Conditions: Presbyopia Refractive Errors Eye Diseases
Keywords: Pharmaceutical Solutions Miotics Ophthalmic Solutions Near Vision Eye Drops INSIGHT 1
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 68
Healthy volunteers: yes

Brief summary:
To evaluate the safety and effectiveness of Aceclidine/Brimonidine (LNZ101) compared with Aceclidine (LNZ100) and vehicle in the treatment of Presbyopia.

Detailed description:

Arms:
arm 1: LNZ101: Aceclidine/Brimonidine combination ophthalmic solution arm 2: LNZ100: Aceclidine ophthalmic solution arm 3: Proprietary Vehicle ophthalmic solution

Interventions: intervention 1: Aceclidine+Brimonidine combination ophthalmic solution intervention 2: Aceclidine ophthalmic solution intervention 3: Vehicle Proprietary Ophthalmic Solution
Intervention descriptions: intervention 1: LNZ101-combination ophthalmic solution intervention 2: LNZ100- aceclidine ophthalmic solution intervention 3: Proprietary Vehicle Ophthalmic Solution

Protocol document:
Prot_000.pdf: 








 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
  
 
 


 
 
 
 
 
 
 
  
 
 










 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 








 
 
 
 
 
 
 
 
 
 
 
















 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 










 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 










 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
    
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 

SAP_001.pdf: 




Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 3 of 35
Table of Contents
1.
Introduction...............................................................................................................................6
2.
Study Objectives ......................................................................................................................6
2.1
Study Variables ........................................................................................................................6
2 2
Primary Variables
6
2.5
Safety Variables .......................................................................................................................7
2.7
Statistical Hypotheses..............................................................................................................7
3.
Study Design and Procedures .................................................................................................8
3.1
General Study Design ..............................................................................................................8
3.2
Schedule of Visits and Assessments .......................................................................................8
4.
Study Treatments...................................................................................................................10
4.1
Method of Assigning Subjects to Treatments ........................................................................10
4.2
Masking and Unmasking........................................................................................................11
5.
Sample Size and Power Considerations................................................................................11
6.
Data Preparation ....................................................................................................................12
6.1
Input Data...............................................................................................................................12
6.2
Output Data............................................................................................................................12
7.
Analysis Populations..............................................................................................................12
7.1
Modified Intent-to-Treat..........................................................................................................12
7.2
Intent-to-Treat.........................................................................................................................13
7.3
Per Protocol............................................................................................................................13
7.4
Safety .....................................................................................................................................13
8.
General Statistical Considerations.........................................................................................13
8.1
Unit of Analysis.......................................................................................................................13
8.2
Missing or Inconclusive Data Handling ..................................................................................13
8.3
Definition of Baseline .............................................................................................................14
8.5
Data Analysis Conventions ....................................................................................................15
8.6
Adjustments for Multiplicity.....................................................................................................15
9.
Disposition of Subjects...........................................................................................................15
10.
Demographic and Pretreatment Variables.............................................................................16
10.1 Demographic Variables..........................................................................................................16
10.2 Pretreatment Variables ..........................................................................................................16
11.
Medical History and Concomitant Medications......................................................................17


Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 4 of 35
11.1 Medical History.......................................................................................................................17
11.2 Concomitant Medications.......................................................................................................17
12.
Dosing Compliance and Treatment Exposure .......................................................................17
12.1 Dosing Compliance ................................................................................................................17
13.
Efficacy Analyses...................................................................................................................18
13.1 Primary Analysis ....................................................................................................................18
15.
Safety Analyses .....................................................................................................................22
15.1 Adverse Events ......................................................................................................................22
15.2 Best-Corrected Distance Visual Acuity at 40 cm in Letter Score...........................................24
15.3 Low-Luminance Best-Corrected Distance Visual Acuity........................................................24
15.4 Slit Lamp Biomicroscopy Examination and Dilated Fundoscopy...........................................24
15.5 Conjunctival Hyperemia .........................................................................................................24
15.6 Intraocular Pressure...............................................................................................................25
15.7 Urine Pregnancy Test ............................................................................................................25
16.
Other Analyses.......................................................................................................................25
16.1 Patient Reported Outcome Questionnaire.............................................................................25
16.2 Monocular and Binocular Uncorrected Distance Visual Acuity..............................................25
16.3 Drop Instillation Assessment..................................................................................................25
17.
Changes from Protocol-Stated Analyses...............................................................................26
18.
References.............................................................................................................................26
19.
Revision History .....................................................................................................................26


