Clinical trial NCT03281538
Conditions: Uremic Pruritus
Keywords: CR845 difelikefalin Pruritus Chronic Itch Itch Itching hemodialysis Uremic Pruritus Dialysis CKD CKD-associated pruritus CKD-aP ESRD (end stage renal disease) Chronic Kidney Disease Kidney failure, chronic Kidney dysfunction Generalized pruritus
Sponsor: Cara Therapeutics, Inc.
Start date: 2017-08-14; Completion date: 2020-02-11
Enrollment: 288 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label multicenter, long-term extension safety study to evaluate the safety of IV CR845 administered after each dialysis session over a Treatment Period of up to 52 weeks.

Detailed description:
This is an open-label multicenter, long-term extension safety study to evaluate the safety of IV CR845 administered after each dialysis session over a Treatment Period of up to 52 weeks. This study will consist of a Screening Visit, a 52 week Treatment Period, and a Follow-up Visit. Informed consent will be obtained prior to performing any study-specific procedures. All patients will have a Screening Visit, which can be performed anytime within 14 days prior to the first dose of study drug, to confirm eligibility.

Clinical laboratory tests, electrocardiograms (ECGs), vital signs, adverse events, and concomitant medications will be monitored throughout the study. Blood samples for inflammatory biomarkers will be collected from all patients prior to dialysis on Day 1 and periodically until the End of Treatment or Early Termination Visit. Blood samples will also be collected periodically for clinical laboratory tests.

Arms: arm 1: CR845 0.5mcg/kg IV medication administered three times/week after dialysis
Interventions: intervention 1: CR845
Intervention descriptions: intervention 1: IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Cara Therapeutics Inc. 
CR845-CLIN3101 
26 Apr2019 
Confidential 
Page 5 of58 
5.
Continues to experience chronic kidney disease-associated
pruritus since the previous study (ie, CR845-CLIN2005
[Part BJ or CR845-CLIN2101 [Part A]); de novo patients
experiencing chronic kidney disease-associated pruritus at the
time of Screening
6.
If female:
a.
Is not of childbearing potential (surgically sterile or
postmenopausal, as defined in Section 6.5.1.6); or
b.
Has a negative serum pregnancy test at screening and
agrees to use acceptable contraceptive measures ( as
defined in Section 6.5.1.6) from the time of informed
consent until the safety Follow-up Visit or 7 days after
the last dose of study drug, whichever is later.
7.
If male, agrees not to donate sperm after the first dose of study
drug until 7 days after the last dose, and agrees to use a
condom with spermicide or abstain from heterosexual
intercourse during the study until 7 days after study drug
administration. (Note: No restrictions are required for a
vasectomized male provided his vasectomy was performed
2:4 months prior to dosing);
8.
Has a dry body weight of 2:40.0 kg at screening (prescription
target dry body weight);
9.
Has adequacy of dialysis, defined as meeting 1 of the following
criteria during the 3 months prior to screening:
a.
2:2 single-pool Kt/V measurements 2: 1.2; or
b.
urea reduction ratio measurements 2:65%; or
c.
1 single-pool Kt/V measurement 2:1.2 and 1 urea
reduction ratio measurement 2:65%
10. For de novo patients only, has recorded up to 4 Worst Itching
Intensity NRS scores at dialysis visits over the week prior to
the first dose (including the score on Day 1 of dosing), and has
at least 1 of the NRS scores >4.
Amendment 1.2 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
  
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 


 
 
 
    
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 


 
 
 
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
   
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
  
 
 
 
    
  
 
 
  
 
 
  
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
  
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
   
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
    
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

SAP_001.pdf: 
Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3101 
 
09 March 2020 
Version:  CARA_CR845-CLIN3101_final_v1_1_SAP_20200309.docx 
Page 1 of 43 
 
 
STATISTICAL ANALYSIS PLAN 
 09 March 2020 Final v1.1 
 
 
 
 
 
AN OPEN-LABEL, MULTICENTER, EXTENSION STUDY TO EVALUATE 
THE LONG-TERM SAFETY OF INTRAVENOUS CR845 IN HEMODIALYSIS 
PATIENTS WITH CHRONIC KIDNEY DISEASE-ASSOCIATED PRURITUS 
 
 
 
 
PROTOCOL NUMBER CR845-CLIN3101 
 
 
 
 
 
 
 
SPONSORED BY 
 
Cara Therapeutics, Inc. 
4 Stamford Plaza 
Stamford, CT 06902 
Telephone:  (203) 406-3700 
 
 
PREPARED BY 
 
Rho, Inc. 
2635 E NC Hwy 54 
Durham, NC 27713 
Telephone:  (919) 408-8000 
Fax: (919) 408-0999 
 
 
 
This document is confidential and proprietary to Cara Therapeutics. 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 Cara Therapeutics, except that this document 
may be disclosed to appropriate Institutional Review Boards under the condition that they keep the 
information confidential. 
DOCUMENT VERSION CONTROL 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3101 
 
09 March 2020 
Version:  CARA_CR845-CLIN3101_final_v1_1_SAP_20200309.docx 
Page 2 of 43 
Version 
Number 
Date 
Comments/Changes 
1.0 
19 September 2019 
 
1.1 
09 March 2020 
 SMQ and K-M analyses removed 
 Correction to potassium normal range and 
hemoglobin units 
 
Minor edits and clarifications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3101 
 
09 March 2020 
Version:  CARA_CR845-CLIN3101_final_v1_1_SAP_20200309.docx 
Page 5 of 43 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 7 
1. 
PURPOSE OF THE ANALYSES .............................................................................. 8 
2. 
PROTOCOL SUMMARY .......................................................................................... 9 
2.1 
Study Objectives ........................................................................................... 9 
2.2 
Overall Study Design and Plan ..................................................................... 9 
2.3 
Study Population ......................................................................................... 10 
2.4 
Treatment Regimens................................................................................... 10 
2.5 
Treatment Group Assignments or Randomization ....................................... 10 
2.6 
Sample Size Determination ......................................................................... 11 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS.................................. 12 
4. 
ANALYSIS POPULATIONS ................................................................................... 14 
5. 
STUDY SUBJECTS ............................................................................................... 15 
5.1 
Disposition of Subjects ................................................................................ 15 
5.2 
Protocol Deviations ..................................................................................... 16 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......................... 17 
6.1 
Demographic Characteristics ...................................................................... 17 
6.2 
Baseline Characteristics .............................................................................. 17 
6.3 
Medical History ........................................................................................... 18 
6.4 
Prior and Concomitant Medications ............................................................. 18 
6.4.1 
Prior Medication ................................................................................. 19 
6.4.2 
Concomitant Medication .................................................................... 19 
6.4.3 
Anti-itch Medication ........................................................................... 19 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................ 20 
8. 
EFFICACY EVALUATION ..................................................................................... 22 
9. 
SAFETY EVALUATION ......................................................................................... 23 
9.1 
Overview of Safety Analysis Methods ......................................................... 23 
9.2 
Adverse Events ........................................................................................... 23 
9.3 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .... 27 
9.4 
Clinical Laboratory Evaluation ..................................................................... 27 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to Safety .. 28 
9.5.1 
Vital Signs .......................................................................................... 28 
9.5.2 
12-Lead ECGs ................................................................................... 29 
10. OTHER ANALYSES .............................................................................................. 31 
10.1 
Hospitalizations, Emergency Department Encounters / Observational 
Stays ........................................................................................................... 31 
10.2 
Missed Dialysis Visits and Incidence of Infection ......................................... 31 
10.3 
ESA and Iron .............................................................................................. 31 
10.4 
Inflammatory Biomarkers ............................................................................ 31 
11. INTERIM ANALYSES AND DATA MONITORING ................................................. 32 
12. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ........................ 33 
13. STATISTICAL APPENDIX ..................................................................................... 34 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3101 
 
