Conditions: Heart Failure Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1222
Healthy volunteers: no

Brief summary:
Primary Objective:

To compare the effect of sotagliflozin to placebo on the total occurrences of cardiovascular (CV) death, hospitalization for heart failure (HHF), and urgent visit for heart failure (HF) in hemodynamically stable participants after admission for worsening heart failure (WHF)

Secondary Objectives:

To compare the effects of sotagliflozin to placebo on:

* The total occurrences of HHF and urgent visit for HF
* The occurrence of CV death
* The occurrence of all-cause mortality
* The total occurrences of CV death, HHF, urgent visit for HF, non-fatal myocardial infarction (MI), and non-fatal stroke
* Change in Kansas City Cardiomyopathy Questionnaire-12(KCCQ-12) score
* Change in estimated glomerular filtration rate (eGFR)

Detailed description:
The estimated study duration for a given participants will be approximately 3 to 24 months.

Arms:
arm 1: Sotagliflozin 200 mg tablet once daily, with possible up-titration in the first 8 months to 400 mg, for up to 21.2 months. arm 2: Matching placebo to sotagliflozin 200 mg once daily, with possible up-titration in the first 8 months to matching placebo to sotagliflozin 400 mg, for up to 21.6 months.

Interventions: intervention 1: Sotagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: tablet

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

Route of administration: oral

Protocol document:
Prot_000.pdf: 


 
 
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Page 1 
 
 
AMENDED CLINICAL TRIAL PROTOCOL 01 
 
COMPOUND: sotagliflozin/SAR439954 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 
Study to Evaluate the Effects of SOtagLiflozin on Clinical Outcomes in 
HemodynamIcally STable Patients with Type 2 Diabetes POST Worsening 
Heart Failure 
STUDY NUMBER: EFC15156 
STUDY NAME: SOLOIST-WHF Trial 
 
EudraCT  
2017-003510-16 
IND Number 
 
Regulatory agency identifying number(s):  
WHO universal trial 
number: 
U1111-1190-7891 
Approval Date: 
17-Dec-2018 
Total number of pages:
142 
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Amended Clinical Trial Protocol 01  
17-Dec-2018 
SAR439954-EFC15156 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
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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Amended Clinical Trial Protocol 01  
17-Dec-2018 
SAR439954-EFC15156 - sotagliflozin 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 3 
DOCUMENT HISTORY 
Document  
Country/countries  
impacted by  
amendment 
Date, version 
Amended Clinical Trial Protocol 01 
All 
17-Dec-2018; version 1 (electronic 1.0) 
Original Protocol 
 
05-Jan-2018; version 1 (electronic 1.0) 
 
Amended protocol 01 (17-Dec-2018) 
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10 (a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The procedures related to the endpoint of detection of premature ventricular complexes in the 
subgroup of patients with an implantable cardioverter defibrillator or cardiac resynchronization 
therapy device are not operationally feasible. Therefore, the protocol has been amended to remove 
this endpoint. The mechanistic sub study will not be conducted for this study as the procedures for 
the assessments are not operationally feasible; the protocol has been amended accordingly. 
Following advice from the external steering committee which provides scientific and clinical 
leadership for the study, a new objective and endpoint have been added to compare sotagliflozin 
versus placebo on the time of first occurrence of cardiovascular death and hospitalization for heart 
failure, in subgroups of patients who started first IMP dose before and after hospital discharge. 
The protocol has been revised to clarify the use of the clinical laboratory and 12-lead ECG 
assessments obtained by the time of hospitalization due to heart failure to formally screen the 
patients, thereby reducing the redundancy of procedures in recently hospitalized patients. This 
facilitates the Screening and Randomization on the same day.  
The order of secondary endpoints has been revised and the multiplicity testing procedure has been 
updated from fixed sequence approach to graphical approach in response to U.S. Food and Drug 
Administration (FDA) recommendation.  
In addition, minor editorial corrections, and document formatting revisions have been made 
throughout the document. 
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Amended Clinical Trial Protocol 01  
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Page 4 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
Clinical Trial summary: Study Objective: 
Secondary objectives, Endpoints: 
Secondary endpoints, Statistical 
considerations 
Section 5.2: Secondary objectives 
Section: 9.1.2 Secondary efficacy endpoints 
Re-ordered secondary objectives and 
secondary endpoints. 
Re-ordered as per FDA 
recommendation. 
Clinical Trial Summary: Other Objective, 
Other endpoint 
Section 5.3: Other Objectives 
Section 9.1.3: Other endpoint 
Objective and endpoint added to 
compare sotagliflozin versus placebo on 
the time of first occurrence of 
cardiovascular death and hospitalization 
for heart failure in subgroups of patients 
who started first IMP dose prior vs after 
hospital discharge (or urgent care facility 
where appropriate).  
New endpoint is added following advice 
from the external steering committee 
which provides scientific and clinical 
leadership for the study. 
Clinical Trial Summary: Other Objective, 
Other endpoint,  
Section 1.2: Study Flow Chart 
Section 5.3: Other objectives 
Section 9.1.3: Other efficacy endpoints 
Section 10.1.2.3: On-site Visit 5 (Week 4) 
Section 10.1.2.4: On-site Visit 6 (Month 4) 
Deleted other objective to compare 
sotagliflozin versus placebo on the 
occurrence of premature ventricular 
complexes in the subgroup of patients 
with an implantable cardioverter 
defibrillator or cardiac resynchronization 
therapy device at Baseline. 
All corresponding measurements and 
endpoint are removed. 
The objective, corresponding 
measurements, and endpoint are 
removed as the procedures for these 
assessments were not operationally 
feasible. 
Clinical Trial Summary: Study Objective; 
Study design; Main selection criteria: 
inclusion criteria and exclusion criteria; 
Endpoints;  
Section 5.4: Mechanistic substudy 
Section 6.1 Description of the study 
Section 7.1.3 Mechanistic substudy 
Section 7.2.3 Mechanistic substudy 
Deleted information regarding 
mechanistic substudy. 
Mechanistic substudy will not be 
performed for this study as the 
procedures for the assessments are not 
operationally feasible for the sites. 
Clinical Trial Summary: Statistical 
consideration: Multiplicity adjustment 
Section 11.4.2.4: Multiplicity considerations 
The fixed sequence approach changed 
to an alpha passing concept (eg, Bretz et 
al.) to allow for testing important 
secondary endpoint(s) without requiring 
previous tested endpoints to be 
statistically significant. 
Changed based on FDA 
recommendation. 
Clinical Trial Summary: Main selection 
criteria-Exclusion criteria 
Section 7.2.1 Exclusion criteria related to 
study methodology: E 12 
Deleted hypertrophic obstructive 
cardiomyopathy from E 12. 
This information is repeated in E 13. 
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Amended Clinical Trial Protocol 01  
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Page 5 
Section # 
and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary: Study committees 
Deleted Independent Expert Committee 
Removed as the mention of independent 
expert committees is not part of the 
clinical trial summary protocol template.  
These additional committees are 
described further in the text of the 
protocol. 
Section 1.2 Study flow Chart; Footnote k 
Section :9.2.2.1: Urinalysis 
Section 10.1.2.1: On-site Visit 2 (Day 1) 
Randomization 
Section 10.1.2.4: On-site Visit 6 (Month 4) 
Section 10.1.2.5: On-site Visits 7 to 12 
(Months 8,12,16,20,24,28) 
Section 10.1.3.1: Premature End-of-
Treatment Visit 
Section 10.1.4.1: Study closeout Visit for 
patients who do not prematurely 
permanently discontinue investigational 
medicinal product 
Section 10.1.4.2: Study closeout Visit for 
patients who prematurely permanently 
discontinue investigational medicinal 
product 
Removed urine glucose testing 
throughout the protocol. 
Suggested by the Steering committee to 
remove reporting of urine glucose results 
as it may potentially unblind the 
Investigators and the Sponsor.  
Section 8.7.1: Treatment accountability and 
compliance 
Deleted sentence regarding telephone 
visit. 
Although the protocol specifies that the 
patient may be contacted by telephone to 
inquire about safety status (including 
outcomes), there are no mandatory 
telephone visits in this study. 
Section 9.1.3.2: Kansas City 
Cardiomyopathy Questionnaire-12 
Deleted sentence on open-ended 
questions within KCCQ-12 questionnaire. 
Removed as the KCCQ-12 questionnaire 
does not include open-ended questions.  
Section 10.4.2: Serious adverse events 
waived from expedited regulatory reporting 
to regulatory authorities 
Deleted renal adverse events from AEs 
waived from expedited reporting.  
Renal events will not be waived from 
regulatory reporting to health authorities. 
Section 11.4.3.1: Analysis of adverse 
events; Death and serious adverse events 
Deleted details of the analysis of death. 
Changes are being implemented to be 
consistent with Sponsor protocol 
template. The details will be further 
specified in the SAP. 
Section 17: Appendix F: Diabetic 
ketoacidosis 
Deleted the text to complete the 
“Possible DKA” in eCRF. 
This information is not relevant for 
instructions targeted to the patient 
audience. These instructions were more 
relevant to the investigator and provided 
separately. 
Section 10.4.2: Serious adverse events 
waived from expedited regulatory reporting 
to regulatory authorities 
Added unstable angina to the list of CV 
events waived from expedited reporting. 
To be consistent with feedback from 
Health Authorities. 
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Amended Clinical Trial Protocol 01  
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Page 6 
Section # 
and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary: Main selection 
criteria-Exclusion criteria: E 18 
Section 7.2.1 Exclusion criteria related to 
study methodology: E 18 
Modified E 18 to include hypersensitivity 
to any of the excipients included in 
placebo. 
Exclusion criterion modified as per 
request from a health authority.  
Clinical trial summary: Exclusion criteria 
E29 
Section 1.2: Study Flow Chart: footnote m 
Section 7.2.2: Exclusion criteria: Exclusion 
criteria related to the current knowledge of 
sotagliflozin, E 29 
Section 9.2.2: Laboratory safety variables 
Revised to include additional tests on 
pregnancy to be performed as per 
Investigator’s discretion or at frequency 
specified by local regulations. 
Revised as per the request from health 
authority and ethics committee of certain 
countries, to perform pregnancy tests 
every 3 months. 
Section 1.2 Study flow chart; footnote k 
Section 10.1.2.5: On-site Visits 7 to 12 
(Months 8,12,16,20,24,28) 
Added the measurement of HbA1c to be 
performed at month 16 (Visit 9) 
The HbA1c should be performed every 
4 months to be consistent with glycemic 
monitoring throughout the study. 
Section 1.2 Study flow chart; footnote l 
Section 10.1.5.1: Follow-Up Visit 
Added the measurement of eGFR to the 
assessments to be conducted at the 
follow-up visit performed 10 days ± 4 
days after discontinuation of study 
treatment. 
Sotagliflozin may cause hemodynamic 
changes in renal function. Per, FDA 
recommendation, eGFR to be measured 
after discontinuation of study treatment. 
Section 4.3: Benefit/Risk Profile 
Added potential benefits of sotagliflozin 
outweigh potential risks for patients with 
T1D and T2D. 
Updated to be consistent with IB and 
program level information. 
Section 8.8.2: Management of blood 
pressure and renal function 
Section 10.1.2.1 On-site Visit 2 (Day 1) 
Randomization 
Corrected to 'all attempts should be 
made not to modify or discontinue the 
ACE-i/ARB, which should be at optimum 
or maximally tolerated doses’. 
Corrected to provide guidance to 
Investigators to ensure patients will 
receive standard of care with approved 
therapies consistent with clinical 
guidelines.  
Section 8.8.3 Management of heart failure 
Section 9.1.3.3: Concomitant medication by 
class 
Section 10.1.2.1: On-site Visit 2 (day 1) 
randomization 
Defined direct renin inhibitors as RAAS 
inhibitors. 
Clarified as direct renin inhibitors are part 
of the Renin-Angiotensin-Aldosterone 
System. 
Section 14.5: Data protection 
General Data Protection Regulation 
reference added. 
Included as per ethics committee 
request. 
Section 17: Appendix C: KCCQ-12 
questionnaire 
A watermarked KCCQ-12 questionnaire 
added to Appendix C. 
The PRO questionnaires should be 
indicated with a footnote with the version 
number and with a watermark “for review 
only”. 
Section 8.8.5: Other medications 
P glycoprotein substrates and labels of P 
glycoprotein substrates added as other 
prohibited medications. 
To clarify the questions from local 
countries and provide further clinically 
relevant information to investigators. This 
information also supplements guidance 
from the IB. 
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Page 7 
Section # 
and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary: Other objective, 
other endpoint 
Section 5.3: Other objectives 
Section 9.1.3: Other efficacy endpoints 
Clarified objective and endpoint related 
to the clinical events in patients with 
LVEF >50% to LVEF ≥50% and re-
arranged in Section 5.3. 
Clarified so that the patients with 
LVEF =50% will not be missed from 
analysis. 
Clinical Trial Summary: Main selection 
criteria, Inclusion criteria 
Section 7.1.1: Inclusion criteria: At the 
Screening Visit 
Clarified that the sites that plan to enroll 
patients who are not hospitalized (ie, 
admitted for at least 24 hours) should be 
qualified by Sponsor at the pre-site visit 
or a site visit to ensure the existence of 
appropriate facilities. 
Sponsor must ensure appropriate 
facilities are present in sites enrolling 
patients who are not hospitalized. 
Clinical Trial Summary: Main selection 
criteria-Inclusion criteria I 02 and I 08 
Section 7.1.1: Inclusion criteria: At the 
Screening Visit I 02 
Section 7.1.2: Inclusion criteria: At the 
Randomization Visit I 08 
Clarified the inclusion of patients 
receiving treatment with IV loop diuretics 
and transitioning from IV to 
administration of oral loop diuretics.  
Change is being implemented to further 
clarify for Investigators that patients must 
specifically be receiving loop diuretics at 
a minimum. The use of thiazide or other 
types of diuretics alone does not qualify 
the patient for the study. 
Clinical Trial Summary: Main selection 
criteria-Exclusion criteria :E 06 
Section 1.2: Study Flow Chart: footnote h 
Section 7.2.1: Exclusion criteria related to 
study methodology: E 06 
Clarified exclusion of patients whose 
LVEF measurement is not available 
within 12 months prior to Screening 
instead of Randomization. 
To be consistent across the document. 
Clinical Trial Summary: Exclusion criteria 
E 06 
Section 7.2.2: Exclusion criteria E06 
Modified to include all diagnostic imaging 
to document historical LVEF at 
Screening. 
Included all imaging modalities to 
document historical LVEF at Screening. 
Clinical Trial Summary: Main selection 
criteria-Exclusion criteria :E 07 
Section 7.2.1: Exclusion criteria related to 
study methodology: E 07 
Clarified that patients with end-stage HF 
requiring LVAD, IABP or any mechanical 
support at the time of randomization will 
be excluded, but patients will not be 
excluded if IABP was used during index 
event. 
Clarified that temporary use of IABP 
during index event does not exclude the 
patient from the study.  
Clinical Trial Summary: Main selection 
criteria-Exclusion criteria: E 25 
Section 7.2.1 Exclusion criteria related to 
the current knowledge of sotagliflozin: E 25 
Clarified that patients with severe kidney 
disease will be excluded based on the 
eGFR value at Screening visit and not 
based on laboratory results during 
Randomization. 
Eligibility for patients with severe kidney 
disease is assessed based on Screening 
eGFR value. 
Clinical Trial Summary: Inclusion criteria 
I 09  
Section 1.2: Study Flow Chart: footnote i 
Section 7.1.2: Inclusion criteria I 09 
Section 10.1.1.1: On site Visit 1 (Week-2) 
Screening Visit 
Clarified that if sites are unable to 
perform laboratory assessments at 
Screening locally, the tests can be done 
by central laboratory. 
Since a number of sites are unable to 
perform the laboratory assessment 
locally, the tests may be done at the 
central laboratory. 
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Page 8 
Section # 
and Name 
Description of Change 
Brief Rationale 
Clinical Trial Summary: Other endpoint 
Section 9.1.3: Other efficacy endpoints 
Time point specified for changes from 
baseline in loop diuretics. 
Clarified time points for statistical 
analysis. 
Section 1.2: Study Flow Chart: footnote n 
Section 9.2.2.1: Urinalysis 
Modified to clarify urinalysis will be 
performed at the local laboratory at 
Visit 1 and subsequently at the central 
laboratory. If the urinalysis is positive for 
nitrite and leukocyte esterase or blood, 
reflexive testing will be performed at the 
local laboratory at Visit 1, and at the 
central laboratory for subsequent visits. 
Availability of urinalysis results for nitrite 
and leukocyte esterase performed at the 
local laboratory may facilitate a diagnosis 
of urinary tract infection during screening.  
Section 1.2: Study Flow Chart: footnote o 
Section 6.1.1: Study Design, Screening 
period 
Section 6.1.2: Study Design: Randomized 
double-blind treatment period 
Section 10.1.1: Study procedures: 
Screening period 
Section 10.1.2: Study procedures: 
Randomization double-blind treatment 
period 
Clarified that blood samples for BNP or 
NT-proBNP collected at Screening to 
assess the patient’s eligibility will be 
analyzed by the local laboratory. In 
addition, a blood sample for NT-proBNP 
will be collected at Randomization before 
taking IMP, and at any subsequent visits 
(when NT-proBNP is scheduled to be 
collected) will be analyzed by the central 
laboratory. 
Clarified which BNP and NT-proBNP 
samples (at the Screening visit versus 
the Randomization visit and subsequent 
study visits) will be analyzed by the local 
laboratory and which ones will be 
analyzed by the central laboratory. 
Clinical trial Summary: Exclusion criteria, E 
30 
Section 1.2: Study Flow Chart: footnote o 
Section 7.2.1: Exclusion criteria related to 
study methodology, E 30 
Section 8.8.5: Other medications 
Section 9.2.2: Laboratory Safety variable: 
Table 2 footnotes 
Section 10.1.2.2 On-site Visits 3 (Week 1) 
and 4 (Week 2) 
Clarified that digoxin assessment is 
performed using either serum or plasma, 
and that if sites are unable to perform the 
test locally the assessment will be done 
by central laboratory. 
Since several sites are unable to perform 
the digoxin assessment locally, the tests 
may be done at the central laboratory. 
Section 6.1.2 Randomized double-blind 
treatment period  
Section 8.1: Table 1 footnotes 
Clarified the timing of the first IMP 
dosage for patients who come to the 
Randomization visit after having food. In 
such scenario, only those patients who 
are not fasting will be allowed to start 
treatment the following day before the 
first meal. 
The IMP dose should be taken when 
fasting, before first meal of the day. 
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Section # 
and Name 
Description of Change 
Brief Rationale 
Section 1.2: Study Flow Chart: footnotes c 
and i; 
Section 9.2.4: Electrocardiogram variables 
Section 10.1.1.1: On site Visit 1 (Week-2) 
Screening Visit 
Modified to allow collection of historical 
data for laboratory and ECG 
assessments performed as standard of 
care after the Index event to formally 
screen the patients. Additionally, the 
Screening labs required to determine 
eligibility is clarified.  Serum pregnancy 
test must be collected at Screening. 
Added collection of historical data for 
height if the patient is on bed rest at 
Screening. 
Laboratory and ECG assessment are 
completed as standard of care for the 
patient population in this study since they 
are hospitalized.  
In order to reduce the redundancy of 
procedures, historical data following the 
Index Event obtained in the routine 
clinical management of the patient while 
hospitalized, can be used for Screening. 
Clinical Trial Summary: Footnotes r 
Clarified that Investigators should ensure 
to follow up all AEs until clinical recovery, 
or until death. 
In order to ensure safety of the patients 
AEs should be followed up until clinical 
recovery which may continue beyond last 
planned visit. 
Section 6.4.5 Safety events requiring 
ongoing monitoring 
Section 8.3.1: Methods of blinding 
Section 10.4.1.4: Events of special interest 
Modified the title of subsection 6.4.5 to 
remove reference to adjudication. Also 
removed ‘adjudication’ from Section 
8.3.1. Clarified that the safety 
committees will review the adverse 
events leading to amputation(s). 
The events referred to in this section do 
not require adjudication, but require 
ongoing monitoring. Safety committee 
will review the adverse events leading to 
amputation(s). 
Section 10.1.2: Study procedures: 
Randomization double-blind treatment 
period 
Clarified that fasting is not necessary 
before blood draw. 
Laboratory assessments performed at 
these time points need not be taken after 
fasting. 
Section 10.3.1: Temporary treatment 
discontinuation with investigational 
medicinal products 
Clarified that there is no defined limit for 
temporary discontinuation as the patient 
is expected to participate in the study for 
several years. 
Not limiting the duration for temporary 
treatment discontinuation is standard for 
cardiovascular outcomes studies and an 
intention to treat analysis. 
Section 10.4.1.3: Adverse event of special 
interest 
Clarified the definition of overdose. 
Defined to provide more clarity. 
Section 10.4.1.2: Serious Adverse Event 
Section 10.4.1.3: Adverse event of special 
interest 
Section 10.5: Obligation of the sponsor 
Section 11.4.3.3: Analysis of adverse 
events of special interest 
Clarified that the AESI criteria for ALT 
increase is defined as ALT ≥3 ULN (if 
baseline ALT < ULN) or ALT ≥2 times 
the baseline value (if baseline 
ALT ≥ ULN). Further clarified potential 
difference of AESI ALT elevation vs. SAE 
ALT elevation which may include 
assessment of bilirubin or degree of ALT 
elevation in asymptomatic patients. 
Clarified to maintain consistency 
throughout the document and across the 
Sotagliflozin program. 
Clinical Trial Summary: Inclusion criteria 
I 06 
Section 7.1.1: At the Screening Visit, I 06 
Clarified that a legally acceptable 
representative too can sign the informed 
consent. 
Added to address comments and 
questions from Ethic committee and 
Health Authorities.  
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Page 10 
Section # 
and Name 
Description of Change 
Brief Rationale 
Section 1.2 Study flow Chart 
Section 8.7.1: Treatment accountability and 
compliance 
Section 10.1.2.1: On-site Visits 2 (Day 1) 
Randomization 
Section 10.1.2.2: On-site Visits 3 (Week 1) 
and 4 (Week 2) 
Section 10.1.2.3: On-site Visits 5 (Week 4) 
Separated IMP accounting and 
compliance in the study flow chart and 
deleted the accountability of IMP at Visit 
3, 4, and 5.  
IMP accountability cannot be checked 
during the visits where IMP is not 
dispensed. 
Section 1.2: Study Flow Chart: footnote g 
Section 8.7.1: Treatment accountability and 
compliance 
Section 8.7.2: Return and/or destruction of 
treatments 
Section 10.1.2.3: On-site Visit 5 (Week 4) 
Clarified that in-use, used, and unused 
bottles should be brought back at Visit 6. 
Pharmacies unable to comply with 
planned IMP accountability checks at 
each visit as it is not operationally 
feasible. 
Clinical Trial Summary: Study Design 
Flowchart footnote f 
Section 6.1.2: Study Design, Randomized 
double-blind treatment period 
Section 10.1.2: Study procedures, 
Randomized double-blind treatment period 
Clarified that Screening and 
Randomization visits can be conducted 
on the same day. 
There is maximum 14 days between 
Screening and Randomization, and 
Randomization should occur prior to 
discharge or within 3 days after 
discharge, hence both visits can be on 
the same day. 
Section 1.1: Graphical study design: 
footnote b  
Section 7.1.1: Inclusion criteria: At the 
Screening Visit: I 02 
Patient admitted to the hospital or had 
unplannedurgent HF visit to ED, Heart 
Failure Unit, or infusion center for WHF 
associated with intravascular volume 
overload (the Index Event), as 
determined by Investigator (based on 
appropriate supportive documentation). 
Typographical error 
Throughout the document 
Minor editorial, typographical error 
corrections, and document formatting 
revisions have been made throughout 
the document. 
Minor changes, therefore have not been 
summarized 
Abbreviations: ACE-I = angiotensin-converting enzyme inhibitor; AE = adverse event; AESI = adverse event of special interest; ALT = alanine 
transaminase; ARB = angiotensin receptor blocker; BNP = b type natriuretic peptide; CV = cardiovascular; DKA = diabetic ketoacidosis; 
ECG = electrocardiogram; eCRF = electronic case report form; ED = emergency department; eGFR = glomerular filtration rate; FDA = Food and 
Drug Administration; HbA1c = glycated hemoglobin; HF = heart failure; IABP = intra-aortic balloon pump; IB = investigator’s brochure; 
IMP = investigational medicinal product; IV = intravenous; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVAD = left ventricular assist 
device; LVEF = left ventricle ejection fraction; NT-proBNP = N-terminal B-type natriuretic peptide; PRO = patient reported outcome; RAAS = renin-
angiotensin-aldosterone system; SAP = statistical analysis plan; T1D = type 1 diabetes mellitus; T2D = type 2 diabetes mellitus; ULN = upper limit of 
normal; WHF = worsening heart failure. 
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Page 11 
CLINICAL TRIAL SUMMARY 
COMPOUND: sotagliflozin/SAR439954 
STUDY No.: EFC15156  
STUDY NAME: SOLOIST-WHF Trial 
TITLE 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, 
Multicenter Study to Evaluate the Effects of SOtagLiflozin on Clinical 
Outcomes in HemodynamIcally STable Patients with Type 2 
Diabetes POST Worsening Heart Failure 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
3 
STUDY OBJECTIVES 
 
