A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Net Clinical Benefit of Sotagliflozin as Adjunct to Insulin Therapy in Type 1 Diabetes
Phase: PHASE3
Conditions: Type 1 Diabetes Mellitus (T1DM), High Level of Sugar (Glucose) in the Blood
Sponsor: Lexicon Pharmaceuticals

CLINICAL STUDY PROTOCOL 
Protocol Number: 
LX4211.1-312-T1DM 
LX4211.312 (Abbreviated number) 
EudraCT Number: 
Investigational Phase: 
2015-001709-15 
3 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Placebo-
controlled, Parallel-group, Multicenter Study to Evaluate 
the Net Clinical Benefit of Sotagliflozin as Adjunct to 
Insulin Therapy in Type 1 Diabetes  
Amendment 1 Date: 
Original Version Date: 
Sponsor: 
16 October 2015 
19 May 2015 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone:  (281) 863-3000 
Medical Director: 
 
Lexicon Pharmaceuticals, Inc. 
16 October 2015 
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NCT02531035

Protocol No. LX4211.312 
Investigator Signature Page 
Protocol Number: 
LX4211.312 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Placebo-
controlled, Parallel-group, Multicenter Study to 
Evaluate the Net Clinical Benefit of Sotagliflozin as 
Adjunct to Insulin Therapy in Type 1 Diabetes  
Amendment 1 Date: 
Original Version Date: 
16 October 2015 
19 May 2015 
Sponsor: 
Lexicon Pharmaceuticals, Inc. 
8800 Technology Forest Place 
The Woodlands, TX 77381-1160 
Telephone:  (281) 863-3000 
By my signature below, I hereby attest that I have read and that I understand and will abide 
by all the conditions, instructions, and restrictions contained in the attached protocol and will 
conduct the study in accordance with all of the laws and regulations applicable to the 
jurisdiction in which the study is conducted. 
Additionally, I will not initiate this study without written and dated approval from the 
appropriate Institutional Review Board (IRB) or Ethics Review Committee (ERC), and I 
understand that any changes in the protocol must be approved in writing by Lexicon, the 
IRB/ERC, and, in certain cases, the Food and Drug Administration (FDA) or other applicable 
regulatory agencies, before they can be implemented, except where necessary to eliminate 
hazards to patients. 
Principal Investigator (Signature) 
Date 
Principal Investigator’s Name (Print) 
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Protocol No. LX4211.312 
1.
Synopsis
Name of Study 
Drug 
Sotagliflozin (LX4211) 
Protocol Number 
LX4211.1-312-T1DM 
LX4211.312 (Abbreviated number) 
Protocol Title 
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-
group, Multicenter Study to Evaluate the Net Clinical Benefit of 
Sotagliflozin as Adjunct to Insulin Therapy in Type 1 Diabetes  
Phase of 
Development 
Phase 3 
Number of Study 
Sites 
Approximately 134 sites with global distribution 
Primary Objective 
The primary objective of this study is to demonstrate the superiority 
of sotagliflozin 400 mg versus placebo in the proportion of patients 
with glycosylated hemoglobin A1C (A1C) <7.0% at Week 24 and no 
episode of severe hypoglycemia and no episode of diabetic 
ketoacidosis (DKA) after randomization. 
Secondary 
Objectives 
Secondary objectives of this study are to evaluate the change from 
Baseline of sotagliflozin versus placebo in hierarchical order on the 
following: 
•
A1C
•
Body weight
•
Systolic blood pressure (SBP)
•
Bolus insulin dose
Other Objectives 
Other objectives of this study are: 
To compare changes in several parameters in response to sotagliflozin 
versus placebo, as assessed by evaluations with specified cut points, 
and at specified time intervals during the 24-week double-blind 
Treatment Period including:  
•
Parameters assessed as secondary objectives (A1C, body
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Protocol No. LX4211.312 
weight, SBP, bolus insulin dose) 
•
Proportion of patients with A1C reduction ≥0.4% and no
increase in body weight
•
Proportion of patients with A1C reduction ≥0.5% and no
episode of severe hypoglycemia
•
Proportion of patients meeting success criteria for A1C and
insulin
•
Fasting plasma glucose (FPG)
•
Total and basal (or non-bolus) insulin dose
•
Diastolic blood pressure (DBP)
•
Hypoglycemic events
•
Measures of kidney function
•
Patient-reported satiety (substudy)
•
Safety of sotagliflozin 400 mg versus placebo
Methodology 
This study is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study.  
Adult patients diagnosed with type 1 diabetes mellitus (T1D), and 
body mass index (BMI) ≥18.5 kg/m2 who have inadequate glycemic 
control with insulin therapy (administered by subcutaneous injections 
or continuous subcutaneous insulin infusion [CSII]) are eligible for 
enrollment in this study as long as they meet all inclusion and no 
exclusion criteria.  
Patients will continue treatment with insulin(s) or insulin analog(s) 
during the study. During the study, self-monitored blood glucose 
(SMBG) values will be reviewed by the Investigator and insulin doses 
adjusted if the SMBG trends do not meet standard of care (SOC) T1D 
target goals. 
Note:  Subsequently, in this document, the term “insulin” includes 
insulin analog(s). The term “insulin analog” may also appear, as 
needed for clarity. Bolus insulin refers to regular insulin or fast-acting 
insulin analog administered via subcutaneous (SC) or inhaled route. 
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Protocol No. LX4211.312 
All patients will have a Screening Period of up to 2 weeks. The 
single-blind placebo Run-in Period will begin at Week -2. In order to 
qualify for randomization, patients must demonstrate ≥80% 
compliance to taking the expected amount of placebo tablets during 
the Run-in Period.  
Following randomization, patients will have a 24-week double-blind 
Treatment Period and a 30-day Follow-up Period. Thirty days after 
the last dose of double-blind study drug a telephone call will be made 
to all patients to record information on serious adverse events (SAEs), 
events of special interest (EOSI), and any adverse event (AE) that was 
ongoing at the time of the End-of-Treatment (EOT) or Early 
Withdrawal (EW) visit.  
Approximately 1400 patients ≥18 years of age will be randomly 
assigned in a 1:1 ratio between the following 2 treatment groups, as 
an adjunct to their insulin therapy: 
•
Sotagliflozin 400 mg as two (2) 200-mg tablets, once daily, before
the first meal of the day
•
Placebo as two (2) placebo tablets (identical to sotagliflozin in
appearance), once daily, before the first meal of the day
The treatment randomization schedule will be centralized and 
stratified by BMI at Screening (<25 kg/m2, ≥25 kg/m2), Week -2 A1C 
(≤9%, >9%) and use of CSII at Screening (Yes, No). The desired 
balances will be accomplished by use of randomly permuted blocks of 
fixed size. 
The glycemic goals recommended for this study are to treat A1C and 
blood glucose to the following targets: A1C <7.0%, 
fasting/preprandial capillary plasma glucose 80-130 mg/dL 
(4.4-7.2 mmol/L), and 2-hour/peak postprandial capillary plasma 
glucose <180 mg/dL (<10.0 mmol/L). Goals may be adapted based on 
individual patient considerations consistent with American Diabetes 
Association (ADA)/European Association for the Study of Diabetes 
(EASD) Guidelines. 
Insulin adjustment algorithms will be provided in the Site File 
Notebook to serve as reference, which may be modified based on the 
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Protocol No. LX4211.312 
Investigator’s clinical assessment. 
In order to avoid influencing the patients’ and or Investigators’ 
behavior, A1C and FPG results will be masked to study staff after 
randomization laboratories have been obtained. However, if the A1C 
is >11.0% at Week 16 or any determination thereafter, the value will 
be unmasked to the study sites to allow for appropriate diabetic 
management. In addition, the central laboratory urinalysis (UA) will 
not report urine glucose results to maintain the blind. 
Adjudication of all deaths, EOSI, including major adverse 
cardiovascular events (MACE)/other cardiovascular (CV) events, 
clinical or laboratory findings associated with potential drug-induced 
liver injury (DILI), severe hypoglycemia (or hypoglycemia reported 
as an SAE), and DKA events will be performed in a blinded manner 
by independent Clinical Endpoint Committee(s) (CEC[s]) composed 
of the appropriate experts. Details will be provided in the CEC 
Charter(s). 
An independent Data Monitoring Committee (DMC) will meet on a 
regular basis to review accumulating clinical study safety data. 
Following each meeting, the DMC will make a recommendation to 
the Sponsor regarding the study. Details describing the DMC 
processes and procedures are outlined in a separate DMC Charter. 
To maintain continuous blinding and study integrity, the analysis will 
be conducted by an independent statistician, and measures will be 
taken to ensure the validity of the data and integrity of the study's 
conduct. 
This study will also include a substudy in which patients will use a 
daily diary for the self-assessment of satiety (appetite). The substudy 
will include a subset of enrolled patients. 
The study design is presented graphically below: 
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Protocol No. LX4211.312 
Number of Patients 
A total of approximately 1400 patients are expected to be randomly 
assigned to treatment. Assuming a 20% dropout rate, approximately 
1120 patients are expected to complete the 24-week, double-blind 
Treatment Period while remaining on study treatment. A centralized 
randomization plan will be used to assign patients to study 
treatments.  
A subset of 280 patients will be recruited to participate in the satiety 
substudy. Assuming a 20% dropout rate, approximately 224 patients 
are expected to complete the 24-week double-blind Treatment 
Period while remaining on study treatment. 
Patients 
Eligible patients for this study will be ≥18 years of age, with a 
BMI ≥18.5 kg/m2, a confirmed diagnosis of T1D, and inadequate 
glycemic control on insulin therapy alone.  
Treatments 
The following study drug will be added as an adjunct to insulin 
therapy: 
•
Sotagliflozin 400 mg as two (2) 200-mg tablets, once daily,
before the first meal of the day  OR
•
Placebo as two (2) placebo tablets (identical to sotagliflozin
tablets in appearance), once daily, before the first meal of the
day
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Protocol No. LX4211.312 
Route of 
Administration 
Oral 
Duration of 
Participation 
Approximately 32 weeks, as follows: 
•
Screening Period (up to 2 weeks)
•
2-week single-blind placebo Run-in Period
•
24-week double-blind Treatment Period
•
Follow-up phone call 30 days after the last dose of double-blind
study drug
Inclusion Criteria 
Patients must meet all of the following criteria listed below to be 
considered eligible to participate in the study. For patients not 
meeting eligibility requirements, the reason for exclusion must be 
recorded. Note:  Patients not eligible because of laboratory result(s) 
may have the laboratory test(s) repeated once during the Screening 
Period at the discretion of the Investigator to determine eligibility: 
1) Patient has given written informed consent to participate in
the study in accordance with local regulations
2) Adult patients 18 years and older with a diagnosis of T1D
made at least 1 year prior to informed consent
3) Patients are being treated with insulin(s) or insulin analog(s)
4) Non-fast acting insulin dose is stable (±20%) for 2 weeks
prior to the Screening Visit
5) At the Screening Visit, A1C must be between 7.0% and
11.0%, inclusive
6) BMI ≥18.5 kg/m2
7) Must be willing and able to perform SMBG and complete
the study diary as required per protocol
8) Females of childbearing potential must use an adequate
method of contraception to avoid pregnancy throughout the
duration of the study and for 30 days after the last dose of
study drug. Females of childbearing potential include any
female who has experienced menarche and who has not
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Protocol No. LX4211.312 
undergone successful surgical sterilization (hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy) or is not 
postmenopausal. Postmenopause is defined as no menses for 
≥12 months without another cause. For females with 
questionable menopausal history (eg, irregular menstrual 
periods and age >40 years) a documented serum follicle-
stimulating hormone (FSH) level must be ≥30 mIU/mL.  
9) Females of childbearing potential must have a negative
serum or urine pregnancy test prior to the start of study
drug. In the case of positive urine pregnancy testing, a
negative serum sample for pregnancy testing, to confirm
that the patient is not pregnant, must be obtained prior to
start of study.
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded 
from participating in the study. For patients not meeting eligibility 
requirements, the reason for exclusion must be recorded. Note:  
Patients not eligible because of laboratory result(s) may have the 
laboratory test(s) repeated once during the Screening Period at the 
discretion of the Investigator to determine eligibility:   
1) Therapies and/or medications
a) Use of antidiabetic agent other than insulin(s) or insulin
analog(s) at the time of screening (any medication other
than insulin or insulin analog used for treatment of T1D
must be washed out for at least 8 weeks prior to the
Screening Visit)
b) Any prior exposure to sotagliflozin
c) Use of sodium-glucose cotransporter (SGLT) inhibitors
within 8 weeks prior to Screening.  Note:  Patients
taking an SGLT inhibitor may have that prohibited
medication stopped, and may be considered for entry
into the study if they have not been taking the prohibited
medication for at least 8 weeks prior to Screening.
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Protocol No. LX4211.312 
d) Chronic systemic corticosteroid use, defined as any dose
of systemic corticosteroid taken for more than
4 consecutive weeks within the 6 months prior to the
Screening Visit. Note:  Topical, inhaled, ocular, or nasal
sprays containing corticosteroids are allowed.
2) Diabetes-related conditions:
a) Type 2 diabetes mellitus or severely uncontrolled T1D
as determined by the Investigator
b) History of severe hypoglycemic event within 1 month
prior to the Screening Visit
c) History of DKA or nonketotic hyperosmolar state within
1 month of Screening OR ≥2 episodes of DKA or
nonketotic hyperosmolar state within 6 months of
Screening
3) Laboratory results
a) Estimated glomerular filtration rate (eGFR)
<45 mL/min/1.73 m2 at Screening, as determined by the
4 variable Modification of Diet in Renal Disease
(MDRD) equation
b) Fasting triglycerides >600 mg/dL (>6.77 mmol/L).
Note:  Patients who fail Screening based on this
criterion must have their fasting status verified, may
have triglyceride-lowering medications adjusted, and be
reevaluated during Screening.
c) Abnormal liver function at Screening defined as any of
the following:  aspartate aminotransferase (AST) >2X
upper limit of the normal reference range (ULN),
alanine aminotransferase (ALT) >2X ULN, serum total
bilirubin (TB) >1.5X ULN. Note:  If it is the opinion of
the Investigator and the Medical Monitor that an
increase in bilirubin is due to Gilbert’s syndrome, then
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Protocol No. LX4211.312 
the patient may participate. 
d) Screening beta-hydroxy butyrate (BHB) >0.6 mmol/L
4) Reproductive status:
a) Females who are pregnant or breastfeeding or intend to
be during the course of the study
5) Gastrointestinal/hepatic:
a) By known history, serologic evidence of current
infectious liver disease (hepatitis A, B, or C), including
antihepatitis A virus (immunoglobulin M), hepatitis B
surface antigen, or antihepatitis C virus. Note:  Patients
with isolated positive hepatitis B surface antibody may
be included.
b) Difficulty swallowing such that the patient cannot take
the study drug
c) History of pancreatitis within 12 months of screening, or
any prior history of recurrent pancreatitis
6) Renal:
a) Initiation of chronic dialysis within 30 days prior to the
Screening Visit or expected to occur within 180 days
after the Screening Visit
b) Renal disease that required treatment with
immunosuppressive therapy, or a history of dialysis or
renal transplant
c) History of hereditary glucose-galactose malabsorption
or primary renal glucosuria
7) Cardiovascular:
a) New York Heart Association Class III or IV heart failure
within 3 months prior to Screening Visit
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Protocol No. LX4211.312 
b) Hypertensive urgency or emergency within 30 days
prior to randomization. Note:  Patients with uncontrolled
hypertension at Screening will be allowed to enter the
study provided that they are being aggressively treated
for hypertension according to local guidelines.
Examples of guidelines current at the time of protocol
writing include those from the ADA and the European
Society of Cardiology
c) Patients with unstable/symptomatic or life-threatening
arrhythmia or heart block. Note:  Asymptomatic atrial
fibrillation is not considered to be life-threatening and
patients with asymptomatic atrial fibrillation will be
permitted to enter the study.
d) Patient has had any of the following within 3 months
prior to the Screening Visit:
i.
Hospitalization due to unstable angina
ii.
Myocardial infarction (MI)
iii.
Coronary artery bypass graft (CABG) or
percutaneous transluminal coronary angioplasty
iv.
Transient ischemic attack (TIA) or significant
cerebrovascular disease
8) Hematologic:
a) History of hemoglobinopathies (sickle cell anemia,
thalassemia major, sideroblastic anemia) or other
disorder that may interfere with A1C determination
b) Donation or loss of >400 mL of blood or blood
product(s) within 8 weeks prior to Screening
9) Immune system: Known severe immunocompromised
status, including, but not limited to, patients who have
undergone organ transplantation. Note:  Patients with
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Protocol No. LX4211.312 
human immunodeficiency virus (HIV) may participate if the 
Investigator considers them otherwise suitable candidates 
for this study. 
10) Malignancy or active treatment for malignancy (ie, radiation
or chemotherapy, including monoclonal antibodies) within 5
years prior to the Screening Visit. Note:  Patients with
squamous or basal cell carcinomas of the skin, carcinomas
in situ of the cervix or uterus, ductal breast cancer in situ,
resected low-grade prostate cancer, or other malignancies
that in the opinion of the Investigator and the Medical
Monitor are considered cured, may participate.
11) Current eating disorder or increase or decrease of weight
within the 12 weeks prior to Screening by more than 10%
12) Known allergies, hypersensitivity, or intolerance to
sotagliflozin or any inactive component of sotagliflozin or
placebo (ie, microcrystalline cellulose, croscarmellose
sodium [disintegrant], talc, silicone dioxide, and magnesium
stearate [nonbovine]), unless the reaction is deemed
irrelevant to the study by the Investigator
13) Administration of any other investigational drug or
participation in an interventional clinical research study
within 30 days or 5 half-lives (whichever is longer) of
planned Screening Visit
14) History of alcohol or illicit drug abuse (using Diagnostic
and Statistical Manual of Mental Disorders, 5th edition
criteria) within 12 months prior to the Screening Visit
15) Patient is a study coordinator, employee of an Investigator
or Investigator’s site, or immediate family member of any of
the aforementioned
16) Any condition that, in the opinion of the Investigator, may
render the patient unable to complete the study
17) The presence of a clinically significant medical history,
physical examination, or laboratory finding that, in the
opinion of the Investigator or the Sponsor, may interfere
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Protocol No. LX4211.312 
with any aspect of study conduct or interpretation of results. 
The Investigator or the Sponsor will supply justification for 
exclusion, if applicable. 
Sample Size 
Determination 
The sample size will be based on satisfying design assumptions 
made for the primary efficacy endpoint. The primary efficacy 
endpoint is a binomial proportion, a composite measure of glycemic 
control and safety. We have assumed that the majority of treatment 
effect will be observed in the glycemic control portion of the 
endpoint and for planning purposes, the rates of severe 
hypoglycemia and DKA will be equal in both treatment groups. 
Little data are available to estimate the <7% A1C component of the 
endpoint in this patient population. Data reviewed from the 
LX4211.1-202 Phase 2 trial in type 2 diabetes mellitus (T2DM) 
patients and from other pertinent literature sources suggests that a 
difference between treatment groups of at least 0.15 may be 
expected for this variable. We will assume this effect size for the 
primary endpoint, but will perform an adjustment for the expected 
proportion of patients not having a DKA or severe hypoglycemia 
event. A conservative assumption is made that the rates of DKA and 
severe hypoglycemia are independent and their union is estimated 
to be ≤0.15. It is expected that 0.85 of the patients will not have a 
DKA or a severe hypoglycemic event over the course of the study. 
Adjusting the 0.15 effect size estimate by this value yields a target 
effect size for the primary endpoint ≈0.12. Since the underlying 
placebo rate is unknown for the composite outcome, we will 
assume a maximum variance construct under the alternative 
hypothesis for binomial proportions to estimate the sample size 
(ie, the mean of the pooled response rates is 0.50). Assuming a 
2-sided test with α = 0.05 and 90% power, 380 patients are needed 
per treatment group to detect a difference in binomial proportions 
of at least 0.12 for the primary endpoint. The sample size estimate 
will be adjusted for dropouts in a manner to reflect that the primary 
analysis will be conducted in the modified Intent-to-Treat (mITT) 
patients. Dropouts are expected to be primarily a function of 
noncompliance: patients stopping early their randomized treatment, 
but followed to the 24-week visit. It is further assumed that the 
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Protocol No. LX4211.312 
dropped (noncompliant) sotagliflozin patients will respond as the 
placebo patients and that there will be no drop-in patients in the 
placebo group. These assumptions net an adjusted effect size for 
detection of 0.12 x (1-0.20) ≈ 0.10, where the dropout rate over 24 
weeks is assumed to be 20%. Based on this adjusted effect size, 544 
patients are required per treatment group, for a total of 
1088 patients across the 2 treatment groups.  
The occurrence of severe hypoglycemia is an important safety 
component of the primary endpoint. It is desirable that the study 
sample includes enough patients so that a reliable estimate of 
treatment difference can be obtained for this outcome. Based on a 
literature review, it seems reasonable to assume that the rate of 
severe hypoglycemia, defined as the number of patients 
experiencing at least 1 such episode divided by the number of mITT 
patients (ie, a binomial proportion), is ≤0.10 over a 24-week period. 
We will assume this rate is the same in both treatment groups, 
yielding an expected difference of 0.0. A 2-sided 95% confidence 
interval (CI) based on normal approximation methods and corrected 
for continuity is associated with a distance value (ω) of 0.033 for a 
sample size of 700 patients per group; ω is the extended distance 
from the observed difference in one or both directions. The upper 
bound of this CI will exclude values greater than 0.05; ie, a 50% 
increase in the expected placebo rate.  
Based on the considerations mentioned above, a sample size of 700 
patients per treatment group (1400 total patients) seems to be an 
appropriate target for the study.  
For the satiety substudy, assuming a dropout rate of 20% over the 
course of the study, a sample size of approximately 224 patients 
(112 per treatment group) demonstrating a change greater than 30% 
would be necessary to obtain statistical power at the recommended 
0.80 level (alpha = 0.05). To achieve this number of patients for 
evaluation, 280 patients will be recruited to participate in the 
substudy. 
Statistical Methods 
All primary efficacy analyses will be based on the mITT 
population. Supportive analysis of the efficacy data will be 
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Protocol No. LX4211.312 
performed using the Per-protocol (PP) population. 
Primary analysis of the primary efficacy endpoint at Week 24 will 
use a Cochran-Mantel-Haenszel (CMH) test stratified by BMI at 
Screening (<25 kg/m2, ≥25 kg/m2), Week -2 A1C (≤9%, >9%) and 
use of CSII at Screening (Yes, No). Missing observations will be 
imputed as non-responders. A point estimate of treatment effect will 
be based on the sotagliflozin minus difference in binomial 
proportions. A 2-sided 95% CI will be estimated on the observed 
difference and will be based on normal approximation methods 
using a continuity correction factor. The individual components of 
the endpoint will be summarized separately using descriptive 
statistics. 
Sensitivity analysis of the primary endpoint will use a single 
imputation method to obtain a rectangular dataset. Imputations will 
be based on use of the last observation carried forward (LOCF) 
algorithm. The stratified CMH test will be applied to this imputed 
dataset. The stratified CMH test will also be applied to the PP 
dataset as an additional sensitivity analysis. 
Primary analysis of the continuous efficacy endpoints will use 
mixed-effects model for repeated measures (MMRM) statistics 
based on the restricted maximum likelihood (REML) method for 
estimation. The analysis model will include fixed, categorical 
effects of treatment, BMI at Screening (<25 kg/m2, ≥25 kg/m2),
Week -2 A1C (≤9%, >9%) and use of CSII at Screening (Yes, No), 
time (study week), baseline-dependent variable-by-time interaction, 
and a treatment-by-time interaction. An unstructured (co)variance 
structure will be used to model the within-patient errors. Other 
structures will be explored by use of Akaike’s information criteria 
should the unstructured (co)variance structure not result in model 
convergence. The Kenward-Roger approximation will be used to 
estimate the denominator degrees of freedom. The adjusted mean 
change from Baseline by each study week for each treatment group 
will be estimated in the framework of this model, as well as the 
between-group differences (comparing sotagliflozin to placebo) and 
the 95% CIs for the adjusted mean. All post-Baseline observations 
collected at scheduled visits will be used in the MMRM, including 
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Protocol No. LX4211.312 
data collected after the discontinuation of study drug. An analysis 
of covariance (ANCOVA) will be applied where only 
1 post-Baseline scheduled visit occurs; ie, the MMRM analysis 
omitting the time-related effects. 
For binary endpoints estimated as binomial proportions, the 
frequency and proportion of patients achieving the outcome will be 
presented by treatment group at each assessed study week. The 
primary analysis of these endpoints will use a CMH test stratified 
by the different levels of the randomization stratification factors of 
BMI at Screening (<25 kg/m2, ≥25 kg/m2), Week -2 A1C (≤9%, 
>9%) and use of CSII at Screening (Yes, No). These treatment 
group comparisons will be performed at Week 24 only. The earlier 
study weeks will use descriptive analyses to summarize the data. 
These descriptive statistics will include the patient counts and 
proportions, point estimates of treatment effect, and 95% CIs of the 
treatment effect. Missing observations at Week 24 will be imputed 
as non-responders; only the observed data will be summarized at 
the earlier study visits. Endpoints comprised of multiple outcomes 
will use descriptive methods to summarize each component by 
treatment group at each study week. 
The test for superiority of sotagliflozin versus placebo based on the 
primary efficacy endpoint will be performed at the 2-sided 
0.05 α-level. If this null hypothesis is rejected, a sequential 
procedure will be used to maintain the overall Type I error rate at a 
2-sided, 0.05 α-level across analyses of the secondary endpoints at 
Week 24. The secondary endpoints will be specified in a hierarchy 
and the first listed will be tested at the same Type I error used for 
the primary endpoint comparison (α = 0.05). If this test rejects the 
null hypothesis, then the next listed secondary endpoint will be 
tested at the same Type I error rate. This testing sequence will 
continue as long as the null hypothesis is rejected at the 0.05 α-
level. The testing sequence will be broken at the first instance that a 
null hypothesis is not rejected. Once the sequence is broken, no 
later hypothesis in the hierarchy will be tested. The order of testing 
will be: 
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Protocol No. LX4211.312 
1) A1C change from Baseline at Week 24
2) Body weight at Week 24 change from Baseline (absolute
and percent change; the absolute change will be used in the
sequence of analyses)
3) SBP change from Baseline at Week 16 in the subset of
patients with Baseline SBP ≥130 mm Hg
4) Percent change from Baseline in bolus insulin dose at
Week 24
In addition, raw P-values and 95% CIs will be computed for tests of 
all secondary endpoint hypotheses. These raw or unadjusted 
statistics will be used as descriptive summaries of the data and will 
not be used for formal testing of the hypotheses. 
Safety Assessments 
Safety and tolerability of sotagliflozin will be assessed by 
collection and analysis of AEs, EOSI, laboratory variables, vital 
signs, electrocardiograms (ECGs), and physical examinations. 
Safety Data Analysis 
Analysis of the safety data will be based on the Safety Population. 
Additional analyses may be performed on other populations or 
subpopulations.  
Safety analysis will be descriptive. 