09 March 2020 
Version:  CARA_CR845-CLIN3101_final_v1_1_SAP_20200309.docx 
Page 6 of 43 
14. REFERENCES ....................................................................................................... 35 
15. APPENDICES ........................................................................................................ 36 
15.1 
Schedule of Events ..................................................................................... 37 
15.2 
Custom MedDRA Query (CMQ) Categories and Preferred Terms .............. 40 
15.3 
Treatment-emergent Adverse Events of Special Interest and Preferred 
Terms ......................................................................................................... 43 
 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3101 
 
09 March 2020 
Version:  CARA_CR845-CLIN3101_final_v1_1_SAP_20200309.docx 
Page 7 of 43 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
CMQ 
Custom MedDRA Query 
CRF 
case report form 
CSR 
Clinical Study Report 
ECG 
electrocardiogram 
ESA 
erythropoiesis-stimulating agent 
ESRD 
end-stage renal disease 
H 
above laboratory reference range 
IV 
intravenous or intravenously 
L 
below laboratory reference range 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
within laboratory reference range 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
 
 
 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3101 
 
09 March 2020 
Version:  CARA_CR845-CLIN3101_final_v1_1_SAP_20200309.docx 
Page 8 of 43 
1. 
PURPOSE OF THE ANALYSES 
CR845-CLIN3101 is an open-label, multicenter, long-term safety study (both as an 
extension to prior protocols and with de novo subjects) to evaluate the safety of 
intravenous (IV) CR845 in hemodialysis subjects with Chronic Kidney Disease-
associated pruritus.  Treatment of IV CR845 at a dose of 0.5 mcg/kg is administered after 
each dialysis session over a Treatment Period of up to 52 weeks.  This study is sponsored 
by Cara Therapeutics, Inc. 
This statistical analysis plan (SAP) provides a detailed description of the strategy and 
statistical methodology to be used for analysis of data in the CR845-CLIN3101 protocol.  
The purpose of the SAP is to ensure the credibility of the study findings by 
pre-specifying the statistical approaches to the analysis of study data prior to database 
lock.  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 Clinical 
Study Report (CSR). 


Cara Therapeutics 
CONFIDENTIAL 
Statistical Analysis Plan 
Protocol No. CR845-CLIN3101 
 
09 March 2020 
Version:  CARA_CR845-CLIN3101_final_v1_1_SAP_20200309.docx 
Page 9 of 43 
2. 
PROTOCOL SUMMARY 
2.1 
Study Objectives 
The primary objective of the study is to evaluate the safety of IV CR845 at a dose of 
0.5 mcg/kg administered after each dialysis session over a Treatment Period of up to 
52 weeks in hemodialysis subjects who previously participated in the phase 2 studies 
CR845-CLIN2005 (Part B) or CR845-CLIN2101 (Part A) and in hemodialysis subjects 
who had not been previously exposed to CR845 and did not previously participate in the 
phase 2 studies CR845-CLIN2005 (Part B) or CR845-CLIN2101 (Part A) (de novo 
subjects). 
2.2 
Overall Study Design and Plan 
This is a multicenter, open-label, phase 3 study to evaluate the long-term safety of IV 
CR845, administered after each dialysis session for up to 52 weeks in subjects who 
participated in CR845-CLIN2005 (Part B) or CR845-CLIN2101 (Part A) and in de novo 
hemodialysis subjects who had not been previously exposed to CR845 and were not part 
of the phase 2 clinical studies CR845-CLIN2005 (Part B) or CR845-CLIN2101 (Part A).  
This study will consist of a Screening Visit, a 52-week study drug Dosing Period, an End 
of Treatment Visit, and a Follow-up Visit.  All subjects will have a Screening Visit, 
which can be performed anytime within 14 days prior to the first dose of study drug, to 
confirm eligibility. 
Day 1 of the Treatment Period will be defined as the day of administration of the first 
dose of study drug.  Each subject will receive CR845 at a dose of 0.5 mcg/kg after each 
dialysis session, 3 times per week for up to 52 weeks and approximately 156 doses of 
study drug.  All scheduled study visits during the Treatment Period will be conducted on 
dialysis days. 
Clinical laboratory tests, electrocardiograms (ECGs), vital signs, adverse events, and 
concomitant medications will be monitored throughout the study.  Blood samples for 
inflammatory biomarkers will be collected from all subjects prior to dialysis on Day 1 
and periodically until the End of Treatment or Early Termination Visit, per the schedule 
of events (Appendix 15.1).  Blood samples will also be collected periodically for clinical 
laboratory tests. 
The number of and reason(s) for missed dialysis will be recorded throughout the study.  
Incidence of infection, hospitalizations, emergency department encounters or observation 
stays, and/or use of antibiotics will also be recorded, with reason for infection if 
available.  Iron and erythropoiesis-stimulating agent (ESA) use will be recorded 
throughout the study. 
The last dose of study drug will be administered at the last dialysis visit on Week 52, or 
at early termination.  The End of Treatment Visit will be conducted at the dialysis visit 
following the last dose. 


