Clinical trial NCT03315143
Conditions: Heart Failure Type 2 Diabetes Mellitus Chronic Kidney Diseases
Sponsor: Lexicon Pharmaceuticals
Start date: 2017-12-19; Completion date: 2020-07-08
Enrollment: 10584 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study was to compare the effect of sotagliflozin to placebo on total occurrences of cardiovascular (CV) death, hospitalization for heart failure \[HHF\], and urgent visit for heart failure \[HF\] in participants with type 2 diabetes, cardiovascular risk factors, and moderate to severely impaired renal function.

Detailed description:

Arms: arm 1: Sotagliflozin 200 mg tablet once daily, with possible up-titration in the first 6 months to 400 mg, for up to 28.9 months. arm 2: Matching placebo to sotagliflozin 200 mg once daily, with possible up-titration in the first 6 months to matching placebo to sotagliflozin 400 mg, for up to 29.6 months.
Interventions: intervention 1: Sotagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Sotagliflozin was administered as a tablet(s), orally once daily. intervention 2: Placebo was administered as a tablet(s) (identical to the sotagliflozin tablet in appearance), orally once daily.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter Study to Demonstrate the Effects of Sotagliflozin on 
Cardiovascular and Renal Events in Patients with Type 2 Diabetes, 
Cardiovascular Risk Factors and Moderately Impaired Renal Function 
NCT Number: 
NCT03315143 
Document Date: 
Protocol Version 1: 29-August-2018 
 
 


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 01
COMPOUND: sotagliflozin/SAR439954
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 
Study to Demonstrate the Effects of Sotagliflozin on Cardiovascular and Renal 
Events in Patients with Type 2 Diabetes, Cardiovascular Risk Factors and 
Moderately Impaired Renal Function 
STUDY NUMBER: EFC14875
STUDY NAME: The SCORED Trial
Version Number:
1
EudraCT
2017-002644-32
IND Number
WHO universal trial number
U1111-1187-8703
Date:
29-Aug-18
Total number of pages:
133
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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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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Country/countries 
impacted by 
amendment
Date, version
Amended Clinical Trial Protocol 01
India only
29-Aug-18, version 1 (electronic 1.0)
Amended Clinical Trial Protocol 01 CA and 
US
Canada and United 
States of America only
12-Jan-18, version 1 (electronic 1.0)
Protocol Amendment 01 CA and CA
Canada and United 
States of America only
12-Jan-18, version 1 (electronic 1.0)
Original Protocol
07-Sep-17, version 2 (electronic 3.0)
Amended protocol 01 (29-Aug-18)
OVERALL RATIONALE FOR THE AMENDMENT
In order to meet the requirements of the health authority of India, the study protocol is being 
amended to exclude patients with HbA1c greater than 10% at Screening and to add rescue criteria 
for patients with uncontrolled hyperglycemia.
Please note that this protocol amendment is applicable to the following country only: India.
Protocol amendment summary of changes table
Section # and Name
Description of Change
Brief Rationale
Clinical Trial Summary (Study 
population), 7.2 Exclusion 
criteria, 10.1.1.1 On-site Visit 1
Update exclusion criteria with upper limit of 
HbA1c
To comply with an Indian health authority 
requirement
8.8.1 Antihyperglycemic 
concomitant medication 
Add rescue criteria for patients with 
uncontrolled hyperglycemia
To comply with an Indian health authority 
requirement
Appendix F Country-specific 
requirements 
Add an appendix documenting country-
specific requirements
To comply with a process change at Sanofi
Appendix G Protocol 
amendment history
Add an appendix documenting protocol 
amendment history
To comply with a process change at Sanofi
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CLINICAL TRIAL SUMMARY
COMPOUND: 
sotagliflozin/SAR439954
STUDY No.: EFC14875
STUDY NAME: SCORED
TITLE
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to 
Demonstrate the Effects of Sotagliflozin on Cardiovascular and Renal Events in Patients 
with Type 2 Diabetes, Cardiovascular Risk Factors and Moderately Impaired Renal 
Function. The SCORED trial.
INVESTIGATOR/TRIAL 
LOCATION
Multinational, multicenter
PHASE OF DEVELOPMENT
3
STUDY OBJECTIVES
Primary objectives:
The 2 primary objectives of this study are to demonstrate that, when compared to placebo 
in patients with type 2 diabetes (T2D), cardiovascular (CV) risk factors, and moderately 
impaired renal function, sotagliflozin:

Is non-inferior to placebo on the composite endpoint of CV death, non-fatal 
myocardial infarction (MI), or non-fatal stroke (3-point major adverse CV events 
[MACE])

Reduces the composite endpoint of CV death or hospitalization for heart failure 
(HHF)
Secondary objectives:

The secondary objectives of this study are to demonstrate that, when compared 
to placebo in patients with T2D, CV risk factors, and moderately impaired renal 
function, sotagliflozin:
-
Reduces the composite endpoint of CV death, non-fatal MI or non-fatal 
stroke (3-point MACE)
-
In patients with Baseline estimated glomerular filtration (eGFR) 
≥30 mL/min/1.73 m2, reduces the composite renal endpoint of sustained 
≥50% decrease in eGFR from Baseline (for ≥30 days), chronic dialysis, 
renal transplant, or sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)
-
In patients with Baseline eGFR ≥30 mL/min/1.73 m2 and Baseline urinary 
albumin-to-creatinine-ratio [UACR] ≥300 mg/g (34 mg/mmol), reduces the 
composite renal endpoint of sustained ≥50% decrease in eGFR from 
Baseline (for ≥30 days), chronic dialysis, renal transplant, or sustained 
eGFR <15 mL/min/1.73 m2 (for ≥30 days)
-
Reduces the composite endpoint of CV death, HHF, or urgent heart failure 
(HF) visit (defined in Appendix E),
-
Reduces CV death
-
Reduces all-cause mortality

To assess the safety and tolerability of sotagliflozin in patients with T2D, CV risk 
factors, and moderately impaired renal function
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Other:

To demonstrate that, when compared to placebo in patients with T2D, CV risk 
factors, and moderately impaired renal function, sotagliflozin:
-
In patients with Baseline eGFR ≥30 mL/min/1.73 m2, reduces the 
composite endpoint of sustained ≥50% decrease in eGFR from Baseline 
(for ≥30 days), chronic dialysis, renal transplant, sustained eGFR 
<15 mL/min/1.73 m2 (for ≥30 days), or CV or renal death
-
Reduces the composite endpoint of CV death, non-fatal MI, non-fatal 
stroke, or unstable angina requiring hospitalization (4-point MACE)
-
In patients with Baseline eGFR ≥30 mL/min/1.73 m2, reduces the 
composite renal endpoint of worsening nephropathy, defined as: new onset 
or progression to macro albuminuria (≥300 mg/g [34 mg/mmol]) 
accompanied by a UACR value increase of ≥30% from Baseline, sustained 
≥50% decrease in eGFR from Baseline (for ≥30 days), chronic dialysis, 
need for renal transplant, eGFR <15 mL/min/1.73 m2 (for ≥30 days), or
renal death

To compare sotagliflozin versus placebo with respect to change from Baseline to 
6 months, 12 months, and 24 months in the following endpoints: 
-
Hemoglobin A1c (HbA1c)
-
Body weight
-
Blood pressure (BP)
-
Urinary albumin-to-creatinine ratio
-
Estimated glomerular filtration rate
-
Hematocrit
-
Hemoglobin
-
Albumin
-
Total protein

To compare sotagliflozin versus placebo with respect to change from Baseline to 
6 months and 12 months in the following endpoints: 
-
N-terminal pro-B-type natriuretic peptide (NT-proBNP)
-
High-sensitivity troponin T (hsTnT)
-
High-sensitivity C-reactive protein (hsCRP)

To compare sotagliflozin versus placebo with respect to change from Baseline in 
the following endpoints: 
-
Proportion of patients not taking insulin at baseline who start insulin during 
the study
STUDY DESIGN
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study in approximately 10,500 patients with T2D, CV risk factors, and 
moderately impaired renal function. The study will consist of 3 periods: a Screening period
of 1 to 4 weeks, a randomized, Double-blind Treatment period, and a Post-treatment 
period. The dose of sotagliflozin or matched placebo should be increased from 200 mg to 
400 mg in the first 6 months of the randomized Double-blind Treatment period, if tolerated.
Patients who meet all eligibility criteria at Screening (Visit 1) will come back for the 
Randomization Visit (Visit 2) between 7 and 28 days later and, if they are still eligible for 
the study, they will be randomized 1:1 to sotagliflozin or placebo. Patients will start 
sotagliflozin 200 mg or matching placebo at Visit 2 after Randomization. 
Randomization will be stratified by region (North America, Latin America, Western Europe, 
Eastern Europe, and rest of the world) and by HF-related criteria (Yes/No). 
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HF-related criteria is ‘Yes’ when a patient meets at least 1 of the following major CV risk 
factors: 
1.
Ejection fraction (EF) ≤40% documented within the past year
2.
Hospitalization for HF during the previous 2 years
At Week 4 (Visit 3), clinical safety and tolerability will be assessed (including vital signs
and collection of adverse events [AEs], including events of special interest [EOSIs],
adverse events of special interest [AESIs] and serious adverse events [SAEs]). If in the 
opinion of the Investigator the patient’s clinical condition is satisfactory and the patient has 
tolerated the investigational medicinal product (IMP) well without evidence of dehydration,
symptomatic hypotension (eg, dizziness, lightheadedness), or other AEs intolerable to the 
patient such as severe polyuria or nocturia, the dose will be increased to 400 mg of 
sotagliflozin or matching placebo.
If the dose is not up-titrated for safety reasons, all attempts will be made to up-titrate the 
dose at 1 of the next 2 subsequent visits: Visit 4 (Week 8) or, if not Visit 4, then Visit 5 
(Week 26). The 400 mg dose (or 200 mg in those who cannot tolerate up-titration by 
Visit 5) will be maintained for the duration of the remaining double-blind study treatment 
period. If, at any time during the study, a patient does not tolerate 400 mg, the dose of 
sotagliflozin or matching placebo may be down titrated to 200 mg once daily (qd) or 
temporarily discontinued, or if medically necessary, permanently discontinued. All IMP 
discontinuation should initially be considered as temporary unless permanent 
discontinuation is mandated by the protocol.
The study is event driven. Therefore, it will continue until approximately 844 events of CV 
death or HHF and approximately 1189 3-point MACE are positively adjudicated. All 
randomized patients will be asked to return to the study site for a Study Closeout Visit 
once the date the required number of events are projected to be positively adjudicated has 
been determined. The timing and window of this visit will be communicated to sites.
All randomized patients will be followed from Randomization until their Follow-up Visit (or 
Study Closeout Visit, for patients who prematurely permanently discontinued from IMP) or 
death, whichever comes first.
Patients will continue taking IMP after a CV or renal endpoint occurs unless they have 
prematurely permanently discontinued treatment or the criteria for permanent treatment 
discontinuation have otherwise been met. Patients with a suspected renal event (reduction 
of eGFR) should be brought in for an unscheduled visit and have a repeat assessment of 
renal function 30 to 45 days following the onset of the event to confirm it is sustained. If 
acute renal failure is suspected, further clinical evaluation should be performed as per 
local standard of care, including confirmation of renal laboratory parameters, and 
consideration should be given to a nephrology referral.
A dual-energy X-ray absorptiometry (DXA) sub-study will be performed at participating 
sites in a subset of approximately 190 patients and will compare sotagliflozin and placebo 
for changes from Baseline to end of treatment in bone mineral density (BMD) and markers 
of bone and calcium metabolism.
Premature Treatment Discontinuation 
All IMP discontinuation should initially be considered as temporary unless permanent 
discontinuation is mandated by the protocol. 
If a patient prematurely permanently discontinues treatment with IMP, the patient will be 
asked to undergo a premature End-of-Treatment (pEOT) Visit as soon as possible.
Subsequently, every effort will be made to have the patient return to the site/be reached by 
phone at the time corresponding to their scheduled visits, until the end of the study. 
Patients will continue to be followed after a CV or renal endpoint occurs. 
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If a patient refuses to continue in the study after premature IMP discontinuation, and the 
pEOT Visit is <10 days after the last IMP administration, then every effort should be made 
to secure a follow-up contact is performed at least 14 days (±4 days) after the last IMP 
intake with procedures normally performed at the Follow-up Visit. If the patient does not 
agree to on-site visits, he/she will be contacted by telephone to inquire about safety status 
(including hospitalizations and endpoints). Every effort should be made to collect endpoint 
information and vital status at least once a year and at the time of Study Closeout.
End of study
All randomized patients will be asked to return to the study site for a Study Closeout Visit 
when approximately 844 primary CV events of CV death or HHF and approximately 
1189 3-point MACE are positively adjudicated. The timing and window of this visit will be 
communicated to sites. For patients who previously prematurely permanently discontinued 
IMP, the Study Closeout Visit will be the final study visit and no further visits are planned. 
Patients still taking the IMP at the time of the Study Closeout Visit (ie, who have not 
prematurely permanently discontinued IMP) will have their final study visit (Follow-up Visit) 
14 days (±4 days) after their Study Closeout Visit.
Patients who have withdrawn from the study cannot be rerandomized in the study.
STUDY POPULATION 
Main selection criteria:
Inclusion criteria:
Mandatory Inclusion Criteria (all 4 criteria are necessary)
I 01.
Signed written informed consent
I 02.
Type 2 diabetes with HbA1c ≥7% (53 mmol/mol) at Screening (central 
laboratory)
I 03.
Estimated glomerular filtration rate ≥25 and ≤60 mL/min/1.73 m2 by the 
4 variable Modification of Diet in Renal Disease (MDRD) equation (at Screening, 
based on central laboratory)
I 04.
Patients either:
-
Age ≥18 years with at least 1 (one) of the major CV risk factors listed below 
OR
-
In the absence of a major CV risk factor, age ≥55 years with at least 2 (two) 
of the minor CV risk factors listed below
In order to be considered eligible to participate in the study, patients must meet all 4 (four) 
of the mandatory criteria. Patients can be eligible if they have both major and minor CV 
risk factors, as long as 1 of the 2 conditions in Inclusion Criterion Number 4 is met. Major 
and minor CV risk factors are listed below. 
Major CV risk factors (at least 1 criterion to fulfill Inclusion Criterion 
Number 4) 
A)
Hospitalization for HF during previous 2 years
B)
Ejection fraction (EF) ≤40%
Documented within the past year by previous imaging modality (such as 
echocardiogram, MUltiple Gated Acquisition (MUGA) scan, Magnetic 
Resonance Imaging (MRI), positron emission tomography (PET), single-photon 
emission computed tomography (SPECT), left ventricular (LV) angiography) 
Note: An echocardiogram to assess EF at the time of Screening MUST be 
performed in all patients if an assessment of EF has not been documented 
within 1 year prior to Screening
C)
Diagnosis of left ventricular hypertrophy
By either electrocardiogram (ECG) or echocardiogram
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D)
Coronary artery calcium (CAC) score ≥300 Agatston Units
Documented by coronary artery CT scan
Note: a coronary artery CT scan MAY be performed to measure the CAC score 
if required for eligibility if not previously documented
E)
N-terminal pro-B-type natriuretic peptide ≥400 pg/mL (47 pmol/L) 
At Screening, based on central laboratory 
F)
High-sensitivity troponin T >15.0 pg/mL (0.015 µg/L) for men and >10.0 pg/mL 
(0.010 µg/L) for women 
During Screening period, based on central laboratory
G)
High-sensitivity C-reactive protein >3 mg/L (28.6 nmol/L) 
At Screening, based on central laboratory, if the Investigator does not consider 
the elevation to be due to an acute inflammatory condition (eg, acute infection)
H)
Urinary albumin-to-creatinine ratio ≥300 mg/g (34 mg/mmol) 
At Screening, based on central laboratory
Minor CV risk factors (if no major CV risk factors, at least 2 criteria to 
fulfill Inclusion Criterion Number 4) 
I)
Body mass index ≥35 kg/m2 at Screening
J)
Dyslipidemia despite maximally-tolerated statin therapy: 
-
Low-density lipoprotein cholesterol >130 mg/dL (>3.36 mmol/L)
                                          Or
-
High-density lipoprotein cholesterol <40 mg/dL (<1.03 mmol/L) for men or 
<50 mg/dL (<1.29 mmol/L) for women
Based on the last measured and documented laboratory measurement in the 
previous 6 months
K)
Currently smoking tobacco 
Consumes an average of at least 1 cigarette, pipe, or cigar per day, at 
Screening
L)
Coronary artery calcium score >100 and <300 Agatston Units 
Documented by coronary artery CT scan
Note: a coronary artery CT scan MAY be performed to measure the CAC score 
if required for eligibility if not previously documented
M)
Urinary albumin-to-creatinine ratio ≥30 mg/g and <300 mg/g (3 and 
34 mg/mmol) 
During Screening period, based on central laboratory
N)
Systolic blood pressure >140 mmHg and diastolic blood pressure >90 mmHg 
despite antihypertensive therapy at the Screening Visit 
O)
Family history of premature coronary heart disease (defined as MI or coronary 
revascularization procedure) in a first degree relative 
In a male relative <55 years or in a female relative <65 years 
Exclusion criteria:
E 01.
History of diabetic ketoacidosis or nonketotic hyperosmolar coma within 
3 months prior to the Screening Visit or between Screening and 
Randomization
E 02.
Antihyperglycemic treatment (if applicable) has not been stable in the 
12 weeks prior to Screening or between Screening and Randomization, in the 
opinion of the Investigator 
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E 03.
Patients who are planning to start a sodium-glucose linked transporter-2 
(SGLT2) inhibitor (other than study drug) during the study. This includes 
patients who, in the opinion of the Investigator, based on their comorbid 
profile, are likely to receive an SGLT2 inhibitor (other than study drug) during 
the study
E 04.
Any SGLT2 inhibitor <1 month prior to the Screening Visit, or between 
Screening and Randomization
E 05.
Lower extremity complications (such as skin ulcers, infection, osteomyelitis,
and gangrene) identified during the Screening period, and still requiring 
treatment at Randomization
E 06.
Any allergic reaction to any SGLT2 inhibitor or sotagliflozin
E 07.
Blood pressure ≥180 mmHg (systolic) or ≥110 mmHg (diastolic) at both the 
Screening and Randomization Visits
E 08.
Hospitalization for hypertensive emergency within 3 months prior to 
Randomization
E 09.
End-stage HF: requiring LV assist device, intra-aortic balloon pump (IABP), or 
any type of mechanical support at the time of Screening
E 10.
Planned coronary revascularization procedures, electrophysiologic device 
implantation, cardiac mechanical support implantation, or other cardiac 
surgery after Randomization 
E 11.
History of dialysis within 1 year prior to Randomization
E 12.
History of solid organ transplant
E 13.
Serum creatinine altering drugs ≤30 days before Screening, or between 
Screening and Randomization (trimethoprim, cimetidine, cephalosporins, 
probenecid, aminoglycosides, ketoconazole). Please note that diuretics are 
allowed within 30 days of Screening
E 14.
Clofibrate, fenofibrate, dronedarone, or ranolazine treatment that has not 
been at a stable dose in the 30 days prior to Screening or between Screening 
and Randomization or a dose adjustment is expected during the study based 
on the judgement of the Investigator
E 15.
Use of systemic glucocorticoids (excluding topical application or inhaled 
forms) for more than 10 consecutive days within 3 months prior to Screening 
Visit or for more than 10 consecutive days between Screening and 
randomization
E 16.
Digoxin plasma level >1.2 ng/mL (in a patient treated with digoxin at Screening, 
based on local laboratory*)
E 17.
Use of any investigational drug(s) within 5 half-lives prior to the Screening 
Visit or between Screening and Randomization
E 18.
Severe disease or short life expectancy making implementation of the 
protocol or interpretation of the study results difficult (CV disease [including 
congestive HF New York Heart Association IV], respiratory, hepatic, 
neurological [including stroke in 3 months prior to Screening], psychiatric, or 
active malignant tumor (except for non-melanoma skin cancers, which are not 
exclusionary) or other major systemic disease [including any diseases with 
evidence of malabsorption or severe anemia])
E 19.
Presence of any other conditions (eg, geographic, social) actual or 
anticipated, that the Investigator feels would restrict or limit the patient’s 
participation for the duration of the study 
E 20.
Patient is the Investigator or any Sub-investigator, research assistant, 
pharmacist, study coordinator, other staff or relative thereof directly involved 
in the conduct of the protocol
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E 21.
Any country-related specific regulation that would prevent the patient from 
entering the study (eg, individuals committed to an institution by virtue of an 
order issued either by the judicial or the administrative authorities)
E 22.
Pregnant (demonstrated by serum pregnancy test at Screening) or 
breastfeeding women
E 23.
Women of childbearing potential not willing to use a highly-effective 
method(s) of birth control during the study treatment period and the follow-up 
period, or who are unwilling or unable to be tested for pregnancy (see 
contraceptive guidance in Appendix A), during the study
E 24.
Laboratory findings at the Screening Visit: 
-
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>3 times the upper limit of the normal laboratory range (ULN) (1 repeat is 
allowed)*
-
Total bilirubin >1.5 times the ULN (except in case of Gilbert’s syndrome)
-
Specific to India: HbA1c >10% (86 mmol/mol) (central laboratory); see 
Appendix F
One time rescreening is allowed at the Investigator’s medical judgment for any 
manageable reasons that caused the Screening failure and if the patient is likely to be 
eligible before the enrollment completion.
*If a patient meets exclusion criteria E 16 or E 24, a one-time repeat testing is allowed for 
digoxin level, ALT, or AST without the need to rescreen the patient.
Further eligibility criteria for inclusion in the DXA sub-study are detailed in Appendix B.
Total expected number of 
patients:
10,500
Expected number of sites:
Approximately 900 sites
STUDY TREATMENTS
Investigational medicinal 
products 
Formulation:
Sotagliflozin and placebo
Oral tablet
Route of administration:
by mouth
Dose regimen:
Sotagliflozin: 
From Visit 2 to Visit 3: Sotagliflozin 200 mg administered as 1 (one) 200-mg tablet qd
before the first meal of the day 
From Visit 3, as tolerated: Sotagliflozin 400 mg administered as 2 (two) 200-mg tablets 
qd before the first meal of the day
Placebo:
From Visit 2 to Visit 3: Placebo administered as 1 (one) placebo tablet (identical to 
sotagliflozin 200-mg tablets in appearance) qd before the first meal of the day 
From Visit 3, as tolerated: Placebo administered as 2 (two) placebo tablets (identical to 
sotagliflozin 200-mg tablets in appearance) qd before the first meal of the day
Noninvestigational 
medicinal products
There are no noninvestigational medicinal products in this study.
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ENDPOINTS 
Primary efficacy endpoints:

Time to the first occurrence of any of the following clinical events:
-
Cardiovascular death
-
Non-fatal MI
-
Non-fatal stroke

Time to the first occurrence of any of the following clinical events:
-
Cardiovascular death
-
Hospitalization for heart failure
Secondary efficacy endpoints:

Time to the first occurrence of any of the following clinical events in patients with 
Baseline eGFR ≥30 mL/min/1.73 m2:
-
Sustained ≥50% decrease in eGFR from Baseline (for ≥30 days)
-
Chronic dialysis
-
Renal transplant
-
Sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)

Time to the first occurrence of any of the following clinical events in patients with 
Baseline eGFR ≥30 mL/min/1.73 m2 and Baseline UACR ≥300 mg/g 
(34 mg/mmol):
-
Sustained ≥50% decrease in eGFR from Baseline (for ≥30 days)
-
Chronic dialysis
-
Renal transplant
-
Sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)

Total number (ie, including recurrent events) of the following clinical events:
-
Cardiovascular death
-
Hospitalization for heart failure
-
Urgent HF visit (defined in Appendix E)

Time to CV death

Time to all-cause mortality
Other efficacy endpoints:

Time to the first occurrence of any of the following clinical events in patients with 
Baseline eGFR ≥30 mL/min/1.73 m2:
-
Sustained ≥50% decrease in eGFR from Baseline (for ≥30 days)
-
Chronic dialysis
-
Renal transplant
-
Sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)
-
Cardiovascular death
-
Renal death

Time to first occurrence of any CV death, non-fatal MI, non-fatal stroke, or 
unstable angina requiring hospitalization 

Time to worsening nephropathy in patients with Baseline eGFR 
≥30 mL/min/1.73 m2, defined as: new onset or progression to macro albuminuria 
(≥300 mg/g [34 mg/mmol]) accompanied by a UACR value increase of ≥30% 
from Baseline, or sustained ≥50% decrease in eGFR from Baseline (for 
≥30 days), or need for renal transplant, chronic dialysis, 
eGFR <15 mL/min/1.73 m2 (for ≥30 days), or renal death
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
Changes from Baseline to 6 months, 12 months, and 24 months in:
-
Hemoglobin A1c 
-
Body weight
-
Blood pressure
-
Urinary albumin-to-creatinine ratio
-
Estimated glomerular filtration rate
-
Hematocrit
-
Hemoglobin
-
Albumin
-
Total protein

Changes from Baseline to 6 months and 12 months in: 
-
N-terminal pro-B-type natriuretic peptide
-
High sensitivity troponin T
-
High sensitivity C-reactive protein

Proportion of patients who start insulin (who are not taking insulin at baseline)
Safety endpoints:

All AEs, including AESIs, EOSIs, and SAEs

Severe hypoglycemia (also an EOSI)

Clinical laboratory results and vital signs (including heart rate, BP)

For patients in the DXA sub-study, change from Baseline in: 
-
Bone mineral density
-
The following markers of bone and calcium metabolism: serum and urinary 
calcium; serum 25-hydroxyvitamin D; serum 1,25 dihydroxyvitamin D;
serum and urinary phosphorus; serum parathyroid hormone (PTH); serum 
N telopeptide of type 1 collagen (NTX); serum β-C-terminal telopeptide of 
type 1 collagen (β CTX 1); serum N-terminal propeptide of type 1 
procollagen (P1NP); serum magnesium
ASSESSMENT SCHEDULE
See Section 1.1 and Section 1.2
STATISTICAL 
CONSIDERATIONS
Sample size determination:
The study is powered based on the endpoints of time to CV death or first HHF and time to 
3-point MACE, based on the following trial design assumptions:

A recruitment period of approximately 24 months with approximately 3.6%, 
20.0%, 36.5%, and 39.9% of patients recruited during each of the 4 (four) 
6-month periods; 

Approximately 27 months of follow-up after the last patient is randomized, with 
treatment duration ranging from 27 to 51 months 

2% annual censoring rate 
It is estimated that approximately 10,500 patients are needed to obtain approximately 
844 positively-adjudicated CV deaths and HHF assuming a 3.5% annual event rate in the 
placebo group and a risk reduction of 20% (Hazard Ratio=0.8) and 1189 3-point MACEs
assuming a 4.5% yearly event rate in the placebo group and a risk reduction of 15% 
(hazard ratio=0.85) comparing sotagliflozin versus placebo.
This will provide:

99% power to demonstrate non-inferiority on 3-point MACE

90% power to demonstrate the superiority in CV death/HHF

80% power to demonstrate the superiority in 3-point MACE
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Amended Clinical Trial Protocol 01
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The study is event driven. Therefore, it will continue until approximately 
844 positively-adjudicated CV death or HHF events will have occurred (ie, number of 
patients with CV death or at least 1 HHF) and approximately 1189 3-point MACEs
(ie, number of patients with at least one 3-point MACE) have occurred.
Analysis population:
The primary analysis population will be the intent-to-treat (ITT) population that includes all 
randomized patients irrespective of compliance with the study protocol and procedures.
The safety analysis will be conducted on the safety population that includes all randomized 
patients who have received at least 1 dose of double-blind treatment.
Analysis of the primary endpoints:
The time to the first occurrence of the composite 3-point MACE endpoint (CV death, 
non-fatal MI, non-fatal stroke) will be analyzed using Cox proportional hazards model with 
treatment (sotagliflozin, placebo), region, and HF-related criteria (Yes/No) as the factors. 
The hazard ratio between sotagliflozin and placebo will be estimated along with the 
associated 2-sided 95% confidence interval (CI). Non-inferiority will be claimed if the upper 
bound (UB) of the 2-sided 95% CI is less than 1.3 (as specified in the 2008 Food and Drug 
Administration [FDA] Guidance for Industry: Diabetes Mellitus- Evaluating Cardiovascular 
Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes). 
Kaplan-Meier curves of the cumulative incidence rate will be provided by treatment 
groups.
The time to the first event of CV death or HHF will be analyzed using the same Cox 
proportional hazards model described above with treatment (sotagliflozin, placebo), 
region, and HF-related criteria (Yes/No) as the factors. The hazard ratio between 
sotagliflozin and placebo will be estimated along with the associated 2-sided 95% CI. The 
stratified log-rank test will be used to compare the time-to-first-event curves. 
Kaplan-Meier curves of the cumulative incidence rate will also be provided by treatment 
groups.
All randomized patients will be followed from Randomization until their Follow-up Visit (or 
Study Closeout Visit, for patients who prematurely permanently discontinued from IMP) or 
death, whichever comes first. The primary analysis will be based on the ITT approach that 
includes events occurring from Randomization to the Follow-up Visit (or Study Closeout 
Visit, if no Follow-up Visit is available), even after the patient has discontinued the study 
treatment. In the ITT approach, all randomized patients will be included and analyzed as 
randomized.
Analysis of the secondary endpoints:
Secondary endpoints will be analyzed using the same Cox proportional hazards model 
described above with treatment (sotagliflozin, placebo), region and HF-related criteria 
(Yes/No) as the factors. The hazard ratio between sotagliflozin and placebo will be 
estimated along with the associated 2-sided 95% CI. The stratified log-rank test will be 
used to compare the time-to-first-event curves.
Kaplan-Meier curves of the cumulative incidence rate will also be provided by treatment 
groups.
The total number (ie, including recurrent events) of events of CV death, HHF or urgent HF 
visit will be analyzed using extended Cox proportional hazards model for recurrent events
with treatment (sotagliflozin, placebo), region and HF-related criteria (Yes/No) as factors.
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Multiplicity adjustment
To control the family-wise Type-1 error rate at 0.05 (1-sided alpha=0.025), a 
fixed-sequence testing procedure will be applied to the primary endpoints. The hierarchy 
will be:
1.
Non-inferiority of sotagliflozin versus placebo on 3-point MACE
2.
Superiority of sotagliflozin versus placebo on time to first event of CV death or 
HHF
If the hypotheses above are met, the family-wise Type-1 error rate at 0.05 (1-sided 
alpha=0.025) will be controlled by the Hochberg procedure for the first 2 secondary 
endpoints listed below:

Superiority of sotagliflozin versus placebo on 3-point MACE 

Superiority of sotagliflozin versus placebo in patients with Baseline eGFR 
≥30 mL/min/1.73 m2 on a composite renal endpoint of sustained ≥50% 
decrease in eGFR from Baseline (for ≥30 days), chronic dialysis, renal 
transplant, or sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)
If the hypotheses above are statistically significant, a fixed-sequence testing procedure will 
be applied to the other secondary endpoints listed below. The hierarchy will be:
1.
Superiority of sotagliflozin versus placebo in patients with Baseline eGFR 
≥30 mL/min/1.73 m2 and Baseline UACR ≥300 mg/g (34 mg/mmol) on a 
composite renal endpoint of sustained ≥50% decrease in eGFR from Baseline 
(for ≥30 days), chronic dialysis, renal transplant, or sustained eGFR 
<15 mL/min/1.73 m2 (for ≥30 days)
3.
Superiority of sotagliflozin versus placebo on the composite endpoint of CV 
death, HHF, or urgent HF visit (defined in Appendix E)
4.
Superiority of sotagliflozin versus placebo on CV death
5.
Superiority of sotagliflozin versus placebo on all-cause mortality 
Interim Analysis
If a CV meta-analysis of the other sotagliflozin Phase 3 studies does not meet the 
1.8 boundary (as specified in the 2008 FDA Guidance for Industry: Diabetes Mellitus-
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes), 
an interim analysis will be conducted in this trial. Details will be described in a dedicated 
CV safety Statistical Analysis Plan.
Analysis of other endpoints
The analysis of other time to event endpoints will be analyzed using the same Cox 
proportional hazards model as for the primary endpoints, with treatment (sotagliflozin, 
placebo), region and HF-related criteria (Yes/No) as the factors. 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.
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DURATION OF STUDY 
PERIOD (per patient)
All patients will have a Screening period of 1 to 4 weeks. The study is event driven, 
therefore the duration of the randomized, Double-blind Treatment period for each patient 
(unless they discontinue IMP prematurely) will be determined when approximately 
844 positively-adjudicated primary events of CV death or HHF and approximately 
1189 positively-adjudicated 3-point MACEs have occurred.
The estimated study treatment duration for a given patient will be approximately 27 to 
51 months, assuming approximately 24 months of recruitment, and approximately 
27 months of follow-up after the last patient is randomized.
Patients still taking the IMP at the time of the Study Closeout Visit (ie, who have not 
prematurely permanently discontinued IMP) will have their final study visit (Follow-up Visit) 
14 days (±4 days) later.
STUDY COMMITTEES
Executive Committee:  
Yes    
No
Steering Committee:  
Yes    
No
Data Monitoring Committee: 
Yes    
No
Adjudication Committee:  
Yes    
No
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1
FLOW CHARTS
1.1
GRAPHICAL STUDY DESIGN
a: The Randomization Day is always Day 1. The Randomization is stratified by region and heart failure-related criteria (see Section 6.1.2).
b: At Visit 3 (Week 4), the dose of IMP will be increased to 400 mg or matching placebo (2 tablets) unless, in the opinion of the Investigator, up-titration is not appropriate for safety reasons. If up-titration does not 
occur at Visit 3 for safety reasons, all attempts will be made to up-titrate at Visit 4 (Week 8) or Visit 5 (Week 26). The 400 mg dose (or 200 mg in those who cannot tolerate up-titration by Visit 5) or corresponding 
matching placebo will be maintained for the duration of the remaining Double-blind Treatment period.
c: The study is event driven. Therefore, the study will continue until approximately 844 positively-adjudicated primary CV events of CV death or HHF and approximately 1189 positively-adjudicated 3-point MACEs have 
occurred. 
d: All randomized patients will be asked to return to the study site for a Study Closeout Visit when approximately 844 primary CV events of CV death or HHF and approximately 1189 3-point MACE are positively
adjudicated. Patients who prematurely permanently discontinue IMP will also attend a pEOT Visit as soon as possible after the last dose of IMP and will then continue study visits as per the original study schedule. 
Patients will continue to be followed after a CV or renal endpoint occurs irrespective of whether they are receiving IMP. If the patient does not agree to site visits, he/she will be contacted by telephone to inquire about 
safety status (including hospitalizations and endpoints).
e: A FU Visit will take place 14 days (±4 days) after the Study Closeout Visit for patients who do not prematurely permanently discontinue IMP.
CV cardiovascular; FU follow-up; HHF hospitalization for heart failure; IMP investigational medicinal product; MACE major adverse cardiovascular event; pEOT Premature End-Of-Treatment; R Randomization V visit; 
Wk week.
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1.2
STUDY FLOW CHART
Screening
Randomized Double-blind Treatment period
Patients who 
prematurely 
permanently 
discontinue IMP 
Patients who do not 
prematurely 
permanently 
discontinue IMP 
Visit
1
2
3
4
5
6/7a
8
9/10a
11/17/23
12/13/15/16/18/19/21/22/
24/25/27/28a
14/20/26
Month
0
1
2
6
8/10
12
14/16
18/30/42
20/22/26/28/32/34/38/40/
44/46/50/52
24/36/48
pEOTb
Study 
Closeout 
Visitc
Study 
Closeout 
Visitc
FU Visitd
Week
-1 to -4
0
4
8
26
35/44

52
61/70

78/130/
182
87/96/113/122/139/148/165
/174/191/200/217/226 
104/156/
208
Day 
(Window [days])
-7 to -28
1
28
(±3)
56
(±7)
182
(±10)
245/308
(±10)
364
(±10)
427/490
(±10)
546/910/
1274 (±10)
609/672/791/854/973/1036/
1155/1218/1337/1400/
1519/1582 (±10)
728/1092/
1456 (±10)
b
c
c
Study 
Closeout
+14 (±4)
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographics
X
Patient contact 
information to be 
collected/updated
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical/surgical history
X
Medication history
X
Body weight, heighte
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
IRT contact
X
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense IMP
X
X
X
X
X
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Page 18
Screening
Randomized Double-blind Treatment period
Patients who 
prematurely 
permanently 
discontinue IMP 
Patients who do not 
prematurely 
permanently 
discontinue IMP 
Visit
1
2
3
4
5
6/7a
8
9/10a
11/17/23
12/13/15/16/18/19/21/22/
24/25/27/28a
14/20/26
Month
0
1
2
6
8/10
12
14/16
18/30/42
20/22/26/28/32/34/38/40/
44/46/50/52
24/36/48
pEOTb
Study 
Closeout 
Visitc
Study 
Closeout 
Visitc
FU Visitd
Week
-1 to -4
0
4
8
26
35/44

52
61/70

78/130/
182
87/96/113/122/139/148/165
/174/191/200/217/226 
104/156/
208
Day 
(Window [days])
-7 to -28
1
28
(±3)
56
(±7)
182
(±10)
245/308
(±10)
364
(±10)
427/490
(±10)
546/910/
1274 (±10)
609/672/791/854/973/1036/
1155/1218/1337/1400/
1519/1582 (±10)
728/1092/
1456 (±10)
b
c
c
Study 
Closeout
+14 (±4)
IMP accountability and
compliance
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationg
X
Xg
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
Xh
X
X
X
LABORATORY TESTINGi
HbA1c and hematology 
X
X
X
X
X
X
X
X
Xj
Chemistry, eGFR
X
X
X
X
X
X
X
X
X
X
X
Xj
Lipids
X
X
X
X
X
Pregnancy (WOCBP)k
X
X
X
X
X
X
X
X
X
X
X
Urinalysisand UACRl
X
X
X
X
X
X
X
X
X
X
X
24-hour urine albumin 
and creatininel
X
NT-proBNP, hsTnT, 
and hsCRPm
X
X
Xm
Xm
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Screening
Randomized Double-blind Treatment period
Patients who 
prematurely 
permanently 
discontinue IMP 
Patients who do not 
prematurely 
permanently 
discontinue IMP 
Visit
1
2
3
4
5
6/7a
8
9/10a
11/17/23
12/13/15/16/18/19/21/22/
24/25/27/28a
14/20/26
Month
0
1
2
6
8/10
12
14/16
18/30/42
20/22/26/28/32/34/38/40/
44/46/50/52
24/36/48
pEOTb
Study 
Closeout 
Visitc
Study 
Closeout 
Visitc
FU Visitd
Week
-1 to -4
0
4
8
26
35/44

