Clinical trial NCT03066830
Conditions: Type 2 Diabetes Mellitus
Sponsor: Lexicon Pharmaceuticals
Start date: 2017-02-24; Completion date: 2019-04-30
Enrollment: 507 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate the superiority of Sotagliflozin 400 milligrams (mg) versus placebo on Hemoglobin A1c (HbA1c) reduction at Week 26 in participant with type 2 diabetes (T2D) who have inadequate glycemic control with a Sulfonylurea alone or in combination with Metformin.

Secondary Objectives:

* To compare Sotagliflozin 400 mg versus placebo based on:
* Change from baseline in fasting plasma glucose (FPG).
* Change from baseline in systolic blood pressure (SBP) for participants with baseline SBP ≥130 millimeter of mercury (mm Hg).
* Change from baseline in SBP for all participants.
* Change from baseline in body weight.
* Percentage of participants with HbA1c \<6.5% and \<7.0%.
* To evaluate the safety of Sotagliflozin 400 mg versus placebo throughout the 79-week trial.

Detailed description:
The duration per participants is up to 85 weeks, including a Screening Period consisting of a Screening phase of up to 2 weeks and a 2-week single-blind Run-in phase, a 26-week double blind Core Treatment Period, a 53 week double blind Extension, and a 2-week post treatment Follow-up period to collect safety information.

Arms: arm 1: Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks. arm 2: Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Interventions: intervention 1: Sotagliflozin (SAR439954) intervention 2: Placebo intervention 3: Metformin intervention 4: Sulfonylurea
Intervention descriptions: intervention 1: Pharmaceutical form: tablet

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

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

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

Route of administration: oral

Protocol documents:
Prot_000.pdf: 
Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin 
Added to a Sulfonylurea alone or in combination with Metformin in 
Patients with Type 2 Diabetes Who Have Inadequate Glycemic 
Control on a Sulfonylurea Alone or with Metformin 
NCT Number: NCT03066830 
  Document Date: Protocol Version 2: 21-December-2017 


 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
 
 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 02 
COMPOUND: sotagliflozin/SAR439954 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study 
to Evaluate the Efficacy and Safety of Sotagliflozin Added to a Sulfonylurea alone 
or in combination with Metformin in Patients with Type 2 Diabetes Who Have 
Inadequate Glycemic Control on a Sulfonylurea Alone or with Metformin 
STUDY NUMBER: EFC14835 
STUDY NAME: SOTA-SU (SOTAgliflozin added to SUlfonylurea) 
VERSION DATE / STATUS: Approval date (20-Dec-2017) / Approved 
Protocol Amendment 02 
Version number: 1 (electronic 1.0) 
Date :20-Dec-2017 
Amended Clinical Trial Protocol 01 
Version number: 1 (electronic 1.0) 
Date :17-Jan-2017 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date: 17-Jan-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 2.0) 
Date : 04-Nov-2016 
EudraCT 
2016-002826-35 
IND Number(s) 
 
Version Number: 
1 
WHO universal trial number 
U1111-1186-2612 
Date: 
20-Dec-2017 
Total number of pages: 
112 
 
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Amended Clinical Trial Protocol No. 02  
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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
COMPOUND: sotagliflozin/SAR439954 
STUDY No.: EFC14835  
TITLE 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 
Study to Evaluate the Efficacy and Safety of Sotagliflozin Added to a 
Sulfonylurea alone or in combination with Metformin in Patients with Type 2 
Diabetes Who Have Inadequate Glycemic Control on a Sulfonylurea Alone 
or with Metformin 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVES 
 
Primary objective: 
The primary objective of this study is to demonstrate the superiority of 
sotagliflozin 400 mg versus placebo on hemoglobin A1c (HbA1c) reduction 
at Week 26 in patients with type 2 diabetes (T2D) who have inadequate 
glycemic control with a sulfonylurea alone or in combination with metformin. 
Secondary objectives: 
• 
To compare sotagliflozin 400 mg versus placebo for:  
- 
Change from Baseline in fasting plasma glucose (FPG) at 
Week 26 
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in systolic blood pressure (SBP) at 
Week 12 for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline in SBP at Week 12 for all patients 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• 
To evaluate the safety of sotagliflozin 400 mg versus placebo 
throughout the 79-week trial 
Other: 
• 
To compare sotagliflozin versus placebo based on other blood 
pressure (BP) endpoints 
• 
To compare sotagliflozin versus placebo with respect to change 
from Baseline in the following endpoints: 
- 
Estimated glomerular filtration rate (eGFR) 
- 
Reduction in body weight by ≥2%, ≥5%, and ≥10% 
• 
To compare sotagliflozin versus placebo for: 
- 
Change from Baseline in HbA1c at Week 79 
- 
Change from Baseline in FPG at Week 79 
- 
Change from Baseline in body weight at Week 79 
• 
To compare the use of rescue medications for hyperglycemia in 
the sotagliflozin and placebo treatment groups 
• 
To assess plasma concentrations of sotagliflozin and its 
3-O-glucuronide metabolite 
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STUDY DESIGN 
This is a Phase 3, multicenter, randomized, double-blind, placebo-
controlled, parallel-group study. 
Patients taking a sulfonylurea (≥half the maximum recommended dose as 
per local label or maximum tolerated dose [documented]) as monotherapy or 
in combination with metformin (≥1500 mg per day or maximum tolerated 
dose [documented]) each at a stable dose for at least 12 weeks before 
enrollment will be eligible for Screening. The number of patients taking a 
sulfonylurea and metformin will be limited to 330 patients, to ensure 
sufficient numbers of sulfonylurea monotherapy patients. 
All patients will have a Screening Period comprised of an up to 2-week 
Screening phase and a 2-week, single-blind placebo Run-in phase prior to 
randomization. In order to qualify for randomization, patients must 
demonstrate compliance based upon tablet count (≥80%) during the Run-in 
phase. 
Randomization will be stratified by:  
• 
HbA1c at Screening (≤8.5%, >8.5%) 
• 
Metformin use at Screening (Yes, No) 
• 
SBP at Screening (<130 mmHg, ≥130 mmHg) 
Following randomization, patients will have a 26-week, double-blind Core 
Treatment Period, a 53-week double-blind Extension Period, and a 2-week 
post-treatment Follow-up Visit. 
Patients will be randomly assigned 1:1 to 1 of the following 2 treatment 
groups: 
• 
Sotagliflozin 400 mg as two (2) 200 mg tablets, once daily 
• 
Placebo as two (2) placebo tablets (identical to sotagliflozin in 
appearance), once daily 
HbA1c and FPG will be masked to study sites and patients after 
randomization. Additionally, urinalysis by dipstick will not include the 
measurement of urine glucose.  
Early termination 
If a patient discontinues treatment with investigational medicinal product 
(IMP) early during the double-blind Core Treatment Period or the double-
blind Extension Period, the patient will have a Premature End-of-Treatment 
(EOT) Visit and a Follow-up Visit 2 weeks after the last dose of IMP. In 
addition, every effort will be made to have all patients return to the site at the 
time corresponding to their scheduled visits, particularly the Week 26 Visit 
and Week 79 Visit  emphasizing the collection of primary and main 
secondary endpoints. 
If a patient does not agree to site visits, he/she will be contacted by 
telephone to inquire about their safety status, particularly at the time of the 
initially scheduled Week 79 Visit. 
The study design is presented graphically at the end of the synopsis. 
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STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
• 
Patients with T2D taking a sulfonylurea (≥half the maximum 
recommended dose as per local label or maximum tolerated dose 
[documented]) as monotherapy or in combination with metformin 
(≥1500 mg per day or maximum tolerated dose [documented]) 
each at a stable dose for at least 12 weeks without a dose 
adjustment before Screening 
Note: The number of patients taking a sulfonylurea and metformin 
will be limited to 330 patients, to ensure sufficient numbers of 
sulfonylurea monotherapy patients. 
• 
Signed written informed consent 
Major exclusion criteria: 
• 
At the time of Screening age <18 years or < legal age of majority, 
whichever is greater 
• 
Type 1 diabetes mellitus 
• 
Body Mass Index (BMI) ≤20 or >45 kg/m2 at Screening 
• 
HbA1c <7% or HbA1c >10% via central laboratory test at 
Screening 
• 
FPG >15 mmol/L (>270 mg/dL) measured by the central 
laboratory at Screening (Visit 1) and confirmed (>15 mmol/L [>270 
mg/dL]) by a repeat test before randomization 
• 
Women of childbearing potential with no effective contraceptive 
method (see Appendix A) 
• 
Treated with an antidiabetic pharmacological regimen other than a 
sulfonylurea at a stable dose with or without metformin within 
12 weeks preceding the Screening Visit 
• 
Previous insulin use >1 month (at any time, aside from treatment 
of gestational diabetes) 
• 
History of gastric surgery including history of gastric banding or 
inflammatory bowel disease within 3 years before the Screening 
Visit 
• 
History of diabetic ketoacidosis or nonketotic hyperosmolar coma 
within 12 weeks prior to the Screening Visit 
• 
History of severe hypoglycemia within 6 months prior to the 
Screening Visit 
• 
Mean blood pressure after 3 separate measurements >180 mmHg 
(SBP) or >100 mmHg (diastolic blood pressure [DBP]) 
• 
Patients with severe anemia, severe cardiovascular (including 
congestive heart failure New York Heart Association [NYHA] IV), 
respiratory, hepatic, neurological, psychiatric, or active malignant 
tumor or other major systemic disease or patients with short life 
expectancy making implementation of the protocol or 
interpretation of the study results difficult 
• 
Aspartate aminotransferase and/or alanine aminotransferase: 
>3 times the upper limit of the normal laboratory range (ULN) 
• 
Total bilirubin: >1.5 times ULN (except in case of Gilbert’s 
syndrome) 
• 
Use of systemic glucocorticoids (excluding topical or ophthalmic 
application or inhaled forms) for more than 10 consecutive days 
within 90 days prior to the Screening Visit 
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• 
Patient who has taken other investigational drugs or prohibited 
therapy for this study within 3 months or 5 half-lives, whichever is 
longer, prior to Screening or randomization 
• 
Pregnancy, breastfeeding 
• 
Patient is unwilling to perform self-monitoring of blood glucose 
(SMBG), and complete the patient diary as required per protocol 
• 
Patient with contraindication to sulfonylurea as per local labeling 
• 
Patient with contraindication to metformin as per local labeling if 
the patient uses sulfonylurea in combination with metformin 
Total expected number of patients 
500 randomized patients. 
STUDY TREATMENTS 
 
Investigational medicinal products 
• 
Sotagliflozin 400 mg as two (2) 200 mg tablets, once daily, before 
the first meal of the day 
• 
Placebo as two (2) placebo tablets (identical to sotagliflozin 200 
mg tablets in appearance), once daily, before the first meal of the 
day 
Noninvestigational medicinal  
products  
• 
Sulfonylurea tablets administered as per Principal Investigator 
• 
Metformin tablets, administered as per Principal Investigator 
• 
The doses of sulfonylurea and metformin should be maintained 
stable throughout the study unless down-titration is required for 
safety reasons 
• 
Rescue therapy (see Rescue therapy section, below) 
 
Rescue therapy 
The threshold values are defined as follows, depending on study period: 
• 
FPG >270 mg/dL (15.0 mmol/L) from Randomization up through 
the scheduled Week 8 visit 
• 
FPG >240 mg/dL (13.3 mmol/L) after the Week 8 visit up through 
the scheduled Week 12 visit 
• 
FPG >200 mg/dL (11.1 mmol/L) after the Week 12 visit through 
the end of the 26-week Core Treatment Period 
• 
FPG >170 mg/dL (9.4 mmol/L) or HbA1c ≥8.0% after the Week 26 
Visit through the end of the treatment period (Week 79) 
Routine fasting SMBG and central laboratory alerts on FPG (and HbA1c at 
Week 26 and onward) are set up to ensure that glycemic parameter results 
remain under predefined thresholds. 
• 
If one fasting SMBG value exceeds the specific glycemic limit on 
one day, the patient checks it again during the two following days. 
If all the values in three consecutive days exceed the specific limit, 
the patient should contact the Investigator and a central laboratory 
FPG measurement (and HbA1c at Week 26 and onward) be 
performed as soon as possible, preferably within 7 days, to 
confirm the hyperglycemia 
• 
Upon receipt of a central laboratory rescue alert, a central 
laboratory re-test must be completed and confirmed as exceeding 
the threshold for rescue before rescue therapy is initiated. The re-
test confirmation should be performed as soon as possible, but 
within 7 days of receipt, by unscheduled visit 
 
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In the event that a confirmatory FPG and/or HbA1c exceeds the threshold, 
the Investigator should ensure that no reasonable explanation exists for 
insufficient glucose control and in particular that: 
• 
The increased FPG has been tested at a fasting status  
(ie, no food intake for ≥8 hours) 
• 
Investigational medicinal product is given at the planned dose 
• 
There is no intercurrent disease, which may jeopardize glycemic 
control (eg, infectious disease) 
• 
Compliance to treatment is appropriate 
• 
Compliance to diet and lifestyle is appropriate 
If any of the above can reasonably explain the insufficient glycemic control, 
the Investigator should consider not initiating rescue medication and should 
undertake appropriate action, ie: 
• 
Assess plasma glucose in fasting condition (ie, after at least 8 
hours fast) 
• 
Initiate an evaluation and treatment of intercurrent disease (to be 
reported in AE/concomitant medication parts of the e-CRF and the 
medical record) 
• 
Stress the absolute need to be compliant with treatment 
• 
Organize a specific interview with the patient and a Registered 
Dietician or other qualified nutrition professional to reinforce the 
absolute need to be compliant with diet and lifestyle 
recommendations, and schedule a FPG/HbA1c assessment at the 
next visit 
If none of the above mentioned reasons can be found, or if appropriate 
action fails to decrease FPG/HbA1c under the threshold values, rescue 
medication may be introduced. 
Open-label rescue medication(s) to treat hyperglycemia will be at the 
discretion of the Investigator and in accordance with local standard of care 
and prescribing practice. Except for sodium-glucose co-transporter Type 2 
(SGLT2) inhibitors, and additional metformin and sulfonylurea, any approved 
medication(s) including oral antidiabetic drugs, glucagon-like peptide 
1 receptor agonists, or insulin can be prescribed to treat the hyperglycemia. 
Metformin will also be permitted for patients on sulfonylurea only at 
Screening. The patient continues the study treatment (blinded) and stays in 
the study in order to collect efficacy and safety information. The planned 
visits and assessments should occur until the last scheduled visit. For 
patients with renal impairment, contraindications to antihyperglycemic drugs 
should be taken into consideration. 
ENDPOINTS 
 
 
Primary endpoint: 
Change from Baseline to Week 26 in HbA1c 
Secondary efficacy endpoints: 
• 
Change from Baseline to Week 26 in FPG 
• 
Change from Baseline to Week 26 in body weight 
• 
Change from Baseline to Week 12 in SBP for patients with 
Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 12 in SBP for all patients 
• 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
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Other efficacy endpoints: 
• 
Change from Baseline to Week 12 in SBP for patients with 
Baseline SBP <130 mmHg 
• 
Proportion of patients with reduction in body weight by ≥2%, ≥5%, 
and ≥10% from Baseline 
• 
Change from Baseline to Week 12 in DBP 
• 
Proportion of patients achieving SBP <130 mmHg for those with 
Baseline SBP ≥130 mmHg 
• 
Proportion of patients achieving DBP <80 mmHg for those with 
Baseline DBP ≥80 mmHg 
• 
Proportion of patients requiring rescue for hyperglycemia. 
• 
Change from Baseline in: 
- 
Serum creatinine 
- 
eGFR 
• 
Change from Baseline to Week 79 in HbA1c 
• 
Change from Baseline to Week 79 in FPG 
• 
Change from Baseline to Week 26 in SBP for all patients and for 
patients with Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 79 in SBP for all patients and for 
patients with Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 79 in body weight 
Safety endpoints: 
• 
Adverse events (AEs), hypoglycemia (all, severe, and/or 
documented symptomatic hypoglycemia), Events of Special 
Interest (EOSI), Adverse Events of Special Interest (AESI), AEs 
leading to discontinuation from the IMP, serious adverse events 
(SAEs), and deaths 
• 
Clinical laboratory results, including fasting lipids, vital signs, and 
electrocardiogram (ECG) results 
Pharmacokinetic endpoints:  
• 
Plasma concentrations of sotagliflozin and its metabolite pre-dose 
at Weeks 4, 18, 26, 52, 79 and 1 hour 30 minutes post-dose at 
Week 26 and 79 
ASSESSMENT SCHEDULE 
See Study Flowchart, Section 1.2. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The sample size/power calculation is based on the primary variable, change 
from Baseline to Week 26 in HbA1c. 
Assuming a common standard deviation (SD) of 1.2% and using a 2-sided 
test at a 0.05 α-level, 250 patients per arm will have at least 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. 
The number of patients taking a sulfonylurea and metformin will be limited to 
330 patients, to ensure sufficient numbers of sulfonylurea monotherapy 
patients. 
Analysis population: 
Efficacy analyses will be based on the intention-to-treat (ITT) population, 
defined as all randomized patients, irrespective of compliance with the study 
protocol and procedures. 
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Primary analysis: 
Analysis of the primary efficacy endpoint (change from Baseline to Week 26 
in HbA1c) will be performed on the ITT population, using HbA1c 
measurements obtained during the study, including those obtained after IMP 
discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from Baseline to Week 
26 will be analyzed with missing values imputed by control-based multiple 
imputation method under the missing not at random framework.  
• 
For placebo patients, missing data will be imputed based on the 
placebo group data 
• 
For patients in the sotagliflozin group, missing data will be imputed 
as if the patients were on placebo throughout the study, where all 
patients’ measurements including the on-treatment measurements 
will be considered as if the measurements were from the placebo 
in the imputation model 
Each of the complete datasets will be analyzed by an Analysis of 
Covariance (ANCOVA) model with treatment groups (sotagliflozin, placebo), 
randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of 
metformin use at Screening (Yes, No), randomization stratum of 
SBP (<130, ≥130 mmHg), and country as fixed effects, and Baseline HbA1c 
value as a covariate. Results from each complete dataset will be combined 
to provide the adjusted mean change in HbA1c from Baseline to Week 26 
for each treatment group, as well as the between-group difference 
(comparing sotagliflozin versus placebo) and the 95% confidence interval 
(CI) for the difference.  
Summary statistics (for screening value, Baseline value, observed values, 
and observed changes from Baseline) at scheduled visits will be provided 
for each treatment group. The summary will include the number of 
observations, mean, SD, standard error (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 (using observed cases [OC]). 
Analysis of secondary efficacy endpoints: 
The secondary endpoints will be analyzed using a similar approach to the 
primary efficacy endpoint, with missing values imputed by control-based 
multiple imputation method under the missing not at random framework.  
For each of the continuous secondary endpoints, each of the complete 
datasets will be analyzed by the ANCOVA model with treatment groups 
(sotagliflozin, placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), 
randomization stratum of metformin use at Screening (Yes, No), 
randomization stratum of SBP (<130 mmHg, ≥130 mmHg), and country as 
fixed effects, and Baseline secondary endpoint value as a covariate. For the 
analysis of SBP in patients with Baseline SBP ≥130 mmHg, the 
randomization stratum of SBP will not be included in the ANCOVA model. 
Results from each complete dataset will be combined to provide the 
adjusted mean change from Baseline to Week 26 for each treatment group, 
as well as the between-group difference (comparing sotagliflozin versus 
placebo) and the 95% CI for the difference.  
The categorical secondary efficacy variables of HbA1c <6.5%, <7% at Week 
26 will be analyzed using a Cochran-Mantel-Haenszel method stratified by 
randomization stratum of HbA1c (≤8.5%, >8.5%), randomization stratum of 
metformin use at Screening (Yes, No), and randomization stratum of SBP 
(<130, ≥130 mmHg). 
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Page 10 
Analysis of other efficacy endpoints 
The analysis of other endpoints will be descriptive with no formal testing. 
Summary statistics at scheduled visits using observed cases will be 
provided by each treatment group. Graphical presentations will also be used 
to illustrate trends over time. 
Analyses of safety data 
All safety summaries will be descriptive; no statistical significance tests will 
be performed on safety data. These analyses will be based on the Safety 
Population, which is defined as all randomized patients who receive at least 
1 dose of double-blind treatment, regardless of the amount of treatment 
administered. Patients will be analyzed for safety analyses according to the 
treatment actually received. The safety analyses will be provided for the 
26-week Core Treatment Period and for the entire treatment period. 
DURATION OF STUDY PERIOD (per 
patient)  
Up to 85 weeks, including a Screening Period consisting of a Screening 
phase of up to 2 weeks and a 2-week single-blind Run-in phase, a 26-week 
double blind Core Treatment Period, a 53 week double blind Extension 
Period, a 2-week post treatment Follow-up period to collect safety 
information. 
STUDY COMMITTEES 
Steering Committee:  
 Yes    
 No 
Data monitoring committee: 
 Yes    
 No 
Clinical Endpoint Committees:  
 Yes    
 No 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
Abbreviations: HbA1c: hemoglobin A1c; R: randomization; T2D: type 2 diabetes; V: visit; W: week; : telephone visit. 
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1.2 
STUDY FLOW CHART 
Screening Period 
 
Screening 
Run-In 
Double-Blind Core Treatment Perioda 
Double-Blind Extension 
Periodb 
Follow-up 
VISIT 
1 
2 
3  
Baseline 
4 
 
5 
6c 
 
7 
8 
9 
10 
11 
12 
13 
14 
 
Week 
-4 
-2 
0 
1 
4 
8 
12 
18 
26 
39 
52 
65 
79 
81 
Day (window [days]) 
 
-14 
(±3) 
1 
(-) 
7  
(±3) 
28 
(±3) 
56 
(±3) 
84 
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
455 
(±7) 
551  
(-3 to +4) 
565 
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heightd 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signse 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Abbreviatedf 
 
X 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
 
Diet & exercise instruction 
 
X 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
Instruction on basic GU hygiene & 
hydration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Interactive response technology 
(IRT) contact 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense glucose meter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening Period 
 
Screening 
Run-In 
Double-Blind Core Treatment Perioda 
Double-Blind Extension 
Periodb 
Follow-up 
VISIT 
1 
2 
3  
Baseline 
4 
 
5 
6c 
 
7 
8 
9 
10 
11 
12 
13 
14 
 
Week 
-4 
-2 
0 
1 
4 
8 
12 
18 
26 
39 
52 
65 
79 
81 
Day (window [days]) 
 
-14 
(±3) 
1 
(-) 
7  
(±3) 
28 
(±3) 
56 
(±3) 
84 
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
455 
(±7) 
551  
(-3 to +4) 
565 
(±3) 
Dispense diary 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Collect/review diary 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Instruction on diabetic ketoacidosis 
symptoms,  
glucose testing 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dispense IMP 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
IMP accounting & compliance 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMBGg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGh 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Laboratory testingi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FPG 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Clinical chemistry, hematologyj 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Fasting lipids 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
Pregnancy test (WOCBP)k  
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
FSH and/or estradiol as neededk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma concentrationl 
 
 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
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Screening Period 
 
Screening 
Run-In 
Double-Blind Core Treatment Perioda 
Double-Blind Extension 
Periodb 
Follow-up 
VISIT 
1 
2 
3  
Baseline 
4 
 
5 
6c 
 
7 
8 
9 
10 
11 
12 
13 
14 
 
Week 
-4 
-2 
0 
1 
4 
8 
12 
18 
26 
39 
52 
65 
79 
81 
Day (window [days]) 
 
-14 
(±3) 
1 
(-) 
7  
(±3) 
28 
(±3) 
56 
(±3) 
84 
(±3) 
126 
(±3) 
182 
(±3) 
273 
(±7) 
364 
(±7) 
455 
(±7) 
551  
(-3 to +4) 
565 
(±3) 
Urinalysis (dipstick and 
microscopy)m 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Evaluate for glycemic rescue 
 
 
 
To be assessed and reported throughout the treatment period 
 
Hypoglycemia 
To be assessed and reported throughout the study 
AEs/SAEs/AESIs/EOSIs 
To be assessed and reported throughout the studyp 
a If a patient discontinues treatment with investigational medicinal product (IMP) early during the 26-Week Core Treatment Period, the patient will have a Premature End-of-Treatment (EOT) Visit and a Follow-up 
Visit 2 weeks after the last dose of IMP. In addition, every effort will be made to have all patients return to the site at the time corresponding to their scheduled visits, particularly the Week 26 Visit and Week 79 
Visit. If the patient does not agree to a site visit, they will be contacted by telephone to inquire about safety status. If a patient discontinues (or completes) treatment and study at the same time, a single visit will be 
performed using the procedure normally planned for the EOT visit. 
b If a patient completes the Core Treatment, but discontinues IMP during the Extension Period, the patient will have a Premature EOT Visit, and a Follow-up Visit 2 weeks after the last dose of IMP. Every effort will 
be made to have all patients return to the site at the time corresponding to their quarterly visits (ie, every 13 weeks) during the Extension Period, particularly the Week 79 Visit. If the patient does not agree to a site 
visit, at the time corresponding to their Week 79 Visit, all attempts will be made to contact the patient to inquire about safety status. If a patient discontinues (or completes) treatment and study at the same time, a 
single visit will be performed using the procedure normally planned for the EOT visit. 
c At Visits 4 (Week 1), 6 (Week 8) and 14 (2 weeks after the last dose of IMP) patients will be contacted by telephone, and not seen on-site.  
d Height to be measured only at screening. 
e Vital sign measurements (sitting BP and heart rate): 3 separate seated BP and heart rate measurements should be taken with at least 1 minute between readings, following a 5-minute rest period and prior to 
phlebotomy (see Section 9.2.1.4 and detailed instructions in Appendix C). 
f 
The abbreviated physical exam should focus on cardiac and respiratory systems, as well as any areas important for assessment of adverse events if necessary. 
g See Section 9.2.1.6 for details of SMBG measurements. Glucose meters used for SMBG display results as plasma glucose concentration. Patients should measure their fasting plasma glucose at least 3 times per 
week (including on day of each on-site study visit). After Visit 9 (Week 26), if fasting SMBG values are <120 mg/dL, over a 2-week period, the Investigator can instruct patients to self-monitor blood glucose once a 
week (on day of on-site study visit for weeks with on-site study visits). 
h The 12-lead electrocardiogram (ECG) recordings should be obtained prior to IMP administration. The ECG will be evaluated as “normal” or “abnormal”. 
i 
All laboratory assessments occur prior to IMP administration on the day of the visit. 
j 
Clinical chemistry, hematology: please see list in Table 2. 
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k Serum pregnancy testing only at screening; urine pregnancy testing subsequently. Serum pregnancy test results must be reviewed prior to the Run-In phase for all women of childbearing potential (WOCBP) 
unless there is documented history of menopause (based on documented follicle-stimulating hormone [FSH] and estradiol levels – if results not documented then FSH and estradiol will be tested at Screening visit) 
or they are surgically sterile. Any positive urine test results must be confirmed based on serum pregnancy test. The Investigator may perform additional tests at their discretion or as required by local regulations. 
l 
Pre-dose plasma concentration samples (ie, of sotagliflozin and sotagliflozin-3-O-glucuronide) should be drawn with the other laboratory assessments at Week 4, Week 18, Week, 26, Week 52, and Week 79. 
Post-dose plasma concentration samples should be drawn 1 hour 30 minutes after sotagliflozin administration at Week 26 and Week 79. The date and time of the last intake of study drug prior to visits where 
pharmacokinetic (PK) samples are taken should be recorded by the patient in the patient diary. Patients should be reminded of this at visits preceding PK time points to ensure these details are captured. In the 
case of premature IMP discontinuation, PK samples should not be drawn at the premature EOT visit, nor at any subsequent visits. 
m Urinalysis performed by the central laboratory includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte 
esterase. Microscopy includes detection of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. In the event of abnormal urinalysis findings suspicious of urinary 
tract infection, urine culture should be performed. Positive urine culture determination will be based upon the criteria of the reporting laboratory.  
 
p All serious adverse events (SAEs), adverse events (AEs), AEs of special interest (AESIs), and Events of Special Interest (EOSIs) will be collected starting with signing informed consent and continue until the end 
of the study. All AEs that occur during treatment should be followed until study completion (or until patients leave the study) or until the event has resolved, the condition has stabilized, or the patient is lost to 
follow-up. All patients will have a follow-up visit 2 weeks after the last dose of IMP to collect safety information. 
 
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2 
TABLE OF CONTENTS 
 
1 
FLOW CHARTS.............................................................................................................................11 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................11 
1.2 
STUDY FLOW CHART ..................................................................................................................12 
2 
TABLE OF CONTENTS ................................................................................................................16 
2.1 
LIST OF TABLES...........................................................................................................................22 
2.2 
LIST OF FIGURES.........................................................................................................................22 
3 
LIST OF ABBREVIATIONS ..........................................................................................................23 
4 
INTRODUCTION AND RATIONALE.............................................................................................25 
4.1 
BACKGROUND: SOTAGLIFLOZIN AND DISEASE .....................................................................25 
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS ................................................................26 
4.3 
RATIONALE FOR SELECTION OF DOSE ...................................................................................27 
4.4 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS..................................................27 
4.5 
BENEFIT/RISK OF SOTAGLIFLOZIN...........................................................................................28 
5 
STUDY OBJECTIVES ...................................................................................................................30 
5.1 
PRIMARY.......................................................................................................................................30 
5.2 
SECONDARY ................................................................................................................................30 
5.3 
OTHER...........................................................................................................................................30 
6 
STUDY DESIGN ............................................................................................................................31 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................31 
6.1.1 
Screening Period............................................................................................................................31 
6.1.1.1 
Screening phase (Visit 1)...............................................................................................................31 
6.1.1.2 
Run-in phase (Visit 2).....................................................................................................................31 
6.1.2 
Double-blind Core Treatment Period (Week 0 to Week 26) ..........................................................32 
6.1.3 
Double-blind Extension Period (Week 27 to Week 79)..................................................................32 
6.1.4 
Follow-up period.............................................................................................................................33 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................33 
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6.2.1 
Duration of study participation for each patient .............................................................................33 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................33 
6.3 
INTERIM ANALYSIS......................................................................................................................33 
6.4 
STUDY COMMITTEES..................................................................................................................33 
6.4.1 
Steering Committee .......................................................................................................................33 
6.4.2 
Data Monitoring Committee ...........................................................................................................34 
6.4.3 
Clinical Endpoint Committee(s)......................................................................................................34 
6.4.4 
Safety adjudication of events requiring ongoing monitoring ..........................................................34 
7 
SELECTION OF PATIENTS..........................................................................................................35 
7.1 
INCLUSION CRITERIA..................................................................................................................35 
7.2 
EXCLUSION CRITERIA ................................................................................................................35 
7.2.1 
Exclusion criteria related to study methodology ............................................................................35 
7.2.2 
Exclusion criteria related to the diabetes history and treatment....................................................37 
7.2.3 
Exclusion criteria related to the current knowledge of sotagliflozin ...............................................37 
8 
STUDY TREATMENTS .................................................................................................................39 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................39 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS.....................................................................39 
8.2.1 
Sulfonylurea and metformin...........................................................................................................39 
8.2.2 
Rescue therapy..............................................................................................................................40 
8.3 
BLINDING PROCEDURES............................................................................................................41 
8.3.1 
Methods of blinding........................................................................................................................41 
8.3.2 
Randomization code breaking during the study.............................................................................42 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................42 
8.5 
PACKAGING AND LABELING ......................................................................................................43 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................43 
8.7 
RESPONSIBILITIES ......................................................................................................................44 
8.7.1 
Treatment accountability and compliance......................................................................................44 
8.7.2 
Return and/or destruction of treatments ........................................................................................45 
8.8 
CONCOMITANT MEDICATION.....................................................................................................45 
8.8.1 
Prohibited prior and concomitant medications...............................................................................45 
8.8.2 
Concomitant diabetes therapy .......................................................................................................46 
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8.9 
POSTSTUDY TREATMENT..........................................................................................................46 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................47 
9.1 
EFFICACY ENDPOINTS ...............................................................................................................47 
9.1.1 
Primary efficacy endpoint...............................................................................................................47 
9.1.2 
Secondary efficacy endpoints........................................................................................................47 
9.1.3 
Other efficacy endpoints ................................................................................................................47 
9.1.4 
Assessment methods of efficacy endpoints...................................................................................48 
9.1.4.1 
Hemoglobin A1c.............................................................................................................................48 
9.1.4.2 
Fasting plasma glucose measurement ..........................................................................................48 
9.1.4.3 
Body weight measurement ............................................................................................................48 
9.1.4.4 
Blood pressure endpoint measurements .......................................................................................48 
9.1.4.5 
Kidney function parameter measurement......................................................................................49 
9.1.4.6 
Proportion of patients requiring rescue for hyperglycemia ............................................................49 
9.2 
SAFETY ENDPOINTS ...................................................................................................................49 
9.2.1 
Assessment methods of safety endpoints .....................................................................................50 
9.2.1.1 
Adverse events ..............................................................................................................................50 
9.2.1.2 
Hypoglycemia.................................................................................................................................50 
9.2.1.3 
Laboratory safety variables............................................................................................................50 
9.2.1.4 
Vital signs and physical exam........................................................................................................52 
9.2.1.5 
Electrocardiogram variables ..........................................................................................................52 
9.2.1.6 
Self-monitoring of blood glucose....................................................................................................52 
9.2.1.7 
Diabetic ketoacidosis .....................................................................................................................53 
9.3 
OTHER ENDPOINTS.....................................................................................................................53 
9.3.1 
Pharmacokinetics...........................................................................................................................53 
9.3.1.1 
Sampling time ................................................................................................................................54 
9.3.1.2 
Pharmacokinetics handling procedure...........................................................................................54 
9.3.1.3 
Bioanalytical method......................................................................................................................54 
 
54 
 
55 
9.6 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................56 
10 
STUDY PROCEDURES ................................................................................................................57 
10.1 
VISIT SCHEDULE..........................................................................................................................57 
10.1.1 
Screening Period............................................................................................................................57 
10.1.1.1 Screening phase ............................................................................................................................58 
10.1.1.2 Run-in phase..................................................................................................................................59 
10.1.2 
Double-blind randomized Core Treatment Period (Day 1 to Week 26).........................................60 
10.1.2.1 On-site Randomization Visit on Day 1 (Visit 3; Baseline; Week 0)................................................60 
10.1.2.2 On-site visits at Weeks 4, 12, and 18 (Visits 5, 7, and 8) ..............................................................61 
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10.1.2.3 Telephone visit at Week 1 (Visit 4) and Week 8 (Visit 6)...............................................................62 
10.1.2.4 On-site Visit 9 at Week 26 (End of core treatment period) ............................................................62 
10.1.3 
Double-blind Extension Period.......................................................................................................63 
10.1.3.1 On-site visits at Weeks 39, 52, and 65 (Visits 10 to 12) ................................................................64 
10.1.3.2 On-site Visit 13 at Week 79 – End of treatment.............................................................................65 
10.1.4 
Post-treatment Follow-up period....................................................................................................65 
10.1.4.1 Telephone visit at Week 81 (Visit 14) ............................................................................................66 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................66 
10.2.1 
Source data to be found in patient’s file.........................................................................................66 
10.2.2 
Source data verification requirements for screen failures .............................................................67 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................67 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product................................67 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product ...............................67 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................68 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................68 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................69 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................70 
10.4.1 
Definitions of adverse events.........................................................................................................70 
10.4.1.1 Adverse event ................................................................................................................................70 
10.4.1.2 Serious adverse event ...................................................................................................................70 
10.4.1.3 Adverse event of special interest...................................................................................................71 
10.4.1.4 Events of special interest ...............................................................................................................72 
10.4.2 
General guidelines for reporting adverse events ...........................................................................72 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................73 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................74 
10.4.5 
Guidelines for reporting events of special interest.........................................................................74 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................74 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................74 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................75 
10.6.1 
Hypoglycemia.................................................................................................................................75 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................77 
11 
STATISTICAL CONSIDERATIONS..............................................................................................78 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................78 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................78 
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11.3 
ANALYSIS POPULATIONS...........................................................................................................79 
11.3.1 
Efficacy populations .......................................................................................................................79 
11.3.1.1 Intention–to-treat population ..........................................................................................................79 
11.3.2 
Safety population ...........................................................................................................................79 
11.4 
STATISTICAL METHODS .............................................................................................................80 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................80 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................80 
11.4.1.2 Compliance ....................................................................................................................................81 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................81 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................81 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................82 
11.4.2.3 Analyses of other efficacy endpoints .............................................................................................83 
11.4.2.4 Multiplicity considerations ..............................................................................................................83 
11.4.3 
Analyses of safety data..................................................................................................................84 
11.4.3.1 Analysis of adverse events ............................................................................................................84 
11.4.3.2 Analyses of hypoglycemia .............................................................................................................86 
11.4.3.3 Analyses of adverse events of special interest..............................................................................86 
11.4.3.4 Analyses of events of special interest............................................................................................86 
11.4.3.5 Analyses of laboratory variables....................................................................................................86 
11.4.3.6 Analyses of vital sign variables ......................................................................................................86 
11.4.3.7 Analyses of 12 lead ECG status ....................................................................................................87 
11.4.4 
Analyses of pharmacokinetic variables..........................................................................................87 
11.5 
INTERIM ANALYSIS......................................................................................................................87 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................88 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................88 
12.2 
INFORMED CONSENT .................................................................................................................88 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................88 
13 
STUDY MONITORING...................................................................................................................90 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................90 
13.2 
RESPONSIBILITIES OF THE SPONSOR OR SERVICE PROVIDER .........................................90 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................90 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................91 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................91 
14 
ADDITIONAL REQUIREMENTS...................................................................................................92 
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14.1 
CURRICULUM VITAE....................................................................................................................92 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................92 
14.3 
CONFIDENTIALITY .......................................................................................................................92 
14.4 
PROPERTY RIGHTS.....................................................................................................................93 
14.5 
INSURANCE COMPENSATION....................................................................................................93 
14.6 
DATA PROTECTION.....................................................................................................................93 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................94 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................94 
14.8.1 
By the Sponsor...............................................................................................................................94 
14.8.2 
By the Investigator .........................................................................................................................95 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................95 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................95 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................97 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................98 
17 
APPENDICES..............................................................................................................................100 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION..........................................................................................101 
APPENDIX B RECOMMENDATIONS ON BASIC GENITOURINARY HYGIENE, MAINTAINING 
HYDRATION AND RECOGNIZING DIABETIC KETOACIDOSIS.....................................104 
APPENDIX C MEASUREMENT OF BLOOD PRESSURE AND PULSE RATE......................................107 
APPENDIX D GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI .........................................................................................108 
 
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2.1 
LIST OF TABLES 
Table 1 - Summary of investigational medicinal products.............................................................................39 
Table 2 - Blood safety parameters ................................................................................................................51 
Table 3 - Samples identification ....................................................................................................................54 
 
2.2 
LIST OF FIGURES 
Figure 1 - Hypoglycemia classification in Study EFC14835..........................................................................76 
 
 
 