Primary objectives: 
• 
To demonstrate that sotagliflozin reduces cardiovascular (CV) 
mortality and morbidity (composite of CV death or 
hospitalization for heart failure [HHF]) compared to placebo in 
hemodynamically stable patients with type 2 diabetes (T2D) 
and heart failure (HF) with a left ventricular ejection fraction 
(LVEF) <50%, after admission for worsening heart failure 
(WHF). 
• 
To demonstrate that sotagliflozin reduces CV mortality and 
morbidity (composite of CV death or HHF) compared to 
placebo in hemodynamically stable patients with T2D and 
heart failure, irrespective of LVEF, after admission for WHF 
(total patient population). 
Secondary objectives: 
• 
To demonstrate that, when compared to placebo, in the total 
patient population, sotagliflozin reduces the total number (ie, 
including recurrent events) of the following clinical events:  
- 
Cardiovascular death, HHF, or urgent HF visit (see 
Appendix B) 
• 
To demonstrate that, when compared to placebo, sotagliflozin 
reduces:  
- 
Cardiovascular death in patients with LVEF <50% 
- 
All-cause mortality in patients with LVEF <50% 
- 
The composite of positively adjudicated sustained 
≥50% decrease in estimated glomerular filtration 
rate (eGFR) from Baseline (for ≥30 days), chronic 
dialysis, renal transplant or positively adjudicated 
sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days) 
in the total patient population 
- 
Cardiovascular death in the total patient population 
- 
All-cause mortality in the total patient population 
• 
To demonstrate the safety and tolerability of sotagliflozin in the 
total patient population  
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Other: 
• 
To compare sotagliflozin versus placebo on the occurrence of 
the following events in the total patient population: 
- 
Hospitalization for heart failure or urgent HF visit 
(see Appendix B) within 30 days of Randomization 
- 
At least 50% decrease in eGFR from Baseline (for 
≥30 days)  
- 
Myocardial infarction (MI; fatal and nonfatal)  
- 
Stroke (fatal and nonfatal) 
• 
To compare sotagliflozin versus placebo with respect to the 
proportion of patients with ≥1 new onset of atrial fibrillation, 
atrial flutter, or ventricular arrhythmia from Randomization in 
the total patient population 
• 
To demonstrate that sotagliflozin reduces CV mortality and 
morbidity (composite of CV death or HHF) compared to 
placebo in hemodynamically stable patients with T2D and HF 
with LVEF <40%, after admission for WHF 
• 
To demonstrate that sotagliflozin reduces CV mortality and 
morbidity (composite of CV death or HHF) compared to 
placebo in hemodynamically stable patients with T2D and HF 
with LVEF ≥40% to <50%, after admission for WHF 
• 
To demonstrate that sotagliflozin reduces CV mortality and 
morbidity (composite of CV death or HHF) compared to 
placebo in hemodynamically stable patients with T2D and HF 
with LVEF ≥50% after admission for WHF 
• 
To demonstrate that, when compared to placebo, sotagliflozin 
reduces all-cause mortality in patients with LVEF <40% 
• 
To compare sotagliflozin versus placebo in the total patient 
population with respect to changes from Baseline in the 
following endpoints: 
- 
Hemoglobin A1c 
- 
Body weight 
• 
To compare sotagliflozin versus placebo with respect to 
changes in Kansas City Cardiomyopathy Questionnaire-12 
(KCCQ-12) scores from Baseline in the total patient 
population 
• 
To compare sotagliflozin versus placebo with respect to 
changes in N-terminal B-type natriuretic peptide (NT-proBNP) 
from Baseline in the total patient population  
• 
To compare sotagliflozin versus placebo with respect to 
changes in loop diuretics from Baseline in the total patient 
population  
• 
To compare sotagliflozin versus placebo for changes in 
hemoconcentration from Baseline in the total patient 
population  
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• 
To compare sotagliflozin versus placebo for changes in 
hemoconcentration from Baseline in patients with LVEF <40% 
• 
To compare sotagliflozin versus placebo on the time to first 
occurrence of either of the  following clinical events in 
subgroups of patients who started first IMP dose prior vs. after 
hospital discharge (or urgent care facility where appropriate): 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
STUDY DESIGN 
This study is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study in about 
4000 hemodynamically stable patients with T2D who have been 
admitted to the hospital, a HF unit, infusion center, or Emergency 
Department (ED) for WHF with intravascular volume overload. The 
study will consist of 3 periods: 
• 
A Screening period (up to 14 days)  
• 
A Randomized, double-blind treatment period that will include 
an initial up-titration period  
• 
A Post-treatment period of 14 days (±4 days).  
The Screening and Randomization visits may be conducted on the same 
day. Patients who meet all eligibility criteria will be randomized 1:1 to 
sotagliflozin or placebo at the Randomization Visit (Visit 2 [Day 1]) that 
will take place prior to hospital discharge or within 3 days after discharge 
(from hospital, HF unit, infusion center, or ED). Randomization will be 
stratified by LVEF (LVEF <50% and LVEF ≥50%) and region (North 
America, Latin America, Western Europe, Eastern Europe, and rest of 
the world). The number of patients with LVEF ≥50% will be limited to 
approximately 1100, to ensure sufficient number of patients (ie, 
approximately 2900) with LVEF <50%. 
The double-blind study treatment will be initiated at Visit 2 (Day 1) 
after the patient has been randomized (ie, after a patient is 
hemodynamically stable and ready to transition from intravenous [IV] 
to oral diuretic therapy). Patients will receive sotagliflozin 200 mg or 
placebo at Visit 2 and will continue this regimen once daily (qd) until 
the next visit. 
Patients will return a week later at Visit 3 (Day 8). Clinical safety and 
tolerability (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]) will be 
assessed and blood (including serum creatinine) and urine 
laboratory samples will be collected. Patients will continue to receive 
sotagliflozin 200 mg or matching placebo qd until the next visit.  
Patients will return a week later at Visit 4 (Day 15). Clinical safety and 
tolerability (including vital signs and collection of AEs, including EOSIs, 
AESIs, and SAEs) will be assessed and laboratory results from the 
prior week (including serum creatinine) will be reviewed, and new 
laboratory samples (blood and urine) will be collected. 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 volume depletion, symptomatic hypotension (eg, 
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dizziness, lightheadedness), or other AEs intolerable to the patient 
such as severe polyuria or nocturia, the dose will be up-titrated to 
sotagliflozin 400 mg or matching placebo qd until the next visit. 
The patient will then return for Visits at Month 1 (Day 29), Month 4, 
and every 4 months thereafter until the end of the study.  
If the patient does not meet up-titration criteria for safety reasons 
(eg, hypotension), the Investigator will have the option of either 
continuing IMP at the dose of 200 mg or placebo, with the optional 
adjustment of concomitant medications, or discontinuing IMP 
temporarily. If the dose is not up-titrated for safety reasons, the 
Investigator should make all attempts to up-titrate the dose at 1 of 
the next 3 subsequent visits: Visit 5 (Month 1), Visit 6 (Month 4), or 
Visit 7 (Month 8). In patients who cannot reach the dose of 400 mg 
or matching placebo during the first 8 months after Randomization 
(Visit 7), the dose of 200 mg or matching placebo will be used 
throughout the study. If at any time during the study, the dose of 
400 mg or placebo is not well-tolerated, the dose can be 
down-titrated (to 200 mg or matching placebo), 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. 
Sotagliflozin/metabolite levels may be analyzed via routine blood 
samples collected throughout the study. 
Throughout the course of the study, if the double-blind treatment is 
down-titrated or temporarily discontinued, every effort should be 
made to resume the higher dose of double-blind treatment as early 
as possible (unless there are safety concerns) so that patients are 
kept on the maximal tolerated study dose of double-blind treatment 
for as long as possible throughout the double-blind period of the trial. 
This is an event-driven study. The study will end when 
approximately 947 primary events have been positively adjudicated (ie, 
number of patients with at least 1 positively adjudicated primary event) 
in patients with LVEF <50%, AND approximately 1341 primary events 
have been positively adjudicated (ie, number of patients with at least 1 
positively adjudicated primary event) in the total patient population. 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. 
Patients will continue taking IMP after a CV or renal endpoint occurs 
unless the criteria for permanent treatment discontinuation have 
otherwise been met. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
At the Screening Visit 
The Screening Visit should be no more than 14 days prior to 
Randomization.  
Please note: sites that plan to enroll patients who have not been 
hospitalized (ie, admitted for at least 24 hours) will need to be 
qualified by the Sponsor at the pre-site visit or a site visit to 
ensure the existence of appropriate facilities. 
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I 01. 
Either:  
A) Diagnosis of T2D, based on appropriate supportive 
documentation for patients with a diagnosis of T2D prior to 
the Index Event  
OR  
B) For patients diagnosed with T2D at the time of the Index 
Event, laboratory evidence is required as follows: 
• 
Fasting plasma glucose ≥126 mg/dL  
OR  
• 
Random plasma glucose ≥200 mg/dL OR HbA1c ≥6.5% 
I 02. 
Patient admitted to the hospital or had urgent HF visit to ED, 
HF Unit, or infusion center for WHF with intravascular 
volume overload (the Index Event), as determined by 
Investigator (based on appropriate supportive 
documentation) and defined by: 
• 
Presence of ≥2 of the following clinical signs and symptoms of 
congestion: 
- 
Dyspnea 
- 
Jugular venous distention 
- 
Pitting edema in lower extremities (>1+) 
- 
Rales heard on auscultation 
- 
Radiographic pulmonary congestion 
AND  
• 
Patient received treatment with IV loop diuretics  
I 03. 
Patient had a diagnosis of HF ≥3 months prior to Screening 
(based on appropriate supportive documentation)  
I 04. 
Prior chronic treatment (or prescription) with a loop diuretic 
(eg, furosemide, torsemide, bumetanide) for ≥30 days prior 
to the Index Event 
I 05. 
Patients with LVEF <40% should be on beta-blockers and 
RAAS inhibitors as per local guidelines unless 
contraindicated 
I 06. 
Patient or a legally acceptable representative has signed 
written informed consent to participate in the study in 
accordance with local regulations  
At the Randomization Visit 
Prior to hospital discharge if applicable, or within 3 days after 
discharge from hospital, ED, HF unit, or infusion center 
I 07. 
Patient is hemodynamically stable, defined as:  
• 
Systolic blood pressure ≥100 mmHg, AND  
• 
No requirement for IV inotropic therapy or IV vasodilators 
(except for nitrates) and no treatment with IV inotropic or IV 
vasodilators within 2 days prior to Randomization AND 
• 
No requirement for mechanical ventilation or oxygen therapy 
in the last 24 hours 
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I 08. 
Transitioning from IV to oral diuretics defined as:  
• 
Intravenous diuretic has been discontinued, AND 
• 
Chronic oral loop diuretic has been prescribed and/or 
administered 
I 09. 
At least 1 of the following laboratory values between 
admission for the Index Event and Randomization (based on 
local laboratory or central laboratory):  
• 
B-type natriuretic peptide (BNP) ≥150 pg/mL (≥450 pg/mL for 
patients with atrial fibrillation) 
OR  
• 
N-terminal B-type natriuretic peptide ≥600 pg/mL 
(≥1800 pg/mL for patients with atrial fibrillation) 
Note: The presence or absence of atrial fibrillation in order to 
determine the appropriate cut-off for a given BNP/NT-proBNP 
sample should be evaluated using the latest available 
electrocardiogram (ECG; or telemetry data) performed prior to 
that BNP/NT-proBNP sample. 
Exclusion criteria: 
E 01. 
Age <18 years (or legal age for the country of 
participation) or >85 years at the Screening Visit 
E 02. 
Index Event (admission for worsening HF associated 
with intravascular volume overload – see I 02) primarily 
triggered by pulmonary embolism, cerebrovascular 
accident, or acute myocardial infarction (AMI) 
Note: Troponin elevations are frequently seen in patients with 
WHF and therefore are not sufficient for a diagnosis of AMI. In 
order to exclude patient due to AMI, concomitant objective 
evidence of AMI from ECG, and/or cardiac imaging and/or 
coronary angiography should be available. 
E 03. 
Index Event (admission for WHF – see I 02) for WHF 
not caused primarily by intravascular volume overload. 
For example, Index Event triggered by significant 
arrhythmia (eg, sustained ventricular tachycardia, or 
atrial fibrillation/flutter with sustained ventricular 
response >130 beats per minute, or bradycardia with 
sustained ventricular arrhythmia <45 beats per minute), 
infection severe anemia, or exacerbation of chronic 
obstructive pulmonary disease (COPD) 
E 04. 
Hospitalization for index event >2 weeks 
E 05. 
Acute coronary syndromes within 3 months prior to 
Randomization 
E 06. 
Ejection fraction not assessed by the time of 
Randomization (ie, no LVEF assessment performed 
following the Index Event and no LVEF measurement 
available within 12 months prior to Screening via 
imaging modality (such as echocardiogram, Multiple 
Gated Acquisition (MUGA) scan, Magnetic Resonance 
Imaging (MRI), positron emission tomography (PET), 
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single-photo emission computed tomography (SPECT), 
left ventricular (LV) angiography) 
E 07. 
End-stage HF defined as requiring left ventricular assist 
devices (LVAD), intra-aortic balloon pump (IABP), or 
any type of mechanical support at the time of 
Randomization. 
E 08. 
Cardiac surgery (coronary artery bypass graft), 
percutaneous coronary intervention (PCI), implantation 
of cardiac device (including biventricular pacemaker), or 
cardiac mechanical support implantation within 1 month 
prior to Randomization or planned during the study 
E 09. 
Hemodynamically significant uncorrected primary 
cardiac valvular disease (please note that secondary 
mitral regurgitation or tricuspid regurgitation due to 
dilated cardiomyopathy is not excluded) 
E 10. 
Significant pulmonary disease contributing substantially 
to the patients’ dyspnea such as forced expiratory 
volume in 1 second (FEV1) <1 liter or need for chronic 
steroid therapy, or any kind of primary right heart failure 
such as primary pulmonary hypertension or recurrent 
pulmonary embolism 
E 11. 
Heart failure caused by postpartum cardiomyopathy 
diagnosed within the past 6 months 
E 12. 
Heart failure from uncorrected thyroid disease, active 
myocarditis, known amyloid cardiomyopathy 
E 13. 
Obstructive hypertrophic cardiomyopathy 
E 14. 
History of stroke within 3 months prior to Randomization 
E 15. 
History of dialysis within 1 year prior to Randomization  
E 16. 
History of solid organ transplant or inclusion on a 
transplant list (if a heart transplant, defined as status 1 
transplant) 
E 17. 
Use of any investigational drug(s) for 5 half-lives prior to 
Screening 
E 18. 
Hypersensitivity to sotagliflozin active substance or to 
any of the excipients including those in the placebo  
E 19. 
Patients who are planning to start a sodium-glucose 
cotransporter 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 20. 
Any SGLT2 inhibitor <1 month prior to the Screening 
Visit, or between Screening and Randomization  
E 21. 
Patients with respiratory, hepatic, neurological, 
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) or patients with short life expectancy (defined 
as ≤1 year) that, according to the Investigator, will 
preclude their safe participation in this study, and will 
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make implementation of the protocol or interpretation of 
the study results difficult  
E 22. 
Presence of any other conditions (eg, geographic, 
social) actual or anticipated, that the Investigator feels 
would restrict or limit the patient’s participation or 
compliance with all HF therapy, including study 
medication, for the duration of the study  
E 23. 
Patient is the Investigator or any Subinvestigator, 
research assistant, pharmacist, study coordinator, other 
staff or relative thereof directly involved in the conduct of 
the protocol 
E 24. 
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 25. 
Severe kidney disease as defined by eGFR 
<30 mL/min/1.73 m² at the Screening Visit by the 4 
variable Modification of Diet in Renal Disease (MDRD) 
equation 
E 26. 
Any infection requiring intravenous antibiotics and/or with 
pyrexia (defined as temperature >38 °C [100.4 °F]) at 
time of Randomization 
E 27. 
History of diabetic ketoacidosis or nonketotic 
hyperosmolar coma within 3 months prior to the 
Screening Visit 
E 28. 
Lower extremity diabetic complications (such as skin 
ulcers, infection, osteomyelitis and gangrene) identified 
during the Screening period, and still requiring treatment 
at Randomization 
E 29. 
Pregnant (demonstrated by serum pregnancy test at 
Screening) or breastfeeding women 
Women of childbearing potential (WOCBP) as defined in 
Appendix A, 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. The 
Investigators may perform additional tests at their 
discretion or at frequency specified by local regulations 
E 30. 
Digoxin level >1.2 ng/mL (in a patient treated with digoxin, 
and based on last local or central laboratory value 
available prior to Randomization)* 
E 31. 
Laboratory findings (based on Screening value or last 
available value before Randomization, whichever is later)**  
• 
Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 times the upper limit of normal 
(ULN)  
• 
Total bilirubin >1.7 times the ULN (except in case of Gilbert’s 
syndrome)  
• 
Serum potassium >5.5 mEq/L 
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Note: A patient should not be randomized more than once. 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 completion of enrollment.  
*If a patient meets exclusion criteria E 30 a one-time repeat testing is 
allowed for digoxin level without the need to rescreen the patient.  
**If a patient meets exclusion criterion E 31:  
• 
A one-time repeat testing is allowed for ALT or AST without 
the need to rescreen the patient 
• 
Repeat testing for serum potassium is allowed for 3 days after 
Screening without the need to rescreen the patient 
Total expected number of patients 
Approximately 4000 
Expected number of sites 
Approximately 800 sites 
STUDY TREATMENT(s) 
 
Investigational medicinal product(s) 
Sotagliflozin and placebo 
Formulation: 
Tablet 
Route(s) of administration: 
Oral 
Dose regimen: 
Sotagliflozin:  
During the first 2 weeks: one (1) sotagliflozin 200-mg tablet qd 
before the first meal of the day 
At Week 3 and beyond: sotagliflozin 400 mg administered as two (2) 
200-mg tablets qd before the first meal of the day, as tolerated. 
Placebo: 
During the first 2 weeks: one (1) placebo tablet qd (identical to 
sotagliflozin 200-mg tablets in appearance) before the first meal of 
the day 
At Week 3 and beyond: placebo administered as two (2) 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. 
ENDPOINTS 
 
Primary endpoints: 
• 
Time to first occurrence of either of the following clinical events 
in patients with LVEF <50%: 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
• 
Time to first occurrence of either of the following clinical events 
in the total patient population:  
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
Secondary endpoints: 
• 
Total number (ie, including recurrent events) of the following 
clinical events in the total patient population: 
- 
Cardiovascular death  
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- 
Hospitalization for heart failure 
- 
Urgent HF visit  
• 
Time to CV death in patients with LVEF <50% 
• 
Time to all-cause mortality in patients with LVEF <50% 
• 
Time to first occurrence of the composite of positively 
adjudicated sustained ≥50% decrease in eGFR from Baseline 
(for ≥30 days), chronic dialysis, renal transplant, or positively 
adjudicated sustained eGFR <15 mL/min/1.73 m2 (for ≥30 
days) in the total patient population 
• 
Time to CV death in the total patient population 
• 
Time to all-cause mortality in the total patient population 
Other endpoints: 
The following endpoints are assessed in the total patient population:  
• 
Proportion of patients with HHF or urgent HF visit (see 
Appendix B) within 30 days of Randomization 
• 
Changes in KCCQ-12 scores from Baseline to Week 2, Month 
1, Month 4, Month 8, Month 12, then annually 
• 
Time to ≥50% decrease in eGFR from Baseline 
• 
Proportion of patients with ≥1 new onset of atrial fibrillation, 
atrial flutter, or ventricular arrhythmia from Randomization 
• 
Time to first MI (fatal and nonfatal)  
• 
Time to first stroke (fatal and nonfatal) 
• 
Changes from Baseline to Month 1 and Month 4 for 
NT-proBNP 
• 
Changes from baseline in loop diuretics at day 180 and/or end 
of treatment visit 
• 
Changes in hemoconcentration from Baseline at Week 2, 
Month 1, Month 4, Month 12, and EOT 
• 
Changes from Baseline to Month 4, Month 12, and 
Month 24 in: 
- 
Hemoglobin A1c  
- 
Body weight 
• 
Time to first occurrence of either of the following clinical events 
in subgroups of patients who started first IMP dose prior vs. 
after hospital discharge (or urgent care facility where 
appropriate):  
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
The following endpoints are assessed in subgroups of patients 
defined by LVEF:  
• 
Time to first occurrence of either of the following clinical events 
in patients with LVEF <40%: 
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- 
Cardiovascular death 
- 
Hospitalization for heart failure 
• 
Time to first occurrence of either of the following clinical events 
in patients with LVEF ≥40% to <50%: 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
• 
Time to first occurrence of either of the following clinical events 
in patients with LVEF≥50%: 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
• 
Time to all-cause mortality in patients with LVEF <40% 
• 
Changes in hemoconcentration from Baseline at Week 2, 
Month 1, Month 4, Month 12, and EOT in patients with 
LVEF <40% 
• 
Safety endpoints: 
• 
All AEs, including AEs leading to premature treatment 
discontinuation, AESIs, EOSIs, and SAEs 
• 
Severe hypoglycemia (also an EOSI) 
• 
Clinical laboratory results and vital signs (including heart rate, 
blood pressure)  
ASSESSMENT SCHEDULE 
Visits scheduled during the double-blind treatment 
period: 
Clinic/on-site visits: Weeks 1, 2, 4, Month 4, then every 4 months 
until the end of the study. 
STATISTICAL CONSIDERATIONS 
 
The study will recruit approximately 4000 patients over an estimated 
recruitment period of 29 months with approximately 3 months of 
follow-up after the last patient is randomized. To ensure sufficient 
number of patients with LVEF <50%, the number of patients with 
LVEF ≥50% will be limited to approximately 1100. 
It is estimated to accrue approximately 947 primary events (first 
occurrence of CV death or HHF positively adjudicated by a Clinical 
Endpoint Committee [CEC]) in patients with LVEF <50% and 
approximately 1341 positively adjudicated primary events (first 
occurrence of CV death or HHF, positively adjudicated by CEC) in 
the total patient population, based on the following trial design 
characteristics and assumptions: 
• 
A recruitment period of approximately 29 months 
• 
Approximately 3 months of follow-up after the last patient is 
randomized 
• 
29.2%, 39.7%, and 44.5% event rate by Month 6, Month 12, 
and Month 24, respectively, in the placebo group (by 
assuming yearly hazard rate at Months 1, 2, 3, 4, 5, 6, 12, 24, 
and 36 be 1.06, 0.87, 0.74, 0.62, 0.49, 0.36, 0.32, 0.08, and 
0.05, respectively) 
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• 
hazard ratio (HR) = 0.81 for sotagliflozin versus placebo for 
patients with LVEF <50% and for patients with LVEF ≥50%  
• 
2% annual censoring rate 
This will provide:  
• 
90% power (with α=0.05, 2-sided) to demonstrate superiority 
for the primary endpoint (first occurrence of CV death or HHF) 
comparing sotagliflozin versus placebo in patients with LVEF 
<50% 
• 
More than 90% power (with α=0.05, 2-sided) to demonstrate 
superiority for the primary CV endpoint (first occurrence of CV 
death or HHF) comparing sotagliflozin versus placebo in the 
total patient population.  
Analysis population: 
The analysis population for primary and secondary efficacy 
endpoints will be the intent-to-treat (ITT) population that includes all 
randomized patients irrespective of compliance with the study 
protocol and procedures. Efficacy analyses will be conducted 
according to the treatment assigned at the Randomization Visit 
irrespective of the treatment received.  
The safety analysis will be conducted on the safety population that 
includes all randomized patients who have received ≥1 dose of 
double-blind treatment. Safety analyses according to the treatment 
that the patients actually received. 
Primary analysis: 
The time to the first occurrence of CV death or HHF in patients with 
LVEF <50% will be analyzed by using stratified log-rank test with 
region (North America, Latin America, Western Europe, Eastern 
Europe, and rest of the world) as stratification factor. Stratified Cox 
proportional hazards model with region as stratification factor and 
treatment (sotagliflozin, placebo) as fixed effect factor will be used to 
provide the HR estimation between sotagliflozin and placebo along 
with its associated 2-sided 95% confidence interval (CI).  
The time to the first occurrence of CV death or HHF in the total 
patient population will be analyzed by using stratified log-rank test 
with LVEF (<50%, ≥50%) and region (North America, Latin America, 
Western Europe, Eastern Europe, and rest of the world) as 
stratification factors. Stratified Cox proportional hazards model with 
LVEF (<50%, ≥50%) and region as stratification factors and 
treatment (sotagliflozin, placebo) as fixed effect factor will be used to 
provide the HR estimation between sotagliflozin and placebo along 
with its associated 2-sided 95% CI. 
Kaplan-Meier curves of the cumulative incidence rate will also be 
provided by treatment groups. 
All randomized patients (irrespective of whether they experienced 
efficacy event[s] or whether they permanently early discontinued 
double-blind treatment) will be followed from Randomization until 
their Follow-up Visit (or Study Closeout Visit, for patients who 
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prematurely permanently discontinued from IMP) or death, 
whichever comes first. The analyses of CV efficacy endpoints will be 
based on the positively adjudicated CV endpoint events occurring 
from Randomization to the patient’s end of study date, including 
events occurring after patients have discontinued study treatment, 
unless otherwise specified. 
Analysis of secondary endpoints: 
Extended Cox proportional hazards model for recurrent events with 
treatment (sotagliflozin, placebo), LVEF (<50%, ≥50%) and region 
(North America, Latin America, Western Europe, Eastern Europe, 
and rest of the world) as factors will be used to analyze the 
secondary endpoint of total number (ie, including recurrent events) of 
CV deaths, HHF or urgent HF visit in the total patient population. 
For the following secondary endpoints:  
• 
Time to CV death in patients with LVEF <50%  
• 
Time to all-cause mortality in patients with LVEF <50%  
• 
Time to first occurrence of the composite of positively 
adjudicated sustained ≥50% decrease in eGFR from Baseline 
(for ≥30 days), chronic dialysis, renal transplant or positively 
adjudicated sustained eGFR <15 mL/min/1.73 m2 (for ≥30 
days) in the total patient population 
• 
Time to CV death in the total patient population  
• 
Time to all-cause mortality in the total patient population 
Stratified log-rank test with LVEF (<50%, ≥50%) and region (North 
America, Latin America, Western Europe, Eastern Europe, and rest 
of the world) as stratification factor will be used for the analysis. 
Stratified Cox proportional hazards model with LVEF (<50%, ≥50%) 
and region as stratification factors and with treatment (sotagliflozin, 
placebo) as fixed effect factor will be used to provide the HR 
estimation between sotagliflozin and placebo along with its 
associated 2-sided 95% CI. The LVEF factor will not be included in 
the statistical model as stratification factor if the endpoint is defined 
in patients with LVEF <50%. 
For secondary endpoint analyses, all randomized patients 
(irrespective of whether they experienced efficacy event[s] or 
whether they permanently early discontinued double-blind treatment) 
will be followed up until death or the end of study. The secondary 
endpoint events occurring from Randomization to the patient’s study 
end date, including the events that occurred after treatment 
discontinuation, will all be included in the analysis, unless otherwise 
specified.  
Multiplicity adjustment: 
The graphical approach (1) will be used to strongly control the 
family-wise type 1 error rate at 0.05 level. 
 
An initial graph as below will be used to control the type-1 error.  
 
