Clinical trial NCT04784533
Conditions: Alopecia Areata
Keywords: CTP-543
Sponsor: Concert Pharmaceuticals
Start date: 2021-02-26; Completion date: 2023-05-16
Enrollment: 317 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is designed to evaluate the regrowth of hair with CTP-543 and subsequent durability of that regrowth following dose reduction in adult patients with moderate to severe alopecia areata.

Detailed description:

Arms: arm 1: Participants received CTP-543 8 milligrams (mg) tablets, orally, twice daily (BID) for up to 24 weeks. arm 2: Participants received CTP-543 12 mg tablets, orally, BID for up to 24 weeks. arm 3: Participants who received CTP-543 8 mg during Period 1 of Part A and achieved an absolute severity of alopecia tool (SALT) score of ≤20 at Week 24, received CTP-543 4 mg tablets, orally, BID, for up to 24 weeks. arm 4: Participants who received CTP-543 12 mg during Period 1 of Part A and achieved an absolute SALT score of ≤20 at Week 24, received CTP-543 8 mg tablets, orally, BID, for up to 24 weeks. arm 5: Participants who received CTP-543 8 mg during Period 1 of Part A and achieved an absolute SALT score of ≤20 at Week 24, received CTP-543 matched placebo tablets, orally, BID, for up to 24 weeks. arm 6: Participants who received CTP-543 12 mg during Period 1 of Part A and achieved an absolute SALT score of ≤20 at Week 24, received CTP-543 matched placebo tablets, orally, BID, for up to 24 weeks. arm 7: Participants who received CTP-543 8 mg during Period 1, followed by CTP-543 4 mg during Period 2 of Part A and met the criteria for loss of regrowth maintenance (LOM) (absolute SALT score of \> 20), received re-treatment with CTP-543 8 mg tablets, orally, BID, for up to 24 weeks. arm 8: Participants who received CTP-543 12 mg during Period 1, followed by CTP-543 8 mg during Period 2 of Part A and met the criteria for LOM (absolute SALT score of \> 20), received re-treatment with CTP-543 12 mg tablets, orally, BID, for up to 24 weeks. arm 9: Participants who received CTP-543 8 mg during Period 1, followed by CTP-543 matched placebo during Period 2 of Part A and met the criteria for LOM (absolute SALT score of \> 20), received re-treatment with CTP-543 8 mg tablets, orally, BID, for up to 24 weeks. arm 10: Participants who received CTP-543 12 mg during Period 1, followed by CTP-543 matched placebo during Period 2 of Part A and met the criteria for LOM (absolute SALT score of \> 20), received re-treatment with CTP-543 12 mg tablets, orally, BID, for up to 24 weeks.
Interventions: intervention 1: CTP-543 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral dosing intervention 2: Oral dosing

Protocol documents:
Prot_000.pdf: 
Official Title: 
   A Study to Evaluate Maintenance of Hair Regrowth Following Dose Reduction
NCT Number: 
 NCT04784533 
Document Dates:   Protocol Amendment 3: 09 September 2022 
     of CTP-543 in Adult Patients With Moderate to Severe Alopecia Areata 








 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 




 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
  
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
  
 
  
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
  
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
    
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
    
   
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
    
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
  
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
   
 
 
 
 
    
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
  
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
   
  
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 




 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
   
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
   
 
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 












CTP-543 
08 January 2021 
Protocol CP543.2004 
Concert Pharmaceuticals, Inc. 
CONFIDENTIAL & PROPRIETARY 
5 
1. 
SUMMARY OF CHANGES: AMENDMENT 1.1 (08 January 2021)
A Study to Evaluate Maintenance of Hair Regrowth Following Dose Reduction of CTP-543 
in Adult Patients with Moderate to Severe Alopecia Areata 
CP543.2004, Protocol Amendment #1 dated 07 January 2021 
Amendment #1.1 dated 08 January 2021 
The main purpose of this amendment #1 to original protocol dated 13 November 2020, is to 
modify the Schedule of Assessments and Section 11.3 (Photographs). Photographs of the scalp 
will be taken at any time a SALT assessment is performed throughout the course of the study.  
ments for the Photography line 
item and modifications to the language in Section 11.3 have been made.  Additionally, a clerical 
error was identified in the Schedule of Assessments where a pregnancy test at Week 28 of Part 
A, Period 2 was erroneously missed.  The error has been corrected.  


CTP-543 
07 January 2021 
Protocol CP543.2004 
Concert Pharmaceuticals, Inc. 
CONFIDENTIAL & PROPRIETARY 
5 
1. 
SUMMARY OF CHANGES: AMENDMENT 1 (07 January 2021)
A Study to Evaluate Maintenance of Hair Regrowth Following Dose Reduction of CTP-543 
in Adult Patients with Moderate to Severe Alopecia Areata 
CP543.2004, Protocol Amendment #1 
07 January 2021 
The main purpose of this amendment #1 to original protocol dated 13 November 2020, is to 
modify the Schedule of Assessments and Section 11.3 (Photographs). Photographs of the scalp 
will be taken at any time a SALT assessment is performed throughout the course of the study.  
sequently added to the Schedule of Assessments for the Photography line 
item and modifications to the language in Section 11.3 have been made.  

SAP_001.pdf: 


Concert Pharmaceuticals, Inc.
Statistical Analysis Plan – CP543.2004
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STATISTICAL ANALYSIS PLAN
STUDY TITLE:
A STUDY TO EVALUATE MAINTENANCE OF HAIR REGROWTH
FOLLOWING DOSE REDUCTION OF CTP-543 IN ADULT PATIENTS
WITH MODERATE TO SEVERE ALOPECIA AREATA
PROTOCOL NUMBER:
CP543.2004
SPONSOR:
Concert Pharmaceuticals, Inc.
IND NUMBER:
131,423
PREPARED BY:
This document is confidential and proprietary to Concert Pharmaceuticals, Inc. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Concert Pharmaceuticals, Inc.,
except that this document may be disclosed to appropriate Institutional Review Boards under the condition that 
they keep the information confidential.




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Concert Pharmaceuticals, Inc.
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TABLE OF CONTENTS
1. 
LIST OF ABBREVIATIONS.......................................................................................7 
2. 
PURPOSE OF THE ANALYSES................................................................................8 
3. 
PROTOCOL SUMMARY............................................................................................9 
4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................12 
5. 
ANALYSIS SAMPLES..............................................................................................15 
6. 
STUDY SUBJECTS...................................................................................................16 
6.1. 
Disposition of Subjects...............................................................................................16 
6.2. 
Demographic and Other Baseline Characteristics......................................................18 
6.3. 
Prior and Concomitant Medications...........................................................................19 
6.4. 
Medical History ..........................................................................................................20 
7. 
STUDY OPERATIONS.............................................................................................21 
7.1. 
Protocol Deviations ....................................................................................................21 
7.2. 
Randomization............................................................................................................21 
7.3. 
Measures of Treatment Compliance...........................................................................22 
8. 
ENDPOINT EVALUATION .....................................................................................23 
8.1. 
Overview of Efficacy Analysis Methods....................................................................23 
8.1.1. 
Multicenter Studies.....................................................................................................23 
8.1.2. 
Assessment Time Windows........................................................................................23 
8.1.3. 
Timing of Analyses.....................................................................................................24 
8.1.4. 
Multiple Comparisons/Multiplicity ............................................................................24 
8.2. 
Primary Endpoints ......................................................................................................24 
8.2.1. 
Computation of the Primary Endpoints......................................................................25 
8.2.2. 
Primary Analysis of the Primary Endpoints ...............................................................25 
8.2.3. 
Sensitivity Analyses of the Primary Analysis ............................................................25 
8.2.4. 
Secondary Analyses of the Primary Endpoint............................................................25 
8.3. 
Key Secondary Endpoints...........................................................................................25 
8.4. 
Secondary Endpoints ..................................................................................................25 
8.4.1. 
Secondary SALT Endpoints .......................................................................................26 
8.4.2. 
Secondary SPRO Endpoints .......................................................................................27 
8.4.3. 
Clinical Global Impression of Improvement (CGI-I).................................................27 
8.4.4. 
Clinical Global Impression of Severity (CGI-S) ........................................................28 


