Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 954
Healthy volunteers: no

Brief summary:
Primary Objective:

To demonstrate the non-inferiority of Sotagliflozin 400 milligrams (mg) compared to Glimepiride on hemoglobin A1c (HbA1c) reduction at Week 52 in participants with Type 2 Diabetes (T2D) who have inadequate glycemic control with metformin.

Secondary Objectives:

To demonstrate the superiority of Sotagliflozin 400 mg compared to Glimepiride on change in body weight, systolic blood pressure (SBP) in participants with baseline SBP ≥130 millimeter of mercury (mmHg), SBP in all participants, and proportion of participants with at least 1 documented symptomatic hypoglycemic event (≤70 milligrams per deciliter \[mg/dL\]).

* To demonstrate the superiority of Sotagliflozin 400 mg compared to placebo on change in HbA1c, body weight, SBP in participants with baseline SBP ≥130 mmHg, SBP in all participants.
* To demonstrate the superiority of Sotagliflozin 200 mg compared to placebo on change in HbA1c.
* To demonstrate the non-inferiority of Sotagliflozin 400 mg compared to Glimepiride on change in HbA1c.
* To demonstrate the superiority of Sotagliflozin 400 mg compared to Glimepiride on change in HbA1c.
* To evaluate the safety and tolerability of Sotagliflozin compared to Glimepiride and placebo.

Detailed description:
Up to 58 weeks, including a Screening Period consisting of a Screening phase of up to 2 weeks, a 2-week single-blind placebo Run-in phase, a 52-week double-blind Treatment Period, and a 2-week post-treatment Follow-up period to collect safety information.

Arms:
arm 1: Following a 2-week run-in period, two Sotagliflozin 200 mg, tablets, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks. arm 2: Following a 2-week run-in period, one Sotagliflozin 200 mg, tablet and one Sotagliflozin-matching placebo tablet, and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks. arm 3: Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets, and combination of two Glimepiride capsules with adequate dose strengths per dose titration (titrated up to 6mg), taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks. arm 4: Following a 2-week run-in period, two Sotagliflozin-matching placebo tablets and two Glimepiride-matching placebo capsules, taken orally once daily before the first meal of the day in the double-blind treatment period up to 52 weeks.

Interventions: intervention 1: Sotagliflozin (SAR439954) intervention 2: Glimepiride intervention 3: Metformin intervention 4: Placebo intervention 5: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: tablet

Route of administration: oral intervention 2: Pharmaceutical form: capsule

Route of administration: oral intervention 3: Pharmaceutical form: tablet

Route of administration: oral intervention 4: Pharmaceutical form: tablet

Route of administration: oral intervention 5: Pharmaceutical form: capsule

Route of administration: oral

Protocol document:
Prot_000.pdf: 
Official Title: A 52-week Randomized, Double-blind, Double-dummy, Active- and 
Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the 
Efficacy and Safety of Sotagliflozin compared to Glimepiride or 
Placebo Added to Metformin in Patients with Type 2 Diabetes who 
have Inadequate Glycemic Control with Metformin Monotherapy 
NCT Number: NCT03332771 
Document Date: Protocol Version 2: 11-April-2018




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
  
 
 
    
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
   
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
  
   
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
  
   
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
   
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
   
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
      
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
    
 
 
   
 
   
 
 
 
 
 
 
 
 
   
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
    
 
  
  
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
  
   
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
  
 
   
  
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
   
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
   
 
  
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  
  
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
  
  
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
   
 
  
 
 
 
 
  
 
 
 
  
 
 
 
  
   
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
  
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
   
  
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
    
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
  
 
 
 
  
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
  
   
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
       
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
   
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
  
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
  
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
 
  
  
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
  
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






 
 
 
 
 
 
 
 
 
 
  
    
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 








 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
   
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
  
 
 
 
   
 
 
  
 
 
   
 
 
 
 
   
 
 
  
 
 
 
   
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
  
  
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
    
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
   
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
     
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
   
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
  
 
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
  
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



SAP_001.pdf: 
Official Title: A 52-week Randomized, Double-blind, Double-dummy, Active- and 
Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the 
Efficacy and Safety of Sotagliflozin compared to Glimepiride or 
Placebo Added to Metformin in Patients with Type 2 Diabetes who 
have Inadequate Glycemic Control with Metformin Monotherapy 
NCT Number: NCT03332771 
Document Date: SAP Version 3: 15-April-2020 


Lexicon Pharmaceuticals, Inc. 
Sotaglifozin/ LX4211 
Protocol No.: EFC14838 
A 52-week Randomized, Double-blind, Double-dummy, Active- and Placebo-
controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and  
Safety of Sotagliflozin compared to Glimepiride or Placebo Added to Metformin in 
Patients with Type 2 Diabetes who have Inadequate Glycemic Control with 
Metformin Monotherapy 
Covance Study ID: 000000155206 
Statistical Analysis Plan  
Version: 3 
DATE OF ISSUE: 03-Apr-2020 
Author: 
 
Lexicon Pharmaceuticals, Inc.  
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Covance Clinical Development Services 
206 Carnegie Center 
Princeton, NJ 08540-6233 




Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 3 of 95
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................................. 3
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 6
1
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 8
1.1
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 8
1.2
OBJECTIVES ................................................................................................................................... 9
1.2.1
Primary objectives ............................................................................................................................ 9
1.2.2
Secondary objectives ....................................................................................................................... 9
1.2.3
Other objectives ............................................................................................................................... 9
1.3
DETERMINATION OF SAMPLE SIZE ........................................................................................... 10
1.4
STUDY PLAN ................................................................................................................................. 10
1.5
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 13
1.6
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 15
2
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 20
2.1
ANALYSIS ENDPOINTS ............................................................................................................... 20
2.1.1
Demographic and baseline characteristics .................................................................................... 20
2.1.2
Prior or concomitant medications ................................................................................................... 22
2.1.2.1
Rescue therapy .............................................................................................................................. 22
2.1.2.2
Prohibited, prior and concomitant medications .............................................................................. 22
2.1.3
Efficacy endpoints .......................................................................................................................... 23
2.1.3.1
Primary efficacy endpoint(s) .......................................................................................................... 23
2.1.3.2
Secondary efficacy endpoint(s) ...................................................................................................... 23
2.1.3.3
Other efficacy endpoint(s) .............................................................................................................. 24
2.1.4
Safety endpoints ............................................................................................................................ 24
2.1.4.1
Hypoglycemia ................................................................................................................................. 25
2.1.4.2
Adverse events variables ............................................................................................................... 27
2.1.4.3
Deaths ............................................................................................................................................ 31
2.1.4.4
Laboratory safety variables ............................................................................................................ 31
2.1.4.5
Vital signs variables ....................................................................................................................... 32
2.1.4.6
Physical examination ..................................................................................................................... 32
2.1.4.7
Electrocardiogram variables .......................................................................................................... 33
2.1.5
Quality-of-life endpoints ................................................................................................................. 33
2.2
DISPOSITION OF PATIENTS ....................................................................................................... 33


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 4 of 95
2.2.1
Randomization and drug dispensing irregularities ......................................................................... 35
2.3
ANALYSIS POPULATIONS ........................................................................................................... 36
2.3.1
Efficacy populations ....................................................................................................................... 36
2.3.1.1
Intent-to-treat population ................................................................................................................ 36
2.3.1.2
Completers population ................................................................................................................... 36
2.3.2
Safety population ........................................................................................................................... 37
2.4
STATISTICAL METHODS ............................................................................................................. 37
2.4.1
Demographics and baseline characteristics .................................................................................. 37
2.4.2
Prior or concomitant medications ................................................................................................... 38
2.4.3
Extent of investigational medicinal product exposure and compliance ......................................... 38
2.4.3.1
Extent of investigational medicinal product exposure .................................................................... 38
2.4.3.2
Compliance .................................................................................................................................... 39
2.4.4
Analyses of efficacy endpoints ....................................................................................................... 40
2.4.4.1
Analysis of primary efficacy endpoint(s) ........................................................................................ 40
2.4.4.2
Analyses of secondary efficacy endpoints ..................................................................................... 44
2.4.4.3
Analysis of other efficacy endpoints ............................................................................................... 47
2.4.4.4
Multiplicity issues ........................................................................................................................... 47
2.4.5
Analyses of safety data .................................................................................................................. 48
2.4.5.1
Analyses of hypoglycemia ............................................................................................................. 49
2.4.5.2
Analyses of adverse events ........................................................................................................... 50
2.4.5.3
Deaths ............................................................................................................................................ 54
2.4.5.4
Analyses of laboratory variables .................................................................................................... 54
2.4.5.5
Analyses of vital sign variables ...................................................................................................... 56
2.4.5.6
Analyses of electrocardiogram variables ....................................................................................... 56
2.4.5.7
Analyses of physical examination variables .................................................................................. 56
2.4.6
Analyses of quality of life variables ................................................................................................ 56
2.5
DATA HANDLING CONVENTIONS .............................................................................................. 57
2.5.1
General conventions ...................................................................................................................... 57
2.5.2
Data handling conventions for secondary efficacy variables ......................................................... 57
2.5.3
Missing data ................................................................................................................................... 58
2.5.4
Windows for time points ................................................................................................................. 60
2.5.5
Unscheduled visits ......................................................................................................................... 62
2.5.6
Pooling of centers for statistical analyses ...................................................................................... 63
2.5.7
Statistical technical issues ............................................................................................................. 63
3
INTERIM ANALYSIS ..................................................................................................................... 64
4
DATABASE LOCK ........................................................................................................................ 65
5
SOFTWARE DOCUMENTATION ................................................................................................. 66


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 5 of 95
6
REFERENCES ............................................................................................................................... 67
7
LIST OF APPENDICES ................................................................................................................. 68
APPENDIX A
MAPPING OF INCLUSION AND EXCLUSION CRITERIA UNDER THE ORIGINAL 
PROTOCOL AND AMENDMENT .................................................................................................. 69
APPENDIX B
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 71
APPENDIX C
LIST OF PTS FOR SELECT EOSIS (MEDDRA V22) ......................................................... 77
APPENDIX D
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 88
APPENDIX E
STUDY FLOW CHART ........................................................................................................ 91


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 6 of 95
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
ATC: 
anatomical therapeutic chemical  
BMI: 
body mass index 
BP: 
blood pressure 
BUN: 
blood urea nitrogen 
CEC: 
Clinical Endpoint Committee 
CI: 
confidence interval 
CMH: 
Cochran-Mantel-Haenszel 
CPK: 
creatine phosphokinase 
CRO: 
contract research organization 
CSR: 
clinical study report 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DCCT: 
diabetes control and complications trial  
DILI: 
drug-induced liver injury 
DKA: 
diabetic ketoacidosis 
DMC: 
Data Monitoring Committee 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EMA: 
European Medicines Agency 
EOSI: 
event of special interest 
FPG: 
fasting plasma glucose 
HbA1c: 
hemoglobin A1c 
HDL-C: 
high density lipoprotein cholesterol 
HLGT: 
high level group term 
HLT: 
high level term 
HR: 
heart rate 
IFCC: 
International Federation of Clinical Chemistry and Laboratory Medicine  
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
KM: 
Kaplan-Meier 
LDH: 
lactic acid dehydrogenase 
LDL-C: 
low density lipoprotein cholesterol 


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 7 of 95
LLN: 
lower limit of normal 
LLT: 
lower level term 
LS: 
least-squares 
MACE: 
major adverse cardiovascular events 
MAR: 
missing at random 
MDRD: 
modification of diet in renal disease 
MedDRA: 
medical dictionary for regulatory activities 
MI: 
multiple imputation 
MNAR: 
missing not at random 
MTD: 
maximal tolerable dose 
NIMP: 
noninvestigational medicinal product 
PCSA: 
potentially clinically significant abonormality 
PD: 
pharmacodynamics 
P-gp: 
P-glycoprotein 
PK: 
pharmacokinetic 
PPG: 
postprandial glucose 
PQAT: 
patient qualitative assessment of treatment 
PRAC: 
Pharmacovigilance Risk Assessment Committee 
PT: 
preferred term 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SD: 
standard deviation 
SE: 
standard error 
SGLT: 
sodium-glucose linked transporter 
SMBG: 
self-monitoring of blood glucose 
SOC: 
system organ class 
T2D: 
type 2 diabetes 
TC: 
total cholesterol 
TEAE: 
treatment-emergent adverse event 
TG: 
triglycerides 
ULN: 
upper limit of normal 
UTI: 
urinary tract infection 
VTE: 
venous thrombotic event 
WBC: 
white blood cell 
WHO-DD: 
World Health Organization-drug dictionary 


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 8 of 95
1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
This study is a Phase 3 randomized, double-blind, double-dummy, active- and placebo-controlled, 
parallel-group, multicenter study that is anticipated to enroll approximately 930 patients. 
The study will consist of a Screening Period comprised of an up to 2 weeks Screening Phase and a 
2-week single-blind placebo Run-in Phase, a 52-week double-blind and double-dummy Treatment 
Period, and a 2-week post-treatment Follow-up Period (patients who prematurely discontinue the 
study treatment are expected to continue in the study). 
In order to qualify for randomization, patients must demonstrate compliance during the Run-in 
Phase based upon tablet and capsule as assessed at the discretion of the 
Investigator.  Eligible patients will be randomized centrally by an Interactive Response 
Technology (IRT) using a permuted-block randomization schedule with a fixed block size.  
Randomization will be stratified by hemoglobin A1c (HbA1c)  and 
systolic blood pressure (SBP) at the screening visit 
Following randomization, patients will be treated in a double-blind and double-dummy manner 
for 52 weeks.  A total o will be randomly assigned at a 2:1:2:1 ratio 
to the following four treatment groups on top of open-label metformin: 

Sotagliflozin 400 mg group: sotagliflozin 400 mg, given as two 200 mg tablets, and 
two glimepiride-matching placebo capsules, taken orally once daily before the first meal 
of the day (N = 310 patients). 