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Note: =0.001.  
In the graph, there are two primary hypotheses (H1 and H2) and six 
secondary hypotheses (H3, H4, H5, H6, H7, H8) defined as below:   
H1: Time to first occurrence of CV death or HHF in patients with 
LVEF <50% 
H2: Time to first occurrence of CV death or HHF in the total 
patient population 
H3: Total number (ie, including recurrent events) of CV death, 
HHF, or urgent HF visit in total patient population 
H4: Time to CV death in patients with LVEF <50%  
H5: Time to all-cause mortality in patients with LVEF <50% 
H6: Time to first occurrence of the composite of positively 
adjudicated sustained ≥50% decrease in eGFR from 
Baseline (for ≥30 days), chronic dialysis, renal transplant, 
or positively adjudicated sustained eGFR <15 mL/min/1.73 
m2 (for ≥30 days) in total patient population 
H7: Time to CV death in total patient population  
H8: Time to all-cause mortality in total patient population  
All tests will be two-sided. Significance levels 
 
(
) are initially 
defined such that they sum up to 
. 
The details of this method will be provided in the Section 11.4.2.4 
and SAP (statistical analysis plan). 
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Analysis of other endpoints: 
The analysis of other time to event endpoints will be performed using 
the same stratified Cox proportional hazards model as for the 
second primary endpoint, with LVEF (<50%, ≥50%) and region 
(North America, Latin America, Western Europe, Eastern Europe, 
and rest of the world) as stratification factors and treatment 
(sotagliflozin, placebo) as fixed effect factor. The LVEF factor will not 
be included in the statistical model as stratification factor if the 
endpoint is defined in subgroup of patients defined by LVEF (eg, 
LVEF<40%). Analysis of other endpoints will be descriptive with no 
statistical testing. Summary statistics at scheduled visits using 
observed data will be provided by each treatment group. Graphical 
presentations will also be used to illustrate trends over time if 
applicable. 
Analyses of Safety Data: 
All safety summaries will be descriptive; no statistical hypothesis 
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 ≥1 dose of double-blind treatment, regardless of the 
amount of treatment administered. 
DURATION OF STUDY PERIOD (per 
patient)  
The estimated study duration for a given patient will be 
approximately 3 to 32 months, assuming approximately 29 months of 
recruitment, and approximately 3 months of follow-up after the last 
patient is randomized. 
All randomized patients (irrespective of whether they experienced 
efficacy event[s] or whether they permanently early discontinued 
double-blind treatment) 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. 
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 Prior diagnosis of HF ≥3 months prior to Screening (based on appropriate supportive documentation). 
b Index Event: Patient admitted to the hospital or had urgent HF visit to ED, Heart Failure Unit, or infusion center for WHF associated with intravascular volume overload as determined by Investigator (based on 
appropriate supportive documentation) and further defined in I 02. 
c The Randomization Day is always Day 1. 
d For titration details, please refer to Section 8.1.1 
e This is an event-driven study. 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. 
f 
A FU Visit will take place 14 days (±4 days) after the Study Closeout Visit for patients who do not prematurely permanently discontinue IMP. 
ED = Emergency Department; FU = Follow-up; HF = heart failure; IMP = investigational medicinal product; T2D = type 2 diabetes; R = Randomization; V = visit; WHF = worsening heart failure; Wk = Week. 
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e See Section 9.2.3.1 for details of full and abbreviated physical examinations. 
f 
Screening and Randomization visits may be conducted on the same day.  
g The in-use, used and unused bottles should be brought back to the sites at Visit 6.  
h If an LVEF assessment has not been performed within the last 12 months prior to Screening (Visit 1), an echocardiogram should be obtained between Screening and Randomization (Visit 2). If ECG assessment 
was done as standard of care, the most recent ECG collected after the Index event, can be used to formally screen the patients.  
i 
All laboratory assessments including serum chemistry (sodium, potassium, chloride, carbondioxide, Blood urea nitrogen, creatinine, eGFR, glucose, alanine aminotransferase, aspartate aminotransferase, total 
bilirubin, alkaline phosphatase and total protein) and hematology completed at Screening (Visit 1) are to be performed at Site Local Laboratory. If sites are unable to perform laboratory tests locally, the tests can 
be done by central laboratory. At Randomization and at subsequent visits, laboratory assessments (with the exception of digoxin) are to be performed using central laboratory. At the Randomization Visit (Visit 2), 
laboratory samples will be collected prior to first dose of double-blind IMP. If the laboratory assessments were done as standard of care, the most recent results collected after the Index event may be used to 
formally screen the patients. However serum pregnancy testing must be collected at Screening. 
j 
Blood samples for BNP or NT-proBNP should be collected at screening via a local laboratory, if not collected earlier following the specific Index event. After Visit 1 blood samples for NT-proBNP will be collected 
via a central laboratory.   
k After Month 4 (Visit 6), HbA1c will be performed at Month 8 (Visit 7), Month 12 (Visit 8), Month 16 (Visit 9), Month 20 (Visit 10), and Month 24 (Visit 11). 
l 
Sotagliflozin/metabolite levels may be analyzed via routine blood samples collected throughout the study, eGFR will be measured at the follow-up visit after discontinuation of study treatment. 
m Serum pregnancy testing only at Screening (Visit 1); 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 at frequency specified by local regulations. For women of non-productive potential (Appendix A), FSH and/or estradiol levels should be tested in case the definition of 
postmenopausal or premenopausal can’t be satisfied, eg, no medical document of hysterectomy or cessation of menses without an alternative medical cause is <12 months. 
n At Visit 1 only, urinalysis will be performed by the local laboratory, for all subsequent visits urinalysis 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 urinalysis is positive for nitrite and leukocyte esterase or blood, reflexive testing will be performed (see Section 9.2.2.1). 
o In patients treated with digoxin at Screening, digoxin levels may be measured in either serum or plasma at Screening (Visit 1), Week 2 (Visit 4) and 2 to 4 weeks after an up-titration has been implemented (eg, at 
Week 4 if up-titration occurred at Week 2, or at an unscheduled visit, if up-titration occurred after Week 2). If no up-titration is implemented, there is no requirement for digoxin level assessment beyond Week 2. 
Throughout the study, additional digoxin level assessments are to be performed as per Investigators’ judgment. All digoxin levels will be performed at a Site Local Laboratory, if sites are unable to do the tests 
locally, the test should be done by central laboratory.  
r 
All AEs, including AESIs, EOSIs, SAEs, and severe hypoglycemia will be collected starting with signing informed consent. All AEs that occurred during treatment should be followed for ≥30 days following the last 
dose of IMP or until the event has resolved, the condition has stabilized, the etiology of the event is determined to be not related to IMP, or until death. 
AE adverse event; AESI adverse event of special interest; BNP b-type natriuretic peptide; BP blood pressure; CRT cardiac resynchronization therapy; DNA deoxyribonucleic acid; ECG electrocardiogram; 
ED Emergency Department; eGFR estimated glomerular filtration rate; EOSI events of special interest; EOT End-of-Treatment; FSH follicle-stimulating hormone; HbA1c hemoglobin A1c; HF heart failure; HHF 
hospitalization for heart failure; IC Infusion Center; IMP investigational medicinal product; IRT Interactive Response Technology; KCCQ-12 Kansas City Cardiomyopathy Questionnaire-12; LVEF left ventricular ejection 
fraction; M month; NT-proBNP N-terminal B-type natriuretic peptide; pEOT premature End-of-Teatment; SAE serious adverse event; WOCBP women of childbearing potential.  
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 01 ..............................................................................................1 
1 
FLOW CHARTS.............................................................................................................................26 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................26 
1.2 
STUDY FLOW CHART ..................................................................................................................27 
2 
TABLE OF CONTENTS ................................................................................................................30 
2.1 
LIST OF TABLES...........................................................................................................................36 
2.2 
LIST OF FIGURES.........................................................................................................................36 
3 
LIST OF ABBREVIATIONS ..........................................................................................................37 
4 
INTRODUCTION AND RATIONALE.............................................................................................40 
4.1 
BACKGROUND: DISEASE AND PRELIMINARY THERAPEUTIC OBSERVATIONS .................40 
4.2 
BACKGROUND: SOTAGLIFLOZIN...............................................................................................43 
4.3 
BENEFIT/RISK PROFILE ..............................................................................................................44 
4.4 
RATIONALE FOR CURRENT STUDY ..........................................................................................45 
4.4.1 
Rationale for selection of dose.......................................................................................................46 
4.4.2 
Rationale for study design and control groups ..............................................................................47 
5 
STUDY OBJECTIVES ...................................................................................................................49 
5.1 
PRIMARY.......................................................................................................................................49 
5.2 
SECONDARY ................................................................................................................................49 
5.3 
OTHER...........................................................................................................................................49 
6 
STUDY DESIGN ............................................................................................................................51 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................51 
6.1.1 
Screening period............................................................................................................................51 
6.1.2 
Randomized double-blind treatment period...................................................................................51 
6.1.3 
Post-treatment period.....................................................................................................................53 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................53 
6.2.1 
Duration of study participation for each patient .............................................................................53 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................54 
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6.3 
INTERIM ANALYSIS......................................................................................................................54 
6.4 
STUDY COMMITTEES..................................................................................................................54 
6.4.1 
Executive Committee .....................................................................................................................54 
6.4.2 
Steering Committee .......................................................................................................................54 
6.4.3 
Data Monitoring Committee ...........................................................................................................54 
6.4.4 
Adjudication Committee .................................................................................................................54 
6.4.5 
Safety events requiring ongoing monitoring ..................................................................................55 
7 
SELECTION OF PATIENTS..........................................................................................................56 
7.1 
INCLUSION CRITERIA..................................................................................................................56 
7.1.1 
At the Screening Visit.....................................................................................................................56 
7.1.2 
At the Randomization Visit.............................................................................................................57 
7.2 
EXCLUSION CRITERIA ................................................................................................................57 
7.2.1 
Exclusion criteria related to study methodology ............................................................................58 
7.2.2 
Exclusion criteria related to the current knowledge of sotagliflozin ...............................................59 
8 
STUDY TREATMENTS .................................................................................................................61 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................61 
8.1.1 
Dose up-titration and adjustments .................................................................................................61 
8.1.1.1 
Dose up-titration.............................................................................................................................61 
8.1.1.2 
Dose adjustments ..........................................................................................................................62 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................62 
8.3 
BLINDING PROCEDURES............................................................................................................62 
8.3.1 
Methods of blinding........................................................................................................................62 
8.3.2 
Randomization code breaking during the study.............................................................................63 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................63 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING .............................64 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................64 
8.7 
RESPONSIBILITIES ......................................................................................................................64 
8.7.1 
Treatment accountability and compliance......................................................................................65 
8.7.2 
Return and/or destruction of treatments ........................................................................................65 
8.8 
CONCOMITANT MEDICATION.....................................................................................................66 
8.8.1 
Management of glycemia and diabetes complications ..................................................................66 
8.8.2 
Management of blood pressure and renal function .......................................................................66 
8.8.3 
Management of heart failure..........................................................................................................67 
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8.8.4 
Prohibited medications...................................................................................................................67 
8.8.5 
Other medications..........................................................................................................................67 
8.9 
POST-STUDY TREATMENT.........................................................................................................68 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................69 
9.1 
EFFICACY ENDPOINTS ...............................................................................................................69 
9.1.1 
Primary efficacy endpoints.............................................................................................................69 
9.1.2 
Secondary efficacy endpoints........................................................................................................69 
9.1.2.1 
Estimated glomerular filtration rate and dialysis ............................................................................70 
9.1.3 
Other efficacy endpoints ................................................................................................................70 
9.1.3.1 
Hemoglobin A1c.............................................................................................................................71 
9.1.3.2 
Kansas City Cardiomyopathy Questionnaire-12............................................................................71 
9.1.3.3 
Concomitant medications by class.................................................................................................72 
9.2 
SAFETY ENDPOINTS ...................................................................................................................72 
9.2.1 
Adverse events ..............................................................................................................................72 
9.2.1.1 
Adverse events of special interest .................................................................................................73 
9.2.1.2 
Events of special interest ...............................................................................................................73 
9.2.2 
Laboratory safety variables............................................................................................................73 
9.2.2.1 
Urinalysis........................................................................................................................................74 
9.2.3 
Vital signs.......................................................................................................................................75 
9.2.3.1 
Physical examinations ...................................................................................................................75 
9.2.3.2 
Foot care ........................................................................................................................................75 
9.2.4 
Electrocardiogram variables ..........................................................................................................76 
9.3 
OTHER ENDPOINTS.....................................................................................................................76 
9.3.1 
Health economic variables.............................................................................................................76 
 
76 
 
76 
 
77 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................77 
10 
STUDY PROCEDURES ................................................................................................................79 
10.1 
VISIT SCHEDULE..........................................................................................................................79 
10.1.1 
Screening period............................................................................................................................79 
10.1.1.1 On site Visit 1 (Week -2) Screening Visit.......................................................................................80 
10.1.2 
Randomized double-blind treatment period...................................................................................81 
10.1.2.1 On-site Visit 2 (Day 1) Randomization...........................................................................................82 
10.1.2.2 On-site Visits 3 (Week 1) and 4 (Week 2)......................................................................................83 
10.1.2.3 On-site Visit 5 (Week 4).................................................................................................................83 
10.1.2.4 On-site Visit 6 (Month 4) ................................................................................................................84 
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10.1.2.5 On-site Visits 7 to 12 (Months 8, 12, 16, 20, 24, 28) .....................................................................85 
10.1.3 
Premature End-of Treatment .........................................................................................................86 
10.1.3.1 Premature End-of-Treatment Visit .................................................................................................86 
10.1.4 
Study Closeout...............................................................................................................................87 
10.1.4.1 Study Closeout Visit for patients who do not prematurely permanently discontinue 
investigational medicinal product...................................................................................................87 
10.1.4.2 Study Closeout Visit for patients who prematurely permanently discontinue investigational 
medicinal product...........................................................................................................................88 
10.1.5 
Follow-up........................................................................................................................................89 
10.1.5.1 Follow-Up Visit ...............................................................................................................................89 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................90 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................90 
10.3.1 
Temporary treatment discontinuation with investigational medicinal products..............................91 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................92 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................92 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................93 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................93 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................94 
10.4.1 
Definitions of adverse events.........................................................................................................94 
10.4.1.1 Adverse event ................................................................................................................................94 
10.4.1.2 Serious adverse event ...................................................................................................................94 
10.4.1.3 Adverse event of special interest...................................................................................................95 
10.4.1.4 Events of special interest ...............................................................................................................96 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................97 
10.4.3 
General guidelines for reporting adverse events ...........................................................................97 
10.4.4 
Instructions for reporting serious adverse events ..........................................................................98 
10.4.5 
Guidelines for reporting adverse events of special interest...........................................................99 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................99 
10.4.7 
Guidelines for reporting events of special interest.........................................................................99 
10.4.8 
Guidelines for reporting product complaints (investigational medicinal product) ........................100 
10.5 
OBLIGATIONS OF THE SPONSOR ...........................................................................................100 
10.6 
SAFETY INSTRUCTIONS ...........................................................................................................100 
10.6.1 
Severe hypoglycemia...................................................................................................................100 
10.7 
ADVERSE EVENTS MONITORING............................................................................................101 
11 
STATISTICAL CONSIDERATIONS............................................................................................102 
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11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................102 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................103 
11.3 
ANALYSIS POPULATIONS.........................................................................................................103 
11.3.1 
Efficacy populations .....................................................................................................................103 
11.3.1.1 Intent–to-treat /modified intent-to-treat population.......................................................................103 
11.3.2 
Safety population .........................................................................................................................103 
11.3.3 
Patient-reported outcome analysis populations...........................................................................104 
11.4 
STATISTICAL METHODS ...........................................................................................................104 
11.4.1 
Extent of study treatment exposure and compliance...................................................................104 
11.4.1.1 Extent of investigational medicinal product exposure..................................................................104 
11.4.1.2 Compliance ..................................................................................................................................105 
11.4.2 
Analyses of efficacy endpoints.....................................................................................................105 
11.4.2.1 Analysis of primary efficacy endpoints.........................................................................................105 
11.4.2.2 Analyses of secondary efficacy endpoints...................................................................................106 
11.4.2.3 Other endpoints............................................................................................................................106 
11.4.2.4 Multiplicity considerations ............................................................................................................106 
11.4.3 
Analyses of safety data................................................................................................................108 
11.4.3.1 Analysis of adverse events ..........................................................................................................109 
11.4.3.2 Analysis of severe hypoglycemia.................................................................................................111 
11.4.3.3 Analysis of adverse events of special interest .............................................................................111 
11.4.3.4 Analysis of events of special interest...........................................................................................111 
11.4.3.5 Analysis of laboratory variable.....................................................................................................111 
11.4.3.6 Analysis of vital sign variables .....................................................................................................112 
11.4.4 
Analyses of patient reported outcomes (health-related quality of life/health economics 
variables)......................................................................................................................................112 
11.5 
INTERIM ANALYSIS....................................................................................................................112 
12 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................................113 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................113 
12.2 
INFORMED CONSENT ...............................................................................................................113 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC).................................................................................................113 
13 
STUDY MONITORING.................................................................................................................115 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................115 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................115 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................115 
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13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST....................................................................................................................................116 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................116 
14 
ADDITIONAL REQUIREMENTS.................................................................................................117 
14.1 
CURRICULUM VITAE..................................................................................................................117 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................117 
14.3 
CONFIDENTIALITY .....................................................................................................................117 
14.4 
PROPERTY RIGHTS...................................................................................................................118 
14.5 
DATA PROTECTION...................................................................................................................118 
14.6 
INSURANCE COMPENSATION..................................................................................................119 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................119 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................119 
14.8.1 
By the Sponsor.............................................................................................................................119 
14.8.2 
By the Investigator .......................................................................................................................120 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................120 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................120 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................122 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................123 
17 
APPENDICES..............................................................................................................................128 
APPENDIX A 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION............................................................................................................................129 
APPENDIX B 
DEFINITION OF URGENT HEART FAILURE VISIT.........................................................132 
APPENDIX C KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE-12 ...........................................134 
APPENDIX D GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................136 
APPENDIX E 
GUIDANCE FOR THE FOLLOW-UP OF ACUTE WORSENING OF RENAL 
FUNCTION...................................................................................................................................140 
APPENDIX F DIABETIC KETOACIDOSIS ..............................................................................................141 
 
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2.1 
LIST OF TABLES 
Table 1 - Investigational medicinal products .................................................................................................61 
Table 2 - Chemistry parameters....................................................................................................................74 
 
2.2 
LIST OF FIGURES 
Figure 1 - Study LX4211.1-201-T2DM - Mean (+/- SE) Change from Baseline in 24-hour urinary glucose 
excretion by treatment on Days 1, 14, and 28 (Efficacy population).............................................................44 
 
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3 
LIST OF ABBREVIATIONS 
 
ACE-i: 
angiotensin-converting enzyme inhibitor 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AHA: 
American Heart Association 
ALT: 
alanine aminotransferase 
AMI: 
acute myocardial infarction 
ARB: 
angiotensin receptor blocker 
ARNI: 
angiotensin receptor/neprilysin inhibitor 
AST: 
aspartate aminotransferase 
BHB: 
beta-hydroxybutyrate 
bid: 
twice daily 
BNP: 
b-type natriuretic peptide 
BP: 
blood pressure 
CEC: 
Clinical Endpoint Committee 
CI: 
confidence interval 
COPD: 
chronic obstructive pulmonary disease 
CRT: 
cardiac resynchronization therapy 
CSR: 
clinical study report 
CV: 
cardiovascular 
CVD: 
cardiovascular disease 
DILI: 
drug-induced liver injury 
DKA: 
diabetic ketoacidosis 
DMC: 
Data Monitoring Committee 
DRF: 
discrepancy resolution form 
EC: 
Executive Committee 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
ED: 
emergency department 
eGFR: 
estimated glomerular filtration rate 
EOSI: 
event of special interest 
ESC: 
European Society of Cardiology 
FDA: 
Food and Drug Administration 
FEV1: 
forced expiratory volume in 1 second 
GCP: 
good clinical practice 
GI: 
gastrointestinal 
GLP-1: 
glucagon-like peptide-1 
GP: 
general practitioner 
HbA1c: 
hemoglobin A1c 
HF: 
heart failure 
HFmEF: 
heart failure with mid-range ejection fraction 
HFpEF: 
heart failure with preserved ejection fraction 
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HHF: 
hospitalization for heart failure 
HLGT: 
high-level grouped term 
HLT: 
high-level term 
HR: 
hazard ratio 
HRrEF: 
heart failure with reduced ejection fraction 
IABP: 
intra-aortic balloon pump 
IB: 
Investigator’s Brochure 
ICD: 
implantable cardioverter-defibrillator 
ICF: 
informed consent form 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
IV: 
intravenous 
KCCQ-12: 
Kansas City Cardiomyopathy Questionnaire-12 
LV: 
left ventricular 
LVAD: 
left ventricular assist device 
LVEF: 
left ventricular ejection fraction 
MDRD: 
modification of diet in renal disease 
MI: 
myocardial infarction 
MRA: 
mineralocorticoid receptor antagonist 
MRI: 
Magnetic Resonance Imaging 
MUGA: 
MUltiple Gated Acquisition 
NHE3: 
sodium-hydrogen exchanger 3 
NT-proBNP: 
N-terminal B-type natriuretic peptide 
PCI: 
percutaneous coronary intervention 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamics 
pEOT: 
premature End-of-Treatment 
PET: 
positron emission tomography 
PK: 
pharmacokinetics 
PRO: 
patient-reported outcome 
PT: 
preferred term 
PYY: 
peptide YY 
qd: 
once daily 
RAAS: 
renin-angiotensin-aldosterone system 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
Steering Committee 
SD: 
standard deviation 
SGLT1: 
sodium-glucose cotransporter 1 
SGLT2: 
sodium-glucose cotransporter 2 
SMQ: 
standardized Medical Dictionary for Regulatory Activities query 
SOC: 
system organ class 
SPECT: 
single-photo emission computed tomography 
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SUSAR: 
suspected unexpected severe adverse reaction 
T1D: 
type 1 diabetes 
T2D: 
type 2 diabetes 
TEAE: 
treatment-emergent adverse event 
UGE: 
urinary glucose excretion 
ULN: 
upper limit of normal 
US: 
United States 
WHF: 
worsening heart failure 
WOCBP: 
women of childbearing potential 
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4 
INTRODUCTION AND RATIONALE 
4.1 
BACKGROUND: DISEASE AND PRELIMINARY THERAPEUTIC OBSERVATIONS 
Heart failure (HF), the most common cause of hospitalization of patients over the age of 65, 
encompasses a wide spectrum of diseases and results from any structural or functional impairment 
of ventricular filling or ejection of blood. Classic symptoms include dyspnea and fatigue (2). 
Prevalence is approximately 5.7 million in the United States (US; ≥20 years age) and over 
23 million worldwide. In the US, prevalence is projected to increase 46% from 2012 to 2020 to 
8 million (≥18 years of age) (3, 4). Outpatient care has improved significantly with therapies such 
as angiotensin-converting enzyme inhibitors (ACE-i), angiotensin receptor blockers (ARBs), 
mineralocorticoid receptor antagonists (MRAs), and implantable cardioverter-defibrillator 
(ICD)/cardiac resynchronization therapy (CRT) devices. However, mortality and readmission 
rates remain high (5). 
Among patients aged ≥55 years, the average incidence of hospitalization for heart failure (HHF) is 
11.6 per 1000 people per year; and recurrent hospitalized HF is 6.6 per 1000 people per year (6). 
Readmission for HF within 30 days of discharge occurs in approximately 24% of cases (7). The 
total cost for HF in 2012 was estimated at approximately 30.7 billion dollars and is projected to 
increase by almost 127% to 69.7 billion dollars (from 2012 to 2030) (2). Recognizing this burden on 
the US health care system, readmission for HF is a focus of pay for performance initiatives. In the 
US, the Patient Protection and Affordable Care Act, enacted in 2010, imposed financial penalties for 
hospitals with the highest readmission rates during the first 30 days after discharge (8). 
In addition, the European Medicines Agency has recently recognized that patients hospitalized due 
to acute decompensation of chronic HF and stabilized by standard therapy are usually excluded 
from clinical trials investigating new therapies for acute or chronic HF. Hence the condition known 
as “post-worsening HF” represents a specific unmet medical need, particularly in patients with type 
2 diabetes (T2D), since the rates of hospitalization for HF in patients with diabetes is substantially 
higher compared to HF patients without diabetes (9, 10, 11, 12). 
Heart failure can be divided into 2 or 3 main categories, depending on the region, based on 
measurement of the left ventricular ejection fraction (LVEF): HF with preserved ejection fraction 
(HFpEF; EF ≥50%); heart failure with mid-range ejection fraction (HFmEF; LVEF ≥40 
and <50%); and heart failure with reduced ejection fraction (HRrEF; <40%). Heart failure with 
mid-range ejection fraction is becoming a category of interest and was recently referenced in the 
2016 European Society of Cardiology (ESC) Heart Failure Guidelines (9). The American Heart 
Association (AHA) guidelines refer to an intermediate category but do not label it HFmEF (10). A 
2016 analysis of 99 825 admissions between January 2005 and September 2013 from 
305 hospitals in the Get with the Guidelines-HF database showed the prevalence of HF as 
follows: 49% with HFrEF; 13% with HFmEF; and 38% with HFpEF (11). 
The diagnosis of HF can be challenging in some patients since symptoms are nonspecific. 
Echocardiogram can help establish the diagnosis if the LVEF is <40%, classifying the patient into 
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the HFrEF category. HFmEF and HFpEF are more challenging to diagnose and elevated levels of 
natriuretic peptides (both b-type natriuretic peptide [BNP] and N-terminal B-type natriuretic 
peptide [NT-proBNP]) can aid in establishing the diagnosis. B-type natriuretic peptide and 
NT-proBNP are natriuretic peptides found in the heart. In response to volume overload and 
subsequent myocardial stretch, proBNP is secreted and then cleaved to NT-proBNP and BNP 
(12). The natriuretic peptides have been shown to predict clinical outcomes in clinical trials and 
have been used as surrogate markers of cardiovascular (CV) function. In a recent trial conducted 
in 149 patients with LVEF >45%, the PARAMOUNT trial, changes in NT-proBNP were used to 
compare the effect of sacubitril/valsartan with valsartan alone. The study showed that 
sacubitril/valsartan reduced NT-proBNP levels to a significantly greater extent (783 pg/mL at 
Baseline and 605 pg/mL at 12 weeks) compared with valsartan alone (862 pg/mL at Baseline and 
835 pg/mL at 12 weeks) over 12 weeks (13). 
Although ACE-i, beta-blockers, and MRAs are recommended in patients with HFrEF to reduce 
the risk of HF hospitalization and death, they have failed to reduce mortality in patients with 
HFmEF and HFpEF. Of note, diuretics are used to treat symptoms in all HF patients, regardless of 
LVEF status. In addition, both the AHA and ESC HF Guidelines discuss the use of new 
compound sacubitril/valsartan, the first in the class of angiotensin receptor neprilysin inhibitors 
(ARNIs) in HFrEF (9, 10). 
There have been 2 clinical trials done to date in the post-worsening heart failure population. 
ASTRONAUT was conducted in HHF patients with reduced LVEF, randomized to either 
aliskiren or placebo a median of 5 days after admission (14). EVEREST was conducted in HHF 
patients with reduced LVEF, randomized to either tolvaptan or placebo (for a minimum of 
60 days) within 48 hours of admission (15). The mechanism of action of these 2 drugs differs 
from each other and SGLT2 inhibitors, and neither drug reduced CV death or HHF (at 6 or 
12 months after discharge for ASTRONAUT and for a median follow-up of 9.9 months for 
EVEREST). Both trials were conducted in patients both with and without diabetes. 
Type 2 diabetes is a growing epidemic worldwide that is associated with a high incidence of 
macrovascular and microvascular complications (16). The Emerging Risk Factors Collaboration 
has recently reported that patients with T2D have a doubled risk of CV death compared to patients 
without diabetes (17). Cardiovascular complications of diabetes include myocardial infarction 
(MI), stroke, and HF (18). In patients with diabetes the prevalence of HF is much higher 
compared to the general population and increases with age (19, 20, 21). One in 5 patients with 
diabetes aged over 65 years suffers from HF (21). 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 (21, 22, 23, 24). Despite these compelling 
data, HF is often omitted from the list of diabetes complications because its pathogenesis is 
multifactorial, including coronary artery disease, hypertension, diabetic cardiomyopathy, and 
extracellular fluid volume expansion; hence it does not fit into the traditional classification of 
diabetes complications as either microvascular or macrovascular. 
Recent data indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors may reduce HF 
morbidity and mortality in patients with T2D. These antihyperglycemic agents lower blood 
glucose levels, in part, through the inhibition of renal glucose reabsorption thereby enhancing 
renal glucose excretion (25). In 2015, the EMPA-REG OUTCOME trial showed that the SGLT2 
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inhibitor, empagliflozin, when added to standard of care, reduced the risk of CV death (a 
component of the primary composite endpoint) and HHF in patients with T2D and established CV 
disease (CVD), including 10% with HF at screening (26). In 2017, the CANVAS program showed 
that canagliflozin, when added to standard of care, reduced the risk of a composite outcome of CV 
death, nonfatal MI or nonfatal stroke in patients with T2D and established CVD or at high risk for 
CV events (27). Of note, the FDA recently approved empagliflozin for reducing the risk of CV 
death in adult patients with T2D and established CVD (28). 
The mechanisms supporting the CV benefit of SGLT2 inhibitors have not been fully elucidated, 
but several experts have speculated that the hemodynamic effect of SGLT2-inhibition is the main 
driver. Sodium-glucose cotransporter 2 inhibitors may affect volume status via either or both of 
the following mechanisms: sodium and volume reduction and/or a decrease in arterial pressure. 
The diuresis and beneficial effect on maladaptive renal arteriolar responses may have led to 
improvement in both systolic and diastolic function, thereby lowering HHF and sudden cardiac 
death. Sodium-glucose cotransporter 2 inhibitors induce a considerable diuresis with early loss of 
urinary glucose and sodium. However, in contrast to regular diuretics, SGLT2 inhibitors induce a 
sustained reduction in plasma volume, not accompanied by electrolyte imbalance, or rebound 
activation of the renin-angiotensin system to the degree that would be expected given the large 
reduction in volume (29, 30, 31). In EMPA-REG OUTCOME (32), empagliflozin resulted in an 
approximate 4% increase in the hematocrit. In patients with HF, impaired 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 or CANVAS 
study population was not characterized, but it has been suggested that a substantial proportion of 
the trials’ population might have had mild HF or some form of preclinical HF or diabetic 
cardiomyopathy at Baseline (31, 32). The beneficial CV effects of empagliflozin and canagliflozin 
were consistent across subgroups including patients with versus without HF at Baseline (32, 27). 
In addition to inhibition of SGLT2 in the proximal tubules, SGLT2 inhibitors also down-regulate 
sodium-hydrogen exchanger 3 (NHE3), which is primarily responsible for tubular sodium 
reuptake following filtration and that is markedly upregulated in experimental models of HF (33). 
Cardiorenal protection has also been postulated to be linked to decreased sodium reabsorption by 
inhibition of intestinal NHE3 by sodium-glucose cotransporter 1 (SGLT1) inhibition (34). 
In addition to the hemodynamic hypothesis, another hypothesis has been postulated to explain the 
CV benefit of empagliflozin. Under conditions of mild, persistent hyperketonemia, such as those 
that prevail during treatment with SGLT2 inhibitors, β-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 (35). 
Sodium-glucose cotransporter 2 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 (36). Type 2 diabetes is associated with 
upregulation of the SGLT2 tubular transporters. Sodium-glucose cotransporter 2 inhibitors block 
tubular glucose reabsorption along with sodium reabsorption in the proximal renal tubules, 
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leading to increased sodium delivery to the macula densa. Increased distal tubule sodium delivery 
results in tubule-glomerular feedback, afferent glomerular arteriolar vasoconstriction, and 
subsequent reduction in glomerular capillary pressure and decreased hyperfiltration. This renal 
effect may contribute to cardioprotection by minimizing volume overload, neurohormonal 
activation, and proinflammatory pathways, which are all contributors to the cardiorenal 
syndrome (37). 
4.2 
BACKGROUND: SOTAGLIFLOZIN 
Sotagliflozin, a dual inhibitor of SGLT2 and SGLT1, is in clinical development for the treatment 
of type 1 diabetes (T1D) and T2D (38). In addition to this heart failure outcomes trial, another 
outcomes trial will be conducted in parallel in patients with T2D, renal impairment and high CV 
risk. Sodium-glucose cotransporter 1 receptors are expressed predominantly in the gastrointestinal 
(GI) tract and are 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 (39), pharmacologic inhibition of SGLT1 by sotagliflozin has not produced these 
effects in preclinical models or patients with T1D or T2D. 
Increased renal glucose excretion and therefore osmotic diuresis, one of the main hypotheses of 
the mechanism of action on HF, has been seen in patients with T2D who have received 
sotagliflozin. 
In Study LX4211.202, a Phase 2 study of sotagliflozin in combination with metformin in T2D 
patients, mean urinary glucose excretion (UGE) was increased over Baseline to Week 12 by a 
mean of 47.7 g/day and 58.9 g/day at 200 mg and 400 mg doses per day (40). 
In Study LX4211.1.201, a Phase 2 study in T2D patients, both sotagliflozin dose groups (150 and 
300 mg) had statistically significant increased 24-hour total UGE compared to the placebo group, 
and the greatest treatment effect was observed on Day 1 post-treatment. The increases in UGE in 
the sotagliflozin 300 mg dose group were consistently higher than in the sotagliflozin 150 mg 
dose group, suggesting a possible dose-response relationship in the treatment effect on 24-hour 
total UGE. The UGE increases were maintained throughout the course of the study in both dose 
groups, although they diminished slightly over 28 days of treatment, possibly due to improved 
glycemic control. These trends are considered a result of the pharmacologic activity of 
sotagliflozin on SGLT2 inhibition. Figure 1 illustrates the mean change from Baseline in UGE 
over time (41). 
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Figure 1 - Study LX4211.1-201-T2DM - Mean (+/- SE) Change from Baseline in 24-hour urinary 
glucose excretion by treatment on Days 1, 14, and 28 (Efficacy population) 
 
