = baseline observation carried forward; FAS = Full Analysis Set; 
MCP-Mod = Multiple Comparison Procedure – Modeling; OBPM = automated office blood pressure measurement; 
PPS = Per-Protocol Set; SiDBP = sitting diastolic blood pressure. 
 
13.6.3 Subgroup analyses 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
DBP_MCPMOD
_AGE 
T 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) by Age 
PPS 
 
LAYMCP2 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
DBP_MCPMOD
_AGE 
F 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) by Age 
PPS 
 
LAYMCP6 
DBP_MCPMOD
_SEX 
T 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) by Sex 
PPS 
 
LAYMCP2 
DBP_MCPMOD
_SEX 
F 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) by Sex 
PPS 
 
LAYMCP6 
DBP_MCPMOD
_RACE 
T 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) by Race  
PPS 
 
LAYMCP2 
DBP_MCPMOD
_RACE 
F 
MCP-Mod estimation of 
dose-response in change 
from baseline to Week 8 
in mean trough sitting 
diastolic blood pressure 
(SiDBP) by Race 
PPS 
 
LAYMCP6 
* T = Summary Table; F = Figure. 
MCP-Mod = Multiple Comparison Procedure – Modeling; PPS = Per-Protocol Set; SiDBP = sitting diastolic blood 
pressure. Age category: < 65 vs ≥ 65 years. 
 




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Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
SBP_MCPMO
D 
F 
MCP-Mod estimation of dose-
response in change from 
baseline to Week 8 in sitting 
systolic blood pressure 
(SiSBP) 
PPS, 
FAS 
 
LAYMCP3 
SBP_MCPMO
D_SEL 
F 
MCP-Mod estimation of 
response at study doses in 
change from baseline to Week 
8 in mean trough sitting 
systolic blood pressure 
(SiSBP) - Best fitting model 
PPS, 
FAS 
Yes 
LAYMCP4 
SBP_MCPMO
D_SEL 
F 
MCP-Mod estimation of 
response at study doses in 
change from baseline to Week 
8 in mean trough sitting 
systolic blood pressure 
(SiSBP) - Best fitting model 
PPS, 
FAS 
 
LAYMCP5 
SBP_ANCOVA 
T 
ANCOVA for change from 
baseline to Week 8 in mean 
trough sitting systolic blood 
pressure (SiSBP) - ACT-
132577 vs placebo 
PPS, 
FAS 
Yes 
LAYBETW00
1 
SBP_ANCOVA 
F 
ANCOVA for change from 
baseline to Week 8 in mean 
trough sitting systolic blood 
pressure (SiSBP) - ACT-
132577 vs placebo 
PPS, 
FAS 
Yes 
LAYFOR 
SBP_ANCOVA
_L 
T 
ANCOVA for change from 
baseline to Week 8 in mean 
trough sitting systolic blood 
pressure (SiSBP) - Lisinopril 
vs placebo 
PPS, 
FAS 
Yes 
LAYBETW00
1 
 
 
 
 
 
 


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Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
SBP_MIXED_
W2_W4_W8 
T 
Mixed Model for changes 
from baseline to Weeks 2, 4 
and 8 in sitting systolic blood 
pressure (SiSBP, OC) - ACT-
132577 vs placebo 
FAS 
 
LAYBETW00
1 
SBP_MIXED_
W2_W4_W8_M
CP1 
T 
Mixed Model for changes 
from baseline to Weeks 2, 4 
and 8 in sitting systolic blood 
pressure (SiSBP, OC) - MCP-
Mod test for dose-response at 
Week 8 
FAS 
 
LAYMCP1 
SBP_MIXED_
W2_W4_W8_M
CP2 
T 
Mixed Model for changes 
from baseline to Weeks 2, 4 
and 8 in sitting systolic blood 
pressure (SiSBP, OC) - MCP-
Mod estimation of dose-
response at Week 8 
FAS 
 
LAYMCP2 
SBP_MIXED_
W2_W4_W8_L 
T 
Mixed Model for changes 
from baseline to Weeks 2, 4 
and 8 in mean trough sitting 
systolic blood pressure 
(SiSBP, OC) - Lisinopril vs 
placebo 
FAS 
 
LAYBETW00
1 
 
 
 
 
 
 
SBP_MIXED_
AVER8 
T 
Mixed Model for changes 
from baseline to Weeks 2, 4 
and 8 in sitting systolic blood 
pressure (SiSBP, OC) - ACT-
132577 vs placebo 
PPS, 
FAS 
 
LAYBETW00
1 


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Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
SBP_MIXED_
AVER8_MCP1 
T 
Mixed Model for average 
change from baseline to 
Weeks 2, 4 and 8 in sitting 
systolic blood pressure 
(SiSBP, OC) - MCP-Mod test 
for dose-response 
PPS, 
FAS 
 
LAYMCP1 
SBP_MIXED_
AVER8_MCP2 
T 
Mixed Model for average 
change from baseline to 
Weeks 2, 4 and 8 in sitting 
systolic blood pressure 
(SiSBP, OC) - MCP-Mod 
estimation of dose-response 
PPS, 
FAS 
 
LAYMCP2 
SBP_MIXED_
AVER8_L 
T 
Mixed Model for average 
change from baseline to 
Weeks 2, 4 and 8 in mean 
trough sitting systolic blood 
pressure (SiSBP, OC) - 
Lisinopril vs placebo 
PPS, 
FAS 
 
LAYBETW00
1 
SBP_MCPMOD
_AGE 
T 
MCP-Mod estimation of dose-
response in change from 
baseline to Week 8 in mean 
trough sitting systolic blood 
pressure (SiSBP) by Age  
PPS 
 
LAYMCP2 
SBP_MCPMOD
_AGE 
F 
MCP-Mod estimation of dose-
response in change from 
baseline to Week 8 in mean 
trough sitting systolic blood 
pressure (SiSBP) by Age 
PPS 
 
LAYMCP6 
SBP_MCPMOD
_SEX 
T 
MCP-Mod estimation of dose-
response in change from 
baseline to Week 8 in mean 
trough sitting systolic blood 
pressure (SiSBP) by Sex  
PPS 
 
LAYMCP2 


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Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
SBP_MCPMOD
_SEX 
F 
MCP-Mod estimation of dose-
response in change from 
baseline to Week 8 in mean 
trough sitting systolic blood 
pressure (SiSBP) by Sex 
PPS 
 
LAYMCP6 
SBP_MCPMOD
_RACE 
T 
MCP-Mod estimation of dose-
response in change from 
baseline to Week 8 in mean 
trough sitting systolic blood 
pressure (SiSBP) by Race  
PPS 
 
LAYMCP2 
SBP_MCPMOD
_RACE 
F 
MCP-Mod estimation of dose-
response in change from 
baseline to Week 8 in mean 
trough sitting systolic blood 
pressure (SiSBP) by Race 
PPS 
 
LAYMCP6 
 
 
 
 
 
 
COR_DBP_SB
P 
F 
Correlation between change 
from baseline in Diastolic and 
Systolic Blood Pressure by 
Visit and Treatment Group 
PPS 
 
LAYCORR 
CRR_DBP 
T 
Control and response rates at 
Week 8 for sitting diastolic 
blood pressure (SiDBP) as 
measured by OBPM 
PPS 
 
LAYCAT002 
CR_DBP_LOG
REG1 
T 
Logistic regression for control 
rates at Week 8 for sitting 
diastolic blood pressure 
(SiDBP) as measured by 
OBPM < 90 mmHg 
PPS 
 
LAYLOGR 


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Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
CR_DBP_LOG
REG2 
T 
Logistic regression for control 
rates at Week 8 for sitting 
diastolic blood pressure 
(SiDBP) as measured by 
OBPM < 85 mmHg 
PPS 
 
LAYLOGR 
CR_DBP_LOG
REG_MCP1 
T 
Logistic regression for control 
rates at Week 8 for sitting 
diastolic blood pressure 
(SiDBP) as measured by 
OBPM < 90 mmHg - MCP-
Mod test for dose-response 
PPS 
 
LAYMCP1 
CR_DBP_LOG
REG_MCP2 
T 
Logistic regression for control 
rates at Week 8 for sitting 
diastolic blood pressure 
(SiDBP) as measured by 
OBPM < 90 mmHg - MCP-
Mod estimation of dose-
response 
PPS 
 
LAYMCP2 
RR_DBP_LOG
REG 
T 
Logistic regression for 
response rates at Week 8 for 
sitting diastolic blood pressure 
(SiDBP) as measured by 
OBPM 
PPS 
 
LAYLOGR 
CRR_SBP 
T 
Control and response rates at 
Week 8 for sitting systolic 
blood pressure (SiSBP) as 
measured by OBPM 
PPS 
 
LAYCAT002 
CR_SBP_LOG
REG1 
T 
Logistic regression for control 
rates at Week 8 for sitting 
systolic blood pressure 
(SiSBP) as measured by 
OBPM < 140 mmHg 
PPS 
 
LAYLOGR 


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Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
CR_SBP_LOG
REG2 
T 
Logistic regression for control 
rates at Week 8 for sitting 
systolic blood pressure 
(SiSBP) as measured by 
OBPM < 135 mmHg 
PPS 
 
LAYLOGR 
CR_SBP_LOG
REG_MCP1 
T 
Logistic regression for control 
rates at Week 8 for sitting 
systolic blood pressure 
(SiSBP) as measured by 
OBPM < 140 mmHg - MCP-
Mod test for dose-response 
PPS 
 
LAYMCP1 
CR_SBP_LOG
REG_MCP2 
T 
Logistic regression for control 
rates at Week 8 for sitting 
systolic blood pressure 
(SiSBP) as measured by 
OBPM < 140 mmHg - MCP-
Mod estimation of dose-
response 
PPS 
 