52
61/70

78/130/
182
87/96/113/122/139/148/165
/174/191/200/217/226 
104/156/
208
Day 
(Window [days])
-7 to -28
1
28
(±3)
56
(±7)
182
(±10)
245/308
(±10)
364
(±10)
427/490
(±10)
546/910/
1274 (±10)
609/672/791/854/973/1036/
1155/1218/1337/1400/
1519/1582 (±10)
728/1092/
1456 (±10)
b
c
c
Study 
Closeout
+14 (±4)
ADDITIONAL TESTING TO MEET INCLUSION CRITERIA
Cardiac CT for calcium 
scoren
X
Echocardiogramn
X
OTHER TESTING
DXA scan, 
25-hydroxyvitamin D 
and markers of bone 
and calcium 
metabolism (subset of 
patients)o
Xo
Xo
Xo
Xo
Plasma digoxin 
(if applicable)r
Xr
Xr
Xr
Xr
AEs/SAEs/AESIs/EOSIs/
severe hypoglycemia and
endpoint eventss
Throughout the study
a
Telephone visit.
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b
If a patient prematurely permanently discontinues treatment with IMP, the patient will undergo a pEOT Visit as soon as possible. Patients will then continue in the study with all study procedures/visits except those 
associated with IMP administration. Patients will continue to be followed after a CV or renal endpoint occurs irrespective of their treatment status. If the patient does not agree to site visits, he/she will be contacted 
by telephone to inquire about safety status (including hospitalizations and endpoints).
c
All randomized patients will be asked to return to the study site for a Study Closeout Visit when approximately 844 primary CV events of CV death or HHF and approximately 1189 3-point MACE are positively
adjudicated. The timing and window of this visit will be communicated to sites. For patients who previously prematurely permanently discontinued IMP, the Study Closeout Visit will be the final study visit and no 
further visits are planned.
d
Patients still taking the IMP at the time of the Study Closeout Visit (ie, who have not prematurely permanently discontinued IMP) will have their final study visit (Follow-up Visit) 14 days (±4 days) after their Study 
Closeout Visit.
e
Height to be measured only at Screening.
f
Vital sign measurements (BP and heart rate) should be measured in a seated position.
g
The dose of any concomitant RAAS inhibitors and beta-blockers should be collected at Baseline and at all study visits. For patients receiving RAAS inhibitors and/or beta blockers, the Investigator will need to 
confirm that patient is receiving the optimal or maximally tolerated dose, or otherwise record the reason for taking a lower dose.
h
The 12-lead ECG recording at Day 1 (Visit 2) should be obtained prior to first dose of double-blind IMP. 
i
All laboratory assessments performed at Day 1 (Visit 2) should occur prior to first dose of double-blind IMP. 
j
The following laboratory assessments will be performed at the Follow-up Visit: eGFR, hemoglobin/hematocrit, albumin, and total protein
k
Serum pregnancy testing only at Screening; urine pregnancy testing subsequently. 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
A urine dipstick will be performed by the Central laboratory and includes assessment of specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte esterase. If the dipstick is positive 
for nitrite and leukocyte esterase or blood, reflexive testing will be performed (see Section 9.2.2.1). Urinary albumin-to-creatinine ratio will also be performed. Screening UACR will be measured by spot urine. If the 
Screening UACR is <300 mg/g (34 mg/mmol), but >100 mg/g (11 mg/mmol) then a 24-hour urine collection for measurement of UACR will be performed.
m ALL patients MUST have NT-proBNP, hsTnT, and hsCRP assessed at Screening. Patients also have these biomarkers assessed at Visit 5 (Week 26) and Visit 8 (Week 52). If the patient prematurely permanently 
discontinues study treatment before attending Visit 8, NT-proBNP, hsTnT, and hsCRP should be assessed at the pEOT Visit.
n
If a patient has a diagnosis of T2D, age ≥18 years, a HbA1c ≥7% (53 mmol/mol), and an eGFR ≥25 and ≤60 mL/min/1.73 m2, and does not have either 1 major or 2 minor risk factors based upon available 
information, additional testing (echocardiogram and/or coronary artery CT scan) MAY be ordered. A Coronary artery CT scan MAY be performed to measure the coronary artery calcium score if required for 
eligibility if not previously documented. An echocardiogram will be performed at Screening in ALL patients who have not an ejection fraction documented within the past year. If both tests have not been 
documented and are needed to meet inclusion criterion 04, they can be ordered at the same time. 
o
Approximately 190 patients (95 females and 95 males) will be enrolled into the DXA sub-study. 25-hydroxyvitamin D will be drawn at the Screening Visit to allow assessment of eligibility for the sub-study. The 
DXA scan and 24-hour urine collection (for calcium, creatinine, and phosphorus) will be performed during the Screening period prior to Randomization for patients who sign the dedicated informed consent form 
and otherwise meet the eligibility criteria for the sub-study at the time of the Screening Visit; urine samples specific to the sub-study (see Appendix B) should be returned prior to or at Visit 2 (Randomization). 
Serum markers of bone and calcium metabolism will otherwise be performed at Day 1 (Visit 2). At the end of treatment (pEOT Visit for patients who prematurely permanently discontinue and the Study Closeout
Visit for patients who completed treatment), a DXA scan, 24-hour urine collection and serum markers of bone and calcium metabolism will be performed. Specific to Canada and USA: Fasting serum markers 
(see Appendix F)
Markers of bone and calcium metabolism include: serum and urinary calcium, serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum and urinary phosphorus, serum PTH, markers of bone resorption 
(serum NTX, serum β-CTX-1), and bone formation (serum P1NP).
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r
In patients treated with digoxin, digoxin levels should be measured at Screening and at Visit 3 (Week 4). Digoxin levels should be reassessed 2 to 4 weeks after an up-titration has been implemented (at an 
unscheduled visit, if indicated). If no up-titration is implemented, there is no requirement for digoxin level assessment beyond Visit 3. Throughout the study, additional digoxin plasma level assessments to be 
performed as per Investigators’ judgment. All digoxin levels will be performed as local laboratory measurements. 
s
All AEs, including AESIs, EOSIs, SAEs, and severe hypoglycemia will be collected starting with signing informed consent. The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until stabilization, 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. Patients with a suspected renal event (reduction of eGFR) should have a repeat 
assessment of renal function 30 to 45 days following the onset of the event to confirm it is sustained. If acute renal failure is suspected, further clinical evaluation should be performed as per local standard of care, 
including confirmation of renal laboratory parameters, and consideration should be given to a nephrology referral.
AE adverse event; AESI adverse event of special interest; β-CTX-1 beta carboxy-terminal telopeptide cross-linked type 1 collagen; BP blood pressure; CT computed tomography; CV cardiovascular; DXA dual-energy 
x-ray absorptiometry; DNA deoxyribonucleic acid; ECG electrocardiogram; eGFR estimate glomerular filtration rate; EOSI event of special interest; FU follow-up; HbA1c hemoglobin A1c; HHF hospitalization for heart 
failure; hsCRP high-sensitivity C-reactive protein; hsTnT high-sensitivity troponin T; IMP investigational medicinal product; IRT interactive response technology; MACE major adverse cardiovascular event; 
NT-proBNP N-terminal prohormone of brain natriuretic peptide; NTX N-terminal telopeptide; pEOT premature End-Of-Treatment; P1NP procollagen type 1 amino-terminal propeptide; PTH parathyroid hormone;
RAAS renin-angiotensin-aldosterone system; SAE serious adverse event; T2D type 2 diabetes; UACR urinary albumin-to-creatinine-ratio; WOCBP women of childbearing potential.
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2
TABLE OF CONTENTS
AMENDED CLINICAL TRIAL PROTOCOL 01 ..............................................................................................1
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................................................3
DOCUMENT HISTORY...................................................................................................................................3
OVERALL RATIONALE FOR THE AMENDMENT........................................................................................3
CLINICAL TRIAL SUMMARY ........................................................................................................................4
1
FLOW CHARTS.............................................................................................................................16
1.1
GRAPHICAL STUDY DESIGN ......................................................................................................16
1.2
STUDY FLOW CHART ..................................................................................................................17
2
TABLE OF CONTENTS ................................................................................................................22
2.1
LIST OF TABLES...........................................................................................................................28
3
LIST OF ABBREVIATIONS ..........................................................................................................29
4
INTRODUCTION AND RATIONALE.............................................................................................32
4.1
BACKGROUND: DISEASE AND PRELIMINARY THERAPEUTIC OBSERVATIONS .................32
4.2
BACKGROUND: SOTAGLIFLOZIN...............................................................................................34
4.3
BENEFIT/RISK PROFILE ..............................................................................................................35
4.4
RATIONALE FOR CURRENT STUDY ..........................................................................................35
4.4.1
Rationale for selection of dose.......................................................................................................36
4.4.2
Rationale for Study Design and Control Groups............................................................................37
5
STUDY OBJECTIVES ...................................................................................................................38
5.1
PRIMARY.......................................................................................................................................38
5.2
SECONDARY ................................................................................................................................38
5.3
OTHER...........................................................................................................................................38
5.4
DUAL-ENERGY X-RAY ABSORPTIOMETRY SUB-STUDY ........................................................39
6
STUDY DESIGN ............................................................................................................................40
6.1
DESCRIPTION OF THE STUDY...................................................................................................40
6.1.1
Screening period............................................................................................................................40
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6.1.2
Randomized Double-blind Treatment period .................................................................................40
6.1.3
Post-treatment period.....................................................................................................................42
6.2
DURATION OF STUDY PARTICIPATION ....................................................................................42
6.2.1
Duration of study participation for each patient .............................................................................42
6.2.2
Determination of end of clinical trial (all patients) ..........................................................................42
6.3
INTERIM ANALYSIS......................................................................................................................42
6.4
STUDY COMMITTEES..................................................................................................................42
6.4.1
Executive Committee .....................................................................................................................42
6.4.2
Steering Committee .......................................................................................................................43
6.4.3
Data Monitoring Committee ...........................................................................................................43
6.4.4
Adjudication Committee .................................................................................................................43
6.4.5
Independent Expert Committee to Evaluate Liver Injury ...............................................................43
7
SELECTION OF PATIENTS..........................................................................................................44
7.1
INCLUSION CRITERIA..................................................................................................................44
7.2
EXCLUSION CRITERIA ................................................................................................................46
8
STUDY TREATMENTS .................................................................................................................48
8.1
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................48
8.1.1
Dose up-titration and adjustments .................................................................................................48
8.1.1.1
Dose up-titration.............................................................................................................................48
8.1.1.2
Dose adjustments ..........................................................................................................................49
8.2
NONINVESTIGATIONAL MEDICINAL PRODUCTS.....................................................................49
8.3
BLINDING PROCEDURES............................................................................................................49
8.3.1
Methods of blinding........................................................................................................................49
8.3.2
Randomization code breaking during the study.............................................................................50
8.4
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................50
8.5
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING .............................51
8.6
STORAGE CONDITIONS AND SHELF LIFE................................................................................51
8.7
RESPONSIBILITIES ......................................................................................................................51
8.7.1
Treatment accountability and compliance......................................................................................52
8.7.2
Return and/or destruction of treatments ........................................................................................52
8.8
CONCOMITANT MEDICATION.....................................................................................................53
8.8.1
Antihyperglycemic concomitant medication...................................................................................53
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8.8.2
Other concomitant medications .....................................................................................................53
8.8.3
Forbidden concomitant medication................................................................................................54
8.8.3.1
Prohibited Medications...................................................................................................................54
8.8.3.2
Other Medications..........................................................................................................................54
8.9
POST-STUDY TREATMENT.........................................................................................................55
9
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................56
9.1
EFFICACY ENDPOINTS ...............................................................................................................56
9.1.1
Primary efficacy endpoints.............................................................................................................56
9.1.1.1
Definitions of cardiovascular and renal components of efficacy endpoints (primary, 
secondary, and other) ....................................................................................................................56
9.1.2
Secondary efficacy endpoints........................................................................................................56
9.1.2.1
Estimated glomerular filtration rate and dialysis ............................................................................57
9.1.3
Other efficacy endpoints ................................................................................................................57
9.1.3.1
Hemoglobin A1c.............................................................................................................................58
9.1.3.2
Body weight....................................................................................................................................58
9.1.3.3
Blood pressure...............................................................................................................................58
9.1.3.4
Urinary albumin-to-creatinine ratio.................................................................................................58
9.1.3.5
Hematocrit, hemoglobin, albumin, and total protein ......................................................................59
9.1.3.6
Antihyperglycemics ........................................................................................................................59
9.2
SAFETY ENDPOINTS ...................................................................................................................59
9.2.1
Adverse events, adverse events of special interest, and events of special interest......................59
9.2.1.1
Adverse events of special interest .................................................................................................59
9.2.1.2
Events of special interest ...............................................................................................................60
9.2.2
Laboratory safety variables............................................................................................................60
9.2.2.1
Urinalysis........................................................................................................................................61
9.2.2.2
Markers of bone and calcium metabolism .....................................................................................62
9.2.3
Vital signs and physical exam........................................................................................................62
9.2.4
Electrocardiogram variables ..........................................................................................................62
9.2.5
Severe hypoglycemia.....................................................................................................................62
9.2.6
Change in bone mineral density ....................................................................................................62
9.3
OTHER ENDPOINTS.....................................................................................................................63
9.3.1
Health economic variables.............................................................................................................63
.63
63
63
63
9.5
APPROPRIATENESS OF MEASUREMENTS ..............................................................................64
10
STUDY PROCEDURES ................................................................................................................65
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10.1
VISIT SCHEDULE..........................................................................................................................65
10.1.1
Screening period............................................................................................................................65
10.1.1.1 On-site Visit 1 (Week -4) Screening Visit.......................................................................................66
10.1.2
Randomized Double-blind Treatment period .................................................................................67
10.1.2.1 On-site Visit 2 (Day 1) Randomization...........................................................................................68
10.1.2.2 On-site Visit 3 (Week 4).................................................................................................................69
10.1.2.3 On-site Visit 4 (Week 8).................................................................................................................70
10.1.2.4 On-site Visit 5 (Week 26), and all subsequent on-treatment, on-site visits ...................................70
10.1.2.5 Telephone visits .............................................................................................................................71
10.1.3
Premature End-of-Treatment.........................................................................................................72
10.1.3.1 Premature End-of-Treatment Visit .................................................................................................72
10.1.4
Study Closeout...............................................................................................................................73
10.1.4.1 Study Closeout Visit for patients who do not prematurely permanently discontinue 
investigational medicinal product...................................................................................................74
10.1.4.2 Study Closeout Visit for patients who prematurely permanently discontinue investigational 
medicinal product...........................................................................................................................75
10.1.5
Follow-up........................................................................................................................................75
10.1.5.1 Follow-up Visit................................................................................................................................75
10.2
DEFINITION OF SOURCE DATA..................................................................................................76
10.3
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................77
10.3.1
Temporary treatment discontinuation with investigational medicinal product(s) ...........................77
10.3.2
Permanent treatment discontinuation with investigational medicinal product ...............................78
10.3.3
List of criteria for permanent treatment discontinuation.................................................................78
10.3.4
Handling of patients after permanent treatment discontinuation ...................................................79
10.3.5
Procedure and consequence for patient withdrawal from study....................................................79
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................80
10.4.1
Definitions of adverse events.........................................................................................................80
10.4.1.1 Adverse event ................................................................................................................................80
10.4.1.2 Serious adverse event ...................................................................................................................80
10.4.1.3 Adverse events of special interest .................................................................................................82
10.4.1.4 Events of special interest ...............................................................................................................82
10.4.2
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................83
10.4.3
General guidelines for reporting adverse events ...........................................................................84
10.4.4
Instructions for reporting serious adverse events ..........................................................................85
10.4.5
Guidelines for reporting adverse events of special interest...........................................................85
10.4.6
Guidelines for reporting events of special interest.........................................................................85
10.4.7
Guidelines for management of specific laboratory abnormalities ..................................................85
10.4.8
Guidelines for reporting product complaints (investigational medicinal product) ..........................86
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10.5
OBLIGATIONS OF THE SPONSOR .............................................................................................86
10.6
SAFETY INSTRUCTIONS .............................................................................................................87
10.6.1
Severe hypoglycemia.....................................................................................................................87
10.7
ADVERSE EVENTS MONITORING..............................................................................................87
11
STATISTICAL CONSIDERATIONS..............................................................................................88
11.1
DETERMINATION OF SAMPLE SIZE...........................................................................................88
11.2
DISPOSITION OF PATIENTS .......................................................................................................88
11.3
ANALYSIS POPULATIONS...........................................................................................................89
11.3.1
Efficacy populations .......................................................................................................................89
11.3.1.1 Intent–to-treat population ...............................................................................................................89
11.3.2
Safety population ...........................................................................................................................89
11.4
STATISTICAL METHODS .............................................................................................................89
11.4.1
Extent of study treatment exposure and compliance.....................................................................89
11.4.1.1 Extent of investigational medicinal product exposure....................................................................90
11.4.1.2 Compliance ....................................................................................................................................90
11.4.2
Analyses of efficacy endpoints.......................................................................................................90
11.4.2.1 Analysis of primary efficacy endpoints...........................................................................................90
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................91
11.4.2.3 Multiplicity considerations ..............................................................................................................92
11.4.3
Analyses of safety data..................................................................................................................92
11.4.3.1 Analysis of adverse events ............................................................................................................93
11.4.3.2 Analysis of severe hypoglycemia...................................................................................................94
11.4.3.3 Analysis of adverse events of special interest ...............................................................................94
11.4.3.4 Analysis of events of special interest.............................................................................................95
11.4.3.5 Analysis of laboratory variables .....................................................................................................95
11.4.3.6 Analysis of vital sign variables .......................................................................................................96
11.5
INTERIM ANALYSIS......................................................................................................................96
12
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................97
12.1
ETHICAL AND REGULATORY STANDARDS ..............................................................................97
12.2
INFORMED CONSENT .................................................................................................................97
12.3
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................97
13
STUDY MONITORING...................................................................................................................99
13.1
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................99
13.2
RESPONSIBILITIES OF THE SPONSOR.....................................................................................99
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13.3
SOURCE DOCUMENT REQUIREMENTS..................................................................................100
13.4
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST....................................................................................................................................100
13.5
USE OF COMPUTERIZED SYSTEMS........................................................................................100
14
ADDITIONAL REQUIREMENTS.................................................................................................101
14.1
CURRICULUM VITAE..................................................................................................................101
14.2
RECORD RETENTION IN STUDY SITES ..................................................................................101
14.3
CONFIDENTIALITY .....................................................................................................................101
14.4
PROPERTY RIGHTS...................................................................................................................102
14.5
DATA PROTECTION...................................................................................................................102
14.6
INSURANCE COMPENSATION..................................................................................................103
14.7
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................103
14.8
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................103
14.8.1
By the Sponsor.............................................................................................................................103
14.8.2
By the Investigator .......................................................................................................................104
14.9
CLINICAL TRIAL RESULTS ........................................................................................................104
14.10
PUBLICATIONS AND COMMUNICATIONS ...............................................................................104
15
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................105
16
BIBLIOGRAPHIC REFERENCES...............................................................................................106
17
APPENDICES..............................................................................................................................111
Appendix A 
Contraceptive guidance and collection of pregnancy information .......................................111
Appendix B
Dual-energy x-ray absorptiometry sub-study.......................................................................114
Appendix C
General guidance for the follow-up of laboratory abnormalities by sanofi ..........................120
Appendix D
Guidance for the follow-up of acute worsening of renal function.........................................124
Appendix E 
Definition of urgent heart failure visit ...................................................................................125
Appendix F
Country-specific requirements ..............................................................................................127
Amendment for India ...................................................................................................................................127
Amendment for Canada and United States of America ..............................................................................128
Appendix G
Protocol amendment history................................................................................................133
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2.1
LIST OF TABLES
Table 1 - Investigational medicinal products .................................................................................................48
Table 2 - Chemistry parameters....................................................................................................................60
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3
LIST OF ABBREVIATIONS
AE:
adverse event
AESI:
adverse event of special interest
ALT:
alanine aminotransferase
AST:
aspartate aminotransferase
BMD:
bone mineral density
BMI:
body mass index
BNP:
B-type natriuretic peptide
BP:
blood pressure
CAC:
coronary artery calcium
CEC:
Clinical Endpoint Committee
CI:
confidence interval
CKD:
chronic kidney disease
CPK:
creatinine phosphokinase
CSR:
clinical study report
CV:
cardiovascular
CVD:
cardiovascular disease
CVOT:
cardiovascular outcomes trial
DB:
database
DBP:
diastolic blood pressure
DILIs:
drug-induced-liver injuries
DKA:
diabetic ketoacidosis
DKD:
diabetic kidney disease
DMC:
data monitoring committee
DRF:
discrepancy resolution form
DXA:
dual-energy X-ray absorptiometry
EC:
Executive Committee 
ECG:
electrocardiogram
e-CRF:
electronic case report form
EF:
ejection fraction
eGFR:
estimated glomerular filtration rate
EMA:
European Medicines Agency
EOSI:
event of special interest
FDA:
Food and Drug Administration
GCP:
good clinical practice
GI:
gastrointestinal
GLP-1:
glucagon-like peptide – 1
GP:
general practitioner
HbA1c:
hemoglobin A1c
HF:
heart failure
HHF:
hospitalization for heart failure
HLGT:
high-level grouped term
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HLT:
high-level term
hsCRP:
high-sensitivity C-reactive protein
hsTnT:
high-sensitivity troponin T
IABP:
intra-aortic balloon pump
ICF:
informed consent form
IEC:
independent ethics committee
IMP:
investigational medicinal product
INN:
international nonproprietary name
IRB:
institutional review board
IRT:
Interactive Response Technology
ITT:
intent-to-treat
LV:
left ventricular
MACE:
major adverse cardiovascular event
MDRD:
modification of diet in renal disease 
MI:
myocardial infarction
NI:
non-inferiority
NT-proBNP:
N-terminal pro-B-type natriuretic peptide
NTX:
N telopeptide of type 1 collagen
P1NP:
N-terminal propeptide of type 1 procollagen
PCSA:
potentially clinically significant abnormality
PD:
pharmacodynamic
pEOT:
premature End-of-Treatment
PET:
positron emission tomography
P-gp:
P-glycoprotein
PI:
principal investigator
PPG:
postprandial glucose 
PT:
preferred term
PTH:
parathyroid hormone
PYY:
peptide YY 
qd:
once daily
RAAS:
renin-angiotensin-aldosterone system
SAE:
serious adverse event
SAP:
statistical analysis plan
SBP:
systolic blood pressure
SC:
steering committee
SD:
standard deviation
SGLT1:
sodium-glucose linked transporter-1
SGLT2:
sodium-glucose linked transporter-2
SMQ:
standardized MedDRA query
SOC:
system organ class
SPECT:
single-photon emission computed tomography
SUSAR:
suspected unexpected serious adverse reaction
T1D:
type 1 diabetes
T2D:
type 2 diabetes
TEAE:
treatment-emergent adverse event
UACR:
urinary albumin-to-creatinine ratio
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UB:
upper bound
UGE:
urinary glucose excretion
ULN:
upper limit of normal
WOCBP:
women of childbearing potential
β-CTX 1:
beta-C-terminal telopeptide of type 1 collagen
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4
INTRODUCTION AND RATIONALE
4.1
BACKGROUND: DISEASE AND PRELIMINARY THERAPEUTIC OBSERVATIONS
Type 2 diabetes (T2D) is a growing epidemic worldwide that is associated with a high incidence 
of macrovascular and microvascular complications (1). Type 2 diabetes is associated with 
cardiovascular (CV) risk factors such as dyslipidemia, hypertension, and obesity (2). The 
Emerging Risk Factors Collaboration has recently reported that patients with T2D have a doubled 
risk of CV death compared to patients without diabetes (2). Although microvascular 
complications have been shown to be decreased by glucose-lowering therapies, the effect on 
macrovascular outcomes is not as clear (3, 4, 5, 6). Therefore, it is important to evaluate the CV 
safety of glucose-lowering drugs, as specified in the 2008 Food and Drug Administration (FDA)
Guidance Document (Guidance for Industry: Diabetes Mellitus - Evaluating Cardiovascular Risk 
in New Antidiabetic Therapies to Treat Type 2 Diabetes; 7) and the 2016 European Medicines 
Agency (EMA) Reflection paper on assessment of cardiovascular safety of medical products (8).
The prevalence of T2D is increasing, and it is projected that 439 million individuals worldwide
will be affected by 2030 (9). As the frequency of diabetes increases, so will its complications, 
including renal impairment, CV death, and heart failure (HF). Hence, the development of 
glucose-lowering therapies effective at decreasing the risk of CV death and HF and/or the 
progression of renal impairment is a growing unmet medical need.
In patients with diabetes the prevalence of HF is considerably higher compared to the general 
population and increases with age (10, 11, 12). One in 5 patients with diabetes aged over 65 years 
suffers from HF (12). In addition, several observational studies and clinical trials have shown that 
HF patients with diabetes have increased CV morbidity and mortality compared to HF patients 
without diabetes (12, 13, 14, 15). 
Approximately 50% of patients with T2D have chronic kidney disease (CKD), defined as a 
persistent elevated urinary albumin excretion (urinary albumin-to-creatinine ratio [UACR] 
≥30 mg/g [3 mg/mmol]), renal impairment (defined as a persistent reduction in estimated 
glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), or both (16). 
Recent data indicate that sodium-glucose linked transporter-2 (SGLT2) inhibitors may address the 
growing unmet medical need of treatment for prevention of CV death and HF and progression of 
renal impairment in patients with T2D (17). These antihyperglycemic agents lower blood glucose 
levels through the inhibition of renal glucose reabsorption thereby enhancing renal glucose 
excretion. In 2015, the EMPA-REG OUTCOME trial showed that empagliflozin, another SGLT2 
inhibitor, when added to standard of care, reduced the risk of CV death (a component of the 
primary composite endpoint) and HF requiring hospitalization in patients with T2D and 
established CV disease (CVD), including 10% with HF at screening (18). In 2017, the CANVAS 
program showed that canagliflozin, when added to standard of care, reduced the risk of a 
composite outcome of CV death, non-fatal myocardial infarction (MI) or non-fatal stroke in 
patients with T2D and established CVD or at high risk for CV events (19). Of note, the FDA 
recently approved empagliflozin for reducing the risk of CV death in adult patients with T2D and 
established CVD (20).
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The mechanisms supporting the CV benefit of empagliflozin have not been fully elucidated, but 
several experts have speculated that the hemodynamic effects of SGLT2-inhibition are the main 
driver (21, 22, 23). Empagliflozin may have affected volume status via either or both of the 
following mechanisms: a sodium and volume reduction, and/or a decrease in arterial pressure. The 
possible diuresis and beneficial effect on maladaptive renal arteriolar responses may have led to 
improvement in both systolic and diastolic function, thereby lowering HF hospitalization and 
sudden cardiac death. Empagliflozin induces a considerable diuresis with early loss of urinary 
glucose and sodium, resulting in an approximate 4% increase in the hematocrit. Diuretics are an 
essential treatment in HF because renal perfusion and neurohumoral activation lead to sodium and 
water retention, the hallmark of the HF syndrome. Patients with diabetes, subclinical cardiac 
dysfunction, and renal impairment may be especially sensitive to fluid retention. The cardiac 
function of the EMPA-REG OUTCOME study population was not characterized, but it has been 
suggested that a substantial proportion of the trial’s population might have had mild HF or some 
form of preclinical HF or diabetic cardiomyopathy (23, 24). The beneficial CV effects of 
empagliflozin were consistent across subgroups including patients with versus without HF at 
baseline (24).
In addition to the hemodynamic hypothesis, there is another hypothesis: under conditions of mild, 
persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, 
b-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference 
to fatty acids. This fuel selection improves the transduction of oxygen consumption into work 
efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows 
SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy 
with the metabolic substrate shift (25).
The SGLT2 inhibitors have complex renal effects and, despite their diuretic action, may suppress, 
rather than stimulate the renin-angiotensin-aldosterone system (RAAS), which would be 
beneficial in preventing and treating HF (26). Type 2 diabetes is associated with upregulation of 
the SGLT2 tubular transporters. Sodium-glucose linked transporter-2 inhibitors block tubular 
glucose reabsorption along with sodium reabsorption in the proximal renal tubules, leading to 
increased sodium delivery to the macula densa. Increased distal tubule sodium delivery results in 
tubuloglomerular feedback, afferent glomerular arteriolar vasoconstriction, and subsequent 
reduction in glomerular capillary pressure. The reduction in intraglomerular hypertension inhibits 
the hyperfiltration that is characteristic of both type 1 diabetes (T1D) and T2D and is responsible 
for the tubulointerstitial fibrosis that is postulated to be the major determinant of the progression 
of diabetic kidney disease (DKD).
In the EMPA-REG OUTCOME study, a pre-specified secondary endpoint was a composite of the 
following renal outcomes: progression to macroalbuminuria, doubling of serum creatinine, 
initiation of renal-replacement therapy, or renal death (hazard ratio=0.61; 95% confidence interval 
[CI]: 0.53 -0.70; p<0.001). A slower progression of kidney disease with empagliflozin was also 
observed in a post-hoc assessment of renal outcomes (progression to macroalbuminuria was 
excluded from the endpoint [27]). In CANVAS (19), a prespecified secondary outcome was 
progression of albuminuria (Hazard ratio=0.73; 95% CI: 0.67 to 0.79). However, since the 
hypothesis testing plan was hierarchical, superiority for the first secondary outcome (all-cause 
mortality) was not shown and therefore hypothesis testing was discontinued. A key prespecified 
exploratory composite outcome was: a sustained 40% reduction in the eGFR, the need for renal 
replacement therapy or death from renal causes (Hazard ratio= 0.60; 95% CI: 0.47 to 0.77).
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4.2
BACKGROUND: SOTAGLIFLOZIN
Sotagliflozin, a potent, dual inhibitor of SGLT2 and sodium-glucose linked transporter-1 
(SGLT1), is in clinical development for the treatment of T1D and T2D (28). Sodium-glucose 
linked transporter-1 is expressed predominantly in the gastrointestinal (GI) tract, and is 
responsible for the majority of glucose absorption by the small intestine. Inhibition of SGLT1 in 
the GI tract delays glucose absorption, and stimulates L cells in both the ileum and the colon to 
secrete glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), gut hormones involved in 
pancreatic beta-cell function and appetite control, respectively. Although a complete lack of 
functional SGLT1 may be associated with symptoms of glucose and galactose malabsorption (29), 
pharmacologic inhibition of SGLT1 by sotagliflozin has not produced these effects in preclinical 
models or patients with T1D or T2D.
Sotagliflozin may have unique effects on both CKD and on blood pressure (BP). Study 
LX4211.1-107 was a Phase 1 study performed in patients with T2D with moderate to severe renal 
impairment (defined as a Screening eGFR of 15 to 59 mL/min/1.73 m2). In patients with an eGFR 
between 15 to <45 mL/min/1.73 m2, no reduction in postprandial glucose (PPG) on Day 7 
compared to Day 1 was seen. However, urinary glucose excretion (UGE) decreased by 
approximately 50% in these patients. This finding suggests that the PPG effect is not due only to 
SGLT2 inhibition. The study also showed a statistically significant increase of GLP-1 induced by 
sotagliflozin, consistent with SGLT1 inhibition, delayed glucose absorption, and L cell 
stimulation. These results indicate that sotagliflozin still enhanced glycemic control in patients 
with T2D and renal impairment, which was consistent with the mechanism of action of 
sotagliflozin as a dual inhibitor of SGLT1 and SGLT2. These results support the hypothesis that 
sotagliflozin has a potential to improve glycemic control in this population through clinically 
meaningful SGLT1 inhibition. In addition, UGE statistically significantly increased following 
sotagliflozin dosing compared to placebo, suggesting that inhibition of renal glucose reabsorption 
via SGLT2 inhibition was at least partially maintained for patients with moderate to severe renal 
impairment.
In addition, dual inhibition of the SGLT1 and SGLT2 receptors may be responsible for the potent 
antihypertensive effect of sotagliflozin, which appears to be substantially more pronounced than 
the effect reported with selective SGLT2 inhibition. Study LX4211.1-202 was a Phase 2b study in 
patients with T2D on the combination of sotagliflozin and metformin, with inadequate glycemic 
control on metformin monotherapy. A mean difference of change in systolic blood pressure (SBP) 
from baseline to Week 12 of -3.9, -5.7, and -4.5 mmHg for 200 mg once daily (qd), 200 mg twice 
daily and 400 mg qd of sotagliflozin, respectively, was seen. Sotagliflozin induces a 
dose-dependent reduction of SBP in hypertensive patients. In study LX4211.1 202 DM, a 
prespecified sub-analysis of patients with a baseline BP ≥130 mmHg showed that SBP decreased 
by 7 and 14 mmHg (placebo-subtracted), respectively, in the 200 mg qd and 400 mg qd groups. 
Blood pressure changes with treatment were of a magnitude comparable to approved 
antihypertensive agents, and they were obtained without hypotension in a population whose 
baseline mean SBP was 125 mmHg and whose baseline mean diastolic blood pressure (DBP) was 
79 mmHg. While clinically meaningful changes in BP were demonstrated, the population was not 
selected for the presence of hypertension and severe hypertension was excluded. Concomitant 
antihypertensive medications were allowed and adjustments in their dose were permitted as 
needed. The BP reductions therefore reflect a real world practice setting. However, their time 
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course over the day, their potential impact on severe hypertension, and their influence or 
interaction with other medications, have yet to be determined. Therefore, based on its effect on 
plasma volume and renal hemodynamics, chronic treatment with sotagliflozin is expected to both 
reduce the CV risk and the progression of DKD in patients with T2D.
4.3
BENEFIT/RISK PROFILE
Sotagliflozin, a dual inhibitor of SGLT1 and SGLT2, is being developed for the treatment of T1D 
and T2D. Multiple-dose (up to 12 week) administration in patients with T1D and T2D produced 
improvements in several metabolic parameters, including levels of fasting glucose, 
hemoglobin A1c (HbA1c), PPG, GLP-1, and PYY. Sotagliflozin also enabled patients with T1D 
to control their daily glucose levels while decreasing their daily insulin doses in one of the 
Phase 1 studies implemented to date (28). These data suggest that sotagliflozin will be of 
therapeutic benefit to patients with T1D and T2D.
Although a complete lack of functional SGLT1 may be associated with symptoms of glucose and 
galactose malabsorption (29), pharmacologic inhibition of SGLT1 by sotagliflozin has not 
produced these effects in preclinical models or patients with diabetes evaluated so far. No 
significant safety concerns have been identified in the sotagliflozin clinical program, and 
sotagliflozin has been well-tolerated in all completed studies. Serious adverse events (SAEs) and 
discontinuations due to adverse events (AEs) have been uncommon and have been balanced 
between treatment and control groups. Suspected adverse reactions that have occurred in ≥3.0% of 
patients in sotagliflozin clinical studies include headache, nausea, and diarrhea, all of which 
occurred at a numerically greater rate in patients treated with sotagliflozin than with controls. 
However, these events have been infrequent, the majority were mild to moderate in intensity, with 
most resolving spontaneously. Overall, no imbalance was observed in the events of hypoglycemia 
in the sotagliflozin program.
Overall, the potential benefits of sotagliflozin therapy for patients with T1D and T2D, including 
improvement in glycemic control and the reductions in weight and BP, outweigh the potential 
risks. The favorable benefit-risk assessment to date supports the further development. 
More information on the safety of sotagliflozin and on the clinical program can be found in the 
Investigator Brochure.
4.4
RATIONALE FOR CURRENT STUDY
This study is designed to demonstrate the CV and renal effects of sotagliflozin in patients with 
T2D, high CV risk, and moderate renal impairment. One of the major objectives of this study is to 
fulfill the regulatory mandate that any new therapy for T2D must demonstrate that its use does not 
result in an unacceptable increase in CV risk. In concordance with the 2008 FDA guidance 
document for new therapies for T2D, non-inferiority (NI) of sotagliflozin versus placebo with a 
1.3 NI margin (upper bound [UB] of the 95% CI [CI of the estimated risk ratio <1.3]) will be 
assessed on 3-point major adverse CV event (MACE; CV death, non-fatal MI or non-fatal stroke)
as the first primary objective. 
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The second primary objective of the study is to evaluate if sotagliflozin decreases the risk versus
placebo of CV death or hospitalization for heart failure (HHF) in patients with T2D, high CV risk
factors and moderate renal impairment. 
Secondary objectives include assessment of superiority of sotagliflozin versus placebo on 3-point 
MACE and on the progression of CKD in patients with T2D, high CV risk factors, and moderate
renal impairment.
4.4.1
Rationale for selection of dose
In healthy subjects, sotagliflozin was well-tolerated following single doses up to 2,000 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 2,000 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 400 mg sotagliflozin.
The starting dose of sotagliflozin (200 mg qd) and the maintenance dose (400 mg qd) were
selected based on the results of the Phase 2b study LX4211.1 202 DM. In this study, doses of 
sotagliflozin 75 mg qd, 200 mg qd, 200 mg twice daily, and 400 mg qd were tested over a 
12-week, double-blind period. At 12 weeks, the 200 mg qd and 400 mg qd doses lowered HbA1c 
by a mean of 0.52% and 0.92%, respectively (p<0.001 for both arms), while placebo lowered 
HbA1c by a mean of 0.09%. The overall incidence of AEs on sotagliflozin 200 mg qd and 
400 mg qd doses was similar to placebo, hence the 200 mg dose was less effective than the 
400 mg qd dose and did not present clear advantages in safety or tolerability. Both doses are 
currently undergoing further evaluation in phase 3 glucose-control studies.
Sotagliflozin induces an acute, but modest, decrease in eGFR. Since the study population consists 
of patients at increased risk of acute kidney injury (ie, patients with moderately impaired renal 
function), study treatment will begin with the low dose of sotagliflozin (200 mg qd) and will be 
increased to the maintenance dose of 400 mg qd, once tolerability of the low dose has been 
established by the Investigator.
Recent studies have demonstrated that SGLT2-inhibitors decrease the risk of CV death and 
hospitalization for HF in patients with T2D and high CV risk. The underlying mechanism(s) for 
the CV benefit are still under investigation, but the hemodynamic effects of SGLT2-inhibitors 
have been speculated to play a major role (21, 22, 23) since these compounds decrease plasma 
volume and reduce BP likely resulting in improved systolic and diastolic function. It should be 
noted that in EMPA-REG OUTCOME (18) an approximate 4% increase in the hematocrit was 
observed in the empagliflozin arm compared with the placebo arm, and a post hoc univariate 
analysis suggested that a change in hematocrit was the key mediator of the CV benefit (30). A 
strong correlation with the cardioprotective effect of empagliflozin was also shown for albumin 
and hemoglobin, collectively suggesting the importance of changes in plasma volume. Several 
other studies have indicated that a reduction in plasma volume in patients with HF is associated 
with improved outcome (31, 32, 33, 34).
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In study LX4211.1 202 DM sotagliflozin induced a dose-dependent increase of hematocrit 
albumin, and hemoglobin. The mean change (standard deviation [SD]) in hematocrit from 
baseline to Week 12 was 0.9 (2.52), 2.0 (2.47), and 1.9 (2.78) % in patients receiving sotagliflozin 
200 mg qd, 200 mg twice daily, and 400 mg qd, respectively, versus -0.5 (2.98) % in the placebo 
arm. The mean change (SD) in albumin from baseline to Week 12 (SD) was 0.0 (0.279) , 
0.09 (0.243), and 0.12 (0.242) g/dL in patients receiving sotagliflozin 200 mg qd, 200 mg twice 
daily, and 400 mg qd, respectively, versus -0.04 (0.273) g/dL in the placebo arm. The mean 
change (SD) in hemoglobin from baseline to Week 12 (SD) was 0.29 (0.775) , 0.55 (0.688), and 
0.60 (0.820) g/dL in patients receiving sotagliflozin 200 mg qd, 200 mg twice daily, and 400 mg 
qd, respectively, versus -0.19 (1.084) g/dL in the placebo arm. In addition, in the same study, a 
prespecified sub-analysis of patients with a baseline BP ≥130 mmHg showed that SBP decreased 
by 7 and 14 mmHg (placebo-subtracted), respectively, in the 200 mg qd and 400 mg qd groups.
Therefore, given the observed higher efficacy of the 400 mg dose on glycemic control, 
hemoconcentration, and BP reduction and given the potential benefit of these changes on CV
outcomes, the dose of 400 mg was chosen as the proposed maintenance dose for the study.
4.4.2
Rationale for Study Design and Control Groups
This study is a pivotal, Phase 3, CV outcomes trial (CVOT); hence, it has been designed as a 
randomized, double-blind, event-driven study with external, blinded adjudication. The study will 
continue until approximately 844 positively-adjudicated CV death or HHF events and 
approximately 1189 positively-adjudicated 3-point MACE have occurred.
In order to demonstrate the effects of sotagliflozin on CV and renal outcomes, the patients will be 
randomized to sotagliflozin or placebo in addition to standard of care treatments. This approach 
will ensure the scientific rigor of the comparison. Patients with established CVD (eg, prior acute 
MI or coronary revascularization) will not be eligible for the trial if treatment with an SGLT2
inhibitor is planned during the course of the study.
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5
STUDY OBJECTIVES
5.1
PRIMARY 