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3 
LIST OF ABBREVIATIONS 
 
ADA: 
American Diabetes Association 
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
Analysis of Covariance 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
BP: 
blood pressure 
CEC: 
Clinical Endpoint Committee 
CI: 
confidence interval 
CRF: 
case report form 
CRO: 
contract research organization 
CSR: 
clinical study report 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DILI: 
drug-induced liver injury 
DKA: 
diabetic ketoacidosis 
DMC: 
Data Monitoring Committee 
DRF: 
discrepancy resolution form 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOSI: 
events of special interest 
EOT: 
end-of-treatment 
FDA: 
Food and Drug Administration 
FPG: 
fasting plasma glucose 
FSH: 
follicle stimulating hormone 
GCP: 
Good Clinical Practice 
GI: 
gastrointestinal 
GLP-1: 
glucagon-like peptide-1 
HbA1c: 
hemoglobin A1c 
HLGT: 
high-level group term 
HLT: 
high level term 
HRT: 
hormonal replacement therapy 
IB: 
Investigator's Brochure 
ICF: 
informed consent form 
ICH: 
International Council on Harmonisation 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IRT: 
interactive response technology 
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ITT: 
intention-to-treat 
MACE: 
major adverse cardiovascular events 
MI: 
myocardial infarction 
NIMP: 
noninvestigational medicinal product 
OC: 
observed cases 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
P-gp: 
p-glycoprotein 
PI: 
principal investigator 
PK: 
pharmacokinetic 
PPG: 
postprandial glucose 
PT: 
preferred term 
PYY: 
peptide YY 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SC: 
Steering Committee 
SD: 
standard deviation 
SE: 
standard error 
SGLT: 
sodium-glucose co-transporter 
SGLT1: 
sodium-glucose contransporter type 1 
SGLT2: 
sodium-glucose cotransporter type 2 
SMBG: 
self-monitoring of blood glucose 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
T1D: 
type 1 diabetes mellitus 
T2D: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse event 
TG: 
triglyceride 
UGE: 
urinary glucose excretion 
ULN: 
upper limit of the normal laboratory range 
US: 
United States 
WOCBP: 
women of child-bearing potential 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
BACKGROUND: SOTAGLIFLOZIN AND DISEASE 
Sotagliflozin is a dual inhibitor of the sodium-glucose cotransporters type 1 and 2 (SGLT1 and 
SGLT2) being developed for use in type 2 diabetes (T2D), a metabolic disorder characterized by 
hyperglycemia that results from a combination of increased insulin resistance and beta cell 
dysfunction. The microvascular complications of diabetes are well known and can result in 
impaired renal function, retinopathy and neuropathy. Other comorbidities that are frequently 
associated with diabetes are hypertension, obesity, and cardiovascular (CV) disease. Recently, the 
Centers for Disease Control and Prevention released a report stating that if current trends 
continue, 1 in 3 Americans will have diabetes by the year 2050. According to the most recent 
International Diabetes Federation Diabetes Atlas, the estimates in 2015 were that 1 in 11 adults 
have diabetes, which means 415 million people; estimated to rise to 642 million by 2040 (1). 
According to the World Health Organization, there are about 60 million people with diabetes in 
the European Region, or about 10.3% of men and 9.6% of women aged 25 years and over (2). 
While these numbers include both people with T2D and type 1 diabetes (T1D), over 90% of 
adults with diabetes have T2D. Diabetes is among the leading causes of death by disease and is a 
leading cause of heart disease, stroke, blindness, kidney disease, and amputation (1, 2). 
Despite the fact that the population of people with diabetes is growing, none of the current 
therapies is curative and the results of treatment are variable. 
Although lifestyle changes, including diet, exercise, and education, are valuable components of 
diabetes treatment, the vast majority of people with T2D require pharmacological therapy to 
control the disease. In the United States (US) and Europe, metformin is the standard first-line 
therapy in the absence of any contraindications or tolerability issues, as per guidance from the 
American Diabetes Association (ADA; 3).  
Despite the numerous treatment options available, monotherapy fails in many patients as beta-cell 
function continues to deteriorate leading to progressively increasing hyperglycemia. Aggressive 
glycemic control with the currently available agents often leads to side effects, most notably 
weight gain and an increased frequency of hypoglycemia. These concerns emphasize the need to 
develop new agents that effectively and safely lower glucose in patients with diabetes. 
In patients with diabetes, it is desirable to maintain blood glucose in the normal range without 
exhausting the ability of the pancreatic beta-cells to produce insulin. Glucose is transported across 
the cell membrane by 2 different types of glucose transporters: glucose-facilitated transporters and 
SGLT proteins (4). In the kidney, after blood is filtered by the glomerulus, glucose passes into the 
urine, but 99% is reabsorbed, primarily via SGLT2, which is responsible for 90% of glucose 
reabsorption, while 10% is reabsorbed by SGLT1. When functional SGLT2 is lacking in humans, 
a significant amount of glucose remains in the urine and is removed from the body (5). This way 
of reducing blood glucose is not an insulin-dependent mechanism and therefore hyperglycemia 
may be reduced while the pancreas is spared from an increased demand for insulin production that 
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is caused by hyperglycemia. Since obesity is a significant comorbidity in T2D, and insulin 
resistance is increased in obesity, the caloric loss from glucose in the urine may represent an 
additional benefit resulting in decreased weight, which should result in decreased insulin 
resistance (5).  
The SGLT1 is expressed predominantly in the gastrointestinal (GI) tract; SGLT1 is responsible 
for the majority of glucose absorption by the small intestine (6). Inhibition of SGLT1 in the GI 
tract prevents glucose from being absorbed. Additionally, there is accumulating evidence that 
SGLT1 inhibition stimulates secretion of glucagon-like peptide-1 (GLP-1) and peptide YY 
(PYY), gut hormones involved in pancreatic beta-cell function and appetite control, respectively. 
Reduced glucose absorption in the proximal intestine leads to more glucose being delivered 
distally, which allows L cells in both the ileum and the colon to sense glucose and its byproducts, 
and as a result, they secrete GLP-1 and PYY. Although a complete lack of functional SGLT1 may 
be associated with symptoms of glucose and galactose malabsorption (7), pharmacologic 
inhibition of SGLT1 by sotagliflozin has not produced these effects in preclinical models or 
patients with T2D. Selective inhibitors of the SGLT1 transporter are in early stages of 
development. 
Extensive clinical studies conducted for selective SGLT2 inhibitors have established this class as 
effective agents for the treatment of T2D (3, 8) and have led to approvals by the US Food and 
Drug Administration (FDA) and the European Medicines Agency (EMA). Studies with 
sotagliflozin, a potent, dual inhibitor of SGLT2 and SGLT1, have shown that this agent produces 
significant glucosuria in preclinical animal models, healthy human volunteers, and patients with 
T2D. Single and multiple-dose administration of sotagliflozin to healthy human subjects has 
resulted in dose-dependent increases in glucosuria. Multiple-dose (28-day) administration in 
patients with diabetes produced improvements in several metabolic parameters, including urinary 
glucose excretion (UGE), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), GLP-1, and 
PYY. These data suggest that sotagliflozin should be of therapeutic benefit to patients with T2D.  
4.2 
CLINICAL TRIALS OF SOTAGLIFLOZIN IN HUMANS 
Approximately 780 subjects (639 assigned to sotagliflozin and 141 assigned to placebo) have 
participated in completed clinical studies of sotagliflozin. No significant safety concerns have 
been identified in the sotagliflozin drug program, and sotagliflozin has been well-tolerated in all 
studies to date. Serious adverse events (SAEs) and discontinuations due to adverse events (AEs) 
have been infrequent and have been balanced between treatment and comparator groups. Reports 
of treatment-emergent adverse events (TEAE) across all sotagliflozin studies for which data are 
available were generally balanced between treatment and comparator groups. The most frequently 
reported TEAEs (≥2.0%) were headache, nausea, diarrhea, constipation, and dizziness, all of 
which were reported at a frequency greater than placebo. However, the majority were described as 
mild to moderate, and most resolved spontaneously.  
In completed and ongoing clinical trials, no safety issues in addition to those already described in 
the current Investigator’s Brochure (IB) were observed. In general, no significant imbalances of 
SAE/AEs between sotagliflozin and comparators were observed in completed studies. 
Cumulatively, during the clinical trial program 8 SAEs were reported by 6 patients (4 T2D and 
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2 T1D), all of which were assessed as unrelated to study drug; those reported by 4 T2D patients 
who received sotagliflozin included pulmonary embolism, deep vein thrombosis, bile duct stone, 
cholangitis and lower limb fracture, while a myocardial infarction (MI) was experienced by a 
patient receiving placebo. Two SAEs of diabetic ketoacidosis (DKA) were reported by 2 T1D 
patients receiving 400 mg once daily sotagliflozin in the Phase 2 T1D study 
LX4211.1-203-TIDM; both SAEs were assessed as due to failure of insulin delivery via insulin 
pump.  
Inhibition of SGLT2 and SGLT1 is expected to improve glycemic control, but may also 
potentially increase the risk of hypoglycemia when given with insulin or insulin secretagogues 
like sulfonylurea. Other medicines in the SGLT2 class have had a low incidence of hypoglycemia 
in general, but when used in combination with insulin or insulin secretagogues, an increase in 
hypoglycemia has been observed. 
A drug interaction study with digoxin, a sensitive P-glycoprotein (P-gp) substrate, indicated that 
sotagliflozin acts as a weak P-gp inhibitor. Thus, sotagliflozin increases systemic exposure of 
digoxin and other substrates of P-gp (9). 
More information on the safety of sotagliflozin and on the clinical program can be found in the 
IB. 
4.3 
RATIONALE FOR SELECTION OF DOSE 
The proposed sotagliflozin 400 mg once-daily dose is based on the results of the Phase 2b study 
LX4211.1-202-DM. In this study, sotagliflozin doses of 75 mg once daily, 200 mg once daily, 
200 mg twice daily, and 400 mg once daily sotagliflozin were tested over a 12-week, double-blind 
period. The sotagliflozin 400 mg once daily dose was chosen for further evaluation based on its 
HbA1c lowering effect and the overall safety and tolerability observed at this dose. At 12 weeks, 
the sotagliflozin 400 mg dose lowered HbA1c by a mean of 0.93%, while placebo lowered HbA1c 
by a mean of 0.14%. Lower sotagliflozin doses were less effective than the 400 mg dose and did 
not have any advantages in safety or tolerability. The overall incidence of AEs on sotagliflozin 
400 mg once daily was similar to that seen with placebo.  
From a safety perspective, sotagliflozin was well-tolerated across studies. In healthy subjects 
sotagliflozin was well-tolerated following single doses up to 2000 mg, and in multiple doses up to 
800 mg over 10 days. Furthermore, in a thorough QT study, single doses of sotagliflozin 
(800 mg and 2000 mg) were well tolerated and did not prolong the QT interval. Additionally, 
evaluation of metabolites in urine and plasma of healthy subjects resulted in no safety concerns 
following single doses of sotagliflozin 400 mg. In patients with T2D, single doses of sotagliflozin 
400 mg in combination with sitagliptin, and multiple doses up to sotagliflozin 400 mg in 
combination with metformin over 12 weeks were also well-tolerated.  
4.4 
RATIONALE FOR STUDY DESIGN AND CONTROL GROUPS 
This study is designed to demonstrate the efficacy and safety of sotagliflozin when used as add-on 
therapy to a sulfonylurea (alone or in combination with metformin) in patients with T2D who 
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have inadequate glycemic control. Sotagliflozin plus a sulfonylurea (alone or in combination with 
metformin) will be compared to placebo plus a sulfonylurea (alone or in combination with 
metformin). Based on the study design, the protocol stipulates that patients be provided 
antidiabetic agent rescue therapy according to a predefined algorithm. Safety, tolerability, 
pharmacokinetic (PK) and pharmacodynamic (PD) effects of sotagliflozin are supported by 
Phase 1 and Phase 2 studies and animal toxicology data in rats up to 26 weeks and dogs up to 
39 weeks as well as 2 year carcinogenicity data in rats.  
To achieve balanced randomization for assessment of the primary endpoint, randomization will be 
stratified based on preexisting metabolic control (Screening HbA1c ≤8.5% versus >8.5%) as well 
as metformin use at Screening (Yes, No). Another stratification factor (systolic blood pressure 
[SBP] <130 mmHg versus ≥130 mmHg) has been added to ensure balance in randomization for a 
secondary endpoint (change from Baseline to Week 12 in SBP for patients with Baseline 
SBP ≥130 mmHg).  
A placebo control will be used to allow for an unbiased assessment of treatment effects and safety 
data. Bias will be minimized by randomizing the patients to treatment groups, blinding the 
patients, the Investigators, the Sponsor, and the service provider to the treatment allocations, and 
by adjudicating the endpoints in a blinded fashion. 
The number of patients taking a sulfonylurea and metformin will be limited to 330 patients, to 
ensure sufficient numbers of sulfonylurea monotherapy patients. 
A parallel-group, randomized placebo controlled design was selected because trial participants are 
exposed to a single treatment and assignment to that treatment is based solely on chance. This 
design is free of the limitations of competing designs such as crossover in which there may be a 
carryover of effect from one treatment to the second treatment. Although this carryover effect can 
be minimized with a washout period, it is possible that some longer term effects may persist. 
While the sample size of the parallel group design is larger to account for more variability when 
participants cannot serve as their own control, the above mentioned limitations of the crossover 
design have led the randomized controlled trial design to be the standard for therapeutic 
confirmatory trials for regulatory approval such as this trial. 
4.5 
BENEFIT/RISK OF SOTAGLIFLOZIN 
Sotagliflozin is currently being investigated as an adjunct to diet and exercise to improve 
glycemic control in adults with T2D. The development program will also provide efficacy and 
safety data for sotagliflozin in combination with other antidiabetic medications. In addition the 
program will evaluate clinical outcomes in patients with high CV risk and in patients with renal 
impairment. The use of sotagliflozin in the treatment of T1D is also being studied in a separate 
development program. 
Sotagliflozin may benefit a wide variety of patients with diabetes based on multiple potential 
beneficial effects of dual SGLT2/SGLT1 inhibition, and its insulin-independent mechanism of 
action. Improvements in HbA1c, FPG, and postprandial glucose (PPG) were observed with 
sotagliflozin in multiple studies. As anticipated from the mechanism of action, treatment with 
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sotagliflozin resulted in increased UGE (from inhibition of SGLT2) as well as increased incretin 
levels (from inhibition of SGLT1). In addition, the improvements in body weight, blood pressure 
(BP), and triglycerides (TG) observed with sotagliflozin treatment have the potential to benefit 
patients with diabetes through their effects on common diabetic comorbidities.  
Phase 2 data indicated that sotagliflozin may reduce SBP by 10 to 15 mmHg in patients with SBP 
≥130 mmHg at Baseline, while having little effect in patients with SBP <130 mmHg, and did not 
induce hypotension. Since this could be of benefit to patients with T2D, this finding is being 
followed up as a secondary objective in this trial. 
Overall, sotagliflozin has been well-tolerated in all studies to date, with the majority of events 
assessed as mild to moderate; most of which resolved spontaneously. SAEs and discontinuations 
due to AEs have been limited and balanced between treatment and comparator groups.  
Events of special interest (EOSI) are evaluated based on either their potential link to the drug’s 
mechanism of action, events that occur in other SGLT-inhibitor drugs, or regulatory 
interest/guidance for diabetes products, but found not to be in imbalance in clinical trials. In 
addition to the identified and potential risks (genital mycotic infections [male and female], 
metabolic acidosis, DKA, urinary tract infections, volume depletion, severe hypoglycemia) for the 
sotagliflozin program, other EOSI have been defined. These EOSI are: major adverse cardiac 
events (MACE) and other CV events, venous thrombotic events, diarrhea, pancreatitis, bone 
fractures, renal events, malignancies of special interest (including but not limited to: breast, 
bladder, renal cell, Leydig cell, pancreatic, prostate, and thyroid cancer), and AEs leading to 
amputation. 
The improvement in glycemic control, the reductions in weight and BP, and the tolerability and 
safety profile of sotagliflozin to date, demonstrate a favorable benefit-risk assessment for 
sotagliflozin. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY  
The primary objective of this study is to demonstrate the superiority of sotagliflozin 400 mg 
versus placebo on HbA1c reduction at Week 26 in patients with T2D who have inadequate 
glycemic control with a sulfonylurea alone or in combination with metformin. 
5.2 
SECONDARY  
• 
To compare sotagliflozin 400 mg versus placebo for:  
- 
Change from Baseline in FPG at Week 26 
- 
Change from Baseline in body weight at Week 26 
- 
Change from Baseline in SBP at Week 12 for patients with Baseline SBP ≥130 mmHg 
- 
Change from Baseline in SBP at Week 12 for all patients 
- 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
• To evaluate the safety of sotagliflozin 400 mg versus placebo throughout the 79-week trial 
5.3 
OTHER 
• To compare sotagliflozin versus placebo based on other BP endpoints 
• To compare sotagliflozin versus placebo with respect to change from Baseline in the 
following endpoints: 
- 
Estimated glomerular filtration rate (eGFR) 
- 
Reduction in body weight by ≥2%, ≥5%, and ≥10% 
• To compare sotagliflozin versus placebo for: 
- 
Change from Baseline in HbA1c at Week 79 
- 
Change from Baseline in FPG at Week 79 
- 
Change from Baseline in body weight at Week 79 
• To compare the use of rescue medications for hyperglycemia in the sotagliflozin and 
placebo treatment groups 
• To assess plasma concentrations of sotagliflozin and its 3-O-glucuronide metabolite 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This study is a Phase 3, multicenter and multinational, 1:1 randomized, double-blind, 
placebo-controlled, parallel group study that is anticipated to enroll approximately 500 patients. 
The study will comprise a Screening Period consisting of a Screening phase of up to 2 weeks and 
a 2-week single blind Run-in phase, a double-blind Core Treatment Period, a double-blind 
Extension Period, and a Follow-up Period. 
The study design is presented graphically at the end of the synopsis. 
6.1.1 Screening Period 
6.1.1.1 Screening phase (Visit 1) 
The Screening phase will last up to 2 weeks. The Screening phase must be long enough to collect 
the data required to establish whether the patient satisfies the inclusion/exclusion criteria. 
Patients taking a sulfonylurea (≥half the maximum recommended dose as per local label or 
maximum tolerated dose [documented]) as monotherapy or in combination with metformin 
(≥1500 mg per day or maximum tolerated dose [documented]) each at a stable dose for at least 
12 weeks before enrollment will be eligible for Screening. The number of patients taking a 
sulfonylurea and metformin will be limited to 330 patients, to ensure sufficient numbers of 
sulfonylurea monotherapy patients. 
At the Screening Visit after signing of the informed consent form (ICF), eligibility criteria will be 
assessed and Screening assessments will be performed. Women of childbearing potential 
(WOCBP) not willing to use effective method(s) of birth control or who are unwilling or unable to 
be tested for pregnancy will be excluded from the study; guidance on highly effective 
contraceptive methods and collection of pregnancy information is provided in Appendix A. 
If another contraceptive method is used (such as a barrier method), it should be used in 
combination with one of the highly effective methods in Appendix A (such as an oral 
contraceptive). 
The Interactive Response Technology (IRT; either Interactive Voice Response System or 
Interactive Web Response System) will be contacted at Visit 1 for notification of screening and 
for patient number allocation. 
6.1.1.2 Run-in phase (Visit 2) 
The Run-in phase will last 2 weeks. Patients will be treated in a single-blind manner with placebo 
(2 tablets) once daily during the Run-in phase, starting from Visit 2. 
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6.1.2 Double-blind Core Treatment Period (Week 0 to Week 26) 
Eligible patients will be randomized on Day 1 (Visit 3). In order to qualify for randomization, 
patients must demonstrate compliance during the single-blind placebo Run-in phase based upon 
tablet count (≥80%), and as assessed at the Investigator’s discretion.  
Randomization will be stratified by: 
• HbA1c at Screening (≤8.5%, >8.5%) 
• Metformin use at Screening (Yes, No) 
• SBP at Screening (<130 mmHg, ≥130 mmHg) 
Following randomization, patients will be treated in a double-blind manner for 26 weeks. 
Approximately 500 patients ≥18 years of age (or ≥ legal age of majority if greater) will be 
randomly assigned 1:1 to 1 of the following 2 treatment groups: 
• Sotagliflozin 400 mg as two 200 mg tablets, once daily 
• Placebo as two placebo tablets (identical to sotagliflozin 200 mg tablets in appearance), 
once daily 
Fasting glucose (plasma or serum) and HbA1c (both measured at central laboratory) will be 
masked to study sites after randomization until study end. To prevent partial unblinding, the 
central laboratory urine dipstick will not include the measurement of urine glucose. 
All Visits will be on-site with the exception of Visit 4 (Week 1) and Visit 6 (Week 8), which will 
be telephone visits. 
If a patient discontinues treatment with investigational medicinal product (IMP) early during the 
26-week Core Treatment Period, the patient will have a Premature End-of-Treatment (EOT) Visit 
and a Follow-up Visit 2 weeks after the last dose of IMP. In addition, every effort will be made to 
have all patients return to the site at the time corresponding to their scheduled visits, particularly 
the Week 26 Visit and Week 79 Visit. If the patient does not agree to site visits, they will be 
contacted by telephone to inquire about their safety status at the time of initially scheduled 
Week 79 Visit. 
6.1.3 Double-blind Extension Period (Week 27 to Week 79) 
From Week 27 to 79, patients will be in a 53-week double-blind Extension Period. Patients will 
continue to receive the blinded medication (sotagliflozin or placebo) to which they were 
randomized on Day 1. Patients who received rescue medication during the 26-week Core 
Treatment Period will continue on the same rescue medication during the double-blind Extension 
Period (unless the Investigator considers a change necessary for safety reasons). 
If a patient completes the Core Treatment Period, but discontinues IMP during the Extension 
Period, the patient will have a Premature EOT Visit and a Follow-up Visit 2 weeks after the last 
dose of IMP. 
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In addition, every effort will be made to have all patients (including those who discontinue 
treatment early, prior to the Week 26 Visit) return to the site at the time corresponding to their 
quarterly visits (ie, every 13 weeks) during the Extension Period, particularly the Week 79 Visit. 
If the patient does not agree to site visits, at the time corresponding to their Week 79 Visit, all 
attempts will be made to contact the patients to inquire about their safety status. 
6.1.4 Follow-up period 
Following the last dose of IMP (either as scheduled or prematurely), a post-treatment follow-up 
should be scheduled for all patients 14 days (±3 days) after permanent IMP discontinuation. This 
will be a telephone visit. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The total duration of the study for each patient will be 85 weeks and includes a Screening phase of 
up to 2 weeks, a 2-week single-blind Run-in phase, a 26-week double-blind core treatment period 
followed by a 53-week double-blind treatment extension, and a 2-week Follow-up Period after 
completion of study treatment. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the “last patient last visit” planned with the protocol, 
including follow-up visit. 
The Sponsor can terminate the trial prematurely based on the advice of the independent Data 
Monitoring Committee (DMC) or other unforeseen developments. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
6.4 
STUDY COMMITTEES 
6.4.1 Steering Committee 
The Steering Committee (SC) is composed of experts in diabetes and scientists with clinical and 
methodological expertise. 
This Committee, led by a Chair, is responsible for producing and conducting a scientifically sound 
study and for ensuring accurate reporting of the study. In that capacity, the SC must address and 
resolve scientific issues encountered during the study. The members will remain blinded until 
completion of the study. 
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Among its responsibilities, the SC will receive blinded study status reports from Sponsor, and will 
review the recommendations from the DMC throughout the study. The SC members will 
participate in face-to-face meetings at regular intervals throughout the study and in regularly 
scheduled teleconferences. 
Detailed activities and responsibilities of the SC are provided in the SC charter. 
6.4.2 Data Monitoring Committee 
A DMC with members who are independent from the Sponsor and the Investigators will meet on 
a regular basis, and will be responsible for: 
• Review of accumulating clinical trial safety data by treatment 
• Making a recommendation to the Sponsor regarding the study following each meeting 
Safety data to be reviewed will be unblinded and include events and outcomes described below 
for adjudication, as well as any additional safety data considered relevant. Details describing the 
DMC processes and procedures are outlined in a separate DMC Charter. To maintain continuous 
blinding and study integrity, the analysis will be conducted by an independent statistician, and 
measures will be taken to ensure the validity of the data. 
6.4.3 Clinical Endpoint Committee(s) 
The Clinical Endpoint Committees (CEC) is/are comprised of experts in cardiology and 
nephrology (and other appropriate medical specialties such as neurology and endocrinology, as 
needed) who are independent of the Sponsor and the contract research organization (CRO). The 
CECs will review and adjudicate all deaths, MACE/selected CV events (MI, stroke, unstable 
angina leading to hospitalization, and heart failure leading to hospitalization), selected renal 
events, bone fracture, and DKA. 
The details regarding the CEC processes and procedures will be outlined in the CEC Charter(s).  
6.4.4 Safety adjudication of events requiring ongoing monitoring 
Two independent committees will review safety events that require ongoing monitoring to ensure 
timing protocol amendments in case a safety signal is identified. These events are: 1) potential 
cases of drug-induced liver injuries (DILI), and 2) cases of amputations.  
The two committees will review the cases in a treatment-blinded manner and will present their 
assessment to the DMC. 
The members, roles and responsibilities of the two committees will be described in a separate 
Charter. 
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7 
SELECTION OF PATIENTS 
Note: A patient should not be randomized more than once. In cases where original screen failure 
was due to reasons expected to change at rescreening and based upon the Investigator’s clinical 
judgment, the patient can be rescreened once prior to entering Run-in for this study.  
7.1 
INCLUSION CRITERIA 
I 01. Patients with T2D currently treated with diet and exercise and on a sulfonylurea (≥half the 
maximum recommended dose as per local label or the maximum tolerated dose 
[documented]) for ≥12 weeks with or without metformin (≥1500 mg per day or the 
maximum tolerated dose [documented]) each at a stable dose for at least 12 weeks before 
Screening 
Note: The number of patients taking a sulfonylurea and metformin will be limited to 
330 patients, to ensure sufficient numbers of sulfonylurea monotherapy patients. 
I 02. Signed written informed consent 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. Age <18 years at Screening or < legal age of majority, whichever is greater 
E 02. Type 1 diabetes 
E 03. Body Mass Index (BMI) ≤20 or >45 kg/m² at Screening 
E 04. Previous use of any antidiabetic drug other than a sulfonylurea or metformin unless the 
other antidiabetic drug has been discontinued for a period of at least 12 weeks before the 
Screening Visit 
E 05. Use of systemic glucocorticoids (excluding topical or ophthalmic application, nasal spray 
or inhaled forms) for more than 10 consecutive days within 90 days prior to the Screening 
Visit 
E 06. Use of weight loss medications or medications known to lead to weight gain within 
12 weeks or weight change of 5 kg or more during the 12 weeks before Screening 
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E 07. Likelihood of requiring treatment during the study period with drugs not permitted by the 
study protocol (eg, long-term systemic glucocorticoids) and refusing or unable to take 
alternative treatment 
E 08. Patients who have previously participated in any clinical trial of sotagliflozin/LX4211 
E 09. Patients with severe anemia, severe cardiovascular (including congestive heart failure 
New York Heart Association IV), respiratory, hepatic, neurological, psychiatric, or active 
malignant tumor or other major systemic disease or patients with short life expectancy 
making implementation of the protocol or interpretation of the study results difficult 
E 10. History of chronic hepatitis or serologic evidence by known history of current infectious 
liver disease (hepatitis B or C) including hepatitis B surface antigen or antihepatitis C 
virus (patients with isolated positive hepatitis B Surface antibody may be included) 
E 11. Hemoglobinopathy or hemolytic anemia, transfusion of blood or plasma products, or 
blood donation within 12 weeks prior to Screening 
E 12. History of drug or alcohol abuse within 6 months prior to screening 
E 13. Patient is an employee of the Sponsor, or is the Investigator or any Sub-investigator, 
research assistant, pharmacist, study coordinator, other staff or relative thereof directly 
involved in conducting the study 
E 14. Patient who has taken other investigational drugs or prohibited therapy for this study 
within 12 weeks or 5 half-lives, whichever is longer, prior to Screening 
E 15. Current enrollment in any other clinical study involving an investigational study treatment 
or any other type of medical research 
E 16. Patient is unwilling to perform self-monitoring of blood glucose (SMBG) and complete 
the patient diary as required per protocol 
E 17. Patient insufficiently compliant during Run-in phase based upon tablet count (<80%) or in 
the opinion of the Investigator 
E 18. Patient with contraindication to sulfonylurea as per local labeling 
E 19. Patient with contraindication to metformin as per local labeling if the patient is taking 
sulfonylurea in combination with metformin 
E 20. Any country-related specific regulation that would prevent the patient from entering the 
study 
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7.2.2 Exclusion criteria related to the diabetes history and treatment  
E 21. Hemoglobin A1c <7% or >10% measured by the central laboratory at Screening 
E 22. Fasting plasma glucose >15 mmol/L (>270 mg/dL) measured by the central laboratory at 
Screening (Visit 1), and confirmed by a repeat test (>15 mmol/L [>270 mg/dL]) before 
randomization 
E 23. Previous use of any types of insulin for >1 month (at any time, except for treatment of 
gestational diabetes) 
E 24. History of DKA or nonketotic hyperosmolar coma within 12 weeks prior to the Screening 
Visit 
E 25. History of severe hypoglycemia (requiring assistance of another person) within 6 months 
prior to the Screening Visit 
7.2.3 Exclusion criteria related to the current knowledge of sotagliflozin  
E 26. Pregnant (confirmed by serum pregnancy test at Screening) or breast-feeding women 
E 27. Women of childbearing potential not protected by highly effective method(s) of birth 
control and/or who are unwilling or unable to be tested for pregnancy (see Appendix A) 
E 28. Mean BP after 3 separate measurements >180 mmHg (SBP) or >100 mmHg (diastolic 
blood pressure [DBP]) 
E 29. History of hypertensive urgency or emergency within 12 weeks prior to randomization 
unless patient is being aggressively treated for hypertension according to local guidelines 
Examples of guidelines current at the time of protocol writing include those from the 
ADA (10) and the European Society of Cardiology (11) 
E 30. History of gastric surgery including history of gastric banding or inflammatory bowel 
disease within 3 years before the Screening Visit 
E 31. Difficulty swallowing such that the patient cannot take the IMP 
E 32. Known allergies, hypersensitivity, or intolerance to sotagliflozin or any inactive 
component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose 
sodium [disintegrant], talc, silicone dioxide, and magnesium stearate [nonbovine]), unless 
the reaction is deemed irrelevant to the study by the Investigator 
E 33. Intolerance to any SGLT2 inhibitor 
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E 34. Laboratory findings with the central laboratory tests at Visit 1: 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × the upper 
limit of the normal laboratory range (ULN) 
- 
Total bilirubin >1.5 × ULN (except in case of Gilbert’s syndrome) 
- 
Neutrophils <1,500/mm3 (or according to ethnic group; see Appendix D for details) 
and/or platelets <100,000/mm3 
- 
Amylase and/or lipase >3 × ULN 
- 
Fasting triglycerides >600 mg/dL (>6.77 mmol/L) unless value determined to be due 
to nonfasting status in which case it may be repeated once 
E 35. Severe renal disease as defined by eGFR of <30 mL/min/1.73m2 at screening by the 
4 variable Modification of Diet in Renal Disease equation 
E 36. Renal disease that required treatment with immunosuppressive therapy or a history of 
dialysis or renal transplant or initiation of chronic dialysis within 4 weeks prior to the 
Screening Visit or expected to occur within 180 days after the Screening Visit 
E 37. History of hereditary glucose-galactose malabsorption or primary renal glucosuria 
 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The IMPs are sotagliflozin 200 mg and matching placebo. Patients will be provided with 70 tablet 
bottle(s) of sotagliflozin 200 mg or matching placebo. Table 1 provides a summary of each IMP. 
Table 1 - Summary of investigational medicinal products 
IMP: 
Sotagliflozin 
Placebo 
Name of the IMPs 
Sotagliflozin (SAR439954) 
Placebo 
Pharmaceutical form 
Sotagliflozin (SAR439954) will be supplied as 
200 mg tablets 
Placebo will be supplied as tablets (identical to 
sotagliflozin 200 mg tablets in appearance) 
Dose, timing and route of 
administration 
Two 200 mg tablets, taken orally once daily, 
before first meal of the day 
Two tablets, taken orally once daily, before 
first meal of the day  
Duration of treatment 
79 weeks following randomization including a 
26-week double-blind Core Treatment Period 
and a 53-week double-blind Extension 
2 weeks during single-blind Run-in phase 
79 weeks following randomization including a 
26-week double-blind Core Treatment Period 
and a 53-week double-blind Extension 
Storage conditions  
Store between +15°C and +30°C  
(59°F and 86°F) 
Store between +15°C and +30°C  
(59°F and 86°F) 
IMP: Investigational medicinal product 
 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS 
8.2.1 Sulfonylurea and metformin 
Patients are enrolled with a background therapy consisting of a sulfonylurea alone or in 
combination with metformin. Background sulfonylurea and metformin are considered as 
noninvestigational medicinal products (NIMP). Sulfonylurea and metformin (commercial 
formulations) will be administered orally according to the locally approved label. 
The dose of sulfonylurea must be ≥half the maximum recommended dose as per local label or 
maximum tolerated dose (maximum tolerate dose needs to be documented). If applicable, the dose 
of metformin must be ≥1500 mg/day or maximum tolerated dose (maximum tolerate dose needs 
to be documented). Sulfonylurea and metformin doses must be stable for at least 12 weeks before 
Screening. 
The doses of sulfonylurea and, if applicable, metformin, should be stable throughout the study 
unless down-titration is required for safety reasons. 
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Sulfonylurea and metformin treatment are to be reported in the electronic case report form 
(e-CRF). This information should include specific drug name, dose, route of administration, and 
frequency. 
The cost of the background treatment sulfonylurea or metformin not covered by health insurance 
will be reimbursed where permitted by local regulations. 
8.2.2 Rescue therapy 
The threshold values are defined as follows, depending on study period: 
• FPG >270 mg/dL (15.0 mmol/L) from Randomization up through the scheduled Week 8 
Visit 
• FPG >240 mg/dL (13.3 mmol/L) after the Week 8 visit up through the scheduled Week 12 
Visit 
• FPG >200 mg/dL (11.1 mmol/L) after the Week 12 Visit through the end of the 26-week 
Core Treatment Period 
• FPG >170 mg/dL (9.4 mmol/L) or HbA1c ≥8.0% after the Week 26 Visit through the end 
of the treatment period (Week 79) 
Routine fasting SMBG (see Section 9.2.1.6) and central laboratory alerts on FPG (and HbA1c at 
Week 26 and onward) are set up to ensure that glycemic parameter results remain under 
predefined thresholds.  
• If one fasting SMBG value exceeds the specific glycemic limit on one day, the patient 
checks it again during the two following days. If all the values in three consecutive days 
exceed the specific limit, the patient should contact the Investigator and a central 
laboratory FPG measurement (and HbA1c at Week 26 and onward) be performed as soon 
as possible, preferably within 7 days, to confirm the hyperglycemia 
• Upon receipt of a central laboratory rescue alert, a central laboratory re-test must be 
completed and confirmed as exceeding the threshold for rescue before rescue therapy is 
initiated. The re-test confirmation should be performed as soon as possible, but within 
7 days of receipt, by unscheduled visit 
In the event that a confirmatory FPG and/or HbA1c exceeds the threshold, the Investigator should 
ensure that no reasonable explanation exists for insufficient glucose control and in particular that: 
• The increased FPG has been tested at a fasting status (ie, no food intake for ≥8 hours) 
• Investigational medicinal product is given at the planned dose 
• There is no intercurrent disease, which may jeopardize glycemic control (eg, infectious 
disease) 
• Compliance to treatment is appropriate 
• Compliance to diet and lifestyle is appropriate 
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If any of the above can reasonably explain the insufficient glycemic control, the Investigator 
should consider not initiating rescue medication and should undertake appropriate action, ie: 
• Assess plasma glucose in fasting condition (ie, after at least 8 hours fast) 
• Initiate an evaluation and treatment of intercurrent disease (to be reported in 
AE/concomitant medication parts of the e-CRF and the medical record) 
• Stress the absolute need to be compliant with treatment 
• Organize a specific interview with the patient and a Registered Dietician or other qualified 
nutrition professional to reinforce the absolute need to be compliant with diet and lifestyle 
recommendations, and schedule a FPG/HbA1c assessment at the next visit 
If none of the above mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, rescue medication may be introduced. 
Open-label rescue medication(s) to treat hyperglycemia will be at the discretion of the 
Investigator and in accordance with local standard of care and prescribing practice. Except for 
SGLT2 inhibitors, and additional metformin and sulfonylurea, any approved medication(s) 
including oral antidiabetic drugs, GLP-1 receptor agonists, or insulin can be prescribed to treat the 
hyperglycemia. Metformin will also be permitted for patients on sulfonylurea only at Screening. 
The patient continues the study treatment (blinded) and stays in the study in order to collect 
efficacy and safety information. The planned visits and assessments should occur until the last 
scheduled visit. For patients with renal impairment, contraindications to antihyperglycemic drugs 
should be taken into consideration.  
Rescue therapy is considered a NIMP. Rescue therapy is to be reported in the e-CRF. This 
information should include specific drug name, dose, route of administration, and frequency. 
If not covered by health insurance, the cost of the rescue therapy will be reimbursed where 
permitted by local regulations. 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
To maintain blinding, sotagliflozin and placebo tablets and packaging will be blinded and 
indistinguishable. 
During the double-blind treatment period each treatment package will be labeled with a number, 
which is generated by a computer program from Sanofi. Investigators will not have access to the 
randomization (treatment) code except under circumstances described in Section 8.3.2. 
The randomization and the treatment allocation will be performed centrally by an IRT. The study 
biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the patient 
randomization list from which it allocates treatment arms to the patients. 
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 At Visit 3 (Baseline), assessment results are reviewed and Baseline assessments 
are completed, the IRT is contacted for randomization and allocation of the treatment package(s).  
After Visit 3 (Baseline) the IRT is contacted again each time new treatment package(s) allocation 
is required by the protocol. For each randomized patient, the IRT will allocate treatment package 
number(s) corresponding to the treatment group assigned. Treatment packages are allocated by 
the IRT using their treatment kit number(s). 
A randomized patient is defined as a patient who is registered and assigned with a treatment kit 
number from the IRT, as documented in the IRT. 
A patient may not be enrolled in this study more than once (ie, enter run-in, or be randomized 
twice). In cases where original screen failure was due to reasons expected to change at rescreening 
and based upon the Investigator’s clinical judgment, the patient can be rescreened once prior to 
entering Run-in for this study. In these cases, a patient will need to sign a new ICF, be registered 
as a re-screened patient in IRT and assigned a new patient number in IRT (first Screening Visit is 
to be registered as screen failure in IRT), and again complete Screening Visit 
procedures/assessments. 
8.5 
PACKAGING AND LABELING 
Packaging will be undertaken in accordance with the administration schedule. The content of the 
labeling is in accordance with the local regulatory specifications and requirements. 
The appropriate number of packages will be dispensed to cover up to the next dispensing visit 
(please refer to Section 1.2). Storage conditions and use-by-end date are part of the label text. 
Treatment labels will indicate the treatment number (used for treatment allocation and reported in 
the e-CRF). 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures. 
Control of IMP storage conditions, especially control of temperature and instructions for handling 
the Sanofi compound should be managed according to the rules provided by the Sponsor. 
The expiry date and storage conditions are written on the IMP labels. The IMP should be stored 
between +15°C and +30°C (59°F and 86°F). 
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8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMPs will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor or Delegate. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor or Delegate, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for 
direct-to-patient shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
8.7.1 Treatment accountability and compliance 
Accounting and compliance for IMPs will be performed at Visit 3 and all subsequent 
on-treatment, on-site visits.  
The Investigator will check the compliance to the IMP dose schedule based on the patient diary 
and will then complete the appropriate Site treatment and patient treatment log forms. Returned 
IMP will be counted by site staff. In addition the dosing information will be recorded on the 
appropriate pages of the e-CRF. 
For NIMPs sulfonylurea and (if applicable) metformin, name, start and end date of treatment, total 
daily dose, etc, will be documented in the source documents. Compliance to sulfonylurea and 
metformin will be checked by interviewing the patient and reviewing the patient diary at each 
visit and documented in the source documents and in the e-CRF. 
Rescue therapy (see Section 8.2.2) is to be reported in the e-CRF. This information should include 
specific drug name, dose, route of administration, and frequency. 
If compliance is inadequate as determined by the Principal Investigator (PI), patients will be 
trained again and mentored. If suboptimal compliance continues after training and mentoring, 
patients may be discontinued at the discretion of the PI after discussion with the Sponsor/CRO’s 
medical monitor. 
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8.7.2 Return and/or destruction of treatments 
Patients are to return all IMP (unused, in use or empty bottle[s]) at each on-site visit (or final 
assessment on-treatment visit in case of permanent premature discontinuation), as described in 
Section 1.2.  
All used, partially-used or unused IMPs will be retrieved by the Sponsor or Delegate. A detailed 
site and patient treatment log of the returned IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. 
For NIMP not provided by the Sponsor (ie, sulfonylurea, metformin, and rescue therapy), tracking 
is to be undertaken by the Investigator (or pharmacist if appropriate) according to the system 
proposed by the Sponsor/CRO. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP. 
The IMP includes placebo and sotagliflozin 400 mg. 
All concomitant medications should be documented on the Medications page of the e-CRF. This 
includes all NIMP treatments that are taken by the patients at any time during the clinical trial, 
beginning at Visit 1.  
Additionally, all medications taken in the 3 months prior to Visit 1 and prior use of SGLT2 
inhibitors should be reported. 
8.8.1 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 before the rescue therapy 
Note: short-term use (<10 consecutive days) of the prohibited medication, eg, short-acting 
insulin for treatment of acute illness or surgery is allowed. 
• Systemic use of glucocorticoids for more than 10 consecutive days (topical, ophthalmic, 
nasal spray or inhaled applications are allowed) 
• Initiation of any weight loss drugs (eg, phentermine, orlistat) 
• Investigational medicinal products in any other clinical study 
SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, or empagliflozin), additional sulfonylurea and 
metformin are not allowed for rescue or post IMP therapy until the end of study. 
Reduction of digoxin dose should be considered because sotagliflozin acts as a weak P-gp 
inhibitor and increases systemic exposure to digoxin. Patients taking sotagliflozin with 
concomitant digoxin should have digoxin concentrations monitored and doses reduced as needed. 
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In addition, other P-gp substrates may be affected and the labels of P-gp substrate drugs should be 
consulted with regards to monitoring and dose adjustments. 
Other medications which are unlikely to interfere with the PK or PD of the IMP or confound 
interpretation of the study endpoints are allowed as needed 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. 
After premature permanent discontinuation of the IMP, any treatments (other than SGLT2 
inhibitors, and additional sulfonylurea and metformin) are permitted, as deemed necessary by the 
Investigator. 
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. 
8.8.2 Concomitant diabetes therapy 
For patients in both groups, background sulfonylurea and (if applicable) metformin should be 
stable throughout the study unless down-titration is required for safety reasons. 
The rescue medication(s) that will be used to treat hyperglycemia when a patient’s hyperglycemia 
reaches the rescue threshold are also defined as NIMPs. Except for SGLT2 inhibitors, additional 
metformin and sulfonylurea, any approved medication(s) including oral antidiabetic drugs, 
GLP-1 receptor agonists, or insulin can be prescribed at the Investigator’s discretion to treat the 
hyperglycemia. Metformin will also be permitted for patients on sulfonylurea only at Screening. 
The regimen of the rescue medications will be in accordance with local standard of care and 
prescribing practice. 
8.9 
POSTSTUDY TREATMENT 
Because sotagliflozin may reduce BP, adjustment of antihypertensive medication may be needed 
during the study in patients with hypertension. Conversely, monitoring for an increase in BP 
should be performed after withdrawal of study medication. If the BP is elevated after withdrawal 
of study treatment, the Investigator should consider adding or adjusting antihypertensive 
medication. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY ENDPOINTS 
9.1.1 Primary efficacy endpoint 
• 
Change from Baseline to Week 26 in HbA1c (%) 
9.1.2 Secondary efficacy endpoints 
The continuous secondary efficacy endpoints are: 
• 
Change from Baseline to Week 26 in FPG 
• 
Change from Baseline to Week 26 in body weight 
• 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 12 in SBP for all patients 
• 
Proportion of patients with HbA1c <6.5%, <7.0% at Week 26 
9.1.3 Other efficacy endpoints 
• 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP <130 mmHg 
• 
Proportion of patients with reduction in body weight by ≥2%, ≥5%, and ≥10% from 
Baseline 
• 
Change from Baseline to Week 12 in DBP 
• 
Proportion of patients achieving SBP <130 mmHg for those with Baseline SBP 
≥130 mmHg 
• 
Proportion of patients achieving DBP <80 mmHg for those with Baseline DBP ≥80 mmHg 
• 
Proportion of patients requiring rescue for hyperglycemia 
• 
Change from Baseline in: 
- 
Serum creatinine 
- 
eGFR 
• 
Change from Baseline to Week 79 in HbA1c 
• 
Change from Baseline to Week 79 in FPG 
• 
Change from Baseline to Week 26 in SBP for all patients and for patients with Baseline 
SBP ≥130 mmHg 
• 
Change from Baseline to Week 79 in SBP for all patients and for patients with Baseline 
SBP ≥130 mmHg 
• 
Change from Baseline to Week 79 in body weight 
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9.1.4 Assessment methods of efficacy endpoints 
9.1.4.1 Hemoglobin A1c 
Hemoglobin A1c will be assessed at Screening (Visit 1) and all on-site visits during the 
double-blind treatment period with the exception of Week 18 (Visit 8). 
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified level I 
“National Glycohemoglobin Standardization Program” central laboratory to allow estimation of 
the change from Baseline to Week 26 in HbA1c and the proportion of patients with HbA1c 
<6.5%, <7.0% at Week 26. 
If a patient needs to receive rescue antidiabetic medication, assessment of HbA1c should be 
performed before the introduction of the rescue medication. 
9.1.4.2 Fasting plasma glucose measurement 
Plasma glucose is measured in the fasting state at Screening (Visit 1) and all on-site visits during 
the treatment period. For the eligibility and efficacy assessments of the study, FPG is measured at 
a central laboratory to allow estimation of change from Baseline to Week 26 in FPG. 
9.1.4.3 Body weight measurement 
Body weight is measured at all on-site Visits. Body weight will be measured to allow the 
estimation of change from Baseline to Week 26 in body weight and reduction in body weight by 
≥2%, ≥5%, and ≥10% from Baseline. 
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. The same scale should be used throughout the study, 
and calibrated on a regular basis as recommended by the manufacturer. Calibration documents 
should be filed in the study file. 
The use of balance scales is recommended. The floor surface on which the scale rests must be 
hard and should not be carpeted or covered with other soft material. The scale should be balanced 
with both weights at zero and the balance bar aligned. The patient should stand in the center of the 
platform as standing off-center may affect measurement. The weights are moved until the beam 
balances (the arrows are aligned). The weight is read and recorded in the e-CRF and Source Data. 
Self-reported weights are not acceptable; patients must not read the scales themselves. 
9.1.4.4 Blood pressure endpoint measurements 
Systolic BP and DBP will be assessed at all on-site visits. Blood pressure measurements must be 
taken as described in Section 9.2.1.4 with details provided in Appendix C. 
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9.1.4.5 Kidney function parameter measurement 
Serum creatinine will be assessed at Baseline (Visit 3) and selected on-site visits (see Study 
Flowchart in Section 1.2). A central laboratory will analyze samples and estimate change from 
Baseline in serum creatinine and eGFR. 
9.1.4.6 Proportion of patients requiring rescue for hyperglycemia 
The use of rescue medications for hyperglycemia will be assessed and reported throughout the 
treatment period. Routine alerts on FPG and/or HbA1c will be sent to the Investigator from the 
central laboratory to ensure that glycemic parameter results remain within predefined thresholds. 
For details and further actions should FPG and/or HbA1c values fall above thresholds, refer to 
Section 8.2.2. 
9.2 
SAFETY ENDPOINTS 
Assessments for safety include AEs, SMBG, clinical laboratory assessments, physical 
examination, electrocardiogram (ECG), weight, and vital signs. An independent DMC will meet 
on a regular basis to review accumulating clinical trial safety data. 
Adjudication of all deaths, MACE/other selected CV events (MI, stroke, unstable angina leading 
to hospitalization, and heart failure leading to hospitalization), selected renal events, bone 
fracture, and DKA will be performed in a blinded manner by a CEC(s) comprised of experts. 
Details will be provided in the charter of the CEC(s). Further details are available in Section 6.4. 
Two expert committees will review all potential cases of DILIs and cases of amputation in a 
treatment-blinded manner to evaluate causality. 
The following safety endpoints will be assessed: 
• Adverse events, AEs leading to discontinuation from the IMP, adverse events of special 
interest (AESIs), events of special interest (EOSIs), SAEs and deaths 
• Hypoglycemia (all, severe, and/or documented symptomatic hypoglycemia) 
• Clinical laboratory results (including fasting lipids; see Section 9.2.1.3) 
• Vital signs and ECG results. 
Observation period of safety endpoints 
The observation period of safety data will be divided into 3 segments: 
• The pre-treatment period is defined as the time between the date of the informed consent 
and the first dose of double-blind IMP 
• The on-treatment period (TEAE period) is defined as the time from the first dose of 
double-blind IMP up to 10 days (1 day for hypoglycemia) after the last dose of 
double-blind IMP, regardless of the introduction of rescue therapy. The 10-day interval is 
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chosen based on the half-life of the IMP (approximately 5 times the half-life of 
sotagliflozin in patients with moderate renal dysfunction) 
• The post-treatment period is defined as the time starting 11 days after the last dose of 
double-blind IMP (after the on-treatment period) 
The Baseline value for safety endpoints in the safety population is the last available value (or the 
average of all values for creatinine or eGFR) prior to the first administration of double-blind IMP. 
9.2.1 Assessment methods of safety endpoints 
9.2.1.1 Adverse events 
Adverse events including SAEs, AESIs, and EOSIs will be assessed. Refer to Section 10.4 to 
Section 10.7 for details. 
9.2.1.1.1 Adverse events of special interest 
Adverse events of special interest are listed in Section 10.4.1.3, reporting requirements for AESI 
are presented in Section 10.4.4. 
9.2.1.1.2 Events of special interest 
Events of special interest are separate from AESIs. For a list of events defined as EOSIs and their 
reporting requirements see Section 10.4.1.4 and Section 10.4.5, respectively. 
9.2.1.2 Hypoglycemia 
Hypoglycemia will be assessed from the signing of the ICF until 2 weeks after the last dose of 
IMP (note: for patients who discontinue treatment before Week 79, safety data will be collected 
until scheduled study end). Patients will also complete the hypoglycemia specific page (as part of 
the patient diary) from Visit 1 onwards, which will be regularly reviewed by Investigators. See 
Section 10.6.1 for further details. 
9.2.1.3 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry, 
amylase, lipase, lipid profile) and urinalysis, according to the schedule presented in Section 1.2. 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Table 2 lists the hematology, clinical 
chemistry, and other blood safety parameters to be assessed by the central laboratory. 
In addition, for WOCBP a serum pregnancy test is performed at Screening, and urine pregnancy 
tests are taken at all on-site visits during the double-blind treatment period excluding Visit 4 
(Week 1). Any positive urine test results must be confirmed by a serum pregnancy test. The 
Investigator may perform additional tests at their discretion or as required by local regulations. 
Serum follicle-stimulating hormone (FSH) and estradiol will be measured in menopausal women 
at Screening (Visit 1, Week -4) (see Appendix A for definition of menopausal women). 
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Table 2 - Blood safety parameters 
Clinical chemistry 
Hematology 
Other blood parameters 
Sodium 
Complete blood count (CBC) 
Lipid profile 
Potassium 
Differential 
Total cholesterol (TC) 
Chloride 
Platelet count 
High-density lipoprotein cholesterol (HDL-C) 
Carbon dioxide (bicarbonate) 
Hemoglobin 
Low-density lipoprotein cholesterol (LDL-C) will be 
calculated by Friedwald equation 
Blood urea nitrogen (BUN) 
Hematocrit 
Non-HDLC will be calculated as the difference between 
TC and HDLC 
Creatinine (eGFR will be calculated) 
 
Triglycerides (TG) 
Glucose (serum) 
 
Other chemistry tests  
Alanine aminotransferase (ALT) 
 
 
Aspartate aminotransferase (AST) 
 
 
Total bilirubin (TB) 
 
 
Alkaline phosphatase (ALP) 
 
 
Uric acid 
 
 
Calcium 
 
 
Phosphorus 
 
 
Total protein 
 
 
Albumin 
 
 
Magnesium 
 
 
Creatine phosphokinase (CPK) 
 
 
Lactic acid dehydrogenase (LDH)  
 
 
Amylase 
 
 
Lipase 
 
 
All assessments to be performed by central laboratory. All assessments measured in serum. 
9.2.1.3.1 Urinalysis 
Urinalysis (urine dipstick with microscopy) will be performed by central laboratory at Screening 
(Visit 1), Baseline (Visit 3), Week 26 (Visit 9), and Week 79 (Visit 13). To prevent partial 
unblinding, the central laboratory urinalysis dipstick will not include the measurement of urine 
glucose. 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 
In the event of abnormal urinalysis findings, suspicious of urinary tract infection, urine culture 
should be performed. Additionally, urine culture should be performed if at any point the PI 
suspects the presence of a urinary tract infection. If the urine dipstick is positive for blood, the 
central laboratory will perform reflexive testing to include microscopy. Additional testing will be 
performed according to the judgment of the Investigator. Referral to urology/urologic evaluation 
is recommended for new or unexplained cases of confirmed hematuria (urology/urologic 
evaluation is not required where hematuria is considered to be related to diabetic nephropathy). 
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9.2.1.4 Vital signs and physical exam 
A complete physical exam (including sitting BP and heart rate, temperature and respiratory rate) 
will be performed at Visit 1 (Screening), Visit 9 (Week 26), and Visit 13 (Week 79). Abbreviated 
physical exams (including sitting BP and heart rate) will be performed at all other on-site visits. 
The abbreviated physical exam should focus on cardiac and respiratory systems, as well as any 
areas important for assessment of AEs if necessary.  
Three separate seated BPs and heart rate measurements should be taken with at least 1 minute 
between measurements following a 5-minute rest period, and prior to phlebotomy. Full details and 
directions for the measurement of BP are presented in Appendix C.  
9.2.1.5 Electrocardiogram variables 
The ECG assessment of “normal” or “abnormal” will be analyzed. 
A 12-lead ECG record is performed locally at Screening (Visit 1), Week 26 (Visit 9), and 
Week 79 (Visit 13). 
The 12-lead ECG should be performed after at least 10 minutes in a supine position and prior to 
IMP administration. The Investigator should review the ECG and document the interpretation, 
sign and date it on the ECG print out and report it in the e-CRF. Each ECG trace is analyzed in 
comparison with the screening recorded trace. All original traces are kept as source data. 
Note: Any new ECG abnormality should be rechecked for confirmation and reported as 
appropriate for that finding. 
9.2.1.6 Self-monitoring of blood glucose 
A meter for self-assessment of blood glucose will be dispensed at the Run-in visit (Visit 2). 
In addition to home measurements of self-monitored blood glucose, self-monitoring of blood 
glucose will be performed at the Run-in Visit (Visit 2), Baseline (Visit 3) and all subsequent 
on-site visits. Glucose meters used for SMBG display results as plasma glucose concentration. 
Patients will also receive a patient diary at all on-site visits with the exception of Visit 13 (End of 
Treatment visit). The diary will be reviewed at all on-site visits from Visit 2 to Visit 13. 
Self-assessed blood glucose levels will be entered in the patient diary.  
Patients will be asked to self-assess fasting blood glucose levels at least 3 times a week from the 
Run-in Visit (Visit 2) to the end of the Treatment Period including on day of each on-site study 
visit. After Visit 9 (Week 26), if SMBG values are <120 mg/dL over a two-week period, the 
Investigator can (at their own discretion) instruct patients to self-monitor blood glucose once a 
week (on day of on-site study visit for weeks with on-site study visits).  
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Patients will also be requested to self-assess blood glucose levels whenever they experience any 
illnesses (eg, cold, flu), or symptoms of hyperglycemia or hypoglycemia. Symptoms of 
hypoglycemia may include shakiness, dizziness, sweating, hunger, headache, pale skin color, 
sudden moodiness or behavior changes (such as crying for no apparent reason), clumsy or jerky 
movements, seizure, difficulty paying attention or confusion, or tingling sensations around the 
mouth. Patients will be instructed to record the presence or absence of hypoglycemic episodes or 
hypoglycemic symptoms in the patient diary provided. 
Patients will also be instructed to record SMBG values that are ≤70 mg/dL (≤3.9 mmol/L) in the 
patient diary. Patients should be instructed to contact the site if fasting SMBG values over 
3 consecutive days are:  
• >270 mg/dL (15.0 mmol/L) from Randomization up through the scheduled Week 8 Visit 
• >240 mg/dL (13.3 mmol/L) after the Week 8 visit up through the scheduled Week 12 Visit 
• >200 mg/dL (11.1 mmol/L) after the Week 12 Visit and through the end of the 26-week 
double-blind Core Treatment Period 
• >170 mg/dL (9.4 mmol/L) after the Week 26 Visit through the end of the Extension 
treatment period 
9.2.1.7 Diabetic ketoacidosis 
Patients will be provided with instructions on how to recognize the symptoms of DKA and 
instructed to contact the site (or seek emergency medical services if after business hours) if these 
symptoms develop.  Patients should have a full clinical evaluation with laboratory testing for 
possible DKA by the Investigator or emergency medical services physician. If such evaluation 
and laboratory testing confirm the presence of metabolic acidosis, then appropriate treatment 
should be implemented and the “Possible DKA” e-CRF should be completed. See Appendix B for 
further details. 
9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics 
The PK endpoint is: 
• Plasma concentrations of sotagliflozin and its metabolite pre-dose at Week 4, 18, 26, 52, 
79, and 1 hour 30 minutes post-dose at Week 26 and 79 
Pharmacokinetic data may be subjected to a population PK analysis, which will be reported 
separately to the clinical study report (CSR).  
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9.6 
APPROPRIATENESS OF MEASUREMENTS  
The addition of sotagliflozin to background therapy consisting of sulfonylurea treatment with or 
without metformin is expected to lower HbA1c over 26 weeks of treatment (primary efficacy 
analysis).  
The concentration of HbA1c reflects the glycemic history of the previous 120 days and is thus an 
index of mean glycemia, documenting glycemic control over the past 2 to 12 weeks. 
Hemoglobin A1c has also been shown to correlate with the development of long-term 
complications of diabetes, and reduction of HbA1c is known to reduce the risk of long-term 
microvascular complications. Therefore, HbA1c is considered an appropriate primary endpoint for 
assessing the effect of a treatment on glycemic control. The duration of study treatment (26 weeks 
for the primary HbA1c endpoint) is considered to be sufficient for achieving stable conditions 
with IMP and for enabling an adequate assessment of time-dependent changes in HbA1c. 
The problem of weight gain in T2D is widely recognized. More than 80% of individuals with T2D 
are overweight, many at the time of diagnosis. Consequently, iatrogenic weight gain is not only 
unwelcome, but represents an important clinical issue that can become a barrier to the successful 
management of glycemic control. Therefore, in this study assessing change in body weight from 
Baseline to Week 26 is a secondary endpoint.  
Improvement in FPG has been observed with sotagliflozin in multiple studies. Therefore 
assessment of FPG is relevant in this study. This parameter is also considered by regulatory 
agencies to be supportive of the efficacy of an antidiabetic agent. 
Phase 2 data indicated that sotagliflozin may reduce SBP by 10 to 15 mmHg in patients with 
SBP ≥130 mmHg at Baseline, while having no significant effect in patients with SBP 
<130 mmHg, and did not induce hypotension. Since this could be of benefit to patients with T2D, 
this finding is being followed up as a secondary objective in this trial, as well as the potential in 
patients with DBP >80 mmHg. Although effects on BP in Phase 2 data were observed with the 
400 mg dose at 12 weeks, the effects will be examined at Weeks 12, 26, and 79. 
The other efficacy and safety assessments in this study are standard, well-established 
measurements for a Phase 3 study evaluating the treatment of T2D in adult patients.  
The length of the study is considered appropriate for detection of the primary endpoint given the 
power estimates (see Section 11). 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The visit schedule and procedures/assessments are listed in the “Study Flow Chart” (Section 1.2). 
The aim of this section is to provide details on how some of the procedures/assessments should be 
performed. 
This is an out-patient study and consists of 11 on-site visits and 3 telephone visits, although 
optional on-site and/or telephone visits can be scheduled at any time for any reason during the 
study whenever considered necessary by the Investigator. 
The patients need to be fasting for on-site visits Visit 1 through Visit 13 (Week -4 through 
Week 79), unless instructed otherwise by the Investigator. Throughout the study, “fasting” is 
defined as 8 hours without food.  
Note: If the patient is not fasting at the visits specified above, the blood sample will not be 
collected and a new appointment should be given to the patient for the following day if possible, 
with instruction to be fasted (other procedures can be performed as scheduled). All laboratory 
assessments will occur prior to IMP administration on the day of the visit. 
The Run-in visit (Visit 2) can be performed as soon as the results of all Screening tests are 
available and the patient is confirmed to be eligible for participation in the study. The visit 
window for Visit 4 through Visit 9 is ±3 days. Visits 10, 11, and 12 should occur at the scheduled 
timepoint ±7 days. Visit 13 (EOT) should occur from Day 548 to Day 555. For the Follow-up 
(Visit 14), the visit should occur within a window of ± 3 days, 2 weeks after the last dose of IMP. 
If one visit date is changed, the next visit should occur according to the original schedule, 
ie calculated from the date of Baseline visit (Visit 3, Week 0). 
For a complete list of procedures scheduled for each study visit please refer to the Study flowchart 
(Section 1.2), which details the procedures to be performed. 
All data obtained during the trial visits are reviewed by the Investigator and Sub-investigators 
who are qualified in the treatment of T2D and are trained on the study. 
10.1.1 Screening Period 
The Screening Period is up to 4 weeks and includes the Screening phase and the Run-in phase. 
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• Assessment of the patient’s medical and surgical history: to include history of T2D, 
treatment and complications (eye, kidney, amputations, etc); history of smoking/tobacco 
use; history of alcohol and drug abuse 
• Patient diary is dispensed and instructions/training are provided 
• 12-lead ECG 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Hepatitis serology 
- 
Serum pregnancy testing for WOCBP or serum FSH and estradiol for postmenopausal 
women 
- 
Hematology 
- 
Clinical chemistry to include amylase and lipase 
- 
Fasting lipids 
- 
Urinalysis (dipstick and microscopy) 
• Patients are instructed to return to the site for Visit 2 (Week -2) 
10.1.1.2 Run-in phase 
The Run-in phase is 2 weeks and includes Visit 2 (Week -2).  
10.1.1.2.1 On-site Visit 2 (Run-in, Week -2) 
The following procedures/assessments will be performed at Visit 2 (Week -2): 
• Measurement of body weight 
• Abbreviated physical examination including vital signs (SBP and DBP, and heart rate). 
After 5 minutes resting, seated SBP, DBP, and heart rate will be assessed 3 times with at 
least 1 minute between each measurement (see Appendix C for details) 
• Diet and exercise instruction 
• Blood glucose meter is dispensed and instructions/training are provided 
• Instruction on basic GU hygiene and hydration (see Appendix B) 
• IRT to be notified (registration of run-in, allocation of single-blind run-in kit) 
• Patient diary is collected/reviewed and a new diary dispensed. Instruction/training is 
provided as needed 
• AEs/SAEs/AESI/EOSI and hypoglycemia occurring since Visit 1 (if any) are reported. 
• Run-in kit/placebo is dispensed 
• Changes in concomitant medication are reported 
• Fasting SMBG is assessed 
• Patients are instructed to return to the site in the fasting state for Visit 3 (Randomization) 
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10.1.2 Double-blind randomized Core Treatment Period (Day 1 to Week 26) 
Upon successful completion of the Run-in phase, patients will be randomly allocated to either 
sotagliflozin 400 mg or placebo for the double-blind treatment period. All randomized patients 
will be followed at regular on-site visits for the duration of the treatment period. Visit 4 (Week 1) 
and Visit 6 (Week 8) are telephone visits.  
In addition to routine laboratory testing, the following will be performed at specified time points: 
plasma concentration. 
The date and time of the last intake of IMP prior to visits where PK samples are taken should be 
recorded by the patient in the patient diary. Patients should be reminded of this at visits preceding 
PK time points to ensure these details are captured. 
In the event of abnormal urinalysis findings, urine cultures should be performed (microbial 
testing). Additionally, urine cultures should be performed if at any point the PI suspects the 
presence of a urinary tract infection. 
10.1.2.1 On-site Randomization Visit on Day 1 (Visit 3; Baseline; Week 0) 
The following procedures will be performed at this visit: 
• Exclusion criteria are to be reviewed, including assessment of compliance during Run-in 
phase 
• Concomitant medications are assessed 
• Measurement of body weight 
• Abbreviated physical examination including vital signs (SBP and DBP, and heart rate). 
After 5 minutes resting, seated SBP, DBP and heart rate will be assessed 3 times with at 
least 1 minute between each measurement (see Appendix C for details) 
• IMP accounting and compliance for single-blind placebo Run-in phase 
• IRT to be notified and randomization will occur 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Diet and exercise instruction 
• Patient diary is collected/reviewed and a new diary dispensed. Instruction/training is 
provided as needed 
• Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• Fasting SMBG is assessed 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose 
- 
HbA1c 
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- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
- 
Hematology 
- 
Clinical chemistry to include amylase and lipase 
- 
Urinalysis (dipstick and microscopy) 
• Additional laboratory testing at this visit: 
 