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 5 of 35 
List of Abbreviations 
 
AE
Adverse Event
ANOVA
Analysis of Variance
ATC
Anatomical Therapeutic Chemical 
BCDVA
Best-Corrected Distance Visual Acuity
BID
Bis in die (Twice Daily)
CI 
Confidence Interval
CRF
Case Report Form
CS 
Clinically Significant
CSR
Clinical Study Report
eCRF 
Electronic Case Report Form
EDC
Electronic Data Capture 
ETDRS
Early Treatment of Diabetic Retinopathy Study
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure
ITT
Intent-to-Treat
LOCF 
Last Observation Carried Forward
logMAR
Logarithm of the Minimum Angle of Resolution 
MedDRA
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NCS
Not Clinically Significant
PDF
Portable Document Format
PP
Per Protocol 
PT
Preferred Term 
RDC
Remote Data Capture
RTF
Rich Text Format
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SD 
Standard Deviation 
SDC
Statistics & Data Corporation
SOC
System Organ Class
TEAE 
Treatment-Emergent Adverse Event 
VA
Visual Acuity 
WHO DDE 
World Health Organization Drug Dictionary Enhanced
 




Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 7 of 35
2.5
Safety Variables
The safety variables include the following:
o
Loss of BCDVA
o
Low-luminance BCDVA
o
Slit-lamp biomicroscopy and fundoscopy
o
Conjunctival redness
o
Intraocular pressure (IOP)
 
)
o
Adverse Events (reported, elicited, and observed)
2.7
Statistical Hypotheses
The clinical hypothesis is that LNZ101 is non-inferior to LNZ100 and superior to vehicle in improving near 
vision in subjects with presbyopia. Additional hypothesis for this study is LNZ101 also improves efficacy 
duration in comparison to LNZ100.










Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 12 of 35 
6. Data Preparation 
6.1 
Input Data 
Study data will primarily be recorded on the electronic case report forms (eCRFs) supplied by SDC using 
iMEDNET EDC (electronic data capture) system.  
When all prerequisites for database lock have been met, including availability of all masked external data, 
the database will be locked. Following database lock, approval will be obtained from the Sponsor to unmask 
the study. Once the study has been unmasked, unmasked laboratory data will be sent to SDC. Any changes 
to the database after data have been locked can only be made with the approval of the Sponsor in 
consultation with SDC.  
Final analysis will be carried out after the following have occurred: 
 
Database lock has occurred, including receipt of all final versions of external vendor data, with 
written authorization provided by appropriate SDC and Sponsor personnel 
 
Protocol deviations have been identified and status defined (major/minor deviations) 
 
Analysis populations have been determined 
 
Randomized treatment codes have been unblinded 
6.2 
Output Data 
Data from EDC will be transferred to Biostatistics and incorporated into standard formats following the Study 
Data Tabulation Model (SDTM). Data will then be mapped to analysis datasets using the Analysis Data 
Model (ADaM).  Both SDTM- and ADaM-formatted data will be used to create the subject listings, while all 
tables and figures will be based on the ADaM-formatted data. 
SDTM will follow the SDTM version 1.4 model and will be implemented using the SDTM Implementation 
Guide version 3.3 and the SDTM Controlled Terminology version 2022-03-25. ADaM data will follow the 
ADaM version 2.1 model and will be implemented using the ADaM Implementation Guide version 1.3. Both 
SDTM and ADaM will be validated using Pinnacle 21 version 2.2. Any discrepancies in the validation will 
be noted in reviewer’s guides accompanying the final data transfers. 
Define.xml will be created for SDTM and ADaM using the Define-XML version 2.0 model. 
7. Analysis Populations 
7.1 
Modified Intent-to-Treat 
The mITT Population consists of subjects with study eye baseline/pre-treatment monocular BCDVA at 40 
and a non-missing monocular BCDVA at 40 cm at 1 hour-post dose at each visit. 
Pairwise comparisons between treatments and changes from pre-treatment will use the mITT Population. 
Because inclusion in the mITT is assessed at each treatment visit separately it is possible subjects are 
included at some visits/treatments but not at others. All data will be included and no subjects will be 
excluded because of protocol violations/deviations. 