Sotagliflozin 200 mg group: sotagliflozin 200 mg, given as one 200 mg tablet and 
one sotagliflozin-matching placebo tablet, and two glimepiride-matching placebo capsules, 
taken orally once daily before the first meal of the day (N = 155 patients). 

Glimepiride group: two sotagliflozin-matching placebo tablets, and combination of 
two glimepiride (or matching placebo) capsules with adequate dose strengths per dose 
titration (titrated up to 6 mg), taken orally once daily before the first meal of the day 
(N = 310 patients). 

Placebo group: two sotagliflozin-matching placebo tablets and two glimepiride-matching 
placebo capsules, taken orally once daily before the first meal of the day 
(N = 155 patients). 
Fasting plasma glucose (FPG; plasma or serum) and HbA1c will be masked to study sites and 
patients after randomization until study end.  Additionally, urinalysis by dipstick will not include 
the measurement of urine glucose. 


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 9 of 95
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objective of this study is to demonstrate the non-inferiority of sotagliflozin 400 mg 
compared to glimepiride on HbA1c reduction at Week 52 in patients with Type 2 diabetes (T2D) 
who have inadequate glycemic control with metformin. 
1.2.2 Secondary objectives  

To demonstrate the superiority of sotagliflozin 400 mg compared to glimepiride on: 
-
Change in body weight from Baseline to Week 52,  
-
,  
-
Change in SBP from Baseline to Week 12 in all patients,  
-
The proportion of patients with at least one documented symptomatic hypoglycemic 
70 mg/dL) during the 52-week Treatment Period. 

To demonstrate the superiority of sotagliflozin 400 mg compared to placebo on change in 
HbA1c from Baseline to Week 26.  

To demonstrate the superiority of sotagliflozin 200 mg compared to placebo on change in 
HbA1c from Baseline to Week 26. 

To demonstrate the superiority of sotagliflozin 400 mg compared to placebo on: 
-
Change in body weight from Baseline to Week 26,  
-
,  
-
Change in SBP from Baseline to Week 12 in all patients. 

To demonstrate the non-inferiority of sotagliflozin 200 mg compared to glimepiride on 
change in HbA1c from Baseline to Week 52. 

To demonstrate the superiority of sotagliflozin 400 mg compared to glimepiride on change 
in HbA1c from Baseline to Week 52. 

To evaluate the safety of sotagliflozin compared to glimepiride and placebo over 52 weeks 
of treatment. 
1.2.3 Other objectives  
To evaluate sotagliflozin compared to glimepiride and placebo with respect to: 

Change in FPG. 

The number of hospital visits due to hypoglycemia. 

Change in estimated glomerular filtration rate (eGFR). 


Statistical Analysis Plan 
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Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 10 of 95

Change in SBP for all patients, the subset of patients with baseline SBP <130 mmHg and 
the subset of patients . 

Change in diastolic blood pressure (DBP) for all patients and the subset of patients with 
 mmHg. 

The proportion of patients requiring rescue medication for hyperglycemia. 

The proportion of patients with HbA1c <6.5%, <7.0%. 

The proportion of patients with HbA1c <6.5%, <7.0% and no documented symptomatic 
. 

Patient Qualitative Assessment of Treatment (PQAT). 
1.3 
DETERMINATION OF SAMPLE SIZE  
The sample size/power calculations were performed based on the primary endpoint of change of 
HbA1c from Baseline to Week 52 in the intent-to-treat (ITT) population.  Assuming a common 
standard deviation (SD) of 1.1%, and the true difference between sotagliflozin 400 mg and 
glimepiride is zero, 310 patients in the sotagliflozin 400 mg and glimepiride groups will ensure 
that the upper bound of the 2-sided 95% confidence interval (CI) of the adjusted mean difference 
is below 0.3% with at least 90% power.  This sample size will have 80% power to test the 
non-inferiority of change of HbA1c from Baseline to Week 52 in completers, with a 30% dropout 
rate. 
A sample size of 310 patients in sotagliflozin 400 mg group and 155 patients in placebo group 
will have more than 99% power to detect a treatment difference of 0.6% in mean HbA1c change 
from Baseline to Week 26 between sotagliflozin 400 mg and placebo (SD 1.2%; 2-sided 
5% significance level). 
A sample size of 155 patients in sotagliflozin 200 mg group and 155 patients in placebo group 
will have 95% power to detect a treatment difference of 0.5% in mean HbA1c change from 
Baseline to Week 26 between sotagliflozin 200 mg and placebo (SD 1.2%; 2-sided 
5% significance level). 
The total sample size is 930 patients to be randomized (sotagliflozin 400 mg group: 310; 
sotagliflozin 200 mg group: 155; glimepiride: 310; placebo: 155). 
1.4 
STUDY PLAN  
A patient should not be randomized more than once.  In case where original screen failure was 
due to reasons expected to change at re-screening and based upon the Investigators clinical 
judgment, the patient can be rescreened once prior to entering Run-in for this study. 
The investigational medicinal products (IMPs) are sotagliflozin (400 and 200 mg) and glimepiride 
(1 mg titrated up to 6 mg).  Patients will be provided with kits containing wallets of sotagliflozin 
or sotagliflozin-matching placebo (supplied as tablets identical to sotagliflozin 200 mg in 


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 11 of 95
appearance) and kits containing wallets of glimepiride (supplied as 1, 2, and 4 mg capsules) or 
glimepiride-matching placebo (supplied as capsules).  Treatment kits will be provided to the sites 
containing the appropriate number of IMP for the given Treatment Period (including visit 
windows). 
All patients will receive treatment at a fixed dose of sotagliflozin (or matching placebo) as 
assigned at randomization throughout the 52-week study period.  All patients will receive 
glimepiride (or glimepiride-matching placebo) on Day 1 starting from 1 mg daily.  Glimepiride 
(or glimepiride-matching placebo) will be titrated (or mock-titrated) up to 6 mg (or maximum 
tolerated dose [MTD]).  Titration will be possible at 5 dose levels (1, 2, 3, 4, and 6 mg) through a 
combination of glimepiride (or matching placebo) capsules with different dose strengths.  
Titration will occur during the first 18 weeks post-randomization; the glimepiride dose will have 
to remain stable after the first 18 weeks, unless a dose reduction is required for safety reasons. 
In case of recurrent hypoglycemia, down-titration of glimepiride (or matching placebo) can be 
performed at any time during the study for the patients taking a daily dose higher than 2 mg of 
glimepiride.  In the glimepiride blister delivered to the patient, the first column will correspond to 
the lower dose strength.  If an unscheduled phone visit is prompted due to recurrent 
hypoglycemia, the Investigator may use discretion to advise patients to temporarily (<7 days) 
decrease glimepiride/matching placebo dose by omitting the capsule of lower dose until they are 
able to return to the site to be evaluated and receive a new treatment kit as needed.  In this case, an 
on-site visit should occur as soon as possible within 7 days. 
The study flowchart can be found in Appendix E.  


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 12 of 95
Figure 1 - Graphical study design 




Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 13 of 95
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). 
The protocol history table below gives the timing, rationale, and key details of major changes to 
the protocol statistical section. 
The first patient was enrolled on 01 December 2017.  There are no planned interim analyses. 
Table 1 - Protocol amendment statistical changes  
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical 
changes 














































Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 14 of 95
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical 
changes 














































































Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 15 of 95
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical 
changes 









































1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
In this section summarize major changes in statistical analysis features made in approved 
statistical analysis plan (SAP) versions, and there are no changes after study start (after the first 
patient was enrolled). 
The SAP history table below gives the timing, rationale, and key details for major changes to the 
statistical analysis features in the SAP.  Changes also incorporated in a protocol amendment are 
cross-referenced to Table 1.
Table 2 - Statistical analysis plan statistical changes  
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 











Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 16 of 95
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 
















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
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
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




Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 17 of 95
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 

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
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






























Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 18 of 95
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 




Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 19 of 95
SAP 
version  
number 
Date 
approved 
Rationale 
Description of statistical changes 























































Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 20 of 95
2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline value (with the exception of serum creatinine and eGFR) is defined generally as the 
last available value before the first dose of double-blind IMP or the last available value prior to 
randomization for patients who were randomized but never exposed to IMP. 
For serum creatinine and eGFR, the baseline value is defined as the average of all values before 
the first dose of double-blind IMP for those randomized and exposed or before randomization for 
those who were randomized but never exposed to IMP. 
All baseline safety and efficacy parameters are presented along with the summary statistics in the 
safety and efficacy sections (Section 2.4.5 and Section 2.4.4). 
Demographic characteristics 
Demographic characteristics to be summarized are: 

Age (years) derived as: (Year of informed consent - Year of birth). 

to <5 years). 

Gender (Male, Female). 

Race (White, Black or African American, Asian, American Indian or Alaska native, 
Native Hawaiian or other pacific islander, Multiple, Unknown). 

Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown). 

HbA1c (%) at screening visit. 

.5%, >8.5%) at screening visit (based on IRT data). 

SBP at screening visit. 

Randomization strata of SBP (<130 mmHg,  (based on IRT 
data). 

Baseline body mass index (BMI) (kg/m2) derived as: (Weight in kg)/(Height in meters)2. 

2). 

Country. 


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 21 of 95
Disease characteristics at screening or baseline 
Disease history includes: 

Duration of diabetes (years) derived as: (Date of informed consent - Date of diagnosis of 
diabetes + 1)/365.25. 

ars). 

Age at diagnosis of diabetes (years) derived as: Year of diagnosis of diabetes - Year of 
birth. 

Duration of metformin treatment (years): (date of informed consent - date of first intake of 
metformin + 1)/365.25. 

Daily dose of metformin (mg) at baseline. 

Categorized daily dose of metformin at baseline (<1500, 1500 to <2500, 2500 mg). 

Baseline diabetic microvascular complications (Yes, No) (ie, diabetic retinopathy, diabetic 
neuropathy, diabetic peripheral neuropathy [sensory or motor], diabetic autonomic 
neuropathy, diabetic nephropathy, and diabetic foot infection). 

eGFR at screening (mL/min/1.73 m2). 

eGFR categories at screening (<15 mL/min/1.73 m2 [End s
<30 mL/min/1.73 m2 /1.73m2 [Moderate 
/1.73m2 [Mild decrease in GFR], and 
 mL/min/1.73 m2 [Normal]). 

Prior antihypertensive medication identified by therapeutic class as agents acting on the 
renin-angiotensin system, beta blocking agents, diuretics (a sub-category: loop diuretics 
identified by pharmacological class as high-ceiling diuretics), calcium channel blockers, 
and antihypertensives according to World Health Organization-Drug Dictionary 
(WHO-DD). 
Medical or surgical history 
Medical history and medical findings include: 

Physical examination. 

Medical or surgical history. 

Medical history cardiovascular. 

Surgical history amputation. 

Alcohol habits. 

Tobacco smoking habits. 


class (SOC) 
currently in effect at Covance at the time of database lock. 


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 22 of 95
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications  
All medications taken within three months before the Screening visit (any time for prior SGLT2) 
and until the end of the study are to be reported in the electronic case report form (e-CRF). 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Covance at the time of database lock. 

Prior medications are those the patient used prior to first administration of double-blind 
IMP.  Prior medications can be discontinued before first administration or can be ongoing 
during treatment phase.   

Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from the 1st administration of double-blind IMP to the date of last administration 
+ 10 days.  A given medication can be classified both as a prior medication and as a 
concomitant medication.   

