Conditions: Diabetic Macular Edema Retinal Disease Macular Edema Diabetes Mellitus Diabetic Retinopathy Retinal Degeneration Retinal Diseases Eye Diseases Edema
Keywords: DME
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 52
Healthy volunteers: no

Brief summary:
The goal of this clinical trial is to assess the efficacy and safety of multiple doses of foselutoclax (UBX1325) in patients with Diabetic Macular Edema. The main questions the study aims to answer are:

* Assess the efficacy of foselutoclax compared to aflibercept
* Assess the safety and tolerability of foselutoclax

Detailed description:
This study is intended to assess the efficacy and safety of foselutoclax, a phosphate pro-drug, and its active parent molecule (UBX0601, a BCL-xL inhibitor) following repeat intravitreal (IVT) injections of foselutoclax in patients with Diabetic Macular Edema (DME).

Approximately 50 patients will be enrolled and randomized 1:1 into either the foselutoclax arm,10 μg given 8 weeks apart, or the control arm of aflibercept, 2 mg every 8 weeks in order to assess the primary objective. All patients will be followed for approximately 36 weeks.

The injector will be unmasked but the evaluator will remain masked throughout the study.

This study will enroll participants ≥18 years of age with active DME disease despite treatment, with best corrected visual acuity (BCVA) between 70 to 30 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (equivalent to 20/40 to 20/250 on the Snellen chart). Once patients meet inclusion/exclusion criteria, patients will receive 3 run-in injections of aflibercept approximately 4 weeks apart, with the last aflibercept injection 4-6 weeks prior to Day 1.

Arms:
arm 1: Prior to randomization, participants will receive 3 IVT injections of aflibercept over 4-week intervals. Upon randomization, participants will receive 2 mg aflibercept (50 μl of 40 μg/μl solution) IVT on Day 1, Weeks 8, and 16. A sham procedure will also be administered on Day 1. arm 2: Prior to randomization, participants will receive 3 IVT injections of aflibercept over 4-week intervals. Upon randomization, participants will receive 10 μg foselutoclax (50 μl of 0.2 μg/μl solution) IVT on Day 1 and Weeks 8 and 16. 2 mg aflibercept (50 μl of 40 μg/μl solution) will also be administered on Day 1.

Interventions: intervention 1: Aflibercept intervention 2: foselutoclax
Intervention descriptions: intervention 1: Anti-VEGF control intervention 2: Experimental drug

Protocol document:
Prot_000.pdf: 










 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
  
 
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 












 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 






 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
    
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 








 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
   
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
  
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
    
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
    
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 








 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
    
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
PROTOCOL NUMBER: UBX1325-04
A Phase 2b, Prospective, Multicenter, Randomized, Double-Masked, Active-Controlled Study 
to Assess the Efficacy and Safety of Repeat Intravitreal Injections of Foselutoclax (UBX1325)
in Patients with Diabetic Macular Edema (Aspire)
PHASE 2B
Version 1.0
Date: 04 February 2025
Prepared by:
Cencora PharmaLex
1 West 1st Avenue
Conshohocken, PA 19428
 
 
 
 
 
 




Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 3 of 26     
 
Revision History 
 
Version 
Date 
Summary of Revision 
1.0
February 4, 2025 
Creation of document 
 
 
 
 
 
 
 
 


Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 4 of 26     
 
 
Table of Contents 
List of Abbreviations 
6 
2. 
Introduction 
7 
1.1. 
Design overview
7 
1.2. 
Study objectives 
7 
1.3 
Study endpoints 
7 
3. 
Study Methods 
9 
3.1 
Trial design 
9 
3.2 
Study population 
10 
3.3 
Randomization and masking 
10 
3.4 
Determination of sample size 
10 
4. 
General Methods 
11 
4.1 
General considerations 
11 
4.2 
Study Day and Baseline 
11 
4.3 
Definition of visit window 
12 
4.4 
Timing of analyses 
12 
4.5 
Early termination 
12 
4.6 
Interim analysis 
12 
4.7 
Multiple testing and error control 
12 
5. 
Analysis Sets 
13 
6. 
Subject Disposition
14 
7. 
Demographics and Baseline Characteristics
14 
7.1 
Demographics and baseline characteristics 
14 
7.2 
Medical history 
14 
7.3 
Prior and concomitant medications and procedures 
14 
8. 
Safety Analysis 
15 
8.1 
Adverse events 
15 
Adverse events after randomization 
15 
8.2 
Intraocular Pressure 
16 
8.3 
Laboratory data 
16 
 
 
 
 


Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 5 of 26     
 
8.4 
Vital signs 
17 
8.5
Physical examinations
17
9. 
Efficacy Analysis 
17 
9.1 
Primary endpoint 
17 
9.2 
Secondary endpoints 
18 
9.3 
Exploratory endpoints and analyses 
19 
10. Quality Assurance 
21 
10.1 Software and programming specifications 
21 
10.2
File management and data security
22
11. Changes in the Statistical Analysis Plan from the Protocol Analysis Plan 
22 
12. Appendices 
23 
12.1 Appendix A  Schedule of Events (Protocol Table 1) 
23 
12.2 Appendix B  Analysis Visit Windowing Rules for Unscheduled and Early Termination 
Visits 26 
 
 
 
 
 


Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 6 of 26     
 
List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event
ANCOVA 
Analysis of covariance 
AUC 
Area under the curve 
ATC4
Anatomical Therapeutic Chemical level 4
BCVA 
Best corrected visual acuity 
CFBL
Change from baseline
CI 
Confidence interval 
CST 
Central subfield thickness 
DME
Diabetic macular edema
DRSS 
Diabetic retinopathy severity scale 
EDC 
Electronic data capture 
ET 
Early termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FE 
Fellow eye
GLP-1 
Glucagon-like peptide-1 
HbA1c
Hemoglobin A1C
IOP 
Intraocular pressure 
IQR 
Inter quartile range 
IVT
Intravitreal
LoA 
List of Analyses  
LS
Least squares
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 
NCI CTCAE v5.0 
National Cancer Institute Common Terminology Criteria for Adverse 
Events version 5.0 
OCT 
Optical coherence tomography 
PT 
Preferred term
SAE
Serious adverse event
SAP 
Statistical analysis plan 
SD-OCT 
Spectral domain optical coherence tomography 
SOC
System organ class
SE 
Study eye 
TEAE
Treatment-emergent adverse event
US 
United States 
VA 
Visual acuity
VEGF
Vascular endothelial growth factor
WHO
World Health Organization 
 
 
 
 
 
 


Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 7 of 26     
 
2. Introduction 
The statistical analysis plan (SAP) provides the detailed methodology for summary and statistical 
analyses of data collected in study UBX1325-04. This SAP is based on the Protocol Version 3.0 
Amendment 2 dated 26 March 2024. Specifications for tables, figures, and listings will be 
provided in a separate document known as the List of Analyses (LoA). 
 
1.1. Design overview 
This study is a phase 2b, prospective, multicenter, randomized, double-masked, active-controlled 
study to assess the efficacy and safety of repeat intravitreal injections of foselutoclax (UBX1325) 
in patients with diabetic macular edema (Aspire). Approximately 50 patients will be enrolled and 
randomized 1:1 into either the foselutoclax (UBX1325) arm, 10 µg given 8 weeks apart or an anti-
vascular endothelial growth factor (VEGF) control arm of aflibercept, 2 mg every 8 weeks to 
assess the primary objective. This is a multi-site trial with 21 sites in the US. All patients will be 
followed for approximately 36 weeks following a 3-month run-in period. The total duration of 
the trial from screening to last patient visit will be approximately 19 months. The injector was 
unmasked but the evaluator was masked throughout the study.  
 
1.2. Study objectives 
1.2.1 Primary objective 
 Assess the efficacy of foselutoclax (UBX1325) compared to aflibercept. 
 
1.2.2 Secondary objectives 
 Assess other measures of efficacy of foselutoclax (UBX1325) compared to aflibercept. 
 Assess the safety and tolerability of foselutoclax (UBX1325). 
 
1.2.3 Exploratory objective 
 Assess efficacy parameters and retinal structure improvement after treatment of 
foselutoclax (UBX1325) compared to anti-VEGF alone. 
 
1.3 Study endpoints 
1.3.1 Primary endpoint
 The primary objective of non-inferiority will be evaluated by comparing the difference 
between treatments in Best corrected visual acuity (BCVA) mean change from 
baseline to average of Week 20 and Week 24 
 
1.3.2 Secondary endpoints
1. Changes in BCVA from baseline to each visit through Week 36 
2. Change in BCVA from Week 24 to Week 36 
 
 
 
 
 
 
 
 
 


Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 8 of 26     
 
3. Change in central subfield thickness (CST) from baseline to each visit through Week 
36 as assessed by spectral domain optical coherence tomography (SD-OCT) and read 
by a Central Reading Center 
4. Changes in BCVA area under the curve (AUC) from baseline to Week 36 and from 
Week 8 to Week 36, as well as the average of the last 2 visits 
5. Changes in BCVA from baseline to last observation at or prior to Week 36 
6. 
Early Treatment Diabetic 
Retinopathy Study (ETDRS) letters in BCVA from baseline in the study eye (SE) to Week 
24 and week 36 
7. Proportion of participants who do not require rescue to week 24 and week 36 
8. Measures from SD-OCT, anterior segment evaluation, posterior segment evaluation, 
and color fundus photography 
9. Percentage of participants with at least 1 treatment-emergent adverse event (TEAE) 
10. Percentage of participants with at least 1 treatment-emergent ocular adverse event 
in the SE or the fellow eye (FE) 
11. Percentage of participants with at least 1 treatment-emergent non-ocular adverse 
event (AE) 
12. Percentage of participants with at least 1 treatment-emergent serious adverse event 
 
1.3.3 Exploratory endpoints 
1. Change in Diabetic Retinopathy Severity Scale (DRSS) score from Baseline to Week 36 
2. Change from baseline (CFBL) in BCVA and change from baseline in CST by subgroups: 
a. Baseline BCVA ( 60 letters and >60 letters)  
b. BCVA at first run-in injection pre-dose ( 60 letters and >60 letters) 
c. Baseline CST (
 
 
d. CST at first run-in injection (
 
e. 
 
f. Baseline HbA1c ( 7% and >7%) 
g. Baseline duration of diabetes (by aggregate median) 
3. Proportion of subjects with no macular fluid at Week 24 and 36 
4. Responder analysis based on change in BCVA and CST 
a. Response is defined as change from baseline in BCVA at Week 
 ETDRS letters 
b. Response is defined as change from baseline in CST at Week 24 -
 