The 2 primary objectives of this study are to demonstrate that, when compared to placebo 
in patients with T2D, CV risk factors, and moderately impaired renal function, 
sotagliflozin:
-
Is non-inferior to placebo on the composite endpoint of CV death, non-fatal MI, or 
non-fatal stroke (3-point MACE)
-
Reduces the composite endpoint of CV death or HHF
5.2
SECONDARY 

The secondary objectives of this study are to demonstrate that, when compared to placebo 
in patients with T2D, CV risk factors, and moderately impaired renal function, 
sotagliflozin:
-
Reduces the composite endpoint of CV death, non-fatal MI or non-fatal stroke (3-point 
MACE)
-
In patients with Baseline eGFR ≥30 mL/min/1.73 m2, reduces the composite renal 
endpoint of sustained ≥50% decrease in eGFR from Baseline (for ≥30 days), chronic 
dialysis, renal transplant, or sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)
-
In patients with Baseline eGFR ≥30 mL/min/1.73 m2 and Baseline UACR ≥300 mg/g 
(34 mg/mmol), reduces the composite renal endpoint of sustained ≥50% decrease in 
eGFR from Baseline (for ≥30 days), chronic dialysis, renal transplant, or sustained 
eGFR <15 mL/min/1.73 m2 (for ≥30 days)
-
Reduces the composite endpoint of CV death, HHF, or urgent HF visit (defined in
Appendix E)
-
Reduces CV death
-
Reduces all-cause mortality 

To assess the safety and tolerability of sotagliflozin in patients with T2D, CV risk factors, 
and moderately impaired renal function
5.3
OTHER

To demonstrate that, when compared to placebo in patients with T2D, CV risk factors, and 
moderately impaired renal function, sotagliflozin:
-
In patients with Baseline eGFR ≥30 mL/min/1.73 m2, reduces the composite endpoint 
of sustained ≥50% decrease in eGFR from Baseline (for ≥30 days), chronic dialysis, 
renal transplant, sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days), or CV or renal 
death 
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-
Reduces the composite endpoint of CV death, non-fatal MI, non-fatal stroke, or 
unstable angina requiring hospitalization (4-point MACE)
-
In patients with Baseline eGFR ≥30 mL/min/1.73 m2, reduces the composite renal 
endpoint of worsening nephropathy, defined as: new onset or progression to macro 
albuminuria (≥300 mg/g [34 mg/mmol]) accompanied by a UACR value increase of 
≥30% from Baseline, sustained ≥50% decrease in eGFR from Baseline (for ≥30 days), 
chronic dialysis, need for renal transplant, eGFR <15 mL/min/1.73 m2 (for ≥30 days), 
or renal death 

To compare sotagliflozin versus placebo with respect to change from Baseline to 
6 months, 12 months, and 24 months in the following endpoints: 
-
Hemoglobin A1c
-
Body weight
-
Blood pressure
-
Urinary albumin-to-creatinine ratio
-
Estimated glomerular filtration rate
-
Hematocrit
-
Hemoglobin
-
Albumin
-
Total protein

To compare sotagliflozin versus placebo with respect to change from Baseline to 6 months
and 12 months in the following endpoints: 
-
N-terminal pro-B-type natriuretic peptide (NT-proBNP)
-
High-sensitivity troponin T (hsTnT)
-
High-sensitivity C-reactive protein (hsCRP)

To compare sotagliflozin versus placebo with respect to change from Baseline in the 
following endpoints: 
-
Proportion of patients not taking insulin at baseline who start insulin during the study
5.4
DUAL-ENERGY X-RAY ABSORPTIOMETRY SUB-STUDY
The primary objective of the sub-study is to assess the impact of sotagliflozin on bone and 
calcium metabolism and bone quality in patients with T2D, CV risk factors, and moderately 
impaired renal function. Additional details of the sub-study are presented in Appendix B.
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6
STUDY DESIGN
6.1
DESCRIPTION OF THE STUDY
This study is a Phase 3, multicenter and multinational, randomized, double-blind, 
placebo-controlled, parallel-group study in approximately 10,500 patients with T2D, CV risk 
factors, and moderately impaired renal function. The study will consist of 3 periods: 

A Screening period of 1 to 4 weeks

A randomized, Double-blind Treatment period including up-titration (the dose of 
sotagliflozin or matched placebo should be increased from 200 mg to 400 mg in the first 
6 months of the randomized Double-blind Treatment period, if tolerated)

A 14-day Post-treatment period
Approximately 190 patients (95 females and 95 males) will participate in the dual-energy X-ray 
absorptiometry (DXA) sub-study at participating sites. Full details of the DXA sub-study are 
presented in Appendix B.
6.1.1
Screening period
The Screening period will last 1 to 4 weeks. The period must be long enough to collect the data 
required to establish whether the patient satisfies the inclusion/exclusion criteria. 
At the Screening Visit after signing of the informed consent form (ICF), eligibility criteria will be 
assessed and Screening assessments will be performed. 
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.
6.1.2
Randomized Double-blind Treatment period
Patients who meet all eligibility criteria during the Screening period will come back for the 
Randomization Visit (Visit 2) between 7 and 28 days later and, if they are still eligible for the 
study, they will be randomized 1:1 to sotagliflozin or placebo. 
Randomization will be stratified by region (North America, Latin America, Western Europe, 
Eastern Europe, and rest of the world) and by HF-related criteria (Yes/No). 
HF-related criteria is ‘Yes’ when a patient meets at least 1 of the major CV risk factors: 
1. Ejection fraction (EF) ≤40% documented within the past year
2. Hospitalization for HF during previous 2 years
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Patients will receive 200 mg sotagliflozin (or matched placebo) from Randomization onwards. At 
Visit 3 (Week 4), if in the opinion of the Investigator the patient’s clinical condition is satisfactory 
and the patient has tolerated the investigational medicinal product (IMP) well, the dose will be 
increased to 400 mg sotagliflozin or matched placebo as described in Section 8.1.1.1. If IMP dose 
is not increased at Visit 3 (eg, for safety reasons) it will be increased at Visit 4 (Week 8) or Visit 5 
(Week 26), if possible. The 400 mg dose (or 200 mg in those who cannot tolerate up-titration by 
Visit 5) will be maintained for the duration of the remaining double-blind study treatment period.
Antihyperglycemic therapy should remain unchanged for the first 12 weeks after Randomization. 
However, in cases of medical necessity, addition of antihyperglycemic therapy, dose adjustment 
or discontinuation of antihyperglycemic therapy could occur (see Section 8.8).
After Visit 3, patients will attend on-site visits at Weeks 8 (Visit 4) and 26 (Visit 5). After Visit 5, 
patients will attend on-site visits every 6 months. In between each on-site visit, starting with Visit 
5, patients will be contacted by phone twice at 9 week intervals (ie, 9 weeks after the on-site visit 
and again 18 weeks after the on-site visit) to collect drug accountability information, concomitant 
medications, endpoint events, and AEs. 
All randomized patients, will be followed from Randomization until their Follow-up Visit (or 
Study Closeout Visit, for patients who prematurely permanently discontinued from IMP) or death, 
whichever comes first. 
The study is event driven, therefore, it will continue until approximately 844 primary CV events 
of CV death or HHF and approximately 1189 3-point MACEs are positively adjudicated. All 
randomized patients will be asked to return to the study site for a Study Closeout Visit once the 
date the required number of events are projected to be positively adjudicated has been determined. 
The timing and window of this visit will be communicated to sites.
If a patient permanently discontinues treatment with IMP prematurely, the patient will undergo a 
premature End-of-Treatment (pEOT) Visit as soon as possible. Every effort will then be made to 
have the patients return to the site at the times corresponding to their scheduled visits, until the 
Study Closeout Visit. For patients who prematurely permanently discontinue IMP, the Study 
Closeout Visit will be the final study visit and no further visits are planned. Study Closeout Visit 
procedures will differ for patients who do not prematurely permanently discontinue IMP and 
those who do prematurely permanently discontinue IMP (see Section 10.1.4.1 and 
Section 10.1.4.2, respectively). 
See Section 10.3.2 for details on patients who refuse to continue in the study after premature IMP 
discontinuation.
All patients will continue to be followed after a CV or renal endpoint occurs. Patients with a 
suspected renal event (reduction of eGFR) should be brought in for an unscheduled visit and have 
a repeat assessment of renal function 30 to 45 days following the onset of the event to confirm it 
is sustained. If acute renal failure is suspected, further clinical evaluation should be performed as 
per local standard of care, including confirmation of renal laboratory parameters, and 
consideration should be given to a nephrology referral. Patients will continue with IMP treatment 
after a CV or renal endpoint occurs unless they have prematurely permanently discontinued 
treatment or the criteria for permanent treatment discontinuation have otherwise been met
(see Section 10.3.3).
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6.1.3
Post-treatment period
Patients still taking the IMP at the time of the Study Closeout Visit (ie, who have not prematurely 
permanently discontinued IMP) will have their final study visit (Follow-up Visit) 14 days 
(±4 days) after their Study Closeout Visit.
6.2
DURATION OF STUDY PARTICIPATION
6.2.1
Duration of study participation for each patient
All patients participate in a Screening period of 1 to 4 weeks. The study is event driven, therefore 
the duration of the study for each patient will be determined by when approximately 844 primary 
events of CV death or HHF and approximately 1189 3-point MACEs have been 
positively-adjudicated.
The estimated study treatment duration for a given patient will be approximately 27 to 51 months, 
assuming approximately 24 months of recruitment, and approximately 27 months of follow-up, 
after the last patient is randomized.
6.2.2
Determination of end of clinical trial (all patients)
All randomized patients will be asked to return to the study site for a Study Closeout Visit when 
approximately 844 primary CV events of CV death or HHF and approximately 1189 3-point 
MACE are positively adjudicated. The timing and window of this visit will be communicated to 
sites. For patients who previously prematurely permanently discontinued IMP, the Study Closeout 
Visit will be the final study visit and no further visits are planned. Patients still taking the IMP at 
the time of the Study Closeout Visit (ie, who have not prematurely permanently discontinued 
IMP) will have their final study visit (Follow-up Visit) 14 days (±4 days) after their Study 
Closeout Visit.
6.3
INTERIM ANALYSIS
Refer to Section 11.5 for details of a potential interim analysis.
6.4
STUDY COMMITTEES
6.4.1
Executive Committee 
The Executive Committee (EC) will oversee all the sotagliflozin outcomes trials. The EC is 
responsible for supporting the Sponsor in designing a scientifically sound study. The EC is also 
responsible for ensuring accurate reporting of the study results. 
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6.4.2
Steering Committee
The Steering Committee (SC) is responsible for supporting the Sponsor and EC, in designing a 
scientifically sound study. In this capacity, the SC shall address and resolve scientific issues 
encountered during the study. The Chair and Co-Chair of the SC will be members of the EC. 
6.4.3
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will meet on a regular basis to review 
accumulating unblinded clinical study data. Following each meeting, the DMC will make a 
recommendation to the Sponsor regarding the study. 
6.4.4
Adjudication Committee
An independent Clinical Endpoint Committee (CEC) will review and adjudicate all events of 
death, MACE (CV death, non-fatal MI or non-fatal stroke), selected CV and renal events, diabetic 
ketoacidosis (DKA) and bone fractures in a treatment-blinded manner. 
6.4.5
Independent Expert Committee to Evaluate Liver Injury
An expert committee will review all potential cases of drug-induced liver injuries (DILIs) in a 
treatment blinded manner to evaluate causality.
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7
SELECTION OF PATIENTS
7.1
INCLUSION CRITERIA
Mandatory Inclusion Criteria (all 4 criteria are necessary)
I 01.
Signed written informed consent 
I 02.
Type 2 diabetes with HbA1c ≥7% (53 mmol/mol) at Screening (central laboratory)
I 03.
Estimated glomerular filtration rate ≥25 and ≤60 mL/min/1.73 m2 by the 4 variable 
Modification of Diet in Renal Disease (MDRD) equation (at Screening, based on central 
laboratory)
I 04.
Patients either:
-
Age ≥18 years with at least 1 (one) of the major CV risk factors listed below OR
-
In the absence of a major CV risk factor, age ≥55 years with at least 2 (two) of the 
minor CV risk factors listed below
In order to be considered eligible to participate in the study, patients must meet all 4 (four) of the 
mandatory criteria. Patients can be eligible if they have both major and minor CV risk factors, as 
long as 1 of the 2 conditions in Inclusion Criterion Number 4 is met. Major and minor CV risk 
factors are listed below.
Major CV risk factors (at least 1 criterion to fulfill Inclusion Criterion Number 4) 
A) Hospitalization for HF during previous 2 years
B) Ejection Fraction (EF) ≤40% 
Documented within the past year by previous imaging modality (such as echocardiogram,
MUltiple Gated Acquisition (MUGA) scan, Magnetic Resonance Imaging (MRI), positron 
emission tomography (PET), single-photon emission computed tomography (SPECT), left 
ventricular (LV) angiography)
Note: An echocardiogram to assess EF at the time of Screening MUST be performed in 
all patients if an assessment of EF has not been documented within 1 year prior to 
Screening
C) Diagnosis of left ventricular hypertrophy 
By either electrocardiogram (ECG) or echocardiogram 
D) Coronary artery calcium (CAC) score ≥300 Agatston Units 
Documented by coronary artery CT scan
Note: a coronary artery CT scan MAY be performed to measure the CAC score if 
required for eligibility if not previously documented
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E) N-terminal pro-B-type natriuretic peptide ≥400 pg/mL (47 pmol/L) 
At Screening, based on central laboratory
F) High-sensitivity troponin T >15.0 pg/mL (0.015 µg/L) for men and >10.0 pg/mL
(0.010 µg/L) for women 
At Screening, based on central laboratory
G) High-sensitivity C-reactive protein >3 mg/L (28.6 nmol/L)
At Screening, based on central laboratory, if the Investigator does not consider the 
elevation to be due to an acute inflammatory condition (eg, acute infection)
H) Urinary albumin-to-creatinine ratio ≥300 mg/g (34 mg/mmol)
At Screening, based on central laboratory
Minor CV risk factors (if no major CV risk factors, at least 2 criteria to fulfill Inclusion 
Criterion Number 4) 
I)
Body mass index (BMI) ≥35 kg/m2 at Screening
J) Dyslipidemia despite maximally-tolerated statin therapy: 
-
Low-density lipoprotein cholesterol >130 mg/dL (>3.36 mmol/L)
Or
-
High-density lipoprotein cholesterol <40 mg/dL (<1.03 mmol/L) for men or 
<50 mg/dL (<1.29 mmol/L) for women
Based on the last measured and documented laboratory measurement in the previous 
6 months
K) Currently smoking tobacco 
Consumes an average of at least 1 cigarette, pipe, or cigar per day, at Screening
L) Coronary artery calcium score >100 and <300 Agatston Units 
Documented by coronary artery CT scan
Note: a coronary artery CT scan MAY be performed to measure the CAC score if 
required for eligibility if not previously documented
M) Urinary albumin-to-creatinine ratio ≥30 mg/g and <300 mg/g (3 and 34 mg/mmol)
During Screening period, based on central laboratory
N) Systolic Blood Pressure >140 mmHg and DBP >90 mmHg despite antihypertensive 
therapy at the Screening Visit 
O) Family history of premature coronary heart disease (defined as MI or coronary 
revascularization procedure) in a first degree relative 
In a male relative <55 years or in a female relative <65 years 
To participate in the DXA sub-study, patients also need to provide signed written informed 
consent for the sub-study (see Appendix B).
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7.2
EXCLUSION CRITERIA
E 01. History of DKA or nonketotic hyperosmolar coma within 3 months prior to the Screening 
Visit or between Screening and Randomization
E 02. Antihyperglycemic treatment (if applicable) has not been stable in the 12 weeks prior to 
Screening or between Screening and Randomization, in the opinion of the Investigator 
E 03. Patients who are planning to start a SGLT2 inhibitor (other than study drug) during the 
study. This includes patients who, in the opinion of the Investigator, based on their 
comorbid profile, are likely to receive an SGLT2 inhibitor (other than study drug) during 
the study
E 04. Any SGLT2 inhibitor <1 month prior to the Screening Visit, or between Screening and 
Randomization
E 05. Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and 
gangrene) identified during the Screening period, and still requiring treatment at 
Randomization
E 06. Any allergic reaction to any SGLT2 inhibitor or sotagliflozin
E 07. Blood pressure ≥180 mmHg (systolic) or ≥110 mmHg (diastolic) at both the Screening and
Randomization Visits
E 08. Hospitalization for hypertensive emergency within 3 months prior to Randomization
E 09. End-stage HF: requiring LV assist device, intra-aortic balloon pump (IABP), or any type of 
mechanical support at the time of Screening
E 10. Planned coronary revascularization procedures, electrophysiologic device implantation, 
cardiac mechanical support implantation, or other cardiac surgery after Randomization 
E 11. History of dialysis within 1 year prior to Randomization
E 12. History of solid organ transplant
E 13. Serum creatinine altering drugs ≤30 days before Screening, or between Screening and 
Randomization (trimethoprim, cimetidine, cephalosporins, probenecid, aminoglycosides, 
ketoconazole). Please note that diuretics are allowed within 30 days of Screening
E 14. Clofibrate, fenofibrate, dronedarone, or ranolazine treatment that has not been at a stable 
dose in the 30 days prior to Screening or between Screening and Randomization or a dose 
adjustment is expected during the study based on the judgement of the Investigator
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E 15. Use of systemic glucocorticoids (excluding topical application or inhaled forms) for more 
than 10 consecutive days within 3 months prior to Screening Visit or for more than 
10 consecutive days between Screening and randomization
E 16. Digoxin plasma level >1.2 ng/mL (in a patient treated with digoxin, at Screening based on 
local laboratory*)
E 17. Use of any investigational drug(s) within 5 half-lives prior to the Screening Visit or 
between Screening and Randomization
E 18. Severe disease or short life expectancy making implementation of the protocol or
interpretation of the study results difficult (CV disease [including congestive HF New 
York Heart Association IV], respiratory, hepatic, neurological [including stroke in 
3 months prior to Screening], psychiatric, or active malignant tumor [except for 
non-melanoma skin cancers, which are not exclusionary] or other major systemic disease 
[including any diseases with evidence of malabsorption or severe anemia])
E 19. Presence of any other conditions (eg, geographic, social) actual or anticipated, that the 
Investigator feels would restrict or limit the patient’s participation for the duration of the 
study 
E 20. Patient is the Investigator or any Sub-investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol
E 21. Any country-related specific regulation that would prevent the patient from entering the 
study (eg, individuals committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities)
E 22. Pregnant (demonstrated by serum pregnancy test at Screening) or breastfeeding women
E 23. Women of childbearing potential (WOCBP) not willing to use a highly-effective method(s)
of birth control during the study treatment period and the follow-up period or who are 
unwilling or unable to be tested for pregnancy (see contraceptive guidance in 
Appendix A), during the study
E 24. Laboratory findings at the Screening Visit: 
-
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the 
upper limit of the normal laboratory range (ULN)(1 repeat is allowed)*
-
Total bilirubin >1.5 times the ULN (except in case of Gilbert’s syndrome)
-
Specific to India: HbA1c >10% (86 mmol/mol) (central laboratory); see Appendix F
One time rescreening is allowed at the Investigator’s medical judgment for any manageable 
reasons that caused the Screening failure and if the patient is likely to be eligible before the 
enrollment completion. 
*If a patient meets exclusion criteria E 16 or E 24, a one-time repeat testing is allowed for digoxin 
level, ALT, or AST without the need to rescreen the patient. Refer to Section 10.1.1 for details on 
rescreening. Further eligibility criteria for inclusion in the DXA sub-study are detailed in
Appendix B.
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8
STUDY TREATMENTS
8.1
INVESTIGATIONAL MEDICINAL PRODUCTS
The IMPs are sotagliflozin and matching placebo. Sotagliflozin will be supplied in 200-mg 
tablets. Patients will be provided with 70-tablet bottles of sotagliflozin 200-mg tablets or matching 
placebo. Each patient will be supplied with the appropriate number of bottles according to the 
dispensing scheme indicated in the study flow chart. Table 1 provides a summary of each IMP.
Table 1 - 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 in appearance)
Dose, timing and route of 
administration
1 or 2 200-mg tablets (depending on visit 
number and dose titration statusa), taken 
orally once daily, before first meal of the day
1 or 2 tablets (depending on visit number and 
dose titration statusa), taken orally once daily, 
before first meal of the day 
Duration of treatment
The estimated study treatment duration will be 
approximately 27 to 51 months
The estimated study treatment duration will be 
approximately 27 to 51 months
Storage conditions at 
clinical site:
Store between +15°C and +30°C 
(59°F and 86°F)
Store between +15°C and +30°C 
(59°F and 86°F)
Storage conditions by 
patient:
Store between +15°C and +30°C 
(59°F and 86°F)
Store between +15°C and +30°C 
(59°F and 86°F)
Storage conditions (when 
not in use):
Store between +15°C and +30°C 
(59°F and 86°F)
Store between +15°C and +30°C 
(59°F and 86°F)
a
Details of up-titration of IMP can be found in Section 8.1.1.1
IMP: investigational medicinal product
8.1.1
Dose up-titration and adjustments
8.1.1.1
Dose up-titration
Patients receive 200 mg sotagliflozin or matched placebo from Visit 2 (Day 1; Randomization) 
onwards. Unless there are safety concerns, the dose should be up-titrated to 400 mg sotagliflozin 
or matched placebo at Visit 3 (Week 4), or if not, then Visit 4 (Week 8) or Visit 5 (Week 26). 
Please see below for details.
If, at Visit 3 (Week 4), in the opinion of the Investigator the patient’s clinical condition is 
satisfactory and the patient has tolerated the IMP well without evidence of dehydration,
symptomatic hypotension (eg, dizziness, lightheadedness), or other AEs intolerable to the patient 
such as severe polyuria or nocturia, the dose will be increased to 400 mg of sotagliflozin or 
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matching placebo. If the Investigator chooses not to increase the dose of IMP for safety reasons 
(eg, hypotension), the Investigator may continue IMP at the 200 mg dose, with adjustment of the 
patient’s concomitant medications, as needed. If the Investigator feels that it is not in the patient’s 
best interest to continue IMP, the Investigator may discontinue IMP. Please note that IMP should 
be discontinued temporarily unless the criteria for permanent treatment discontinue have been met 
(see Section 10.3). If the dose is not up-titrated for safety reasons, all attempts will be made to 
up-titrate the dose at 1 of the next 2 subsequent visits: Visit 4 (Week 8) or, if not Visit 4, then 
Visit 5 (Week 26), if at all possible. 
The 400 mg dose (or 200 mg in those who cannot tolerate up-titration by Visit 5) will be 
maintained for the duration of the remaining double-blind study treatment period.
8.1.1.2
Dose adjustments
If, at any time during the study, a patient does not tolerate 2 tablets of IMP qd (corresponding to 
sotagliflozin 400 mg or matching placebo), consideration should be given to reducing the dose to 
1 tablet qd (corresponding to sotagliflozin 200 mg or matching placebo) prior to any decision to 
temporarily discontinue treatment if it is felt to be safe to do so according to the Investigator’s 
judgment. In this case, the 200 mg dose will be maintained for the duration of the remaining
double-blind study treatment period.
All IMP discontinuation should initially be considered as temporary unless permanent 
discontinuation is mandated by the protocol (see Section 10.3.3). 
Guidelines for reinitiation of IMP after temporary discontinuation are described in Section 10.3.1. 
8.2
NONINVESTIGATIONAL MEDICINAL PRODUCTS
There are no noninvestigational medicinal products in this study.
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 to the patients.
The CEC will review and adjudicate events in a blinded manner. 
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For each randomized patient, the IRT will allocate a treatment package number corresponding to 
the treatment group assigned. After Visit 2, the IRT is contacted again each time new treatment 
package(s) allocation is required by the protocol. Treatment packages are allocated by the IRT 
using their treatment kit number.
A patient may not be enrolled in this study more than once (ie, being randomized twice). A patient 
can be rescreened once in case of manageable exclusion as deemed by the Investigator (see 
Section 10.1.1).
8.5
INVESTIGATIONAL MEDICINAL PRODUCT 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 ensure that the patient has enough IMP 
for daily administration 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 electronic case report form [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).
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 IMP 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.
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Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc.) must be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure (see Section 10.4.8).
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, 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
Accountability and compliance for IMPs will be performed at Visit 3 and all subsequent on-site 
visits up to the Study Closeout Visit (or pEOT if patient prematurely permanently discontinues 
study treatment). Compliance will also be assessed during telephone visits.
Measures taken to ensure and document IMP compliance and accountability are described below:

The Investigator or designee will obtain the treatment kit number(s) via IRT and he/she 
will dispense the treatment kit(s) to the patient

The in-use, used, and unused bottle(s) should be brought back at all on-site visits for 
accounting purposes

The Investigator or designee will complete the corresponding treatment log form

The Investigator/study coordinator will enter data in the appropriate e-CRF pages, 
according to data recorded in the treatment log form

The monitor will check data consistency according to the monitoring plan
If compliance is inadequate as determined by the Principal Investigator (PI), patients will be 
trained again and mentored.
8.7.2
Return and/or destruction of treatments
Patients are to return all IMP (in-use, used, and unused bottle[s]) at each on-site visit. At Visits 3 
and 4 (Weeks 4 and 8), because no IMP resupply is planned during these visits, patients will be 
sent home after these visits with the in-use bottle(s) dispensed at Randomization.
Patients are to return all the used, in-use, and unused IMP at their Study Closeout Visit or pEOT 
Visit, as applicable.
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will 
not destroy the in-use and unused IMP unless the Sponsor provides written authorization.
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8.8
CONCOMITANT MEDICATION
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s).
All concomitant medications should be documented in the e-CRF. Additionally, all medications 
taken in the month prior to Visit 1 should be reported.
8.8.1
Antihyperglycemic concomitant medication
Antihyperglycemic therapy shall be unchanged for the first 12 weeks after Randomization.
However, in cases of medical necessity, addition of antihyperglycemic therapy, dose adjustment 
or discontinuation of antihyperglycemic therapy can occur.
For patients with a Screening HbA1c <7.5% (58.5 mmol/mol) and treated with either insulin, 
glinide, or sulfonylurea, the doses of the glucose-lowering medications may be decreased at 
Randomization in order to prevent possible hypoglycemia. 
After the first 12 weeks post Randomization and during the remaining Double-blind Treatment 
period, the management of glycemia will be left to the Investigator’s and/or treating provider’s 
judgment, informed by clinical guidelines and local/regional standards of care. The Investigator 
and/or treating provider will therefore be allowed to undertake appropriate action, ie,

Adjust the dose of the background antihyperglycemic treatment

Prescribe an additional antihyperglycemic medication according to its labeling (no SGLT2 
inhibitor should be used)

Remove an antihyperglycemic treatment
Specific to India: Rescue criteria for patients with uncontrolled hyperglycemia (see Appendix F).
Antihyperglycemic therapy is to be reported in the e-CRF.
8.8.2
Other concomitant medications
Concomitant medications such as antihypertensive medications, statins, and anti-platelet therapy 
should be used to manage risk factors per standard of care. Renin-angiotensin-aldosterone system 
inhibitors should be at optimal or maximally tolerated doses in accordance with the Investigator's 
and/or treating provider’s judgment.
The dose of any concomitant RAAS inhibitors and beta-blockers should be collected at Baseline 
and at all study visits. For patients receiving RAAS inhibitors and/or beta blockers, the 
Investigator will need to confirm that patient is receiving the optimal or maximally tolerated dose, 
or otherwise record the reason for taking a lower dose.
During the double-blind study treatment period, the management of hypertension will be left to 
the Investigator’s and/or treating provider’s judgment, informed by clinical guidelines. For 
patients with a SBP <110 mmHg, at Randomization, the doses of the diuretic or other 
antihypertensive medication may be decreased in order to prevent possible hypotension. However, 
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all attempts should be made not to modify or discontinue the angiotensin-converting enzyme 
inhibitor/angiotensin II receptor blocker, which should be at optimum or maximally tolerated 
doses.
If clinically significant volume depletion occurs during co-administration of IMP with loop 
diuretics, or in vulnerable populations, consideration should be given to temporarily withhold IMP 
administration.
8.8.3
Forbidden concomitant medication
8.8.3.1
Prohibited Medications 
During the study treatment period, the following medications are prohibited:

Any SGLT2 inhibitor (other than IMP)

Non-approved drug(s) (ie, investigational drugs) other than sotagliflozin 
8.8.3.2
Other Medications 
For patients who are taking digoxin, the Investigator has to consider if an adjustment of the dose 
level of coadministered digoxin is necessary because sotagliflozin acts as a weak P-glycoprotein 
(P-gp) inhibitor and increases systemic exposure to digoxin. Thus, sotagliflozin increases 
systemic exposure of digoxin. For the total study population in study LX4211.114, the geometric 
LS mean Cmax, AUC0-tlast, and AUC0-∞for digoxin administered in the presence of steady-state 
sotagliflozin compared to digoxin administered alone were 51.9%, 31.1%, and 26.9% higher, 
respectively.
Patients taking sotagliflozin with concomitant digoxin should have digoxin concentrations 
monitored and doses reduced as needed. If digoxin treatment is being managed by another 
physician (ie, not the Investigator or Sub-investigator), he/she should be informed about this 
potential interaction. In patients treated with digoxin, digoxin levels should be measured at 
Screening and at Visit 3 (Week 4). Digoxin levels should be reassessed 2 to 4 weeks after an 
up-titration has been implemented (at an unscheduled visit, if indicated). If no up-titration is 
implemented, there is no requirement for digoxin level assessment beyond Visit 3. Throughout the 
study, additional digoxin plasma level assessments to be performed as per Investigators’ 
judgment. 
In addition, sotagliflozin could also increase the exposure of other P-gp substrates 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 pharmacokinetics or 
pharmacodynamics of the IMP or confound interpretation of the study endpoints are allowed as 
needed. However, doses of chronically administered medicines should be kept fixed during the 
trial if at all possible.
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8.9
POST-STUDY 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 discontinuation of study treatment. If 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 endpoints

Time to the first occurrence of any of the following clinical events:
-
Cardiovascular death
-
Non-fatal MI
-
Non-fatal stroke

Time to the first occurrence of any of the following clinical events:
-
Cardiovascular death
-
Hospitalization for heart failure
Selected CV and renal events assessed as endpoints will be adjudicated by the CEC 
(see Section 6.4.4).
Of note, suspected events according to the Investigator but not confirmed by the CEC will not be 
part of the primary efficacy outcome; their description will be provided separately.
9.1.1.1
Definitions of cardiovascular and renal components of efficacy endpoints 
(primary, secondary, and other)
Detailed outcome definitions are provided in a specific CEC Manual of Operations. Definitions of 
the CV endpoints will be consistently defined across the sotagliflozin project and therefore will be 
finalized before the DB lock of the first Phase 3 T2D study. Renal and other trial specific 
endpoints may be amended and updated during the course of the trial and will be finalized prior to 
the DB lock of the study. 
9.1.2
Secondary efficacy endpoints

Time to the first occurrence of any of the following clinical events in patients with 
Baseline eGFR ≥30 mL/min/1.73 m2:
-
Sustained ≥50% decrease in eGFR from Baseline (for ≥30 days)
-
Chronic dialysis
-
Renal transplant
-
Sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)

Time to the first occurrence of any of the following clinical events in patients with 
Baseline eGFR ≥30 mL/min/1.73 m2 and Baseline UACR ≥300 mg/g (34 mg/mmol):
-
Sustained ≥50% decrease in eGFR from Baseline (for ≥30 days)
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-
Chronic dialysis
-
Renal transplant
-
Sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)

Total number (ie, including recurrent events) of the following clinical events:
-
Cardiovascular death
-
Hospitalization for heart failure
-
Urgent HF visit (defined in Appendix E)

Time to CV death

Time to all-cause mortality 
9.1.2.1
Estimated glomerular filtration rate and dialysis
Serum creatinine will be assessed as part of serum clinical chemistry at all on-site visits by central 
laboratory. Estimated glomerular filtration rate will be calculated by the central laboratory using 
the MDRD equation. The Baseline eGFR value for each patient will be the average of all values 
assessed by the central laboratory from Screening up to and including Randomization.
Patients with a suspected renal event (reduction of eGFR) should have a repeat assessment of 
renal function 30 to 45 days following the onset of the event to confirm it is sustained. If acute 
renal failure is suspected, further clinical evaluation should be performed as per local standard of 
care, including confirmation of renal laboratory parameters, and consideration should be given to 
a nephrology referral.
9.1.3
Other efficacy endpoints

Time to the first occurrence of any of the following clinical events in patients with 
Baseline eGFR ≥30 mL/min/1.73 m2:
-
Sustained ≥50% decrease in eGFR from Baseline (for ≥30 days) 
-
Chronic dialysis 
-
Renal transplant
-
Sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)
-
Cardiovascular death
-
Renal death

Time to first occurrence of any CV death, non-fatal MI, non-fatal stroke, or unstable 
angina requiring hospitalization 

Time to worsening nephropathy in patients with Baseline eGFR ≥30 mL/min/1.73 m2, 
defined as: new onset or progression to macro albuminuria (≥300 mg/g [34 mg/mmol]) 
accompanied by a UACR value increase of ≥30% from Baseline, or sustained ≥50% 
decrease in eGFR from Baseline (for ≥30 days), or need for renal transplant, chronic 
dialysis, eGFR <15 mL/min/1.73 m2 (for ≥30 days), or renal death
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
Changes from Baseline to 6 months, 12 months, and 24 months in:
-
Hemoglobin A1c 
-
Body weight
-
Blood pressure
-
Urinary albumin-to-creatinine ratio
-
Estimated glomerular filtration rate
-
Hematocrit
-
Hemoglobin
-
Albumin
-
Total protein

Changes from Baseline to 6 months and 12 months in: 
-
N-terminal pro-B-type natriuretic peptide
-
High sensitivity troponin T
-
High sensitivity C-reactive protein

Proportion of patients who start insulin (who are not taking insulin at baseline)
9.1.3.1
Hemoglobin A1c
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 in HbA1c.
9.1.3.2
Body weight
Body weight is measured at all on-site Visits. Height will be measured only at Screening.
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder.
It is recommended that the same scale should be used throughout the study when possible.
9.1.3.3
Blood pressure
Sitting BP will be assessed at all on-site visits.
9.1.3.4
Urinary albumin-to-creatinine ratio
Urinary albumin-to-creatinine ratio will be collected at Screening and at all on-site visits. Further 
details are provided in Section 9.2.2.1.
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9.1.3.5
Hematocrit, hemoglobin, albumin, and total protein
Hematocrit, hemoglobin, albumin, and total protein are collected as described in Section 9.2.2.
9.1.3.6
Antihyperglycemics
All antihyperglycemics are collected as described in Section 8.8.1. Details of the analysis will be 
included in the Statistical Analysis Plan (SAP). 
9.2
SAFETY ENDPOINTS