 
 
 
• IMP is dispensed 
• Patients are instructed to return to the site in the fasting state for Visit 5 (Week 4) and a 
telephone call is scheduled in 1 week (Visit 4) 
• For accountability and compliance purposes, patients are instructed to return to the site 
with their used, in-use, and unused bottle(s) dispensed during Visit 3 
10.1.2.2 On-site visits at Weeks 4, 12, and 18 (Visits 5, 7, and 8) 
The following will be performed at these visits: 
• IRT to be notified 
• IMP re-supply 
• IMP accountability and compliance 
• Patient diary is collected/reviewed and a new diary dispensed. Instructions/training are 
provided as needed 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Patients are evaluated for glycemic rescue (see Section 9.1.4.6) 
• Measurement of body weight 
• Abbreviated physical examination including vital signs (SBP and DBP, and heart rate). 
After 5 minutes resting, seated SBP, DBP and heart rate will be assessed 3 times with at 
least 1 minute between each measurement (see Appendix C for details) 
• Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• Fasting SMBG is assessed 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose (all visits) 
- 
HbA1c (all visits except Visit 8) 
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- 
Urine pregnancy testing for WOCBP (all visits, any positive urine test results must be 
confirmed by a serum pregnancy test) 
- 
Clinical chemistry (including amylase and lipase) and hematology (Visit 7 only) 
• Additional laboratory testing at these visits: 
- 
Pre-dose plasma concentration samples are collected and sent to the appropriate 
laboratory (Visits 5 and 8 only) 
• IMP is dispensed 
• Patients are instructed to return to the site in the fasting state for their next on-site visit and 
next telephone visit is scheduled (if appropriate) 
• 
Patients should be reminded to record in the diary the date and time of IMP intake on the 
day before their next visit (reminders at Visits 7 and 8) 
• For accountability and compliance purposes, patients are instructed to return to the site 
with all used, unused, and in-use bottle(s) at the next visit 
10.1.2.3 Telephone visit at Week 1 (Visit 4) and Week 8 (Visit 6) 
The following will be performed at this visit: 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Patients are evaluated for glycemic rescue (see Section 9.1.4.6) 
• Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• Fasting SMBG is assessed 
• Patients are instructed to return to the site in the fasting state for Visit 5 and Visit 7, 
respectively. They should be reminded to record in the diary the date and time of IMP 
intake on the day before their next visit (reminder at Visit 4 only) 
10.1.2.4 On-site Visit 9 at Week 26 (End of core treatment period) 
The following will be performed at this visit: 
• IRT to be notified 
• IMP accountability and compliance 
• Patient diary is collected/reviewed and a new diary dispensed. Instructions/training are 
provided as needed 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Patients are evaluated for glycemic rescue (see Section 9.1.4.6) 
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• Measurement of body weight 
• Complete physical examination including vital signs (SBP and DBP, temperature, heart 
rate, and respiratory rate). After 5 minutes resting, seated SBP, DBP, and heart rate will be 
assessed 3 times with at least 1 minute between each measurement (see Appendix C for 
details) 
• Diet and exercise instruction is provided 
• Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• 12-lead ECG, prior to IMP administration 
• Fasting SMBG is assessed 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
- 
Clinical chemistry (including amylase, lipase, lipid profile) and hematology 
- 
Urinalysis (dipstick and microscopy) 
• Additional laboratory testing at this visit: 
 
 
- 
Pre-dose and 1 hour 30 minute post-dose plasma concentration samples are collected 
and sent to the appropriate laboratory 
• IMP is dispensed 
• Patients are instructed to return to the site in fasting state in 13 weeks for Visit 10 
• For accountability and compliance purposes, patients are instructed to return to the site 
with all used, unused, and in-use bottle(s) at Visit 10 
10.1.3 Double-blind Extension Period 
Upon completion of the double-blind core treatment period, patients will remain on the same 
blinded treatment throughout a 53-week double-blind Extension Period for a total treatment 
duration of 79 weeks. 
The double-blind Extension Period will consist of 4 visits, occurring at Week 39 (Visit 10), 
Week 52 (Visit 11), Week 65 (Visit 12), and EOT visit at Week 79 (Visit 13). 
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10.1.3.1 On-site visits at Weeks 39, 52, and 65 (Visits 10 to 12) 
The following will be performed at these visits: 
• IRT to be notified 
• IMP accounting and compliance 
• Patient diary is collected/reviewed and a new diary dispensed. Instruction/training is 
provided as needed 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Patients are evaluated for glycemic rescue (see Section 9.1.4.6) 
• Measurement of body weight 
• Abbreviated physical examination including vital signs (SBP and DBP, and heart rate). 
After 5 minutes resting, seated SBP, DBP and heart rate will be assessed 3 times with at 
least 1 minute between each measurement (see Appendix C for details) 
• Diet and exercise instruction is provided (Visit 11 only) 
• Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• Fasting SMBG is assessed 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
- 
Clinical chemistry (including amylase and lipase) and hematology 
- 
Lipid profile (Visit 11 only) 
• Additional laboratory testing at these visits: 
- 
Pre-dose plasma concentration samples are collected and sent to the appropriate 
laboratory (Visit 11 only) 
• IMP is dispensed 
• Patients are instructed to return to the site in the fasting state for their next visit. They 
should be reminded to record in the diary the date and time of IMP intake on the day 
before their next visit (reminders at Visit 10 and Visit 12) 
• For accountability and compliance purposes, patients are instructed to return to the site 
with all used, unused, and in-use bottle(s) at the next visit 
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10.1.3.2 On-site Visit 13 at Week 79 – End of treatment 
The following will be performed at this visit: 
• IRT to be notified 
• IMP accountability and compliance 
• Patient diary is collected/reviewed 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Patients are evaluated for glycemic rescue (see Section 9.1.4.6) 
• Measurement of body weight 
• Complete physical examination including vital signs (SBP and DBP, temperature, heart 
rate, and respiratory rate). After 5 minutes resting, seated SBP, DBP, and heart rate will be 
assessed 3 times with at least 1 minute between each measurement (see Appendix C for 
details) 
• Diet and exercise instruction is provided 
• Instruction on DKA symptoms and basic GU hygiene and hydration (see Appendix B) is 
provided 
• 12-lead ECG, prior to IMP administration 
• Fasting SMBG is assessed 
• The following laboratory testing (by the central laboratory): 
- 
Fasting plasma glucose 
- 
HbA1c 
- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
- 
Clinical chemistry (including amylase, lipase, and lipid profile) and hematology 
- 
Urinalysis (dipstick and microscopy) 
• Additional laboratory testing at this visit: 
 
 
- 
Pre-dose and 1 hour 30 minute post-dose plasma concentration samples are collected 
and sent to the appropriate laboratory (this is not necessary if the patient discontinued 
study treatment early) 
• A telephone call for last study visit (Visit 14) is scheduled in 2 weeks 
10.1.4 Post-treatment Follow-up period 
The post-treatment follow-up period will include a telephone visit 2 weeks after the last dose of 
IMP. 
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10.1.4.1 Telephone visit at Week 81 (Visit 14)  
The following will be performed at this visit: 
• IRT notified for end of study 
• Concomitant medications are assessed 
• AEs/SAEs/AESI/EOSI and hypoglycemia (if any) are reported 
• Screening and last BP readings are reviewed, and post-treatment antihypertensive 
medication is added or adjusted as per instructions given in Section 8.9 
• The patient is instructed to schedule future follow-up with their own personal physician 
10.2 
DEFINITION OF SOURCE DATA 
10.2.1 Source data to be found in patient’s file 
Evaluations recorded in the e-CRF must be supported by appropriately signed source 
documentation related but not limited to the following: 
• Agreement and signature of ICF with the study identification 
• Study identification (name) 
• Patient number, confirmation of randomization, treatment batch number, dates and doses 
of study medication administration 
• Medical, surgical, diabetes history, including information on: 
- 
Demography, inclusion and exclusion criteria 
- 
Last participation in a clinical trial 
- 
Contraception method for WOCBP 
- 
Previous and concomitant medication 
• Dates and times of visits and assessments including examination results 
• Vital signs, height, body weight, laboratory reports, Investigation results (eg, ECG traces, 
imaging reports) 
• Adverse events and follow-up: 
- 
In case of SAE, the site should file in the source documents at least copies of the 
hospitalization reports and any relevant examination reports documenting the 
follow-up of the SAE 
• Date of premature treatment discontinuation (if any) and reason 
• Date of premature study discontinuation (if any) and reason 
• Nursing notes 
• Dietician’s notes 
• Physician’s notes 
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10.2.2 Source data verification requirements for screen failures 
For screen failure patients, the following source data must be verified: patient's identification 
details, the informed consent signed by the patient, the study identification (name), dates of study 
visits and the main reasons for screen failure. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, the 
patient should remain in the study and followed for the remainder of the study duration to collect 
vital safety status and endpoint data. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and gangrene) 
requiring treatment should lead to temporary discontinuation of IMP. Reinitiating treatment with 
the IMP will be done under close and appropriate clinical/and or laboratory monitoring once the 
Investigator will have considered according to his/her best medical judgment that the occurrence 
of the concerned event was unlikely to be related to the IMP. 
It is in the interest of the patient to monitor their blood glucose during the temporary 
discontinuation period, therefore regular determination of SMBG is to be performed and 
documented (see Section 9.2.1.6). 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the e-CRF when considered as confirmed. 
Temporary treatment discontinuation decided by the Investigator corresponds to more than 1 dose 
not administered to the patient. 
Use of any different anti-hyperglycemic medication during the time of temporary treatment 
discontinuation (ie, insulin during a hospitalization) is recorded as concomitant medication with 
the name and doses recorded in the e-CRF. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product 
Permanent treatment discontinuation is defined as any treatment discontinuation associated with 
the definitive decision from the Investigator or the patient not to re-expose the patient to the IMP 
at any time. 
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with the study treatment. 
10.4.1.2 Serious adverse event 
A serious adverse event is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event, 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
• Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc) 
• Development of drug dependence or drug abuse 
• ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase >10 × ULN 
• Suicide attempt or any event suggestive of suicidality 
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• Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
• Bullous cutaneous eruptions 
• Cancers diagnosed during the study or aggravated during the study 
• Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor may be appropriate. Such events may require further investigation in 
order to characterize and understand them. AESIs may be added or removed during a study by 
protocol amendment. 
The AESI for this study are: 
• Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in a study with IMP/NIMP: 
- 
Pregnancy occurring in a female patient included in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2) 
- 
In the event of pregnancy in a female patient, IMP should be discontinued 
- 
Follow-up of the pregnancy in a female patient or in a female partner of a male patient 
is mandatory until the outcome has been determined 
• Symptomatic overdose with IMP/NIMP: 
- 
A symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the Investigator or spontaneously notified by the patient and resulting in 
clinical symptoms and/or signs accompanied by administration of more than twice the 
intended daily dose within a 24-hour period. It will be recorded in the e-CRF as an 
AESI with immediate notification “Symptomatic OVERDOSE (accidental or 
intentional)” in all cases and will be qualified as an SAE only if it fulfills the SAE 
criteria 
- 
(Please note that an Asymptomatic overdose with the IMP/NIMP, accidental or 
intentional, defined administration of more than twice the intended daily dose within a 
24-hour period, without clinical symptoms and/or signs, either suspected by the 
Investigator or spontaneously notified by the patient, not based on accountability 
assessment. It will be recorded as an AE “Asymptomatic OVERDOSE, accidental or 
intentional”) 
• ALT increase >3 × ULN (refer to related flowchart, Appendix D) 
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10.4.1.4 Events of special interest 
An EOSI is a serious or non-serious AE of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring may be appropriate. Such events 
may require further investigation in order to characterize and understand them. These events 
should be reported on the specific e-CRF page (where applicable) and will only qualify for 
expedited reporting when serious (fulfilling SAE criteria). 
The EOSI for this study are: 
• Major adverse cardiovascular events (MACE [cardiovascular death, MI, or stroke]) and 
other specific CV events (eg, heart failure leading to hospitalization) 
• Severe hypoglycemia (see Section 10.6.1) 
• Genital mycotic infections (to include vulvovaginal candidiasis in females and candidal 
balanitis in males) 
• Urinary tract infections 
• Clinically relevant volume depletion and events related/possibly related to volume 
depletion 
• Diarrhea 
• Pancreatitis 
• Bone fractures 
• Venous thrombotic events to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism) 
• Diabetic ketoacidosis 
• 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 carcinoma) 
• Adverse event leading to an amputation 
10.4.2 General guidelines for reporting adverse events 
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the ICF until the end of the study as defined by the protocol for that patient, 
are to be recorded on the corresponding page(s) or screen(s) of the e-CRF 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s) 
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• In this study, the use of concomitant medications including antidiabetic medications may 
make it difficult to assess the causal relationship, particularly for hypoglycemia. 
Global Safety Officer with input from other appropriate study team members will 
determine the causal relationship when it is not clearly provided by the Investigator 
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor 
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient 
• Laboratory, vital signs or ECG abnormalities are to be recorded as AEs if they are 
medically relevant based on the Investigator’s medical judgment, eg:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI or EOSI 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the Monitoring team and 
Pharmacovigilance after approval of the Investigator within the e-CRF 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges 
• All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification 
• A back-up plan (using a paper case report form [CRF] process) is available and should be 
used when the e-CRF system does not work 
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Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor/CRO must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
10.4.5 Guidelines for reporting events of special interest 
If an EOSI fulfills the criteria of an SAE, reporting should be performed according to the 
instructions for reporting of SAEs (see Section 10.4.3). Otherwise, reporting should follow the 
instructions for an AE (see Section 10.4.2). 
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix D. 
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• Neutropenia 
• Thrombocytopenia 
• Increase in ALT 
• Acute renal insufficiency 
• Suspicion of rhabdomyolysis 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction [SUSAR]), to the regulatory authorities, independent 
ethics committees (IECs)/institutional review boards (IRBs) as appropriate and to the 
Investigators 
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations 
• The following AESIs to those regulatory authorities who require such reporting: 
- 
Pregnancy 
- 
Symptomatic overdose 
- 
ALT increase >3 × ULN 
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Adverse events that are considered expected will be specified by the reference safety information 
provided in the current IB.  
If required, unblinding of SUSARs will be the responsibility of the Sponsor. 
The Sponsor will report all safety observations made during the conduct of the trial in the CSR. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypoglycemia 
During the study, patients are instructed to document any hypoglycemic episodes in their study 
diary. The hypoglycemia will be reported in the specific e-CRF page with onset date and time, 
symptoms and/or signs, the SMBG value if available, and the treatment. If the event fulfills SAE 
criteria, the hypoglycemia will also be reported as an SAE. 
Hypoglycemia is categorized according to the ADA workgroup on hypoglycemia classification 
(12)(13) and summarized in Figure 1. 
In addition to the threshold of ≤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. 
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Figure 1 - Hypoglycemia classification in Study EFC14835 
 
PG: plasma glucose; SAE: serious adverse event. 
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. 
Note: “requiring assistance of another person” means that the patient could not help himself or 
herself to treat the hypoglycemia. Assisting a patient out of kindness, when assistance is not 
required, should not be considered a “requires assistance” incident. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure should also be 
reported as an SAE. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L 
(≤70 mg/dL).  
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Clinical symptoms that are considered to result from a hypoglycemic episode are eg, increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL).   
Note: low plasma glucose values without symptoms or signs should not be reported more than 
once within 30 minutes. Repeated low glucose values within a short period could be due to 
malfunction of the device, error testing or following up a low glucose reading. The Investigator 
should try not to document false low SMBG values or redundant low glucose values as 
asymptomatic hypoglycemic events. Further clarification with the patients is needed. 
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 
glucose concentration ≤3.9 mmol/L [≤70 mg/dL]), ie, symptoms treated with oral carbohydrate 
without a test of plasma glucose.  
Relative hypoglycemia 
Relative hypoglycemia, recently termed “pseudo-hypoglycemia” (14), is an event during which 
the 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). 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final CSR. 
 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size/power calculations are based on the primary variable, change from Baseline to 
Week 26 in HbA1c. Assuming a common standard deviation (SD) of 1.2% and using a 2-sided 
test at a 0.05 α-level, 250 patients per arm will have at least 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. 
The number of patients taking a sulfonylurea and metformin will be limited to 330 patients, to 
ensure sufficient numbers of sulfonylurea monotherapy patients. 
11.2 
DISPOSITION OF PATIENTS 
The total number of patients for each of the following categories will be presented in the CSR: 
• Screened patients: patients who have signed the ICF 
• Run-in patients 
• Randomized patients: patients with a treatment kit number allocated and recorded in IRT 
database, and regardless of whether the treatment kit was used or not 
• The safety population (ie, randomized and treated patients) 
• The intention-to-treat (ITT) population (as defined in Section 11.3.1.1 and analyzed as 
randomized) 
• The randomization strata (HbA1c at Screening [≤8.5%, >8.5%], metformin use at 
Screening (Yes, No), and SBP [<130, ≥130 mmHg]). The discrepancy between the strata 
assigned by IRT and the information reported on e-CRF will be listed for all randomized 
patients 
• Patients who have completed the 26-week main treatment period 
• Patients who discontinued the IMP during the 26-week main treatment period, and the 
reasons for treatment discontinuation 
• Patients who have completed the entire treatment period 
• Patients who discontinued the IMP during the entire treatment period, and the reasons for 
treatment discontinuation 
• Patients who have completed the study 
• Patients who discontinued the study, and the reasons for study discontinuation 
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For all categories of patients except screened, percentages will be calculated using the number of 
randomized patients as denominator for each treatment group. 
A list of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. Similarly, a list of patients prematurely discontinued from the 
study, along with reasons for discontinuation, will be provided. 
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 safety 
experience of patients treated and not randomized will be reported separately, and these patients 
will not be in the safety population. 
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. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 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. 
11.3.1.1 Intention–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. 
11.3.2 Safety population 
Safety analyses will be based on the safety population, defined as all randomized patients who 
receive at least 1 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, but their 
safety data will be presented separately 
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized 
• When a patient is exposed to both sotagliflozin and placebo, the patient will be analyzed in 
the sotagliflozin group 
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• 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 
11.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of observations 
available (N), mean, SD, minimum, median, and maximum. Categorical data will be summarized 
by treatment group using count and percentage. 
In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from Baseline) by scheduled visits will be provided on observed cases (OC), ie, inclusion of only 
patients having non-missing assessments at a specific visit. 
The Baseline value 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. 
Analysis of demographics and Baseline characteristics, prior and concomitant medications will be 
provided in detail in the statistical analysis plan (SAP). 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received in the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The extent of study treatment exposure will be assessed by the duration of treatment exposure 
during the study.  
The duration of treatment exposure will be the total number of days of administration of the 
double-blind IMP, regardless of unplanned intermittent discontinuations. The duration of IMP 
exposure will be calculated as: 
(Date of the last double-blind IMP taken – Date of the first double-blind IMP taken) + 1. 
The number (%) of patients randomized and exposed to double-blind IMP will be presented by 
specific time periods for each treatment group. The time periods of interest will be defined in the 
SAP. 
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Descriptive statistics of duration of treatment exposure (number, mean, SD, minimum, median, 
and maximum) and cumulative exposure in patient-year will also be presented by treatment group 
in the safety population. 
11.4.1.2 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, above-planned and under-planned dosing percentages, will be summarized 
descriptively (N, mean, SD, median, minimum, and maximum). The percentage of patients with 
compliance <80% will be summarized. In addition, the number and percentage of patients with at 
least 1 above-planned dosing administration will be given, as well as the number and percentage 
of patients with 0, >0 to 20%, and >20% under-planned dosing administrations. 
11.4.2 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population. 
Statistical testing will be performed for primary endpoint and secondary endpoints at Week 26 (or 
Week 12 for SBP). All efficacy variables after Week 26 will only be summarized by descriptive 
statistics without formal statistical testing. 
11.4.2.1 Analysis of primary efficacy endpoint 
The statistical test will be two-sided tests at a nominal 5% significance level. 
Analysis of the primary efficacy endpoint (change from Baseline to Week 26 in HbA1c; 
see Section 9.1.1) will be performed on the ITT population, using HbA1c measurements obtained 
from visits during the study, including those obtained after IMP discontinuation or introduction of 
rescue therapy. 
The primary efficacy endpoint of change in HbA1c from Baseline to Week 26 will be analyzed 
with missing values imputed by control-based multiple imputation method under the missing not 
at random framework.  
• 
For placebo patients, missing data will be imputed based on the placebo group data 
• 
For patients in the sotagliflozin group, missing data will be imputed as if the patients were 
on placebo throughout the study, where all patients’ measurements including the 
on-treatment measurements will be considered as if the measurements were from the 
placebo in the imputation model 
Each of the complete datasets will be analyzed by an Analysis of Covariance (ANCOVA) model 
with treatment groups (sotagliflozin, placebo), randomization stratum of HbA1c (≤8.5%, >8.5%), 
randomization stratum of metformin use at Screening (Yes, No), randomization stratum of SBP 
(<130, ≥130 mmHg), and country as fixed effects, and Baseline HbA1c value as a covariate. 
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Results from each complete dataset will be combined to provide the adjusted mean change in 
HbA1c from Baseline to Week 26 for each treatment group, as well as the between-group 
difference (comparing sotagliflozin versus placebo) and the 95% confidence interval (CI) for the 
difference.  
Summary statistics (for screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for each treatment group. The summary will 
include the number of observations, mean, SD, standard error (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 (using OC). 
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 
• Ethnicity (Hispanic, Not Hispanic) 
• Age group (<50 years, ≥50 to <65 years, ≥65 years) 
• Gender 
• Baseline BMI level (<30, ≥30 kg/m2) 
• Baseline HbA1c (≤8.5%, >8.5%) 
• Metformin use at Screening (Yes, No) 
• Baseline SBP (<130 mmHg, ≥130 mmHg) 
• Country 
The treatment effects across the subgroups defined for each of these factors will be estimated for 
the change from Baseline to Week 26 in HbA1c in the ITT population, and using a similar 
approach to the analysis for the primary efficacy endpoint. The adjusted estimates of treatment 
mean differences (sotagliflozin versus placebo) with SE and 95% CIs will be provided as 
appropriate across the subgroups. 
In the event that the subgroup factor is identical or similar to a randomization strata factor 
(eg, Baseline HbA1c category), only the subgroup factor will be included in the model in order to 
avoid the issue of collinearity in the analysis. 
11.4.2.2 Analyses of secondary efficacy endpoints 
The secondary endpoints (see Section 9.1.2) will be analyzed using a similar approach to the 
primary efficacy endpoint with missing values imputed by control-based multiple imputation 
method under the missing not at random framework.  
• For placebo patients, missing data will be imputed based on the placebo group data 
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• For patients in the sotagliflozin group, missing data will be imputed as if the patients were 
on placebo group throughout the study 
For each of the continuous secondary endpoints, each of the complete datasets will be analyzed by 
an ANCOVA model with treatment groups (sotagliflozin, placebo), randomization stratum of 
HbA1c (≤8.5%, >8.5%), randomization stratum of metformin use at Screening (Yes, No), 
randomization stratum of SBP (<130 mmHg, ≥130 mmHg), and country as fixed effects, and 
Baseline secondary endpoint value as a covariate. For the analysis of SBP in patients with 
Baseline SBP ≥130 mmHg, the randomization stratum of SBP will not be included in the 
ANCOVA model. Results from each complete dataset will be combined to provide the adjusted 
mean change from Baseline to Week 26 (or Week 12 for SBP) for each treatment group, as well 
as the between-group difference (comparing sotagliflozin versus placebo) and the 95% CI for the 
difference.  
The categorical secondary efficacy variables of HbA1c <6.5%, <7% at Week 26 will be analyzed 
using a Cochran-Mantel-Haenszel method stratified by randomization stratum of HbA1c 
(≤8.5%, >8.5%), randomization stratum of metformin use at Screening (Yes, No), and 
randomization stratum of SBP (<130 mmHg, ≥130 mmHg). The proportion in each treatment 
group will be provided, as well as the difference of proportions between sotagliflozin and placebo 
with associated 2-sided 95% CI. For HbA1c responders at Week 26 (<6.5%, <7% respectively), 
all values at Week 26 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. 
For all 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 
(using OC). 
11.4.2.3 Analyses of other efficacy endpoints 
The analysis of other endpoints (see Section 9.1.3) will be descriptive with no formal testing. 
Summary statistics at scheduled visits using OC will be provided by each treatment group. 
Graphical presentations will also be used to illustrate trends over time. 
11.4.2.4 Multiplicity considerations 
To control the family-wise type I error, a fixed-sequence testing procedure will be applied. 
Once the main study primary variable (change from Baseline to Week 26 in HbA1c) is 
statistically significant at α = 0.05 (2-sided), a hierarchical testing procedure will be performed to 
test the following main study secondary efficacy variables by the following prioritized order. The 
testing will stop as soon as an endpoint is found to be not statistically significant at α = 0.05 
(2-sided): 
• 
Change from Baseline to Week 26 in FPG 
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• 
Change from Baseline to Week 26 in body weight 
• 
Change from Baseline to Week 12 in SBP for patients with Baseline SBP ≥130 mmHg 
• 
Change from Baseline to Week 12 in SBP for all patients 
• 
Proportion of patients with HbA1c <7.0% at Week 26 
No multiplicity adjustment will be made on other secondary efficacy variables than mentioned 
above. 
11.4.3 Analyses of safety data 
Safety endpoints are presented in Section 9.2. The summary of safety results will be presented by 
treatment group. The safety data will be summarized for the 26-week Core Treatment Period and 
the entire treatment period separately, unless specified otherwise. All safety analyses will be 
performed on the Safety population as defined in Section 11.3.2 using the following common 
rules: 
The following definitions will be applied to laboratory parameters and vital signs: 
• 
The potentially clinically significant abnormality (PCSA) values for clinical laboratory 
tests and vital signs are defined as abnormal values considered medically important by the 
Sponsor’s Global Pharmacovigilance and Epidemiology department and in effect at the 
time of the final SAP approval. PCSA criteria for parameters not cited in the protocol as 
safety parameters will not be analyzed 
• 
PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage 
The “observation periods” defined in Section 9.2.1 are applicable for classification of AEs, 
determination of on-treatment PCSA values and the last on-treatment value for the laboratory, 
vital sign and ECG parameters. 
11.4.3.1 Analysis of adverse events 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
Treatment-emergent AEs are AEs that developed or worsened (according to the Investigator’s 
opinion) or became serious during the on-treatment period. 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
The primary focus of AE reporting in the CSR will be on TEAEs. Pre- and post-treatment AEs 
will be described separately. 
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All adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage 
(%) of patients experiencing an AE. 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.  
Summaries of all TEAEs in each treatment group will include: 
• The overview of AEs, summarizing number (%) of patients with any: 
- 
TEAE 
- 
Serious TEAE 
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
• The number (n) and percentage (%) of patients with at least one TEAE by primary SOC, 
HLGT, HLT and PT 
• Summary of TEAEs by maximal severity (severe, moderate, mild), presented by primary 
SOC and PT 
• Summary of TEAEs possibly related to IMP, presented by primary SOC, HLGT, HLT and 
PT 
A detailed listing of TEAE summaries will be provided in the SAP. 
Death and serious adverse events 
Death and treatment-emergent SAEs will be summarized and presented as number and percent of 
patients in each treatment group. 
The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (on-study, on-treatment, post-study) 
summarized on the safety population by treatment received 
• Death in nonrandomized patients or randomized and not treated patients 
• TEAE 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 order of SOC and alphabetic order of HLGT, HLT, and 
PT 
Adverse events leading to permanent treatment discontinuation 
Treatment-emergent AEs leading to permanent treatment discontinuation will be summarized and 
presented as number and percent of patients in each treatment group. 
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11.4.3.2 Analyses of hypoglycemia 
The number (%) of patients and rate in patient years (2 types: the number of patients with events 
or the total number of events per 100 patient-year) of all hypoglycemia, severe hypoglycemia, and 
documented symptomatic hypoglycemia will be summarized by treatment group respectively. 
Their pattern of occurrence over time will also be assessed, as appropriate. 
11.4.3.3 Analyses of adverse events of special interest 
Pregnancy and overdose will be included in overall AE summaries if any are reported. 
ALT increase >3 × ULN is included in laboratory PCSA summary if any. 
11.4.3.4 Analyses of events of special interest 
The number (%) of patients with each EOSI event will be summarized by treatment group. All 
events reported by the Investigators on the AE forms for special interest will be listed along with 
the adjudication outcome (if applicable). 
11.4.3.5 Analyses of laboratory variables 
The number and percentage of patients with PCSA or by the pre-defined categories (if no PCSA 
criterion is defined) at any evaluation during the on-treatment period will be summarized for each 
clinical laboratory test within each treatment group. The summaries will include patients in the 
safety population who have at least one laboratory test performed during the on-treatment period 
and, when required by the definition of the abnormality, with an available Baseline value and 
available laboratory normal ranges. 
Descriptive statistics will be used to summarize the laboratory results and the changes from 
Baseline by visit and for the last on-treatment value within each treatment group. Shift tables and 
other tabular and graphical methods may be used to present the results for laboratory tests of 
interest. Listings will be provided with flags indicating the out of laboratory range values as well 
as the PCSA values. 
Liver function tests, namely ALT, AST, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
post-Baseline visit by Baseline status will be displayed by treatment group for each parameter. 
11.4.3.6 Analyses of vital sign variables 
The number and percentage of patients with PCSA at any evaluation during the on-treatment 
period will be summarized for each vital sign parameter within each treatment group. The 
summaries will include patients in the safety population who have at least one parameter to be 
analyzed during the on-treatment period. Descriptive statistics will be used to summarize the 
results and the changes from Baseline by visit and for the last on-treatment value within each 
treatment group. Tabular and graphical methods may be used to present the results for parameters 
of interest. Listings will be provided with flags indicating the PCSA values. 
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11.4.3.7 Analyses of 12 lead ECG status 
A shift table will be provided to present the ECG on-treatment status according to the Baseline 
status within each treatment group. 
11.4.4 Analyses of pharmacokinetic variables 
The PK endpoint is presented in Section 9.3.1. Individual plasma concentrations of sotagliflozin 
and of its 3-O-glucuronide at nominal sampling times will be listed.  
Concentration data will be summarized by visit and, if appropriate, within visit by nominal 
sampling times (pre-dose, 1 hour 30 minute post-dose), using descriptive statistics by N, 
geometric mean, coefficient of variation, median, minimum, and maximum at each visit/nominal 
sampling time point for sotagliflozin-treated patients. 
11.5 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned for this study. The study will not be terminated 
early for excellent efficacy. 
An independent DMC will 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). 
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The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, IB with any addenda or labeling documents (summary of 
product characteristics, package insert), Investigator’s curriculum vitae, etc) and the date of the 
review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC, before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the IB or labeling information, will 
be sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). 
The Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Sub-investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The 
Sub-investigators will be supervised by and work under the responsibility of the Investigator. 
The Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR OR SERVICE PROVIDER 
The Sponsor and/or service provider of this clinical trial is responsible to regulatory authorities for 
taking all reasonable steps to ensure the proper conduct of the clinical trial as regards ethics, 
clinical trial protocol compliance, and integrity and validity of the data recorded on the CRFs. 
Thus, the main duty of the monitoring team is to help the Investigator and the Sponsor maintain a 
high level of ethical, scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE and EOSI documentation, IMP allocation, 
patient compliance with the IMP regimen, IMP accountability, concomitant therapy use and 
quality of data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
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ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the CRFs (eg, patient's medical file, appointment 
books, original laboratory records, etc). These personnel, bound by professional secrecy, must 
maintain the confidentiality of all personal identity or personal medical information (according to 
confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate e-CRFs (according to 
the technology used) designed by the Sponsor/service provider to record (according to Sponsor 
instructions) all observations and other data pertinent to the clinical investigation in a timely 
manner. All e-CRFs should be completed in their entirety in a neat, legible manner to ensure 
accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor/CRO as soon as they are entered in the 
e-CRF. 
The computerized handling of the data by the Sponsor/service provider may generate additional 
requests (DRF) to which the Investigator is obliged to respond by confirming or modifying the 
data questioned. The requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor/service provider and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-investigator will be signed, dated and provided to the Sponsor/service 
provider prior to the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the IB, and the results obtained during 
the course of the clinical trial, is confidential, prior to the publication of results. The Investigator 
and any person under his/her authority agree to undertake to keep confidential and not to disclose 
the information to any third party without the prior written approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial. 
The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Sub-investigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub-investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.6 
DATA PROTECTION 
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations 
Patient race and ethnicity (race: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, not reported, unknown; ethnicity: 
Hispanic, Not Hispanic) will be collected in this study because these data are required by several 
regulatory authorities (eg, on African American population for FDA, on Japanese population for 
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• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• Noncompliance of the Investigator or Sub-Investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
• The total number of patients are included earlier than expected 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
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shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the ICF. The Investigator must receive 
an IRB/IEC approval/favorable opinion concerning the revised ICF prior to implementation of the 
change and patient signature should be re-collected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. International Diabetes Federation Diabetes Atlas 7th Edition.  
http://www.diabetesatlas.org/resources/2015-atlas.html. Accessed 24 October 2016 
2. World Health Organization, Regional Office for Europe, Data and Statistics. 
http://www.euro.who.int/en/health-topics/noncommunicable-diseases/diabetes/data-and-
statistics. Accessed 24 October 2016. 
3. American Diabetes Association. Standards of Medical Care in Diabetes – 2013. Diabetes 
Care. 2013 Jan;36(Suppl 1):S11-S66. 
4. Castaneda-Sceppa C, Castaneda F. Sodium-dependent glucose transporter protein as a 
potential therapeutic target for improving glycemic control in diabetes. Nutr Rev. 2011 Dec; 
69(12):720-9. 
5. Mudalier S. Sodium–Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal 
Glucose Transport; From Bench to Bedside. Diabetes Care. 2015;38:2344–53. 
6. Hediger HA. Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. 
Nature. 1987;330:379-81. 
7. Wright EM. I. Glucose galactose malabsorption. Am J Physiol. 1998;275:G879-G882. 
8. Raskin P. Sodium–glucose cotransporter inhibition: therapeutic potential for treatment of type 
2 diabetes mellitus.  Diabetes Metab Res Rev 2013; 29: 347–56. 
9. Lexicon Pharmaceuticals, Inc. Clinical Study Report for: A Phase 1, Randomized, Double 
blind, Placebo controlled, Ascending Single and Multiple Dose Study to Determine the Safety 
and Tolerability of Orally Administered LX4211 in Healthy Human Subjects (LX4211.1-114- 
NRM). 
10. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. 
Management of hyperglycemia in type 2 diabetes: a patient-centered approach position 
statement of the American Diabetes Association (ADA) and the European Association for the 
Study of Diabetes (EASD). Diabetes care. 2012 Jun;35(6):1364-79. 
11. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC 
guidelines for the management of arterial hypertension: the Task Force for the Management of 
Arterial Hypertension of the European Society of Hypertension (ESH) and of the European 
Society of Cardiology (ESC). Eur Heart J. 2013;34(28):2159–219. 
12. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005 May;28(5):1245-9. 
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13. FDA Guidance for Industry:  Diabetes Mellitus - Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. Lines 1144 – 1215. Available from: 
http://www.fda.gov/downloads/ 
Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071624.pdf. Accessed 24 
October 2016 
14. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and The Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95. 
 
 
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17 
APPENDICES 
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Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
2. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient 
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the highly effective contraception methods if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Women of reproductive potential (WOCBP) must use a highly effective method of contraception 
during the treatment period and the post-treatment follow up period (14 ±3 days). If another 
contraceptive method is used (such as a barrier method), it should be used in combination with 
one of the highly effective methods (such as an oral contraceptive). 
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Female patients: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya 
• 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated 
with inhibition of ovulation: 
- 
Oral 
- 
Intravaginal 
- 
Transdermal 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation: 
- 
Oral 
- 
Injectable 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
• 
Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If 
not, an additional highly effective method(s) of contraception should be used. Spermatogenesis cycle is 
approximately 90 days.) 
• 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the patient.) 
NOTE: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for patients participating in clinical studies. 
 
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COLLECTION OF PREGNANCY INFORMATION 
Male patients with partners of reproductive potential who become pregnant  
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male study patient who becomes pregnant while participating in this study. This applies 
only to patients who receive study treatment 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor/CRO within 24 hours of learning of the partner’s pregnancy 
• 
Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure 
Female patients who become pregnant  
• The Investigator will collect pregnancy information on any female patient, who becomes 
pregnant while participating in this study 
• 
Information will be recorded on the appropriate form and submitted to the Sponsor/CRO 
within 24 hours of learning of a participant's pregnancy 
• 
Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date  
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy will be reported as an AE or SAE 
• 
A spontaneous abortion is always considered to be an SAE and will be reported as such 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the Sponsor as 
described in Section 10.4.1.2. While the Investigator is not obligated to actively seek this 
information in former study patients, he or she may learn of an SAE through spontaneous 
reporting 
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Appendix B 
Recommendations on basic genitourinary hygiene, maintaining 
hydration and recognizing diabetic ketoacidosis 
Patients with T2D are at risk for developing genitourinary (GU) infections. The following 
guidelines should be communicated to females and uncircumcised males regarding GU infections. 
Patient communication cards will be printed with the following: 
For females: 
“The following advice may be useful in helping you to keep your bladder and urethra free from 
infection: 
• Go to the toilet as soon as you feel the need to urinate, rather than holding it in 
• Wipe from front to back after going to the toilet 
• Practice good hygiene by washing your genitals every day, and before having sex 
• Empty your bladder after having sex”  
For uncircumcised males: 
“The following advice may be useful in helping you to keep the foreskin free from infection: 
• Wash the end of your penis and foreskin with soap and water (do not let soap get in the 
opening) 
• After your shower or bath, dry the end of your penis and foreskin properly and replace the 
foreskin 
• Also, when you urinate, slide the foreskin back enough so that urine does not get on the 
foreskin-this helps to keep it clean” 
Maintaining Hydration: 
Sodium-glucose co-transporter type 2 inhibitors are associated with osmotic diuresis and volume 
depletion, which may lead to dizziness or hypotension, especially in the elderly. Before initiating 
study drug (at Screening, Run-in and Randomization) and during all on-site study visits thereafter, 
assess volume status in patients with renal impairment, the elderly, in patients with low SBP, or if 
receiving diuretics, angiotensin-converting-enzyme inhibitors, or angiotensin receptor blockers. 
All patients will be advised to maintain proper fluid intake and to consider increasing it if they 
sense greater thirst, more urine production, or if they feel dizzy or faint. 
Patient communication cards will be printed with the following for patients with T2D: 
“The following advice may be useful in helping you to maintain proper hydration and prevent 
dehydration: 
• Dehydration is when your body loses too much fluid, frequently due to diarrhea or 
increased urination 
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• Consider increasing the amount of fluids you drink if: 
- 
You sense greater thirst than usual 
- 
You have a dry mouth or cracked lips 
- 
You have a fever 
- 
You have diarrhea or vomiting 
- 
You urinate more frequently or in larger amounts than usual 
- 
You get up in the middle of the night to urinate (more than usual) 
- 
You feel dizzy or light-headed 
- 
You exercise, or when it is hot outside” 
Recognizing Diabetic Ketoacidosis 
Potential gastrointestinal (GI) adverse events occurring with sotagliflozin may mask presenting 
symptoms of diabetic ketoacidosis (DKA). Patient communication cards will be printed with the 
following: 
“If you have any of these symptoms on the list, then contact your study site immediately for 
assistance with managing your diabetes: 
• Inability to maintain oral intake 
• Generalized weakness 
• Abdominal (belly) pain 
• Increased weight loss 
• Fever 
• Frequent urination, including at night 
• Fruity-scented breath 
• Confusion 
• Acute illness 
• Consistently elevated blood glucose 
• Feeling very thirsty or drinking a lot 
• Nausea or vomiting 
• Having trouble thinking clearly or feeling tired 
It is possible to have DKA even if your blood glucose is not elevated. Regardless of your blood 
glucose level, if you have any of these symptoms on the list, then contact your study site 
regarding the need to be evaluated for possible DKA, which will include specific blood testing. If 
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your study site is closed and your study doctor is not available, go to the nearest emergency room 
for evaluation. 
If you are scheduled for a procedure or surgery that requires you to not take any food or liquids, 
please contact your study doctor for instructions on continuing study drug. In such cases your 
study doctor may advise you NOT to take your study drug from the day prior to the procedure or 
surgery until after the procedure or surgery is complete, and you are taking food and liquids as 
you normally do.” 
Whenever adverse event (AE) data is collected or the patient reports DKA or intercurrent illness 
(including infections), generalized weakness, increased weight loss, GI symptoms including 
nausea, vomiting, or abdominal pain or other symptoms or signs that the Investigator believes 
may be consistent with DKA, then the site will determine if an assessment for DKA is 
appropriate. If laboratory testing confirms presence of metabolic acidosis, then the “Possible 
DKA” electronic case report form (e-CRF) will be completed. 
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Appendix C 
Measurement of Blood Pressure and Pulse Rate 
Equipment 
1. Blood pressure measurements will be taken by an automated BP monitor or a manual 
sphygmomanometer. The same equipment should be used throughout the study and should 
be calibrated as per manufacturer recommendation 
2. Bladder Length – Should nearly or completely encircle the patient’s arm. For many adults, 
the standard “adult” size bladder is not long enough and the “large” size bladder is 
recommended 
3. Bladder Width – Should be at least 40% of the bladder length 
Patient Factors 
Extraneous variables associated with the measurement of BP should be minimized. These include: 
1. Food intake, caffeine-containing beverages, cigarette smoking, or strenuous exercise 
within 2 hours prior to measurement 
2. Full urinary bladder 
3. The patient should not be allowed to talk while BP is being measured 
4. The patient should be placed in the examination room and the cuff should be placed on the 
patient’s nondominant arm. The proper sized cuff should fit snugly with the lower edge 
2 to 3 cm above the antecubital fossa 
5. The patient should be allowed to sit quietly in a comfortably warm place (temperature 
around 25°C or 77°F) for 5 minutes with the arm supported at heart level, preferably with 
the cuff in place and with no restrictive clothing on the arm. The patient should be 
encouraged not to tense his or her muscles 
Nondominant Arm 
The patient’s nondominant arm should be the arm declared by the patient as being nondominant. 
The nondominant arm should then be used for all seated BP measurements throughout the study. 
Measurement Technique 
At all other on-site visits, following the 5-minute rest period, 3 separate seated BPs should be 
measured in the arm selected at Visit 1, with at least 1 minute between BP measurements and with 
the cuff fully deflated between measurements. 
All 3 BPs will be recorded in the patient’s electronic case report form (e-CRF). The mean of the 
3 seated BPs will constitute the BP value for that visit. 
Three seated pulse rate measurements will be obtained. The mean of the 3 seated pulse rate 
measurements will constitute the pulse rate value for that visit. 
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SAP_001.pdf: 
Offi ci al Titl e:  
A R a n d o mi z e d, D o u bl e -bli n d, Pl a c e b o -c o ntr oll e d, P ar all el -gr o u p, 
M ulti c e nt er  St u d y  t o 
E v al u at e t h e 
Effi c a c y a n d 
S af et y of 
S ot a glifl o zi n A d d e d t o a S ulf o n yl ur e a al o n e  or i n c o m bi n ati o n wit h 
M etf or mi n i n P ati e nt s wit h T y p e 2 Di a b et e s W h o H a v e  I n a d e q u at e 
Gl y c e mi c C o ntr ol o n a S ulf o n yl ur e a Al o n e or wit h M etf or mi n  
N C T N u m b er:  
N C T 0 3 0 6 6 8 3 0  
D o c u m e nt D at e( s): 
S A P V er si o n 3: 2 0  F e br u ar y 2 0 2 0 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
L e xi c o n P h ar m a c e uti c al s, I n c.  
Pr ot o c ol N o.: E F C 1 4 8 3 5  
A R a n d o mi z e d, D o u bl e -bli n d, Pl a c e b o -c o ntr oll e d, P ar all el -gr o u p, M ulti c e nt er St u d y 
t o E v al u at e t h e Effi c a c y a n d S af et y of S ot a glifl o zi n A d d e d t o a S ulf o n yl ur e a al o n e 
or i n c o m bi n ati o n wit h M etf or mi n i n  P ati e nt s wit h T y p e 2 Di a b et e s W h o H a v e 
I n a d e q u at e Gl y c e mi c C o ntr ol o n a S ulf o n yl ur e a Al o n e or wit h M etf or mi n 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
D A T E O F I S S U E: 1 9 F e br u ar y 2 0 2 0  
A ut h or: 
 