5. Duration of rescue-free interval 
6. Time to first rescue 
7. Reason for rescue  
8. Change in BCVA and CST from run-in period to randomization 
 
NOTE:  The endpoints related to Fluorescein Angiography (FA) may be analyzed if needed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 9 of 26     
 
3. Study Methods
3.1 Trial design 
The study is a Phase 2b, double masked, randomized, parallel group, multicenter study of 
foselutoclax (UBX1325) in patients with Diabetic macular edema (DME). The study will enroll 
approximately 50 patients, who will be randomized in a 1:1 ratio to receive foselutoclax 
(UBX1325) 10 µg given 8 weeks apart or an anti-VEGF control arm of aflibercept 2 mg every 8 
weeks to assess the primary objective. All patients will be followed for approximately 36 weeks. 
Prior to randomization, participants will receive 3 IVT injections of aflibercept approximately 4 
weeks apart. After this run-in period, participants will be randomly assigned to 1 of 2 treatment 
arms: 
 Foselutoclax (UBX1325) arm: Participants will receive 10 µg foselutoclax (UBX1325) 
(50 µl of 0.2 µg/µl solution) IVT on Day 1 and Weeks 8 and 16. 2 mg aflibercept (50 µl 
of 40 µg/µl solution) will also be administered on Day 1. 
 Anti-VEGF control arm: Participants will receive 2 mg aflibercept (50 µl of 40 µg/µl 
solution) IVT on Day 1 and Weeks 8 and 16. A sham procedure will also be 
administered on Day 1.  
 
The injector will be unmasked but the evaluator will remain masked throughout the study. A 
schematic representation of the study design is presented below (Figure 1 from the study 
protocol). Schedule of visits and assessments is presented in Appendix A. 
 
Figure 1  
Schematic of Phase 2b Study 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 10 of 26     
 
3.2 Study population 
This study will enroll patients who are at least 18 years old and have been diagnosed as having 
DME (as defined by the AAO PPP DME Guidelines 2019) with BCVA in the study eye of 70 to  
30 (inclusive) ETDRS letters (equivalent to 20/40 to 20/250 on the Snellen chart, respectively) at 
all Screening run-in visits and Day 1. 
 
3.3 Randomization and masking 
Randomization personnel of the Sponsor, or designee generated the randomization schedule 
prior to the start of the study. An interactive web response system will be used for patient 
randomization. All randomization information will be stored in a secured area, accessible only by 
authorized personnel. 
 
This study is double-masked. Patients, Investigators, VA technicians, photographers, 
some Clinical Research Coordinators, Central Reading Center personnel, and the Sponsor are 
masked. Sites have a qualified injector who is unmasked in order to perform the IVT injection(s) 
[foselutoclax (UBX1325) and/or aflibercept], and/or sham procedure, as well as certain post-
injection assessments on Visits 1 (Day 1), 3 (Week 8), and 5 (Week 16). 
Specifically, the unmasked injector will do the anterior segment exam, central retinal artery 
perfusion exam, Intraocular pressure (IOP) (IOP could be done by a qualified unmasked 
designee), and AE assessment. Other supporting activities, such as Study Drug preparation and 
Study Drug accountability, will be performed by designated unmasked personnel. The Screening 
visits through Visit 1 (Day 1) randomization will be conducted by unmasked or masked personnel 
as well.  However, after randomization is completed, unmasked personnel will not be involved in 
any other study procedures outside of visits when an IVT injection is required, including Visits 
where a rescue injection was necessitated. In addition to conducting the Screening visits through 
Visit 1 (Day 1) randomization, the unmasked personnel may likewise complete the corresponding 
data entry but will be restricted thereafter to view-only access in electronic data capture (EDC). 
The randomization code will not be revealed to anyone to maintain the integrity of the double-
masking. 
 
*This section is taken from study protocol version 3. Detailed information about randomization 
and masking can be found in protocol version 3 document.  
 
3.4 Determination of sample size   
With 20 patients per arm, 10% early study discontinuation, a non-inferiority margin of -4.5  
letters, a standard deviation in BCVA of 7, a correlation between repeated measures of 0.5, 
 
 
corresponding power is 78%. 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 


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Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
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A masked sample size re-estimation was conducted. The residual standard deviation from the 
primary mixed model for repeated measures (MMRM) analysis applied to the masked BCVA data 
was reviewed to assess the variability, and the sample size was increased to 25 per arm.  
 
For the masked sample size re-estimation, the following details applied.  Baseline was defined as 
the day 1 value of BCVA (i.e., the value on day of randomization). The primary analysis was 
MMRM based on the treatment policy estimand in which post-rescue data is included in the 
analysis, with a model in which BCVA change from baseline (in the study eye) is the dependent 
variable and the independent variables are baseline BCVA (in study eye), study week 
(categorical), and baseline BCVA-by-week interaction. Within-patient errors were modeled using 
a heterogeneous compound symmetric (type = CSH) structure.  All BCVA measurements (in study 
eye) available on day 1 and later were included in the analysis. 
 
4. General Methods 
4.1 General considerations 
All study parameters will be listed, and a selected list of parameters will be summarized 
descriptively by treatment arm and overall. The descriptive statistics will include number of 
patients, mean, standard deviation, median, minimum, and maximum for continuous parameters 
and frequency and percent for categorical parameters. 
 