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8.4.5. 
Patient Global Impression of Improvement (PGI-I)...................................................28 
8.4.6. 
Patient Global Impression of Severity (PGI-S) ..........................................................28 
8.4.7. 
Quality of Hair Patient Reported Outcome (QPRO)..................................................28 
8.5. 
Other Endpoints..........................................................................................................29 
8.5.1. 
Time to First LOM (Part A only) ...............................................................................29 
8.6. 
Examination of Subgroups .........................................................................................29 
9. 
SAFETY EVALUATION ..........................................................................................30 
9.1. 
Overview of Safety Analysis Methods.......................................................................30 
9.2. 
Extent of Exposure .....................................................................................................30 
9.3. 
Adverse Events...........................................................................................................30 
9.4. 
Deaths, Serious Adverse Events, and Other Significant Adverse Events ..................32 
9.5. 
Clinical Laboratory Evaluation...................................................................................32 
9.6. 
Vital Signs, Physical Findings, and Other Observations Related to Safety ...............33 
9.6.1. 
Vital Signs ..................................................................................................................33 
9.6.2. 
Physical Examinations................................................................................................34 
9.6.3. 
Other Safety Measures................................................................................................34 
9.6.3.1. 
12-Lead Electrocardiogram ........................................................................................34 
10. 
PHARMACOKINETIC EVALUATION...................................................................35 
11. 
OTHER ANALYSES.................................................................................................36 
12. 
INTERIM ANALYSES AND DATA MONITORING .............................................37 
13. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL.....................38 
14. 
REFERENCES ...........................................................................................................39 
15. 
APPENDIX...................................................................................................................1 
15.1. 
Study Flow Chart..........................................................................................................1 
15.2. 
Schedule of Events .......................................................................................................2 
15.3. 
Standardized MedDRA Query Values for COVID-19.................................................5 
15.4. 
List of Planned Tables, Listings, and Figures...............................................................7 
16. 
ATTACHMENTS.......................................................................................................22 


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LIST OF TABLES
Table 1: 
List of Abbreviations....................................................................................................7 
Table 2: 
Analysis Windows for Unscheduled and Early Termination Visits...........................23 


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1. LIST OF ABBREVIATIONS
Table 1:
List of Abbreviations
Abbreviation
Term
ATC
Anatomical-Therapeutic-Chemical
BID
Twice daily dosing
CGI-I
Clinician Global Impression of Improvement
CGI-S
Clinician Global Impression of Severity
CI
Confidence interval
CSR
Clinical study report
CTCAE
Common terminology criteria for adverse events
ECG
Electrocardiogram
eCRF
Electronic case report form
FDA
Food and Drug Administration
LS
Least squares
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed effect model of repeated measures
PCS
Potentially clinically significant
PGI-I
Patient Global Impression of Improvement
PGI-S
Patient Global Impression of Severity
PML
Progressive multifocal leukoencephalopathy
QPRO
Quality of Hair Patient Reported Outcome
SALT
Severity of Alopecia Tool
SAP
Statistical analysis plan
SPRO
Satisfaction of Hair Patient Reported Outcome 
TEAE
Treatment-emergent adverse events
WHO
World Health Organization


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2. PURPOSE OF THE ANALYSES
This statistical analysis plan (SAP) provides a detailed description of the strategy and statistical 
methodology to be used for analysis of data from the CP543.2004 protocol, amendment 3.0,
dated 09SEP2022.
This study will be ongoing at the time of the New Drug Application (NDA) submission. A
database freeze will be implemented, and an abbreviated report will be included in support of the 
NDA submission. Ongoing safety data will also be submitted with the 120-day safety update 
report.
The purpose of this SAP is to describe the pre-specified statistical approaches to the analysis of 
study data prior to database freeze for the NDA submission and prior to database lock for the 
final report. In addition to the analyses pre-specified for the final clinical study report (CSR) 
upon study completion, this SAP will also describe the subset of analyses to be provided in the 
abbreviated report for the NDA submission.
This analysis plan is meant to supplement the study protocol. If differences occur between 
analyses described in the SAP and the current protocol, those found in this SAP will assume 
primacy. Any deviations from this plan will be described in the applicable study report.


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3. PROTOCOL SUMMARY
This is a two part, double-blind, randomized, multicenter study to evaluate the regrowth of hair 
with CTP-543 and subsequent durability of that regrowth following dose reduction or drug 
discontinuation in adult patients with moderate to severe alopecia areata. Patients will be 
between 18 and 65 years of age and experiencing an episode of hair loss associated with alopecia 
areata lasting at least 6 months and not exceeding 10 years. Patients not currently being treated 
for alopecia areata or with other treatments that might affect hair regrowth or immune response 
must have at least 50% hair loss as measured by the Severity of Alopecia Tool (SALT) at
Screening and Baseline.
The study is divided into 2 Parts:
Part A: Period 1 (Treatment Phase) and Period 2 (Dose Modification Phase)
Part B: Re-Treatment Phase
Part A
Period 1
Patients will be screened up to 28 days prior to initiation of study drug. Patients will provide
appropriately-obtained informed consent prior to initiating any screening procedures. Patients 
meeting initial screening criteria will be eligible to continue to the Day 1 (Baseline) visit for 
review of eligibility and baseline assessments, including SALT assessment, physical 
examination, clinical laboratory assessments, electrocardiograms (ECGs) and vital signs. Patients 
meeting all inclusion criteria and none of the exclusion criteria are eligible to enter Part A, 
Period 1 of the study.
Part A, Period 1 is a double-blind Treatment Period where patients will be randomized to receive 
either 8 mg BID or 12 mg BID CTP-543 for 24-weeks. Randomization will be stratified by scalp 
hair loss into
2) complete or near-complete
rst dose of 
study drug in the clinic on Day 1 and will be instructed to take study drug daily approximately 
every 12 hours for the duration of Period 1. Other baseline assessments for Part A, Period 1 will 
include Patient and Clinician Global Impression of disease Severity (CGI-S and PGI-S), and 
Patient Reported Outcome for Satisfaction (SPRO) and Hair Quality (QPRO). Blood samples for 
pharmacokinetic assessment will be taken periodically. At End of Treatment (EOT) for Part A, 
Period 1, treatment success (Responders) will be defined as patients from each dose group 
Period 2 
of the study. Patients having an absolute SALT score > 20 will be defined as a Non-Responder
and will have the opportunity to continue receiving treatment in the Open-Label Extension study
(CP543.5001) or they will complete treatment at Week 24 and return in 4 weeks for the Post-
Treatment Safety Follow-up.
Period 2
In Part A, Period 2, patients will be re-randomized to receive either a lower dose of CTP-543
(4 mg BID for patients previously receiving 8 mg BID or 8 mg BID for patients previously 


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receiving the 12 mg BID) or placebo. Patients in Part A, Period 2 will stay on their assigned dose 
for a maximum of 24 weeks or until they meet the criteria for loss of regrowth maintenance 
(LOM), defined as an absolute SALT score >20. Any patient meeting the LOM criteria at any 
assessment timepoint during Part A, Period 2 will enter Part B of the study and return to their 
original CTP-543 treatment from Part A, Period 1 (8 mg BID or 12 mg BID). Patients not 
the opportunity to continue receiving treatment in the Open-Label Extension study (CP543.5001) 
or they will complete treatment at Week 24 and return in 4 weeks for the Post-Treatment Safety 
Follow-up. The study design is depicted in the Study Flow Chart of the Appendix (Section 15.1).
An interim analysis to support regulatory activities related to an upcoming CTP-543 New Drug 
Application (NDA) submission will be conducted. The focus of the interim analyses will be on 
safety data and will occur following completion of Part A, Period 1. Additionally, after Part A, 
Period 1 completion, a PK population analysis will be completed. The PK analysis will be
conducted by an outside vendor. This analysis will be described in a separate analysis plan and a 
separate report will be generated.  
The primary efficacy assessment will be conducted when all patients have completed Part A, 
Period 2.  An analysis of safety data will also be conducted. This analysis will be included in the 
NDA submission as an abbreviated report. Site personnel and patients will remain blinded to 
individual patient study treatments.
Part B
Any patient from Part A, Period 2 meeting the LOM criteria (SALT > 20) will enter into Part B 
of the study and return to their original 8 mg BID or 12 mg BID dose assigned in Part A, 
Period 1. Patients will stay on their assigned dose for 24 weeks regardless of whether they meet 
the criteria for Restoration of Regrowth (ROR) or not. ROR is defined as the patient’s attainment 
Assessment of treatment response using SALT for efficacy 
will occur monthly during the 24-week period. Patients will have the opportunity to continue 
receiving treatment in the Open-Label Extension study (CP543.5001) or they will complete 
treatment at Week 24 and return in 4 weeks for the Post- Treatment Safety Follow-up.
Patient safety will be monitored throughout the trial by the Investigator and supported by regular 
review by the Medical Monitor. Chemistry and hematology laboratory values will be assessed 
under fasted conditions bi-weekly for the first month of the treatment period (Part A, Period 1 
and Part B), followed by every 4 weeks through the remainder of the study (all Parts). Lipid 
levels will be assessed every 4 weeks throughout the study. In light of the COVID-19 pandemic, 
challenges in the conduct of study visits may arise from quarantines, site closures, and/or travel 
limitations. To ensure the safety of trial participants and to minimize risk to trial integrity, 
alternative methods for drug dispensation and assessments, including telemedicine visits and 
clinical laboratory blood draws at a local laboratory or via a Home Health Care agency, may be 
offered for those trial participants who may no longer have access to the investigational site. 
Significant cytopenias or other hematologic abnormalities will be managed by severity through 
dose interruption or discontinuation, and signs and symptoms of infection will be closely
monitored and treated promptly. Patients who experience intolerable symptoms during treatment 
may discontinue treatment at the judgement of the Investigator, but will be followed for safety 


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and efficacy assessments for the remainder of the study unless they withdraw consent. Patients 
may withdraw consent at any time.