Treatment-emergent adverse events (TEAEs) are defined as AEs 
reported after the first dose of double-blind study drug. Treatment-
emergent adverse event summaries will include the overall 
incidence (number of patients with the event) and number of events 
by system organ class and preferred term, overall incidence sorted 
by descending frequency across treatment groups, events by 
maximum intensity, events by relationship to study treatment, and 
events leading to discontinuation of study drug; SAEs and EOSI 
will also be summarized. Listings will be provided for deaths, 
SAEs, and discontinuations due to AEs. Additional summaries or 
listings of AEs may also be provided. 
Vital signs, laboratory results, ECG results, and physical 
examination findings will be summarized descriptively at each time 
point. Actual and change from Baseline data will be calculated and 
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Protocol No. LX4211.312 
summarized as appropriate. In addition, shift table analyses will be 
presented for the laboratory data.  
The efficacy analysis of hypoglycemic events will be conducted 
using MMRM and CMH tests. Since these data also serve as a 
measure of safety, additional analyses will be conducted. The first 
analysis will be performed using CMH tests stratified by the 
randomization factors at each clinic visit. These tests will provide 
inferential and descriptive summaries of the relative risk estimate 
for each of the 2 hypoglycemic event definitions: ≤70 mg/dL by 
SMBG, and ≤55 mg/dL by SMBG. The patient incidence of these 
hypoglycemic events will be counted over the week prior to the 
scheduled clinic visit used in the analysis. The second analysis of 
these data will examine the relative risk for each of the 
hypoglycemic event definitions over the entire Treatment Period by 
use of a generalized linear model (GLM). The GLM will include 
fixed, categorical effects of treatment, BMI at Screening (<25 
kg/m2, ≥25 kg/m2), Week -2 A1C (≤9%, >9%), use of CSII at 
Screening (Yes, No), and an offset term for study duration. The 
events will be modeled as a negative binomial process.  
Meta-analysis 
The occurrence of the following events will be statistically 
analyzed using data from this study combined with other Phase 2/3 
trials conducted in T1D and T2DM patients: severe hypoglycemia, 
DKA, DILI, and MACE. Details of the analysis models and related 
assumptions will be documented in separate meta-analysis plans. 
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Protocol No. LX4211.312 
Table of Contents 
1.
Synopsis ........................................................................................................................ 3
Table of Contents ................................................................................................................ 20 
2.
List of Abbreviations and Definitions of Terms ............................................................ 26
3.
Introduction ................................................................................................................. 30
3.1 
Background Sotagliflozin (LX4211) and Disease ............................................ 30 
3.1.1 
The Potential Role of Dual SGLT1 and SGLT2 Inhibition................. 30 
3.1.1.1 
Potential Effects on Mealtime Glycemic Control............ 32 
3.2 
Sotagliflozin Pharmacology ............................................................................ 33 
3.2.1 
Studies in Mice ................................................................................. 33 
3.2.1.1 
Nondiabetic, Diet-induced, Obese Mice ......................... 33 
3.2.1.2 
Diabetic Mice ................................................................ 33 
3.2.2 
Studies in Rats .................................................................................. 34 
3.2.3 
Studies in Dogs................................................................................. 34 
3.2.4 
Summary of Pharmacology ............................................................... 34 
3.3 
Sotagliflozin Toxicology ................................................................................. 35 
3.3.1 
Toxicology Studies in Rats ............................................................... 35 
3.3.2 
Toxicology Studies in Dogs .............................................................. 36 
3.4 
Reproductive Toxicity ..................................................................................... 36 
3.5 
Clinical Trials of Sotagliflozin in Humans ....................................................... 37 
3.5.1 
Digoxin Drug-Drug Interaction (DDI) Study .................................... 37 
3.5.2 
Clinical Trials in T1D ....................................................................... 38 
3.6 
Rationale for Current Study ............................................................................ 38 
3.6.1 
Rationale for Selection of Dose ........................................................ 38 
3.6.2 
Rationale for Study Design and Control Groups ............................... 39 
3.6.3 
Rationale for Patient-reported Outcomes: Satiety Substudy .............. 40 
3.7 
Benefit/Risk of Sotagliflozin ........................................................................... 40 
4.
Study Objectives .......................................................................................................... 42
4.1 
Primary Objective ........................................................................................... 42 
4.2 
Secondary Objectives ...................................................................................... 42 
4.3 
Other Objectives ............................................................................................. 42 
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Protocol No. LX4211.312 
5.
Investigational Plan ...................................................................................................... 43
5.1 
Overall Study Design ...................................................................................... 43 
Figure 5.1-1: Study Schema ................................................................................................ 44 
5.1.1 
Screening Period............................................................................... 45 
5.1.2 
Single-blind Placebo Run-in Period .................................................. 45 
5.1.3 
Unscheduled Visits ........................................................................... 45 
5.1.4 
24-Week Double-blind Treatment Period .......................................... 46 
5.1.5 
Follow-up Period .............................................................................. 46 
6.
Study Population .......................................................................................................... 46
6.1 
Inclusion Criteria ............................................................................................ 46 
6.2 
Exclusion Criteria ........................................................................................... 47 
6.3 
Cessation of Study Drug and Termination of Study Participation..................... 51 
6.3.1 
Temporary Cessation of Study Drug ................................................. 51 
6.3.2 
Permanent Cessation of Study Drug .................................................. 51 
6.3.3 
Termination of Study Participation and/or Withdrawal of Consent .... 52 
6.3.4 
Lost-to-Follow-Up ............................................................................ 53 
6.4 
Criteria for Termination of the Study or Study Site .......................................... 54 
6.4.1 
Early Termination of the Study ......................................................... 54 
6.4.2 
Early Termination of a Study Center ................................................. 54 
6.5 
Method of Assigning Patients to Treatment ..................................................... 55 
6.6 
Replacement of Patients .................................................................................. 55 
7.
Treatment ..................................................................................................................... 55
7.1 
Study Drug Identification ................................................................................ 55 
Table 7.1-1: Study Drug Identification................................................................................. 56 
7.2 
Single-blind Placebo Run-in Period................................................................. 56 
7.3 
24-Week Double-blind Treatment Period ........................................................ 56 
7.4 
Study Drug Adjustment/Interruption ............................................................... 57 
7.5 
Handling and Dispensing of Study Drug ......................................................... 58 
7.5.1 
Dispense Study Drug and Record Compliance .................................. 58 
7.5.2 
Return of Study Drug ....................................................................... 59 
7.5.3 
Destruction of Study Drug ................................................................ 59 
7.6 
Concomitant Medications ............................................................................... 60 
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7.6.1 
Glycemic Goals and Adjustment of Insulin Dose .............................. 60 
7.6.1.1 
Glycemic Goals ............................................................. 60 
7.6.1.2 
Assessment of Glycemia and Adjustment of Insulin ....... 60 
7.6.1.3 
Entering SMBG and Insulin Data into the eCRF ............ 61 
7.6.1.4 
Insulin Adjustment on Day 1 .......................................... 62 
7.6.1.5 
Insulin Adjustment Strategy ........................................... 63 
7.6.1.6 
Unmasking of Patients Not Meeting Glycemic Targets ... 63 
7.6.2 
Concomitant Antihypertensive Medication and Treatment of 
Hypertension .................................................................................... 64 
7.6.3 
Concomitant Lipid Medication and Dyslipidemia/Lipid Management
 ......................................................................................................... 65 
7.6.4 
Other Concomitant Medications ....................................................... 65 
7.7 
Blinding and Unblinding of Study Drug .......................................................... 65 
8.
Efficacy, Pharmacokinetic, Safety, and Other Assessments/Procedures ......................... 66
8.1 
Assessment of Efficacy ................................................................................... 66 
8.1.1 
A1C .................................................................................................. 66 
8.1.2 
Fasting Plasma Glucose and SMBG .................................................. 67 
8.1.3 
Insulin .............................................................................................. 67 
8.1.4 
Kidney Function ............................................................................... 67 
8.1.5 
Body Weight and Blood Pressure ...................................................... 67 
8.1.6 
Patient-reported Outcome:  Satiety (Substudy) .................................. 67 
8.2 
Assessment of Safety ...................................................................................... 68 
8.2.1 
Adverse Events ................................................................................. 68 
8.2.2 
SMBG Procedures ............................................................................ 68 
8.2.3 
Selected Laboratory Tests ................................................................. 69 
Table 8.2.3-1: Central Laboratory Assessments ................................................................... 70 
8.2.3.1 
Urinalysis ...................................................................... 70 
8.2.3.2 
Contraception and Pregnancy Testing............................. 71 
8.2.3.3 
Collecting Fasting Blood Sample and Urine for Storage . 72 
8.2.4 
Vital Signs ........................................................................................ 73 
8.2.5 
Physical Examinations, Height, and Weight ...................................... 73 
8.2.6 
Electrocardiograms ........................................................................... 74 
8.2.7 
Demographics .................................................................................. 74 
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Protocol No. LX4211.312 
8.2.8 
Medical History ................................................................................ 74 
8.2.9 
Other Assessments ............................................................................ 74 
8.3 
Study Procedures and Assessments by Visit .................................................... 74 
8.3.1 
General Guidelines ........................................................................... 74 
8.3.2 
Guidelines for Diet and Exercise during Study .................................. 75 
8.3.3 
Restrictions during Study .................................................................. 76 
9.
Safety Reporting .......................................................................................................... 76
9.1 
Adverse Events ............................................................................................... 76 
9.2 
Serious Adverse Events ................................................................................... 78 
9.3 
Suspected Unexpected Serious Adverse Reactions .......................................... 80 
9.4 
Precautions ..................................................................................................... 81 
9.4.1 
Pregnancy ......................................................................................... 81 
9.5 
Events of Special Interest ................................................................................ 81 
9.5.1 
Hypoglycemia or Symptoms Suggestive of Hypoglycemia ............... 82 
9.5.2 
Diabetic Ketoacidosis ....................................................................... 85 
Table 9.5.2-1 
Diagnostic Criteria for DKA for Patients Not Treated with 
Investigational Agents .................................................................................................. 86 
9.6 
Safety Monitoring and Oversight Committees ................................................. 87 
9.6.1 
Data Monitoring Committee ............................................................. 87 
9.6.2 
Clinical Endpoint Committee ............................................................ 87 
9.6.3 
Steering Committee .......................................................................... 88 
10. Statistical Methodology ............................................................................................... 88
10.1 
Determination of Sample Size ......................................................................... 88 
10.2 
Analysis Populations ....................................................................................... 90 
10.2.1 
Randomized Population .................................................................... 90 
10.2.2 
Modified Intent-to-Treat and Per-Protocol Populations ..................... 90 
10.2.3 
Safety Population ............................................................................. 90 
10.3 
Study Endpoints .............................................................................................. 90 
10.3.1 
Efficacy Endpoints ........................................................................... 90 
10.3.1.1 
Primary Efficacy Endpoint ............................................. 90 
10.3.1.2 
Secondary Efficacy Endpoints ....................................... 91 
10.3.1.3 
Other Efficacy Endpoints ............................................... 91 
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Protocol No. LX4211.312 
10.3.2 
Safety Endpoints............................................................................... 92 
10.4 
Statistical Methods .......................................................................................... 92 
10.4.1 
Efficacy Analyses ............................................................................. 92 
10.4.2 
Subgroup Analyses ........................................................................... 94 
10.4.3 
Safety Analyses ................................................................................ 94 
10.4.3.1 
Adverse Events .............................................................. 95 
10.4.4 
Meta-analyses ................................................................................... 96 
11. Study Management ...................................................................................................... 96
11.1 
Data Handling and Quality Assurance ............................................................. 97 
11.1.1 
Data Recording ................................................................................. 97 
11.1.2 
Description of General Procedure ..................................................... 97 
11.2 
Monitoring ...................................................................................................... 97 
11.3 
Audits and Inspections .................................................................................... 98 
11.4 
Amendments ................................................................................................... 98 
11.5 
Record Keeping .............................................................................................. 98 
11.5.1 
Drug Accountability ......................................................................... 98 
11.5.2 
Health Insurance Portability and Accountability Act of 1996 and 
Subsequent Updates .......................................................................... 98 
11.5.3 
Financial Disclosure ......................................................................... 99 
11.5.4 
Access to Original Records ............................................................... 99 
11.5.5 
Retention of Study Documents ......................................................... 99 
12. Administrative Structure of the Study ........................................................................ 100
13. Appendix A – Schedule of Assessments (Study LX4211.312) .................................... 101
14. Appendix B – Ethical and Regulatory Standards ........................................................ 104
15. Appendix C – Investigator Obligations ...................................................................... 106
16. Appendix D – Calculations ........................................................................................ 111
17. Appendix E – Algorithm for Liver Safety Laboratory Abnormality Signals ................ 112
18. Appendix F – Recommendations on Basic Genitourinary Hygiene, Maintaining
Hydration and Recognition of DKA and its Management ........................................... 116 
19. Appendix G – Measurement of Blood Pressure and Pulse Rate .................................. 120
20. Appendix H – Satiety Visual Analog Scale ................................................................. 121
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Protocol No. LX4211.312 
21. Appendix I – Study Procedure by Visit ....................................................................... 122
22. References ................................................................................................................. 129
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2.
List of Abbreviations and Definitions of Terms
Abbreviation 
Definition 
A1C 
hemoglobin A1C 
ACE 
angiotensin-converting enzyme 
ACR 
albumin:creatinine ratio 
ADA 
American Diabetes Association  
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ARB 
angiotensin receptor blockers 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
β-HCG 
β-human chorionic gonadotropin 
BHB 
beta-hydroxy butyrate 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CABG 
coronary artery bypass graft 
CBC 
complete blood count 
CCR 
calcium:creatinine ratio 
CEC 
Clinical Endpoint Committee 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CPK 
creatine phosphokinase 
CRA 
clinical research associate 
CRO 
contract research organization 
CSII 
continuous subcutaneous insulin infusion  
CV 
cardiovascular 
DBP 
diastolic blood pressure 
DDI 
DILI 
drug-drug interaction 
drug-induced liver injury 
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Protocol No. LX4211.312 
Abbreviation 
Definition 
Table is continued on the next page 
DKA 
diabetic ketoacidosis 
DMC 
Data Monitoring Committee 
DVT 
deep vein thrombosis 
EASD 
European Association for the Study of Diabetes 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ED50 
daily dose causing 50% maximal glucose excretion in the first 
24 hours following dosing 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOSI 
event(s) of special interest 
EOT 
end-of-Treatment 
ERC 
Ethics Review Committee 
EW 
early Withdrawal 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GCR 
glucose:creatinine ratio 
GD 
gestational day 
GI 
gastrointestinal 
GLM 
generalized linear model 
GLP 
Good Laboratory Practice 
GLP-1 
glucagon-like peptide 1 
GU 
genitourinary 
HDL-C 
high-density lipoprotein cholesterol 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HPF 
high-power field 
I/C 
insulin to carbohydrate ratio 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
Continued on the next page 
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Protocol No. LX4211.312 
Abbreviation 
Definition 
IDMS 
isotope dilution mass spectrometry 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IOB 
insulin on board 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Web Response System 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein cholesterol 
LOCF 
last observation carried forward 
MACE 
major adverse cardiovascular event(s) 
MDRD 
Modification of Diet in Renal Disease  
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
mITT 
modified Intent-to-Treat 
MMRM 
mixed-effects model for repeated measures 
NASH 
nonalcoholic steatohepatitis 
NOAEL 
no observed adverse effect level 
NSAID 
nonsteroidal anti-inflammatory drug 
OGTT 
OTC 
oral glucose tolerance test  
over-the-counter 
PP 
Per-protocol 
PPG 
postprandial glucose 
PSDD 
Patient Satiety Daily Diary  
PSDD-NRS 
Patient Satiety Daily Diary-Numeric Rating Scale 
PV&DSS 
Pharmacovigilance & Drug Safety Services 
PYY 
peptide YY 
RBC 
red blood cell 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SGLT 
sodium-glucose cotransporter 
SGLT1 
sodium-glucose cotransporter type 1 
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Protocol No. LX4211.312 
Abbreviation 
Definition 
Continued on the next page 
SGLT2 
sodium-glucose cotransporter type 2 
SMBG 
self-monitored blood glucose 
SOC 
standard(s) of care 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
T1D 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
TB 
total bilirubin 
TC 
total cholesterol 
TEAE 
treatment-emergent adverse event 
TG 
triglyceride(s)s 
TIA 
transient ischemic attack 
TSH 
thyroid stimulating hormone 
UA 
urinalysis 
UGE 
urinary glucose excretion  
ULN 
upper limit of the normal reference range 
US 
United States 
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Protocol No. LX4211.312 
3.
Introduction
3.1 
Background Sotagliflozin (LX4211) and Disease 
Incidence of Type 1 diabetes mellitus (T1D) varies widely globally, ranging from 0.1/100,000 
per year in China and Venezuela to 36.5/100,000 per year in Finland.[1] Every year in the 
United States (US), on average more than 15,000 young people under the age of 20 years are 
diagnosed with T1D (Centers for Disease Control, 2011).[2] Maintaining glycemic control 
without hypoglycemia is a key therapeutic goal in T1D, to foster both near-term and long-
term health. To date, this has only been achieved by maintaining strict dietary discipline with 
vigilant glucose monitoring linked to appropriate exogenous insulin use throughout the day. 
Chronic insulin use to maintain tight glycemic control presents significant challenges for 
patients, both logistically and medically, with constant approximations and adjustments made 
to accommodate various meals and activity levels. The challenges and inherent imperfections 
of such calculations contribute to the tendency of many T1D patients to maintain blood 
glucose levels at the high end or above recommended glycemic targets, in order to avoid the 
immediate dangers of hypoglycemia, ultimately at the expense of suffering long-term 
consequences of chronic high blood sugar. 
Despite the broad availability of insulin therapy for T1D, there remain large segments of the 
patient population for whom adequate glycemic control is not consistently achieved. For 
example, according to the T1D registry,[3] (~30% <15 years old, ~70% <30 years old), of the 
26,127 total registrants, 23% have poor glycemic control with inability to achieve a 
hemoglobin A1C (A1C) <9.0%, while ~17% of registrants with the same standards of care 
(SOC) and medical providers are able to attain an A1C <7.0%. It is likely that a spectrum of 
pathophysiological and socioeconomic drivers contribute to the wide disparity in glycemic 
control that is observed, and that certain groups within the T1D population find it particularly 
difficult to maintain glycemic control with currently available therapies. 
Given the challenges associated with improving treatment outcomes for groups that have a 
history of especially poor control, there is a need to identify a safe and simple 
pharmacological treatment that can consistently improve glycemic control when added to 
insulin regimens. Importantly, attention must also be given to the goal of improving the 
quality of life in T1D patients by reducing insulin injection burden and the need for strict 
glucose monitoring.  
3.1.1 
The Potential Role of Dual SGLT1 and SGLT2 Inhibition 
Sotagliflozin (LX4211) is a novel, orally delivered, small molecule dual inhibitor of sodium-
glucose cotransporter type 1 (SGLT1) and sodium-glucose cotransporter type 2 (SGLT2) that 
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Protocol No. LX4211.312 
was designed to reduce glucose absorption in the gastrointestinal (GI) tract via SGLT1 
inhibition and renal glucose reabsorption via SGLT2 inhibition. Lexicon’s studies of 
knockout mice lacking either SGLT1 or SGLT2, or both, led to the discovery that inhibiting 
both targets pharmacologically could achieve metabolic and glycemic control without 
causing hypoglycemia.  
Note: Sotagliflozin and investigational drug LX4211 are used interchangeably in this 
protocol. 
Because sotagliflozin is a dual inhibitor of SGLT1 and SGLT2 and is unlike the selective 
SGLT2 modulators currently in development, sotagliflozin provides a potentially unique 
mechanism of action. 
The sodium-glucose cotransporter (SGLT) inhibitors currently approved for treatment of type 
2 diabetes mellitus (T2DM) (canagliflozin, dapagliflozin[4] or empagliflozin[5]) or with 
clinical data in T1D, (dapagliflozin and empagliflozin) are selective SGLT2 inhibitors and 
therefore primarily target the kidney, where SGLT2 reabsorbs ~90% of filtered glucose. 
SGLT1 is the primary transporter for absorption of glucose and galactose in the intestine. 
SGLT1 inhibition by sotagliflozin delays and reduces glucose absorption in the proximal 
intestine thereby improving postprandial glycemic control with lower peak glucose levels and 
decreased glycemic variability. In addition, more glucose delivery distally triggers increased 
L-cell release of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), a natural peptide 
hormone response associated with enhanced glycemic and appetite control, findings that have 
been substantiated with numerous animal and human mechanistic studies.[6,7] The overall 
sotagliflozin treatment effect is a reduction in glucose load through a balanced inhibition of 
SGLT1 and SGLT2, offering the potential for T1D patients to achieve better glycemic control 
in combination with insulin therapies.  
With sotagliflozin, the desirable effects of SGLT2 inhibition are maintained and 
complemented with SGLT1 inhibition in the GI tract to produce clinically meaningful 
reductions in postprandial glucose (PPG). The net result is improved glycemic control with 
lower urinary glucose excretion (UGE) than seen with selective SGLT2 inhibitors. The latter 
is an important finding which is predicted to allow sotagliflozin to maintain efficacy in 
patients with renal impairment as well as reduce the side effects associated with high UGE 
such as genitourinary (GU) tract infections. Notably, a recently completed proof-of-concept 
study in 30 T2DM patients with moderate to severe renal impairment (estimated glomerular 
filtration rate [eGFR] 15-59 mL/min/1.73 m2) randomly assigned 1:1 to placebo or 400 mg 
sotagliflozin showed a significant decrease in PPG excursion and an increase in GLP-1 
secretion in these patients with high unmet medical need, in which SGLT2 inhibitors have 
little efficacy, while maintaining a favorable safety and pharmacokinetic profile. After 1 
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Protocol No. LX4211.312 
week, patients on sotagliflozin had a 50-60 mg/dL reduction in PPG compared to Baseline. 
Notably, this difference was preserved in the patient subgroup with severe renal impairment; 
efficacy is usually reduced in patients with severe renal impairment with selective SGLT2 
inhibitors. 
3.1.1.1 
Potential Effects on Mealtime Glycemic Control 
Mealtime insulin without sotagliflozin: Under the current mealtime treatment paradigm for 
T1D, exogenous insulin administration determines both glycemic control (PPG excursion 
triggered by ingested carbohydrate) and energy flux (facilitated glucose transport into cells) – 
therefore coupling 2 treatment objectives with a single insulin dose. As a result, to maintain 
normoglycemia after carbohydrate ingestion, which is usually excessive for most patients, the 
amount of insulin required is usually greater than the amount required for optimal energy flux 
over a very narrow range – resulting in a narrow therapeutic index.  
Mealtime insulin with sotagliflozin: Based on results from oral glucose tolerance tests 
(OGTT) in controlled settings in multiple studies, sotagliflozin’s unique dual mechanism of 
action is expected to act as a buffer against postprandial hyperglycemia with a daily capacity 
of approximately 60-100 g glucose. In some individuals, this capacity could buffer the entire 
carbohydrate content of more than 1 meal a day. This is explained below.  
Assuming a 2000 calorie diet, and a diet consisting of 40% carbohydrates, 
800 calories (200 g) is derived from carbohydrates (for simplification, 100% of 
carbohydrates are assumed to be glucose). For a diet consisting of 60% carbohydrates, 
1200 calories (300 g) is derived from carbohydrates. On average, each meal may 
contain 65 g of glucose in the 40% carbohydrate, 2000 calorie diet, and 100 g of 
glucose in the 60% carbohydrate diet. 
With the glucose-buffering capacity afforded by sotagliflozin, mealtime glycemic control is 
expected to be influenced by both mealtime insulin and sotagliflozin, thereby decoupling 
glycemic control from energy flux. As a result, it is expected that: 
•
Energy flux will continue to be primarily determined by insulin dose.
•
Glycemic control will be determined by both insulin dose and sotagliflozin, thereby
requiring lower insulin doses to maintain glycemic goals, and also less precision of
insulin dosing due to reduced variability in blood glucose.
•
Less insulin will be required at mealtime to meet the goal of avoiding postprandial
hyperglycemia.
•
This will, in effect, lower the insulin to carbohydrate (I/C) ratio.
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Protocol No. LX4211.312 
•
This will result in a requirement for less mealtime insulin on board (IOB), for a given
amount of carbohydrate.
•
Less mealtime IOB will lower the risk of hypoglycemia.
Current experience in humans is described in Section 3.5. 
3.2 
Sotagliflozin Pharmacology 
Sotagliflozin is a dual inhibitor of SGLT1 and SGLT2, designed to reduce glucose absorption 
in the GI tract via SGLT1 inhibition and renal glucose reabsorption via SGLT2 inhibition. 
Unlike selective SGLT2 modulators currently in development, sotagliflozin provides dual 
inhibition, representing a potentially unique mechanism of action.  
3.2.1 
Studies in Mice 
3.2.1.1 
Nondiabetic, Diet-induced, Obese Mice 
Administration of single doses of sotagliflozin to nondiabetic mice improved glucose 
tolerance. Repeat-dose administration to diabetic mice not only improved glucose tolerance, 
but also lowered A1C.  
The acute effect of sotagliflozin on facilitating glucose excretion in the nondiabetic, diet-
induced, obese mouse was evaluated in 5 studies, each of which examined a control and 1 or 
more of the following doses of sotagliflozin:  0.003, 0.03, 0.1, 0.3, 3, 10, 30, and 60 mg/kg. 
Sotagliflozin caused a dose-dependent increase in glucose excretion over the 24-hour period 
immediately following dosing. The minimally effective dose was 0.1 mg/kg. The daily dose 
causing 50% maximal glucose excretion in the first 24 hours following dosing (ED50) was 
calculated to be approximately 1.8 mg/kg. Single doses of 10 mg/kg and 60 mg/kg 
sotagliflozin caused a pharmacologic effect for at least 72 hours after dosing. 
The acute effect of sotagliflozin on oral glucose tolerance in the nondiabetic, diet-induced, 
obese mouse was evaluated at the following doses:  0.03, 0.3, 3, and 30 mg/kg. Sotagliflozin 
produced a dose-dependent improvement in glucose tolerance. Based upon the area under the 
plasma concentration-time curve (AUC) from Time 0 to Hour 4 values and, under these 
experimental conditions where sotagliflozin was concomitantly administered with dextrose at 
the start of the OGTT, the minimally effective dose of sotagliflozin for improving glucose 
tolerance in the normal mouse was found to be 3 mg/kg. 
3.2.1.2 
Diabetic Mice 
The effect of repeated daily treatment with sotagliflozin on lowering blood glucose in the 
diabetic mouse was evaluated in 2 studies. The first study examined the effect of vehicle 
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Protocol No. LX4211.312 
versus sotagliflozin oral suspension (5 mL/kg dose volume) for 25 days at 1 and 10 mg/kg in 
mice with established hyperglycemia. 
Sotagliflozin, at both 1 mg/kg and 10 mg/kg, produced a decrease in A1C concentrations. The 
reduction following treatment with sotagliflozin failed to reach statistical significance due to 
an unexpected decrease in A1C concentrations in the vehicle treated mice. Sotagliflozin did 
produce the expected significant increase in UGE. Fed blood glucose concentrations were 
also reduced by sotagliflozin. 
