Conditions: Ovarian Cancer Breast Cancer
Keywords: Ovarian Cancer; Breast Cancer, Olaparib
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 202
Healthy volunteers: no

Brief summary:
A Prospective, Multicentre, Phase-IV Clinical Trial of Olaparib in Indian Patients with Platinum Sensitive Relapsed Ovarian Cancer who are in Complete or Partial Response Following Platinum based Chemotherapy and Metastatic Breast Cancer with germline BRCA (BReast CAncer gene) 1/2 Mutation

Detailed description:
A Prospective, Multicentre, Phase-IV Clinical Trial of Olaparib in Indian Patients with Platinum Sensitive Relapsed Ovarian Cancer who are in Complete or Partial Response Following Platinum based Chemotherapy and Metastatic Breast Cancer with germline BRCA(BReast CAncer gene)1/2 Mutation As per recommendation from DCGI(Drug Controller general of of India), the current phase-IV study is planned with the aim to assess the safety in Indian subjects receiving olaparib as per the approved label indications in India in accordance with the requirements of the Health Authorities of India. This study attempts to descriptively elucidate the safety of Olaparib in Indian subjects receiving olaparib as per the Indian regulatory approved indications in India. The data obtained from the present study will help to understand the safety profile of olaparib in Indian patients.

Arms:
arm 1: Intervention: Drug: Olaparib

Interventions: intervention 1: Olaparib
Intervention descriptions: intervention 1: Tablet

Protocol document:
Prot_000.pdf: 






 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 












 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
    
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
    
 
 
  
 
   
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
  
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
   
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
   
 
 
 
  
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
   
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
 
 
 
 
  
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
   
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
   
 
 
  
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 









SAP_001.pdf: 
Statistical Analysis Plan 
 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                             FINAL Dated 13JAN2023                            
AstraZeneca Confidential                                                                                                        Page 1 of 73                              
 
 Statistical Analysis Plan 
  
 
 
AstraZeneca Pharma India Limited 
 
 
D0816R00025 
 
 
A Prospective, Multicentre, Phase-IV Clinical Trial of 
Olaparib in Indian Patients with Platinum Sensitive 
Relapsed Ovarian Cancer who are in Complete or Partial 
Response Following Platinum Based Chemotherapy and 
Metastatic Breast Cancer with Germline BRCA1/2 Mutation 
(SOLI Study) 
 
 
 
Document Version: FINAL  
Document Date: 13JAN2023 
 
 
 
 
 
 
Information described herein is confidential and may be disclosed only with the 
express written permission of the sponsor. 
 
 
 
















 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                            FINAL DATED 13JAN2023                           
AstraZeneca Confidential                                                                                                        Page 9 of 73                              
safety profile of olaparib in routine clinical practice as assessed by the incidence of 
AEs (serious and non-serious) observed during trial. 
Assuming the true incidence rate of any adverse event (mentioned as part of the 
labelling information of Olaparib) of severity grade 3 or higher to be 40%, 
corresponding data from approximately 190 Indian adult patients satisfying the 
protocol specified eligibility criteria will be required in this study for estimating the 
sample (study based) incidence rate with 7% error margin and using 95% confidence 
interval. In this study, we expect to recruit 160 patients from platinum sensitive 
relapsed ovarian cancer and 40 patients from gBRCAm positive metastatic breast 
cancer as per the Indian HA approved indication to satisfy the Lynparza MA 
conditional approval. 
3. Efficacy and Safety Variables 
3.1 Primary Efficacy Endpoint(s) 
Not Applicable. 
 
3.2 Secondary Efficacy Endpoints 
Not Applicable. 
 
3.3 Safety Variables 
The safety variables to be analysed include: 
  
x 
Adverse Events  
x 
Clinical laboratory tests (haematology and clinical chemistry) 
x 
Physical examination results  
x 
Vital parameters  
x 
World Health Organization (WHO) performance status (PS) 
x 
Deaths, as observed by participating physician  
4. Pharmacokinetic/Pharmacodynamic variables 
Not Applicable. 
5. Analysis populations 
5.1 Enrolled 
All patients who sign the ICF (Informed Consent Form) and are screened with 
eligibility verified as per the Inclusion-Exclusion criteria mentioned in study protocol 
are considered to be enrolled.  
 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                            FINAL DATED 13JAN2023                           
AstraZeneca Confidential                                                                                                        Page 10 of 73                            
This population will be used for presenting data on patient disposition, demographic 
and baseline characteristics, medical or surgical history and prior and concomitant 
medications and for any patient data that will be collected on screening visit only. 
 