Source: CSR Figure 14.2.1.1 
4.3 
BENEFIT/RISK PROFILE 
Studies with sotagliflozin have shown that this agent produces significant UGE in preclinical 
animal models, healthy human volunteers, and patients with T2D.  
No significant safety concerns have been identified in the sotagliflozin clinical program, and 
sotagliflozin has been generally 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, the majority of these events were mild to moderate in intensity, with most 
resolving spontaneously. Overall, no imbalance was observed in the events of hypoglycemia in 
the sotagliflozin clinical program, and there have been no events of severe hypoglycemia or SAEs 
related to hypoglycemia in the completed studies. However, concomitant use of sulfonylurea and 
insulin may increase the risk for hypoglycemia. 
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Single- and multiple-dose administration of sotagliflozin to healthy human subjects has resulted in 
dose-dependent increases in UGE. Multiple-dose (up to 12 weeks) administration in patients with 
T1D and T2D produced improvements in several metabolic parameters, including levels of fasting 
glucose, postprandial glucose, glycosylated hemoglobin A1c (HbA1c), GLP-1, hemoglobin, and 
PYY. Sotagliflozin also enabled patients with T1D to control their daily glucose levels while 
decreasing their daily insulin doses in 1 of the Phase 1 studies implemented to date (42). These 
data suggest that sotagliflozin will be of therapeutic benefit to patients with T1D and T2D.  
Overall, the potential benefits of sotagliflozin therapy for patients with T1D and T2D outweigh 
the potential risks. In Phase 1 and 2 studies, sotagliflozin has been generally safe and well-
tolerated in patients with T1D and in patients with T2D with and without renal impairment. The 
favorable benefit-risk assessment to date supports the further development. 
Benefit-risk in patients with type 2 diabetes and heart failure  
Heart failure is a common comorbidity and complication of T2D. Patients with HF have 
particularly poor outcomes and 5-year survival rates of <25% (43). The condition known as 
post-worsening heart failure (WHF) represents a specific unmet medical need in patients with 
T2D, since the rates of hospitalization for HF in patients with diabetes are substantially higher 
compared to those for HF patients without diabetes (9, 10, 11, 12). 
Recent data point to the beneficial effects of SGLT2 inhibitors in reducing CV death and HF in 
patients with T2D. The EMPA-REG OUTCOME trial (26) showed that empagliflozin, when 
added to standard of care, reduced the risk of CV death and HF requiring hospitalization in 
patients with T2D and established CVD, including 10% with HF at screening. The CANVAS 
program (27) showed that canagliflozin, when added to standard of care, reduced the risk of a 
composite outcome of CV death, nonfatal MI or nonfatal stroke in patients with T2D and 
established CVD or at high risk for CV events (19). Finally, the real-world database study 
CVD-REAL, conducted in more than 300 000 T2D patients, showed that treatment with a SGLT2 
inhibitor (canagliflozin, dapagliflozin, or empagliflozin) was associated with a decreased risk of 
HHF (hazard ratio [HR]=0.61; 95% confidence interval [CI]: 0.51 to 0.73; p<0.001) and all-cause 
death (HR=0.49; 95% CI: 0.41 to 0.57; p<0.001) (44). 
Taken together, the CV benefits observed to date in T2D patients treated with SGLT2 inhibitors 
and the high unmet medical need of post-WHF support the development of sotagliflozin in 
patients with T2D and post-WHF. 
Overall, the potential benefits of sotagliflozin therapy for patients with T2D and HF outweigh the 
potential risks.  
More information on the safety of sotagliflozin and on the clinical program can be found in the 
Investigator’s Brochure (IB). 
4.4 
RATIONALE FOR CURRENT STUDY 
The main objectives of the study are to demonstrate whether sotagliflozin reduces the composite 
of CV death and HHF as compared to placebo in diabetic patients after admission for WHF. 
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In all patients, double-blind treatment (sotagliflozin or placebo) will be added to the standard of 
care, evidence-based background therapies for their underlying diabetes and HF conditions.  
The randomization will be stratified according to LVEF (<50% or ≥50%) since they represent 
2 distinct forms of HF. However, both forms lead to significant congestion and have the potential 
to be improved by an agent such as sotagliflozin. 
Although ACE-i, beta-blockers and MRAs are recommended in patients with HFrEF to reduce the 
risk of HHF and death, they have failed to reduce mortality in patients with HF and preserved EF. 
Therefore, in order to evaluate the effect of sotagliflozin on patients across the spectrum of LVEF 
values, there are 2 primary endpoints. The first in patients with a LVEF <50% and the second in 
the total patient population. The cut-off of 50% was chosen to group HFrEF and HFmEF patients 
(a very small subgroup, 13% [11]) together, since HFmEF patients are a category of interest. 
In order to do a robust analysis of the potential improvement in patients with LVEF <50%, 
recruitment will begin with all patients (LVEF <50% and LVEF ≥50%). Enrollment of patients 
with LVEF ≥50% will be capped at ~27% of the total patient population and enrollment of 
patients with LVEF <50% will continue to reach the total patient population. In addition, since an 
intermediate category has recently emerged (LVEF between 40% and 49%) for which little 
information on outcome is available, an exploratory subgroup analysis will also be performed 
using the 3 categories (<40%, 40 to 49% and ≥50%). 
In addition, since this patient population is burdened with repeated hospitalizations and visits to 
the emergency department (ED) or HF acute unit (where available) with major financial 
consequences for healthcare systems and utilization of public health care resources, the study will 
also assess, in addition to the occurrence of a primary event, the occurrence of the total number of 
CV deaths and HHF or urgent HF visits (see Appendix B) throughout the course of the study. 
Finally, the effect of sotagliflozin on CV death alone and all-cause mortality will be analyzed.  
4.4.1 Rationale for selection of dose 
In healthy subjects, sotagliflozin was well-tolerated following single doses up to 2000 mg, and in 
multiple doses up to 800 mg over 10 days. Furthermore, in a thorough QT study, single doses of 
sotagliflozin (800 mg and 2000 mg) were well-tolerated and did not prolong the QT interval. 
Additionally, evaluation of metabolites in urine and plasma of healthy subjects resulted in no 
safety concerns following single doses of 400 mg sotagliflozin. 
Both dosages (the starting dose of sotagliflozin [200 mg once daily [qd] and the maintenance dose 
[400 mg qd]) are currently undergoing evaluation in Phase 3 glucose-control studies. For the 
clinical development of sotagliflozin in patients with diabetes the dose selected was 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 (bid), and 400 mg qd were tested over a 12-week, double-blind 
period. At 12 weeks, the 200 mg 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 0.14%. 
The overall incidence of AEs on sotagliflozin 200 mg and 400 mg qd doses were similar to 
placebo, hence the 200 mg dose was less effective than the 400 mg dose and did not present clear 
advantages in safety or tolerability. 
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The mechanism(s) supporting the decreased risk of CV death and HHF observed in patients with 
T2D treated with SGLT2 inhibitors are still under investigation, but the CV benefit does not 
appear to be related to the glucose lowering effect of these medications. In fact, a major role has 
been speculated to be played by their hemodynamic effects (29, 30, 31) since these compounds 
decrease plasma volume and reduce blood pressure (BP) likely resulting in improved systolic and 
diastolic function. It should be noted that in EMPA-REG OUTCOME (26) 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. 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. 
In Study LX4211.1 202 DM (40) 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 bid 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 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 bid and 
400 mg qd, respectively versus (0.273) -0.04 g/dL in the placebo arm. The mean change (SD) in 
hemoglobin from Baseline to Week 12 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 bid 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 systolic BP 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 
cardiovascular outcomes, the dose of 400 mg was chosen as the proposed maintenance dose for 
the study. 
Sotagliflozin induces an acute, but modest, decrease in estimated glomerular filtration rate 
(eGFR). Since the study population includes 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. 
4.4.2 Rationale for study design and control groups 
This study is a pivotal, randomized, double-blind, placebo-control Phase 3, outcomes trial planned 
to be conducted in the post WHF population with T2D. A placebo control group, in addition to 
standard of care, has been selected since no treatment is indicated or has been proven to be safe 
and effective in patients with diabetes and a recent admission for WHF. In addition to receiving 
double-blind treatment, all patients in the study will receive background evidence-based, standard 
of care treatment for their underlying diabetes and HF conditions, as per Investigator’s discretion. 
The study will be an event-driven study and will continue until approximately 947 positively 
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adjudicated primary events (ie, number of patients with at least 1 positively adjudicated primary 
event) have been observed in patients with LVEF <50%, AND approximately 1341 positively 
adjudicated primary events (ie, number of patients with at least 1 positively adjudicated primary 
event) have been observed in the total patient population. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY  
• To demonstrate that sotagliflozin reduces CV mortality and morbidity (composite of CV 
death or HHF) compared to placebo in hemodynamically stable patients with T2D and HF 
with LVEF <50%, after admission for WHF 
• To demonstrate that sotagliflozin reduces CV mortality and morbidity (composite of CV 
death or HHF) compared to placebo in hemodynamically stable patients with T2D and HF, 
irrespective of LVEF, after admission for WHF (total patient population) 
5.2 
SECONDARY  
• To demonstrate that, when compared to placebo, in the total patient population, 
sotagliflozin reduces the total number (ie, including recurrent events) of the following 
clinical events:  
- 
Cardiovascular death, HHF, or urgent HF visit (see Appendix B) 
• To demonstrate that, when compared to placebo, sotagliflozin reduces:  
- 
Cardiovascular death in patients with LVEF <50% 
- 
All-cause mortality in patients with LVEF <50% 
- 
The composite of positively adjudicated sustained ≥50% decrease in eGFR from 
Baseline (for ≥30 days), chronic dialysis, renal transplant or positively adjudicated 
sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days) in the total patient population 
- 
Cardiovascular death in the total patient population 
- 
All-cause mortality in the total patient population 
• To demonstrate the safety and tolerability of sotagliflozin in the total patient population 
5.3 
OTHER 
• To compare sotagliflozin versus placebo on the occurrence of the following events in the 
total patient population: 
- 
Hospitalization for heart failure or urgent HF visit (see Appendix B) within 30 days of 
Randomization 
- 
At least 50% decrease in eGFR from Baseline (for ≥30 days)  
- 
Myocardial infarction (fatal and nonfatal)  
- 
Stroke (fatal and nonfatal) 
• To compare sotagliflozin versus placebo with respect to the proportion of patients with 
≥1 new onset of atrial fibrillation, atrial flutter, or ventricular arrhythmia from 
Randomization in the total patient population 
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• To demonstrate that sotagliflozin reduces CV mortality and morbidity (composite of CV 
death or HHF) compared to placebo in hemodynamically stable patients with T2D and HF 
with LVEF <40%, after admission for WHF 
• To demonstrate that sotagliflozin reduces CV mortality and morbidity (composite of CV 
death or HHF) compared to placebo in hemodynamically stable patients with T2D and HF 
with LVEF ≥40% to <50%, after admission for WHF 
• To demonstrate that sotagliflozin reduces CV mortality and morbidity (composite of CV 
death or HHF) compared to placebo in hemodynamically stable patients with T2D and HF 
with LVEF ≥50% after admission for WHF 
• To demonstrate that, when compared to placebo, sotagliflozin reduces all-cause mortality 
in patients with LVEF <40% 
• To compare sotagliflozin versus placebo in the total patient population with respect to 
change from Baseline in the following endpoints: 
- 
Hemoglobin A1c 
- 
Body weight 
• To compare sotagliflozin versus placebo with respect to changes in Kansas City 
Cardiomyopathy Questionnaire-12 (KCCQ-12) scores from Baseline in the total patient 
population 
• To compare sotagliflozin versus placebo with respect to changes in NT-proBNP from 
Baseline in the total patient population  
• To compare sotagliflozin versus placebo with respect to changes in loop diuretics from 
Baseline in the total patient population  
• To compare sotagliflozin versus placebo for changes in hemoconcentration from Baseline 
in the total patient population 
• To compare sotagliflozin versus placebo for changes in hemoconcentration from Baseline 
in patients with LVEF <40% 
• To compare sotagliflozin versus placebo on the time to first occurrence of either of the  
following clinical events in subgroups of patients who started first IMP dose prior vs. after 
hospital discharge (or urgent care facility where appropriate): 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study in about 4000 hemodynamically stable patients with T2D who have been admitted to the 
hospital, a HF unit, infusion center, or ED for WHF with intravascular volume overload. The 
study will consist of 3 periods: 
• A Screening period (up to 14 days)  
• A randomized, double-blind treatment period that will include an initial up-titration period  
• A Post-treatment period of 14 days (±4 days) 
6.1.1 Screening period 
The Screening period will last up to 14 days. The Screening period duration provides sites the 
ability to collect the data required to establish whether the patient satisfies the inclusion/exclusion 
criteria. Patients will have been admitted to hospital, HF unit, infusion center, or ED for WHF 
associated with intravascular volume overload (Index Event; see Section 7.1.1 for definition) prior 
to the Screening Visit (Visit 1). 
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. 
Blood samples for BNP or NT-proBNP should be collected by the local laboratory at Screening 
before Randomization, if not collected earlier following the specific Index event.  
6.1.2 Randomized double-blind treatment period 
Patients who meet all eligibility criteria during the Screening period will have Randomization 
Visit (Visit 2) up to 14 days later and, if they are still eligible for the study, they will be 
randomized 1:1 to sotagliflozin or placebo. The Screening and Randomization visits may be 
conducted on the same day. 
The Randomization Visit (Visit 2; Day 1) should occur prior to hospital discharge if applicable, or 
within 3 days after discharge from hospital, ED, HF unit, or infusion center. A blood sample for 
NT-proBNP will be collected and sent to the central laboratory at Randomization before taking 
IMP. The sample for NT-proBNP will be sent to the central laboratory for all other subsequent 
visits. 
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Patients will be stratified by LVEF (LVEF <50% and LVEF ≥50%) and region (North America, 
Latin America, Western Europe, Eastern Europe, and rest of the world). The number of patients 
with LVEF ≥50% will be limited to approximately 1100, to ensure sufficient number of patients 
(ie, approximately 2900) with LVEF <50%. 
The double-blind study treatment will be initiated at Visit 2 (Day 1) after the patient has been 
randomized (ie, after patient is hemodynamically stable and ready to transition from intravenous 
[IV] to oral diuretic therapy). Patients will receive sotagliflozin 200 mg or placebo at that visit and 
will continue this regimen qd until the next visit. If the randomization visit occurs after the patient 
has had their first meal of the day, the patient is allowed to take the first dose the following day, 
before the first meal. 
Patients will return a week later at Visit 3 (Day 8). Clinical safety and tolerability (including vital 
signs and collection of AEs, including events of special interest [EOSIs], adverse events of special 
interest [AESIs], and SAEs) will be assessed and blood (including serum creatinine) and urine 
laboratory samples will be collected. Patients will continue to receive sotagliflozin 200 mg or 
matching placebo qd until the next visit. 
Patients will return a week later at Visit 4 (Day 15). Clinical safety and tolerability (including 
vital signs and collection of AEs, including EOSIs, AESIs, and SAEs) will be assessed and 
laboratory results from the prior week (including serum creatinine) will be reviewed, and new 
laboratory samples (blood and urine) will be collected. 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 volume depletion, symptomatic hypotension 
(eg, dizziness, lightheadedness), or other AEs intolerable to the patient such as severe polyuria or 
nocturia, the dose will be up-titrated to sotagliflozin 400 mg or matching placebo qd until the next 
visit. 
The patient will then return for Visits at Month 1 (Day 29), Month 4, and every 4 months 
thereafter until the end of the study.  
If the patient does not meet up-titration criteria for safety reasons (eg, hypotension), the 
Investigator will have the option of either continuing IMP at the dose of 200 mg or placebo, with 
the optional adjustment of concomitant medications, or discontinuing IMP temporarily. If the dose 
is not up-titrated for safety reasons, the Investigator should make all attempts to up-titrate the dose 
at 1 of the next 3 subsequent visits: Visit 5 (Month 1), Visit 6 (Month 4), or Visit 7 (Month 8). In 
patients who cannot reach the dose of 400 mg or matching placebo during the first 8 months after 
Randomization (Visit 7), the dose of 200 mg or matching placebo will be used throughout the 
study. If at any time during the study, the dose of 400 mg or placebo is not well-tolerated, the dose 
can be down-titrated (to 200 mg or matching placebo), 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. 
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 
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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). 
This is an event-driven study. The study will end when approximately 947 primary events have 
been positively adjudicated (ie, number of patients with at least 1 positively adjudicated primary 
event) in patients with LVEF <50%, AND approximately 1341 primary events have been 
positively adjudicated (ie, number of patients with at least 1 positively adjudicated primary event) 
in the total patient population. 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 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 (this repeat renal assessment may occur beyond the last planned visit per protocol). 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 (see Appendix E). Patients will continue with IMP treatment 
after a CV or renal endpoint occurs unless the criteria for permanent treatment discontinuation 
have otherwise been met (see Section 10.3.3). 
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 will participate in a Screening period of up to 14 days. The study observation period 
starts at Randomization and lasts until the end of the study (the last study visit [eg, Follow-up 
Visit for patients who complete study treatment per protocol, or Study Closeout Visit for patients 
who prematurely permanently discontinue study treatment] of patient). The study is event-driven, 
therefore the duration will be determined as described in Section 6.1.2. 
The estimated study duration will be approximately 3 to 32 months, assuming approximately 
29 months of recruitment, and approximately 3 months of follow-up after the last patient is 
randomized. 
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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 947 primary events have been positively adjudicated (ie, number of patients with at 
least 1 positively adjudicated primary event) in patients with LVEF <50%, AND approximately 
1341 primary events have been positively adjudicated (ie, number of patients with at least 
1 positively adjudicated primary event) in the total patient population. 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 
No interim analysis is planned. 
6.4 
STUDY COMMITTEES 
6.4.1 Executive Committee 
The Executive Committee (EC) will oversee the 2 sotagliflozin outcome trials, ie, the present HF 
trial, and the other CV outcomes trial that will be conducted in parallel in patients with T2D, renal 
impairment and high CV risk. 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. 
6.4.2 Steering Committee 
The Steering Committee (SC) is responsible for supporting the Sponsor and EC, in designing a 
scientifically sound study. The SC is also responsible for addressing and resolving 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, selected CV and renal events, diabetic ketoacidosis (DKA), and bone fractures in a 
treatment-blinded manner. 
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6.4.5 Safety events requiring ongoing monitoring 
Two independent committees will review safety events to ensure timing of protocol amendments 
in case a safety signal is identified. These events are: 1) potential cases of drug-induced liver 
injuries (DILI), and 2) AEs leading to amputations.  
The 2 independent committees will review the cases in a treatment-blinded manner and will 
present their assessment to the DMC. 
The 2 committees’ composition and roles/responsibilities will be described in a charter. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
7.1.1 At the Screening Visit 
The Screening Visit should be no more than 14 days prior to Randomization.  
Please note: sites that plan to enroll patients who have not been hospitalized (ie, admitted for at 
least 24 hours) will need to be qualified by the Sponsor at the pre-site visit or a visit to ensure 
the existence of appropriate facilities. 
I 01. Either:  
A) Diagnosis of T2D, based on appropriate supportive documentation for patients with a 
diagnosis of T2D prior to the Index Event  
OR  
B) For patients diagnosed with T2D at the time of the Index Event, laboratory evidence is 
required as follows: 
• Fasting plasma glucose ≥126 mg/dL  
OR  
• Random plasma glucose ≥200 mg/dL OR HbA1c ≥6.5% 
I 02. Patient admitted to the hospital or had urgent HF visit to ED, Heart Failure Unit, or 
infusion center for WHF associated with intravascular volume overload (the Index Event), 
as determined by Investigator (based on appropriate supportive documentation) and 
defined by: 
• Presence of ≥2 of the following clinical signs and symptoms of congestion: 
- 
Dyspnea 
- 
Jugular venous distention 
- 
Pitting edema in lower extremities (>1+) 
- 
Rales heard on auscultation 
- 
Radiographic pulmonary congestion 
AND  
• Patient received treatment with IV loop diuretics  
I 03. Patient had a diagnosis of HF ≥3 months prior to Screening (based on appropriate 
supportive documentation)  
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I 04. Prior chronic treatment (or prescription) with a loop diuretic (eg, furosemide, torsemide, 
bumetanide) for ≥30 days prior to the Index Event 
I 05. Patients with LVEF <40% should be on beta-blockers and RAAS inhibitors as per local 
guidelines unless contraindicated 
I 06. Patient or a legally acceptable representative has signed written informed consent to 
participate in the study in accordance with local regulations 
7.1.2 At the Randomization Visit  
Prior to hospital discharge if applicable, or within 3 days after discharge from hospital, ED, HF 
unit, or infusion center. 
I 07. Patient is hemodynamically stable, defined as: 
• Systolic blood pressure ≥100 mmHg, AND  
• No requirement for IV inotropic therapy or IV vasodilators (except for nitrates) and no 
treatment with IV inotropic or IV vasodilators within 2 days prior to Randomization AND 
• No requirement for mechanical ventilation or oxygen therapy in the last 24 hours 
I 08. Transitioning from IV to oral diuretics defined as:  
• Intravenous diuretic has been discontinued, AND 
• Chronic oral loop diuretic has been prescribed and/or administered  
I 09. At least 1 of the following laboratory values between admission for the Index Event and 
Randomization (based on local or central Laboratory):  
• B-type natriuretic peptide ≥150 pg/mL (≥450 pg/mL for patients with atrial fibrillation) 
OR  
• N-terminal B-type natriuretic peptide ≥600 pg/mL ≥1800 pg/mL for patients with atrial 
fibrillation) 
Note: The presence or absence of atrial fibrillation in order to determine the appropriate 
cut-off for a given BNP/NT-proBNP sample should be evaluated using the latest available 
electrocardiogram (ECG) or telemetry data performed prior to that BNP/NT-proBNP 
sample.  
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 2 subsections:  
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7.2.1 Exclusion criteria related to study methodology 
E 01. Age <18 years (or legal age for the country of participation) or >85 years at the Screening 
Visit 
E 02. Index Event (admission for WHF associated with intravascular volume overload – see  
I 02) primarily triggered by pulmonary embolism, cerebrovascular accident, acute 
myocardial infarction (AMI) 
Note: Troponin elevations are frequently seen in patients with WHF and therefore are not 
sufficient for a diagnosis of AMI. In order to exclude patient due to AMI, concomitant 
objective evidence of AMI from ECG, and/or cardiac imaging and/or coronary 
angiography should be available. 
E 03. Index Event (admission for WHF – see I 02) for WHF not caused primarily by 
intravascular volume overload. For example, Index Event triggered by significant 
arrhythmia (eg, sustained ventricular tachycardia, or atrial fibrillation/flutter with sustained 
ventricular response >130 beats per minute, or bradycardia with sustained ventricular 
arrhythmia <45 beats per minute), infection, severe anemia, or exacerbation of chronic 
obstructive pulmonary disease (COPD) 
E 04. Hospitalization for index event >2 weeks  
E 05. Acute coronary syndromes within 3 months prior to Randomization 
E 06. Ejection fraction not assessed by the time of Randomization (ie, no LVEF assessment 
performed following the Index Event and no LVEF measurement available within 
12 months prior to Screening via imaging modality (such as echocardiogram, MUGA scan, 
MRI, PET, SPECT, LV angiography) 
E 07. End-stage HF defined as requiring left ventricular assist devices (LVADs), intra-aortic 
balloon pump (IABP), or any type of mechanical support at the time of Randomization. 
E 08. Cardiac surgery (coronary artery bypass graft), percutaneous coronary intervention (PCI), 
implantation of cardiac device (including biventricular pacemaker), or cardiac mechanical 
support implantation within 1 month prior to Randomization or planned during the study 
E 09. Hemodynamically significant uncorrected primary cardiac valvular disease (please note 
that secondary mitral regurgitation or tricuspid regurgitation due to dilated cardiomyopathy 
is not excluded) 
E 10. Significant pulmonary disease contributing substantially to the patients’ dyspnea such as 
forced expiratory volume in 1 second (FEV1) <1 liter or need for chronic steroid therapy, 
or any kind of primary right heart failure such as primary pulmonary hypertension or 
recurrent pulmonary embolism 
E 11. Heart failure caused by postpartum cardiomyopathy diagnosed within the past 6 months 
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E 12. Heart failure from uncorrected thyroid disease, active myocarditis, known amyloid 
cardiomyopathy 
E 13. Obstructive hypertrophic cardiomyopathy 
E 14. History of stroke within 3 months prior to Randomization 
E 15. History of dialysis within 1 year prior to Randomization 
E 16. History of solid organ transplant or inclusion on a transplant list (if a heart transplant, 
defined as status 1 transplant) 
E 17. Use of any investigational drug(s) for 5 half-lives prior to Screening 
E 18. Hypersensitivity to sotagliflozin active substance or to any of the excipients including 
those in the placebo 
E 19. 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 20. Any SGLT2 inhibitor <1 month prior to the Screening Visit, or between Screening and 
Randomization 
E 21. Patients with respiratory, hepatic, neurological, 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) 
or patients with short life expectancy (defined as ≤1 year) that, according to the 
Investigator, will preclude their safe participation in this study, and will make 
implementation of the protocol or interpretation of the study results difficult 
E 22. Presence of any other conditions (eg, geographic, social) actual or anticipated, that the 
Investigator feels would restrict or limit the patient’s participation or compliance with all 
HF therapy, including study medication, for the duration of the study 
E 23. Patient is the Investigator or any Subinvestigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol 
E 24. 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) 
7.2.2 Exclusion criteria related to the current knowledge of sotagliflozin  
E 25. Severe kidney disease as defined by eGFR <30 mL/min/1.73 m² at the Screening Visit by 
the 4 variable Modification of Diet in Renal Disease (MDRD) equation 
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E 26. Any infection requiring intravenous antibiotics and/or with pyrexia (defined as temperature 
>38 °C [100.4 °F]) at time of Randomization 
E 27. History of DKA or nonketotic hyperosmolar coma within 3 months prior to the Screening 
Visit 
E 28. Lower extremity diabetic complications (such as skin ulcers, infection, osteomyelitis and 
gangrene) identified during the Screening period, and still requiring treatment at 
Randomization 
E 29. Pregnant (demonstrated by serum pregnancy test at Screening) or breastfeeding women.  
WOCBP as defined in Appendix A, 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. The Investigators may perform additional tests at their discretion or at frequency 
specified by local regulations 
E 30. Digoxin level >1.2 ng/mL (in a patient treated with digoxin, and based on last local or 
central laboratory value available prior to Randomization)* 
E 31. Laboratory findings (based on Screening value or last available value before 
Randomization, whichever is later):** 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper 
limit of normal (ULN)  
• Total bilirubin >1.7 times the ULN (except in case of Gilbert’s syndrome)  
• Serum potassium >5.5 mEq/L 
Note: A patient should not be randomized more than once. 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 completion of enrollment. * If a patient meets 
exclusion criteria E 30, a one-time repeat testing is allowed for digoxin level without the need to 
rescreen the patient.  
** If a patient meets exclusion criterion E 31:  
• A one-time repeat testing is allowed for ALT or AST without the need to rescreen the 
patient 
• Repeat testing for serum potassium is allowed for 3 days after Screening without the need 
to rescreen the patient 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS  
IMPs are tablets of sotagliflozin 200 mg and matching placebo. Patients will be provided with 
70-tablet bottles of sotagliflozin 200 mg or matching placebo included in 1 box. 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 placebo. 
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 mealb of the day 
1 or 2 tablets (depending on visit number 
and dose titration statusa), taken orally 
once daily, before first mealb of the day  
Duration of treatment 
The estimated study treatment duration will 
be approximately 3 to 32 months 
The estimated study treatment duration 
will be approximately 3 to 32 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) 
a Details of up-titration of IMP can be found in Section 8.1.1.1. 
b If the randomization visit occurs after the patient has had their first meal of the day, the patient is allowed to take the first dose the following 
day, before the first meal. 
IMP: investigational medicinal product 
8.1.1 Dose up-titration and adjustments 
8.1.1.1 Dose up-titration 
Patients will receive sotagliflozin 200 mg or placebo from Visit 2 and will continue this regimen 
qd until the next visit. 
Patients will return a week later at Visit 3 (Day 8). Clinical safety and tolerability (including vital 
signs and collection of AEs, including EOSIs, AESIs, and SAEs) will be assessed and blood 
(including serum creatinine) and urine laboratory samples will be collected. Patients will continue 
to receive sotagliflozin 200 mg or matching placebo qd until the next visit. 
Patients will return a week later at Visit 4 (Day 15). Clinical safety and tolerability (including 
vital signs and collection of AEs, including EOSIs, AESIs, and SAEs) will be assessed and 
laboratory results from the prior week (including serum creatinine) will be reviewed, and new 
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laboratory samples (blood and urine) will be collected. If, in the opinion of the Investigator the 
patient’s clinical condition is satisfactory and the patient has tolerated the IMP well without 
evidence of volume depletion, symptomatic hypotension (eg, dizziness, lightheadedness), or other 
AEs intolerable to the patient such as severe polyuria or nocturia, the dose will be up-titrated to 
sotagliflozin 400 mg or matching placebo qd until the next visit. 
If the patient does not meet up-titration criteria for safety reasons (eg, hypotension), the 
Investigator will have the option of either continuing IMP at the 200 mg dose or placebo, with the 
optional adjustment of concomitant medications, or discontinuing IMP temporarily. If the dose is 
not up-titrated for safety reasons, the Investigator should make all attempts to up-titrate the dose at 
1 of the next 3 subsequent visits: Visit 5 (Month 1), Visit 6 (Month 4), or Visit 7 (Month 8). In 
patients who cannot reach the dose of 400 mg or matching placebo during the first 8 months after 
Randomization (Visit 7), the dose of 200 mg or matching placebo will be used throughout the 
study. If at any time during the study, the 400 mg dose or placebo is not well-tolerated, the dose 
can be down-titrated (to 200 mg or matching placebo), 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. 
8.1.1.2 Dose adjustments 
If at any time during the study, the 400 mg dose or placebo is not well-tolerated, the dose can be 
down-titrated (to 200 mg or matching placebo), temporarily discontinued, or if medically 
necessary, permanently discontinued. 
Throughout the course of the study, if the double-blind treatment is down-titrated or temporarily 
discontinued, every effort should be made to resume the higher dose of double-blind treatment as 
early as possible (unless there are safety concerns) so that patients are kept on the maximal 
tolerated study dose of double-blind treatment for as long as possible throughout the double-blind 
period of the trial. 
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 PRODUCT(S) 
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. 
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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 the 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 treatment-blinded manner. The two safety 
committees will review potential cases of DILI and AEs leading to amputation in a 
treatment-blinded manner. 
8.3.2 Randomization code breaking during the study 
In case of an AE, the code must only be broken in circumstances when knowledge of the IMP is 
required for treating the patient. 
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. Code breaking can be 
performed by a local study Investigator, Sponsor physician, or healthcare professional with direct 
responsibility for patient care. If the blind is broken, the Investigator must document the date, time 
of day, and reason for code breaking. The identity of the unblinded personnel, how the code was 
broken, and the treatment kit number should also be recorded. The Sponsor should also be 
informed when unblinding occurs, however note that when documenting the reason for 
unblinding, the Investigator must not provide any detail regarding the nature of the IMP. The 
Investigator should not divulge IMP detail to the Sponsor’s representative or to any staff members 
until database closure. Furthermore, when completing forms (eg, AE, SAE, adjudication 
information), the study treatment should not be disclosed on the forms. If the code is broken by 
the Investigator (or other medical doctor in an emergency situation), the patient must be 
permanently withdrawn from IMP administration but shall continue to be followed in the study. 
Refer to Section 10.5 for suspected unexpected serious adverse drug reaction unblinding by the 
Sponsor. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
The randomized treatment kit number list will be generated centrally by Sanofi. The IMPs are 
packaged in accordance with this list. 
Patients will be randomized to receive either sotagliflozin or placebo qd during the randomized 
double-blind treatment period. Randomization (ratio 1:1) will be stratified by LVEF (<50% or 
≥50%) and region (North America, Latin America, Western Europe, Eastern Europe, and rest of 
the world).  
The randomization and the treatment package allocation are performed centrally by an IRT. At the 
Screening Visit the Investigator or designee has to contact the IRT to receive the patient number. 
 