The second repeat-dose study in diabetic mice examined the effect of sotagliflozin at 1 mg/kg 
on slowing the progression to severe hyperglycemia in young mice. Mice in the control group 
exhibited an increase in A1C, whereas mice treated with sotagliflozin did not exhibit such 
increases. UGE was increased with sotagliflozin, both at the start of dosing and at the end of 
the 5-week dosing period. In addition, diabetic mice treated with sotagliflozin daily for 5 
weeks exhibited improved glucose tolerance. 
3.2.2 
Studies in Rats 
The acute effect of sotagliflozin on facilitating glucose excretion in the nondiabetic rat was 
evaluated in 4 studies, each of which examined a vehicle control and one or more of the 
following doses of sotagliflozin:  0.3, 1, 3, 10, and 50 mg/kg. Sotagliflozin resulted in a 
dose-dependent increase in glucose excretion during the first 24 hours following dosing. All 
doses evaluated produced a significant increase in glucose excretion. The ED50 was 
calculated as 0.75 mg/kg; the effect increased with increasing dose up to the highest dose 
tested (50 mg/kg). At doses of 1 mg/kg and above, the pharmacologic effect of sotagliflozin 
was maintained for at least 2 days following a single oral dose. 
3.2.3 
Studies in Dogs 
The acute effect of sotagliflozin on facilitating glucose excretion in the nondiabetic dog was 
evaluated in 2 studies, each of which included a predose (Baseline) control value and 1 of the 
following doses of sotagliflozin:  0.003, 0.01, 0.03, 0.1, 0.3, and 3 mg/kg. Sotagliflozin 
resulted in a dose-dependent increase in glucose excretion during the first 24 hours following 
dosing. The minimally effective dose for facilitating glucose excretion was 0.1 mg/kg. The 
ED50 was calculated to be 0.2 mg/kg. At doses of 0.1 mg/kg and above, the pharmacologic 
effect of sotagliflozin was maintained for at least 2 days following a single oral dose. 
3.2.4 
Summary of Pharmacology 
The preclinical pharmacology studies of sotagliflozin were designed to evaluate the 
compound’s mechanism of action and effects in vivo. Sotagliflozin consistently facilitated 
significant glucose excretion in nondiabetic, diet-induced obese mice, and normal rats and 
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Protocol No. LX4211.312 
dogs in a dose-dependent fashion during the first 24 hours following oral administration. 
Depending on the species and the dose of sotagliflozin, the pharmacologic effect of the 
compound could be maintained for 48 hours or longer. The ED50 for sotagliflozin was 
1.8 mg/kg/day in the mouse. The ED50 was approximately 0.75 mg/kg/day for rats and 
approximately 0.2 mg/kg/day for dogs. Importantly, sotagliflozin reduced hyperglycemia in a 
diabetic mouse model and improved glucose tolerance in both diabetic and nondiabetic mice. 
Detailed pharmacology information may be found in the Investigator’s Brochure. 
3.3 
Sotagliflozin Toxicology 
Toxicology studies including Good Laboratory Practice (GLP)-compliant mammalian 
toxicology, genetic toxicology, and safety pharmacology have been completed with 
sotagliflozin. Chronic toxicology studies with sotagliflozin have been completed in the rat 
and the dog. Results from these studies are summarized in Sections 3.3.1, 3.3.2, and 3.4. 
Additional details can be found in the Investigator’s Brochure. 
3.3.1 
Toxicology Studies in Rats 
A 26-week chronic toxicology study with sotagliflozin has been completed in the rat. Doses 
administered were 30, 75, or 300 mg/kg/day. Results showed that sotagliflozin produced 
nonadverse clinical effects and pathology changes, most of which reversed (or exhibited 
reversibility) during the recovery phase. Clinical effects included relative decreases in body 
weight gain and body weight change for males given 75 mg/kg/day and animals given 
300 mg/kg/day, and increased food consumption for all groups given sotagliflozin. Clinical 
pathology changes included minor hematology findings, higher urine volume, increased urine 
calcium and inorganic phosphorus excretion, increased serum urea nitrogen concentration, 
and minimally higher serum alanine aminotransferase (ALT) activity at all dose levels; and 
higher serum alkaline phosphatase (ALP) activity and serum gamma glutamyltransferase 
activity for animals given 300 mg/kg/day. Administration of sotagliflozin at all dose levels 
resulted in declines in bone turnover and calciotropic hormone levels. The trends for 
decreases in bone turnover markers at the low dose were generally marginal and not 
considered biologically significant. 
Postmortem observations included increased kidney weights at all dose levels (reversed in 
males and was reversing in females with recovery) and reversible increased adrenal weights 
without microscopic correlates in males given ≥75 mg/kg/day and females given 
300 mg/kg/day. Microscopic findings included reversible minimal to slight dilatation of renal 
cortical tubules in males given ≥30 mg/kg/day and females given ≥75 mg/kg/day; reversible 
transitional cell hyperplasia/hyperkeratosis within the renal pelvis and 
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hyperplasia/hypertrophy in the urinary bladder for females given 300 mg/kg/day; an 
increased severity of prostatic inflammation at the terminal and recovery sacrifices in males 
given ≥75 mg/kg/day; minimal to moderate increased trabecular bone adjacent to the growth 
plate of the sternum in males given ≥30 mg/kg/day and females given ≥75 mg/kg/day; and 
hyperplasia/hyperkeratosis of the nonglandular stomach at the junction of glandular stomach 
for males given ≥30 mg/kg/day that was still present at the recovery sacrifice in animals 
given 75 or 300 mg/kg/day. Based on the results of this study, the no observed adverse effect 
level (NOAEL) for sotagliflozin administered by oral gavage for at least 26 weeks to male 
and female rats is 30 and 75 mg/kg/day, respectively. These dose levels correspond with a 
Week 26 maximum observed plasma concentration (Cmax) of 2360 ng/mL and AUC0-24 hours 
values of 15,077 ng•hr/mL for males, with respective values of 13,333 ng/mL and 
84,145 ng•hr/mL for females. 
3.3.2 
Toxicology Studies in Dogs 
A 39-week chronic toxicology study with sotagliflozin has been completed in the dog. Doses 
administered were 20, 60, or 200 mg/kg/day. Results showed that sotagliflozin produced 
nonadverse clinical effects and pathology changes, most of which reversed or exhibited 
reversibility during the recovery phase. Clinical effects included clinical observations typical 
for animals given 200 mg/kg/day and increased food consumption for all groups given 
sotagliflozin. Clinical pathology changes were reversible and included effects on urinalysis 
(UA) and urine excretion tests at all dose levels and minimal to mild effects on serum glucose 
during Week 13 at all dose levels and during Week 40 of the dosing phase at >60 mg/kg/day. 
Anatomic pathology findings were noted at all dose levels and were limited to reversible 
increased kidney weights without microscopic correlates and reversible decreased 
hepatocellular glycogen. Based on the results of this study, the NOAEL for sotagliflozin 
administered by oral gavage for at least 39 weeks to male and female beagle dogs is 
200 mg/kg/day, the highest dose level evaluated. This dose level corresponds with Cmax and 
AUC0-24 hours values of 21,867 ng/mL and 158,334 ng•hr/mL, respectively, for males and of 
20,867 ng/mL and 143,795 ng•hr/mL, respectively, for females at Week 39 of the dosing 
phase. 
3.4 
Reproductive Toxicity 
Initial reproductive toxicity studies assessing maternal, embryo/fetal toxicity and teratogenic 
potential have been conducted in both pregnant rats and rabbits. The NOAEL for maternal 
toxicity and developmental toxicity for sotagliflozin in Sprague-Dawley rats is 
100 mg/kg/day. This dose corresponds to a gestational day (GD) 17 Cmax of 7183 ng/mL and 
AUC0-24 hours of 78,012 ng•hr/mL. The NOAEL for maternal reproductive function and 
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Protocol No. LX4211.312 
embryo-fetal developmental toxicity for sotagliflozin in New Zealand White rabbits was 
200 mg/kg/day, the highest dose tested in this study. This dose corresponds to a GD20 Cmax of 
5623 ng/mL and AUC0-24 hours of 18,145 ng•hr/mL.  
3.5 
Clinical Trials of Sotagliflozin in Humans 
More than 600 subjects have participated in clinical studies of sotagliflozin. No significant 
safety concerns have been identified in the sotagliflozin drug program, and sotagliflozin has 
been well-tolerated in all studies to date. Serious adverse events (SAEs) and discontinuations 
due to adverse events (AEs) have been infrequent and have been balanced between treatment 
and comparator groups. Reports of treatment-emergent adverse events (TEAEs) across all 
sotagliflozin studies for which data are available were generally balanced between treatment 
and comparator groups. Headache was reported as a possible adverse reaction that occurred 
in ≥5% of subjects in sotagliflozin clinical studies, and was reported at a greater rate in 
sotagliflozin-treated subjects than placebo; however, most were assessed as mild to moderate, 
and most resolved spontaneously.  
There was no common theme or imbalances in SAEs, nor were there significant imbalances 
between sotagliflozin and comparators in AEs. Cumulatively, during the clinical trial program 
8 SAEs were reported by 6 patients (4 T2DM and 2 T1D), all of which were assessed as 
unrelated to study drug; those reported by 4 T2DM patients in the Phase 2 study 
LX4211.1-202-T2DM who received sotagliflozin included pulmonary embolism, deep vein 
thrombosis (DVT), bile duct stone, cholangitis and lower limb fracture, while a myocardial 
infarction (MI) was experienced by a patient receiving placebo. Two SAEs of diabetic 
ketoacidosis (DKA) were reported by 2 subjects treated with sotagliflozin in the Phase 2 T1D 
study LX4211.1-203-T1DM; both SAEs were assessed by the Investigator as due to failure of 
insulin delivery via insulin pump. In both cases, the patients had full recovery and resumed 
study drug within 48-72 hours of onset of DKA. 
More information on the safety of sotagliflozin and on the clinical program can be found in 
the Investigator’s Brochure. 
3.5.1 
Digoxin Drug-Drug Interaction (DDI) Study 
Study LX4211.1-114-NRM was a drug-drug interaction study in healthy subjects, where 
LX4211 was shown to increase systemic exposure of digoxin, a sensitive P-gp substrate. 
Least squares mean digoxin Cmax, AUC0-last, and AUC0-inf increased by 51.9%, 31.1%, 
and 26.9%, respectively, following administration of digoxin in the presence of steady-state 
LX4211 compared to administration of digoxin alone. It can be concluded from these results 
that LX4211 acts as a mild P-gp inhibitor and may therefore result in elevation of digoxin 
levels. Given these data, it may be necessary to decrease digoxin dose by approximately  
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30-50% or to modify the digoxin dosing frequency when sotagliflozin is administered. All 
patients should be evaluated about concurrent medication at each visit and those taking 
concomitant digoxin should have digoxin concentrations monitored. If the digoxin is being 
managed by another physician, that physician should also be informed about this potential 
interaction. Additionally, we recommend that the patient’s concomitant medications be 
evaluated as to whether they are P-gp substrates and the drug labels of these drugs be 
reviewed to determine if dosage reductions are recommended. 
3.5.2 
Clinical Trials in T1D 
Sotagliflozin has been evaluated in a 4-week, multicenter, randomized, double-blind, 
placebo-controlled, proof-of-concept trial in the US (LX4211.1-203-T1DM). A total of 36 
patients, 18-55 years of age, with inadequately controlled T1D with an A1C range at Baseline 
of 7.0-9.0% have completed the study. Prior to the double-blind portion, the trial was initiated 
with an open-label “pioneer” group of 3 patients, in order to determine the appropriate 
recommended reduction in mealtime bolus insulin.  
During the double-blind expansion phase, the threshold for correction insulin to treat 
hyperglycemia was lowered, with patient-specific threshold and algorithm determined by the 
Investigators based on individual goals. The study met the primary endpoint of reduction in 
total daily bolus insulin, as well as exploratory endpoint of 0.55% reduction in A1C after 29 
days of treatment, both of which were highly statistically and clinically significant. Two 
reports of DKA were reported by 2 separate patients treated with sotagliflozin. Both events 
were reported by the Investigators as related to pump failure and unrelated to study drug. No 
events of severe hypoglycemia or SAE related to hypoglycemia have been reported. 
3.6 
Rationale for Current Study 
3.6.1 
Rationale for Selection of Dose 
The proposed 400 mg once-daily dose is based on the results of the Phase 2b study 
LX4211.1-202-DM. In that study, doses of 75 mg once daily, 200 mg once daily, 200 mg 
twice daily, and 400 mg once daily sotagliflozin were tested over a 12-week, double-blind 
period. The 400 mg once daily dose was chosen for further evaluation based on its A1C 
lowering effect and the overall safety and tolerability observed at this dose. At 12 weeks, the 
400 mg dose lowered A1C by a mean of 0.92%, while placebo lowered A1C by a mean of 
0.09%. Lower doses were less effective than the 400 mg dose and did not have any 
advantages in safety or tolerability. The overall incidence of AEs on 400 mg once daily was 
similar to placebo. A maximum dose of sotagliflozin has not been established in terms of 
either safety or A1C reduction.  
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From a safety perspective, sotagliflozin was well-tolerated across studies. In healthy subjects, 
sotagliflozin was well-tolerated following single doses up to 2000 mg, and in multiple doses 
up to 800 mg over 10 days. Furthermore, in a thorough QT study, single doses of 
sotagliflozin (800 mg and 2000 mg) were well-tolerated and did not prolong the QT interval. 
Additionally, evaluation of metabolites in urine and plasma of healthy subjects resulted in no 
safety concerns following single doses of 400 mg sotagliflozin. In patients with T2DM, 
single doses of 400 mg in combination with sitagliptin, and multiple doses up to 400 mg in 
combination with metformin over 12 weeks, were also well-tolerated.  
3.6.2 
Rationale for Study Design and Control Groups 
This study is designed to demonstrate the efficacy and safety of sotagliflozin when used as 
adjunct therapy in normal weight and overweight/obese patients with T1D treated with 
insulin. Sotagliflozin will be compared to placebo, consistent with regulatory guidance. The 
24-week duration for assessment of A1C, which is a component of the primary efficacy 
endpoint, is assessed to be sufficient for achieving steady state conditions for sotagliflozin. 
Moreover, the “net benefit” primary endpoint chosen for this study (proportion of patients 
with A1C <7.0% at Week 24 and no episode of severe hypoglycemia and no episode of 
DKA) is clinically relevant. In this study, self-monitored blood glucose (SMBG) values will 
be reviewed by the Investigator and insulin doses adjusted if the SMBG trends are not 
meeting SOC T1D target goals.  
Bias will be minimized by stratified allocation to treatment groups made based on body mass 
index (BMI) at Screening (<25 kg/m2, ≥25 kg/m2), Week -2 A1C (≤9%, >9%) and use of 
continuous subcutaneous insulin infusion (CSII) at Screening (Yes, No). 
A placebo control will be used to allow for an unbiased assessment of treatment effects and 
safety data. The comparison with placebo is justified since patients will continue use of 
prescribed insulin therapy, and the patients’ glycemic status will be monitored and 
adjustments made to insulin dose based on prespecified glycemic targets. 
Bias will be minimized by randomly assigning the patients to treatment groups; blinding the 
patients, the Investigators, and the Sponsor to the treatment allocations; and by adjudication 
of death and event(s) of special interest (EOSI) in a blinded fashion. 
A parallel-group design was selected because it is free of the assumptions underlying 
competing designs (eg, crossover). Inclusion of patients with eGFR ≥45 mL/min/1.73 m2 is 
justified based on study LX4211.107, which demonstrated glycemic efficacy in diabetic 
patients with moderate to severe renal impairment (eGFR 15-59 mL/min/1.73 m2). 
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3.6.3 
Rationale for Patient-reported Outcomes: Satiety Substudy 
This substudy is designed to demonstrate the effects of sotagliflozin on patient self-reported 
satiety. Based on the dual mechanism of action of sotaglifozin, it is anticipated that 
sotagliflozin will increase satiety. As result of dual inhibition, more glucose delivered distally 
will trigger increased L-cell release of GLP-1 and PYY, a natural peptide hormone response 
associated with enhanced glycemic and appetite control; these findings have been 
substantiated with numerous animal and human mechanistic studies.[8,9] 
The instrument selected for the study, the Patient Satiety Daily Diary (PSDD) utilizes the 
Patient Satiety Daily Diary Numeric Rating Scale (PSDD-NRS).[8,9,10]  
Patient-reported satiety is measured on an 11-point numeric rating scale as a daily diary 
measured prior to first meal. This single item measure has been utilized in diabetes studies to 
assess increased fullness as well as decreased hunger ratings relative to change in glucose and 
insulin responses. Numeric rating scales of satiety are well-accepted by Regulatory Agencies 
and are both sensitive to change and able to discriminate along the clinical severity 
continuum. 
The PSDD is described in Section 8.1.6 and included in Appendix H. 
3.7 
Benefit/Risk of Sotagliflozin 
In this study, sotagliflozin is being investigated as an adjunct to insulin treatment in patients 
with T1D with poor glycemic control. The attributes of sotagliflozin, a dual SGLT1 and 
SGLT2 inhibitor, and its insulin-independent mechanism of action are well-suited to address 
the needs of this population with high unmet medical need. While insulin has been available 
as a life-saving therapeutic option for patients with T1D, the risk of hypoglycemia inherent 
with insulin use significantly limits the ability to achieve target glycemic goals for many 
patients with T1D. As a result, many patients with T1D purposely maintain 
hyperglycemia.[11] As noted earlier, based on the T1D registry[3], only approximately 17% 
of registered T1D patients are able to achieve a target A1C <7.0%. Six to 10% of deaths in 
young patients with T1D are directly attributable to hypoglycemia, likely from cardiac 
arrhythmias.[12] A recent publication evaluating national trends for US Hospital admissions 
related to hyperglycemia and hypoglycemia reported an increase in rates of admission for 
severe hypoglycemia among diabetic patients 65 years and older during the period between 
1999 to 2011.[13] Patients with T1D who are able to achieve target goals are only able to do 
so with rigorous monitoring of glucose, insulin dosing, dietary intake and lifestyle 
management, factors which increase burden and negatively impact quality of life. Therefore, 
ability of an oral agent like sotagliflozin to potentially achieve glycemic control safely when 
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Protocol No. LX4211.312 
added to insulin, without increasing the risk of hypoglycemia offers an attractive potential for 
patients with T1D. 
Improvements in A1C, fasting plasma glucose (FPG), and PPG were observed with 
sotagliflozin in multiple studies in patients with T2DM. Glycemic efficacy with A1C and 
PPG reduction, reduction in total bolus and total daily insulin, and a trend towards reducing 
hypoglycemic events were also observed in the Phase 2 T1D study. As anticipated from the 
mechanism of action, treatment with sotagliflozin resulted in increased UGE (from inhibition 
of SGLT2) as well as increased incretin levels (from inhibition of SGLT1). In addition, the 
reductions in body weight, blood pressure (BP), and triglycerides observed with sotagliflozin 
treatment have the potential to benefit patients with diabetes through their effects on common 
diabetic comorbidities.  
In patients with T1D, the glucose-buffering capacity afforded by sotagliflozin and mealtime 
glycemic control is expected to be influenced by both mealtime insulin and sotagliflozin, 
thereby decoupling glycemic control from energy flux. As a result, it is anticipated that 
patients will need lower and less precise doses of insulin to reduce variability in blood 
glucose. The lower amount of IOB at mealtime should reduce the risk of hypoglycemia. The 
ability to maintain better glycemic control with a simplified insulin regimen provided by 
sotagliflozin offers the possibility of long-term health benefits. The anticipated lower insulin 
requirement may also lead to lower risk of hypoglycemic events and improved quality of life. 
Few safety issues have been identified in the sotagliflozin drug program. To date, 
sotagliflozin has been well-tolerated in all studies, with the majority of AEs assessed as mild 
to moderate in severity, and with most resolved spontaneously. Two patients in the 
sotagliflozin group in the T1D proof of concept study reported an event of DKA; in each case 
basal insulin was within 7% of baseline, and the event was attributed by the Investigator to 
insulin pump-related etiologies. Both cases were associated with high blood glucose readings 
>300 mg/dL, a finding expected in DKA and notable in that this value did not appear to be 
masked by sotagliflozin treatment. Based on the SGLT2 inhibitor mechanism of action, GU 
infections are recognized as a potential risk that will be monitored as an EOSI in all Phase 3 
clinical trials. In completed trials to date, the rate of GU infections has been low and well 
balanced across sotagliflozin and placebo treatment groups. With the exception of DKA noted 
above, SAEs and discontinuations due to AEs have been uncommon and have been balanced 
between sotagliflozin and placebo or comparator groups. These have been uncommon and 
have responded to standard treatment.  
Therefore, we believe sotagliflozin presents a favorable benefit-risk assessment based on its 
tolerability and safety profile known to date.  
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Protocol No. LX4211.312 
4.
Study Objectives
4.1 
Primary Objective 
The primary objective of this study is to demonstrate the superiority of sotagliflozin 400 mg 
versus placebo in the proportion of patients with glycosylated A1C <7.0% at Week 24 and no 
episode of severe hypoglycemia and no episode of DKA after randomization. 
4.2 
Secondary Objectives 
Secondary objectives of this study are to evaluate the change from Baseline of sotagliflozin 
versus placebo in hierarchical order on the following: 
•
A1C
•
Body weight
•
Systolic blood pressure (SBP)
•
Bolus insulin dose
4.3 
Other Objectives 
Other objectives of this study are: 
To compare changes in several parameters in response to sotagliflozin versus placebo, as 
assessed by evaluations with specified cut points, and at specified time intervals during the 
24-week double-blind Treatment Period including:  
•
Parameters assessed as secondary objectives (A1C, body weight, SBP, bolus insulin
dose)
•
Proportion of patients with A1C reduction ≥0.4% and no increase in body weight
•
Proportion of patients with A1C reduction ≥0.5% and no episode of severe
hypoglycemia
•
Proportion of patients meeting success criteria for A1C and insulin
•
FPG
•
Total and basal (or non-bolus) insulin dose
•
Diastolic blood pressure (DBP)
•
Hypoglycemic events
•
Measures of kidney function
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Protocol No. LX4211.312 
•
Patient-reported satiety (substudy)
•
Safety of sotagliflozin 400 mg versus placebo
5.
Investigational Plan
5.1 
Overall Study Design 
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-
group study.  
Adult patients with T1D and BMI ≥18.5 kg/m2 with inadequate glycemic control with insulin 
therapy (administered by subcutaneous injections] or CSII are eligible for enrollment in this 
study if they meet all inclusion and no exclusion criteria. Inclusion and exclusion criteria are 
listed in Section 6.1 and Section 6.2. 
A total of 1400 patients will be randomly assigned 1:1 between the following 2 treatment 
groups: 
•
Sotagliflozin 400 mg as two (2) 200-mg tablets, once daily, before the first meal of
the day
•
Placebo as two (2) placebo tablets (identical to sotagliflozin in appearance), once
daily, before the first meal of the day
It should be noted that all tablets (placebo and 200-mg) are identical in appearance. 
Patients will continue treatment with insulin(s) or insulin analog(s) during the study. 
Note:  Subsequently, in this document, the term “insulin” includes insulin analogs. The term 
“insulin analog” may also appear, as needed for clarity. Bolus insulin refers to regular insulin 
or fast-acting insulin analog which may be administered via subcutaneous (SC) or inhaled 
route. 
During the study, SMBG values will be reviewed by the Investigator and insulin doses 
adjusted if the SMBG trends do not meet SOC T1D target goals. Suggested insulin titration 
algorithms are provided in the Site File Notebook. These algorithms may be modified based 
on the Investigator’s clinical assessment. Further details are presented in Section 7.6.1.  
Patients will participate in the study for up to 32 weeks. The study includes a Screening 
Period of up to 2 weeks, followed by a 2-week single-blind placebo Run-in Period, a 
24-week, double-blind Treatment Period, and a 30-day Follow-up Period. The study periods 
are described in detail in Section 5.1.1 to Section 5.1.5.   
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Protocol No. LX4211.312 
Efficacy measures are described in Section 8.1. The definition of efficacy endpoints and the 
methods used to analyze efficacy are described in Section 10.3.1 and Section 10.4.1, 
respectively. 
Safety assessments are presented in detail in Section 8.2 and Section 9. Safety endpoints are 
defined in Section 10.3.2 and the methods used to summarize safety measures are described 
in Section 10.4.3. 
This study will also include a substudy designed to evaluate satiety (appetite) in a subset of 
enrolled patients. Up to 280 patients (140 per treatment group) will be recruited for this 
substudy. Additional details are presented in Section 8.1.6. 
The study design is summarized in Figure 5.1-1. 
Figure 5.1-1: Study Schema 
Adjudication of all deaths, EOSI, including major adverse cardiovascular events 
(MACE)/selected cardiovascular (CV) events, clinical or laboratory findings associated with 
drug-induced liver injury (DILI), DKA, and severe hypoglycemia episodes (as well as 
hypoglycemia reported as an SAE) will be performed in a blinded manner by independent 
Clinical Endpoint Committee(s) (CEC[s]) composed of the appropriate experts. Details will 
be provided in the CEC(s) Charter(s). 
An independent Data Monitoring Committee (DMC) will meet on a regular basis to review 
accumulating clinical study safety data, as described in Section 9.6.1.  
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Protocol No. LX4211.312 
5.1.1 
Screening Period 
Written informed consent will be obtained from all patients before beginning any study 
related screening procedures. The collection of SAEs will begin after the patient has signed 
informed consent. Participation in the satiety substudy will be discussed at this time.  
5.1.2 
Single-blind Placebo Run-in Period 
Patients will begin the single-blind placebo Run-in Period at Week -2. 
At the beginning of the single-blind placebo Run-in Period, patients electing to participate in 
the satiety substudy will receive packets of satiety daily diaries. The patients will be 
instructed to complete the paper diary each day before the first meal of the day for the 
duration of the single-blind placebo Run-in Period (14 days, ±3 days). Patients will be 
reminded to bring the diaries with them on Day 1 (Baseline).  
Patients will receive diet and exercise counseling according to nutritional recommendations 
for a healthy lifestyle consistent with American Diabetes Association (ADA)[14], the 
European Association for the Study of Diabetes (EASD)[15], or similar local guidelines, with 
a goal of weight maintenance to be followed for the study duration.  
Glucose meter, BHB meter and supplies will be dispensed at the Run-in visit. Patients will 
also be educated on the use of the glucose meter and BHB meter provided for use during this 
study and use of the study diary to record insulin doses, SMBG, and hypoglycemic events 
(please see Section 7.6.1.3 for SMBG and insulin data required for CRF entry). 
Compliance with the administration of single-blind placebo tablets and compliance with 
recording data in the study diary will be assessed during the single-blind placebo Run-in 
Period. Patients must demonstrate good compliance with placebo tablets (≥80%) during the 
single-blind placebo Run-in Period to be eligible for randomization. Compliance will be 
calculated as specified in Section 7.5.1. 