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A final safety Follow-up Visit will be conducted 7 to 10 days after the End of Treatment 
or Early Termination Visit.  
The study schematic is shown below: 
 
 
2.3 
Study Population 
The study population includes males and females 18 years of age or older who either 
participated in CR845-CLIN2005 (Part B) or CR845-CLIN2101 (Part A) or are de novo 
subjects.  All subjects must currently be on hemodialysis for end-stage renal disease 
(ESRD).  Subjects who previously participated in CR845-CLIN2005 (Part B) or 
CR845-CLIN2101 (Part A) must have been categorized as experiencing moderate to 
severe uremic pruritus in those studies and must have continued to experience chronic 
kidney disease-associated pruritus since the study.  De novo subjects must be 
experiencing chronic kidney disease-associated pruritus at the time of screening.  A full 
list of inclusion and exclusion criteria may be found in Section 6.2 of the protocol. 
Subjects providing informed consent will be screened for inclusion in the study before 
enrollment and dosing; all eligibility criteria must be met before a subject is enrolled.  No 
waivers of entry criteria will be approved for this study.  Rescreening will be considered 
on an individual subject basis and must first be approved by the Sponsor or Medical 
Monitor.  
2.4 
Treatment Regimens 
All subjects will receive 0.5 mcg/kg CR845 as a single IV bolus 3 times a week 
immediately after each dialysis session for up to 52 weeks.  
2.5 
Treatment Group Assignments or Randomization 
As this is an open-label, single-treatment study, all subjects will be assigned to a dose of 
0.5 mcg/kg, and no randomization will occur.  As described below in section 3, results 
will be displayed by the treatment received previously (or de novo), thus “treatment 
group” will be used throughout this document to refer to those groupings. 


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2.6 
Sample Size Determination 
Up to 300 male and female hemodialysis subjects who previously participated in either 
CR845-CLIN2005 (Part B) or CR845-CLIN2101 (Part A) or are de novo subjects will be 
enrolled in this study at up to 35 clinical sites.  No sample size calculation was performed 
to select this sample size. 


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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
This section discusses general policies to be employed in the analysis and reporting of the 
data from the study.  Departures from these general policies may be given in the specific 
detailed sections of this SAP.  When this situation occurs, the rules set forth in the 
specific section take precedence over the general policies. 
Unless otherwise specified, all displays will summarize results by the following groups:  
 All Doses CR845 Treated from Previous Studies 
 Placebo Treated from Previous Studies 
 De Novo 
 All Subjects 
Note that the previous studies included multiple dose levels for CR845; these subjects 
will not be displayed separately in the analyses for this protocol; all dose levels will be 
pooled for the active subjects from the previous studies.  Additionally, only data collected 
under this protocol will be displayed in these analyses. 
For categorical variables, summary statistics will consist of the number and percentage of 
subjects in each category.  All percentages will be rounded to 1 decimal point.  The 
number and percentage of subjects will always be presented in the form XX (XX.X%) 
where the percentage is in parentheses.  To ensure completeness, all summaries for 
categorical and discrete variables will include all categories, even if none of the subjects 
had a response in a particular category.  Unless otherwise noted, for all percentages, the 
number of subjects in the analysis population for the treatment group will be the 
denominator. 
For continuous variables, summary statistics will consist of the number of subjects with 
data, mean, median, standard deviation, minimum value, and maximum value.  The 
summary statistic n will be the number of subjects with non-missing values.  All means 
and medians will be reported to 1 more significant digit than the values being analyzed. 
Standard errors will be reported to 2 more significant digits than the values being 
analyzed.  The minimum and maximum will be reported to the same number of 
significant digits as the values being analyzed. 
No tests of hypothesis of treatment group differences are planned; however, should they 
be performed as part of exploratory and ad hoc analyses, the associated p value will be 
reported. All p values will be rounded to 3 decimal places; p values that round to 0.000 
will be presented as “<.001”.  No leading zero will be shown for p values.  P values will 
be considered descriptive in nature; there will be no adjustments for multiple 
comparisons.  
In general, the baseline value will be considered the last non-missing measurement 
observed prior to the first dose of study drug in the current protocol. 
Data from all sites will be pooled for the purpose of analysis. 


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Data will be listed by treatment in the preceding study (see above) or de novo status, and 
by subject.  In general, listings will be sorted in the order that columns are displayed, 
starting with the first column on the left (treatment).  Subject listings of data will be 
presented for the safety population unless specified otherwise (e.g. screen failure listing, 
disposition listing). 
SAS statistical software, version 9.4 or higher, will be used for all analyses. 
Subject identifiers presented in the listings are the identifiers assigned in the current 
study, CR845-CLIN3101. 


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4. 
ANALYSIS POPULATIONS 
The Safety Population will be used for all analyses; this will include all enrolled patients 
who received at least 1 dose of study drug. 
 


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5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
The number of subjects enrolled, screen failed, treated, completed, or discontinued from 
the study treatment, along with the reason for treatment discontinuation, will be presented 
for subjects from the previous studies (by treatment), de novo subjects, and overall. 
Subjects completing follow-up will also be presented.  The number of subjects included 
the Safety Population will also be tabulated. 
The following provides the definitions of the aforementioned groups: 
 Enrolled subjects are all subjects who sign informed consent.  
 Subjects who failed screening are all subjects who failed screening due to 
inclusion/exclusion criteria and are marked as such on the disposition CRF. 
Subjects that fail screening, are rescreened and are enrolled will be counted both 
here and with the applicable outcome of their successful enrollment.  Those that 
screen fail twice will only be counted once here. 
 Treated subjects are all subjects who received at least 1 dose of study drug. 
 Treatment completers are treated subjects with “Yes” noted for the question “Did 
the subject complete the Treatment Period? (from baseline to week 52)” on the 
Study Completion Status case report form (CRF) page.  
 Subjects who discontinued the treatment are subjects with “No” noted for the 
question “Did the subject complete the Treatment Period? (from baseline to 
week 52)” on the Study Completion Status CRF page.  Reasons for treatment 
discontinuation are also collected on this CRF. 
 Follow-up completers are treated subjects with “Yes” noted for the question “Did 
the subject complete the whole study? (Screening through Follow-up)” on the 
Study Completion Status CRF page.  
 Safety Population includes any treated subject. 
For all categories of subjects (except the enrolled subjects, screen failure subjects, and 
treated subjects), percentages will be calculated using the number of subjects in the 
Safety Population as the denominator. 
Additionally, time to study drug discontinuation for any reason, time to study drug 
discontinuation due to adverse event, and time to death for any reason will be displayed 
separately with Kaplan-Meier plots.  In the case that subjects are discontinued from 
treatment administratively to halt the study in preparation for a marketing application, 
these subjects will be treated as completer/censored for the purposes of these displays.  
For time to study drug discontinuation, subjects will be censored at the time they 
complete study treatment.  For time to study drug discontinuation due to adverse event, 
subjects will be censored at the time they complete study treatment or discontinue for 
another reason.   For time to death for any reason, subjects will be censored at the time 
they complete study treatment or discontinue for a reason other than death. 