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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 6 and all subsequent on-site 
visits up to the Study Closeout Visit (or pEOT if patient prematurely permanently discontinues 
study treatment).   
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 Visit 6. 
• 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, 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 Visit 6. 
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). 
The IMP includes sotagliflozin and placebo. 
All concomitant medications should be documented on the Medications page of the e-CRF. This 
includes all treatments that are taken by the patients at any time during the clinical trial, beginning 
at Visit 1. Additionally, all medications taken in the month prior to Visit 1 and prior use of 
SGLT2 inhibitors should be reported. 
8.8.1 Management of glycemia and diabetes complications 
During the double-blind study treatment period, the management of glycemia and diabetes 
complications will be left to the physician’s judgment, informed by clinical guidelines. While 
participating in this study, the patient should continue regularly scheduled visits with the 
physician (ie, diabetologist or internist) who manages their diabetes. 
Investigators will monitor the glycemic status, potassium levels, and diabetic complications 
(including DKA) of patients throughout the study and should consult with relevant experts (eg 
diabetologists or nephrologists) as appropriate.  
Diabetic ketoacidosis, including atypical (euglycemic) DKA, is the most serious emergency in 
patients with T1D and T2D. It is possible that GI or other AEs occurring with sotagliflozin may 
mask presenting symptoms of DKA. Because sotagliflozin lowers blood glucose by insulin 
independent SGLT1 and SGLT2 inhibition, it is possible for DKA to be present with normal or 
low blood glucose. Therefore, the Investigator must still consider a DKA event even if blood 
glucose is low or normal. Please refer to Appendix F for further details regarding DKA. 
For patients with HbA1c <7.5% at time of Screening, and who are 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. 
Patients should be instructed regarding careful attention to foot care and proper management of 
foot injuries in order to prevent ulcer formation. (Refer to Section 9.2.3.2 for further details). 
8.8.2 Management of blood pressure and renal function 
During the double-blind study treatment period, the management of BP (in hypertensive patients), 
potassium, and renal function (in patients with chronic kidney disease) will be left to the 
Investigator’s judgment, informed by clinical guidelines; the Investigator should consult with 
relevant experts (eg nephrologists) as appropriate.  
For patients with a systolic blood pressure <110 mmHg at Randomization, the doses of any 
diuretic or other antihypertensive medication may be decreased in order to prevent possible 
hypotension. However, all attempts should be made not to modify or discontinue the ACE-i/ARB, 
which should be at optimum / maximally tolerated doses. If a patient who is on an ACE-i/ARB 
does not tolerate the combination of the ACE-i/ARB with IMP due to hypotension/volume 
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depletion, and one of the two agents (either the ACE-i/ARB or IMP) needs to be withheld, the 
ACE-i/ARB should be maintained and the IMP should be withheld (temporarily if possible). 
If clinically significant volume depletion occurs during coadministration of IMP with loop 
diuretics, or in vulnerable populations, consideration should be given to first reducing or 
discontinuing the loop diuretic, prior to temporarily withholding IMP administration. 
8.8.3 Management of heart failure 
Throughout the duration of the study, patients should be treated with drugs and devices for their 
HF condition, as per local guidelines. 
In patients with HFrEF (LVEF <40%), several medications are considered lifesaving (ie, have 
been shown to reduce CV morbidity and mortality). These include RAAS inhibitors (ACE-i, 
ARB, ARNIs, MRAs, direct renin inhibitors) and beta-blockers. As a consequence, almost all 
patients with HFrEF (LVEF <40%) should receive 1 or several lifesaving medications at an 
optimal or maximal tolerated dose. The Investigator will confirm that patient is receiving the 
optimal or maximally tolerated dose, or otherwise record the reason for taking a lower dose. 
Every effort should be made to maintain such treatments at optimal or maximal tolerated doses 
throughout the duration of the trial. 
In rare instances, patients could be enrolled without using concomitant lifesaving drugs. In such 
cases, the e-CRF will collect reasons for not using such treatments. 
In all patients, change in doses of lifesaving drugs and use of devices (eg, ICD, CRT) will also be 
collected in the e-CRF. If a device is indicated per guidelines and not implanted, the reasons for 
not using the device will be collected. 
8.8.4 Prohibited medications 
During the study treatment period, the following medications are prohibited: 
• Any SGLT2 inhibitor  
• Investigational drugs other than sotagliflozin  
8.8.5 Other medications 
For patients who are taking digoxin or P glycoprotein substrates and labels of P glycoprotein 
substrates, 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 inhibitor and increases 
systemic exposure to 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 
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physician (ie, not the Investigator or Subinvestigator), he/she should be informed about this 
potential interaction. In patients treated with digoxin, digoxin levels may be measured using either 
serum or plasma at Screening and at Visit 4 (Week 2). If sites are unable to perform the test 
locally the assessment will be done by central laboratory. 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 4. 
Throughout the study, additional digoxin level assessments to be performed as per Investigators’ 
judgment. Other medications that are unlikely to interfere with the pharmacokinetics (PK) or 
pharmacodynamics (PD) 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. 
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 
The primary efficacy endpoints are: 
• Time to first occurrence of either of the following clinical events in patients with 
LVEF <50%: 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
• Time to first occurrence of either of the following clinical events in the total patient 
population: 
- 
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). 
Detailed outcome definitions will be 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 database 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 database lock of this study. 
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. 
9.1.2 Secondary efficacy endpoints 
• Total number (ie, including recurrent events) of the following clinical events in the total 
patient population: 
- 
Cardiovascular death  
- 
Hospitalization for heart failure 
- 
Urgent HF visit  
• Time to CV death in patients with LVEF <50% 
• Time to all-cause mortality in patients with LVEF <50% 
• Time to first occurrence of the composite of positively adjudicated sustained ≥50% 
decrease in eGFR from Baseline (for ≥30 days), chronic dialysis, renal transplant, or 
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positively adjudicated sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days) in the total 
patient population 
• Time to CV death in the total patient population 
• Time to all-cause mortality in the total patient population 
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 is defined as the value assessed 
by the central laboratory at 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 (this repeat 
renal assessment may occur beyond the last planned visit per protocol). 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 (see Appendix E). 
9.1.3 Other efficacy endpoints 
All the following endpoints are assessed in the total patient population:  
• Proportion of patients with HHF or urgent HF visit (see Appendix B) within 30 days of 
Randomization 
• Changes in KCCQ-12 scores from Baseline to Week 2, Month 1, Month 4, Month 8, 
Month 12, then annually 
• Time to ≥50% decrease in eGFR from Baseline 
• Proportion of patients with ≥1 new onset of atrial fibrillation, atrial flutter, or ventricular 
arrhythmia from Randomization 
• Time to first MI (fatal and nonfatal)  
• Time to first stroke (fatal and nonfatal) 
• Changes from Baseline to Month 1 and Month 4 for NT-proBNP 
• Changes from baseline in loop diuretics at day 180 and/or end of treatment visit  
• Changes in hemoconcentration from Baseline at Week 2, Month 1, Month 4, Month 12, 
and EOT 
• Changes from Baseline to Month 4, Month 12, and Month 24 in: 
- 
Hemoglobin A1c  
- 
Body weight 
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• Time to first occurrence of either of the following clinical events in subgroups of patients 
who started first IMP dose prior vs. after hospital discharge (or urgent care facility where 
appropriate): 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
The following endpoints are assessed in subgroups of patients defined by LVEF:  
• Time to first occurrence of either of the following clinical events in patients with 
LVEF <40%: 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
• Time to first occurrence of either of the following clinical events in patients with 
LVEF ≥40% to <50%: 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
• Time to first occurrence of either of the following clinical events in patients with 
LVEF ≥50%: 
- 
Cardiovascular death 
- 
Hospitalization for heart failure 
• Time to all-cause mortality in patients with LVEF <40% 
• Changes in hemoconcentration from Baseline at Week 2, Month 1, Month 4, Month 12, 
and EOT in patients with LVEF <40% 
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 Kansas City Cardiomyopathy Questionnaire-12 
The Kansas City Cardiomyopathy Questionnaire is a validated questionnaire assessing the 
health-related quality of life of patients with congestive HF (45). A 12-item version of this 
questionnaire (KCCQ-12) will be used in this study, capturing symptom frequency (4 items), 
physical (4 items) and social limitations (3 items), and quality of life impairment (2 items) as a 
result of HF (46). An overall summary score as well as 4 domain scores can be calculated ranging 
from 0 to 100 where 100 denotes the highest health status.  
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The KCCQ-12 will be completed by all patients as described in the Study Flow Chart 
(Section 1.2). The KCCQ-12 should take less than 10 minutes for patients to complete (see 
Appendix C). 
The patients will be requested to complete the KCCQ-12 questionnaire by themselves during the 
selected clinical visits, independently from Investigator, site staff and any help from friends or 
relatives. In case patients are too weak to complete the KCCQ-12 by themselves, it could be 
interviewer-administered. In this case, interviewers will be allowed to help patients completing 
the KCCQ-12 by reading each question aloud and strictly recording the patient’s responses 
without influencing or interpreting them. If the patient is unable to give a response verbally or by 
pointing, the questionnaire should be considered as missing. 
For validity purposes, patients will be asked to answer all the questions of the questionnaires at 
the start of the visits before any other procedures or tests, in a quiet place, and while on site to 
return the completed questionnaires to the Investigator or his/her designee on the same day. 
In case of premature permanent IMP discontinuation, the KCCQ-12 will be completed by patients 
at the visit planned for the last dosing day with IMP and afterwards as normally planned. 
9.1.3.3 Concomitant medications by class 
All concomitant medications (eg, beta-blockers, loop diuretics, ACE inhibitors, direct renin 
inhibitors, ARNis, ARBs, MRAs) are collected as described in Section 8.8. Details of the analysis 
will be included in the statistical analysis plan (SAP). 
9.2 
SAFETY ENDPOINTS 
• All AEs including AESIs, EOSIs, and SAEs 
• Severe hypoglycemia (also an EOSI) 
• Clinical laboratory results including vital signs (including heart rate, BP) 
9.2.1 Adverse events 
Adverse events including AEs leading to premature treatment discontinuation, 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. 
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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. 
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 10.4.7, 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 
laboratory values obtained at the local laboratory will be used for screening purposes and for 
safety review and will not be included for analysis. 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 frequency specified by local regulations. For 
women of non-productive potential (Appendix A), follicle stimulating hormone and/or estradiol 
levels should be tested in case the definition of postmenopausal or premenopausal cannot be 
satisfied, eg, no medical document of hysterectomy or cessation of menses without an alternative 
medical cause is <12 months. 
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Table 2 - Chemistry parameters 
Serum clinical chemistry 
Serum 
hematology 
Serum lipid profile 
Digoxin 
Sodium 
Complete blood 
count (CBC) 
Total cholesterol (TC) 
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 
 
 
 
Phosphorus 
 
 
 
Total protein 
 
 
 
Albumin 
 
 
 
Magnesium 
 
 
 
Creatine phosphokinase (CPK) 
 
 
 
Lactic acid dehydrogenase (LDH)  
 
 
 