All AEs including adverse events of special interest (AESIs), events of special interest 
(EOSIs), and SAEs

Severe hypoglycemia (also an EOSI)

Clinical laboratory results and vital signs (including heart rate, BP)

For patients in the DXA sub study, change from Baseline in:
-
Bone mineral density (BMD)
-
The following markers of bone and calcium metabolism: serum and urinary calcium;
serum 25-hydroxyvitamin D; serum 1,25 dihydroxyvitamin D; serum and urinary 
phosphorus, serum parathyroid hormone (PTH); serum N telopeptide of type 1 
collagen (NTX); serum β-C-terminal telopeptide of type 1 collagen (β-CTX 1); serum 
N-terminal propeptide of type 1 procollagen (P1NP); serum magnesium
Safety observation periods are as defined in Section 11.4.3.1. 
9.2.1
Adverse events, adverse events of special interest, and events of special interest
Adverse events including SAEs, AESIs, and EOSIs will be assessed. Refer to Section 10.4 to 
Section 10.7 for details.
All AEs will be collected starting from signing informed consent. The Investigator should take 
appropriate measures to follow all AEs until clinical recovery is complete and laboratory results 
have returned to normal, or until stabilization, 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.
9.2.1.1
Adverse events of special interest
Adverse events of special interest are listed in Section 10.4.1.3, reporting requirements for AESIs
are presented in Section 10.4.5.
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9.2.1.2
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 10.4.6, respectively.
9.2.2
Laboratory safety variables
The clinical laboratory data consist of blood analyses (including hematology, clinical chemistry, 
and lipids) and urinalysis (including dipstick and reflexive microscopy and culture, as applicable). 
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. The 
schedule for assessment of clinical laboratory data is shown in Section 1.2.
Pregnancy tests will be performed for WOCBP at all on-site visits (except the Follow-up Visit). 
Serum pregnancy testing is only performed at Screening; urine pregnancy testing subsequently. 
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.
Table 2 - Chemistry parameters
Serum clinical chemistry
Serum
hematology
Serum lipid profile
Plasma digoxin
Sodium
Complete blood 
count (CBC)
Total cholesterol (TC)
Plasma digoxin 
(if applicable)a
Potassium
White blood cell 
count with 
differential
High-density lipoprotein 
cholesterol (HDL-C)
Chloride
Platelet count
Low-density lipoprotein 
cholesterol (LDL-C) will be 
calculated by Friedwald equation
Carbon dioxide (bicarbonate)
Hemoglobin
Non-HDL-C (calculated as the 
difference between TC and 
HDL-C)
Blood urea nitrogen (BUN)
Hematocrit
Triglycerides (TG)
Creatinine (eGFR will be 
calculated)b
Glucose (serum)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Total bilirubin (TB)
Alkaline phosphatase (ALP)
Uric acid
Calcium
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Serum clinical chemistry
Serum
hematology
Serum lipid profile
Plasma digoxin
Phosphorus
Total protein
Albumin
Magnesium
Creatine phosphokinase (CPK)
Lactic acid dehydrogenase (LDH)
All assessment measured in serum except, if applicable, plasma digoxin assessment.
a
In patients treated with digoxin, digoxin levels should be measured at Screening and at Visit 3 (Week 4). Digoxin levels should be 
reassessed 2 to 4 weeks after an up-titration has been implemented (at an unscheduled visit, if indicated). If no up-titration is 
implemented, there is no requirement for digoxin level assessment beyond Visit 3. Throughout the study, additional digoxin plasma 
level assessments to be performed as per Investigators’ judgment. If applicable, plasma digoxin assessment should be performed via 
a local laboratory.
b
Estimated glomerular filtration rate (eGFR) will be calculated by the Modification of Diet in Renal Disease (MDRD) equation.
9.2.2.1
Urinalysis
A urine dipstick will be performed by the central laboratory and will include assessment of 
specific gravity, pH, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte 
esterase.
If the urine dipstick is positive for nitrite and leukocyte esterase, the central laboratory will 
perform reflexive testing to include microscopy and urine culture (microscopy includes detection 
of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine 
sediment). If additional testing is needed it will be performed according to the judgment of the 
Investigator. Referral to urology/urologic evaluation is recommended for recurrent urinary tract 
infections despite appropriate use of antibiotics.
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).
Screening UACR will be measured by spot urine and will be assessed throughout the study. The 
Baseline UACR value for each patient will be the average of all values assessed by the central 
laboratory from Screening up to and including randomization.
If the Screening UACR is <300 mg/g (34 mg/mmol), but >100 mg/g (11 mg/mmol), then a 
24-hour urine collection for measurement of UACR will be performed.
24-hour urine collection will also be performed for patients in the DXA sub-study. 
See Appendix B for further details.
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9.2.2.2
Markers of bone and calcium metabolism
Samples for markers of bone and calcium metabolism will be collected as part of the DXA 
sub-study. See Appendix B for details. 
9.2.3
Vital signs and physical exam
Vital signs (sitting BP and heart rate) measurements will be made at every on-site visit.
General physical examinations will be performed according to the schedule in Section 1.2.
Examination of the lower extremities to evaluate for any evidence of foot ulcers or infection 
should be performed as part of the general physical examination. Lower extremity complications 
(such as skin ulcers, infection, osteomyelitis, and gangrene) requiring treatment should lead to 
temporary discontinuation of IMP.
9.2.4
Electrocardiogram variables
A 12-lead ECG record is performed locally at Randomization (Visit 2), the pEOT Visit (if patient 
prematurely discontinues study treatment), and the Study Closeout Visit. The 12-lead ECG should 
be performed after at least 10 minutes in the supine position and be obtained at Randomization 
prior to first dose of double-blind IMP.
The ECGs will be interpreted locally by the Investigator. Any clinically significant abnormality 
should be documented as medical history, an AE/SAE or endpoint as applicable 
(see Section 10.4). All ECG traces will be kept as source data.
9.2.5
Severe hypoglycemia
Severe hypoglycemia will be collected from signature of the informed consent and continue until 
the Follow-up Visit (or Study Closeout Visit, for patients who prematurely permanently 
discontinued from IMP). See Section 10.6.1 for the definition of severe hypoglycemia.
Patients will be asked whether they have experienced any signs/symptoms consistent with an 
episode of severe hypoglycemia during all on-site and telephone visits. Patients will be asked to 
report any episodes of severe hypoglycemia to the site immediately, and not wait for the next 
scheduled visit.
Episodes of non-severe hypoglycemia should be reported as standard AEs, if the episode of 
hypoglycemia meets the criteria for AE reporting.
9.2.6
Change in bone mineral density
Patients in the DXA sub-study will have the change from Baseline in BMD assessed. 
See Appendix B for details. 
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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 outpatient study that consists of 5 on-site visits in the first 6 months. Subsequently, 
on-site visits are every 6 months until the Study Closeout Visit. Additionally, in between each 
on-site visit, starting with Visit 5, patients will be contacted by phone twice at 9-week intervals 
(ie, 9 weeks after the on-site visit and again 18 weeks after the on-site visit) to collect endpoint 
events, IMP administration information, and safety data. If occurrence of a renal event is 
suspected at a telephone visit, arrangements should be made for the patient to attend an 
unscheduled on-site visit to confirm. 
The visit windows for Visit 3 and Visit 4 are ±3 days and ±7 days, respectively. The window for 
all subsequent visits is ±10 days. Patients still taking the IMP at the time of the Study Closeout 
Visit (ie, who have not prematurely permanently discontinued IMP) will have their final study 
visit (Follow-up Visit) 14 days (±4 days) after their Study Closeout Visit.
If 1 visit date is changed, the next visit should occur according to the original schedule, ie,
calculated from the date of the Randomization Visit (Visit 2, Day 1).
All data obtained during the trial visits are reviewed by the Investigator and/or Sub-investigators 
who are qualified in the treatment of T2D and are trained on the study.
10.1.1 Screening period
The Screening period will be 1 to 4 weeks in duration, and includes Visit 1 (up to Week -4). It 
must be long enough to collect the data required to establish whether the patient satisfies the 
inclusion/exclusion criteria.
Patients will undergo Screening assessments at Visit 1 following signing of the ICF. Patients who 
meet the inclusion criteria as noted in Section 7.1 and have no exclusion criteria as noted in 
Section 7.2, will be randomized at Visit 2 (Day 1).
In cases where a patient fails Screening due to reasons expected to change upon rescreening based 
on the Investigator’s clinical judgment, the patient can be rescreened once. In these cases, the 
patient should be registered as a screen failure in IRT. The patient will then need to sign a new 
ICF, be registered as a rescreen in IRT and assigned a new patient number, and again complete 
Screening Visit procedures/assessments. 
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
The following laboratory testing (by local laboratory):
-
Plasma digoxin (if applicable, see Section 9.2.2)

The following tests may be performed if needed:
-
24-hour urine collection for all patients with UACR at screening >100 and <300 mg/g 
(11 and 34 mg/mmol; see Section 7.1)
-
Echocardiogram in all patients if an EF has not been documented in previous year
-
Cardiac CT for CAC if needed to meet eligibility criteria but not previously
documented (see Section 7.1)
Note: If a patient has a diagnosis of T2D, age ≥18 years, a HbA1c ≥7%
(53 mmol/mol), and an eGFR ≥25 and ≤60 mL/min/1.73 m2, and does not have either 
1 major or 2 minor risk factors based upon available information, additional testing 
(echocardiogram and/or coronary artery CT scan) MAY be ordered. If both tests are 
needed to meet I 04, they can be ordered at the same time.
Specific to India: HbA1c ≥7% (53 mmol/mol) to ≤10% (86 mmol/mol) (central 
laboratory); see Appendix F.

For patients participating in the DXA sub-study:
-
A sample will be taken for 25-hydroxyvitamin D
-
24-hour urine collection will need to be scheduled during Screening/prior to the 
Randomization Visit (Visit 2) (see Appendix B)
-
A DXA scan will need to be scheduled during Screening/prior to the Randomization 
Visit (Visit 2) for eligibility assessment (see Appendix B)
-
Specific for Canada and USA: To remind patients to fast prior to Visit 2 (see
Appendix F)
Note: If a patient has had a BMD value documented within the last year and the 
T-score is not <-2.0 at any site the patient may proceed to Randomization prior to 
receiving the results of the BMD value performed during Screening.

An appointment will be made for Visit 2
10.1.2 Randomized Double-blind Treatment period
The randomized Double-blind Treatment period starts at Visit 2 (Day 1, Randomization) and 
continues until the Study Closeout Visit. Patients will continue with IMP treatment after a CV or 
renal endpoint occurs unless they have prematurely permanently discontinued treatment or the 
criteria for permanent treatment discontinuation have otherwise been met. Whether taking IMP or 
not, patients will continue to be followed after a CV or renal endpoint occurs.
Guidance for dose increases (Visits 3 to 5) and other dose adjustments can be found in 
Section 8.1.1.1, Section 8.1.1.2, and Section 10.3.1.
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Study Closeout Visit procedures will differ for patients who do not prematurely permanently 
discontinue IMP and those who do prematurely permanently discontinue IMP (see 
Section 10.1.4.1 and Section 10.1.4.2, respectively).
Endpoint events, severe hypoglycemic episodes, and other AEs should be captured at each patient 
contact, including questioning the patient about any lower extremity abnormalities (such as, 
sores/ulcers or infections). Lower extremity complications (such as skin ulcers, infection, 
osteomyelitis, and gangrene) requiring treatment should lead to temporary discontinuation of 
IMP. Patients with a suspected renal event (reduction of eGFR) should have a repeat assessment 
of renal function 30 to 45 days following the onset of the event to confirm it is sustained. If acute 
renal failure is suspected, further clinical evaluation should be performed as per local standard of 
care, including confirmation of renal laboratory parameters, and consideration should be given to 
a nephrology referral.
10.1.2.1 On-site Visit 2 (Day 1) Randomization
The following procedures/assessments will be performed at Visit 2 (Day 1):

Review of inclusion/exclusion criteria

Measurement of body weight

Vital signs (sitting BP, heart rate)
AEs, including SAEs/AESIs/EOSIs (including severe hypoglycemia) and endpoint events (if any) 
are collected (if a renal endpoint relating to a reduction in eGFR is suspected, see Section 9.1.2.1)

Concomitant medications are assessed
-
It is critical that background medications at time of Randomization are accurately and 
fully captured
-
The dose of any concomitant RAAS inhibitors and beta-blockers should be collected 
at Baseline and at all study visits. Where patients are receiving RAAS inhibitors 
and/or beta-blockers at lower than the optimal or maximally tolerated dose, the reason 
for this should also be recorded.

Contact information is reviewed and updated if needed (address, email, home, and cell 
phone number) for patient, patient’s family and patient’s 
GP/cardiologist/diabetologist/nephrologist (as applicable, to be recorded in source 
documents)

12-lead ECG, prior to IMP administration

The following laboratory testing; prior to IMP administration:
-
Chemistry (including eGFR)
-
Lipids
-
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test)
-
Urinalysis (dipstick) and UACR
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10.1.2.3 On-site Visit 4 (Week 8)
The following procedures/assessments will be performed at Visit 4 (Week 8):

Measurement of body weight

Vital signs (sitting BP, heart rate)

IMP accounting and compliance

AEs, including SAEs/AESIs/EOSIs (including severe hypoglycemia) and endpoint events 
(if any) are collected (if a renal endpoint relating to a reduction in eGFR is suspected, see 
Section 9.1.2.1)

Concomitant medications are assessed

Contact information is reviewed and updated if needed (address, email, home, and cell 
phone number) for patient, patient’s family and patient’s 
GP/cardiologist/diabetologist/nephrologist (as applicable, to be recorded in source 
documents)

The following laboratory testing:
-
Chemistry (including eGFR)
-
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test)
-
Urinalysis (dipstick) and UACR

The following laboratory testing (by local laboratory):
-
Plasma digoxin (if applicable, see Section 9.2.2)

If the dose was not increased to 2 tablets qd (sotagliflozin 400 mg or matching placebo) at 
Visit 3 a dose increase should be performed if the Investigator feels that it is safe to do so;
see Section 8.1.1.1

An appointment for Visit 5 will be made; for accountability and compliance purposes, 
patients are instructed to return to the site with their unused, in-use and empty bottle(s) at 
Visit 5
10.1.2.4 On-site Visit 5 (Week 26), and all subsequent on-treatment, on-site visits
The following procedures/assessments will be performed (except when noted) at on-site Visits 5 
(Week 26), 8 (Week 52), 11 (Week 78), 14 (Week 104), 17 (Week 130), 20 (Week 156), 23 
(Week 182), and 26 (Week 208) up until the end of study:

Measurement of body weight

Vital signs (sitting BP, heart rate)

General physical exam (Visits 8 [Week 52], 14 [Week 104], 20 [Week 156], 
26 [Week 208], and every other on-site, on-treatment visit thereafter)

IRT contact for IMP resupply
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If a potential CV or renal event is identified during a telephone visit, arrangements should be 
made for the patient to attend an unscheduled on-site visit to further evaluate/confirm, when 
possible.
The following procedures/assessments will be performed at telephone visits: 

AEs, including SAEs/AESIs/EOSIs (including severe hypoglycemia) and endpoint events 
(if any) are collected (if a renal endpoint relating to a reduction in eGFR is suspected, see 
Section 9.1.2.1)

Concomitant medications are assessed

IMP compliance

Contact information is reviewed and updated if needed (address, email, home, and cell 
phone number) for patient, patient’s family and patient’s 
GP/cardiologist/diabetologist/nephrologist (as applicable, to be recorded in source 
documents)

For accountability and compliance purposes, patients are instructed to return to the site 
with their unused, in-use and empty bottle(s) at their next on-site visit
10.1.3 Premature End-of-Treatment
Patients who prematurely permanently discontinue IMP will attend a pEOT Visit as soon as 
possible. These patients will be asked to continue in the study, attending scheduled visits, if at all 
possible until the end of the study, and will continue to be followed after a CV or renal endpoint
occurs. 
If the patient does not agree to on-site visits, he/she will be contacted by telephone to inquire 
about safety status (including hospitalizations and outcomes). Every effort should be made to
collect endpoint information and vital status at least once a year and at the time of Study Closeout.
If a patient refuses to continue in the study after premature IMP discontinuation, and the pEOT 
Visit is <10 days after the last IMP administration, see Section 10.3.2 for guidance.
10.1.3.1 Premature End-of-Treatment Visit
The following procedures/assessments will be performed at the pEOT Visit for patients who 
prematurely permanently discontinue study treatment:

Measurement of body weight

Vital signs (sitting BP, heart rate) and physical examination

IRT contacted for end of treatment 

IMP accounting and compliance 

AEs, including SAEs/AESIs/EOSIs (including severe hypoglycemia) and endpoint events 
(if any) are collected (if a renal endpoint relating to a reduction in eGFR is suspected, see 
Section 9.1.2.1)
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10.1.4.1 Study Closeout Visit for patients who do not prematurely permanently 
discontinue investigational medicinal product
The following procedures/assessments will be performed at the Study Closeout Visit for patients 
who do not prematurely permanently discontinue IMP:

Measurement of body weight

Vital signs (sitting BP, heart rate) and physical examination

IRT contacted for end of treatment 

IMP accounting and compliance 

AEs, including SAEs/AESIs/EOSIs (including severe hypoglycemia) and endpoint events 
(if any) are collected (if a renal endpoint relating to a reduction in eGFR is suspected, see 
Section 9.1.2.1)

Contact information is reviewed and updated if needed (address, email, home, and cell 
phone number) for patient, patient’s family and patient’s 
GP/cardiologist/diabetologist/nephrologist (as applicable, to be recorded in source 
documents)

Concomitant medications are assessed

12-lead ECG

The following laboratory testing:
-
HbA1c
-
Hematology
-
Chemistry (including eGFR)
-
Lipids
-
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test)
-
Urinalysis (dipstick) and UACR

For patients at participating sites who are participating in the DXA sub-study:
-
DXA scan
-
Markers of bone and calcium metabolism (see Appendix B for full list). Specific for 
Canada and USA: Fasting markers (see Appendix F)

An appointment for the Follow-up Visit will be made
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10.1.4.2 Study Closeout Visit for patients who prematurely permanently discontinue 
investigational medicinal product
The following procedures/assessments will be performed at the Study Closeout Visit for patients 
who prematurely permanently discontinue IMP:

Measurement of body weight

Vital signs (sitting BP, heart rate) and physical examination

IRT contacted for end of study 

AEs, including SAEs/AESIs/EOSIs (including severe hypoglycemia) and endpoint events 
(if any) are collected (if a renal endpoint relating to a reduction in eGFR is suspected, see 
Section 9.1.2.1)

Concomitant medications are assessed

12-lead ECG

The following laboratory testing:
-
HbA1c
-
Hematology
-
Chemistry (including eGFR)
-
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test)
-
Urinalysis (dipstick) and UACR
10.1.5 Follow-up
Patients still taking the IMP at the time of the Study Closeout Visit (ie, who have not prematurely 
permanently discontinued IMP) will have their final study visit (Follow-up Visit) 14 days 
(±4 days) after their Study Closeout Visit.
10.1.5.1 Follow-up Visit
Patients who have attended a pEOT Visit do not need to attend this Visit. The following 
procedures/assessments will be performed at this Visit:

Measurement of body weight

Vital signs (sitting BP, heart rate)

AEs, including SAEs/AESIs/EOSIs (including severe hypoglycemia) and endpoint events 
(if any) are collected (if a renal endpoint relating to a reduction in eGFR is suspected, see 
Section 9.1.2.1)

The following laboratory testing:
-
Estimated glomerular filtration rate
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-
Hemoglobin/hematocrit
-
Albumin 
-
Total protein

IRT contacted for end of study
10.2
DEFINITION OF SOURCE DATA
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 treatment 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 AESI/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

In case of endpoint events, 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 event

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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10.3
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. Where the patient is taking 2 tablets of IMP qd
(corresponding to sotagliflozin 400 mg or matching placebo), consideration should be given to 
reducing the dose to 1 tablet of IMP qd (corresponding to sotagliflozin 200 mg) prior to temporary 
treatment discontinuation (see Section 8.1.1.2). In this case, the 200 mg dose will be maintained 
for the duration of the remaining double-blind study treatment period.
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s)
All IMP discontinuation should initially be considered as temporary unless permanent 
discontinuation is mandated by the protocol (see Section 10.3.3), and the Investigator should 
make best effort to resume IMP treatment as early as practically possible. There is no defined 
limit to the duration of temporary discontinuation.
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.
Reinitiation of treatment with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator is satisfied that, according to his/her best medical 
judgment, the IMP was unlikely to be responsible for the event concerned.
Temporary discontinuation of IMP due to intolerance should be followed by reinitiation of 
1 tablet of IMP qd (sotagliflozin 200 mg/matching placebo). Temporary discontinuation for any 
other reason should be followed by reinitiation of IMP at the last dose tolerated prior to 
discontinuation where possible.
For all confirmed temporary treatment discontinuations, the start date and end date of the period 
with no IMP treatment should be recorded by the Investigator in the appropriate pages of the 
e-CRF. Additionally, temporary discontinuation should be recorded in the IRT. 
Patients who temporarily discontinue IMP should be reassessed at every visit to determine 
whether it is possible to safely resume IMP. If a decision has been made that the discontinuation is 
permanent, then the patient should be considered as permanently discontinued and the 
corresponding e-CRF page should be completed. Please note that permanent discontinuation 
should be a last resort.
Temporary treatment discontinuation corresponds to more than 1 dose not administered to the 
patient as decided by the Investigator.
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10.3.2 Permanent treatment discontinuation with investigational medicinal product
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator not to re-expose the patient to the IMP at any time during 
the study, or from the patient not to be re-exposed to the IMP whatever the reason.
If a patient refuses to continue in the study after premature IMP discontinuation, and the pEOT 
Visit is <10 days after the last IMP administration, then every effort should be made to secure a 
follow-up contact is performed at least 14 days (±4 days) after the last IMP intake with procedures 
normally performed at the Follow-up Visit (see Section 10.1.5.1). If the patient does not agree to 
on-site visits, he/she will be contacted by telephone to inquire about safety status (including
hospitalizations and endpoints). Every effort should be made to collect endpoint information and 
vital status at least once a year and at the time of Study Closeout.
If after permanent treatment discontinuation, a patient who has withdrawn consent for treatment 
has reconsidered the decision to permanently discontinue treatment and wishes to later resume 
IMP, and if the Investigator has determined there is no safety reason prohibiting the patient from 
resuming IMP and the selection criteria for the study are still met, the patient may resume IMP 
with Sponsor approval.
10.3.3 List of criteria for permanent treatment discontinuation
Patients may withdraw from treatment with the IMP at any time for any reason or this may be the 
Investigator’s decision. Patients should discuss stopping study medication with the site before 
doing so in order that questions can be addressed, concomitant therapy can be adjusted if needed, 
and a follow-up assessment arranged. All efforts should be made to document the reasons for 
treatment discontinuation and this should be documented in the e-CRF.
Patients who report a CV or renal endpoint as described in Section 10.4.2 should remain on IMP
until the end of the study, unless there is a safety concern.
The following reasons shall lead to permanent IMP discontinuation:

At the patient’s own request (ie, withdrawal of consent for treatment) (note that this is 
regardless of whether or not the patient continues in the study)

If, in the Investigator's opinion, continuation with the administration of the study treatment 
would be detrimental to the patient's well-being

Pregnancy (in female patients)

Any code breaking requested by the Investigator

Specific request of the Sponsor

Patient requires dialysis or renal transplantation

Estimated glomerular filtration <15 mL/min/1.73 m2
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Note: the central laboratory will alert the Investigator for eGFR values 
<15 mL/min/1.73 m2. A repeat determination should be performed within 2 weeks, and 
study treatment discontinued if the repeat eGFR is <15 mL/min/1.73 m2 (unless a 
reversible cause is identified [eg, short-term illness or transient volume depletion], in 
which case an additional repeat determination can be performed after resolution of the 
short-term illness).
Any abnormal laboratory value will be immediately rechecked for confirmation before making a 
decision to permanently discontinue IMP for the concerned patient.
10.3.4 Handling of patients after permanent treatment discontinuation
Every effort should be made to maintain patients in the study. All patients will be followed until 
the last visit according to the study procedures specified in this protocol, or up to recovery or 
stabilization of any AE to be followed-up as specified in this protocol, whichever comes last. The 
scientific value of the complete collection of data will be explained to patients, and site personnel 
will receive training regarding strategies for patient retention, and access to tools to assist with 
this during the study. 
For patients who prematurely permanently discontinue the IMP, a pEOT Visit (see Section 10.1.3) 
will be scheduled as soon as possible after time of discontinuation (the latest at the next on-site 
visit). The reason for the IMP discontinuation shall be clearly specified.
For patients who discontinue IMP but remain in the study, the remaining visits should occur as 
scheduled where possible. All efforts should be made to continue to follow the patients for 
primary and secondary endpoints, after the discontinuation of treatment. 
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed.
Patients participating in the DXA sub-study shall continue participation in the sub-study if they 
permanently discontinue IMP; their final DXA scan should be performed at the pEOT Visit.
10.3.5 Procedure and consequence for patient withdrawal from study
Patients may withdraw from the study before study completion if they decide to do so, at any time 
and irrespective of the reason without any effect on their care. However, if patients no longer wish 
to take the IMP, they will be encouraged to remain in the study and attend the remaining visits.
The Investigators should discuss with them key visits to attend. The value of critical study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study.
Patients who withdraw from the study treatment should be explicitly asked about the contribution 
of possible AEs to their decision, and any AE information elicited must be documented. 
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All study withdrawals must be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the patient’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented.
In addition, a patient may withdraw his/her consent to stop participating in the study. Withdrawal 
of consent for treatment (ie, treatment discontinuation at patient request) should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical record checks. The site should document any case of withdrawal of 
consent.
For patients who fail to return to the site or otherwise withdraw from the study, unless the patient 
withdraws consent for follow-up, the Investigator must make the best effort to re-contact the 
patient (eg, contact patient’s family or private physician, review available registries, or health care 
DBs) to determine the patient’s health status, including at least his/her vital status (including time 
of death). Attempts to contact such patients (3 phone call attempts followed by a certified letter) 
must be documented in the patient’s records (eg, times and dates of attempted telephone contact, 
receipt for sending a registered letter). If a patient withdraws consent for follow-up, the 
Investigator should still make best efforts to determine the patient’s health status, including at 
least his/her vital status (including time of death), where permitted by local regulations. The 
patient’s final vital status will be confirmed at the time of the study close-out visit.
Patients who have withdrawn from the study cannot be rerandomized in the study. Their inclusion 
and treatment numbers must not be reused. 
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 (AE) 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 this treatment. Cardiovascular and renal efficacy endpoints, and their 
components, specified in this study (as per Section 10.4.2) will not generally be considered as 
AEs, and will be waived from expedited reporting to Health Authorities, Investigators, 
institutional review boards (IRBs)/independent ethics committees (IECs), etc. For further details 
please refer to Section 10.4.2.
10.4.1.2 Serious adverse event
A serious adverse event (SAE) is any untoward medical occurrence (with the exception of those 
events waived as efficacy endpoints, see Section 10.4.2) that at any dose:

Results in death, or

Is life-threatening, or
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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, or

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 1 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 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN

Suicide attempt or any event suggestive of suicidality

Syncope, loss of consciousness (except if documented as a consequence of blood
sampling)

Bullous cutaneous eruptions

Cancers diagnosed during the study or worsened during the study, including but not 
limited to breast, bladder, renal cell, Leydig cell, pancreatic, prostate, and thyroid 
follicular cell carcinoma

Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study

Venous thrombotic events to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism)

Pancreatitis

Bone fractures

Events leading to amputation(s)

Diabetic ketoacidosis
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10.4.1.3 Adverse events of special interest
An adverse event of special interest (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 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified, 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:
-
It will qualify as an SAE only if it fulfills 1 of the seriousness criteria (see
Section 10.4.1.2).
-
In the event of pregnancy in a female participant, IMP should be discontinued. 
-
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined.

Symptomatic overdose (serious or non-serious) with IMP:
-
A symptomatic overdose (accidental or intentional) with the IMP 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 of IMP within a 24-hour period. It will be recorded in the e-CRF 
as “Symptomatic OVERDOSE (accidental)” or “Symptomatic OVERDOSE 
(intentional)”, as applicable. It will be qualified as an SAE only if it fulfills the SAE 
criteria.
(Please note that an asymptomatic overdose with the IMP, accidental or intentional, is 
an event defined as 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 
“Asymptomatic overdose, intentional”; it will not be recorded as an AESI)

ALT increase >3 x ULN (refer to related flow chart, Appendix C)
10.4.1.4 Events of special interest
An event of special interest (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 in e-CRF (where applicable) and will only qualify for 
expedited reporting when serious (fulfilling SAE criteria). Please refer to the study e-CRF 
completion guidelines for additional details on e-CRF completion.
A dedicated safety analysis will be performed as described in Section 11.4.3.4 and in the SAP to 
evaluate whether there is an imbalance in any of the below events with sotagliflozin relative to 
placebo.
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The EOSI for this study are:

Venous thrombotic events to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism)

Pancreatitis

Bone fractures

Events leading to amputation(s)

Diabetic ketoacidosis 

Malignancies of special interest (breast, bladder, renal cell, Leydig cell, pancreatic, 
prostate, and thyroid follicular cell carcinoma)

Genital mycotic infections (to include vulvovaginal candidiasis in females and candidal 
balanitis in males)

Urinary tract infections

Diarrhea

Clinically relevant volume depletion and events related/possibly related to volume 
depletion

Severe hypoglycemia (see Section 10.6.1)
10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities
Unlike most studies where the primary efficacy variable is the resolution or improvement of an 
existing condition, in this study efficacy endpoints include the occurrence of life-threatening 
events. Indeed, participants to this study are recruited precisely because they are at high risk for 
these life-threatening events. They are therefore expected to have at least 1 primary and secondary 
CV or renal efficacy endpoint during the course of the study.
Cardiovascular and renal efficacy endpoints will be reported (within 1 working day) in the e-CRF. 
Detailed process for the exchanges with the CEC will be described in a specific Manual of 
Operations.
In light of the above, suspected CV and renal efficacy endpoints as specified in this protocol will 
not be considered as AEs, will not be reported to pharmacovigilance, and are waived from 
regulatory reporting to Health Authorities except if the Investigator, according to his/her best 
medical judgment, considers these events as related to the IMP taking into consideration the 
patient’s underlying disease. In that case, the Investigator will report it within 24 hours to the 
Sponsor. 
Expedited reporting for the following CV and renal endpoints will be waived:

Cardiovascular death

Any MI 

Any stroke 

Unstable angina requiring hospitalization
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
Heart failure leading to hospitalization

Urgent HF visit (as defined in Appendix E)

Sustained ≥50% decrease in eGFR from Baseline (for ≥30 days)

Events leading to chronic dialysis 

Sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)

Events leading to renal transplant
If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship 
between the drug and the event (suspected unexpected serious adverse reaction [SUSAR]), the 
event must be reported, even if it is a component of the study endpoint.
10.4.3 General guidelines for reporting adverse events

All AEs, regardless of seriousness or relationship to IMP, 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.

For this study, an endpoint assessment/adjudication committee is in place. This committee 
reviews important endpoints reported by the Investigators to determine whether the 
endpoints meet protocol-specified criteria. This is a periodic process, occurring after 
internal processing of the reported event (endpoint). The event as categorized by the 
Investigator will remain as such, even if judged differently by the adjudication committee 
later.

Whenever possible, a 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).

The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until stabilization, 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 judgement 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
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10.4.4 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 Sponsor after approval 
of the Investigator within the e-CRF or after a standard delay.

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 Sponsor. 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 CRF process) is available and should be used when the 
e-CRF system does not work.
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.
10.4.5 Guidelines for reporting adverse events of special interest 
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4, even if not fulfilling a seriousness criterion, 
using the corresponding screens in the e-CRF.
10.4.6 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 10.4.4). Otherwise, reporting should follow the 
instructions for an AE (see Section 10.4.3).
10.4.7 Guidelines for management of specific laboratory abnormalities
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in
Appendix C. The study population will be enrolled with preexisting impairment of renal function; 
rapid change in renal function of greater than 30% as compared with the mean of the prior two 
study visits should be followed up as described in Appendix D.
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The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices:

Neutropenia

Thrombocytopenia

Increase in ALT

Increase in creatine phosphokinase suspected to be of non-cardiac origin and not related to 
intensive physical activity

Acute worsening of renal function (see Appendix D)
In the event that the ‘general guidance for the follow-up of laboratory abnormalities by Sanofi’ 
Appendix C requires discontinuation of IMP, temporary discontinuation should be considered 
unless otherwise specified (please see Section 10.3.1).
10.4.8 Guidelines for reporting product complaints (investigational medicinal product)
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team (ie, site monitor) that will complete a product complaint form within required timelines.
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE.
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 (SUSAR), to 
the regulatory authorities, IECs/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 with IMP
-
ALT increase >3 x ULN
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.
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10.6
SAFETY INSTRUCTIONS
10.6.1 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. 
Plasma glucose values may not be available during such an event, 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. The definition of severe 
symptomatic hypoglycemia includes all episodes in which neurological impairment was severe 
enough to prevent self-treatment and which were thus thought to place participants at risk for 
injury to themselves or others.
Note: “requiring assistance of another person” means that the patient could not help himself or 
herself. Assisting a patient out of kindness, when assistance is not required, should not be 
considered a “requires assistance” incident.
Severe hypoglycemia will be reported as an AE. Additional information will be recorded 
including symptoms and/or signs, associated glucose value (if available), whether assistance was 
required and the treatment.
Severe hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria. For example, 
events of seizure, unconsciousness or coma must be reported as SAEs.
The definition of severe hypoglycemia is based on the American Diabetes Association workgroup 
on hypoglycemia classification (36, 37).
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 study is powered based on the endpoints of time to CV death or first HHF and time to 3-point 
MACE. In order to achieve the targeted number of events of 844 CV death/HHF and 1189 3-point 
MACE, it is estimated that approximately 10,500 patients will be randomized over an estimated 
24 months of enrollment period with approximately 27 months of follow-up after the last 
randomized patients.
This is based on the following trial design assumptions:

A recruitment period of approximately 24 months with approximately 3.6%, 20.0%, 
36.5%, and 39.9% of patients recruited during each of the 4 (four) 6-month periods

Approximately 27 months of follow-up after the last patient is randomized, with treatment 
duration ranging from 27 to 51 months

A 2% annual censoring rate

A 3.5% annual event rate of CV death/HHF and 4.5% annual event rate of 3-point MACE 
in the placebo group
This will provide: 

99% power to demonstrate NI on 3-point MACE

90% power to demonstrate the superiority in CV death/HHF

80% power to demonstrate the superiority in 3-point MACE
The actual end date of the study is event driven. Therefore, the study will continue until 
approximately 844 events of CV death or HHF and approximately 1189 3-point MACE are 
positively adjudicated.
Calculations were made using nQuery Advisor 7.0 simulation for the log-rank test with user 
defined survival rates, accrual, and drop-outs.
11.2
DISPOSITION OF PATIENTS
Screened patients are defined as any patient who signed the informed consent. 
Randomized patients consist of all patients, with signed informed consent, with a treatment kit 
number allocated and recorded in the IRT DB, regardless of whether the treatment kit was used or 
not. These patients form the randomized population.
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population. 
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For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately.
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population.
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 the Randomization Visit (as randomized), irrespective of the treatment 
group actually received.
11.3.1.1 Intent–to-treat population
Intent-to-treat (ITT) population: all randomized population analyzed according to the treatment 
group allocated by randomization. 
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 
according to the treatment to which the patient was treated the longest duration.
11.4
STATISTICAL METHODS
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 within the safety population.
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11.4.1.1 Extent of investigational medicinal product exposure
Duration of IMP exposure is defined as: last dose date – first dose date + 1 day, regardless of 
unplanned intermittent discontinuations. 
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.
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.
The number (%) of patients with an up-titration as well as number (%) of patients with an 
up-titration followed by a down-titration will be summarized.
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 will be summarized descriptively (N, mean, SD, median, min, and max). 
The percentage of patients with compliance <80% will be summarized. 
11.4.2 Analyses of efficacy endpoints
All efficacy analyses will be performed on the ITT population. All events occurring from 
Randomization to the patient’s Follow-up Visit (or Study Closeout Visit, if patient prematurely 
permanently discontinues), inclusive, will be included, unless otherwise specified.
11.4.2.1 Analysis of primary efficacy endpoints
The time to the first occurrence of the composite 3-point MACE endpoint (CV death, non-fatal 
MI, non-fatal stroke) will be analyzed using a Cox proportional hazards model with treatment 
(sotagliflozin, placebo), region (North America, Latin America, Western Europe, Eastern Europe, 
and rest of the world), and HF-related criteria (yes, no) as the factors. The hazard ratio between 
sotagliflozin and placebo will be estimated along with the associated 2-sided 95% CI. 
Non-inferiority will be claimed if the UB of the 2-sided 95% CI is less than 1.3. 
The time to the first occurrence of the composite CV death or HHF will be analyzed using the 
same Cox proportional hazards model described above with treatment (sotagliflozin, placebo), 
region (North America, Latin America, Western Europe, Eastern Europe, and rest of the world)
and HF-related criteria (yes, no) as the factors. The stratified log-rank test will be used to compare 
the 2 treatment groups. Superiority will be claimed if the p-value is less than 0.05 (and NI on 
3-point MACE is met).
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Kaplan-Meier curves of the cumulative incidence rate will be provided by treatment groups for 
both primary endpoints. Patients who do not experience a primary outcome event will be 
considered censored at their final study visit (for patients who completed the study), or date of 
non-CV death, or date of last contact when information on efficacy endpoints has been retrieved 
(for patients who discontinued the study). Underlying assumptions of the Cox proportional 
hazards model will be checked using graphical methods. If proportionality is not observed, the 
Mantel-Haenszel test will be performed.
In addition, the primary analysis will be supported by a sensitivity analysis including events from 
patient’s Randomization up to 30 days after the last administration of IMP (or study completion), 
but not beyond the patient’s Follow-up Visit (or Study Closeout Visit, if patient prematurely 
permanently discontinued), using the same Cox model described above.
Subgroup analysis
Subgroup analyses will be conducted for the primary endpoints with respect to region, HF-related 
criteria, age group, gender, race, Baseline BMI group, Baseline UACR group, and Baseline eGFR 
group. Additional subgroups and analysis details will be provided in the SAP.
11.4.2.2 Analyses of secondary efficacy endpoints
Secondary time to event endpoints will be analyzed using the same Cox proportional hazards 
model described above with treatment, region, and HF criteria as factors. The hazard ratios 
between sotagliflozin and placebo will be estimated along with the associated 2-sided 95% CIs. 
The stratified log-rank tests will be used to compare the time-to-first-event curves. Secondary 
endpoints will be tested and claimed as described in the multiplicity considerations section
(Section 11.4.2.3). Kaplan-Meier curves of the cumulative incidence rates will be provided by 
treatment groups.
The total number of events of CV death, HHF, or urgent HF visit will be analyzed using the 
Andersen-Gill approach (38), a generalization of the Cox proportional hazards model for recurrent 
events with treatment, region, and HF-related criteria as factors. For standard errors in the 
Andersen-Gill model, a robust variance estimator that allows for heterogeneity in HF rates 
between patients will be used (39).
Other endpoints
Other time to event endpoints will be analyzed using the same Cox proportional hazards model 
described for the primary endpoints with treatment, region, and HF criteria as factors. Nominal 
p-values from the stratified log-rank test may be provided.
Summary statistics of results and changes from Baseline in HbA1C, body weight, BP, UACR, and 
eGFR at scheduled visits using observed cases with no formal testing will be provided. Graphical 
presentations will also be used to illustrate trends over time. Baseline for eGFR and UACR is 
defined as the average of all values assessed by the central laboratory from Screening up to and 
including Randomization. For the remaining parameters, baseline is defined as the last available 
value before the first dose of double-blind IMP or the last available value on or before the day of 
randomization for patients who were randomized but never exposed to IMP.
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11.4.2.3 Multiplicity considerations
To control the family-wise type I error at alpha=0.05 level (1-sided alpha=0.025), a 
fixed-sequence testing procedure will be applied to the primary endpoints. The hierarchy will be:
1. Non-inferiority of sotagliflozin versus placebo on 3-point MACE
2. Superiority of sotagliflozin versus placebo on time to first event of CV death or HHF
If the hypotheses above are met, the family-wise Type-1 error rate at 0.05 (1-sided alpha=0.025)
will be controlled by the Hochberg procedure for the first 2 secondary endpoints listed below:

Superiority of sotagliflozin versus placebo on 3-point MACE 

Superiority of sotagliflozin versus placebo in patients with Baseline eGFR 
≥30 mL/min/1.73 m2 on a composite renal endpoint of sustained ≥50% decrease in eGFR 
from Baseline (for ≥30 days), chronic dialysis, renal transplant, or sustained eGFR 
<15 mL/min/1.73 m2 (for ≥30 days)
If the hypotheses above are statistically significant, a fixed-sequence testing procedure will be
applied to the other secondary endpoints listed below. The hierarchy will be:
1. Superiority of sotagliflozin versus placebo in patients with Baseline eGFR 
≥30 mL/min/1.73 m2 on a composite renal endpoint and Baseline UACR ≥300 mg/g 
(34 mg/mmol) of sustained ≥50% decrease in eGFR from Baseline (for ≥30 days), chronic 
dialysis, renal transplant, or sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days)
2. Superiority of sotagliflozin versus placebo on the composite endpoint of CV death, HHF, 
or urgent HF visit (defined in Appendix E)
3. Superiority of sotagliflozin versus placebo on CV death
4. Superiority of sotagliflozin versus placebo on all-cause mortality
Inferential conclusions about successive secondary hypotheses require statistical significance of 
the prior one. No further multiplicity adjustments will be made for other efficacy endpoints or 
subgroup analyses for which nominal p-values will be provided for descriptive purpose only.
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. All safety analyses will be performed on the Safety population as defined in 
Section 11.3.2 using the following common rules:
The Baseline value is generally defined as the last available value before the first dose of 
double-blind IMP. 
The following definitions will be applied to laboratory parameters and vital signs:

The potentially clinically significant abnormality (PCSA) values 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.
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
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 below are applicable for classification of AEs, determination 
of on-treatment PCSA values and the last on-treatment value for the laboratory, and vital sign 
parameters. 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 (treatment-emergent AE [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. The 10-day interval is chosen based on the half-life of the 
IMP 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). 
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. Efficacy events that are waived from reporting as AEs are described 
in Section 10.4.2. 
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 period. 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:
-
Treatment-emergent AE
-
Serious TEAE
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-
Treatment-emergent AE leading to death
-
Treatment emergent AE leading to permanent treatment discontinuation

The number (n) and percentage (%) of patients with at least 1 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) and 
adjudicated reasons, summarized on the safety population by treatment received

Death in nonrandomized patients or randomized and not treated patients

All AEs 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

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
TEAEs leading to permanent treatment discontinuation will be summarized and presented as 
number and percent of patients in each treatment group.
11.4.3.2 Analysis of severe hypoglycemia
The number (%) of patients and rate in patient years (2 types: the number of patients with events 
and the total number of events per 100 patient-year) of severe hypoglycemia will be summarized 
by treatment group respectively. Their pattern of occurrence over time will also be assessed, as 
appropriate.
11.4.3.3 Analysis of adverse events of special interest
Pregnancy and symptomatic overdose with IMP will be included in overall AE summaries if any 
are reported. An ALT increase >3 x ULN is included in laboratory PCSA summary if any.
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11.4.3.4 Analysis 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).
The incidence of each EOSI will be summarized by treatment group. The selection of PTs will be 
based on standardized MedDRA query (SMQ) for each corresponding item wherever possible and 
will be further detailed in the SAP.
The incidence of liver-related AEs will be summarized by treatment group. The selection of PTs 
will be based on SMQ Hepatic disorder. Time to liver-related treatment discontinuation and time 
to liver death may also be provided based on hepatic disorder SMQ.
11.4.3.5 Analysis of laboratory variables
The number and percentage of patients with PCSA or by the predefined 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 1 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 tests
The 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 
Postbaseline visit by Baseline status will be displayed by treatment group for each parameter. The 
proportion of patients with PCSA values at any Postbaseline visit will also be displayed by 
duration of exposure for each treatment group.
Time to onset of the initial ALT and AST elevation (>3 x ULN) and total bilirubin elevation 
(>2 x ULN) will be analyzed for each parameter using Kaplan-Meier estimates, using the 
midpoint of the time interval between the first assessment showing the elevation and the previous 
assessment, presented by treatment group. Consideration should be given to the impact of the 
spacing of scheduled tests. A graph of distribution of peak values of ALT versus peak values of 
total bilirubin will also be presented. Note that the ALT and total bilirubin values are presented on 
a logarithmic scale. The graph will be divided into 4 quadrants with a vertical line corresponding 
to 3 x ULN for ALT and a horizontal line corresponding to 2 x ULN for total bilirubin.
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The normalization (to 1 x ULN or return to Baseline if Baseline > ULN) of elevated liver 
function tests will be summarized by categories of elevation (3 x ULN, 5 x ULN, 10 x ULN, 
20 x ULN for ALT and AST; 1.5 x ULN for alkaline phosphatase; and 1.5 x ULN and 2 x ULN 
for total bilirubin), with the following categories of normalization: never normalized, normalized 
after permanent discontinuation of study drug. Note that a patient will be counted only under the 
maximum elevation category. 
11.4.3.6 Analysis 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 1 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.
11.5
INTERIM ANALYSIS
If a CV meta-analysis of other T2D sotagliflozin Phase 3 studies does not meet the pre-marketing 
requirement, in accordance with the 2008 FDA Guidance for Industry: Diabetes Mellitus-
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes (35), an 
interim analysis will be conducted in this trial and included in the initial New Drug Application
submission. 
The alpha-spending to control the overall type I error at the 1-sided α=0.025 for assessing the 
1.8 criterion is as follows: spend 1-sided α=0.02 for the meta-analysis (ie, assessment using UB of 
96% CI) and 1-sided α=0.005 for the interim analysis in this CVOT (ie, assessment using UB of 
99% CI). The 1.8 boundary will be assessed using the time to first occurrence of any 
positively-adjudicated MI, stroke, CV death, or hospitalization for unstable angina (4-point 
MACE). This interim analysis will be conducted when the expected number of events will 
provide sufficient power.
To maintain the blind, either the DMC and independent statistical group or a Sanofi fire-walled 
group, independent of the study, will perform the interim analysis. Additional details will be 
described in separate documents (eg, DMC charter, DMC SAP, and a dedicated CV safety SAP).
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The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, Investigator’s Brochure with any addenda or labeling 
documents [summary of product characteristics, package insert], Investigator’s curriculum vitae 
[CV], 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 Investigator’s Brochure 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(s) and delegated Investigator staff undertake(s) to perform the clinical trial in 
accordance with this clinical trial protocol, ICH guidelines for GCP and the applicable regulatory 
requirements.
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 e-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
The Sponsor 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 e-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 documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use, and quality of 
data.
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13.3
SOURCE DOCUMENT REQUIREMENTS
According to the ICH GCP, the monitoring team must check the e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-CRF. The ICF will 
include a statement by which the patient allows the Sponsor’s duly authorized personnel, the 
ethics committee (IRB/IEC), and the regulatory authorities to have direct access to original 
medical records which support the data on the e-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 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 as soon as they are entered in the e-CRF.
The computerized handling of the data by the Sponsor 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 trial master file.
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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 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 Investigator's Brochure, 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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14.6
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. 
14.7
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities.
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information.
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents.
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection.
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections.
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor.
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections.
14.8
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE
14.8.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following: 

The information on the product leads to doubt as to the benefit/risk ratio

Patient enrollment is unsatisfactory

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
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
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 30 (thirty) 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, 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 
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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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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BIBLIOGRAPHIC REFERENCES
1. Emerging Risk factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et 
al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a 
collaborative meta-analysis of 102 prospective studies. Lancet. 2010;375(9733):2215-22.
2. Emerging Risk factors Collaboration, Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, 
Butterworth AS, et al. Association of cardiometabolic multimorbidity with mortality. JAMA. 
2015;314(1):52-60.
3. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al. Effects of 
intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(214):2545-59.
4. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. 
Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl 
J Med. 2008;358(24):2560-72.
5. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications in 
patients with type 2 diabetes (UKPDS 33).  Lancet. 1998;352(9131):837-53.
6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive 
glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-89.
7. U.S. Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). Guidance for Industry: Diabetes Mellitus —
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 
December 2008.
8. European Medicines Agency, 2015 Committee for Medicinal Products for Human Use 
(CHMP). Reflection paper on assessment of cardiovascular safety profile of medicinal 
products. 25 February 2016. EMA/CHMP/50549.
9. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 
2030. Diabetes Res Clin Pract. 2010;87(1):4-14.
10. Thrainsdottir IS, Aspelund T, Thorgeirsson G, Gudnason V, Hardarson T, Malmberg K, et al. 
The association between glucose abnormalities and heart failure in the population-based 
Reykjavik study. Diabetes Care. 2005;28(3):612-6.
11. Juhaeri J, Gao S, Dai WS. Incidence of heart failure, stroke and acute myocardial infarction 
among Type 2 diabetic patients using insulin glargine and other insulin. Pharmacoepidemiol 
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12. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr. Heart failure 
prevalence, incidence and mortality in the elderly with diabetes. Diabetes Care. 
2004;27(3):699-703.
13. Vaur L, Gueret P, Lievre M, Chabaud S, Passa P, DIABHYCAR Study Group (type 2 
DIABetes, Hypertension, CARdiovascular Events and Ramipril) study. Development of 
congestive heart failure in type 2 diabetic patients with microalbuminuria or proteinuria: 
observations from the DIABHYCAR study. Diabetes care. 2003;26(3):855-60.
14. Carr AA, Kowey PR, Devereux RB,  Brenner BM, Dahlöf B, Ibsen H, et al. Hospitalization 
for new heart failure among subjects with diabetes mellitus in the RENAAL and LIFE studies. 
Am J Cardiol. 2005;96(11):1530-6.
15. Cubbon RM, Adams B, Rajwani A,  Mercer BN, Patel PA, Gherardi G, et al. Diabetes 
mellitus is associated with adverse prognosis in chronic heart failure of ischemic and non-
ischemic aetiology. Diab Vasc Dis Res. 2013;10(4):330-6.
16. Murphy D, McCulloch CE, Lin F, Banerjee T, Bragg-Gresham JL, Eberhardt MS, et al. 
Trends in prevalence of chronic kidney disease in the United States. Ann Intern Med. 
2016;165(7):473-81.
17. Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 Inhibition and 
cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely 
mechanisms? Diabetologia. 2016;59(7):1333-9.
18. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, 
cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-
28.
19. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin 
and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 doi: 
10.1056/NEJMoa1611925. [Epub ahead of print]
20. U.S. Food and Drug Adminstration. FDA approves Jardiance to reduce cardiovascular death in 
adults with type 2 diabetes.  
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm. Accessed 
Dec. 5, 2016. 
21. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 Inhibitors and cardiovascular 
risk: Lessons Learned from the EMPA-REG OUTCOME study. Diabetes Care. 
2016;39(5):717-25.
22. McMurray J. EMPA-REG – The “diuretic hypothesis”. J Diabetes Complications. 
2016;30(1):3-4.
23. Raz I, Cahn A. SGLT2 inhibitors and heart failure – clinical implications. Nat Rev Cardiol. 
2016;13(4):185-6.
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24. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, et al. Heart failure outcomes 
with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the 
EMPA-REG OUTCOME trial. Eur Heart J. 2016;37(19):1526-34.
25. Ferannini E, Mark M, Mayoux E. Cardiovascular Protection in the EMPA-REG OUTCOME 
Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016;39(7):1108-14.
26. Skrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal 
protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015;24(1):96-103.
27. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. 
Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 
2016;375(4):323-34.
28. Sands AT, Zambrowicz BP, Rosenstock J, Lapuerta P, Bode BW, Garg SK, et al. 
Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as an adjunct therapy to insulin in type 1 
diabetes. Diabetes Care. 2015;38(7):1181-8.
29. Wright EM. Glucose galactose malabsorption. Am J Physiol. 1998;275(5Pt1):G879-82.
30. Zinman B, McGuire DK, Wanner C, Lachin JM, Inzucchi SE, Herman WH. Update from 
EMPA-REG OUTCOME Trial. 3-CT-SY29 at the American Diabetes Association Annual 
Scientific Meeting New Orleans, June 2016.
31. Greene SJ, Gheorghiade M, Vaduganathan M, Ambrosy AP, Mentz RJ, Subacius H, et al. 
EVEREST Trial investigators. Haemoconcentration, renal function, and post-discharge 
outcomes among patients hospitalized for heart failure with reduced ejection fraction: insights 
from the EVEREST trial. Eur J Heart Fail. 2013;15(12):1401-11.
32. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive 
decongestion during the treatment of decompensated heart failure on renal function and 
survival. Circulation. 2010;122(3):265-72.
33. van der Meer P, Postmus D, Ponikowski P, Cleland JG, O'Connor CM, Cotter G, et al. The 
predictive value of short-term changes in hemoglobin concentration in patients presenting with 
acute decompensated heart failure. J Am Coll Cardiol. 2013;61(19):1973-81.
34. Oh J, Kang SM, Hong N, Youn JC, Han S, Jeon ES, et al. Hemoconcentration is a good 
prognostic predictor for clinical outcomes in acute heart failure: data from the Korean Heart 
Failure (KorHF) Registry. Int J Cardiol. 2013;168(5):4739-43.
35. U.S. Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). Guidance for Industry Diabetes Mellitus —
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 
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36. 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;28(5):1245-9.
37. 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 July 12, 2016
38. Andersen PK, Borgan O, Gill RD,  Keiding, N. Statistical Models Based on Counting 
Processes. 1992 New York: Springer-Verlag.
39. Lin DY, Wei LJ. The robust inference for the Cox proportional-hazards model. J Am Stat 
Assoc. 1989;84:1074-8.
40. Janssen Pharmaceuticals Inc. Endocrinologic and Metabolic Drugs Advisory Committee: 
Canagliflozin as an Adjunctive Treatment to Diet and Exercise Alone or Co-administered with 
Other Antihyperglycemic Agents to Improve Glycemic Control in Adults with Type 2 
Diabetes Mellitus. Available from: http: 
//www.fda.gov/downloads/AdvisoryCommittees/.../UCM334551.pdf.
41. Bristol-Myers Squibb Company, Astra Zeneca AB. FDA Advisory Committeee Background 
Document: Dapagliflozin. Available from 
https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/E
ndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM262996.pdf
42. FDA, Center for Drug Evaluation and Research. Chong WH. Cross discipline team leader 
review. Jardiance (empagliflozin) - NDA 204629. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204629Orig1s000MedR.pdf
43. FDA, Center for Drug Evaluation and Research. Pucino F. Clinical review.  Farxiga 
(dapagliflozin) – NDA 202293. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000MedR.pdf
44. Bilezikian JP, Watts NB, Usiskin K, Polidori D, Fung A, Sullivan D, et al. Evaluation of Bone 
Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With 
Canagliflozin. J Clin Endocrinol Metab. 2016;101:44-51.
45. Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, and Meininger G. Effects 
of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus J Clin Endocrinol 
Metab. 2016;101:157-66.
46. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and 
moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but 
does not improve glycemic control. Kidney Intl. 2014;85:962-71.
47. Scheen AJ & Paquot N. Metabolic effects of SGLT2 inhibitors beyond increased glucosuria: 
A review of the clinical evidence. Diabetes & Metabolism. 2014;40:S4-11.
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48. Cariou B & Charbonnel B. Sotagliflozin as a potential treatment for type 2 diabetes mellitus. 
Expert Opinion on Investigational Drugs. 2015;24(12):1647-56.
49. Soltani S, Hunter GR, Kazemi A, Shab-Bidar S.The effects of weight loss approaches on bone 
mineral density in adults: a systematic review and meta-analysis of randomized controlled 
trials. Osteoporosis International. 2016;27(9):2655-71.
50. Tiirosh A, de Souza RJ, Sex Differences in the Effects of Weight Loss Diets on Bone Mineral 
Density and Body Composition: POUNDS LOST Trial. J Clin Endocrinol Metab. 
2015;100:2463-71.
51. Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Stockbridge NL, et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials. 
Draft Definitions for CDISC July 3, 2014.
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17
APPENDICES
Appendix A Contraceptive guidance and collection of pregnancy information
DEFINITIONS
Woman of childbearing potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy.
3. Postmenopausal female
-
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 hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use 1 of the non-hormonal 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.
CONTRACEPTION GUIDANCE
Female participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 1.
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Table 1: Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly

Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationb
-
oral
-
intravaginal
-
transdermal

Progestogen-only hormone contraception associated with inhibition of ovulation
-
oral
-
injectable
Highly Effective Methods That Are User Independenta

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation
-
Intrauterine device (IUD)
-
Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion
Vasectomized partner
A vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
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 treatment. 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 participant.
NOTES:
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 participants 
participating in clinical studies.
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COLLECTION OF PREGNANCY INFORMATION
Male participants with partners who become pregnant 

The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants 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 within 24 hours of learning of the partner’s pregnancy. The 
female 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, the follow-up will be no longer than 1 year 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 participants who become pregnant 

The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 1 year 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.
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 poststudy pregnancy-related SAE 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 participants, he or she may learn of an SAE through spontaneous 
reporting.

The Investigator must immediately discontinue study treatment for any female participant 
who becomes pregnant while participating in the study.
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Appendix B
Dual-energy x-ray absorptiometry sub-study
INTRODUCTION
A key safety objective of this study is to evaluate the effects of sotagliflozin on bone mass 
measured by the change in BMD throughout the treatment duration. Evaluation of bone safety is 
relevant due to findings of hyperostosis and decreases in bone turnover observed in animal studies
with other compounds in the class (40, 41). These effects have been hypothesized to be associated 
with off-target SGLT1 inhibition leading to an increased intestinal calcium absorption and 
changes in calcium homeostasis and vitamin D metabolism (40, 41). Small and inconsistent 
changes in bone biomarkers and no imbalance in fracture rate were reported in clinical trials with 
dapagliflozin and empagliflozin (42, 43). Changes in bone markers (increase in β-CTX-1) after 
1 year and a small decrease in BMD after 2 years were reported with canagliflozin treatment (44), 
although the clinical significance is unknown. These clinical findings were inconsistent with the 
preclinical data and could be explained at least in part by the weight loss occurred with 
canagliflozin treatment (44). An increased risk of fractures was observed in older patients 
participating in the canagliflozin CV outcomes trial (CANVAS; 45) and in a 2-year study with 
dapagliflozin in patients with renal impairment (46), but in both cases, the findings were not seen 
in the pooled data from Phase 3 studies. It is possible that these subgroups present higher 
susceptibility to hemodynamic events or falls, which could be associated with fractures (46).
Preclinical studies with sotagliflozin in rats showed increases in trabecular bone and small 
reversible decreases in calciotropic hormone and bone markers (P1NP, osteocalcin, 
1,25-dihydroxyvitamin D), which were not considered biologically significant. No clinically 
significant changes in calcium and bone biomarkers have been observed in clinical studies with 
sotagliflozin. However, as changes in bone markers and BMD were reported in clinical studies 
with canagliflozin (40), this study will also further assess the effects of sotagliflozin on bone 
mass, markers of calcium metabolism and bone turnover in this group of patients at higher risk for 
osteoporosis and fractures. In order to assess the risk of fractures with sotagliflozin treatment, the 
number of fractures will be evaluated and independently adjudicated in this study and in the 
totality of sotagliflozin Phase 3 studies, including in patients with various degrees of renal 
impairment. 
Clinically meaningful weight loss is observed with SGLT2 inhibitors (47) and a significant weight 
reduction is expected and as a result of the dual SGLT1-2 inhibition with sotagliflozin (48). 
Reduction of BMD is reported following weight loss interventions (49, 50) and decline in 
estradiol levels was observed in association with weight loss in women treated with canagliflozin 
in a 2- year study (44). Decrease in estradiol levels affects bone turnover and can represent an 
additional negative effect to bone mass. Selected markers of bone formation and resorption and 
other biochemical parameters of relevance to bone metabolism will also be evaluated in this trial.
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PRIMARY OBJECTIVE
To compare sotagliflozin versus placebo with respect to changes in BMD in patients with 
T2D, CV risk factors, and moderately impaired renal function.
SECONDARY OBJECTIVES
To compare sotagliflozin versus placebo in patients with T2D, CV risk factors, and 
moderately impaired renal function with respect to:

Changes in markers of bone and calcium metabolism
STUDY DESIGN
A total of approximately 190 patients (approximately 95 female and 95 male) will participate in 
the DXA sub-study. Patients participating in the sub-study will complete a dedicated informed 
consent. 
Patients who agree to participate in the sub-study will have a DXA scan performed at Baseline 
along with the collection of laboratory markers of bone and calcium metabolism. Investigations 
will be repeated at the pEOT Visit (if discontinuing treatment early) or at the Study Closeout
Visit (patients who completed treatment [ie, without prematurely permanently discontinuing 
IMP]). If a patient prematurely withdraws from the sub-study, they will be encouraged to 
continue in the main trial.
ENDPOINTS
Primary endpoint:

Change from Baseline in BMD (lumbar spine, total hip, and femoral neck) measured by 
DXA
Secondary endpoints:

Change from Baseline in: 
-
The following markers of bone and calcium metabolism: serum and urinary calcium, 
serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, serum and urinary 
phosphorus, serum PTH, serum NTX, serum β-CTX-1, serum P1NP, serum 
magnesium
SUB-STUDY PROCEDURES
Select sites from this trial will be asked to participate in the DXA sub-study. Sites selected to 
participate in the sub-study will have IRB/EC approval for the main study and for the sub-study, 
and an additional informed consent. Patients who have signed informed consent for the main 
study of this trial at these select sites and are deemed eligible for the study at Screening will be 
asked to participate in the sub-study. Once the additional written informed consent is obtained for 
the sub-study, the patients will undergo the following assessments. Written informed consent 
must be obtained prior to any study investigations.
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Specific to Canada and USA: Instructions for patients for fasting visits (see Appendix F)
VISIT SCHEDULE
Screening period (at the Week -4 Screening Visit [Visit 1] and before Day 1 [Randomization,
Visit 2])

Assessment of eligibility criteria 

For patients who at the time of the screening Visit meet the inclusion criteria for the DXA 
sub-study and do not meet any known exclusion criterion:

DXA scan for BMD
Note: It is recommended that the same DXA instrument is used for both study 
assessments.

Sample for central laboratory assessment: 
-
Serum: 25-hydroxyvitamin D (at Visit 1)
-
24-hour urine collection (calcium, phosphorus, creatinine). Urine samples should be 
returned prior to or at Visit 2 (Randomization)
Visit 2 (Day 1)

Assessment of eligibility criteria

Samples for central laboratory assessment of markers of bone and calcium for patients 
who meet all entry criteria as follows: 
-
Serum: calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, PTH, 
NTX, β-CTX-1, and P1NP.  Specific for Canada and USA: Fasting morning samples 
(see Appendix F)
Premature End-of-Treatment/Study Closeout Visit

DXA scan for BMD
Note: It is recommended that the same DXA instrument is used for both study 
assessments.

Samples for central laboratory assessment of markers of bone and calcium as follows: 
-
24-hour urine collection: calcium, phosphorus, creatinine
-
Serum: Calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, PTH, 
NTX, β-CTX-1, and P1NP. Specific for Canada and USA: Fasting morning serum 
samples (see Appendix F)
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SELECTION OF PATIENTS
Approximately 190 patients (95 female and 95 male) will participate in the sub-study. In order to 
be eligible for this sub-study, all patients must meet eligibility criteria for the main EFC14875 
study and the additional eligibility criteria outlined for this sub-study.
Additional Inclusion Criteria:

Signed written informed consent for DXA sub-study of EFC14875 protocol
Additional Exclusion Criteria:

Patient who withdraws consent for DXA sub-study of EFC14875 protocol during the 
Screening period (patient who is not willing to continue)

Patient unable to complete the DXA testing during the Screening period, or any 
contraindications to DXA testing, or conditions making interpretation of the DXA results 
difficult (eg, imaging procedure requiring contrast within 10 days prior to Screening, 
recent administration of radionuclides [within 10 half-lives of the injected tracer])

Women who have been postmenopausal (or undergone bilateral oophorectomy) for less 
than 5 years

Bone mineral density T-score <-2.0 at any site (ie, lumbar spine, total hip, or femoral 
neck) measured by DXA obtained during the screening period.
Note: If a patient has had a BMD documented within the last 1 year and the T-score is not 
<-2.0 at any site the patient may proceed to Randomization prior to receiving the results of 
the BMD performed during screening.

Hypercalcemia based on total serum calcium level >10.5 mg/dL (2.63 mmol/L) at 
Screening by central laboratory

Diagnosis of vitamin D deficiency within 12 months prior to the Screening Visit or serum 
25-hydroxyvitamin D levels ≤20 ng/mL at Screening by central laboratory 

History of fracture within 12 months of screening (except for fractures of the fingers, 
hands, toes, feet, face, and skull)

Treatment with medications known to affect bone mass or increase risk of fractures within 
36 months prior to the Screening Visit (eg, bisphosphonates, selective estrogen receptor 
modulators, calcitonin, teriparatide, denosumab, aromatase inhibitors, androgen 
deprivation therapy), or anticonvulsants (eg, carbamazepin, phenytoin, and phenobarbital) 
within 36 months prior to the Screening Visit. Use of hormonal replacement that includes 
systemic or transdermal estrogen and testosterone is excluded unless is stable for at least 
24 months prior to screening

Use of a thiazolidinedione or a SGLT2 inhibitor within 24 months of the Screening Visit
Patients who are not eligible for the sub-study based on the additional eligibility criteria may still 
take part in the main study.
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Patients who wish to withdraw their participation in this sub-study may do so at any time. If they 
do so, they will be encouraged to continue participation in the main study.
Patients who discontinue the main study, must also discontinue participation in the sub-study.
Patients who prematurely permanently discontinue study treatment (regardless of the reason)
should perform the sub-study procedures at their pEOT Visit and continue with all study visits 
as otherwise planned until their Study Closeout Visit.
STATISTICAL CONSIDERATIONS
The statistical analysis of the DXA sub-study will be fully developed in the SAP.
This sub-study will involve approximately 190 randomized patients (95 female and 95 male) who 
are randomized in the main study, give informed consent to participate in this sub-study, and are 
enrolled in the sub-study through the IRT. The analysis will be conducted on the safety 
population.
The primary and safety endpoints will be descriptive (results and change from Baseline); no 
statistical tests will be performed. Summaries will include number of observations available, 
mean, SD, minimum, median, and maximum.
Additional summaries by gender and postmenopausal females may also be produced.
SAFETY REPORTING
Adverse events and SAEs will be captured and reported in accordance with the main EFC14875 
study (see Section 10.4 to Section 10.7).
ADMINISTRATION
Informed Consent
A separate informed consent will be obtained from patients who voluntarily agree to participate in 
the sub-study. The ICF reflecting this sub-study will be submitted for review and approval to the
IRB/EC charged with this responsibility.
Confidentiality
Data collection and handling by the Sponsor for this sub-study will be will be in accordance with 
that described in the main EFC14875 protocol and in accordance with local guidelines (see 
Section 14.3 and Section 14.5), and every effort will be made to protect patient confidentiality.
When the results are published, they will be done so anonymously.
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Institutional Review Board/Ethics Committee
This sub-study, the ICF for this sub-study, and any advertisement for patient recruitment will be
submitted for review and approval to the IRB/EC charged with this responsibility.
Records Retention
Investigators must retain records pertaining to this sub-study as described in the main EFC14875
study protocol (see Section 14.2).
Miscellaneous
Section 10.4.1 to Section 17 will also apply to the sub-study.
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Appendix D
Guidance for the follow-up of acute worsening of renal function
Rapid change in renal function of greater than 30% as compared with the mean of the prior two 
study visits 

Evaluate if the patient is taking medications which alter serum creatinine such as: 
trimethoprim, fenofibrate, non-steroidal anti-inflammatory agents, cimetidine, 
cephalosporins, probenecid, aminoglycosides, amphotericin, ketoconazole, clofibrate, 
contrast agents

Evaluate if any of the following conditions are present that may alter serum creatinine:
-
Significant increase or decrease in blood pressure due to changes in antihypertensive 
therapy or diuretic treatment
-
Plasma volume depletion or expansion
-
Flu-like symptoms
-
Infected urine
-
Obstructive uropathy
-
New onset or exacerbation of heart failure

If any of the above conditions are met, the Investigator should take corrective measures to 
resolve and schedule an interim visit to evaluate the serum creatinine/GFR and the 
patient’s clinical status 1 week from the institution of corrective measures. Patients with a 
suspected renal event (reduction of eGFR) should have a repeat assessment of renal 
function 30 to 45 days following the onset of the event to confirm it is sustained. If acute 
renal failure is suspected, further clinical evaluation should be performed as per local 
standard of care, including confirmation of renal laboratory parameters, and consideration 
should be given to a nephrology referral.

Permanent discontinuation of IMP should be a last resort, and if IMP needs to be withheld, 
it should be done so temporarily when possible. Permanent discontinuation of IMP is 
required if eGFR <15 mL/min/1.73m2 that has been confirmed on repeated testing and in 
the absence of a reversible cause (see protocol Section 10.3.3).
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Appendix E Definition of urgent heart failure visit
An urgent HF visit is defined as an event that meets all of the following (adapted from 51):

The patient has an urgent, unscheduled office/practice or emergency department visit for a 
primary diagnosis of HF, but not meeting the criteria for a HF hospitalization

All signs and symptoms for HF hospitalization must be met, including:
-
Symptoms as noted in Section I below 
-
Physical examination findings/laboratory evidence of new or worsening HF, as 
indicated in Section II below 

The patient receives initiation or intensification of treatment specifically for HF, as 
detailed in section III (below) (note that oral diuretic therapy will not be sufficient)
Section I Symptoms:
The patient exhibits documented new or worsening symptoms due to HF on presentation, 
including at least ONE of the following:
A) Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal nocturnal 
dyspnea)
B) Decreased exercise tolerance
C) Fatigue
D) Other symptoms of worsened end-organ perfusion or volume overload (as detailed in the 
CEC charter)
Section II Physical examination findings/laboratory evidence
The patient has objective evidence of new or worsening HF, consisting of at least TWO physical 
examination findings OR ONE physical examination finding and at least ONE laboratory 
criterion, including:
A) Physical examination findings considered to be due to HF, including new or worsened:
1. Peripheral edema
2. Increasing abdominal distention or ascites (in the absence of primary hepatic disease)
3. Pulmonary rales/crackles/crepitations
4. Increased jugular venous pressure and/or hepatojugular reflux 
5. S3 gallop
6. Clinically significant or rapid weight gain thought to be related to fluid retention
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B) Laboratory evidence of new or worsening HF, if obtained within 24 hours of presentation, 
including:
1. Increased B-type natriuretic peptide (BNP)/NT-proBNP concentrations consistent with 
decompensation of HF (such as BNP >500 pg/mL or NT-proBNP >2,000 pg/mL). In 
patients with chronically elevated natriuretic peptides, a significant increase should be 
noted above baseline
2. Radiological evidence of pulmonary congestion
3. Non-invasive diagnostic evidence of clinically significant elevated left- or right-sided 
ventricular filling pressure or low cardiac output. For example, echocardiographic criteria 
could include: E/e’ >15 or D-dominant pulmonary venous inflow pattern, plethoric inferior 
vena cava with minimal collapse on inspiration, or decreased left ventricular outflow tract 
minute stroke distance (time velocity integral)
OR
4. Invasive diagnostic evidence with right heart catheterization showing a pulmonary 
capillary wedge pressure (pulmonary artery occlusion pressure) ≥18 mmHg, central 
venous pressure ≥12 mmHg, or a cardiac index <2.2 L/min/m2
Section III Initiation or intensification of treatment specifically for HF
At least ONE of the following:
A) Intravenous diuretic or vasoactive agent (eg, inotrope, vasopressor, or vasodilator)
B) Mechanical or surgical intervention, including:
1. Mechanical circulatory support (eg, intra-aortic balloon pump, ventricular assist device, 
extracorporeal membrane oxygenation, total artificial heart)
2. Mechanical fluid removal (eg, ultrafiltration, hemofiltration, dialysis)
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Appendix F
Country-specific requirements
Amendment for India
Clinical Trial Summary and Section 7.2
Exclusion criteria (Section 7.2)
The following text has been added to E 24. Laboratory findings at the Screening Visit:
Specific to India: HbA1c >10% (86 mmol/mol) (central laboratory); see Appendix F
Section 10.1.1.1 On-site Visit 1 (Week -4) Screening Visit (Section 10.1.1.1)
The following text has been added:
Specific to India: HbA1c ≥7% (53 mmol/mol) to ≤10% (86 mmol/mol) (central laboratory); see 
Appendix F.
Section 8.8.1 Antihyperglycemic concomitant medication (Section 8.8.1)
The following text:
After the first 12 weeks post Randomization and during the remaining Double-blind Treatment 
period, the management of glycemia will be left to the Investigator’s and/or treating provider’s 
judgment, informed by clinical guidelines and local/regional standards of care. The Investigator 
and/or treating provider will therefore be allowed to undertake appropriate action, ie,

Adjust the dose of the background antihyperglycemic treatment

Prescribe an additional antihyperglycemic medication according to its labeling (no SGLT2 
inhibitor should be used)

Remove an antihyperglycemic treatment
Antihyperglycemic therapy is to be reported in the e-CRF.
Is replaced with: 
After the first 12 weeks post Randomization and during the remaining Double-blind Treatment 
period, the management of glycemia will be left to the Investigator’s and/or treating provider’s 
judgment, informed by clinical guidelines and local/regional standards of care. The Investigator 
and/or treating provider will therefore be allowed to undertake appropriate action, ie,

Adjust the dose of the background antihyperglycemic treatment

Prescribe an additional antihyperglycemic medication according to its labeling (no SGLT2 
inhibitor should be used)

Remove an antihyperglycemic treatment
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Specific to India: Rescue criteria for patients with uncontrolled hyperglycemia (see Appendix F).
Antihyperglycemic therapy is to be reported in the e-CRF.
Related to this amendment for India:
It has to be noted that at any time during the study after 12 weeks, if, in the opinion of the 
Investigator/treating healthcare provider, glucose control is not adequate over a sustained period 
of time, despite up-titration of background antihyperglycemic therapy, rescue medication should 
be considered, if medically indicated. The choice of rescue medication should be based on the 
Investigator’s/treating healthcare provider’s medical judgment, taking into consideration the 
patient’s clinical status, co-morbidities and background therapy, in accordance with clinical 
guidelines such as the Research Society for the Study of Diabetes in India (RSSDI) clinical 
practice recommendations for the management of Type 2 diabetes mellitus, American Diabetes 
Association (ADA), Standards of Medical Care in Diabetes or European Association for the Study 
of Diabetes (EASD) management of hyperglycaemia in Type 2 diabetes. All medication must be 
administered in accordance with the local prescribing information, taking into account potential 
contraindications for the individual patient. Other SGLT2 inhibitors must not be used.
Amendment for Canada and United States of America
Section 1.2
Study Flow Chart (Section 1.2)
The following text in Footnote ‘o’:
Approximately 190 patients (95 females and 95 males) will be enrolled into the DXA sub-study. 
25-hydroxyvitamin D will be drawn at the Screening Visit to allow assessment of eligibility for 
the sub-study. The DXA scan and 24-hour urine collection (for calcium, creatinine, and 
phosphorus) will be performed during the Screening period prior to Randomization for patients 
who sign the dedicated informed consent form and otherwise meet the eligibility criteria for the 
sub-study at the time of the Screening Visit; urine samples specific to the sub-study 
(see Appendix B) should be returned prior to or at Visit 2 (Randomization).
Serum markers of bone and calcium metabolism will otherwise be performed at Day 1 (Visit 2). 
At the end of treatment (pEOT Visit for patients who prematurely permanently discontinue and 
the Study Closeout Visit for patients who completed treatment), a DXA scan, 24-hour urine 
collection and serum markers of bone and calcium metabolism will be performed.
Is replaced with:
Approximately 190 patients (95 females and 95 males) will be enrolled into the DXA sub-study. 
25-hydroxyvitamin D will be drawn at the Screening Visit to allow assessment of eligibility for 
the sub-study. The DXA scan and 24-hour urine collection (for calcium, creatinine, and 
phosphorus) will be performed during the Screening period prior to Randomization for patients 
who sign the dedicated informed consent form and otherwise meet the eligibility criteria for the 
sub-study at the time of the Screening Visit; urine samples specific to the sub-study 
(see Appendix B) should be returned prior to or at Visit 2 (Randomization).
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Fasting serum Serum markers of bone and calcium metabolism will otherwise be performed at 
Day 1 (Visit 2). At the end of treatment (pEOT Visit for patients who prematurely permanently 
discontinue and the Study Closeout Visit for patients who completed treatment), a DXA scan, 
24-hour urine collection and fasting serum markers of bone and calcium metabolism will be 
performed.
Section 10.1.1.1
On-site Visit 1 (Week -4) Screening Visit (Section 10.1.1.1)
The following text:

For patients participating in the DXA sub-study:
-
A sample will be taken for 25-hydroxyvitamin D
-
24-hour urine collection will need to be scheduled during Screening/prior to the 
Randomization Visit (Visit 2) (see Appendix B)
-
A DXA scan will need to be scheduled during Screening/prior to the Randomization 
Visit (Visit 2) for eligibility assessment (see Appendix B )
Note: If a patient has had a BMD value documented within the last year and the T 
score is not <-2.0 at any site the patient may proceed to Randomization prior to 
receiving the results of the BMD value performed during Screening.
Is replaced with:

For patients participating in the DXA sub-study:
-
A sample will be taken for 25-hydroxyvitamin D
-
24-hour urine collection will need to be scheduled during Screening/prior to the 
Randomization Visit (Visit 2) (see Appendix B)
-
A DXA scan will need to be scheduled during Screening/prior to the Randomization 
Visit (Visit 2) for eligibility assessment (see Appendix B)
-
Please remind patients to fast prior to Visit 2 (see Appendix B)
Note: If a patient has had a BMD value documented within the last year and the T 
score is not <-2.0 at any site the patient may proceed to Randomization prior to 
receiving the results of the BMD value performed during Screening.
Section 10.1.2.1
On-site Visit 2 (Day 1) Randomization (Section 10.1.2.1)
The following text:

For patients at sites participating in the DXA sub-study who have consented to, and are 
eligible for, DXA sub-study:
-
Markers of bone and calcium metabolism (see Appendix B for details)
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Is replaced with:

For patients at sites participating in the DXA sub-study who have consented to, and are 
eligible for, DXA sub-study:
-
Fasting markers Markers of bone and calcium metabolism (see Appendix B for details)
Section 10.1.3.1
Premature End-of-Treatment Visit (Section 10.1.3.1)
The following text:

For patients at participating sites who are participating in the DXA sub-study:
-
DXA scan
-
Markers of bone and calcium metabolism (including 24-hour urine collection; see 
Appendix B for full list)
Is replaced with:

For patients at participating sites who are participating in the DXA sub-study:
-
DXA scan
-
Fasting markers Markers of bone and calcium metabolism (including 24-hour urine 
collection; see Appendix B for further details full list)
Section 10.1.4.1
Study Closeout Visit for patients who do not prematurely discontinue 
investigational medicinal product (Section 10.1.4.1) 
The following text:

For patients at participating sites who are participating in the DXA sub-study:
-
DXA scan
-
Markers of bone and calcium metabolism (see Appendix B for full list)
Is replaced with:

For patients at participating sites who are participating in the DXA sub-study:
-
DXA scan
-
Fasting markers Markers of bone and calcium metabolism (see Appendix B for further
details full list)
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Section 11.4.2.2
Analyses of secondary efficacy endpoints (Section 11.4.2.2)
The following text:
Other endpoints
Other time to event endpoints will be analyzed using the same Cox proportional hazards model
described for the primary endpoints with treatment, region, and HF criteria as factors. Nominal
p-values from the stratified log-rank test may be provided.
Summary statistics of results and changes from Baseline in HbA1C, body weight, BP, UACR, and
eGFR at scheduled visits using observes cases with no formal testing will be provided. Graphical
presentations will also be used to illustrate trends over time. Baseline for eGFR and UACR is
defined as the average of all values assessed by the central laboratory from Screening up to and
including Randomization. For the remaining parameters, baseline is defined as the last available
value before the first dose of double-blind IMP or the last available value on or before the day of
randomization for patients who were randomized but never exposed to IMP.
Is replaced with:
Other endpoints
Other time to event endpoints will be analyzed using the same Cox proportional hazards model
described for the primary endpoints with treatment, region, and HF criteria as factors. Nominal
p-values from the stratified log-rank test may be provided.
Summary statistics of results and changes from Baseline in HbA1C, body weight, BP, UACR, and
eGFR at scheduled visits using observes observed cases with no formal testing will be provided. 
Graphical presentations will also be used to illustrate trends over time. Baseline for eGFR and 
UACR is defined as the average of all values assessed by the central laboratory from Screening up 
to and including Randomization. For the remaining parameters, baseline is defined as the last 
available value before the first dose of double-blind IMP or the last available value on or before 
the day of randomization for patients who were randomized but never exposed to IMP.
Appendix B
Dual-energy X-ray absorptiometry sub-study (Appendix B)
SUB-STUDY PROCEDURES
The following text:
Select sites from this trial will be asked to participate in the DXA sub-study. Sites selected to 
participate in the sub-study will have IRB/EC approval for the main study and for the sub-study, 
and an additional informed consent. Patients who have signed informed consent for the main 
study of this trial at these select sites and are deemed eligible for the study at Screening will be 
asked to participate in the sub-study. Once the additional written informed consent is obtained for 
the sub-study, the patients will undergo the following assessments. Written informed consent must 
be obtained prior to any study investigations.
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Is replaced with:
Select sites from this trial will be asked to participate in the DXA sub-study. Sites selected to 
participate in the sub-study will have IRB/EC approval for the main study and for the sub-study, 
and an additional informed consent. Patients who have signed informed consent for the main 
study of this trial at these select sites and are deemed eligible for the study at Screening will be 
asked to participate in the sub-study. Once the additional written informed consent is obtained for 
the sub-study, the patients will undergo the following assessments. Written informed consent must 
be obtained prior to any study investigations.
Note:  Patients should be instructed to come to Visit 2 (Day 1) and other fasting visits (either 
premature end-of-treatment or study closeout visit) in the morning after at least an 8 hour fast.  
This includes no food or drink other than water, and no medications, multivitamins or dietary 
supplements for the duration of the fast.  Attempts should be made to perform blood sampling at 
the premature-end-of-treatment/study closeout visit at approximately the same time of day as the 
samples performed on the day of randomization.
Visit 2 (Day 1)
The following text:

Samples for central laboratory assessment of markers of bone and calcium for patients 
who meet all entry criteria as follows:
-
Serum: calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, PTH, 
NTX, β-CTX-1, and P1NP
Is replaced with:

Fasting morning samples Samples for central laboratory assessment of markers of bone 
and calcium metabolism for patients who meet all entry criteria as follows:
-
Serum: calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, PTH, 
NTX, β-CTX-1, and P1NP
Premature End-of-Treatment/Study Closeout Visit
The following text:

Samples for central laboratory assessment of markers of bone and calcium as follows:
-
24-hour urine collection: calcium, phosphorus, creatinine
-
Serum: Calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, PTH, 
NTX, β-CTX-1, and P1NP
Is replaced with:

Samples for central Central laboratory assessment of markers of bone and calcium 
metabolism, including fasting morning serum samples, as follows:
-
24-hour urine collection: calcium, phosphorus, creatinine
-
Serum: Calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, PTH, 
NTX, β-CTX-1, and P1NP.
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Appendix G
Protocol amendment history
Protocol Amendment 01: 12-Jan-2018 Canada and United States of America only

Change to the conditions under which laboratory assessments for the bone sub-study at the 
randomization and end of treatment visits are being conducted
In section(s): Study Flow Chart, sections 10.1 & Appendix B of the protocol
Rationale: In order to secure the reliability of the markers of bone turnover, the study protocol is 
being amended to secure that this testing is performed under controlled conditions, including after 
an overnight fast and in the early morning hours in order to limit the impact of circadian rhythms 
and meal intake on the markers of bone turnover in order to reduce these controllable sources of 
variability.  
In addition, other minor changes are listed in the description of changes.
Please note that this protocol amendment is applicable to the following regions only:  Canada and 
the United States of America.
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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 D e m o n str at e t h e Eff e ct s of S ot a glifl o zi n o n 
C ar di o v a s c ul ar a n d R e n al E v e nt s i n P ati e nt s wit h T y p e 2 Di a b et e s, 
C ar di o v a s c ul ar Ri s k F a ct or s a n d M o d er at el y I m p air e d R e n al F u n cti o n  
N C T N u m b er:  
N C T 0 3 3 1 5 1 4 3  
D o c u m e nt  D at e : 
S A P V er si o n 1: 2 1 A u g u st 2 0 2 0  




P a g e 2 
S T A TI S TI C A L A N A L Y SI S P L A N 
A R a n d o mize d, D o u ble- bli n d, Pl a ce b o-c o ntr olle d, P ar allel- gr o u p,  M ultice nter 
St u d y t o De m o nstr ate t he Effect s of S ot a glifl ozi n o n C ar di o v ascul ar a n d Re n al 
E ve nts i n P atie nts wit h T y pe 2 D i a betes, C ar di o v asc ul ar Ris k F a ct ors a n d 
M o der atel y I m p aire d Re n al F u nc ti o n; T he S C O R E D Tri al, E F C 1 4 8 7 5 
D A T E O F I S S U E: 2 1- A u g- 2 0 2 0 
T otal n u m ber of pa ges:  
3 8 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er – E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
P a g e 3 
T A B L E O F C O N T E N T S 
S T A TI S TI C A L A N A L Y SI S P L A N  .................................................................................................................. 2 
T A B L E O F C O N T E N T S  .................................................................................................................................. 3 
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  ........................................................................ 5 
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  .............................................................................. 7 
1. 1  
B A C K G R O U N D  ................................................................................................................................ 7 
1. 2  
O BJ E C TI V E S  .................................................................................................................................... 8 
1. 2. 1  
Pri mar y o bjecti ves  .............................................................................................................................. 8 
1. 2. 2  
Sec o n dar y o bjecti ves  .......................................................................................................................... 8 
1. 3  
D E T E R MI N A TI O N O F S A M P L E SI Z E  .............................................................................................. 9 
1. 4  
S T U D Y P L A N  ................................................................................................................................... 9 
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  ................................................................... 1 1 
2. 1  
A N A L Y SI S E N D P OI N T S  ................................................................................................................ 1 1 
2. 1. 1  
De m o gra p hic a n d baseli ne c haracteristics  ........................................................................................... 1 1 
2. 1. 2  
Baseli ne me dicati o n a n d de vice  ......................................................................................................... 1 2 
2. 1. 3  
Efficac y e n d p oi nts  ............................................................................................................................ 1 3  
2. 1. 3. 1  
Pri mar y efficac y e n d p oi nt(s)  .............................................................................................................. 1 3 
2. 1. 3. 2  
Sec o n dar y efficac y e n d p oi nt(s)  .......................................................................................................... 1 3 
2. 1. 3. 3  
Ot her efficac y e n d p oi nts  .................................................................................................................... 1 4 
2. 1. 4  
Safet y e n d p oi nts  ............................................................................................................................... 1 5 
2. 1. 4. 1  
A d verse e ve nt varia bles ..................................................................................................................... 1 6 
2. 1. 4. 2  
La b orat or y safet y varia bles  ................................................................................................................ 1 8 
2. 1. 4. 3  
Vital si g ns varia bles  .......................................................................................................................... 1 8 
2. 2  
DI S P O SI TI O N O F P A TI E N T S  ......................................................................................................... 1 8 
2. 3  
A N A L Y SI S P O P U L A TI O N S  ............................................................................................................ 2 0 
2. 3. 1  
Ra n d o mize d p o p ulati o n  ..................................................................................................................... 2 0 
2. 3. 2  
Efficac y p o p ulati o ns  ......................................................................................................................... 2 0 
2. 3. 3  
Safet y p o p ulati o n  .............................................................................................................................. 2 0 
2. 4  
S T A TI S TI C A L M E T H O D S  .............................................................................................................. 2 0 
2. 4. 1  
De m o gra p hics a n d baseli ne c haracteristics  .......................................................................................... 2 0 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er – E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
P a g e 4 
2. 4. 2  
C o nc o mita nt me dicati o ns  .................................................................................................................. 2 0 
2. 4. 3  
E xte nt of i n vesti gati o nal me dici nal pr o d uct e x p os ure a n d d ose t itrati o n ................................................. 2 0 
2. 4. 4  
A nal yses of efficac y e n d p oi nts  ........................................................................................................... 2 1 
2. 4. 4. 1  
A nal yses of pri mar y efficac y e n d p oi nt  ................................................................................................ 2 1 
2. 4. 4. 2  
A nal yses of sec o n dar y efficac y e n d p oi nts  ........................................................................................... 2 3 
2. 4. 4. 3  
M ulti plicit y iss ues  ............................................................................................................................ 2 3  
2. 4. 4. 4 A d diti o nal efficac y a nal ysis(es)  .............................................................................................................. 2 3 
2. 4. 5  
A nal yses of safet y data  ...................................................................................................................... 2 4 
2. 4. 5. 1 A nal yses of a d verse e ve nts  ..................................................................................................................... 2 4 
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 
2. 5. 1 Ge neral c o n ve nti o ns  ................................................................................................................................. 2 5 
2. 5. 2 Data h a n dli n g c o n ve nti o ns f or sec o n dar y efficac y varia ble s ........................................................................ 2 6 
2. 5. 3  
Missi n g data  ..................................................................................................................................... 2 6 
2. 5. 4  
Wi n d o ws f or ti me p oi nts  ................................................................................................................... 2 7 
R E F E R E N C E S ................................................................................................................... ........................... 2 8 
A P P E N DI X A C A L C U L A TI O N/ D E RI V A TI O N O F TI M E- T O- E V E N T E N D P OI N T S  ................................. 2 9 
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 D E O SI ( M E D D R A V 2 3. 0)  ...................................................... 3 2 
A p p e n di x C K e y C h a n g e s t o Ori gi n al Pl a n n e d A n al y si s a n d Pr ot o c o l ................................................. 3 7 


St ati sti c al A n al y si s Pl a n  
2 1- A u g- 2 0 2 0 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
P a g e 5 
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 E 
A d verse e ve nt 
A E SI 
A d ve rse e ve nts of s pecial i nterest
B MI 
B o d y  mass i n de x
C V 
Car di o vasc ular 
D A O H 
Da ys ali ve a n d o ut of h os pital 
e G F R 
Esti mat e d gl o mer u lar filtrati o n rate 
E O SI 
E ve nts of s pecial i nterest 
H b A 1c 
He m o g l o bi n A 1c
H F 
Heart fail ure
H H F 
H os pitalizati o n f or heart fail ure 
I M P 
I n vesti gati o nal me dici nal pr o d uct 
I T T 
I nte nt-t o-treat 
L V E F 
Left ve ntric ula r ejecti o n fracti o n 
MI 
M y ocar dial i nfarcti o n


St ati sti c al A n al y si s Pl a n  
2 1- A u g- 2 0 2 0 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
P a g e 6 
P D A O H  
Perce nt da y s ali ve a n d o ut of h os pital
P T 
Preferre d ter m 
S B P 
S yst olic bl o o d press ure 
W H F 
W orse ni n g heart fail ure 
 


St ati sti c al A n al y si s Pl a n  
2 1- A u g- 2 0 2 0 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
P a g e 7 
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  
B A C K G R O U N D 
S C O R E D is a P hase 3, m ultice nt er, ra n d o mize d, d o u ble- bli n d, pla ce b o-c o ntr olle d, parallel gr o u p,  stratifie d st u d y of s ota glifl ozi n f or 
t he treat me nt of patie nts wit h ty pe 2 dia betes ( T 2 D), car di o vas c ular ris k fact ors, a n d m o derate t o se ver el y i m paire d re nal f u n cti o n. 
 
After scree ni n g, patie nts w h o met all eli gi bilit y criteria were ce ntrall y ra n d o mize d via i n a 1: 1 rati o t o s ota glifl ozi n or pl ace b o at t he 
ra n d o mizati o n visit. Ra n d o mizati on was stratifie d b y r e gi o n ( N o rt h A merica, Lati n A merica, Wester n E ur o pe, Easter n E ur o pe, a n d 
rest of t he w orl d) a n d b y H F-relate d criteria ( Yes/ N o).  
 
T he ori gi nal pla n was t o pr o vi de  a p pr o xi matel y 2 7 m o nt hs of f oll o w- u p after t he last patie nt was ra n d o mize d , wit h treat me nt d urati o n 
ra n gi n g fr o m 2 7 t o 5 1 m o nt hs. H o we ver, t he decisi o n t o cl ose S C O R E D was ma de i n Marc h 2 0 2 0 be f ore meeti n g t his o bjecti ve. 
  
A rece nt p u blicati o n i n t he J o ur na l of t he A merica n C olle ge of Car di ol o g y disc usse d m ore br oa dl y h o w cli nical trials ha ve bee n  
disr u pte d b y t he C O VI D- 1 9 pa n de mic. 1 It descri be d iss ues relati n g t o recr uit me nt, f oll o w- u p, a n d p har mace utical s p o ns or access t o 
ca pital. It referre d t o t he s ot a glifl ozi n pr o gra m as a n e xa m ple  w here cli nical trials ha ve bee n pre mat urel y ter mi nate d. 
Rec o m me n dati o ns i ncl u de d caref ul c o nsi derati o n of statistical i ss ues relati n g t o p ote ntial l oss of p o wer, i ncrease d varia bilit y i n data, 
a n d c halle n ges i n a dj u dicati o n of  e ve nts. Si milarl y, t he F D A has iss ue d g ui da nce s pecific t o C O VI D- 1 9 rec o g nizi n g t he p ote ntia l f or 
disr u pti o n of cli nical trials a n d i de ntif yi n g s o me of t he data a n d statistical iss ues t hat nee d  t o be a d dresse d b y i n vesti gat ors a n d 
s p o ns ors.2 
 
T his pla n descri bes statistical efficac y a nal yses t o be c o n d uct e d b y a n i n de pe n de nt aca de mic statisticia n a n d se par atel y verif ie d b y 
t he Le xic o n statistical tea m. It a d dresses iss ues relate d t o t h e earl y ter mi nati o n of S C O R E D. T hese iss ues ha ve bee n re vie we d a n d t he 
rec o m me n de d ste ps ha ve bee n c h ose n i n a bli n de d fas hi o n, wit h o u t t he use of a n y u n bli n de d i nteri m a nal ysis. 
 


St ati sti c al A n al y si s Pl a n  
2 1- A u g- 2 0 2 0 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
P a g e 8 
T he ter mi nati o n of f oll o w- u p i n S C O R E D di d n ot all o w e n o u g h ti me t o a me n d t he st u d y pr ot oc ol. C ha n ges t o t he i nte n de d a nal ysis  
pla n are reflecte d i n t his d oc u m e nt, rat her t ha n t he pr ot oc ol, a n d t his pla n ta kes prece de nce w he re t here are differe nces bet wee n t he 
t w o d oc u me nts. 
 
T he ke y efficac y f oc us is o n t ota l (first a n d p ote ntiall y s u bseq ue nt) i n vesti gat or-re p orte d e ve n ts. T his f oc us ca pt ures t he i mpact of 
treat me nt i n act ual practice. Rec urre nt h os pitalizati o n f or hea rt fail ure, a n d ur ge nt heart fail ure visits, as rec o g nize d a n d treate d b y t he 
me dical c o m m u nit y, are ver y fre q ue nt a n d ha ve a si g nifica nt cli nical a n d s ocietal i m pact. I n c o ntrast, a sta n dar d assess me nt o f ti me 
t o a first e ve nt ma y n ot ca pt ure t he t otalit y of t he effects of treat me nt.3 T he n u m ber of t otal i n vesti gator-re p orte d e ve nts i n S C O R E D 
is a meas ure of hi g h cli nical rele va nce, a n d c o nse q ue ntl y it is  a p pr o priate t o s u m marize t he effects of s ota glifl ozi n i n S C O R E D. 
 
W hile o utc o mes st u dies ha ve bee n  perf or me d o n S G L T i n hi biti o n i n patie nts wit h re nal i m pair me nt, t he y ha ve bee n perf or me d wit h 
selecti ve S G L T 2 i n hi bit ors w h ose efficac y is belie ve d t o be al m ost e ntirel y re nal de pe n de nt. I n c o ntrast, s ota glifl ozi n i n hi bi ts b ot h 
S G L T 1 a n d S G L T 2. I n hi biti o n of S G L T 1 b y s ota glifl ozi n is i n t he gastr oi ntesti nal tract a n d ma y be  be neficial t o patie nts re gardless 
of t he de gree of re nal i m pair me n t. A ge n o mic st u d y of re d uce d fu ncti o n variati o ns i n t he S G L T 1 g e ne f o u n d t hese variati o ns wer e 
ass ociate d wit h less c o n gesti ve he art fail ure a n d l o wer m ortali t y.4 F urt her m ore, a s maller st u d y of sota glifl ozi n i n patie nts wit h  T 2 D 
a n d se vere re nal i m pair me nt wa s rece ntl y c o ncl u de d, a n d it pr o vi de d e vi de nce of cli nicall y mea ni n gf ul A 1 C re d ucti o n at o ne year 
wit h s ota glifl ozi n 4 0 0 m g c o m par e d t o place b o. T heref ore, s ota g lifl ozi n ma y be ass ociate d wit h efficac y a n d safet y pr ofiles t hat 
differ fr o m t h ose of a p pr o ve d S G L T 2 i n hi bit ors. 
1. 2  
O B J E C TI V E S 
1. 2. 1  Pri m ar y o bjecti ves 
T he pri mar y o bjecti ve of t he st u d y is t o c o m pare t he effect of s ota glifl ozi n t o place b o o n t otal occ urre nces of car di o vasc ular ( C V) 
deat h, h os pitalizati o n f or heart fail ure [ H H F], a n d ur ge nt visit f or heart fail ure [ H F] i n patients wit h t y pe 2 dia betes, car d i o vasc ular 
ris k fact ors, a n d m o derate t o sever el y i m paire d re nal f u ncti o n.  
1. 2. 2  Sec o n d ar y o bjecti ves 
 


St ati sti c al A n al y si s Pl a n  
2 1- A u g- 2 0 2 0 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
P a g e 9 
 T o c o m pare t he effects of s o ta glifl ozi n t o place b o o n: 
o  T otal occ urre nces of H H F a n d ur ge nt visit f or H F 
o  Occ urre nces of car di o vasc ular deat h 
o  T otal occ urre nces of car di o vasc ular deat h, H H F, ur ge nt H F visit, n o n-fatal str o ke, a n d n o n-fatal m y ocar dial i nfarcti o n 
o  T otal occ urre nces of car di o vasc ular deat h, H H F, ur ge nt H F visit , a n d H F w hile h os pitalize d 
o  First occ urre nce of a s ustai ne d ≥5 0 % decrease i n esti mate d gl o m er ular filtrati o n rate (e G F R) fr o m baseli ne (f or ≥3 0 
da ys), c hr o nic dial ysis, re nal tra ns pla nt or s ustai ne d e G F R < 1 5  m L/ mi n/ 1. 7 3 m 2 (f or ≥3 0 da ys) 
o  All-ca use m ortalit y 
o  T otal occ urre nces of car di o vasc ular deat h, n o n-fatal str o ke, a n d n o n-fatal m y ocar dial i nfarcti o n 
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 ori gi nall y ass u me d sa m ple si ze a n d pr ojecte d d urati o n of f oll o w- u p were base d o n a hazar d r ati o of 0. 8 0 f or a c o m p osite of  C V 
deat h a n d H H F, pl us t he ai m of d e m o nstrati n g s u peri orit y i n t he  c o m p osite e n d p oi nt of C V deat h, n o n-fatal str o ke, a n d n o n-fatal 
m y ocar dial i nfarcti o n. Gi ve n t he  earl y ter mi nati o n of S C O R E D, the st u d y is n ot p o were d f or t hese ass u m pti o ns. H o we ver, a n 
e xa mi nati o n of efficac y is rele va nt beca use hazar d rati os less t ha n 0. 8 0 ha ve bee n re p orte d wit h S G L T i n hi biti o n i n car di o vasc ular 
o utc o mes st u dies, a n d t he pr ofile of s ota glifl ozi n ( wit h gastr o i ntesti nal S G L T 1 i n hi biti o n i n ad diti o n t o S G L T 2 i n hi biti o n) ma y differ 
fr o m t hat of selecti ve S G L T 2 i n hi bit ors.4 A nal yses are t heref ore c o n d ucte d wit h o ut a n y ne w sa m ple size calc ulati o ns. 
1. 4  
S T U D Y P L A N 
T he f oll o wi n g fi g ure prese nts gra p hicall y t he st u d y desi g n. 


St ati sti c al A n al y si s Pl a n  
2 1- A u g- 2 0 2 0 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
P a g e 1 0 
 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
1 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  De m o gr a p hi c a n d b aseli ne c h ar acteristics 
T he Baseli ne e G F R, he m o gl o bi n A 1c ( H b A 1c), a n d ot her la b orat or y para meter val ues f or eac h 
patie nt are defi ne d as t he val ue assesse d b y t he ce ntral la b ora t or y at Ra n d o mizati o n.  
F or t he re mai ni n g para meters, baseli ne is defi ne d as t he last a vaila ble val ue bef ore t he first d ose 
of d o u ble- bli n d i n vesti gati o nal me dici nal pr o d uct (I M P) or t he last a vaila ble val ue o n or bef ore 
t he da y of 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. 
De m o gr a p hic c h ar acteristics 
Ke y de m o gra p hic varia bles i ncl u de:  
 A ge ( years)  
 Se x ( Male, Fe male) 
 Race ( Asia n, Blac k or Africa n A merica n, W hite, Ot her) 
 Re gi o n ( N ort h A merica, Lati n A m erica, Wester n E ur o pe, Easter n E ur o pe, a n d rest of t he 
w orl d) 
Me dic al hist ory 
T he patie nt’s me dical/s ur gical hist or y was c ollecte d a n d c o de d usi n g t he versi o n of Me dical 
Dicti o nar y f or Re g ulat or y Acti v ities ( Me d D R A) c urre ntl y i n eff ect at t he ti me of data base l oc k.  
Me dic al hist ory a n d C V ris k f act ors:  
 D urati o n of dia betes ( years) 
 N u m ber ( n) a n d % wit h a n y maj or C V ris k fact or, a n d n ( %) wit h eac h 
o  H os pitalizati o n f or H F d uri n g pre vi o us 2 years 
o  L V E F cate g or y ≤4 0 % 
o  Dia g n osis of L V H b y electr oca r di o gra m or ec h ocar di o gra m 
o  C or o nar y arter y calci u m ( C A C ) sc ore ≥3 0 0 A gatst o n U nits 
o  N T- pr o B N P ≥4 0 0 p g/ ml 
o  Ele vate d hi g h-se nsiti vit y tr o p o ni n T ( b y se x a n d f or o verall p o p ulati o n meeti n g 
criteria): > 1 5. 0 p g/ m L f or me n  a n d > 1 0. 0 p g/ m L f or w o me n 
o  Hi g h-se nsiti vit y C-reacti ve pr otei n > 3 m g/ L 
o  Uri nar y al b u mi n-t o-creati ni ne rati o ≥3 0 0 m g/ g [ macr oal b u mi n uria] 
 N ( %) of eac h mi n or C V ris k fac t or i n t he o verall p o p ulati o n, an d a m o n g t h ose wit h n o 
maj or C V ris k fact or, n ( %) w h o ha ve a ge ≥5 5 years wit h at least  2 mi n or C V ris k fact ors 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
1 2 
 
o  B MI ≥3 5 
o  D ysli pi de mia des pite ma xi mall y t olerate d stati n t hera p y (f or o v erall p o p ulati o n 
meeti n g criteria, f or L D L, f or H D L i n o verall p o p ulati o n, a n d f or H D L b y se x): 
L D L > 1 3 0 m g/ d L, or H D L < 4 0 m g/ d L f or me n or < 5 0 f or w o me n 
o  C urre ntl y s m o ki n g t o bacc o 
o  C or o nar y arter y calci u m ( C A C) sc ore > 1 0 0 a n d < 3 0 0 A gatst o n U nit s 
o  U A C R ≥3 0 t o 3 0 0 [ micr oal b u mi n uria] 
o  S yst olic bl o o d press ure > 1 4 0 m m H g a n d diast olic bl o o d press ure > 9 0 m m H g 
des pite a nti h y perte nsi ve t he ra p y at t he Scree ni n g visit 
o  Fa mil y hist or y of pre mat ure heart disease ( defi ne d as MI or c or o nar y 
re vasc ularizati o n pr oce d ure) in a first- de gree relati ve,  
 
 Car di o vasc ular hist or y:  
o  Pri or m y ocar dial i nfarcti o n 
o  Pri or str o ke 
o  Pri or c or o nar y re vasc ularizati o n 
o  Peri p heral vasc ular disease 
o  Heart fail ure 
o  Atrial fi brillati o n 
Dise ase c h ar acteristics at b aseli ne   
 Mea n L V E F res ult ( %), a n d n( %) f or L V E F cate g or y ( < 4 0 %, ≤4 0 t o < 5 0 %, ≥5 0 %) 
 e G F R ( m L/ mi n/ 1. 7 m 2), a n d n( %) f or eac h e G F R cate g or y: < 1 5 (e n d sta ge re nal disease), 
≥1 5 t o < 3 0 (se vere decrease i n G F R), ≥3 0 t o < 4 5, a n d ≥4 5  
 U A C R ( m g/ g), a n d n( %) f or eac h U A C R cate g or y: < 3 0 [ n or mal], ≥3 0  t o 3 0 0 
[ micr oal b u mi n uria], ≥3 00 [ macr oal b u mi n uria] 
 H b A 1c ( %), a n d n( %) f or eac h H b A 1c cate g or y: < 7, ≥7 t o < 8, ≥8 t o < 9, ≥9 t o < 1 0, ≥1 0 
Ot her c h ar acteristics at b aseli ne 
 B o d y mass i n de x ( B MI) (( wei g ht i n k g)/( hei g ht i n m) 2) 
 S B P ( m m H g) 
 Heart rate  
 Me dia n N T- pr o B N P (I Q R) — p g/ ml 
2. 1. 2  B aseli ne me dic ati o n a n d de vice 
Baseli ne me dicati o ns are t h ose wit h a start date pri or t o ra n d o mizati o n ( or a missi n g start date) 
a n d a n e n d date after ra n d o miza ti o n or n o e n d date d uri n g t he st u d y ( use classifie d as o n g oi n g). 
T he n u m bers a n d pr o p orti o ns b y tr eat me nt gr o u p of t he f oll o wi n g  me dicati o ns are t o be 
descri be d: 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
1 3 
 
He art f ail ure me dic ati o ns 
Di uretic, A C E i n hi bit or, A R B, Sac u bitril – valsarta n, Beta- bl oc ke r, Mi neral oc ortic oi d rece pt or 
a nta g o nist, Di gitalis  
Di a betes me dic ati o ns 
Bi g ua ni de, S ulf o n yl urea, D P P- 4 i n hi bit or, G L P- 1 rece pt or a g o nis t, I ns uli n, T Z D 
Ot her c ar di ov asc ul ar me dic ati o ns 
Stati ns, a n y n o n-stati n li p i d l o weri n g me dicati o n 
He art f ail ure device 
I C D/ C R T 
2. 1. 3  Effic ac y e n d p oi nts 
Efficac y e n d p oi nt e ve nts wit h o ns et date pri or t o ra n d o mizati o n will n ot be i ncl u de d i n efficac y 
a nal ysis. T hese e ve nts will be c o nsi dere d pre-treat me nt a d verse e ve nts.  
I n t he a nal yses of ti me t o a first e ve nt or t he t otal occ urre nces (first a n d s u bse q ue nt) of a n e ve nt: 
 Deat hs n ot i ncl u de d a m o n g t he e ve nts i n t he e n d p oi nt will be tr eate d as c o m peti n g e ve nts 
 Patie nts ali ve at t he e n d of t he  st u d y will be ri g ht ce ns or e d on t he date t he y were last 
k n o w n t o be ali ve 
 E ve nt t y pes a n d dates i ncl u de d i n  t he a nal yses will be t h ose as re p orte d b y t he 
i n vesti gat ors 
 I n t he case w here t he e xact date of occ urre nce of a n e ve nt is not k n o w n, t he date will be 
i m p ute d as descri be d i n A p pe n di x A Calc ulati o n/ Deri vati o n of ti me-t o-e ve nt e n d p oi nts. 
2. 1. 3. 1  
Pri m ary effic acy e n d p oi nt(s) 
T he pri mar y e n d p oi nt is t he t ota l occ urre nces (first a n d p ote ntiall y s u bse q ue nt) after 
ra n d o mizati o n of C V deat h, H H F, a n d ur ge nt H F visit. 
2. 1. 3. 2  
Sec o n d ary effic acy e n d p oi nt(s) 
 
 
T otal occ urre nces of H H F a n d ur ge nt H F visits after ra n d o mizati o n 
 
Occ urre nce of C V deat h after ra n d o mizati o n 
 
T otal occ urre nces after ra n d o miz ati o n of C V deat h, H H F, n o n-fatal str o ke, a n d n o n-fatal 
m y ocar dial i nfarcti o n 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
1 4 
 
 
T otal occ urre nces after ra n d o miz ati o n of C V deat h, H H F, ur ge nt H F visit, a n d H F w hile 
h os pitalize d 
 
First occ urre nce after ra n d o miza ti o n of t he c o m p osite of s ustai ne d ≥5 0 % decrease i n 
e G F R fr o m baseli ne (f or ≥3 0 da ys), c hr o nic dial ysis, re nal tra n s pla nt, or s ustai ne d e G F R 
< 1 5 m L/ mi n/ 1. 7 3 m 2 (f or ≥3 0 da ys) i n t he t otal patie nt p o p ulati o n 
 
Occ urre nce of all-ca use m ortalit y after ra n d o mizati o n 
 
T otal occ urre nces after ra n d o miz ati o n of C V deat h, n o n-fatal st r o ke, a n d n o n-fatal 
m y ocar dial i nfarcti o n 
T he pri mar y a nal ysis of re nal e v e nts will be base d o n t he f oll o wi n g defi niti o n, base d o n 
i n vesti gat or-rep orte d o utc o mes. 
E n d p oi nt d efi niti o n s of r e n al e v e nt s f or r e n al e n d p oi nt a n al y si s  
E v e nt 
E n d p oi nt d efi niti o n 
S ust ai n e d ≥5 0 % 
d ecr e as e i n e G F R fr o m 
b as eli n e 
     c o nfir m e d ≥5 0 % d ecr e as e i n e G F R f or ≥3 0 d ays O R wit h n o r e p e at e G F R ≥3 0 d ays  as r ec or d e d 
i n e C R F “ e G F R d ecr e as e”  
 
S ust ai n e d e G F R < 1 5 
m L/ mi n/1. 7 3 m 2 
      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 O R wit h n o r e p e at e G F R ≥3 0 d ays as 
r ec or d e d i n e C R F “ e G F R d ecr e as e”  
 
C hr o nic di alysis  
      ( a) di alysis last 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 nal 
Ev e nt – Di alysis”, O R 
      ( b) a ns w er e d Y es 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  
 “ 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”. P Ts of R e n al tr a ns pl a nt, R e n al a n d 
p a ncr e as tr a ns pla nt, R e n al a n d liv er tr a ns pl a nt b as e d o n M e d D R A v 2 3. 0. 
 