LAYMCP2 
RR_SBP_LOG
REG 
T 
Logistic regression for 
response rates at Week 8 for 
sitting systolic blood pressure 
(SiSBP) as measured by 
OBPM 
PPS 
 
LAYLOGR 
24H_DBP_CH
G 
T 
Change from baseline to Week 
8 in 24-hour mean diastolic 
blood pressure (DBP) as 
measured by ABPM by 
treatment group 
PPS 
 
LAYBASE00
1 
24H_DBP_AN
COVA 
T 
ANCOVA for change from 
baseline to Week 8 in 24-hour 
mean diastolic blood pressure 
(DBP) as measured by ABPM 
- ACT-132577 vs Placebo 
PPS 
Yes 
LAYBETW00
1 


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Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
24H_DBP_AN
COVA_L 
T 
ANCOVA for change from 
baseline to Week 8 in 24-hour 
mean diastolic blood pressure 
(DBP) as measured by ABPM 
- Lisinopril vs Placebo 
PPS 
Yes 
LAYBETW00
1 
 
 
 
 
 
 
24H_SBP_CHG 
T 
Change from baseline to Week 
8 in 24-hour mean systolic 
blood pressure (SBP) as 
measured by ABPM by 
treatment group 
PPS 
 
LAYBASE00
1 
24H_SBP_ANC
OVA_L 
T 
ANCOVA for change from 
baseline to Week 8 in 24-hour 
mean systolic blood pressure 
(SBP) as measured by ABPM 
- Lisinopril vs Placebo  
PPS 
Yes 
LAYBETW00
1 
OBPM 
L 
Listing of mean trough sitting 
diastolic (SiDBP), mean 
trough sitting systolic blood 
pressure (SiSBP) and pulse 
rate measured by OBPM with 
control and response rates 
FAS 
 
L_OBPM 
 
 
 
 
 
 
ABPM24_DBP
_BAS 
F 
Mean diastolic blood pressure 
(DBP) per hour as measured 
by ABPM at baseline 
PPS 
 
LAY_ABPM 
ABPM24_DBP
_WK8 
F 
Mean diastolic blood pressure 
(DBP) per hour as measured 
by ABPM at Week 8 
PPS 
 
LAY_ABPM 


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Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
ABPM24_DBP
_WK8_DIF 
F 
Difference in mean diastolic 
blood pressure (DBP) per hour 
as measured by ABPM 
PPS 
 
LAY_ABPM 
ABPM24_DBP
_TTPR 
T 
Trough to peak ratio for 
diastolic blood pressure (DBP) 
measured by ABPM 
PPS 
 
LAY_TTPR 
ABPM24_SBP_
BAS 
F 
Mean systolic blood pressure 
(SBP) per hour as measured by 
ABPM at baseline 
PPS 
 
LAY_ABPM 
ABPM24_SBP_
WK8 
F 
Mean systolic blood pressure 
(SBP) per hour as measured by 
ABPM at Week 8 
PPS 
 
LAY_ABPM 
ABPM24_SBP_
WK8_ DIF 
F 
Difference in mean systolic 
blood pressure (SBP) per hour 
as measured by ABPM 
PPS 
 
LAY_ABPM 
ABPM24_SBP_
TTPR 
T 
Trough to peak ratio for 
systolic blood pressure (SBP) 
measured by ABPM 
PPS 
 
LAY_TTPR 
* T = Summary Table; F = Figure.  
ABPM = ambulatory blood pressure monitoring; ANCOVA = analysis of covariance; DBP = diastolic blood pressure; 
FAS = Full Analysis Set; MCP-Mod = Multiple Comparison Procedure – Modeling; OBPM = automated office blood 
pressure measurement; PPS = Per-Protocol Set; SBP = systolic blood pressure; SiDBP = sitting diastolic blood 
pressure; SiSBP = sitting systolic blood pressure. 
ABPM analyses are based on the subset of the PPS described in Section 5.5. 
Age category: < 65 vs ≥ 65 years. 
13.8 Other efficacy analyses 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
DAY_DBP_
CHG 
T 
Change from baseline to 
Week 8 in 24-hour mean 
daytime diastolic blood 
pressure (DBP) as measured 
by ABPM by treatment group 
PPS 
 
LAYBASE0
01 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
DAY_DBP_
ANCOVA 
T 
ANCOVA for change from 
baseline to Week 8 in mean 
daytime diastolic blood 
pressure (DBP) as measured 
by ABPM 
PPS 
 
LAYBETW0
01 
 
 
 
 
 
 
NIGHT_DBP
_CHG 
T 
Change from baseline to 
Week 8 in 24-hour mean 
night time diastolic blood 
pressure (DBP) as measured 
by ABPM by treatment group 
PPS 
 
LAYBASE0
01 
NIGHT_DBP
_ANCOVA 
T 
ANCOVA for change from 
baseline to Week 8 in mean 
night time diastolic blood 
pressure (DBP) as measured 
by ABPM 
PPS 
 
LAYBETW0
01 
 
 
 
 
 
 
DAY_SBP_
CHG 
T 
Change from baseline to 
Week 8 in 24-hour mean 
daytime systolic blood 
pressure (DBP) as measured 
by ABPM by treatment group 
PPS 
 
LAYBASE0
01 
DAY_SBP_
ANCOVA 
T 
ANCOVA for change from 
baseline to Week 8 in mean 
daytime systolic blood 
pressure (SBP) as measured 
by ABPM 
PPS 
 
LAYBETW0
01 
 
 
 
 
 
 
NIGHT_SBP
_CHG 
T 
Change from baseline to 
Week 8 in 24-hour mean 
night time systolic blood 
pressure (SBP) as measured 
by ABPM by treatment group 
PPS 
 
LAYBASE0
01 


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Doc No D-17.304 
 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
NIGHT_SBP
_ANCOVA 
T 
ANCOVA for change from 
baseline to Week 8 in mean 
night time systolic blood 
pressure (SBP) as measured 
by ABPM 
PPS 
 
LAYBETW0
01 
 
 
 
 
 
 
MIXED_DB
P_W2_W4_
W8_W10 
T 
Mixed model for changes 
from baseline to Weeks 2, 4, 
8 and 10 in mean trough 
sitting 
diastolic 
blood 
pressure (SiDBP, OC) as 
measured by OBPM 
PPS 
 
LAYBETW0
01 
MIXED_SBP
_W2_W4_W
8_W10 
T 
Mixed model for changes 
from baseline to Weeks 2, 4, 
8 and 10 in mean trough 
sitting systolic blood pressure 
(SiSBP, OC) as measured by 
OBPM 
PPS 
 
LAYBETW0
01 
ABPM 
L 
Listing of individual diastolic 
and systolic blood pressure 
measured by ABPM 
FAS 
 
LSTCSR09
32 
DN_ABPM 
L 
Listing of 24-hour mean, 
daytime mean and night time 
mean diastolic and systolic 
blood pressure measured by 
ABPM 
FAS 
 
LSTCSR09
32 
* T = Summary Table; L = Listing.  
ABPM = ambulatory blood pressure monitoring; ANCOVA = analysis of covariance; DBP = diastolic blood pressure; 
FAS = Full Analysis Set; MCP-Mod = Multiple Comparison Procedure – Modeling; OBPM = automated office blood 
pressure measurement; PPS = Per-Protocol Set; SBP = systolic blood pressure; SiDBP = sitting diastolic blood 
pressure; SiSBP = sitting systolic blood pressure. 
ABPM analyses are based on the subset of PPS subjects describe d in Section 5.5. 


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13.9 Safety analyses 
13.9.1 Adverse events 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
AEOV 
T 
Overview of double-blind 
treatment-emergent adverse 
events (AEs) 
SAF 
Yes 
LAYAE004 
TEAESCPR 
T 
Double-blind treatment-
emergent adverse events 
(AEs) by primary system 
organ class (SOC) and 
preferred term 
SAF 
 
LAYAE001 
TEAEPR 
T 
Double-blind treatment-
emergent adverse events 
(AEs) by preferred term 
SAF 
 
LAYAE002 
TEAERESC
PR 
T 
Double-blind treatment-
emergent adverse events 
(AEs) related to study 
treatment by primary system 
organ class (SOC) and 
preferred term 
SAF 
 
LAYAE001 
TEAEREPR 
T 
Double-blind treatment-
emergent adverse events 
(AEs) related to study 
treatment by preferred term 
SAF 
 
LAYAE002 
TEAEPRIN 
T 
Double-blind treatment-
emergent adverse events 
(AEs) by maximum intensity 
SAF 
 
LAYAE003 
AEOV 
T 
Overview of run-in 
treatment-emergent adverse 
events (AEs) 
RIS 
 
LAYAE004 
TEAEPR 
T 
Run-in treatment-emergent 
adverse events (AEs) by 
preferred term 
RIS 
 
LAYAE002 


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Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
AE 
L 
Listing of adverse events 
(AEs) 
RIS 
 
LSTCSR071 
* T = Summary Table; L = Listing.  
 AE = adverse event; RIS = Run-in Set; SAF = Safety Set.  
13.9.2 Deaths 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
DEATH 
L 
Listing of deaths 
SAF 
 
LSTCSR072 
* L= Listing,  
 SAF=Safety set. 
 
13.9.3 Serious adverse events 
Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
TESAESCPR 
T 
Double-blind treatment-
emergent serious 
adverse events (SAEs) 
by primary system organ 
class (SOC) and 
preferred term 
SAF 
Yes 
LAYAE001 
TESAEPR 
T 
Double-blind treatment-
emergent serious 
adverse events (SAEs) 
by preferred term  
SAF 
 
LAYAE002 
TESAERESCPR 
T 
Double-blind treatment-
emergent serious 
adverse events (SAEs) 
related to study 
treatment by preferred 
term 
SAF 
 
LAYAE002 


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Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
TESAEPR 
T 
Run-in treatment-
emergent serious 
adverse events (SAEs) 
by preferred term  
RIS 
 
LAYAE002 
SAE 
L 
Listing of serious 
adverse events (SAEs) 
RIS 
 
LSTCSR071 
* T = Summary Table; L = Listing.  
RIS = Run-in Set; SAE = serious adverse event; SAF = Safety Set; SOC = system organ class. 
 