Posttreatment medications are those the patient took in the period running from the 
11th day after the last administration of double-blind IMP up to the end of the study. 
Any technical details related to computation, dates, imputation for missing dates are described 
in Section 2.5. 
2.1.2.1 Rescue therapy  
Except for SGLT2 inhibitors and sulfonylurea, any approved medication(s) including oral 
antidiabetic drugs or insulin can be prescribed to treat the hyperglycemia at the discretion of the 
investigator.  Rescue therapy is considered a noninvestigational medicinal product (NIMP). 
2.1.2.2 Prohibited, prior and concomitant medications  
During the study Treatment Period, the following medications are prohibited: 

Initiation of any antidiabetic agents, including oral or injectable antihyperglycemic agents 
other than the IMP and metformin are not allowed before the rescue therapy.  The existing 
background medication (NIMP) should not be modified before the rescue. 

SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin), and sulfonylurea are 
not allowed for rescue. 

Systemic use of glucocorticoids for more than 10 consecutive days (topical, ophthalmic, 
intra-articular, nasal spray or inhaled applications are allowed). 

IMPs in any other clinical trial. 


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 23 of 95

Modification of antihypertensive medication before Week 12 is not allowed unless for 
safety reasons. 

Initiation of any weight loss drugs (eg, phentermine, orlistat). 
Patients taking sotagliflozin with concomitant digoxin should have digoxin concentrations 
monitored and doses reduced as needed.  In addition, other P-glycoprotein (P-gp) substrates may 
be affected and the labels of P-gp substrate drugs should be consulted with regards to monitoring 
and dose adjustments. 
Note: short term use (<10 consecutive days) of the prohibited medication eg, short-acting insulin 
for treatment of acute illness or surgery is allowed. 
Other medications which are unlikely to interfere with the pharmacokinetic (PK) or 
pharmacodynamics (PD) of the IMP or confound interpretation of the study endpoints are allowed 
as needed and following discussion between the Investigator and the Sponsor/CRO.  However, 
doses of chronically administered medicines should be kept fixed during the trial if at all possible. 
The dose of all antihypertensive agents should be kept constant during the 12 weeks following 
randomization and no antihypertensive agents should be added or withdrawn for the 12 weeks 
following randomization unless it is considered necessary for safety reasons. 
2.1.3 Efficacy endpoints  
All efficacy measurements collected during the study will be considered for analyses, including 
those obtained after IMP discontinuation or introduction of rescue therapy (see Section 2.5.4). 
Hemoglobin A1c (HbA1c), FPG, serum creatinine, and eGFR are measured/calculated in a central 
laboratory (see study flowchart in Appendix E).  Body weight, SBP and DBP (see Section 2.1.4.5) 
are measured at on-site visits by the investigator.  Patients requiring rescue are identified as those 
-
Efficacy variables will be summarized in both standard international units and conventional units 
when applicable. 
2.1.3.1 Primary efficacy endpoint(s)  
Comparison of sotagliflozin 400 mg versus glimepiride in change from Baseline to Week 52 in 
HbA1c (%). 
2.1.3.2 Secondary efficacy endpoint(s)  
Secondary endpoints (sotagliflozin 400 mg dose): 

Change from Baseline to Week 26 in HbA1c. 

Change from Baseline to Weeks 26 and 52 in body weight. 


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
. 

Change from Baseline to Week 12 in SBP for all patients. 

Proportion of patients with at least one documented symptomatic hypoglycemic event 
ng the 52-week Treatment Period. 
Secondary endpoints (sotagliflozin 200 mg dose): 

Change from Baseline to Weeks 26 and 52 in HbA1c. 
2.1.3.3 Other efficacy endpoint(s)  
Other efficacy endpoints (sotagliflozin 400 mg and 200 mg doses): 

Change from Baseline to Weeks 26 and 52 in FPG. 

Number of hospital visits due to hypoglycemia during the 52-week Treatment Period. 

Change from Baseline in eGFR. 

Change from Baseline to Weeks 26 and 52 in SBP for all patients and the subset with 
. 

Change from Baseline to Weeks 12, 26, and 52 in SBP for patients with baseline 
SBP <130 mmHg. 

Change from Baseline to Weeks 12, 26, and 52 in DBP for all patients and the subset with 
. 

Proportion of patients requiring rescue treatment for hyperglycemia during the 52-week 
Treatment Period. 

The proportion of patients with HbA1c <6.5%, <7.0% at Week 52. 

The proportion of patients with HbA1c <6.5%, <7.0% at Week 52 and no documented 
-week Treatment Period. 

PQAT at Weeks 26 and 52. 
2.1.4 Safety endpoints  
Assessments for safety include adverse events (AEs), self-monitoring of blood glucose (SMBG), 
clinical laboratory assessments, physical examination, electrocardiogram (ECG), weight, and vital 
signs.  The following safety endpoints will be assessed: 

Adverse events, AEs leading to discontinuation from the IMP, AEs of special interest 
(AESIs), events of special interest (EOSIs), serious adverse events (SAEs), and deaths. 

Hypoglycemia (all, severe and/or documented symptomatic). 

Safety laboratory results (including amylase, lipase, and fasting lipids). 

Vital signs and ECG results. 


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Observation period  
The observation period will be divided into 4 epochs:

The screening epoch is defined as the time from the signed informed consent date up to 
the first administration of the double-blind IMP.

The treatment epoch is defined as the time from the first administration of the 
double-bind IMP to the last administration of the double-blind IMP. 

The residual treatment epoch is defined as the time from the last administration of the 
double-blind IMP up to 10 days (1 day for hypoglycemia) after the last administration of 
the double-bind IMP. 
The treatment-emergent adverse event (TEAE) period will include both treatment and residual 
treatment epochs. 

The posttreatment epoch is defined as the period of time starting the day after the end of 
the TEAE period up to the last protocol-planned visit or the resolution/stabilization of all 
SAEs, AESIs and EOSIs, whichever is the latest. 
The on-study observation period is defined as the time from start of double-blind treatment until 
the end of the study (defined as the last scheduled visit for those who completed the study and the 
date collected on e--
complete the study). 
The post-study observation period is defined as the time from the day after the end of the study 
until the resolution/stabilization of all SAEs, AESIs and EOSIs if applicable. 
2.1.4.1 Hypoglycemia  
Hypoglycemia will be identified as events recorded on the dedicated e-CRF 
information
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions.  These episodes may 
be associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma.  
Self-monitored plasma glucose values may not be available, but neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
Severe hypoglycemia is identified in e-documented as, 
1. TCountermeasure Administration, ticked the option 
. 
And 
2. T. 


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Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 

 mg/dL). 
Clinical symptoms that are considered to result from a hypoglycemic episode are for example 
increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, 
palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
Documented symptomatic hypoglycemia is identified in e-
those documented as, 
1. TCountermeasure AdministrationNOT ticked the option 
Not Capable of Treating . 
And  
2. To . 
And 
3. W3.9 mmol/L (70 mg/dL).  
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with  mg/dL). 
Asymptomatic hypoglycemia is identified in e-
documented as, 
1. TCountermeasure AdministrationNOT ticked the option 
Not .  
And 
2. T, ticked .  
And 
3. W3.9 mmol/L (70 mg/dL).  
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination (but that was presumably caused by a plasma 

without a test of plasma glucose. 
Probable symptomatic hypoglycemia is identified in e-
documented as, 


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1. TNOT ticked the option 
Not Capable of Treating Self and Required As.  
And 
2. Tticked .  
And 
3. With no plasma glucose value before countermeasure.  
And  
4. T
, ticked . 
Relative hypoglycemia 
-
patient reports typical symptoms of hypoglycemia, and interprets the symptoms as indicative of 
hypoglycemia, but with a measured plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
Relative hypoglycemia is identified in e-documented 
as, 
1. TCountermeasure AdministrationNOT ticked the option 
Not Capable of Treating Self and Requ.  
And 
2. T, ticked .  
And 
3. With a plasma glucose value before countermeasure >3.9 mmol/L (>70 mg/dL).  
3.9 mmol/L (70 mg/dL), hypoglycemia episodes with a plasma 
glucose of <3.0 mmol/L (<54 mg/dL) will be analyzed separately.  
Any hypoglycemic event fulfilling the criteria of a SAE or leading to unconsciousness, coma, or 
seizure will also be recorded as a SAE (see Section 2.1.4.2). 
2.1.4.2 Adverse events variables  
Adverse event observation period  

Pretreatment adverse events are AEs that developed or worsened or became serious from 
the signed informed consent date up to first administration of double-bind IMP. 

Treatment-emergent adverse events (TEAEs) are AEs that developed or worsened or 
became serious during the TEAE period. 

Posttreatment adverse events are AEs that developed or worsened or became serious 
during the posttreatment period. 


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All AEs (including SAE, AESI and EOSI) will be coded to a LLT, PT, HLT, HLGT, and 
associated primary SOC using the version of MedDRA currently in effect at Covance at the time 
of database lock. 
The occurrence of AEs (including SAE, AESI and EOSI) will be recorded from the time of signed 
informed consent until the end of the study (see Section 2.1.4) or the resolution/stabilization of all 
SAE, AESI and EOSI. 
AESI include: 

Pregnancy. 

Symptomatic overdose with IMP/NIMP. 

Alanine aminotransferase (ALT) increase >3 times upper limit of normal (ULN). 
EOSI include:  

Major adverse cardiovascular events (MACE [cardiovascular death, myocardial infarction, 
or stroke]) and other specific CV events (eg, heart failure requiring hospitalization).  

Severe hypoglycemia. 

Genital mycotic infections (to include vulvovaginal candidiasis in females and candida 
balanitis in males). 

Urinary tract infections (UTIs). 

Clinically relevant volume depletion and events related/possibly related to volume 
depletion. 

Diarrhea. 

Pancreatitis. 

Bone fractures. 

Venous thrombotic events (VTEs) to include deep venous thrombosis and 
thromboembolism (to include pulmonary embolism). 

Diabetic ketoacidosis (DKA). 

Renal events, to include 50% decline in eGFR, end stage kidney disease, renal death. 

Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid cancer). 

Adverse events leading to an amputation. 
The Clinical Endpoint Committees (CECs) will, in a blinded manner, review and adjudicate all 
deaths, MACE/selected CV events (myocardial infarction, stroke, unstable angina requiring 
hospitalization, and heart failure requiring hospitalization), selected renal events, bone fracture, 
and DKA. 
Two independent committees will review safety events that require ongoing monitoring in case a 
safety signal is identified.  These events are: 1) potential cases of drug-induced liver injury 


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Page 29 of 95
(DILI), and 2) cases of amputations.  The two committees will review the cases in a 
treatment-blinded manner and will present their assessments to the Data Monitoring Committee 
(DMC). 
AESI and EOSI will be identified based on criteria in Table 3.  
Table 3 - Criteria for AESI and EOSI  
AE Grouping 
Criteria 
AESI 










EOSI adjudicated 




















EOSI Renal events where select events adjudicated 
















Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 30 of 95
AE Grouping 
Criteria 

















EOSI not adjudicated






























EOSI AE leading to an amputation 














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2.1.4.3 Deaths  
The deaths observation period are per the observation periods defined above.  

Death on-study: deaths occurring during the on-study observation period. 

Death on-treatment: deaths occurring during the TEAE period. 

Death poststudy: deaths occurring after the end of the study. 
2.1.4.4 Laboratory safety variables  
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry, 
amylase, lipase and lipid profile) and urinalysis.  Clinical laboratory values will be summarized in 
both standard international units and conventional units when applicable. 
Blood samples for clinical laboratories will be collected at designated visits (see study flowchart 
in Appendix E).  The following laboratory data will be measured at a central laboratory: 

Hematology  
-
Red blood cells and platelets: hemoglobin, hematocrit, red blood cell, platelets count,  
-
White blood cells: white blood cell, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils. 


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
Clinical chemistry  
-
Metabolism: glucose (serum), creatine phosphokinase (CPK),        
-
Electrolytes and minerals: sodium, potassium, chloride, bicarbonate (ie, carbon 
dioxide), calcium, phosphorus, magnesium,  
-
Renal function: blood urea nitrogen (BUN), creatinine, uric acid,         
-
Liver function: total protein, albumin, ALT, aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total bilirubin, Lactic acid dehydrogenase (LDH).       

Lipid parameters (fasting): total cholesterol (TC), high density lipoprotein cholesterol 
(HDL-C), low density lipoprotein cholesterol (LDL-C) (calculated by Friedwald equation, 
see Section 2.5.1), Non-HDL-C (calculated as the difference between TC and HDL-C), 
triglycerides (TG). 

Pancreatic enzymes: lipase, amylase. 
Urine samples will be collected at designated visits (see study flowchart in Appendix E).  The 
central urinalysis includes: 

Urine dipstick includes: specific gravity, pH, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, and leukocyte esterase. 