5.2 Safety Analysis Set 
All patients randomly assigned to Study treatment and who take at least 1 dose of 
study drug.  
6. Data Handling 
6.1 Time points and Visit Windows 
 
Day 1 is defined as the day of first dose of study drug (i.e. Day 1 in treatment 
Phase phase).  
The baseline value will be defined as last value collected prior to the first dose of 
study drug. 
Relative days after Day 1 are calculated as (assessment date – Day 1 date) + 1.  
Relative days prior to Day 1 are calculated as (assessment date – Day 1 date).  The 
day prior to Day 1 is Day -1.  
Safety will be evaluated throughout the evaluation phase and during the follow - up 
of patients who discontinue treatment before end of Treatment Phase by physical 
exams including vital signs, AE/SAE monitoring, laboratory evaluations and recording 
of concomitant medications. The sponsor shall provide the laboratory investigations 
for safety evaluation including haematology and biochemistry as mentioned in the 
Time and Events Schedule in the protocol to monitor the safety throughout the study 
period. A window period of +/- 3 days will be allowed for visits 3 – 9. 
All data will be analyzed using nominal study visits as defined in the Study Schedule 
and CRF.   
 
6.2 Handling of Dropouts, Missing Data, and Outliers 
Missing results/events will not be imputed. 
  
Adverse events and concomitant medications with completely or partially missing 
assessment dates will have imputation performed as explained below for the 
purposes of calculation of durations or relativity to study medication.  
 
For the end of a concomitant medication or adverse event:  
 
x 
If only Day of end date is missing:  
 
The last date of the month and year reported or the date of the final contact 
with the patient, whichever is earlier, will be used as the end date;  
 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                            FINAL DATED 13JAN2023                           
AstraZeneca Confidential                                                                                                        Page 11 of 73                            
x 
If Day and Month of end date are missing: 
 
The last date of year i.e. December 31 of the year reported or the date of the 
last study contact with the patient, whichever is earlier, will be used as the end 
date;  
 
x 
If Year of end date or complete end date is missing:  
 
If the adverse event or concurrent medication continues after the last study 
contact date, then no end date or time will be estimated.  
 
For the start of a concomitant medication or adverse event:  
 
x 
If only Day of start date is missing:  
o If the start year and month of medication/event are the same as that 
for the first dose date, then following approach will be used:  
 
¾ If the end date of medication/event is NOT before the first dose 
date or end date of medication/event is completely missing, 
then  
 
Impute the start day as the day of first dose date;  
¾ Otherwise, impute the start day as 1.  
 
o If the start year and month of medication/event are NOT same as that 
for the first dose date, then 
  
¾ Impute the start day as 1.  
 
x 
If Day and Month of start date are missing:  
 
o If start year of medication/event is same as first dose year, then following 
approach will be used:  
 
i. 
For medication, impute the start Month as January and the Day as 1;  
 
ii. 
For adverse event,  
 
¾ If the end date of event is NOT before the first dose date or end 
date of event is completely missing, then  
o Impute the start Month and Day as the Month and Day of 
first dose date;  
¾ Otherwise, impute the start Month as January and the Day as 1;  
 
o If start year of medication/event is NOT same as first dose year, then 
  
¾ Impute start Month as January and the Day as 1.  
 