5.1.3 
Unscheduled Visits 
During the course of the study, additional contact by telephone call, or unscheduled site visit, 
(or both) may be considered, based on Investigator’s discretion. Assessments completed 
during these visits (on-site or by telephone call), may include evaluation of SMBG data, 
insulin doses, AEs (eg, volume depletion, elevated creatinine), hypoglycemic events, etc. The 
Unscheduled Visit electronic case report form (eCRF) will be completed for each 
unscheduled telephone contact or site visit. 
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Protocol No. LX4211.312 
5.1.4 
24-Week Double-blind Treatment Period 
Following completion of the single-blind placebo Run-in Period, eligible patients will enter 
the 24-week, double-blind Treatment Period. Patients will be randomly assigned 1:1 in 
parallel between the 2 treatment groups: sotagliflozin 400 mg or placebo.  
The double-blind Treatment Period includes 5 clinic visits (Baseline, and Weeks 4, 8, 16, 
and 24). 
For all patients, clinic visits should be scheduled in the morning at approximately the same 
time of day. 
In regard to patients taking antihypertensive medications, the Investigator will be asked to 
maintain dosages unchanged between Baseline and Week 16, if this is consistent with proper 
medical management of the patient. 
For patients in the satiety substudy, the satiety daily diaries completed during the single-blind 
placebo Run-in Period will be collected at Day 1 (Baseline). At the visit scheduled for 
Week 16, these patients will receive packets of satiety daily diaries. At the beginning of 
Week 23, patients will receive a telephone call to remind them to start recording information 
onto the satiety daily diaries. The patients will be instructed to complete the paper diary each 
day, before the first meal of the day for the last 2 weeks of the double-blind Treatment Period 
(ie, during Week 23 and during Week 24, a total of 14 days, ±3 days). The diaries will be 
returned to the site at the visit scheduled for the end of Week 24.  
5.1.5 
Follow-up Period 
All patients will have a contact 30 days after the last dose of study drug to obtain information 
on SAEs, EOSI, and any AEs that were ongoing at the time of the EOT/EW Visit.  
6.
Study Population
Patients included in this study will be ≥18 years of age with a confirmed diagnosis of T1D 
and inadequate glycemic control on insulin therapy alone. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria listed below to be considered eligible to 
participate in the study. For patients not meeting eligibility requirements, the reason for 
exclusion must be recorded. Note:  Patients not eligible because of laboratory result(s) may 
have the laboratory test(s) repeated once during the Screening Period at the discretion of the 
Investigator to determine eligibility: 
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Protocol No. LX4211.312 
1) Patient has given written informed consent to participate in the study in accordance
with local regulations
2) Adult patients 18 years and older with a diagnosis of T1D made at least 1 year prior to
informed consent
3) Patients are being treated with insulin(s) or insulin analog(s)
4) Non-fast acting insulin dose is stable (±20%) for 2 weeks prior to the Screening Visit
5) At the Screening Visit, A1C must be between 7.0% and 11.0%, inclusive
6) BMI ≥18.5 kg/m2
7) Must be willing and able to perform SMBG and complete the study diary as required
per protocol
8) Females of childbearing potential must use an adequate method of contraception to
avoid pregnancy throughout the duration of the study and for 30 days after the last
dose of study drug. Females of childbearing potential include any female who has
experienced menarche and who has not undergone successful surgical sterilization
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not
postmenopausal. Postmenopause is defined as no menses for ≥12 months without
another cause. For females with questionable menopausal history (eg, irregular
menstrual periods and age >40 years) a documented serum follicle-stimulating
hormone (FSH) level must be ≥30 mIU/mL.
9) Females of childbearing potential must have a negative serum or urine pregnancy test
prior to the start of study drug. In the case of positive urine pregnancy testing, a
negative serum sample for pregnancy testing, to confirm that the patient is not
pregnant, must be obtained prior to start of study.
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participating in the 
study. For patients not meeting eligibility requirements, the reason for exclusion must be 
recorded. Note:  Patients not eligible because of laboratory result(s) may have the laboratory 
test(s) repeated once during the Screening Period at the discretion of the Investigator to 
determine eligibility:   
1) Therapies and/or medications:
a) Use of antidiabetic agent other than insulin(s) or insulin analog(s) at the time of
screening (any medication other than insulin or insulin analog used for treatment
of T1D must be washed out for at least 8 weeks prior to the Screening Visit)
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Protocol No. LX4211.312 
b) Any prior exposure to sotagliflozin
c) Use of SGLT inhibitors within 8 weeks prior to Screening. Note:  Patients taking
an SGLT inhibitor may have that prohibited medication stopped, and may be
considered for entry into the study if they have not been taking the prohibited
medication for at least 8 weeks prior to Screening.
d) Chronic systemic corticosteroid use, defined as any dose of systemic
corticosteroid taken for more than 4 consecutive weeks within the 6 months prior
to the Screening Visit. Note:  Topical, inhaled, ocular, or nasal sprays containing
corticosteroids are allowed.
2) Diabetes-related conditions:
a) Type 2 diabetes mellitus, or severely uncontrolled T1D as determined by the
Investigator
b) History of severe hypoglycemic event within 1 month prior to the Screening Visit
c) History of DKA or nonketotic hyperosmolar state within 1 month of Screening
OR ≥2 episodes of DKA or nonketotic hyperosmolar state within 6 months of
Screening
3) Laboratory Results:
a) Estimated glomerular filtration rate <45 mL/min/1.73 m2 at Screening, as
determined by the 4 variable Modification of Diet in Renal Disease (MDRD)
equation
b) Fasting triglycerides >600 mg/dL(>6.77 mmol/L). Note:  Patients who fail
Screening based on this criterion must have their fasting status verified, may have
triglyceride-lowering medications adjusted, and be reevaluated during Screening.
c) Abnormal liver function at Screening defined as any of the following:  aspartate
aminotransferase (AST) >2X upper limit of the normal reference range (ULN),
ALT >2X ULN, serum total bilirubin (TB) >1.5X ULN. Note:  If it is the opinion
of the Investigator and the Medical Monitor that an increase in bilirubin is due to
Gilbert’s syndrome, then the patient may participate.
d) Screening beta-hydroxy butyrate (BHB) >0.6 mmol/L
4) Reproductive status:
a) Females who are pregnant or breastfeeding or intend to be during the course of the
study
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5) Gastrointestinal/hepatic:
a) By known history, serologic evidence of current infectious liver disease (hepatitis
A, B, or C), including antihepatitis A virus (immunoglobulin M), hepatitis B
surface antigen, or antihepatitis C virus. Note:  Patients with isolated positive
hepatitis B surface antibody may be included.
b) Difficulty swallowing such that the patient cannot take the study drug
c) History of pancreatitis within 12 months of screening, or any prior history of
recurrent pancreatitis
6) Renal:
a) Initiation of chronic dialysis within 30 days prior to the Screening Visit or
expected to occur within 180 days after the Screening Visit
b) Renal disease that required treatment with immunosuppressive therapy, or a
history of dialysis or renal transplant
c) History of hereditary glucose-galactose malabsorption or primary renal glucosuria
7) Cardiovascular:
a) New York Heart Association Class III or IV heart failure within 3 months prior to
Screening Visit[16]
b) Hypertensive urgency or emergency within 30 days prior to randomization. Note:
Patients with uncontrolled hypertension at Screening will be allowed to enter the
study provided that they are being aggressively treated for hypertension according
to local guidelines. Examples of guidelines current at the time of protocol writing
include those from the ADA[14] and the European Society of Cardiology.[15]
c) Patients with unstable/symptomatic or life-threatening arrhythmia or heart block.
Note:  Asymptomatic atrial fibrillation is not considered to be life-threatening and
patients with asymptomatic atrial fibrillation will be permitted to enter the study.
d) Patient has had any of the following within 3 months prior to the Screening Visit:
i.
Hospitalization due to unstable angina
ii.
MI
iii.
Coronary artery bypass graft (CABG) or percutaneous transluminal coronary
angioplasty
iv.
Transient ischemic attack (TIA) or significant cerebrovascular disease
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8) Hematologic:
a) History of hemoglobinopathies (sickle cell anemia, thalassemia major,
sideroblastic anemia) or other disorder that may interfere with A1C determination
b) Donation or loss of >400 mL of blood or blood product(s) within 8 weeks prior to
Screening
9) Immune system: Known severe immunocompromised status, including, but not
limited to, patients who have undergone organ transplantation. Note:  Patients with
human immunodeficiency virus (HIV) may participate if the Investigator considers
them otherwise suitable candidates for this study.
10) Malignancy or active treatment for malignancy (ie, radiation or chemotherapy,
including monoclonal antibodies) within 5 years prior to the Screening Visit. Note:
Patients with squamous or basal cell carcinomas of the skin, carcinomas in situ of the
cervix or uterus, ductal breast cancer in situ, resected low-grade prostate cancer, or
other malignancies that in the opinion of the Investigator and the Medical Monitor are
considered cured, may participate.
11) Current eating disorder or increase or decrease of weight within the 12 weeks prior to
Screening by more than 10%
12) Known allergies, hypersensitivity, or intolerance to sotagliflozin or any inactive
component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose
sodium [disintegrant], talc, silicone dioxide, and magnesium stearate [nonbovine]),
unless the reaction is deemed irrelevant to the study by the Investigator
13) Administration of any other investigational drug or participation in an interventional
clinical research study within 30 days or 5 half-lives (whichever is longer) of planned
Screening Visit
14) History of alcohol or illicit drug abuse (using Diagnostic and Statistical Manual of
Mental Disorders, 5th edition criteria [17]) within 12 months prior to the Screening
Visit
15) Patient is a study coordinator, employee of an Investigator or Investigator’s site, or
immediate family member of any of the aforementioned
16) Any condition that, in the opinion of the Investigator, may render the patient unable to
complete the study
17) The presence of a clinically significant medical history, physical examination, or
laboratory finding that, in the opinion of the Investigator or the Sponsor, may interfere
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with any aspect of study conduct or interpretation of results. The Investigator or the 
Sponsor will supply justification for exclusion, if applicable. 
6.3 
Cessation of Study Drug and Termination of Study 
Participation 
It is important to distinguish among 3 terms: 
•
Temporary cessation of study drug administration – refers to temporarily halting study
drug administration, which may be resumed at a later date.
•
Permanent cessation of study drug administration - refers to permanent cessation of
study drug administration.
•
Termination of study participation – refers to withdrawal of consent, or refusal to
participate in any further clinic visits or procedures.
6.3.1 
Temporary Cessation of Study Drug 
If a patient misses more than 3 consecutive doses, the patient should contact the site for 
instructions. Upon visiting the site for a scheduled visit, if a patient is documented to have 
interrupted study drug for >5 consecutive days, the site must notify the Sponsor and/or the 
Sponsor’s designee to obtain appropriate instructions. The Medical Monitor will assess the 
clinical scenario (with escalation to the Sponsor for input, if needed) and respond to the site. 
Some patients with liver function abnormalities may be required to temporarily cease taking 
study drug. There has been no liver signal identified in preclinical and clinical studies to date. 
The proactive algorithm is designed to establish uniform and complete follow-up of patients 
with liver chemistry abnormalities and prevent unintentional re-challenge. 
Temporary cessation of study drug that is resumed at a later date does not constitute 
permanent cessation or “discontinuation.” Only patients who are permanently ceasing study 
drug administration should be deemed as permanently stopping study drug. 
6.3.2 
Permanent Cessation of Study Drug 
Study drug administration may be halted for any of the following reasons:  
•
A life-threatening or serious adverse effect
•
Noncompliance, including refusal of the study drug and/or failure to adhere to the
study requirements as specified in the study protocol
•
The Investigator decides that, in the interest of the patient, it is not medically
acceptable to continue participation in the study
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Protocol No. LX4211.312 
•
The Sponsor decides to terminate the study
•
The patient meets specific criteria for liver function abnormalities
o
Note: There has been no liver signal identified in preclinical and clinical studies
to date. The proactive algorithm is designed to establish uniform and complete
follow-up of patients with liver chemistry abnormalities and prevent
unintentional re-challenge.
Temporary or permanent cessation of study drug administration is NOT considered to be 
withdrawal of consent from study participation unless the patient explicitly withdraws 
informed consent. 
6.3.3 
Termination of Study Participation and/or Withdrawal of 
Consent 
A patient has the right to discontinue study participation at any time, for any reason, and may 
leave the study without specifying a reason. The Investigator should make all efforts to obtain 
information about possible underlying AEs leading to the decision to withdraw from study 
participation. Any AE, EOSI, and SAE information elicited must be documented in the 
patient’s source documents and the eCRF.  
Unless a patient who prematurely discontinues trial participation specifically withdraws 
consent for any follow-up contact, all patients will continue to be contacted as specified in 
the protocol through the end of the study. There are a number of options for continuing 
follow-up once a patient decides to cease taking study drug. Investigators and site staff 
should encourage patients to allow as much follow-up as possible, and will need to clearly 
identify which aspects of the clinical trial the participants are discontinuing. Whenever 
possible, documentation should be collected in writing as to which of the following options 
the patient has chosen. 
•
The patient opts to permanently cease taking study drug only. In this case, the patient
continues to complete all study activities per protocol.
•
The patient is not willing to continue planned clinic visits/assessments, but will agree
to phone call assessments in accord with the clinic visit schedule.
•
The patient is not willing to continue planned clinic visits/assessments or phone call
assessments, but will allow the Investigator access to their medical records and end-
of-study telephone contact.
•
The patient is not willing to be contacted but does allow the Investigator access to
their medical records/contact with their care provider. In this case, the patient agrees
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to continue as a study participant by allowing information collected from his/her 
medical records to be used for research purposes. The patient does not agree to be 
contacted via phone, email, and/or postal mail for follow-up visits and/or study 
updates. 
•
The patient is not willing to allow any direct contact, access to medical records, or
contact with care provider. In this case, public records may be used to confirm vital
status at end of study.
•
The patient formally withdraws consent (ideally in writing, as detailed below) to
participate further in any component of the study. In this case, the patient does not
want any further medical information to be used for this research. Information that
has already been obtained will remain as part of the research record, but no additional
information will be added to the research record.
For the purposes of this protocol, only patients who are not willing to allow any direct 
contact, access to medical records, or contact with care provider will be deemed as patients 
who have withdrawn consent.  
If a patient decides to withdraw consent from the study participation, it is necessary to ensure 
that relevant safeguards are put in place to maintain the individual’s safety in the case of any 
future safety issues that are discovered. In this case, the decision to withdraw informed 
consent should be put in writing and, if possible, signed by the patient or patient’s 
representative. A copy of this document should be maintained at the study site (with key data 
items recorded in the eCRF). This written information should specify which aspect(s) of the 
study consent is being withdrawn as described below. In accordance with International 
Conference on Harmonisation (ICH) guidelines, Food and Drug Administration (FDA) 
guidance, and other international ethical directives, data that have already been collected and 
incorporated into the study database, including the results of laboratory assays, will continue 
to be processed. In addition, every effort should be made to have the patient return to the 
clinic for a final EOT visit as described in Appendix A.  
If the patient or the patient’s representative refuses to withdraw consent in writing, the site 
must document and the Investigator must attest by signature, the reason for the patient’s 
failure to withdraw the consent in writing. The Sponsor or designee should be immediately 
notified.  
6.3.4 
Lost-to-Follow-Up 
If a patient repeatedly fails to return for any scheduled visit(s) and cannot be contacted or 
located by the site staff, Investigators will be expected to continue to try to contact those 
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patients until the end of the trial. This level of diligence is necessary in order to obtain (at a 
minimum) vital status (whether the patient is alive), and thus avoid being lost to follow-up 
for efficacy and safety assessment. All sites will receive training on how vital status may be 
monitored in accordance with local practices/regulations for patients who are unable to be 
contacted. 
6.4 
Criteria for Termination of the Study or Study Site 
6.4.1 
Early Termination of the Study 
If the Steering Committee, Sponsor, DMC, or regulatory officials discover conditions arising 
during the study that indicate that the study should be halted or terminated, this action may be 
taken after appropriate consultation between the Steering Committee, Sponsor, and the DMC. 
Full details on the roles of the Steering Committee and DMC will be provided in each 
committee's respective charter. Conditions that may warrant termination of the study include, 
but are not limited to, the following: 
•
The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled
in the study
•
A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or
development of the study drug
6.4.2 
Early Termination of a Study Center 
Conduct of the study at a particular center may be terminated for the following reasons: 
•
Failure of the Investigator to enroll patients into the study at an acceptable rate
•
Failure of the Investigator to comply with pertinent FDA, European Medicines
Agency (EMA), and/or other applicable Regulatory Authorities regulations
•
Submission of knowingly false information from the research facility to the Sponsor,
Sponsor-designated contract research organization (CRO) or vendors, study monitor,
or the FDA, EMA, and/or other applicable Regulatory Authorities
•
Insufficient adherence to protocol requirements
The Investigator also has the right to withdraw from participating in the study at any time. 
If a study center or Investigator is terminated, the Sponsor will make all efforts possible to 
have another investigative site assume responsibility for continuing trial activities.  
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Study termination and follow-up will be performed in compliance with the conditions set 
forth in the following sections of the Code of Federal Regulations (CFR): 21 CFR 312.50 and 
21 CFR 312.56, and other local Regulatory Authorities.  
6.5 
Method of Assigning Patients to Treatment 
Patients will be randomly assigned between 2 parallel treatment groups in a 1:1 manner. The 
treatment randomization schedule will be centralized and stratified by BMI at Screening 
(<25 kg/m2, ≥25 kg/m2), Week -2 A1C (≤9%, >9%), and use of CSII at Screening (Yes, No). 
The schedule will also account for the substudy in satiety. The desired balances will be 
accomplished by use of randomly permuted blocks of fixed size. An Interactive Voice/Web 
Response System (IXRS) will be used as a central mechanism to assign patients to study 
treatment. The study is double-blind so the study treatment assigned to each patient will not 
be revealed to the Investigator, patient, Sponsor, or designee until the decision is made to 
unblind the study. Data from individual patients may be unblinded if deemed medically 
necessary by the Investigator, or as required by local regulation in the case of an unexpected 
SAE.  
6.6 
Replacement of Patients 
Patients will not be replaced in this study. 
7.
Treatment
Patients will take single-blind placebo tablets once daily, orally, before the first meal of the 
day during the single-blind placebo Run-in Visit (see Section 7.2)  
Patients will take sotagliflozin 400 mg or placebo (in identical tablet form), once daily, orally, 
before the first meal of the day, during the double-blind Treatment Period (see Section 7.3). 
The study drug eCRF will be completed each time study drug is dispensed 
(see Section 7.5.1).  
7.1 
Study Drug Identification 
The identity, potency, strength, and appearance of the study drugs used are presented in Table 
7.1-1. It should be noted that the placebo and 200-mg tablets will be identical in appearance.  
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Table 7.1-1: Study Drug Identification 
Product 
Potency/Strength Appearance 
Sotagliflozin (LX4211) Film-
Coated Tablet 
200 mg 
White, oval shaped 
coated tablets 
Placebo for Sotagliflozin 
(LX4211) Film-Coated Tablet 
N/A 
White, oval shaped 
coated tablets 
7.2 
Single-blind Placebo Run-in Period 
Upon determination of eligibility, each patient will be assigned placebo tablets to complete 
the 2-week single-blind Run-in Period. Each bottle will be labeled with a 1-panel, blinded 
label. Prior to dispensation, the Investigator/qualified designee will complete spaces on the 
bottle label to specify the Patient Number and Date Dispensed. In addition, the protocol 
number, batch number, the number of tablets, route of administration, directions for use, 
bottle number, storage conditions, and use by date will be indicated on the label.  
During the 2-week single-blind placebo Run-in Period, patients will take placebo tablets once 
daily, before the first meal of the day. The tablets should be taken with water and should be 
taken whole. 
 On days of clinic visits, patients should be instructed not to take their dose of single-blind 
placebo tablets in the morning. . On days of clinic visits, site personnel will provide 
instructions to the patients for dosing with single-blind placebo tablets based on scheduled 
procedures. The date and time of the last dose of placebo tablets prior to the clinic visit will 
be recorded in the eCRF. 
In order to qualify for randomization, patients must have ≥80% compliance to taking the 
expected amount of placebo tablets during the 2-week single-blind placebo Run-in Period. In 
addition, patients should also demonstrate compliance with entering required data in the 
study diary.  
Details concerning the methods used for the titration of insulin to maintain glycemic targets 
in this time period are presented in Section 7.6.1.2.  
7.3 
24-Week Double-blind Treatment Period 
On Day 1 of the double-blind Treatment Period, patients will be randomly assigned in a 1:1 
ratio between the following 2 treatment groups, as an adjunct to their insulin therapy: 
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•
Sotagliflozin 400 mg as two (2) 200-mg tablets, once daily, before the first meal of
the day
•
Placebo as two (2) tablets (identical to sotagliflozin tablets in appearance), once daily,
before the first meal of the day
Upon randomization, and at each dispensing visit thereafter, patients will be provided 
individual bottles of study drug. Sufficient quantity of study drug will be provided to allow 
prescribed daily dosing until the next scheduled dispensing visit. Each dispensing unit 
(bottle) will be labeled with a 1-panel, double-blind label printed in black. Prior to 
dispensation, the Investigator/qualified designee will complete spaces on the study drug label 
to specify the Patient Number, and Date Dispensed. In addition, the protocol number, batch 
number, quantity of tablets, route of administration, directions for use, bottle number, storage 
conditions, and use-by date will be indicated.  
Except on days of clinic visits, patients should be instructed to dose with double-blind study 
drug before the first meal of the day. Two tablets of double-blind study drug should be taken 
with water and should be taken whole. If a patient misses a dose by more than 12 hours, that 
dose should be skipped and the next dose should be taken as scheduled. No double doses 
should be taken, and dose reductions are not permitted. 
On days of clinic visits, double-blind study drug will not be taken the morning of a scheduled 
clinic visit. Patients will take the assigned dose of double-blind study drug for that day per 
site personnel instructions based on scheduled procedures. The date and time of 
administration of the last dose of study drug prior to the clinic visit will be recorded in the 
eCRF. Details concerning the methods used for the titration of insulin to maintain glycemic 
targets in this time period are presented in Section 7.6.1.2.   
7.4 
Study Drug Adjustment/Interruption 
The dosage of double-blind study drug may not be adjusted throughout the study. For safety 
reasons, should a patient experience an adverse event, the study drug may be temporarily 
interrupted. 
Upon visiting the site for a scheduled visit, if a patient is documented to have interrupted 
study drug for >5 consecutive days, the site must notify the Medical Monitor and/or designee 
and be in receipt of a response prior to continuing the patient in the study on study drug. The 
Medical Monitor will assess the clinical scenario (if needed with escalation to the Sponsor for 
input) and respond to the site on a case-by-case basis as to the appropriateness of continuing 
the patient in study on study drug.  
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In cases of clinically significant volume depletion, study drug may be temporarily 
discontinued until the event has resolved. The Medical Monitor must be informed of these 
cases.  
Note:  If serum creatinine increases by ≥30% above the baseline value during the study, then 
the Investigator should consider assessment of: volume status, diuretic dosage, discontinuing 
nonsteroidal anti-inflammatory drugs (NSAIDs), and other relevant testing including renal 
imaging techniques, as appropriate. 
Sodium-glucose cotransporter type 2 inhibitors are associated with osmotic diuresis and 
volume depletion, which may lead to dizziness or hypotension, especially in the elderly. All 
patients will be advised to maintain proper fluid intake and to consider increasing it if they 
sense greater thirst, increased urination, or if they feel dizzy or faint. 
7.5 
Handling and Dispensing of Study Drug 
The Sponsor will be responsible for ensuring that the quality of the study drug is adequate for 
the duration of the trial. Study drugs, both active and placebo, should be stored at 15-30°C 
(59-86°F) in induction-sealed bottles as determined by the Sponsor and defined in the 
Investigator’s Brochure. 
Study drug should be stored in a secure area according to local regulations. It is the 
responsibility of the Investigator to ensure that study drug is only dispensed to study patients. 
The study drug must be dispensed only from official study sites by authorized personnel 
according to local regulations.  
All study drug supplies that will be used in the study must be maintained securely under the 
direct responsibility of the Investigator or delegated by the Investigator to the hospital 
pharmacist, or other personnel licensed to store and dispense drugs. All drugs shall be 
dispensed in accordance with the Investigator’s prescription, and it is the Investigator’s 
responsibility to ensure that an accurate record of drugs issued and returned is maintained. 
7.5.1 
Dispense Study Drug and Record Compliance 
The Investigator must maintain accurate records of study drug receipt, dispensing 
information, and disposition. Sponsor will provide forms to facilitate inventory control, if the 
staff at the investigational site does not have an established system that meets these 
requirements. 
Patients will be instructed to bring their empty bottles and any unused study drug to each 
clinic visit. Pill counts will be performed at each clinic visit by a member of the site staff to 
determine compliance. Pill count will be recorded on the study drug eCRF.  
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Treatment compliance will be calculated as: 
(Number of tablets dispensed – Number of tablets returned) X 100 
Number of tablets expected to be taken 
The number of tablets expected to be taken should be 2 times the number of days since the 
last visit. The Investigator/qualified designee will remind patients at each visit regarding the 
importance of following the protocol defined schedule for taking study drug. Reasons for not 
following study drug administration as described in the protocol should be clearly recorded in 
the source documents.  
Patients will be deemed “compliant” if their calculated compliance is between 80% and 
120%, inclusive. If a patient’s compliance is noted to be less than 80% or greater than 120% 
on 2 consecutive visits, the patient should be counseled by study personnel, and the 
Sponsor/designee should be contacted to recommend appropriate study continuation. 
7.5.2 
Return of Study Drug 
Bottles of used, partially used, and unused study drug products should be retained until the 
clinical research associate (CRA) has been able to complete drug accountability and 
reconciliation. 
Upon completion or termination of the study, all unused and/or partially used study drug must 
be returned to the Sponsor or designee, if not authorized by the Sponsor to be destroyed at the 
site.  
All study drug returned to the Sponsor or designee or other authorized party must be 
accompanied by the appropriate documentation and be clearly identified by protocol number 
and study site number on the outermost shipping container. Returned supplies should be in 
the original bottles (eg, bottles that have clinical labels attached). Empty bottles should not be 
returned to the Sponsor or designee. It is the Investigator’s responsibility to arrange for 
disposal of all empty bottles, provided that procedures for proper disposal have been 
established according to applicable federal, state, local, and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. The return of unused 
study drug should be arranged by the assigned site Monitor. 
7.5.3 
Destruction of Study Drug 
If study drug is to be destroyed at the site, it is the Investigator’s responsibility to ensure that 
arrangements have been made for the disposal, written authorization has been granted by the 
Sponsor, procedures for proper disposal have been established according to applicable 
regulations and guidelines and institutional procedures, and appropriate records of the 
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disposal have been documented and provided to the Sponsor or designee. Unused study drug 
can only be destroyed after being inspected and reconciled by the responsible CRA. 
7.6 
Concomitant Medications 
Concomitant medications, supplements, or products used to maintain health taken from 2 
weeks prior to the Screening Visit through the End of Study, including those specified in the 
inclusion/exclusion criteria, must be recorded in the source documents. Dose modifications 
of any other long-term (stable dose) medications that the patients are on at study entry are 
discouraged during the study period; any modification of concomitant medications from 
Screening and throughout the study period must be recorded in the source documents with 
justification for the change.  