Urine microscopy includes, but is not limited to: detection of formed cellular elements, 
casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. 
For creatinine and calculated eGFR, potentially clinically significant abnormality (PCSA) 
summaries will be presented in the safety section while descriptive summaries in the efficacy 
section. 
Technical formulas are described in Section 2.5.1. 
2.1.4.5 Vital signs variables  
Vital signs include: heart rate (HR), sitting systolic and diastolic blood pressure (SBP and DBP), 
temperature, and respiratory rate (see study flowchart in Appendix E for designated visits).  They 
will be performed after the patient has been seated for at least five minutes.  Blood pressure (BP) 
and HR will be assessed three times with at least one minute between each measurement 
following the 5-minute rest period, and prior to phlebotomy.  The mean of the three measurements 
will be analyzed for each vital sign variable (HR, SBP, and DBP). 
2.1.4.6 Physical examination  
A complete physical exam will be performed at Visit 1 (Screening) Visit 10 (Week 26) and 
Visit 12 (Week 52).  determined by the Investigator will 
be reported in the e-CRF by body system. 


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2.1.4.7 Electrocardiogram variables  
The 12-lead ECGs will be performed at Visit 1 (Screening), Visit 10 (Week 26) and Visit 12 
(Week 52).  -CRF as determined 
by the investigator. 
2.1.5 Quality-of-life endpoints  
The PQAT includes a 7-point Likert Scale for the patient to evaluate his/her subjective response 
to the treatment (-3 to +3 including 0 for a neutral response) and two free-text response questions 
to describe key advantages and disadvantages. 
The PQAT will be administered to English-speaking patients at sites in English-speaking 
countries. 
The patients will be asked to complete it electronically from home just before the on-site visits 
planned at Weeks 26 (Visit 10) and 52 (Visit 12).  They will be asked to do it by themselves 
without any help from friends or relatives. 
At the beginning of the Weeks 26 (Visit 10) and 52 (Visit 12) patient visits, Investigators will 
have to review patient answers (accessible on a web platform) in order to identify any potential 
AEs reported by patients within the open-ended questions. 

appropriate data analysis software. 
The analysis method for this exploratory analysis will be provided in a separate SAP and the 
analyses results will be documented in a separate report. 
If a patient discontinues treatment with IMP during the Treatment Period, the patient will be asked 
to complete this qualitative assessment of treatment at time of discontinuation. 
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as all patients who signed the informed consent.   
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used or not. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report (CSR) using a flowchart diagram or summary table: 

Screened patients. 

Run-in patients: patients who had a run-in record in IRT. 


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
Screen failure patients (including failures during run-in) and reasons for screen failure 
(see Appendix A for details on the mapping of inclusion and exclusion criteria under the 
original protocol and Amendment). 

Nonrandomized but treated patients. 

Randomized patients. 

Randomized but not treated patients. 

Randomized and treated patients. 

Patients who have completed the 52-week double-blind Treatment Period as scheduled. 

Patients who did not complete the 52-week double-blind Treatment Period as scheduled 
and the reasons for permanent treatment discontinuation. 

Patients who have completed the study as scheduled. 

Patients who did not complete the study as scheduled and the reasons for study 
discontinuation. 

 of study status (completed, not completed) and corresponding end of 
treatment status (completed, not completed). 

Status at last study contact. 
For screened, run-in, screen failure, and nonrandomized but treated patients, percentages will be 
calculated using the number of screened patients as the denominator.  All other categories of 
patients will be presented by treatment group and the percentages will be calculated using the 
number of randomized patients within each treatment group as the denominator.  Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group.  Patients prematurely discontinued from treatment and/or study, along with reasons for 
discontinuation, will also be listed.  
A summary of the distribution of patients by country and center will also be provided (overall 
number of patients screened, run-in, randomized, and treated, as well as number of patients 
randomized, discontinued from study treatment, and discontinued from study for each treatment 
group). 
Patients treated but not randomized, patients randomized but not treated and patients randomized 
but not treated as randomized will be identified and described in separate listings.  The patients of 
the third category (randomized and not treated as randomized) will be part of efficacy and safety 
analyses (see Section 2.3).  Patients randomized but not treated will be included in efficacy 
analysis.  Safety data of patients treated but not randomized will be reported separately. 
The randomization %] and SBP at Screening 
[<130,  assigned by IRT will be summarized.  The percentages will be calculated 
using the number of randomized patients as the denominator.  The discrepancy between the strata 
assigned by IRT and the information reported on e-CRF will be listed for all randomized patients. 
Kaplan-Meier (KM) plots of the cumulative incidence of double-blind IMP discontinuations due 
to any reason and due to AEs will be provided for the double-blind Treatment Period separately 


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(see Section 2.5.4).  A listing of these patients, along with the reason for discontinuation of 
treatment, study completion status and the reason for discontinuation of study, will be provided.  
All important deviations including randomization and drug-dispensing irregularities will be 
summarized in tables giving numbers and percentages of deviations by randomized treatment 
group. 
Additionally, the analysis populations for safety and efficacy defined in Section 2.3 will be 
summarized in a table by number of patients in the randomized population.  

Efficacy population: ITT population.  

Safety population. 
2.2.1 Randomization and drug dispensing irregularities  
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error. 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages).  Nonrandomized but treated patients will be described separately.  Listings with 
additional relevant details will be provided in appendices. 
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to: 


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Randomization and drug allocation irregularities 







2.3 
ANALYSIS POPULATIONS  
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population. 
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
2.3.1 Efficacy populations  
Efficacy analyses will be based on the treatment group allocated by the IRT according to the 
randomization schedule at randomization visit (as randomized), irrespective of the treatment 
actually received. 
2.3.1.1 Intent-to-treat population  
Efficacy analyses will be based on the ITT population, defined as all randomized patients, 
irrespective of compliance with the study protocol and procedures.  Patients will be analyzed for 
efficacy analyses according to the treatment group to which they are randomized. 
2.3.1.2 Completers population  
The completers population is a subset of the ITT population who complete the 52-week Treatment 
Period and do not start rescue therapy.  Sensitivity and subgroup analyses for the primary 
endpoint of change from Baseline to Week 52 HbA1c comparisons will be conducted on this 
population. 


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2.3.2 Safety population  
Safety analyses will be based on the safety population, defined as all randomized patients who 
receive at least one dose of double-blind IMP (regardless of the amount of treatment 
administered).  Patients will be analyzed for safety analyses according to the treatment actually 
received. 
In addition: 

Nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately. 

Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population as randomized. 

For patient receiving both sotagliflozin and placebo during the trial, the treatment group 
allocation for as-treated analysis will be sotagliflozin group (depending on the treatment 
kits taken [400 mg or 200 mg]). 

For patients receiving both sotagliflozin 400 mg (treatment kits) and 200 mg (treatment 
kits) during the trial, the treatment group allocation for as-treated analysis will be 
sotagliflozin 200 mg group. 

For patients receiving both sotagliflozin and glimepiride during the trial, the treatment 
group allocation for as-treated analysis will be sotagliflozin group (depending on the 
treatment kits taken [400 mg or 200 mg]). 

For patients receiving both glimepiride and placebo during the trial, the treatment group 
allocation for as-treated analysis will be glimepiride group. 

Randomized patients will be excluded from the safety population only if there is 
documented evidence (ie, all study dates recorded as no medication taken) that patients 
have not taken the study medication.  If a patient is dispensed double-blind IMP and is lost 
to follow-up without any documented evidence, the patient will be considered exposed. 
2.4 
STATISTICAL METHODS  
2.4.1 Demographics and baseline characteristics  
Continuous data will be summarized using the number of available data, mean, SD, median, 
minimum, and maximum for each treatment group.  Categorical and ordinal data will be 
summarized using the number and percentage of patients in each treatment group.  
Parameters will be summarized on the randomized population analyzed in the treatment group to 
which they were randomized.  Analyses for the safety population will be included in the 
appendices if the size of the safety population is different (>10%) from the size of that in the 
primary analysis population (ie, randomized patients) for any treatment group. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups using descriptive statistics.  


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P-values on demographic and baseline characteristic data will not be calculated.  
No specific description of the safety parameters will be provided at baseline.  If relevant, the 
baseline values will be described along with each safety analysis. 
No specific description of the efficacy parameters will be provided at baseline.  If relevant, the 
baseline values will be described along with each efficacy analysis. 
2.4.2 Prior or concomitant medications  
The prior, concomitant and posttreatment medications will be presented in the randomized 
population for each treatment group (and overall for the summary of prior medications), using 
counts and percentages of patients.  Statistical tests for the between-group differences will not be 
performed. 
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomical therapeutic chemical (ATC) class (anatomic category) 
and the first three digits of the ATC class (therapeutic category).  A given medication may be 
linked to more than one ATC classes.  All ATC codes corresponding to a medication will be 
summarized, and patients will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication.  Therefore patients may be counted several times for the same 
medication.  
Prior medications will be presented by anatomic and therapeutic categories and sorted by 
decreasing frequency of ATC based on the overall incidence across treatment groups.  In case of 
equal frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be 
used. 
Concomitant and posttreatment medications will be presented by anatomic and therapeutic 
categories and sorted by decreasing frequency of ATC based on the incidence in the sotagliflozin 
400 mg group.  In case of equal frequency regarding ATCs (anatomic or therapeutic categories), 
alphabetical order will be used.  
Antihypertensive medications will be presented separately by pharmacological class, chemical 
class and standardized medication name. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2) unless otherwise specified. 
2.4.3.1 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure, and actual dose 
information. 


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Duration of IMP exposure is defined as last double-blind IMP dose date - first double-blind IMP 
dose date + 1 day, regardless of unplanned intermittent discontinuations (see Section 2.5.3 for 
calculation in case of missing or incomplete data). 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number of 
patients exposed, mean, SD, median, minimum, and maximum).  In addition, duration of 
treatment exposure will also be summarized categorically by numbers and percentages for each of 
the following categories and cumulatively according to these categories: 

1 to 28 days. 

29 to 56 days. 

57 to 84 days.  

85 to 126 days. 

127 to 182 days. 

183 to 364 days.  

>364 days. 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 
Number and percentage of patients by final dose at the end of the treatment will also be presented 
by each active treatment group.  
Glimepiride (matching placebo) dose information will be assessed using ITT population by the 
following variables for each treatment group according to the treatment group to which they are 
randomized: 

The final dose at the end of the titration period, recorded at Visit 9 (Week 18). 

The final dose at the end of the treatment. 

Maximal tolerable dose: the MTD recorded at Visit 9 (Week 18) if MTD is checked in 
e-CRF. 
Dose information variables will be summarized descriptively (number, mean, SD, median, 
minimum, and maximum). 
Number and percentage of patients by final dose of glimepiride (matching placebo), MTD status 
and MTD at the end of the titration period (recorded at Visit 9), and by final dose of glimepiride 
(matching placebo) at the end of the treatment will also be presented by each treatment group. 
2.4.3.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol.  No imputation will be made for patients with 
missing or incomplete data.  Treatment compliance will be calculated and presented for 
glimepiride or matching placebo (Capsule) and sotagliflozin or matching placebo (Tablet) 
separately by treatment group. 


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Percentage of compliance for a patient will be defined as the number of days that the patient was 
compliant to Capsule or Tablet, respectively, divided by the total number of days that the patient 
was planned to take IMP during the treatment epoch defined in Section 2.1.4 (ie, from the first 
date to the last date of double-blind IMP administration). 
Above-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a higher dose level of Capsule or higher dose of Tablet than planned, respectively, 
divided by the total number of days that the patient was planned to take IMP during the treatment 
epoch. 
Under-planned dosing percentage for a patient will be defined as the number of days that the 
patient took a lower dose level of Capsule or lower dose of Tablet than planned, respectively, 
divided by the total number of days that the patient was planned to take IMP during the treatment 
epoch. 
Treatment compliance, above-planned, and under-planned dosing percentages will be summarized 
for Capsule and Tablet separately and descriptively as quantitative variables (number, mean, SD, 
median, minimum, and maximum).  The percentage of patients whose compliance is <80% will 
be summarized separately for Capsule and Tablet.  In addition, numbers and percentages of 
patients with at least one day above-planned dose will also be provided separately for Capsule and 
Tablet, as well as numbers and percentages of patients with (0, 20%], and >20% of days 
under-planned dose. 
Cases of overdose (see study protocol for further details) will constitute AEs/SAEs and be 
analyzed as such.  More generally, dosing irregularities will be listed in Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints  
Efficacy analyses will be performed on the ITT population using the efficacy assessments 
collected during the study, including those obtained after IMP discontinuation or introduction of 
rescue therapy, unless otherwise specified. 
Missing data for efficacy analyses are identified through steps described in Section 2.5.3.  
2.4.4.1 Analysis of primary efficacy endpoint(s)  
For the primary efficacy endpoint, the following null and alternative hypotheses will be tested: 

H0: µT - µC . 