13.9.4 Adverse events leading to treatment discontinuation 
Output name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock 
layout(AEs)  
TEAEPDSCPR 
T 
Double-blind treatment-
emergent adverse events 
(AEs) leading to premature 
discontinuation of study 
treatment by primary 
system organ class (SOC) 
and preferred term 
SAF 
Yes 
LAYAE001 
TEAEPDPR 
T 
Double-blind treatment-
emergent adverse events 
(AEs) leading to premature 
discontinuation of study 
treatment by preferred term 
SAF 
 
LAYAE002 
TEAEPDPR 
T 
Run-in treatment-emergent 
adverse events (AEs) 
leading to premature 
discontinuation of study 
treatment by preferred term 
RIS 
 
LAYAE002 
AEPD 
L 
Listing of adverse events 
(AEs) leading to premature 
discontinuation of study 
treatment 
SCR 
 
LSTCSR071 
* T = Summary Table; L = Listing.  
AE = adverse event; RIS = Run-in Set; SAF = Safety Set; SOC = system organ class. 


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13.10 Electrocardiogram (ECG) 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
ECG_CHG 
T 
ECG parameters: changes from 
baseline to end of double-blind 
treatment 
SAF 
 
LAYBASE00
1 
ECGQTCP
T 
T 
Number of subjects with 
double-blind treatment-
emergent ECG abnormalities 
(based on Fridericia’s formula) 
SAF 
 
LAYECG001 
ECGMA 
L 
Listing of 12-lead ECG 
variables in subjects with at 
least one double-blind 
treatment-emergent ECG 
abnormalities 
SAF 
 
LSTCSR0931 
ECG 
L 
Listing of 12-lead ECG 
variables and abnormalities 
SCR 
 
LSTCSR093 
* T = Summary Table; L = Listing.  
ECG = electrocardiogram; SAF = Safety Set; SCR = Screened Set. 
 
13.11 Laboratory tests 
Output name 
Display* 
Title 
(Description) 
Analysis 
set(s) 
Key 
Mock layout 
HEMAV_VIS 
T 
Hematology 
parameters: 
absolute values by 
visit 
SAF 
 
LAYLAB003a 
HEM_CHG 
T 
Hematology 
parameters: 
changes from 
baseline to 
post-baseline visits 
SAF 
Yes 
LAYLAB002a 


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Output name 
Display* 
Title 
(Description) 
Analysis 
set(s) 
Key 
Mock layout 
HEM_CHG 
F 
Mean change from 
baseline to post-
baseline visits in 
hemoglobin by 
treatment group 
SAF 
 
LAYTIME 
CHEAV_VIS 
T 
Chemistry 
parameters: 
absolute values by 
visit 
SAF 
 
LAYLAB003a 
CHE_CHG 
T 
Chemistry 
parameters: 
changes from 
baseline to 
post-baseline visits 
SAF 
 
LAYLAB002a 
 
 
 
 
 
 
UACRAV_VIS 
T 
Urine parameter: 
UACR absolute 
values by visit 
SAF 
 
LAYLAB003a 
UACR_CHG 
T 
Urine parameter: 
UACR changes 
from baseline to 
post-baseline visits 
SAF 
Yes 
LAYLAB002a 
 
T 
Definition of 
abnormal 
laboratory values 
NA 
 
 
HEM_TEMA 
T 
Hematology 
parameters: 
treatment-emergent 
marked 
abnormalities  
SAF 
 
LAYLAB001 
CHE_TEMA 
T 
Chemistry 
parameters: 
treatment-emergent 
marked 
abnormalities 
SAF 
 
LAYLAB001 
CHE_ALT_BIL 
T 
Number of 
subjects with ALT 
> 3 × ULN and 
bilirubin > 2 × 
ULN 
SAF 
 
LAYCAT002 


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Output name 
Display* 
Title 
(Description) 
Analysis 
set(s) 
Key 
Mock layout 
LABMLA 
L 
Listing of 
definitions of 
marked laboratory 
abnormality 
- 
 
L_LABMLA 
LAB 
L 
Listing of 
individual 
laboratory 
measurements 
(SI units) 
SCR 
 
LSTCSR081 
HEM_CHG 
F 
Density of change 
from baseline to 
post-baseline visits 
in hemoglobin by 
treatment group 
SAF 
 
LAYDENS 
HEM_MCPMOD1 
T 
MCP-Mod test for 
dose-response in 
change from 
baseline to Week 8 
in hemoglobin 
SAF 
 
LAYMCP1 
HEM_MCPMOD2 
T 
MCP-Mod 
estimation of 
dose-response in 
change from 
baseline to Week 8 
in hemoglobin 
SAF 
 
LAYMCP2 
HEM_MCPMOD 
F 
MCP-Mod 
estimation of dose-
response in change 
from baseline to 
Week 8 in 
hemoglobin 
SAF 
 
LAYMCP3 
* T = Summary Table; L = Listing; F = Figure.  
ALT = alanine aminotransferase; MCP-Mod = Multiple Comparison Procedure – Modeling; SAF = Safety Set; SCR = 
Screened Set; SI = Standard International; UACR = urine albumin-to-creatinine ratio; ULN =upper limit of normal; NA 
= not applicable. 
 


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13.12 Physical examination, vital signs and body weight 
Output 
name 
Display
* 
Title (Description) 
Analysis 
set(s) 
Key 
Mock layout 
VSW_VI
S 
T 
Pulse rate and body weight: 
values by visit 
SAF 
 
LAYBASE0
01 
VSW_C
HG 
T 
Pulse rate and body weight: 
changes from baseline to 
post-baseline visit 
SAF 
Yes 
LAYBASE0
01 
VSW_C
HG 
F 
Mean change from baseline to 
post-baseline visits in body 
weight by treatment group 
SAF 
 
LAYTIME 
VSW_C
HG 
F 
Density of change from baseline 
to post-baseline visits in body 
weight by treatment group 
SAF 
 
LAYDENS 
VSW 
L 
Listing of pulse rate and body 
weight 
SCR 
 
LSTCSR091 
PHYSF 
L 
Listing of physical findings 
SCR 
 
LSTCSR094 
WGT_M
CPMOD
1 
T 
MCP-Mod test for dose-response 
in change from baseline to Week 
8 in body weight 
SAF 
 
LAYMCP1 
WGT_M
CPMOD
2 
T 
MCP-Mod estimation of dose-
response in change from baseline 
to Week 8 in body weight 
SAF 
 
LAYMCP2 
WGT_M
CPMOD 
F 
MCP-Mod estimation of dose-
response in change from baseline 
to Week 8 in body weight 
SAF 
 
LAYMCP3 
* T = Summary Table; L = Listing; F = Figure.  
MCP-Mod = Multiple Comparison Procedure – Modeling; SAF = Safety Set; SCR = Screened Set. 
13.13 Other safety variables 
Not applicable. 




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14 REFERENCES 
[D-16.063] A multi-center, double-blind, double-dummy, randomized, placebo- and 
active-reference, parallel group, Phase 2 dose-finding study with ACT-132577 in 
subjects with essential hypertension (grade 1 and 2). Actelion Pharmaceuticals Ltd; 
Protocol AC-080A201, 30 May 2016. 
[Bornkamp 2016] Bornkamp B, Pinheiro J, Bretz F. Planning and analyzing dose finding 
experiments. 2016. Available from: cran.r-project.org/web/packages/DoseFinding. 
Accessed on: 27 July 2016. 
[Bretz 2005] Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and 
modeling techniques in dose-response studies. Biometrics. 2005;61(3):738-48. 
[EMA 2010] European Medicines Agency, EMA/CPMP/EWP/1776/99 Rev. 1. Guideline 
on Missing Data in Confirmatory Clinical Trials.  
Available from:  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
0/09/WC500096793.pdf  
[EMA 2014] European Medicines Agency, EMA/CHMP/SAWP/757052/2013. 
Qualification Opinion of MCP-Mod as an efficient statistical methodology for 
model-based design and analysis of Phase II dose finding studies under model 
uncertainty.  
Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedu
ral_guideline/2014/02/WC500161027.pdf 
[FDA 2007]. Food and Drug Administration, Center for Drug Evaluation and Research. 
Medical reviews of Aliskiren. 
Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021985s000toc.cfm 
[Leung 2016]. Leung AA, Nerenberg K, Daskalopoulou SS, McBrien K, Zarnke KB, 
Dasgupta K, et al. Hypertension Canada’s 2016 Canadian Hypertension Education 
Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of 
Risk, Prevention, and Treatment of Hypertension. Canadian Journal of Cardiology. 
2016;32:569–88. 
[O’Brien 2013] O’Brien E, Parati G, Stergiou G. Ambulatory blood pressure 
measurement - What is the international consensus. Hypertension. 2013;62:988-94. 
[Omboni 1995] Omboni S, Parati G, Zanchetti A, Mancia G. Calculation of trough: peak 
ratio 
of 
antihypertensive 
treatment 
from 
ambulatory 
blood 
pressure: 
methodological aspects. Journal of Hypertension 1995;13:1105-12. 


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[Pinheiro 2006] Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding 
studies combining multiple comparisons and modeling procedures. J Biopharm 
Stat. 2006;16(5):639-56. 
[Pinheiro 2014] Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding 
under model uncertainty using general parametric models. Statistics in Medicine 
2014;33(10):1646-61. 
 