The following medications are not permitted during the Treatment Period: 
•
Any marketed or investigational antidiabetic agent, other than insulin(s) or insulin
analog(s) (any medication other than insulin or insulin analog used for treatment of
T1D must be washed out for at least 8 weeks prior to the Screening Visit)
•
Chronic systemic corticosteroid use, defined as any dose of systemic corticosteroid
taken for more than 2 consecutive weeks. Note:  Topical, inhaled, ocular, or nasal
spray corticosteroids are allowed.
•
The use of SGLT inhibitors (other than double-blind study drug) is not permitted
during the Treatment Period
7.6.1 
Glycemic Goals and Adjustment of Insulin Dose 
7.6.1.1 
Glycemic Goals 
The glycemic goals recommended for this study are to treat A1C and blood glucose to the 
following targets: A1C <7.0%, fasting/preprandial capillary plasma glucose 80-130 mg/dL 
(4.4-7.2 mmol/L), and 2-hour/peak postprandial capillary plasma glucose <180 mg/dL 
(<10.0 mmol/L). Goals may be adapted based on individual patient considerations consistent 
with ADA/EASD Guidelines.[14,15] 
Suggested insulin adjustment algorithms are provided in the Site File Notebook to serve as 
reference, which may be modified based on the Investigator’s clinical assessment. 
7.6.1.2 
Assessment of Glycemia and Adjustment of Insulin 
For all patients, a study diary will be provided to record insulin doses, and episodes of 
hypoglycemia, as well as presence or absence of symptoms associated with these 
hypoglycemic episodes. The primary SMBG data sources will be glucose meter data from the 
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Protocol No. LX4211.312 
web-based portal and/or point-of-care glucose meter download/meter memory review. These 
primary data sources are supplemented by other available data, study diary, and laboratory 
blood glucose values. Additionally, for patients using CSII as the method of insulin delivery, 
the pump memory or downloaded pump data will provide daily basal, daily bolus, and total 
daily insulin data. Data to be recorded in the eCRF is outlined below. SMBG values obtained 
using the glucose meter provided for this study will be reviewed and guidance for the 
adjustment of insulin doses will be provided as per Section 7.6.1.4 and Section 7.6.1.5.  
Upon review of SMBG data, if results do not meet the glycemic goals recommended for this 
study, then Investigators will assess the need for a change in insulin dosing. Following any 
change in insulin dosing, a follow-up call should be arranged within 1 week, to assess 
response to the therapy change, and any need for additional change(s). The recommended 
target for fasting/preprandial glucose is 80-130 mg/dL (4.4-7.2 mmol/L). Good clinical 
judgment is to be exercised while titrating the basal insulin dose, which should not be titrated 
any more frequently than every 3-4 days. Recommended target for 1-2-hour PPG by SMBG 
is <180 mg/dL, while avoiding hypoglycemia. Goals may be adapted for individual patients, 
if deemed necessary.  
Patients who experience hypoglycemia as a result of a missed meal, unusual exercise, or 
alcohol use should receive counseling on the correction of these behaviors.  
If needed, additional contact should be made available for patients to discuss dose 
adjustments in between scheduled site visits. During these visits (on-site or phone), patients 
will report their SMBG data, insulin doses and hypoglycemic events to the study site. 
The dose of double-blind study treatment will not be adjusted at any time during the study. 
7.6.1.3 
Entering SMBG and Insulin Data into the eCRF 
Patients will perform SMBG as instructed during the 3-5 days (consecutive or non-
consecutive) prior to each clinic visit (see Section 8.2.2). 
Calculation of SMBG Data for eCRF: 
Self-monitored blood glucose values from the preceding 3-5 days (consecutive or non-
consecutive) prior to each clinic visit will be assessed. Self-monitored blood glucose data will 
be obtained from as many available sources as possible, which include but are not limited to: 
(1) the memory of the glucose meter; (2) meter download, (3) SMBG from web-portal,; and 
(4) paper diary. The SMBG will be reviewed to obtain the glucose values for the preceding 3 
to 5 days and the glucose values will be reviewed by the site to identify any unusual high or 
low values or any trends which may require a change in insulin dose(s). The patient should be 
questioned to obtain a possible explanation for unusual high or low values, and to confirm 
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that the values (from the glucose meter’s memory and/or from other data sources) were 
obtained from the patient. A “clinical average” will be calculated from the acceptable 
available glucose values that have been collected and entered into the eCRF. (The “clinical 
average” does not imply arithmetic mean)  
Calculation of Insulin Data for eCRF: 
Insulin doses during the preceding 3-5 days (consecutive or non-consecutive) prior to each 
clinic visit will be assessed. Insulin dosing data will be obtained from as many available 
sources as possible which include but are not limited to: (1) the memory of the glucose meter 
if insulin data is entered into the meter; (2) meter download if insulin data is entered into the 
meter; (3) insulin pump memory; (4) insulin pump download; (5) insulin pump data from 
web portal; and (6) study diary. For each day with complete insulin data, the daily bolus (for 
all patients, for patients on pre-mixed insulin, the bolus is defined as the rapid acting 
component; eg, a patient receiving a daily total of 50 IU of Novolin® 70/30 insulin, 15 units 
(0.3 x 50) is assessed as the “daily bolus” insulin), daily basal (for patients using insulin 
pumps and patients using subcutaneous injections), daily non-bolus (for patients receiving 
intermediate insulin; eg, a patient taking a daily total of 50 IU of Novolin 70/30 insulin, 35 
units (0.7 x 50) is assessed as the “daily non-bolus” insulin) and total daily insulin (for all 
patients) will be calculated. Based on results of at least 3 days of data, the mean daily bolus, 
mean daily basal and mean total daily insulin (bolus + basal) will be calculated. These 
calculated values will be entered into the eCRF.  
7.6.1.4 
Insulin Adjustment on Day 1 
All patients will take the first dose of double-blind study drug at the site. The study drug is to 
be administered prior to the first meal of the day (which is typically breakfast for most 
patients). For the first meal on Day 1, patients will be instructed to decrease their calculated 
(or usual) mealtime carbohydrate bolus insulin by 30%.  
Subsequent adjustments in insulin dosing will be made based on SMBG trends, as assessed 
by the Investigator. 
The mealtime insulin adjustment recommendations for Day 1 are based on results from the 
T1D study (LX4211.1-203-T1DM). It is expected that the I/C ratio will be decreased by 
approximately 30% with sotagliflozin treatment. It is also predicted that such an adjustment 
will convey appropriate margins of safety for both the treated and placebo groups. The I/C 
ratio will be subsequently adjusted as frequently as required by the Investigator to meet 
glycemic goals recommended for this study. It is expected that the Investigator will evaluate 
the postprandial blood glucose after the first dose of study drug and continue the 30% 
reduction in the mealtime I/C ratio if these values are in an acceptable range, and make 
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changes to the I/C ratio as clinically indicated for subsequent meals. The Investigator is 
encouraged to access the SMBG glucose uploaded from the patient’s meter, and/or other 
appropriate sources of blood glucose data at least daily for the first few days after initiation of 
study drug and assess if further changes in insulin reduction are required. No change in high 
blood glucose correction factor (sliding scale), basal (or non-bolus) insulin, or basal rate is 
recommended at initiation of study drug, although the Investigator is not prohibited from 
making any changes in any insulin dose consistent with meeting glycemic goals 
recommended for this study.  
7.6.1.5 
Insulin Adjustment Strategy 
•
The need for insulin adjustments will be evaluated by the Investigator with the goal of
maintaining or improving glycemic control consistent with the glycemic target ranges,
local SOC, and the individual needs of the patient (see Section 7.6.1.2).
•
Suggested insulin adjustment algorithms are provided in the Site File Notebook to
serve as reference, which may be modified based on the Investigator’s clinical
assessment.
•
When insulin is adjusted, it is recommended that any changes be made in increments
of 10% or less, as assessed appropriate by the Investigator.
•
During the course of the study, increases in insulin that affect the appropriate insulin
action time period should be considered if the SMBG pattern or trajectory over
3-5 days is assessed as above the patient’s individualized target range, and there is no
evidence of hypoglycemia in the insulin-action time period (see Section 7.6.1.2).
•
During the course of the study, decreases in insulin, which affect the appropriate
insulin-action time period, should be considered if the SMBG pattern or trajectory is
assessed as below the patient’s individualized target range.
7.6.1.6 
Unmasking of Patients Not Meeting Glycemic Targets 
In order to avoid influencing patient and/or Investigator behavior, A1C and FPG results will 
be masked to study staff after randomization laboratories have been obtained. However, if the 
A1C is >11.0% at Week 16 or any determination thereafter, the A1C result will be unmasked 
to allow for appropriate diabetic management. 
If an Investigator is unmasked to an A1C value >11.0%, the Investigator should ensure that 
no reasonable explanation exists for insufficient glucose control and evaluate possible causes, 
such as: 
•
Appropriate basal and mealtime insulin titration
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•
Compliance with treatment
•
Compliance with diet and exercise
•
Intercurrent disease
Note:  The central laboratory UA will not include the measurement of urine glucose. 
7.6.2 
Concomitant Antihypertensive Medication and Treatment of 
Hypertension 
Patients with elevated SBP and/or DBP, either naïve to medication or on therapy may enter 
the study. However, it is mandatory that their BP be treated aggressively and according to 
current local guidelines. Examples of guidelines current at the time of protocol writing 
include those from the ADA[14] and the European Society of Cardiology.[15] 
The current ADA recommendations for the treatment goals for hypertension are: 
•
Patients with diabetes and hypertension should be treated to an SBP goal of
<140 mm Hg.
•
A lower systolic target, such as <130 mm Hg, may be appropriate for certain
individuals, such as younger patients, if it can be achieved without undue treatment
burden.
•
Patients with diabetes should be treated to a DBP <90 mm Hg. A lower diastolic
target, such as <80 mmHg, may be appropriate for certain individuals, such as
younger patients, if they can be achieved without undue treatment burden.
•
Patients with a BP >120/80 mm Hg should be advised on lifestyle changes to reduce
BP.
Patients admitted to the study with BP exceeding that mandated by Good Clinical Practice 
(GCP) or regional SOC guidelines must be appropriately treated by either the Investigator or 
the referring physician. 
The Investigator is asked to keep antihypertensive medication dosages unchanged between 
Baseline and Week 16, if this is consistent with proper medical management of the patient, 
since BP will be evaluated as an endpoint at Week 16. Since sotagliflozin may cause 
intravascular volume contraction, symptomatic hypotension may occur after initiating 
sotagliflozin particularly in patients with impaired renal function, elderly patients, and 
patients on either diuretics or medications that interfere with the renin-angiotensin-
aldosterone system (eg, angiotensin-converting-enzyme [ACE] inhibitors, angiotensin 
receptor blockers [ARB], or patients with low SBP. Before initiating sotagliflozin in patients 
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with 1 or more of these characteristics, volume status should be assessed and corrected and 
patients monitored for signs and symptoms after initiating therapy. 
7.6.3 
Concomitant Lipid Medication and Dyslipidemia/Lipid 
Management 
Patients with hyperlipidemia/dyslipidemia should be treated in accordance with local and 
regional SOC.  
7.6.4 
Other Concomitant Medications 
Initiation or adjustments of therapies for BP, lipids, and renal function will be left to the 
Investigator’s discretion. All concomitant therapy should be driven towards achievement of 
levels recommended by local or regional SOC. The Screening and Run-in Periods will 
provide an opportunity to adjust concomitant medications as needed towards achievement of 
metabolic targets, but these medications may be adjusted at any time during the study. The 
Investigator should instruct the patient to notify the site about any new medications he or she 
takes after the start of the study. All medications and significant non-study drug therapy that 
the patient takes after the start of study treatment should be listed on the Concomitant 
Medication eCRF.  
Starting any over-the-counter (OTC) medications or use of herbal supplements during the 
study should be strongly discouraged unless medically necessary. If use of a supplement is 
reported, it must be documented in the source documents. 
Concomitant medications taken from 2 weeks prior to the Screening Visit through the End of 
Study, including those specified in the inclusion/exclusion criteria, must be recorded in the 
source documents and eCRF. Any modification of concomitant medications from Screening 
and throughout the study period must be recorded in the source documents and eCRF pages.  
7.7 
Blinding and Unblinding of Study Drug 
In this treatment-blinded study, the designated group and treatment assigned to each patient 
will not be revealed to the Investigator, the patient, or the Sponsor or designee, until the 
decision is made to unblind the study. Data from individual patients may be unblinded if 
deemed medically necessary by the Investigator or as required by local regulation in the case 
of an unexpected SAE. The IXRS will be used to perform emergency unblinding by 
authorized individuals. 
Because of the glycosuric effect of sotagliflozin, urine glucose values will be masked to all 
study staff. 
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The randomization schedule will be maintained by the designee performing IXRS for this 
study. Investigators, study site personnel associated with this trial, patients, and the Sponsor 
and its designee involved in the conduct of the study will remain blinded to individual 
patients’ treatment assignments until database lock. 
During the study, the blind is to be broken only when the safety of a patient is at risk and the 
treatment plan is dependent on the study treatment received. If the unblinding occurs without 
the knowledge of the Sponsor and/or designee, the Investigator must notify the Sponsor 
and/or designee as soon as possible and no later than the next business morning. All 
circumstances surrounding a premature unblinding must be clearly documented in the source 
records.  
The Sponsor or designee will not release the randomization schedule to any party except 
upon formal written request by the Sponsor. The request must be approved by the appropriate 
Sponsor personnel, according to the Sponsor’s standard operating procedures (SOPs). Details 
of any disclosure of the randomization schedule will be recorded in the site’s study files and 
the Trial Master File. A copy will also be sent to the Sponsor and/or designee. The blinding of 
the study will be broken after the database has been locked. To maintain continuous blinding 
and study integrity, analysis will be conducted by an independent statistician, and measures 
will be taken to ensure the validity of the data. Details describing the DMC processes and 
procedures will be outlined in a separate DMC Charter.  
8.
Efficacy, Pharmacokinetic, Safety, and Other
Assessments/Procedures
A Schedule of Assessments, with detailed time points, is provided in Appendix A. Study 
procedures and assessments are presented by visit in Appendix I. The efficacy endpoints 
derived from these assessments/procedures and the methods used to analyze these data are 
described in Section 10.3.1 and Section 10.4.1. 
8.1 
Assessment of Efficacy 
It should be noted that the primary efficacy endpoint includes assessments of the incidence of 
severe hypoglycemia and DKA. These are discussed in Section 9.5.1 and Section 9.5.2, 
respectively. 
8.1.1 
A1C  
Fasting blood samples will be used for the assessment of A1C. 
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Protocol No. LX4211.312 
8.1.2 
Fasting Plasma Glucose and SMBG 
Blood glucose values determined by SMBG will be obtained from data downloaded from the 
SMBG meter, the study diary and values obtained during clinic visits. The SMBG procedure 
is described in Section 8.2.2. 
In the evaluation of safety, hypoglycemia (based on SMBG) and symptoms suggestive of 
hypoglycemia will be assessed as described in Section 9.5.1.  
8.1.3 
Insulin 
The usage of insulin (or insulin analog) will be assessed from diary data for all patients. In 
addition, for patients using CSII, insulin data will be accessed from the pump download. 
8.1.4 
Kidney Function 
Urinary albumin, calcium, glucose, and creatinine will be obtained from urine samples and 
used to derive albumin:creatinine ratio (ACR), calcium:creatinine ratio (CCR), and 
glucose:creatinine ratio (GCR).  
Serum creatinine will be obtained from clinical chemistry samples and used in the calculation 
of MDRD eGFR (Appendix D).  
8.1.5 
Body Weight and Blood Pressure 
The methods used to evaluate BP (SBP and DBP) and body weight are presented in 
Section 8.2.4 (Vital Signs) and Section 8.2.5 (Physical Examinations, Height, and Weight), 
respectively. The information will be evaluated for efficacy at the time points described in 
Section 10.3.1.2 and Section 10.3.1.3. 
8.1.6 
Patient-reported Outcome:  Satiety (Substudy) 
In the satiety substudy, the patients will be instructed to complete the satiety daily diary each 
day before the first meal of the day during the 2-week single-blind placebo Run-in Period (14 
days, ±3 days) and for the last 14 days, ±3 days of the double-blind Treatment Period (each 
day during Weeks 23 and 24). The instrument used will be the PSDD. The diary is presented 
in Appendix H. 
Patient satiety will be evaluated using a 11-point PSDD-NRS. Patients will be asked to 
indicate their average level of hunger (satiety) over the past 24-hour period from 0 ‘very full’ 
to 10 ‘very hungry’. 
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8.2 
Assessment of Safety 
Assessments for safety include AEs, SMBG, clinical laboratory assessments, 
electrocardiograms (ECGs), physical examination, weight, and vital signs. 
Adjudication of all deaths, MACE/other selected CV events, DILI, severe hypoglycemia (and 
SAEs of hypoglycemia), and DKA will be performed in a blinded manner by a committee(s) 
composed of experts. Details will be provided in the charter of the adjudication committee(s). 
Please refer to Section 9.6 for details. 
8.2.1 
Adverse Events 
Monitoring and reporting of AEs (including SAEs, EOSI, and AEs leading to 
discontinuation) are described in detail in Section 9.  
8.2.2 
SMBG Procedures 
Glucose meters will be supplied to all patients at the start of the Run-in Period at Week -2 in 
order to perform SMBG.  
Fingerstick fasting blood glucose by SMBG will be measured in the clinic with the study-
provided meter at each visit per the schedule in Appendix A. These results should be recorded 
in the eCRF. (If the study-provided meter is not available at a particular visit, then another 
glucose meter may be utilized). 
Patients should be instructed to self-assess blood glucose levels regularly to allow appropriate 
glycemic control and insulin titration.  
Fasting pre-breakfast SMBG: 
•
Patients should be encouraged to check fasting pre-breakfast SMBG daily for the
entire duration of the study.
5-point SMBG profile: 
•
5-point SMBG profile (fasting pre-breakfast, before and 2 hours after lunch, before
dinner and bedtime) will be performed on at least 3 days per week before each visit
for the duration of the treatment period.
8-point SMBG profile: 
•
It is recommended that at least one (1) 8-point SMBG profile be performed during the
week prior to the clinic visit (fasting [before] and 2 hours after breakfast, before and 2
hours after lunch, before and 2 hours after dinner, bedtime, and once during the
nocturnal period [typically 02:00 or 03:00]).
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In addition, it is recommended that: 
•
The Investigator considers SMBG in the nocturnal period if fasting or bedtime SMBG
readings are lower than goal, or there are unexplained high fasting SMBG results,
which could be consistent with recovery from nocturnal hypoglycemia.
•
Patients should perform SMBG prior to exercise, when they suspect low blood
glucose, after treating low blood glucose until they are normoglycemic, and prior to
critical tasks such as driving.
•
SMBG frequency and timing should be dictated by the patient’s specific needs and
goals.
•
Patients will be requested to monitor blood glucose levels with increased frequency
whenever they experience any illnesses (eg, cold, flu), or symptoms of hyperglycemia
or hypoglycemia.
Symptoms of hypoglycemia may include shakiness, dizziness, sweating, hunger, headache, 
pale skin color, sudden moodiness or behavior changes (such as crying for no apparent 
reason), clumsy or jerky movements, seizure, difficulty paying attention or confusion, or 
tingling sensations around the mouth. Patients will be instructed to record any hypoglycemic 
episodes or presence of hypoglycemic symptoms (Yes or No) in the study diary provided. 
Patients will also be instructed to record SMBG values that are ≤70 mg/dL (≤3.9 mmol/L) in 
the study diary.  
8.2.3 
Selected Laboratory Tests 
All laboratory tests will be sent to the central lab for analysis, with the exception of urine 
pregnancy test, point of care BHB and fingerstick glucose, which will be assessed at the site 
per Appendix A. 
Blood and urine derived central laboratory tests for hematology, serum chemistry (including 
lipid profile), hormones, and other assessments are presented in Table 8.2.3-1. This table also 
includes laboratory tests such as FSH (females, if necessary to confirm postmenopausal 
status), thyroid stimulating hormone (TSH) (at Screening only; if abnormal, free thyroxine 
will be measured), and serum pregnancy tests (for females of childbearing potential). Details 
describing the UA (dipstick and microscopic examination) are presented in Section 8.2.3.1. 
Details concerning pregnancy testing are presented in Section 8.2.3.2. 
The Schedule of Assessment is presented in Appendix A. 
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Table 8.2.3-1: Central Laboratory Assessments 
Serum Chemistry 
-Sodium 
-Potassium 
-Chloride 
-Carbon dioxide (bicarbonate) 
-Blood urea nitrogen (BUN) 
-Creatinine 
-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) 
-Lactate dehydrogenase (LDH)  
Hematology 
Lipid Profile 
-Complete blood count (CBC) 
-Differential 
-Platelet count 
-Hemoglobin 
-Hematocrit 
-Total cholesterol (TC) 
-Triglycerides (TGs) 
-High-density lipoprotein cholesterol (HDL-C) 
-Low-density lipoprotein cholesterol (LDL-C) 
will be calculated by Friedwald equation 
-Non-HDL-C will be calculated as the difference 
between TC and HDL-C 
Other Blood Samples 
Urine 
-A1C 
-Fasting plasma glucose (FPG) 
-Serum pregnancy test - females only 
-Follicle-stimulating hormone (FSH)  
(if necessary to confirm postmenopausal status) 
-Beta-hydroxy butyrate (BHB) (point-of-care and central lab) 
-Anion gap 
-Thyroid stimulating hormone (TSH) (at Screening only, if 
abnormal, free thyroxine will be measured) 
Dipstick (including ketones) 
-Calcium  
-Albumin 
-Glucose (blinded to all study staff) 
-Creatinine  
-Urine pregnancy test (β human chorionic 
gonadotropin [β-HCG]) - females only 
8.2.3.1 
Urinalysis 
Urinalysis (urine dipstick with microscopy) by a central laboratory will be performed at the 
time points shown in Appendix A.  
Urine dipstick includes: 
•
Specific gravity
•
pH
•
Protein
•
Blood
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Protocol No. LX4211.312 
•
Ketones
•
Bilirubin
•
Urobilinogen
•
Nitrate
•
Leukocyte esterase
Urine microscopy includes, but is not limited to, the detection of formed cellular elements, 
casts, bacteria, yeast, parasites, and crystals in centrifuged urine sediment. 
In an effort to minimize bias in the study, Investigators, staff, and the Sponsor or designee 
will be blinded to urine glucose results until after database lock. Investigators and the study 
staff will be instructed that they are not to perform local UA with reagent strips (dipstick) for 
the same reason. In order to evaluate a urinary tract infection, the Investigator should request 
microscopic and culture as clinically indicated, but should not use a dipstick.  
If a dipstick analysis for the presence of ketones is deemed clinically necessary, the dipstick 
should not provide glucose data. The Ketostix® (ketones only) reagent strip or similar is 
appropriate for this purpose; use of the Keto-Diastix® (ketones and glucose) reagent strip is 
not appropriate. Sites and study personnel will remain blinded to the urine glucose and GCR 
data. The urinary glucose data will be analyzed after unblinding of the database.  
Referral to urology is recommended for all patients with gross hematuria or high-grade 
hematuria (>50 red blood cells [RBCs]/high-power field [HPF]) on a single UA. 
Referral to urology and urologic evaluation is recommended for males or females with 
asymptomatic microscopic hematuria or symptomatic hematuria (unilateral flank pain, lower 
irritative voiding symptoms, recurrent urinary tract infections despite appropriate use of 
antibiotics, etc) that produces >3 RBC/HPF on 2 of 3 properly performed and collected UAs. 
(Note:  Urine specimens should be collected >48 hours after exercise. The UA should also be 
done when the urine is fresh, if possible, by a standardized methodology to avoid the lysis of 
formed elements from heat or chemical breakdown.) If there is an identifiable benign 
etiology for an isolated episode of hematuria, such as vigorous exercise, sexual activity, 
trauma, viral illness, or infection, it will be noted as part of the medical record. However, 
multiple episodes that meet the above criteria should be referred.  
8.2.3.2 
Contraception and Pregnancy Testing 
Females of childbearing potential who participate in this study must use reliable 
contraceptive methods. For this study, females are considered to be of childbearing potential, 
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i.e. fertile following menarche and until becoming post-menopausal unless permanently 
sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. 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 post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy.     
For this study the following methods of contraception are considered to be acceptable 
effective contraceptive measures (based on annual failure rate of <1% when used consistently 
and correctly): 
•
Combined (estrogen and progestogen containing) hormonal contraception associated
with inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal
•
Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS)
•
Bilateral tubal occlusion
•
Vasectomised partner
Serum pregnancy testing is performed at Screening. Urine pregnancy testing for females of 
childbearing potential based on urine samples will be performed as specified in Appendix A. 
Any positive urine test results must be confirmed based on serum pregnancy test. The 
Investigator may perform additional tests at their discretion or as required by local 
regulations. 
8.2.3.3 
Collecting Fasting Blood Sample and Urine for Storage 
Fasting blood sample and spot urine sample will be collected in all patients on Day 1 and 
Week 24 (or at EOT/EW for patients who discontinue the study), frozen, and archived for 
potential evaluation of safety biomarkers as needed for additional study analyses.  These 
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Protocol No. LX4211.312 
samples will be collected and stored in accordance with all national and local regulations, and 
after the patient has completed the informed consent process. If no analysis of the sample is 
performed, it will be destroyed when safety assessments required for regulatory submission 
of this study are complete. No genetic testing will be performed on these samples. 
8.2.4 
Vital Signs 
Vital signs (pulse rate, respiration rate, temperature, and BP) will be measured as per the 
schedule in Appendix A.  
An automatic sphygmomanometer will be dispensed to sites. For BP, the patient will have 3 
measurements taken on the nondominant arm while seated (see Appendix G). Prior to the first 
measurement, the patient should remain seated at rest for at least 5 minutes. Following the 5-
minute rest period, 3 separate seated BPs should be measured with at least 1 minute between 
BP measurements and with the cuff fully deflated between measurements. The value for 
analysis and entry criteria (Screening) will be the mean of these 3 measurements. It is 
recommended that BPs be assessed by the same person, if feasible, using the same calibrated 
equipment, on the same arm. Additional measurements may be obtained if clinically 
indicated.  
Three seated pulse rate measurements will be obtained. The mean of the 3 seated pulse rate 
measurements will constitute the pulse rate value for that visit. 
Note:  Vital sign measurements should be measured after the patient has been seated for at 
least 5 minutes and prior to phlebotomy.  
8.2.5 
Physical Examinations, Height, and Weight 
Complete physical examinations will be performed at Screening, and Week 24 (or EOT). A 
complete physical examination will include, at minimum, a review of the patient’s general 
appearance, head, eyes, ears, nose and throat, neck, heart, lungs, abdomen, back and 
extremities, skin, and general neurological system.  
A symptom-related brief physical exam will only occur if the patient is experiencing 
symptoms or AEs. If a symptom-related brief physical exam is required, it should include a 
review of all body systems that relate to the symptoms and/or AE the patient is experiencing. 
Height (without shoes) will be measured once, during Screening. 