Le xic o n P h ar m a ce utic als, I nc.  
8 8 0 0 Tec h n ol o g y F orest Place 
T he W o o dla n ds, T X 7 7 3 8 1- 1 1 6 0 
C o v a nce Cli nic al De vel o p me nt Ser vices  
2 0 6 Car ne gie Ce nter 
Pri ncet o n, NJ 0 8 5 4 0- 6 2 3 3 




St ati s ti c al A n al y si s Pl a n 
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D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 of 8 1  
V E R SI O N HI S T O R Y  
Versi o n St at us  
Versi o n D ate  
 Fi nal 1. 0 
 0 7 A u g ust 2 0 1 8 
 Fi nal 2. 0  
0 3 J u ne 2 0 1 9 
 Fi nal 3. 0  
1 9  Fe br u ar y 2 0 2 0  
 


St ati s ti c al A n al y si s Pl a n 
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 of 8 1  
T A B L E O F C O N T E N T S  
A P P R O V A L S  
V E R SI O N HI S T O R Y  
T A B L E O F C O N T E N T S  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
1  
O V E R VI E W A N D I N V E S TI G A TI O N A L P L A N  
1. 1  
S T U D Y D E SI G N A N D R A N D O MI Z A TI O N  
1. 2  
O B J E C TI V E S  
1. 2. 1  
Pri m ar y o bj e cti v e s  
1. 2. 2  
S e c o n d ar y o bj e cti v e s  
1. 2. 3  
Ot h er o bj e cti v e s  
1 . 3 
D E T E R MI N A TI O N O F S A M P L E SI Z E  
1. 4  
S T U D Y P L A N  
1. 5  
M O DI FI C A TI O N S T O T H E  S T A TI S TI C A L S E C TI O N  O F T H E P R O T O C O L  
1. 6  
S T A TI S TI C A L M O DI FI C A TI O N S M A D E I N T H E S T A TI S T I C A L A N A L Y SI S P L A N 
2  
S T A TI S TI C A L A N D A N A L Y TI C A L P R O C E D U R E S  
2. 1  
A N A L Y SI S E N D P OI N T S  
2. 1. 1  
D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s  
2. 1. 2  
Pri or or c o n c o mit a nt m e di c ati o n s  
2. 1. 2. 1  
R e s c u e t h er a p y  
2. 1. 2. 2  
Pr o hi bit e d pri or a n d c o n c o mit a nt m e di c ati o n s  
2. 1. 3  
Effi c a c y e n d p oi nt s  
2. 1. 3. 1  
Pri m ar y effi c a c y e n d p oi nt( s)  
2. 1. 3. 2  
S e c o n d ar y effi c a c y e n d p oi nt( s)  
2. 1. 3. 3  
Ot h er effi c a c y e n d p oi nt( s)  
2. 1. 4  
S af et y e n d p oi nt s  
2. 1. 4. 1  
H y p o gl y c e mi a  
2. 1. 4. 2  
A d v er s e e v e nt s v ari a bl e s  
2. 1. 4. 3  
D e at h s  
2. 1. 4. 4  
L a b or at or y s af et y v ari a bl e s  
2. 1. 4. 5  
Vit al si g n s v ari a bl e s  
2. 1. 4. 6  
P h y si c al e x a mi n ati o n  


St ati s ti c al A n al y si s Pl a n 
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D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 of 8 1  
2. 1. 4. 7  
El e ctr o c ar di o gr a m v ari a bl e s  
2. 1. 5  
P h ar m a c o ki n eti c v ari a bl e s  
2. 2  
DI S P O SI TI O N O F P A TI E N T S  
2. 2. 1  
R a n d o mi z ati o n a n d dr u g di s p e n si n g irr e g ul ariti e s  
2. 3  
A N A L Y SI S P O P U L A TI O N S  
2. 3. 1  
Effi c a c y p o p ul ati o n s  
2. 3. 1. 1  
I nt e nt-t o-tr e at p o p ul ati o n 
2. 3. 2  
S af et y p o p ul ati o n  
2. 3. 3  
P h ar m a c o ki n eti c p o p ul ati o n  
2. 4  
S T A TI S TI C A L M E T H O D S  
2. 4. 1  
D e m o gr a p hi c s a n d b a s eli n e c h ar a ct eri sti c s  
2. 4. 2  
Pri or or c o n c o mit a nt m e di c ati o n s  
2. 4. 3  
E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e a n d c o m pli a n c e  
2. 4. 3. 1  
E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e  
2. 4. 3. 2  
C o m pli a n c e  
2. 4. 4  
A n al y s e s of effi c a c y e n d p oi nt s  
2. 4. 4. 1  
A n al y si s o f pri m ar y effi c a c y e n d p oi nt 
2. 4. 4. 2  
A n al y s e s of s e c o n d ar y effi c a c y e n d p oi nt s  
2. 4. 4. 3  
A n al y s e s of ot h er effi c a c y e n d p oi nt s  
2. 4. 4. 4  
M ulti pli cit y i s s u e s  
2. 4. 5  
A n al y s e s of s af et y d at a  
2. 4. 5. 1  
A n al y s e s of h y p o gl y c e mi a  
2. 4. 5. 2  
A n al y s e s of a d v er s e e v e nt s  
2. 4. 5. 3  
D e at h s  
2. 4. 5. 4  
A n al y s e s of l a b or at or y v ari a bl e s  
2. 4. 5. 5  
A n al y s e s of vit al si g n v ari a bl e s  
2. 4. 5. 6  
A n al y s e s of el e ctr o c ar di o gr a m v ari a bl e s  
2. 4. 5. 7  
A n al y s e s of p h y si c al e x a mi n ati o n v ari a bl e s  
2. 4. 6  
A n al y s e s of p h ar m a c o ki n eti c v ari a bl e s  
2. 5  
D A T A H A N D LI N G C O N V E N TI O N S  
2. 5. 1  
G e n er al c o n v e nti o n s  
2. 5. 2  
D at a h a n dli n g c o n v e nti o n s f or s e c o n d ar y effi c a c y v ari a bl e s  
2. 5. 3  
Mi s si n g d at a  
2. 5. 4  
Wi n d o w s f or ti m e p oi nt s / M e a s ur e m e nt s f or a n al y s e s  
2 . 5. 5 
U n s c h e d ul e d vi sit s  
2. 5. 6  
P o oli n g of c e nt er s f or st ati sti c al a n al y s e s  
2. 5. 7  
St ati sti c al t e c h ni c al i s s u e s  
3  
I N T E RI M A N A L Y SI S 


St ati s ti c al A n al y si s Pl a n 
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
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4  
D A T A B A S E L O C K  
5  
S O F T W A R E D O C U M E N T A TI O N  
6  
R E F E R E N C E S  
7  
LI S T O F A P P E N DI C E S  
A P P E N DI X A  P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T  A B N O R M A LI TI E S C RI T E RI A  
A P P E N DI X B  LI S T O F P T S F O R S E L E C T E O SI S ( M E D D R A V 2 2 . 0) 
A P P E N DI X C  S U M M A R Y O F S T A TI S TI C A L A N A L Y S E S  
A P P E N DI X D  S T U D Y F L O W C H A R T  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
 
LI S T O F A B B R E VI A TI O N S A N D  D E FI NI TI O N O F T E R M S  
A Es:  
a d verse e ve nts  
A E SI:  
a d verse e ve nts of s p ecial i nterest  
A L T:  
ala ni ne a mi n otra nsferas e  
A N C O V A:  
a nal ysis of c o varia nce  
A S T:  
as partate a mi n otra nsferas e  
B L O Q:  
bel o w li mit of q ua ntificati o n  
A T C:  
a nat o mical t her a pe utic c he mical  
B MI:   
b o d y mass i n de x 
B U N:   
bl o o d urea nitr o ge n  
C E C:  
cli nical e n d p oi nt c o m mittee  
CI:  
c o nfi de nce i nter val 
C M H:  
C oc hra n -Ma nt el -Hae nszel  
C V:  
car di o vas c ular, car di o vas c ular  
D B P:   
diast olic bl o o d press ure 
D C C T:   
dia betes c o ntr ol a n d c o m plicati o ns trial  
DI LI:   
dr u g-i n d uce d li ver i nj ur y  
D M C:  
Data M o nit ori n g C o m mittee  
E C G:  
electr ocar di o gr a m  
e-C R F:  
electr o nic case re p ort f or m  
e G F R:  
esti mate d gl o mer ular filtrati o n rate  
E M A/ P R A C:   
E ur o pea n Me dici nes A ge nc y/ P har m ac o vi gila nce Ris k Assess me nt C o m mittee 
E O SI:   
eve nts of s peci al i nterest  
E O T:   
e n d of treat me nt 
F P G:  
fasti n g plas ma gl u c ose 
G d:  
gli be ncl a mi de  
G d M R:  
gli be ncl a mi de M R  
G p:  
gli pizi de  
G p X L:  
gli pizi de X L  
Gz:  
gliclazi de  
Gz M R:  
gliclazi de M R  
H b A 1c:   
he m o gl o bi n A 1c 
H L G T:   
hi g h le vel gr o u p t er m 
H L T:  
hi g h le vel ter m 
H R:  
heart r ate  
I F C C: 
I nter nati o nal Fe derati o n of Cli nical C he mistr y a n d La b orat or y M e dici ne  
I M P:  
i n vesti gati o nal me dici nal pr o d uct 
I N N:  
i nter nati o nal n o n pr o priet ar y na me 
I R T:  
i nteracti ve r es p o nse tec h n ol o g y 
I T T: 
i nte nt-t o-treat 
K M:  
Ka pla n -Mei er  
L L T:   
l o wer le vel ter m  
M A C E:  
maj or a d vers e car di o vasc ular e ve nts  


St ati s ti c al A n al y si s Pl a n 
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 8 of 8 1  
M A R:   
missi n g at ra n d o m 
M D R D:  
m o dificati o n of diet i n re nal disease  
Me d D R A:  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
MI:  
m ulti ple i m p utati o n  
M N A R:   
missi n g n ot at ra n d o m 
NI M P:   
n o ni n vesti gati o nal me dici nal pr o d uct 
P C S A:  
p ote ntiall y cli nicall y si g nifica nt a b n or malit y  
P D:  
p har mac o d y n a mic  
P K:  
p har mac o ki netic 
P T:  
preferre d t er m  
S A E:  
seri o us a d vers e e v e nts 
S B P:   
s yst olic bl o o d press ure 
S D:  
sta n dar d de viati o n 
S O C:  
s yste m or ga n class 
T 2 D:  
t y pe 2 dia b etes mellit us 
T E A E:  
treat me nt-e mer ge nt a d v erse e ve nt  
U L N:   
u p per li mit of n or mal 
W H O -D D:  
W orl d Healt h Or ga nizati o n -Dr u g Dicti o nar y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


St ati s ti c al A n al y si s Pl a n 
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 9 of 8 1  
1                   O V E R VI E W A N D I N V E S TI G A TI O N A L P L A N   
1. 1              S T U D Y D E SI G N A N D R A N D O MI Z A TI O N  
T his i s a P hase 3, m ultice nter a n d m ulti nati o nal, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, 
parallel - gr o u p st u d y. Pati e nts will be ra n d o ml y assi g ne d 1: 1 t o t he f oll o wi n g 2 treat me nt gr o u ps 
•  
S ota glifl ozi n 4 0 0 m g. 
•  
Place b o.  
All patie nts will ha ve a Scree ni n g Per i o d c o m prise d of a n u p t o 2-wee k Scree ni n g P hase a n d a 
2- wee k, si n gle - bli n d place b o R u n-i n P hase pri or t o ra n d o mizati o n. F oll o wi n g ra n d o mizati o n, 
patie nts will ha ve a 2 6 - w ee k, d o u ble- bli n d C ore Treat me nt Peri o d, a 5 3- wee k d o u ble- bli n d 
E xte nsi o n Peri o d, a n d a 2- wee k p ost-treat me nt F oll o w- u p peri o d t o c ollect safet y i nf or mati o n 
( patie nts w h o pre mat urel y disc o nti n ue t he st u d y treat me nt are e x pecte d t o c o nti n ue i n t he st u d y).  
At t he e n d of t he scree ni n g peri o d, eli gi ble p atie nts will be ce ntrall y ra n d o mize d ( u si n g per m ute d 
bl oc k ra n d o mizati o n sc he d ule) via a n I nteracti ve Res p o nse Tec h n ol o g y (I R T). T he ra n d o mizati o n 
will be stratifie d b y  
•  
He m o gl o bi n A 1 c ( H b A 1 c) at Scree ni n g ( ≤8. 5 %, > 8. 5 %).  
•  
Metf or mi n use at Scree ni n g ( Yes, N o).  
•  
S yst olic bl o o d press ure ( S B P) at Scree ni n g ( < 1 3 0 m m H g, ≥1 3 0 m m H g).  
It is a ntici pate d t o ra n d o mize a t otal of a p pr o xi matel y 5 0 0 p atie nts.  
1. 2              O B J E C TI V E S  
1. 2. 1        Pri m ar y o bj e cti v e s  
T he pri mar y o bjecti ve of t his st u d y is t o de m o nstrate t he s u peri orit y of s ota glifl ozi n 4 0 0 m g ve rs us 
place b o o n H b A 1c re d ucti o n at Wee k 2 6 i n patie nts wit h t y p e 2 dia betes mellit us ( T 2 D)  w h o ha ve 
i na de q uate gl yce mic c o ntr ol wit h a s ulf o n yl urea al o ne or i n c o m bi nati o n wit h metf or mi n. 
1. 2. 2        S e c o n d ar y o bj e cti v e s  
•  
T o c o m pare s ota glifl ozi n 4 0 0 m g vers us place b o f or:  
-          C ha n ge fr o m Baseli ne i n fasti n g pl as ma gl uc ose ( F P G) at Wee k 2 6,  
-          C ha n ge fr o m Baseli ne i n b o d y w ei g ht at Wee k 2 6, 
-          C ha n ge fr o m Baseli ne i n S B P at Wee k 1 2 f or patie nts wit h baseli ne S B P ≥1 3 0 
m m H g,  


St ati s ti c al A n al y si s Pl a n 
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 1 0  of 8 1  
-          C ha n ge fr o m Baseli ne i n S B P at Wee k 1 2 f or all patie nts,  
-          Pr o p orti o n of patie nts wit h H b A 1c < 6. 5 %, < 7. 0 % at Wee k 2 6. 
•  
T o e val uate t he s afet y of s ota glifl oz i n 4 0 0 m g vers us place b o t hr o u g h o ut t h e 7 9-wee k 
trial. 
1. 2. 3        Ot h er o bj e cti v e s  
•  
T o c o m pare s ota glifl ozi n vers us place b o base d o n ot her bl o o d press ure e n d p oi nts.  
•  
T o c o m pare s ota glifl ozi n vers us place b o wit h res p ect t o c ha n ge fr o m Baseli ne o n t he 
f oll o wi n g e n d p oi nts: 
-          Esti mate d gl o mer ular filtrati o n rate (e G F R),  
-          Re d ucti o n i n b o d y w ei g ht b y ≥2 %, ≥5 %, a n d ≥1 0 %. 
•  
T o c o m pare s ota glifl ozi n vers us place b o f or:  
-          C ha n ge fr o m Baseli ne i n H b A 1c at Wee k 7 9, 
-          C ha n ge fr o m Baseli ne i n F P G at Wee k 7 9,  
-          C ha n ge fr o m Baseli ne i n b o d y w ei g ht at Wee k 7 9. 
•  
T o c o m pare t h e use of r esc ue me dicati o ns f or h y p er gl yce mia i n t he s ota glifl ozi n a n d 
place b o treat me nt gr o u ps.  
•  
T o assess plas ma c o n ce ntrati o ns of s ota glifl ozi n a n d its 3 - O- gl u c ur o ni de m eta b olite. 
1. 3              D E T E R MI N A TI O N O F S A M P L E SI Z E  
T he sa m ple size/ p o wer calc ulati o ns are b ase d o n t he pri mar y varia ble, c h a n ge fr o m Baseli ne t o 
Wee k 2 6 i n H b A 1c. Ass u mi n g a c o m m o n sta n dar d de viati o n ( S D) of 1. 2 % a n d usi n g a 2-si de d 
test at a 0. 0 5 α-le v el, 2 5 0 patie nts per ar m will ha v e 9 9 % p o wer t o detect a treat me nt differe n ce of 
0. 6 % i n mea n H b A 1 c c h a n ge fr o m Bas eli ne t o Wee k 2 6 bet w ee n s ota glifl ozi n 4 0 0 m g a n d 
place b o.  
T he n u m ber of p atie nts ta ki n g a s ulf o n yl urea a n d metf or mi n will be li mite d t o 3 3 0 patie nts, t o 
e ns ure s ufficie nt n u m bers of s ulf o n yl urea m o n ot h era p y patie nts. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
  
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
 
1. 4              S T U D Y P L A N  
 
T he st u d y fl o wc hart ca n be f o u n d i n A p pe n di x D.  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
 
1. 5              M O DI FI C A TI O N S T O T H E  S T A TI S TI C A L S E C TI O N  O F T H E P R O T O C O L  
T his secti o n s u m marizes maj or c ha n ges t o t he pr ot oc ol statistical secti o n wit h e m p hasis o n 
c ha n ges aft er st u d y start (after t h e first patie nt w as e nr olle d).   
T he pr ot oc ol hist or y ta bl e bel o w gi ves t he ti mi n g, rati o nale, a n d k e y details of maj or c ha n ges t o 
t he pr ot oc ol statistical secti o n.  
T he first patie nt was e nr olle d o n Fe b 2 4, 2 0 1 7. T h ere w ere n o pl a n ne d i nteri m a nal yses.  
T a bl e  1 - Pr ot o c ol a m e n d m e nt st ati sti c al c h a n g e s  
A m e n d m e nt  
N u m b er  
D at e 
A p pr o v e d  
R ati o n al e  
D e s cri pti o n of st ati sti c al c h a n g e s  
2  
2 0 -D ec -2 0 1 7  
5 h alf -liv es of s ot a glifl ozi n pr ol o n g e d 
t o 1 0 d ays c o nsi d eri n g p ati e nts wit h 
m o d er at e r e n al d ysf u ncti o n 
5 h alf -liv es of I M P u p d at e d fr o m 5 d ays t o 
1 0  d ays; T E A E p eri o d u p d at e d acc or di n gly  
2  
2 0 -D ec -2 0 1 7  
Bas eli n e e G F R d efi n e d as 
r ec o m m e n d e d by C DI S C T h er a p e utic 
Ar e a D at a St a n d ar ds Us er G ui d e f or 
Di a b etic Ki d n ey Dis e as e  
F or s er u m cr e ati ni n e a n d e G F R, t h e b as eli n e 
v al u e is d efi n e d as t h e av er a g e of all v al u es 
b ef or e t h e first d os e of d o u bl e -bli n d I M P f or 
t h os e r a n d o miz e d a n d ex p os e d or b ef or e 
r a n d o miz ati o n f or t h os e w h o w er e r a n d o miz e d 
b ut n ev er ex p os e d t o I M P.  
2  
2 0 -D ec -2 0 1 7  
T h e eff ect i n b o dy w ei g ht  is 
c o nsi d er e d m or e cl os ely ass oci at e d 
wit h t h e pl a n n e d i n dic ati o n  
C h a n g e i n t h e or d er of s ec o n d ary o bj ectiv es, 
e n d p oi nts a n d m ulti plicity c o nsi d er ati o ns  
2  
2 0 -D ec -2 0 1 7  
Ur g e nt c or o n ary r ev asc ul ariz ati o n n ot 
a dj u dic at e d by C E C t o b e c o nsist e nt 
wit h o utc o m e tri als  
Ur g e nt c or o n ary r ev asc ul ariz ati o n n ot i ncl u d e d 
i n a dj u dic ati o n r el at e d a n alys es 
 
2  
2 0 -D ec -2 0 1 7  
A E l e a di n g t o st u dy disc o nti n u ati o n is 
l ess cli nic ally r el ev a nt t h a n A E 
l e a di n g t o tr e at m e nt disc o nti n u ati o n 
D el et e A Es l e a di n g t o disc o nti n u ati o n fr o m t h e 
st u dy fr o m s af ety e n d p oi nts 
 
2  
2 0 -D ec -2 0 1 7  
T o u n d erst a n d tr e at m e nt eff ects ov er 
t h e e ntir e st u dy d ur ati o n  
 
Sev er al o bj ectiv es/ e n d p oi nts “bl o o d pr ess ur e 
e n d p oi nts at W e ek 2 6 a n d W e ek 7 9, H b A 1c, 
F P G a n d b o dy w ei g ht e n d p oi nts at W e ek 7 9” 
w er e a d d e d  
 
1 . 6             S T A TI S TI C A L M O DI FI C A TI O N S M A D E I N T H E S T A TI S TI C A L A N A L Y SI S P L A N  
T he statistical a nal ysis pla n hist or y ta bl e bel o w gi ves t he ti mi n g, rati o nale, a n d ke y details f or 
maj or c ha n ges t o t he statistical a nal ysis feat ures i n t he statistical a nal ysis  pl a n.  C ha n ges als o 
i nc or p orate d i n a pr ot oc ol a me n d me nt are cr oss-refere n ce d t o Ta bl e  1. 






St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 1 5  of 8 1  
2                   S T A TI S TI C A L A N D A N A L Y TI C A L P R O C E D U R E S  
2. 1              A N A L Y SI S E N D P OI N T S  
2 . 1. 1       D e m o gr a p hi c a n d b a s eli n e c h ar a ct eri sti c s  
T he baseli ne v al ue f or all varia bles ( wit h t he e x ce pti o n of ser u m creati ni ne a n d e G F R) is defi ne d 
as t he last a vaila ble v al ue bef ore t h e first d ose of d o u ble -bli n d i n vesti gati o n al me dici nal pr o d uct 
(I M P), or t he last a v aila ble val ue pri or t o ra n d o mizati o n f or patie nts w h o were ra n d o mize d b ut 
ne ver e x p ose d t o I M P. 
F or ser u m creati ni ne a n d e G F R, t he b aseli ne val ue is defi ne d as t he a v era ge of all val ues bef ore 
t he first d ose of d o u ble- bli n d I M P f or t h ose ra n d o mize d a n d e x p ose d or bef ore ra n d o mizati o n f or 
t h ose w h o wer e ra n d o mi ze d b ut ne ver e x p ose d t o I M P. 
Baseli ne s afet y a n d efficac y par a meters are pres e nte d al o n g wit h t he s u m mar y st atistics f or safet y 
a n d effi cac y s ecti o ns ( S ecti o n 2. 4. 4  a n d Secti o n  2. 4. 5 ). 
De m o gr a p hic c h ar acteristics  
De m o gra p hic c har acteristics t o be s u m marize d are:  
•  
A ge ( years) d eri ve d as: ( Year of i nf or me d c o nse nt - Year of birt h).  
•  
A ge cat e g ories:  ( < 5 0, ≥5 0 t o < 6 5, ≥6 5 t o < 7 5, ≥7 5 years). 
•  
Ge n der ( Male, Fe male).  
•  
Race ( W hite, Blac k or Africa n A m erica n, Asia n, A merica n I n dia n or Alas ka nati ve, 
Nati ve Ha w aiia n or ot her pacific isla n der, M ulti ple, U n k n o w n). 
•  
Et h nicit y ( His pa nic or Lati n o,  N ot His pa nic or Lati n o, U n k n o w n). 
•  
H b A 1c ( %) at scree ni n g visit.  
•  
Ra n d o mizati o n strata of H b A 1c ( ≤8. 5 %, > 8. 5 %) at scree ni n g ( data fr o m I R T). 
•  
Ra n d o mizati o n strata of metf or mi n use ( Yes, N o) at scree ni n g ( data fr o m I R T). 
•  
Mea n S B P at scr ee ni n g.  
•  
Ra n d o mizati o n strata of S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g) at scree ni n g ( dat a fr o m I R T). 
•  
Baseli ne b o d y m ass i n de x ( B MI) ( k g/ m 2) deri ve d as: ( Wei g ht i n k g)/( H ei g ht i n meters)2. 
•  
Baseli ne B MI cate g ories ( < 3 0, ≥3 0 k g/ m 2). 
•  
C o u ntr y. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 1 6  of 8 1  
Dise ase c h ar acteristics at scree ni n g or b aseli ne  
Dis ease hist or y i ncl u des:  
•  
D urati o n of dia bet es ( years) deri ve d as:  ( Dat e of i nf or me d c o ns e nt – Date of dia g n osis of 
dia betes + 1)/ 3 6 5. 2 5. 
•  
D urati o n of dia bet es cate g ories: ( < 1 0, ≥1 0 years). 
•  
A ge at dia g n osis of dia betes ( years): ( Year of di a g n osis of dia betes – Year of birt h).  
•  
Metf or mi n use at scr ee ni n g ( Yes, N o).  
•  
D urati o n of metf or mi n tr eat me nt (f or t h os e patie nts w h o use d metf or mi n at scree ni n g) 
( years): ( date of i nf or me d c o nse nt - date of first i nta ke of metf or mi n + 1)/ 3 6 5. 2 5. 
•  
Dail y d os e of metf or mi n ( m g) at  baseli ne (f or t h os e patie nts w h o use d metf or mi n at 
scree ni n g). 
•  
Cate g orize d dail y d ose of metf or mi n at baseli ne f or t h ose patie nts w h o use d metf or mi n at 
scree ni n g  ( < 1 5 0 0,  ≥ 1 5 0 0 t o < 2 5 0 0,  ≥2 5 0 0 m g). 
•  
D urati o n of s ulf o n yl urea treat me nt ( years): ( d ate of i nf or me d c o ns e nt - date of first i nta ke 
of s ulf o n yl ur ea + 1)/ 3 6 5. 2 5. 
•  
S ulf o n yl urea at scr ee ni n g b y i nter n ati o nal n o n pr o prietar y na m e (I N N) a n d f or m ulati o n.   
•  
Dail y d os e of s ulf o n yl urea at baseli ne b y I N N a n d f or m ulati o n. 
•  
Cate g orize d dail y d ose of s ulf o n yl urea at baseli ne b y I N N:  
-          Gli be ncla mi de ( G d) a n d Gli be ncla m i de M R ( G d M R):  
-         < 1 0 m g/ da y ( G d) or < 6 m g/ da y ( G d M R),  
-         ≥1 0 - ≤2 0 m g/ da y ( G d) or ≥6 - ≤1 2 m g/ da y ( G d M R),  
-         > 2 0 m g/ da y ( G d) or > 1 2 m g/ da y ( G d M R). 
-          Gliclazi de ( Gz) a n d Gliclazi de M R ( Gz M R):  
-         < 1 6 0 m g/ da y ( Gz) or < 6 0 m g/ da y ( Gz M R), 
-         ≥1 6 0 - ≤3 2 0 m g/ da y ( Gz) or ≥6 0 - ≤1 2 0 m g/ d a y ( Gz M R), 
-         > 3 2 0 m g/ da y ( Gz) or > 1 2 0 m g/ da y ( Gz M R). 
-          Gli me piri de:  
-         < 4 m g/ da y, 
-         ≥4 - ≤8 m g/ da y, 
-         > 8 m g/ da y. 
-          Gli pizi de ( G p) a n d Gli pizi de X L ( G p X L): 
-         < 2 0 m g/ da y ( G p) or < 1 0 m g/ da y ( G p X L), 
-         ≥2 0 - ≤4 0 m g/ da y ( G p) or ≥1 0 - ≤2 0 m g/ da y ( G p X L), 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 1 7  of 8 1  
-         > 4 0 m g/ da y ( G p) or > 2 0 m g/ da y ( G p X L). 
-          Gli q ui d o ne: 
-         < 9 0  m g/ da y,  
-         ≥9 0 - ≤1 8 0 m g/ da y,  
-         > 1 8 0 m g/ da y.  
•  
Baseli ne di a betic micr o v asc ular c o m plicati o ns ( Y es, N o) (ie, di a betic reti n o pat h y, dia b etic 
ne ur o pat h y, dia betic n e p hr o pat h y, dia betic peri p h eral ne ur o pat h y (se ns or y or m ot or), 
dia betic a ut o n o mic ne ur o pat h y, a n d dia betic f o ot i nfecti o n). 
•  
e G F R at scree ni n g ( m L/ mi n/ 1. 7 3 m 2). 
•  
e G F R cate g ories at scree ni n g ( < 1 5 m L/ mi n/ 1. 7 3 m 2  [ E n d sta ge re nal diseas e], ≥1 5 t o 
< 3 0  m L/ mi n/ 1. 7 3 m2 [ Se vere decrease i n G F R], ≥3 0 t o < 6 0 m L/ mi n/ 1. 7 3 m2  [ M o derate 
decrease i n G F R], ≥6 0 t o < 9 0 m L/ mi n/ 1. 7 3 m 2  [ Mil d decreas e i n G F R], a n d 
≥9 0 m L/ mi n/ 1. 7 3 m 2  [ N or mal]). 
•  
Pri or a nti h y perte nsi ve m e dicati o n i de n tifie d b y t h era pe utic class as a ge nts acti n g o n t h e 
re ni n-a n gi ote nsi n s yste m, beta bl oc ki n g a ge nts, di uretics (a s u b-cate g or y: l o o p di uretics 
i de ntifie d b y p h ar mac ol o gical class as hi g h-ceili n g di uretics), cal ci u m c ha n nel bl oc kers, 
a n d a nti h y p erte nsi ves ac c or di n g t o W orl d Healt h Or ga nizati o n- Dr u g Dicti o nar y 
( W H O-D D).  
 Me dic al or s ur gic al hist ory 
Me dical hist or y a n d me dical fi n di n gs i ncl u d e:  
•  
P h ysical e x a mi nati o n.  
•  
Me dical or s ur gical hist or y.  
•  
Me dical hist or y car di o vasc ular.  
•  
S ur gical hist or y a m p utati o n.  
•  
Alc o h o l ha bits. 
•  
T o bacc o s m o ki n g ha bits.  
Me dical a n d s ur gical hist or y will be c o de d t o a “l o wer le vel ter m ( L L T)”, “ preferre d t er m ( P T)”, 
“ hi g h le v el ter m ( H L T)”, “ hi g h le v el gr o u p ter m ( H L G T)”, a n d ass oci ate d pri mar y “s yste m or ga n 
class ( S O C)” usi n g t he v ersi o n of Me dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A) 
c urre ntl y i n effect at C o va nce at t he ti me of data b ase l oc k.  
A n y tec h nical d etails relate d t o c o m p utati o n, dates, a n d i m p utati o ns f or missi n g dates are 
descri be d i n S ecti o n 2. 5 . 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 1 8  of 8 1  
2. 1. 2        Pri or or c o n c o mit a nt m e di c ati o n s  
All me dicati o ns ta ke n wit hi n 3 m o nt hs bef ore t he scree ni n g visit (a n y ti me f or pri or S G L T 2) a n d 
u ntil t he e n d of t he st u d y are t o be re p orte d i n t he electr o nic case re p ort f or m (e -C R F).  
All me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n -Dr u g Dicti o nar y  W H O -D D 
usi n g t he versi o n c urr e ntl y i n effect at C o va nce at t he ti me of data bas e l oc k.  
•  
Pri or me dicati o ns are t h ose t he patie nt use d pri or t o first a d mi nistr ati o n of t he d o u ble-
bli n d I M P.  Pri or me dicati o ns ca n be disc o nti n ue d bef ore first a d mi nistrati o n or ca n be 
o n g oi n g d uri n g treat me nt p hase. 
•  
C o nc o mita nt me dicati o ns are a n y treat me nts recei ve d b y t h e patie nt c o n c o mita ntl y t o t he 
I M P, fr o m t he 1st a d mi nistrati o n of d o u ble-bli n d I M P t o t he date of last a d mi nistrati o n + 
1 0 da ys.  A gi ve n me dicati o n ca n be classifie d b ot h as a pri or me dicati o n a n d as a 
c o nc o mita nt me dicati o n.  
•  
P osttreat me nt me dicati o ns are t h ose t he p atie nt t o o k i n t he peri o d r u n ni n g fr o m t he 1 1t h 
da y after t he last a d mi nistrati o n of d o u ble- bli n d I M P u p t o t he e n d of t he st u d y. 
Bac k gr o u n d s ulf o n yl urea a n d metf or mi n are c o nsi dere d as n o ni n v esti gati o n al me dici nal pr o d ucts 
( NI M P). S ulf o n yl ur ea a n d metf or mi n (c o m mercial f or m ulati o ns) will be a d mi nistere d orall y 
acc or di n g t o t he l ocall y a p pr o ve d la bel.  
A n y tec h nical d etails relate d t o c o m p utati o n, dates, i m p utati o n f or missi n g dates are descri be d i n 
Secti o n  2. 5 . 
2. 1. 2. 1       R e s c u e t h er a p y  
E x ce pt f or S G L T 2 i n hi bit ors a n d a d diti o nal metf or mi n a n d s ulf o n yl urea, a n y a p pr o ve d 
me dicati o n(s) i ncl u di n g oral a nti dia betic dr u gs, G L P - 1 rece pt or a g o nists, or i ns uli n ca n be 
prescri be d at t he I n v esti gat or’s discreti o n t o treat t he h y p er gl yce mia. Metf or mi n will als o be 
per mitte d f or patie nts o n s ulf o n yl ur ea o nl y at Scree ni n g. Res c ue t hera p y is c o nsi dere d a NI M P. 
2. 1. 2. 2       Pr o hi bit e d pri or a n d c o n c o mit a nt m e di c ati o n s  
D uri n g t h e st u d y tr eat me nt peri o d, t he f oll o wi n g me dicati o ns are pr o hi bite d: 
•  
I nitiati o n of a n y a nti dia betic a ge nts, i ncl u di n g oral or i njecta ble a nti h y per gl yce mic a ge nts 
ot her t ha n t he I M P bef or e t he res c ue t hera p y.  
N ote: s h ort ter m use ( < 1 0 c o nsec uti ve da ys) of t h e pr o hi bite d me dicati o n, e g, s h ort- acti n g 
i ns uli n f or treat me nt of ac ute ill ness or s ur ger y is all o we d. 
•  
S yste mic use of gl uc o c ortic oi ds f or m ore t ha n 1 0 c o nsec uti ve da ys (t o pical, o p ht hal mic, 
nasal s pra y or i n h ale d a p plicati o ns are all o w e d).  
•  
I nitiati o n of a n y wei g ht l oss dr u gs (e g, p he nter mi ne, orlistat).  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 1 9  of 8 1  
•  
I n v esti gati o nal me dici nal pr o d ucts i n a n y ot her cli nical st u d y.  
S G L T 2 i n hi bit ors (e g, ca na glifl ozi n, da pa glifl ozi n, or e m pa glifl ozi n), a d diti o nal s ulf o n yl urea a n d 
metf or mi n are n ot all o w e d f or res c ue or p ost I M P t hera p y u ntil t he e n d of st u d y. 
Re d ucti o n of di g o xi n d ose s h o ul d be c o nsi dere d b eca use s ot a glifl ozi n acts as a wea k 
P- gl yc o pr ot ei n i n hi bit or a n d i ncreases s yste mic e x p os ure t o di g o xi n. 
Ot her me dicati o ns w hic h are u nli kel y t o i nterfere wit h t he p har mac o ki netic ( P K) or 
p har mac o d y n a mic ( P D) of t he I M P or c o nf o u n d i nter pretati o n of t he st u d y e n d p oi nts are all o w e d 
as nee de d f oll o wi n g disc ussi o n bet wee n t he I n v esti gat or a n d t h e S p o ns or. H o we ver, d oses of 
c hr o nicall y a d mi nistere d me dici nes s h o ul d be ke pt fi x e d d uri n g t he trial if at all p ossi ble. 
After pr e mat ure p er ma n e nt disc o nti n u ati o n of t he I M Ps, a n y treat me nts ( ot her t ha n S G L T 2 
i n hi bit ors) are per mitte d, as dee me d n ecess ar y b y t he I n vesti gat or. 
T he d ose of all a nti h y perte nsi ve a ge nts s h o ul d be ke pt c o nsta nt d uri n g t he 1 2 wee ks f oll o wi n g 
ra n d o mizati o n a n d n o a nti h y pert e nsi ve a ge nts s h o ul d be a d de d or wit h dra w n f or t he 1 2 wee ks 
f oll o wi n g r a n d o mizati o n u nless it is c o nsi dere d necessar y f or safet y reas o ns. 
2. 1. 3        Effi c a c y e n d p oi nt s  
All efficac y meas ure me nts c ollecte d d uri n g t he st u d y will be c o nsi dere d f or a nal yses, i ncl u di n g 
t hose o btai ne d after I M P disc o nti n uati o n or i ntr o d ucti o n of resc u e t hera p y (see Secti o n  2. 5. 4 ). 
H b A 1c, F P G, s er u m cr eati ni ne, e G F R are meas ure d/calc ulate d i n a ce ntral la b orat or y (s ee st u d y 
fl o wchart i n D ).  B o d y w ei g ht, S B P a n d diast olic bl o o d press ure ( D B P) (s ee Secti o n  2. 1. 4. 5 ) are 
meas ure d at o n -site visits b y t he i n vesti gat or. Patie nts re q uiri n g resc u e are i de ntifie d as t h ose wit h 
t he reas o n f or treat me nt tic ke d “r esc ue t h era p y” i n e-C R F “ Me di cati o n” pa ge.  
Efficac y vari a bles will be s u m marize d i n b ot h sta n dar d i nter nati o nal u nits a n d c o n ve nti o nal u nits 
w he n a p plica bl e.  
2. 1. 3. 1       Pri m ar y effi c a c y e n d p oi nt( s)  
•  
C ha n ge fr o m Baseli ne t o Wee k 2 6 i n H b A 1c ( %).  
2. 1. 3. 2       S e c o n d ar y effi c a c y e n d p oi nt( s)  
•  
C ha n ge fr o m Baseli ne t o Wee k 2 6 i n F P G.  
•  
C ha n ge fr o m Baseli ne t o Wee k 2 6 i n b o d y w ei g ht. 
•  
C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or patie nts wit h baseli ne S B P ≥1 3 0 m m H g. 
•  
C ha n ge fr o m Base li ne t o Wee k 1 2 i n S B P f or all patie nts. 
•  
Pr o p orti o n of patie nts wit h H b A 1c < 6. 5 %, < 7. 0 % at Wee k 2 6. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 0  of 8 1  
2. 1. 3. 3       Ot h er effi c a c y e n d p oi nt( s)  
•  
C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or patie nts wit h baseli ne S B P < 1 3 0 m m H g. 
•  
Pr o p orti o n of patie nts wit h re d ucti o n i n b o d y w ei g ht b y ≥2 %, ≥5 %, a n d ≥1 0 % fr o m 
Baseli ne.  
•  
C ha n ge fr o m Baseli ne t o Wee k 1 2 i n D B P.  
•  
Pr o p orti o n of patie nts ac hie vi n g S B P < 1 3 0 m m H g f or t h ose wit h baseli ne S B P 
≥1 3 0 m m H g.  
•  
Pr o p orti o n of patie nts ac hie vi n g D B P < 8 0 m m H g f or t h ose wit h baseli ne D B P ≥8 0 
m m H g.  
•  
Pr o p orti o n of patie nts re q uiri n g resc ue f or h y per gl yce mia.  
•  
C ha n ge fr o m Baseli ne i n:  
-          Ser u m creati ni ne,  
-          e G F R. 
•  
C ha n ge fr o m Baseli ne t o Wee k 7 9 i n H b A 1c.  
•  
C ha n ge fr o m Baseli ne t o Wee k 7 9 i n F P.  
•  
C ha n ge fr o m Baseli ne t o Wee k 2 6 i n S B P f or all patie nts a n d f or patie nts wit h baseli ne 
S B P ≥1 3 0 m m H g.  
•  
C ha n ge fr o m Baseli ne t o Wee k 7 9 i n S B P f or all patie nts a n d f or patie nts wit h baseli ne 
S B P ≥1 3 0 m m H g.  
•  
C ha n ge fr o m Baseli ne t o Wee k 7 9 i n b o d y w ei g ht.  
2. 1. 4        S af et y e n d p oi nt s  
T he safet y  a nal ysis will be base d o n t he re p orte d a d verse e v e nts ( A Es), h y p o gl yce mia, a n d ot her 
safet y i nf or mati o n, s uc h as cli nical la b orat or y dat a, vital si g ns, electr ocar di o gra m ( E C G), a n d 
p h ysical e x a mi nati o n, etc.  
O bserv ati o n peri o d  
T he o bser vati o n peri o d will be di vi de d i nt o 4 e p oc hs: 
•  
T he scree ni n g e p oc h is defi ne d as t he ti me fr o m t he si g ne d i nf or me d c o ns e nt date u p t o 
t he first a d mi nistrati o n of t he d o u ble-bli n d I M P.   
•  
T he tre at me nt e p oc h is defi ne d as t he ti me fr o m t he first a d mi nistrati o n of t he 
d o u ble- bli n d I M P t o t he l ast a d mi nistrati o n of t he d o u ble- bli n d I M P. T his e p oc h i ncl u des 
t he 2 6- wee k d o u ble- bli n d c ore treat me nt peri o d a n d t he 5 3- wee k d o u ble- bli n d e xte nsi o n 
treat me nt peri o d. T h e c or e treat me nt peri o d is t he ti me fr o m t he first a d mi nistrati o n of 
d o u ble- bli n d I M P  t o t he last a d mi nistrati o n of d o u ble- bli n d I M P o n or b ef ore 
Visit  9/ Wee k 2 6 ( or Da y 1 8 2 if Visit 9/ Wee k 2 6 date is missi n g). 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 1  of 8 1  
•  
T he resi d u al tre at me nt  e p oc h is defi ne d as t he ti me fr o m t he last a d mi nistrati o n of t he 
d o u ble- bli n d I M P u p t o 1 0 d a ys ( 1 da y f or h y p o gl yce mia) after t he l ast a d mi nistrati o n of 
d o u ble- bli n d I M P.  
T he treat me nt - e mer ge nt a d verse e ve nt ( T E A E) peri o d will i ncl u de b ot h treat me nt a n d resi d ual 
treat me nt e p oc hs ( See t h e T E A E peri o d f or t he c ore treat me nt peri o d i n Secti o n  2. 5. 4 ). 
•  
T he p osttre at me nt  e p oc h is defi ne d as t he peri o d of ti me starti n g t he d a y after t he e n d of 
t he T E A E peri o d u p t o t h e last pr ot oc ol- pla n ne d visit or t he res ol uti o n/sta bilizati o n of all 
seri o us a d vers e e v e nts ( S A E), a d verse e v e nts of s pecial i nterest ( A E SI) a n d e ve nts of 
s pecial i nterest ( E O SI), w hic he ver is lat er. 
T he o n-st u d y o bser v ati o n peri o d is defi ne d as t h e ti me fr o m start of d o u ble- bli n d treat me nt u ntil 
t he e n d of t he st u d y ( defi ne d as t he last sc he d ul e d visit f or t h ose w h o c o m plete d t he st u d y a n d t he 
date c ollecte d o n e - C R F pa ge “ C o m pleti o n of E n d of St u d y/ F oll o w- u p ” f or t h ose w h o di d n ot 
c o m plete t he st u d y).  
T he p ost-st u d y o bs er vati o n peri o d is defi ne d as t h e ti me fr o m t he da y after t he e n d of t he st u d y 
u ntil t he res ol uti o n/sta bilizati o n of all S A E, A E SI a n d E O SI if a p plica bl e.  
2. 1. 4. 1       H y p o gl y c e mi a  
H y p o gl yce mia will be i d e ntifie d as e v e nts rec or de d o n t he de dicate d e -C R F “ H y p o gl yce mic e ve nt 
i nf or mati o n” pa ge, a n d will be cate g orize d as f oll o ws (see st u d y pr ot oc ol f or f urt her d etails):  
Severe hy p o glyce mi a  
Se vere h y p o gl yce mia is a n e ve nt r e q uiri n g assista nce of a n ot h er pers o n t o acti vel y a d mi nister 
car b o h y dr ate, gl uca g o n, i ntra ve n o us gl uc ose or ot her res us citati ve acti o ns. T hese e pis o des ma y b e 
ass ociate d wit h s uffici e nt ne ur o gl yc o pe nia t o i n d u ce seiz ure, u nc o ns ci o us ness or c o ma. 
Self - m o nit ore d plas ma gl uc ose val ues ma y n ot b e a vaila ble, b ut ne ur ol o gical rec o v er y attri b uta ble 
t o t he rest orati o n of plas ma gl uc os e t o nor mal is c o nsi dere d s ufficie nt e vi de nce t hat t he e ve nt w as 
i n d uce d b y a l o w plas ma gl uc ose c o nce ntrati o n. 
Se vere h y p o gl yce mia is i de ntifie d i n e - C R F “ H y p o gl yce mic e ve nt i nf or mati o n” pa ge as t h ose 
d oc u me nte d as,  
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n”, tic ke d t he o pti o n “ S u bject was N ot 
Ca pa ble of Tr eati n g Self a n d Re q uire d Assista nce”, a n d  
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ Yes”.  
D oc u m e nte d sy m pt o m atic  h y p o gl yce mi a  
D oc u me nte d s y m pt o matic h y p o gl yce mia is a n e v e nt d uri n g w hic h t y pical s y m pt o ms of 
h y p o gl yce mia acc o m pa nie d b y a meas ure d plas m a gl u c ose c o n ce ntrati o n of ≤3. 9 m m ol/ L 
( ≤7 0 m g/ d L).  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 2  of 8 1  
Cli nical s y m pt o ms t hat are c o nsi der e d t o res ult fr o m a h y p o gl yce mic e pis o de are e g, i ncrease d 
s weati n g, ner v o us n ess, ast he nia/ wea k ness, tre m or, dizzi ness, i ncrease d a p p etite, pal pitati o ns, 
hea dac he, slee p dis or d er, c o nf usi o n, seiz ures, u nc o nsci o us ness, or c o ma. 
D oc u me nte d s y m pt o matic h y p o gl yce mia is i de ntifie d i n e -C R F “ H y p o gl yce mic e ve nt 
i nf or mati o n” pa ge as t h ose d oc u me nte d as: 
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n”, N O T tic ke d t he o pti o n “ S u bject was 
N ot Ca pa ble of Tr eati n g Self a n d Re q uire d Assist a nce”, a n d,  
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ Yes”, a n d,  
3.  Wit h a plas ma gl uc ose v al ue bef ore c o u nt er meas ure ≤3. 9 m m ol/ L ( ≤7 0 m g/ d L). 
Asy m pt o m atic hy p o glyce mi a   
As y m pt o matic h y p o gl yce mia is a n e ve nt n ot acc o m pa nie d b y t y pical s y m pt o ms of h y p o gl yce mia 
b ut wit h a meas ure d plas ma gl uc os e c o nce ntrati o n ≤3. 9 m m ol/ L ( ≤7 0 m g/ d L).  
As y m pt o matic h y p o gl yce mia is i de ntifie d i n e -C R F “ H y p o gl yce mic e ve nt i nf or mati o n” pa ge as 
t h ose d oc u me nte d as:  
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n”, N O T tic ke d t he o pti o n “ S u bject was 
N ot Ca pa ble of Tr eati n g Self a n d Re q uire d Assist a nce”, a n d,  
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ N o”, a n d,  
3.  Wit h a plas ma gl uc ose v al ue bef ore c o u nt er meas ure ≤3. 9 m m ol/ L ( ≤7 0 m g/ d L). 
 