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4. GENERAL ANALYSIS AND REPORTING CONVENTIONS
The following is a list of general analysis and reporting conventions to be applied to this study, 
unless otherwise specified. Departures from these general policies will be described, if 
applicable, in the appropriate sections of this SAP. When this situation occurs, the rules set forth 
in the specific section take precedence over the general policies.
All data displays (tables, listings, and figures) will have a header showing the sponsor company 
name, protocol number, page number, and display status (i.e. “DRAFT” or “FINAL”), as well as 
a footer indicating file name and run date/time.  Summary tables and data listings will be 
summarized by treatment group for efficacy and exposure, and by treatment group and overall 
otherwise. All data for analysis may be listed by-patient.
Specifically, for each Part and Period of the study, the summary table layout will be as follows:
For Part A, Period 1 tables:
Treatment Phase
CTP-543
8 mg BID
CTP-543
12 mg BID
Total
For Part A, Period 2 tables:
Dose Reduction
Drug Discontinuation
CTP-543
8 mg BID to
4 mg BID
CTP-543
12 mg BID to
8 mg BID
CTP-543
8 mg BID to 
Placebo
CTP-543
12 mg BID to 
Placebo
Total
For Part B tables:
Dose Reduction
Drug Discontinuation
CTP-543
8 mg BID to 
4mg BID to
8 mg BID
CTP-543
12 mg BID to 
8 mg BID to
12 mg BID
CTP-543
8mg BID to
Placebo to
8 mg BID
CTP-543
12 mg BID to 
Placebo to
12 mg BID
Total
Note that for all efficacy and exposure tables, the total column will not be displayed.
Categorical variables will be summarized using counts (n) and percentages (%) and will be 
presented in the form “n (xx.x).”  If a count is 0, no percentage will be shown. If a percentage is 
100%, 100 will be shown.  To ensure completeness, summaries for categorical variables will 
include all categories, even if no patients had a response in a particular category. Unless 
otherwise specified, the denominator for each percentage will be based on the number of patients 
in the population being summarized (header n).  Percentages will be rounded to one decimal 
place.   
Continuous variables will be summarized using mean, standard deviation, minimum, maximum, 
median, and number of patients.  The minimum and maximum will be the same precision as the 


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original collected data. The mean and median will be reported to an additional level of precision 
than the original observations, and the standard deviation will be reported to two additional 
levels of precision than the original observations.  The precision for some original collected data 
and derived variables are longer than required for clinical interpretation (eg, >15 decimals). In 
these situations, the number of decimal places will be determined by the table of precision 
included as an attachment.
All efficacy summaries are descriptive with no statistical hypothesis testing. Confidence intervals 
and estimated treatment differences will be rounded to one additional decimal place from the 
original data, or a maximum of two decimal places. Standard error will be reported to an 
additional level of precision. Results which cannot be determined will be displayed as “NA”, 
“NE”, or similar.
Treatment start date for each part and period will be defined as the date of randomization or re-
randomization for the respective part or period. If the treatment start date for Part A Period 2 is 
equal to the treatment end date for Part A Period 1 as collected on the eCRF, it will be assumed 
that the treatment day is associated with Part A Period 2. One day will be subtracted from the 
treatment end date for Part A Period 1. Similarly, if the treatment start date for Part B is equal to 
the treatment end date for Part A Period 2, it will be assumed that the treatment day is associated 
with Part B. One day will be subtracted from the treatment end date for Part A Period 2.
Date of last dose is collected on the Treatment Discontinuation/Completion eCRF page for each 
part/period. For patients with missing or partial date of last dose, or for patients who are ongoing 
at the time of the NDA submission, the date of last dose (ie, treatment end date) will be imputed. 
Date of last dose will be imputed as follows:
For entirely missing dates for patients who are not ongoing or for partial dates where the 
month and day are missing, date of last dose will be imputed as the last visit date that is 
not a follow-up visit within a period or part.
For partial dates where only the day is missing, the day will be imputed as the last day of 
the month. If this imputed date is after the treatment start date of the next part or period,
or the study discontinuation date of that part or period, the day will be imputed to one day 
before the treatment start date of the next part or period.
For patients who are ongoing, date of last dose will be imputed as the data cut date.
Summary tables and data listings: 
No preliminary rounding will be performed; rounding will only occur after analysis. Note 
that for the clinical purposes of moving patients through parts and periods, SALT scores 
were rounded to the nearest integer prior to determining the SALT 20 criterion. 
Data from patients excluded from an analysis population will be presented in the data 
listings but will not be included in the calculation of summary statistics, where 
applicable.


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Data from each patient will be separated by a blank line. Within a data listing, if a 
descriptive item appears line after line (e.g., repetition of a patient number, date, visit, 
etc.), only the first occurrence will be displayed (e.g., in Listing of Vital Signs, patient 
number, date and visit will only be displayed on first row when presenting all parameters 
collected at same visit). Repetition of actual results or outcomes (e.g., adverse events, lab 
results, vital sign values, etc.) will not be collapsed. 
Data listings will be sorted by treatment, patient, and date and/or time of assessment, as 
applicable. Data listings may be separated by study part.
There will be 3 baselines in this study, defined as follows: 
o
Part A Period 1 baseline is the last observation obtained on or before the day of 
dosing of study drug in Part A Period 1. 
o
Part A Period 2 baseline is the last observation obtained on or before the day of 
dosing of study drug in Part A Period 2.
o
Part B baseline is the last observation obtained on or before the day of dosing of 
study drug in Part B.
Unless otherwise noted, values reported as greater than or less than some quantifiable 
limit (e.g., “< 2.0”) will be summarized as using the numeric equivalent in summary 
tables and figures (e.g. “<2.0” will be analyzed as 2.0). The reported value will be used in 
listings. 
Mock tables and data listings will be provided as attachments to this analysis plan. Minor 
changes to the mocks after formal SAP approval will not necessitate re-approval unless changes 
to the text of the SAP are required.
All statistical deliverables will be produced, validated, and reviewed for accuracy/consistency in 
accordance with 
. standard operating procedures and the processes described in the 
statistical validation plan.
SAS® (SAS Institute, Cary, North Carolina) statistical software, version 9.4 or later, will be used 
for all analyses. Adverse Events and Medical History will be coded in Medical Dictionary for 
Regulatory Activities (MedDRA) Version 23.1 or later. Concomitant medications will be coded 
in World Health Organization (WHO) Drug Version 2020-SEP or later, and Anatomical-
Therapeutic-Chemical (ATC) classification and preferred term will be used for summaries.


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5. ANALYSIS SAMPLES
The Efficacy Population will include all patients who are randomized in the study, dispensed 
study drug, and have at least 1 post-treatment SALT assessment.
The Safety Population will include all patients who receive study drug during the Treatment 
Period.
The Pharmacokinetic (PK) population will include all patients who received study drug in Part 
A, Period 1 and had at least 1 post-treatment blood draw.
All populations will be analyzed by the treatment received. In the event patients incorrectly 
receive treatment associated with a different treatment group per Part and/or Period of the study, 
they will be analyzed “as treated” if the patient received that treatment for more than 50% of 
doses for that Period/Part.


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6. STUDY SUBJECTS
6.1. Disposition of Subjects
Disposition will be summarized by randomized treatment group and overall for all patients 
screened in the study for each of Part A Period 1, Part A Period 2, and Part B. The number and 
percentage of patients who are randomized, treated, prematurely discontinued, and completers 
will be summarized. Unless otherwise specified, percentages will be based on the number of 
patients randomized in the applicable study part.
The following disposition information will be summarized for Part A Period 1:
The number of patients screened. Patients who rescreened will be counted only once.
The number of patients randomized.
The number and percentage of randomized patients within the Efficacy, Safety, and PK
Populations.
The number and percentage of randomized patients who:
o
completed treatment in Part A Period 1 per the Treatment 
Discontinuation/Completion eCRF page, where completed includes the following 
subcategories: complete-entering Part A Period 2, complete-entering Open Label, 
and complete-safety follow-up.
o
prematurely discontinued treatment in Part A Period 1.
The frequency and percentage of each discontinuation reason. The 
denominator for the percentage of each discontinuation reason will be the 
number of patients who discontinued treatment in Part A Period 1.
o
prematurely discontinued treatment in Part A Period 1 due to COVID-19
The frequency and percentage of reasons related to COVID-19. The 
denominator for the percentage of reasons related to COVID-19 will be 
the number of patients who discontinued treatment due to COVID-19.
o
completed the study in Part A Period 1 per the Study Discontinuation/Completion
eCRF page, where completed includes the following subcategories: complete-
entering Part A Period 2, complete-entering Open Label, and complete-safety 
follow-up.
o
prematurely discontinued the study in Part A Period 1.
The frequency and percentage of each study discontinuation reason.  The 
denominator for the percentage of each discontinuation reason will be the
number of patients who discontinued the study in Part A Period 1.
o
prematurely discontinued the study due to COVID-19
the frequency and percentage of reasons related to COVID-19. The 
denominator for the percentage of reasons related to COVID-19 will be 
the number of patients who discontinued treatment due to COVID-19.