 


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15 APPENDICES 
A. 
Protocol synopsis 
TITLE 
Multi-center, 
double-blind, 
double-dummy, 
randomized, 
placebo- and active-reference, parallel group, Phase 2 
dose-finding study with ACT-132577 in subjects with essential 
hypertension (grade 1 and 2) 
OBJECTIVES 
Primary objective 
The primary objective of the study is to explore the 
dose-response of ACT-132577 on diastolic blood pressure 
(DBP) in subjects with essential hypertension (grade 1 and 2). 
Secondary objectives 
Evaluate the dose-response of ACT-132577 on: 
• Systolic blood pressure (SBP) 
• Control and response rates of blood pressure (BP)  
• 24-h ambulatory blood pressure monitoring (ABPM) 
Evaluate the safety and tolerability of a once a day oral regimen 
of 4 doses of ACT-132577. 
Other objectives 
Other objectives are described in Section 2.3.  
DESIGN 
Prospective, 
multi-center, 
double-blind, 
double-dummy, 
randomized, placebo- and active-reference, parallel group, 
Phase 2 dose-finding study  
PERIODS 
Pre-screening:  
Subjects without a confirmation of hypertension are offered the 
possibility of having their BP measured (at trough if subjects 
are on antihypertensive treatment) with an automated office BP 
device before entering the screening period.  
Screening: 
Visit 1 (screening period) lasts up to 72 h to allow for informed 
consent to be obtained and study assessments to be performed 
(e.g., laboratory tests) to determine whether the subject is 
eligible for the study.  
Run-in Period (Period I) is a single-blind (SB) placebo period 
of between 4 to 6 weeks.  
It commences at the end of Visit 1 and ends at Visit 4 / 
Randomization (after completion of the baseline 24-h ABPM 


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recording on the last dose of SB study treatment (placebo).  
For subjects on anti-hypertensive treatment at first visit 
(Visit 1) the SB placebo period is 6 weeks including a 2-week 
wash-out period for anti-hypertensive treatment. 
For anti-hypertensive treatment naïve subjects at first visit, the 
SB placebo period is 4 weeks. Visit 1 is combined with Visit 2. 
Treatment Period (Period II) is a double-blind (DB) 
treatment period of 8 weeks which starts at Visit 4 / 
Randomization with the first dose of DB study treatment and 
ends at Visit 7 / Part 2 (after completion of 24-h ABPM 
recording on the last dose of DB study treatment).  
Withdrawal Period (Period III) is an SB placebo period of 
2 weeks which starts at Visit 7 / Part 2 with the first dose of SB 
study treatment (placebo) and ends at Visit 8 (withdrawal 
End-of-Treatment [WD-EOT]). 
Follow-up Period starts after the last dose of withdrawal study 
treatment and ends at least 2 weeks thereafter, by the follow-up 
telephone call, or follow-up visit only for women of 
childbearing potential to perform a pregnancy test at the site. 
End-of-Study (EOS) for a single subject is defined as the date 
of the follow-up telephone call or the date of the follow-up 
visit. 
If a subject withdraws consent and does not wish to participate 
in further visits, the date of consent withdrawal is EOS for this 
subject. If a subject is declared lost to follow-up [see also 
Section 9.2] date of last contact is EOS for this subject.  
The overall study is considered completed when all subjects 
have completed their safety follow-up telephone call or 
follow-up visit. 
PLANNED DURATION 
Approximately 16 months from First subject first visit (i.e., 
Screening Visit) to Last subject last visit (i.e., 30-day follow-up 
telephone call / visit). 
SITE(S) 
/ COUNTRY(IES) 
Approximately 100 sites in 3 to 4 countries in North America 
and Israel (planned). 
SUBJECTS / GROUPS 
Approximately 1000 subjects will be enrolled in the SB 
placebo run-in period, in order to have at least 540 subjects 
randomized in 6 groups (90 subjects per group) in a 1:1:1:1:1:1 


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ratio. 
At least 420 subjects (70 per group) are expected to complete 
the trial. 
INCLUSION CRITERIA 
This study will enroll adult male and female subjects aged 18 to 
75 years with mild-to-moderate (grade 1 and 2) essential 
hypertension with or without ongoing anti-hypertensive 
treatment. 
Women of childbearing potential must have a negative 
pregnancy test at screening and randomization, and must agree 
to use reliable methods of contraception from Visit 1 
(Screening) until up to 30 days after DB study treatment 
discontinuation.  
Eligible subjects must be able and willing to give informed 
consent for participation in the clinical study.  
For the complete list of inclusion criteria, please see Section 
4.3.  
EXCLUSION CRITERIA 
Subjects with severe hypertension (grade 3) or secondary 
hypertension.  
Subjects with clinically relevant medical or surgical conditions 
that, in the opinion of the investigator, would put the subject at 
risk by participating in the study.  
For the complete list of exclusion criteria, please see 
Section 4.4.  
STUDY TREATMENTS 
Investigational treatment  
ACT-132577 5 mg, 10 mg (2 × 5 mg), 25 mg, and 50 mg 
administered as capsules orally once a day (o.d.) in the morning 
irrespective of food intake during the DB treatment period.  
Comparator  
Lisinopril is used as active reference drug. It is administered as 
20 mg capsules orally o.d. in the morning irrespective of food 
intake during the DB treatment period. 
Placebo 
Placebo matching ACT-132577 and placebo matching 
lisinopril capsules will be administered concomitantly orally 
o.d. during the SB placebo run-in period and SB placebo 
withdrawal period to all subjects and during the DB treatment 
period to those subjects who have been randomized to the 


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placebo group. 
CONCOMITANT 
THERAPY 
Allowed concomitant therapy 
Treatments considered necessary for the subject’s wellbeing 
and not categorized as prohibited concomitant medications are 
allowed during the study.  
Intermittent use of topical/nasal corticosteroid applications are 
allowed during the study. 
In addition, the following therapies are allowed with the 
provision that they have been initiated at least one month prior 
to the Screening visit (Visit 1) and that the dose is kept stable 
until the WD-EOT visit (i.e., Visit 8):  
• Hormonal contraceptives. 
• Estrogen-replacement treatment. 
• Non-steroidal anti-inflammatory drugs (e.g., low dose 
acetylsalicylic acid for prevention of cardiovascular 
disease). 
• Selective serotonin reuptake inhibitors and anxiolytics. 
Forbidden concomitant therapy 
The following concomitant therapies are forbidden from 
Screening visit (i.e., Visit 1) until the WD-EOT visit (i.e., 
Visit 8), see Section 5.2.4: 
• Any drug, including ophthalmic preparation, which may 
affect blood pressure, see Appendix 3. Endothelin receptor 
antagonists (ERAs) and PDE5 inhibitors. 
• Strong inhibitors or inducers of cytochrome P450 3A4 
isoenzyme (CYP3A4), see Appendix 4. 
ENDPOINTS 
Primary efficacy endpoint(s) 
The primary efficacy variable is the change from baseline to 
Week 8 of DB treatment period (Period II) in mean trough 
sitting DBP (SiDBP), measured by office blood pressure 
measurement (OBPM). 
Secondary efficacy endpoints 
Secondary efficacy variables include (measured by OBPM, 
unless specified otherwise): 
• Change from baseline to Week 8 of DB treatment period 
(Period II) in mean trough sitting systolic BP (SiSBP); 
• Control and response rates at Week 8 of DB treatment 


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period (Period II) based on trough SiDBP [defined as in 
Section 7.2.1.1]; 
• Control and response rates at Week 8 of DB treatment 
period (Period II) based on trough SiSBP [defined as in 
Section 7.2.1.1]; 
• Change from baseline to Week 8 of DB treatment period 
(Period II) in 24-h mean DBP, measured by ABPM; 
• Change from baseline to Week 8 of DB treatment period 
(Period II) in 24-h mean SBP, measured by ABPM; 
• Trough to peak ratio for DBP based on ABPM. 
Other efficacy endpoints 
Other efficacy endpoints are described in Section 6.1.3. 
Safety endpoints 
• Treatment-emergent adverse events (AEs);  
• AEs leading to premature discontinuation of study 
treatment; 
• Treatment-emergent deaths; 
• Treatment-emergent serious adverse events; 
• Treatment-emergent ECG abnormalities; 
• Treatment-emergent marked laboratory abnormalities; 
• Changes from baseline to Weeks 2, 4 and 8 of DB 
treatment period (Period II) in laboratory parameters; 
• Changes from baseline to Weeks 4 and 8 of DB treatment 
period (Period II) in ECG parameters (PR, QRS, QT, QTcB, 
QTcF); 
• Changes from baseline to Weeks 2, 4 and 8 of DB 
treatment period (Period II) in body weight and heart rate. 
See Section 10.1.1 for definition of ‘treatment-emergent’. 
Pharmacokinetic/pharmacodynamic endpoints 
Pharmacokinetic / pharmacodynamic endpoints are described 
in Section 6.3. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
The Full Analysis Set (FAS) includes all subjects randomized 
to a study treatment, who have a baseline mean trough SiDBP. 
The Per-Protocol Set (PPS) includes all subjects from the FAS 