Weight will be measured at Screening and at all other clinic visits. The patient should be 
weighed at approximately the same time of day, wearing minimal clothing (ie, no coat/shoes), 
and using the same calibrated scale at each visit, where possible. BMI will be calculated. 
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Protocol No. LX4211.312 
8.2.6 
Electrocardiograms 
The 12-lead ECG will be performed as per the schedule in Appendix A. The 12-lead ECG 
recordings should be conducted prior to the morning study drug administration. ECGs should 
be recorded either prior to phlebotomy or at least 30 minutes after phlebotomy. 
All ECGs will be sent to a central ECG vendor for evaluation. Details on processing will be 
provided to the sites in a separate ECG manual. 
8.2.7 
Demographics 
The following variables will be recorded on the appropriate eCRF: age, sex, and 
race/ethnicity (as permitted by local regulations). 
8.2.8 
Medical History 
A general medical history will be collected at the Screening Visit and Week -2. The eCRF 
will include specific questions about relevant exclusion criteria, for example, a history of 
DKA. 
8.2.9 
Other Assessments 
Other assessments will be completed as per the schedule Appendix A and include: informed 
consent, medication history, FSH for females who are postmenopausal, and TSH (at 
Screening only; if abnormal, free thyroxine will be measured).  
8.3 
Study Procedures and Assessments by Visit 
Study procedures and assessments are presented by visit in Appendix A and Appendix I. 
8.3.1 
General Guidelines 
The timing of the visits and follow-up telephone contacts for this trial are given relative to the 
day of randomization. The patients should be encouraged to return for their visits as close to 
the scheduled visit date as possible. Patients should be encouraged to fast (with the exception 
of water or noncaffeinated, zero-calorie beverages) for at least 8 hours before collection of 
any fasting laboratory samples. If the patient is unable to fast as above, the scheduled “fasting” 
laboratory samples will still be collected and the non-fasting status will be noted in the eCRF and 
on the laboratory requisition form. ALL data collected will be used in the evaluations, 
including data that may originate outside the investigative site, such as non-visit 
(unscheduled) clinical laboratory evaluations.  
Any events that occur between scheduled visits should be recorded by the Investigator as 
soon as they come to his or her attention.  
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Note:  If serum creatinine increases by ≥30% above the Baseline value during the study, then 
the Investigator should consider assessment of: volume status, diuretic dosage, discontinuing 
NSAIDs, and other relevant testing including renal imaging techniques, as appropriate. 
Sodium-glucose cotransporter type 2 inhibitors are associated with osmotic diuresis and 
volume depletion, which may lead to dizziness or hypotension, especially in the elderly. All 
patients will be advised to maintain proper fluid intake and to consider increasing it if they 
sense greater thirst, more urine production, or if they feel dizzy or faint. Investigators should 
consider closer monitoring of renal function in patients assessed to be at risk for deterioration 
of renal function. This may include evaluation of relevant laboratory tests at an unscheduled 
visit a week after initiating double-blind study drug.  
Visits should be scheduled in the morning, at approximately the same time of day. 
Prior to each visit, patients should be contacted and reminded of the date and time of their 
appointment. 
In addition, the patient should be instructed to: 
1. Bring the study drug bottles (used and unused) to the clinic. Note:  Patients should not
take study drug on the day of the visit until instructed by site staff. Patients should be
instructed to take their basal insulin on the day of the visit, but not to take bolus
insulin on the day of the visit until instructed by site staff.
2. Bring glucose meter and study diary to the clinic visit
Study assessments will be done according to the following detailed visit schedule presented 
in the subsequent sections.  
At each visit, patients will be asked if to their knowledge any EOSI has occurred since the 
last visit. 
8.3.2 
Guidelines for Diet and Exercise during Study 
Instructions for diet and exercise will be provided to patients. All patients will be provided 
with guidance on diet and exercise consistent with ADA guidelines for individuals with T1D, 
including training in carbohydrate counting during the Screening and single-blind Run-in 
Periods. Compliance with diet and lifestyle recommendations will be discussed with the 
patient throughout the study and specifically in case of insufficient glycemic control. In 
addition, guidance will be provided to all patients regarding GU hygiene and on maintaining 
general hydration (Appendix F). 
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8.3.3 
Restrictions during Study 
Restrictions during the study are described below: 
1. Patients must maintain compliance with the dietary and physical activity changes and
goals communicated at Screening and during the single-blind placebo Run-in Period.
2. Patients should be encouraged to maintain stable diet and exercise activities consistent
with their normal practices at study entry and for the duration of the study.
3. Strenuous exercise should be avoided for 24 hours before planned clinic visits due to
possible effect on safety laboratory assessments.
4. Addition of new concomitant medications will be restricted as per Section 7.6.
5. Females of childbearing potential must practice an acceptable method of birth control,
as detailed in Section 8.2.3.2.
9.
Safety Reporting
9.1 
Adverse Events 
Non-serious AE collection (including EOSI) will be initiated after the first dose of double-
blind study drug. 
Any sign, symptom, or illness occurring prior to the first dose of double-blind study drug will 
be captured in the medical history. Treatment-emergent adverse events are defined as any 
AEs reported after the first dose of double-blind study drug.  
An AE includes any noxious, pathological, or unintended change in anatomical, 
physiological, or metabolic functions as indicated by physical signs or symptoms occurring in 
any phase of the clinical study whether or not associated with the study drug and whether or 
not considered related to the study drug. This definition includes an exacerbation of 
preexisting medical conditions or events, historical conditions not present prior to study 
treatment, which reappear following study treatment, intercurrent illnesses, hypersensitivity 
reactions, drug interaction, or the significant worsening of the disease under investigation that 
is not recorded elsewhere in the eCRF. Anticipated day-to-day fluctuations of pre-existing 
conditions that do not represent a clinically significant exacerbation or worsening need not be 
considered AEs. 
Any treatment-emergent abnormal laboratory result which is assessed as clinically significant 
by the Investigator should be recorded as an AE. In the event of clinically significant 
abnormal laboratory test values, the tests should be repeated and followed up until they have 
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returned to the normal range and/or an adequate explanation of the abnormality is 
determined.  
Adverse events should not be solicited with leading questions that suggest specific signs or 
symptoms. Rather, AEs should be solicited by asking the patient a non-leading question such 
as:  “Do you feel different in any way since receiving the dose or since the last assessment?” 
The Investigator will evaluate all AEs with regard to the maximum intensity and relationship 
to study drugs, as follows: 
Maximum intensity should be assigned using 1 of the following 3 severity grades 
Mild: 
aware of event but easily tolerated 
Moderate: 
discomfort, enough to cause interference with usual activity 
Severe: 
incapacitating:  patient unable to work or perform usual activity 
Relationship to study drug 
Not related: 
• Does not follow a reasonable temporal sequence from
administration of the drug
• Event is reasonably explained by other factors, including
underlying disease, complications, concomitant drugs, or
concurrent treatment; there is no reasonable causal link between
the study drug and the AE
Unlikely related: 
• Temporal sequence from administration of the study drug to
event onset suggests a doubtful or improbable causal
relationship
• Alternative explanation (including underlying disease,
complications, concomitant drugs, or concurrent treatment) is
plausible and more likely
Possibly related: 
• That follows a reasonable temporal sequence from
administration of the drug (including the course after withdrawal
of the drug), or
• For which the possibility of the study drug being the causative
factor (eg, existence of similar reports attributed to the suspected
drug and its analogs; reactions attributable to the
pharmacological effect) could not be excluded, although other
factors such as underlying disease, complications, concomitant
drugs, or concurrent treatment are presumable
Probably related: 
• That follows a reasonable temporal sequence from
administration of the drug (including the course after withdrawal
of the drug), and
• For which the possibility of factors other than the drug, such as
underlying disease, complications, concomitant drugs, or
concurrent treatment, could not be excluded as the cause
Definitely related: 
• Follows a clear temporal sequence from administration of the 
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study drug 
• Could not be possibly explained by the known characteristics of
the patient’s clinical state, environmental or toxic factors, or 
other modes of therapy administered to the patient 
• Disappears or decreases on cessation or reduction in dose of the
study drug 
• Reappears or worsens when the study drug is re-administered
• Follows a response pattern known to be associated with
administration of the study drug
The degree of certainty with which an AE is attributed to treatment with study drug (or 
alternative causes, eg, natural history of the underlying diseases, concomitant therapy, etc.) 
will be determined by how well the event can be understood in terms of known 
pharmacology of the study drug and/or reaction of a similar nature being previously observed 
with the study drug or the class of study drug. 
All AEs that occurred during treatment should be followed for at least 30 days following the 
last dose of study drug or until the event has resolved, the condition has stabilized, the 
etiology of the event is determined to be not related to study drug, or the patient is lost to 
follow-up. For each patient for whom an AE was reported that did not resolve before the end 
of the reporting period, follow-up information on the subsequent course of events must be 
submitted to the Sponsor. This requirement indicates that follow-up may be required for some 
AEs after the patient has completed his/her participation in the study. 
9.2 
Serious Adverse Events 
All SAEs will be collected starting with signing informed consent and continue until 30 days 
after the last dose of study drug. Specific information regarding collection of CV events is 
described in Section 9.5 (Events of Special Interest). 
An SAE is defined as any event that results in any of the following outcomes: 
1. Death;
2. Life-threatening situation, defined as one in which a patient is at immediate risk, in
the Investigator’s opinion, of death from the reaction as it occurs. This does not
include an event that might have caused death if it had occurred in a more severe
form;
3. Persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions;
4. Inpatient hospitalization or prolonging of an inpatient hospitalization;
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5. Congenital anomaly/birth defect in the offspring of a patient who received study drug;
or
6. Medical or surgical intervention that is necessary to prevent 1 of the outcomes listed
in this definition
The term “hospitalization” refers to any surgery or treatment that requires a formal admission 
into the hospital regardless of length of stay. This term does not include an emergency room 
visit or admission to an outpatient facility.  
Hospitalization for preplanned elective surgery or routine clinical procedures, which are not 
the result of an AE, need not be considered AEs. If anything untoward is reported during the 
procedure, this must be reported as an AE and either ‘serious’ or ‘non-serious’ attributed 
according to the standard criteria. Additionally, if the elective procedure had to be performed 
sooner than planned due to a worsening of the underlying medical condition, then the 
worsening medical condition would need to be reported as an AE. 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported as 
follows: 
•
Complete the SAE form utilizing the AE eCRF in the electronic data capture
(EDC) system and submit within 24 hours of learning of the event.
The CRO will provide the Investigators with blank SAE forms, which are to be completed in 
the event that access to the EDC system is not available. If the EDC system cannot be 
accessed, the completed SAE forms will be faxed to the Covance Pharmacovigilance & Drug 
Safety Services (PV&DSS) number below. Once the EDC system is available, the SAE 
information must be entered within 24 hours of the system availability. 
Information not available at the time of the initial report must be documented in the EDC 
within 24 hours of receipt of the new information. Substantiating data such as relevant 
hospital or medical records and diagnostic test reports should be also submitted via fax to: 
Covance Pharmacovigilance & Drug Safety Services (PV&DSS) at: 
Region 
Telephone Number 
Fax Number 
United States 
+1 (888) 724-4908 
+1 (888) 887-8097 
Outside United States 
+44 1628 548171 
+44 1628 540028 
An SAE that occurs after completion of the study but, in the opinion of the Investigator, is 
related to the study drug, should be reported as described for an SAE. If an AE does not meet 
the FDA’s definition of “serious” but is considered by the Investigator to be related to the 
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Protocol No. LX4211.312 
study drug and of such clinical concern as to influence the overall assessment of safety, it 
must be reported as defined for an SAE. 
All patients (including discontinued patients) with an SAE must be followed until the event 
resolves or reaches a new Baseline, but for a minimum of 30 days after the last dose of study 
drug. Additionally, if the patient has died, the Investigator will obtain appropriate records to 
determine the cause of death, which include but are not limited to death certificate, hospital 
records, or autopsy results. 
9.3 
Suspected Unexpected Serious Adverse Reactions 
The applicable Regulatory Authorities and all participating Investigators shall be notified by 
a written expedited safety report of any suspected adverse reaction that is both serious and 
unexpected (eg, suspected unexpected serious adverse reaction [SUSAR]), no later than 15 
calendar days from the “date learned” of the event. An AE is considered to be an adverse 
reaction if the relationship between the AE and the study drug is classified by the Investigator 
and/or Sponsor as “possibly related,” “probably related,” or “definitely related.” In addition, 
the applicable Regulatory Authorities will be notified within 7 calendar days of any 
unexpected fatal or life-threatening suspected adverse reaction. An unexpected AE is any 
adverse drug event which is not listed in the current Investigator’s Brochure or is not listed at 
the specificity or severity that has been observed. Suspected adverse reaction means any AE 
for which there is a reasonable possibility that the drug caused the AE. The following 
examples provide types of evidence that would suggest a causal relationship between the 
drug and the AE: (A) a single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson 
Syndrome); (B) one or more occurrences of an event that is not commonly associated with 
drug exposure, but is otherwise uncommon in the population exposed to the drug (eg, tendon 
rupture); (C) an aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the study population independent of drug therapy) that 
indicates those events occur more frequently in the drug treatment group than in a concurrent 
or historical control group. 
An untoward and unintended response to a non-study drug is, by definition, not a SUSAR. 
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9.4 
Precautions 
9.4.1 
Pregnancy 
Any patient who becomes pregnant during the study must be discontinued from treatment 
immediately and should be followed through delivery or termination of the pregnancy. In 
pregnancies that progress to term, any congenital abnormalities/birth defects in the offspring 
of a patient who received study drug should be reported as an SAE. The outcome of the 
pregnancy and the presence or absence of a congenital abnormality will be documented by 
completion of a Pregnancy Questionnaire and a Pregnancy Outcome Form in accordance 
with GCP and ICH guidelines and the Sponsor’s SOPs. Female patients should also notify the 
Investigator if they become pregnant within 30 days after last dose of study drug. The 
Sponsor must be notified of all pregnancies reported to the Investigator (see Section 9.2 for 
contact information). 
9.5 
Events of Special Interest 
Events of Special Interest will be captured from first dose of double-blind study drug until 30 
days after last dose of study drug.  
Events of Special Interest are characterized as: 
A) Specific events that may be related to the mechanism of action of the drug, or which may
be of special concern because of toxicity issues associated with the study drug or study
drug class. For example, by increasing the urinary excretion of glucose, SGLT inhibitors
also increase urinary output. This may lead to volume depletion in some patients. In order
to provide better information about the incidence and extent of this AE, additional
information will be collected about any reports of volume depletion or AEs associated
with volume depletion.
B) Rare events not known to be related to the mechanism of action of the drug or class,
which are of interest to the Sponsor.
All hypoglycemic events are considered EOSI. With the exception of hypoglycemia, all EOSI 
are considered to be AEs and should be reported on the AE eCRF as described in Section 9.1. 
For each EOSI reported, sites will be prompted to complete an EOSI Targeted Questionnaire. 
(In case an EOSI meets criteria to be reported as an SAE, please follow procedures as 
described in Section 9.2).  
•
Events of Special Interest are:
o
Hypoglycemia (see Section 9.5.1)
o
DKA, including all cases of metabolic acidosis (see Section 9.5.2)
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Protocol No. LX4211.312 
o
Volume depletion
o
MACE and specific CV Events
o
Genital mycotic infections
o
Urinary tract infections
o
Diarrhea
o
Pancreatitis
o
Bone fractures
o
Venous thrombotic events
o
DILIs
o
Renal events
o
Malignancies of special interest (breast, bladder, renal cell, Leydig cell,
pancreatic, and prostate)
Note:  Other AEs may be determined to be of special interest. As applicable, relevant Medical 
Dictionary for Regulatory Activities (MedDRA) terms will be described in the Statistical 
Analysis Plan (SAP). 
The following EOSI will be adjudicated in a treatment blinded fashion: severe hypoglycemia 
(or hypoglycemia reported as an SAE), DKA (including all cases of metabolic acidosis), 
MACE/other specified CV events, and DILI. 
For the EOSI that require adjudication, the site will need to collect and submit copies of 
supporting source documents to the Sponsor’s designee. Specific instructions regarding this 
process will be provided in the Site File Notebook. Algorithms defining the evaluation of 
liver laboratory abnormalities (possible DILI) are located in Appendix E. 
Details regarding the membership, remit, and operations of the adjudication committee will 
be contained in the respective charter.  
9.5.1 
Hypoglycemia or Symptoms Suggestive of Hypoglycemia 
Hypoglycemia is a common complication of insulin therapy.  According to recent data, severe 
hypoglycemia is common in T1D with at least one SH event in the prior 3 months reported 
by 6% of the 2,561 participants in a survey of those with T1D. The highest occurrence being 
in those age 50 years and older [18]. Whenever the patient has symptoms suggestive of 
hypoglycemia, SMBG should be performed prior to treatment of the event with carbohydrate 
administration unless safety considerations necessitate immediate treatment prior to 
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confirmation with SMBG. For every episode of hypoglycemia, regardless of severity, the 
patients should complete the appropriate hypoglycemia data in the study diary provided by 
the study site. In addition, especially in case of recurrent episodes of hypoglycemia, the 
patients should be encouraged to contact their study site for instructions on appropriate 
management of their diabetes.  
Patients are instructed to contact the Investigator as soon as possible following any severe 
hypoglycemic episode for review of data and to assess if a change in insulin therapy is 
required.  
The patient will record whether symptoms of hypoglycemia were present or absent for each 
episode of documented hypoglycemia on the provided study diary as soon as possible after 
the episode, so that this information can be reviewed by the site during the next visit. 
Documentation for duration of a hypoglycemic episode is only required for cases of severe 
hypoglycemia. 
Treatment of documented hypoglycemia requires the ingestion of carbohydrates (glucose). In 
most cases, 15 to 20 grams of glucose is the preferred treatment. A rise in blood sugar and 
change in symptoms should occur within 15 to 20 minutes. Re-treatment may be required in 
certain instances. The patient should be instructed to retest blood glucose 15 to 20 minutes 
after treatment, and re-treat every 15 to 20 minutes if hypoglycemia has not resolved.  
Standardized definitions of hypoglycemia are being utilized across the sotagliflozin 
development program. The definitions and procedures described below will be implemented 
across the sotagliflozin program.  
In the sotagliflozin program, hypoglycemic events will be categorized as either (1) Severe 
Hypoglycemia or (2) Documented Hypoglycemia. An episode may meet criteria for both 
categories. In accordance with the February 2008 FDA draft Diabetes Guidance[19], and the 
2012 EMA Diabetes Guideline[20], hypoglycemic events reported in this trial will be 
classified as severe hypoglycemia, documented symptomatic hypoglycemia, or documented 
asymptomatic hypoglycemia per the following definitions:   
1. Severe hypoglycemia: Severe hypoglycemia has occurred if the answer is yes to any
of the following 3 questions:
a.
Did the patient have an episode of suspected hypoglycemia treated with any
form of carbohydrate or with glucagon that required the assistance of others to
treat?
b. Did the patient lose consciousness during the episode?
-OR- 
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Protocol No. LX4211.312 
c.
Did the patient have a seizure during the episode? Note: “patient requires the
assistance of others to treat” means that the neurologic impairment was severe
enough to prevent self-treatment in the opinion of those providing assistance
to treat. Note:  Assisting a patient out of kindness, when assistance is not
required, should not be considered as “requiring the assistance of others to
treat.”
2. Documented symptomatic and asymptomatic hypoglycemia:
a.
Documented symptomatic hypoglycemia:  An event during which typical
symptoms of hypoglycemia are accompanied by a concurrent fingerstick
(SMBG) or venous glucose result of ≤70 mg/dL [≤3.9 mmol/L].
-OR- 
b. Documented asymptomatic hypoglycemia: An event not accompanied by 
typical symptoms of hypoglycemia but with a measured fingerstick (SMBG) 
or venous glucose result of ≤70 mg/dL [≤3.9 mmol/L] 
Hypoglycemia is considered an EOSI for the sotagliflozin program. The Investigator will 
record all occurrences of documented hypoglycemia or severe hypoglycemia in the 
Hypoglycemia Reporting eCRF. In case an event meets criteria for both documented and 
severe hypoglycemia, both sections of the Hypoglycemia Reporting eCRF will be completed. 
Hypoglycemia data will be assessed at each visit by evaluating all available glycemic data.  
The primary data sources will be glucose meter data from the web-based portal and/or 
point-of-care glucose meter download/meter memory review. These primary data sources are 
supplemented by other available data, study diary, and laboratory blood glucose values.  
Because the analysis for hypoglycemia will be based on data recorded on the Hypoglycemia 
Reporting eCRF and not the AE eCRF, it is requested that the Investigator not submit 
hypoglycemic events on the AE eCRF unless the episode meets criteria for an SAE (as 
described in Section 9.2). However, the Investigator is not prohibited from characterizing 
hypoglycemia as an AE. Any event of hypoglycemia reported as an AE will be cross-checked 
to ensure that the event is also reported on the Hypoglycemia Reporting eCRF.  
All hypoglycemia events reported by the Investigator as severe and/or reported as SAEs will 
be adjudicated by experts blinded to the treatment assignment. Details regarding processes to 
be followed will be described in the CEC Charter.  
Hypoglycemia will be analyzed as incidence of patients (%) with at least 1 hypoglycemic 
event and the number of severe hypoglycemic events per patient per year of exposure, and 
the number of documented hypoglycemic events per patient per day. Subanalysis of total 
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documented hypoglycemia (symptomatic plus asymptomatic), documented symptomatic 
hypoglycemia, documented asymptomatic hypoglycemia and severe hypoglycemic events 
will be performed. 
Severe and documented hypoglycemia will be further characterized as follows: 
•
Nocturnal hypoglycemia defined by the time of day: any hypoglycemia of the above
categories that occurs between 00:00 and 05:59 hours, regardless of whether the
patient was awake or woke up because of the event
•
Daytime hypoglycemia defined by the time of day: any hypoglycemia that occurs
between 06:00 to 23:59
Severe hypoglycemia will be further characterized as: 
•
Nocturnal hypoglycemia by sleep status: hypoglycemia waking up the patient from
sleep after having gone to bed in the evening and before getting up in the morning
before administration of any insulin
9.5.2 
Diabetic Ketoacidosis 
Diabetic ketoacidosis is the most serious hyperglycemic emergency in patients with T1D and 
T2DM. According to recent data, DKA is common in T1D with at least one DKA event in the 
prior 3 months reported by 3% of the 2,561 participants in a survey of those with T1D.The 
highest occurrence being in young adults (5%), and those with high A1C (up to 12% in those 
with A1C ≥ 9%) [18]. In adult patients mortality of less than 2% has been reported in 
controlled clinical studies; mortality is increased in the elderly and patients with life-
threatening concomitant illnesses. 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. Other common symptoms 
include generalized weakness, weight loss, nausea, vomiting, and abdominal pain. The 
laboratory triad of hyperglycemia, ketonemia, and metabolic acidosis defines DKA. A 
commonly used classification of mild, moderate, and severe DKA is described below in Table 
9.5.2-1. In regard to the 2 cases of DKA that occurred with empagliflozin,[5] it was noted 
that 1 patient presented with plasma glucose of 17.0 mmol/L (306 mg/dL) and another 
presented with plasma glucose of 11.8 mmol/L (212 mg/dL). The authors noted, 
“Specifically, both patients presented with plasma glucose concentrations that could be 
interpreted as lower than typically associated with diabetic ketoacidosis.” In the sotagliflozin 
T1D phase 2 study, (LX4211.203), the 2 cases with DKA that occurred on sotagliflozin had 
blood glucose values of 30.7 mmol/L (553 mg/dL) and 20.9 mmol/L (376 mg/dL). However, 
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Protocol No. LX4211.312 
it is possible that DKA could present with glucose values ≤250 mg/dL in patients treated with 
sotagliflozin. 
Table 9.5.2-1 Diagnostic Criteria for DKA for Patients Not Treated with Investigational 
Agents 
Mild 
Moderate 
Severe 
Plasma glucose (mg/dL) 
>250 
>250 
>250 
Arterial pH 
7.25 - 7.30 
7.00 - 7.24 
<7.0 
Serum bicarbonate (mEq/L) 
15 - 18 
10 - <15 
<10 
Urine ketonesa 
Positive 
Positive 
Positive 
Serum ketonesa 
Positive 
Positive 
Positive 
Effective serum osmolality (mOsm/kg)b 
Variable 
Variable 
Variable 
Anion gapc 
>10 
>12 
>12 
Alteration in sensorial or mental 
obtundation 
Alert 
Alert/drowsy 
Stupor/coma 
aNitroprusside reaction method 
bEffective serum osmolality = 2[Na+ (mEq/L)] + [glucose (mg/dL)/18] 
 In the table, anion gap = [Na+] – [Cl- + HCO3
-] with the normal anion gap referenced as “between 7 and 9 
mEq/L, and an anion gap > 10-12 mEq/L indicates the presence of increased anion gap metabolic acidosis”. 
However, the normal range for each of the individual measurements varies depending upon the specific 
methodology used. In addition, the serum potassium can be included in the anion gap measurement, resulting in 
a normal range that is approximately 4 mEq/L higher than the number calculated using the preceding equation. 
As a result, interpretation of the anion gap should be based on the laboratory reference range for the anion gap, 
and considering baseline values for the individual patient. 
Source: Adapted from Kitabchi, 2009 [21]  
The therapeutic goals in DKA management include restoration of circulatory volume and 
tissue perfusion, decreasing serum glucose, clearance of serum ketoacids, and correction of 
electrolyte abnormalities.  
Instructions for the patient and site staff: 
At every clinic visit blood BHB (central laboratory and point-of-care) testing will be 
conducted. At visits where UA is performed, the evaluation will include urine ketone 
determination by dipstick. 
It is possible that GI or other AEs occurring with LX4211 may mask presenting symptoms of 
DKA (Appendix F). These symptoms include but are not limited to: inability to maintain oral 
intake, generalized weakness, excessive thirst, abdominal pain, nausea, vomiting, rapid 
weight loss, fever, frequent urination, fruity-scented breath, confusion, acute illness and/or 
consistently elevated blood glucose. Therefore, it is important that patients with GI 
complaints or intercurrent illness be instructed by the site to measure their blood or urine 
ketone or blood BHB levels. 
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Protocol No. LX4211.312 
(Note: In some patients alcohol may be a possible trigger for ketosis). 
If ketosis is present (moderate or higher for urine ketones or blood BHB level is >0.6 
mmol/L), then the patient will be asked to contact the Investigative site immediately. In this 
situation, the investigator should consider instructing the patient to take rapid acting insulin 
by syringe (not insulin pump) as well as eat carbohydrates in order to reverse the ketosis.  
After rechecking the ketones, the investigator should consider instructing the patient to take 
additional doses of rapid acting insulin every 2 hours until elevated ketones are normalized.  
Because the amount of insulin needed to lower ketones will also lower blood glucose, it is 
necessary for the patient to increase carbohydrate intake. Typically this would be 15-30 
grams of carbohydrate each hour provided by a glucose containing sports drink or oral 
rehydration fluid. The site will evaluate if an assessment for metabolic acidosis is 
appropriate. If laboratory testing confirms presence of metabolic acidosis, then the “Possible 
DKA” eCRF will be completed.  If nausea and vomiting are present and the patient is unable 
to keep liquids down the patient should be evaluated in an Emergency Room. 