The following reporting conventions will be implemented: 
 All statistical tests will be conducted as 2-sided tests unless otherwise specified. 
 Confidence intervals (CIs) will be presented as 2-sided 95% and 90% CIs unless otherwise 
specified.  For safety outcomes, a 95% CI will be used. 
 All mean and median values will be formatted to one more decimal place than the 
measured value. Standard deviation values will be formatted to two more decimal places 
than the measured value. 
 All percentages will be rounded to one decimal place. The number and percentage of 
responses will be presented in the form xx (xx.x), where the percentage is in the 
parentheses. The percentage will be omitted when the numerator is zero. In the case the 
numerator is equal to the denominator, the percentage should be presented as (100) 
instead of (100.0). 
 All analysis and summary tables will have the analysis population sample size (i.e., number 
of participants) wherever applicable. 
 
4.2 Study Day and Baseline 
Study Day 1 is defined as the day of injection after randomization.  Subsequent days are 
numbered consecutively (i.e., Day 2, Day 3) and are calculated as: visit date - dosing date + 1.  
 
 
 
 
 
 
 
 
 


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Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
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Before Day 1, study days are numbered sequentially with negative values (i.e., Day -1, Day -2) 
and are calculated as: visit date - dosing date.  There is no Day 0. 
 
Baseline value will be the last measurement taken on or before Day 1.  It will be taken from the 
pre-dose assessment on Day 1 unless otherwise noted. 
 
4.3 Definition of visit window 
Unless otherwise specified, data from the actual planned post-baseline visit will be used in the 
analysis (Appendix A). Post-baseline unscheduled visits and early termination visits will be mapped 
to a planned visit and will only be used in the analysis if the actual planned visit result is missing. The 
rules are described in appendix B. The assignment of the baseline visit is handled by a separate 
algorithm for this study, not by the visit windowing rules. See Section 4.2 above. 
 
4.4 Timing of analyses 
Analyses to evaluate safety, tolerability, efficacy, and exploratory outcomes will utilize data from 
screening through Week 36 of follow-up.  Separate data locks and analyses will occur for data 
collected through Week 24 and Week 36. 
 
4.5 Early termination 
Patients who drop out of the study prematurely will have study data collected at the Early 
Termination Visit (see Appendix A).  The numbers and proportions of participants who terminate 
study participation prematurely, by arm and overall, will be tabulated (see section 6).   
 
4.6 Interim analysis
A masked sample size re-estimation was performed as described above in the section on sample 
size determination.  This will have no impact on the type I error for later analyses.  
 
Separate data locks and analyses will be conducted for data collected through Week 24 and 36. 
The analysis of the primary endpoint at Week 24 data lock will be considered the primary analysis 
for assessing the effect of treatment, with all type I error spent at this analysis. 
At the Week 24 data lock, analyses from baseline through Week 24 will be conducted. 
At the Week 36 data lock, analyses will be conducted from baseline through Week 24, baseline 
through Week 36, and Week 24 through Week 36 (to assess maintenance of treatment effect). 
 
4.7 Multiple testing and error control 
No formal adjustment for multiple comparisons is planned.   
 
 
 
 


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5. Analysis Sets 
The following analysis sets are defined: Randomized Set, Full Analysis Set, Safety Analysis Set for 
the Run-in Period, Safety Analysis Set after Randomization, and Per Protocol Analysis Set. 
 
Randomized Set 
Randomized set includes all subjects who were randomized to study treatment arms for the 
study. 
 
Full Analysis Set 
The Full Analysis Set will include all randomized subjects who received study treatment,  
have a baseline BCVA assessment, and at least one post-baseline BCVA assessment. The  
Full Analysis Set will be the primary population for evaluating all efficacy variables. For analysis, 
subjects will be grouped by randomized treatment arm.  
 
Safety Analysis Set for the Run-in Period
The Safety Analysis Set for the Run-in Period is an analysis set that will be used only for evaluating 
safety variables during the run-in period. This analysis set will include patients who were 
screened and received at least one dose of aflibercept during the run-in period. For analysis, 
subjects will be grouped by actual treatment received or screen failure. The screen failures will 
be defined as the subjects who failed the screening after run-in 1 aflibercept. 
 
Safety Analysis Set after Randomization 
The Safety Analysis Set after Randomization will include all patients who received study 
treatment. The Safety Analysis Set will be the primary population for evaluating all safety 
variables and patient characteristics. For analysis, subjects will be grouped by actual treatment 
received. 
 
Per Protocol Analysis Set 
The Per Protocol Analysis Set will include all subjects from the Full Analysis Set that have no 
protocol deviations
.  A list of such deviation 
categories will be defined prior to the unmasking of the treatment assignment data and will be 
used to identify the Per Protocol Analysis Set; any subject with a deviation category on the list 
will be excluded from the Per Protocol Analysis Set. The Per Protocol Analysis Set will be the 
primary population for conducting the sensitivity analysis of efficacy due to protocol deviations. 
For analysis, subjects will be grouped by randomized treatment arm.  
 
 
 
 
 
 
 
 
 
 
 
 
 


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6. Subject Disposition 
The number of patients screened, screen failures (overall, at run-in 1, run-in 2, run-in 3 and Day 
1), randomized, completed the study, analysis population will be summarized for the study. The 
following data will be summarized for each treatment arm and overall, for all screened subjects: 
 Randomized 
 Completed study 
 Did not complete study  
Patients in each analysis population: (Full, randomized, per protocol, and Safety sets)
 
A protocol deviation listing will be provided that includes the start/end date of the deviation and 
the deviation description.  A listing of subject disposition data will also be provided. A listing for 
the reasons for the patients that did not qualify for this study will also be provided. 
7. Demographics and Baseline Characteristics 
Demographics and baseline characteristics, including medical history, prior and concomitant 
medications, will be summarized using the Safety Analysis Set after Randomization. These data 
will be listed and summarized for the study overall, as well as for each treatment arm. 
 