H1: µT - µC <0.3%. 
Where µT and µC are the mean changes from Baseline in HbA1c at Week 52 for sotagliflozin and 
glimepiride groups, respectively. 


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The null hypothesis will be tested at a 1-sided alpha level of 0.025 using a non-inferiority margin 
of 0.3% of HbA1c change by comparing the upper bound of the 2-sided 95% CI for the adjusted 
mean treatment difference between sotagliflozin and glimepiride with 0.3%. 
Primary analysis 
The primary efficacy endpoint of change in HbA1c from Baseline to Week 52 will be analyzed by 
an Analysis of Covariance (ANCOVA) model using HbA1c values measured at baseline and 
Week 52 (observed or imputed).  The missing data at endpoint will be imputed by multiple 
imputation (MI) methods as detailed below.  To be concise, the following texts related to 
imputation are generalized to accommodate primary as well as continuous secondary efficacy 
endpoints. 
Missing endpoint data at Week 52 or Week 26 (or Week 12 for SBP) visit will be imputed using a 
model built separately in each treatment group and estimated from the patients in the same treatment 
group who prematurely discontinue the IMP before the Week 52 or Week 26 (or Week 12 for SBP) 
visit but have measurements for the endpoint (ie, retrieved dropouts). The imputation model will 
include the randomization strata and the corresponding baseline value. In cases of non-convergence 
during the imputations, the offending stratum will be identified and then will be dropped from the 
model. Considering that the number of retrieved dropout patients in each treatment group is 
expected to be small, a simple imputation model based on regression will be used with baseline 
measurement included as the predictor.  This will serve as the primary model of imputation for 
missing data should sampling criteria be satisfied (see below). 
An alternative (back-up) imputation method will be used if the number of patients who prematurely 
discontinue the IMP before the Week 52 or Week 26 (or Week 12 for SBP) visit but have 
measurements for the endpoint is less than five (< 5) in any treatment groups (ie, insufficient number 
of retrieved dropouts to support the imputation method described above).  This criterion will be 
assessed for each primary or continuous secondary efficacy endpoint separately. 
In the back-up imputation method, missing post-baseline endpoint values at Week 52 or Week 26 
(or Week 12 for SBP) will be imputed by the washout Multiple Imputation (MI) method under the 
missing not at random (MNAR) framework. 
Missing endpoint data at the Week 52 or Week 26 (or Week 12 for SBP) in all treatment groups 
(sotagliflozin 200 mg and 400 mg, glimepiride and placebo) are imputed from a model estimated 
from patients in the placebo group who have the endpoint data available. 
For patients in the sotagliflozin 400 mg, sotagliflozin 200 mg and glimepiride groups with missing 
data at Week 52 or Week 26 (or Week 12 for SBP), their missing values will be imputed using 
observed baseline and the observed primary endpoint data from placebo completers; no intermittent 
values from either placebo or the active treatment groups will be used.  
For placebo patients, missing data will be imputed based on the placebo group data. Intermittent 
observed values will be used while imputing missing values at Week 52 or Week 26 (or Week 12 
for SBP). In cases that a non-monotone missing data pattern occurs at the intermediate visits, these 
data points will be first imputed in the placebo group using the Markov Chain Monte Carlo 


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(MCMC) option in PROC MI to achieve a monotone missing pattern for all placebo patients.  The 
Week 52 or Week 26 (or Week 12 for SBP) endpoint values will be subsequently imputed from the 
multiple copies of the original dataset where each copy will have a monotone missing pattern. 
The imputation models for the washout MI method will include the randomization strata and the 
corresponding baseline value. Missing data will be imputed using the regression method. 
In cases of non-convergence during the imputations, especially for the MCMC application in the 
placebo non-monotone datasets, graphical measures (eg, trace and autocorrelation plots) will be 
used to identify the offending variable and once detected, that variable(s) will be dropped from the 
model and the imputations will be re-run. These re-run models will use the same seed number and 
number of imputations as used in the original models.  
Using either imputation method, missing endpoint data will be imputed 2000 times to generate 
multiple datasets with complete data.  Other details of the imputation procedures such as the seed 
number and sort ordering are specified in the SAS programs. The change from baseline to Week 52 
(or Week 12 for SBP) will be derived from observed and imputed HbA1c values at Week 52 (or 
Week 12 for SBP).  Each of the complete datasets after the imputation will be analyzed using the 
ANCOVA model with treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, glimepiride, 
and placebo groups), randomization stratum .5%), randomization 
stratum of and country as fixed factors, and baseline 
HbA1c value as a covariate.  Results from each analysis will be combined formula 
to provide the adjusted mean change in HbA1c from Baseline to Week 52 (or Week 12 for SBP) 
for each treatment group, as well as the between-group differences and their associated 95% CIs.  
If the upper bound of the 2-sided 95% CI for the adjusted mean difference (sotagliflozin 400 mg 
versus glimepiride) in HbA1c change from Baseline to Week 52 is <0.3%, then non-inferiority will 
be declared. 
Sensitivity analyses 
A sensitivity analysis will be conducted with the 52-week treatment completers (ie, all patients 
who complete the 52-week Treatment Period and do not start rescue therapy) using the Week 52 
values and the same missing data imputation method (washout imputation method) and ANCOVA 
model described above. 
Tipping-point analysis based on the same MI method as applied to the primary analysis will be 
performed to examine the robustness of the results from the primary analysis.  Patients who were 
randomized to sotagliflozin 400 mg group and had no HbA1c data at Week 52 will be given a 
penalty.  The penalty will be gradually increased to evaluate at which level the conclusion of the 
analyses in terms of statistically non-inferior to glimepiride is changed.  The tipping point is the 
penalty level, at which the magnitude of efficacy reduction in patients without HbA1c data at 
Week 52 creates a shift in the treatment effect of sotagliflozin 400 mg from being statistically 
non-inferior to glimepiride to statistically inferior to glimepiride.  Least-squares (LS) mean 
difference between sotagliflozin and glimepiride and its associated 95% CI will be provided for 
each penalty level.  The steps to perform the tipping point analysis are as follows: 


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1. Missing data will be imputed using the same MI method as applied to the primary 
analysis. 
2. The imputed HbA1c value at Week 52 in the sotagliflozin 400 mg group will be penalized  
by adding a penalty f %\^( f  ,*1%) in each complete dataset. 
3. Change from Baseline at Week 52 in HbA1c will be analyzed using the same ANCOVA 
model as specified in the primary analysis in each complete dataset. 
4. Results will be combined formula. 
5. For noninferiority of sotaglifozin 400 mg versus glimepiride on HbA1c reduction, Steps 2 
kf 0 n`cc Y\ i\g\Xk\[ n`k_ `eZi\d\ekXc g\eXckp Xk f %`\( f( .f( /f( w& lek`c k_\ lgg\i Yfle[ 
of the 2-sided 95% CI for the adjusted mean difference is 0.3%. The range of penalty values 
will include the non-inferiority margin of 0.3% to evaluate bias toward the null. 
6. For superiority of sotaglifozin 400 mg versus placebo on HbA1c reduction, steps 2 to 4 will 
Y\ i\g\Xk\[ n`k_ `eZi\d\ekXc g\eXckp Xk f %`\( f( .f( /f( w& letil the p-value for treatment 
effect of sotaglifozin 400 mg compared to placebo estimated in Steps 2 to 4 is 0.05. 

Similarly, the tipping point analysis will be conducted for the sotaglifozin 400 mg versus 
glimepiride non-inferiority endpoint only if the primary efficacy endpoint analysis yields a 
statistically significant finding and the upper bound of the 2-sided 95% CI associated with the non-
inferiority test is < 0.3%. 
In addition to the tipping point analyses, if the retrieved dropout imputation is applied to the primary 
analysis, the analysis based on the washout imputation (ie, the backup imputation method) will be 
presented as a sensitivity analysis. 
Assessment of treatment effect by subgroup 
Descriptive analyses will be performed on the primary endpoint to summarize the treatment 
effects across subgroups defined by the following Baseline or Screening factors: 

Race (White, Black or African American, Asian, Other) (any race groups with fewer than 
5 patients may be combined with  category as appropriate). 

Ethnicity (Hispanic, Not Hispanic). 

Age group (<50 year (any category with fewer than five 
patients may be combined with another category as appropriate). 

Gender (Male, Female). 

2). 

. 

Base. 


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
 m2 [Moderate decrease in 
<90 mL/min/1.73 m2  m2 [Normal]). 

Durati

Country. 
The treatment effects (sotagliflozin 400 mg versus glimepiride) across the subgroups defined for 
each of these factors will be estimated for the change from Baseline to Week 52 in HbA1c in the 
ITT population, and using the retrieved dropouts method if there are at least 5 patients in each 
study treatment group who discontinued but have the endpoint. Otherwise, the washout 
imputation method will be used.  The ANCOVA model will include treatment groups 
(sotagliflozin 400 mg, sotagliflozin 200 mg, glimepiride, and placebo), randomization stratum of 
%, >8.5%), randomization stratum of SBP at Screening (<130 mmHg, 
r, treatment-by-subgroup factor and country as fixed factors, and 
baseline HbA1c value as a covariate.  The adjusted estimates of treatment mean differences 
(sotagliflozin 400 mg versus glimepiride) with standard error (SE) and 95% CIs will be provided 
as appropriate across the subgroups.  A graphical presentation of the results (ie, forest plot) will 
also be provided. 
In the event that the subgroup factor is identical or similar to a randomization strata factor 
(eg, Baseline HbA1c category or Baseline SBP category) or country, only the subgroup factor 
(as a single factor or an interaction term) will be included in the model in order to avoid the issue 
of collinearity in the analysis.  The corresponding strata factor or country will not be included in 
the model. 
Summary statistics at scheduled visits 
Summary statistics (for screening value, baseline value, observed postbaseline value and its 
changes from baseline) at scheduled visits will be provided for each treatment group.  The 
summary will include the number of observations, mean, SD, SE, minimum, median, and 
maximum.  Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits. 
Similar presentations will be provided excluding measurements after rescue therapy during the 
52-week double-blind treatment period. 
2.4.4.2 Analyses of secondary efficacy endpoints  
For continuous secondary efficacy parameters (see Section 2.1.3) with missing data at baseline, 
missing data will be imputed using MI under the missing at random (MAR) assumption.  Missing 
data at baseline will be imputed using regression method that includes randomization stratum of 
Screening Screening SBP (<130, 
 mmHg), and baseline value in the imputation model. 
Each continuous secondary efficacy endpoint (Section 2.1.3) will be analyzed using a similar 
ANCOVA model including the measurements at baseline and endpoint (observed or imputed). 


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The missing data at endpoint will be imputed by the retrieved dropouts if there are at least 5 
patients in each study treatment group who discontinued but have the endpoint. Otherwise, the 
washout imputation method will be used. After the imputation, each of the complete datasets will 
be analyzed by an ANCOVA model. 
The ANCOVA model will include treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, 
glimepiride, and placebo

baseline secondary endpoint value as a covariate. For the analysis of SBP in patients with baseline 

complete dataset will be combined using Rubins formula to provide the adjusted mean change 
from Baseline to Week 52 (or Week 12 for SBP) for each treatment group, as well as the between-
group differences and the 95% CIs for the differences. 
For all continuous secondary endpoints, summary statistics at scheduled visits will be provided for 
each treatment group.  The summary will include the number of observations, mean, SD, SE, 
minimum, median, and maximum.  Graphical presentations will also be used to examine trends over 
time using mean values (±SE) and mean changes from Baseline (±SE) at each of the scheduled 
visits.  In addition, SBP will be summarized descriptively at each visit for those with baseline SBP 
130 mmHg. 140 mmHg. 
The categorical secondary efficacy variables of HbA1c <6.5%, <7% at Week 52 will be analyzed 
respectively using a Cochran-Mantel-Haenszel (CMH) method stratified by randomization stratum 

proportion in each treatment group will be provided, as well as the difference of proportions 
between sotagliflozin 400 mg and placebo with associated 2-sided 95% CI. For HbA1c responders 
at Week 52 (<6.5%, <7% respectively), all values at Week 52 will be used to determine whether a 
patient is a responder or not, even if they are measured after IMP discontinuation or rescue 
medication use. Patients who have no HbA1c measurement at Week 26 will be treated as non-
responders. Summary tables and graphs will also be provided by treatment group at scheduled visits. 
For between-group comparison, a sensitivity analysis will be performed respectively for HbA1c 
<6.5% responder analysis by excluding patients whose HbA1c values at baseline are <6.5%, and 
for HbA1c <7% responder analysis by excluding patients whose HbA1c values at baseline are <7% 
using the same CMH test mentioned above. Similarly, by-visit summary may also be provided 
excluding those patients. 
The categorical secondary endpoint, the proportion of patients with at least one documented 
3.9 mmol/L [70 mg/dL]) during the 52-week Treatment 
Period, will be analyzed respectively using a Cochran-Mantel-Haenszel (CMH) method stratified 
by randomization stratum of Srandomization stratum of 
S The proportion in each treatment group will be 
provided, as well as the difference of proportions between sotagliflozin 400 mg group and 
glimepiride group with its associated 2-sided 95% CI.  Summary tables and graphs will also be 
provided by treatment group at scheduled visits. 
Sensitivity analyses 


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Tipping-point analysis similar to that is described in Section 2.4.4.1 will be performed to evaluate 
the robustness of the treatment effect on HbA1c data for the following comparisons, using the 
same MI method and similar ANCOVA model for the primary endpoint analysis: 

Superiority comparison of sotagliflozin 400 mg and placebo on change from Baseline to 
Week 26. 