2. 1. 3. 3  
Ot her effi c acy e n d p oi nts  
 
First occ urre nce of C V deat h, H H F, or ur ge nt H F visit after ra n d o mizati o n 
 
First occ urre nce of C V deat h, H H F, ur ge nt H F visit, or h os pital izati o n wit h H F after 
ra n d o mizati o n 
 
T he t otal occ urre nces of H H F after ra n d o mizati o n 
 
First occ urre nce of C V deat h, H H F, n o nfatal MI, or n o nfatal str o ke 
 
First occ urre nce of C V deat h, n o nfatal MI, or n o nfatal str o ke 
 
First occ urre nce of MI (fatal a n d n o n-fatal)  
 
First occ urre nce of str o ke (fatal a n d n o n-fatal) 
 
First occ urre nce of atrial fi brillati o n or atrial fl utter (a d ve rse e ve nts [ A Es] wit h preferre d 
ter ms [ P T] of atrial fi brillati o n or atrial fl utter) 
 
First occ urre nce of se vere h y p o gl yce mia 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
1 5 
 
 
T otal occ urre nces of t he f oll o wi n g h y p o gl yce mia cate g ories 
o  Se vere h y p o gl yce mia 
o  H y p o gl yce mia wit h d oc u me nte d gl uc ose val ue < 5 4 m g/ d L 
o  H y p o gl yce mia wit h d oc u me nte d gl uc ose val ue < 7 0 m g/ d L 
 
First occ urre nce after ra n d o miza ti o n of t he c o m p osite of s ustai ne d ≥4 0 % decrease i n 
e G F R fr o m baseli ne (f or ≥3 0 da ys), c hr o nic dial ysis, re nal tra n s pla nt, or s ustai ne d e G F R 
< 1 5 m L/ mi n/ 1. 7 3 m 2 (f or ≥3 0 da ys) i n t he t otal patie nt p o p ulati o n 
 
First occ urre nce after ra n d o miza ti o n of t he c o m p osite of s ustai ne d ≥3 0 % decrease i n 
e G F R fr o m baseli ne (f or ≥3 0 da ys), c hr o nic dial ysis, re nal tra n s pla nt, or s ustai ne d e G F R 
< 1 5 m L/ mi n/ 1. 7 3 m 2 (f or ≥3 0 da ys) i n t he t otal patie nt p o p ulati o n 
 
T he rate of decli ne i n e G F R after Wee k 4 ( m L/ mi n/ 1. 7 3 m 2) t o t he e n d of t he st u d y 
 
Da ys ali ve a n d o ut of h os pital ( D A O H) a n d perce nt D A O H ( P D A O H) 
 
C ha n ges fr o m baseli ne i n  
o  N T- pr o B N P i n t he o verall p o p ulati o n 
o  N T- pr o B N P a m o n g t h ose wit h baseli ne N T- pr o B N P ≥4 0 0 p g/ ml 
o  He mat ocrit 
o  He m o gl o bi n A 1c 
- 
I n t he o verall p o p ulati o n, a n d i n s u b gr o u ps defi ne d b y baseli ne e G F R ( < 3 0, 
≥3 0 t o < 4 5, ≥4 5 t o < 6 0, a n d ≥3 0 t o < 6 0) 
o  B o d y wei g ht 
o  U A C R 
- 
I n t he o verall p o p ulati o n, a n d i n s u b gr o u ps defi ne d b y baseli ne U A C R ( < 3 0 
m g/ g [ n or mal], ≥3 0 t o 3 0 0 [ micr oal b u mi n uria], ≥3 0 0 [ macr oal b u mi n uria]) 
- 
A n d i n s u b gr o u ps defi ne d b y baseli ne e G F R < 3 0 m L/ mi n/ 1. 7 3 m 2, ≥3 0 t o 
< 4 5, ≥4 5 t o < 6 0, a n d ≥3 0 t o < 6 0 
o  S yst olic bl o o d press ure 
- 
I n t he o verall p o p ulati o n, a n d i n s u b gr o u ps defi ne d b y baseli ne S B P ( < 1 3 0  
m m H g, ≥1 3 0, < 1 4 0, ≥1 4 0) 
 
All ti me-t o-e ve nt e n d p oi nts are assesse d base d o n i n vesti gat or- re p orte d e ve nts. 
Car di o vasc ular deat h i ncl u des deat h of u n deter mi ne d ca use. 
2. 1. 4  S afet y e n d p oi nts 
T he peri o d of safet y o bser vati o n starts fr o m t he ti me w he n t he patie nt gi ves i nf or me d c o nse nt a n d 
is di vi de d i nt o t hree peri o ds: 
 Pre-treat me nt peri o d: defi ne d fr o m t he si g ne d i nf or me d c o nse nt u p t o t he first d ose of 
d o u ble- bli n d I M P 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
1 6 
 
 Treat me nt-e mer ge nt a d verse e ve nt ( T E A E) peri o d: defi ne d as t he ti me fr o m t he first d ose 
of d o u ble- bli n d I M P t o t he last d ose of d o u ble- bli n d I M P d ose + 1 0 da ys ( 1 da y f or se vere 
h y p o gl ye mcia) 
 P ost-treat me nt peri o d: defi ne d as t he ti me starti n g t he da y aft er t he e n d of t he T E A E 
peri o d 
2. 1. 4. 1  
A dverse ev e nt v ari a bles 
Occ urre nces of A Es (i ncl u di n g seri o us a d verse e ve nts [ S A Es], a n d A Es of s pecial i nterest 
[ A E SIs] are 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. 
All A Es will be c o de d t o a L o wes t Le vel Ter m ( L L T), P T, HI h g Level Ter m ( H L T), Hi g h Le vel 
Gr o u p Ter m ( H L G T), a n d ass ociate d  pri mar y S yste m Or ga n Class ( SO C) usi n g t he versi o n of 
Me d D R A c urre ntl y i n effect at t h e ti me of t he data base l oc k. 
A d verse e ve nt o bser vati o n peri o ds: 
 
Pre-treat me nt A Es are A Es t hat de vel o pe d or w orse ne d or beca me seri o us d uri n g t he pre-
treat me nt peri o d; 
 
Treat me nt-e mer ge nt A Es are a d vers e e ve nts t hat de vel o pe d or w orse ne d or beca me seri o us 
d uri n g t he T E A E peri o d; 
 
P ost-treat me nt A Es are A Es t hat de vel o pe d or w orse ne d or beca me seri o us d uri n g t he 
p ost-treat me nt peri o d. 
A dverse eve nts of s peci al i nterest 
 Pre g na nc y of a fe male patie nt e n tere d i n a st u d y as well as preg na nc y occ urri n g i n a fe male 
part ner of a male patie nt e n tere d i n a st u d y wit h I M P 
 S y m pt o matic o ver d ose (seri o us or n o nseri o us) wit h I M P 
 A L T ≥3 x U L N (if Baseli ne A L T < U L N) or A L T ≥2 ti mes t he Baseli ne val ue (if Baseli ne 
A L T ≥ U L N) 
Eve nts of s peci al I nterest  
 
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) 
 
Pa ncreatitis 
 
B o ne fract ures 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
1 7 
 
 
A d verse e ve nts lea di n g t o a m p utati o n(s) 
 
Dia betic ket oaci d osis 
 
Mali g na ncies 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 f oll ic ular cell carci n o ma) 
 
Ge nital m yc otic i nfecti o ns (t o i ncl u de v ul v o va ginal 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 ns 
 
Diarr hea 
 
Cli nicall y rele va nt v ol u me de ple ti o n a n d e ve nts relate d/ p ossi bly relate d t o v ol u me 
de pleti o n 
 
F o ur nier’s ga n gre ne 
E O SI will be i de ntifie d base d o n criteria i n t he f oll o wi n g ta bl e. Of n ote, dr u g-i n d uce d li ver i nj ur y 
is n ot liste d as a n E O SI, b ut it will be descri be d i n t he sa me ma n ner, wit h a prese ntati o n of t he 
n u m ber a n d perce nta ge of e ve nts i n eac h treat me nt gr o u p. Se vere  h y p o gl yce mia is a E O SI t hat 
will be a nal yze d i n t he gr o u p of ot her e n d p oi nts. 
I de ntific ati o n criteri a f or E O SI 
A E Gr o u pi n g 
Criteri a 
B o n e Fr act ur es 
I nv esti g at or’s o pi ni o n: e C R F f or m “ Adv ers e Ev e nts” a n d its ass oci at e d c o m pl e m e nt ary 
f or m “ B o n e Fr act ur e”;  
Di a b etic k et o aci d osis  
I nv esti g at or’s o pi ni o n: e C R F f or m “ A dv ers e Ev e nts” a n d its ass oci at e d c o m pl e m e nt ary 
f or m “ M E T A B O LI C A CI D O SI S/ S U S P E C T E D D K A” 
V e n o us t hr o m b otic ev e nts  
I d e ntifi e d by usi n g M e d D R A pr ef err e d t er ms list e d i n A p p e n dix B 
P a ncr e atitis 
I d e ntifi e d by usi n g M e d D R A pr ef err e d t er ms list e d 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, etc) 
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 14 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 ali g n ant a n d u ns p ecifi e d 
( S M Q)” [ 2 0 0 0 0 15 2] 
L ey di g-c ell c a nc er: P Ts i n A p p e n dix B 
                                      T hyr oi d c a nc er: P Ts i n Ap p e n dix 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 A p p e n dix B 
                                       Bl a d d er c a nc er: P Ts i n Ap p e n dix B 
G e nit al myc otic inf ecti o ns   
I d e ntifi e d by usi n g M e d D R A pr ef err e d t er ms list e d i n A p p e n dix B 
Uri n ary tr act i nf ecti o n   
I d e ntifi e d by usi n g M e d D R A pr ef err e d t er ms list e d i n A p p e n dix B 
Di arr h e a 
N arr o w s e arc h on “ N o ni nf ecti o us di arr h o e a ( S M Q)” pl us t h e f oll o wi n g P Ts ( M e d D R A 
v 2 3. 0):  G astr o ent eritis, A nti di arr h o e al s u p p ortiv e c ar e, E nt eritis, E nt eritis l e uk o p e nic, 
E nt er oc olitis, E nt er oc olitis h a e m orr h a gic 
V ol u m e d e pl eti o n  
I d e ntifi e d by usi n g M e d D R A pr ef err e d t er ms list e d i n A p p e n dix B 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
1 8 
 
A E Gr o u pi n g 
Criteri a 
S ev er e hy p o glyc e mi a   
Fi nis h e C R F f or m “ Hy p o glyc e mia ev e nt i nf or m atio n” a n d m e et t h e crit eri a:   
T o t h e q u esti o n “ Assist a nc e R e q uir e d”, tick e d t h e o pti o n “ R e q uir ed assist a nc e b ec a us e 
s u bj ect w as n ot c a p a bl e of h el pi n g s elf”, a n d  
T o t h e q u esti o n “ W er e Sy m pt o ms Pr es e nt”, tick ed “ Yes”.  
E O SI A E r elat e d wit h a m p ut ati o n ( n o n-tr a u m ati c)  
A m p ut ati o n ( n o n-tr a u m atic)  
I d e ntifi e d o n t h e 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 l e a di n g t o a m p utati o n ( n o n-
tr a u m atic) 
‘ 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’ 
P ot e nti al c a s e s of F o ur ni er’s Ga n gr e n e  
P ot e nti al c as es of F o ur ni er’s 
g a n gr e n e a  
I d e ntifi e d by usi n g M e d D R A pr ef err e d t er ms list e d 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 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 f or t h e m.   
a  P ot e nti al c as es of F o ur ni er’s g a n gr e n e: n ot a n E O SI p er pr ot oc ol; a n alyz e d d u e t o a w ar ni n g r el e as e d by he alt h a ut h oriti es i n 3 Q 2 0 1 8 a b o ut 
r ar e occ urr e nc es of a s eri o us i nf ecti o n of t h e g e nit al ar e a wit h F D A- a p pr ov e d S G L T 2 i n hi bit ors f or di a b et es. 
 
2. 1. 4. 2  
L a b or at ory s afety v ari a bles 
 
T he cli nical la b orat or y data t o be a nal yze d i ncl u de meas ures of  he mat ol o g y, cli nical c he mistr y, 
re nal f u ncti o n, li ver f u ncti o n, a n d li pi ds. Cli nical la b orat or y val ues will be a nal yze d i n 
c o n ve nti o nal u nits. 
2. 1. 4. 3  
Vit al si g ns v ari a bles 
Vital si g ns i ncl u de wei g ht, hear t rate, a n d s yst olic a n d diast olic bl o o d press ure i n sitti n g p ositi o n. 
2. 2  
DI S P O SI TI O N O F P A TI E N T S 
Scree ne d patie nts are defi ne d as a n y patie nts w h o si g ne d t he i n f or me 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 ha d a 
treat me nt kit n u m ber all ocate d an d rec or de d i n t he I R T data base , re gar dless of w het her t he 
treat me nt kit was use d. T hese patie nts f or m t he ra n d o mize d p o p ulati o n. 
F or a n y patie nt ra n d o mize d m ore t ha n o nce, o nl y t he data ass oci ate d wit h t he first r a 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 nce ass ociate d wit h a n y later 
ra n d o mizati o n will be assesse d se paratel y. Patie nts w h o are n ot  ra n d o mize d will n ot be i n t he 
safet y p o p ulati o n. 
F or patie nt st u d y stat us, t he t ot al 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 nte d i n t he cli nical st u d y re p ort usi n g a fl o wc hart dia gra m or s u m mar y ta ble: 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
1 9 
 
 
Scree ne d patie nts 
 
Scree n fail ure patie nts a n d reas o ns f or scree n fail ure 
 
N o nra n d o mize d b ut treate d patie nts 
 
Ra n d o mize d patie nts 
 
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 c o m plete t he st u d y tr eat me nt peri o d as per pr ot oc o l (as per e- C R F treat me nt 
stat us f or m) 
N ote: patie nts w h o die w hile o n tr eat me nt will be treate d as treat me nt c o m pleters 
 
Patie nts w h o disc o nti n ue d st u d y t reat me nt b y mai n reas o n f or per ma ne nt treat me nt 
disc o nti n uati o n (as per e- C R F treat me nt stat us f or m) 
 
Patie nts w h o c o m plete t he st u d y as sc he d ule d (i.e. s u bject status is deat h or c o m plete d o n 
t he C o m pleti o n of e n d of st u d y eC R F f or m or a st u d y cl ose- o ut v isit was perf or me d 
t hr o u g h alter nati ve c o ntact d urin g t he st u d y cl ose- o ut peri o d) 
 
Patie nts w h o di d n ot c o m plete t he st u d y as sc he d ule d a n d t he re as o ns f or st u d y 
disc o nti n uati o n  
 
Stat us at last st u d y c o ntact (a s per e- C R F S u bjects Stat us f or m)   
 
Patie nts w h o ha d k n o w n vital stat us d uri n g t he st u d y cl ose- o ut peri o d  
Patie nts ra n d o mize d b ut n ot treat e d will be i ncl u de d i n t he eff icac y a nal ysis. 
 
T he n u m ber ( %) of patie nts w h o pr e mat urel y disc o nti n ue d t he st u d y f or pri mar y efficac y e ve nts 
will be s u m marize d. T he mai n reas o n f or st u d y disc o nti n uati o n w ill be s u m marize d o verall a n d 
acc or di n g t o w het her or n ot t he p atie nts ha d a pri mar y efficac y  e n d p oi nt c o nfir me d b y C E C pri or 
t o st u d y disc o nti n uati o n. A patie nt will be c o nsi dere d as ha vi ng disc o nti n ue d t he st u d y f or C V 
deat h a n d H H F if t he date of t h e last i nf or mati o n o n efficac y e n d p oi nts ( prese nce or a bse nce) is 
bef ore his/ her sc he d ule d St u d y Cl ose o ut Visit.  
D ur ati o n of patie nt i n st u d y ( St u d y d urati o n re gar dless of o n t reat me nt or n ot) is defi ne d as e n d 
st u d y visit date – ra n d o mizati o n date + 1 da y. T he st u d y d urati o n will be s u m marize d acc or di n g t o 
mea n, me dia n, a n d ra n ge f or eac h  treat me nt gr o u p a n d f or t he o verall p o p ulati o n.  
A d diti o nall y, t he a nal ysis p o p ulat i o ns f or safet y a n d efficac y will be s u m marize d i n a ta ble b y 
n u m ber of patie nts o n t he ra n d o mize d p o p ulati o n.  
 
Ra n d o mizati o n 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 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 0 
 
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 ra 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.  
2. 3. 1  R a n d o mize d p o p ul ati o n 
T he ra n d o mize d p o p ulati o n i ncl u de s a n y patie nt w h o has bee n allocate 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 patie nt ra n d o mize d m ore t ha n o nce, o nl y t he data ass oci ate 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.  
2. 3. 2  Effic ac y p o p ul ati o ns 
T he pri mar y efficac y a nal ysis p o p ulati o n will be t he I T T p o p ula ti o n. 
2. 3. 3  S afet y p o p ul ati o n 
T he safet y p o p ulati o n is defi ne d  as t he ra n d o mize d p o p ulati o n wh o act uall y recei ve d at least 1 
d ose or part of a d ose of t he I M P , a nal yze d acc or di n g t o t he treat me nt act uall y recei ve d 
2. 4  
S T A TI S TI C A L M E T H O D S 
2. 4. 1  De m o gr a p hi cs a n d b aseli ne c h ar acteristics 
Para meters will be s u m marize d o n t he ra n d o mize d p o p ulati o n b y t reat me nt gr o u p a n d o verall 
usi n g descri pti ve statistics.  
U nless ot her wise s pecifie d, par a meters will be s u m marize d o n t h e ra n d o mize d p o p ulati o n 
a nal yze d i n t he treat me nt gr o u p t o w hic h t he y were ra n d o mize d. Si milar a nal yses will be d o ne o n 
t he safet y p o p ulati o n a n d will be i ncl u de d i n t he a p pe n dices if  t he 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 he ra n d o mize d p o p ulati o n f or  a n y treat me nt gr o u p. 
P- val ues o n de m o gra p hic a n d base li ne c har acteristic data will not be calc ulate d.  
2. 4. 2  C o nc o mit a nt me dic ati o ns 
Baseli ne me dicati o ns a n d de vices  will be prese nte d f or t he ra n do mize d p o p ulati o ns a n d 
s u m marize d b y treat me nt gr o u p. 
2. 4. 3  E xte nt of i n vesti g at i o n al me dici n al pr o d uct e x p os ure a n d d ose titr ati o n 
T he e xte nt of I M P: e x p os ure a n d c o m plia nce will be assesse d a n d  s u m marize d b y act ual treat me nt 
recei ve d wit hi n t he safet y p o p ulati o n. 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 1 
 
D urati o n of I M P e x p os ure i n da ys,  re gar dless of i nter mitte nt disc o nti n uati o ns, is defi ne d as: 
Last d ose of d o u ble- bli n d I M P – first d ose of d o u ble- bli n d I M P + 1 
T he n u m ber ( %) of patie nts wit h  a n u p-titrati o n t o 4 0 0 m g o verall (at Visit 5 [ Wee k 2 6]) will als o 
be s u m marize d i n t he s ota glifl ozi n gr o u p. 
2. 4. 4  A n al yses of effic ac y e n d p oi nts 
All efficac y a nal yses will be per f or me d base d o n t he I T T a p pr oac h t hat will i ncl u de e ve nts 
occ urri n g, f or a gi ve n patie nt , fr o m t he date of ra n d o mizati o n t o t heir date last k n o w n ali ve, 
i ncl u di n g e ve nts t hat occ ur after t he patie nt has disc o nti n ue d t he st u d y I M P. 
2. 4. 4. 1  
A n al yses of pri m ar y effi c ac y e n d p oi nt 
T he a nal ysis of t he pri mar y ef ficac y e n d p oi nt will be t he c o m paris o n bet wee n t he t w o treat me nts 
usi n g a Wal d test stratifie d b y re gi o n ( N ort h A merica, Lati n A m erica, Wester n E ur o pe, Easter n 
E ur o pe, a n d rest of w orl d) a n d H F -relate d criteria ( yes/ n o). T his pri mar y c o m paris o n will be a 2-
si de d test at t he 0. 0 5 t y pe 1 err or le vel f or t he f oll o wi n g h y pot heses: 
H 0: H R = 1 vers us H 1: H R ≠1 
T he esti mates of t he hazar d rat i o ( H R) a n d c orres p o n di n g 2-si ded 9 5 % c o nfi de nce i nter val ( CI) 
will be pr o vi de d b y a mar gi nal  C o x pr o p orti o nal hazar d m o del stratifie d b y re gi o n a n d ejecti o n 
fracti o n, wit h n o n-car di o vasc ular ( n o n- C V) deat h treate d as a co m peti n g e ve nt. B y usi n g a r o b ust 
sa n d wic h c o varia nce matri x estimate, t he m o del all o ws f or t he p ossi bilit y of m ulti ple e ve nts 
wit hi n a gi ve n patie nt. If a gi ve n patie nt has m ore t ha n o ne e v e nt o n a gi ve n da y, t he e ve nt ti mes 
will be varie d b y 0. 1 da y s o t ha t e ver y e ve nt ti me is u ni q ue. 
T o deter mi ne w het her t he treat me nt effect o n t he pri mar y e n d p oi nt is diff ere nt bef ore a n d after 
1 8 0 da ys (t he last o p p ort u nit y f or  u p-titrati o n i n S C O R E D), a mar gi nal pr o p orti o nal hazar ds 
m o del t hat all o ws t he treat me nt H R t o var y bef ore a n d after 1 8 0  da ys will be c o m pare d wit h t he 
m o del i n w hic h t he treat me nt H R is ass u me d c o nsta nt o ver ti me, t o test w het her a n o nc o nsta nt H R 
pr o vi des a better fit t o t he o bser ve d data. 
As a se nsiti vit y a nal ysis, a n o n- treat me nt a nal ysis will be perf or me d f or t he pri mar y e n d p oi nt, 
usi n g t he sa me met h o d a b o ve b ut o nl y i ncl u di n g e ve nts t hr o u g h 3 0 da ys after last d ose. A n ot her 
o n-treat me nt se nsiti vit y a nal ysis will i ncl u de o nl y e ve nts t hr o u g h 7 da ys after last d ose. 
T he c u m ulati ve i nci de nce f u ncti o n ( CI F) will als o be c o nstr ucte d t o esti mate t he pri mar y efficac y 
e n d p oi nt rate b y treat me nt gr o u p.  5 T he a bs ol ute ris k r e d ucti o n ( AR R) will be esti mate d b y t he 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 2 
 
differe nce bet wee n treat me nt gr o u p s i n t he n u m ber of e ve nts per 1 0 0 patie nt- years of f oll o w- u p. 
Res ults will be pr o vi de d f or b ot h t he pri mar y efficac y e n d p oi nt  o verall a n d its i n di vi d ual 
c o m p o ne nts ( C V deat h, H H F, ur ge n t H F visit). I n a d diti o n, a fi gure s u m marizi n g t he n u m bers of 
first a n d s u bse q ue nt e ve nts will be c o nstr ucte d. Bars f or s ota g lifl ozi n a n d place b o will be 
pr o vi de d f or t he n u m bers of firs t e ve nts, sec o n d e ve nts, t hir d e ve nts, a n d a cate g or y of “f o urt h a n d 
s u bse q ue nt e ve nts.”  5 Wit hi n eac h bar t he n u m ber of CV deat h, H H F, a n d ur ge nt H F vis it e ve nts 
will be se parate d b y c ol or. 
Pr o p orti o nal hazar ds m o del f or t he pri mar y e n d p oi nt will be c o nstr ucte d f or s u b gr o u ps defi ne d b y 
t he f oll o wi n g:  
 Prese nce/a bse nce of H F-relate d criteria 
o  H F-relate d criteria are  prese nt w he n a patie nt meets at least 1 of: E F ≤4 0 % 
d oc u me nte d wit hi n t he past year , or h os pitalizati o n f or H F d urin g t he pre vi o us 2 
years 
 L V E F i n t w o cate g ories ( < 5 0 %, ≥5 0 %) 
 L V E F i n t hree cate g ories ( < 4 0 %, ≥4 0 % < 5 0 %, ≥5 0 %) 
 L V E F i n t w o cate g ories ( < 5 0 %, ≥5 0 %) a m o n g t h ose wit h H F-relate d  criteria 
 L V E F i n t hree cate g ories ( < 4 0 %, ≥4 0 % < 5 0 %, ≥5 0 %) a m o n g t h ose wi t h H F-relate d 
criteria 
 Prese nce/a bse nce of maj or C V ris k fact or 
 Hist or y of C V D ( defi ne d as m y ocar dial i nfarcti o n, str o ke, c or o n ar y re vasc ularizati o n, or 
peri p heral vasc ular disease) 
 Re gi o n ( N ort h A merica, Lati n A mer ica, E ur o pe, Rest of t he w orl d)  
 A ge ( < 6 5, ≥6 5)  
 Ge n der ( male, fe male) 
 Race/et h nicit y ( Asia n, blac k or Africa n A merica n, W hite, His pa n ic, ot her)  
 Baseli ne e G F R ( < 3 0 m L/ mi n/ 1. 7 3 m 2, ≥3 0 t o < 4 5, ≥4 5 t o < 6 0) 
 Baseli ne cate g or y of U A C R ( < 3 0 m g/ g, ≥3 0 m g/ g) 
 Baseli ne B MI gr o u p ( < 3 0, ≥3 0 k g/ m 2) 
 N T- pr o B N P ( ≤Me dia n, > Me dia n) 
 M R A at Baseli ne (a m o n g t h ose wit h H F-relate d criteria) 
 G L P- 1 rece pt or a g o nist at Baseli ne 
 Sac u bitril- valsarta n at Baseli ne (a m o n g t h ose wit h H F-relate d c riteria) 
 I C D/ C R T at Baseli ne 
 I ns uli n at Baseli ne 
 Atrial fi brillati o n or fl utter at Baseli ne 
 Left ve ntric ular h y pertr o p h y ( L V H) at Baseli ne 
 Mai n ca use of heart fail ure (isc he mic vs. n o n-isc he mic or u n k n o w n) 
F or eac h fact or, a mar gi nal C o x pr o p orti o nal hazar d m o del strat ifie d b y re gi o n a n d H F-relate d 
criteria ( n ote t hat w he n re gi o n i s t he s u bject of t he a nal ysis stratificati o n will o nl y be b y H F-
relate d criteria; si milarl y w he n H F-relate d criteria is t he s u b ject of t he a nal ysis, stratificati o n will 
o nl y be b y re gi o n) wit h n o n- C V dea t h as a c o m petin g e ve nt will be c o nstr ucte d, i ncl u di n g t he 
treat me nt, t he fact or, a n d t he treat me nt- b y-fact or i nteracti o n ter ms as c o variates. T he treat me nt 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 3 
 
H F a n d CI will be esti mate d fr o m t his C o x m o del f or eac h s u b gr ou p. P- val ues f or i nteracti o n 
ter ms will be pr o vi de d, a n d t h ose < 0. 0 5 will be c o nsi dere d stat isticall y si g nifica nt a n d t heref ore 
s u g gesti ve of heter o ge neit y i n t he treat me nt effect. Res ults will be als o prese nte d b y a f orest pl ot. 
2. 4. 4. 2  
A n alyses of sec o n d ary effi c acy e n d p oi nts 
Met h o ds f or c o ntr olli n g t he o vera ll t y pe- 1 err or rate w he n testi n g t he sec o n dar y efficac y 
e n d p oi nts are descri be d i n t he S ecti o n M ulti plicit y iss ues. 
Ti me-t o-e ve nt sec o n dar y efficac y  e n d p oi nts will be a nal yze d usin g t he sa me statistical 
met h o d ol o g y as f or t he pri mar y e n d p oi nt.  Deat hs t hat are n ot p art of a gi ve n e n d p oi nt will be 
treate d as c o m peti n g e ve nts. 
2. 4. 4. 3  M ulti plicity iss ues 
I n or der t o ha n dle m ulti ple mai n sec o n dar y e n d p oi nts, t he o verall t y pe- 1 err or will be c o ntr olle d 
b y t he use of a se q ue ntial i nfere ntial a p pr oac h. Statistical si g nifica nce of t he pri mar y e n d p oi nt is 
re q uire d bef ore dra wi n g i nfere ntial c o ncl usi o ns a b o ut t he first sec o n dar y e n d p oi nt at t he 0. 0 5 2-
si de d al p ha le vel. I nfere ntial c o ncl usi o ns a b o ut s uccessi ve sec o n dar y e n d p oi nts re q ui re statistical 
si g nifica nce of t he prior o ne. T he or der of tests is detaile d i n Secti o n 2. 1. 3. 2. T his fi xe d 
hierarc hical a p pr oac h will e ns u re a str o n g c o ntr ol of t he o verall t y pe- 1 err or rate at t he re q uire d 
0. 0 5 2-si de d le vel. 
2. 4. 4. 4 A d diti o n al effic acy a n alysis(es) 
Ot her efficac y e n d p oi nt s t hat are t otal occ urre nces of e ve nts or t he ti me t o a first e ve nt will be 
a nal yze d usi n g t he sa me statist ical met h o d ol o g y as f or t he pri mar y e n d p oi nt. If t he e n d p oi nt 
c o ncer ns t he first e ve nt, t he n o nl y t he first e ve nt e x perie nce d  b y a gi ve n patie nt will be i ncl u de d 
i n t he a nal ysis. Deat hs t hat are n ot part of a gi ve e n d p oi nt will be treate d as c o m peti n g e ve nts. 
F or t he a nal yses of D A O H a n d P D A O H, t otal p ote ntial f oll o w- u p t i me f or eac h patie nt is defi ne d 
as t he n u m ber of da ys fr o m date of ra n d o mizati o n u ntil t he pati e nt’s date last k n o w n ali ve, or Ma y 
1, 2 0 2 0 (t he date sites were i nstr ucte d t o c o m plete e n d of st u d y c o ntacts wit h patie nts; patie nts 
k n o w n t o ha ve die d after t his da te will be ce ns ore d as ali ve o n Ma y 1, 2 0 2 0) if t he patie nt die d. 
T he t otal n u m ber of da ys s pe nt i n h os pital will be deri ve d fr o m  t he i n vesti gat or re p orts. If a 
patie nt die d, t he n u m ber of da ys dea d will be calc ulate d as t he  ti me i nter val bet wee n t heir date of 
deat h a n d Ma y 1, 2 0 2 0. D A O H will be calc ulate d b y s u btracti n g d a ys i n h os pital a n d da ys dea d 
fr o m t otal p ote ntial f oll o w- u p time; if a patie nt s ur vi ve d wit h o ut h os pitalizati o n, D A O H will be 
e q ual t o t he p ote ntial f oll o w- u p ti me f or t hat patie nt. 
D A O H, da ys dea d, a n d da ys i n h os pi tal will be c o m pare d bet wee n treat me nt gr o u ps b y rate rati os 
( R Rs) fr o m a P oiss o n re gressi o n m odel wit h a l o g li n k f u ncti o n a n d Pears o n χ 2 scali n g of sta n dar d 
err ors t o acc o u nt f or p ote ntial o ver dis persi o n. I n a d diti o n t o treat me nt gr o u p, t he l o garit h m of 
p ote ntial f oll o w- u p ti me will be use d as a n offset varia ble i n t he m o del. Gi ve n t he e x pectati o n t hat 
a fracti o n of patie nts will s ur vi ve wit h o ut h os pitalizati o n u nt il t he e n d of f oll o w- u p (i.e., 
P D A O H = 1 0 0 %), P D A O H will be c o m pa re d bet wee n treat me nt gr o u ps wit h o ne-i nflate d beta 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 4 
 
re gressi o n. I n t his a p plicati o n t he m o del will j oi ntl y esti mate  t he treat me nt o d ds rati o ( O R) of 
s ur vi vi n g u ntil t he e n d of t he st u d y wit h o ut h os pitalizati o n (i.e., P D A O H = 1 0) %) a n d t he treat me nt 
o R of hi g her mea n P D A O H a m o n g t he s u bset of patie nts w h o die d o r ha d at least o ne 
h os pitalizati o n or die d d uri n g f o ll o w- u p ((i.e. p D A O H < 1 0 0 %). Plots of t he distri b uti o n of D A O H 
will be c o nstr ucte d, as well as s u m maries of reas o ns f or h os pit alizati o ns (e. g. H F, ot her efficac y 
e ve nt, n o n-efficac y a d verse e ve nt, etc.). 
C ha n ges fr o m baseli ne i n N T- pr o B N P, he mat ocrit, H b A 1c, U A C R, b o d y wei g ht, a n d S B P will be 
a nal yze d usi n g t he sa me met h o ds as f or c ha n ge i n e G F R. 
2. 4. 5  
A n al yses of s afet y d at a 
T he s u m mar y of safet y res ults wil l be prese nte d b y treat me nt gro u p.  All safet y a nal ysis will be 
perf or me d o n t he safet y p o p ulati o n.  
Ge ner al c o m m o n r ules 
All safet y a nal yses w ill 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. 3, u nless 
ot her wise s pecifie d, usi n g t h e f oll o wi n g c o m m o n r ules: 
 
T he baseli ne val ue ( wit h t he e x ce pti o n of la b para meters, li ke e G F R a n d H b A 1 C) is 
defi ne d as t he last a vaila ble va l ue bef ore t he first d ose of d ou ble- bli n d I M P. Baseli ne 
e G F R, H b A 1 C a n d ot her la b para mete rs val ues are t he val ues assesse d b y t he ce ntral 
la b orat or y at ra n d o mizati o n visit.   
 
T here will be n o i m p utati o n of mis si n g val ues f or cli nical la b orat or y test res ults, vital si g n 
meas ure me nts i n t he safet y a na l yses a n d t here will be n o h y p ot hesis testi n g f or res ults 
fr o m safet y a nal yses.  
2. 4. 5. 1 A n alyses of a dverse eve nts 
Ge ner alities 
A n alysis of a dverse eve nts 
T he f oll o wi n g s u m maries of treat me nt e mer ge nt a d verse e ve nts wi ll be ge nerate d f or t he safet y 
p o p ulati o n. 
 
O ver vie w of T E A E, s u m marizi n g n u m ber ( %) of patie nts b y treat me nt gr o u p 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 
 All T E A Es relate d t o I M P b y pri mar y S O C 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 5 
 
A n alysis of tre at me nt-e mer ge nt seri o us a dverse eve nts 
 All treat me nt-e mer ge nt S A Es b y pri mar y S O C 
 All treat me nt-e mer ge nt S A Es re late d t o I M P b y pri mar y S O C 
A n alysis of tre at me nt-e mer ge nt a dverse ev e nts le a di n g t o per m a ne nt disc o nti n u ati o n  
 All T E A Es lea di n g t o per ma ne nt d isc o nti n uati o n b y pri mar y S O C 
 All T E A E S lea di n g t o deat h b y pri mar y S O C a n d preferre d ter m 
 
A n alysis of eve nts of s peci al i nterest   
 
T he selecti o n of P Ts will be bas e d o n sta n dar dize d Me d D R A q uer y  ( S M Q) f or eac h 
c orres p o n di n g ite m.  
A n o ver vie w ta ble of E O SI, s u m ma rizi n g n u m ber ( %) of patie nts wit h a n y of f oll o wi n g cate g ories 
will be pr o vi de d: 
 At least o ne T E A E E O SI b y cate g or y of se vere h y p o gl yce mia, ge ni tal m yc otic i nfecti o n, 
uri nar y tract i nfecti o n, v ol u me de pleti o n a n d e ve nts relate d/ p o ssi ble relate d t o v ol u me 
de pleti o n, diarr hea, pa ncreatitis , b o ne fract ure, ve n o us t hr o m botic e ve nt, a m p utati o n, 
dia betic, ket oaci d osis, mali g na nc y of s pecial i nterest 
 
Dr u g-i n d uce d liver i nj ury 
T hese e ve nts will be prese nte d  i n t he sa me ma n ner as E O SI. 
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 Ge ner al c o n ve nti o ns 
T he date of t he last d ose of I M P  is e q ual t o t he last date of ad mi nistrati o n re p orte d o n t he I M P 
a d mi nistrati o n case re p ort f or m pa ge. 
T he f oll o wi n g f or m ulas will be u se d f or c o m p utati o n of par a meters. 
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 varia ble M o dificati o n of Diet 
i n Re nal Disease (M D R D) f or m ula:  


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 6 
 
Sta n dar d u nit: e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 x [ Ser u m Creati ni ne ( μ m ol/ L)/ 8 8. 4] - 1. 1 5 4 x A ge 
( year) - 0 2 0 3 x 1. 2 1 2 (if Blac k) x 0. 7 4 2 (if fe male) 
2. 5. 2 D at a h a n dli n g c o n ve nti o ns f or sec o n d ar y effic ac y v ari a ble s 
R ules defi ne d f or t he pri mar y e fficac y varia ble will a p pl y t o ti me-t o-e ve nt of sec o n dar y efficac y 
varia bles.  
2. 5. 3  
Missi n g d at a 
F or cate g orical varia bles, patie nts wit h missi n g data are n ot i ncl u de d i n calc ulati o ns of 
perce nta ges u nless ot her wise s pec ifie d.  W he n rele va nt, t he n u m ber of patie nts wit h missi n g data 
is prese nte d. 
Deri ve d varia bles will be c o nsi d ere d missi n g if a n y of t he ori g i nal varia bles re q uire d t o calc ulate 
t he m are missi n g. F or e xa m ple, if eit her a baseli ne assess me nt or a n e n d p oi nt assess me nt is 
missi n g f or a partic ular patie 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 pe 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 nte n de d p o p ulati o n ma y ha ve missi n g da ta.   
Ha n dli n g of missi n g or i nc o m plete dates of ti me-t o-e ve nt efficac y e n d p oi nts 
R ules f or i m p utati o n are detaile d i n Secti o n 2. 1. 3. 
H a n dli n g of c o m p ut ati o n of tre a t me nt d ur ati o n if I M P st art of tre at me nt d ate is missi n g  
 
Date/ti me of first a d mi nistrati o n is t he first n o n- missi n g star t 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’ f or m.  
 
F or a patie nt w h o was ra n d o mize d  a n d dis pe nse d a d o u ble- bli n d treat me nt kit:  
 If t he date of first I M P is missin g, t he date of t he first I M P a d mi nistrati o n will be set t o t he 
date of ra n d o mizati o n.  
 If t he date of first a d mi nistrati o n is partiall y missi n g wit h the m o nt h a n d year prese nt, t he 
da y will be set t o t he date of ra n d o mizati o n if ra n d o mizati o n was i n t he sa me m o nt h. If 
ra n d o mizati o n was i n t he m o nt h pri or t o t he first dr u g a d mi nistrati o n t he missi n g da y will 
be i m p ute d as t he first da y of t he m o nt h.  
 
A patie nt w h o is ra n d o mize d b ut n ot e x p ose d is i de ntifie d b y ‘ N ot ta ke n’ tic ke d i n t he e- C R F 
‘ First d ose I M P’ f or m.  
H a n dli n g of a dverse eve nts wit h missi n g or p arti al d ate/ti me of o nset  
Missi n g or partial a d verse e ve nt  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 ve nt o nset date/ti me i nf or mati o n d oes n ot i n dicate t hat t he a d verse e ve nt starte d pri or t o 
treat me nt, t he a d verse e ve nt will be classifie d as occ urri n g after treat me nt i nitiati o n.  N o 
i m p utati o n of a d verse e ve nt e n d dates/ti mes will be perf or me d.  T hese data i m p utati o ns are f or 
cate g orizati o n p ur p ose o nl y.  T he re is n o i m p utati o n f or date/ti me of a d verse e ve nt res ol uti o n. 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 7 
 
H a n dli n g of a dverse eve nts w he n d ate a n d ti me 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 fi rst I M P a d mi nistrati o n is missin g, a d verse e ve nts will be 
c o nsi dere d t o occ ur after treat me nt i nitiati o n if t he y occ urre d  o n or after t he da y of ra n d o mizati o n.  
 