7.1 Demographics and baseline characteristics 
Demographic and baseline characteristics include age, sex, race, ethnicity, weight, height, and 
other parameters as appropriate, e.g., anti-VEGF medication used immediately prior to Screening 
Run-In #1. These variables will be listed and summarized using descriptive statistics, based on the 
Safety Analysis Set after Randomization. Any variables that are found to differ by treatment arm 
may be considered for inclusion in statistical models as covariates. 
 
7.2 Medical history 
Medical history will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by system organ class (SOC) and preferred term (PT) by 
treatment arm and total.  A patient will be counted only once for multiple events within each 
SOC/PT. Medical History, including a detailed ophthalmic history reported prior to dosing, will be 
listed by patient. 
 
7.3  Prior and concomitant medications and procedures 
Prior medications and procedures are the medications/procedures that the patient stopped prior 
to the first screening visit. Concomitant medications/procedures are medications/procedures 
that the patient continued after the first screening visit or started after the first screening visit 
through end of study. Prior and concomitant medications will be coded using the latest version 
of World Health Organization (WHO) Drug Dictionary and summarized by Anatomical Therapeutic 
Chemical level 4 (ATC4) and PT by study arm and total. Prior and concomitant procedures will be 
 
 
 
 
 
 
 
 


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Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
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coded using MedDRA terms (as for medical history). A patient will be counted only once for 
multiple events within each higher-level category (ATC4, SOC) and PT.  
 
Prior and concomitant medications and procedures will be summarized in table form.  Listings of 
prior and concomitant medications and procedures will also be provided.  
 
8. Safety Analysis 
8.1 Adverse events 
The adverse events are summarized separately for run-in period only and for period after 
randomization. 
Adverse events after randomization 
Ocular and systemic safety and tolerability of a repeat Intravitreal (IVT) injection of UBX1325 will 
be evaluated by treatment emergent adverse events (TEAEs). A TEAE is an adverse event that 
first occurs or worsens after study drug initiation or is a serious adverse event (SAE).  Summary 
tables will include only TEAEs, and listings will include all adverse events reported in the clinical 
database. The Safety Analysis Set after Randomization will be used as the analysis population for 
the below summaries. 
 
The following summaries of TEAE data will be tabulated by study arm and overall: 
 Percentage of participants with at least one TEAE 
 Percentage of participants with at least one treatment-emergent ocular AE in the SE or 
FE 
 Percentage of participants with at least one treatment-emergent non-ocular AE 
 Percentage of participants with at least one treatment-emergent serious adverse event 
 Percentage of participants with at least one TEAE related to the investigational product 
(study drug, active control, or sham)
 Percentage of participants with at least one TEAE related to a post-randomization 
injection procedure 
 
An overall summary table of TEAEs will include the above-mentioned categories as well as the 
number and percentage of patients experiencing at least one grade >=3 TEAE, serious TEAE, or 
TEAE leading to death.  Adverse events are graded according to NCI CTCAE v.4.03 in which a 
severe adverse event is classified as grade 3.  Relatedness to study drug will be graded as 
 related
 related
 related
not 
an investigation of the temporal sequence, the 
therapy administered to the patient. TEAEs will be summarized for Baseline through Week 24 
and Baseline through Week 36. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
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For summaries by SOC and PT, a patient will only be counted once for each PT and once for the 
overall count for a SOC. However, patients may be included in more than one PT category 
within a SOC. For summaries which also include severity, a patient who experiences the same 
event more than once will have the event with the worst severity counted in the summary. 
Summaries by SOC and PT will be presented by SOC alphabetically then by descending 
frequency of PT within SOC based on the overall column. 
 
A table summarizing the count and the percentage of the non-serious TEAE that occurred in 5% 
of subjects, grouped by SOC, PT, and severity will be presented. The results will be presented for 
both treatment arms and overall.
 
Adverse events during run-in period 
Ocular and systemic safety of run-in aflibercept injections will be evaluated by AE during run-in 
period. An AE during the run-in period is an adverse event that first occurs or worsens after the 
first run-in dose of aflibercept or is a serious adverse event (SAE).  The Safety Analysis Set for 
the Run-in Period will be used as the analysis population. 
 
Summary tables will include only AE during run-in period and prior to randomization. 
 Overall summary of AE during run-in period 
 Ocular AE by SOC, PT, and severity, by eye (SE & FE) and by study arm, screen failure, 
and overall 
 Non-ocular AE by SOC, PT, and severity, by study arm, screen failure, and overall
 
8.2 Intraocular Pressure 
Intraocular Pressure (IOP) will be measured using Goldmann applanation tonometry or 
equivalent tonometer in both eyes at all scheduled visits. Tonometry should be performed prior 
to pupillary dilation when possible. IOP will be summarized for each eye by visit and by dose using 
descriptive statistics. Change from baseline in IOP will be summarized by visit and treatment 
group. The Safety Analysis Set after randomization will be used as the analysis population. 
Intraocular pressure data will be listed for both eyes at each visit as study eye and non-study eye. 
 