Pr o b a ble sy m pt o m atic hy p o glyce mi a  
Pr o ba ble s y m pt o matic h y p o gl yce mia is a n e ve nt d uri n g w hi c h s y m pt o ms of h y p o gl yce mia are n ot 
acc o m pa ni e d b y a plas m a gl u c ose deter mi nati o n, ( b ut t h at was pres u ma bl y ca use d b y a pl as ma 
gl uc ose c o nce ntrati o n ≤3. 9 m m ol/ L [ ≤7 0 m g/ d L]), ie, s y m pt o ms treate d wit h oral car b o h y drate 
wit h o ut a test of plas ma gl uc ose.  
Pr o ba ble s y m pt o matic h y p o gl yce mia is i de ntifie d i n e - C R F “ H y p o gl yce mic e ve nt i nf or mati o n” 
pa ge as t h ose d o c u me nte d as,  
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n”, N O T tic ke d t he o pti o n “ S u bject was 
N ot Ca pa ble of Tr eati n g Self a n d Re q uire d Assist a nce”, a n d,  
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ Yes”, a n d, 
3.  Wit h n o plas ma gl uc ose val ue bef ore c o u nt er meas ure, a n d,  
4.  T o t he q uesti o n “ Di d t his c o u nter meas ure lea d a si g nifica nt i m pr o ve me nt or pr o m pt 
rec o ver y? ”, tic ke d “ Yes”. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 3  of 8 1  
Rel ative hy p o glyce mi a  
Relati ve h y p o gl yce mia, r ece ntl y ter me d “ pse u d o h y p o gl yce mia”, is a n e v e nt d uri n g w hic h t he 
pat ie nt re p orts t y pical s y m pt o ms of h y p o gl yce mia, a n d i nter prets t he s y m pt o ms as i n dicati ve of 
h y p o gl yce mia, b ut wit h a meas ure d plas ma gl u c os e c o nce ntrati o n > 3. 9 m m ol/ L ( > 7 0 m g/ d L). 
Relati ve h y p o gl yce mia is i de ntifie d i n e -C R F “ H y p o gl yce mic e ve nt i nf or mati o n ” pa ge as t h ose 
d oc u me nte d as, 
1.  T o t he q uesti o n “ C o u nter meas ure A d mi nistrati o n”, N O T tic ke d t he o pti o n “ S u bject was 
N ot Ca pa ble of Tr eati n g Self a n d Re q uire d Assist a nce”,  
2.  T o t he q uesti o n “ Were S y m pt o ms Prese nt”, tic ke d “ Yes”, a n d,  
3.  Wit h a plas ma gl uc ose v al ue bef ore c o u nt er meas ure > 3. 9 m m ol/ L ( > 7 0 m g/ d L).  
I n a d diti o n of t he t hres h ol d of ≤3. 9 m m ol/ L ( ≤7 0 m g/ d L), h y p o gl yce mia e pis o des wit h a plas ma 
gl uc ose of < 3. 0 m m ol/ L ( < 5 4 m g/ d L) will be a nal yz e d se paratel y. 
A n y h y p o gl yce mic e v e nt f ulfilli n g t he criteria o f a S A E or lea di n g t o u nc o nsci o us ness, c o ma, or 
seiz ure will als o be rec or de d as a S A E (Secti o n  2. 1. 4. 2 ).  
2. 1. 4. 2       A d v er s e e v e nt s v ari a bl e s  
A E o bserv ati o n peri o d  
•  
Pret re at me nt A Es  ar e A Es t hat de vel o pe d or w orse ne d or beca me s eri o us fr o m t he 
si g ne d i nf or me d c o nse nt date u p t o first a d mi nistrati o n of d o u ble-bli n d I M P.  
•  
T E A Es  are A Es t hat de v el o pe d or w ors e ne d or b eca me seri o us d uri n g t h e T E A E peri o d. 
•  
P osttre at me nt A Es  are A Es t hat de vel o pe d or w orse ne d or b eca m e seri o us d uri n g t he 
p osttreat me nt peri o d. 
All A Es (i ncl u di n g S A Es, A E SI a n d E O SI) will be c o de d t o a L L T, P T, H L T, H L G T, a n d 
ass ociate d S O C usi n g t he versi o n of Me d D R A c urre ntl y i n effect at C o va nce at t he ti me of 
data base l oc k.  
T he occ u rre n ce of A Es (i ncl u di n g S A Es, A E SI a n d E O SI) will be rec or de d fr o m t he ti me of 
si g ne d i nf or me d c o nse nt u ntil t he e n d of t he st u d y (see Secti o n  2. 1. 4 ) or t he 
res ol uti o n/sta bilizati o n of all S A E, A E SI a n d E O SI.  
A E SI i ncl u de 
•  
Pre g n a nc y.  
•  
S y m pt o matic o v er d ose wit h I M P/ NI M P.  
•  
Ala ni ne a mi n otra nsf eras e ( A L T) i n crease > 3  × u p per li mit of n or mal ( U L N).  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 4  of 8 1  
E O SI  i ncl u de  
•  
Maj or a d vers e car di o vas c ular e v e nts ( M A C E [car di o vasc ular deat h, m y o car dial i nfarcti o n, 
o r str o ke]) a n d ot her s p ecific car di o v asc ular ( C V) e ve nts (e g, h eart fail ure re q uiri n g 
h os pitalizati o n).   
•  
Se vere h y p o gl yce mia.  
•  
Ge nital m yc otic i nfecti o ns (t o i ncl u de v ul v o va gi nal ca n di diasis i n fe males a n d ca n di da 
bala nitis i n males).  
•  
Uri nar y tract i nfecti o n.  
•  
Cli nicall y rele v a nt v ol u me de pleti o n a n d e v e nts rel ate d/ p ossi bl y rel ate d t o v ol u me 
de pleti o n.  
•  
Diarr hea.  
•  
Pa ncreatitis.  
•  
B o ne fract ures.  
•  
Ve n o us t hr o m b otic e ve nts, t o i ncl u de dee p ve n o us t hr o m b osis a n d t hr o m b oe m b olis m (t o 
i ncl u de p ul m o nar y e m b olis m). 
•  
Dia be tic ket oaci d osis. 
•  
Re nal e ve nts, t o i ncl u de 5 0 % decli ne i n e G F R, e n d sta ge ki d n e y disease, re nal deat h.  
•  
Mali g na n cies of s pecial i nterest ( breast, bla d der, re nal cell, Le y di g cell, pa ncreatic, 
pr ostate, a n d t h yr oi d ca n cer).  
•  
A E lea di n g t o a n a m p utati o n.  
A Cli nical E n d p oi nt C o m mittee ( C E C) will, i n a bli n de d ma n ner, re vie w a n d a dj u dicate all 
deat hs, m y o car di al i nfar cti o n, str o ke, u nsta ble a n gi na re q uiri n g h os pitalizati o n, a n d heart fail ure 
re q uiri n g h os pitalizati o n, selecte d r e nal e v e nts, b o ne fract ure, a n d diabetic ket oaci d osis.  
T w o i n de pe n de nt c o m mittees will re vie w safet y e ve nts t hat re q uire o n g oi n g m o nit ori n g t o e ns ure 
ti mi n g pr ot oc ol a me n d m e nts i n case a s afet y si g n al is i de ntifie d. T hese e v e nts are: 1) p ote ntial 
cases of dr u g-i n d uce d li ver i nj ur y ( DI LI), an d 2) cases of a m p utati o ns. T he t w o c o m mittees will 
re vie w t he cases i n a treat me nt- bli n de d ma n ner a n d will prese nt t heir assess me nt t o t he D M C. 
 A E SI a n d E O SI will be i de ntifie d base d o n criteri a i n Ta ble  3.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 5  of 8 1  
T a bl e 3 - Crit eri a f or A E SI a n d E O SI  
A E Gr o u pi n g  
Crit eri a  
A E SI  
 