 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                            FINAL DATED 13JAN2023                           
AstraZeneca Confidential                                                                                                        Page 14 of 73                            
 
7.4 Demographics and Other Baseline Characteristics 
 
Demographic and baseline characteristics will be summarized and listed for all 
enrolled patients.  Standard descriptive statistics will be presented for: 
¾ Continuous variables: 
x 
Age (years) 
x 
Weight at screening(kg); 
x 
Height at screening(cm); 
x 
Body mass index (kg/m2) [calculated as (weight/height2) where weight is in 
kg and height is in m]; 
¾ Categorical variables: 
x 
child bearing potential 
x 
WHO PS at screening 
x 
Histology type at screening 
x 
Stage/FIGO stage at screening 
x 
Biopsy tissue type at screening 
x 
Organ involved at screening 
x 
gBRCA result at screening 
x 
Size or Direct Extent of Primary Tumor at Screening 
x 
Degree of Spread of Cancer to Regional Lymph Nodes at Screening 
x 
Distant Metastases at Screening 
x 
Previous Cancer Therapy Regimen 
No formal tests of statistical significance will be performed on the demographic 
and baseline data. 
 
7.4.1 Medical and Surgical History 
Medical and surgical history will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) [Version 24.1].  
All medical or surgical history will be listed for each enrolled patient.  
The standard descriptive statistics will be used for summarizing all enrolled patients 
with any medical or surgical history by system organ class (SOC) and preferred 
term (PT).   


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                            FINAL DATED 13JAN2023                           
AstraZeneca Confidential                                                                                                        Page 15 of 73                            
 
7.4.2 Prior and Concomitant Medication 
Medications received prior to or concomitantly with study drug will be coded by 
using the WHODrug Dictionary [Version Sep2021].  
Prior medications and concomitant medications are defined as follows: 
Prior medications are those taken prior to the first dose date of study drug.  
Concomitant medications are those that were taken while on study drug including 
the ones that started before the first dose of study drug. The medications that 
started after the discontinuation of study drug will also be termed as 'Concomitant'. 
Prior medications and concomitant medications will be listed together and 
summarized separately for all the enrolled patients. 
Standard descriptive statistics will be used to summarize patients using various 
prior or concomitant medications/procedures using Anatomical therapeutic class 
(ATC-Level 2) and Preferred Term (PT). 
 
7.5 Efficacy 
No efficacy analyses will be performed on the patients enrolled in this study. 
 
7.5.1 Primary Efficacy Analysis 
Not Applicable. 
 
7.5.2 Secondary Efficacy Analysis 
Not Applicable. 
 
7.5.3 Sensitivity Analysis 
Not Applicable. 
 
7.5.4 Subgroup Analysis 
Not Applicable. 
 
7.5.5 Exploratory Analysis 
Not Applicable. 
 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                            FINAL DATED 13JAN2023                           
AstraZeneca Confidential                                                                                                        Page 16 of 73                            
7.6 Safety 
7.6.1 Extent of Exposure 
Duration of study drug exposure will be defined in days as: 
  
Date of last dose – Date of first dose + 1 day 
Duration of exposure will be listed and summarized using standard descriptive 
statistics for all the patients included in the Safety Analysis Set. 
 
7.6.2 Adverse Events 
All adverse events (AEs) recorded on the CRF will be coded by System Organ Class 
(SOC) and Preferred Term (PT) using the MedDRA dictionary [Version 24.1]. 
Assessment of AE severity will be based on the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE, latest version). 
Treatment –Emergent AEs (TEAEs) are events with start date on or after the date 
of first dose of study drug. Also, the adverse events that are a consequence of a 
pre-existing condition that has worsened later during the treatment phase (i.e. 
events having start date before the date of first dose of study drug and have 
worsened in severity while on study treatment) will be termed as “Treatment-
Emergent”.  
AEs (both in terms of MedDRA preferred terms and CTCAE grade) will be listed 
individually by patient.  
 
Any AE occurring before treatment with olaparib will be included in the data listings 
but will not be included in the summary tables of AEs.  
 