8.3 Laboratory data 
Laboratory safety parameters are measures of hematology and serum chemistry.  These 
measures will be obtained at Screening, Week 36, and Unscheduled Visits/ET (if applicable). 
Actual values and CFBL will be summarized for each treatment arm, and 95% confidence 
intervals will be calculated for the mean CFBL for each treatment arm.  A shift table of the 
changes from baseline to Week 36 and ET will also be presented. A shift table is a table that 
shows the progression of values over time. The Safety Analysis Set after randomization will be 
used as the analysis population. 
 
 
 
 
 
 
 


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Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
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8.4 Vital signs 
Vital signs will be taken at all study visits. Actual values and CFBL for each vital sign parameter 
will be summarized for each treatment arm at each visit, and 95% confidence intervals will be 
calculated for the mean CFBL for each treatment arm and visit.  The Safety Analysis Set after 
randomization will be used as the analysis population. 
 
8.5 Physical examinations 
Complete physical examinations will be performed at Screening, Visit 10 (Week 36), or 
Unscheduled Visits/ET. The physical examination data will be listed. The Safety Analysis Set 
after randomization will be used as the analysis population. 
 
9. Efficacy Analysis 
9.1 Primary endpoint 
The primary assessment of efficacy will be based on a non-inferiority test comparing UBX1325 vs 
Aflibercept mean change from baseline to Week 24.  
 
The primary estimand consists of the following: 
 Treatment regimen: foselutoclax (UBX1325) 10 µg fixed dose given at Baseline, Week 8, 
and Week 16 vs. aflibercept 2 mg given at Baseline, Week 8, and Week 16 
 Population: Full Analysis Set 
 Endpoint: BCVA ETDRS letters 
 Summary measure: the difference between treatments in mean change from baseline to 
the average of Weeks 20 and 24.  If the lower bound of the two-sided 90% confidence 
-4.5, UBX1325 will 
be declared not inferior to aflibercept. If the lower bound of the 90% confidence interval 
is > 0, UBX1325 will be declared superior to aflibercept. 
 
Intercurrent events: a treatment policy strategy will be used to account for the 
intercurrent event of use of rescue medication, and a hypothetical strategy will be used 
to account for the intercurrent event of early study discontinuation. 
 
Change in BCVA from Baseline will be analyzed using restricted-maximum likelihood based mixed 
models for repeated measures (MMRM). BCVA will be assessed using the ETDRS chart starting at 
4 meters at Screening, on Visits 1-10 and Unscheduled Visits/ET. The model specifications will 
depend on the objective.   
 
For the primary analysis, the model will include the change from baseline to each study visit as 
the dependent variable, and the independent variables will include continuous baseline BCVA, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
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categorical study arm (treatment or active), categorical study visit, and arm-by-visit interaction, 
along with the BCVA baseline-by-visit interaction.  Within-patient errors will be modeled using 
an unstructured covariance structure. If this analysis fails to converge, more parsimonious error 
correlation structures will be tested in the following order: heterogeneous Toeplitz, 
heterogeneous compound symmetric, and compound symmetric. Analysis for this objective will 
include data from baseline through Week 24. Least squares (LS) mean estimates of the difference 
between treatment arms and the within-arm values of change from baseline BCVA will be 
presented for each visit and for the mean of Weeks 20 and 24 with 90% confidence intervals for 
each estimated difference.  All type I error (  = 0.10) will be spent at the analysis of the primary 
endpoint at the Week 24 database lock. 
 
A supportive analysis will be done in the same way as the primary analysis except that it will be 
limited to data collected prior to or on the date of first receipt of off-schedule aflibercept 
(hypothetical strategy). 
 
When BCVA outliers occur, a sensitivity analysis excluding the outliers will be performed. If 
deemed appropriate, other sensitivity analyses may also be considered to assess the impact of 
outliers. An outlier is defined using the 3(IQR) Criterion: an observation is classified as an outlier 
if it is below Q1  1.5(IQR) or above Q3 + 1.5(IQR). A far outlier is an observation that is below Q1 
 3(IQR) or above Q3 + 3(IQR).  
 
A per protocol sensitivity analysis will also be performed repeating the same primary analysis 
methods on the Per Protocol Analysis Set to determine the impact of protocol deviations on the 
results.  
 
9.2 Secondary endpoints 
For secondary endpoints (1)-(4) a similar MMRM modeling approach as described in the previous 
section will also be used for the analyses.  These analyses will include (1) & (2) analyses of change 
in BCVA from Baseline over time, (3) change in CST from Baseline over time as assessed by SD-
OCT and read by a Central Reading Center, and (4) BCVA AUC over time.  The model specifications 
will be updated as per the secondary endpoints (1)-(4).  
 
For (1), (3), and (4), separate analyses will be run from Baseline through Week 24 and Baseline 
through Week 36.  Also, for (4), an additional analysis will be run on change from Week 8 to Week 
36.  For (2), an analysis will be run on change from Week 24 to Week 36.  Analyses through Week 
24 will also present the results for the mean of Weeks 20 and 24.  Analyses through Week 36 will 
also present the results for the mean of Weeks 20 and 24 and the results for the mean of Weeks 
32 and 36. 
 