Pr e g n a ncy  
e- C R F “ Pr e g n a ncy”  
Sy m pt o m atic ov er d os e wit h 
I M P/ NI M P 
“ Ov er d os e of I M P” or “ Ov er d os e of NI M P” c h eck e d a n d “ Sy m pt o m atic ov er d os e” c h eck e d i n 
e- C R F “ Ov er d os e”  
A L T i ncr e as e > 3 × U L N  
e- C R F “ A L T i ncr e as e”  
E O SI a dj u di c at e d  
C ar di ov asc ul ar d e at h  
P ositiv ely a dj u dic at e d by C E C: “ C ar di ov asc ul ar” or “ U n d et er mi n e d” as t h e pri m ary c a us e of 
d e at h  
My oc ar di al i nf arcti o n, U nst a bl e 
A n gi n a r e q uiri n g h os pit aliz ati o n  
P ositiv ely a dj u dic at e d by C E C: Y es t o  t h e q u esti o n “ D o es t h e ev e nt m e et t h e d efi niti o n of a n 
MI f or t his st u dy ?”, or Yes t o t h e q u esti o n “If ev e nt is n ot a n MI, d o es t h e ev e nt m e et t h e 
d efi niti o n of a n U A R e q uiri n g a d missi o n t o h os pit al or e m er g e ncy r o o m, f or t his st u dy ?”  
Str ok e  
P ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ D o es t h e ev e nt m e et t h e d efi niti o n of a 
Str ok e f or t his st u dy ?”  
H e art f ail ur e r e q uiri n g 
h os pit aliz ati o n  
P ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ D o es t h e ev e nt m e et t h e d efi niti o n of a 
H e art F ail ur e Ev e nt  f or t his st u dy ?”  
B o n e fr act ur es  
P ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ Di d t h e Fr act ur e occ ur ?”  
Di a b etic k et o aci d osis  
P ositiv ely a dj u dic at e d by C E C: Y es t o t h e q u esti o n “ D o es t his ev e nt m e et t h e crit eri a t o b e a 
D K A ev e nt ?”  
E O SI R e n al e v e nt s w h ere s el e ct e v e nt s a dj u di c at e d  
S ust ai n e d ≥5 0 % d ecr e as e i n e G F R  ( 1) F or ≥5 0 % d ecr e as e i n e G F R fr o m b as eli n e, 
      ( 1 a) c o nfir m e d ≥5 0 % d ecr e as e i n G F R f or ≥3 0 d ays wit h n o r ev ersi bl e c a us e as 
r ec or d e d i n e-C R F “e G F R d ecr e as e”, O R  
      ( 1 b) p ositiv ely a dj u dic at e d by C E C: Yes t o t h e q u esti o n “ D o es t h e s u bj ect m e et t h e 
crit eri a of C K D pr o gr essi o n” f or ≥5 0 % d ecr e as e i n e G F R. 
S ust ai n e d e G F R < 1 5 m L/ mi n/ 1. 7 3 
m 2  
( 2) F or e G F R < 1 5 m L/ mi n/ 1. 7 3 m2, 
      ( 2 a) c o nfir m e d e G F R < 1 5 m L/ mi n/ 1. 7 3 m 2 f or ≥3 0 d ays wit h n o r ev ersi bl e c a us e as 
r ec or d e d i n e-C R F “e G F R d ecr e as e”, O R  
       ( 2 b) p ositiv ely a dj u dic at e d by C E C: Yes t o t h e q u esti o n “ D o es t h e s u bj ect m e et t h e 
crit eri a of C K D pr o gr essi o n”. 
C hr o nic di alysis  
( 3) F or di alysis,  
      ( 3 a) di alysis l ast e d f or ≥9 0 d ays ( e g, e n d d at e – st art d at e + 1 ≥9 0) as r ec or d e d i n e-C R F 
“ R e n al Ev e nt – Di alysis”, O R  
      ( 3 b) p ositiv ely a dj u dic at e d by C E C: Yes t o t h e q u esti o n “. D o es t h e s u bj ect m e et t h e 
crit eri a f or E S R D”. 
R e n al tr a ns pl a nt*  
( 4) “ R e n al tr a ns pl a nt” c a pt ur e d i n e-C R F “ Ot h er pr oc e d ur e f or m”, w h er e a dj u dic ati o n is n ot 
r e q uir e d. P Ts of R e n al tr a ns pl a nt ( 1 0 0 3 8 5 3 3), R e n al a n d p a ncr e as tr a ns pl a nt ( 1 0 0 5 2 2 7 8), 
R e n al a n d liv er tr a ns pl a nt ( 1 0 0 5 2 2 7 9) b as e d o n M e d D R A v 2 2. 0.  
R e n al d e at h  
( 5) R e n al d e at h as p ositiv ely a dj u dic at e d by C E C: “ D e at h - N o n -C ar di ov asc ul ar ( R e n al)” as 
t h e pri m ary c a us e of d e at h 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 6  of 8 1  
A E Gr o u pi n g  
Crit eri a  
E O SI n ot a dj u di c at e d*  
S ev er e hy p o glyc e mi a  
Al g orit h m s p ecifi e d i n Secti o n  2. 1. 4. 1  b as e d o n e -C R F “ Hy p o glyc e mic Ev e nts”  
G e nit al myc otic i nf ecti o ns  
P Ts i n A p p e n dix B  
Uri n ary tr act i nf ecti o ns  
P Ts i n A p p e n dix B  
Cli nic ally r el ev a nt v ol u m e d e pl eti o n 
a n d ev e nts r el at e d/ p ossi bly r el at e d 
t o v ol u m e d e pl eti o n 
P Ts i n A p p e n dix B  
Di arr h e a  
N arr o w s e arc h o n “ N o ni nf ecti o us di arr h o e a ( S M Q)” [ 2 0 0 0 0 2 1 8] pl us t h e f oll o wi n g P Ts 
( M e d D R A v 2 2. 0):  G astr o e nt eritis ( 1 0 0 1 7 8 8 8), Anti di arr h o e al s u p p ortiv e c ar e ( 1 0 0 5 56 6 0), 
E nt eritis ( 1 0 0 1 4 8 6 6), Ent eritis l e uk o p e nic ( 1 0 0 1 4 8 7 7), Ent er oc olitis ( 1 0 0 1 4 8 9 3), Ent er oc olitis 
h a e m orr h a gic ( 1 0 0 1 4 8 9 6)  
P a ncr e atitis  
P Ts i n A p p e n dix B  
V e n o us t hr o m b otic ev e nts  
P Ts i n A p p e n dix B  
M ali g n a nci es of s p eci al i nt er est  
Br e ast c a nc er: N arr o w s e arc h o n “ Br e ast c a nc er: N arr o w s e arc h o n “ Br e ast n e o pl as ms, 
m ali g n a nt a n d u ns p ecifi e d ( S M Q)” [ 2 0 0 0 0 1 4 9]  
Pr ost at e c a nc er: N arr o w s e arc h o n “ Pr ost at e n e o pl as ms, m alig n a nt a n d u ns p ecifi e d ( S M Q)” 
[ 2 0 0 0 0 1 5 2] 
L ey di g -c ell c a nc er: P Ts of L ey di g c ell t u m o ur of t h e t estis ( 1 0 0 2 4 4 0 7) a n d Ov ari a n S ert oli-
L ey di g c ell t u m o ur ( 1 0 0 7 3 2 7 0) b as e d o n M e d D R A v 2 2. 0  
T hyr oi d c a nc er: P Ts i n Ap p e n d ix B 
R e n al c ell c a nc er: P Ts i n A p p e n dix B  
P a ncr e atic c a nc er: P Ts i n Ap p e n dix B  
Bl a d d er c a nc er: P Ts i n Ap p e n dix B  
E O SI A E l e a di n g t o a n a m p ut ati o n  
A E l e a di n g t o a n a m p ut ati o n  
“ A E C orr ecti o n” as t h e r e as o n f or a m p ut ati o n i n e-C R F “ Ot h er Pr oc e d ur es r el at e d t o 
A m p ut ati o n”  
A E p ot e nti ally l e a di n g t o a n 
a m p ut ati o n *  
P Ts i n A p p e n dix B  
* S e arc h t er ms will b e u p d at e d usi n g t h e M e d D R A v ersi o n c urr e ntly i n eff ect at C ov a nc e  at t h e ti m e of d at a b as e l ock f or E O SI i d e ntifi e d by t h e m.  
*  A E p ot e nti ally l e a di n g t o a n a m p ut ati o n: n ot b el o n g t o t h e E O SI list d efi n e d i n pr ot oc ol, t h e it e m is i ncl u d e d a n d a n alyz e d d u e t o t h eir 
rel ev a nc e i n re g ar ds t o l o w er li m b c o m plic ati o ns a n d a m p ut ati o ns as a re q uire m e nt fro m h e alt h a ut h oriti es.. 
2. 1. 4. 3       D e at h s  
T he deat hs o bser vati o n p eri o d ar e per t he o bs er vati o n peri o ds defi ne d a b o v e.  
•  
Deat h o n -st u d y:  deat hs o cc urri n g d uri n g t he o n-st u d y o bser vati o n peri o d. 
•  
Deat h o n -tr eat me nt:  deat hs occ urri n g d uri n g t he T E A E peri o d. 
•  
Deat h p ost- st u d y:  d eat hs occ urri n g after t h e e n d of t he st u d y.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 7  of 8 1  
2. 1. 4. 4       L a b or at or y s af et y v ari a bl e s  
Cli nical la b orat or y data c o nsist s of bl o o d a nal ysis (i ncl u di n g he m at ol o g y, cli nical c he mistr y, 
a m ylas e, li pase a n d li pi d pr ofile) a n d uri nal ysis.  Cli nical la b orat or y val ues will be s u m marize d i n 
b ot h sta n dar d i nter nati o n al u nits a n d c o n ve nti o nal u nits w he n a p plica ble. 
Bl o o d sa m ples f or cli nical la b orat ories will be c ollecte d at desi g nat e d visits (see st u d y fl o wc h art 
i n D ).  T he f oll o wi n g la b orat or y data will be meas ure d at a ce ntral la b orat or y:  
•  
He mat ol o g y  
-          Re d bl o o d cells a n d platelets: he m o gl o bi n, he mat ocrit, re d bl o o d cell, platelets 
c o u nt,  
-          W hite bl o o d cells: w hite bl o o d cell, ne utr o p hils, l y m p h o c yt es, m o n oc ytes, 
bas o p hils, e osi n o p hils. 
•  
Cli nical c he mistr y  
-          Meta b olis m: gl uc ose (ser u m), creati ne p h os p h o ki nase ( C P K),        
-          Electr ol yt es a n d mi n erals: s o di u m, p otassi u m, c hl ori de, bicar b o nate (i e, car b o n 
di o xi de), calci u m, p h os p h or us, ma g n esi u m,  
-          Re nal f u ncti o n: bl o o d urea nitr o ge n ( B U N), creati ni ne, uric aci d, 
-          Li ver f u ncti o n: t otal pr otei n, al b u mi n, A L T, as partate a mi n otra ns ferase ( A S T), 
al kali ne p h os p hatase ( A L P), t otal bilir u bi n,  Lactic aci d de h y dr o ge nase ( L D H).       
•  
Li pi d par a meters (fasti n g): t otal c h olester ol ( T C), hi g h de nsit y li p o pr otei n c h olester ol 
( H D L- C), l o w d e nsit y li p o pr otei n c h olester ol ( L D L-C) (cal c ulate d b y Frie d wal d e q uati o n, 
See Secti o n  2. 5. 1 ), N o n-H D L -C (calc ulate d as t he differe nce bet wee n T C a n d H D L -C), 
tri gl yceri des ( T G). 
•  
Pa ncreatic e nz y mes: li pase, a m yl ase.  
Uri ne sa m ples wil l be c ollecte d at desi g nat e d visits (see st u d y fl o wc h art i n . T he f oll o wi n g 
la b orat or y dat a will be meas ure d at a ce ntral la b orat or y:  
•  
Uri ne di pstic k i ncl u des: s pecific gra vit y, p H, pr otei n, bl o o d, ket o nes, bilir u bi n, 
ur o bili n o ge n, nitrite, a n d le u k oc yt e e sterase. 
•  
Uri ne micr osc o p y i ncl u d es, b ut is n ot li mite d t o: detecti o n of f or m e d cell ul ar ele me nts, 
casts, bacteria, yeast, par asites, a n d cr ystals i n ce ntrif u ge d uri ne se di me nt.  
Ser u m gl uc os e will be pr ese nte d as efficac y p ara meters i n  Secti o n  2. 4. 4 . F or creati ni ne a n d 
calc ulate d e G F R, P ote ntiall y Cli nicall y Si g nifica nt A b n or malit y ( P C S A) s u m maries will be 
prese nte d i n t he safet y secti o n w hile descri pti ve s u m maries i n t he effi cac y secti o n.  
Tec h nical f or m ulas ar e d escri be d i n Secti o n 2. 5. 1 . 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 8  of 8 1  
2. 1. 4. 5       Vit al si g n s v ari a bl e s  
Vital si g ns i ncl u de:  heart rate ( H R), s yst olic a n d diast olic bl o o d press ure, te m perat ure, a n d 
res pirat or y r ate.  T h e y will be perf or me d after t he patie nt has bee n s eate d f or at least 5 mi n utes. 
Bl o o d press ur e a n d H R will be assesse d 3 ti mes wit h at least 1 mi n ute bet wee n eac h 
meas ure me nt. T h e mea n of t he 3 meas ure me nts will be a nal yze d f or eac h vital  si g n varia bl e ( H R, 
S B P, a n d D B P). 
2. 1. 4. 6       P h y si c al e x a mi n ati o n  
A c o m plete p h ysical e x a m will be perf or me d at Visit 1 ( Scree ni n g), Visit 9 ( Wee k 2 6) a n d Visit 
1 3 ( Wee k 7 9). “ N or mal”, “ A b n or mal” or “ N ot d o n e” as det er mi ne d b y t he I n vesti gat or will be 
re p orte d i n t he e- C R F b y b o d y s yste m.  
2. 1. 4. 7       El e ctr o c ar di o gr a m v ari a bl e s  
1 2-lea d E C Gs will be perf or me d at Visit 1 ( Scree ni n g), Visit 9 ( Wee k 2 6), a n d Visit 1 3( Wee k 
7 9). E C G stat us of “ n or mal” or “a b n or mal” will be re p ort e d i n t he e- C R F as deter mi ne d  b y t he 
i n vesti gat or.  
2. 1. 5        P h ar m a c o ki n eti c v ari a bl e s  
P har mac o ki netic varia bles i ncl u de t he plas ma c o n ce ntrati o n of s ota glifl ozi n a n d its 
3- O- gl uc ur o ni d e meta b olite i n t he s ota glifl ozi n 4 0 0 m g gr o u p. 
2. 2              DI S P O SI TI O N O F P A TI E N T S  
T his sec ti o n descri bes p atie nt dis p ositi o n f or b ot h patie nt st u d y stat us a n d t he patie nt a nal ysis 
p o p ulati o ns. 
Scree ne d p atie nts ar e defi ne d as all patie nts w h o h a ve si g n e d t he i nf or m e d c o nse nt.   
Ra n d o mize d patie nts c o nsist of all patie nts wit h a si g ne d i nf or me d c o nse nt f or m w h o ha ve h a d a 
treat me nt kit n u m ber all o cate d a n d rec or de d i n t he I R T dat a base, re gar dless of w het her t h e 
treat me nt kit was use d or n ot. 
F or patie nt st u d y stat us, t he t otal n u m ber of patie nts i n eac h of t he f oll o wi n g cate g ories will be 
prese nt e d i n t he C S R usi n g a fl o wc hart dia gra m or s u m mar y ta bles:  
•  
Scree ne d p atie nts.  
•  
R u n i n patie nts: patie nts w h o ha d a r u n-i n rec or d i n I R T.  
•  
Scree n f ail ure patie nts (i ncl u di n g fail ures d uri n g r u n-i n) a n d reas o ns f or s cree n fail ure.  
•  
N o nra n d o mize d b ut treat e d pat ie nts. 
•  
Ra n d o mize d patie nts.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 2 9  of 8 1  
•  
Ra n d o mize d b ut n ot treate d patie nts.  
•  
Ra n d o mize d a n d treate d patie nts.  
•  
Patie nts w h o ha ve c o m pl ete d t he 2 6- w ee k d o u ble- bli n d c ore treat me nt peri o d (see 
Secti o n  2. 5. 4 ) as per pr ot oc ol.  
•  
Patie nts di d n ot c o m plete t he 2 6- wee k d o u ble -bli n d c ore treat me nt peri o d (see 
Secti o n  2. 5. 4 ) as per pr ot oc ol a n d t he reas o ns f or per ma ne nt treat me nt disc o nti n uati o n. 
•  
Patie nts w h o ha ve c o m pl ete d t he 7 9- w ee k e ntire treat me nt peri o d as p er pr ot oc ol 
( d o u ble- bli n d c ore treat m e nt peri o d a n d e xte nsi o n treat me nt peri o d).  
•  
Patie nts w h o di d n ot c o m plete t he 7 9- wee k e ntire treat me nt peri o d as per pr ot oc ol, a n d t he 
reas o ns f or per ma n e nt treat me nt disc o nti n uati o n.  
•  
Patie nts w h o ha ve c o m pl ete d t he st u d y as per pr ot oc ol.  
•  
Patie nts w h o di d n ot c o m plete t he st u d y as per pr ot oc ol a n d t he reas o ns f or st u d y 
disc o nti n uati o n.  
•  
Patie nts’ e n d of st u d y stat us (c o m plete d, n ot c o m plete d) a n d c orres p o n di n g e n d of e ntire 
treat me nt stat us (c o m plet e d, n ot c o m plete d).  
•  
Stat us at last st u d y c o ntact.  
F or scree n e d, r u n i n, scr ee n fail ure, a n d n o nra n d o mize d b ut treate d patie nts, perce nt a ges will be 
calc ulate d usi n g t he n u m ber of scree n e d patie nts as t he de n o mi nat or. All ot her cat e g ories of 
patie nts will be prese nte d b y treat me nt gr o u p a n d t he perce nta ges will be calc ulate d usi n g t he 
n u m ber of ra n d o mize d patie nts wit hi n eac h treat me nt gr o u p as t he de n o mi nat or.  Reas o ns f or 
treat me nt disc o nti n uati o n will be s u p plie d i n ta bles gi vi n g n u m bers a n d p erce nta ges b y treat me nt 
gr o u p.  Patie nts pr e mat ur el y disc o nti n ue d fr o m treat me nt a n d/ or st u d y, al o n g wit h reas o ns f or 
disc o nti n uati o n, will als o be liste d.  
A s u m mar y of t he distri b uti o n of patie nts b y c o u ntr y a n d ce nt er will als o be pr o vi de d ( o verall 
n u m ber of patie nts scr ee ne d, r u n-i n, ra n d o mize d, a n d treate d, as well as n u m ber of patie nts 
ra n d o mize d, disc o nti n ue d fr o m st u d y treat me nt, a n d disc o nti n ue d fr o m st u d y f or eac h treat me nt 
gr o u p).  
Patie nts treate d b ut n ot ra n d o mize d, patie nts ra n d o mize d b ut n ot treate d a n d patie nts ra n d o mize d 
b ut n ot treate d as r a n d o mize d will be i de ntifie d a n d descri be d i n se p arat e listi n gs. T he patie nts of 
t he t hir d cate g or y (ra n d o mize d a n d n ot treate d as ra n d o mize d) will be part of efficac y a n d safet y 
a nal ys es (Secti o n  2. 3 ). P atie nts ra n d o mize d b ut n ot treate d will be i ncl u de d i n efficac y a n al ysis. 
Safet y d ata of p atie nts treate d b ut n ot ra n d o mize d will be re p orte d se p aratel y.  
T he ra n d o mizati o n strata [ H b A 1c at Scree ni n g ( ≤8. 5 %, > 8. 5 %), M etf or mi n use at scree ni n g ( Y es, 
N o), a n d mea n S B P at Scree ni n g ( < 1 3 0, ≥1 3 0 m m H g)] assi g ne d b y I R T will be s u m marize d. T he 
perce nt a ges will be calc ulate d usi n g t he n u m ber of ra n d o mize d patie nts as t he de n o mi nat or. T he 
discre pa n c y bet wee n t he strata assi g ne d b y I R T a n d t he i nf or mati o n re p ort e d o n e- C R F will be 
liste d f or all ra n d o mize d patie nts. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 0  of 8 1  
Ka pla n - Mei er ( K M) pl ots of t he c u m ulati ve i nci d e nce of d o u bl e- bli n d I M P disc o nti n uati o ns d ue 
t o a n y r eas o n a n d d ue t o A E will be pr o vi de d f or t he e ntire 7 9- wee k d o u bl e- bli n d treat me nt peri o d 
se parat el y. A listi n g of t h ese patie nts, al o n g wit h t he reas o n f or disc o nti n uati o n of treat me nt, 
st u d y c o m pleti o n stat us a n d t he reas o n f or disc o nti n uati o n st u d y, will be pr o vi de d.  
All i m p orta nt de viati o ns i ncl u di n g ra n d o mizati o n a n d dr u g- dis pe nsi n g irre g ularities will be 
s u m marize d i n ta bles gi vi n g n u m bers a n d perce nt a ges of de vi ati o ns b y ra n d o mize d treat me nt 
gr o u p. 
A d diti o nall y, t he a n al ysis p o p ulati o ns f or safet y, efficac y, a n d p h ar mac o ki netics defi ne d i n  
Secti o n  2. 3  will be s u m marize d i n a ta ble b y n u m b er of patie nts i n t he ra n d o mize d p o p ulati o n.  
•  
Efficac y p o p ulati o n: i nte nt- t o-treat (I T T) p o p ulati o n.  
•  
Safet y p o p ulati o n.  
•  
P K p o p ulati o n.  
2. 2. 1        R a n d o mi z ati o n a n d dr u g di s p e n si n g irr e g ul ariti e s  
Ra n d o mizati o n a n d dr u g- dis pe nsi n g irre g ularities occ ur w h e ne ver: 
1.  A ra n d o mizati o n is n ot i n acc or d a nce wit h t he pr ot oc ol- defi ne d ra n d o mizati o n met h o d, 
s uc h as a) a n i neli gi ble patie nt is ra n d o mize d, b) a patie nt is ra n d o mize d base d o n a n 
i nc orrect strat u m, c) a p atie nt is ra n d o mize d t wice, or d) i n a d y na mic ra n d o mizati o n 
sc he me t he tr eat me nt assi g n me nt is, i n fact, n ot ra n d o m, d ue t o a c o m p uter pr o gra m err or. 
 O R  
3.  A patie nt is di s pe nse d a n I M P kit n ot all ocate d b y t he pr ot oc ol- defi n e d ra n d o mizati o n, 
s uc h as a) a patie nt at a n y ti me i n t he st u d y is dis pe nse d a differe nt treat m e nt kit t ha n as 
ra n d o mize d ( w hic h ma y or ma y n ot c o ntai n t he c orrect-as-ra n d o mize d I M P), or b) a 
n o nra n d o mize d patie nt is treate d wit h I M P res er ve d f or ra n d o mize d patie nts. 
Ra n d o mizati o n a n d dr u g- dis pe nsi n g irre g ularities will be m o nit ore d t hr o u g h o ut t he st u d y a n d 
re vie we d o n a n o n g oi n g basis.  
All ra n d o mizati o n a n d dr u g- dis pe nsi n g irre g ulariti es will be d oc u me nte d i n t he C S R.  If t he 
n u m ber of irr e g ularities is lar ge e n o u g h t o ma k e a ta b ular s u m mar y usef ul, t he irre g ularities will 
be cate g orize d a n d s u m marize d a m o n g ra n d o mize d patie nts ( n u m ber a n d p erce nt a ges).  
N o nra n d o mize d, treate d patie nts will be descri be d se parat el y. Listi n gs wit h a d diti o nal, rele va nt 
details will be pr o vi de d i n a p pe n dices.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 1  of 8 1  
Ra n d o mizati o n a n d dr u g- dis pe nsi n g irre g ularities t o be pr os pecti vel y i de ntifie d i ncl u de b ut are 
n ot li mite d t o:  
R a n d o mi z ati o n a n d dr u g all o c ati o n irr e g ul ariti e s  
Kit dis p e ns ati o n wit h o ut I R T tr a ns acti o n  
Err o n e o us kit dis p e ns ati o n  
Kit n ot av ail a bl e  
R a n d o miz ati o n by err or  
P ati e nt r a n d o miz e d t wic e  
Str atific ati o n err or  
P ati e nt s witc h e d t o a n ot h er sit e  
2. 3              A N A L Y SI S P O P U L A TI O N S  
Patie nts treate d wit h o ut bei n g r a n d o mize d will n ot be c o nsi dere d ra n d o mize d a n d will n ot be 
i ncl u de d i n a n y efficac y p o p ulati o n.   
T he ra n d o mize d p o p ulati o n i ncl u des a n y patie nt w h o has bee n all ocate d t o a ra n d o mize d 
treat me nt re gar dless of w het her t he treat me nt kit was use d. 
F or a n y  p atie nt ra n d o mize d m ore t ha n o nce, o nl y t he data ass o ciate d wit h t he first ra n d o mizati o n 
will be use d i n a n y a nal ysis p o p ulati o n.  T he safet y e x perie n ce ass o ciate d wit h a n y lat er 
ra n d o mizati o n will be assesse d se paratel y. 
T he safet y e x perie nce of patie nts  treate d a n d n ot ra n d o mize d will be re p ort e d se paratel y, a n d 
t hese patie nts will n ot be i n t he safet y p o p ulati o n. 
2. 3. 1        Effi c a c y p o p ul ati o n s  
Efficac y a nal ys es will be base d o n t he treat me nt gr o u p all ocate d b y t he I R T acc or di n g t o t he 
ra n d o mizati o n sc he d ule at ra n d o mizati o n visit (as ra n d o mize d), irres pecti ve of t he treat me nt 
act uall y recei ve d.  
2. 3. 1. 1       I nt e nt-t o-tr e at p o p ul ati o n 
Efficac y a nal ys es will be base d o n t he I T T p o p ul ati o n, defi ne d as all ra n d o mize d patie nts, 
irres pecti ve of c o m plia nce wit h t he st u d y pr ot o c ol a n d pr oce d ures. Patie nts will be a nal yze d f or 
efficac y acc or di n g t o t he treat me nt gr o u p t o w hic h t he y are ra n d o mize d. 
2. 3. 2        S af et y p o p ul ati o n  
Safet y a nal yses will be base d o n t he safet y p o p ulati o n, defi ne d as all ra n d o mize d patie nts w h o 
recei v e at least o ne d os e or part of a d os e of d o u bl e- bli n d I M P(re gar dless of t he a m o u nt of 
treat me nt a d mi nistere d). Patie nts will be a nal yze d acc or di n g t o t he treat me nt act uall y recei ve d.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 2  of 8 1  
I n a d diti o n:  
•  
N o nra n d o mize d b ut treat e d patie nts will n ot be part of t he safet y p o p ul ati o n; h o we ver, 
t heir safet y dat a will be prese nte d se p aratel y. 
•  
Ra n d o mize d patie nts f or w h o m it is u nclear w het h er t he y t o o k t he I M P will be i ncl u de d i n 
t he safet y p o p ulati o n as r a n d o mize d. 
•  
W he n a patie nt is e x p ose d t o b ot h place b o a n d s ot a glifl ozi n, t he patie nt will be a nal yz e d i n 
t he s ota glifl ozi n 4 0 0 m g gr o u p. 
•  
Ra n d o mize d patie nts will be e x cl u de d fr o m t he safet y p o p ulati o n o nl y if t here is 
d oc u me nte d e vi de n ce (i e, all st u d y dates rec or de d as n o me dicati o n ta ke n) t hat patie nts 
ha ve n ot ta ke n t he st u d y treat me nt. If a patie nt is dis pe nse d d o u ble- bli n d I M P a n d is l ost t o 
f oll o w- u p wit h o ut a n y d o c u me nte d e vi de n ce, t he p atie nt will be c o nsi dere d e x p ose d. 
2. 3. 3        P h ar m a c o ki n eti c p o p ul ati o n  
F or P K a n al ys es, t he P K p o p ulati o n is d efi ne d as all safet y p atie nts w h o c o ntri b ute wit h at least 
1 vali d plas ma c o nce ntrati o n of s ota glifl ozi n or its 3- O- gl uc ur o ni d e meta b olite. T he P K data will 
be a nal yz e d acc or di n g t o t he treat me nt act uall y recei ve d ( See Sect i o n 2. 3. 2 ).  
2. 4              S T A TI S TI C A L M E T H O D S  
2. 4. 1        D e m o gr a p hi c s a n d b a s eli n e c h ar a ct eri sti c s  
C o nti n u o us data will be s u m marize d usi n g t he n u m ber of o bser v ati o ns a vaila ble, mea n, S D, 
me dia n, mi ni m u m, a n d ma xi m u m f or e ac h treat me nt gr o u p.  Cat e g orical a n d or di nal data will be 
s u m marize d usi n g t he c o u nt a n d perce nta ge of patie nts i n eac h treat me nt gr o u p. 
Para meters will be s u m m arize d base d o n t he ra n d o mize d p o p ulati o n a nal yz e d i n t he treat me nt 
gr o u p t o w hi c h t he y were ra n d o mize d.  A nal ys es f or t he safet y p o p ulati o n will be i ncl u de d i n t he 
a p pe n dices if t h e size of t he safet y p o p ulati o n is differe nt ( > 1 0 %) fr o m t he size of t hat i n t he 
pri mar y a nal ysis p o p ulati o n (ie, ra n d o mize d patie nts) f or a n y treat me nt gr o u p. 
Para meters  d escri be d i n Secti o n 2. 1. 1  will be s u m marize d b y treat me nt gr o u p a n d o verall ( p o ol e d 
acr oss treat me nt gr o u ps) usi n g descri pti ve statistics.  
P- val ues o n t he treat me nt differe n ce f or t he de m o gra p hic a n d b aseli ne c h aracteristic data will n ot 
be calc ul ate d.  
I n ge ner al, n o s pecifi c descri pti o n of t he safet y p ara meters will be pr o vi de d at baseli ne.  If 
rele va nt, t he b aseli ne val ues will be descri be d al o n g wit h eac h safet y a n al ysis. 
I n ge ner al, n o s pecifi c descri pti o n of t he effi cac y para meters will be pr o vi de d at baseli ne.  If 
rele va nt, t he b aseli ne val ues will be descri be d al o n g wit h eac h efficac y a n al ysis. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 3  of 8 1  
2. 4. 2        Pri or or c o n c o mit a nt m e di c ati o n s  
T he pri or, c o n c o mita nt a n d p os ttreat me nt me dicati o ns will be prese nte d i n t he ra n d o mize d 
p o p ulati o n f or eac h treat me nt gr o u p (a n d o verall f or t he s u m mar y of pri or me dicati o ns), usi n g 
c o u nts a n d per ce nta ges. N o statistical test f or t he bet wee n - gr o u p differe n ce will be perf or me d. 
Me dicat i o ns will be s u m marize d b y treat me nt gr o u p acc or di n g t o t he W H O- D D dicti o nar y, 
c o nsi deri n g t he first di git of t he a nat o mical t hera p e utic c he mical ( A T C) class (a nat o mic cat e g or y) 
a n d t he first 3 di gits of t h e A T C class (t hera pe utic cate g or y).  A gi ve n me di cati o n ma y be 
classifie d i n m ore t ha n 1 A T C class. All A T C c o d es c orres p o n di n g t o a me dicati o n will be 
s u m marize d, a n d a patie nt will be c o u nte d o nce wit hi n eac h A T C cate g or y (a nat o mic or 
t hera pe utic) li n ke d t o t he me dicati o n. T heref ore a patie nt ma y b e c o unte d s e veral ti mes f or t he 
sa me me dicati o n.  
Pri or me dicati o ns will be prese nte d b y a nat o mic a n d t hera pe utic cate g ori es a n d s orte d b y 
decreasi n g fr e q ue nc y of A T C base d o n t he o verall i nci de nce acr oss treat me nt gr o u ps.  I n case of 
e q ual fr e q ue nc y re gar di n g A T Cs ( a nat o mic or t hera pe utic cate g ories), al p h a betical or d er will be 
use d. 
C o nc o mita nt a n d p osttreat me nt me dicati o ns will be prese nt e d b y a nat o mic a n d t hera p e utic 
cate g ories a n d s orte d b y decreasi n g fre q ue nc y i n t he s ota glifl ozi n 4 0 0 m g gr o u p. I n cas e of e q u al 
fre q ue n c y re gar di n g A T Cs (a nat o mic or t hera pe utic cate g ories), al p ha b etical or der will be use d.  
2. 4. 3        E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e a n d c o m pli a n c e  
T he e xte nt of I M P e x p os ure a n d c o m plia n ce will be assesse d a n d s u m mari ze d b y act ual treat me nt 
wit hi n t he safet y p o p ulati o n ( Secti o n 2. 3. 2 ). 
2. 4. 3. 1       E xt e nt of i n v e sti g ati o n al m e di ci n al pr o d u ct e x p o s ur e  
T he e xte nt of I M P e x p os ure will be assess e d  b y t he d urati o n of I M P e x p os ure. 
D urati o n of I M P e x p os ure is defi ne d as last d ose d ate of d o u ble- bli n d I M P – first d ose date of 
d o u ble- bli n d I M P + 1 d a y, r e gar dl ess of u n pla n ne d i nter mitte nt disc o nti n uati o ns (see Secti o n 
2. 5. 3  f or cal c ulati o n i n case of missi n g or i nc o m pl ete data).  D urati o n of I M P e x p os ure will be 
s u m marize d descri pti vel y as a q ua ntitati ve varia ble ( n u m ber of p atie nts e x p ose d, mea n, S D, 
me dia n, mi ni m u m, a n d ma xi m u m).  I n a d diti o n, d urati o n of treat me nt e x p os ure will als o be 
s u m marize d cate g oricall y b y n u m bers a n d perce nta ges f or eac h of t he f oll o wi n g cate g ories a n d 
c u m ulati vel y acc or di n g t o t hese cate g ories:  
•  
1 t o 2 8 da ys,  
•  
2 9 t o 5 6 da ys,  
•  
5 7 t o 8 4 da ys,  
•  
8 5 t o 1 2 6 da ys,  
•  
1 2 7 t o 1 8 2 da ys,  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 4  of 8 1  
•  
1 8 3 t o 3 6 4 da ys,  
•  
3 6 5 t o 5 5 1 da ys,  
•  
> 5 5 1 da ys.  
A d diti o nall y, t he c u m ulati ve d urati o n of treat me nt e x p os ure will be pr o vi de d, defi ne d as t he s u m 
of t he d urati o n of tr eat me nt e x p os ure f or all patie nts, a n d will be e x presse d i n patie nt years.  
N u m ber a n d p erce nta ge of patie nts b y fi nal d ose at t he e n d of t he treat me nt will als o be prese nte d 
b y eac h tr eat me nt gr o u p.  
2. 4. 3. 2       C o m pli a n c e   
A gi ve n a d mi nistrati o n will be c o nsi dere d n o nc o m plia nt if t he patie nt di d n ot ta ke t he pla n ne d 
d ose of treat me nt as re q uire d b y t h e pr ot oc ol. N o i m p utati o n will be ma de f or patie nts wit h 
missi n g or i nc o m plete data.  
Perce nta ge of c o m plia n ce f or a p atie nt will be defi ne d as t he n u m ber of d a ys t hat t he patie nt w as 
c o m plia nt di vi de d b y t he t otal n u m ber of da ys t hat t he patie nt was pla n ne d t o ta ke d uri n g t he 
treat me nt e p oc h d efi ne d i n Secti o n  2. 1. 4  (ie, fr o m t he first date t o t he last d ate of d o u ble- bli n d 
I M P a d mi nistrati o n).  
A b o ve- pla n ne d d osi n g p erce nt a ge f or a patie nt will be defi ne d as t he n u m b er of da ys t hat t he 
patie nt t o o k a hi g h er d os e t ha n pla n ne d di vi de d b y t he t otal n u m ber of da ys t hat t he patie nt was 
pla n ne d t o ta ke d uri n g t h e treat me nt e p o c h.  
U n der- pla n n e d d osi n g perce nta ge f or a patie nt will be defi ne d as t h e n u m ber of da ys t hat t he 
patie nt t o o k a l o wer d ose t ha n pla n ne d di vi de d b y t he t otal n u m ber of da ys t hat t he patie nt was 
pla n ne d t o ta ke d uri n g t h e treat me nt e p o c h. 
Treat me nt c o m plia nce, a b o ve- pla n ne d, a n d u n d er - pla n ne d d osi n g perce nta ges will be s u m marize d 
descri pti vel y as q ua ntitati ve varia bles ( n u m b er, m ea n, S D, me dia n, mi ni m u m, a n d ma xi m u m). 
T he per ce nta ge of patie nts w h ose c o m plia nce is < 8 0 % will be s u m marize d. I n a d diti o n, n u m bers 
a n d perce nta ges of patie nts wit h at least 1 da y a b o ve - pla n ne d d os e a d mi nistrati o n will be 
pr o vi de d, as well as n u m bers a n d perce nt a ges of p atie nts wit h ( 0, 2 0 %], a n d > 2 0 % of da ys 
u n der- pla n n e d d ose a d mi nistrati o ns. 
Cases of o ver d os e (see st u d y pr ot o c ol f or f urt her d etails) will c o nstit ute A Es/ S A Es a n d be 
a nal yze d as s uc h. M or e ge nerall y, d osi n g irre g ularities will be liste d i n Secti o n 2. 2. 1 . 
2. 4. 4        A n al y s e s of effi c a c y e n d p oi nt s  
Efficac y a nal ys es w ill be perf or me d o n t he I T T p o p ulati o n usi n g t he efficac y ass ess me nts 
c ollecte d d uri n g t he st u d y, i ncl u di n g t h ose o btai n e d after I M P disc o nti n uati o n or i ntr o d ucti o n of 
resc ue t h era p y, u nless ot her wise s pecifie d. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 5  of 8 1  
Statistical testi n g will be perf or me d f or pr i mar y e n d p oi nt a n d s o me sec o n dar y e n d p oi nts at 
Wee k  2 6 ( or Wee k 1 2 f or S B P) as s pecifie d i n f oll o wi n g s u bsecti o ns. All efficac y varia bl es after 
Wee k 2 6 will o nl y be s u m marize d b y des cri pti ve statistics wit h o ut f or mal statistical testi n g.  
Missi n g data f or e fficac y a nal ys es is i de ntifie d t hr o u g h ste ps des cri be d i n S ecti o n  2. 5. 4 . 
2. 4. 4. 1       A n al y si s of pri m ar y effi c a c y e n d p oi nt  
T he statistical test will be t w o -si de d tests at a n o mi nal 5 % si g nifica nce le vel. 
Pri m ar y a n al ysis  
T he pri mar y efficac y e n d p oi nt of c ha n ge i n H b A 1 c fr o m baseli ne t o Wee k 2 6 will be a nal yze d b y 
a n A nal ysis of C o varia n ce ( A N C O V A ) m o del usi n g H b A 1 c val ues m eas ure d at baseli ne a n d 
Wee k 2 6 ( o bser ve d or i m p ute d). T he missi n g d ata at e n d p oi nt will be i m p ute d b y m ulti ple 
i m p utati o n [ MI]) met h o ds as detaile d bel o w. T o b e c o ncise, t he f oll o wi n g t e xts relate d t o 
i m p utati o n are ge neralize d t o acc o m m o date pri mar y as well as c o nti n u o us sec o n dar y effi cac y 
e n d p oi nts. 
Missi n g e n d p oi nt data at Wee k  2 6 ( or Wee k 1 2 f or S B P) visit will be i m p ute d usi n g a m o del b uilt 
se parat el y i n eac h tr eat m e nt gr o u p a n d esti mate d fr o m t he patie nts i n t he sa me treat me nt gr o u p 
w h o pre mat ur el y disc o nti n ue t he I M P bef ore t he Wee k 2 6 ( or Wee k 1 2 f or S B P) visit b ut ha v e t he 
meas ure me nt f or t he e n d p oi nt (ie, retrie ve d dr o p o uts). T he i m p utati o n m o del will i ncl u de t he 
ra n d o mizati o n strata a n d t he c orr es p o n di n g b aseli ne val ue. I n cases of n o n-c o n ver ge n ce d uri n g 
t he i m p utati o ns, t he offe n di n g strat u m will be i de ntifie d a n d t he n will be dr o p pe d fr o m t he m o del. 
C o nsi deri n g t hat t he n u m ber of r etrie ve d dr o p o ut patie nts i n eac h treat me nt gr o u p is e x pecte d t o 
be s mall, a si m ple i m p utati o n m o del base d o n re gressi o n will be use d wit h baseli ne meas ure me nt 
i ncl u de d as t he pr e dict or. This will ser ve as t he pri mar y m et h o d of i m p utati o n f or missi n g data 
s h o ul d sa m pli n g criteri a be satisfie d (see bel o w). 
A n alter nati ve ( bac k - u p) i m p utati o n met h o d will be use d if t he n u m ber of p atie nts w h o 
pre mat urel y disc o nti n ue t he I M P bef ore t he Wee k 2 6 ( or Wee k 1 2 f or S B P) visit b ut ha ve t he 
meas ure me nt f or t he e n d p oi nt is < 5 i n a n y treat me nt gr o u ps (ie, a n i ns ufficie nt n u m ber of 
retrie ve d dr o p o uts t o s u p p ort t he i m p utati o n met h o d descri be d a b o ve). T his criteri o n will be 
assesse d f or eac h pri mar y a n d c o nti n u o us sec o n d ar y efficac y e n d p oi nt. 
I n t he b ac k- u p i m p utati o n met h o d, missi n g p ost- baseli ne e n d p oi nt val ues at Wee k 2 6 ( or Wee k 1 2 
f or S B P) will be i m p ute d b y t he w as h o ut M ulti ple I m p utati o n ( MI) met h o d u n der t he missi n g n ot 
at ra n d o m ( M N A R) fra m e w or k.  
Missi n g e n d p oi nt data at t he Wee k 2 6 ( or Wee k 1 2 f or S B P) i n all treat me nt gr o u ps (s ota glifl ozi n 
4 0 0 m g a n d place b o) ar e i m p ute d fr o m a m o del esti mate d fr o m patie nts i n t he place b o gr o u p w h o 
ha ve t he e n d p oi nt dat a a v aila ble.  
F or patie nts i n t he s ota glifl o zi n 4 0 0 m g gr o u p wit h missi n g data at Wee k 2 6 ( or Wee k 1 2 f or 
S B P), t heir missi n g val ues will be i m p ute d usi n g o bser ve d bas eli ne a n d t he o bser ve d pri mar y 
e n d p oi nt data fr o m place b o c o m pleters; n o i nter mitte nt val ues fr o m eit her place b o or t he acti ve 
treat me nt gr o u ps will be use d.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 6  of 8 1  
F or place b o patie nts, missi n g data will be i m p ute d base d o n t he place b o gr o u p data. I nter mitte nt 
o bser ve d val u es will be use d w hile i m p uti n g missi n g val u es at Wee k 2 6 ( or Wee k 1 2 f or S B P). I n 
cases t hat a n o n - m o n ot o ne missi n g data p atter n occ urs at t he i nter me di ate visits, t hese data p oi nts 
will be first i m p ute d i n t he place b o gr o u p usi n g t h e Mar k o v C hai n M o nte Carl o ( M C M C) o pti o n 
i n P R O C MI t o ac hie ve a m o n ot o ne missi n g patter n f or all place b o patie nts. T he Wee k 2 6 ( or 
Wee k 1 2 f or S B P) e n d p oi nt val ues will be s u bse q ue ntl y i m p ute d fr o m t he m ulti ple c o pies of t he 
ori gi nal dat aset w here eac h c o p y will ha ve a m o n ot o ne missi n g patter n. 
T he i m p utati o n m o dels f or t he was h o ut MI met h o d will i ncl u de t he ra n d o mizati o n strata a n d t he 
c orres p o n di n g b aseli ne v al ue. Missi n g data will be i m p ute d usi n g t he re gressi o n met h o d.   
I n cases of n o n-c o n v er ge nce d uri n g t he i m p utati o ns, es peciall y f or t h e M C M C a p plicati o n i n t he 
place b o n o n- m o n ot o ne d atasets, gra p hical meas ures (e g, trace a n d a ut oc orrelati o n pl ots) will be 
use d t o i de ntif y t he offe n di n g vari a ble a n d o n ce d etecte d, t hat varia ble(s) will be dr o p pe d fr o m t he 
m o del a n d t he i m p utati o ns will be re -r u n. T h ese re-r u n m o dels will use t he sa me see d n u m ber a n d 
n u m ber of i m p utati o ns as use d i n t he ori gi n al m o dels.          
Usi n g eit her i m p utati o n met h o d, missi n g e n d p oi nt data will be i m p ute d 2 0 0 0 ti mes t o ge nerate 
m ulti ple data sets wit h c o m plete data. Ot her d etails of t he i m p utati o n pr oce d ures s uc h as t he s ee d 
n u m ber a n d s ort or d eri n g are s pecifie d i n t he S A S pr o gra ms. T he H b A 1c c h a n ge fr o m b aseli ne t o 
Wee k 2 6 ( or Wee k 1 2 f or S B P)  will be deri ve d fr o m o bser ve d a n d i m p ute d H b A 1c val ues at 
Wee k 2 6  ( or Wee k 1 2 f or S B P).   
Eac h of t he c o m plete d datasets after t h e i m p utati o n will be a nal yze d usi n g t he A nal ysi s of 
C o varia nce ( A N C O V A) m o del wit h treat me nt gr o u ps (s ota glifl ozi n 4 0 0 m g, place b o), 
ra n d o mizati o n strat u m of H b A 1c ( ≤8. 5 %, > 8. 5 %), ra n d o mizati o n strat u m of metf or mi n use at 
Scree ni n g ( Y es, N o), ra n d o mizati o n strat u m of S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g), a n d c o u ntr y as 
fi x e d fact ors, a n d bas eli ne val ue of t he effi cac y e n d p oi nt as a c o vari ate.  
Res ults fr o m eac h a n al ysis will be c o m bi ne d usi n g R u bi n’s f or m ula, t o pr o vi de t he a dj uste d mea n 
c ha n ge i n H b A 1 c fr o m b aseli ne t o Wee k 2 6 ( or Wee k 1 2 f or S B P) f or eac h treat me nt gr o u p, as 
well as t he bet wee n - gr o u p differe n ce (c o m pari n g s ota glifl ozi n 4 0 0 m g vers us place b o) a n d its 
ass ociate d 9 5 % c o nfi de n ce i nter val ( CI).  
Se nsitivity a n alyses  
Ti p pi n g p oi nt a nal ysis base d o n t he sa me MI met h o d as a p plie d t o t he pri m ar y a nal ysis will be 
perf or me d t o e x a mi ne t he r o b ust ness of t he res ults fr o m t he pri mar y a n al ysis. Patie nts w h o were 
ra n d o mize d t o s ota glifl ozi n 4 0 0 m g gr o u p a n d h a d n o H b A 1c data at Wee k 2 6 will be gi ve n a 
pe nalt y. T h e pe n alt y will be gra d uall y i ncreas e d t o e val uate a t w hic h le vel t he c o ncl usi o n of t he 
a nal ys es i n ter ms of statistical si g nifica n ce is c h a n ge d. T h e ti p pi n g p oi nt is t he pe nalt y l e vel, at 
w hic h t he ma g nit u de of efficac y re d u cti o n i n patie nts wit h o ut H b A 1c data at Wee k 2 6 creat es a 
s hift i n t he treat me nt eff ect of s ota glifl ozi n 4 0 0 m g fr o m bei n g statisticall y si g nifica ntl y better 
t ha n place b o t o a n o n-statisticall y si g nifica nt effect. L S mea n differe nce b et wee n s ota glifl ozi n 
4 0 0 m g a n d place b o a n d its ass ociate d p- val ue will be pr o vi de d f or eac h p e nalt y le v el. T he ste ps 
t o perf or m t he ti p pi n g p oi nt a nal ysis are as f oll o ws: 
1.  Missi n g data will be i m p ute d usi n g t he sa m e MI met h o d as a p plie d t o t he pri mar y 
a nal ysis .. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 7  of 8 1  
2.  T he i m p ute d H b A 1c val u e at Wee k 2 6 i n t he s ota glifl ozi n 4 0 0 m g gr o u p will be pe nalize d  
b y a d di n g a pe nalt y δ ( e g, δ = 0. 1 %) i n eac h c o m plete dataset .. 
3.  C ha n ge fr o m bas eli ne at Wee k 2 6 i n H b A 1c will be a nal yz e d usi n g t h e sa me A N C O V A 
m o del as s pecifie d i n t he pri mar y a nal ysis i n eac h c o m plete dataset .. 
4.  Res ults will be c o m bi ne d acr oss c o m plete d atasets us i n g R u bi n’s f or m ula.. 
5.  Ste ps 2 t o 4 will be re peate d wit h i ncre me ntal pe n alt y at δ (ie, δ, 2 δ, 3 δ, … …) u ntil t he 
p- val ue f or treat me nt eff ect of s ota glifl ozi n 4 0 0 m g c o m pare d t o place b o esti mate d i n 
Ste p  4 is > 0. 0 5. 
T he ti p pi n g p oi nt a nal ysis will be perf or me d o n t h e I T T p o p ulati o n. T he ti p pi n g p oi nt a nal ysis 
will be perf or me d f or t he pri mar y varia bl e o nl y if t hat varia ble (c ha n ge fr o m baseli ne t o Wee k 2 6 
i n H b A 1c c o m pari n g s ot a glifl ozi n 4 0 0 m g vs. place b o) is statistical si g nifi ca nt at α = 0. 0 5 ( 2-
si de d).  
I n a d diti o n t o t he ti p pi n g p oi nt a nal yses, if t h e retri e ve d dr o p o ut i m p utati o n is a p plie d t o t he 
pri mar y a nal ysis, t he a n al ysis base d o n t he was h o ut i m p utati o n met h o d (ie, t he bac k u p i m p utati o n 
met h o d) will be prese nte d as a se nsiti vit y a n al ysis.  
Patie nts i n t his st u d y ha v e u n der g o ne s a m pli n g f or plas ma le vels of s ota glifl ozi n a n d its mai n 
acti ve meta b olite i n or der t o perf or m p o p ulati o n P K a nal ysis.  Patie nts ma y be i de ntifie d as t h ose 
w h o ha ve n o det ecta ble l e vels of acti ve st u d y dr u g or met a b olite i n t he ir sa m ples (ie, Bel o w Li mit 
of Q ua ntificati o n or B L O Q).  W he n sa m ple a nal ysis has bee n c o m plete d a n d t he st u d y has b ee n 
u n bli n de d, e x pla nati o ns f or s o me of t hese p atie nts ma y b e f o u n d: k n o w n n o n- c o m plia nce or 
sa m pli n g occ urri n g after treat me nt ha d bee n disc o nti n ue d.  I n ot her cases, dr u g i nta k e hist or y 
relati ve t o t he ra n d o mizati o n assi g n me nt ma y n ot be f ull y e x plai ne d.  T he I T T-base d a nal yses 
s pecifie d i n t his d oc u me nt pr o vi des f or a c o nser v ati ve assess me nt of t he efficac y d ata s h o ul d 
patie nts ha ve bee n s u bjecte d t o t hese u ne x plai ne d n o n-c o m plia nce fi n di n gs or P K ‘a n o malies’. T o 
pr o vi de a br o a der p ers pecti ve o n t he i m pact of t hese a p pare nt err ors i n c o m plia nce, a d diti o nal 
se nsiti vit y a nal yses of t h e pri mar y efficac y e n d p oi nt a n d c o nti n u o us efficac y e n d p oi nts ma y b e 
c o n d ucte d. T he n ee d t o p erf or m s uc h a nal yses, t heir s pecifics, a n d res ults will be pr o vi de d i n t he 
Cli nical St u d y Re p ort ( C S R), if a p plica ble. T he a nal ysis met h o ds a p plie d t o t he patie nt 
s u b p o p ulati o ns defi ne d b y t he o cc urre nce of t he P K a n o malies (e g, e x cl usi o n of patie nts wit h P K 
a n o malies fr o m t he I T T dataset) will i ncl u de t he A N C O V A m o del usi n g t he retrie v e d dr o p o ut 
a n d/ or was h o ut MI met h o ds pre vi o usl y s pecifie d i n t his secti o n. 
Assess m e nt of tre at m e nt effect by s u b gr o u p  
Descri pti ve a n al ys es w ill be perf or me d o n t he pri mar y e n d p oi nt t o s u m marize t he treat me nt 
effects acr oss s u b gr o u ps defi ne d b y t he f oll o wi n g Baseli ne or Scree ni n g fact ors: 
•  
Race ( W hite, Blac k or Africa n A m erica n, Asia n, Ot her) (a n y race gr o u ps wit h fe wer t h a n 
5 patie nts ma y b e c o m bi ne d wit h “ Ot her” cat e g or y as a p pr o priat e).  
•  
Et h nicit y ( His pa nic, N ot His pa nic).  
•  
A ge gr o u p ( < 5 0, ≥5 0 t o < 6 5, ≥6 5 years) (a n y cate g or y wit h fe wer t ha n 5 p atie nts ma y b e 
c o m bi ne d wit h a n ot her cate g or y as a p pr o priat e).  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 8  of 8 1  
•  
Ge n der ( Male, Fe male).  
•  
Baseli ne B MI le v el ( < 3 0, ≥3 0 k g/ m²).  
•  
Baseli ne H b A 1c ( ≤8. 5 %, > 8. 5 %).  
•  
Metf or mi n use at Scree ni n g ( Yes, N o).  
•  
Baseli ne m ea n S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g).  
•  
Baseli ne e G F R ( ≥3 0 t o < 6 0 m L/ mi n/ 1. 7 3 m 2 [ M o derate d ecrease i n G F R], ≥6 0 t o 
< 9 0  m L/ mi n/ 1. 7 3 m2 [ Mil d decrease i n G F R], a n d ≥9 0 m L/ mi n/ 1. 7 3 m2 [ N or mal]). 
•  
D urati o n of dia bet es ( < 1 0, ≥1 0 years).  
•  
C o u ntr y.  
T he treat me nt effects (s ota glifl ozi n 4 0 0 m g vers us place b o) acr oss t he s u b gr o u ps defi ne d f or eac h 
of t hese fact ors will be esti mate d f or t he c h a n ge fr o m Baseli ne t o Wee k 2 6 i n H b A 1c i n t he I T T 
p o p ulati o n , a n d usi n g t h e sa me MI met h o d as a p plie d t o t he pri mar y a nal ysis. T he A N C O V A 
m o del will i ncl u de treat me nt gr o u ps (s ota glifl ozi n 4 0 0 m g, place b o), ra n d o mizati o n strat u m of 
H b A 1c ( ≤8. 5 %, > 8. 5 %), ra n d o mizati o n strat u m of metf or mi n use at Scree ni n g ( Y es, N o), 
ra n d o mizati o n strat u m of S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g), s u b gr o u p fact or, treat me nt-b y -
s u b gr o u p fact or, a n d c o u ntr y as fi x e d fact ors a n d baseli ne H b A 1 c val ues as a c o vari ate. T he 
a dj uste d esti mates of treat me nt mea n differe nces (s ota glif l ozi n 4 0 0 m g vers us place b o) wit h 
sta n dar d err or ( S E) a n d 9 5 % CIs will be pr o vi de d as a p pr o priat e acr oss t he s u b gr o u ps. A 
gr a p hical pr ese ntati o n of t he res ults (ie, f orest pl ot) will als o be pr o vi de d.  
I n t he cas e t hat t he s u b gr o u p fact or is i de ntical or si milar t o a ra n d o mizati o n strata fact or 
(e g, baseli ne H b A 1c, metf or mi n use at scree ni n g, or baseli ne mea n S B P cat e g or y), o nl y t he 
s u b gr o u p fact or (as a si n gle f act or or a n i nteracti o n ter m) will be i ncl u de d i n t he m o del i n or der t o 
a v oi d t he iss ue of c olli nearit y i n t he a nal ysis. T he c orres p o n di n g strata fact or will n ot be i ncl u de d 
i n t he m o del. 
S u m m ary st atistics at sc he d ule d visits  
S u m mar y statistics (f or s cree ni n g v al ue, bas eli ne val ue, o bser v e d p ost -bas eli ne val ue a n d its 
c ha n ges fr o m baseli ne) at sc he d ule d visits will be pr o vi de d f or eac h treat m e nt gr o u p. T he 
s u m mar y will i ncl u de t he n u m ber of o bser v ati o ns, mea n, S D, S E, mi ni m u m, me dia n, a n d 
ma xi m u m. Gra p hical prese ntati o ns will als o be use d t o e x a mi ne tre n ds o ver ti me usi n g mea n 
val ues ( ± S E) a n d mea n c ha n ges fr o m b aseli ne ( ± S E) at eac h of t he s c he d ul e d visits.  
Si milar prese ntati o ns will be pr o vi de d e x cl u di n g meas ure me nts after resc u e t hera p y d uri n g t h e 
e ntire 7 9- w ee k d o u ble- bli n d treat me nt peri o d. 
2. 4. 4. 2       A n al y s e s of s e c o n d ar y effi c a c y e n d p oi nt s  
F or c o nti n u o us sec o n dar y efficac y para meters wit h missi n g data at bas eli ne, missi n g baseli ne d ata 
will be i m p ute d usi n g MI u n der t he missi n g at ra n d o m ( M A R) ass u m pti o n. Missi n g data at 
baseli ne will be i m p ute d usi n g re gressi o n met h o d t hat i ncl u des ra n d o mizati o n strat u m of H b A 1c 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 3 9  of 8 1  
( ≤8. 5 %, > 8. 5 %), ra n d o mizati o n strat u m of metf or mi n use at Scree ni n g ( Y es, N o), ra n d o mizati o n 
strat u m of S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g), a n d baseli ne val ue i n t he i m p utati o n m o del.. 
Eac h c o nti n u o us sec o n d ar y efficac y e n d p oi nt ( Secti o n  2. 1. 3. 2 ) will be a nal yz e d usi n g a si milar 
A N C O V A m o del i ncl u di n g t he meas ure m e nts at baseli ne a n d e n d p oi nt ( o bs er ve d or i m p ute d). 
T he missi n g data at e n d p oi nt will be i m p ute d b y t he retrie v e d dr o p o uts if t here are at least 5 
patie nts i n eac h st u d y treat me nt gr o u p w h o disc o nti n ue d b ut ha ve t he e n d p oi nt. Ot her wise, t he 
was h o ut i m p utati o n met h o d will be use d acc or di n g t o t he criteri o n descri be d i n  Secti o n 2. 4. 4. 1 . 
After t he i m p utati o n, eac h of t he c o m plete dat asets will be a nal yze d b y a n A N C O V A m o del.   
T he A N C O V A m o del will i ncl u de treat me nt gr o u ps (s ota glifl ozi n 4 0 0 m g, place b o), 
ra n d o mizati o n strat u m of H b A 1c ( ≤8. 5 %, > 8. 5 %), ra n d o mizati o n strat u m of metf or min use at 
Scree ni n g ( Y es, N o), ra n d o mizati o n strat u m of S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g), a n d c o u ntr y as 
fi x e d effects, a n d t h e c orres p o n di n g b aseli ne sec o n dar y e n d p oi nt val ue as a c o variate. F or t h e 
a nal ysis of S B P i n patie nts wit h baseli ne S B P ≥1 3 0 m m H g, t he ra n d o mizati o n strat u m of S B P 
will n ot be i ncl u de d i n t he A N C O V A m o del. Res ults fr o m eac h c o m plet e d ataset will be 
c o m bi ne d usi n g R u bi n’s f or m ula t o pr o vi de t he a dj uste d mea n c ha n ge fr o m Baseli ne t o Wee k 2 6 
( or Wee k 1 2 f or S B P) f or eac h tr eat me nt gr o u p, as well as t he bet wee n-gr o u p differe n ce 
(c o m pari n g s ota glifl ozi n 4 0 0 m g vers us place b o) a n d t he 9 5 % CI f or t he differe n ce.  
F or all c o nti n u o us sec o n dar y e n d p oi nts, s u m mar y statistics at sc he d ule d visits will be pr o vi de d f or 
eac h tr eat me nt gr o u p. T h e s u m mar y wil l i ncl u de t he n u m ber of o bs er vati o ns, mea n, S D, S E, 
mi ni m u m, me dia n, a n d ma xi m u m. Gra p hical prese ntati o ns will als o be use d t o e x a mi ne tre n ds 
o ver ti me usi n g mea n val ues ( ± S E) a n d mea n c ha n ges fr o m baseli ne ( ± S E) at eac h of t he 
sc he d ule d visits. I n a d diti on, S B P will be s u m marize d descri pti vel y at eac h visit f or t h ose patie nts 
wit h baseli ne S B P ≥1 4 0 m m H g.  
T he cate g orical sec o n dar y efficac y varia bles of H b A 1c < 6. 5 %, < 7 % at Wee k 2 6 will be a nal yz e d 
res pecti vel y usi n g a C oc hra n-Ma ntel - Hae nszel ( C M H) met h o d stratifie d b y ra n d o mizati o n 
strat u m of H b A 1c ( ≤8. 5 %, > 8. 5 %), ra n d o mizati o n strat u m of metf or mi n use at Scree ni n g ( Yes, 
N o), a n d r a n d o mizati o n strat u m of S B P ( < 1 3 0 m m H g, ≥1 3 0 m m H g). T h e pr o p orti o n i n eac h 
treat me nt gr o u p will be pr o vi de d, as well as t he differe nce of pr o p orti o ns b et wee n s ota glifl ozi n 
4 0 0 m g a n d place b o wit h t he ass ociate d 2-si d e d 9 5 % CI. F or H b A 1c res p o n ders at Wee k  2 6 
( < 6. 5 %, < 7 % res p ecti vel y), all val ues at Wee k 2 6 will be use d t o deter mi ne w het her a p atie nt is a 
res p o n der or n ot, e ve n if t he y are meas ure d after I M P disc o nti n uati o n or resc ue me dicati o n use. 
Patie nts w h o ha ve n o H b A 1c meas ur e me nt at Wee k 2 6 will be treate d as n o n -res p o n ders. 
S u m mar y ta bles a n d gra p hs will als o be pr o vi de d b y treat me nt gr o u p at sc h e d ule d visits. 
F or bet w ee n - gr o u p c o m p aris o n, a se nsiti vit y a n al ysis will be perf or me d res pecti vel y f or H b A 1c 
< 6. 5 % res p o n d er a n al ysis b y e x cl u di n g p atie nts w h ose H b A 1c v al ues at baseli ne are < 6. 5 %, a n d 
f or H b A 1c < 7 % r es p o n d er a nal ysis b y e x cl u di n g patie nts w h ose H b A 1c v al ues at baseline are 
< 7 % usi n g t h e sa me C M H test me nti o ne d a b o ve. Si milarl y, b y- visit s u m mar y ma y als o be 
pr o vi de d e x cl u di n g t h ose patie nts. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 0  of 8 1  
2. 4. 4. 3       A n al y s e s of ot h er effi c a c y e n d p oi nt s  
T he a nal ysis of ot her e n d p oi nts (see Secti o n  2. 1. 3  ) will be descri pti ve wit h n o f or mal testi n g. 
S u m mar y statistics at sc h e d ule d visits base d o n o bser ve d val u e will be pr o vi de d b y eac h treat me nt 
gr o u p. Gra p hical pres e ntati o ns will als o be use d t o ill ustrate tre n ds o ver ti me as a p pr o pri ate.   
T he n u m ber ( %) of p atie nts w h o use d resc u e t hera p y will be s u m marize d b y treat me nt gr o u p 
d uri n g t he c ore (see Secti o n  2. 5. 4 ) a n d t he e ntire d o u ble- bli n d treat me nt peri o ds. A K M c ur ve f or 
t he ti me t o first resc ue t h era p y will be pr o vi d e d b y treat me nt gr o u p . A  list of patie nts w h o use d 
resc ue t h era p y will als o b e pr o vi de d (see Secti o n  2. 5. 4 ). 
2. 4. 4. 4       M ulti pli ci t y i s s u e s 
T o c o ntr ol t he fa mil y- wise t y pe I err or, a fi x e d se q ue nce testi n g pr o ce d ure will be a p plie d.  
O nce t he pri mar y h y p ot h esis  (s u peri orit y of t he c h a n ge fr o m Bas eli ne t o Wee k 2 6 i n H b A 1c  
c o m pari n g s ota glifl ozi n 4 0 0 m g vers us place b o) is statisticall y si g nifica nt f or t he pri mar y effi cac y 
e n d p oi nt  at α = 0. 0 5 ( 2-si de d), t he f oll o wi n g sec o n dar y h y p ot hesis base d o n c ha n ge fr o m Baseli ne 
sc ores will be teste d i n t h e f oll o wi n g pri oritize d or der: 
1.  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n F P G. 
2.  C ha n ge fr o m Baseli ne t o Wee k 2 6 i n b o d y w ei g ht. 
3.  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or patie nts wit h baseli ne S B P ≥1 3 0 m m H g. 
4.  C ha n ge fr o m Baseli ne t o Wee k 1 2 i n S B P f or all patie nts. 
5.  Pr o p orti o n of patie nts wit h H b A 1c < 7. 0 % at Wee k 2 6. 
If a n y h y p ot hesis is f o u n d t o be n ot statisticall y si g nifica nt, t he testi n g pr oce d ure will be st o p pe d 
a n d t he f oll o wi n g h y p ot h eses will n ot be teste d. 
N o m ulti plicit y a dj ust me nt will be ma de o n ot her sec o n dar y effi cac y v aria bles t ha n me nti o ne d 
a b o ve. 
2. 4. 5        A n al y s e s of s af et y d at a  
T he s u m mar y  of safet y r es ults will be prese nte d b y treat me nt gr o u p.  
Safet y e n d p oi nts are pres e nte d i n Secti o n  2. 1. 4 . T he s u m mar y of safet y res ults will be prese nte d 
b y treat me nt gr o u p. T he safet y data wi ll be s u m marize d f or t he 2 6-wee k c ore treat me nt peri o d a n d 
t he 7 9-wee k e ntire tr eat me nt peri o d se paratel y, u nless ot her wise s pecifie d.  
T he “ o bser v ati o n peri o d” defi ne d i n Secti o n  2. 1. 4  is a p plica ble i n all safet y a nal ys es f or t h e 
classificati o n of A Es, d eter mi nati o n of treat me nt -e mer ge nt P C S A val ues a n d t he last o n -treat me nt 
val ue f or t he l a b orat or y, vital si g n a n d E C G.  
Ge ner al c o m m o n r ules  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 1  of 8 1  
All safet y a nal yses will be perf or me d o n t he safet y p o p ulati o n as defi ne d i n Secti o n 2. 3. 2 , u nless 
ot her wise s pecifie d, usi n g t he f oll o wi n g c o m m o n r ules: 
•  
Safet y d ata i n patie nts w h o d o n ot bel o n g t o t he s afet y p o p ulati o n (e g, e x p ose d b ut n ot 
ra n d o mize d) will be liste d se parat el y. 
•  
T he baseli ne v al ue ( wit h t he e x ce pti o n of ser u m creati ni ne a n d e G F R)  is defi ne d as t he 
last a vaila ble val ue b ef or e t he first d ose of d o u ble- bli n d I M P, wit h t he e x ce pti o n of 
creati ni ne a n d e G F R, w h ere t he b aseli ne val ue is defi ne d as t he a vera ge of all val ues 
bef ore t h e first d ose of d o u ble- bli n d I M P  . 
•  
P C S A val ues are defi n e d as a b n or mal val u es c o nsi dere d me dicall y i m p orta nt b y t he 
S p o ns or acc or di n g t o pr e defi ne d criteria/t hres h ol ds base d o n literat ure re vi e w a n d defi ne d 
b y t he S p o ns or f or cli nical la b orat or y tests, vital si g ns, a n d E C G ( A p pe n di x A ). 
•  
P C S A criteria will deter mi ne w hic h patie nts ha d at least 1 P C S A d uri n g t h e T E A E peri o d, 
ta ki n g i nt o acc o u nt all e v al uati o ns perf or m e d d uri n g t he T E A E peri o d, i ncl u di n g 
n o nsc he d ule d or re peate d e val uati o ns.  T he n u m ber of all s uc h patie nts will be t he 
n u merat or f or t he treat me nt -e mer ge nt P C S A perce nta ge.  
•  
T he treat me nt - e mer ge nt P C S A de n o mi nat or b y gr o u p f or a gi ve n p ara met er will be base d 
o n t he n u m ber of patie nts assesse d f or t h at gi v e n p ara meter d uri n g t he T E A E peri o d b y 
treat me nt gr o u p i n t he safet y p o p ul ati o n. 
•  
F or la b or at or y para meters cite d i n t he pr ot oc ol as efficac y e n d p oi nts (i ncl u di n g H b A 1 c 
a n d plas ma gl uc ose etc.), P C S A s u m maries will n ot be pr o vi de d. T hese p ara meters will be 
s u m marize d i n efficac y S ecti o n  2. 4. 4 . F or creati ni ne a n d e G F R, P C S A s u m maries will be 
prese nte d i n safet y Sect i o n 2. 4. 5  w hile descri pti v e s u m maries i n effi cac y Secti o n  2. 4. 4 . 
•  
F or q ua ntitati ve safet y para meters b ase d o n ce ntral la b orat or y/rea di n g meas ure me nts, 
descri pti ve s tatistics will be use d t o s u m marize res ults a n d c ha n ge fr o m bas eli ne val ues b y 
visit a n d treat me nt gr o u p f or t he 7 9- w ee k e ntire treat me nt peri o d o nl y. S u m maries will 
i ncl u de t he last o n-treat me nt val ue. T he last o n-treat me nt val ue is c o m m o nl y defi ne d as 
t he val ue c ollect e d at t he sa me da y/ti me of t he last a d mi nistrati o n of I M P f or t he 7 9-wee k 
e ntire treat me nt peri o d. If t his val ue is missi n g, t his last o n -treat me nt val ue will be t he 
cl osest val ue pri or t o t he last a d mi nistrati o n of I M P d uri n g t he 7 9- w ee k e n tire treat me nt 
peri o d.    
•  
T he a nal ysis of t he safet y varia bles will be ess e ntiall y des cri pti ve a n d n o st atistical testi n g 
is pla n ne d.  Relati ve ris ks vers us place b o a n d t heir 9 5 % CIs ma y be pr o vi d e d, if rele v a nt. 
•  
Selecte d saf et y a nal yses will be s u m marize d b y a ge, ge n der, racial s u b gr o u ps, a n d ot her 
perti ne nt s u b gr o u ps (see details i n Secti o n  2. 4. 5. 1  a n d Secti o n  2. 4. 5. 2 ). 
2. 4. 5. 1       A n al y s e s of h y p o gl y c e mi a  
A nal ys es of h y p o gl yce mia will be perf or me d o n t h e T E A E peri o ds as defi n e d i n Secti o n  2. 1. 4 . 
H y p o gl yce mia will be cl assifie d as se v ere h y p o gl yce mia, d oc u me nt e d s y m pt o matic 
h y p o gl yce mia, as y m pt o matic h y p o gl yce mia, pr o ba ble s y m pt o matic h y p o gl yce mia or relati ve 
h y p o gl yce mia Secti o n  2. 1. 4. 1 . 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 2  of 8 1  
T he n u m ber ( %) of p atie nts wit h a n y h y p o gl yce mia, se vere h y p o gl yce mia, a n d  d oc u me nte d 
s y m pt o matic h y p o gl yce mia will be s u m marize d res pecti vel y b y treat me nt gr o u p d uri n g t h e T E A E 
peri o d, as well as t he i n ci de nce r ate i n patie nt years. T w o t y pes of i nci de nce rates will be 
prese nte d: t he n u m ber of patie nts wit h at least 1 e v e nt per 1 0 0 patie nt years (calc ulat e d as t he 
n u m ber of patie nts wit h at least 1 e ve nt / t otal e x p os ure i n 1 0 0 patie nt years), a n d t he n u m ber of 
e ve nts per 1 0 0 p atie nt- years [ calc ulate d as t he t otal n u m ber of e ve nts / (t otal e x p os ure i n 
1 0 0 patie nt -years)]. N ote: here e x p os ure (i n da ys) is d urati o n of T E A E peri o d, ie, d urati o n of I M P 
treat me nt i n da ys + 1 (Secti o n  2. 1. 4 ). 
T he s u m mar y of fre q ue n c y a n d i nci de n ce rate i n patie nt years f or se vere h y p o gl yce mia or 
d oc u me nte d s y m pt o mati c h y p o gl yce mia will be pr o vi de d as a p pr o priate b y ge n d er ( M ale, 
Fe male), a ge gr o u p ( < 5 0, ≥5 0 t o < 6 5, ≥6 5 years),race ( W hite, Blac k or Afri ca n A meri ca n, Asia n, 
Ot her) a n d M etf or mi n us e at Scree ni n g ( Yes, N o).  
A K M c ur ve will als o be pr o vi de d b y treat me nt gr o u p f or t he ti me t o fi rst se vere h y p o gl yce mia or 
d oc u me nte d s y m pt o mati c h y p o gl yce mia d uri n g t he T E A E peri o d f or t he 7 9- wee k e ntire treat me nt 
peri o d o nl y. 
D oc u me nte d s y m pt o matic h y p o gl yce mia ma y b e prese nte d b y ≤3. 9 m m ol/ L ( ≤7 0 m g/ d L) a n d 
< 3. 0 m m ol/ L ( < 5 4 m g/ d L) res pecti vel y, as a p pr o priate.  
 A listi n g of patie nts f or all e ve nts re p ort e d o n t he de dicate d e-C R F “ H y p o gl yce mic e ve nt 
i nf or mati o n” pa ge will be pr o vi de d wit h eac h cate g or y fla g ge d (i e, se vere h y p o gl yce mia, 
d oc u me nte d s y m pt o mati c h y p o gl yce mia, as y m pt o matic h y p o gl yce mia, pr o ba ble s y m pt o matic 
h y p o gl yce mia a n d r elati ve h y p o gl yce mia).  
2. 4. 5. 2       A n al y s e s of a d v er s e e v e nt s  
Ge ner alities  
T he pri mar y f o c us of a d v erse e v e nt re p orti n g will be o n T E A Es.  Pretreat m e nt a n d p osttreat me nt 
A Es will be descri be d s e paratel y.  
If a n A E date/ti me of o ns et ( occ urre n ce, w orse ni n g, or b ec o mi n g seri o us) is i nc o m plete, a n 
i m p utati o n al g orit h m will be use d t o classif y t he a d verse e v e nt as pretreat m e nt, 
treat me nt-e mer ge nt, or p osttreat me nt.  T he al g orit h m f or i m p uti n g date/ti me of o nset will be 
co nser vati ve a n d will classif y a n A E as treat me nt e mer ge nt u nless t here is defi niti ve i nf or mati o n 
t o deter mi ne it is pretreat me nt or p osttreat me nt.  Details o n classificati o n of A Es wit h missi n g or 
partial o nset dates are pr o vi de d i n Secti o n 2. 5. 3 . 
A d verse e ve nt i nci de n ce ta bles will be prese nte d b y S O C, H L G T, H L T, a n d P T, s orte d b y t he 
i nter nati o nall y a gree d or der f or S O Cs a n d al p ha b etic or der f or H L G T, H L T a n d P T wit hi n a S O C, 
t he n u m ber ( n) a n d per ce nta ge ( %) of patie nts e x perie nci n g a n a d verse e v e nt.  M ulti ple 
occ urr e nces of t he sa me e ve nt i n t he sa me patie nt will be c o u nte d o nl y o n ce i n t he ta bles wit hi n a 
treat me nt p hase.  T h e de n o mi nat or f or c o m p utati o n of perce nta ges is t he s afet y p o p ulati o n wit hi n 
eac h tr eat me nt gr o u p.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 3  of 8 1  
S orti n g wit hi n ta bles e ns ures t he sa me prese ntati o n f or t he set of all A Es wit hi n t he o bser vati o n 
peri o d ( pretreat me nt, tr eat me nt -e mer ge nt, a n d p osttreat me nt).  F or t hat p ur p ose, t he ta ble of all 
T E A Es prese n t e d b y pri mar y S O C a n d P T (s orte d b y t he i nter n ati o nall y a gree d S O C or der a n d 
decreasi n g fr e q ue nc y of P Ts wit hi n S O Cs i n t he s ota glifl ozi n 4 0 0 m g gr o u p) will defi ne t he 
prese ntati o n or der f or all ot her si milar ta bles u nless ot her wise s pecifie d. I n case of e q ual 
fre q ue n c y re gar di n g P Ts, al p ha betical or d er will b e use d. 
A n alysis of all T E A Es  
T he f oll o wi n g T E A E s u m maries will be ge nerate d d uri n g t he 2 6- wee k c ore a n d t he 7 9- wee k 
e ntire treat me nt peri o ds r es pecti vel y i n t he safet y p o p ulati o n. 
•  
O ver vie w of T E A Es, s u m marizi n g n u m ber ( %) of patie nts wit h a n y 
-          T E A E,  
-          Seri o us T E A E,  
-          T E A E lea di n g t o deat h, 
-          T E A E lea di n g t o per ma ne nt treat me nt disc o nti n uati o n. 
•  
All T E A Es b y pri mar y S O C, s h o wi n g n u m ber ( %) of patie nts wit h at least 1  T E A E, s orte d 
b y i nter n ati o nall y a gree d or der of pri mar y S O C.  
•  
All T E A Es b y pri mar y S O C, H L G T, H L T, a n d P T, s h o wi n g n u m ber ( %) of patie nts wit h 
at least 1 T E A E s orte d b y t he S O C i nter nati o nall y a gree d or der.  T he ot her le vels ( H L G T, 
H L T, P T) will be prese nt e d i n al p ha betical or der.  
•  
N u m ber ( %) of patie nts e x perie nci n g T E A E(s) prese nte d b y P T, s ort e d b y d ecreasi n g 
i nci de nce of P T i n t he s ota glifl ozi n 4 0 0 m g gr o u p. 
•  
All T E A Es b y pri mar y S O C a n d P T, s h o wi n g t he n u m ber ( %) of patie nts wit h at least 
1 T E A E, s orte d b y t he i nter nati o nall y a gree d S O C or der a n d b y d ecreasi n g i nci de nce of 
P Ts wit hi n eac h S O C i n t he s ota glifl ozi n 4 0 0 m g gr o u p. T his s orti n g or d er will be a p plie d 
t o all ot her si milar ta bles, u nless ot her wise s pecifie d. 
•  
All T E A Es re gar dless of relati o ns hi p a n d relat e d t o I M P b y pri mar y S O C, H L G T, H L T 
a n d P T, s h o wi n g t he n u m ber ( %) of patie nts wit h at least 1 T E A E, s orte d b y t he 
i nter nati o nall y a gree d S O C or der.  T he ot h er le v els ( H L G T, H L T, P T) will be prese nte d i n 
al p ha betical or d er.  
•  
All T E A Es b y ma xi mal se ver it y, pres e nte d b y pri mar y S O C a n d P T, s h o wi n g t he n u m ber 
( %) of p atie nts wit h at least 1 T E A E b y se verit y (i e, mil d, m o derate, or se v ere), s orte d b y 
t he s orti n g or d er defi ne d a b o ve. 
•  
C o m m o n T E A Es ( P Ts wit h a n i nci de nce ≥2 % i n a n y treat me nt gr o u p) b y pri mar y S O C, 
H L G T, H L T, a n d P T, s orte d b y i nter n ati o nall y a gree d or der of S O Cs. T he ot her le vels 
( H L G T, H L T, P T) will be prese nt e d i n al p ha betic or der.  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 4  of 8 1  
•  
C o m m o n  T E A Es ( P Ts wit h a n i nci de nce ≥2 % i n a n y treat me nt gr o u p) will be pr o vi de d as 
a p pr o priate b y pri mar y S O C, a n d P T a n d  b y d e m o gra p hic fact ors i ncl u di n g ge n d er ( M ale, 
Fe male), a ge gr o u p ( < 5 0, ≥5 0 t o < 6 5, ≥6 5 years of a ge), race ( W hite, Blac k or Africa n 
A merica n, Asi a n, ot her), baseli ne S B P cat e g or y ( < 1 3 0 m m H g, ≥1 3 0 m m H g), Metf or mi n 
use at Scree ni n g ( Yes, N o) , a n d baseli ne e G F R cate g or y ( ≥3 0 t o < 6 0 m L/ mi n/ 1. 7 3 m2  
[ M o derate decreas e i n G F R], ≥6 0 t o < 9 0 m L/ mi n/ 1. 7 3 m2  [ Mil d decrease i n G F R], a n d 
≥9 0 m L/ mi n/ 1. 7 3 m 2  [ N or mal]). S O C will be s orte d b y i nter n ati o nall y a gree d or der a n d 
t he P T b y decreasi n g i n ci de nce wit hi n eac h S O C i n t he s ota glifl ozi n 4 0 0 m g gr o u p, as 
descri be d a b o ve.  
•  
T E A Es ( P Ts wit h a n i nci de nce ≥5 % i n a n y treat m e nt gr o u p) b y pri mar y S O C, H L G T, 
H L T, a n d P T, s orte d b y i nter nati o nall y a gree d or d er of S O Cs. T he ot her l e vels ( H L G T, 
H L T, P T) will be prese nt e d i n al p ha betic or d er.  
A n alysis of all tre at m e nt e m er ge nt S A E(s ) 
•  
All treat me nt -e mer ge nt S A Es b y pri mar y S O C, H L G T, H L T, a n d P T, s h o wi n g t he n u m ber 
( %) of p atie nts wit h at least 1 seri o us T E A E, s orte d b y t he i nter n ati o nall y a gree d S O C 
or der.   T he ot h er le v els ( H L G T, H L T, P T) will be prese nte d i n al p h a betical or der  
•  
All treat me nt -e mer ge nt S A Es re gar dless of relati o ns hi p a n d relate d t o I M P, b y pri mar y 
S O C, H L G T, H L T, a n d P T, s h o wi n g t he n u m ber ( %) of p atie nts wit h at least 1 treat me nt-
e mer ge nt S A E, s orte d b y t he i nter nati o nall y a gree d S O C or der.  T he ot her le vels ( H L G T, 
H L T, P T) will be prese nt e d i n al p ha betical or der.  
A n alysis of all T E A E(s) le a di n g t o tre at m e nt disc o nti n u ati o n  
•  
All T E A E lea di n g t o treat me nt disc o nti n uati o n, b y pri mar y S O C, H L G T, H L T, a n d P T, 
s h o wi n g t he n u m ber ( %) of patie nts s orte d b y t he i nter nati o nall y a gree d S O C or der.  T he 
ot her le vels ( H L G T, H L T, P T) will be prese nte d i n al p ha betical or d er. 
A n alysis of A E SI  
T he s u m maries of A E SI will be prese nte d f or t he 7 9- wee k e ntire treat me nt peri o d  o nl y i n t he 
safet y p o p ulati o n. 
Pre g n a nc y a n d o ver d os e will be i ncl u de d i n o verall A E s u m maries if a n y are re p ort e d. A L T 
i ncreas e > 3 x U L N is i ncl u de d i n la b orat or y P C S A s u m mar y if a n y.  
T he n u m ber ( %) of p atie nts wit h a n A E SI will be s u m marize d b y P T a n d b y treat me nt gr o u p 
d uri n g t he 7 9- wee k e ntir e treat me nt peri o d o nl y. C orres p o n di n g listi n gs will be pr o vi de d as 
a p pr o priatel y.  
A n alysis of E O SI  
T he s u m maries of E O SI will be prese nte d f or t he 7 9- wee k e ntire treat me nt peri o d o nl y i n t he 
safet y p o p ulati o n. 
C V eve nts, b o ne fr act ure a n d D K A  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 5  of 8 1  
F or E O SIs t hat are a dj u dicate d (ie, d eat hs, m y ocar dial i nfarcti o n, str o ke, a n d u nsta ble a n gi na 
re q uiri n g h os pitalizati o n, heart f ail ure re q uiri n g h os pitalizati o n, b o ne fract ure, a n d dia b etic 
ket oaci d osis), t he n u m ber ( %) of patie nts wit h a n E O SI p ositi vel y a dj u dicate d b y C E C will be 
s u m marize d b y treat me nt gr o u p. All E O SIs s e nt f or a dj u dicati o n a n d/ or re p orte d b y t h e 
i n vesti gat ors i n t he s pecific A E f or ms will be liste d al o n g wit h t he a dj u dicati o n o utc o me. 
Re n al eve nts  
F or t he E O SI re nal e ve nts w here s electe d e ve nts are a dj u dicat e d, t he n u m b er ( %) of patie nts wit h 
a n y re nal e ve nts i de ntifie d i n  Ta ble  3 i n Secti o n  2. 1. 4. 2  w ill be s u m marize d b y treat me nt gr o u p. 
T he f oll o wi n g re nal e ve nts will be liste d al o n g wit h t he a dj u dicati o n o utc o me if a p plica ble, 
i ncl u di n g e v e nts,  
i. 
rec or d e d i n e-C R F “ G F R decrease”,  
ii. 
rec or d e d i n e-C R F “ Re nal E ve nt – Dial ysis”,  
iii. 
i de ntifie d as “ Re nal tr a nspla nt” i n e- C R F “ Ot h er pr oce d ure”,  
Re nal deat h will be part of all deat hs s pecifie d a b o ve.  
Ot her E O SIs  
F or E O SIs t hat are n ot a dj u dicate d, t he n u m ber ( %) of patie nts wit h at least o ne e ve nt will be 
s u m marize d b y treat me nt gr o u p a n d b y P T (as i de ntifie d i n Ta ble  3 i n Secti o n  2. 1. 4. 2 ).  
Se vere h y p o gl yce mia will be i ncl u de d i n t he s u m mar y of h y p o gl yce mia ( See Secti o n  2. 5. 1 ). 
A E lea di n g t o a n a m p utati o n is descri be d i n t he secti o n bel o w. 
A n alysis of A m p ut ati o n  
T he n u m ber ( %) of p atie nts wit h a m p utati o n will be s u m marize d b y treat m e nt gr o u p a n d b y P T 
a n d L L T d uri n g t he st u d y (ie, re gar dless of o n- or p ost-treat me nt).  A m p ut ati o n is a pr oce d ure 
rec or d e d i n e- C R F “ Ot her Pr oce d ur es relat e d t o A m p utati o n”. Patie nts w h o ha d a pr oce d ure 
relate d t o a m p utati o n will be liste d. 
T he n u m ber ( %) of p atie nts wit h a n “ A E lea di n g t o a n a m p utati o n” will be s u m mari ze d b y 
treat me nt gr o u p a n d b y P T.  T he “ A E lea di n g t o a n a m p utati o n” is deter mi ne d b y t h e A E 
i de ntifier rec or de d i n e-C R F “ Ot her Pr o ce d ures rel ate d t o A m p utati o n” w he n “ A E c orrecti o n” is 
c h ose n as t he reas o n f or t he a m p utati o n pr oce d ure.  
I n a d diti o n, t he n u m ber ( %) of patie nts wit h a n “ A E p ote ntiall y lea di n g t o a n a m p utati o n” will be 
s u m marize d b y treat me nt gr o u p a n d b y P T (as i de ntifie d i n Ta ble  3 i n Secti o n  2. 1. 4. 2 ; t hese P Ts 
i n Ta ble  3 wer e re q u este d b y t he E ur o pea n M e dici nes A ge nc y/ P har mac o vi gila nce Ris k 
Assess me nt C o m mittee[ E M A/ P R A C] Assess me nt Re p ort 9 Fe br u ar y 2 0 1 7).  Ass ociate d list will 
be pr o vi de d as w ell, wit h patie nts w h o ha d a n a m p utati o n pr oce d ure fla g ge d. “ A E p ote ntiall y 
lea di n g t o a n a m p utati o n” re pr ese nts t he c o n diti o n t hat ma y p ote ntiall y lea d t o t he a m p utati o n 
pr oce d ur e, b ut n ot i n all cases a n a m p utati o n has occ urre d (as p er t he E M A/ P R A C re q uest).  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 6  of 8 1  
 A n alysis of pretre at m e nt a n d p osttre at m e nt A Es  
•  
All pretreat me nt A Es b y pri mar y S O C a n d P T, s h o wi n g t he n u m ber ( %) of patie nts wit h at 
least 1 pretreat me nt A E, s orte d b y t h e i nter nati o nall y a gree d S O C or der a n d decreasi n g 
i nci de nce of P Ts wit hi n eac h S O C i n t he s ota glifl o zi n 4 0 0 m g gr o u p. 
•  
All p osttreat me nt A Es b y pri mar y S O C a n d P T, s h o wi n g t he n u m ber ( %) of patie nts wit h 
at least 1 p osttreat me nt A E, s orte d b y t he i nter nati o nall y a gree d S O C or d er a n d decreasi n g 
i nci de nce of P Ts wit hi n eac h S O C i n t he s ota glifl o zi n 4 0 0 m g gr o u p. 
Listi n gs  
S u p p orti ve A E listi n gs will be pr o vi de d f or all A Es, S A Es, a n d deat h, A Es lea di n g t o treat me nt 
disc o nti n uati o n a n d/ or deat h, a n d E O SI as a p pr o priate. Listi n g of all A Es, S A Es a n d A Es lea di n g 
t o treat me nt disc o nti n uati o n a n d/ or deat h will i ncl u de at least t he f oll o wi n g i nf or mati o n, s orte d b y 
treat me nt, patie nt i de ntifi cati o n, a n d o nset date: treat me nt, patie nt i de ntificati o n, c o u ntr y, a ge, 
ge n d er, r ace, B MI, pri mar y S O C, P T, re p orte d ter m, o nset date, st u d y d a y (relati ve d a y t o t he start 
date of d o u ble- bli n d treat me nt), A E d urati o n, d urati o n of e x p os ure, i nte nsit y, c orrecti ve treat me nt, 
acti o n ta ke n wit h I M P, d ate of treat me nt disc o nti n uati o n (if rele v a nt), rel ati o ns hi p t o I M P or 
NI M P, o utc o me, d ate of deat h (if a n y), seri o us ness, seri o us ness criteri a, a n d A E stat us (“ E” f or a 
T E A E; a n d “ P” f or a n o n -st u d y p ost-treat me nt A E). 
2. 4. 5. 3       D e at h s  
T he f oll o wi n g s u m maries of deat hs will be ge nerate d. 
•  
N u m ber ( %) of patie nts w h o die d b y st u d y p eri o d ( o n-st u d y, o n-treat me nt, p ost- st u d y). 
•  
Deat hs i n n o nra n d o mize d patie nts or ra n d o mize d b ut n ot treate d patie nts. 
•  
T E A Es lea di n g t o deat h ( deat h as a n o utc o m e o n t he A E e- C R F p a ge as re p orte d b y t h e 
I n v esti gat or) b y pri mar y S O C , H L G T, H L T, a n d P T s h o wi n g n u m ber ( %) of patie nts 
s orte d b y i nter nati o nall y a gree d S O C or d er, wit h H L G T, H L T, a n d P T prese nte d i n 
al p ha betical or d er wit hi n eac h S O C.  
2. 4. 5. 4       A n al y s e s of l a b or at or y v ari a bl e s  
La b orat or y p ara m eters will be gr o u pe d a n d s u m marize d b y bi ol o gical f u ncti o n as descri be d i n 
Secti o n  2. 1. 4. 4 . 
T he s u m mar y statistics (i ncl u di n g n u m ber, m ea n, me dia n, Q 1, Q 3, sta n dar d de viati o n, mi ni m u m 
a n d ma xi m u m) of all la b orat or y vari a bles (ce ntral la b orat or y val u es a n d c h a n ges fr o m bas eli ne) 
will be calc ulate d f or eac h a p plica ble visit or st u d y ass ess me nt (scree ni n g, baseli ne, eac h 
p ost baseli ne ti me p oi nt, last o n- treat me nt val u e) b y treat me nt gr o u p.   
T he i nci de nce of P C S As (list pr o vi de d i n A p pe n di x A ) at a n y ti me d uri n g t he T E A E peri o d will 
be s u m marize d f or eac h l a b orat or y test b y bi ol o gical f u ncti o n a n d treat me nt gr o u p w h ate ver t he 
baseli ne le vel a n d/ or acc or di n g t o t he f oll o wi n g b aseli ne stat us cate g ories:  
•  
N or mal/ missi n g.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 7  of 8 1  
•  
A b n or mal acc or di n g t o P C S A criteri o n or criteria.  
F or para meters f or w hi c h n o P C S A criteria are d efi ne d, si milar ta ble(s) usi n g t he n or m al ra n ge 
will be pr o vi de d. 
All meas ure me nts c ollecte d d uri n g t he T E A E p eri o d, i ncl u di n g val ues fr o m u nsc he d ule d visits, 
will be c o nsi dere d f o r t he P C S A s u m maries. T hese s u m maries will i ncl u de patie nts i n t he safet y 
p o p ulati o n w h o ha ve at l east 1 assess me nt perf or me d d uri n g t he T E A E peri o d. W he n a P C S A 
defi niti o n i n v ol ves a c ha n ge fr o m baseli ne v al ue, patie nts m ust als o ha ve a baseli ne val ue t o be 
i ncl u de d i n t he s u m maries, a n d w he n re q uire d b y t he defi niti o n of t he a b n or malit y, patie nts m ust 
als o ha ve a v aila ble la b or at or y n or mal ra n ges.  
A listi n g of patie nts wit h at least 1 p ost - baseli ne P C S A ( or o ut of n or mal ra n ge w he n n o P C S A 
criteri o n is defi ne d) will be pr o vi de d a n d will dis pla y t he e ntire patie nts’ pr ofile acr oss ti me f or all 
para meters bel o n gi n g t o t he c orr es p o n di n g bi ol o gi cal f u ncti o n. I n di vi d ual d ata listi n gs will 
i ncl u de t he f oll o wi n g fla gs w h e n a p plica ble: 
•  
Baseli ne v al ues will be fl a g ge d “ B”.  
•  
N or mal la b orat or y ra n ges, a vaila ble f or m ost la b orat or y para meters, will be i de ntifie d as 
U L N a n d L L N. Bas eli ne, last o n -treat me nt val ue, a n d i n di vi d ual data will be fla g ge d “ L” 
if t he val ue is bel o w t he L L N a n d will be fla g ge d “ H” if it is a b o ve the U L N.  
•  
La b orat or y P C S A criteri a will be use d f or t he c orres p o n di n g l a b orat or y p ara meters. 
Val ues reac hi n g a P C S A li mit will be fla g ge d ( +, + +, -, or -- de p e n di n g u p o n t he directi o n 
a n d le vel of t he a b n or malit y). Fla gs f or W B C a n d differe ntial c o u nts will be deter mi ne d 
usi n g data e x presse d i n i nter nati o nal u nits.  
F or para meters w h ose P C S A criteria are m ulti ples of t he U L N, t he p ara meter’s val ue will als o be 
e x presse d as a m ulti ple of t he U L N i n t he i n di vi d ual data pr o vi de d. 
Dr u g -i n d uce d liver i nj ury 
T he li v er f u ncti o n tests, na mel y A S T, A L T, A L P, a n d t otal bilir u bi n, are use d t o assess p ossi ble 
dr u g-i n d uce d li ver t o xicit y.  T he pr o p orti o n of pati e nts wit h P C S A val ues at a n y p ost b aseli ne visit 
b y bas eli ne stat us will be dis pla ye d b y treat me nt gr o u p f or eac h para met er.  T he pr o p orti o n of 
patie nts wit h P C S A val ues at a n y p ost baseli ne visit will als o be dis pla ye d b y d urati o n of e x p os ure 
f or eac h treat me nt gr o u p ( o nl y if a ta b ulati o n s u m mar y is n ecess ar y).  
Listi n g of p ossi ble H y’s l a w cas es i de ntifie d b y treat me n t gr o u p (e g, p atie nts wit h a n y ele vate d 
A L T > 3  ×  U L N, a n d ass o ciate d wit h a n i ncrease i n bilir u bi n ≥2 ×  U L N) wit h A L T, A S T, A L P, 
t otal bilir u bi n, a n d t he f oll o wi n g c o m ple me ntar y para meters (if a v aila ble):  c o nj u gate d bilir u bi n 
a n d pr ot hr o m bi n ti me/i nter nati o nal n or malize d rati o ,creati ne p h os p h o ki nas e, ser u m creati ni ne, 
c o m plete bl o o d c o u nt, a nti- H A V I g M, a nti -H Bc I g M, a nti -H C V a n d H C V R N A , a nti -C M V I g M 
a n d a nti- H E V I g M a nti b o dies, a ut o-a nti b o dies: a nti- n uclear, a nti -D N A, a nti -s m o ot h m uscle, 
E pstei n -Barr vi r us, her pes vir uses, a n d a nti-L K M.   