Any AE occurring within 28 days of discontinuation of study drug (i.e., the last dose 
of olaparib) will be included in the AE summaries.  
An overall summary of adverse events will be summarized using standard 
descriptive statistics for the following:  
x 
AEs  
x 
Non-TEAEs 
x 
TEAEs  
x 
Grade 3 and above TEAEs  
x 
Grade 3 and above treatment-related TEAEs  
x 
Treatment-related TEAEs  
x 
Treatment-related serious TEAEs  
x 
TEAEs leading to dose reduction/ interruption/ discontinuation  
x 
Treatment related TEAEs leading to dose reduction/ interruption/ discontinuation  
x 
Serious TEAEs  
x 
Fatal TEAEs  
x 
Related Fatal TEAEs 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                            FINAL DATED 13JAN2023                           
AstraZeneca Confidential                                                                                                        Page 17 of 73                            
x 
Adverse Events of Special Interest (AESIs) [MDS (Myelodysplastic Syndrome), 
AML (Acute Myeloid Leukamia), Pneumonitis/ILD, Secondary Malignancies] 
 
Using standard descriptive statistics, following summaries will be presented by SOC 
and PT:  
x 
TEAEs  
x 
Treatment-related TEAEs 
x 
Treatment-emergent SAEs  
x 
Grade 3 and above TEAEs  
x 
Grade 3 and above treatment-related TEAEs  
x 
TEAEs leading to dose reduction/ interruption/ discontinuation 
  
In the above summaries, patients with more than one AE within a particular SOC are 
counted only once for that SOC.  Similarly, patients with more than one AE within a 
particular PT are counted only once for that PT.   
 
Following adverse events data listings will also be presented for individual patients. 
x 
Any adverse event 
x 
Serious adverse event 
x 
TEAEs leading to drug interruption 
x 
TEAEs leading to drug reduction/  
x 
TEAEs leading to drug discontinuation 
x 
AESI 
 
7.6.3 Laboratory Evaluations 
Data for the following haematology, clinical chemistry, coagulation and urinalysis 
parameters captured on CRF will be listed for all the patients who are included in 
the Safety Analysis Set.  
The haematology and clinical chemistry data will be summarized using standard 
descriptive statistics for each laboratory parameter at baseline and for observed 
values and changes from baseline at each post-baseline visit. 
The coagulation and urinalysis data will be provided in listings only for each patient 
for all available visits. 




 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                            FINAL DATED 13JAN2023                           
AstraZeneca Confidential                                                                                                        Page 19 of 73                            
post-baseline, only data from scheduled visits will be included in the summary 
tables. The vital signs data will be listed for each patient for all the available visits. 
 
7.6.5 Electrocardiograms (ECGs) 
The ECG data will be summarized using standard descriptive statistics classified by 
normal, abnormal not clinically significant, abnormal clinically significant and not 
evaluable categories for all patients included in Safety Analysis Set. The ECG data 
will be listed for each patient for every visit. 
The baseline value will be defined as last value collected prior to the first dose of 
study drug. 
 
7.6.6 Physical Examination 
For physical examination status and various body systems, the data will be 
summarized using standard descriptive statistics classified by normal, abnormal 
clinical significant and abnormal nonclinical significant categories for all scheduled 
visits for the Safety Analysis Set. 
Physical examination results will be listed for each patient for all the available visits. 
The baseline value will be defined as last value collected prior to the first dose of 
study drug. 
 
7.6.7 WHO Performance Status (PS) 
WHO PS classified as; (1= Normal activity, 2=Restricted activity, 3=In bed less 
than or equal to 50% of the time, 4=In bed more than 50% of the time, 5=100% 
bedridden) will be summarized per scheduled visit using standard descriptive 
statistics and listed for each patient for all available visits for the Safety Analysis 
Set. 
The baseline value will be defined as last value collected prior to the first dose of 
study drug. 
 