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The following disposition information will be summarized for Part A Period 2:
The number of patients randomized.
The number and percentage of randomized patients within the Efficacy and Safety
Populations.
The number and percentage of randomized patients who:
o
completed treatment in Part A Period 2 per the Treatment 
Discontinuation/Completion eCRF page, where completed includes the following 
subcategories: complete-LOM achieved-entering Part B, complete-entering Open 
Label, and complete-safety follow-up.  
o
prematurely discontinued treatment in Part A Period 2.
The frequency and percentage of each discontinuation reason.  The 
denominator for the percentage of each discontinuation reason will be the 
number of patients who discontinued treatment in Part A Period 2.
o
prematurely discontinued treatment in Part A Period 2 due to COVID-19
The frequency and percentage of reasons related to COVID-19. The 
denominator for the percentage of reasons related to COVID-19 will be 
the number of patients who discontinued treatment due to COVID-19.
o
completed the study in Part A Period 2 per the Study Discontinuation/Completion
eCRF page, where completed includes the following subcategories: complete-
LOM achieved-entering Part B, complete-entering Open Label, and complete-
safety follow-up.
o
prematurely discontinued the study in Part A Period 2.
The frequency and percentage of each study discontinuation reason.  The 
denominator for the percentage of each discontinuation reason will be the 
number of patients who discontinued the study in Part A Period 2.
o
prematurely discontinued the study due to COVID-19
the frequency and percentage of reasons related to COVID-19. The 
denominator for the percentage of reasons related to COVID-19 will be 
the number of patients who discontinued treatment due to COVID-19.
The following disposition information will be summarized for Part B:
The number of patients re-randomized.
The number and percentage of re-randomized patients within the Efficacy and Safety 
Populations.


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The number and percentage of re-randomized patients who:
o
completed treatment in Part B per the Treatment Discontinuation/Completion
eCRF page, where completed includes the following subcategories: complete-
entering Open Label and complete-safety follow-up.
o
prematurely discontinued treatment in Part B.
The frequency and percentage of each discontinuation reason.  The 
denominator for the percentage of each discontinuation reason will be the 
number of patients who discontinued treatment in Part B.
o
prematurely discontinued treatment in Part B due to COVID-19 
The frequency and percentage of reasons related to COVID-19. The 
denominator for the percentage of reasons related to COVID-19 will be 
the number of patients who discontinued treatment due to COVID-19.
o
completed the study in Part B per the Study Discontinuation/Completion eCRF 
page, where completed includes the following subcategories: complete-entering 
Open Label and complete-safety follow-up.
o
prematurely discontinued the study in Part B.
The frequency and percentage of each study discontinuation reason.  The 
denominator for the percentage of each discontinuation reason will be the 
number of patients who discontinued the study in Part B.
o
prematurely discontinued the study due to COVID-19
the frequency and percentage of reasons related to COVID-19. The 
denominator for the percentage of reasons related to COVID-19 will be 
the number of patients who discontinued treatment due to COVID-19.
The number and percentage of patients randomized within each treatment group will also be 
summarized by investigative site for each Part and Period of the study.
Disposition and patient visits will also be presented for each patient in patient data listings. 
Patient data listings will list date of informed consent, date of first/last treatment, date of end of 
treatment/early treatment termination, date of end of study/early study termination, and reasons 
for treatment or study discontinuation. A Kaplan Meier curve of time to early treatment 
termination for any reason by study part will also be presented for the Safety Population. Patients 
who have completed treatment will be censored at date of last treatment or a maximum of 24
weeks. Consort diagrams may also be presented.
Screen failures will be provided in a separate listing. Rescreened patients who later enrolled will 
not be listed as screen failures.
6.2. Demographic and Other Baseline Characteristics
Demographic characteristics (i.e., sex, ethnic origin, race, age, and calculated body mass index)
will be collected at the Screening Visit, between Day -28 and -1, and detailed on the eCRF. 
Demographic characteristics will be summarized using descriptive statistics for all randomized 
patients by treatment group and overall, for each of Part A Period 1, Part A Period 2, and Part B.


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Baseline characteristics will be summarized using descriptive statistics for all randomized 
patients by treatment group and overall, for each study part, and will include the following: 
Baseline total SALT score
o
Note: Baseline total SALT score for Part A Period 2 will be the last SALT score 
obtained prior to dosing in Part A, Period 2 (ie, Week 24 SALT assessment from 
Part A, Period 1).  Part B baseline total SALT score will be the last SALT score 
obtained in Part A, Period 2 prior to re-randomization into Part B.
and < 95); complete or near-compl
duration of current episode in years (calculated as: [date of randomization – date of 
current episode onset + 1] / 365.25)
nasal hair involvement
For Part A Period 1, whether the patient has experienced any past and/or concomitant diseases, 
conditions, or exposures to serious infections (such as HIV), or past surgeries will also be 
summarized with baseline characteristics.
Other co-morbidities may be identified and included as baseline characteristics. 
All demographics and baseline characteristics will also be listed within a by-patient data listing 
for all randomized patients.
6.3. Prior and Concomitant Medications
Concomitant medications will be recorded in the eCRF from Screening through the Follow-Up 
Visit at Week 28, for all Parts/Periods of the study. All medications will be coded using the 
WHO Drug Dictionary Version 2020-SEP.
Medications are classified as prior if the medication started prior to the first dose date of study 
drug or as concomitant if used on or after the first dose date of study drug for a given 
Part/Period.
Prior and concomitant medications will be summarized with counts and percentages separately
for the Safety Population by treatment group, WHO Drug ATC classification level 2 and 
preferred term. For each summary, a patient will be counted only once for each medication. 
Prior medications will be summarized for Part A Period 1 only. Concomitant medications will be 
summarized for each Part/Period. 
Partial and completely missing dates will be imputed for the purposes of classifying concomitant 
medications as follows:
Partial dates will be imputed following the same algorithm as in Section 9.3 for 
Treatment-emergent adverse events (TEAEs).
For an entirely missing start date (i.e. day, month, and year are missing), the start date 
will be set to the date of administration of study drug for the given Part/Period unless the 


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stop date is prior to the date of administration of study drug, in which case the start date 
will be set to the stop date.
For an entirely missing stop date (i.e. day, month, and year are missing), the medication 
will be treated as ongoing.
Partial dates will be compared to the start and end dates of each Part/Period to determine the 
study drug administration date that will be used to be imputed. 
Prior and concomitant medications will also be listed by-patient.
6.4. Medical History
Medical history will be coded with the MedDRA terminology Version 23.1 and summarized as
counts and percentages for the Safety Population by treatment group, system organ class, and 
preferred term for Part A Period 1. A patient will be counted only once for each condition.  
Conditions will be listed, including the verbatim investigator description of the relevant medical 
condition, the coded terms (system organ class, preferred term), start date, end date, and whether 
or not the condition is ongoing.