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5.2 
Protocol Deviations 
Protocol deviations will be identified in several ways:  through programmatic checks, 
through medical reviews, and by clinical research associates during site monitoring. 
Deviations will be classified as minor or major prior to the database lock.  Protocol 
deviations/violations will be summarized.  All protocol deviations will be listed. 


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6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline characteristics were collected during the Screening Visit for 
CR845-CLIN3101 and will reflect what was reported at that time (age, for example, will 
be age at the CR845-CLIN3101 screening, not the age at the time of participation in the 
initial study). 
Descriptive statistics will be provided for all demographic and baseline characteristics 
based on the Safety Population.  For categorical variables, the number and percentage of 
subjects in each category will be presented.  For continuous variables, summaries will 
include the number of subjects with data, mean, median, standard deviation, minimum, 
and maximum. 
All demographic and other baseline characteristics will be provided in a listing. 
6.1 
Demographic Characteristics 
Demographic and baseline variables will be summarized by treatment group and include 
the following: 
 Age at screening (years) as recorded on the CRF 
 Age category at screening (<45, 45-<65, 65-<75, ≥75 years) 
 Gender 
 Ethnicity  
 Race  
 Target dry body weight (kg) 
 
6.2 
Baseline Characteristics 
Baseline characteristics of the disease will also be summarized by treatment group and 
include the following: 
 Prior anti-itch medication use 
 Duration of pruritus (years) 
 Years since diagnosis of ESRD 
 Years since diagnosis of chronic kidney disease 
 Years on chronic hemodialysis 
 Etiology of chronic kidney disease 
 Average Baseline Worst Itching Intensity NRS (de novo subjects only) 
 Maximum Baseline Worst Itching Intensity NRS (de novo subjects only) 
Duration of pruritus (years) will be calculated as: 
(Date of the Screening Visit – the start date of the pruritus+ 1)/365.25 
Similarly, years since ESRD will be calculated as: 


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(Date of the Screening Visit – first date of ESRD+ 1)/365.25  
Years since chronic kidney disease will be calculated as: 
      (Date of the Screening Visit – first date of CKD+ 1)/365.25. 
Years on chronic hemodialysis will be calculated as: 
(Date of the Screening Visit – date of first chronic hemodialysis + 1)/365.25 
For each of the above, if partial dates are recorded, the first day of the month will be 
imputed for missing day, and January for missing month. 
Baseline Worst Itching Intensity NRS is calculated as the average of all available scores 
for de novo subjects prior to dosing.  NRS scores are collected at Dialysis Visits 1, 2, 3, 
and 4.  Maximum baseline Worst Itching Intensity NRS will be the maximum value of all 
available scores per subject. 
6.3 
Medical History 
Medical history data consisted of a fixed list of conditions to be checked off and any 
additional self-reported medical conditions not contained on the list.  Both types of 
medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) version 20.0; however, the pre-specified medical history will use the fixed 
list of conditions as preferred terms and map to the most appropriate system organ class 
(SOC) based on MedDRA and medical review.  Medical history terms that were not pre-
specified will be coded for SOC and preferred term.  Both types of conditions (selected 
from the fixed list or self-reported) will be combined and summarized by MedDRA SOC, 
preferred term, and treatment group.  Both types of conditions will also be reported 
together for separate summaries of conditions related to dialysis, and conditions not 
related to dialysis.  The data will also be listed, including the verbatim investigator 
description of the relevant medical condition, the coded terms (SOC, preferred term), 
start date, end date, and whether or not the condition is ongoing. 
A separate coding listing will be created with all the distinct levels of SOC, preferred 
terms, and the verbatim investigator description reported in the study.  Sorting will be 
alphabetically by SOC, preferred term, and then verbatim description. 
 
6.4 
Prior and Concomitant Medications 
All medications, including any anti-itch medications, are recorded within 14 days prior to 
the start of treatment through the Follow-Up Visit.  These will be coded using the June 
2017 DDE B2 World Health Organization Drug Dictionary.  All prior and concomitant 
medications will be listed.  Additionally, a listing for unique medications and their 
corresponding coding will be presented. 


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6.4.1 
Prior Medication 
Prior medications (including vitamins and herbal supplements) are defined as 
medications collected on the Previous or Concomitant Medications CRF page that the 
subject has taken any time during the last month prior to the first dose of study drug on 
Day 1.  If the medication started prior to treatment start date, but was ongoing or ended 
after treatment start date, the medication will be counted as both prior and concomitant.  
Prior medications will be summarized in a table by treatment group using the Safety 
Population.  Medications will be reported by drug class (Anatomical Therapeutic 
Chemical Level 3) and ingredient; a subject will be counted only once for each 
class/ingredient. In the case of partial dates, if the available information is consistent with 
a date prior to the first dose, then the medication will be included on the summary of 
prior medications. 
6.4.2 
Concomitant Medication  
Concomitant medications are defined as medications collected on the Previous or 
Concomitant Medications CRF page that are taken (regardless of when they started) from 
after the start of the first dose of study drug on Day 1 through the end of the study (i.e., 
Follow-Up Visit).  Concomitant medications will be summarized by treatment group for 
the Safety Population.  Medications will be reported by drug class (Anatomical 
Therapeutic Chemical Level 3) and ingredient; a subject will be counted only once for 
each class/ingredient.  In the case of partial dates, if the available information is 
consistent with dates overlapping with the period study drug was taken, then the 
medication will be included on the summary of concomitant medications. 
6.4.3 
Anti-itch Medication 
Prescribed anti-itch medications are identified as medications where “Yes” is checked on 
the Previous or Concomitant Medications CRF page to the question “Was this 
medication used to treat pruritus?”   
The prior and concomitant medication summaries described in Sections 6.4.1 and 6.4.2 
will be repeated for the prescribed anti-itch medications, but will be reported by 
ingredient only and not by drug class.   