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 13 of 35 
 
7.2 
 Intent-to-Treat 
The Intent-to-Treat (ITT) population consists of the study eye with Visit 1 baseline monocular BCDVA at 40 
cm meeting the logMAR requirements listed in inclusion criteria in Section 5.3 of the protocol. All data will 
be included and no subjects will be excluded because of protocol violations/deviations. The ITT population 
will be analyzed as randomized and will be used for the sensitivity analyses on the primary and secondary 
monocular efficacy endpoints.  
7.3 
Per Protocol 
The Per Protocol (PP) population is a subset of the ITT population and includes subjects with no major 
protocol violations/deviations likely to affect the primary efficacy endpoint. This population will be analyzed 
as treated for confirmatory and sensitivity analyses. 
7.4 
Safety 
The Safety population includes all randomized subjects who receive at least one dose of study medication. 
The Safety population will be analyzed as treated and will be used for the safety analyses. No data will be 
excluded for any reason. 
8. General Statistical Considerations 
8.1 
Unit of Analysis 
The unit of analysis in this study will be the study eye for all efficacy and safety summaries. The study eye 
is defined as below. 
Dynamic Study Eye: One eye per subject will be designated as the study eye at each visit. The Dynamic 
Study Eye is the eye at each visit with the highest logMAR score for baseline monocular BCDVA at 40 
cm. If both eyes have the same BCDVA at 40 cm, the study eye will be selected as the eye with the least 
hyperopic sphere (i.e., most negative value if both are negative, smallest positive value if both are 
positive, negative value if one is positive and one is negative) determined by manifest refraction within 3 
months of Visit 1 or at Visit 1. If both eyes have equal sphere, the right eye will be selected as the study 
eye. 
Additionally, non-ocular adverse events (AE) and medical history will be presented at the subject level.  
The non-study eye will be referred to as the fellow eye. Non-study eye safety summaries will also be 
presented as appropriate. 
8.2 
Missing or Inconclusive Data Handling 
In general, there will be no imputation of missing data other than for partial or missing dates where complete 
dates are required to flag data as treatment-emergent or concomitant with treatment. Partial/missing start 
and end dates for AEs and concomitant medications will be imputed as follows: 


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 14 of 35 
Partial/missing start date:  
 
Dates with missing day only will be imputed as the 1st of the month unless the month and year are 
same as the month and year of first dose of study medication, in which case missing day will be 
imputed as the first dose day of study medication.  
 
Dates with both day and month missing will be imputed as 1 Jan unless the year is same as the 
year of first dose of study medication, in which case missing day and month will be imputed as the 
first dose day and month of study medication. 
 
Completely missing dates will be imputed as the first dose date of study medication unless the end 
date is on or before the first dose date of study medication, in which case missing date will be 
imputed as 1 Jan of the same year as the end date. 
Partial/missing end date:  
 
Dates with missing day only will be imputed as the last day of the month unless the month and year 
are the same as the month and year of the last dose of study medication, in which case missing 
day will be imputed as the last dose day of study medication.  
 
Dates with both day and month missing will be imputed as 31 Dec unless the year is same as the 
year of the last dose of study medication, in which case missing day and month will be imputed as 
the last dose day and month of study medication.  
 
If the ongoing flag is missing or “Yes” then the date will not be imputed unless death date is 
available, in which case the missing date will be imputed as the death date. If ongoing is “No” then 
the missing end date will be imputed as the last dose date. 
 
If the imputed date is after the date of death, then the end date will be set equal to the date of 
death.  
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc.). 
8.3 
Definition of Baseline 
As this is a crossover study, every subject will receive a different treatment at Visits 
  For all 
safety and efficacy analysis, baseline refers to the assessment done prior to treatment administration at 
each visit or if there are multiple pre-dose assessments, it is the last measurement prior to the first dose of 
study medication. Change from baseline will be calculated as follow-up visit/time point – baseline. 
 