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who have a mean trough SiDBP at Week 8 of DB treatment 
period (Period II) and do not have any major protocol 
deviation. Major protocol deviations will be described in the 
Statistical Analysis Plan.  
The Safety Set includes all subjects who received at least one 
dose of study treatment in DB treatment period (Period II).  
Statistical hypotheses 
The null hypothesis to be tested is that there is no 
dose-response for the primary endpoint. 
H0: μ0 = μ1 = μ2 = μ3 = μ4 
Here, μi denotes the mean change from baseline to Week 8 in 
mean trough SiDBP (µ) for ACT-132577 dose (i) (where i = 0 
corresponds to placebo). A value of μi < 0 corresponds to a 
decrease in SiDBP. 
The alternative hypothesis is that there is a monotonic 
dose-response for the primary endpoint. 
H1: μ0 ≥ μ1 ≥ μ2 ≥ μ3 ≥ μ4 and μi > μj for at least one i > j or 
μ0 ≤ μ1 ≤ μ2 ≤ μ3 ≤ μ4 and μi < μj for at least one i > j 
Note that larger values of μi –corresponding to less decrease (or 
more increase) from baseline to Week 8 in mean trough SiDBP 
with increasing dose of ACT-132577– are less favorable. The 
first part of the alternative hypothesis corresponds to 
ACT-132577 being superior to placebo. 
Type I and II errors and power 
The type I error (α) is set to 0.05 (two-sided). The type II error 
is set to 0.10 and therefore the power to 90%. 
Primary analysis 
The primary analysis will be conducted on the PPS. 
Change from baseline to Week 8 in mean trough office SiDBP 
will be analyzed using the MCP-Mod approach. In brief, it 
consists of a set of Multiple Contrast Tests (MCTs) to establish 
the existence of a dose-response and a set of pre-specified 
dose-response models to describe the dose-response curve.  
Six candidate dose-response models will be considered: linear, 
linear in log-dose, quadratic, Emax, sigmoidal Emax and logistic. 
The analysis will be performed using the R-package 
DoseFinding. A dose-response relationship is demonstrated if 




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A blinded sample size re-estimation will be performed by the 
sponsor after 100 subjects have been randomized and their 
Week 8 BP data are available for analysis. The sample size will 
be recalculated considering the overall SD of the primary 
endpoint (change from baseline to Week 8 in mean trough 
SiDBP, measured by OBPM) in the PPS. The recalculated size 
of the PPS is expected to be between 280 subjects and the 
originally foreseen 420 subjects. The associated number of 
subjects to be randomized will also be re-estimated and is 
expected to be between 300 subjects and the originally planned 
540 subjects. See Section 11.5.3 for more details. 
STUDY COMMITTEES 
An Independent Liver Safety Data Review Board (an external 
expert 
committee 
of 
hepatologists) 
provides 
ongoing 
assessment and advice regarding any hepatic events that may 
require further evaluation during the study.  




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ABPM date blood 
pressure reading 
ABPM time of blood 
pressure reading 
ABPM diastolic blood 
pressure (mmHg) 
ABPM systolic blood 
pressure (mmHg) 
18MAY2016 
11:20 
100 
146 
18MAY2016 
11:40 
114 
150 
18MAY2016 
12:00 
109 
140 
18MAY2016 
12:23 
122 
167 
18MAY2016 
12:43 
73 
91 
18MAY2016 
13:00 
109 
148 
18MAY2016 
13:20 
95 
147 
18MAY2016 
13:40 
94 
141 
18MAY2016 
14:00 
95 
126 
18MAY2016 
14:20 
89 
120 
18MAY2016 
14:40 
84 
135 
18MAY2016 
15:00 
96 
140 
18MAY2016 
15:20 
95 
139 
18MAY2016 
15:40 
82 
138 
18MAY2016 
16:03 
100 
135 
18MAY2016 
16:23 
103 
144 
18MAY2016 
16:40 
98 
137 
18MAY2016 
17:20 
102 
147 
18MAY2016 
17:43 
93 
145 
18MAY2016 
18:00 
93 
159 
18MAY2016 
18:20 
107 
151 
18MAY2016 
18:40 
95 
135 
18MAY2016 
19:00 
100 
129 
18MAY2016 
19:20 
99 
130 
18MAY2016 
19:40 
96 
129 
18MAY2016 
20:00 
101 
129 
18MAY2016 
20:20 
94 
126 
18MAY2016 
20:40 
91 
124 
18MAY2016 
21:00 
86 
118 
18MAY2016 
21:23 
83 
116 
18MAY2016 
21:40 
90 
123 
18MAY2016 
22:00 
86 
121 


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ABPM date blood 
pressure reading 
ABPM time of blood 
pressure reading 
ABPM diastolic blood 
pressure (mmHg) 
ABPM systolic blood 
pressure (mmHg) 
18MAY2016 
22:40 
94 
169 
18MAY2016 
23:00 
95 
150 
18MAY2016 
23:30 
97 
135 
19MAY2016 
00:03 
144 
180 
19MAY2016 
01:00 
83 
117 
19MAY2016 
01:30 
74 
129 
19MAY2016 
02:00 
70 
127 
19MAY2016 
02:30 
62 
124 
19MAY2016 
03:00 
60 
121 
19MAY2016 
03:30 
66 
127 
19MAY2016 
04:00 
71 
137 
19MAY2016 
04:30 
95 
140 
19MAY2016 
05:00 
97 
140 
19MAY2016 
05:30 
92 
161 
19MAY2016 
06:00 
111 
180 
19MAY2016 
06:20 
115 
178 
19MAY2016 
06:40 
121 
177 
19MAY2016 
07:00 
117 
173 
19MAY2016 
07:20 
120 
177 
19MAY2016 
07:40 
112 
173 
19MAY2016 
08:00 
113 
161 
19MAY2016 
08:20 
130 
221 
19MAY2016 
09:00 
121 
167 
19MAY2016 
09:20 
100 
177 
19MAY2016 
09:40 
117 
174 
19MAY2016 
10:20 
117 
179 
19MAY2016 
10:43 
89 
161 
19MAY2016 
11:00 
92 
190 
19MAY2016 
11:04 
104 
158 
ABPM = ambulatory blood pressure monitoring. 


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Example calculations. The total duration of the ABPM (24h 35 mins) was shorter than 
25 hours, so all measurements were included in the calculation of the 24-hour mean DBP 
and SBP for this subject at this visit. The calculations based on these data are: 
• The areas under the DBP and SBP curves are 8,640,870 and 12,956,970 mmHg 
sec, respectively. Dividing both areas by the time span of 88,500 seconds gives a 
24-hour means of 97.6 and 146.4 mmHg, respectively. 
• The mean daytime DBP = (3,705,300 + 801,570) / (37,860 + 7440) = 99.5 mHg. 
• The mean daytime SBP = (5,224,530 + 1,295,970) / (37,860 + 7440) = 
143.9 mmHg. 
• The mean night time DBP = 1,411,200 / 18,000 = 78.4 mmHg. 
• The mean night time SBP = 2,438,100 / 18,000 = 135.5 mmHg. 
Note that measurements between 21:00 on the first day and 01:00 on the second day 
(limits excluded) and between 06:00 and 09:00 on the second day (limits excluded) are 
included in the calculation of the 24-hour means, but not in the calculation of the daytime 
or night time means. 




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D. 
Document history 
Version 
Effective Date 
Reason 
1.0 
8 May 2017 
New 
2.0 
15 May 2017 
Update pre-unblinding 
 


 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
FOR SAMPLE SIZE RE-ESTIMATION 
 
STUDY AC-080A201 
 
 
Purpose of Analysis 
Blinded Sample Size Re-estimation 
Investigational Drug 
ACT-132577 
Protocol Number 
AC-080A201 
Idorsia Document Number 
D-17.086 
Document Status/Version Number 
Final Version 2 
Date 
3 November 2017 
 
 
Author 
, Expert Statistician 
Reviewers 
 Senior Expert Statistician 
 
, VP Science Medical Expert 
 
 
 
 
 
 
 
Property of Idorsia Pharmaceuticals Ltd 
 
Confidential 
 
May not be used, divulged, published or otherwise disclosed  
without the consent of Idorsia Pharmaceuticals Ltd 


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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................4
1
INTRODUCTION .........................................................................................................5
2
STUDY DESIGN AND FLOW ....................................................................................5
2.1
Study design ...................................................................................................5
2.2
Study visit and assessment schedule ..............................................................6
3
OBJECTIVES ...............................................................................................................9
4
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL ...................................................................................................9
5
DEFINITIONS OF VARIABLES ................................................................................9
5.1
Screening failures ...........................................................................................9
5.2
Subject characteristics ....................................................................................9
5.3
Study treatment exposure and compliance .....................................................9
5.4
Study discontinuation .....................................................................................9
5.5
Efficacy variables ...........................................................................................9
5.5.1
Primary efficacy endpoint(s) ..............................................................9
5.5.2
Secondary efficacy endpoint .............................................................10
5.6
Safety variables .............................................................................................10
6
DEFINITION OF PROTOCOL DEVIATIONS .........................................................10
7
ANALYSIS SETS .......................................................................................................10
7.1
Definitions of analysis sets ...........................................................................10
7.1.1
All Randomized Set ..........................................................................10
7.1.2
Full Analysis Set ...............................................................................10
7.1.3
Per-Protocol Set ................................................................................10
8
DEFINITION OF SUBGROUPS ................................................................................10
9
GENERAL STATISTICAL METHODOLOGY ........................................................11
10 STATISTICAL ANALYSES ......................................................................................15
10.1
Overall testing strategy .................................................................................15
10.2
General rules for data presentations .............................................................15
10.3
Display of patient disposition and analysis sets ...........................................16