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7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
For this study, the duration of treatment for each individual subject is expected to be 
52 weeks, for a total of approximately 156 doses of study drug administered immediately 
following each dialysis session.   
The following variables will be summarized by treatment group:  
 Duration of treatment (weeks), from first dose to Week 52  
 Duration of continuous treatment (weeks), defined as the longest treatment period 
with no gap in treatment greater than 28 days spanning first dose to Week 52 
 Total duration of treatment (weeks), from first dose to Week 52; for this, gaps 
greater than 28 days will be removed from the exposure 
 Duration of study, from first dose to end of participation date (weeks) 
 Number of subjects with continuous treatment of at least 12 weeks, 24 weeks, 36 
weeks, 48 weeks  
 Number of subjects with total duration of treatment of 12 weeks, 24 weeks, 36 
weeks, 48 weeks 
 Average dose per administration (mcg/kg)  
 Total number of doses actually received (1-12, 13-24, 25-36, etc.) 
 Number of missed doses  
 Total number of dialysis visits logged (1-12, 13-24, 25-36, etc.) 
 Number of missed dialysis visits 
 Total treatment exposure in subject-years 
 Percentage of planned doses  
 Percentage of planned dialysis 
 Number of subjects with extra doses 
 Number of subjects with extra dialysis visits 
 
Duration of treatment (weeks) = ((Date of first dialysis after last dose) – (Date of first 
dose) + 1)/7. 
Duration of continuous treatment (weeks) = Duration of treatment, if subject has no gap 
between treatments that exceeds 28 days, divided by 7.  A gap length is defined as Dose 
date(later) – Dose date (earlier) – 1; thus, a subject dosed on Day 1 and Day 28 would 
have a gap of 26 days.  If a subject has 1 or more gaps, the longest of the gap-free periods 
will be the duration of continuous treatment.  This will be calculated as (date of first 
dialysis after last dose in selected period) – (Date of first dose in selected period) + 1. 
Total duration of treatment (weeks) = Duration of treatment, if subject has no gap 
between treatments that exceeds 28 days, divided by 7.  See continuous treatment above 
for the definition of a gap.  For subjects with gaps, the total duration of treatment will be 


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the sum of all the gap-free spans, with each period duration defined as:  (Date of first 
dialysis after last dose in selected period) – (Date of first dose in selected period) + 1.  In 
cases of single isolated doses, the duration will run to the next dialysis or 3 days, 
whichever is smaller. 
Duration of study (weeks) = ((End of participation date, including follow-up) – (Date of 
first dose) + 1)/7.   The end of participation date is derived as the latest of the last visit 
date, the last drug exposure, the latest disposition date or the death date.  If the subject 
has a death date, any later dates in the database are ignored. 
Subject-years = Duration of treatment (days) of all subjects divided by 365.25. 
 
Percent of Planned doses = 100* (1 – (number of missed doses / (number of actual doses 
+ number of missed doses – number of extra doses))). 
 
Percent of Planned dialysis = 100* (1 – (number of missed dialysis visits / (number of 
actual dialysis visits + number of missed dialysis visits – number of extra dialysis 
visits))). 
If a subject receives additional dialysis during a given week for any reason, an additional 
dose of CR845 will be administered following dialysis.  A maximum of 4 doses per week 
is allowed.  No additional doses will be given for subjects receiving an additional 
unscheduled ultrafiltration treatment.  The number of subjects getting such an extra 
treatment will be summarized. 
Missed and extra doses/dialysis will be determined as follows: 
1. Individual weeks for each subject are examined. 
2. Each subject should have 3 doses per week up to Week 52.  Anything more will 
be counted as extra doses; anything less will be counted as missed doses. 
3. Subjects who do not complete through Week 52 will be checked for how far they 
were into the week that they discontinued: 1,2 days means that they should have 
1 dose; 3,4 days = 2 doses; 5 or more days =3 doses.  This will be compared with 
actual doses for that week to determine missed/extra. 
4. The missed and extra doses are then summed across each subject’s weeks to get 
the total missed and extra doses/dialysis. 


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8. 
EFFICACY EVALUATION 
No efficacy analyses will be performed. 


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9. 
SAFETY EVALUATION 
9.1 
Overview of Safety Analysis Methods 
The following assessments will be used to evaluate the safety of CR845 in hemodialysis 
subjects with moderate-to-severe pruritus: 
 Adverse events  
 Clinical laboratory parameters  
 Vital signs 
 12-lead ECG 
All safety analysis will be performed using the Safety Population based on the treatment 
the subject actually received after randomization in the prior study (or de novo status). 
All safety endpoints will be summarized by prior study treatment group/de novo status 
(and visit as appropriate). 
9.2 
Adverse Events 
The period of adverse event reporting will start after the signing of the informed consent 
form through the Follow-up Visit, or Early Termination Visit if the Follow-up Visit was 
not conducted, or 7 days after the last dose if Early Termination Visit and Follow-up 
Visit were both missing.  All adverse events that occur during this reporting period will 
be collected for all subjects, including subjects who are deemed to be a screen failure. 
All tabular adverse event summaries will be for treatment-emergent adverse events 
(TEAEs).  Treatment-emergent adverse events are defined as those events that: 
 Start any time after the first dose of study drug up to the Follow-up Visit or Early 
Termination Visit (or 7 days after the last dose if no Early Termination Visit was 
conducted), whichever is later.  
Given that worsening of a pre-existing condition should be captured as an adverse event 
if the frequency, intensity, or character of the condition worsens after the use of study 
drug as judged by the investigator, for purposes of analysis, TEAEs are identified as any 
adverse event starting after the first dose of the study drug up to the Follow-up Visit or 
Early Termination Visit (or 7 days after the last dose if no early termination visit was 
conducted). 
For events with missing start dates, the following criteria will be used: 
 If the start date for a particular event is missing, then the event is considered 
treatment emergent. 
 If the start time is missing and the start date is the same as the first dosing date, 
then the event is considered treatment emergent. 
If it cannot be determined whether or not an event is treatment emergent due to a missing 
or partial date, then the event will be assumed to be treatment emergent. 


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All adverse events will be coded to SOC and preferred term using MedDRA version 20.0.  
MedDRA will be used to map adverse events verbatim to SOC and preferred term for 
standardization and summary purposes. 
The incidence of TEAEs will be summarized.  If a subject experienced more than 
one episode of an adverse event, the subject will be counted once for that preferred term.  
If a subject had more than one adverse event in a SOC, the subject will be counted only 
once in that SOC.  The summary tables will include incidence of overall SOC as well as 
for preferred terms within each SOC.  Incidence will be presented for SOC by decreasing 
frequency overall and then alphabetically and by PT within each SOC by decreasing 
frequency overall and then alphabetically. 
The investigator is to record the severity of each adverse event as mild, moderate, or 
severe.  If the same TEAE occurs for a subject on multiple occasions, the TEAE will be 
categorized according to the highest severity rating for that TEAE in that subject.  If the 
severity of the TEAE is not reported, then the severity of the TEAE will be counted as 
severe.  For each treatment group, the incidence within each category will be presented.   
The investigator is to record their opinion on the relationship of each adverse event to 
study drug (not related and related). If a subject experiences the same adverse event 
multiple times, the event with the strongest relationship to study drug will be counted. 
For each treatment group, the incidence within each category will be presented. For the 
summary of TEAEs by relationship to study drug, if the relationship is missing, it will be 
counted as related. 
Separate tables summarizing the incidence of TEAEs of special interest (AESIs), will be 
presented by treatment group.  Selected preferred terms shown in Appendix 15.3 are 
combined into the following categories:  
 Gait disturbance  
 Fall 
 Dizziness 
 Somnolence 
 Seizure 
 Syncope 
 Mental status changes 
 Mood changes 
 Unusual feeling, sensation 
 Tachycardia 
 Palpitation 
Incidence rate will be calculated for AESIs, serious TEAEs, and TEAEs leading to death. 
Incidence rate for serious TEAEs and TEAEs leading to death will be summarized by 
SOC and preferred term.  Incidence rate for AESIs will be summarized by preferred term 