a In patients treated with digoxin at Screening, digoxin levels should be measured at Screening and at Visit 4 (Week 2). 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 4. Throughout the study, additional digoxin level 
assessments to be performed in either serum or plasma as per Investigators’ judgment. If applicable, digoxin level assessment 
should be performed via a local laboratory, if sites are unable to perform the test locally, the test should be done by central 
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 
At Visit 1 only, urinalysis will be performed by the local laboratory. For all subsequent visits the 
urinalysis 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 
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urinalysis is positive for nitrite and leukocyte esterase or blood, reflexive testing will be 
performed at the local laboratory at Visit 1, and at the central laboratory for subsequent visits. 
Reflexive testing includes microscopy and urine culture (microscopy includes detection of formed 
cellular elements, casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment). 
If the urine dipstick is positive for nitrite and leukocyte esterase or blood, 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). 
9.2.3 Vital signs 
Vital signs (sitting BP and heart rate) measurements will be made at every on-site visit and should 
be measured in a seated position. 
9.2.3.1 Physical examinations 
• A complete physical examination will be performed as per clinical practice in order to 
assess the health status of the participant at Screening and evaluate the inclusion/exclusion 
criteria, and at pEOT (if applicable) and Study Closeout Visits. 
• At all other on-site visits, an abbreviated physical examination focused on any affected 
body area or organ system and other symptomatic or related organ system(s) will be 
performed. 
• All physical examinations, including abbreviated physical examinations, will include 
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 and this 
examination should be documented on the e-CRF. Lower extremity complications (such as 
skin ulcers, infection, osteomyelitis, and gangrene) requiring treatment should lead to 
temporary discontinuation of IMP. 
9.2.3.2 Foot care 
Patients should be instructed regarding careful attention to foot care and proper management of 
foot injuries in order to prevent ulcer formation (47, 48, 49). 
Patients or caregivers should be instructed to perform daily foot inspection. Gentle cleansing 
should be performed regularly with soap and water, followed by liberal use of moisturizers in 
order to help maintain healthy skin and help resist skin breakdown and injury. 
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demonstrate whether sotagliflozin reduces the composite of CV death and HHF as compared to 
placebo in diabetic patients after hospitalization for WHF. In order to further evaluate the effect of 
sotagliflozin on patients across the spectrum of LVEF values, there are 2 primary endpoints. The 
first endpoint is in patients with a LVEF <50% and the second in the total patient population. 
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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 6 on-site visits in the first 4 months. Subsequently, 
on-site visits are every 4 months until the Study Closeout Visit. 
The visit windows for Visits 3, 4, and 5 are ±3 days. The window for Visits 6 to 12 and, if 
applicable, the pEOT Visit, is ±7 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 Subinvestigators 
who are qualified in the treatment of T2D and are trained on the study. 
10.1.1 Screening period 
The Screening period will be up to 14 days in duration, and includes Visit 1 (Week -2). The 
Screening period duration provides sites the ability 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).  
Blood samples for BNP or NT-proBNP should be collected by the local laboratory at Screening 
before Randomization, if not collected earlier following the specific Index event. 
In cases where a patient fails Screening due to reasons expected to change during Screening 
period, 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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- 
Serum pregnancy testing for WOCBP 
- 
Urinalysis (dipstick) 
- 
Digoxin (if applicable, see Section 9.2.2) 
Note: If the laboratory assessments were done as standard of care, the historical data 
collected after the Index event may be used for Screening. However, serum pregnancy 
test must be collected at Screening. If sites are unable to perform the screening tests 
locally, the assessment can be done by central laboratory. 
• An appointment will be made for Visit 2 
10.1.2 Randomized double-blind treatment period 
The Screening and randomization visits may be conducted on the same day. 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 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. 
A blood sample for NT-proBNP will be collected by the central laboratory at Randomization 
before taking IMP, and for any subsequent visits when NT-proBNP is scheduled to be collected. 
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. 
Sotagliflozin/metabolite levels may be analyzed via routine blood samples collected throughout 
the study. Fasting is not necessary before the blood draw for laboratory assessments from Visit 2. 
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 (this 
repeat renal assessment may occur beyond the last planned visit per protocol). 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 
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• KCCQ-12 questionnaire 
• An appointment for Visit 3 will be made 
10.1.2.2 On-site Visits 3 (Week 1) and 4 (Week 2) 
The following procedures/assessments will be performed at Visits 3 and 4 (Weeks 1 and 2): 
• 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) 
• Abbreviated physical examination, including lower extremities 
• IMP compliance 
• 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 (as 
applicable, to be recorded in source documents). Alternate contact information for patients 
(ie, relative or friend) should also be reviewed as a backup 
• The following laboratory testing: 
- 
Hematology 
- 
Chemistry (including eGFR) 
- 
Sotagliflozin/metabolite levels may be analyzed via routine blood samples collected at 
these visits  
- 
Urinalysis (dipstick) 
• The following laboratory testing (by local laboratory): 
- 
Digoxin (Visit 4 ONLY) (if applicable, see Section 9.2.2). If sites are unable to 
perform the test locally the assessment will be done by central laboratory. 
• KCCQ-12 questionnaire (Visit 4 ONLY) 
• An appointment for Visit 4 will be made at Visit 3  
10.1.2.3 On-site Visit 5 (Week 4) 
The following procedures/assessments will be performed at Visit 5 (Month 1): 
• Measurement of body weight 
• Vital signs (sitting BP, heart rate) 
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• 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) 
• Abbreviated physical examination, including lower extremities 
• IMP compliance 
• 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 (as 
applicable, to be recorded in source documents). Alternate contact information for patients 
(ie, relative or friend) should also be reviewed as a backup 
• The following laboratory testing: 
- 
Hematology 
- 
Chemistry (including eGFR) 
- 
NT-proBNP 
- 
Sotagliflozin/metabolite levels may be analyzed via routine blood samples collected at 
this visit  
- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
• KCCQ-12 questionnaire 
• An appointment for Visit 6 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 6). 
10.1.2.4 On-site Visit 6 (Month 4) 
The following procedures/assessments will be performed at Visit 6 (Month 4): 
• 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) 
• Abbreviated physical examination, including lower extremities 
• IRT contact 
• IMP is dispensed 
• IMP accounting and compliance 
• Concomitant medications are assessed  
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• 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 (as 
applicable, to be recorded in source documents). Alternate contact information for patients 
(ie, relative or friend) should also be reviewed as a backup 
• The following laboratory testing: 
- 
NT-proBNP 
- 
HbA1c 
- 
Hematology 
- 
Chemistry (including eGFR) 
- 
Lipids 
- 
Sotagliflozin/metabolite levels may be analyzed via routine blood samples collected at 
this visit 
- 
Urine pregnancy testing for WOCBP (any positive urine test results must be confirmed 
by a serum pregnancy test) 
• KCCQ-12 questionnaire 
• An appointment for Visit 7 will be made 
10.1.2.5 On-site Visits 7 to 12 (Months 8, 12, 16, 20, 24, 28) 
The following procedures/assessments will be performed (except when noted) at on-site Visits 7 
(Month 8), 8 (Month 12), 9 (Month 16), 10 (Month 20), 11 (Month 24), and 12 (Month 28), up 
until the end of study: 
• 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) 
• Abbreviated physical examination, including lower extremities 
• IRT contact 
• IMP is dispensed 
• IMP accounting and compliance 
• 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 (as 
applicable, to be recorded in source documents). Alternate contact information for patients 
(ie, relative or friend) should also be reviewed as a backup 
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• 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) 
• Complete physical examination, including lower extremities 
• IRT contact 
• Concomitant medications are assessed  
• 12-lead ECG 
• The following laboratory testing: 
- 
NT-proBNP  
- 
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) 
• KCCQ-12 questionnaire 
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: 
• Vital signs (sitting BP, heart rate) 
• Abbreviated physical examination, including lower extremities 
• Measurement of eGFR  
• IRT contact 
• 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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10.2 
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 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued until the Study Closeout Visit 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 must be fully documented in the 
e-CRF. In any case, the patient should remain in the study and be followed for the remainder of 
the study duration to collect vital safety status and endpoint data. Where the patient is taking 
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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 products 
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. This is in part due to the fact that a patient is 
expected to participate in the study for a period potentially lasting several years. 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 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. 
If DKA is suspected or confirmed, study treatment should be stopped immediately and should not 
be re-started unless another cause for the ketoacidosis is identified and resolved. 
In addition, IMP administration should be stopped in patients admitted to the hospital for major 
surgical procedures or due to serious illness. 
If a patient who is on an ACE-i/ARB does not tolerate the combination of the ACE-i/ARB with 
IMP due to hypotension/volume depletion, and one of the two agents (either the ACE-i/ARB or 
IMP) needs to be withheld, the ACE-i/ARB should be maintained, and the IMP should be 
withheld (temporarily if possible). 
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 responsibility of the IMP in the occurrence of the concerned event was unlikely. 
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 
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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. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
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 ≥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 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reason(s) for treatment discontinuation and this should be documented in the 
e-CRF. 
Patients who report a CV or renal endpoint as described in Section 10.4.1.4 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 
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• Estimated glomerular filtration <15 mL/min/1.73 m2  
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 or ECG parameter will be immediately rechecked for 
confirmation before making a decision of permanent discontinuation of the 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. 
10.3.5 Procedure and consequence for patient withdrawal from study 
The 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. 
The Investigators should discuss with them key visits to attend. The value of all their 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 patient contacts should be distinguished from withdrawal of consent for non-patient 
contact follow-up, medical records check. The site should document any case of withdrawal of 
consent. 
For patients who fail to return to the site, unless the patient withdraws consent for contact, the 
Investigator must make the best effort to recontact the patient, and to determine his/her 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 Closeout 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 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, independent ethics committee 
(IECs)/institutional review boards (IRBs), 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 10.4.1.4) that at any dose: 
• Results in death, or 
• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
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• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent 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 ED 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 
(Please refer to related flowchart in Appendix E) 
- 
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 aggravated during the study 
- 
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 
- 
Adverse events leading to amputation(s) 
- 
Diabetic ketoacidosis  
10.4.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) 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 
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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 AESIs 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 be qualified 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 (see Appendix A). 
• Symptomatic overdose (serious or nonserious) with IMP 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined as administration of more than twice the intended daily dose of 
IMP within a 24-hour period..  
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 
• ALT ≥3 ULN (if baseline ALT < ULN) or ALT ≥2 times the baseline value (if baseline 
ALT ≥ ULN) (Please refer to related flowchart in Appendix D).  
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. 
The EOSIs for this study are: 
• Venous thrombotic events to include deep venous thrombosis and thromboembolism (to 
include pulmonary embolism) 
• Pancreatitis 
• Bone fractures 
• Adverse events leading to amputation(s) 
• Diabetic ketoacidosis (see Section 10.4.7 for further details) 
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• 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. 
All Cardiovascular events 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 all CV events 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 all CV events will be waived: 
• Cardiovascular death 
• Any MI 
• Unstable angina 
• Any stroke 
• Heart failure leading to hospitalization 
• Urgent HF visit (as defined in Appendix B) 
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. 
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• 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, 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 progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
At the prespecified study end-date, patients who experience an ongoing SAE or an AESI 
should be followed until resolution, stabilization, or death and related data will be 
collected.  
• 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:  
- 
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 
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 monitoring team 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 representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient’s identity is protected and the patient’s 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
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• 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 management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix D. 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 
2 study visits should be followed up as described in Appendix E. 
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 E) 
In the event that the ‘general guidance for the follow-up of laboratory abnormalities by Sanofi’ 
Appendix D requires discontinuation of IMP, temporary discontinuation should be considered 
unless otherwise specified (please see Section 10.3.1). 
10.4.7 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). 
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Whenever AE data is collected or the patient reports DKA or intercurrent illness (including 
infections), generalized weakness, increased weight loss, GI symptoms including nausea, 
vomiting, or abdominal pain or other symptoms or signs that the Investigator believes may be 
consistent with DKA, the site will determine if an assessment for DKA, such as assessing blood 
beta-hydroxybutyrate level (BHB), is appropriate. If BHB or other laboratory testing confirms the 
presence of metabolic acidosis, then the “Possible DKA” e-CRF will be completed. 
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 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 ≥3 ULN (if baseline ALT < ULN) or ALT ≥2 times the baseline value (if 
baseline ALT ≥ ULN) (Please refer to related flowchart in Appendix D). 
Adverse events that are considered expected will be specified by the reference safety information 
provided in the current IB.  
If required, unblinding of SUSARs will be the responsibility of the Sponsor. 
The Sponsor will report all safety observations made during the conduct of the trial in the CSR. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, IV glucose, or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness, or coma. Plasma 
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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. 
If the event fulfills SAE criteria, the severe hypoglycemia will also be reported as an SAE. 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 (50, 51). 
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 by primary endpoints of time to first occurrence of CV death or HHF in 
patients with LVEF <50%, and in the total patient population. In order to achieve the target 
number of events of 947 first occurrence of CV death/HHF in patients with LVEF <50% and 
1341 first occurrences of CV death/HHF in the total patient population, it is estimated that 
approximately 4000 patients will be randomized over an estimated 29 months of recruitment 
period with approximately 3 months of follow-up after the last patient is randomized. 
The sample size calculation is based on the following trial design assumptions:  
• A recruitment period of approximately 29 months 
• Approximately 3 months of follow-up after the last patient is randomized 
• 29.2%, 39.7% and 44.5% event rate by Month 6, Month 12, and Month 24, respectively, in 
the placebo group (by assuming yearly hazard rate at Months 1, 2, 3, 4, 5, 6, 12, 24, and 36 
be 1.06, 0.87, 0.74, 0.62, 0.49, 0.36, 0.32, 0.08, and 0.05, respectively)  
• Hazard ratio (HR) = 0.81 for sotagliflozin versus placebo for patients with LVEF <50% 
and for patients with LVEF ≥50%  
• 2% annual censoring rate  
This will provide:  
• 90% power (with α=0.05, 2-sided) to demonstrate superiority of the primary endpoint 
(first occurrence of CV death or HHF) comparing sotagliflozin versus placebo in patients 
with LVEF <50%. 
• More than 90% power (with α=0.05, 2-sided) to demonstrate superiority of the primary 
CV endpoint (first occurrence of CV death or HHF) comparing sotagliflozin versus 
placebo in the total patient population.  
This is an event-driven study. Therefore, the study will continue until approximately 947 primary 
events (first occurrence of CV death or HHF) have been positively adjudicated in patients with 
LVEF <50%, AND approximately 1341 primary events (first occurrence of CV death or HHF) 
have been positively adjudicated in total patient population, and ≥3 months follow-up for the last 
randomized patient.  
Calculations were based log-rank test with user defined survival, accrual and drop-out rates by 
using EAST 6.4.  
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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 database, 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. 
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 
actually received. 
11.3.1.1 Intent–to-treat /modified intent-to-treat population 
Intent-to-treat (ITT) population: all randomized patients 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 ≥1 dose of double-blind IMP (regardless of the amount of treatment administered). 
Patients will be analyzed for safety 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 with the longest duration. 
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11.3.3 Patient-reported outcome analysis populations 
The patient-reported outcome (PRO) KCCQ-12 evaluation will be based on patients included in 
the efficacy population who have Baseline PRO assessment, at least 1 IMP administration, and at 
least 1 post-baseline PRO assessment. 
11.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of observations 
available, mean, SD, minimum, median, and maximum.  
Categorical data will be summarized by treatment group using count and percentage (%). 
In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from Baseline) by scheduled visits will be provided on observed cases (OC), ie, inclusion of 
patients having non-missing assessments at a specific visit only. 
Baseline for eGFR is defined as the value assessed by the central laboratory at 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. 
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 for the safety population. 
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 
for 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. 
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11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the 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, minimum, and 
maximum). The percentage of patients with compliance <80% will be summarized. 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoints 
The time to the first occurrence of CV death or HHF in patients with LVEF <50% will be 
analyzed by using stratified log-rank test with region (North America, Latin America, Western 
Europe, Eastern Europe, and rest of the world) as stratification factor. Stratified Cox proportional 
hazards model with region (North America, Latin America, Western Europe, Eastern Europe, and 
rest of the world) as stratification factor and treatment (sotagliflozin, placebo) as fixed effect 
factor will be used to provide the HR estimation between sotagliflozin and placebo along with its 
associated 2-sided 95% confidence interval (CI). 
The time to the first occurrence of CV death or HHF in the total patient population will be 
analyzed by using stratified log-rank test with LVEF (<50%, ≥50%) and region (North America, 
Latin America, Western Europe, Eastern Europe, and rest of the world) as stratification factors. 
Stratified Cox proportional hazards model with LVEF (<50%, ≥50%) and region (North America, 
Latin America, Western Europe, Eastern Europe, and rest of the world) as stratification factors 
and treatment (sotagliflozin, placebo) as fixed effect factor will be used to provide the HR 
estimation between sotagliflozin and placebo along with its associated 2-sided 95% CI. 
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 complete the study), or date of 
non-CV death, or date of last contact when information on efficacy endpoints has been retrieved 
(for patients who discontinue the study). Underlying assumptions of the Cox proportional hazards 
model will be checked using graphical methods. If proportionality is not observed, further 
sensitivity analysis will be performed (details will be specified in the SAP). 
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 up to study 
completion (whichever is later), but not beyond the patient’s end of study date (Follow-up Visit 
for patient completed study or Study Closeout Visit for patient prematurely permanently 
discontinued study), using the same stratified log-rank test and stratified Cox proportional hazards 
model described above. 
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Subgroup analysis 
Subgroup analyses will be conducted for the primary endpoints with respect to LVEF (for second 
primary endpoint only), region, age, gender, race, ethnicity, Baseline eGFR, and Baseline BMI 
group. Additional subgroups and analysis details will be provided in the SAP. 
11.4.2.2 Analyses of secondary efficacy endpoints 
The total number (ie, including recurrent events) of CV death, HHF, or urgent HF visit will be 
analyzed using the Andersen-Gill approach (52), a generalization of the Cox proportional hazards 
model for recurrent events with treatment, LVEF, and region as factors. For standard errors in the 
Andersen-Gill model, a robust variance estimator will be used (53). 
Secondary time to event endpoints will be analyzed using the same stratified log-rank test with 
LVEF (<50%, ≥50%) and region (North America, Latin America, Western Europe, Eastern 
Europe, and rest of the world) as stratification factors. Stratified Cox proportional hazards model 
with LVEF (<50%, ≥50%) and region (North America, Latin America, Western Europe, Eastern 
Europe, and rest of the world) as stratification factors and with treatment (sotagliflozin, placebo) 
as fixed effect factor will be used to provide the HR estimation between sotagliflozin and placebo 
along with its associated 2-sided 95% CI. The LVEF factor will not be included in the statistical 
model as stratification factor if the endpoint is defined in patients with LVEF <50%. Kaplan-
Meier curves of the cumulative incidence rates will be provided by treatment groups. 
11.4.2.3 Other endpoints 
Other time to event endpoints will be analyzed using the same stratified Cox proportional hazards 
model described for the second primary endpoint with LVEF and region (North America, Latin 
America, Western Europe, Eastern Europe, and rest of the world) as stratification factors and 
treatment as fixed effect factor. The LVEF will not be included in the statistical model as 
stratification factor if the endpoint is defined in a subgroup of patients by LVEF, eg, LVEF<40%. 
Number (%) of patients with at least 1 new onset of atrial fibrillation, atrial flutter, or ventricular 
arrhythmia since Randomization will be summarized by treatment group. For other endpoint of 
changes in concomitant loop diuretic medications, summary tables will be provided. 
Analysis of other endpoints will be descriptive with no statistical testing. Summary statistics at 
scheduled visits using observed data will be provided by treatment group. Graphical presentations 
will also be used to illustrate trends over time if applicable. 
11.4.2.4 Multiplicity considerations 
The graphical approach (1) will be used to control the family-wise type 1 error rate at 0.05 levels.  
In graphical approach, the testing procedure is fully determined by an initial weighted graph 
where the elementary hypotheses are represented by vertices with associated weights representing 
the local significance levels. The weight associated with a directed edge between any two vertices 
indicates the fraction of the (local) significance level at the initial vertex (tail) that is added to the 
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significance level at the terminal vertex (head) if the hypothesis at the tail is rejected. Together 
with the algorithm as specified by Bretz et al (1) for sequentially updating the graph after rejection 
of a hypothesis, this approach controls the family-wise type I error rate strongly at level α. 
As shown by Bretz et al., (1) the test decisions are independent of the order of rejection. If in a 
step of the algorithm more than one hypothesis can be rejected, the choice of the hypothesis Hi 
does not influence the total set of hypotheses that eventually can be rejected. The initial graph and 
the algorithm unequivocally define the testing strategy.  
Initial Graph:  
 
 
Note: =0.001.  
There are two primary hypotheses and six secondary hypotheses will be included in the multiple 
testing procedure as below:   
Primary hypotheses:  
H1: Time to first occurrence of CV death or HHF in patients with LVEF <50% 
H2: Time to first occurrence of CV death or HHF in the total patient population 
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Secondary Hypotheses  
H3: Total number (ie, including recurrent events) of CV death, HHF, or urgent HF visit in 
total patient population 
H4: Time to CV death in patients with LVEF <50%  
H5: Time to all-cause mortality in patients with LVEF <50%  
H6: Time to first occurrence of the composite of positively adjudicated sustained ≥50% 
decrease in eGFR from Baseline (for ≥30 days), chronic dialysis, renal transplant, or 
positively adjudicated sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days) in total patient 
population 
H7: Time to CV death in total patient population 
H8: Time to all-cause mortality in total patient population  
All tests will be two-sided. Significance levels 
 
(
) are initially defined such that they sum up to 
. 
The procedure is as follows: Test the hypotheses Hi, i=1, 2, …. 8, each at its local significance 
level 
. If a hypothesis Hi can be rejected, reallocate its level to other hypotheses according to a 
pre-specified rule represented by the initial weighted graph. Update the reallocation weights in the 
reduced graph and repeat the testing step for the remaining, non-rejected hypotheses with the 
updated local significance levels. This possibility leads to further rejected null hypotheses with the 
updated local significance levels. The procedure is repeated until no further hypothesis can be 
rejected. 
The reallocation of the local alpha levels is fully determined by the initial graph of the multiple 
testing strategy. 
No further multiplicity adjustments will be made for other efficacy endpoints or subgroup 
analyses for which nominal p-values may 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 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: 
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• 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. Potentially 
clinically significant abnormality criteria for parameters not cited in the protocol as safety 
parameters will not be analyzed. 
• The 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. 
Please note that the same observation period will be used for all safety observations (ie, AE and 
death). 
The “observation periods” of safety data as defined below are applicable for classification of AEs, 
deaths, determination of on-treatment PCSA values and the last on-treatment value for the 
laboratory, vital sign, and ECG parameters. The observation period of safety data will be divided 
into 3 segments: 
• The Screening period is defined as the time from signed informed consent to 
Randomization.  
• 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).  
• On-study observation period is defined as the time from randomization until the end of the 
study. 
11.4.3.1 Analysis of adverse events  
Pre-treatment AEs are AEs that developed or worsened or became serious during the time 
between date of informed consent and the first dose of double-blind IMP. 
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 10.4.1.4. 
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All adverse events 
The number (%) of patients with at least 1 AE will be tabulated 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 by treatment group. Multiple occurrences of 
the same event for the same patient will be counted only once in the tables within a treatment 
period. The denominator for computation of percentages is number of patients within each 
treatment arm in the safety population. 
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 
- 
Treatment-emergent AE leading to death 
- 
Treatment -emergent AE leading to permanent treatment discontinuation 
• The number (%) 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 
Deaths and treatment-emergent SAEs will be summarized and presented as number (%) of 
patients by treatment group. 
The following deaths will be summarized by treatment received for the safety population:  
• Number (%) of patients died by study period (on-study and on-treatment) and the 
adjudicated death reason.  
• Death in nonrandomized patients or randomized but not treated patients. 
• Number (%) of patients with 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, sorted by 
internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT.  
• Number (%) of patients with 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, 
presenting 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 
All TEAEs leading to permanent treatment discontinuation will be summarized and presented as 
number (%) of patients in each treatment group. 
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11.4.3.2 Analysis of severe hypoglycemia 
The number (%) of patients and rate in patient-year (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 will be included in laboratory PCSA summary if any. 
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 interests 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 Medical Dictionary for Regulatory Activities 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 variable  
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 
post-baseline visit by Baseline status will be displayed by treatment group for each parameter. 
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The proportion of patients with PCSA values at any post-baseline 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. 
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 by 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. For each vital sign parameter, its value and change from Baseline will be 
summarized for visit and the last on-treatment value by treatment group. Tabular and graphical 
methods may be used to present the results for parameters of interest. Listings will be provided 
with flags indicating PCSA values. 
11.4.4 Analyses of patient reported outcomes (health-related quality of life/health 
economics variables) 
Summary statistics of KCCQ-12 scores will be provided at scheduled visits by treatment group. 
Graphical presentations will also be used to illustrate trends over time. Further details will be 
provided in the SAP.   
11.5 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned for this study. The study will not be terminated 
early for excellent efficacy. 
An independent DMC was formed to monitor the safety data and benefit/risk in the entire Phase 3 
(outcome and non-outcome) Sotagliflozin program, including this trial. The DMC will regularly 
review the safety data provided by an independent statistical group. Related details are available 
in separate documents (DMC charter and DMC SAP). 
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The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, ICF, IB with any addenda or labeling documents [summary of 
product characteristics, package insert], Investigator’s curriculum vitae [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 IB or labeling information, will 
be sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the 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 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators 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.  
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 informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
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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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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator 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 IB, and the results obtained during 
the course of the clinical trial, is confidential, prior to the publication of results. The Investigator 
and any person under his/her authority agree to undertake to keep confidential and not to disclose 
the information to any third party without the prior written approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators 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, good clinical practice, 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 
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• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
• The total number of patients are included earlier than expected 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a CSR and to provide a summary of study results to 
the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned, the Investigator shall have the right to publish or present independently the results of 
this study in agreement with other Investigators and stakeholders. The Investigator shall provide 
the Sponsor with a copy of any such presentation or publication for review and comment at least 
30 days in advance of any presentation or submission for publication. In addition, if requested by 
the Sponsor, any presentation or submission for publication shall be delayed for a limited time, 
not to exceed 90 days, to allow for filing of a patent application or such other justified measures 
as the Sponsor deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
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shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
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16 
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26. 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 Nov 
26;373(22):2117-28. 
27. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin 
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10.1056/NEJMoa1611925. [Epub ahead of print]. 
28. U.S. Food and Drug Administration. FDA approves Jardiance to reduce cardiovascular death 
in adults with type 2 diabetes. Available from URL: 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm. 
[Accessed 05 December 2016. 
29. 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 
May;39(5):717-25. 
30. McMurray J. EMPA-REG - the “diuretic hypothesis”. J Diabetes Complications. 2016 Jan-
Feb;30(1):3-4. 
31. Raz I and Cahn A. SGLT2 inhibitors and heart failure -- clinical implications. Nat Rev 
Cardiol. 2016 Apr;13(4):185-86. 
32. 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 May 14;37(19):1526-34. 
33. Inoue BH, dos Santos L, Pessoa TD, Antonio EL, Pacheco BP, Savignano FA, et al. Increased 
NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure. Am 
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34. Spencer AG, Labonte ED, Rosenbaum DP, Plato CF, Carreras CW, Leadbetter MR, et al. 
Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and 
inhibits Na+ uptake in humans. Sci Transl Med. 2014 Mar 12;6(227):227ra36. 
35. Ferannini E, Mark M, Mayoux E. Cardiovascular Protection in the EMPA-REG OUTCOME 
Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016 Jul;39(7):1108-14. 
36. Škrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal 
protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015 Jan;24(1):96-103. 
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37. Sha S, Devineni D, Ghosh A, Polidori D, Hompesch M, Arnolds S, et al. Pharmacodynamic 
effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study 
in patients with type 2 diabetes. PLoS One. 2014 Aug 28;9(8):e105638. 
38. Lapuerta P, Zambrowicz B, Strumph P, Sands A. Development of sotagliflozin, a dual 
sodium-dependent glucose transporter 1/2 inhibitor. Diab Vasc Dis Res. 2015 Mar;12(2):101-
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39. Wright EM. Glucose galactose malabsorption. Am J Physiol. 1998 Nov;275(5 Pt 1):G879-82. 
40. LX4211.1-202-DM: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, 
Parallel Group Study to Evaluate the Safety and Efficacy of LX4211 in Combination with 
Metformin in Subjects with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic 
Control on Metformin Monotherapy. Lexicon Pharmaceuticals. 03 June 2014. 
41. LX4211.1.201: A Phase 2, Single-center, Randomized, Double-blind, Placebo-controlled, 
Multiple-dose Study to Determine the Safety and Efficacy of Orally Administered LX4211 in 
Subjects with Type 2 Diabetes Mellitus. Lexicon Pharmaceuticals. 30 July 2010. 
42. 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 Jul;38(7):1181-88. 
43. Weatherley BD, Milo-Cotter O, Felker GM, Uriel N, Kaluski E, Vered Z, et al. Early 
worsening heart failure in patients admitted with acute heart failure–a new outcome measure 
associated with long-term prognosis? Fundam Clin Pharmacol. 2009;23(5):633–639. 
44. Kosiborod  M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of 
heart failure and death in patients initiated on SGLT2 inhibitors versus other glucose-lowering 
drugs: The CVD-REAL Study. Circulation. 2017;136:249-59. 
45. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas 
City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll 
Cardiol. 2000;35(5):1245-1255. 
46. Spertus JA, Jones PG. Development and Validation of a Short Version of the Kansas City 
Cardiomyopathy Questionnaire. Circ Cardiovasc Qual Outcomes. 2015;8(5):469-476. 
47. Armstrong DG, Lavery LA. Diabetic foot ulcers: prevention, diagnosis and classification. Am 
Fam Physician. 1998 Mar 15;57(6):1325-32, 1337-8. 
48. American Diabetes Association. Foot Care. 2014. Available at: 
http://www.diabetes.org/living-with-diabetes/complications/foot-complications/foot-care.html 
[accessed December 2017] 
49. International Diabetes Federation. IDF Clinical Practice Recommendations on the Diabetic 
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50. 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. 
51. 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 
52. Andersen PK, Borgan O, Gill RD,  Keiding, N. Statistical Models Based on Counting 
Processes. 1992 New York: Springer-Verlag. 
53. Lin DY, Wei LJ. The robust inference for the Cox proportional-hazards model. J Am Stat 
Assoc 1989;84:1074–1078. 
54. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, et al. 2014 ACC/AHA 
Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: a 
report of the American College of Cardiology/American Heart Association Task Force on 
Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data 
Standards). Circulation. 2015 Jul 28;132(4):302-61. 
55. European Medicines Agency. SGLT2 inhibitors: PRAC makes recommendations to minimise 
risk of diabetic ketoacidosis. 2016. 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/02/news_d
etail_002470.jsp&mid=WC0b01ac058004d5c1 Accessed November 2017 
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17 
APPENDICES 
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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 
Definition of urgent heart failure visit 
An urgent HF Visit is defined as an event that meets all of the following (in accordance with the 
2014 Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials 
guidance document [54]): 
1. The patient has an urgent, unscheduled office/practice or ED visit for a primary diagnosis 
of HF, but not meeting the criteria for a HF hospitalization  
2. The following signs and symptoms for HF hospitalization (ie, symptoms, physical 
examination findings/laboratory evidence of new or worsening HF) must be met: 
The patient exhibits documented new or worsening symptoms due to HF on presentation, 
including at least ONE of the following symptoms:  
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 (must be 
specified and described by the protocol 
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 heart failure, including new or 
worsened: 
a) Peripheral edema 
b) Increasing abdominal distention or ascites (in the absence of primary hepatic 
disease) 
c) Pulmonary rales/crackles/crepitations 
d) Increased jugular venous pressure and/or hepatojugular reflux 
e) S3 gallop 
f) Clinically significant or rapid weight gain thought to be related to fluid retention 
B) Laboratory evidence of new or worsening HF, if obtained within 24 hours of 
presentation, including: 
a) Increased B-type natriuretic peptide (BNP)/ N-terminal pro-BNP (NT-proBNP) 
concentrations consistent with decompensation of heart failure (such as BNP 
>500 pg/mL or NT-proBNP >2000 pg/mL). In patients with chronically elevated 
natriuretic peptides, a significant increase should be noted above Baseline. 
b) Radiological evidence of pulmonary congestion 
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c) 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 (LVOT) minute stroke 
distance (time velocity integral [TVI])  
OR  
d) 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 
3. The patient receives initiation or intensification of treatment specifically for HF, including 
at least one of the following (NOTE: augmentation of oral diuretic therapy will not be 
considered sufficient): 
A) Intravenous diuretic or vasoactive agent (eg, inotrope, vasopressor, or vasodilator)  
B) Mechanical or surgical intervention, including: 
a) Mechanical circulatory support (eg, intra-aortic balloon pump, ventricular assist 
device, extracorporeal membrane oxygenation, total artificial heart)  
b) Mechanical fluid removal (eg, ultrafiltration, hemofiltration, dialysis) 
 