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10.4
Analyses of subject characteristics ...............................................................16
10.5
Analysis of study treatment exposure and compliance.................................16
10.6
Analysis of the primary efficacy variable(s) ................................................16
10.6.1
Hypothesis and statistical model .......................................................16
10.6.2
Handling of missing data ..................................................................16
10.6.3
Main analysis ....................................................................................16
10.7
Analysis of the secondary efficacy variables ...............................................16
10.8
Analysis of other efficacy variables .............................................................17
10.9
Analysis of safety variables ..........................................................................17
10.10
Analysis of quality of life variables ..............................................................17
10.11
Analysis of pharmacoeconomic variables ....................................................17
10.12
Analysis of epidemiological measures and risk-benefit evaluations ............17
10.13
Analysis of pharmacodynamic variables ......................................................17
10.14
Analysis of pharmacokinetic variables .........................................................17
11 GENERAL DEFINITIONS AND DERIVATIONS ...................................................17
11.1
Time windows ..............................................................................................17
12 HANDLING OF MISSING/INCOMPLETE DATE AND TIME FIELDS ...............18
13 LIST OF SUMMARY TABLES, LISTINGS AND FIGURES .................................18
13.1
Subject disposition ........................................................................................18
13.2
Subject characteristics ..................................................................................19
13.3
Primary efficacy variable ..............................................................................19
13.4
Secondary efficacy analyses .........................................................................20
14 REFERENCES ............................................................................................................20
15 APPENDICES .............................................................................................................21
15.1
Layouts .........................................................................................................21
15.1.1
Layout T1 ..........................................................................................21
15.1.2
Layout T2 ..........................................................................................22
15.1.3
Layout T3 ..........................................................................................23
15.1.4
Layout F1 ..........................................................................................24
15.1.5
Layout F2 ..........................................................................................25
15.2
R Program for power MCP-Mod approach ..................................................26
15.3
R Program to compare group standard deviations ........................................28
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
 
BP   
Blood pressure  
eCRF  
Electronic Case Report Form 
FAS  
Full Analysis Set 
MCP-Mod  
Multiple Comparison Procedure - Modeling 
OBPM  
(Automated) office blood pressure measurement 
PD  
Protocol deviation 
PPS  
Per-Protocol Set 
RND  
All Randomized Set 
SAP  
Statistical Analysis Plan 
SD  
Standard deviation 
SiDBP  
Sitting diastolic blood pressure 
SiSBP  
Sitting systolic blood pressure 
SSR  
Sample size re-estimation 
 


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1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes statistical analyses required for the blinded 
sample size re-estimation (SSR) of Study AC-080A201, the Phase 2 dose-finding trial of 
the ACT-132577 project.  
The objective is to provide the sizes of the Per-Protocol Set (PPS) and Full Analysis Set 
(FAS) which, given the observed variability at this point in time, will guarantee 
approximately 90% power to detect a dose response relationship and provide sufficient 
precision in the estimation of the dose response curve and of doses that will be selected 
for the Phase 3 program of ACT-132577.  
The blinded SSR will be performed by the sponsor after 100 subjects have been 
randomized and their Week 8 blood pressure (BP) data are available for analysis. The 
sample size will be recalculated considering the overall standard deviation (SD) of the 
primary endpoint (change from baseline to Week 8 in mean trough sitting diastolic blood 
pressure [SiDBP], measured by automated office blood pressure measurement [OBPM]) 
in the Per-Protocol Set.  
The re-calculated size of the PPS is expected to be between 280 subjects and the 
originally foreseen 420 subjects. The associated number of subjects to be randomized 
will also be re-estimated and is expected to be between 300 subjects and the originally 
planned 540 subjects. It is anticipated that the size of the PPS will be at least 80% of the 
size of the FAS.  
This SAP is based on Version 3 of the Protocol dated 30 May 2016 [D-16.063]. 
Version 2 of this SAP was generated in order to make editorial corrections—no changes 
were made to analyses or statistical content—and to reflect the transfer of ownership of 
ACT-132577. ACT-132577 was previously developed by Actelion Pharmaceuticals Ltd. 
Actelion was recently acquired by Johnson & Johnson. As part of this transaction, 
Actelion spun off its drug discovery operations and early stage clinical development 
assets into an independent biopharmaceutical company, Idorsia Pharmaceuticals Ltd 
(Idorsia). ACT-132577 is now owned by Idorsia. 
2 
STUDY DESIGN AND FLOW 
2.1 Study design 
Study AC-080A201 is a prospective, multi-center, double-blind, double-dummy, 
randomized, placebo- and active-reference, parallel group, Phase 2 dose-finding study 
with ACT-132577 in subjects with essential hypertension (grade 1 and 2). 
Approximately 1000 subjects are expected to be enrolled into the study (i.e., entered the 
run-in phase), in order to have at least 540 subjects randomized in the 6 following groups 
in a 1:1:1:1:1:1 ratio; placebo, 5 mg ACT-132577, 10 mg ACT-132577, 25 mg 


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ACT-132577, 50 mg ACT-132577, lisinopril 20 mg. At least 420 subjects are expected to 
complete the trial.  
2.2 Study visit and assessment schedule 
Table 1 shows the study visit and assessments schedule. 




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*Electronically transferred to sponsor.  
** Visit 1 (screening) can last up to 72 h for obtaining informed consent and performing required assessments.  
 
1. 
Height is only measured at Visit 1. 
2. 
Serum pregnancy test only for women of childbearing potential. Result is transferred electronically to sponsor. 
3. 
All AEs and SAEs that occur after signing the Informed Consent Form and up to 30 days after last DB study treatment intake must be reported. 
4. 
Historical ECG is accepted if not older than 6 months.  
5. 
Historical blood laboratory data is accepted to check exclusion criterion 15, if not older than 3 months. In such a case, for women of childbearing potential a 
urine pregnancy test must be performed. If no historical report is available, a blood sample to be taken for laboratory analysis (including pregnancy test for 
women of childbearing potential) by central laboratory. 
6. 
Run-in period is 4 weeks before randomization for anti-hypertensive treatment naïve subjects. Visit 1 is combined with Visit 2. Run-in period is 6 weeks 
before randomization for subjects on anti-hypertensive treatment. Visit 1 and Visit 2 must be performed. 
7. 
Only urine pregnancy test for women of childbearing potential. Result is captured in the eCRF. 
8. 
Only for subjects who were on anti-hypertensive drugs at Visit 1 (i.e., had to perform a Visit 2). 
9. 
If subject discontinued study treatment during run-in period (i.e., between run-in visits) or at an in-person run-in visit (e.g., Visit 3), these tests may not be 
performed 
10. Unscheduled visits may be performed at any time during the study and may include all or some of the indicated assessments, based on the judgment of the 
investigator.  
11. For women of childbearing potential a visit must be organized instead of the telephone call to perform the serum pregnancy test at the site. However, if a 
woman of childbearing potential discontinued study treatment during the run-in period, a telephone call can be made instead of the visit.  
12. Upon investigator’s judgment, a home monitoring device will be dispensed to monitor BP at home, if necessary.  
13. Sample to be taken at trough (i.e., prior to study treatment intake).  
 
AE = adverse event; BP = blood pressure; DB = double-blind; ECG = electrocardiogram; eCRF = electronic case report form; EOS = End-of-Study; EOT = End-
of-Treatment; HR = heart rate; PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event; WD = withdrawal. 
 


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3 
OBJECTIVES 
The objective of this Sample Size Re-estimation is to provide the sizes of the PPS and 
FAS which, given the observed variability at this point in time, will guarantee 
approximately 90% power to detect a dose response relationship and provide sufficient 
precision in the estimation of the dose response curve and of doses that will be selected 
for the Phase 3 program of ACT-132577. 
4 
CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
Not applicable. 
5 
DEFINITIONS OF VARIABLES 
Baseline refers to the last non-missing value before double-blind treatment start date. 
5.1 Screening failures 
Not applicable. 
5.2 Subject characteristics 
Not applicable. 
5.3 Study treatment exposure and compliance 
Not applicable. 
5.4 Study discontinuation 
Not applicable. 
5.5 Efficacy variables 
5.5.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is the change from baseline to Week 8 of double-blind 
treatment period (Period II) in mean trough (i.e., 24 hours post-dose) SiDBP, measured 
by OBPM. 
Here, baseline is defined as in Section 5 and Week 8 is the time window of Visit 7 
[Section 11.1]. OBPM SiDBP is measured by BpTRU® (automated; average over five 
measurements) and is collected via electronic data transfer from an external 
. It 
will not be (re-)calculated by the sponsor. 
All assessments (including the unscheduled ones) are considered and re-assigned to the 
most appropriate visit according to the time windows described in Section 11.1. 


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5.5.2 Secondary efficacy endpoint 
Of the secondary efficacy endpoints defined in the protocol, the following is considered 
as supportive for the sample size re-estimation: 
• Change from baseline to Week 8 of double-blind treatment period (Period II) in mean 
trough SiSBP, measured by OBPM. 
Here, baseline is defined as in Section 5 and Week 8 is the time window of Visit 7 
[Section 11.1]. OBPM SiSBP is collected via electronic data transfer and will not be 
(re-)calculated by the sponsor. 
All assessments (including the unscheduled ones) are considered and re-assigned to the 
most appropriate visit according to the time windows described in Section 11.1. 
5.6 Safety variables 
Not applicable.  
6 
DEFINITION OF PROTOCOL DEVIATIONS 
For the purpose of this SSR only two major protocol deviations (PDs) will be considered 
in the definition of the PPS [see Section 7.1.3]. 
• Not completing the double-blind treatment period: no Week 8 (i.e., time window 
Visit 7) efficacy data available. 
• Use of forbidden medication, indicated as protocol deviation (PD code list version 2, 
PV_MM.503). 
7 
ANALYSIS SETS 
7.1 Definitions of analysis sets 
7.1.1 All Randomized Set 
The All Randomized Set (RND) includes all subjects with answer ‘YES’ to the question 
‘Was the subject randomized?’ in the Randomization eCRF. 
7.1.2 Full Analysis Set 
The FAS includes all subjects in the RND Set, who have a baseline mean trough SiDBP.  
7.1.3 Per-Protocol Set 
The PPS includes all subjects from the FAS who have a mean trough SiDBP at Week 8 
(i.e., time window Visit 7) and did not use forbidden medication deviation as defined in 
Section 6. 
8 
DEFINITION OF SUBGROUPS 
Not applicable. 