 
 
 
 
 


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Separate analyses of secondary endpoints (1) - (4) will be performed using two different 
strategies to address intercurrent events.  For each of these endpoints, a hypothetical strategy 
analysis will be performed, limited to data collected prior to or on the date of first receipt of off-
schedule aflibercept.  Also, a treatment policy analysis of each endpoint will be performed for all 
data collected, regardless of receipt of off-schedule aflibercept.  Within-patient errors will be 
modeled using an unstructured covariance structure. If an analysis fails to converge, more 
parsimonious error correlation structures will be tested in the following order: heterogeneous 
Toeplitz, heterogeneous compound symmetric, and compound symmetric. 
For secondary endpoint (2), a linear contrast will be defined to test the difference between 
treatment arms in mean change from baseline between Weeks 24 and 36.  
 
For secondary endpoint (5), the change in BCVA from baseline to last observation at or prior to 
Week 36, mean change from baseline to last observation (one value per patient) will be analyzed 
using an ANCOVA model in which change from baseline is the dependent variable, and the 
independent variables will include continuous baseline BCVA and categorical study arm 
(treatment or active).  Analyses will be done using both the treatment policy strategy & 
hypothetical strategy (as described above).  Analyses will also be conducted using Week 24 as 
the last observation. LS means with standard error bars will be presented as bar plots for both 
treatment groups. 
 
For secondary endpoint (6)
letters in BCVA from baseline in the study eye (SE) to Weeks 24 and 36 will be summarized with 
tables and bar plots. 
 
For secondary endpoint (7), a frequency table of the proportion of participants who received 0, 
1, or 2 or more rescues at each visit will be presented for both Weeks 24 and 36.  Pie charts will 
also be generated to visualize the summary results for week 36, by treatment arm. 
 
For secondary endpoint (8), listings of measures from SD-OCT, anterior segment evaluation, 
posterior segment evaluation, and color fundus photograph will be generated.
 
*Secondary endpoints (9)-(12) analyses are described in section 8.1. 
 
9.3 Exploratory endpoints and analyses 
This section describes the statistical analyses for the exploratory endpoints listed in section 1.3.3 
and some additional exploratory analysis considerations. 
 
For exploratory endpoint (1),  
DRSS Score
 
Change in Diabetic Retinopathy Severity Scale (DRSS) score from Baseline to Week 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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 A frequency table of the change from baseline to Week 36 (measured in number of steps 
on the DRSS scale) will display the count and percentage by treatment arm.  Bar charts 
will present the same results graphically.  The analysis will be done using both the 
treatment policy strategy & hypothetical strategy (as described above). 
 
For exploratory endpoint (2), The following subgroups will be analyzed for change from baseline 
BCVA and change from baseline in CST.  
 Baseline BCVA ( 60 letters and >60 letters)  
 BCVA at first run-in injection pre-dose ( 60 letters and >60 letters) 
 Baseline CST (
 
 CST at first run-in injection (
 
 
 Baseline HbA1c ( 7% and >7%) 
 Baseline duration of diabetes (by aggregate median) 
 
The subgroup category definitions may be adjusted if there is not enough representation of a 
specific subpopulation or treatment group.  The analysis method will be MMRM modeling where 
the dependent variable is change from baseline to each study visit.  The independent variables 
will consist of the independent variables from the primary analysis and the separate models will 
be run for each subgroup.  Within-patient errors will be modeled as for the primary endpoint 
analysis, with an ordered sequence of covariance structures to apply if the first structure applied 
does not result in model convergence. Models will be run using both treatment policy and 
hypothetical strategies to address intercurrent events. Models will be run for Baseline through 
Week 24 and Baseline through Week 36.  LS mean results will be presented for all study visits and 
for the mean of Weeks 20 and 24 and the mean of Weeks 32 and 36. Additionally, a forest plot 
will display the LS mean difference for all subgroups in one graph. 
 
Additional analysis of BCVA and CST with the subgroup as covariate may be performed if a 
clinically significant subgroup difference is observed in the subgroup analysis.
 
For exploratory endpoint (3), Absence of macular fluid is defined as CST  290µm at one or more 
post-baseline visits. The summary table of the proportion of the subjects with no macular fluid 
will be generated for both treatment arms, through week 24 and 36. The difference between the 
proportion of subjects with confidence interval will also be presented. The results will be 
visualized as bar plots. 
 
For exploratory endpoint (4),  
The responder analysis will be conducted separately based on the endpoints BCVA and CST. 
Response based on BCVA will be defined as BCVA change from baseline at Week 
change from baseline at Week 24 -50. The summary tables will display descriptive statistics, by 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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response/no response and by treatment group, for the baseline variables BCVA, CST, DRSS, 
number of prior anti-VEGF injections (prior to randomization), HbA1c, and GLP-1 drug status.  The 
analyses will be repeated for Week 36.  
 
For exploratory endpoint (5)-(7),  
Rescue Summaries 
The following summaries will be presented for anti-VEGF rescue. For the definition of criteria and 
procedure to trigger anti-VEGF rescue, please refer to study protocol version 3.  Rescue is defined 
as post-Day 1, off-cycle anti-VEGF treatments injected in the study eye. 
 Duration of rescue-free interval: Frequency tables of the rescue-free interval (in weeks) 
will be presented as counts and percentages, by treatment arm and through week 36. The 
duration presented will be from prior rescue treatment (or initial study treatment) of no 
rescues (through earlier of the last follow-up date or the specified visit). Pie charts will 
also be generated to visualize the summary results, by treatment arm, and at Week 36. 
 Time to first rescue: Kaplan-Meier plots by treatment arm will be presented to summarize 
the time to first rescue after randomization and the time to first rescue after week 16, at 
week 36 data lock. 
 Patient-specific anti-VEGF summaries: Swimmer plots will be generated to summarize the 
subject-specific anti-VEGF treatments received before and after randomization for the 
two arms. Bar plots will also be generated to summarize the anti-VEGF burden before and 
after randomization. 
 Reason for rescue: Summary table with the reason of anti-VEGF rescue will be presented 
as counts and percentage, by treatment arm, at week 24 and 36. 
 