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7. STUDY OPERATIONS
7.1. Protocol Deviations
A protocol deviation is any noncompliance with the clinical trial protocol or International 
Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 
Good Clinical Practice requirements. The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. Protocol deviations will be recorded on the 
source documents and with an explanation for the deviation. All protocol deviations will also be 
recorded as specified in the monitoring plan.
Protocol deviations will be identified by site staff, through medical reviews, and by clinical 
research associates during site monitoring. Protocol deviations are reviewed by the sponsor on
an ongoing basis during the study to classify deviations as minor or major. Deviations that may 
alter or confound interpretation of the study results will be classified as major deviations.  
Protocol deviations will be summarized as counts and percentages by treatment group, deviation 
severity, and category for all randomized patients by study part. Reported deviation occurrence 
date will be compared to Part A Period 1 randomization date, Part A Period 2 randomization 
date, and Part B re-randomization date to determine the study part where the deviation will be 
summarized. 
Deviations will also be presented by patient in a data listing for all randomized patients.
7.2. Randomization
Part A Period 1
Patients will be randomized such that approximately N = 130 for 12 mg BID and N = 170 for 8 
mg BID) in an attempt to have approximately equal numbers of patients eligible for Part A, 
Period 2. Randomization will be stratified by scalp hair loss into one of the following two 
-complete scalp 
The randomization schedule will be generated prior to study start. Tablets and packaging of 8 mg 
and 12 mg CTP-543 will be identical in appearance.
Part A Period 2
For each dose group, patients identified as Responders in Period 1 will be randomized in a 1:1 
ratio to a dose reduction arm or a placebo (drug discontinuation) arm. For the dose reduction 
arm, patients previously on 12 mg BID in Period 1 will be assigned to 8 mg BID and patients 
previously on 8 mg BID will be assigned to 4 mg BID. Given the previous experience with the 
primary endpoint for Period 1, it is expected that approximately 50 patients from each dose 
group in Period 1 will be Responders. Consequently, it is expected that approximately 25 
patients from each dose group will be assigned to dose reduction and 25 patients will be assigned 
to drug discontinuation in Period 2.
The randomization schedule will be generated at the end of Period 1. Tablets and packaging for 4 
mg CTP-543, 8 mg CTP-543 and placebo will be identical in appearance.


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Part B
For each dose group, patients identified as having a LOM following either dose reduction or
drug discontinuation in Part A, Period 2 will be assigned back to the original dose they received
in Part A, Period 1. Study drug dosing regimen will be blinded by administering 2 x 8 mg tablets
or 2 x 12 mg tablets twice-daily for 24 weeks. Tablets and packaging of 8 mg and 12 mg CTP-
543 will be identical in appearance.
A by-patient listing of randomized treatment group and randomization number will be presented
for each Part/Period.
All study patients, Investigators, and site study staff will be blinded to study drug assignment for 
the duration of the study.  
7.3. Measures of Treatment Compliance
Time on treatment (days) will defined, for each Part/Period, as (date of last dose - date of first 
dose + 1). Dose interruptions will be subtracted from this calculation.
Patients will strive for 100% compliance with the daily dosing schedule. Treatment compliance 
will be summarized as percent of planned dose received for each dosing regimen.  Percent of 
planned dose received will be calculated for each Part/Period as follows:
100*(Tablets Dispensed-Tablets Returned)/(Tablets Expected)
Tablets Expected is defined as the time on treatment multiplied by the expected number of pills 
taken daily (x2 for the 12 mg BID group; x2 for the 8 mg BID group; x2 for the 4 mg BID group; 
x2 for the placebo group), where time on treatment is defined as above, but with dose 
interruptions being ignored in this calculation. Derived patient compliance, compliance per the 
eCRF (80% or higher versus less than 80%), and dosing exceptions will be listed in by-patient 
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8. ENDPOINT EVALUATION
8.1. Overview of Efficacy Analysis Methods
8.1.1. Multicenter Studies
Patients will be enrolled at up to approximately 25 sites; site identifiers will be included in by-
patient listings.
8.1.2. Assessment Time Windows
The visit schedule for all study assessments is provided in Appendix 15.2, by Part. For scheduled 
visits, there will be no reassignment of the analysis visit based on date. Unscheduled visits and 
early termination visits will be reassigned based on the analysis windows in the below table and 
the schedule of events. Assessments in part B will be windowed counting from the part B 
treatment start date. Assessments may only be re-assigned to visits where they were to be 
collected per the schedule of events. The latest assessment in a window will be selected as the 
visit used in summaries, unless otherwise specified.  All visits will be included in by-patient data 
listings.
Table 2:
Analysis Windows for Unscheduled and Early Termination Visits
Safety Analyses
Efficacy Analyses
Nominal Visit
Lower
Target
Upper
Lower
Target
Upper
Screening
-28
-1
-1
-28
-1
-1
Part A,
Visit 2-Randomization
1
1
1
1
1
1
Period 1
Visit 3-Week 2
2
15
22
12
15
18
Visit 4-Week 4
23
29
43
26
29
32
Visit 5-Week 8
44
57
71
54
57
60
Visit 6-Week 12
72
85
99
82
85
88
Visit 7-Week 16
100
113
127
110
113
116
Visit 8-Week 20
128
141
155
138
141
144
Visit 9-Week 24
156
169
183
166
169
172
Visit 10-Week 28 (PAP2 Week 4)
184
197
211
194
197
200
Part A,
Visit 11-Week 32 (PAP2 Week 8)
212
225
239
222
225
228
Period 2
Visit 12-Week 36 (PAP2 Week 12)
240
253
267
250
253
256
Visit 13-Week 40 (PAP2 Week 16)
268
281
295
278
281
284
Visit 14-Week 44 (PAP2 Week 20)
296
309
323
306
309
312
Visit 15-Week 48 (PAP2 Week 24)
324
337
351
334
337
340
Visit B1-Day 1
1
1
1
1
1
1
Part B
Visit B2-Week 2
2
15
22
12
15
18
Visit B3-Week 4
23
29
43
26
29
32
Visit B4-Week 8
44
57
71
54
57
60
Visit B5-Week 12
72
85
99
82
85
88
Visit B6-Week 16
100
113
127
110
113
116
Visit B7-Week 20
128
141
155
138
141
144
Visit B8-Week 24
156
169
183
166
169
172


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8.1.3. Timing of Analyses
All final, planned analyses will be performed after the last patient has completed all study 
assessments in Part B, all relevant study data have been processed and integrated into the 
analysis database, and the database has been locked. Analyses for the abbreviated report for the 
NDA, focused on the primary efficacy for Part A and a safety analysis for Part A, will be 
performed after the last patient completes Part A and the database is frozen. PK analyses and the 
interim analysis (safety data for Part A Period 1) will be performed after the last patient 
completes Part A Period 1 and the database is frozen.
Any post hoc, exploratory analyses completed to support planned study analysis, which were not 
identified in this SAP, will be documented and reported in appendices to the applicable study 
reports. Any results from these unplanned analyses (post hoc) will also be clearly identified in 
the text of the applicable study reports.
8.1.4. Multiple Comparisons/Multiplicity
There will be no adjustment for multiple treatment group comparisons in this Phase 2 study.
8.2. Primary Endpoints
Part A:
This study is designed to be exploratory and descriptive in nature and no formal hypothesis 
testing is planned. Therefore, descriptive statistics will be used to summarize the results 
regarding dose modification following successful hair regrowth for each dose group. In Part A, 
Treatment Period. Only Responders will enter into Part A, Period 2 (Dose Modification) for the 
primary efficacy analysis. For Part A of the study, there are two co-primary efficacy endpoints.
The first co-primary efficacy endpoint is the percentage of patients achieving LOM criteria 
(SALT >20) compared to the pe
for each of the following dose reduction conditions (Period 2 ONLY):
12 mg BID reduced to 8 mg BID
8 mg BID reduced to 4 mg BID
The second co-primary efficacy analysis is the percentage of patients achieving LOM criteria 
compared to the percentage of patients maintaining treatment success for each of the following 
drug discontinuation conditions (Period 2 ONLY):
12 mg BID to Placebo
8 mg BID to Placebo
Part B:
For Part B of the study, the primary efficacy endpoint is the percentage of patients by dose group 
achieving ROR, defined as an absolute SALT score of 
at Week 24 of re-treatment. The 
following treatment sequences will be compared:
Dose reduction in Period 2
o
12 mg BID reduced to 8 mg BID increased to 12 mg BID
o
8 mg BID reduced to 4 mg BID increased to 8 mg BID


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Drug discontinuation in Period 2
o
12 mg BID to placebo to 12 mg BID
o
8 mg BID to placebo to 8 mg BID
8.2.1. Computation of the Primary Endpoints
The SALT is a measure of hair loss that quantifies the amount of scalp surface without hair in a 
pre-specified quadrant of the scalp (right side, top, left side, back), that is further summed after 
applying a quadrant-specific multiplier indicative of scalp surface area contribution, to provide 
an overall score of total hair loss. An example of the SALT assessment can be found in 
Appendix 18.2 of protocol.
The primary endpoints for each Part of the study consist of deriving and categorizing the 
individual overall SALT scores 
.
Due to the variable time on study for each patient within Part A Period 2, the primary analysis 
visit will be the End of Part A Period 2, where the last observed non-missing SALT value is
selected for each patient. Otherwise, missing data will not be imputed for this descriptive, 
exploratory study.
Patterns of missing values across visits will be listed and summarized with numbers and 
percentages by treatment and visit.
8.2.2. Primary Analysis of the Primary Endpoints
This study is designed to be exploratory and descriptive in nature and no formal hypothesis 
testing is planned. Therefore, descriptive statistics will be used to summarize the results for each 
Part/Period.
versus those 
with an absolute SALT score >20, will be reported by treatment group with 95% confidence 
intervals (using the binomial approximation with a Wald continuity correction). This analysis 
will be completed for the Efficacy Population.  The results may also be displayed graphically.
No p-values will be reported.
8.2.3. Sensitivity Analyses of the Primary Analysis
No sensitivity analyses specified.
8.2.4. Secondary Analyses of the Primary Endpoint
No secondary analyses specified.
8.3.Key Secondary Endpoints
No key secondary endpoints specified.
8.4.Secondary Endpoints
Analyses for secondary endpoints will be performed using the Efficacy Population.
Missing values will not be imputed.