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9
GENERAL STATISTICAL METHODOLOGY
A blinded SSR will be performed by the sponsor after 100 subjects have been 
randomized and their Week 8 (time window Visit 7) OBPM data are available for 
analysis. The SSR will consider the overall standard deviation (i.e., based on pooled 
treatment groups as the SSR is blinded) of the primary endpoint (change from baseline to 
Week 8 [time window Visit 7] in mean trough SiDBP, measured by OBPM) in the PPS.
The primary endpoint (change from baseline to Week 8 [time window Visit 7] of 
double-blind treatment period in mean trough SiDBP) will be analyzed using the 
MCP-Mod approach [Bretz 2005, Pinheiro 2006, EMA 2013]. The blinded SSR will be 
based on the average power achieved in the MCP-Mod approach, to detect a dose 
response when the ‘true’ dose-response curve is among the four curves displayed in 
Figure 1
(copied from protocol figure 2). All four assume that the minimum 
response will be obtained with placebo (0 mg) and the maximum response (4–5 mmHg, 
placebo corrected) will be reached at the highest dose of ACT-132577 (50 mg).
Figure 1
Dose response relationships used in power calculations
For each of the four dose-response curves the power will be calculated using the 
powMCT function in the R-package DoseFinding [Bornkamp 2016]. R-code is included 
in Appendix 15.1.
0
1
2
3
4
5
dose
response
0
5
10
25
50


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The calculation requires an estimate of the standard deviation of the primary endpoint 
[see Section 10.6] in the PPS. The average power is displayed in Figure 2 for primary 
endpoint SDs ranging from 6–9 mmHg. (For the original sample size calculation 
9 mmHg was assumed and > 95% power was required for each of the four scenarios 
separately.) 


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Figure 2
Average power to detect dose response
Black SD = 6.0; Red SD = 6.5; Blue SD = 7.0; Green SD = 7.5; Orange SD = 8.0; Purple 
SD = 8.5; Grey SD = 9.0.
The associated sample sizes (PPS) for 80–95% average power are given in Table 2.
20
30
40
50
60
70
0.6
0.7
0.8
0.9
1.0
group size (PPS)
power


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Table 2 
Sample size (PPS) needed for 80–95% power to detect a 
dose-response across various SDs 
 
SD = 6.0 
SD = 6.5 
SD = 7.0 
SD = 7.5 
SD = 8.0 
SD = 8.5 
SD = 9.0 
80% power 
 
 
 
 
 
 
 
- PPS size 
126 
150 
174 
198 
222 
252 
282 
- per group* 
21 
25 
29 
33 
37 
42 
47 
 
 
 
 
 
 
 
 
85% power 
 
 
 
 
 
 
 
- PPS size 
144 
168 
198 
222 
258 
288 
318 
- per group* 
24
28
33
37
43
48
53
90% power 
 
 
 
 
 
 
 
- PPS size 
174 
198 
234 
264 
300 
336 
378 
- per group* 
29 
33 
39 
44 
50 
56 
63 
 
 
 
 
 
 
 
 
95% power 
 
 
 
 
 
 
 
- PPS size 
210 
252 
288 
330 
372 
420 
474 
- per group* 
35 
42 
48 
55 
62 
70 
79 
*Expected number. Power based on the MCT test in the MCP-Mod procedure as implemented in the R DoseFinding 
package, averaged over the four dose-response curves in Figure 2 of this protocol. 
MCP-Mod = Multiple Comparison Procedure - Modeling; MCT = Multiple Contrast Test; PPS = Per-Protocol Set; 
SD = standard deviation. 
 
Here, SD is the standard deviation of the primary endpoint (independent of treatment 
assignment, as this is blinded). It is acknowledged that this could be an overestimation of 
the (unobserved) within group SD, but, given the range of anticipated treatment group 
differences, this overestimation is likely to be small (< 5%; simulation program in 
Appendix 15.2). The re-calculated size of the PPS is expected to be between 280 subjects 
and the originally foreseen 420 subjects. 
The associated number of subjects to be randomized will be calculated by dividing PPS 
size by the proportion of randomized subjects who were included in the PPS. That 
proportion will be estimated based on the same 100 randomized subjects considered for 
the blinded sample size re-estimation. To be conservative, the lower limit of the 95% CI 
around the proportion will be employed, of which some examples are given in Table 3.  


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Table 3 
Number and proportion of subjects in PPS and 95% CIs for the 
proportion at the time of the sample size re-estimation 
Number 
Randomized 
Number 
in PPS 
Proportion 
in PPS 
95% CI* 
100 
95 
0.95 
0.89 
0.98 
100 
90 
0.90 
0.82 
0.95 
100 
85 
0.85 
0.76 
0.91 
100 
80 
0.80 
0.71 
0.87 
*Clopper-Pearson [Clopper 1934] 
The number of subjects to be randomized will also take into account the need to collect sufficient exposure and safety 
data and is expected to be between 300 subjects and the originally planned 540 subjects. 
CI = confidence interval; PPS = Per-Protocol Set. 
 
The re-calculated number of subjects randomized is expected to be between 300 subjects 
and the originally foreseen 540 subjects. 
10 STATISTICAL ANALYSES 
10.1 Overall testing strategy 
The SSR will be based on blinded data. No statistical testing will be performed. 
10.2 General rules for data presentations 
Output titles should include the name of the analysis set used for the analysis, and if 
specific period used, also the time period. 
Table column headers should provide the number of subjects of the used analysis set. 
The footer should provide the following information: 
• the date and time of the data extraction from the database and the cut-off date,  
• the date and time of the output generation,  
• the SAS program that produces the output and the author, 
No acronym/abbreviation should be used unless documented in the footer. 
For categorical parameters, frequencies/numbers and percentages should be used. 
Percentages should be presented with one decimal place (e.g., 18.2%).  
Descriptive statistics for continuous variables are given in Table 4. 


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Table 4 
Descriptive statistics for continuous variables 
Statistics  
Display 
Number of decimals 
Example 
N 
N 
None 
99 
Mean  
Mean  
Original digit + 1   
45.2  
Standard Deviation 
Standard 
Deviation 
Original digit + 1 
38.5 
Median 
Median 
Original digit + 1 
45.3 
Minimum–Maximum 
Min–Max 
Original digit 
125–250 
1st quartile (25%) – 3rd quartile (75%) 
Q1–Q3 
Original digit + 1 
35.2–58.5 
 
10.3 Display of patient disposition and analysis sets 
The number of patients in the FAS and PPS will be tabulated on pooled treatment groups. 
10.4 Analyses of subject characteristics 
Not applicable. 
10.5 Analysis of study treatment exposure and compliance 
Not applicable. 
10.6 Analysis of the primary efficacy variable(s) 
The primary efficacy variable will be analyzed in the PPS and FAS, based on pooled 
treatment groups. 
10.6.1 Hypothesis and statistical model 
Not applicable. 
10.6.2 Handling of missing data 
The PPS analysis will be based on observed data.  
In the FAS, last post-baseline measurement will be carried forward. 
10.6.3 Main analysis 
The changes from baseline to Weeks 2, 4 and 8 of double-blind treatment period (time 
window Visits 5, 6 and 7 respectively) in mean trough SiDBP (measured by OBPM) will 
be summarized using descriptive statistics.  
The distribution of the changes from baseline in SiDBP will be displayed in a density 
plot. 
10.7 Analysis of the secondary efficacy variables 
Secondary efficacy endpoints will be analyzed in the PPS. 


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The changes from baseline to Weeks 2, 4 and 8 of double-blind treatment period (time 
window Visits 5, 6 and 7, respectively) in mean trough SiSBP (measured by OBPM) will 
be summarized using descriptive statistics.  
The distribution of the changes from baseline in SiSBP will be displayed in a density 
plot. 
10.8 Analysis of other efficacy variables 
Not applicable. 
10.9 Analysis of safety variables 
Not applicable. 
10.10 Analysis of quality of life variables 
Not applicable. 
10.11 Analysis of pharmacoeconomic variables 
Not applicable.  
10.12 Analysis of epidemiological measures and risk-benefit evaluations 
Not applicable.  
10.13 Analysis of pharmacodynamic variables 
Not applicable.  
10.14 Analysis of pharmacokinetic variables 
Not applicable.  
11 GENERAL DEFINITIONS AND DERIVATIONS 
11.1 Time windows 
To allow analysis of data at the relevant planned (scheduled) visits, all recorded 
assessments, including unscheduled ones, are re-assigned to the most appropriate visit 
according to the best fitting time-window for that visit [see Table 5]. 