  
 
 
 


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 15 of 35 
 
  
8.5 
Data Analysis Conventions 
All data analysis will be performed by Statistics & Data Corporation (SDC). Statistical programming and 
analyses will be performed using SAS® version 9.4 or higher. Output will be provided in rich text format 
(RTF) for tables, and portable document format (PDF) for tables, listings, and figures using landscape 
orientation. All study data will be listed by subject, randomized sequence, visit (as applicable), and 
treatment based on all randomized subjects unless otherwise specified. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum. Minima and maxima will be reported with 
the same precision as the raw values; means and medians will be presented to one additional decimal 
place than reported in the raw values. Standard deviations will be presented to two additional decimal 
places than reported in the raw values. Summaries for discrete variables will include counts and 
percentages. All percentages will be rounded to one decimal place (i.e., XX.X%). Differences between 
active treatments and placebo will be calculated as active minus placebo and change from baseline will be 
calculated as follow-up visit minus baseline.  
All statistical tests will be two-sided with a significance level of 0.10 
10) unless otherwise specified. 
Confidence intervals (CI) for differences between treatments will be two-sided at 90% confidence. All 
p-values will be rounded to 4 decimal places; p-values less than 0.0001 will be presented as “<0.0001”; p-
values greater than 0.9999 will be presented as “>0.9999.” 
Unless otherwise specified, summaries will be presented by treatment and, where appropriate, visit.  
8.6 
Adjustments for Multiplicity 
There will be no adjustments for multiplicity in testing the primary efficacy endpoint at each time point at a 
distance of 40 cm in this proof of concept study. There will be also be no adjustments for multiplicity for 
multiple treatments  and multiple comparisons to vehicle. 
9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study, and discontinued from the study.  Disposition will be summarized by 
treatment sequence for all randomized subjects. 
The number of subjects in ITT, PP and Safety analysis populations will be displayed by treatment sequence. 
Percentages of number of subjects will be calculated using randomized subjects as the denominator. Since 
inclusion to the mITT Population is assessed at each visit separately, the number and percentage of 
subjects in mITT Population at each visit will be presented by eye, treatment 
. A subject listing 
of inclusion in each of these populations will be presented. 


Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 16 of 35
The number and percentage of subjects prematurely discontinued from the study and the reasons for study 
discontinuation will be summarized by treatment sequence for all randomized subjects.  The reasons for 
study discontinuation that will be summarized include AE, lost to follow-up, physician decision, protocol 
violation, sponsor termination of study, withdrawal by subject, and, other. Discontinuations due to COVID-
19 will also be displayed. A subject listing will be provided which includes the date and reason for premature 
study discontinuation.
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
and overall, for all randomized subjects.  Protocol deviations will be classified as major or minor prior to the 
closure of the database during a masked review of each protocol deviation.    
A subject listing will be provided which includes the date of the deviation, the deviation description, the 
classification of whether the deviation was judged to be major or minor, and whether the deviation was 
COVID-19 related or not.
In addition, subject listings will include randomization/treatment sequence (actual vs assigned), informed 
consent date and exclusions from the PP population.  
10. Demographic and Pretreatment Variables
10.1
Demographic Variables
The demographic variables collected in this study include age, sex, if female, child-bearing potential, race, 
ethnicity, and iris color.  Subjects who record more than one race will be grouped into a single category 
denoted as multi-racial. Iris color will be presented at the subject level with a category for heterochromia. 
Sex, race, ethnicity, and iris color will be presented using descriptive summary statistics with counts and 
percentages. Age (years) will be summarized, overall and by treatment sequence, using continuous 
descriptive statistics. Age will be reported in years and calculated using the following formula:
– date of birth) / 365.25, truncated as an integer
Demographic variables will be summarized for the ITT, Safety and Per-Protocol populations by treatment 
sequence and overall, in tables. A subject listing that includes all demographic variables will be provided. 
10.2
Pretreatment Variables
Pretreatment variables are measured to ensure the safety and eligibility of subjects at Visit 1. Subject level 
listings of the assessments below will be used to present pretreatment information from the ITT population 
at the eye level when appropriate. 