Superiority comparison of sotagliflozin 200 mg and placebo on change from Baseline to 
Week 26. 

Non-inferiority comparison of sotagliflozin 200 mg and glimepiride on change from 
Baseline to Week 52. 

Superiority comparison of sotagliflozin 400 mg and glimepiride on change from Baseline 
to Week 52. 
Missing data will be imputed at Week 26 or Week 52 as appropriate.  The sotagliflozin groups will 
be penalized incrementally by a penalty, and repeated until the upper bound of the 2-sided 95% CI 
is  for the non-inferiority comparison or until the p-value for treatment effect between the 
two treatment groups is >0.05 for the superiority comparison, respectively. 
The tipping-point analysis will be performed only if the respective secondary endpoint comparison 
is statistically significant at a two-sided  = 0.05. 
A sensitivity analysis will also be conducted with the treatment completers (ie, all patients who 
complete the 26-week double-blind treatment period and do not start rescue therapy) for 
noninferiority of sotagliflozin 400 mg versus glimepiride on HbA1c reduction using the same 
ANCOVA model described in Section 2.4.4.1. The washout imputation method will be used, where 
missing endpoint data in all treatment groups are imputed from a model estimated from patients in 
the placebo group who have the endpoint data available. The imputation model will include the 
randomization strata and the corresponding baseline value. Missing data will be imputed using the 
regression method. 
Assessment of treatment effect by subgroup 
Similar to that is described in Section 2.4.4.1, the treatment effects for the following treatment group 
comparisons across subgroups will be estimated for the change from Baseline in HbA1c in the ITT 
population, and using the same MI method for the primary endpoint analysis: 

Sotagliflozin 400 mg group vs. placebo group at Week 26. 

Sotagliflozin 200 mg group vs. placebo group at Week 26. 

Sotagliflozin 200 mg group vs. glimepiride group at Week 52. 
The ANCOVA model will include treatment groups (sotagliflozin 400 mg, sotagliflozin 200 mg, 
glimepiride, and placebo groups), randomization stratum of Screening 5%, >8.5%), 
randomization stratum of Screening Hg), subgroup factor, 
treatment-by-subgroup factor, and country as fixed factors and using baseline HbA1c value as a 


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covariate.  The adjusted estimates of treatment mean differences with SE and 95% CIs will be 
provided as appropriate across the subgroups.  A graphical presentation of the results (ie, forest 
plot) will also be provided. 
2.4.4.3 Analysis of other efficacy endpoints  
The analysis of other endpoints (see Section 2.1.3.3) will be descriptive with no formal testing.  
Summary statistics at scheduled visits based on observed value will be provided by each treatment 
group.  Graphical presentations will also be used to illustrate trends over time as appropriate. 
Hospital visits due to hypoglycemia includes emergency room visit, outpatient visit and any 
hospitalization due to hypoglycemia.  It is identified in e-CRthose 
As a result of this hypoglycemia event, did a hospital 
visit occur?The number (%) of patients with hospital visits due to hypoglycemia will be provided 
by each treatment group during the TEAE period defined for hypoglycemia, as well as the incidence 
rate in patient years if any patients have multiple hospital visits due to hypoglycemia.  The number 
(%) of patients who used rescue therapy and a KM curve for the time-to-first rescue therapy will be 
provided by treatment group.  A list of patients who used rescue therapy will also be provided (see 
Section 2.5.4).   
For the categorical endpoints of HbA1c responders (<6.5% and <7%, respectively) and HbA1c 
responders with no hypoglycemic event, summary tables and graphs will be provided by each 
treatment group at scheduled visits.  All values will be used to determine whether a patient is a 
responder or not at each visit, even if they are measured after IMP discontinuation or rescue 
medication use.  Patients who have no HbA1c measurement at each scheduled visit will be treated 
as non-responders.  For the composite endpoint of HbA1c responders and no documented 
symptomatic hypoglycemic event, a patient will be treated as a responder only if the criterion is 
met for each component. 
2.4.4.4 Multiplicity issues  
To control for the family-wise Type I error, a fixed-sequence testing procedure will be applied. 

The primary endpoint of the HbA1c change from Baseline to Week 52 comparing 
sota = 0.025 (1-sided) using a non-
inferiority margin of 0.3% of HbA1c change.  Once the non-inferiority is declared (the 
upper bound of the 2-sided 95% CI of the adjusted mean difference between sotagliflozin 
400 mg and glimepiride is <0.3%),  the following secondary hypothesis based on change 
from Baseline scores will be tested in the following prioritized order :The superiority of 
sotagliflozin 400 mg compared to glimepiride on: 
-
Change in body weight from Baseline to Week 52, 
-
, 
-
Change in SBP from Baseline to Week 12 in all patients, 


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-
The proportion of patients with at least one documented symptomatic hypoglycemic 
event  mg/dL) during the 52-week Treatment Period. 

The superiority of sotagliflozin 400 mg compared to placebo on the change in HbA1c 
from Baseline to Week 26. 

The superiority of sotagliflozin 200 mg compared to placebo on the change in HbA1c 
from Baseline to Week 26. 

The superiority of sotagliflozin 400 mg compared to placebo on: 
-
Change in body weight from Baseline to Week 26, 
-
, 
-
Change in SBP from Baseline to Week 12 in all patients. 

The non-inferiority of sotagliflozin 200 mg compared to glimepiride on the change in 
HbA1c from Baseline to Week 52. 

The superiority of sotagliflozin 400 mg compared to glimepiride on the change in HbA1c 
from Baseline to Week 52. 
If any hypothesis is found to be not statistically significant, the testing procedure will be stopped 
and the following hypotheses will not be tested. The non-inferiority hypothesis will be declared 
significant if the upper bound of the 2-sided 95% CI for the adjusted mean difference is <0.3. 
The superiority hypothesis will be declared statistically significant 
-sided). 
No multiplicity adjustment will be made on efficacy variables other than those mentioned above. 
2.4.5 Analyses of safety data  
The summary of safety results will be presented by treatment group. 
Section 2.1.4 is applicable to all safety analyses for the 
classification of AEs, determination of treatment-emergent PCSA values and the last on-treatment 
value for the laboratory, vital sign and ECG. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 

Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately. 

The baseline value (with the exception of serum creatinine and eGFR) is defined as the 
last available value before the first dose of double-blind IMP.  For serum creatinine and 
eGFR, the baseline value is defined as the average of all values before the first dose of 
double-blind IMP. 


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
The PCSA values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review and defined 
by the Sponsor for clinical laboratory tests, vital signs, and ECG (Appendix B). 

PCSA criteria will determine which patients had at least one PCSA during the TEAE 
period, taking into account all evaluations performed during the TEAE period, including 
nonscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the on-treatment PCSA percentage.

The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the TEAE period by 
treatment group on the safety population. 

For laboratory parameters cited in the protocol as efficacy endpoints (including HbA1c 
and plasma glucose, etc), PCSA summaries will not be provided.  These parameters will 
be summarized in efficacy Section 2.4.4.  For creatinine and eGFR, PCSA summaries will 
be presented in safety Section 2.4.5 while descriptive summaries in efficacy Section 2.4.4.

For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from Baseline values by 
visit and treatment group.  Summaries will include the last on-treatment value.  The last 
on-treatment value is commonly defined as the value collected at the same day/time of the 
last administration of IMP.  If this value is missing, this last on-treatment value will be the 
closest value prior to the last dose administration. 

The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned.  Relative risks versus comparator (glimepiride or placebo) and their 
95% CIs may be provided, if relevant. 

Selected safety analyses will be summarized by age, gender, racial subgroups, and any 
pertinent subgroups (see details in Section 2.4.5.1 and Section 2.4.5.2). 
2.4.5.1 Analyses of hypoglycemia  
Analyses of hypoglycemia will be performed on the TEAE period as defined in Section 2.1.4.  
Hypoglycemia will be classified as severe hypoglycemia, documented symptomatic 
hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia or relative 
hypoglycemia (see Section 2.1.4.1).  
The number (%) of patients with any hypoglycemia, severe hypoglycemia and documented 
symptomatic hypoglycemia will be summarized respectively by treatment group during the TEAE 
period, as well as the incidence rate in patient years.  Two types of incidence rate will be 
presented: the number of patients with at least 1 event per 100 patient-years (calculated as the 
number of patients with at least 1 event / total exposure in 100 patient-years), and the number of 
events per 100 patient-years (calculated as the total number of events / total exposure in 
100 patient-years).  Note that exposure (in days) here is the duration of TEAE period, ie, duration 
of IMP treatment in days + 1 (see Section 2.1.4). 


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The summary of frequency and incidence rate in patient years for severe hypoglycemia or 
documented symptomatic hypoglycemia will be provided as appropriate by gender (Male, 
ican, Asian, 
Other). 
A KM curve will also be provided by treatment group for the time-to-first severe hypoglycemia or 
documented symptomatic hypoglycemia during the TEAE period (see Section 2.5.4). 
3.9 mmol/L (70 mg/dL) and 
<3.0 mmol/L (<54 mg/dL) respectively, as appropriate. 
A listing of patients for all events reported on the dedicated e-Hypoglycemic event 
information page will be provided with each category flagged (ie, severe hypoglycemia, 
documented symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic 
hypoglycemia, relative hypoglycemia). 
2.4.5.2 Analyses of adverse events  
Generalities 
The primary focus of adverse event reporting will be on TEAEs.  Pretreatment and posttreatment 
AEs will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, 
treatment-emergent, or posttreatment.  The algorithm for imputing date/time of onset will be 
conservative and will classify an adverse event as treatment emergent unless there is definitive 
information to determine it is pretreatment or posttreatment.  Details on classification of adverse 
events with missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted by the 
internationally agreed order for SOCs and in alphabetic order for HLGT, HLT and PT within a 
SOC for each treatment group, the number (n) and percentage (%) of patients experiencing an 
adverse event.  Multiple occurrences of the same event in the same patient will be counted only 
once in the tables within a treatment phase.  The denominator for computation of percentages is 
the safety population within each treatment group. 


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Sorting within tables ensures the same presentation for the set of all AEs within the observation 
period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the table of all 
TEAEs presented by SOC and PT sorted by the internationally agreed SOC order and decreasing 
frequency of PTs within SOCs will define the presentation order for all other tables unless 
otherwise specified.  In case of equal frequency regarding PTs, alphabetical order will be used. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the safety population. 

Overview of TEAEs, summarizing number (%) of patients with any 
-
TEAE, 
-
Serious TEAE, 
-
TEAE leading to death, 
-
TEAE leading to permanent treatment discontinuation. 

All TEAEs by primary SOC, showing number (%) of patients with at least one TEAE, 
sorted by internationally agreed order of primary SOC.  

All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least one TEAE sorted by the SOC internationally agreed order.  The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order. 

Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT in the sotagliflozin 400 mg group.  

All TEAEs by primary SOC and PT, showing the number (%) of patients with at least one 
TEAE, sorted by the internationally agreed SOC order and by decreasing incidence of PTs 
within each SOC in the sotagliflozin 400 mg group.  This sorting order will be applied to 
all other tables, unless otherwise specified. 

All TEAEs regardless of relationship and related to IMP, by primary SOC, HLGT, HLT 
and PT, showing the number (%) of patients with at least one TEAE, sorted by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 

All TEAEs by maximal severity, presented by primary SOC and PT, showing the number 
(%) of patients with at least one TEAE by severity (ie, mild, moderate, or severe), sorted 
by the sorting order defined above. 

Common TEAEs (PTs with an incidence 2% in any treatment group) by primary SOC, 
HLGT, HLT, and PT, sorted by internationally agreed order of SOCs.  The other levels 
(HLGT, HLT, PT) will be presented in alphabetic order. 