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For the secondary endpoints of proportions or percentages of patients achieving specified 
improvement criteria (hereinafter, “secondary responder endpoints”), pairwise treatment group 
differences in percentages and 95% CIs will be calculated in Part A Period 1 only.
Observed counts and percentages of responders will be summarized by treatment group for each 
Part/Period. 95% confidence intervals for percentages of responders and/or non-responders will 
be calculated using the binomial approximation with a Wald continuity correction.
For the secondary endpoints of absolute or relative changes (hereinafter, “continuous secondary 
endpoints”), continuous secondary endpoints will be summarized with descriptive statistics only 
and no treatment differences will be calculated. Descriptive statistics will include the number of 
subjects with data, mean, standard deviation, median, minimum, and maximum.
For Part A Period 1 only, treatment differences for continuous secondary endpoints will be 
assessed with a mixed-effect model of repeated measures (MMRM).  Baseline SALT score will 
be included as a model covariate. Treatment group comparisons at each visit will be based on 
least squares (LS) mean estimates.  An unstructured covariance matrix will be used to model the 
within-subject errors.  Should the model fail to converge, an alternative autoregressive 
covariance matrix will be used instead.  The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom.  Assuming that the data are MAR, the estimates of 
the treatment differences calculated from the MMRM described above are unbiased.  Standard
descriptive statistics will be reported for each time point on the values and changes from baseline 
along with the LS means, standard errors, 95% CIs and differences between treatment groups 
reported with LS means, standard errors, and 95% CIs. P-values will not be displayed.
8.4.1. Secondary SALT Endpoints
The following secondary SALT responder endpoints will be assessed:
Part A
Percentage of patients achieving LOM criteria (SALT > 20) for each dose reduction 
condition at Weeks 4, 8, 12, 16, 20, and 24 (Period 2 ONLY). Note that these timepoints 
in Period 2 are equivalent to Weeks 28, 32, 36, 40, 44, and 48, respectively.
Percentage of patients achieving LOM criteria (SALT > 20) for each drug 
discontinuation condition at Weeks 4, 8, 12, 16, 20, and 24 (Period 2 ONLY). Note that 
these timepoints in Period 2 are equivalent to Weeks 28, 32, 36, 40, 44, and 48, 
respectively.
20 at Weeks 4, 8, 12, 16, 20, 
and 24 (Period 1 ONLY)
Relative change in SALT scores from Baseline at Weeks 4, 8, 12, 16, 20, and 24 (Period
1 ONLY)
Part B:
Percentage of patients achieving the ROR criteria (SALT 
20) at Weeks 4, 8, 12, 16, and 
20
Relative change in SALT scores from Part B Baseline at Weeks 4, 8, 12, 16, 20, and 24


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Secondary endpoints on
or 
SALT >20, will be assessed according to Section 8.4.
The continuous secondary SALT endpoint of relative change in SALT score from baseline at 
Weeks 4, 8, 12, 16, 20, and 24 in Part A Period 1 will be assessed with an MMRM, according to 
Section 8.4. The baseline SALT score will be as follows for each endpoint per Part:
Relative reduction is based on relative change from baseline. 
Relative change in SALT score is derived as percent change of the follow-up SALT score, where 
baseline SALT score is the denominator (i.e. absolute change divided by the baseline score, 
multiplied by 100).
In addition, summary statistics for the mean, mean change, and mean relative change in total 
SALT score from Part A Period 1 baseline will be reported for Part A Period 1, Part A Period 2, 
and Part B. The mean and mean change in total SALT score from Part A Period 2 baseline will 
be reported for Part A Period 2 and Part B. Mean relative change from Part A Period 2 baseline 
will not be calculated as baseline values may be zero by design and would result in undefined 
relative changes. The mean, mean change, and mean relative change in total SALT score from 
Part B baseline will be reported for Part B.
8.4.2. Secondary SPRO Endpoints
The following secondary SPRO responder endpoints will be assessed:
Percentage of responders (defined as “satisfied” or “very satisfied”) on the SPRO scale at 
Weeks 12, 16, 20, and 24 (Part A Period 1 ONLY)
The SPRO is a single item questionnaire answered by the patient, designed to measure how 
satisfied alopecia areata patients are with their hair at the time of the assessment.  The SPRO 
responses are on a scale of 1-5, where 1 = very satisfied, 2 = satisfied, 3 = neither satisfied nor 
dissatisfied, 4 = dissatisfied, and 5 = very dissatisfied.  An example of the SPRO assessment can 
be found in Appendix 18.4.1 of the protocol.
A responder is defined as patients with answers of “very satisfied” or “satisfied” at each post-
treatment visit on the SPRO.  No missing data will be imputed for this endpoint. 
8.4.3. Clinical Global Impression of Improvement (CGI-I)
The CGI-I will be assessed by the Investigator at Weeks 12, 16, 20, and 24, in Part A Period 1 
only. Compared to the patient’s alopecia areata prior to treatment at baseline, the patient’s 
current state of alopecia areata will be assessed according to the Investigator’s perceived change.  
The Investigator may select one of seven numeric choices representing “Very Much Worse” to 
“Very Much Improved”.  To reduce variability, one rater should perform the CGI-I assessment 
for the patient for the duration of the study.  An example of the CGI-I assessment can be found in 
Appendix 18.3.2 of the protocol. 
The percentage of responders (defined as “much improved” or “very much improved”) using the 
CGI-I at Weeks 12, 16, 20, and 24 will be assessed per Section 8.4 in Part A Period 1 only. No 
missing data will be imputed for this endpoint.


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8.4.4. Clinical Global Impression of Severity (CGI-S)
The CGI-S will be assessed by the Investigator and will consider the severity of the patient’s 
alopecia areata at the time of assessment.  The Investigator may select one of seven numeric 
choices representing “Among the most extreme hair loss” to “Normal, no hair loss”. To reduce 
variability, one rater should perform the CGI-S assessment for the patient for the duration of the
study.  An example of the CGI-S assessment can be found in Appendix 18.3.1 of the protocol.
The continuous secondary endpoint of change from baseline in the CGI-S at Weeks 12, 16, 20,
and 24 will be assessed per Section 8.4 in Part A Period 1 only. No missing data will be imputed 
for this endpoint. 
8.4.5. Patient Global Impression of Improvement (PGI-I)
The PGI-I will be assessed by the patient at Weeks 12, 16, 20, and 24 in Part A Period 1 only.
Compared to the patient’s alopecia areata prior to treatment at baseline, the patient’s current state 
of alopecia areata will be assessed according to his/her perceived change.  The patient may select 
one of seven numeric choices representing “Very Much Worse” to “Very Much Improved”.  An 
example of the PGI-I assessment can be found in Appendix 18.3.4 of the protocol.
The secondary PGI-I responder endpoint of percentage of responders (defined as “much 
improved” or “very much improved”) at Weeks 12, 16, 20, and 24 will be assessed per Section 
8.4 in Part A Period 1 only. No missing data will be imputed for this endpoint.
8.4.6. Patient Global Impression of Severity (PGI-S)
The PGI-S will be assessed by the patient and will consider the severity of his/her alopecia areata 
at the time of assessment.  The patient may select one of seven numeric choices representing 
“Among the most extreme hair loss” to “Normal, no hair loss”.  An example of the PGI-S
assessment can be found in Appendix 18.3.3 of the protocol.
The continuous secondary endpoint of change from baseline in the PGI-S at Weeks 12, 16, 20,
and 24 will be assessed per Section 8.4 in Part A Period 1 only. No missing data will be imputed 
for this endpoint. 
8.4.7. Quality of Hair Patient Reported Outcome (QPRO)
The QPRO questionnaire is a 4-item assessment which provides additional details on key 
attributes of patient hair and helps provide context to the SPRO response. Like the SPRO, the 
QPRO responses are on a scale of 1-5, where 1 = very satisfied, 2 = satisfied, 3 = neither 
satisfied nor dissatisfied, 4 = dissatisfied, and 5 = very dissatisfied. An example of the QPRO 
assessment can be found in Appendix 18.4.2 of the protocol.
The continuous secondary endpoints of change from baseline for each individual item of QPRO 
at Weeks 12, 16, 20, and 24 will be assessed per Section 8.4 in Part A Period 1 only. No missing 
data will be imputed for this endpoint. 