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 17 of 35 
 
11. Medical History and Concomitant Medications 
11.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 25.0. 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment sequence at the subject level by System Organ Class (SOC) and Preferred Term (PT) using the 
ITT and Safety Populations. Ocular medical history will be similarly summarized at the subject level.  If a 
subject reports the same PT multiple times within the same SOC, that PT will only be reported once within 
that SOC.  As with the PT, if a subject reports multiple conditions within the same SOC, that SOC will only 
be reported once. 
Tables and listings of medical history will be generated separately for ocular and non-ocular data. 
11.2 
Concomitant Medications 
Concomitant medications will be coded using World Health Organization (WHO) Drug Dictionary Version 
Enhanced B3, March 2022 and summarized to the therapeutic drug class (Anatomical Therapeutic 
Chemical [ATC] 4 classification) and preferred name. If the ATC 4 classification is not provided, then the 
next lowest classification that is provided in the coding dictionary will be used. The preferred name will be 
defined as the active ingredient; if the active ingredient is not provided or includes more than two ingredients 
(e.g., multivitamins), then the drug name will be summarized as the preferred name. Any uncoded terms 
will be summarized under the ATC classification and preferred name of “Uncoded.” 
Concomitant medications for each treatment are defined as those that are in use during dosing or started 
after dosing but ended before the next treatment in the sequence or study completion/discontinuation.. 
Concomitant medications will be summarized using the ITT population. Medications will be tabulated for 
each treatment using frequencies and percentages. Subjects may have more than one medication per ATC 
text. At each level of subject summarization, a subject will be counted once if he/she reports one or more 
medications. Percentages will be based on the number of subjects in each treatment. Tables and listings of 
concomitant medications will be generated separately for ocular and non-ocular data. 
12. Dosing Compliance and Treatment Exposure 
12.1 
Dosing Compliance 
The study drug will be administered by a trained study technician; therefore, dosing compliance and 
exposure cannot be calculated. Treatment administration will be listed by subject. 


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 18 of 35 
13. Efficacy Analyses 
13.1 
Primary Analysis 
The primary efficacy variable in this study is the percentage of subjects with at least a 3-line (15-letter) 
improvement from the pre-dose measurement of 
 monocular BCDVA at 40 cm and 
no loss in BCDVA  5 letters (ETDRS chart at 4 m) 
. Primary 
analysis will use the population as described in Section 7.1. The primary analyses will separately compare 
the LNZ101 treatment versus the vehicle treatment, and the LNZ100 treatment versus the vehicle 
treatment. 
 
Counts and percentages of subjects who meet the primary efficacy criteria described above will be 
presented by treatment and eye. Inferential testing of the percentage of subjects, who meet the primary 
efficacy criteria above, will be done by generating an odds ratio (along with 80% and 90% CIs and p-value) 
from a logistic model (binomial error and logit link) estimated by generalized estimating equation methods. 
This model accounts for the correlations between treatments and periods within a subject. Aspects of the 
model include: 
 
Response Measure: Indicator of whether the subject had at least a 3-line (15-letter) improvement 
 from pre-dose in the monocular assessment of BCDVA at 40 cm and no loss in 
 m). 
 
Fixed effect explanatory measures: sequence, period, and treatment. 
 
Repeated measures correlation will be estimated with an unstructured variance-covariance matrix 
in the GEE model. If the model fails to converge, alternative covariance structures, such as AR(1), 
Toeplitz, or compound symmetry, will be tried in the order specified. 
Example SAS code is shown here: 
proc genmod data=final descending; 
class subjid trtseqan avisitn trtan;
model aval = trtseqan avisitn trtan/ type3 wald corrb dist=binomial 
link=logit alpha=.1;
repeated subject=subjid/type=un  corrw; 
lsmeans trtan/ oddsratio pdiff cl alpha=.1; 
run; 
- 
DESCENDING 
 
- 
ALPHA = option specifies the family-wise error rate, default is .05. (NOTE: code will be run with 
both .05 and .1 for confidence interval output) 
- 
TRTSEQAN 
 