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Appendix C 
Kansas City Cardiomyopathy Questionnaire-12 
 
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Appendix E 
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 
2 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 (this 
repeat renal assessment may occur beyond the last planned visit per protocol). 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/1.73 m2 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 F 
Diabetic ketoacidosis 
Recognizing diabetic ketoacidosis 
Diabetic ketoacidosis, including atypical (euglycemic) DKA, is the most serious emergency in 
patients with T1D and T2D. Common precipitating factors include infections, intercurrent 
illnesses, psychological stress and noncompliance with insulin therapy. Clinical features of DKA 
at presentation can be nonspecific; however most patients complain of polydipsia and polyuria for 
several days before onset of DKA. Symptoms of DKA include rapid weight loss, nausea or 
vomiting, stomach pain, excessive thirst, fast and deep breathing, confusion, unusual sleepiness or 
tiredness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odor to 
urine or sweat (55). 
It is possible that GI or other AEs occurring with sotagliflozin may mask presenting symptoms of 
DKA. Because sotagliflozin lowers blood glucose by insulin independent SGLT1 and SGLT2 
inhibition, it is possible for DKA to be present with normal or low blood glucose. Therefore, the 
Investigator must still consider a DKA event even if blood glucose is low or normal.  
More information can be found in the sotagliflozin IB. 
If DKA is suspected or confirmed, study treatment should be stopped immediately and should not 
be re-started unless another cause for the ketoacidosis is identified and resolved. 
Caution should be exercised in patients with risk factors for ketoacidosis and patients should be 
informed of the risk factors. These include low reserve of insulin-secreting cells, conditions that 
restrict food intake or can lead to severe dehydration, a sudden reduction in insulin or an increased 
requirement for insulin due to illness, surgery or alcohol abuse. 
In addition, IMP administration should be stopped in patients in hospital for major surgical 
procedures or due to serious illness. 
Whenever AE data is collected or the patient reports DKA or intercurrent illness (including 
infections), generalized weakness, increased weight loss, GI symptoms including nausea, 
vomiting, or abdominal pain or other symptoms or signs that the Investigator believes may be 
consistent with DKA, the site will determine if an assessment for DKA, such as assessing blood 
BHB, is appropriate. If BHB or other laboratory testing confirms the presence of metabolic 
acidosis, then the “Possible DKA” e-CRF will be completed. 
Patient communication cards will be printed with the following: 
“If you have any of these symptoms on the list, then contact your study site immediately for 
assistance with managing your diabetes: 
• Inability to maintain oral intake 
• Generalized weakness 
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• Abdominal (belly) pain 
• Increased weight loss 
• Fever 
• Frequent urination, including at night 
• Fruity-scented breath 
• Confusion 
• Acute illness 
• Consistently elevated blood glucose 
• Feeling very thirsty or drinking a lot 
• Nausea or vomiting 
• Having trouble thinking clearly or feeling tired. 
It is possible to have DKA even if your blood glucose is not elevated. Regardless of your blood 
glucose level, if you have any of these symptoms on the list, then contact your study site 
regarding the need to be evaluated for possible DKA, which will include specific blood testing. If 
your study site is closed and your study doctor is not available, go to the nearest emergency room 
for evaluation. 
If you are scheduled for a procedure or surgery that requires you to not take any food or liquids, 
please contact your study doctor for instructions on continuing study drug. In such cases your 
study doctor may advise you NOT to take your study drug from the day prior to the procedure or 
surgery until after the procedure or surgery is complete, and you are taking food and liquids as 
you normally do.” 
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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 
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C o nt e nts 
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 ......... ............................................. 5 
1. 1  
B A C K G R O U N D ................................................................................................................ 5  
1. 2  
O BJ E C TI V E S ..................................................................................................................... 6  
1. 2. 1        Pri mar y o bjecti ve................................. ...................................................................... 6 
1. 2. 2        Sec o n dar y o bjecti ves ............................. .................................................................... 6 
1. 3  
D E T E R MI N A TI O N O F S A M P L E SI Z E .................................. ......................................... 6 
1. 4  
S T U D Y P L A N .................................................... ................................................................ 6 
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 ..... ........................................ 8 
2. 1  
A N A L Y SI S E N D P OI N T S ............................................ ..................................................... 8 
2. 1. 1 De m o gra p hic a n d ba seli ne c haracteristics ........................................................................ 8 
2. 1. 2 Baseli ne me dicati o ns a n d de vices ........................ ............................................................ 9 
2. 1. 3 Efficac y e n d p oi nts ...................................... ...................................................................... 9 
2. 1. 4 Safet y e n d p oi nts ........................................ ..................................................................... 1 1 
2. 1. 5 Q ualit y- of-life e n d p oi nts ( K C C Q- 1 2) ..................... ....................................................... 1 4 
2. 2  
DI S P O SI TI O N O F P A TI E N T S ....................................... ................................................. 1 4 
2. 3  
A N A L Y SI S P O P U L A TI O N S .......................................... ................................................ 1 5 
2. 3. 1 Ra n d o mize d p o p ulati o n ................................... ............................................................... 1 5 
2. 3. 2        Efficac y p o p ulati o n .............................. ................................................................... 1 6 
2. 3. 3        Safet y p o p ulati o n ..................................................................................................... 1 6  
2. 4  
S T A TI S TI C A L M E T H O D S ........................................... .................................................. 1 6 
2. 4. 1        De m o gra p hics a n d ba seli ne c haracteristics ............................................................. 1 6 
2. 4. 2       C o nc o mita nt me dicati o ns ........................... .............................................................. 1 6  
2. 4. 3 E xte nt of i n vesti gati o na l me dici nal pr o d uct e x p os ure a n d d ose titrati o n ....................... 1 6  
2. 4. 4 A nal yses of efficac y e n d p oi nts .......................... ............................................................. 17  
2. 4. 5 A nal yses of safet y data ................................. .................................................................. 2 0 
2. 5 Data ha n dli n g c o n ve nti o ns ................................. ............................................................... 2 2 
2. 5. 1 Ge neral c o n ve nti o ns ..................................... .................................................................. 2 2 
2. 5. 2 Data ha n dli n g c o n ve nti o ns  f or sec o n dar y efficac y varia bles ......................................... 2 2 
2. 5. 3          Missi n g data ................................... ....................................................................... 2 2 
Refere nces .................................................... ............................................................................... 2 4 
A p pe n di x A Assi g n me nt of dates t o e ve nts ................................................................................ 2 5  
A p pe n di x B Ka nsas Cit y Car di o m y o pat h y Q uesti o n naire ........... ............................................... 2 8 
A P P E N DI X C  P Ts f or selecte d E O SI ( Me d D R A v 2 3. 0) .............. ............................................ 3 2 
A p pe n di x D Ke y C ha n ges t o Ori gi na l Pla n ne d A nal ysis a n d Pr ot oc ol ...................................... 3 8 


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0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
Pr o p ert y of t h e 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  
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 sp ecial 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 FR   
Esti mate d gl o mer ular filtrati o n rate
E O SI  
E ve nts of s pecial i nteres t
H b A 1c  
He m o gl 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 ular ejecti o n fracti o n
MI 
M y ocar dial i nfarcti o n
P D A O H  
Perce nt da ys 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  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
Pr o p ert y of t h e 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  
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 O L OI S T is a P hase 3, m ultice nter, ra n d o mize d, d o u ble- bli n d, pl ace b o-c o ntr olle d, parallel gr o u p, 
stratifie d st u d y of s ota glifl ozin f or t he treat me nt of patie nts  wit h w orse ni n g heart fail ure.  
 
After scree ni n g, patie nts w h o me t 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 placeb o at ra n d o mizati o n visit. Ra n d o mizati o n was stratifie d b y baseli ne 
left ve ntric ular ejecti o n fractio n ( L V E F) ( L V E F < 5 0 % a n d L V E F ≥5 0 %) a n d re gi o n ( N ort 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).  
 
T he ori gi nal pla n was t o ra n d o m ize a p pr o xi matel y 4 0 0 0 patie nts. H o we ver, S O L OI S T e nr oll me nt 
was cl ose d i n Marc h 2 0 2 0 bef ore meeti n g t his o bjecti ve.  
 
A rece nt p u blicati o n i n t he J o ur n al of t he A merica n C olle ge of Car di ol o g y disc uss e d h o w cli nical 
trials a n d pr o gra ms ha ve bee n disr u pte d b y t he C O VI D- 1 9 pa n de mic. 1 It pr o vi de d t he 
s ota 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 dic ati o n of e ve nts. S i 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 nt ial 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 paratel y verifie d b y t he Le xic o n statistical tea m. It a d dresses iss ues relate d t o t he 
earl y ter mi nati o n of S O L OI S T. T he se iss ues ha ve bee n re vie we d an 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 fa s hi o n wit h o ut t he use of a n y u nbli n de d i nteri m a nal ysis.   
 
T he ter mi nati o n of e nr oll me nt a n d f oll o w- u p of S O L OI S T 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 r eflecte d i n t his d oc u me 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 here 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 o tal (first a n d p ote ntiall y s u bseq ue nt) i n vesti gat or-re p orte d e ve nts. 
T his f oc us ca pt ures t he i m pact o f treat me nt i n act ual practice. Rec urre nt h os pitalizati o n f or heart 
fail ure, as rec o g nize d a n d treated b y t he me dical c o m m u nit y, is  ver y fre q ue nt a n d has 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 of 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 gat or-re p orte d e ve nts i n 
S O L OI S T is a meas ure of hi g h cli n ical rele va nce, a n d c o nse q ue ntl y is a p pr o priate t o s u m marize 
t he effects of s ota glifl ozi n i n S O L OI S T. 
 
W hile lar ger st u dies ha ve bee n p erf or me d o n S G L T i n hi biti o n i n heart fail ure, t he y ha ve n ot bee n 
perf or me d i n a n ac ute setti n g of w orse ni n g heart fail ure. I n c o ntrast, s ota glifl ozi n has bee n 
i nitiate d at a ti me w he n patie nts ur ge ntl y nee d a d diti o nal treat me nt, a n d t his raises i m p orta nt 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
Pr o p ert y of t h e 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  
q uesti o ns a b o ut safet y a n d effic ac y of S G L T i n hi bit or w he n i nit iate d i n t he h os pital or 
i m me diatel y after disc har ge. F urt her m ore, s ota glifl ozi n i n hi bits b ot h S G L T 1 a n d S G L T 2, i n 
c o ntrast t o a p pr o ve d S G L T i n hi bi t ors t hat o nl y affect S G L T 2. A ge n o mic st u d y of re d uce d 
f u ncti o n variati o ns i n t he S G L T 1 ge ne f o u n d t hese variati o ns were ass ociate d wit h less c o n gesti ve 
heart fail ure a n d l o wer m ortalit y. 4 T he efficac y of s ota glifl ozi n may be t heref ore 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 ve 
T he pri mar y o bjecti ve of t his a n al ysis is t o c o m pare t he effect of s ota glifl ozi n t o place b o o n t he 
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 he m o d y na micall y sta ble patie nts  after a d missi o n f or w orse ni n g heart 
fail ure ( W H F). 
1. 2. 2         Sec o n d ar y o bjecti ves 
T he sec o n dar y o bjecti ves of t he st u d y are t o c o m pare t he effect s of s ota glifl ozi n t o place b o o n:  
 
T he t otal occ urre nces of H H F a n d ur ge nt visit f or H F 
 
T he occ urre nce of C V deat h 
 
T he occ urre nce of all-ca use m ortalit y  
 
T he t otal occ urre nces of C V deat h, H H F, ur ge nt visit f or H F, n o n-fatal m y ocar dial 
i nfarcti o n ( MI), a n d n o n-fatal str o ke 
 
C ha n ge i n K C C Q- 1 2 sc ore 
 
C ha n ge i n esti mate d gl o mer ul ar filtrati o n rate (e G F R) 
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 size of 4, 0 0 0 patie nts was base d o n a hazar d rati o of 0. 8 1 a n d t he 
desire t o e xa mi ne effects i n b ot h t he o verall p o p ulati o n a n d t h ose wit h L V E F > 5 0 %. Gi ve n t he 
earl y ter mi nati o n of S O L OI S T, t he  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 1 ha ve bee n re p orte d wit h 
S G L T i n hi biti o n i n sta ble heart  fail ure, t he p ote ntial f or efficac y ma y differ i n t he setti n g of ac ute 
w orse ni n g of heart fail ure ( w her e efficac y has n ot bee n e xa mi ne d t o date), a n d t he pr ofile of 
s ota glifl ozi n ( wit h gastr oi ntesti nal S G L T 1 i n hi biti o n i n a d ditio 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 T hese a nal yses are c o n d ucted 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. Of n ote, t he p o p ulati o n of S O L OI S T 
is descri be d as o ne wit h T 2 D. W hile a n a me n d me nt t o S O L OI S T allo we d t he e nr oll me nt of 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
Pr o p ert y of t h e 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  
patie nts wit h o ut T 2 D w h o ha d re d u ce d ejecti o n fracti o n, fe w s uc h patie nts were e nr olle d. T he 
pri mar y e n d p oi nt will be e xa mi ne d  f or all patie nts re gar dless of dia g n osis of T 2 D:  
 
   E D = E mer ge nc y De part me nt; F U = F oll o w- u p; H F = heart fail ure; I M P = i n vesti gati o nal me dici nal pr o d uct; T 2 D = t y pe 2 
dia betes; R = Ra n d o mizati o n; V = visit; W H F = w orse ni n g heart f ail ure; W k = Wee k. 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
8 
 
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 hic a n d b aseli ne c h ar acteristics 
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 par a 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 or at 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  
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 effect at t he ti me of data base l oc k.  
Me dic al hist ory of s pecific i nterest i ncl u des:  
 
Dia betes hist or y i nf or mati o n 
 
T y pe 2 dia betes ( yes/ n o) 
 
Heart fail ure hist or y:  
o  Pri nci ple ca use of heart fail ure (isc he mic, n o nisc he mic, u n k n o w n) 
o  Patie nt a d mitte d f or H F at least o ne ti me pri or t o t he i n de x e v e nt ( yes/ n o) 
o  Patie nt’s N Y H A class pri or t o i n de x e ve nt (a p pr o xi matel y 1 m o nt hs pri or t o i n de x 
e ve nt) ( Class I, II, III, I V, a n d u n deter mi ne d) 
 
Atrial fi brillati o n 
Dise ase c h ar acteris tics at b aseli ne   
 
L V E F (% ) 
 
L V E F cate g or y ( < 5 0 %, ≥5 0 %) 
 
e G F R (m L/ mi n/ 1. 7 m 2) 
 
% of patie nts wit h e G F R cate g or y < 6 0 m L/ mi n/ 1. 7 m
2 
 
H b A 1c ( %) 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
9 
 
Ot her c h ar acteristics at b aseli ne  
 
B o d y mass i n de x ( B MI) ( k g/ m 2) 
 
S yst olic bl o o d press ure ( S B P) ( m m H g) 
 
Heart rate ( beats/ mi n) 
 
N T- pr o B N P ( p g/ ml) 
2. 1. 2  B aseli ne me di c ati o ns a n d de vices 
 
Baseli ne me dicati o ns a re t h ose wit h a start date pri or t o ra n d omizati o n ( or a missi n g start 
date) a n d a n e n d date after ra n d o mizati 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 a n d de vices of 
s pecial i nterest will be s u m marize d: 
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 
He art f ail ure device  
I m ple me ntati o n stat us ( yes/ n o) of 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 a n d i nstea d will be treate d as pre-treat me nt a d verse e ve nts. 
I n t he a nal yses of ti me-t o-e ve nt efficac y e n d p oi nts: 
 
Deat hs n ot i ncl u de d a m o n g t he e v e 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 ore 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; a n d 
 
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 da y, m o nt h, 
a n d/ or year are missi n g), t he dat e will be i m p ute d as descri be d i n A p pe n di x . 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 0 
 
2. 1. 3. 1 Pri m ary effic acy e n d p oi nt  
T he pri mar y e n d p oi nt is t he n u m be r of t otal occ urre nces (first a n d p ote ntiall y s u bse q ue nt) of t he 
f oll o wi n g e ve nts: C V deat h, H H F, a n d ur ge nt H F visit after ra n do mizati o n 
2. 1. 3. 2 Sec o n d ary effic acy e n d p oi nts  
 
 
T otal occ urre nces (first a n d p ot e ntiall y s u bse q ue nt) of H H F a n d  ur ge nt H F visits 
 
Ti me fr o m ra n d o mizati o n t o occ urre nce of C V deat h 
 
T otal occ urre nces (first a n d p ot e ntiall y s u bse q ue nt) of C V deat h, H H F, n o n-fatal 
m y ocar dial i nfarcti o n, a n d n o n-fatal str o ke 
 
T otal occ urre nces (first a n d p ot e ntiall y s u bse q ue nt) of H H F, ur ge nt H F visit, C V deat h, 
a n d H F w hile h os pitalize d  
 
Ti me fr o m ra n d o mizati o n t o all-ca use m ortalit y 
 
C ha n ge i n K C C Q- 1 2 sc ores fr o m baseli ne t o M o nt h 4  
 
Rate of decli ne i n e G F R after Wee k 4 ( m L/ mi n/ 1. 7 3 m 2/ year) t o t h e e n d of t he st u d y  
2. 1. 3. 3 Ot her effic acy e n d p oi nt s  
 
First occ urre nce of C V deat h, H H F , or ur ge nt visit f or H F 
 
First occ urre nce of C V deat h or H H F  
 
T otal occ urre nces (first a n d p ot e ntiall y s u bse q ue nt) of H H F aft er ra n d o mizati o n  
 
T otal occ urre nces (first a n d p ot e ntiall y s u bse q ue nt) of ur ge nt H F visits after ra n d o mizati o n  
 
First occ urre nce of C V deat h, H H F, ur ge nt visit f or H F, n o n-fat al m y ocar dial i nfarcti o n, 
a n d n o n-fatal str o ke  
 
First occ urre nce of fatal a n d n o n-fatal MI  
 
First occ urre nce of fat al a n d n o n-fatal str o ke  
 
First occ urre nce of ne w o nset of atrial fi brillati o n or atrial fl utter (a d verse e ve nts ( A Es) 
wit h a preferre d ter ms ( P Ts) of atrial fi brillati o n or atrial f l utter) 
 
First occ urre nce of a c o m p osite  re nal e n d p oi nt, c o nsisti n g of eve nts 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 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) 
 
First occ urre nce of se vere h y p o gl yce mia  
 
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  
 
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)  


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 1 
 
 
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, b o d y wei g ht, a n d S B P  
 
All ti me-t o-e ve nt e n d p oi nts are a ssesse 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. 
T he first occ urre nce of t he c o m p osite re nal e n d p oi nt is defi ne d  as f oll o ws: 
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 u st ai n e d ≥5 0 % 
d e cr e a s e i n e G F R 
fr o m b a s eli n e 
C o nfir m e d ≥5 0 % d e cr e a s e i n e G F R f or ≥3 0 d a y s O R wit h n o r e p e at e G F R ≥3 0 
d a y s  a s r e c or d e d i n e C R F “ e G F R d e cr e a s 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  
Di alysis l ast e d f or ≥9 0 d ays ( e. g. e n d d at e – st art d at e + 1 ≥9 0) as r ec or d e d i n e C R F “ R e n al Ev e nt – 
Di alysis”, or  
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 Err or! 
R ef er e n c e s o urc e n ot 
f o u n d. 
“ 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 ed ur e f or m”. P Ts of R e n al tr a ns pla 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. 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 f r 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. 
 
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 i njecti o n t o  t he last d ose of d o u ble- bli n d I M P d ose + 1 0 da ys. 
 
P ost-treat me nt peri o d: defi ne d a s t he ti me starti n g t he da y after t he e n d of t he T E A E 
peri o d. 
2. 1. 4. 1          A d verse eve nts v ari a bles  
Occ urre nce 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 st u d y. 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 2 
 
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 g h 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 ntere d i n a st u d y as well as p re g na nc y occ urri n g i n a fe male 
part ner of a male patie nt e nt ere d i n a st u d y wit h I M P 
• S y m pt o matic o ver d ose (serio 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 Base li 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  
 
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 ollic 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 gi nal ca n di diasis i n fe males a n d ca n di da 
bala nitis i n males)  
 
Uri nar y tract i nfecti o 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  
 
Se vere h y p o gl yce mia  
 
F o ur nier’s ga n gre ne  


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 3 
 
E O SI will be i de ntifie d base d o n criteria i n t he ta ble bel o w. O f 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 nner, 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. 
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 actur es  
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 “ 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 D 
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 D 
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 a nt 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 D  
                                      T hyr oi d c a nc er: P Ts i n Ap p e n dix D 
R e n al c ell c a nc er: P Ts i n A p p e n dix D  
Pa ncr e atic c a nc er: P Ts i n A p p e n dix D  
                                       Bl a d d er c a nc er: P Ts i n Ap p e n dix D 
G e nit al myc otic i nf 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 D 
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 D 
Di arr h e a  
N arr o w s e arc h o n “ N o ni nf ecti o us di arr h o e a ( S M Q)” [ 2 0 0 0 0 2 1 8] plus t h e f oll o wi n g P Ts 
( M e d D R A v 2 1. 1):  G astr o e nt eritis ( 1 0 0 1 7 8 8 8), A nti di arr h o e al s u p p ortiv e c ar e 
( 1 0 0 5 5 6 6 0), E nt eritis ( 1 0 0 1 4 8 6 6), E nt eritis l e uk op e nic ( 1 0 0 1 4 8 7 7), E nt er oc olitis 
( 1 0 0 1 4 8 9 3), E nt er oc olitis h a e m orr h a gic ( 1 0 0 1 4 8 9 6) 
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 D 
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 mi a ev e nt i nf or m atio n” a n d m e et t he crit eri a:   
T o th e q u esti o n “ Assist a nc e R e quir 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 e d “ Y es”.  
E O SI A E r el at 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 ut ati 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 G a n gre 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 D 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 4 
 
* S e arc h t er ms will b e up 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 S a n ofi 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 h e alt h a ut h oriti es i n 3Q 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 dia 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. 1. 5  Q u alit y- of-life e n d p oi nts ( K C C Q- 1 2) 
A 1 2-ite m versi o n of K C C Q- 1 2 q ue sti o n naire was use d i n S O L OI S T, ca pt uri n g s y m pt o m 
fre q ue nc y ( 4 ite ms), p h ysical ( 4 ite ms) a n d s ocial li mitati o ns ( 3 ite ms), a n d q ualit y of life 
i m pair me nt ( 2 ite ms) as a result of ha vi n g c o n gesti ve H F ( A p pe n di x B Ka nsas Cit y 
Car di o m y o pat h y Q uesti o n naire ). A n o verall s u m mar y sc ore as well as 4 d o mai n sc ores ca n 
be calc ulate d ra n gi n g fr o m 0 t o 1 0 0 w here 1 0 0 de n otes t he hi g he st healt h stat us. 
T he K C C Q- 1 2 was t o be c o m plete d b y all patie nts as descri be d i n  t he st u d y fl o w c hart of 
pr ot oc ol. I n case of pre mat ure per ma ne nt I M P disc o nti n uati o n, t he K C C Q- 1 2 was t o be c o m plete d 
b y patie nts at t he visit pla n ne d f or t he last d osi n g da y wit h IM P a n d after war ds as n or mall y 
pla n ne d.  
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 nf 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 orme 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 ociate d wit h t he first ra n d o mizati o n 
will be use d i n a n y a nal ysis p o p ulati o n. T he safet y e x perie 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 otal n u m ber of patie nts i n eac h of t he f oll o wi n g cate g ories will be 
prese nte d i n t he cli nical st u d y r e p ort usi n g a fl o wc hart dia gra m or s u m mar y ta ble: 
 
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  


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 5 
 
 
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 tr eat 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 stat us 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 e C R F f or m or a st u d y cl ose- o ut visit was perf or me d 
t hr o u g h alter nati ve c o ntact d uri n 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 reas 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 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 n g disc o nti n ue d t he st u d y f or C V deat h, H H F, 
or ur ge nt H F visit if t he date o f t he last i nf or mati o n o n t his e n d p oi nt ( 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 date of 
deat h or last k n o w n ali ve – ra n d o m izati o n date + 1 da y. T he st ud y d urati o n will be s u m marize d 
acc or di n g t o me dia n, 2 5t h per ce ntile, 7 5t h perce ntile, a n d ra n g e 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 f oll o wi n g p o p ulat i o ns will be s u m marize d b y treat me nt gr o u p:  
 
Ra n d o mize d p o p ulati o n  
 
Efficac y p o p ulati o n: i nte nt-t o -treat (I T T) p o p ulati o n  
 
Safet y p o p ulati o n  
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 d es a n y patie nt w h o has bee n all ocate d t o a ra n d o mize d 
treat me nt re gar dless of w het her t he treat me nt kit was use d. 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 6 
 
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 ociate 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 n 
T he efficac y a nal ysis p o p ulati o n will be t he I T T p o p ulati o n, c o nsisti n g of all ra n d o mize d patie nts.  
Patie nts i n t he I T T p o p ulati o n will be a nal yze d acc or di n g t o t h e treat me nt gr o u p all ocate d b y 
ra n d o mizati o n.  
2. 3. 3         S afet y p o p ul ati o n 
T he safet y a nal ysis p o p ulati o n is  defi ne d as t he ra n d o mize d patie nts w h 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 hics a n d b aseli ne c h ar acteristics 
Para meters descri be d a b o ve ( Secti o n 2. 1. 1  De m o gra p hic a n d baseli ne c haracteristics ) will be 
s u m marize d b y treat me nt gr o u p a n d o verall usi n g descri pti ve sta tistics. 
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 baseli ne c har acteristic data will n ot 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 n 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 ati o n a l 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. 
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 w h o we re u p-titrate d t o 4 0 0 m g b y Visit 7 ( M o nt h 8) will als o be 
s u m marize d i n t he s ota glifl ozi n gr o u p. 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 7 
 
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 alyses of pri m ary effi c acy 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 L V E F ( < 5 0 %, ≥5 0 %). 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 p ot hesi s: 
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 st ratifie 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 hat e ver 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 differe nt bef ore a n d after 
2 4 0 da ys (t he e n d of t he wi n d o w f or u p-titrati o n of d ose), a ma r 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 2 4 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 m e 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 re d ucti o n ( AR R) will be esti mate d b y t he 
differe nce bet wee n treat me nt gr o u ps 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 g ure 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 f or t he pri mar y  e n d p oi nt. Bars f or s ota glifl ozi n a n d 
place b o will be pr o vi de d f or t h e n u m bers of first e ve nts, sec o n d e ve nts, a n d a cate g or y of “t hir d 
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 C V deat h, H H F, a n d ur ge nt H F visit 
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:  