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only.  Incidence rate will be calculated as (1000 * the number of events)/total person-
years, where total person-years is the sum across all subjects in the treatment group of the 
individual subject risk times, and individual subject risk time is the number of days from 
first dose to the last day of the period where an event would be deemed to be treatment 
emergent. 
The summary statistics will be presented for the time to first onset among subjects with a 
given AESI will be presented for each AESI.  Additionally, the durations will be 
summarized with descriptive statistics; if a subject has more than one AE within and 
AESI category, the longest duration will be summarized.  This will also be presented for 
a subset of common AEs. 
To explore the duration and temporal relationship of AESIs, a graphical representation of 
occurrences and durations of AEs within each AESI will be presented with subjects on 
the y-axis and time on the x-axis (Swimmer plot). Incidence of infections related to 
uremic pruritus based on adverse events, hospitalizations, and/or use of antibiotics for 
treatment of infection related to uremic pruritus will be also be reported with counts and 
percentages for each treatment group.  Incidence of all infections will be summarized by 
preferred term.  
The following summary tables will be presented for the Safety Population, by treatment 
group and overall: 
 An overall summary showing the number and percentage of subjects with TEAE, 
serious TEAE, related TEAE, severe TEAE, related serious TEAE, TEAE leading 
to dose interruption, TEAE leading to study drug discontinuation, TEAE leading 
to study discontinuation, and TEAE of special interest.  This table will also 
include number of events. 
 Incidence of TEAEs by SOC and preferred term 
 Incidence of serious TEAEs by SOC and preferred term 
 Incidence of related TEAEs by SOC and preferred term 
 Incidence of TEAEs by SOC, preferred term, and maximum severity 
 Incidence of TEAEs leading to study drug discontinuation by SOC and preferred 
term 
 Incidence of most common TEAEs (2% or more of subjects across all treatment 
groups) by preferred term 
 Incidence of TE AESIs by preferred term 
 Incidence of TE AESIs by preferred term reported by 12-week periods 
 Prevalence of TE AESIs by preferred term reported by 12-week periods 
 Incidence rate of TE AESI by preferred term 
 Incidence rate of serious TEAE by SOC and preferred term 
 Incidence rate of TEAEs leading to death by SOC and preferred term 
 Incidence of TEAES categorized based on Custom MedDRA query (CMQ)  


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 Incidence of infections by preferred term 
 Incidence of infections potentially related to uremic pruritis by preferred term 
Treatment-emergent adverse events of special interest will be reported both in the TEAE 
displays and separately by preferred term. The prevalence and incidence of AESIs (by 
special interest term) will be displayed graphically in 12-week intervals. 
Additionally, to calculate the incidence of AESIs by 12-week periods, events will be 
categorized as those with the start date falling from Day 1 (day of first treatment) to Day 
84; Day 85 to Day 168; Day 169 to Day 252; and Day 253 to Day 336.  Four displays 
will be generated: subjects with at least 12 weeks of risk; subjects with at least 24 weeks 
of risk; subjects with at least 36 weeks of risk; and subjects with at least 48 weeks of risk. 
Time at risk is defined as first dose through the Follow-up Visit  or 7 days after last dose , 
if the Follow-up Visit was not conducted.  For example, a subject with last dose on Day 
82 and the Follow-up Visit on Day 87 would have 87 days of risk; a subject with last 
dose on Day 82 and no Follow-up Visit would have 89 days of risk; in both cases, the 
subjects would be considered to have at least 12 weeks of risk.  Subjects that die will 
have their death day as the end of the time at risk.  Within each display, the events will be 
presented by the 12-week periods detailed above.  Denominators will be the number of 
subjects meeting the time at risk criteria for that display. 
Prevalence of AESIs by 12 week period will be calculated in similar manner to the 
incidence.  For the first period, AEs with the start date falling from Day 1 (day of first 
treatment) to Day 84 will be counted.  For subsequent periods, AEs that start or are 
ongoing at any time during that period will be counted.  Denominators will be defined as 
above based on whether the subject had risk time extending into the period.  If a subject 
has more than one event for a preferred term, they will only be counted once for a period. 
In addition, all AEs for each subject will be listed in chronological order including 
subject identifier, age, race, gender, and all related event status information (start and 
stop dates, whether the event was ongoing, study day of onset, severity, seriousness, 
relationship to study drug, action taken with study drug, and outcome).  Note: For the all 
adverse event listing only, any screen failure subject who has an adverse event after 
signing the informed consent form will be included for completeness.  Separate listings 
will be generated for serious adverse events (SAEs), deaths, adverse events leading to 
treatment discontinuation, and adverse events of special interest.  Additionally, a coding 
list of preferred terms and the verbatim text associated with them will be produced. 
The incidence of TEAEs in each CMQ category (see Section 15.2) will be summarized. If 
a subject experienced more than 1 episode of an adverse event, the subject is counted 
once for that preferred term; the total number of subjects reporting an event in the 
category will also be reported.  No statistical tests will be performed on adverse events. 