For exploratory endpoint (8), The below analyses for the BCVA and CST by timepoints from run-
in period through randomization. 
 Descriptive summaries of BCVA and CST actual values and change from screening run-in 
injection 1 (pre-dose) will be summarized as a table from run-in period to randomization, 
grouped by study arm and overall. The Full Analysis Set will be used.  
 Supporting line plots to summarize the mean of actual values and mean change from 
screening run-in injection 1 (pre-dose) from run-in period to randomization will also be 
generated. 
 
10. Quality Assurance 
10.1 
Software and programming specifications 
All statistical programs written to generate TFLs and perform statistical analyses will use either 
SAS version 9.4 or higher, or R version 4.0 or higher.  Every statistical program will be developed 
and reviewed for correctness according to the four-stage process. Stage I of the process requires 
 
 
 
 
 
 
 
 
 
 


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Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
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the creation of specification document describing the intent and project guidelines. Stage II 
comprises of program development based on approved specifications and Stage III involves the 
review process. Independent replication and peer review procedures are the two types of review 
processes. The type of review procedure will be determined based on category of program. Stage 
IV describes generation of reviewed outputs and documentation of adherence to project 
requirements.  
 
10.2 
File management and data security 
Data and program files will be managed according to Cencora folder and file structure 
management.  Electronic file security and integrity will be protected by Cencora network system 
and structure.
11. Changes in the Statistical Analysis Plan from the Protocol Analysis Plan 
The study protocol noted that details of statistical analyses will be provided in the SAP. The only 
changes from the protocol to document in the statistical analysis plan are as follows. 
 The protocol was inconsistent with regards to the time points included in the primary 
estimand (mentioning in some places the mean change from baseline to Week 24 and in 
other places the mean change to the average of Weeks 20 and 24).  This SAP has the 
definitive description of the primary estimand (i.e., using the average of Weeks 20 and 
24). 
 Added secondary endpoints 
o Change in BCVA from Week 24 to Week 36 
o Measures from SD-OCT, anterior segment evaluation, posterior segment 
evaluation, and color fundus photograph 
 Added exploratory analyses 
o Subgroup analyses of BCVA & CST 
o Proportion of subjects with no macular fluid 
o Responder analysis
o
Duration of rescue-free interval
o Time to first rescue 
o Reason for rescue 
o Change in BCVA and CST from run-in period to randomization  
o Line plots to summarize the mean BCVA and mean CST from run-in period 
through randomization. 
 Added the safety analyses for the run-in period in section 8.1 
 
If there are any other discrepancies, the SAP takes precedence over the protocol. 
 
 
 
 
 
 
 
 


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Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
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12. Appendices 
12.1 
Appendix A  Schedule of Events (Protocol Table 1) 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
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Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 25 of 26     
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
  
 
 
 
 
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Unity Biotechnology                                                                                                              Statistical Analysis Plan 
Protocol:  UBX1325-04                                                                                                                               Version 1.0 
 
Confidential                                                                                                                                             Page 26 of 26     
 
12.2 
Appendix B 
 Analysis Visit Windowing Rules for Unscheduled and Early 
Termination Visits 
Unless otherwise specified, data from the planned post-baseline visit (Appendix A) will be used in 
the analysis. Post-baseline unscheduled visits and early termination visits will be mapped to a 
planned visit and will only be used in the analysis if the actual planned visit result is missing, Table 
B.1 presents the analysis visit window mapping for unscheduled and early termination visits.  Note 
that the assignment of the baseline visit is handled by a separate algorithm for this study, not 
by the visit windowing rules (see Section 4.2) 
 
 
Table B.1: Analysis Windows for unscheduled and early term visits 
Planned 
Visit 
Day 
Lower 
Limit 
Upper 
Limit 
Visit
Visit 
Number 
  
-300 
-1 
Screening 
0 
1 
1 
1 
Visit 1 (Baseline) 
1 
29 
2 
43 
Visit 2 
2 
57 
44 
71 
Visit 3 
3 
85 
72 
99 
Visit 4 
4 
113 
100 
127 
Visit 5 
5 
141 
128 
155 
Visit 6 
6 
169 
156 
183 
Visit 7 
7 
197 
184 
211 
Visit 8 
8 
225 
212 
239 
Visit 9 
9 
253 
240 
267 
Visit 10 
10 
 
Rules 
1. If there is one visit in a window, assign that visit to be the analysis visit. 
2. If there is more than one visit in a window, then calculate the absolute difference (in days) 
from the planned visit day to each visit. 
 If a single visit has the smallest absolute difference, then assign that visit as the analysis 
visit.
 
If multiple visits are tied for the smallest absolute difference, take the latest visit as the 
analysis visit. Note: if the latest visit includes both a pre-dose measurement and a post-dose 
measurement, take the pre-dose measurement and associated details (e.g., timing of pre-dose 
measurement) as the results of the analysis visit.