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8.5. Other Endpoints
8.5.1. Time to First LOM (Part A only)
Time to first LOM (in weeks) will be summarized descriptively with Kaplan-Meier methodology
for patients in the Efficacy Population who entered Part A Period 2. Treatment sequence across 
Period 1 and Period 2 (8 mg BID to 4 mg BID, 8 mg BID to placebo, 12 mg BID to 8 mg BID, 
and 12 mg BID to placebo) will be used as strata to present quantiles (25%, median, 75%), if 
estimable. Ninety-five percent confidence intervals for the median will be presented, if 
estimable, using the Brookmeyer and Crowley (1982) method. If KM statistics are not estimable, 
standard descriptive statistics for non-censored patients will be displayed.
First LOM is defined as the first date where a patient has an absolute SALT score >20 in Part A 
Period 2. Time in weeks will be calculated from the date of randomization in Part A Period 2, as 
(date of first LOM (or censored date) - date of Part A Period 2 randomization + 1)/7
Patients who do not experience LOM before completion of Part A Period 2 or otherwise 
prematurely discontinue from Part A Period 2 will be censored at their last study visit date where 
SALT was measured in Part A Period 2 of the study, or a maximum or 24 weeks.
A Kaplan-Meier plot over time will also be presented. 
8.6. Examination of Subgroups
No subgroup analyses are planned.


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9. SAFETY EVALUATION
9.1. Overview of Safety Analysis Methods
All safety summaries will be descriptive with no statistical hypothesis testing and based on the 
Safety Population. Patients will be summarized according to the study drug received (i.e., as
treated), should it differ from the randomized treatment arm.  Safety assessments will be 
summarized by treatment group and overall, for each Part/Period of the study. All safety 
endpoints will be listed in by-patient data listings.
9.2. Extent of Exposure
Study drug exposure will be summarized for each treatment group and overall for each 
Part/Period.  The number of days on which study drug was dosed (at least partially), the number 
of days in the study exposed, and total cumulative dose will be summarized for each treatment 
group. The number and percentage of patients with at least one drug interruption will also be 
summarized.
The total number of days in the study exposed will include/ignore drug interruptions. The total 
number of days on study drug (excluding dose interruptions) and drug compliance will also be 
summarized, per Section 7.3.
9.3. Adverse Events
An adverse event is any untoward medical occurrence that may appear or worsen in a patient 
during the course of a study.  It may be a new intercurrent illness, a worsening concomitant 
illness, an injury, or any concomitant impairment of the patient’s health, including laboratory test 
values, regardless of etiology.  Any worsening (ie, any clinically significant adverse change in 
the frequency or intensity of a pre-existing condition) should be considered an adverse event.  A 
diagnosis or syndrome should be recorded on the adverse event page of the eCRF rather than the 
individual signs or symptoms of the diagnosis or syndrome.  A worsening of the condition under 
study, alopecia areata, will not be reported as an adverse event. 
All patients will be monitored for adverse events during the study.  Assessments may include 
monitoring of the following parameters: the patient’s clinical symptoms, laboratory, physical 
examination findings, or findings from other tests and/or procedures.
Adverse events will be coded using MedDRA version 23.1, and summarized by treatment group, 
system organ class, and preferred term for each Part/Period of the study.
An adverse event reported after informed consent, but before the first dose of study drug (i.e., 
Day 1), will be considered a pre-treatment adverse event.  TEAEs will be defined as any adverse 
event that occurs after administration of the first dose of study drug in each Part/Period (ie, on or 
after the day of the first dose in each Part/Period).  Adverse events will further be considered 
treatment-emergent with respect to a given Part/Period if the adverse event occurred after 
administration of the first dose of study drug in that Part/Period and, if the patient continues onto 
a subsequent period part, prior to the first dose of study drug in the subsequent Part/Period.
Adverse events will be limited to those collected within this protocol (ie, for rollover patients, 
AEs collected under the protocol of the rollover study but not in this study will not be in this 


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study). The number and percentage of patients who report TEAEs will be summarized by 
treatment group, system organ class, and preferred term.
Treatment emergent adverse events will also be summarized by intensity as well as relationship 
to study drug.  
Partial dates will be imputed for the purposes of defining TEAEs as follows:
For a missing start day where the month and year are present, the start day will be set to 
the first day of the month, unless 1) the first day of the month is before the date of 
administration of study drug and the month and year are the same as the month and year 
of the date of administration of study drug, and 2) the end date is on or after the date of 
administration of study drug or the end date is completely missing, in which case the start 
day will be set to the first day of administration of study drug.
For a missing start day and month where the year is present, the start day and month will 
be set to January 1st, unless 1) January 1st is before the date of administration of study 
drug, and 2) the end date is on or after the date of administration of study drug or the end 
date is completely missing, in which case the start day and month will be set to that of the 
first date of administration of study drug.
For an entirely missing start date (ie day, month, and year are missing), the start date will 
be set to the date of administration of study drug in Part A Period 1, unless 1) the stop 
date is prior to the date of administration of study drug in in Part A Period 1 which case 
the start date will be set to the stop date, or 2) the stop date is between the start date of 
Part A Period 2 and the end date of Part A Period 2, in which case, the date will be set to 
treatment start date of Part A Period 2, or 3) the stop date is between the start date of Part 
B and the end date of Part B, in which case, the date will be set to the treatment start date 
of Part B.
For a missing end day where the month and year are present, the end day will be set to 
the last day of the month, unless the month and year are the same as the month and year 
of the last visit date for the patient, in which case the end day will be set to that of the 
patient's last visit date.
For a missing end day and month where the year is present, the end day and month will 
be set to the patient's last visit date, unless the year of the patient's last visit date is greater 
than the end year, in which case the end day and month will be set to December 31st.
For an entirely missing stop date (i.e. day, month, and year are missing), the stop date 
will be imputed as the patient’s last visit date.
Partial dates will be compared to the start and end dates of each Part/Period to determine the 
study drug administration date that will be used to be imputed. 
Patients who report the same preferred term on multiple occasions will be counted once per 
Part/Period for the preferred term: under the highest severity when summarized by severity and 
under the closest relationship to study drug when summarized by relationship.  Missing severity 
or relationship will not be imputed.  If a patient reports multiple preferred terms for a system 
organ class, the patient will be counted only once for that system organ class.


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The number and percentage of patients who experience TEAEs will be summarized by treatment 
group and overall for each Part/Period for the following:
By system organ class and preferred term
By severity/intensity, system organ class, and preferred term
By relationship to study drug, system organ class, and preferred term
Serious adverse events by system organ class and preferred term
Serious adverse events by relationship to study drug, system organ class, and preferred 
term
Adverse events resulting in discontinuation of study drug by system organ class and 
preferred term
Adverse events that result in study drug dose interruption by system organ class and
preferred term
The number of TEAEs (events) will also be reported. By-patient listings will include all adverse 
events. TEAEs will be flagged.
9.4. Deaths, Serious Adverse Events, and Other Significant Adverse Events
A serious adverse event is an adverse event that fulfills the following criteria:
Is fatal (results in death);
Is life-threatening (Note: the term "life-threatening" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event that could 
hypothetically have caused death had it been more severe);
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay);
Results in persistent or significant disability/incapacity (a substantial disruption of the 
patient's ability to conduct normal life functions);
Is a congenital anomaly/birth defect; or
Constitutes an important medical event that may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed above.
Serious adverse events will be summarized according to Section 9.3.
By-patient listings will be provided for any deaths, serious adverse events, and adverse events 
leading to discontinuation of treatment.  TEAEs that result in dose interruption will also be 
identified in these listings.
9.5. Clinical Laboratory Evaluation
Clinical laboratory samples should be collected at the beginning of each clinic visit and just prior 
to a dose on all Study Visit Days and will be processed by a central laboratory.  In the event a