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9.3 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
An SAE is defined as any adverse event occurring at any dose and regardless of causality 
that results in death, is life threatening, requires in-patient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, is a 
congenital anomaly/birth defect, or is an important medical event.   
Serious adverse events will be collected from date the informed consent form is signed up 
to the Follow-up Visit or 7 days following the last dose of study drug, whichever is later. 
Serious adverse events that occur after the Follow-Up Visit and up to 30 days thereafter 
should also be documented on an SAE form if they are deemed by the investigator to be 
“related” to the study drug.  Serious adverse events that occur after the Follow-up Visit 
and up to 30 days thereafter do not need to be documented on an SAE form if they are 
deemed by the investigator to be “not related” to study drug.  A more detailed definition 
of SAEs is provided in Protocol Section 6.5.1.1.3.  The analysis of SAEs is similar to that 
of adverse events described in Section 9.2.   
Subject deaths are captured on the Adverse Events CRF page.  Subject death listings will 
include all death data available including date of death and cause of death.  Additionally, 
SAEs and adverse events resulting in discontinuation will be listed. 
9.4 
Clinical Laboratory Evaluation 
Blood samples will be collected during screening; on Day 1 before study drug 
administration; and at Weeks 4, 12, 24, 36, and 52 (End of Treatment/Early Termination). 
Summaries of actual values and the changes from baseline to each time point (when 
applicable) and the last post-baseline treatment visit will be presented for quantitative 
laboratory parameters (e.g., white blood cell count, lymphocyte count).  Only data from 
the central laboratory will be used.  The last post-baseline treatment visit will be latest 
value recorded for a given parameter, not including the Follow-up visit and unscheduled 
visits following the end of treatment/ early termination visit.  
Baseline is defined as the last measurement taken on or prior to the first day of dosing. 
Note that the Day 1 assessment can be included in the evaluation of baseline if the 
assessment is performed prior to dosing. 
All laboratory evaluation summaries will include the subjects in the Safety Population 
who have at least 1 post-baseline time point (for criteria based on post-baseline 
assessments) and with both a baseline and at least 1 post-baseline time point (for criteria 
evaluating changes from baseline).   
Laboratory values will be reported in Système International units.  If 2 or more 
evaluations occur in the same visit window, the evaluation closest to the target visit day 
will be selected for inclusion in the analysis.  If multiple evaluations are equally close to 
the target visit day, then the latest evaluation will be selected for inclusion in the analysis.   


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Laboratory test results will be classified according to whether the value was below (L), 
within (N), or above (H) the laboratory parameter reference range.  A summary of 
treatment-emergent shifts will compare the baseline L/N/H classification for each 
laboratory test to the highest and/or lowest L/N/H classification during the treatment 
period.  Clinically important laboratory values based on pre-specified criteria appropriate 
for the study population will also be summarized. 
Additionally, alanine aminotransferase, aspartate aminotransferase, bilirubin, and alkaline 
phosphatase will be presented in a separate table: with 3× and 5× upper limit of normal 
(ULN) flagged for alanine aminotransferase and aspartate aminotransferase; 2×ULN 
flagged for bilirubin, and 1.5×ULN flagged for alkaline phosphatase.  Additionally, 
subjects that have alanine aminotransferase or aspartate aminotransferase > 3x ULN and 
total bilirubin >2x ULN will be flagged as potential Hy’s Law cases and summarized.  
These liver function values will be presented in a separate listing with 3 and 5 upper 
limit of normal flagged for alanine aminotransferase and aspartate aminotransferase; 2 
upper limit of normal flagged for total bilirubin; and 1.5 upper limit of normal flagged 
for alkaline phosphatase. 
Additionally, clinically significant laboratory findings will be reported for hemoglobin, 
calcium, serum albumin, and phosphate. Ranges are given below. 
Test 
Low 
High 
Hemoglobin (g/dL) 
<7 
>15 
Calcium (mg/dL) 
<7 
>10.5 
Serum albumin (mg/dL) 
<3 
>5.5 
Phosphate (mg/dL) 
<2.5 
>8 
Potassium (mmol/L) 
<2.5 
>7 
 
All clinical laboratory values will be presented in a listing... 
9.5 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.5.1 
Vital Signs 
Vital signs (including body temperature, heart rate, systolic and diastolic blood pressure, 
and mean arterial pressure) will be collected during screening; on Day 1 before study 
drug administration; at Weeks 4, 12, 24, 36, 52 (End of Treatment/ Early Termination); 
and at the Follow-up Visit.  Additionally, dry body weight will be collected during 
screening; on Day 1 before study drug administration; at Week 4 and every four weeks 
thereafter; and End of Treatment/ Early Termination.  Baseline is defined as the last 
measurement taken on or prior to the first day of dosing.  Note that the Day 1 assessment 
can be included in the evaluation of baseline given that the assessment is performed prior 
to dosing.  


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Summary tables will include descriptive statistics (number of subjects, mean, standard 
deviation, median, minimum, and maximum) for baseline and each post-baseline 
assessment and the last post-baseline treatment visit.  Descriptive statistics will be 
calculated on both the actual score and the change from baseline score.  If 2 or more 
evaluations occur in the same visit window, the evaluation closest to the target visit day 
will be selected for inclusion in the analysis.  If multiple evaluations are equally close to 
the target visit day, then the latest evaluation will be selected for inclusion in the analysis.  
The last post-baseline treatment visit will be latest value recorded for a given parameter, 
not including the Follow-up visit and unscheduled visits following the end of treatment/ 
early termination visit.  
All vital sign summaries (including the analysis of clinically notable values below) will 
include the subjects in the Safety Population who have at least a post-baseline assessment 
(for criteria based on post-baseline assessments) and subjects who have both a baseline 
and at least 1 post-baseline assessment (for criteria evaluating changes from baseline). 
A second summary will focus on the individual subject measures with the intent of 
identifying post-baseline abnormalities defined as clinically notable.  Descriptive 
statistics will be used to summarize the number and percentage of subjects with 
post-baseline results outside the clinically notable ranges specified below. All vital sign 
values will be considered when evaluating the criteria. 
Vital Sign Parameter 
Value 
Systolic blood pressure 
≥180 mm Hg 
≤90 mm Hg 
Diastolic blood pressure 
≥100 mm Hg 
≤60 mm Hg 
Heart rate 
>130 beats per minute 
<55 beats per minute 
 
All vital signs will be listed in by subject, including visit and collection date/time, and 
will be sorted by treatment group, subject identifier, and date/time of assessment. 
9.5.2 
12-Lead ECGs 
Standard 12-lead ECGs will be performed in triplicate with the subject in a supine 
position during screening and at Weeks 12, 24, and 52 (End of Treatment/Early 
Termination). 
Electrocardiogram results include an overall interpretation of “normal,” “abnormal but 
not clinically significant,” or “abnormal and clinically significant.” These results will be 
tabulated by treatment group and overall at each time point and the last post-baseline 
treatment visit. The last post-baseline treatment visit will be latest value recorded, not 
including unscheduled visits following the end of treatment/ early termination visit. 
Values for ECG parameters will also be listed by subject.  


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If 2 or more evaluations occur in the same visit window, the evaluation closest to the 
target visit day will be selected for inclusion in the analysis. If multiple evaluations are 
equally close to the target visit day, then the latest evaluation will be selected for 
inclusion in the analysis. The worst post-baseline result across all visits will be flagged 
and reported separately; this may include measurements that were not in the individual 
visit summaries.  
Clinically significant ECG abnormalities at screening will be recorded as medical history. 
Clinically significant abnormalities or worsening of ECG findings observed after the first 
dose of study drug should be reported as adverse events. 
Electrocardiogram results will be listed for each visit including visit, whether ECG was 
performed (yes/no), explanation (if not performed), assessment date/time, study date, 
overall interpretation, and relevant medical history # or adverse event # if deemed a 
clinically significant abnormality. 