- 
AVISITN 
 
- 
TRTAN
 


Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 19 of 35
-
AVAL
variable, (
3-line improvement in BCDVA at 40 cm  and no loss 
in BCDVA  at 
-line improvement in BCDVA at 40 cm  and no loss in
-
BINOMIAL
it link (Note: SAS default is link 
LOGIT when DIST=BIN) 
The proportion of subjects meeting the primary efficacy criteria in each treatment and eye will also be 
analyzed using the McNemar’s test. This tests for marginal homogeneity and the p-value for this test will 
be reported. An example of McNemar’s test in SAS is:
PROC FREQ DATA=<DATA> (WHERE=(<SELECTION CRITERIA>));
   WEIGHT COUNT;
   TABLES TRTAN_1*TRTAN_2 / AGREE;
   EXACT MCNEM;
RUN;
Note that the WHERE statement <SELECTION CRITERIA> will need to include pairs of treatments
(TRTAN_1, TRTAN_2) with counts of responders and non-responders. The primary endpoint will also be 
analyzed on the ITT and PP populations. 


Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 20 of 35


Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 21 of 35


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 22 of 35 
15. Safety Analyses 
All safety analyses will be conducted using the Safety population. 
15.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether 
or not the event is considered drug-related. An AE can therefore be any unfavorable and unintended sign 
(e.g., an abnormal laboratory finding), symptom, or disease occurring after the first dose of study drug, 
without any judgment about causality. Any pre-existing medical condition that worsens after first 
administration of the study drug will also be considered a new AE. The AE reporting period ends upon study 
exit. Study drug includes the investigational drug under evaluation and vehicle given during any stage of 
the study. All AEs will be coded using MedDRA version 25.0.  
Treatment-emergent adverse events (TEAE) are defined as any event that occurs or worsens on or after 
the first dose of study drug instillation. TEAE for a treatment is defined as an AE that started or worsened 
on or after that specific treatment administration and before the administration of subsequent treatment or 
study completion/discontinuation.. Adverse events recorded in the eCRF which began prior to the first 
treatment will not be included in the summary tables but will be included in the AE data listings. 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as determined 
by the Investigator or reported to him/her by the subject. The assessment of severity is made irrespective 
of relationship to study drug or seriousness of the event and should be evaluated according to the following 
scale: 
 Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere with the subject’s 
daily activities. 


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 23 of 35 
 Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with the 
subject’s daily activities. 
 Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and interferes 
with the subject’s daily activities. 
The relationship of each AE to the study drug is determined by the Investigator using these explanations: 
 Suspected: A reasonable possibility exists that the study drug caused the AE. 
 Not Suspected: A reasonable possibility does not exist that the study drug caused the AE. 
The expectedness of an AE is determined based upon existing safety information about the 
investigational product using these explanations: 
 
Unexpected: an AE that is not listed in the Investigator’s Brochure (IB) or is not listed at the 
specificity or severity that has been observed. 
 
Expected: an AE that is listed in the IB at the specificity and severity that has been observed. 
 
Not applicable: an AE unrelated to the investigational product. 
An overall summary will be presented that includes the number of events and the number and percentage 
of subjects who experienced at least one TEAE, by treatment and overall subjects. This summary will also 
include breakdowns of TEAEs further categorized as ocular (study eye and fellow eye separately) or non-
ocular, treatment-related TEAEs, Treatment-Emergent serious AEs (SAEs), TEAEs leading to early 
treatment discontinuation, TEAEs leading to death, and TEAEs (ocular and non-ocular) by maximum 
severity. 
The following summaries will be presented by treatment, SOC and PT. If a subject reports the same PT 
multiple times within the same SOC, that PT will only be reported once within that SOC. As with the PT, if 
a subject reports multiple conditions within the same SOC, that SOC will only be reported once. In the 
summary, SOCs will be listed in alphabetical order; PTs will be listed in order of descending frequency for 
all subjects within each SOC.   
 
Ocular TEAEs 
 
Non-ocular TEAEs  
 
Treatment-related ocular TEAEs 
 
Treatment-related non-ocular TEAEs.  
 