If a patient is scheduled for a procedure or surgery that requires withholding oral intake 
(NPO), it is recommended that study drug is held from the day prior to procedure or surgery 
and resumed the day after procedure or surgery is complete and patient is tolerating adequate 
oral intake. 
An independent adjudication committee composed of experts in T1D will adjudicate cases of 
DKA (including all cases of metabolic acidosis) in a blinded fashion (see Section 9.6). 
Details regarding processes to be followed will be described in the charter. 
9.6 
Safety Monitoring and Oversight Committees 
9.6.1 
Data Monitoring Committee 
The DMC is an expert advisory group, made up of members independent of the Sponsor 
and/or designee that is responsible for evaluating cumulative safety data at regular intervals. 
The primary objective of the DMC is to monitor patient safety by reviewing the available 
clinical data at scheduled time points. The DMC may also conduct ad hoc meetings, as 
necessary. Following each meeting, the DMC will make a recommendation to the Sponsor 
regarding the study. The details regarding the DMC processes and procedures will be outlined 
in the DMC Charter, which will be finalized prior to the review of any data.  
9.6.2 
Clinical Endpoint Committee 
The CEC(s) is/(are) composed of experts in cardiology and neurology (and other appropriate 
medical specialties such as hepatology and endocrinology) who are independent of the Sponsor 
and the CRO. The CECs will review and adjudicate all deaths, EOSI, including 
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MACE/selected CV events (MI, stroke, hospitalization due to unstable angina, urgent 
coronary revascularizations and hospitalization due to heart failure), clinical or laboratory 
findings associated with DILI, DKA, and severe hypoglycemia episodes (as well as 
hypoglycemia reported as an SAE) in a treatment-blinded fashion. DILI events will also be 
assessed for causality. 
The details regarding the CEC processes and procedures will be outlined in the CEC 
Charter(s), which will be finalized prior to the review of any data. 
9.6.3 
Steering Committee 
The Steering Committee will serve in an advisory capacity to the Sponsor on multiple clinical 
trials in the sotagliflozin development program. This committee will meet at regular intervals 
throughout the program to receive status updates on each of the individual trials and to 
provide recommendations regarding trial status and conduct of the studies in the sotagliflozin 
program included in their remit. The Steering Committee will operate under the principles, 
and have the roles and responsibilities, outlined in the Steering Committee Charter. 
10.
Statistical Methodology
10.1 
Determination of Sample Size 
The sample size will be based on satisfying design assumptions made for the primary efficacy 
endpoint. The primary efficacy endpoint is a binomial proportion, a composite measure of 
glycemic control and safety. We have assumed that the majority of treatment effect will be 
observed in the glycemic control portion of the endpoint and for planning purposes, the rates 
of severe hypoglycemia and DKA will be equal in both treatment groups. Little data are 
available to estimate the <7% A1C component of the endpoint in this patient population. Data 
reviewed from the LX4211.1-202 Phase 2 trial in T2DM and from other pertinent literature 
sources suggests that a difference between treatment groups of at least 0.15 may be expected 
for this variable. We will assume this effect size for the primary endpoint, but will perform an 
adjustment for the expected proportion of patients not having a DKA or severe hypoglycemia 
event. A conservative assumption is made that the rates of DKA and severe hypoglycemia are 
independent and their union is estimated to be ≤0.15. It is expected that 0.85 of the patients 
will not have a DKA or a severe hypoglycemic event over the course of the study. Adjusting 
the 0.15 effect size estimate by this value yields a target effect size for the primary endpoint 
≈0.12. Since the underlying placebo rate is unknown for the composite outcome, we will 
assume a maximum variance construct under the alternative hypothesis for binomial 
proportions to estimate the sample size (ie, the mean of the pooled responses rates is 0.50). 
Assuming a 2-sided test with α = 0.05 and 90% power, 380 patients are needed per treatment 
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group to detect a difference in binomial proportions of at least 0.12 for the primary endpoint. 
The sample size estimate will be adjusted for dropouts in a manner to reflect that the primary 
analysis will be conducted in the modified Intent-to-Treat (mITT) patients. Dropouts are 
expected to be primarily a function of noncompliance: patients stopping early their 
randomized treatment, but followed to the 24-week visit. It is further assumed that the 
dropped (noncompliant) sotagliflozin patients will respond as the placebo patients and that 
there will be no drop-in patients in the placebo group. These assumptions net an adjusted 
effect size for detection of 0.12 x (1-0.20) ≈ 0.10, where the dropout rate over 24 weeks is 
assumed to be 20%. Based on this adjusted effect size, 544 patients are required per treatment 
group, for a total of 1088 patients across the 2 treatment groups.  
The occurrence of severe hypoglycemia is an important safety component of the primary 
endpoint. It is desirable that the study sample includes enough patients so that a reliable 
estimate of treatment difference can be obtained for this outcome. Based on a literature 
review, it seems reasonable to assume that the rate of severe hypoglycemia, defined as the 
number of patients experiencing at least 1 such episode divided by the number of mITT 
patients (ie, a binomial proportion), is ≤0.10 over a 24-week period. We will assume this rate 
is the same in both treatment groups, yielding an expected difference of 0.0. A 2-sided, 95% 
confidence interval (CI) based on normal approximation methods and corrected for continuity 
is associated with a distance value (ω) of 0.033 for a sample size of 700 patients per group; ω 
is the extended distance from the observed difference in one or both directions. The upper 
bound of this CI will exclude values greater than 0.05; ie, a 50% increase in the expected 
placebo rate.  
Based on the considerations mentioned above, a sample size of 700 patients per treatment 
group (1400 total patients) seems to be an appropriate target for the study.  
For the satiety substudy, assuming a dropout rate of 20% over the course of the study, a 
sample size of approximately 224 patients (112 per treatment group) demonstrating a change 
greater than 30% would be necessary to obtain statistical power at the recommended 0.80 
level (alpha = 0.05). To achieve this number of patients for evaluation, 280 patients will be 
recruited to participate in the substudy.  
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10.2 
Analysis Populations 
10.2.1 
Randomized Population 
Randomized patients are those who provide informed consent, and have a randomized kit 
allocated and assigned to study treatment by IXRS. Data summaries using this population 
will include all Baseline data as appropriate (eg, patient demographics).  
10.2.2 
Modified Intent-to-Treat and Per-Protocol Populations 
The mITT population includes all randomly assigned patients who have taken at least 1 dose 
of study drug during the Treatment Period. Treatment group assignment will be based on the 
randomized treatment, which may not match the actual treatment received. 
The Per-protocol (PP) population includes all patients in the mITT population who complete 
treatment through the primary assessment of 24 weeks, and have no significant protocol 
violations that will impact the collection or interpretation of efficacy data. Identification of all 
patients in the PP population will be determined before the database lock and unblinding. The 
PP patients will be assigned to treatment groups based on the treatment they received. 
The Satiety population includes all patients in the mITT population who elect to participate in 
the satiety substudy and completed ≥8 satiety daily diaries (ie, the PSDDs) during the placebo 
Run-in Period. Identification of all patients in the satiety population meeting these criteria 
will be determined before database lock and unblinding. 
10.2.3 
Safety Population 
Safety analyses will be based on the Safety population, defined as all randomly assigned 
patients who have taken at least 1 dose of study drug and are classified according to their 
actual treatment received. 
10.3 
Study Endpoints 
10.3.1 
Efficacy Endpoints 
10.3.1.1 
Primary Efficacy Endpoint 
The primary endpoint is to demonstrate the superiority of sotagliflozin 400 mg versus 
placebo in the proportion of patients with A1C <7.0% at Week 24 and no episode of severe 
hypoglycemia and no episode of DKA after randomization when used as an adjunct in normal 
weight and overweight/obese adult patients with T1D who have inadequate glycemic control 
with insulin therapy. 
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10.3.1.2 
Secondary Efficacy Endpoints  
The secondary efficacy endpoints are to be measured as change from Baseline in sotagliflozin 
400 mg compared to placebo for each of the following listed below: 
•
A1C at Week 24
•
Body weight at Week 24 (absolute and percent change)
•
SBP at Week 16 in the subset of patients with Baseline SBP ≥130 mm Hg
•
Bolus insulin dose at Week 24 (as an average over the 3-5 days prior to the visit)
10.3.1.3 
Other Efficacy Endpoints 
Other efficacy endpoints are: 
•
Secondary endpoints (A1C, body weight, SBP, bolus insulin dose) assessed at
specified cut points and specified time intervals during the 24-week double-blind
Treatment Period
•
Proportion of patients with A1C reduction ≥0.4% and no increase in body weight
•
Proportion of patients with A1C reduction ≥0.5% and no episode of severe
hypoglycemia
•
Proportion of patients meeting success criteria for A1C and insulin
o
Proportion of patients with decrease from Baseline in mean daily bolus insulin
dose of >20% and a decrease from Baseline in A1C of >0.3%. Mean daily bolus
insulin dose is defined as the mean bolus insulin dose as calculated based on
results of at least 3 days of data during the preceding 3-5 days (consecutive or
non-consecutive) prior to the clinic visit.
•
FPG
•
Total and basal (or non-bolus) insulin dose
o
Mean total daily insulin dose by visit (as an average over the 3-5 days prior to the
visit)
o
Mean daily basal (or non-bolus) insulin dose by visit (as an average over the 3-5
days prior to the visit)
•
DBP
•
Hypoglycemic events calculated as a daily average over the week prior to the visit
for:
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Protocol No. LX4211.312 
o
Hypoglycemic events/patient/day (≤70 mg/dL) by SMBG
o
Hypoglycemic events/patient/day (≤55 mg/dL) by SMBG
•
Measures of kidney function:
o
Urine ACR, CCR, and GCR
o
Serum creatinine
o
MDRD eGFR
•
Proportion of patients with satiety increase ≥30% as measured by the PSDD-NRS
(substudy)
•
Change from Baseline in patient-reported satiety as measured by the PSDD-NRS
(substudy)
10.3.2 
Safety Endpoints 
Safety endpoints are as follows: 
•
Incidence of TEAEs, suspected adverse reactions, AEs, AEs leading to
discontinuation from the study drug or study, SAEs, and deaths
•
Change from Baseline in clinical laboratory results, physical examination results, and
vital signs
•
EOSI (see Section 9.5)
10.4 
Statistical Methods 
A more detailed description of the analysis and reporting of data will be provided in an SAP. 
An overview of the main analysis strategy is provided in the following sections. 
10.4.1 
Efficacy Analyses 
All primary efficacy analyses will be based on the mITT population. Supportive analysis of 
the efficacy data will be performed using the PP population. 
Primary analysis of the primary efficacy endpoint at Week 24 will use a Cochran-Mantel-
Haenszel (CMH) test stratified by BMI at Screening (<25 kg/m2, ≥25 kg/m2), Week -2 A1C 
(≤9%, >9%), and use of CSII at Screening (Yes, No). Missing observations will be imputed 
as non-responders. A point estimate of treatment effect will be based on the sotagliflozin 
minus difference in binomial proportions. A 2-sided 95% CI will be estimated on the 
observed difference and will be based on normal approximation methods using a continuity 
correction factor. The individual components of the endpoint will be summarized separately 
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using descriptive statistics. Each of these components will be expressed as a binomial 
proportion: proportion of patients with A1C <7.0% at Week 24, proportion of patients with 
≥1 episodes of DKA after randomization, and proportion of patients with ≥1 episodes of 
severe hypoglycemia after randomization. 
Sensitivity analysis of the primary endpoint will use a single imputation method to obtain a 
rectangular dataset. Imputations will be based on use of the last observation carried forward 
(LOCF) algorithm. The stratified CMH test will be applied to this imputed dataset. The 
stratified CMH test will also be applied to the PP dataset as an additional sensitivity analysis. 
Primary analysis of the continuous efficacy endpoints will use mixed-effects model for 
repeated measures (MMRM) statistics based on the restricted maximum likelihood (REML) 
method for estimation. The analysis model will include fixed, categorical effects of treatment, 
BMI at Screening (<25 kg/m2, ≥25 kg/m2), Week -2 A1C (≤9%, >9%), use of CSII at 
Screening (Yes, No), time (study week), Baseline-dependent variable-by-time interaction, and 
a treatment-by-time interaction. An unstructured (co)variance structure will be used to model 
the within-patient errors. Other structures will be explored by use of Akaike’s information 
criteria should the unstructured (co)variance structure not result in model convergence. The 
Kenward-Roger approximation will be used to estimate the denominator degrees of freedom. 
The adjusted mean change from Baseline by each study week for each treatment group will 
be estimated in the framework of this model, as well as the between-group differences 
(comparing sotagliflozin to placebo) and the 95% CIs for the adjusted mean. All 
post-Baseline observations collected at scheduled visits will be used in the MMRM, 
including data collected after the discontinuation of study drug. An analysis of covariance 
(ANCOVA) will be applied where only 1 post-Baseline scheduled visit occurs; ie, the 
MMRM analysis omitting the time-related effects. 
For binary endpoints estimated as binomial proportions, the frequency and proportion of 
patients achieving the outcome will be presented by treatment group at each assessed study 
week. The primary analysis of these endpoints will use a CMH test stratified by the different 
levels of the randomization stratification factors of BMI at Screening (<25 kg/m2, ≥25 
kg/m2), Week -2 A1C (≤9%, >9%), and use of CSII at Screening (Yes, No). These treatment 
group comparisons will be performed at Week 24 only. The earlier study weeks will use 
descriptive analyses to summarize the data. These descriptive statistics will include the 
patient counts and proportions, point estimates of treatment effect, and 95% CIs of the 
treatment effect. Missing observations at Week 24 will be imputed as non-responders; only 
the observed data will be summarized at the earlier study visits. Endpoints comprised of 
multiple outcomes will use descriptive methods to summarize each component by treatment 
group at each study week. 
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The test for superiority of sotagliflozin versus placebo based on the primary efficacy endpoint 
will be performed at the 2-sided 0.05 α-level. If this null hypothesis is rejected, a sequential 
procedure will be used to maintain the overall Type I error rate at a 2-sided, 0.05 α-level 
across analyses of the secondary endpoints at Week 24. The secondary endpoints will be 
specified in a hierarchy and the first listed will be tested at the same Type I error used for the 
primary endpoint comparison (α = 0.05). If this test rejects the null hypothesis, then the next 
listed secondary endpoint will be tested at the same Type I error rate. This testing sequence 
will continue as long as the null hypothesis is rejected at the 0.05 α-level. The testing 
sequence will be broken at the first instance that a null hypothesis is not rejected. Once the 
sequence is broken, no later hypothesis in the hierarchy will be tested. The order of testing 
will be: 
•
A1C change from Baseline at Week 24
•
Body weight at Week 24 change from Baseline (absolute and percent change; the
absolute change will be used in the sequence of analyses)
•
SBP change from Baseline at Week 16 in the subset of patients with Baseline SBP
≥130 mm Hg
•
Percent change from Baseline in bolus insulin dose at Week 24
In addition, raw P-values and 95% CIs will be computed for tests of all secondary endpoint 
hypotheses. These raw or unadjusted statistics will be used as descriptive summaries of the 
data and will not be used for formal testing of the hypotheses. 
10.4.2 
Subgroup Analyses 
Subgroup analyses of the efficacy variables will be performed, as needed, for the different 
levels of the randomization stratification factors and the subgroups derived by other efficacy 
endpoint definitions (eg, SBP). Of particular interest are subgroup analyses of the efficacy 
variables by Baseline eGFR status (≥45 to <60 mL/min/1.73 m2 versus ≥60 mL/min/1.73 m2), 
Week -2 A1C (≤9.0%, >9.0%), Week -2 A1C (≤7.7% versus ≥7.7%), BMI (<25 kg/m2, ≥25 
kg/m2), use of CSII at Screening (Yes, No), and age at time of T1D diagnosis (≤18 years of 
age, >18 years of age). Additional subgroup analyses may be conducted and will be described 
in the SAP. All subgroup analyses will be exploratory.  
10.4.3 
Safety Analyses 
Safety analysis will primarily involve examination of descriptive statistics and individual 
patient listings for any effects of study treatment on clinical tolerability and safety. 
Summaries will be prepared by treatment group and, as needed, by clinic visit. These 
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Protocol No. LX4211.312 
summaries will be based on the Safety population and other subpopulations as needed. All 
safety data (AEs, EOSI, laboratory test results, vital signs, ECG results, and physical 
examinations) will be provided in listings.  
The evaluation of AEs is described in Section 10.4.3.1.  
Vital signs, physical examination findings, laboratory results, and ECGs will be summarized 
descriptively at each time point. Actual and change from Baseline data will be calculated and 
summarized. In addition, shift table analyses will be presented for the laboratory data. 
The analysis of hypoglycemic events will be conducted per the definitions provided in 
Section 9.5.1 and methods described for binary, continuous, and other variables in 
Section 10.4.1. Since these data also serve as a measure of safety, additional analyses will be 
conducted. The first analysis will be performed using CMH tests stratified by the 
randomization factors at each clinic visit. These tests will provide inferential and descriptive 
summaries of the relative risk estimate for each of the 2 hypoglycemic event definitions: 
≤70 mg/dL and ≤55 mg/dL by SMBG. The patient incidence of these hypoglycemic events 
will be counted over the week prior to the scheduled clinic visit used in the analysis. The 
second analysis of these data will examine the relative risk for each of the hypoglycemic 
event definitions over the entire Treatment Period by use of a generalized linear model 
(GLM). The GLM will include fixed, categorical effects of treatment; BMI at Screening 
(<25 kg/m2, ≥25 kg/m2), Week -2 A1C (≤9%, >9%), use of CSII at Screening (Yes, No), and 
an offset term for study duration. The events will be modeled as a negative binomial process. 
10.4.3.1 
Adverse Events 
All AEs will be coded and listed by body system and preferred term based on MedDRA. 
Summaries using descriptive statistics will be provided for TEAEs, drug-related AEs, and 
AEs by intensity. Treatment-emergent adverse events are those events not present at Baseline, 
but occurring after the start of study treatment, or if existing at Baseline, increasing in 
intensity after the initiation of study drug. When multiple occurrences of the same event are 
reported for the same patient, summaries made by intensity will select the event with the 
highest intensity. In a similar manner, summaries prepared by drug relationship will select the 
event with the greatest degree of relationship when a patient reports multiple occurrences of 
the same event. On-study deaths will be reported for deaths occurring during the active phase 
of the Treatment Period and 30 days after stopping study drug. Also, deaths occurring outside 
the 30-day window, but secondary to an AE reported within the 30-day post-Treatment 
Period, will be reported.  
Treatment-emergent adverse event summaries will include the overall incidence (number of 
patients with the event) and number of events by system organ class and preferred term, 
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Protocol No. LX4211.312 
overall incidence sorted by descending frequency across treatment groups, events by 
maximum intensity, events by relationship to study treatment, and events leading to 
discontinuation of study drug; SAEs and EOSI will also be summarized. Listings will be 
provided for deaths, SAEs and discontinuations due to AEs. Additional summaries or listings 
of AEs may also be provided. 
10.4.4 
Meta-analyses 
The occurrence of the following events will be statistically analyzed using data from this 
study combined with other Phase 2/3 trials conducted in T1D and T2DM patients: severe 
hypoglycemia, DKA, DILI, and MACE. Details of the analysis models and related 
assumptions will be documented in separate meta-analysis plans. 
11.
Study Management
Ethical and Regulatory Standards are presented in Appendix B; Investigator Obligations are 
presented in Appendix C. 
The Investigator is responsible for completing and maintaining adequate and accurate eCRFs 
and source documentation. Source documentation constitutes original records, which may 
include:  progress notes, medication administration records, laboratory reports, ECG tracings, 
discharge summaries, etc.  
All data on the eCRF must be recorded in accordance with the eCRF completion guidelines. 
If a correction is necessary, it should be made by the Investigator or a designated qualified 
individual as specified within the guidelines. All eCRFs should be completed in their entirety 
and stored in a confidential and secure location. The Investigator must sign the Investigator’s 
statement in each patient’s eCRF indicating that the data reported are accurate. 
At the study site, CRAs will verify eCRFs against source documentation using a targeted 
approach consistent with Risk-Based Monitoring guidance. Computer programmed edit 
checks will be run against the database to check for discrepancies and ensure that the data are 
reasonable. The safety database will be reconciled with the clinical database. All issues 
resulting from the computer generated checks and the safety database reconciliation will be 
resolved according to standard data management practices in conjunction with the Sponsor 
and/or designee, clinical study personnel, and the study Investigators. 
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Protocol No. LX4211.312 
11.1 
Data Handling and Quality Assurance 
11.1.1 
Data Recording 
Entries made in the eCRF must be verifiable against source documents (the patient’s medical 
records) with the exception of race and ethnicity. For all other data, source documentation 
must be available. 
In this protocol, all information captured (“entered,” “documented,” “recorded”) becomes 
part of the Sponsor’s database. 
11.1.2 
Description of General Procedure 
The designated CRO will supply each investigational site with access to a web-based EDC 
computer system. Edit checks and data logic checks are at the point of entry and are validated 
according to the CRO’s SOPs. All data entered into the system is transferred to a secure 
database maintained by the CRO. 
Access to the EDC system at the site, for vendors, for the Sponsor and Sponsor’s designee, is 
password protected. Study access is granted to site personnel only after they have been 
trained in the use of the EDC system. 
The EDC system contains a system-generated audit trail that captures any changes made to a 
data field, including who made the change, and the date and time it was made. This 
information is available at the Investigator’s site and at the Sponsor and/or designee. 
Data entries should be made into the EDC system in a timely manner after a clinic visit, but 
not to exceed 10 days after the clinic visit has occurred. All data entered must be supported 
by source documents maintained for all patients enrolled in this study. 
11.2 
Monitoring 
The Sponsor is responsible for ensuring the proper conduct of the study with regard to ethics, 
protocol adherence, site procedures, integrity of the data, and applicable laws and/or 
regulations. At regular intervals during the study and following completion of the study, the 
Sponsor’s and Sponsor’s designee’s study monitors will contact the study site via visits to the 
site, telephone calls, and/or letters in order to review study progress, eCRF completion, and 
address any concerns or questions regarding the study conduct. A risk-based monitoring 
approach is planned for this study, where elements of targeted source data verification 
focusing on critical data and risk-targeted monitoring interventions will be employed. The 
risk-based monitoring approach will be documented in the monitoring plan. During 
monitoring visits, the following aspects of study conduct will be carefully reviewed:  
informed consent of patients, patient recruitment, patient compliance with the study 
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Protocol No. LX4211.312 
procedures, source data verification, drug accountability, use of concomitant therapy by 
patients, general safety documentation and reporting, and quality of data. Records pertaining 
to these aspects are expected to be kept current. 
The Investigator must make study data accessible to the clinical monitor, to the Sponsor 
and/or Sponsor’s designee, and to regulatory inspectors. 
11.3 
Audits and Inspections 
The Sponsor and/or Sponsor’s designee, Regulatory Authority, or Institutional Review Board 
(IRB) or Ethics Review Committee (ERC) may visit the study site at any time during the 
study or after completion of the study to perform audits or inspections. The purpose of a 
Sponsor audit or regulatory inspection is to systematically and independently examine all 
study-related activities and documents to determine whether these activities were conducted 
according to the protocol, GCP, ICH guidelines, and any other applicable regulatory 
requirements. Investigators should contact the Sponsor and/or Sponsor’s designee 
immediately if contacted by a regulatory agency about an inspection at their site. 
11.4 
Amendments 
Any amendments to the protocol will be written by the Sponsor or designee and approved by 
the Sponsor. All amendments must be submitted to the appropriate IRB or ERC for approval 
prior to implementing the changes. In some instances, an amendment may require changes to 
the informed consent form (ICF), which also must be submitted for IRB or ERC approval 
prior to administration to patients. If any changes to the eCRF are required, the Sponsor or 
Sponsor’s designee will issue supplemental or revised eCRF pages. 
11.5 
Record Keeping 
11.5.1 
Drug Accountability 
The Investigator must maintain accurate records of study drug receipt, dispensing 
information, and disposition. If the Investigator cannot account for all clinical supplies at the 
termination of the study, a written explanation must be provided. 
11.5.2 
Health Insurance Portability and Accountability Act of 1996 
and Subsequent Updates 
The Investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, 
the Standards for Individually Identifiable Health Information, 45 CFR Parts 160 and 164 
HIPAA Privacy Regulation and any applicable updates). The Investigator shall ensure that 
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Protocol No. LX4211.312 
study patients authorize the use and disclosure of protected health information in accordance 
with HIPAA Privacy Regulation and other local applicable regulations, and in a form 
satisfactory to the Sponsor. 
11.5.3 
Financial Disclosure 
The Investigator and any sub-Investigator shall provide to the Sponsor and/or Sponsor’s 
designee sufficient accurate financial information to allow the Sponsor and/or Sponsor’s 
designee to submit complete and accurate financial certification or disclosure statements to 
the FDA and/or other applicable Regulatory Authorities. The Investigator shall promptly 
update this information if any relevant changes occur in the course of the study or for 1 year 
following completion of the study. 
11.5.4 
Access to Original Records 
It is an expectation of Regulatory Authorities that monitors, auditors, and representatives of 
national and international government regulatory agency bodies have access to original 
source documentation (see examples in Section 11) to ensure data integrity. “Original” in this 
context is defined as the first documentation of an observation and does not differentiate 
between hard copy and electronic records. 
11.5.5 
Retention of Study Documents 
According to 21 CFR Part 312.62, ICH E6, and the guidance documents applying to clinical 
trials in Volume 10 of the publication "The rules governing medicinal products in the 
European Union," study-related records must be retained for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product. These 
documents should be retained for a longer period, however, if required by applicable 
regulatory requirements or by an agreement with the Sponsor. 
The Investigator must not destroy any study-related records without receiving approval from 
the Sponsor and/or Sponsor’s designee. The Investigator must notify the Sponsor and/or 
Sponsor’s designee in the event of accidental loss or destruction of any study records. If the 
Investigator leaves the institution where the study was conducted, the Sponsor and/or 
Sponsor’s designee must be contacted to arrange alternative record storage options. 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
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Patient (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution, or private practice. Where 
the archiving procedures do not meet the minimum timelines required by the Sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period. 
The Investigator/institution must notify the Sponsor and/or Sponsor’s designee if the archival 
arrangements change (eg, relocation or transfer of ownership). 
The Investigator site file is not to be destroyed without the Sponsor’s and/or Sponsor’s 
designee’s approval. 
The Investigator’s contract will contain all regulations relevant for the investigational site. 
12.
Administrative Structure of the Study
The study will be monitored by the Sponsor and/or designee. The following functions for this 
study will be performed by organizations designated by the Sponsor: medical monitoring, 
data management and statistical analysis, study drug randomization and distribution, routine 
site monitoring, medical writing, SAE reporting, and project management.  Additionally, an 
independent DMC, CEC, and T1D Steering committee will provide oversight.
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13.