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patient is unable to attend an in-clinic visit due to COVID-19, clinical laboratory blood draws 
may be performed by a Home Health Care agency or a local laboratory.  
Clinical laboratory variables will be presented in 4 main ways, for each Part/Period of the study.
First, change from baseline to each scheduled visit. Only post-baseline values on treatment (i.e., 
on the same date or prior to last dose of study drug) will be eligible for change from baseline 
calculations. Summary statistics for the mean and mean change from Part A Period 1 baseline 
will be reported for Part A Period 1, Part A Period 2, and Part B. The mean and mean change 
from Part A Period 2 baseline will be reported for Part A Period 2 and Part B. The mean and 
mean change from Part B baseline will be reported for Part B
Second, treatment-emergent potentially clinically significant (PCS) laboratory values will be 
identified.  Potentially clinically significant values are defined as those that meet Grade 3 or 
Grade 4 toxicity criteria from the CTCAE criteria (or Grade 2 or higher for platelets). Laboratory 
values will be graded using CTCAE version 5.0, for those values included.  CTCAE grades will 
be based solely on numeric results and without regard to other symptoms based on clinical 
judgment. For laboratory parameters whose CTCAE grading is independent of baseline criteria, 
treatment-emergent PCS laboratory values are those in which the baseline value is not PCS and 
the post-baseline value is PCS. For laboratory parameters whose CTCAE grading is dependent 
upon baseline criteria, any post-baseline grading of Grade 3 or Grade 4 (or Grade 2 or higher for 
platelets) will be considered treatment-emergent.  The number and percentage of patients with 
treatment-emergent PCS laboratory values will be summarized by treatment group and overall
for each clinical laboratory variable patient to CTCAE grading. For this analysis, the visit with 
the highest CTCAE grade value within a window will be selected.
Third, box plots of hemoglobin, platelets, and neutrophils will also be provided with dose 
interruption limits included as reference lines (see Protocol Section 10.2.1).
Finally, the count and percentage of abnormal laboratory values per parameter, where applicable, 
will be provided. Additionally, a listing of patients with Abnormal laboratory values will be 
provided.
These analyses will be repeated for serum chemistry results, hematology results, and lipid results 
(where lipid tests include total cholesterol, low-density lipoprotein, high-density lipoprotein, and 
triglycerides). Laboratory results will also be listed. Reference ranges for each clinical 
laboratory parameter will also be summarized in a data listing.
Pregnancy test results will be listed only.
9.6. Vital Signs, Physical Findings, and Other Observations Related to 
Safety
9.6.1. Vital Signs
Vital signs will be measured after the patient has been in a supine or semi-supine position for at 
least 5 minutes and will include blood pressure, pulse rate, respiratory rate, and temperature.  
Height will only be measured at the Screening Visit in Part A Period 1.  Weight and vital signs 
will be measured according to the Schedule of Assessments (Appendix 15.2). Weight and height 
will be used to calculate the patient’s body mass index at Screening.  


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The mean change from Part A Period 1 baseline to each scheduled assessment will be 
summarized descriptively by treatment group and overall for each vital sign variable specified in 
the protocol.
The number and percentage of patients with at least 1 PCS vital sign value, defined as for 
laboratory values in Section 9.5, will be summarized descriptively by treatment group and 
overall.  A listing of vital signs by patient will also be provided.
9.6.2. Physical Examinations
A complete physical examination will consist of an examination of all major organ systems to 
include, but not be limited to, chest auscultation, abdominal auscultation and palpation, head, 
eyes, ears, nose and throat. An assessment for active signs and symptoms of infection including 
tuberculosis and skin examinations for non-melanoma skin cancers will be performed.
Evaluation for progressive multifocal leukoencephalopathy symptoms such as facial droop, 
general weakness, clumsiness, trouble speaking, personality changes, memory problems, and 
vision changes will be assessed. 
Additionally, an assessment for the presence or absence of nasal hair will be performed during 
complete physical exams. Presence or absence of nasal hair will be summarized at baseline,
Week 24 (Part A Period 1), Week 48 (Part A Period 2), and Week 24 (Part B). The presence or 
absence of nasal hair will be summarized as counts and percentages by treatment group and visit
for the Safety Population, for each Part/Period of the study.
Brief physical examinations will include assessment for active signs and symptoms of infection, 
including tuberculosis, skin examinations for non-melanoma skin, and an evaluation for PML
symptoms such as facial droop, general weakness, clumsiness, trouble speaking, personality 
changes, memory problems, and vision changes. Brief physical examinations will be performed 
according the Schedule of Events (Appendix 15.2). 
A listing of the date and type of physical examinations performed will be provided. The listing 
will include presence or absence of nasal hair. Deteriorations from baseline on physical 
examination will be coded as adverse events and summarized as such.
9.6.3. Other Safety Measures
9.6.3.1.
12-Lead Electrocardiogram
Twelve-lead electrocardiograms (ECG) will be performed according to the Schedule of 
Assessments (Appendix 15.2) after the patient has rested in a supine or semi-supine position for 
at least 5 minutes. Individual parameters including heart rate, PR, QT, QTcF (Frederica’s 
correction), QRS, and RR intervals will be collected.  If a patient is unable to attend an in-person 
clinic visit due to COVID-19, an ECG may not be performed.  Missed assessments will be 
recorded in the eCRF as due to COVID-19.
The mean change from Part A Period 1 baseline to each scheduled assessment will be 
summarized descriptively by treatment group and overall for each ECG variable specified in the 
protocol, for each Part/Period of the study.
A listing of ECG results will be provided. A listing of abnormal ECG findings will also be 
provided.


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10.
PHARMACOKINETIC EVALUATION
Pharmacokinetic samples will be collected in Part A, Period 1 at the following time points to 
evaluate plasma concentrations of CTP-543:
Day 1 (post-dose) and Weeks 12 and 24 (variable times post-dose)
The exact time of blood collection as well as the exact time of the preceding dose will be
recorded. All attempts to adhere to the pharmacokinetic schedule should be made. However, the
inability to follow the schedule or to obtain/process a sample will not be considered a protocol
deviation.
Sparse PK sampling was performed in this study in order to contribute to a cross study 
population PK analysis. Covariates from this study and others will include age, gender, race, 
weight (or BMI), for the population PK analysis of CTP-543.  Exposure-response relationships 
for both efficacy and safety parameters will also be assessed. This population PK analysis will be 
described in a separate analysis plan and a separate population PK report will be generated.  The 
data will not be summarized in the CP543.2004 final clinical study report.
A by-patient listing of whether PK sampling was performed will be included in the final clinical 
study report.


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11.
OTHER ANALYSES
In light of the COVID-19 pandemic and recommendations in the FDA guidance document 
“Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency”, 
the following additional listings and summaries will be provided:
Listing of patients affected by COVID-19 related study disruption, defined as missed or 
remote visits or assessments indicated per the eCRF.
Listing of dosing exceptions related to COVID-19.
Summary and listing of protocol deviations related to COVID-19, per Section 7.1.
Summary of TEAEs related to COVID-19 by system organ class and preferred term and 
TEAEs related to COVID-19 leading to study drug discontinuation by system organ class 
and preferred term, per Section 9.3. Relationship to COVID-19 will be determined using 
the Standard MedDRA Query for COVID-19 (Appendix 15.3) and may also include 
preferred terms related to vaccinations if the collected term indicates relation to COVID-
19 (ex: Vaccination complication, Vaccination site pain). Terms may be reviewed by the 
sponsor prior to database lock to finalize the list of preferred terms.
Listing of TEAEs related to COVID-19.
Listing of prior and concomitant medications related to COVID-19, where relationship to 
COVID-19 is defined by the question “Related to COVID-19?” on the Prior and 
Concomitant Medications CRF page.
Summary of number and percentage of randomized patients with missed visits due to 
COVID-19.


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12.
INTERIM ANALYSES AND DATA MONITORING
There is no data monitoring committee planned for this study.
The PK population analyses will be conducted at the end of Part A, Period 1 by the PK vendor. 
Details on the PK population analyses will be provided in a separate analysis plan.
See Section 13.5 of the protocol. An interim analysis to support regulatory activities related to an 
upcoming CTP-543 NDA submission will be conducted. The focus of the interim analyses will 
be on safety data and will occur following completion of Part A, Period 1, addressed in a 
separate Integrated Summary of Safety SAP.
Per protocol Section 8.1, the primary efficacy assessment for Part A will be conducted when all 
patients have completed Part A, Period 2.  An analysis of safety data from Part A will also be 
conducted. These analyses will be submitted as the abbreviated report. The analyses described in 
this document to be included in the abbreviated report for the primary efficacy assessment for 
Part A and safety summary are indicated in the list of planned tables, listings, and figures in 
Appendix 15.4.
Site personnel and patients will remain blinded throughout the entirety of Part A and Part B.
Dissemination of these results will be limited to the unblinded reporting team of the CRO and 
Sponsor management. The Sponsor and CRO personnel who are unblinded will be separate from 
the direct study team. The S
uct, study management, safety and data monitoring 
through the completion of the study. There will be no impact on CP543.2004 study conduct, 
analysis, or reporting. 


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13.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL
The following alterations were made to the original analyses planned in the protocol:
An additional summary of percentage of patients 
20
at Week 4 was added for Part A Period 1.
An additional summary of the presence or absence of nasal hair from physical 
examinations was added for each Part/Period of the study
Details added to protocol definition for analysis populations in Section 13.3. The text 
“Patients will be summarized according to study drug dose received (i.e., as treated) 
should it differ from the randomized arm” was amended to add additional information in
the event that a patient is given only a portion of the incorrect treatment. 
Analyses for COVID-19 were added in Section 11 of the SAP.


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14.
REFERENCES
Not applicable.