B aseli ne defi niti o n f or effic acy d at a 
T he baseli ne f or a gi ve n para meter is defi ne d as t he last a vail a ble meas ure me nt, i ncl u di n g 
u nsc he d ule d assess me nts, assesse d pri or t o t he first a d mi nistra ti o n of d o u ble- bli n d I M P or t he last 
a vaila ble val ue bef ore ra n d o mi zati o n if n ot treate d wit h d o u ble - bli n d I M P.  
2. 5. 4  
Wi n d o ws f or ti me p oi nts 
Data a nal yze d b y ti me p oi nt (la b orat or y safet y data, vital si g n s) will be s u m marize d usi n g t he 
ti me wi n d o ws gi ve n t he ta ble bel o w. T hese ti me wi n d o ws will be a p plica ble f or all a nal yses, a n d 
t he y are defi ne d t o pr o vi de m ore h o m o ge ne o us data f or ti me p oi n t-s pecific a nal yses t hat t he visit 
wi n d o ws s pecifie d i n t he pr ot oc ol. If m ulti ple val ues of a para meter are a vaila ble i n a ti me 
wi n d o w, t he last will be use d i n a gi ve n a nal ysis. 
Ti m e wi n d o w s d efi niti o n s  
Ti m e p oi nt  
T ar g et e d st u d y d a y  
Ti m e wi n d o w  
D ate of R a n d o miz ati o n  
1  
n/ a  
W e ek 4  
2 8  
2 1 t o 3 5  
W e ek 8 
5 6 
4 6 t o 6 6 
W e ek 2 6 
1 8 2 
1 6 8 t o 1 9 6 
M o nt h 1 2  
3 6 4  
3 3 6 t o 3 9 2  
M o nt h 1 4 
4 2 7 
3 9 9 t o 4 5 5 
M o nt h 1 6 
4 9 0 
4 6 2 t o 5 1 8 
 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 8 
 
R E F E R E N C E S 
1.  Ba giella E, B hatt D L, Ga u di n o M . T he C o nse q ue nces of t he C O VI D-1 9 Pa n de mic o n 
N o n- C O VI D- 1 9 Cli nical Trials. J A m C oll C ar di ol . 2 0 2 0 J ul 2 1; 7 6( 3): 3 4 2 – 3 4 5. 
P u blis he d o nli ne 2 0 2 0 Ma y 2 6. d oi: 1 0. 1 0 1 6/j.jacc. 2 0 2 0. 0 5. 0 4 1 
2.  U. S. F o o d a n d Dr u g A d mi nistrati o n. F D A G ui da nce o n C o n d uct of C li nical Trials of 
Me dical Pr o d ucts D uri n g C O VI D- 1 9 P u blic Healt h E mer ge nc y. G ui da nce d oc u me nt. 
Marc h 2 0 2 0. A vaila ble at: htt ps:// w w w.f da. g o v/re g ulat or y-i nf or m ati o n/searc h-f da-
g ui da nce- d oc u me nts/f da- g ui da ncec o n d uct-cli nical-trials- me dical- pr o d ucts- d uri n gc o vi d-
1 9- pa n de mic. Accesse d J ul y 2 3, 2 0 2 0. 
3.  Szare k M, W hite H D, Sc h wartz G G et al. Alir oc u ma b Re d uces T otal  N o nfatal 
Car di o vasc ular a n d Fatal E ve nts:  T he O D Y S S E Y O U T C O M E S Trial. J A m C oll Car di ol. 
2 0 1 9 Fe b 5; 7 3( 4): 3 8 7- 3 9 6. d oi: 1 0. 1 0 1 6/j.jacc. 2 0 1 8. 1 0. 0 3 9. E p u b  2 0 1 8 N o v 1 1 
4.  Sei del ma n n S B, Fe ofa n o va E, Y u B et al.  Ge netic Varia nts i n S G L T 1, Gl uc ose T olera nce, 
a n d Car di o meta b olic Ris k. J A m C oll C ar di ol.  2 0 1 8 Oct 9; 7 2( 1 5): 1 7 6 3- 1 7 7 3. d oi: 
1 0. 1 0 1 6/j.jacc. 2 0 1 8. 0 7. 0 6 1 
5.  Szare k M, A mare nc o P, Calla ha n A et al. At or vastati n Re d uces Fi rst a n d S u bse q ue nt 
Vasc ular E ve nts Acr oss Vasc ular Territ ories: T he S P A R C L Trial. J A m C oll C ar di ol . 
2 0 2 0 Ma y 5; 7 5( 1 7): 2 1 1 0- 2 1 1 8. d oi: 1 0. 1 0 1 6/j.jacc. 2 0 2 0. 0 3. 0 1 5. E p u b 2 0 2 0 Mar 1 6. 
 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
2 9 
 
A P P E N DI X A C A L C U L A TI O N/ D E RI V A TI O N O F TI M E- T O- E V E N T E N D P OI N T S 
 
T his secti o n descri be t he calc u lati o n of t he ti me t o e ve nt a n d t he ti me t hat patie nts wit h o ut e ve nt 
a n d were i n t he st u d y ( u n der ris k).  
F or patie nts wit h a n e ve nt, t he ti me t o e ve nt is calc ulate d as:   
Date of e ve nt – start date + 1 
F or patie nts wit h o ut a n e ve nt, t he  ti me at ris k is calc ulate d as:  
Date of ce ns ori n g – start date + 1 
F or s pecific a nal ysis, e ve nts t h at occ ur a n y ti me d uri n g t he da ta peri o d of t he c orres p o n di n g 
a nal ysis will be c o nsi dere d as eli gi ble e ve nts.  
St art d ate  
I n ge neral, t he start date of a n efficac y e ve nt will be t he date of ra n d o mizati o n u nless ot her wise 
s pecifie d. H o we ver, t he date of first I M P ta ke n will be use d as t he start date f or t he a nal ysis 
(a nal yze d as occ urre nce of a n d ti me t o first e ve nt) of f oll o wi ng e ve nts:  
 A E (i ncl u di n g A E, A E SI, E O SI) 
O nset of eve nt ( d ate of eve nt)  
 
F or c o m p osite o utc o mes, e. g. ti me t o C V deat h a n d H H F, t he earliest o nset date of t he 
c orres p o n di n g c o m p o ne nts will be use d.  
 
F or e ve nts, w hic h are i ncl u de d as a fatal a n d n o n-fatal c o m p o ne nt i nt o a c o m p osite e n d p oi nt 
(a p plies o nl y t o MI a n d str o ke), the o nset of t he e ve nt is c o ns i dere d f or t he deri vati o n of ti me t o 
first occ urre nce, n ot t he date of deat h.  
 
F or all ot her C V deat h t y pes (e. g . s u d de n deat h) t he date of deat h is use d. 
 
F or t he a nal ysis of t he e n d p oi nt s ‘ti me t o C V deat h’ a n d ‘ti me t o all-ca use m ortalit y’, t he ti me t o 
deat h rat her t ha n ti me t o t he fi rst o nset of t he fatal e ve nt will be use d. 
 
F or e ve nts wit h m ulti ple e pis o des, s uc h as se vere h y p o gl yce mia,  t he o nset date of t he first e pis o de 
will be use d. T he sa me a p plies t o ti me-t o- A E a nal ysis. 
 
Ce ns ori n g 
T he u n derl yi n g r ule f or ce ns ori n g is t hat t he ce ns ori n g date s h o ul d be t he last da te t he patie nt is 
k n o w n t o be free of t he e ve nt e n d p oi nt (free of eac h c o m p o ne nt f or c o m p osite e n d p oi nt).   


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
3 0 
 
a.  Ge ner al ce ns ori n g r ule f or pri m ary effic acy e n d p oi nt:  
F or patie nts w h o ha ve n o pri mar y C V e n d p oi nts, t he y will be ce n s ore d usi n g t he f oll o wi n g r ules: 
 Patie nts w h o c o m plete d  t he st u d y will be cens ore d at t heir last st u d y visit date (st u d y 
cl ose- o ut visit date or fi nal f o ll o w- u p visit date, w hic he ver later).  
N ote: If t here are C V e ve nts ha p p e ni n g after t he patie nt’s last st u d y visit a n d t he e ve nt’s 
pri or/relate d e ve nt’s o nset date  is o n or bef ore t he patie nt’s last st u d y visit date, i n t his 
case, t his C V e ve nts will be i n cl u de d i n efficac y a nal ysis.  
 
A n ot her e xa m ple, f or a H H F, if t h e o nset date of its H F is bef o re last st u d y visit a n d its 
res ulte d h os pitalizati o n is after last st u d y visit, t his H H F wi ll be i ncl u de d i n efficac y 
a nal ysis.  
 
 Patie nts w h o die d wit h o ut disc o nti n ui n g t he st u d y bef ore deat h (ie Deat h re p orte d o n t he 
‘ C o m pleti o n of E n d of St u d y’) will be ce ns ore d at t heir date of N o n- C V deat h  
 
 Patie nts w h o disc o nti n ue d t he st u d y will be ce ns ore d at t heir l ater of st u d y disc o nti n uati o n 
date or latest date wit h car di o vasc ular efficac y e n d p oi nt i nf or mati o n ( MI/ U A, heart fail ure, 
cere br o vasc ular e ve nt, or c or o nar y pr oce d ure, a d missi o n t o h os p ital/e mer ge nc y r o o m, 
car diac bi o mar kers) c ollecte d 
 
b.  S pecific ce ns ori n g r ule f or all-c a use m ort ality 
Patie nts w h o di d n ot die will be c e ns ore d at t he latest date of :  e n d of st u d y visit date, date of vital 
stat us (if ali ve), or date last k n o w n t o be ali ve (if L T F U). Us uall y, t his is t he date of ‘ Date of last 
a vaila ble i nf or mati o n’ i n ‘ S u bjec t Stat us’ f or m f or patie nt alive at t hat date.  
c. S pecific ce ns ori n g r ule f or e G F R e n d p oi nt o nly  
Patie nts wit h o ut a n e ve nt will b e c o nsi dere d ce ns ore d at t heir earlier of last la b orat or y sa m ple date 
w here e G F R res ults are a vaila ble. 
Patie nts w h o alrea d y f ulfill t he res pecti ve c o n diti o n at baseline or wit h o ut p ost- ba seli ne la b orat or y 
meas ure me nts will be ce ns ore d at Da y 1.  
d.  S pecific ce ns ori n g r ule f o r c o m p osite re n al e n d p oi nts 
Patie nts wit h o ut t he e ve nt will be c o nsi dere d ce ns ore d at t heir  earlier of last la b orat or y sa m ple 
date w here e G F R res ults are a va ila ble. If a patie nt d oes n’t ha ve t he e G F R meas ure me nts after a 
certai n ti me p oi nt, b ut a dial ysis pr oce d ure n ot meeti n g t he def i niti o n of c hr o nic occ urs after t he 
last e G F R meas ure me nt b ut bef ore t he patie nt’s last st u d y visit date, t he patie nt will be ce ns ore d 
at t he last start date of dial ysis.  
Patie nts w h o alrea d y f ulfil t he res pecti ve c o n diti o n at baseli ne or wit h o ut p ost- baseli ne la b orat or y 
meas ure me nts will be ce ns ore d at Da y 1.  


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
3 1 
 
e. Ce ns ori n g f or severe hy p o glyce mi a or A E ( as p art of ge ner al A E a n alysi s)  
 
T o kee p t he a nal ysis of se vere  h y p o gl yce mia c o nsiste nt wit h t he o verall A E a nal ysis, a patie nt 
wit h o ut a n a d verse e ve nt will be  c o nsi dere d ce ns ore d at t he date of last I M P ta ke n + 1 0 da ys or 
date of deat h, if earlier. F or s e vere h y p o gl yce mia, a patie nt wit h o ut a se vere h y p o gl yce mia will be 
c o nsi dere d ce ns ore d at t he date of last I M P ta ke n + 1 da y or da te of deat h, w hic he ver earlier.  
H a n dli n g of missi n g or i nc o m plete d ates  
If t he o nset dates of ti me-t o-e ve nt e n d p oi nts is missi n g (c o m plete or partial), t he n t he partial 
missi n g o nset date will be i m p u te d b y usi n g t he f oll o wi n g al g orit h m, wit h t he refere nce date bei n g 
t he ra n d o mizati o n date.  
 If o nl y m o nt h of t he e ve nt is k n o w n, t he n t he 1 5t h da y of t his m o nt h will be i m p ute d f or a 
missi n g da y a n d year of t he start date will be i m p ute d as t he y ear, or  
 If o nl y t he year of t he e ve nt is k n o w n, t he n 1st of J ul y will be i m p ute d f or t he missi n g da y 
a n d m o nt h, or  
If t he res ulti n g i m p ute d dates are pri or t o t he ra n d o mizati o n date, i m p ute d date wi ll be reset t o t he 
ra n d o mizati o n date. F or n o n- deat h e ve nt, n o i m p utati o n will be ma de f or c o m pletel y missi n g date. 
F or deat h, t he i m p ute date be t h e latest of all i m p ute d e ve nt dates a n d patie nt’s last trial c o ntact 
date.  
 
 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
3 2 
 
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 D E O SI ( M E D D R A V 2 3. 0) 
 
E O SI 
Prefe rre d T er m  
Ge nital M yc otic I nfecti o ns  
Bala nitis ca n di da
Ge nital M y c otic I nfecti o ns  
Ca n di da cer vicitis
Ge nital M yc otic I nfecti o ns  
F u n g al b ala nitis
Ge nital M y c otic I nfecti o ns  
Ge nital ca n di diasis
Ge nital M yc otic I nfecti o ns  
Ge nital i nfecti o n f u n gal
Ge nital M yc otic I nfecti o ns  
Ur o ge nital i nfecti o n f u n gal
Ge nital M y c otic I nfecti o ns  
V ul v o va g i nal ca n di diasis
Ge nital M yc otic I nfecti o ns  
V ul v o va gi nal m yc otic i nfecti o n
Uri nar y  tr act i nf ecti o ns 
Ne p hritis b acteri al
Uri n ar y  tr act i nf ecti o ns 
Bacterial p y el o ne p hritis
Uri nar y  tr act i nf ecti o ns 
Bacterial uret hritis
Uri n ar y  tr act i nf ecti o ns 
Bla d der ca n di diasis
Uri nar y  tr act i nf ecti o ns 
C y stitis 
Uri nar y  tr act i nf ecti o ns 
C y stitis b acterial
Uri nar y tr act i nf ecti o ns  
C ystitis esc heric hia
Uri nar y tr act i nf ecti o ns  
C ystitis gla n d ularis
Uri nar y tr act i nf ecti o ns  
C ystitis hel mi nt hic
Uri nar y tr act i nf ecti o ns  
C ystitis kle bsiella
Uri nar y  tr act i nf ecti o ns 
C y stitis pse u d o m o nal
Uri nar y tr act i nf ecti o ns  
C ystitis viral
Uri nar y  tr act i nf ecti o ns 
C y t o meg al o vir us uri nar y  tract i nfecti on
Uri nar y tr act i nf ecti o ns  
E m p h yse mat o us c ystitis
Uri nar y  tr act i nf ecti o ns 
E m p h y se mat o us py el o ne p hritis
Uri nar y tr act i nf ecti o ns  
Esc heric hia p yel o ne p hritis
Uri nar y  tr act i nf ecti o ns 
Esc heric hia uri nar y  tract i nf ecti o n
Uri nar y tr act i nf ecti o ns  
F u n g al c ystitis
Uri nar y  tr act i nf ecti o ns 
Ge nit o uri nar y  c hla my dia i nfecti o n
Uri nar y  tr act i nf ecti o ns 
Ge nit o uri nar y  tract g o n oc occal i nfecti o n
Uri nar y  tr act i nf ecti o ns 
Ge nit o uri nar y  tract i nfecti o n
Uri nar y  tr act i nf ecti o ns 
Ki d ne y  i nfecti o n
Uri nar y tr act i nf ecti o ns  
P yelitis 
Uri nar y  tr act i nf ecti o ns 
P y el ocy stitis
Uri nar y tr act i nf ecti o ns  
P yel o ne p hritis
Uri nar y  tr act i nf ecti o ns 
P y el o ne p hritis ac ute
Uri nar y tr act i nf ecti o ns  
P yel o ne p hritis c hr o nic
Uri nar y  tr act i nf ecti o ns 
P y el o ne p hritis f u ng al
Uri nar y  tr act i nf ecti o ns 
P y el o ne p hritis my c o plas mal
Uri nar y  tr act i nf ecti o ns 
P y el o ne p hritis viral
Uri nar y  tr act i nf ecti o ns 
P y o n e p hr osis
Uri n ar y tr act i nf ecti o ns  
Re nal a bscess
U ri n ary  tr act i nf ecti o ns 
Re nal c y st i nfecti o n
Uri n ar y tr act i nf ecti o ns  
Stre pt oc occal uri n ar y tract i nfecti o n
Uri nar y  tr act i nf ecti o ns 
T u berc ul osis of g e nit o uri na ry  sy ste m
Uri nar y tr act i nf ecti o ns  
T u b ul oi nterstitial ne p hritis
Uri n ar y  tr act i nf ecti o ns 
Ureter a bscess
Uri nar y tr act i nf ecti o ns  
Ureteritis
Uri nar y  tr act i nf ecti o ns 
Uret hral a bscess
Uri nar y tr act i nf ecti o ns  
Uret hritis
Uri nar y tr act i nf ecti o ns  
Uret hritis c hla m y dial
Uri na ry  tr act i nf ecti o ns 
Uret hritis g o n oc occal
Uri nar y tr act i nf ecti o ns  
Uret hritis m yc o plas mal
Uri nar y  tr act i nf ecti o ns 
Uret hritis urea plas mal
Uri nar y tr act i nf ecti o ns  
Uri nar y b la d der a bscess
Uri nar y  tr act i nf ecti o ns 
Uri nar y  tract a bscess
Uri nar y  tr act i nf ecti o ns 
Uri nar y  tract i nf ecti o n
Uri n ar y  tr act i nf ecti o ns 
Uri nar y  tract i nf ecti o n bacterial
Uri nar y  tr act i nf ecti o ns 
Uri nar y  tract i nf ecti o n e nter oc occal
Uri nar y tr act i nf ecti o ns  
Uri nar y tract i nf ecti o n f u n gal
Uri nar y tr act i nf ecti o ns  
Uri nar y tr act i nf ecti o n pse u d o m o nal


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
3 3 
 
Uri nar y tr act i nf ecti o ns  
Uri nar y tract i nf ecti o n sta p h yl oc occal
Uri nar y  tr act i nf ecti o ns 
Uri nar y  tract i nf ecti o n viral
Uri n ar y tr act i nf ecti o ns  
Uri nar y tract i nfla m mati o n
Uri nar y  tr act i nf ecti o ns 
Ur o g e nital i nfecti o n bacterial
Uri nar y tr act i nf ecti o ns  
Ur o ge nital i nfecti o n f u n gal
Uri nar y  tr act i nf ecti o ns 
Ur o g e nital tric h o m o niasis
Uri nar y tr act i nf ecti o ns  
Ur ose psis
V ol u me de pleti o n 
Bl o o d os m olarit y  i ncrease d
V ol u me de pleti o n 
Bl o o d press ure a m b ulat or y decrease d
V ol u me de pleti o n 
Bl o o d p ress ure decrease d
V ol u me de pleti o n 
Bl o o d press ure diast olic dec rease d
V ol u me de pleti o n 
Bl o o d press ure i m meas ura ble
V ol u me de pleti o n 
Bl o o d press ure ort h ostatic decrease d
V ol u me de pleti o n 
Bl o o d press ure s yst olic decrease d
V ol u me de pleti o n 
Bl o o d press ure s y st olic i nsp irat ory decrease d
V ol u me de pleti o n 
Ca pillar y  n ail refill test a b n or mal
V ol u me de pleti o n 
Ce ntral ve n o us press ure decrease d
V ol u me de pleti o n 
Circ ulat or y  c olla pse
V ol u me de pleti o n 
Decrease d ve ntric ular prel oa d
V ol u me de pleti o n 
De h y drati o n
V ol u me de pleti o n 
Diast olic h y p ote nsi o n
V ol u me de pleti o n 
Distri b uti ve s h oc k
V ol u me de pleti o n 
Dizzi ness p ost ural
V ol u me de pleti o n 
Fe m oral p ulse decrease d
V ol u me de pleti o n 
H y p o perf usi o n
V ol u me de pleti o n 
H y p ote nsi o n
V ol u me de pleti o n 
H y p o v olae mia
V ol u me de pleti o n 
H y p o v olae mic s h oc k
V ol u me de pleti o n 
Left ve ntric ular e n d- diast olic press ure decrea se d
V ol u me de p leti o n 
Mea n arterial press ure dec rease d
V ol u me de pleti o n 
Ort h ostatic heart rate res p o nse i n crease d
V ol u me de pleti o n 
Ort h ostatic h y p ote nsi o n
V ol u me de pleti o n 
Ort h ostatic i nt olera nce
V ol u me de pleti o n 
Peri p heral circ ulat or y  fail ure
V ol u me de pleti o n 
Peri p heral p ulse decrease d
V ol u me de pleti o n 
P ost ural ort h ostatic tac h y car dia s y n dr o me
V ol u me de pleti o n 
Prere nal fail ure
V ol u me de pleti o n 
Pres y nc o pe
V ol u me de pleti o n 
P ul m o nar y arterial press ure decrease d
V ol u me de pleti o n 
P ul m o nar y  arterial we dg e press ure de crease d
V ol u me de pleti o n 
P ulse a bse nt
V ol u me de pleti o n 
P ulse press ure d ecrease d
V ol u me de pleti o n 
P ulse v ol u me decrease d
V ol u me de pleti o n 
Ra dial p ulse decre ase d
V ol u me de pleti o n 
S h oc k 
V ol u me de pleti o n 
S y nc o pe
V ol u me de pleti o n 
T hirst 
V ol u me de pleti o n 
Tilt ta ble test p ositi ve
V ol u me de pleti o n 
Uri ne fl o w decreas e d
V ol u me de pleti o n 
Uri ne o ut p ut decre ase d
V ol u me de p leti o n 
Ve n o us press ure d ecrease d
V ol u me de pleti o n 
Ve n o us press ure j u g ular decrease d
V ol u me de pleti o n 
V ol u me bl o o d d ecrease d
Pa ncreatitis 
Alc o h olic pa ncreatitis
Pa ncreatitis 
A ut oi m m u ne pa ncreatitis
Pa ncreatitis 
Gre y  T ur ner's sig n 
Pa ncreatitis 
Hae m orr ha gic necr otic pa ncreatitis
Pa ncreatitis 
Here ditar y  pa ncreatitis
Pa ncreatitis 
Isc hae mic pa ncreatitis
Pa ncreatitis 
Oe de mat o us pa ncreatitis
Pa ncreatitis 
Pa ncreatic a bscess
Pa ncreatitis 
Pa ncreatic hae m orr ha ge 
Pa ncreatitis 
Pa ncreatic necr osis
Pa ncreatitis 
Pa ncreatic p hle g m o n
Pa ncreatitis 
Pa ncreatic pse u d oc yst
Pa ncreatitis 
Pa ncreatic pse u d oc yst drai na ge


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
3 4 
 
Pa nc reatitis 
Pa ncreatitis
Pa ncreatitis 
Pa ncreatitis ac ute
Pa ncreatitis 
Pa ncreatitis c hr o nic
Pa ncreatitis 
Pa ncreatitis hae m orr ha g ic
Pa ncreatitis 
Pa ncreatitis hel mi nt hic
Pa ncreatitis 
Pa ncreatitis necr otizi n g
Pa ncreatitis 
Pa ncreatitis rela psi n g
Pa ncreatitis 
Pa ncreat ore nal s y n dr o me
Pa ncreatitis 
Tra u matic p a ncreatitis
Ve n o us t hr o m b otic e ve nts 
Arteri o ve n o us fist ula t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Arteri o ve n o us g raft t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
A xillar y vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Brac hi oce p halic vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
B u d d- C hiari s y n dr o me
Ve n o us t hr o m b otic e ve nts 
Ca ve rn o us si n us t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Cere bral ve n o us t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Dee p vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Dee p vei n t hr o m b osis p ost o perati ve
Ve n o us t hr o m b otic e ve nts 
E m b olis m ve n o us
Ve n o us t hr o m b otic e ve nts 
He patic vei n e m b olis m
Ve n o us t hr o m b otic e ve nts 
He patic vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
I ntracra nial ve n o us si n us t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
J ug ular vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Mese nteric vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Metastatic p ul m o nar y  e m b olis m
Ve n o us t hr o m b otic e ve nts 
O p ht hal mic vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
O varia n v ei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Pa get- Sc hr oetter s y n dr o me
Ve n o us t hr o m b otic e ve nts 
Pel vic ve n o us t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Pe nile vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
P ortal vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
P ort os ple n o mese nteric ve n o us t hr o m b osi s
Ve n o us t hr o m b otic e ve nts 
P ost pr oce d ural p ul m o nar y e m b olis m
Ve n o us t hr o m b otic e ve nts 
P ost t hr o m b otic s y n dr o me
Ve n o us t hr o m b otic e ve nts 
P ost o perati ve t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
P ul m o nar y  e m b olis m
Ve n o us t hr o m b otic e ve nts  
P ul m o nar y micr oe m b oli
Ve n o us t hr o m b otic e ve nts  
P ul m o na ry  t hr o m b osis
Ve n o us t hr o m b otic e ve nts  
P ul m o nar y ve n o us t hr o m b osis
Ve n o us t hr o m b otic e ve nts  
Re nal vei n e m b olis m
Ve n o us t hr o m b otic e ve nts  
Re nal vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts  
Reti nal vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts  
S ple nic vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts  
S u bcla via n vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts  
S u peri or sa g ittal si n us t hr o m b osis
Ve n o us t hr o m b otic e ve nts  
T hr o m b o p hle bitis
Ve n o us t hr o m b otic e ve nts  
T hr o m b o p hle bitis mi g ra ns
Ve n o us t hr o m b otic e ve nts  
T hr o m b o p hle bitis s u p erficial
Ve n o us t hr o m b otic e ve nts  
T hr o m b ose d varic ose vei n
Ve n o us t hr o m b otic e ve nts  
T hr o m b osis c or p ora ca ve rn osa
Ve n o us t hr o m b otic e ve nts  
Tra ns verse si n us t hr o m b osis
Ve n o us t hr o m b otic e ve nts  
Ve na ca va e m b olis m
Ve n o us t hr o m b otic e ve nts  
Ve na ca va t h ro m b osis
Ve n o us t hr o m b otic e ve nts  
Ve n o us t hr o m b osis
Ve n o us t hr o m b otic e ve nts  
Ve n o us t hr o m b osis li m b
Ve n o us t hr o m b otic e ve nts  
Visceral ve n o us t hr o m b osis
T h yr oi d ca nce r 
A na plastic t h yr oi d ca ncer
T h y r oi d ca ncer 
Fa milial me d ullar y  t hy r oi d ca ncer
T h y r oi d ca ncer 
F ollic ular t h y r oi d ca ncer
T h y r oi d ca ncer 
H uert hle cell carci n o ma
T h y r oi d ca ncer 
Me d ullar y  t hy r oi d ca ncer
T h yr oi d ca nce r 
Pa pillar y t h yr oi d ca nce r
T h yr oi d ca ncer 
P o orl y differe ntiat e d t h yr oi d carci n o ma
T h yr oi d ca nce r 
T h yr oi d B-cell l y m p h o ma
T h yr oi d ca ncer 
T h yr oi d ca ncer
T h yr oi d ca nce r 
T h yr oi d ca ncer metastatic


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
3 5 
 
T h yr oi d ca nce r 
T h yr oi d ca ncer rec urre nt
T h y r oi d ca ncer 
T h y r oi d ca ncer stag e 0
T h yr oi d ca nce r 
T h yr oi d ca ncer sta ge I
T h y r oi d ca ncer 
T h y r oi d ca ncer stag e II
T h yr oi d ca ncer 
T h yr oi d ca ncer sta ge III
T h y r oi d ca ncer 
Th y r oi d ca ncer stag e I V
T h yr oi d ca nce r 
T h yr oi d ne o p las m
Re nal cell c a ncer 
Clear cell r e nal cell carci n o ma
Re nal cell c a ncer 
He re ditar y l ei o m y o mat osis re nal c ell carci n o ma
Re nal cell c a ncer 
Metastatic re nal cell carci n o ma
Re nal cell c a ncer 
Pa pillar y re nal cell carci n o ma
Re nal cell c a ncer 
Re nal ca ncer
Re nal cell c a ncer 
Re nal ca ncer metastatic
Re nal cell c a ncer 
Re nal ca n cer rec urre nt
Re nal cell c a ncer 
Re nal ca n cer sta g e I
Re nal cell c a ncer 
Re nal ca ncer sta g e II
Re nal cell c a ncer 
Re nal ca ncer sta g e III
Re nal cell c a ncer 
Re nal ca n cer sta g e I V
Re nal cell c a ncer 
Re nal cell c arci n o ma
Re nal cell c a ncer 
Re nal cell c arci n o ma rec urre nt
Re nal cell c a ncer 
Re nal cell c arci n o ma sta ge I
Re nal cell c a ncer 
Re nal cell c arci n o ma sta ge II
Re nal cell c a ncer 
Re nal cell c arci n o ma sta g e III
Re nal cell c a ncer 
Re nal cell c arci n o ma sta ge I V
Re nal cell c a ncer 
Re nal n e o plas m
Pa ncreatic ca ncer 
Aci nar cell carci n o ma of pa ncreas
Pa ncreatic ca ncer 
A de n ocarci n o ma p a n c reas
Pa ncreatic ca ncer 
C ysta de n ocarci n o ma pa ncreas
Pa ncreatic ca ncer 
Carci n oi d t u m o ur of t he pa ncreas
Pa ncreatic ca ncer 
D uctal a de n ocarci n o ma of pa ncreas
Pa ncreatic ca ncer 
Gastri n o ma  mali g na nt
Pa nc reatic ca ncer 
Gl uca g o n o ma
Pa ncreatic ca ncer 
I ns uli n o ma
Pa ncreatic ca ncer 
I ntra d uctal pa pillary - m uci n o us carci n o ma of pa ncreas
Pa ncreatic ca ncer 
Mali g na nt ne o plas m of islets of La n ger ha ns
Pa ncreatic ca ncer 
M uci n o us c y sta de n ocarci n o ma of pa ncreas
Pa ncreatic ca ncer 
Ne ur ote nsi n o ma
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma metast atic
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma rec urre nt
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma sta g e 0
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma sta g e I
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma sta g e II
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma sta g e III
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma sta g e I V
Pa ncreatic ca ncer 
Pa ncreatic ne o plas m
Pa ncreatic ca ncer 
Pa ncreatic ne ur oe n d ocri ne t u m o u r
Pa ncreatic ca ncer 
Pa ncreatic ne ur oe n d ocri ne t u m o ur metastatic
Pa ncreatic ca ncer 
Pa ncreatic sarc o ma
Pa ncreatic ca ncer 
Pa ncreat o blast o ma
Pa ncreatic ca ncer 
Ser o us c y sta de n ocarci n o ma of p a ncreas
Pa ncreatic ca ncer 
S oli d pse u d o pa pillar y t u m or of t he pa ncreas
Pa ncreatic ca ncer 
S o mat ostati n o ma
Pa ncreatic ca ncer 
Vi p o ma 
Bla d der ca ncer 
Bla d der a de n ocarci n o ma rec urre nt
Bla d der ca ncer 
Bla d der a de n ocarci n o ma sta g e 0
Bla d der ca ncer 
Bla d der a de n ocarci n o ma sta ge I
Bla d de r ca ncer 
Bla d der a de n ocarci n o ma sta g e II
Bla d de r ca ncer 
Bla d der a de n ocarci n o ma sta g e III
Bla d der ca ncer 
Bla d der a de n ocarci n o ma sta g e I V
Bla d de r ca ncer 
Bla d der a de n ocarci n o ma sta g e u ns pecifie d
Bla d der ca ncer 
Bla d der ca ncer
Bla d der ca ncer 
Bla d der ca ncer rec urre nt
Bla d der ca ncer 
Bla d der ca ncer sta ge 0, wit h ca ncer i n sit u
Bla d de r ca ncer 
Bla d der ca ncer sta ge 0, wit h o ut ca nc er i n sit u
Bla d der ca ncer 
Bla d der ca ncer sta g e I, wit h ca ncer i n sit u


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
3 6 
 
Bla d der ca ncer 
Bla d der ca ncer sta ge I,  wit h o ut ca n cer i n sit u
Bla d der ca ncer 
Bla d der ca ncer sta g e II
Bla d der ca ncer 
Bla d der ca ncer sta g e III
Bla d der ca ncer 
Bla d der ca ncer sta g e I V
Bla d der ca ncer 
Bla d der ne o plas m
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma rec urre nt
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma st a ge 0
Bla d der ca nce r 
Bla d der s q ua m o us cell carci n o ma st a g e I
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma st a ge II
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma st a ge III
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma st a g e I V
Bla d de r ca ncer 
Bla d der s q ua m o us cell carci n o ma st a ge u ns pecifie d
Bla d der ca ncer 
Bla d der tra nsiti o nal cell c arci n o ma
Bla d der ca ncer 
Bla d der tra nsiti o nal cell c arci n o ma metastatic
Bla d der ca ncer 
Bla d der tra nsiti o nal cell c arci n o ma rec urre nt
Bla d der ca ncer 
Bla d der tra nsiti o nal cell c arci n o ma st a g e 0
Bla d der ca ncer 
Bla d der tra nsiti o nal cell c arci n o ma st a g e I
Bla d der ca ncer 
Bla d der tra nsiti o nal cell c arci n o ma st a g e II
Bla d der ca ncer 
Bla d der tra nsiti o nal cell c arci n o ma st a ge III
Bla d der ca ncer 
Bla d der tra nsiti o nal cell c arci n o ma st a ge I V
Bla d der ca ncer 
Metastatic carci n o ma of t he bla d der
Bla d der ca ncer 
Ne ur oe n d ocri ne carci n o ma of t h e bla d der
Bla d der ca ncer 
Uri nar y  bla d der sarc o ma


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
3 7 
 
A p p e n di x C K e y C h a n g e s t o Ori gi n al Pl a n n e d A n al y si s a n d Pr ot o c o l 
C h a n g e 
R ati o n ale 
Pri mar y e n d p oi nt a nal y zes t otal occ urre nces 
(first a n d p ote ntiall y s u bse q ue nt) rat her t ha n 
first occ urre nce 
T otal occ urre nces are e x pecte d t o be a m ore 
se nsiti ve i n dicat or of treat me nt be nefit, are 
cli nicall y rele va nt i n a p o p ulati o n at hi g h ris k 
f or heart fail ure, a n d ha ve bee n se nsiti ve t o 
c ha n ge i n se veral car di o vasc ula r o utc o me trials
Pri mar y e n d p oi nt a d ds  ur ge nt H F visit t o 
ori gi nal pla n ne d e n d p oi nt of C V m ortalit y a n d 
H H F 
Ur ge nt H F visits are cli nicall y rele va nt a n d ca n 
be re d uce d b y effecti ve treat me nt 
All e ve nt e n d p oi nts base d o n i n vesti gat or 
re p orti n g rat her t ha n a dj u dicati o n 
A dj u dicati o n was n ot c o m plete d, a n d 
i n vesti gat or-re p orte d e ve nts are cli nicall y 
rele va nt
O nl y o ne pri mar y o bjecti ve is a p plie d t o t he 
o verall p o p ulati o n: i nitiall y t here were c o-
pri mar y o bjecti ves, o ne relati n g t o M A C E n o n-
i nferi orit y ( n o nfatal MI, n o nfatal str o ke, a n d 
C V deat h), t he ot her relati n g t o H H F a n d C V 
deat h 
F oc us o n t he m ost rele va nt a n d c o nsiste nt 
e n d p oi nt t hat has esta b lis he d t he be nefit of 
S G L T i n hi biti o n acr oss s t u dies, at a ti me w he n 
F D A g ui da nce has eli mi nate d t he f or mal 
re q uire me nt f or M A C E n o n-i nferi orit y testi n g 
f or re gistrati o n of pr o d ucts f or t he tr eat me nt of 
ty p e 2 dia betes
List of sec o n dar y e n d p oi nts or dere d t o 
e m p hasize first H H F a n d ur ge nt H F visit, t he n 
C V m ortalit y, f oll o we d b y br oa d car di o vasc ular 
c o m p osite e n d p oi nts, t he n t he c o m p osite re nal 
e n d p oi nt, all-ca use m o rtalit y, a n d fi nall y 
narr o w 3- p oi nt M A C E 
H F ris k i n S C O R E D i n di cates t he e n d p oi nt of 
t otal occ urre nces of HH F a n d ur ge nt H F visit 
ca n be ver y well p o were d, C V m ortalit y is ver y 
i m p orta nt, a n d t he hi g h o verall C V ris k of t he 
S C O R E D p o p ulati o n i n dicates t hat br oa d C V 
c o m p osite e n d p oi nts are h i g hl y rele va nt t o t his 
p o p ulati o n, a n d all-ca use m ortalit y is m ore 
i mp orta nt t ha n 3- p oi nt M A C E 
A d diti o n of A R R, D A O H a n d P D A O H as ot her 
e n d p oi nts 
A R R pr o vi des a pers pecti ve of treat me nt 
be nefit, a n d D A O H a n d P D A O H ca pt ure 
cli nical rele va nce of decrease d h os pitalizati o ns
H y p o gl yce mia safet y m o ve d t o efficac y 
e n d p oi nt 
Re d ucti o ns i n h y p o gl yce mia ha ve bee n see n 
wit h s ota glifl ozi n i n b ot h t y pe 1 dia betes a n d 
T 2 D, i n dicati n g t he val ue of statistical a nal yses 
of h y p o g ly ce mia res ults 
A d de d versi o ns of t he c o m p osite re nal e n d p oi nt  Decli nes of 4 0 % or 3 0 % i n e G F R ma y  be m ore 


St ati sti c al A n al y si s Pl a n  
d d- M m m- y y y y 
Pr o d u ct C o d e- St u d y N u m b er - E F C 1 4 8 7 5 
V er si o n n u m b er: 1. 0 
 
Pr o p ert y of L e xi c o n P h ar m a c e uti c al s - stri ctl y c o nfi d e nti al 
3 8 
 
l o o ki n g at differe nt c ut- offs of e G F R decli ne, 
a d de d e n d p oi nt of e G F R decli ne after Wee k 4, 
a n d a d de d U A C R e n d p oi nt 
c o m m o n t ha n decli nes o f 5 0 %, a n d ma y better 
c haracterize differe nces bet wee n treat me nt 
gr o u ps, o verall e G F R c ha n ge after Wee k 4 ma y 
be a m ore se nsiti ve meas ure of re nal disease 
pr o gressi o n t ha n t he c o m p osite r e nal e n d p oi nt, 
a n d U A C R c ha n ge ma y pr o vi de a rele va nt 
pers pecti ve o n re nal e ffects of s ota glifl ozi n