St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 4 9  of 8 1  
2. 5              D A T A H A N D LI N G C O N V E N TI O N S  
2. 5. 1        G e n er al c o n v e nti o n s  
T he f oll o wi n g f or m ulas will be use d f or c o m p utati o n of para met ers. 
H b A 1c  
T he f or m ula t o c o n v ert H b A 1c fr o m Dia b etes C o ntr ol a n d C o m plicati o ns Trial ( D C C T) ali g ne d 
val ue t o I nter n ati o nal Fe derati o n of Cli nical C he mistr y a n d La b orat or y M e dici ne (I F C C) 
sta n dar dize d val ue is, 
I F C C-H b A 1c ( m m ol/ m ol) = [ D C C T -H b A 1c ( %) - 2. 1 5] × 1 0. 9 2 9. 
Re n al f u ncti o n f or m ul as  
T he esti mate d G F R ( m L/ mi n/ 1. 7 3 m 2) will be calc ulate d usi n g t he 4 v aria bl e M o dificatio n of Diet 
i n Re nal Disease ( M D R D) f or m ula:  
Sta n dar d u nit: e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 ×  [ Ser u m Creati ni ne ( µ m ol/ L)/ 8 8. 4] -1. 1 5 4 ×  
A ge  ( year) -0. 2 0 3 ×  1. 2 1 2 (if Blac k) ×  0. 7 4 2 (if fe m ale). 
 
C o n ve nti o nal u nit: e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 × Ser u m Creati ni ne ( m g/ d L) -1. 1 5 4 × A ge ( year) 
-0. 2 0 3 × 1. 2 1 2 (if Blac k) × 0. 7 4 2 (if Fe m ale). 
C alc ul ati o n of L D L - C 
W he n T G is l o wer t ha n or e q ual t o 4. 5 2 m m ol/ L ( 4 0 0 m g/ d L), L D L- C is calc ulate d usi n g t he 
Frie de wal d e q u ati o n as:  
•  
I n sta n d ar d u nit ( m m ol/ L), T C – H D L -C – T G/ 2. 1 7.  
•  
I n c o n ve nti o nal u nit ( m g/ d L), T C – H D L -C – T G/ 5.  
2. 5. 2        D at a h a n dli n g c o n v e nti o n s f or s e c o n d ar y effi c a c y v ari a bl e s  
Sc he d ule d meas ur e me nts (see Secti o n  2. 5. 4 ) of c o nti n u o us efficac y v aria bl es c ollecte d d uri n g t h e 
st u d y will be use d i n t he a nal ys es i ncl u di n g t h ose o btai ne d after I M P disc o nti n uati o n or 
i ntr o d ucti o n of resc u e t hera p y. C o nti n u o us sec o n dar y efficac y e n d p oi nts will be a nal yze d wit h 
missi n g val ues i m p ute d b y r etrie ve d dr o p o uts MI met h o d or b y t he was h o ut  MI met h o d acc or di n g 
t o t he criteri o n descri be d i n Secti o n  2. 4. 4. 1 . 
F or t he cate g ori cal sec o n dar y efficac y e n d p oi nts, data ha n dli n g c o n ve nti o ns are des cri be d i n 
Secti o n  2. 4. 4. 2 . 
2. 5. 3        Mi s si n g d at a  
F or cate g orical varia bl es, patie nts wit h missi n g data are n ot i ncl u d e d i n calc ulati o ns of 
perce nt a ges u nless ot her wise s pecifie d. W he n rel e va nt, t he n u m ber o f pati e nts wit h missi n g data 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 0  of 8 1  
is prese nte d. 
Deri ve d varia bles will be c o nsi dere d missi n g if a n y of t he ori gi nal varia bl es re q uire d t o calc ulate 
t he m are missi n g. F or e x a m ple, if eit her a baseli n e assess me nt or a n e n d p oi nt assess me nt is 
missi n g f or a p artic u lar p atie nt, t he n c ha n ge fr o m baseli ne at e n d p oi nt will be missi n g. De p e n di n g 
u p o n t he assess me nt, a nal yses ma y n ot i ncl u de all patie nts i n t he a nal ysis p o p ulati o n, beca use 
certai n patie nts i n t he i nt e n de d p o p ulati o n ma y ha ve missi n g data. 
I nc o m plete d ate of first a d mi nistr ati o n of d o u ble- bli n d I M P  
Date/ti me of first a d mi nistrati o n is t he first n o n -missi n g start date/ti me of d o u ble -bli n d I M P 
c o m plete d i n t he e- C R F “ First d ose I M P” m o d ule. 
F or patie nts w h o are ra n d o mize d a n d dis pe nse d a d o u ble- bli n d treat me n t kit b ut w h o are l ost t o 
f oll o w- u p j ust after Visit 3 (e g. o nl y t he treat me nt kit n u m ber is re p orte d i n t he e- C R F “ E x p os ure 
- treat me nt peri o d” m o d ule wit h o ut a n y d ose i nf or mati o n), t he date of first a d mi nistrati o n will be 
i m p ute d usi n g t he date of ra n d o mizati o n. W he n a patie nt is ra n d o mize d b ut n ot e x p ose d, “ N ot 
ta ke n” s h o ul d be tic ke d i n t he e- C R F “ First d ose I M P” m o d ule.  
H a n dli n g of c o m p ut ati o n of tre at m e nt d ur ati o n if I M P e n d of tre at m e nt d ate is missi n g  
F or t he calc ulati o n of t he treat me nt d urati o n, t he d ate of t he last d ose of d o u ble- bli n d I M P is e q ual 
t o t he date of last a d mi nistrati o n re p orte d o n t he e-C R F “ Treat me nt stat us li brar y” p a ge. If t his 
date is missi n g, t he e x p os ure d urati o n s h o ul d be l eft as missi n g. 
T he last d ose a d mi nistrati o n s h o ul d b e clearl y i de ntifie d i n t he e - C R F a n d s h o ul d n ot be 
a p pr o xi mate d b y t he last ret ur ne d p ac ka ge date.  
H a n dli n g of m e dic ati o n missi n g/ p arti al d ates  
N o i m p utati o n of me dicati o n start/e n d dates or ti mes will be perf or me d. If a me dicati o n date or 
ti me is missi n g or partiall y missi n g a n d it ca n n ot b e deter mi ne d w h et her it was ta ke n pri or or 
c o nc o mita ntl y, it will be c o nsi dere d a pri or, c o n c o mita nt, a n d p ost- treat me nt me dicati o n. 
H a n dli n g of A E/ hy p o glyce mi a wit h missi n g or p arti al d ate/ti m e of o nset  
Missi n g or part ial a d v ers e e ve nt/ h y p o gl yce mia o nset dates a n d ti mes will be i m p ute d s o t hat if t he 
partial a d verse e v e nt/ h y p o gl yce mia o nset date/ti me i nf or mati o n d oes n ot i n dicate t hat t he 
A E/ h y p o gl yce mia starte d pri or t o treat me nt or after t he treat me nt -e mer ge nt A E, t he a d verse 
e ve nt/ h y p o gl yce mia will be classifie d as treat me nt -e mer ge nt.   
N o i m p utati o n of a d verse e ve nt e n d dat es/ti mes will be perf or me d. T hese d ata i m p utati o ns are f or 
cate g orizati o n p ur p ose o nl y a n d will n ot be use d i n listi n gs.  N o i m p utati o n is pla n ne d f or 
date/ti me of a d vers e e v e nt res ol uti o n. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 1  of 8 1  
H a n dli n g of A Es/ hy p o glyce mi a w he n d ate a n d ti m e of first I M P a d mi nistr ati o n is missi n g  
W he n t he date a n d ti me of t he first d o u ble- bli n d I M P a d mi nistrati o n is missi n g, t he da y of 
ra n d o mizati o n s h o ul d be c o nsi dere d as t he start date of T E A E peri o d (see S ecti o n  2. 1. 4 ). T he 
e x p os ure d urati o n s h o ul d be ke pt as missi n g. 
H a n dli n g of A Es/ hy p o glyce mi a w he n I M P e n d of tre at m e nt d ate is missi n g  
F or t he p ur p os e of defi ni n g T E A E peri o d, t he d ate of t he last a d mi nistrati o n of d o u ble- bli n d I M P 
is e q ual t o t he date of t he last a d mi nistrati o n re p orte d o n t he e-C R F “ Treat me nt Stat us Li brar y” 
pa ge. If t h e date of l ast a d mi nistrati o n re p orte d o n t he e- C R F “ Treat me nt Stat us  Li brar y” p a ge is  
•  
Partiall y missi n g, it will be i m p ute d wit h a date as late as p ossi ble bef ore or o n t he date of 
last a vaila ble i nf or mati o n o n e- C R F “ C o m pleti o n of E n d of St u d y/ F oll o w- u p”.  
•  
C o m pletel y missi n g, it will be i m p ute d wit h t he date of last a v ai la ble i nf or mati o n o n 
e- C R F “ C o m pleti o n of E n d of St u d y/ F oll o w- u p ” pa ge.  
If t he date of last a vaila bl e i nf or mati o n o n e- C R F “ C o m pleti o n of E n d of St u d y/ F oll o w-u p ” pa ge 
is: 
•  
Partiall y missi n g, it will be i m p ute d wit h a date as late as p ossi ble.  
•  
C o m pletel y mi ssi n g, all a d verse e v e nts occ urre d o n or after t h e first a d mi nistrati o n of 
d o u ble- bli n d I M P will be c o nsi dere d as T E A Es.  
H a n dli n g of missi n g assess m e nt of rel ati o ns hi p of A Es t o I M P  
If t he assess me nt of t he r elati o ns hi p t o I M P is missi n g, t he relati o ns hi p t o I M P has t o be ass u me d 
a n d t he A E c o nsi dere d as s uc h i n t he fre q u e nc y ta bles of p ossi bl y relate d A E, b ut n o i m p utati o n 
s h o ul d be d o ne at t he dat a le vel. 
H a n dli n g of missi n g severity/ gr a des of A E  
If t he se verit y/ gr a de is missi n g f or 1 of t h e treat m e nt-e mer ge nt occ urre n ces of a n A E, t he 
ma xi mal se verit y o n t he r e mai ni n g o cc urre nces will be c o nsi dere d. If t he se verit y is missi n g f or 
all t he occ urre nces, a “ missi n g” cate g or y will be a d de d i n t he s u m mar y ta bl e.  
H a n dli n g of p ote nti ally cli nic ally si g nific a nt a b n or m alities  
If a patie nt h as a missi n g baseli ne he will be gr o u p e d i n t he cate g or y “ n or m al/ missi n g at 
baseli ne.”  
F or P C S As wit h 2 c o n diti o ns, o ne base d o n a c ha n ge fr o m baseli ne v al ue or a n or mal ra n ge a n d 
t he ot her o n a t hr es h ol d val ue, wit h t he first c o n diti o n bei n g missi n g, t he P C S A will be base d o nl y 
o n t he sec o n d c o n diti o n. 
F or a P C S A defi ne d o n a t hres h ol d a n d/ or a n or m al ra n ge, t his P C S A will be deri ve d usi n g t his 
t hres h ol d if t he n or mal ra n ge is missi n g; e g, f or e osi n o p hils t he P C S A is > 0. 5 GI G A/L or > U L N 
if U L N ≥0. 5 GI G A/ L. W he n U L N is missi n g, t he val ue 0. 5 s h o ul d be use d. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 2  of 8 1  
Meas ure me nts fla g ge d as i n vali d b y t he la b orat or y will n ot be s u m marize d or ta ke n i nt o acc o u nt 
i n t he c o m p utati o n of P C S A val ues. 
Li n ke d A Es t h at w orse ne d or bec a m e seri o us  
A n  A E t hat w orse n e d or beca me s eri o us will ha ve a se parate rec or d i n t he data fr o m t he ori gi nal 
e ve nt rec or d wit h a n A E i de ntificati o n n u m ber t hat li n ks t he ne w rec or d t o t he ori gi n al rec or d. A n 
A E t hat w orse n e d or beca me seri o us will be c o nsi dere d a n e w rec urri n g A E i n t he s u m mar y of 
rec urre nt e v e nts or i n t he s u m mar y of e ve nts b y ti me i nter vals. 
H a n dli n g of missi n g d at a f or c o nti n u o us effic acy e n d p oi nts  
See Secti o n  2. 4. 4. 1  a n d Secti o n  2. 4. 4. 2 . 
H a n dli n g of missi n g d at a f or c ate g oric al effic acy e n d p oi nts  
See Secti o n  2. 4. 4. 2 . 
2. 5. 4        Wi n d o w s f or ti m e p oi nt s / M e a s ur e m e nt s f or a n al y s e s 
T he f oll o wi n g ste ps will deci de h o w t he s c he d ule d a n d/ or u nsc he d ule d visits will be use d i n t he 
a nal ys es f or effi cac y v ari a bles a n d t he b y -visit s u m maries f or safet y vari a bles (cli nical la b orat or y 
data i n Secti o n  2. 1. 4. 4  a n d vital si g ns i n  Secti o n  2. 1. 4. 5 ). 
Ste p 1 A sc he d ule d meas ure me nt will be use d if it is a vaila ble; ot her wise, a n u nsc he d ule d 
meas ure me nt (i n cl u di n g t he e n d of treat me nt/st u d y visit f or t h ose pre mat urel y disc o nti n ue d) will 
be use d if it ha p pe ns t o b e o n t he sa me dat e as t he date of t he sc h e d ule d visit. 
Ste p 2 After Ste p 1, if t here are still n o meas ure m e nt f or a gi ve n p ara m eter at a sc he d ule d visit, 
t he a nal ysis wi n d o w bel o w (Ta ble  4) will be a p plie d t o re-all ocate a p ost - b aseli ne u nsc he d ul e d 
meas ure me nt t o a s c he d ule d meas ure m e nt.  
T a bl e  4 - A n al y s e s wi n d o w d efi niti o n  
S c h e d ul e d vi sit p o st b a s eli n e  
T ar g et e d st u d y d a y  
A n al y si s wi n d o w i n st u d y d a y s  
W e ek 4 ( Visit 5)  
2 8  
2 t o 5 5  
W e ek 1 2 ( Visit 7)  
8 4  
5 6 t o 1 0 4  
W e ek 1 8 ( Visit 8)  
1 2 6  
1 0 5 t o 1 5 3  
W e ek 2 6 ( Visit 9)  
1 8 2  
1 5 4 t o 2 2 7  
W e ek 3 9 ( Visit 1 0)  
2 7 3  
2 2 8 t o 3 1 8  
W e ek 5 2 ( Visit 1 1)  
3 6 4  
3 1 9  t o 4 0 9  
W e ek  6 5 ( Visit 1 2)  
4 5 5  
4 1 0 t o 5 0 2  
W e ek 7 9 ( Visit 1 3)  
5 5 1  
≥5 0 3  
St u dy d ays are c alc ul at e d fro m t h e d ay of first a d mi nistrati o n of d o u bl e -bli n d I M P; t h e d ay of first a d mi nistrati o n of I M P ( or t h e d ay of 
ra n d o miz ati o n if n ot ex p os e d) is D ay 1. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 3  of 8 1  
After a p pl yi n g t he a b o ve ti me wi n d o ws, if m ulti ple assess me nts are ass oci ate d t o t he sa me ti me 
p oi nt, t he cl osest fr o m t he tar gete d st u d y d a y will be use d. I n case of e q ualit y, t he last 
meas ure me nt will be use d. Re-all ocate d s c he d ule d visits (ie, visit n u m bers) s h o ul d be se q ue ntial if 
or dere d b y t h e date of m eas ure m e nt.  
After Ste p 2, if t her e ar e still n o meas ure me nt f or a gi v e n para meter at a sc he d ule d visit, data is 
c o nsi dere d missi n g f or efficac y a nal yses, w h ere m ulti ple i m p utati o n w o ul d be a p plie d as 
a p pr o priatel y as descri b e d i n Secti o n  2. 4. 4 . 
Refere nce d a y  
T he ref er e nce d a y f or t h e calc ulati o n of e xte nt of e x p os ure, ti me t o o nset, a n d relati ve da ys will be 
t he da y of t he first a d mi nistrati on of d o u ble- bli n d I M P or t he d a y of ra n d o mizati o n if n ot e x p ose d 
t o d o u ble- bli n d I M P, de n ote d as Da y 1. 
B aseli ne defi niti o n f or effic acy/s afety d at a  
F or t he safet y a n al ys es, t he baseli ne f or a gi ve n p ara meter is defi ne d as t he last a vaila ble 
meas ure me nt ( or t he a v er a ge of all meas ure me nts f or creati ni ne a n d e G F R), i ncl u di n g 
u nsc he d ule d ass ess me nts, assesse d pri or t o t he first a d mi nistrati o n of d o u ble- bli n d I M P. F or t he 
efficac y a n al ys es, t he bas eli ne f or a gi v e n para met er is defi ne d as t he last a vaila ble meas ure me nt 
( or t he a v era ge of all meas ure me nts f or creati ni ne a n d e G F R), i ncl u di n g u nsc he d ule d ass ess me nts, 
assesse d pri or t o t he first a d mi nistrati o n of d o u ble- bli n d I M P or t he last a v aila ble val ue ( or t he 
a vera ge of all meas ure m e nts f or cr eati ni ne a n d e G F R) bef ore ra n d o mizati o n if n ot treate d wit h 
d o u ble- bli n d I M P.  
S u m m ary st atistics by visit f or c o nti n u o us effic acy e n d p oi nts  
S u m mar y statistics ( n u m ber, mea n, S D, S E, mi ni m u m, me dia n, ma xi m u m) of c o nti n u o us efficac y 
e n d p oi nts ( o bser ve d d ata a n d c ha n ge fr o m bas eli ne) will be pr o vi de d at sc h e d ule d visits as per 
pr ot oc ol. S u m maries s h o wi n g dat a b y visit will be prese nte d acc or di n g t o t he visit n u m ber ( or 
re-all ocate d visit n u m ber) a n d la bele d wit h t he tar get e d a p pr o xi mate da y/ w ee k.  
L ast o n- tre at m e nt v al ue f or l a b or at ory v ari a bles a n d vit al si g ns 
T he last o n -treat me nt val ue is t he fi nal meas ure me nt assesse d d uri n g t he treat me nt e p oc h, 
re gar dl ess of t he i ntr o d ucti o n of resc ue t hera p y, i n cl u di n g meas ure me nts at u nsc he d ule d visits. 
Please see d etails i n Secti o n  2. 1. 4  a n d Secti o n  2. 4. 5 . 
Dis pl ay of s afety d at a by visit (l a b or at ory v ari a bles a n d vit al si g ns)  
Descri pti ve statistics ( n u m ber, mea n, S D, mi ni m u m, me dia n, ma xi m u m) of q ua ntitati ve 
la b orat or y varia bles a n d vital si g ns ( o bser v e d data a n d c ha n ge fr o m bas eli ne) d uri n g t he T E A E 
peri o d will be pr o vi de d at sc he d ule d visits. I n a d diti o n, t hese s u m maries will als o i ncl u de a r o w 
f or t he ‘last val u e o n-treat me nt’ t o descri be t he last a vaila ble o n-treat me nt val ue (see a b o ve). 
S u m maries s h o wi n g data b y visit will be prese nte d acc or di n g t o t he visit n u m ber ( or re -all ocate d 
visit n u m ber, see Secti o n  2. 5. 4 ) a n d la bele d wit h t he tar gete d a p pr o xi mate da y/ w ee k. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 4  of 8 1  
As s pecifie d i n t he st u d y pr ot oc ol, la b orat or y d ata fr o m sc he d ule d visits are re p orte d b y ce ntral 
la b orat ories. T h e l ocal r es ults will n ot be use d i n t he effi cac y a nal yses or i n t he definiti o n of 
baseli ne f or b ot h safet y a n d efficac y a n al ys es. I n t he safet y a nal yses, f or para meters wit h P C S A 
defi ne d bas e d o n n or mal ra n ge, l ocal res ults will o nl y be us e d i n t he P C S A s u m mar y if t he y are 
acc o m pa ni e d b y a l ocal l a b orat or y n or m al ra n ge. F or para meters wit h P C S A n ot defi ne d bas e d o n 
n or mal ra n ge, l o cal res ults will be use d i n t he P C S A s u m mar y as a p pr o priat el y.  
W he n a patie nt has m ore t ha n 1 meas ure m e nt fr o m t he ce ntral la b orat or y f or t he sa me la b or at or y 
para meter o n t he sa me d ate, t he a ver a ge of  t he meas ure me nts will be use d. F or t he sa m e 
la b orat or y para meter, if a patie nt has m ore t ha n 1 meas ure me nt o n differe nt dates f or t he sa m e 
sc he d ule d visit, t he val ue cl osest t o t he date of t he visit will be use d f or t he sc he d ule d visit. W he n 
t he val ues f or t he s a me s c he d ule d visit are e q ui dista nt, t he last val ue s h o ul d be use d f or t h e 
sc he d ule d visit. Si milar r ules will be a p plica ble t o a patie nt w h o has m ore t ha n 1 set of 
meas ure me nts f or t he sa me vital si g n para meter (ie, S B P, D B P, or H R) o n t he sa me date.  
2 6- wee k d o u ble bli n d c ore tre at m e nt peri o d  
T he 2 6- wee k d o u ble- bli n d c ore tr eat me nt peri o d is t he ti me fr o m first a d mi nistrati o n of 
d o u ble- bli n d I M P t o t he l ast a d mi nistrati o n of d o u ble- bli n d I M P o n or b ef ore Visit 9/ Wee k 2 6 ( or 
Da y  1 8 2 if Visit 9/ Wee k 2 6 date is missi n g). T his is f or a nal yzi n g sel ecte d efficac y para meters 
(e g, res c ue d patie nts) d uri n g c or e treat me nt peri o d.  
T E A E peri o d f or t he 2 6- wee k d o u ble bli n d c ore tre at m e nt peri o d  
T he T E A E peri o d f or c or e treat me nt peri o d is ( 1) t he ti me fr o m t he first a d mi nistrati o n of t he 
d o u ble- bli n d I M P u p t o 1 0 da ys ( 1 da y f or h y p o gl yce mia) after t he l ast a d mi nistrati o n of I M P if 
t he patie nt disc o nti n ue d treat me nt o n or b ef ore Visit 9 ( or Da y  1 8 2 if Visit 9 date is missi n g), or 
( 2) t he ti me fr o m t he first a d mi nistrati o n of t he d o u ble-bli n d I M P t o t he a d mi nistrati o n at Visit 
9/ Wee k 2 6 ( or Da y 1 8 2 if Visit 9/ Wee k 2 6 date is missi n g) if t he patie nt re mai ne d treate d b e y o n d 
Visit 9/ Wee k 2 6. T his is f or t he p ur p ose of safet y a nal ys es d uri n g t he c ore treat me nt peri o d. 
Ti m e t o eve nt a n alysis   
F or ti me t o e ve nt a n al ysis/ K M pl ot, ti me t o e ve nt (e g, treat me nt disc o nti n uati o n, resc ue t h era p y, 
h y p o gl yce mia, etc) is d efi ne d as t he n u m ber of d a ys fr o m t he date of t h e first a d mi nistrati o n of 
d o u ble- bli n d I M P ( or t he date of r a n d o mizati o n if n ot e x p ose d) t o t he start date of t he first 
occ urr e nce of t he e v e nt d uri n g t he 7 9- wee k d o u ble- bli n d treat me nt peri o d.  
Patie nts w h o di d n ot e x perie nce a n y e v e nt d uri n g t he 7 9- wee k d o u ble- bli n d treat me nt peri o d are 
c o nsi dere d ce ns or e d o bser vati o ns. F or ti me t o treat me nt disc o nti n uati o n/resc ue t hera p y, ce ns ori n g 
date is t he date of E O T. F or ti me t o se vere or d o c u me nte d h y p o gl yce mia, ce ns ori n g date is dat e of 
E O T + 1 or d ate of E O S, w hic he ver is t he earliest. Date of E O S will be use d if date of E O T is n ot 
a vaila ble. Last c o ntact date will be use d if date of E O S is n ot a vaila ble.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 5  of 8 1  
2. 5. 5        U n s c h e d ul e d vi sit s  
U nsc he d ule d visit meas ure me nts of la b orat or y dat a, vital si g ns, a n d E C G will be use d f or 
c o m p utati o n of baseli ne, t he last o n- treat me nt val u e, P C S As a n d t he s hift s u m maries f or safet y or 
efficac y. T he y will be i ncl u de d i n t he b y- visit s u m maries if t he y are re -all ocate d t o sc he d ul e d 
visits (see Secti o n  2. 5. 4 ). 
2. 5. 6        P o oli n g of c e nt er s f or st ati sti c al a n al y s e s  
Ce nter will n ot be i ncl u de d i n t he statistical m o dels f or efficac y a nal yses. H o we ver, all ce nters 
wit hi n a c o u ntr y will be p o ole d, a n d c o u ntr y will be i ncl u de d as a fi x e d effect i n a para metric 
statistical m o del (e g, A N C O V A etc) f or pri mar y a n d sec o n dar y effi cac y e n d p oi nts. C o u ntries wit h 
fe wer t ha n 5 ra n d o mize d patie nts will be gr o u p e d, if patie nts fr o m gr o u pe d c o u ntries are still 
fe wer t ha n 5, t he y will t he n be f urt h er gr o u p e d wit h t he c o u ntr y wit h t he c o u ntr y wit h t he l o west 
n u m ber of patie nts t hat is 5 or m ore.  
2. 5. 7        St ati sti c al t e c h ni c al i s s u e s  
N o ne. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 6  of 8 1  
3                   I N T E RI M A N A L Y SI S 
N o f or mal i nteri m a nal ysis f or efficac y is pla n n e d f or t his st u d y. T he st u d y will n ot be ter mi nate d 
earl y f or e x celle nt effi cac y.  
A n i n de pe n de nt D ata M o nit ori n g C o m mittee ( D M C) will be use d t o m o nit or a n d assess t he s afet y 
of patie nts fr o m t his trial t hr o u g h p eri o dic re vi e w of t he acc u m ulate d safet y dat a pr o vi de d b y a n 
i n de pe n de nt statistical gr o u p. Relate d details are pr o vi de d i n separate d oc u me nts ( D M C c harter 
a n d D M C S A P).  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 7  of 8 1  
4                   D A T A B A S E L O C K  
T he data bas e is pla n ne d t o be l oc ke d a p pr o xi matel y 4 w ee ks after t he last p atie nt last visit.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 8  of 8 1  
5                   S O F T W A R E D O C U M E N T A TI O N  
All s u m maries a n d statistical a nal yses will  be ge nerate d usi n g S A S®  versi o n 9. 2 or hi g h er. 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 5 9  of 8 1  
6                   R E F E R E N C E S  
N o ne. 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 6 0  of 8 1  
7                   LI S T O F A P P E N DI C E S  
A p pe n di x A  P ote ntiall y cli nicall y si g nifica nt a b n or malities crit eria   
A p pe n di x B     List of P Ts f or select E O SIs ( Me d D R A v 2 2. 0)  
A p pe n di x C     S u m mar y of statisti cal a nal yses  
A p pe n di x D  St u d y fl o w c h art  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 6 1  of 8 1  
A p p e n di x A              P ot e nti all y cli ni c all y si g nifi c a nt a b n or m aliti e s crit eri a  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
( Fr o m B T D-0 0 9 5 3 6 M a y 2 1, 2 0 1 4)  
 
 
P ar a m et er  
P C S A  
C o m m e nt s  
 
 
Cli ni c al C h e mi stry  
 
 
A L T  
By distri b uti o n a n alysis :  
> 3 U L N  
> 5 U L N  
> 1 0 U L N  
> 2 0 U L N  
Enzy m es activiti es m ust b e ex pr ess e d i n 
U L N, n ot i n I U/ L.  
C o nc e pt p a p er o n DI LI – F D A dr aft G ui d a nc e 
Oct 2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
C at e g ori es ar e c u m ul ativ e.  
First r o w is m a n d at ory. R o ws f oll o wi n g o n e 
m e nti o ni n g z er o c a n b e d el et e d.  
 
 
A S T  
By distri b uti o n a n alysis :  
> 3 U L N  
> 5 U L N  
> 1 0 U L N  
> 2 0 U L N  
Enz y m es activiti es m ust b e ex pr ess e d i n 
U L N, n ot i n I U/ L.  
C o nc e pt p a p er o n DI LI – F D A dr aft G ui d a nc e 
Oct 2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
C at e g ori es ar e c u m ul ativ e.  
First r o w is m a n d at ory. R o ws f oll o wi n g o n e 
m e nti o ni n g z er o c a n b e d el et e d.  
 
 
Alk ali n e P h os p h at as e  
> 1. 5 U L N  
Enzy m es activiti es m ust b e ex pr ess e d i n 
U L N, n ot i n I U/ L.  
C o nc e pt p a p er o n DI LI – F D A dr aft G ui d a nc e 
Oct 2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
 
 
T ot al Bilir u bi n  
> 1. 5 U L N  
> 2 U L N  
M ust b e ex pr ess e d i n U L N, n ot i n µ m ol/ L or 
m g/ L. C at e g ori es ar e c u m u l ativ e. 
C o nc e pt p a p er o n DI LI – F D A dr aft G ui d a nc e 
Oct 2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
 
 
C o nj u g at e d Bilir u bi n  
> 3 5 % T ot al Bilir u bi n a n d T BI LI > 1. 5 U L N  
C o nj u g at e d bilir u bi n d os e d o n a c as e -by -c as e 
b asis.  
 
 
A L T a n d T ot al Bilir u bi n  
A L T > 3 U L N a n d T BI LI > 2 U L N  
C o nc e pt p a p er o n DI LI – F D A dr aft G ui d a nc e 
Oct 2 0 0 7.  
I nt er n al DI LI W G Oct 2 0 0 8. 
T o b e c o u nt e d wit hi n a s a m e tr e at m e nt 
p h as e, w h at ev er t h e i nt erv al b et w e e n 
m e as ur e m e nt.  
 
 
C P K  
> 3 U L N  
F D A F e b 2 0 0 5.  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 6 2  of 8 1  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
( Fr o m B T D-0 0 9 5 3 6 M a y 2 1, 2 0 1 4)  
 
 
P ar a m et er  
P C S A  
C o m m e nt s  
 
> 1 0 U L N  
A m J C ar di ol April 2 0 0 6.  
C at e g ori es ar e c u m ul ativ e.  
First r o w is m a n d at ory. R o ws f oll o wi n g o n e 
m e nti o ni n g z er o c a n b e d el et e d.  
 
C Lcr ( m L/ mi n)  
( Esti m at e d cr e ati ni n e cl e ar a nc e 
b as e d o n t h e C okcr oft -G a ult 
e q u ati o n)  
< 1 5 ( e n d st a g e r e n al dis e as e)  
≥1 5 - < 3 0 (s ev er e d ecr e as e i n G F R)  
≥3 0 - < 6 0 ( m o d er at e d ecr e as e i n G F R)  
≥6 0 - < 9 0 ( mil d d ecr e as e i n G F R)  
≥ 9 0 ( n or m al G F R)  
F D A dr aft G ui d a nc e 2 0 1 0  
Ph ar m ac oki n etics i n p ati e nts wit h i m p air e d 
r e n al f u ncti o n-st u dy d esi g n, d at a a n alysis, a n d 
i m p act o n d osi n g a n d l a b eli n g 
 
 
e G F R ( m L/ mi n/ 1. 7 3 m 2)  
( Esti m at e of G F R b as e d o n a n 
M D R D e q u ati o n)  
 
< 1 5 ( e n d st a g e r e n al dis e as e)  
≥1 5 - < 3 0 (s ev er e d ecr e as e i n G F R)  
≥3 0 - < 6 0 ( m o d er at e d ecr e as e i n G F R)  
≥6 0 - < 9 0 ( mil d d ecr e as e i n G F R)  
≥ 9 0 ( n or m al G F R)  
F D A dr aft G ui d a nc e 2 0 1 0  
Ph ar m ac oki n etics i n p ati e nts wit h i m p air e d 
r e n al f u ncti o n-st u dy d esi g n, d at a a n alysis, a n d 
i m p act o n d osi n g a n d l a b eli n g 
 
 
Cr e ati ni n e  
≥1 5 0 μ m ol/ L ( Ad ults)  
≥3 0 % c h a n g e fr o m b as eli n e  
≥1 0 0 % c h a n g e fr o m b as eli n e  
Be nic h o u C., 1 9 9 4.  
 
 
 
Uric Aci d  
Hy p er uric e mi a  
Hy p o uric e mi a  
 
> 4 0 8 μ m ol/ L  
< 1 2 0 μ m ol/ L  
H arris o n - Pri nci p l es of i nt er n al M e dici n e 1 7th 
Ed., 2 0 0 8.  
 
 
Bl o o d Ur e a Nitr o g e n  
≥1 7 m m ol/ L  
 
 
 
C hl ori d e  
< 8 0 m m ol/ L  
> 1 1 5 m m ol/ L  
 
 
 
S o di u m  
≤1 2 9 m m ol/ L  
≥1 6 0 m m ol/ L  
 
 
 
P ot assi u m  
< 3 m m ol/ L  
≥5. 5 m m ol/ L  
F D A F e b 2 0 0 5.  
 
 
T ot al C h ol est er ol  
≥7. 7 4 m m ol/ L  
T hr es h ol d f or t h er a p e utic  i nt erv e nti o n. 
 
 
Tri glyc eri d es  
≥4. 6 m m ol/ L  
T hr es h ol d f or t h er a p e utic i nt erv e nti o n.  
 
 
Li p as e mi a  
≥3 U L N  
 
 
 
A myl as e mi a  
≥3 U L N  
 
 
 
Gl uc os e  
Hy p o glyc a e mi a  
Hy p er glyc a e mi a  
 
≤3. 9 m m ol/ L a n d < L L N  
≥1 1. 1 m m ol/ L ( u nf ast e d); ≥7 m mol/ L (f ast e d)  
 
A D A M ay 2 0 0 5.  
A D A J a n 2 0 0 8.  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 6 3  of 8 1  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
( Fr o m B T D-0 0 9 5 3 6 M a y 2 1, 2 0 1 4)  
 
 
P ar a m et er  
P C S A  
C o m m e nt s  
 
 
H b A 1c  
> 8 %  
 
 
 
Al b u mi n  
≤2 5 g/ L  
 
 
 
C R P  
> 2 U L N or > 1 0 m g/ L (if U L N n ot pr ovi d e d)  
 F D A Se pt 2 0 0 5.  
 
 
H e m at ol o g y  
 
 
W B C  
< 3. 0 Gi g a/ L ( N o n -Bl ack); < 2. 0 Gi g a/ L ( Bl ack)  
≥1 6. 0 Gi g a/ L  
I ncr e as e i n W B C: n ot r el ev a nt. 
T o b e i nt er pr et e d o nly if n o diff er e nti al c o u nt 
av ail a bl e.  
 
 
Ly m p h ocyt es  
> 4. 0 Gi g a/ L  
 
 
 
N e utr o p hils  
< 1. 5 Gi g a/ L ( N o n -Bl ack); < 1. 0 Gi g a/ L ( Bl ack)  
I nt er n ati o n al C o ns e ns us m e eti n g o n dr u g-
i n d uc e d bl o o d cyt o p e ni as, 1 9 9 1. 
F D A crit eri a.  
 
 
M o n ocyt es  
> 0. 7 Gi g a/ L  
 
 
 
B as o p hils  
> 0. 1 Gi g a/ L  
 
 
 
E osi n o p hils  
> 0. 5 Gi g a/ L or > U L N (if U L N ≥0. 5 Gi g a/ L)  
H arris o n - Pri nci pl es of i nt er n al M e dici n e 1 7 th 
Ed., 2 0 0 8.  
 
 
H e m o gl o bi n  
≤1 1 5 g/ L ( M al e); ≤9 5 g/ L ( F e m ale)  
≥1 8 5 g/ L ( M al e); ≥1 6 5 g/ L ( F e m al e)  
 
D ecr e as e fr o m Bas eli n e ≥2 0 g/ L  
Crit eri a b as e d u p o n d ecr e as e fr o m b as eli n e 
ar e m or e r el ev a nt t h a n b as e d o n a bs ol ut e 
v al u e. Ot h er c at e g ori es f or d ecr e as e fr o m 
b as eli n e c a n b e us e d ( ≥3 0  g/ L, ≥4 0  g/ L, 
≥5 0  g/ L).  
 
 
H e m at ocrit  
≤0. 3 7 v/v ( M al e)  ; ≤0. 3 2 v/v ( F e mal e) 
≥0. 5 5 v/v ( M al e)  ; ≥0. 5 v/v ( F e m al e) 
 
 
 
R B C  
≥6 T er a/ L  
U nl ess s p ecific a lly r e q uir e d f or p artic ul ar dr u g 
d ev el o p m e nt, t h e a n alysis is r e d u n d a nt wit h 
t h at of H b. 
Ot h er wis e, c o nsi d er F D A crit eri a.  
 
 
Pl at el ets  
< 1 0 0 Gi g a/ L  
≥7 0 0 Gi g a/ L  
I nt er n ati o n al C o ns e ns us m e eti n g o n dr u g-
i n d uc e d bl o o d cyt o p e ni as, 1 9 9 1. 
 
 
Uri n al y si s  
 
 
p H  
≤4. 6  
≥8  
 
 
 
Vit al si g n s  
 
 
H R  
≤5 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 b p m  
T o b e a p pli e d f or all p ositi o ns (i ncl u di n g 
missi n g) exc e pt S T A N DI N G.  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 6 4  of 8 1  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
( Fr o m B T D-0 0 9 5 3 6 M a y 2 1, 2 0 1 4)  
 
 
P ar a m et er  
P C S A  
C o m m e nt s  
 
≥1 2 0 b p m a n d i ncr e as e fr o m b as eli n e ≥2 0 b p m  
 
S B P  
≤9 5 m m H g a n d d ecr e as e fr o m b as eli n e ≥2 0 m m H g  
≥1 6 0 m m H g a n d i ncr e as e fr o m b as eli n e ≥2 0 m m H g  
T o b e a p pli e d f or all p ositi o ns (i ncl u di n g 
missi n g) exc e pt S T A N DI N G.  
 
 
D B P  
≤4 5 m m H g a n d d ecr e as e fr o m b as eli n e ≥1 0 m m H g  
≥1 1 0 m m H g a n d i ncr e as e fr o m b as eli n e ≥1 0 m m H g  
T o b e a p pli e d f or all p ositi o ns (i ncl u di n g 
missi n g) exc e pt S T A N DI N G . 
 
 
Ort h ost atic Hy p ot e nsi o n  
Ort h ost atic S D B  
Ort h ost atic D B P  
 
 
≤- 2 0 m m H g  
≤- 1 0 m m H g  
 
 
 
W ei g ht  
≥5 % i ncr e as e fr o m b as eli n e  
≥5 % d ecr e as e fr o m b as eli n e  
F D A F e b 2 0 0 7.  
 
 
E C G  
 
R ef.: I C H E1 4 g ui d a nc e ( 2 0 0 5) a n d E 1 4 Q & A 
( 2 0 1 2), a n d C ar di ac Saf ety R es e arc h 
C o ns ort i u m W hit e Pa p er o n P R a n d Q R S 
( N a d a et al. A m H e art J. 2 0 1 3; 1 6 5( 4) : 4 8 9-
5 0 0)  
 
 
H R  
< 5 0 b p m  
< 5 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 b p m  
< 4 0 b p m  
< 4 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 b p m  
< 3 0 b p m  
< 3 0 b p m a n d d ecr e as e fr o m b as eli n e ≥2 0 b p m  
 
> 9 0 b p m  
> 9 0 b p m a n d i ncr e as e fr o m b as eli n e ≥2 0 b p m  
> 1 0 0 b p m  
> 1 0 0 b p m a n d i ncr e as e fr o m b as eli n e ≥2 0 b p m  
> 1 2 0 b p m  
> 1 2 0 b p m a n d i ncr e as e fr o m b as eli n e ≥2 0 b p m  
C at e g ori es ar e c u m ul ativ e  
 
 
 
 
 
 
C at e g ori es ar e c u m ul ativ e  
 
 
 
P R  
> 2 0 0 ms  
> 2 0 0 ms a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
> 2 2 0 ms  
> 2 2 0 ms a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
> 2 4 0 ms  
> 2 4 0 ms a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
C at e g ori es ar e c u m ul ativ e  
 
 
 
Q R S  
> 1 1 0 ms  
C at e g ori es ar e c u m ul ativ e  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 6 5  of 8 1  
 
C RI T E RI A f or P O T E N TI A L L Y C LI NI C A L L Y SI G NI FI C A N T A B N O R M A LI TI E S  
f or p h a s e 2/ 3 st u di e s ( o n c ol o g y e x c e pt e d) 
( Fr o m B T D-0 0 9 5 3 6 M a y 2 1, 2 0 1 4)  
 
 
P ar a m et er  
P C S A  
C o m m e nt s  
 
> 1 1 0 ms ec a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
> 1 2 0 ms  
> 1 2 0 ms a n d i ncr e as e fr o m b as eli n e ≥2 5 %  
 
Q T  
> 5 0 0 ms  
 
 
 
Q Tc  
A bs ol ut e v al u es ( ms)  
 
 
> 4 5 0 ms  
> 4 8 0 ms  
> 5 0 0 ms  
 
I ncr e as e fr o m b as eli n e 
I ncr e as e fr o m b as eli n e ] 3 0-6 0] ms  
I ncr e as e fr o m b as eli n e > 6 0 ms 
T o b e a p pli e d t o a ny ki n d of Q T c orr ecti o n 
f or m ul a.  
Abs ol ut e v al u es c at e g ori es ar e c u m ul ativ e  
 
Q Tc > 4 8 0 ms a n d ∆Q Tc > 6 0 ms ar e t h e 2 
P C S A c at e g ori es t o b e i d e ntifi e d i n i n divi d u al 
s u bj ects/ p ati e nts listi n gs. 
 