Common TEAEs (PTs with an incidence 2% in any treatment group) will be provided as 
appropriate by primary SOC and PT and by demographic factors including gender (Male, 

American, Asian, other), baseline SBP category (), and baseline 
eGFR category /1.73 m2 [Modera


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<90 mL/min/1.73 m2 /1.73 m2 [Normal]). SOC 
will be sorted by internationally agreed order and the PT level by decreasing incidence 
within each SOC in the sotagliflozin 400 mg group, as described above.  


HLT, and PT, sorted by internationally agreed order of SOCs.  The other levels (HLGT, 
HLT, PT) will be presented in alphabetic order. 
Analysis of all treatment emergent serious adverse event(s) 

All serious TEAEs by primary SOC, HLGT, HLT, and PT, showing the number (%) of 
patients with at least one serious TEAE, sorted by the internationally agreed SOC order.  
The other levels (HLGT, HLT, PT) will be presented in alphabetical order. 

All serious TEAEs regardless of relationship and related to IMP, by primary SOC, HLGT, 
HLT, and PT, showing the number (%) of patients with at least one serious TEAE, sorted 
by the internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be 
presented in alphabetical order. 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 

All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients sorted by the internationally agreed SOC order.  The 
other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
Analyses of adverse events of special interest 
Pregnancy and overdose will be included in overall AE summaries if any are reported.  ALT 
increase >3 x ULN is included in laboratory PCSA summary if any.  
In addition, the number (%) of patients with an AESI will be summarized by PT and by treatment 
group.  Corresponding listings will be provided as appropriately.
Analyses of events of special interest 
CV events, bone fracture and DKA  
For EOSIs that are adjudicated (ie, deaths, myocardial infarction, stroke, and unstable angina 
requiring hospitalization, heart failure requiring hospitalization, bone fractures, and DKA), the 
number (%) of patients with an EOSI positively adjudicated by CEC will be summarized by 
treatment group.  All EOSIs sent for adjudication and/or reported by the Investigators in the 
specific AE forms will be listed along with the adjudication outcome. 


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Renal events 
For the EOSI renal events where selected events are adjudicated, the number (%) of patients with 
any renal events identified in Table 3 in Section 2.1.4.2 will be summarized by treatment group.  
The following renal events will be listed along with the adjudication outcome if applicable, 
including events,  
A) Recorded in e-
B) Recorded in e-- 
C) I-CRF 
Renal death will be part of all deaths specified above. 
Other EOSIs  
For EOSIs that are not adjudicated, the number (%) of patients with at least one event will be 
summarized by treatment group and by PT (as identified in Table 3 in Section 2.1.4.2.  
Severe hypoglycemia will be included in the summary of hypoglycemia (see Section 2.4.5.1). 
Adverse event (AE) leading to an amputation is described in the section below. 
Analysis of Amputation 
The number (%) of patients with amputation will be summarized by treatment group and by PT 
and LLT during the study (ie, regardless of on- or post-treatment).  Amputation is a procedure 
recorded in e- Patients who had a procedure 
related to amputation will be listed. 
The number (%) of patan 
treatment group and by PT.  
identifier recorded in e-
chosen as the reason for the amputation procedure. 

summarized by treatment group and by PT (as identified in Table 3 in Section 2.1.4.2).  These 
PTs in Table 3 were requested by the European Medicines Agency (EMA)/ Pharmacovigilance 
Risk Assessment Committee (PRAC) Assessment Report, 9 February 2017). The associated list 
will be provided as well, with patients who had an amputation procedure flagged.  

procedure, but not in all cases an amputation has occurred. 


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Analysis of pretreatment and posttreatment adverse events  

All pretreatment AEs by primary SOC and PT, showing the number (%) of patients with at 
least one pretreatment AE, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC in the sotagliflozin 400 mg group. 

All posttreatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least one posttreatment AE, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs within each SOC in the sotagliflozin 400 mg group. 
Listings 
Supportive AE listings will be provided for all AEs, SAEs, death, AEs leading to treatment 
discontinuation and/or death, and EOSI as appropriate.  Listing of all AEs, SAEs and AEs leading 
to treatment discontinuation and/or death, sorted by treatment, patient identification, and onset 
date, will include the following information: treatment, patient identification, country, age, 
gender, race, BMI, primary SOC, PT, reported term, onset date, study day (relative day to the start 
date of double-blind IMP), AE duration, duration of exposure, intensity, corrective treatment, 
action taken with IMP, date of treatment discontinuation (if relevant), relationship to IMP 
(Capsule and Tablet) or NIMP, outcome, date of death (if any), seriousness, seriousness criteria, 
and AE status (En on-study posttreatment AE). 
2.4.5.3 Deaths  
The following summaries of deaths will be generated. 

Number (%) of patients who died by study period (on-study, on-treatment, poststudy). 

Deaths in nonrandomized patients or randomized but not treated patients. 

TEAEs leading to death (death as an outcome on the AE e-CRF page as reported by the 
Investigator) by primary SOC , HLGT, HLT, and PT showing number (%) of patients 
sorted by internationally agreed SOC order, with HLGT, HLT, and PT presented in 
alphabetical order within each SOC.  
2.4.5.4 Analyses of laboratory variables  
Laboratory parameters will be grouped and summarized by biological function as described 
in Section 2.1.4.4. 
The summary statistics (including number, mean, median, Q1, Q3, SD, minimum and maximum) 
of all laboratory variables (central laboratory values and changes from baseline) will be calculated 
for each visit or study assessment (screening, baseline, each postbaseline time point, last 
on-treatment) by treatment group. 
The incidence of PCSAs (list provided in Appendix B) at any time during the TEAE period will 
be summarized for each laboratory test by biological function and treatment group whatever the 
baseline level and/or according to the following baseline status categories:  

Normal/missing. 


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
Abnormal according to PCSA criterion or criteria. 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
All measurements collected during the TEAE period, including values from unscheduled visits, 
will be considered for the PCSA summaries.  These summaries will include patients in the safety 
population who have at least one assessment performed during the TEAE period.  When a PCSA 
definition involves a change from baseline value, patients must also have a baseline value to be 
included in the summaries, and when required by the definition of the abnormality, patients must 
also have available laboratory normal ranges. 
A listing of patients with at least one postbaseline PCSA (or out of normal range when no PCSA 
criterion is defined) will be provided which 
all parameters belonging to the corresponding biological function.  Individual data listings will 
include the following flags when applicable: 

Base. 

Normal laboratory ranges, available for most laboratory parameters, will be identified as 
ULN and lower limit of normal (LLN).  Baseline, last on-treatment value, and individual 
 the value is below the LLN and will be fla
above the ULN. 

Laboratory PCSA criteria will be used for the corresponding laboratory parameters.  
Values reaching a PCSA limit will be flagged (+, ++, -, or -- depending upon the direction 
and level of the abnormality).  Flags for white blood cell (WBC) and differential counts 
will be determined using data expressed in international units. 

expressed as a multiple of the ULN in the individual data provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, ALP, and total bilirubin, are used to assess possible 
drug-induced liver toxicity.  The proportion of patients with PCSA values at any postbaseline visit 
by baseline status will be displayed by treatment group for each parameter.  The proportion of 
patients with PCSA values at any postbaseline visit will also be displayed by duration of exposure 
for each treatment group (only if a tabulation summary is necessary).  
law cases identified by treatment group (eg, patients with any elevated 
ALT>3 x  x ULN) with ALT, AST, ALP, 
total bilirubin, and the following complementary parameters (if available): conjugated bilirubin 
and prothrombin time/international normalized ratio, creatine phosphokinase, serum creatinine, 
complete blood count, anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA, anti-CMV IgM 
and anti-HEV IgM antibodies, auto-antibodies: anti-nuclear, anti-DNA, anti-smooth muscle, 
Epstein-Barr virus, herpes viruses, and anti-LKM.  


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2.4.5.5 Analyses of vital sign variables  
The summary statistics (including number, mean, median, Q1, Q3, SD, minimum and maximum) 
of heart rate, temperature and respiratory rate (observed values or mean of observed values, and 
changes from baseline) will be calculated for each applicable visit or study assessment (baseline, 
each postbaseline time point, last on-treatment) by treatment group. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group for SBP, DBP and HR.  All measurements collected during the TEAE period, including 
values from unscheduled visits, will be considered for the PCSA summaries.  The summaries will 
include patients in the safety population who have at least one assessment performed during the 
TEAE period.  When a PCSA definition involves a change from baseline value, patients must also 
have a baseline value to be included in the summaries. 
A listing of patients with at least one postbaseline PCSA will be provided and will display the 
 Individual data listings will include the 
following flags: 

Base

Parameter values reaching a PCSA limit will be flagged (+, or - depending of the 
direction). 
2.4.5.6 Analyses of electrocardiogram variables  
A shift table will be provided to present the ECG on-treatment status according to the baseline 
status (Normal/Missing, Abnormal) for each treatment group during the TEAE period.  
Supportive listings of patients with abnormal ECG status at any postbaseline visit will be 
provided. 
2.4.5.7 Analyses of physical examination variables  
Shift tables will be provided to present physical examination findings by body system according 
to baseline status (Normal/Missing, Abnormal) for each treatment group during the TEAE period.  
Supportive listings of patients with abnormal findings at any postbaseline visit will be provided. 
2.4.6 Analyses of quality of life variables  
The analysis method for this exploratory analysis will be provided in a separate SAP and the 
analyses results will be documented in a separate report. 


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2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computation of parameters. 
HbA1c 
The formula to convert HbA1c from Diabetes Control and Complications Trial (DCCT) aligned 
value to International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) 
standardized value is, 
IFCC-HbA1c (mmol/mol) = [DCCT-HbA1c (%) - 2.15] x 10.929. 
Renal function formulas  
The estimated GFR (mL/min/1.73 m2) will be calculated using the 4 variable Modification of Diet 
in Renal Disease (MDRD) formula:  
Standard unit: eGFR (mL/min/1.73 m2) = 175 x [Serum Creatinine (µmol/L)/88.4] -1.154 x 
Age (year) -0.203 x 1.212 (if Black) x 0.742 (if Female).
Conventional unit: eGFR (mL/min/1.73 m2) = 175 x Serum Creatinine (mg/dL) -1.154 x 
Age (year) -0.203 x 1.212 (if Black) x 0.742 (if Female). 
Calculation of LDL-C 
When triglycerides (TG) is lower than or equal to 4.52 mmol/L (400 mg/dL), LDL-C is calculated 
using the Friedewald equation as: 

In standard unit (mmol/L), TC - HDL-C - TG/2.17. 

In conventional unit (mg/dL), TC - HDL-C - TG/5. 
2.5.2 Data handling conventions for secondary efficacy variables  
Scheduled measurements (see Section 2.5.4) of continuous efficacy variables collected during the 
study will be used in the analyses including those obtained after IMP discontinuation or 
introduction of rescue therapy.  Continuous secondary efficacy endpoints will be analyzed with 
missing values imputed by the retrieved dropouts MImethod (if there are at least 5 patients in each 
study treatment group who discontinued but have the endpoint) or washout MI method according 
to the criterion described in Section 2.4.4.1. 
For the categorical secondary efficacy endpoints, data handling conventions are described in 
Section 2.4.4.2. 


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2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Derived variables will be considered missing if any of the original variables required to calculate 
them are missing.  For example, if either a baseline assessment or an endpoint assessment is 
missing for a particular patient, then change from baseline at endpoint will be missing.  
Depending upon the assessment, analyses may not include all patients in the analysis population, 
because certain patients in the intended population may have missing data. 
Incomplete date of first administration of double-blind IMP 
Date/time of first administration is the first non-missing start date/time of double-blind IMP 
completed in the e-
For patients who are randomized and dispensed a double-blind treatment kit but who are lost to 
follow-up just after Visit 3 (eg, only the treatment kit number is reported in the e-
- Treatment Period (Capsule)- Treatment Period (Tabletmodule without any 
dose information), the date of first administration will be imputed using the date of randomization.  
for both Capsule and 
Tablet in the e-
Handling of computation of treatment duration if IMP end of treatment date is missing
For the calculation of the treatment duration, the date of the last dose of double-blind IMP is equal 
to the date of last administration reported on the e-CRF Status Lpage.  If this 
date is missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and posttreatment medication. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset
Missing or partial adverse event/hypoglycemia onset dates and times will be imputed so that if the 
partial adverse event/hypoglycemia onset date/time information does not indicate that the adverse 
event/hypoglycemia started prior to treatment or after the TEAE period, the adverse 
event/hypoglycemia will be classified as treatment-emergent.  No imputation of adverse 
event/hypoglycemia end dates/times will be performed.  These data imputations are for 
categorization purpose only and will not be used in listings.  No imputation is planned for 
date/time of adverse event/hypoglycemia resolution. 