Expected TEAEs 
 
Unexpected TEAEs 
 
Treatment-Emergent SAEs 
Summaries of TEAEs by maximum severity will be presented for ocular AEs and non-ocular AEs separately. 
The number of subjects with any TEAEs (along with percentages) will be tabulated by SOC and PT within 


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 24 of 35 
each SOC by treatment. To count the number of subjects with any TEAEs, if a subject has multiple TEAEs 
coded to the same PT within the same SOC, the subject will be counted once under the maximum severity. 
All AEs will be presented in a subject listing. The AEs leading to study treatment discontinuation will be 
listed separately. In addition, all SAEs will be presented in a separate listing. 
15.2 
Best-Corrected Distance Visual Acuity at 40 cm in Letter Score 
The observed and change from baseline in monocular and binocular BCDVA letter score at 40 cm at every 
scheduled visit at all post-treatment time points 
 will be summarized 
in tables by treatment and eye using the Safety population.  
15.3 
Low-Luminance Best-Corrected Distance Visual Acuity  
Monocular and binocular low-luminance BCDVA using an ETDRS chart calibrated for testing at 4 meters 
is conducted 
 Results will be recorded 
in logMAR units.  
The observed and change from baseline low-luminance BCDVA will be summarized for each eye (study 
eye and fellow eye for monocular low-luminance BCVA) and both eyes (for binocular low-luminance BCVA) 
using continuous descriptive statistics by time point for each treatment.  A subject listing of low-luminance 
BCDVA will also be produced.  
15.4 
Slit Lamp Biomicroscopy Examination and Dilated Fundoscopy 
A slit lamp biomicroscopy examination will be conducted on both eyes at all scheduled visits and at the 
last time point for each visit in the eyelid, conjunctiva, cornea, anterior chamber, iris, and lens. The results 
will be graded as normal, not clinically significant (NCS), or clinically significant (CS). 
A table will summarize results using counts and percentages for each treatment at each time point and 
location for each eye.  Percentages will be based on the number of subjects in each treatment with 
responses.  Shift tables and subject level listings will also be provided. 
Dilated fundoscopy will be done at Visit 1 and the results will be provided in a listing.  
15.5 
Conjunctival Hyperemia  
Conjunctival hyperemia is measured 
 Conjunctival redness will be summarized by treatment, for the study and fellow eye separately, 
using continuous descriptive summary statistics in a table. Change from baseline will also be calculated 
and summarized using descriptive summary statistics in a table.  The data for conjunctival redness will be 
presented in a listing. 


Protocol 21-100-0007 SAP, Version 1.0 
29SEP2022 
Confidential & Proprietary 
Page 25 of 35 
15.6 
Intraocular Pressure  
Intraocular pressure is measured 
 Observed  IOP values 
will be summarized by treatment for the study and fellow eye separately, using continuous descriptive 
summary statistics in a table. The data for IOP examinations will be presented in a listing. 
15.7 
Urine Pregnancy Test 
Female subjects of childbearing potential will have a urine pregnancy test at the site at each visit. A subject 
level listing by visit will be produced. 
16. Other Analyses 
16.1 
Patient Reported Outcome Questionnaire  
Subjects will be required to answer Patient Reported Outcome (PRO) questionnaire
 
.  Counts and proportions for the responses to the following questions will be 
presented by treatment on the mITT and Safety Population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
16.2 
Monocular and Binocular Uncorrected Distance Visual Acuity 
Monocular and Binocular uncorrected distance VA at 4 m will be collected a
. The observed and change from baseline logMAR values from these 
assessments  will be summarized in tables by treatment and eye using the safety population. A subject 
listing of Monocular and Binocular uncorrected distance VA will also be produced.
16.3 
Drop Instillation Assessment 
 
 
 
 
 
  


Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 26 of 35
17. Changes from Protocol-Stated Analyses
None.
18. References
Lenz Protocol 21-100-0007 Version 4.0
19. Revision History
Documentation of revision to the SAP will commence after approval of the final version 1.0.
20. Tables
Tables that will be included in the topline delivery are shown in boldface font.


Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 27 of 35


Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 28 of 35


Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 29 of 35




Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 31 of 35






Protocol 21-100-0007 SAP, Version 1.0
29SEP2022
Confidential & Proprietary
Page 34 of 35