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10. 
OTHER ANALYSES 
10.1 
Hospitalizations, Emergency Department Encounters / 
Observational Stays 
The proportion of subjects who were hospitalized as in-patients and the count and 
percentage of those subjects admitted through the emergency department, undergoing 
dialysis, and receiving investigational product during hospitalization will be reported 
along with summary statistics for duration of stay.  This summary will be repeated for 
emergency department encounters/observational stays; additionally, subjects who have 
either hospitalizations or emergency department encounters will be summarized. 
10.2 
Missed Dialysis Visits and Incidence of Infection 
The analysis of missed dialysis visits is described in Section 7, Measurements of 
Treatment Compliance.  The analysis of incidence of infection is described in Section 
9.2, Adverse Events. 
10.3 
ESA and Iron 
All ESA and iron usage will be presented in listings.   
A thorough analysis of these outcomes will be performed and described in a separate 
document. 
10.4 
Inflammatory Biomarkers 
The observed value and the change in inflammatory biomarkers (e.g., interleukin-6, 
interleukin-8, and granulocyte macrophage-colony stimulating factor) from pre-dose to 
the end of the Treatment Period will be presented.  Univariate and multivariate analyses 
of the change in inflammatory biomarkers will be described in an analysis plan, separate 
from this document. 
 


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11. 
INTERIM ANALYSES AND DATA MONITORING 
No interim analysis is planned.  However, an ongoing review of the cumulative safety 
data for this study will be conducted by the Sponsor or designee 


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12. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Reasons for hospitalization and emergency department visits will not be summarized as 
described in Section 8.8.1 of the protocol, but will be presented in a listing. 
As described in Section 10.2 of this document, ESA and iron usage will be presented in a 
separate report, and their analyses are not included in this SAP. 
Baseline single pool Kt/V (spKt/V) will not be summarized with baseline characteristics 
of the disease as described in Section 8.6.3 of the protocol as Kt/V values were not 
collected.  Age will not be re-derived using the formula described in Section 8.6.3, but 
will be used as reported on the CRF. 


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13. 
STATISTICAL APPENDIX 
Not applicable. 


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14. 
REFERENCES 
Not applicable. 


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15. 
APPENDICES 
 


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15.1 
Schedule of Events 
  
 


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15.2 
Custom MedDRA Query (CMQ) Categories and Preferred Terms 
CMQs 
 
Gait Disturbance 
Ataxia 
Balance disorder 
Coordination abnormal 
Gait disturbance 
Gait inability 
Tandem gait test abnormal 
 
Dizziness 
Dizziness 
Dizziness Postural 
Vertigo 
 
Syncope 
Presyncope 
Syncope 
 
Fall & Potentially Drug Related Injury 
Accident 
Back injury 
Contusion 
Fall 
Fracture (all preferred terms containing “fracture”) 
Head injury 
Injury 
Limb injury 
Muscle contusion 
Muscle injury 
Road traffic accident 
Skeletal injury 
Haematoma 
Subdural hematoma 
Epidural haematoma 
Traumatic haematoma 
Periorbital haematoma 
Ecchymosis 
Subdural hematoma 
Subdural haemorrhage 
 
Mood Changes & Behavioral Changes 
Abnormal behavior 
Affect lability 


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Aggression 
Agitation 
Anger 
Anxiety 
Apathy 
Blunted affect 
Crying 
Depressed mood 
Disinhibition 
Dysphoria 
Emotional distress 
Emotional poverty 
Euphoric mood 
Flat affect 
 
Grandiosity 
Hostility 
Inappropriate affect 
 
Listless 
Mood altered 
Mood swings 
Morose 
Nervousness 
Patient uncooperative 
Restlessness 
Social avoidant behavior 
 
Seizures 
Autonomic seizure 
Clonic convulsion 
Drug withdrawal convulsions 
Epilepsy 
Epileptic aura 
Focal dyscognitive seizures 
Generalised tonic-clonic seizure 
Partial seizures 
Partial seizures with secondary generalisation 
 
Seizure 
Seizure cluster 
Simple partial seizures 
Status epilepticus 
Tonic convulsion 
 
Mental Status & Cognitive Changes 


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Acute psychosis 
Delirium 
Altered state of consciousness 
Hallucination (any preferred term containing “Hallucination”) 
Bradyphrenia 
Change in sustained attention 
Cognitive disorder 
Confusional state 
Delusion (any preferred term containing “Delusion”) 
Depressed level of consciousness 
Disorientation 
Encephalopathy 
Illusion 
Judgment impaired 
Lethargy 
Mental impairment 
Mental status changes 
Stupor 
Thinking abnormal 
 
Unusual Feeling, Sensation 
Asthenia 
Depersonalisation/derealisation disorder 
Derealisation 
Dissociation 
Feeling abnormal 
Feeling cold 
Feeling despair 
Feeling drunk 
Feeling guilty 
Feeling hot 
Feeling jittery 
Feeling of body temperature change 
Feeling of despair 
Feeling of relaxation 
Feelings of worthlessness 
Malaise 
Psychiatric symptom 
Sensation of foreign body 
Suffocation feeling 
 
Palpitations & Tachychardia 
Palpitations 
Heart rate irregular 
Heart rate increased 
Tachycardia 


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Atrial tachycardia 
Junctional ectopic tachycardia 
Supraventricular tachycardia 
Ventricular tachycardia 
Sinus tachycardia 
Tachycardia paroxysmal 
Tachyarrhythmia 
Ventricular tachyarrhythmia 
 
Somnolence 
Somnolence 
Sleep disorder 
Abnormal sleep related event 
Microsleep 
Sleep attacks 
Sedation 
 
 
15.3 
Treatment-emergent Adverse Events of Special Interest and 
Preferred Terms 
TEAE of Special Interest 
Terms 
Preferred Terms 
Gait disturbance 
Gait disturbance                      
Falls 
Fall 
Dizziness 
Dizziness 
Somnolence 
Somnolence 
Seizures 
Seizure 
Syncope 
Syncope 
Mental status changes 
Mental status changes 
Mood changes 
Mood altered 
Unusual feeling/sensation 
Feeling abnormal 
Tachycardia 
Sinus tachycardia, Tachycardia, Tachyarrhythmia 
Palpitation 
Palpitations