7.7 Interim Analysis 
No interim analysis will be performed for this study.  
 
8. Changes in Planned Analysis 
Not Applicable. 
 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
D0816R00025     
   FINAL DATED 13JAN2023   
AstraZeneca Confidential  
 Page 20 of 73 
9. Data Issues
Not Applicable. 
10. Additional Listings
Following listings will be produced: 
x 
Pathology at Diagnosis 
x 
Tumour sample 
x 
Germline BRCA test 
x 
Extent of disease upon entry 
x 
Previous cancer therapy 
x 
Deaths during the study 
x 
Discontinuation of study drug 
x 
Laboratory tests for Hepatitis B and C 
x 
Pregnancy test results 
x 
Pregnancy reports 
x 
Bone marrow biopsy 
x 
CT scan reports 
x 
Study drug administration 
x 
Study Drug accountability 
x 
Overdose reports 
x 
Hospital admission details 
x 
Hy’s Law evaluation (if; data permits) 
11. References
1 
ICH. Statistical Principles for Clinical Trials
, Guideline E9, 1998. Available at 
http://www.emea.eu.int/pdfs/human/ich/036396en.pdf 
12. Appendices
Appendix 1: 
Document History 
Document Version, Status, Date 
Summary/Reason for Changes 
Version FINAL, 13 January 2023 
Not applicable; the final version 
13. Table Shells and Specifications
General programming instructions: 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
D0816R00025     
   FINAL DATED 13JAN2023   
AstraZeneca Confidential  
 Page 21 of 73 
Partial birth dates will be imputed as mentioned below for calculation of age- 
If Day or Month of date of birth is missing, then impute the missing month as 
January and missing Day as 01 of the respective year. 
For tables: 
1. The precision of the summary statistics (mean, median, SD, min, max) and
inferential statistics (SE, confidence limits) should be based on the raw data:

Mean and median should be reported with 1 more place after the decimal
as raw data were reported, for example, if raw data were reported as
integer values (xx), the mean should be reported as xx.x.

Standard deviation (SD), SE, and confidence limits (CLs) should be
reported with 2 more places after the decimal as raw data were reported,
for example, if raw data were reported as integer values (xx), the SD, SE,
and CLs should be reported as xx.xx.

Min and max should be reported with the same precision as the raw data.
2. All p-values should be reported with precision 0.xxxx.  If the p-value is less than
0.0001, the p-value should appear in the table as “<0.0001”.
3. Summary statistics for number of patients with data summarized/analyzed
should be lower case ‘n’ or ‘n (%)’.  Capital ‘N’ should only be used in column or
row headers when indicating the total in the denominator, for example (N=xx).
4. For all categorical parameters, in case of missing data, a “missing” category should
be added.
5. When continuous data are being summarized, only the non-missing values should
be used for computing summary statistics.
6. When displaying percentages, if count is 0, no percentage would be displayed.
For Listings: 
For listings, if there is no observation in the listing, display the header portion, and 
display a message of “No observation” in the table body text.


Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
D0816R00025     
 FINAL Dated 13JAN2023 
AstraZeneca Confidential  
     Page 22 of 73   
Data Presentations  
Category 
Sr. No 
Title 
Table 
14.1.1.1 
Patient Disposition - All Patients 
Table 
14.1.2.1 
Summary of Protocol Deviations - All Enrolled Patients 
Table 
14.1.3.1 
Demographic and Baseline Characteristics - All Enrolled Patients 
Table 
14.1.4.1 
Summary of Medical and Surgical History - All Enrolled Patients 
Table 
14.1.5.1 
Summary of Prior Medications - All Enrolled Patients 
Table 
14.1.5.2 
Summary of Concomitant Medications - All Enrolled Patients 
Table 
14.1.6.1 
Extent of Treatment Exposure - Safety Analysis Set 
Table 
14.3.1.1 
Overall Summary of Adverse Events - Safety Analysis Set 
Table 
14.3.1.2 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term - Safety Analysis Set 
Table 
14.3.1.3 
Treatment Emergent Serious Adverse Events by System Organ Class and Preferred Term - Safety Analysis Set 
Table 
14.3.1.4 
Treatment Emergent Grade 3 and above Adverse Events by System Organ Class and Preferred Term - Safety 
Analysis Set 
Table 
14.3.1.5 
Treatment-Related TEAEs by System Organ Class and Preferred Term - Safety Analysis Set 
Table 
14.3.1.6 
Treatment-Related TEAEs and Grade 3 and above by System Organ Class and Preferred Term - Safety Analysis 
Set 
Table 
14.3.1.7 
Treatment Emergent Adverse Events leading to Dose Reduction by System Organ Class and Preferred Term - 
Safety Analysis Set 
Table 
14.3.1.8 
Treatment Emergent Adverse Events leading to Dose Interruption by System Organ Class and Preferred Term - 
Safety Analysis Set 
Table 
14.3.1.9 
Treatment Emergent Adverse Events leading to Dose Discontinuation by System Organ Class and Preferred 
Term - Safety Analysis Set 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
D0816R00025     
   FINAL DATED 13JAN2023   
AstraZeneca Confidential  
 Page 23 of 73 
Category 
Sr. No 
Title 
Table 
14.3.1.10 
Treatment Emergent Adverse Events of Special Interest by System Organ Class and Preferred Term - Safety 
Analysis Set 
Table 
14.3.4.1 
Descriptive Summary of Haematology: Absolute and Change from Baseline values - Safety Analysis Set 
Table 
14.3.4.2 
Descriptive Summary of Clinical Chemistry: Absolute and Change from Baseline values - Safety Analysis Set 
Table  
14.3.4.3 
Shift Table of Haematology – safety Analysis Set 
Table 
14.3.4.4 
Descriptive Summary of Vital Signs: Absolute and Change from Baseline values - Safety Analysis Set 
Table 
14.3.4.5 
Summary of ECG - Safety Analysis Set 
Table 
14.3.4.6 
Summary of Physical Examination– Safety Analysis Set 
Table 
14.3.4.7 
WHO Performance Status - Safety Analysis Set 
Listing 
16.2.1.1 
Screened Patients - All Patients 
Listing 
16.2.1.2 
Patient Disposition – All Enrolled Patients 
Listing  
16.2.1.3 
Patient Visits – All Enrolled Patients 
Listing 
16.2.1.4 
Listing of Study Completion or Withdrawal from study – All Enrolled Patients 
Listing 
16.2.1.5 
Listing of Withdrawal of Main Consent – All Enrolled Patients 
Listing 
16.2.2.1 
Protocol Deviations during the Study – All Enrolled Patients 
Listing 
16.2.4.1 
Demographic and Baseline Characteristics-  All Enrolled patients 
Listing 
16.2.4.2 
Medical and Surgical History – All Enrolled Patients 
Listing 
16.2.4.3 
Pathology at Diagnosis - All Enrolled Patients 
Listing 
16.2.4.4 
Tumour Sample – All Enrolled Patients 
Listing 
16.2.4.5 
Germline BRCA Test – All Enrolled Patients 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
 
 
 
                                                                                                                    
D0816R00025                                                                                                            FINAL DATED 13JAN2023                                                                                           
AstraZeneca Confidential                                                                                                        Page 24 of 73                                                                                            
Category 
Sr. No 
Title 
Listing 
16.2.4.6 
Extent of Disease Upon Entry - All Enrolled Patients 
Listing 
16.2.4.7 
Previous Cancer Therapy - All Enrolled Patients 
Listing 
16.2.4.8 
Prior and Concomitant Medications – All Enrolled Patients 
Listing 
16.2.4.9 
WHO Performance Status - Safety Analysis Set 
Listing 
16.2.4.10 
Physical Examination - Safety Analysis Set 
Listing 
16.2.4.11 
Vital Signs - Safety Analysis Set 
Listing 
16.2.4.12 
ECG Test Results - Safety Analysis Set 
Listing 
16.2.5.1 
Study Drug Exposure  - Safety Analysis Set 
Listing 
16.2.5.2 
Study Drug Accountability - Safety Analysis Set 
Listing 
16.2.5.3 
Discontinuation of Study Drug - Safety Analysis Set 
Listing 
16.2.5.4 
Study Drug Overdose - Safety Analysis Set 
Listing 
16.2.7.1 
Adverse Events - Safety Analysis Set 
Listing 
16.2.7.2 
Treatment Emergent Adverse Events leading to Dose Reduction- Safety Analysis Set 
Listing 
16.2.7.3 
Treatment Emergent Adverse Events leading to Dose Interruption - Safety Analysis Set 
Listing 
16.2.7.4 
Treatment Emergent Adverse Events leading to Treatment discontinuation - Safety Analysis Set 
Listing 
16.2.7.5 
Serious Adverse Events - Safety Analysis Set 
Listing 
16.2.7.6 
Adverse Events of Special interest  - Safety Analysis Set 
Listing 
16.2.7.7 
Listing of Deaths - Safety Analysis Set 
Listing 
16.2.8.1 
Listing of Haematology - Safety Analysis Set 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
D0816R00025     
   FINAL DATED 13JAN2023   
AstraZeneca Confidential  
 Page 25 of 73 
Category 
Sr. No 
Title 
Listing 
16.2.8.2 
Listing of Clinical Chemistry - Safety Analysis Set 
Listing 
16.2.8.3 
Listing of Urinalysis - Safety Analysis Set 
Listing 
16.2.8.4 
Listing of Coagulation - Safety Analysis Set 
Listing 
16.2.8.5 
Listing of Laboratory Test for Hepatitis B and C - Safety Analysis Set 
Listing 
16.2.8.6 
Listing of Hy’s Law Evaluation - Safety Analysis Set 
Listing 
16.2.8.7 
Pregnancy Test – Safety Analysis Set 
Listing 
16.2.9.1 
Pregnancy Report - Safety Analysis Set 
Listing 
16.2.9.2 
Listing of Bone Marrow Biopsy - Safety Analysis Set 
Listing 
16.2.9.3 
Listing of CT scan Report capture - Safety Analysis Set 