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 8 
 
 
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 %)  
 
Re gi o n i n t hree cate g ories ( T he A mericas, 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 ( w hite, blac k , His pa nic, Asia n, ot her)  
 
Baseli ne e G F R ( < 6 0 m L/ mi n/ 1. 7 3 m 2, ≥6 0 m L/ mi n/ 1. 7 3 m2) 
 
Baseli ne B MI ( < 3 0, ≥3 0 k g/ m 2) 
 
N Y H A Class (II, III, I V) 
 
N T- pr o B N P ( ≤Me dia n, > Me dia n) 
 
M R A at Baseli ne 
 
G L P- 1 rece pt or a g o nist at Baseli ne 
 
Sac u bitril- valsarta n at Baseli ne 
 
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 pert r o p h y ( L V H) at baseli ne 
 
Mai n ca use of heart fail ure (is c he mic vs. n o n-isc he mic or u n k n o w n) 
 
Start of first I M P d ose pri or t o vs. after h os pital disc har ge ( or ur ge nt care facilit y w here 
a p pr o priate) 
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 L V E F ( n ote 
t hat w he n re gi o n is t he s u bject of t he a nal ysis stratificati o n will o nl y be b y L V E F; si milarl y w he n 
L V E F is t he s u bject of t he a nal y sis, stratificati o n will o nl y be b y re gi o n) wit h n o n- C V deat h as a 
c o m peti n g e ve nt will be c o nstr uc te d, i ncl u di n g t he treat me nt, the 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 H R a n d CI will be esti mated fr o m t his C o x 
m o del f or eac h s u b gr o u p. P- val ue s 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 statisticall y si g nifica nt a n d t heref ore s u g gesti ve o f heter o ge neit y i n t he treat me nt 
effect. Res ults will be als o pr ese nte d b y a f orest pl ot.  
2. 4. 4. 2 A n alyses of sec o n d ary effic acy e n d p oi nts  
Met h o ds f or c o ntr olli n g t he o ver all t y pe-I 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 Secti o n 2. 4. 4. 3 M ulti plicity 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. 
As wit h t he pri mar y e n d p oi nt, t he  a bs ol ute ris k re d ucti o n ( A R R) of ti me-t o-e ve nt sec o n dar y 
e n d p oi nts will be esti mate d b y t h e differe nce bet wee n treat me nt  gr o u ps 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.  F or t h ose sec o n dar y e n d p oi nts w hic h are a c o m p osite of 
e ve nts, res ults will be pr o vi de d f or b ot h t he o verall c o m p osite a n d its i n di vi d ual c o m p o ne nts. 
A bs ol ute c ha n ge i n K C C Q- 1 2 sc ores  fr o m baseli ne t o M o nt h 4 will be a nal yze d b y a nal ysis of 
c o varia nce ( A N C O V A) wit h treat m e nt gr o u p as fact or a n d baseli ne  K C C Q- 1 2 sc ore a n d 
ra n d o mizati o n stratificati o n factors as c o variates. T he last a v aila ble p ost- baseli ne sc ore will be 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
1 9 
 
carrie d f or war d t o M o nt h 4 if t he patie nt is ali ve at M o nt h 4 b ut t he M o nt h 4 val ue is missi n g. F or 
patie nts w h o die, a w orst sc ore  ( 0) will be i m p ute d f or t he clinical s u m mar y sc ore at all 
s u bse q ue nt sc he d ule d visits after t he date of deat h w here t he cli nical s u m mar y sc ore w o ul d ha ve 
bee n assesse d. 
T he rate of decli ne i n e G F R o bs er ve d o ver ti me will be a nal yze d  b y re peate d- meas ures mi xe d-
effects m o dels wit h a bs ol ute c ha n ge i n e G F R fr o m baseli ne as t h e o utc o me, a ra n d o m effect f or 
i nterce pt, a n d fi xe d effects f or treat me nt, baseli ne val ue, a n d ti me. A n a d diti o nal m o del will be 
de vel o pe d wit h a n i nteracti o n be t wee n treat me nt a n d ti me. T he varia nce-c o varia nce matri x will be 
s pecifie d t o be u nstr uct ure d. 
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-I 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 first seco 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 u si o ns a b o ut s uccessi ve sec o n dar y e n d p oi nts re q uire  statistical 
si g nifica nce of t he pri or o ne. T he or der of tests is detaile d in Secti o n 2. 1. 3. 2 Sec o n d ary effic acy 
e n d p oi nts.  T his fi xe d hierarc hical a p pr oac h will e ns ure a str o n g c o ntr ol of t he o verall t y pe-I 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)  
Ti me-t o-e ve nt ot her efficac y e n d p oi nts will be a nal yze d usi n 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.  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 n 
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 as of 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 ti me; if a patie nt s ur vi ve d wit ho 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 o de 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 pare d be t wee n treat me nt gr o u ps wit h o ne-i nflate d beta 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 ospitalizati o n (ie, P D A O H = 1 0 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 pa tie nts w h o die d or ha d at least o ne h os pitalizati o n or die d 
d uri n g f oll o w- u p (i.e., P D A O H < 1 0 0 % ).  Pl ots of t he distri b uti on of D A O H will be c o nstr ucte d, 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 0 
 
as well as s u m maries of reas o ns f or h os pitalizati 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, 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 will be prese nte d b y treat me nt gr o u p.   
Ge ner al c o m m o n r ules  
All safet y a nal yses will be perf o r me d o n t he safet y p o p ulati o n as defi ne d i n Secti o n 0, u nless 
ot her wise s pecifie d, usi n g t he f oll o wi n g c o m m o n r ules: 
 
T he baseli ne val ue ( wit h t he e xce 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 ar e 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 m issi 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.  
 
All meas ure me nts, sc he d ule d or u nsc he d ule d, fasti n g or n ot fast i n g, will be assi g ne d t o 
a nal ysis wi n d o ws defi ne d i n Secti o n 2. 1. 4.  
2. 4. 5. 1 A n alyses of a dverse eve nts  
Ge ner alities  
A n alysis of tre at me nt-e mer ge nt a dverse eve nts  
T he f oll o wi n g s u m maries of treat m e 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 l ea di n g t o deat h 
-          T E A E l ea 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 a n d pr eferre d ter m 
 All T E A Es relate d t o I M P b y pri m ar y S O C a n d preferre d ter m 
A n alysis of tre at me nt-e mer ge nt seri o us a dverse eve nts 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 1 
 
 All treat me nt-e mer ge nt S A Es b y pri mar y S O C a n d preferre d ter m 
 All treat me nt-e mer ge nt S A Es relate d t o I M P b y pri mar y S O C a n d p referre d ter m 
A n alysis of tre at me nt-e mer ge nt a dverse e ve 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 an d preferre d ter m 
 All T E A Es lea di n g t o deat h b y pr i 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. 4. 5. 2 A n alyses of l a b or at ory v ari a bles 
S u m mar y statistics of all la b orat or y varia bles ( n u m ber, mea n, s ta n dar d de viati o n, me dia n, first 
q uartile, t hir d q uartile, mi ni m u m,  a n d ma xi m u m) will be calc ulate d f or eac h visit or st u d y 
assess me nt b y treat me nt gr o u p d u ri n g t he treat me nt peri o d. 
2. 4. 5. 3 A n alyses of vit al si g ns v ari a bles 
S u m mar y statistics of all la b orat or y varia bles ( n u m ber, mea n, s ta n dar d de viati o n, me dia n, first 
q uartile, t hir d q uartile, mi ni m u m,  a n d ma xi m u m) will be calc ulate d f or eac h visit or st u d y 
assess me nt b y treat me nt gr o u p d u ri n g t he treat me nt peri o d. 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 2 
 
2. 5 D at a h a n dli n g c o n ve nti o ns 
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 use d f or c o m p utati o n of para mete rs. 
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:  
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 ef ficac 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 p ecifie 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 de re d missi n g if a n y of t he ori gi 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.   
H a n dli n g of missi n g or i nc o m plete d a tes of ti me-t o-eve nt effic acy e n d p oi nts 
R ules f or i m p utati o ns are detaile d i n A p pe n di x A Assi g n me nt of dates t o e ve nts . 
H a n dli n g of c o m p ut ati o n of tr e at 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 missi n 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 t he 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 w as i n t he sa me m o nt h. If 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 3 
 
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 oes I M P’ f or m.  
H a n dli n g of a dverse eve nts wit h mi ssi 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 dverse 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. 
H a n dli n g of a dverse eve nts w h e 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 first I M P a d mi nistrati o n is missi n 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 vaila 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, K C C Q- 1 2) will be s u m marize d 
usi n g t he ti me wi n d o ws gi ve n t h e ta ble bel o w. T hese ti me wi n d o w s 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 nt-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 1  
8  
5 t o 1 1  
W e ek 2  
1 5  
1 2 t o 1 8  
W e ek 4  
2 9  
2 2 t o 3 6  
W e ek 1 6 ( M o nth 4)  
1 1 3  
8 5 t o 1 4 1  
Bey on d We ek 16  
N u m b er of w e eks of t h e pl a n n e d visit x 7 
T ar g et e d st u dy d ay ± 2 8 d ays  
 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 4 
 
Refere nces 
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  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 5 
 
 
A p pe n di x A Assi g n me nt of d ates t o e ve nts 
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 t i 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 dat e 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), t he o nset of t he e ve nt is c o nsi 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. 
 
T he ti me t o deat h will be use d f or C V deat h a n d all-ca use m ortalit y rat her t ha n t he ti me t o o nset 
of t he ass ociate d e ve nt ca usi n g t h e deat h. F or e xa m ple, if a patie nt has a fatal str o ke t hat lea ds t o 
deat h se veral da ys later, t he da te of deat h (a later date) will be use d rat her t ha n t he date of str o ke 
o nset. 
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 date 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).   
a.  Ge ner al ce ns ori n g r ule f or pri m ary effic acy e n d p oi nt:  


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 6 
 
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 ce ns 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 pe ni n g after t he patie nt’s last  st u d y visit a n d t he e ve nt’s 
pr ocee di n g/relate d e ve nt’s o nset d ate 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 ncl 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 H F is bef ore l ast 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 later 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 na r y pr oce d ure, a d missi o n t o h os pital/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). Usuall y, t his is t he date of ‘ Date of last 
a vaila ble i nf or mati o n’ i n ‘ S u bj ect Stat us’ f or m f or patie nt ali ve 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 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.  
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 vaila 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 ysi s pr oce d ure n ot meeti n g t he defi 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.  
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 alysis)  
 
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 nalysis, 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 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 7 
 
date of deat h, if earlier. F or s e vere h y p o gl yce mia, a patie nt w it 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-eve nt e n d p oi nts is missi n g (c o m pl ete 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 r a 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 will 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 will be t he latest of all i m p ute d e v e 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  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 8 
 
 
A p pe n di x B K a ns as Cit y C ar di o m y o p at h y Q uesti o n n aire 
 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
2 9 
 
 
 
 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 0 
 
 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 1 
 
 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 2 
 
 
A P P E N DI X C  P Ts f or select e d E O SI ( Me d D R A v 2 3. 0) 
 
E O SI  
Preferre d Te r m 
Ge nital M y c otic I nfecti o ns  
Bala nitis ca n di da
Ge nital M yc otic I nfecti o ns  
Ca n di da cer vicitis
Ge nital M yc otic I nfecti o ns  
F u n gal b ala nitis
Ge nital M y c otic I nfecti o ns  
Ge nital ca n di diasis
Ge nital M y c otic I nfecti o ns  
Ge nital i nfecti o n f u n g al
Ge nital M y c otic I nfecti o ns  
Ur o g e nital i nfecti o n f u n g al
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 tract i nfecti o ns 
Ne p hritis bacterial
Uri nar y tract i nfecti o ns 
Bacterial p yel o ne p hritis
Uri nar y  tract i nfecti o ns 
Bacterial uret hritis
Uri nar y  tract i nfecti o ns 
Bla d der ca n di diasis
Uri nar y tract i nfecti o ns 
C ystitis
Uri nar y  tract i nfecti o ns 
C y stitis bacterial
Uri nar y  tract i nfecti o ns 
C y stitis esc heric hia
Uri nar y tract i nfecti o ns 
C ystitis gla n d ularis
Uri nar y tract i nfecti o ns 
C ystitis hel mi nt hic
Uri nar y tract i nfecti o ns 
C ystitis kle bsiella
Uri nar y  tract i nfecti o ns 
C y stitis pse u d o m o nal
Uri nar y  tract i nfecti o ns 
C y stitis viral
Uri nar y  tract i nfecti o ns 
C y t o meg al o vir us uri nar y  tract i nfecti on


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 3 
 
Uri nar y tract i nfecti o ns 
E m p h yse mat o us c ystitis
Uri nar y  tract i nfecti o ns 
E m p h y se mat o us py el o ne p hritis
Uri nar y tract i nfecti o ns 
Esc heric hia p y el o ne p hritis
Uri nar y  tract i nfecti o ns 
Esc heric hia uri nar y  tract i nfecti o n
Uri nar y tract i nfecti o ns 
F u n gal c ystitis
Uri nar y tract i nfecti o ns 
Ge nit o uri nar y c hla m y dia i nfecti o n
Uri nar y  tract i nfecti o ns 
Ge nit o uri nar y  tract g o n oc occal i nfecti o n
Uri nar y t ract i nfecti o ns 
Ge nit o uri nar y tract i nfecti o n
Uri nar y  tract i nfecti o ns 
K i d ney  i nfecti o n
Uri nar y  tract i nfecti o ns 
P y elitis
Uri nar y tract i nfecti o ns 
P yel oc ystitis
Uri nar y tract i nfecti o ns 
P yel o ne p hritis
Uri nar y tract i nfecti o ns 
P yel o ne p hritis ac ute
Uri nar y  tract i nfecti o ns 
P y el o ne p hritis c hr o nic
Uri nar y  tract i nfecti o ns 
P y el o ne p hritis f u n g al
U ri nar y tract i nfecti o ns 
P yel o ne p hritis m yc o plas mal
Uri nar y  tract i nfecti o ns 
P y el o ne p hritis viral
Uri nar y tract i nfecti o ns 
P y o ne p hr osis
Uri nar y tract i nfecti o ns 
Re nal a bscess
Uri nar y tract i nfecti o ns 
Re nal c yst i nfecti o n
Uri nar y tract i nfecti o ns 
Stre pt oc occal uri n ar y tract i nfecti o n
Uri nar y  tract i nfecti o ns 
T u berc ul osis of g e nit o uri nary  sy ste m
Uri nar y tract i nfecti o ns 
T u b ul oi nterstitial ne p hritis
Uri nar y  tract i nfecti o ns 
Ureter a bscess
Uri nar y tract i nfecti o ns 
Ureteritis
Uri nar y tract i nfecti o ns 
Uret hral a bscess
Uri nar y  tract i nfecti o ns 
Uret hritis
Uri nar y tract i nfecti o ns 
Uret hritis c hla m y dial
Uri nar y  tract i nfecti o ns 
Uret hritis g o n oc occal
Uri nar y  tract i nfecti o ns 
Uret hritis m y c o plas mal
Uri nar y tract i nfecti o ns 
Uret hritis urea plas mal
Uri nar y tract i nfecti o ns 
Uri nar y bla d der a b scess
Uri nar y tract i nfecti o ns 
Uri nar y tr act a bscess
Uri nar y  tract i nfecti o ns 
Uri nar y  tr act i nfecti o n
Uri nar y  tract i nfecti o ns 
Uri nar y  tr act i nfecti o n bacterial
Uri nar y tract i nfecti o ns 
Uri nar y tr act i nfecti o n e nter oc occal
Uri nar y  tract i nfecti o ns 
Uri nar y  tr act i nfecti o n f u ng al
Uri nar y tract i nfecti o ns 
Uri nar y tr act i nfecti o n pse u d o m o nal
Uri nar y tract i nfecti o ns 
Uri nar y tr act i nfecti o n sta p h yl oc occal
Uri nar y tract i nfecti o ns 
Uri nar y tr act i nfecti o n viral
Uri nar y tract i nfecti o ns 
Uri nar y tr act i nfla m mati o n
Uri nar y  tract i nfecti o ns 
Ur o g e nital i nfecti o n bacterial
Uri nar y tract i nfecti o ns 
Ur o ge nital i nfecti o n f u n gal
Uri nar y  tract i nfecti o ns 
Ur o g e nital tric h o m o niasis
Uri nar y tract i nfecti 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 press ure decrease d
V ol u me de pleti o n 
Bl o o d press ure diast olic decrease 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 p ress ure s yst olic i ns pirat or y decrease d
V ol u me de pleti o n 
Ca pillar y  nail 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 ntri c 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


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 4 
 
V ol u me de pleti o n 
Fe m oral p ulse decr ease 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 ntri c ular e n d- diast olic press ure decrea se d
V ol u me de pleti o n 
Mea n arterial press ure decrease d
V ol u me de pleti o n 
Ort h ostatic heart r ate res p o nse i ncrease 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 h eral circ ulat or y fail ure
V ol u me de pleti o n 
Peri p h eral p ulse de crease d
V ol u me de pleti o n 
P ost ural ort h ostatic tac h ycar 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 decrease d
V ol u me de pleti o n 
P ulse v ol u me decr ease 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 pleti o n 
Ve n o us press ure decrease d
V ol u me de pleti o n 
Ve n o us press ure ju g ular decrease d
V ol u me de pleti o n 
V ol u me bl o o d decrease 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 si g n 
Pa ncreatitis 
Hae m or rha g ic necr otic pa ncreatitis
Pa ncreatitis 
Here ditar y  p a 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 nc reatitis 
Pa ncreatic necr osis
Pa ncreatitis 
Pa ncreatic p hle g m o n
Pa ncreatitis 
Pa ncreatic pse u d oc y st
Pa ncreatitis 
Pa ncreatic p se u d oc yst drai na ge 
Pa ncreatitis 
Pa ncreatitis
Pa ncreatitis 
Pa ncreatitis a c 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 pa ncre atitis
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 ver 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 
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


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 5 
 
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 u g 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 vei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
Pa g et- 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 osis
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 na ry micr oe m b oli
Ve n o us t hr o m b otic e ve nts 
P ul m o nar y 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 h ro 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 h ro 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 v ei n t hr o m b osis
Ve n o us t hr o m b otic e ve nts 
S u b cla 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 perficial
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 v er n osa
Ve n o us t hr o m b otic e ve nts 
Tra ns ve rse 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 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
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 yr oi d ca ncer 
Fa milial me d ullar y t h yr oi d ca ncer
T h yr oi d ca nce r 
F ollic ular t h yr oi d ca ncer
T h y r oi d ca ncer 
H uert hle cell carci n o ma
T h yr oi d ca nce r 
Me d ullar y t h yr oi d ca nce r
T h y r oi d ca ncer 
Pa pillar y  t hy r oi d ca ncer
T h yr oi d ca nce r 
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 y r oi d ca ncer 
Th y r oi d ca ncer
T h yr oi d ca nce r 
T h yr oi d ca ncer metastatic
T h y r oi d ca ncer 
Th y r oi d ca ncer r ec 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 ncer 
T h yr oi d ca ncer sta ge I
T h yr oi d ca ncer 
T h yr oi d ca ncer sta ge 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 y r oi d ca ncer 
Th y r oi d ne o plas m
Re nal cell ca nce r 
Clear cell re nal cell carci n o ma
Re nal cell ca nce r 
Here ditar y  l ei o my o mat osis re nal cell carci n o ma
Re nal cell ca nce r 
Metastatic re nal cell carci n o ma
Re nal cell ca ncer 
Pa pillar y re nal cell carci n o ma
Re nal cell ca nce r 
Re nal ca ncer
Re nal cell ca ncer 
Re nal ca ncer metastatic


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 6 
 
Re nal cell ca nce r 
Re nal ca ncer rec urre nt
Re nal cell ca nce r 
Re nal ca nce r st ag e I
Re nal cell ca ncer 
Re nal ca ncer st a ge II
Re nal cell ca nce r 
Re nal ca ncer st a g e III
Re nal cell ca nce r 
Re nal ca ncer st a ge I V
Re nal cell ca nce r 
Re nal cell carci n o ma
Re nal cell ca nce r 
Re nal cell carci n o ma rec urr e nt
Re nal cell ca ncer 
Re nal cell carci n o ma sta ge I
Re nal cell ca nce r 
Re nal cell carci n o ma sta g e II
Re nal cell ca ncer 
Re na l cell carci n o ma stag e III
Re nal cell ca ncer 
Re nal cell carci n o ma sta ge I V
Re nal cell ca ncer 
Re nal ne o plas m
Pa ncreatic ca nce r 
Aci nar cell carci n o ma of pa ncreas
Pa nc reatic ca ncer 
A de n ocarci n o ma p a ncreas
Pa ncreatic ca nce r 
Cy sta de n ocarci n o ma pa ncreas
Pa ncreatic ca nce r 
Carci n oi d t u m o ur of t he pa ncreas
Pa ncreatic ca nce r 
D uctal a de n ocarci n o ma of pa n creas
Pa nc reatic ca ncer 
Gastri n o ma mali g na nt
Pa ncreatic ca ncer 
Gl uca g o n o ma
Pa ncreatic ca ncer 
I ns uli n o ma
Pa ncreatic ca nce r 
I ntra d uctal pa pillar y- m uci n o us carci n o ma of pa ncr eas
Pa ncreatic ca nce r 
Malig na nt ne o plas m of isl ets of La n g er ha ns
Pa ncreatic ca ncer 
M uci n o us c ysta de n ocarci n o ma of pa ncreas
Pa ncreatic ca nce r 
Ne ur ote nsi n o ma
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma
Pa ncreatic ca nce r 
Pa ncreatic carci n o ma metastatic
Pa ncreatic ca nce r 
Pa ncreatic carci n o ma rec urr e nt
Pa ncreatic ca ncer 
Pa ncreatic carci n o ma sta ge 0
Pa ncreatic ca nce r 
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 nce r 
Pa ncreatic carci n o ma sta ge III
Pa ncreatic ca nce r 
Pa ncreatic carci n o ma sta ge 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 nce r 
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 nce r 
Pan creat o blast o ma
Pa ncreatic ca nce r 
Ser o us c ysta de n ocarci n o ma of pa 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 nce r 
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 ge 0
Bla d der ca ncer 
Bla d der a de n ocarci n o ma sta g e I
Bla d der ca ncer 
Bla d der a de n ocarci n o ma sta ge II
Bla d der ca ncer 
Bla d der a de n ocarci n o ma sta ge III
Bla d der ca ncer 
Bla d der a de n ocarci n o ma sta g e I V
Bla d der ca ncer 
Bla d der a de n ocarci n o ma sta ge 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 der ca ncer 
Bla d der ca ncer sta ge 0, wit h o ut ca ncer i n sit u
Bla d der ca ncer 
Bla d der ca ncer sta ge I, wit h ca ncer i n sit u
Bla d der ca ncer 
Bla d der ca ncer sta g e I, wit h o ut ca ncer 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 ge III
Bla d de r 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 sta ge 0
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma sta ge I


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 7 
 
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma sta ge II
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma sta g e III
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma sta ge I V
Bla d der ca ncer 
Bla d der s q ua m o us cell carci n o ma sta g e u ns pecifie d
Bla d der ca ncer 
Bla d de r 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 de r tra nsiti o nal cell c arci n o ma sta ge 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 t ra nsiti o nal cell c arci n o ma sta 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 car ci 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 he b la 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  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 8 
 
A p pe n di x D Ke y C h a n ges t o Ori g i n al Pl a n ne d A n al ysis a n d Pr ot oc ol 
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 t o patie nts wit h 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 mes 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 niti all y t here were c o-
pri mar y o bjecti ves, o ne t o de m o nstrate 
re d ucti o ns i n C V m or bidit y a n d m ortalit y i n 
t h ose wit h L V E F < 5 0 %, a n d o ne t o de m o nstrate 
re d ucti o ns i n C V m or bi dit y a n d m ortalit y i n t he 
o verall p o p ulati o n  
Pri mar y f oc us is o n o verall p o p ulati o n rat her 
t ha n s u b gr o u ps 
C o m p osite re nal e n d p oi nt was m o ve d fr o m a 
sec o n dar y o bjecti ve t o other o bjecti ve; c ha n ge 
i n e G F R o ver ti me was a d de d as a sec o n dar y 
b e nefit 
Gi ve n t he c urre nt f oll o w- u p i n S O L OI S T, 
c ha n ge i n e G F R o ver ti me is a m ore se nsiti ve 
meas ure of re nal be nefit t ha n t he c o m p osite 
re nal e n dp oi nt
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 p italizati 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 m ia 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 
C V deat h a n d H H F i n patie nts wit h L V E F 
< 5 0 %, wit h a n d wit h o ut T 2 D (a sec o n dar y 
e n d p oi nt i n A me n d me nt 2) is n ot i ncl u de d i n 
c urre nt a nal ysis pla n 
Li mite d e nr oll me nt aft er A me n d me nt 2 mea ns  
s u b gr o u p a nal ysis of t h ose wit h o ut T 2 D is n ot 
a de q uatel y p o were d f or a sec o n dar y e n d p oi nt 
All-ca use m ortalit y wa s a sec o n dar y e n d p oi nt 
i n t he orig i nal p r ot oc ol, m o ve d t o “ ot her 
Ori gi nal m o ve t o “ ot her e n d p oi nt” was base d 
o n F D A fee d bac k t hat it w o ul d n ot be i ncl u de d 


St ati sti c al A n al y si s Pl a n  
0 9- 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 5 1 5 6 
V er si o n n u m b er: 1. 0  
 
3 9 
 
e n d p oi nt” i n Pr ot oc ol A me n d me nt 2, a n d 
ret ur ne d t o a sec o n dar y e n d p oi nt i n t his 
a nal ysis pla n 
i n la beli n g, b ut it was ret ur ne d t o sec o n dar y 
e n d p oi nt beca use of its h i g h cli nical rele va nce 
A me n d me nt 2 of S O L OI S T all o we d 
recr uit me nt of patie nts wit h o ut T 2 D 
D A P A- H F res ults i n dicate d t hat S G L T 
i n hi biti o n be nefits a br oa der patie nt p o p ulati o n, 
alt h o u g h e nr oll me nt aft er a me n d me nt 2 was 
ver y li mite d
A me n d me nt 2 of S O L OI S T all o we d e nr oll me nt 
o n t he first da y  of h osp italizati o n
C o nfi de nce i n safet y  of S G L T i n hi biti o n 
i n dicate d t his c o ul d be nefit p atie nts 
A me n d me nt 2 of S O L OI S T e x pa n de d 
ra n d o mizati o n wi n d o w t o 7 da ys after 
h os pitalizati o n 
I n vesti gat ors re p orte d t hat se ve n da ys after 
disc har ge was ofte n t he first ti me t he patie nt 
was see n at t he e n d of a n e pis o de of w orse ni n g 
heart fail ure