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Handling of adverse events/hypoglycemia when date and time of first IMP administration is 
missing
When the date and time of the first double-blind IMP administration is missing, the day of 
randomization should be considered as the start date of TEAE period (see Section 2.1.4).  The 
exposure duration should be kept as missing. 
Handling of adverse events/hypoglycemia when IMP end of treatment date is missing
For the purpose of defining TEAE period, the date of the last administration of double-blind IMP 
is equal to the date of the last administration reported on the e-CR
page.  
If the date of last administration reported on the e-

Partially missing, it will be imputed with a date as late as possible before or on the date of 
last available information on e--.  

Completely missing, it will be imputed with the date of last available information on 
e-- page.  
If the date of last available information on e-Study/Follow- page 
is  

Partially missing, it will be imputed with a date as late as possible. 

Completely missing, all adverse events occurred on or after the first administration of 
double-blind IMP will be considered as TEAEs.  
Handling of missing assessment of relationship of adverse events to IMP (Capsule or Tablet)
If the assessment of the relationship to glimepiride or matching placebo (Capsule) is missing, then 
the relationship to Capsule has to be assumed and the AE considered as such in the frequency 
tables of possibly Capsule-related AEs.  If the assessment of the relationship to sotagliflozin or 
matching placebo (Tablet) is missing, then the relationship to Tablet has to be assumed and the 
AE considered as such in the frequency tables of possibly Tablet-related AEs.  No imputation 
should be done at the data level. 
Handling of missing severity/grades of adverse events 
If the severity/grade is missing for one of the treatment-emergent occurrences of an AE, the 
maximal severity on the remaining occurrences will be considered.  If the severity is missing for 
all the occurrences, the summary table. 
Handling of potentially clinically significant abnormalities 
If a patient has a missing baseline he will be grouped in the category normal/missing at 
baseline.


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For PCSAs with two conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN 
 When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
Linked adverse events that worsened or became serious 
An AE that worsened or became serious will have a separate record in the data from the original 
event record with an AE identification number that links the new record to the original record.  An 
AE that worsened or became serious will be considered a new recurring AE in the summary of 
recurrent events or in the summary of events by time intervals. 
Handling of missing data for continuous efficacy endpoints 
Please see Section 2.4.4.1 and Section 2.4.4.2. 
Handling of missing data for categorical secondary efficacy endpoints 
Please see Section 2.4.4.2. 
2.5.4 Windows for time points  
The following steps will decide how the scheduled and/or unscheduled visits will be used in the 
analyses on efficacy variables and the by-visit summaries for safety variables (clinical laboratory 
data in Section 2.1.4.4 and vital signs in Section 2.1.4.5). 
Step 1: A scheduled measurement will be used if it is available; otherwise, an unscheduled 
measurement (including the end of treatment/study visit for those prematurely discontinued) will 
be used if it happens to be on the same date as the date of the scheduled visit. 
Step 2: After Step 1, if there is still no measurement for a given parameter at a scheduled visit, the 
analysis window below (Table 4) will be applied to re-allocate a postbaseline unscheduled 
measurement to a scheduled measurement. 
Table 4 - Analyses window definition  
Scheduled visit post baseline 
Targeted study day 
Analysis window in study 
days 

















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Scheduled visit post baseline 
Targeted study day 
Analysis window in study 
days 











After applying the above time windows, if multiple assessments are associated to the same time 
point, the closest from the targeted study day will be used.  In case of equality, the last 
measurement will be used.  Re-allocated scheduled visits (ie, visit numbers) should be sequential 
if ordered by the date of measurement. 
After Step 2, if there is still no measurement for a given parameter at a scheduled visit, data are 
considered missing for efficacy analyses, where MI would be applied as appropriately as 
described in Section 2.4.4.  
Reference day 
The reference day for the calculation of extent of exposure, time to onset, and relative days will be 
the day of the first administration of double-blind IMP or the day of randomization if not exposed 
to double-blind IMP, denoted as Day 1. 
Baseline definition for efficacy/safety data 
For the safety analyses, the baseline for a given parameter is defined as the last available 
measurement (or the average of all measurements for creatinine and eGFR), including 
unscheduled assessments, assessed prior to the first administration of double-blind IMP.  For the 
efficacy analyses, the baseline for a given parameter is defined as the last available measurement 
(or the average of all measurements for creatinine and eGFR), including unscheduled assessments, 
assessed prior to the first administration of double-blind IMP or the last available value (or the 
average of all measurements for creatinine and eGFR) before randomization if not treated with 
double-blind IMP.  
Summary statistics by visit for continuous efficacy endpoints 
Summary statistics (number, mean, SD, SE, minimum, median, maximum) of continuous efficacy 
endpoints (observed data and change from baseline) will be provided at scheduled visits as per 
protocol.  Summaries showing data by visit will be presented according to the visit number (or 
re-allocated visit number, see Section 2.5.4) and labeled with the targeted approximate day/week.  
Last on-treatment value for laboratory variables and vital signs 
The last on-treatment value is the final measurement assessed during the treatment epoch, 
regardless of the introduction of rescue therapy, including measurements at unscheduled visits.  
Please see details in Section 2.1.4 and Section 2.4.5. 


Statistical Analysis Plan 
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Display of safety data by visit (laboratory variables and vital signs)  
Descriptive statistics (number, mean, SD, minimum, median, maximum) of quantitative 
laboratory variables and vital signs (observed data and change from baseline) during the TEAE 
period will be provided at scheduled visits.  In addition, these summaries will also include a row 
for the last value on-treatment to describe the last available on-treatment value (see above).  
Summaries showing data by visit will be presented according to the visit number (or re-allocated 
visit number, see Section 2.5.4) and labeled with the targeted approximate day/week. 
As specified in the study protocol, laboratory data from scheduled visits are reported by central 
laboratories.  The local results will not be used in the efficacy analyses or in the definition of 
baseline for both safety and efficacy analyses.  In the safety analyses, local results will only be 
used in the PCSA summary if they are accompanied by a local laboratory normal range. 
When a patient has more than one measurement from the central laboratory for the same 
laboratory parameter on the same date, the average of the measurements will be used.  For the 
same laboratory parameter, if a patient has more than one measurement on different dates for the 
same scheduled visit, the value closest to the date of the visit will be used for the scheduled visit.  
When the values for the same scheduled visit are equidistant, the last value should be used for the 
scheduled visit.  Similar rules will be applicable to a patient who has more than one set of 
measurements for the same vital sign parameter (ie, SBP, DBP, or HR) on the same date. 
Time-to-event analysis  
For time-to-event analysis/KM plot, time-to-event (eg, treatment discontinuation, rescue therapy, 
hypoglycemia, etc) is defined as the number of days from the date of the first administration of 
double-blind IMP (or the date of randomization if not exposed) to the start date of the 
first occurrence of the event during the 52-week double-blind treatment period.  
Patients who did not experience any event during the 52-week double-blind Treatment Period are 
considered censored observations.  For time-to-treatment discontinuation/rescue therapy, 
censoring date is the date of EOT.  For time-to-severe or documented hypoglycemia, censoring 
date is date of EOT + 1 or date of EOS, whichever is the earliest.  Date of EOS will be used if 
date of EOT is not available.  Last contact date will be used if date of EOS is not available. 
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline, the last on-treatment value, PCSAs and the shift summaries for safety or 
efficacy.  They will be included in the by-visit summaries if they are re-allocated to scheduled 
visits (see Section 2.5.4). 


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 63 of 95
2.5.6 Pooling of centers for statistical analyses  
Center will not be included in the statistical models for efficacy analyses.  However, all centers 
within a country will be pooled, and country will be included as a fixed effect in a parametric 
statistical model (eg, ANCOVA model) for the primary and secondary efficacy endpoints.  
Countries with fewer than five randomized patients will be grouped with the country with the 
lowest number of patients that is five or more. 
2.5.7 Statistical technical issues  
None. 


Statistical Analysis Plan 
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Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 64 of 95
3 
INTERIM ANALYSIS  
There are no formal interim analyses for efficacy planned for this study.  The study will not be 
terminated early for excellent efficacy. 
An independent Data Monitoring Committee (DMC) will be used to monitor and assess the safety 
of patients from this trial through periodic review of the accumulated safety data provided by an 
independent statistical group.  Related details are provided in separate documents (DMC Charter 
and DMC SAP). 


Statistical Analysis Plan 
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Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
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COVANCE INC. CONFIDENTIAL 
Page 65 of 95
4 
DATABASE LOCK  
The database lock was on the 12Sep2019. 


Statistical Analysis Plan 
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Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 66 of 95
5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS® Version 9.2 or higher. 


Statistical Analysis Plan 
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Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 67 of 95
6 
REFERENCES  
Not Applicable. 


Statistical Analysis Plan 
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Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 68 of 95
7 
LIST OF APPENDICES  
Appendix A 
Mapping of inclusion and exclusion criteria under the original protocol and 
amendment
Appendix B
Potentially clinically significant abnormalities criteria
Appendix 
CC
List of PTs for select EOSIs (MedDRA V22) 
Appendix 
DD
Summary of statistical analyses 
Appendix E
Study flow chart


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 69 of 95
Appendix A 
Mapping of inclusion and exclusion criteria under the original 
protocol and amendment  
Order 
Original Protocol 
Amendment 1 
CSR Display 
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Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 70 of 95
Order 
Original Protocol 
Amendment 1 
CSR Display 





Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 71 of 95
Appendix B 
Potentially clinically significant abnormalities criteria  
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
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Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 72 of 95
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 


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






















































Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 73 of 95
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 

























































Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 74 of 95
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 
































Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 75 of 95
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
(From BTD-009536 May 21, 2014) 
Parameter 
PCSA 
Comments 



















































Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 76 of 95


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 77 of 95
Appendix C 
List of PTs for select EOSIs (MedDRA V22)  
EOSI 
Preferred Term 
Code 
Preferred Term  































































































Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 78 of 95
EOSI 
Preferred Term 
Code 
Preferred Term  




















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


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 79 of 95
EOSI 
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


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 80 of 95
EOSI 
Preferred Term 
Code 
Preferred Term  
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


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 81 of 95
EOSI 
Preferred Term 
Code 
Preferred Term  

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

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



Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 82 of 95
EOSI 
Preferred Term 
Code 
Preferred Term  
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


Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 83 of 95
EOSI 
Preferred Term 
Code 
Preferred Term  


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Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 84 of 95
EOSI 
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









Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 85 of 95
EOSI 
Preferred Term 
Code 
Preferred Term  
























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
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





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

















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




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
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

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
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
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





















Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 86 of 95
EOSI 
Preferred Term 
Code 
Preferred Term  


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






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


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
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
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



















































Statistical Analysis Plan 
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838 
  
Covance Study ID: 000000155206  
COVANCE INC. CONFIDENTIAL 
Page 87 of 95
EOSI 
Preferred Term 
Code 
Preferred Term  


















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








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
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



















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
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

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

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

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



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













Statistical Analysis Plan
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838
Covance Study ID: 000000155206
COVANCE INC. CONFIDENTIAL
Page 88 of 95
Appendix D
Summary of statistical analyses
EFFICACY ANALYSIS
Endpoint
Analysis
population
Primary
analysis
Supportive
analysis
Subgroup
analysis
Other
analyses
Primary endpoint




























Secondary endpoints















































Statistical Analysis Plan
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838
Covance Study ID: 000000155206
COVANCE INC. CONFIDENTIAL
Page 89 of 95
Endpoint
Analysis
population
Primary
analysis
Supportive
analysis
Subgroup
analysis
Other
analyses
Other endpoints

















































Statistical Analysis Plan
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838
Covance Study ID: 000000155206
COVANCE INC. CONFIDENTIAL
Page 90 of 95
SAFETY ANALYSES
Endpoint
Analysis 
population
Primary
analysis
Supportive
analysis
Subgroup
analysis
Other
analyses

















































Statistical Analysis Plan
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838
Covance Study ID: 000000155206
COVANCE INC. CONFIDENTIAL
Page 91 of 95
Appendix E
Study flow chart









































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Statistical Analysis Plan
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838
Covance Study ID: 000000155206
COVANCE INC. CONFIDENTIAL
Page 92 of 95


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Statistical Analysis Plan
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838
Covance Study ID: 000000155206
COVANCE INC. CONFIDENTIAL
Page 93 of 95


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Statistical Analysis Plan
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838
Covance Study ID: 000000155206
COVANCE INC. CONFIDENTIAL
Page 94 of 95


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



Statistical Analysis Plan
Version:3
Date of Issue: 03-Apr-2020
Lexicon Pharmaceuticals, inc. Protocol No. EFC14838
Covance Study ID: 000000155206
COVANCE INC. CONFIDENTIAL
Page 95 of 95
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