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
D0816R00025     
   FINAL DATED 13JAN2023   
AstraZeneca Confidential  
 Page 26 of 73 
Protocol D0816R00025 
Olaparib      
 Page xx of yy  
Table 14.1.1.1 
Patients Disposition  
All Patients 
Ovarian Cancer 
Breast Cancer 
Both Ovarian Cancer and 
Breast Cancer 
Overall 
Number of Patients Screened      
xx 
xx 
xx 
xx 
Number of Patients Enrolled  
xx 
xx 
xx 
xx 
Number of Patients Enrolled and not Treated 
xx 
xx 
xx 
xx 
Number of Patients Treated* 
xx 
xx 
xx 
xx 
Number (%) of Patients who Completed Study  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number (%) of Patient in Safety Analysis Set 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number (%) of Patients who Discontinued from Study 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Primary Reasons for Discontinuation, n (%)  
  Subject decision 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Eligibility criteria not fulfilled 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 Death   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Subject lost to follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Etc. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  xx (xx.x) 
Percentages are based on the total number of patients treated in the respective cancer type. 
Percentages for primary reason of discontinuation are based on the total number of patients discontinued from the study in the respective cancer type.  
All patients who sign the ICF (Informed Consent Form) and are screened with eligibility verified as per the Inclusion-Exclusion criteria mentioned in study 
protocol are considered to be enrolled.  
*Patients who take at least one dose of study drug.
Safety Analysis Set is defined as patients who take at least one dose of study drug.
Reference Listing:  x.x.x.x 
Program: xx.sas Table Generation: ddmmmyyyy hh:mm:ss  


 Statistical Analysis Plan 
Sponsor Name: AstraZeneca Pharma India Limited 
Sponsor Protocol ID: D0816R00025 
D0816R00025     
   FINAL DATED 13JAN2023   
AstraZeneca Confidential  
 Page 27 of 73 
Protocol D0816R00025 
Olaparib      
 Page xx of yy  
Table 14.1.2.1 
Summary of Protocol Deviations 
All Enrolled patients 
Ovarian Cancer 
(N=xx) 
n (%) 
Breast Cancer 
(N=xx) 
n (%) 
Both Ovarian Cancer 
and Breast Cancer 
(N=xx) 
n (%) 
Overall 
(N=xx) 
n (%) 
Number of patients  with at least one Protocol 
Deviation   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Major Protocol Deviations 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Minor Protocol Deviations  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Number of patients by Major Protocol Deviations 
Category 
 Category 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 Category 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 Category 3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Etc. 
All patients who sign the ICF (Informed Consent Form) and are screened with eligibility verified as per the Inclusion-Exclusion criteria mentioned in study 
protocol are considered to be enrolled. 
Percentages are based on the total number of enrolled patients (N). 
Patients can be categorized in more than one deviation category 
Reference Listing: x.x.x.x 
Program: xx.sas  Table Generation: DDMMMYYYY hh:mm