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15 APPENDICES
15.1 Layouts
15.1.1 Layout T1
ACT-132577
Protocol: AC-080A201/Essential Hypertension
<Title>
Analysis set: <analysis set>
<overall, site x>
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
                                               Blinded
                                               Treatment
                                                 N = XX 
                                                n    (%)
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
Subjects Randomized                            xx  (yy.y)
Subjects Included in FAS                       xx  (yy.y)
Subjects Included in PPS                       xx  (yy.y)
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
Output: XXXX, Produced by xxxxxxxx on ddmmmyyyy hh:mm (CET), Data Extraction Date: ddmmmyyyy, 
Cut-Off Date: ddmmmyyyy
Program: prod_ccm/program_output/program_name.sas
Page x of x


ACT-132577
AC-080A201
3 November 2017, page 22/28
Confidential 
Statistical Analysis Plan
Sample Size Re-estimation
Doc No D-17.086
15.1.2 Layout T2
ACT-132577
Protocol: AC-080A201/Essential Hypertension
<Title>
Analysis set: <analysis set>
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
                                                  Blinded
                                                  Treatment
                                                   N = XX 
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
Age (years)
  n                                                  xx         
  Mean                                              xx.xx         
  Standard Deviation                                xx.xx        
  Median                                            xx.x         
  Q1, Q3                                         xx.x, xx.x     
  Min, Max                                       xx.x, xx.x     
Sex [n (%)]
  Females                                         xx (xx.x)    
  Males                                           xx (xx.x)    
  Missing                                         xx (xx.x)    
Race [n (%)]
  Black or African American                       xx (xx.x)    
  American Indian or Alaska Native               xx (xx.x)    
  Native Hawaiian or Other Pacific Islander       xx (xx.x)    
  Asian                                           xx (xx.x)    
  White                                           xx (xx.x)    
  Other                                          xx (xx.x)    
  Missing                                         xx (xx.x)    
Ethnicity [n (%)]
  Hispanic or Latino                              xx (xx.x)    
  Not Hispanic or Latino                          xx (xx.x)    
  Missing                                         xx (xx.x)    
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
Output: XXXX, Produced by xxxxxxxx on ddmmmyyyy hh:mm (CET), Data Extraction Date: ddmmmyyyy, 
Cut-Off Date: ddmmmyyyy
Program: prod_ccm/program_output/program_name.sas
Page x of x


ACT-132577
AC-080A201
3 November 2017, page 23/28
Confidential 
Statistical Analysis Plan
Sample Size Re-estimation
Doc No D-17.086
15.1.3 Layout T3
ACT-132577
Protocol: AC-080A201/Essential Hypertension
<Title>
Analysis set: <analysis set>
<Parameter (unit)>, Time point x>
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
                                                  Blinded
                                                  Treatment
                                                   N = XX 
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
Observed Values At Baseline
  n                                                  xx            
  Mean                                              xx.xx           
  Standard Deviation                                xx.xx          
Median                                            xx.x           
  Q1, Q3                                        xxx.x, xxx.x      
  Min, Max                                       xx.x, xx.x       
Observed Values At <Time point x>
  n                                                  xx            
  Mean                                              xx.xx           
  Standard Deviation                                xx.xx          
Median                                            xx.x           
  Q1, Q3                                        xxx.x, xxx.x      
  Min, Max                                       xx.x, xx.x       
Absolute Change from Baseline to <Time point x>
  n                                                  xx            
  Mean                                              xx.xx           
  Standard Deviation                                xx.xx          
Median                                           xx.x           
  Q1, Q3                                        xxx.x, xxx.x      
  Min, Max                                       xx.x, xx.x       
ƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒƒ
Output: XXXX, Produced by xxxxxxxx on ddmmmyyyy hh:mm (CET), Data Extraction Date: ddmmmyyyy, 
Cut-Off Date: ddmmmyyyy
Program: prod_ccm/program_output/program_name.sas
Page x of x


ACT-132577 
AC-080A201 
3 November 2017, page 24/28 
Confidential  
Statistical Analysis Plan 
Sample Size Re-estimation 
Doc No D-17.086 
 
15.1.4 Layout F1 
ACT-132577 
Protocol: AC‐080A201/Essential Hypertension 
<Title> 
Analysis set: <analysis set> 
<Parameter (unit)> 
 
 
Some possible SAS statements 
 
proc kde data=<dset>; 
  by avisitn; 
  univar chg (bwm=1)/ out=dens gridl=-40 gridu=20; 
run; 
 
proc gplot data=dens; 
  plot density*value=avisitn/ haxis=axis1 vaxis=axis2; 
  symbol1 c=black i=j l=1; 
  symbol2 c=red i=j l=1; 
  symbol3 c=blue i=j l=1; 
  axis1 order=(-40 to 20 by 5) minor=none; 
  axis2 order=(0 to 0.06 by 0.01) minor=none; 
run; 
 
Density
0 00
0 01
0 02
0 03
0 04
0 05
0 06
Value
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
15
20
Analysis Visit (N)
Week 2
Week 4
Week 8


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AC-080A201 
3 November 2017, page 25/28 
Confidential  
Statistical Analysis Plan 
Sample Size Re-estimation 
Doc No D-17.086 
 
15.1.5 Layout F2 
ACT-132577 
Protocol: AC‐080A201/Essential Hypertension 
<Title> 
Analysis set: <analysis set> 
 
 
 
Some possible SAS statements 
* <dset> has change from baseline in DBP (cdbp) and in SBP (csbp)in separate columns; 
 
proc corr data=<dset>;  
  by avisitn; 
  var csbp cdbp; 
run; 
 
proc glm data=botht noprint; 
  by avisitn; 
  model csbp=cdbp; 
  output out=glmout predicted=pred; 
run; 
proc sort; 
  by avisitn cdbp; 
run; 
 
proc gplot; 
  by avisitn; 
  plot (csbp pred)*cdbp/ overlay; 
 run; 
 
 
Change from baseline in SBP
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
15
20
Change from baseline in DBP
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
15
20


ACT-132577 
AC-080A201 
3 November 2017, page 26/28 
Confidential  
Statistical Analysis Plan 
Sample Size Re-estimation 
Doc No D-17.086 
 
15.2 R Program for power MCP-Mod approach 
# powerDRssr.R JUN 2016 
 
#setwd(“<To be completed>“) 
 
 
## PRELIMINARIES 
 
sigEmax <- function (ed50, ed90) 
{ 
e0 <- 0 
emax <- 1 
hill <- log(9)/(log(ed90)-log(ed50)) 
c(ed50, round(hill,2)) 
} # Emax 
 
# get ed50 and hill 
# based on ed50 and ed90 
black <- sigEmax (ed50=0.125, ed90=0.25) 
red <- sigEmax (ed50=0.125, ed90=0.50) 
blue <- sigEmax (ed50=0.25,  ed90=0.50) 
green <- sigEmax (ed50=0.25,  ed90=0.75) 
 
 
## FUNCTIONS 
 
powerMCT <-function (doses, sigma, n, true){ 
 
candMod <- Mods(linear = NULL, linlog = NULL, quadratic = -0.5, emax = 0.5, 
                sigEmax = c(0.5, 0.5), logistic = c(0.5, 0.5), doses = doses) 
contMat <- optContr(candMod, w = rep(n,length(doses))) 
trueMod <- Mods(sigEmax = true, doses = doses) 
 
power <- powMCT(contMat = contMat, altModels = trueMod, alpha = 0.05, alternative = “two.sided”, n = n, sigma = sigma,  
                placAdj = FALSE, df = NA, critV = TRUE, control = mvtnorm.control()) 
power 
} 
 
 
## MAIN 
 


ACT-132577 
AC-080A201 
3 November 2017, page 27/28 
Confidential  
Statistical Analysis Plan 
Sample Size Re-estimation 
Doc No D-17.086 
 
# load DoseFinding package 
library(DoseFinding) 
 
# doses in the study  
d4 <- c(0, 0.05, 0.10, 0.25, 0.5) 
 
# power  
sigs <- seq (6,9,0.5) 
nn <- seq (20,70,1) 
 
pow<-matrix(NA,length(sigs)*length(nn),6) 
k <- 1 
for (i in 1:length(sigs)){ 
  for (j in 1:length(nn)){ 
    pow[k,1] <- sigs[i] 
    pow[k,2] <- nn[j] 
    pow[k,3] <- round(powerMCT (d4, sigs[i]/5,   nn[j], black), 3) 
    pow[k,4] <- round(powerMCT (d4, sigs[i]/4.5, nn[j], red),   3) 
    pow[k,5] <- round(powerMCT (d4, sigs[i]/4.5, nn[j], blue),  3) 
    pow[k,6] <- round(powerMCT (d4, sigs[i]/4,   nn[j], green), 3) 
    k <- k+1 
  } # j 
} # i 
 
plot(pow[pow[,1]==6,2], rowMeans(pow[pow[,1]==6,3:6]), type=“l”, col=“grey”, 
     xlab=“group size (PPS)”, ylab=“power”, xlim=c(20,70), ylim=c(0.6,1)) 
cols <- c(“black”,”red”,”blue”,”green”,”orange”,”purple”,”grey”) 
 
for (i in 1:7){ 
sel <- pow[pow[,1]==sigs[i],] 
lines(sel[,2], rowMeans(sel[,3:6]), col=cols[i]) 
} 
abline (h=c(0.8, 0.9, 0.95), col=“grey”) 


ACT-132577 
AC-080A201 
3 November 2017, page 28/28 
Confidential  
Statistical Analysis Plan 
Sample Size Re-estimation 
Doc No D-17.086 
 
15.3 R Program to compare group standard deviations 
# simSD.R JUL 2016 
 
# FUNCTIONS 
 
sim <- function (n,means,sd,seed){ 
  set.seed(seed) 
  print(means) 
  k <- length (means) 
  var <- matrix(NA,nrep,2) 
  for (i in 1:nrep){ 
    y <- rep(means, each=n) + rnorm(n*k, 0, sd) 
    var[i,1] <- var(y) # overall variance 
    x <- rep (1:k, each=n) 
    A<-aov(y~as.factor(x)) 
    var[i,2] <- sum(A$residuals^2)/A$df.residual # within group variance 
  } 
var <- colMeans(var) 
print (round(c(var,var[1]/var[2]),2)) 
sd <- sqrt(var) 
round(c(sd,sd[1]/sd[2]),2) 
} 
 
 
# MAIN 
 
nrep <- 1000 
 
m <- seq(0,5,length.out=6) 
sim(n=90, means=m, sd=8, seed=1331) 
 
m <- seq(0,6,length.out=6) 
sim(n=90, means=m, sd=8, seed=1332) 
 
m <- seq(0,8,length.out=6) 
sim(n=90, means=m, sd=8, seed=1333)