 
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
 
A p p e n di x B  Li st of P T s f or s el e ct E O SI s ( M e d D R A v 2 2. 0)  
E O SI  
Pr ef err e d 
T er m C o d e  
Pr ef err e d T er m  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 0 4 0 7 4  
B al a niti s c a n di d a  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 1 8 1 4 3  
G e nit al c a n di di a si s  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 4 7 7 8 4  
V ul v o v a gi n al c a n di di a si s  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 6 1 1 8 0  
G e nit al i nf e cti o n f u n g al  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 6 4 8 9 9  
V ul v o v a gi n al m y c oti c i nf e cti o n  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 6 5 5 8 2  
Ur o g e nit al i nf e cti o n f u n g al  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 7 1 2 0 9  
C a n di d a c er vi citi s  
G e nit al M y c oti c I nf e cti o n s  
1 0 0 7 9 5 2 1  
F u n g al b al a niti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 1 7 8 1  
C y stiti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 1 7 9 0  
C y stiti s e s c h eri c hi a  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 1 7 9 7  
C y stiti s kl e b si ell a  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 1 7 9 9  
C y stiti s p s e u d o m o n al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 7 5 2 5  
F u n g al c y stiti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 1 8 1 8 5  
G e nit o uri n ar y c hl a m y di a i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 2 3 4 2 4  
Ki d n e y i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 5 8 4  
P y eliti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 5 9 6  
P y el o n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 5 9 7  
P y el o n e p hriti s a c ut e  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 6 0 1  
P y el o n e p hriti s c hr o ni c  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 6 0 3  
P y el o n e p hriti s m y c o pl a s m al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 7 6 5 3  
P y o n e p hr o si s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 3 8 3 5 1  
R e n al a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 4 8 2 8  
T u b er c ul o si s of g e nit o uri n ar y s y st e m  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 2 4  
Ur et hr al a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 8 0  
Ur et hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 8 2  
Ur et hriti s c hl a m y di al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 8 3  
Ur et hriti s g o n o c o c c al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 4 9 0  
Ur et hriti s ur e a pl a s m al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 5 7 1  
Uri n ar y tr a ct i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 5 7 2  
Uri n ar y tr a ct i nf e cti o n e nt er o c o c c al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 6 7 0 4  
Ur o g e nit al tri c h o m o ni a si s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 8 3 0 2  
T u b ul oi nt er stiti al n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 8 7 0 9  
Ur o s e p si s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 8 8 3 7  
C y stiti s gl a n d ul ari s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 9 0 5 9  
Uri n ar y tr a ct i nf e cti o n f u n g al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 4 9 1 0 0  
P y el o c y stiti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 1 2 5 0  
Ur et eriti s  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 6 7  of 8 1  
Uri n a r y tr a ct i nf e cti o n s 
1 0 0 5 1 3 5 0  
C yt o m e g al o vir u s uri n ar y tr a ct i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 1 9 5 9  
Uri n ar y bl a d d er a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 2 2 3 8  
E s c h eri c hi a uri n ar y tr a ct i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 4 0 8 8  
Uri n ar y tr a ct i nf e cti o n b a ct eri al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 6 3 5 1  
E m p h y s e m at o u s c y stiti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 8 5 2 3  
Bl a d d er c a n di di a si s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 8 5 9 6  
R e n al c y st i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 5 9 5 1 7  
B a ct eri al p y el o n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s 
1 0 0 6 1 1 8 1  
G e nit o uri n ar y tr a ct g o n o c o c c al i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 1 1 8 2  
G e nit o uri n ar y tr a ct i nf e cti o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 1 3 9 5  
Ur et er a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 2 2 7 9  
Uri n ar y tr a ct i nf e cti o n p s e u d o m o n al  
Uri n ar y tr a ct i nf e cti o n s 
1 0 0 6 2 2 8 0  
Uri n ar y tr a ct i nf e cti o n st a p h yl o c o c c al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 4 8 2 5  
Uri n ar y tr a ct i nf e cti o n vir al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 4 9 2 1  
Uri n ar y tr a ct i nfl a m m ati o n  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 1 9 7  
C y stiti s vir al  
Uri n ar y tr a ct  i nf e cti o n s 
1 0 0 6 5 1 9 8  
C y stiti s b a ct eri al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 1 9 9  
C y stiti s h el mi nt hi c  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 2 1 3  
P y el o n e p hriti s vir al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 2 1 4  
P y el o n e p hriti s f u n g al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 5 8 2  
Ur o g e nit al i n f e cti o n f u n g al 
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 5 5 8 3  
Ur o g e nit al i nf e cti o n b a ct eri al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 6 7 5 7  
Uri n ar y tr a ct a b s c e s s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 6 8 8 2 2  
E m p h y s e m at o u s p y el o n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 7 0 3 0 0  
Str e pt o c o c c al uri n a r y tr a ct i nf e cti o n 
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 7 4 4 0 9  
E s c h eri c hi a p y el o n e p hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 7 5 0 6 3  
Ur et hriti s m y c o pl a s m al  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 7 8 6 6 5  
B a ct eri al ur et hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 8 1 1 6 3  
F u n g al ur et hriti s  
Uri n ar y  tr a ct i nf e cti o n s 
1 0 0 8 1 2 6 2  
C a n di d a ur et hriti s  
Uri n ar y tr a ct i nf e cti o n s  
1 0 0 8 2 0 4 0  
N e p hriti s b a ct eri al  
V ol u m e d e pl eti o n  
1 0 0 0 5 6 9 7  
Bl o o d o s m ol arit y i n cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 3 1  
Bl o o d pr e s s ur e a m b ul at or y d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 3 4  
Bl o o d pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 3 7  
Bl o o d pr e s s ur e di a st oli c d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 4 8  
Bl o o d pr e s s ur e i m m e a s ur a bl e  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 5 8  
Bl o o d pr e s s ur e s y st oli c d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 5 7 6 1  
Bl o o d pr e s s ur e s y st oli c i n s pir at or y d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 7 9 7 9  
C e ntr al v e n o u s pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 0 9 1 9 2  
Cir c ul at or y c oll a p s e  
V ol u m e d e pl eti o n  
1 0 0 1 2 1 7 4  
D e h y dr ati o n  
V ol u m e d e pl eti o n  
1 0 0 1 3 5 7 8  
Di z zi n e s s p o st ur al  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 6 8  of 8 1  
V ol u m e d e pl eti o n  
1 0 0 2 1 0 9 7  
H y p ot e n si o n  
V ol u m e d e pl et i o n 
1 0 0 2 1 1 3 7  
H y p o v ol a e mi a  
V ol u m e d e pl eti o n  
1 0 0 2 1 1 3 8  
H y p o v ol a e mi c s h o c k  
V ol u m e d e pl eti o n  
1 0 0 2 6 9 8 3  
M e a n art eri al pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 3 1 1 2 7  
Ort h o st ati c h y p ot e n si o n  
V ol u m e d e pl eti o n  
1 0 0 3 6 6 5 3  
Pr e s y n c o p e  
V ol u m e d e pl eti o n  
1 0 0 3 7 3 2 7  
P ul m o n ar y art eri al w e d g e pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 4 2 7 7 2  
S y n c o p e  
V ol u m e d e pl eti o n  
1 0 0 4 6 6 4 0  
Uri n e fl o w d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 4 7 2 3 5  
V e n o u s pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 4 7 2 3 9  
V e n o u s pr e s s ur e j u g ul ar d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 4 7 6 8 9  
V ol u m e bl o o d d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 5 0 7 6 0  
Bl o o d ur e a nitr o g e n/ cr e ati ni n e r ati o i n cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 5 0 9 0 5  
D e cr e a s e d v e ntri c ul ar pr el o a d  
V ol u m e d e pl eti o n  
1 0 0 5 3 3 5 6  
Bl o o d pr e s s ur e ort h o st ati c d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 5 9 8 9 5  
Uri n e o ut p ut d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 6 0 0 8 9  
L eft v e ntri c ul ar e n d -di a st oli c pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 6 0 2 3 1  
P ul m o n ar y art eri al pr e s s ur e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 6 3 0 8 0  
P o st ur al ort h o st ati c t a c h y c ar di a s y n dr o m e  
V ol u m e d e pl eti o n  
1 0 0 6 3 9 2 7  
Or t h o st ati c i nt ol er a n c e 
V ol u m e d e pl eti o n  
1 0 0 6 6 0 7 7  
Di a st oli c h y p ot e n si o n  
V ol u m e d e pl eti o n  
1 0 0 6 9 4 3 1  
Ort h o st ati c h e art r at e r e s p o n s e i n cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 6 9 5 8 3  
P ul s e v ol u m e d e cr e a s e d  
V ol u m e d e pl eti o n  
1 0 0 7 2 3 7 0  
Pr er e n al f ail ur e  
P a n cr e atiti s  
1 0 0 3 3 6 2 5  
P a n cr e ati c h a e m orr h a g e  
P a n cr e atiti s  
1 0 0 3 3 6 3 5  
P a n cr e ati c p s e u d o c y st  
P a n cr e atiti s  
1 0 0 3 3 6 3 6  
P a n cr e ati c p s e u d o c y st dr ai n a g e  
P a n cr e atiti s  
1 0 0 3 3 6 4 5  
P a n cr e atiti s  
P a n cr e atiti s  
1 0 0 3 3 6 4 7  
P a n cr e atiti s a c ut e  
P a n cr e atiti s  
1 0 0 3 3 6 4 9  
P a n cr e atiti s c hr o ni c  
P a n cr e atit i s 
1 0 0 3 3 6 5 0  
P a n cr e atiti s h a e m orr h a gi c  
P a n cr e atiti s  
1 0 0 3 3 6 5 4  
P a n cr e atiti s n e cr oti si n g  
P a n cr e atiti s  
1 0 0 3 3 6 5 7  
P a n cr e atiti s r el a p si n g  
P a n cr e atiti s  
1 0 0 4 8 9 8 4  
P a n cr e ati c a b s c e s s  
P a n cr e atiti s  
1 0 0 5 2 4 0 0  
O e d e m at o u s p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 5 6 2 7 7  
P a n cr e at or e n al s y n dr o m e  
P a n cr e atiti s  
1 0 0 5 6 9 7 5  
P a n cr e ati c p hl e g m o n  
P a n cr e atiti s  
1 0 0 5 6 9 7 6  
H er e dit ar y p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 5 6 9 7 7  
Al c o h oli c p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 5 8 0 9 6  
P a n cr e ati c n e cr o si s  
P a n cr e atiti s  
1 0 0 6 5 1 8 9  
P a n cr e atiti s h el mi nt hi c  
P a n cr e atiti s  
1 0 0 6 6 1 2 7  
I s c h a e mi c p a n cr e atiti s 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 6 9  of 8 1  
P a n cr e atiti s  
1 0 0 6 9 0 0 2  
A ut oi m m u n e p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 7 4 8 9 4  
Tr a u m ati c p a n cr e atiti s  
P a n cr e atiti s  
1 0 0 7 6 0 5 8  
H a e m orr h a gi c n e cr oti c p a n cr e atiti s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 3 1 9 2  
Art eri o v e n o u s fi st ul a t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 3 8 8 0  
A xill ar y v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 6 5 3 7  
B u d d -C hi ari s y n dr o m e  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 7 8 3 0  
C a v er n o u s si n u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 0 8 1 3 8  
C er e br al v e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 1 4 5 2 2  
E m b oli s m v e n o u s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 1 9 7 1 3  
H e p ati c v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 2 3 2 3 7  
J u g ul ar v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 2 7 4 0 2  
M e s e nt eri c v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 4 2 7 2  
P el vi c v e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 4 3 2 4  
P e nil e v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 6 2 0 6  
P ort al v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 7 3 7 7  
P ul m o n ar y e m b oli s m  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 7 4 2 1  
P ul m o n ar y mi cr o e m b oli  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 7 4 3 7  
P ul m o n ar y t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 7 4 5 9  
P ul m o n ar y v e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 8 5 4 7  
R e n al v ei n e m b oli s m  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 8 5 4 8  
R e n al v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 3 8 9 0 8  
R eti n al v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 1 6 5 9  
S pl e ni c v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 2 5 6 7  
S u p eri or s a gitt al si n u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 3 5 7 0  
T hr o m b o p hl e biti s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 3 5 8 1  
T hr o m b o p hl e biti s mi gr a n s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 3 5 9 5  
T hr o m b o p hl e biti s s u p erfi ci al  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 3 6 0 5  
T hr o m b o s e d v ari c o s e v ei n  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 4 4 5 7  
Tr a n s v er s e si n u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 7 1 9 3  
V e n a c a v a e m b oli s m  
V e n o u s t hr o m b o ti c e v e nt s 
1 0 0 4 7 1 9 5  
V e n a c a v a t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 7 2 4 9  
V e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 8 5 9 1  
P o st t hr o m b oti c s y n dr o m e  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 4 9 4 4 6  
S u b cl a vi a n v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 5 0 2 1 6  
P a g et -S c hr o ett er s y n dr o m e  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 5 0 9 0 2  
P o st o p er ati v e t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 5 1 0 5 5  
D e e p v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 5 3 1 8 2  
Art eri o v e n o u s gr aft t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 1 2 5 1  
I ntr a cr a ni al v e n o us si n u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 1 4 0 8  
V e n o u s t hr o m b o si s li m b  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 3 3 6 3  
Br a c hi o c e p h ali c v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 3 9 0 9  
P o st pr o c e d ur al p ul m o n ar y e m b oli s m  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 7 0  of 8 1  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 6 8 8 1  
D e e p v e i n t hr o m b o si s p o st o p er ati v e 
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 7 2 7 0  
T hr o m b o si s c or p or a c a v er n o s a  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 6 9 9 0 9  
M et a st ati c p ul m o n ar y e m b oli s m  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 7 2 0 5 9  
O v ari a n v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 7 4 3 4 9  
O p ht h al mi c v ei n t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 7 7 6 2 3  
P ort o s pl e n o m e s e nt eri c v e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 7 7 8 2 9  
Vi s c er al v e n o u s t hr o m b o si s  
V e n o u s t hr o m b oti c e v e nt s  
1 0 0 7 8 8 1 0  
H e p ati c v ei n e m b oli s m  
T h yr oi d c a n c er  
1 0 0 0 2 2 4 0  
A n a pl a sti c t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 1 6 9 3 5  
F olli c ul ar t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 2 7 1 0 5  
M e d ull ar y t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 3 3 7 0 1  
P a pill ar y t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 4 3 7 4 4  
T h yr oi d n e o pl a s m  
T h yr oi d c a n c er  
1 0 0 5 5 1 0 7  
T h yr oi d c a n c er m et a st ati c  
T h yr oi d c a n c er  
1 0 0 6 6 1 3 6  
H u ert hl e c ell c ar ci n o m a  
T h yr oi d c a n c er  
1 0 0 6 6 4 7 4  
T h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 7 0 5 6 7  
T h yr oi d c a n c er st a g e 0  
T h yr oi d c a n c er  
1 0 0 7 1 0 2 7  
T h yr oi d c a n c er st a g e I  
T h yr oi d c a n c er  
1 0 0 7 1 0 2 8  
T h yr oi d c a n c er st a g e II  
T h yr oi d c a n c er  
1 0 0 7 1 0 2 9  
T h yr oi d c a n c er st a g e III  
T h yr oi d c a n c er  
1 0 0 7 1 0 3 0  
T h yr oi d c a n c er st a g e I V  
T h yr oi d c a n c er  
1 0 0 7 2 1 6 2  
T h yr oi d c a n c er r e c urr e nt  
T h yr oi d c a n c er  
1 0 0 7 2 6 1 3  
T h yr oi d B -c ell l y m p h o m a  
T h yr oi d c a n c er  
1 0 0 7 3 1 5 3  
F a mili al m e d ull ar y t h yr oi d c a n c er  
T h yr oi d c a n c er  
1 0 0 7 6 6 0 3  
P o orl y diff er e nti at e d t h yr oi d c ar ci n o m a  
R e n al c ell c a n c er  
1 0 0 3 8 3 8 9  
R e n al c a n c er  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 0  
R e n al c a n c er r e c urr e nt  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 1  
R e n al c a n c er st a g e I  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 2  
R e n al c a n c er st a g e II  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 3  
R e n al c a n c er st a g e III  
R e n al c ell c a n c er  
1 0 0 3 8 3 9 4  
R e n al c a n c er st a g e I V  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 0  
R e n al c ell c ar ci n o m a r e c urr e nt  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 1  
R e n al c ell c ar ci n o m a st a g e I  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 2  
R e n al c ell c ar ci n o m a st a g e II  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 3  
R e n al c ell c ar ci n o m a st a g e III  
R e n al c ell c a n c er  
1 0 0 3 8 4 1 4  
R e n al c ell c ar ci n o m a st a g e I V  
R e n al c ell c a n c er  
1 0 0 5 0 0 1 8  
R e n al c a n c er m et a st ati c  
R e n al c ell c a n c er  
1 0 0 5 0 5 1 3  
M et a st ati c r e n al c ell c ar ci n o m a  
R e n al c ell c a n c er  
1 0 0 6 1 4 8 2  
R e n al n e o pl a s m  
R e n al c ell c a n c er  
1 0 0 6 7 9 4 4  
H er e dit ar y l ei o m y o m at o si s r e n al c ell c ar ci n o m a  
R e n al c ell c a n c er  
1 0 0 6 7 9 4 6  
R e n al c ell c ar ci n o m a  
R e n al c ell c a n c er  
1 0 0 7 3 2 5 1  
Cl e ar c ell r e n al c ell c ar ci n o m a  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 7 1  of 8 1  
R e n al c ell c a n c er  
1 0 0 7 8 4 9 3  
P a pill ar y r e n al c ell c ar ci n o m a  
P a n cr e ati c c a n c er  
1 0 0 1 8 4 0 4  
Gl u c a g o n o m a  
P a n cr e ati c c a n c er  
1 0 0 2 2 4 9 8  
I n s uli n o m a 
P a n cr e ati c c a n c er  
1 0 0 2 5 9 9 7  
M ali g n a nt n e o pl a s m of i sl et s of L a n g er h a n s  
P a n cr e ati c c a n c er  
1 0 0 2 9 3 4 1  
N e ur ot e n si n o m a  
P a n cr e ati c c a n c er  
1 0 0 3 3 6 0 9  
P a n cr e ati c c ar ci n o m a  
P a n cr e ati c c a n c er  
1 0 0 3 3 6 1 0  
P a n cr e ati c c ar ci n o m a m et a st ati c  
P a n cr e ati c c a n c er  
1 0 0 3 3 6 1 3  
P a n cr e ati c c ar ci n o m a r e c urr e nt  
P a n cr e ati c c a n c er  
1 0 0 4 1 3 2 9  
S o m at o st ati n o m a  
P a n cr e ati c c a n c er  
1 0 0 4 7 4 3 0  
Vi p o m a  
P a n cr e ati c c a n c er  
1 0 0 5 1 7 0 9  
G a stri n o m a m ali g n a nt  
P a n cr e ati c c a n c er  
1 0 0 5 2 7 4 7  
A d e n o c ar ci n o m a p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 5 5 0 0 6  
P a n cr e ati c s ar c o m a  
P a n cr e ati c c a n c er  
1 0 0 5 5 0 0 7  
C ar ci n oi d t u m o ur of t h e p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 5 9 3 2 0  
P a n cr e ati c c ar ci n o m a st a g e 0  
P a n cr e ati c c a n c er  
1 0 0 5 9 3 2 1  
P a n cr e ati c c ar ci n o m a st a g e I  
P a n c r e ati c c a n c er 
1 0 0 5 9 3 2 2  
P a n cr e ati c c ar ci n o m a st a g e II  
P a n cr e ati c c a n c er  
1 0 0 5 9 3 2 3  
P a n cr e ati c c ar ci n o m a st a g e III  
P a n cr e ati c c a n c er  
1 0 0 5 9 3 2 6  
P a n cr e ati c c ar ci n o m a st a g e I V  
P a n cr e ati c c a n c er  
1 0 0 6 1 9 0 2  
P a n cr e ati c n e o pl a s m  
P a n cr e ati c c a n c er  
1 0 0 6 7 5 1 7  
P a n cr e ati c  n e ur o e n d o cri n e t u m o ur  
P a n cr e ati c c a n c er  
1 0 0 6 8 9 0 9  
P a n cr e ati c n e ur o e n d o cri n e t u m o ur m et a st ati c  
P a n cr e ati c c a n c er  
1 0 0 6 9 3 4 5  
S oli d p s e u d o p a pill ar y t u m o ur of t h e p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 7 3 3 6 3  
A ci n ar c ell c ar ci n o m a of p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 7 3 3 6 4  
D u ct al a d e n o c ar ci n o m a of p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 7 3 3 6 5  
I ntr a d u ct al p a pill ar y-m u ci n o u s c ar ci n o m a of 
p a n cr e a s  
P a n cr e ati c c a n c er  
1 0 0 7 3 3 6 7  
P a n cr e at o bl a st o m a  
Bl a d d er c a n c er  
1 0 0 0 4 9 8 6  
Bl a d d er a d e n o c ar ci n o m a r e c urr e nt  
Bl a d d er c a n c er  
1 0 0 0 4 9 8 7  
Bl a d d er a d e n o c ar ci n o m a st a g e 0  
Bl a d d er c a n c er  
1 0 0 0 4 9 8 8  
Bl a d d er a d e n o c ar ci n o m a st a g e I  
Bl a d d er c a n c er  
1 0 0 0 4 9 8 9  
Bl a d d er a d e n o c ar ci n o m a st a g e II  
Bl a d d er c a n c er  
1 0 0 0 4 9 9 0  
Bl a d d er a d e n o c ar ci n o m a st a g e III  
Bl a d d er c a n c er  
1 0 0 0 4 9 9 1  
Bl a d d er a d e n o c ar ci n o m a st a g e I V  
Bl a d d e r c a n c er 
1 0 0 0 4 9 9 2  
Bl a d d er a d e n o c ar ci n o m a st a g e u n s p e cifi e d  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 3  
Bl a d d er c a n c er  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 5  
Bl a d d er c a n c er r e c urr e nt  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 6  
Bl a d d er c a n c er st a g e 0, wit h c a n c er i n sit u  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 7  
Bl a d d er c a n c e r st a g e 0, wit h o ut c a n c er i n sit u 
Bl a d d er c a n c er  
1 0 0 0 5 0 0 8  
Bl a d d er c a n c er st a g e I, wit h c a n c er i n sit u  
Bl a d d er c a n c er  
1 0 0 0 5 0 0 9  
Bl a d d er c a n c er st a g e I, wit h o ut c a n c er i n sit u  
Bl a d d er c a n c er  
1 0 0 0 5 0 1 0  
Bl a d d er c a n c er st a g e II  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 7 2  of 8 1  
Bl a d d er c a n c er  
1 0 0 0 5 0 1 1  
Bl a d d er  c a n c er st a g e III  
Bl a d d er c a n c er  
1 0 0 0 5 0 1 2  
Bl a d d er c a n c er st a g e I V  
Bl a d d er c a n c er  
1 0 0 0 5 0 5 6  
Bl a d d er n e o pl a s m  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 5  
Bl a d d er s q u a m o u s c ell c ar ci n o m a r e c urr e nt  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 6  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e 0  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 7  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e I  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 8  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e II  
Bl a d d er c a n c er  
1 0 0 0 5 0 7 9  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e III  
Bl a d d er c a n c er  
1 0 0 0 5 0 8 0  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e I V  
Bl a d d e r c a n c er 
1 0 0 0 5 0 8 1  
Bl a d d er s q u a m o u s c ell c ar ci n o m a st a g e 
u n s p e cifi e d  
Bl a d d er c a n c er  
1 0 0 0 5 0 8 4  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a  
Bl a d d er c a n c er  
1 0 0 5 1 6 9 0  
Uri n ar y bl a d d er s ar c o m a  
Bl a d d er c a n c er  
1 0 0 5 7 3 5 2  
M et a st ati c c ar ci n o m a of t h e bl a d d er  
Bl a d d er c a n c er  
1 0 0 6 6 7 4 9  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a st a g e 0  
Bl a d d er c a n c er  
1 0 0 6 6 7 5 0  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a r e c urr e nt  
Bl a d d er c a n c er  
1 0 0 6 6 7 5 1  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a st a g e I  
Bl a d d er c a n c er  
1 0 0 6 6 7 5 2  
Bl a d d er tr a n si ti o n al c ell c ar ci n o m a st a g e I V 
Bl a d d er c a n c er  
1 0 0 6 6 7 5 3  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a st a g e II  
Bl a d d er c a n c er  
1 0 0 6 6 7 5 4  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a st a g e III  
Bl a d d er c a n c er  
1 0 0 7 1 6 6 4  
Bl a d d er tr a n siti o n al c ell c ar ci n o m a m et a st ati c  
Bl a d d er c a n c er  
1 0 0 7 8 3 4 1  
N e ur o e n d o cri n e c ar ci n o m a of t h e bl a d d er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 3 0 8 4  
Ar efl e xi a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 3 1 7 8  
Art eri al t hr o m b o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 3 2 1 0  
Art eri o s cl er o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 3 2 2 2  
Art eri o s cl er oti c g a n gr e n e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 6 7 8 4  
B ur ni n g s e n s ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 7 9 0 4  
C ell uliti s e nt er o c o c c al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 7 9 0 5  
C ell uliti s g a n gr e n o u s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 7 9 2 1  
C ell uliti s st a p h yl o c o c c al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 0 7 9 2 2  
C ell uliti s str e pt o c o c c al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 1 2 1 7 4  
D e h y dr ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 1 2 6 6 5  
Di a b eti c g a n gr e n e  
P ot e nti all y l e a di n g t o a m p ut ati o n 
1 0 0 1 2 6 7 9  
Di a b eti c n e ur o p at hi c ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 1 2 6 8 0  
Di a b eti c n e ur o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 1 7 7 1 1  
G a n gr e n e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 0 9 3 7  
H y p o a e st h e si a  
P ot e nti all y l e a di n g t o  a m p ut ati o n  
1 0 0 2 1 1 3 7  
H y p o v ol a e mi a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 1 5 1 9  
I m p air e d h e ali n g 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 1 7 8 4  
I nf e ct e d s ki n ul c er 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 2 5 6 2  
I nt er mitt e nt cl a u di c ati o n 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 4 7 7 4  
L o c ali s e d i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 8 8 6 2  
N e cr o si s i s c h a e mi c  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 2 9 3 3 1  
N e ur o p at h y p eri p h er al  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 7 3  of 8 1  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 1 4 9  
O st eiti s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 5 2  
O st e o m y eliti s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 5 3  
O st e o m y eliti s a c ut e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 5 6  
O st e o m y eliti s c hr o ni c  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 6 2  
O st e o m y eliti s s al m o n ell a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 1 2 6 4  
O st e o n e cr o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 3 7 7 5  
P ar a e st h e si a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 4 5 6 8  
P eri p h er al c ol d n e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 4 5 7 6  
P eri p h er al i s c h a e mi a  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 4 6 2 0  
P eri p h er al s e n s or y n e ur o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 4 6 3 6  
P eri p h er al v a s c ul ar di s or d er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 6 1 5 5  
P o or p eri p h er al cir c ul ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 3 6 4 1 0  
P o st o p er ati v e w o u n d i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 0 0 2 6  
S e n s or y di st ur b a n c e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 0 8 4 0  
S ki n er o si o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 0 8 7 2  
S ki n i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 0 9 4 3  
S ki n ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 2 3 4 3  
S u b c ut a n e o u s a b s c e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 3 6 0 7  
T hr o m b o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 8 0 3 1  
W o u n d d e hi s c e n c e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 8 0 3 8  
W o u n d i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 4 9 9 2 7  
Dr y  g a n gr e n e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 0 4 7 3  
A b s c e s s li m b  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 0 5 0 2  
N e ur o p at hi c ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 1 5 4 8  
B ur n i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 2 4 2 8  
W o u n d  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 2 9 4 9  
Art eri al t h er a p e uti c pr o c e d ur e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 3 6 9 2  
W o u n d c o m pli c ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 3 7 1 6  
W o u n d n e cr o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 4 0 4 4  
Di a b eti c mi cr o a n gi o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 6 3 4 0  
Di a b eti c ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 6 4 1 8  
Art eri al b y p a s s o p er ati o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 6 6 7 3  
P eri p h er al s e n s ori m ot or n e ur o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 7 5 1 8  
P eri p h er al a rt er y a n gi o pl a st y 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 7 5 2 5  
P eri p h er al art er y o c cl u si o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 8 0 4 1  
W o u n d s e p si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 8 0 4 2  
W o u n d a b s c e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 9 2 4 5  
A n gi o p a t h y 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 9 3 8 5  
E xtr e mit y n e cr o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 9 4 4 2  
W o u n d i nf e cti o n st a p h yl o c o c c al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 5 9 4 4 4  
W o u n d i nf e cti o n p s e u d o m o n a s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 0 7 3 4  
Di a b eti c f o ot  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 0 8 0 3  
Di a b eti c f o ot i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 0 9 6 3  
Art eri al di s or d er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 0 9 6 5  
Art eri al st e n o si s  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 7 4  of 8 1  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 6 2 7  
A m p u t ati o n 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 6 5 5  
Art eri al gr aft  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 6 5 7  
Art eri al st e nt i n s erti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 6 6 6  
A ut o n o mi c n e ur o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 1 8 1 5  
Di a b eti c v a s c ul ar di s or d er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 1 9 8  
Mi cr o a n gi o p at h y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 2 5 5  
S oft ti s s u e i nf e cti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 5 8 5  
P eri p h er al art eri al o c cl u si v e di s e a s e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 5 9 9  
Art eri al o c cl u si v e di s e a s e  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 6 1 0  
I s c h a e mi c li m b p ai n 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 2 9 3 2  
W o u n d tr e at m e nt  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 4 2 5 0  
St a p h yl o c o c c al o st e o m y eliti s  
P ot e nti all y l e a di n g t o a m p ut ati o n 
1 0 0 6 4 6 0 1  
Ili a c art er y o c cl u si o n 
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 5 2 3 7  
O st e o m y eliti s b a ct eri al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 5 2 3 9  
O st e o m y eliti s f u n g al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 5 2 4 0  
W o u n d i nf e cti o n b a ct eri al  
P ot e nt i all y l e a di n g t o a m p ut ati o n 
1 0 0 6 5 2 4 2  
W o u n d i nf e cti o n f u n g al  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 8 6 5 3  
B o n e a b s c e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 6 9 3 7 9  
P eri p h er al art eri al r e o c cl u si o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 1 7 0  
S ki n w o u n d  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 5 7  
P eri p h er al art er y r e st e n o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 0  
P eri p h er al e n d art er e ct o m y  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 1  
P eri p h er al art er y b y p a s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 2  
P eri p h er al art er y st e nt i n s erti o n  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 3  
P eri p h er al art er y st e n o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 2 5 6 4  
P eri p h er al art er y t hr o m b o si s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 4 3 9 6  
P e n etr ati n g at h er o s cl er oti c ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 5 1 1 8  
S u b p eri o st e al a b s c e s s  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 5 7 1 4  
V a s c uliti c ul c er  
P ot e nti all y l e a di n g t o a m p ut ati o n  
1 0 0 7 6 2 4 6  
S p o nt a n e o u s a m p ut ati o n  
 
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
  
 
D at e of I s s u e : 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
  
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
 
A p p e n di x C  S u m m ar y  of st ati sti c al a n al y s e s  
E F FI C A C Y A N A L Y SI S  
E n d p o i nt 
A n al ysis  
p o p ul ati o n  
Pri m ar y  
a n al ysis  
S u p p orti ve  
a n al ysis  
S u b gr o u p  
a n al ysis  
Ot her  
a n al yses  
Pri m ary e n d p oi nt  
H b A 1c: C h a n g e fr o m 
B as eli n e at W e ek 2 6  
 
I T T 
A N C O V A ( wit h missi n g v al u es 
i m p ut e d by t h e r etri ev e d dr o p o uts 
i m p ut ati o n m et h o d or by w as h o ut 
MI m e t h o d u n d er M N A R 
fr a m e w ork): tr e at m e nt, 
r a n d o miz ati o n str at u m ( H b A1c 
/ m etf or mi n us e/ S B P at scr e e ni n g), 
a n d c o u ntry as fix e d eff ects, a n d 
b as eli n e H b A1c v al u e as a 
c ov ari at e 
Ti p pi n g p oi nt a n alysis;  
 
S u b gr o u ps: r ac e, 
et h nicity, a g e, g e n d er, 
b as eli n e B MI, 
b as eli n e H b A 1c, 
b as eli n e S B P, 
m etf or mi n us e at 
scr e e ni n g, b as eli n e 
e G F R, D ur ati o n of 
di a b et es, a n d c o u ntry  
 
S u m m ary st atistics f or o bs erv e d v al u es 
a n d c h a n g es fr o m b as eli n e by visit.  
Gr a p hic al pr es e nt ati o ns f or m e a n 
c h a n g es fr o m b as eli n e ( ± S E) a n d m e a n 
v al u es ( ± S E) by visit. 
By -visit s u m m ary a n d gr a p h excl u di n g 
m e as ur e m e nts aft er r esc u e t h er a py.  
 
Sec o n d ary e n d p oi nts  
F P G, b o dy w ei g ht: C h a n g e 
fr o m b as eli n e t o W e ek 2 6;  
S B P (f or p ati e nts wit h 
B as eli n e S B P ≥1 3 0  m m H g, 
all p ati e nts): C h a n g e fr o m 
B as eli n e t o W e ek 1 2  
I T T 
A N C O V A ( wit h missi n g v al u es 
i m p ut e d by t h e r etri ev e d dr o p o uts 
i m p ut ati o n m et h o d or by w as h o ut  
MI M et h o d u n d er M N A R 
fr a m e w ork): tr e at m e nt, 
r a n d o miz ati o n str at u m ( H b A1c 
/ m etf or mi n us e / S B P at 
scr e e ni n g), a n d c o u ntry as fix e d 
eff ects, a n d b as eli n e v al u e as a 
c ov ari at e 
N o  
N o  
S u m m ary st atistics f or o bs erv e d v al u es 
a n d c h a n g es fr o m b as eli n e by visit.  
Gr a p hic al pr es e nt ati o ns f or m e a n 
c h a n g es fr o m b as eli n e ( ± S E) a n d me a n 
v al u es ( ± S E) by visit. 
S B P will b e s u m m ariz e d d escri ptiv ely at 
e ac h visit f or t h os e wit h b as eli n e S B P 
≥1 4 0 m m H g  
Pr o p orti o n of p ati e nts wit h 
H b A 1c < 6. 5 %, < 7. 0 % at 
W e ek 2 6  
I T T 
C M H m et h o d str atifi e d o n 
r a n d o miz ati o n str at a ( H b A1c 
/ m etf or mi n us e / S B P at 
scr e e ni n g),  
C M H m et h o d str atifi e d o n 
r a n d o miz ati o n str at a 
( H b A1c / m etf or mi n us e/ 
S B P at scr e e n: excl u di n g 
N o  
By -visit s u m m ary a n d gr a p hs of H b A 1c 
r es p o n d ers ( < 6. 5 %, < 7 %). 
By -visit fr e q u e ncy s u m m ary a n d gr a p hs 
of H b A 1c r es p o n d ers ( < 6. 5 %, < 7 %) 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
  
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 7 6  of 8 1  
E n d p o i nt 
A n al ysis  
p o p ul ati o n  
Pri m ar y  
a n al ysis  
S u p p orti ve  
a n al ysis  
S u b gr o u p  
a n al ysis  
Ot her  
a n al yses  
p ati e nts wit h b as eli n e 
H b A 1c v al u es < 6. 5 % (f or 
< 6. 5 % r es p o n d ers) or 
< 7 % (f or < 7 % 
r es p o n d ers) r es p ectiv ely 
excl u di n g p ati e nts wit h b as eli n e H b A 1c 
v al u es < 6. 5 % or < 7 % r es p ectiv ely. 
Ot her e n d p oi nts  
S B P (f or p ati e nts wit h 
b as eli n e S B P < 1 3 0 m m H g), 
D B P, S er u m cr e ati ni n e, 
e G F R: c h a n g e fr o m B as eli n e  
IT T  
Su m m ary st atistics f or o bs erv e d 
v al u es a n d c h a n g es fr o m b as eli n e 
by visit.  
N o  
N o  
Gr a p hic al pr es e nt ati o ns f or m e a n 
c h a n g es fr o m b as eli n e ( ± S E) a n d m e a n 
v al u es ( ± S E) by visit as a p pr o pri at e. 
Pr o p orti o n of p ati e nts, wit h 
r e d ucti o n i n b o dy w ei g ht by 
≥2 %, ≥5 %, a n d ≥1 0 % fr o m 
B as eli n e; ac hi evi n g S B P 
< 1 3 0 m m H g wit h b as eli n e 
S B P  ≥1 3 0 m m H g; ac hi evi n g 
D B P < 8 0 m m H g wit h b as eli n e 
D B P ≥8 0  m m H g  
I T T 
By -visit fr e q u e ncy s u m m ary 
N o  
N o  
By -visit gr a p hic al pr es e nt ati o n as 
a p pr o pri at e  
Pr o p orti o n of p ati e nts 
r e q uiri n g r esc u e f or 
hy p er glyc e mi a  
 
Su m m ary st atistics  
N o  
N o  
K M pl ot; List of p ati e nts r esc u e d  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
  
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 7 7  of 8 1  
S A F E T Y A N A L Y S E S  
E n d p oi nt  
A n al ysis 
P o p ul ati o n  
Pri m ar y  
a n al ysis  
S u p p orti ve 
A n al ysis  
S u b gr o u p  
a n al ysis  
Ot her  
a n al yses  
Hy p o glyc e mi a  
S af ety  
F oll o w s af ety g ui d eli n es  
N u m b er ( %) of p ati e nts wit h a ny 
hy p o glyc e mi a, s ev er e 
hy p o glyc e mi a, d oc u m e nt e d 
sy m pt o m atic hy p o glyc e mi a 
d uri n g T E A E p eri o d, a n d 
i nci d e nc e r at es i n 1 0 0 p ati e nt-
y e ars. 
 
Sev er e hy p o glyc e mi a or 
d oc u m e nt e d sy m pt o m atic 
hy p o glyc e mi a by s u b gr o u ps: 
r ac e, a g e, g e n d er, m etf or mi n use  
K M pl ot ti m e t o first ev e nt of 
s ev er e hy p o glyc e mi a or 
d oc u m e nt e d sy m pt o m atic 
hy p o glyc e mi a  
D oc u m e nt e d sy m pt o m atic 
hy p o glyc e mi a m ay b e pr es e nt e d by 
< 3. 0 m m ol/ L ( < 5 4 m g/ d L) as 
a p pr o pri at e.  
A dv ers e Ev e nts  
S af ety  
F oll o w s af ety g ui d eli n es  
N o  
C o m m o n T E A Es by s u b gr o u ps: 
r ac e, a g e, g e n d er, b as eli n e S B P, 
m etf or mi n us e, b as eli n e e G F R  
T o b e u p d at e d f or E O SI  
Cli nic al l a b or at ory d at a  
S af ety  
F oll o w s af ety g ui d eli n es  
D escri ptiv e  
N o  
N o  
Vit al si g ns  
S af ety  
F oll o w s af ety g ui d eli n es  
D escri ptiv e  
N o  
N o  
E C G, P hysic al ex a mi n a ti o n 
S af ety  
F oll o w s af ety g ui d eli n es  
Fr e q u e ncy s u m m ary  
N o  
N o  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
  
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 7 8  of 8 1  
A p p e n di x D  St u d y  fl o w c h art 
 
S cr e e ni n g P eri o d  
D o u bl e -Bli n d C or e Tr e at m e nt P eri o d a  
D o u bl e -Bli n d E xt e n si o n 
P eri o d b  
F oll o w -u p  
S cr e e ni n g  
R u n -I n 
VI SI T  
1  
2  
3  
B a s eli n e  
4 
 
5  
6 c 
 
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4  
 
W e e k  
-4 
-2 
0  
1  
4  
8  
1 2  
1 8  
2 6  
3 9  
5 2  
6 5  
7 9  
8 1  
Da y ( wi n d o w [ d a y s])  
 
-1 4  
( ± 3) 
1 
(-) 
7  
( ± 3) 
2 8  
( ± 3) 
5 6 
( ± 3) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 4 
( ± 7) 
4 5 5  
( ± 7) 
5 5 1  
(-3 t o + 4)  
5 6 5  
( ± 3) 
I nf or m e d c o ns e nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n crit eri a 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Excl usi o n crit eri a  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
M e dic al/ S urgic al Hist ory  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
M e dic ati o n  Hist ory  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
B o dy wei g ht, h ei g ht d  
X  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
 
Vit al si g ns e  
X  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
 
P hysic al Ex a mi n ati o n:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co m pl et e  
X  
 
 
 
 
 
 
 
X  
 
 
 
X  
 
A b brevi at e d f 
 
X  
X  
 
X  
 
X  
X  
 
X  
X  
X  
 
 
Di et & ex ercis e i nstructi o n  
 
X  
X  
 
 
 
 
 
X  
 
X  
 
X  
 
I nstructi o n o n b asic G U hy gi e n e & 
hy drati o n  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
  
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 7 9  of 8 1  
 
S cr e e ni n g P eri o d  
D o u bl e -Bli n d C or e Tr e at m e nt P eri o d a  
D o u bl e -Bli n d E xt e n si o n 
P eri o d b  
F oll o w -u p  
S cr e e ni n g  
R u n -I n 
VI SI T  
1  
2  
3  
B a s eli n e  
4 
 
5  
6 c 
 
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4  
 
W e e k  
-4 
-2 
0  
1  
4  
8  
1 2  
1 8  
2 6  
3 9  
5 2  
6 5  
7 9  
8 1  
Da y ( wi n d o w [ d a y s])  
 
-1 4  
( ± 3) 
1 
(-) 
7  
( ± 3) 
2 8  
( ± 3) 
5 6 
( ± 3) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 4 
( ± 7) 
4 5 5  
( ± 7) 
5 5 1  
(-3 t o + 4)  
5 6 5  
( ± 3) 
I nt eractiv e r es p o ns e t ec h n ol o gy 
(I R T) c o nt act 
X  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
Ra n d o miz ati o n  
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
Dis p e ns e gl uc os e m et er  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Dis p e ns e di ary  
X  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
 
 
Coll ect/revi e w di ary  
 
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
 
I nstructi o n o n di a b etic k et o aci d osis 
sy m pt o ms,  
gl uc os e t esti n g  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Dis p e ns e I M P  
 
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
 
 
I M P acc o u nti n g & c o m pli a nc e 
 
 
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
 
Co nc o mit a nt M e dic ati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
S M B G g  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
1 2 -l e a d E C Gh  
X  
 
 
 
 
 
 
 
X  
 
 
 
X  
 
L a b or at ory t esti n g i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
He p atitis s erol o gy  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
F P G  
X  
 
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
 


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
  
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 8 0  of 8 1  
 
S cr e e ni n g P eri o d  
D o u bl e -Bli n d C or e Tr e at m e nt P eri o d a  
D o u bl e -Bli n d E xt e n si o n 
P eri o d b  
F oll o w -u p  
S cr e e ni n g  
R u n -I n 
VI SI T  
1  
2  
3  
B a s eli n e  
4 
 
5  
6 c 
 
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4  
 
W e e k  
-4 
-2 
0  
1  
4  
8  
1 2  
1 8  
2 6  
3 9  
5 2  
6 5  
7 9  
8 1  
Da y ( wi n d o w [ d a y s])  
 
-1 4  
( ± 3) 
1 
(-) 
7  
( ± 3) 
2 8  
( ± 3) 
5 6 
( ± 3) 
8 4 
( ± 3) 
1 2 6 
( ± 3) 
1 8 2 
( ± 3) 
2 7 3 
( ± 7) 
3 6 4 
( ± 7) 
4 5 5  
( ± 7) 
5 5 1  
(-3 t o + 4)  
5 6 5  
( ± 3) 
Hb A 1c  
X  
 
X  
 
X  
 
X  
 
X  
X  
X  
X  
X  
 
Cli nic al c h e mistry, h e m at ol o gy j 
X  
 
X  
 
 
 
X  
 
X  
X  
X  
X  
X  
 
F asti n g li pi ds  
X  
 
 
 
 
 
 
 
X  
 
X  
 
X  
 
Pre g n a ncy t est ( W O C B P) k  
X  
 
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
 
F S H a n d/ or estra di ol as n e e d e d k 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pl as m a c o nc e ntrati o n l 
 
 
 
 
X  
 
 
X  
X  
 
X  
 
X  
 
Uri n alysis (di pstick a n d 
microsc o py) m  
X  
 
X  
 
 
 
 
 
X  
 
 
 
X  
 
Ev al u at e f or glyc e mic resc u e  
 
 
 
T o b e ass ess e d a n d re p ort e d t hro u g h o ut t h e tre a t m e nt p eri o d 
 
Hy p o glyc e mi a  
T o b e ass ess e d a n d re p ort e d t hro u g h o ut t h e st u dy  
A Es/ S A Es/ A E SIs/ E O SIs  
T o b e ass ess e d a n d re p ort e d t hro u g h o ut t h e st u dy p  
a       If a p ati e nt disc o nti n u es tre at m e nt I M P e arly d uri n g t h e 2 6-W e ek C or e Tre at m e nt P eri o d, t h e p ati e nt will h av e a Pre m at ure E n d -of -Tre at m e nt ( E O T) Visit a n d a F oll o w -u p Visit 2  we eks aft er t h e l ast d os e of I M P. 
I n a d diti o n, ev ery eff ort will b e m a d e t o h av e all p ati e nts r et ur n t o t h e sit e at t h e ti m e c orres p o n di n g t o t h eir sc h e d ul e d visits, p artic ul arly t h e W e ek 2 6 Visit. If t h e p ati e nt d o es n ot a gre e t o a sit e visit, t h ey will b e 
c o nt act e d by t el e p h o n e t o i n q uire a b o ut s af ety st at us. If a p ati e nt disc o nti n u es (or c o m pl et es) tre at m e nt a n d st u dy at t h e s a m e ti m e,  a si n gl e visit will b e p erf or m e d usi n g t h e proc e d ure n or m ally pl a n n e d f or t h e 
E O T visit.  


St ati sti c al A n al y si s Pl a n  
V er si o n: 3  
 
  
 
D at e of I s s u e: 1 9 F e br u ar y 2 0 2 0  
L e xi c o n P h ar m a c e uti c al s Pr ot o c ol N o. E F C 1 4 8 3 5  
  
 
C o v a n c e St u d y I D: 0 0 0 0 0 0 1 5 4 2 5 7  
 
C O V A N C E I N C. C O N FI D E N TI A L  
P a g e 8 1  of 8 1  
b       If a p ati e nt c o m pl et es t h e C ore Tre at m e nt, b ut disc o nti n u es I M P d uri n g t h e Ext e nsi o n P eri o d, t h e p ati e nt will h av e a Pre m at ur e E O T Visit, a n d a F oll o w-u p Visit  2 we eks aft er t h e l ast d os e of I M P. Ev ery eff ort will 
b e m a d e t o h av e all p ati e nts ret urn t o t h e sit e at t h e ti m e c orres p o n di n g t o t h eir q u art erly visits (i e, ev ery 1 3 w e eks) d uri n g t h e Ext e nsi o n P eri o d. At t h e ti m e c orres p o n di n g t o t h eir W e ek 7 9 Visit, all att e m pts will b e 
m a d e t o c o nt act t h e p ati e nt t o i n q uire a b o ut s af ety st at us. If a p ati e nt disc o nti n u es (or c o m pl et es) tre at m e nt a n d st u dy at t h e s a m e ti m e, a si n gl e visit will b e p erf or m e d usi n g t h e proc e d ur e n or m ally pl a n n e d f or t h e 
E O T visit.  
c      A t Visits 4 ( W e ek 1), 6 ( W e ek 8) a n d 1 4 (2 w e eks aft er t h e l ast d os e of I M P) p ati e nts will b e c o nt act e d by t el e p h o n e, a n d n ot s e e n o n-sit e.  
d       Hei g ht t o b e m e as ure d o nly at scre e ni n g.  
e       Vit al si g n m e as ure m e nts (sitti n g bl o o d press ure a n d h e art r at e): 3 s e p arat e s e at e d bl o o d pr ess ure a n d h e art rat e m e as ure m e nts s h o ul d b e t ak e n wit h at l e ast 1 mi n ut e b et we e n r e a di n gs, f oll o wi n g a 5 -mi n ut e rest 
p eri o d a n d pri or t o p hl e b ot o my . 
f       T h e a b brevi at e d p hysic al ex a m s h o ul d f oc us o n c ardi ac a n d res pirat ory syst e ms, as w ell as a ny are as i m p ort a nt f or ass ess m e nt of a dv ers e ev e nts if n ec ess ary.  
g       Gl uc os e m et ers us e d f or S M B G dis pl ay res ults as pl as m a gl uc os e c o nc e ntrati o n. P ati e nts s h o ul d m e as ur e t h eir f asti n g pl as m a gl uc os e at l e ast 3 ti m es p er we ek (i ncl u di n g o n d ay of e ac h o n -sit e st u dy visit). Aft er 
Visit 9 ( W e ek 2 6), if f asti n g S M B G v al u es are < 1 2 0 m g/ d L, ov er a 2 -w e ek p eri o d, t h e I nv esti g at or c a n i nstr uct p ati e nts t o s elf -m o nit or bl o o d gl uc os e o nc e a we ek (o n d ay of o n -sit e st u dy visit f or we eks with o n -sit e 
st u dy visits). 
h       T h e 1 2 -l e a d E C G rec ordi n gs s h o ul d b e o bt ai n e d pri or t o I M P a d mi nistr ati o n. T h e E C G will b e ev al u at e d as “n or m al” or “a b n or m al”. 
i       All l a b orat ory ass ess m e nts occ ur pri or t o I M P a d mi nistrati o n o n t h e d ay of t h e visit.  
j       Cli nic al c h e mistry, h e m at ol o gy: pl e as e s e e list i n T a bl e 2 i n prot oc ol.  
k      S eru m pre g n a ncy t esti n g o nly at scre e ni n g; uri n e pr e g n a ncy t esti n g s u bs e q u e ntly. S er u m pre g n a ncy t est res ults m ust b e revi e w e d pri or t o t h e R u n -I n p h as e f or all W O C B P u nl ess t h ere is d oc u m e nt e d hist ory of 
m e n o p a us e (b as e d o n d oc u m e nt e d f ollicl e -sti m ul ati n g h or m o n e [ F S H] a n d estra di ol l ev els – if res ults n ot d oc u m e nt e d t h e n F S H a n d estr a di ol will b e t est e d at Scre e ni n g visit) or t h ey ar e s urgic ally st eril e. A ny 
p ositiv e uri n e t est res ults m ust b e c o nfir m e d b as e d o n s eru m pre g n a ncy t est. T h e I nv esti g at or m ay p erf or m a d diti o n al t ests at t h eir discreti o n or as r e q uire d by l oc al r e g ul ati o ns.  
l       Pre -d os e pl as m a c o nc e ntrati o n s a m pl es (i e, of s ot a glifl ozi n a n d s ot a glifl ozi n - 3- O-gl uc uro ni d e) s h o ul d b e dra w n wit h t h e ot h er l a b orat ory ass ess m e nts at W e ek 4, W e ek 1 8, W e ek, 2 6, W e ek 5 2, a n d W e ek 7 9. 
P ost -d os e pl as m a c o nc e ntr ati o n s a m pl es s h o ul d b e dr a w n 1 h o ur 3 0 mi n ut es aft er s ot a glifl ozi n a d mi nistrati o n at W e ek 2 6 a n d W e ek 7 9. T h e d at e a n d ti m e of t h e l ast i nt ak e of st u dy dru g pri or t o visits wh ere P K 
s a m pl es are t ak e n s h o ul d b e rec ord e d by t h e p ati e nt i n t h e p ati e nt di ary. P ati e nts s h o ul d b e re mi n d e d of t his at visits prec e di n g P K ti m e p oi nts t o e ns ure t h es e d et ails are c a pt ur e d. I n t h e c as e of pre m at ure I M P 
disc o nti n u ati o n, P K s a m pl es s h o ul d n ot b e dra w n at t h e pre m at ure E O T visit, n or at a ny s u bs e q u e nt visits.  
m     Uri n alysis p erf or m e d by t h e c e ntr al l a b orat ory i ncl u d es uri n e di pstick a n d microsc o py. Di pstick i ncl u d es ass ess m e nt of s p ecific gravity, p H, prot ei n, bl o o d, k et o n es, biliru bi n, uro bili n o g e n, nitrit e, a n d l e uk ocyt e 
est eras e. Microsc o py i ncl u d es d et ecti o n of f or m e d c ell ul ar el e m e nts, c asts, b act eri a, y e ast, p arasit es, a n d cryst als i n c e ntrif u g e d uri n e s e di m e nt. I n t h e ev e nt of a b n or m al uri n alysis fi n di n gs s us pici o us of uri n ary 
tract i nf ecti o n, uri n e c ult ur e s h o ul d b e p erf or m e d. P ositiv e uri n e c ult ur e d et er mi n ati o n will b e b as e d u p o n t h e crit eri a of t h e re p orti n g l a b orat ory. A d diti o n ally, uri n e c ult ure s h o ul d b e p erf or m e d if at a ny p oi nt t h e 
Pri nci p al I nv esti g at or s us p ects t h e pr es e nc e of a U TI.  
      
 
      
 
p       All S A Es, A Es, A E SIs, a n d E O SIs will b e c oll ect e d st arti n g wit h si g ni n g i nf or m e d c o ns e nt a n d c o nti n u e u ntil t h e e n d of t h e st u dy. All A Es t h at occ ur d uri n g tr e at m e nt s h o ul d b e f oll o we d u ntil st u dy c o m pl eti o n ( or 
u ntil p ati e nts l e av e t h e st u dy) or u ntil t h e ev e nt h as res olv e d, t h e c o n diti o n h as st a biliz e d, or t h e p ati e nt is l ost t o f oll o w- u p. All p ati e nts will h av e a f oll o w -u p visit 2 we eks aft er t h e l ast d os e of I M P t o c oll ect s af ety 
i nf or m ati o n.