Appendix A – Schedule of Assessments (Study LX4211.312)
Screening 
Single-blind 
Placebo Run-in  
Double-blind Treatment Period 
Follow-up Period 
Week/Visit 
Wk  
-4 
Wk 
-2 [a] 
Day 1 
Baseline [b] 
Wk 
4 
Wk 
8 
Wk 
16 
Wk 24 
or 
EOT/EW 
30 Days Post 
EOT/EW 
[c] 
Window (days) 
- 
±3 
- 
±3 
±3 
±3 
±3 
+7 
Initiation Activities 
Informed consent/assent 
X 
Assess inclusion/exclusion criteria 
X 
X 
X 
Demography 
X 
Complete medical history 
X 
X 
Register patient for Screening in IXRS 
X 
Register patient for Run-in in IXRS 
X 
Randomization 
X 
Procedures/Events 
Complete physical examination [d] 
X 
X 
Symptom-related brief physical examination [d] 
X 
X 
X 
X 
X 
Weight [e] 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Vital signs [f] 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG [g] 
X 
X 
X 
Patient–centered Site Activities 
Review SMBG and make adjustment to insulin dose as 
needed to meet ADA/EASD Guidelines 
X 
X 
X 
X 
X 
Record insulin dose and SMBG data on the eCRF 
X 
X 
X 
X 
X 
Dispense patient study diary and glucose testing strips 
(meter at first visit) [h] 
X 
X 
X 
X 
X 
Dispense Ketostix® or similar to measure urine ketones 
for DKA assessment per Section 9.5.2 [i] 
X 
Dispense BHB meter and testing strips 
X 
Review study diary and record hypoglycemic symptoms 
or events 
X 
X 
X 
X 
X 
Diet and exercise instruction [j] 
X 
X 
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Protocol No. LX4211.312 
Screening 
Single-blind 
Placebo Run-in  
Double-blind Treatment Period 
Follow-up Period 
Week/Visit 
Wk  
-4 
Wk 
-2 [a] 
Day 1 
Baseline [b] 
Wk 
4 
Wk 
8 
Wk 
16 
Wk 24 
or 
EOT/EW 
30 Days Post 
EOT/EW 
[c] 
Window (days) 
- 
±3 
- 
±3 
±3 
±3 
±3 
+7 
Recommendations on basic genitourinary hygiene, 
maintaining hydration and recognition of DKA and its 
management 
X 
X 
X 
X 
Assess compliance 
X 
X 
X 
X 
X 
Record concomitant medications [k] 
X 
X 
X 
X 
X 
X 
X 
Record SAEs [l] 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs [m] 
X 
X 
X 
X 
X 
X 
Record EOSI 
X 
X 
X 
X 
X 
X 
Dispense single-blind placebo tablets 
X 
Dispense double-blind study drug 
X 
X 
X 
Patient Reported Outcome  (Patients in substudy only) 
Dispense satiety daily diaries and review instruction for 
use [n] 
X 
X 
Collect satiety daily diaries [o] 
X 
X 
Laboratory/glycemic Assessments 
A1C [p] 
X 
X 
X 
X 
X 
X 
X 
Fingerstick glucose on site 
X 
X 
X 
X 
X 
X 
X 
Fasting plasma glucose [p] 
X 
X 
X 
X 
X 
X 
Fasting serum chemistry [p] 
X 
X 
X 
X 
X 
X 
Fasting lipid profile [p] 
X 
X 
X 
X 
BHB (central lab) 
X 
X 
X 
X 
X 
X 
X 
BHB (point-of-care) 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
Urine albumin, calcium, glucose, creatinine  
X 
X 
Urinalysis with microscopy 
X 
X 
X 
Pregnancy test (serum) [q] 
X 
Pregnancy test (urine) [q] 
X 
X 
Follicle stimulating hormone (females only) [r] 
X 
Thyroid stimulating hormone [s] 
X 
Fasting blood sample and random urine for storage 
X 
X 
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A1C = hemoglobin A1C; ADA = American Diabetes Association; AE = adverse event; BHB = beta-hydroxy butyrate; BP = blood pressure; EASD = European Association for the Study 
of Diabetes; eCRF = electronic case report form; DKA = diabetic ketoacidosis; ECG = electrocardiogram; EOSI = Events of Special Interest; EOT = End of Treatment; EW = early 
withdrawal; IXRS = Interactive Voice/Web Response System; SAE = serious adverse event; SMBG = self-monitored blood glucose; Wk = Week 
a.
The duration of the single-blind placebo Run-in Period is 14 days, ±3 days.
b.
All laboratory assessments occur prior to first dose of double-blind study drug. All visit dates will be scheduled based on the date of randomization with a ±3 days visit
window allowed.
c.
All patients will have a follow-up telephone contact 30 days after the last dose of study drug to collect information on any SAEs, any EOSI, or AEs that were ongoing at the 
time of the EOT/EW Visit.
d.
A complete physical examination will include, at minimum, a review of the patient’s general appearance, head, eyes, ears, nose and throat, neck, heart, lungs, abdomen,
back and extremities, skin, and general neurological system. A symptom related brief physical exam will only occur if the patient is experiencing symptoms or AEs. If a
symptom related brief physical exam is required, it should include a review of all body systems that relate to the symptoms and/or AE the patient is experiencing.
e.
Patients should be weighed at approximately the same time of day, wearing minimal clothing, ie, no coat/shoes, using the same calibrated scale where possible.
f.
Vital sign measurements should be measured after the patient has been seated for at least 5 minutes and prior to phlebotomy.
g.
The 12- lead ECG recordings should be obtained prior to the morning study drug administration. ECG recording should be recorded either prior to phlebotomy or at least
30 minutes after phlebotomy.
h.
The patient will be provided with a study diary and glucose monitoring supplies for use at home. These supplies will be provided to all sites by the Sponsor.
i.
After the initial dispensation at the Screening Visit, additional Ketostix® (or similar) will be dispensed on an as needed basis.
j.
Counseling frequency may be increased at the discretion of the Investigator.
k.
Concomitant medications taken from 2 weeks prior to the Screening Visit through the EOT, including those specified in the inclusion/exclusion criteria, must be recorded in
the source documents.
l.
All SAEs will be collected starting with signing informed consent/assent and continue until 30 days after the last dose of study drug.
m.
The collection of AEs will start after the first dose of double-blind study drug. All AEs ongoing at the EOT/EW visit should be followed for at least 30 days following the
last dose of study drug or until the event has resolved, the condition has stabilized, the etiology of the event is determined to be not related to study drug, or the patient is
lost to follow-up.
n.
Patients participating in the satiety substudy will be instructed to complete their satiety daily diaries before the first meal of the day. The patients will be instructed to
complete the diaries each day during the 14day, ±3 days single-blind placebo Run-in Period and each day for the last 14 days, ±3 days of the double-blind Treatment
Period (during Week 23 and Week 24).
o.
Entries on the satiety daily diaries should be reviewed and recorded on the eCRF.
p.
Fasting blood samples should be taken after the patient has fasted for at least 8 hours; patients should only drink water or noncaffeinated, zero-calorie beverages. If the
patient is unable to fast as above, the scheduled “fasting” laboratory samples will still be collected, and the non-fasting status will be noted in the eCRF.
q.
Serum pregnancy test must be performed at Screening, and the result reviewed prior to beginning the single-blind Run-in Period for all females with childbearing potential
unless there is documented history of menopause or they are surgically sterile. All other required pregnancy tests can be performed via a urine test. Baseline urine test
result must be reviewed prior to Randomization. The Investigator may perform additional tests at their discretion or as required by local regulations.
r.
If necessary, follicle-stimulating hormone will be measured at Screening to confirm postmenopausal status.
s.
If abnormal, free thyroxine will be measured.
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14.
Appendix B – Ethical and Regulatory Standards
This study is to be conducted according to international standards of Good Clinical Practice 
(GCP), applicable regional regulations, and applicable institutional research policies and 
procedures.  
Specific regulations should be followed as applicable including: 
•
Volume 10 of the publications "The rules governing medicinal products in the European
Union"
•
21 CFR Part 11 – Electronic Records
•
21 CFR Part 50 – Protection of Human Subjects
•
21 CFR Part 54 – Financial Disclosure
•
21 CFR Part 56 – Institutional Review Boards
•
21 CFR Part 312 – Investigational New Drug Application
•
Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to
Monitoring, August 2011
•
Current Guidance for Institutional Review Boards and Clinical Investigators
•
ICH E6 – Guidance for Industry, E6 Good Clinical Practice:  Consolidated Guidance
Additionally, this protocol and any amendments will be submitted to a properly constituted 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB), in agreement with 
local legal prescriptions, for formal approval of the study conduct. The decision of the 
IEC/IRB concerning the conduct of the study will be made in writing to the Investigator and 
a copy of this decision will be provided to the Sponsor and/or Sponsor’s designee before 
commencement of this study. The Investigator should provide a list of IEC/IRB members and 
their affiliate to the Sponsor and/or Sponsor’s designee. 
All patients for this study will be provided a consent form describing this study and providing 
sufficient information for patients to make an informed decision about their participation in 
this study. This consent form will be submitted with the protocol for review and approval by 
the IEC/IRB for the study. The formal consent of a patient, using the IEC/IRB-approved 
consent form, must be obtained before that patient undergoes any study procedure. The 
consent form must be signed by the patient or legally acceptable surrogate, and the 
Investigator-designated research professional obtaining the consent.  
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Protocol No. LX4211.312 
Copies of GCP guidances and regulations are available from the Sponsor and/or Sponsor’s 
designee upon request (eg, ICH GCP, relevant local regulations such as sections of the US 
Code of Federal Regulations, the Declaration of Helsinki). The purpose of these regulations 
and legal obligations is to define the standards and principles for the proper conduct of 
clinical trials that have been developed by the medical, scientific, and regulatory 
communities.  
The ethical standards defined within GCP are intended to ensure that: 
•
Human patients are provided with an adequate understanding of the possible risks of their
participation in the study, and that they have a free choice to participate or not;
•
The study is conducted with diligence and in conformance with the protocol in such a
way as to ensure the integrity of the findings;
•
The potential benefits of the research justify the risks.
Lexicon Pharmaceuticals, Inc., is the Sponsor of the Investigational New Drug (IND) 
Application. The Sponsor and/or designee is responsible for the following: 
•
Selecting qualified Investigators,
•
Providing Investigators with the information they need to properly conduct an
investigation,
•
Ensuring proper monitoring of the investigation,
•
Ensuring that the study is conducted according to the general investigational plan and the
clinical protocol contained in the IND,
•
Maintaining the IND and the Clinical Trial Application,
•
Ensuring that applicable Regulatory Authorities and all participating Investigators are
properly informed of significant new information regarding adverse effects or risks
associated with the drug being studied,
•
Ensuring the study is conducted in accordance to FDA and ICH guidelines and
regulations.
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Protocol No. LX4211.312 
15.
Appendix C – Investigator Obligations
Per Title 21 of the US Government Code of Federal Regulations (21 CFR) Parts 50 and 56, 
the study protocol and the final version of the patient Informed Consent Form (ICF) will be 
approved by the Institutional Review Board (IRB) or Ethics Review Committee (ERC) 
before enrollment of any patients. The opinion of the IRB or ERC will be dated and given in 
writing. A copy of the letter of approval from the IRB or ERC and a copy of the approved 
ICF will be received by the Sponsor prior to shipment of study drug supplies to the 
Investigator. 
The Investigator will ensure that the IRB or ERC will be promptly informed of all changes in 
the research activity and of all unanticipated problems including risk to patients. The 
Investigator will also ensure that no changes will be made to the protocol without IRB or 
ERC approval. 
As a part of the IRB’s or ERC’s requirement for continuing review of approved research, the 
Investigator will be responsible for submitting periodic progress reports to the IRB or ERC at 
intervals appropriate to the degree of patient risk involved, but no less than once per year. 
Written informed consent must be given freely and obtained from every patient prior to 
clinical trial participation. The rights, safety, and wellbeing of the trial patients are the most 
important considerations and should prevail over interests of science and society. 
As described in Good Clinical Practice (GCP) guidelines, study personnel involved in 
conducting this trial will be qualified by education, training, and experience to perform their 
respective task(s). Study personnel will not include individuals against whom sanctions have 
been invoked after scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
Quality assurance systems and procedures will be implemented to assure the quality of every 
aspect of the study. 
Principal Investigators must provide the Sponsor with a fully executed Form FDA 1572 
(Statement of Investigator) and all updates on a new fully executed Form FDA 1572. 
Principal Investigators must provide the Sponsor with his/her own curriculum vitae and 
current curriculum vitae for each sub-Investigator listed on Form FDA 1572. 
Protection of Human Subjects (21 CFR Part 50) 
Informed consent must be obtained from every patient before entry into a clinical study. It 
must be given freely and not under duress. Consent must be documented by use of an IRB- or 
ERC-approved consent form and signed by the patient or the patient’s legally authorized 
representative. Non-English-speaking patients must be presented with a consent form written 
in a language that they understand. A copy of the signed consent form must be given to the 
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Protocol No. LX4211.312 
patient signing it. Another copy must be kept in the Investigator’s files and made available to 
the FDA and/or other applicable Regulatory Authorities representatives upon request. If, for 
any reason, patient risk is increased as the study progresses, a revised, IRB- or ERC-approved 
consent form must be signed by the patient. Before the study begins, a sample of the consent 
form must be provided to the Sponsor and/or Sponsor’s designee for review. The FDA and/or 
other applicable Regulatory Authorities may reject otherwise scientifically valid studies if 
proper informed consent has not been obtained from all patients. 
Only in the case of a life-threatening incident may an investigational product be used without 
prior signed consent. In such an emergency situation, separate certifications must be written 
both by a physician not participating in the study and by the Investigator. The certifications, 
along with the protocol and informed consent, must be sent to the IRB or ERC within 
5 working days. In this situation, the Investigator may not administer any subsequent product 
to that patient until informed consent and IRB or ERC approval are obtained. 
Informed Consent 
Written informed consent must be obtained from each patient prior to entry in the study. One 
copy of the signed informed consent document will be given to the patient, and another will 
be retained by the Investigator. Additionally, the participant must be allowed adequate time to 
consider the potential risks and benefits associated with his/her participation in the study.  
In situations where the participant is not legally competent to provide consent (ie, mentally 
incapacitated), written consent must be obtained from a parent, legal guardian, or legal 
representative. In these situations, the consent must be signed and dated by a witness. 
The informed consent document must have been reviewed and approved by the Sponsor or 
the designated CRO and by the Investigator’s IRB or ERC prior to the initiation of the study. 
The document must contain the 8 basic elements of informed consent and may contain the 
6 additional elements described in 21 CFR Part 50. Every consent form must include the 
following 8 elements: 
•
A statement that the study involves research, an explanation of the purpose of the research
and the expected duration of the patient’s participation, a description of the procedures to
be followed, and identification of any procedures that are experimental
•
A description of any reasonably foreseeable risks or discomforts to the patient
•
A description of any benefits to the patient or to others that may reasonably be expected
from the research
•
A disclosure of appropriate alternative procedures or course of treatment, if any, that
might be advantageous to the patient
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Protocol No. LX4211.312 
•
A statement describing the extent, if any, to which confidentiality of records identifying
the patient will be maintained and noting the possibility that the FDA and/or other
applicable Regulatory Authorities and representatives may inspect the records
•
An explanation as to whether any compensation or medical treatments are available if
injury occurs for research involving more than minimal risk. The explanation should
involve a description of the compensation or treatment available, or a statement
describing where further information may be obtained.
•
An explanation of whom to contact for answers to pertinent questions about the research
and the patient’s rights and whom to contact in the event of a research related injury
•
A statement that participation is voluntary, that refusal to participate will involve no
penalty or loss of benefits to which the patient is otherwise entitled, and that the patient
may discontinue participation at any time without penalty or loss of benefits to which the
patient is otherwise entitled
When appropriate, one or more of the following elements of information shall also be 
included in the consent form: 
•
A statement that the particular treatment or procedure may involve risks to the patient (or
to the embryo or fetus, if the patient is or may become pregnant) which are currently
unforeseeable
•
Anticipated circumstances under which the patient’s participation may be terminated by
the Investigator without regard to the patient’s consent
•
Any additional costs the patient may incur from participation in the research
•
The consequences of a patient’s decision to withdraw from the research and procedures
for orderly termination of participation by the patient
•
A statement that significant new findings developed during the course of the research that
may relate to the patient’s willingness to continue participation will be provided to the
patient
•
The approximate number of patients involved in the study
The Declaration of Helsinki includes further details regarding the specific requirements for 
informed consent.  
Nothing in these regulations is intended to limit the authority of a physician to provide 
emergency medical care to the extent the physician is permitted to do so under applicable 
federal, state, or local laws. 
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Protocol No. LX4211.312 
The informed consent requirements in these regulations are not intended to preempt any 
applicable federal, state, or local laws that require additional information to be disclosed in 
order that informed consent be legally effective.  
Study Documentation 
IRB or ERC Review/Approval 
The protocol and informed consent for this study, including advertisements used to recruit 
participants, must be reviewed and approved by an appropriate IRB or ERC prior to 
enrollment of participants in the study. It is the responsibility of the Investigator to assure that 
all aspects of the ethical review are conducted in accordance with the current Declaration of 
Helsinki, International Conference on Harmonisation (ICH), GCP, and/or local laws, 
whichever provide the greatest level of protection. A letter documenting the IRB’s or ERC’s 
approval, which specifically identifies the study/protocol and a list of the committee 
members, must be received by the Sponsor and/or Sponsor’s designee prior to initiation of 
the study. Amendments to the protocol will be subject to the same requirements as the 
original protocol. 
A progress report with a request for reevaluation and reapproval will be submitted by the 
Investigator to the IRB or ERC at intervals required by the IRB/ERC, and not less than 
annually. A copy of the report will be sent to the Sponsor.  
When the Sponsor and/or Sponsor’s designee provides the Investigator with a Safety Report, 
the Investigator must promptly forward a copy to the IRB or ERC. 
After completion or termination of the study, the Investigator will submit a final report to the 
IRB or ERC and to the Sponsor, if required. This report should include:  deviations from the 
protocol, the number and types of participants evaluated, the number of participants who 
discontinued (with reasons), results of the study, if known, and significant adverse events 
(AEs), including deaths. 
Study Files 
The Investigator is required to maintain complete and accurate study documentation in 
compliance with current GCP standards and all applicable federal, state, and local laws, rules, 
and regulations related to the conduct of a clinical study. Study documents include, but are 
not limited to, the Investigator’s Brochure, drug accountability records, Sponsor/Investigator 
correspondence, IRB or ERC correspondence, protocol and amendments, information 
regarding monitoring activities, patient exclusion records, electronic case report forms 
(eCRFs), and data queries. 
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Protocol No. LX4211.312 
Confidentiality 
The anonymity of participating patients must be maintained. Patients will be identified by 
their initials and an assigned patient number on eCRFs and other documents submitted to the 
clinical monitor. Documents that will be submitted to the clinical monitor and that identify 
the patient (eg, the signed informed consent document) must be maintained in strict 
confidence by the Principal Investigator, except to the extent necessary to allow auditing by 
Regulatory Authorities, the clinical monitor, or Sponsor and/or Sponsor’s designee’s 
personnel. 
All information regarding the nature of the proposed investigation provided by the Sponsor 
and/or Sponsor’s designee to the Investigator (with the exception of information required by 
law or regulations to be disclosed to the IRB or ERC, the patient, or the applicable 
Regulatory Authorities) must be kept in confidence by the Investigator. 
Drug Accountability 
The Investigator or designee is responsible for accountability of the investigational product at 
the site. The Investigator or designee must maintain records of the product’s delivery to the 
site, inventory at the site, use by each patient, and return to the Sponsor or designee, or 
alternative disposition of any unused product. These records must include dates, quantities, 
batch/serial/lot numbers, and expiration dates (if applicable). 
The Investigator should ensure that the investigational product is used only in accordance 
with the protocol. 
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Protocol No. LX4211.312 
16.
Appendix D – Calculations
Calculation of estimated glomerular filtration rate (eGFR): 
Use these eGFR calculators to estimate kidney function for adults and children. 
At this time, all laboratories should be using creatinine methods calibrated to be isotope 
dilution mass spectrometry (IDMS) traceable. In the US and other countries, nearly all 
methods from the major global manufacturers now have calibration traceable to an IDMS 
reference measurement procedure. Consequently, the calculators for older nonstandardized 
creatinine methods are no longer available on this web site. 
In adults (patients 18 years and older), the recommended equation for estimating eGFR from 
serum creatinine is the Modification of Diet in Renal Disease (MDRD) Study equation. The 
IDMS-traceable version of the MDRD Study equation is used. Either equation below may be 
used based on whether the laboratory reports conventional units or SI units: 
Conventional Units (for use predominantly in the US): 
http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-conventional-unit.asp 
SI Units (for use predominately outside the US): 
http://nkdep.nih.gov/lab-evaluation/gfr-calculators/adults-SI-units.asp 
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Protocol No. LX4211.312 
17.
Appendix E – Algorithm for Liver Safety Laboratory
Abnormality Signals
Reference: 
2009 FDA Guidance for Industry “Drug-Induced Liver Injury – Premarketing Clinical 
Evaluation” 
Step 1: Confirmation of Elevated ALT and/or AST: 
Contact the Medical Monitor to discuss the case and procedures to follow. 
In general, an increase of serum ALT and/or AST to >3X ULN should be followed by repeat 
testing within 48 to 72 hours of all 4 of the usual serum measures (ALT, AST, ALP, and TB) 
to confirm the abnormalities and to determine if they are increasing or decreasing. 
If symptoms persist or repeat testing shows serum ALT and/or AST >3X ULN for subjects 
with normal baseline measures or 2-fold increases above baseline values for subjects with 
elevated values before drug exposure, it is appropriate to initiate close observation to 
determine whether the abnormalities are improving or worsening (see below). If close 
monitoring is not possible, the drug should be discontinued. 
Step 2: If Possible Liver Signal identified, Close Observation Required: 
Contact the Medical Monitor to discuss the case and procedures to follow. 
It is critical to initiate close observation immediately upon detection and confirmation of 
early signals of possible DILI, and not to wait until the next scheduled visit or monitoring 
interval. A threshold of aminotransferase levels ≥3X ULN seems reasonable, as lesser 
elevations are common and nonspecific. If additional testing, beyond that specified in the trial 
protocol, is carried out, it is important that the subject’s information be added to the case 
report forms and database.  
Close observation includes: 
•
Repeating liver enzyme and serum bilirubin tests 2 or 3 times weekly. Frequency of
retesting can decrease to once a week or less if abnormalities stabilize or the trial drug has
been discontinued and the subject is asymptomatic
•
Obtaining a more detailed history of symptoms and prior or concurrent diseases
•
Obtaining a history of concomitant drug use (including nonprescription medications and
herbal and dietary supplement preparations), alcohol use, recreational drug use, and
special diets
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Protocol No. LX4211.312 
•
Ruling out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic
hepatitis; non-alcoholic steatohepatitis (NASH); hypoxic/ischemic hepatopathy; and
biliary tract disease
•
Obtaining a history of exposure to environmental chemical agents
•
Obtaining additional tests to evaluate liver function, as appropriate (eg, International
Normalized Ratio [INR], direct bilirubin)
•
Considering gastroenterology or hepatology consultations
Step 3: Decision to Stop Study Drug Administration: 
Contact the Medical Monitor to discuss the case and procedures to follow. 
Discontinuation of treatment should be considered if: 
•
ALT or AST >8X ULN
•
ALT or AST >5X ULN for more than 2 weeks
•
ALT or AST >3X ULN and (TB >2X ULN or INR >1.5)
•
ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Step 4: Evaluate Data for Alternate Causes of Liver Signal: 
Contact the Medical Monitor to discuss the case and procedures to follow. 
An important purpose of close observation is to gather additional clinical information to seek 
other possible causes of the observed liver test abnormalities, such as one of the following 
common causes:  
•
Acute viral hepatitis. The usual onset of hepatocellular DILI is indistinguishable from
acute viral hepatitis A or B. Hepatitis C is much less often acute in its onset and tends to
be insidious, but it sometimes can resemble acute DILI. The presence of acute viral
hepatitis A, B, and C should be evaluated by serological markers. Viral hepatitis D
(requires concomitant hepatitis B infection) and E are relatively rare in the United States.
Hepatitis E is more common in developing countries, including Southeast Asia, and
should be considered in recent travelers to those countries and in patients in trials
conducted in those countries. Also rare are hepatocellular liver injuries caused by Epstein-
Barr virus, cytomegalovirus, herpes simplex virus, toxoplasmosis, varicella, and
parvovirus, although these infections are seen more typically in immuno-suppressed
individuals. Adolescent and young adult patients with possible DILI should be tested for
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Protocol No. LX4211.312 
Epstein-Barr virus. Hepatitis is common among transplant patients with cytomegalovirus 
disease.  
•
Alcoholic and autoimmune hepatitis. Acute alcoholic hepatitis usually is recurrent, with a
history of bingeing exposure to alcohol preceding episodes, and it has some characteristic
features, such as associated fever, leukocytosis, right upper quadrant pain and tenderness,
hepatomegaly, and AST >ALT, that may help distinguish it from other causes of liver
injury. Other features of the physical examination may include the presence of stigmata of
cirrhosis, such as spider nevi, palmar erythema, estrogenic changes in males, and
Dupuytren’s contractures. Alcoholic and autoimmune hepatitis should be assessed by
history, physical examination, and laboratory testing, including serologic testing (eg,
antinuclear or other antibodies).
•
Hepatobiliary disorders. Biliary tract disease, such as migration of gallstones or
intrahepatic lesions, more often causes cholestatic injury initially and should be
investigated with gall bladder and ductal imaging studies, especially if ALP is increased.
Malignant interruption of the biliary tract also should be considered.
•
NASH. NASH may be seen in obese, hyperlipoproteinemic, and/or diabetic patients and
may be associated with fluctuating aminotransferase levels, and hepatic and sometimes
splenic enlargement. It is sometimes associated with cirrhosis and portal hypertension.
•
Cardiovascular causes. Cardiovascular disease, especially right heart failure and
hypotension or any cause of impaired oxygenation of the liver, may cause acute
centrilobular hypoxic cell necrosis (ischemic hepatitis) with rapid and sometimes
spectacular increases of serum aminotransaminase (eg, aminotransaminase >10,000 U/L).
Cardiovascular dysfunction or impaired liver oxygenation, including hypotension or right
heart failure, should be assessed by physical examination and history.
•
Concomitant treatments. It is critical to discover concomitant treatments, including
exposure to nonprescription and dietary supplement products that might be responsible
for injury. Many people take multiple drugs, perhaps less often in controlled clinical trials
because of exclusion criteria, but subjects may not report taking disallowed drugs or other
agents. The possible exposure to occupational chemical agents may not be volunteered
unless subjects are specifically questioned.
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Protocol No. LX4211.312 
Step 5: Follow-Up to Resolution: 
Contact the Medical Monitor to discuss the case and procedures to follow. 
All trial subjects showing possible DILI should be followed until all abnormalities return to 
normal or to the baseline state. DILI may develop or progress even after the causative drug 
has been stopped. Results should be recorded on the case report form and in the database. 
Note that longer follow-up can sometimes reveal an off-drug repetition of what had appeared 
to be DILI, indicating that liver injury was related to underlying liver disease. 
Step 6: Rechallenge: 
Contact the Medical Monitor to discuss the case and procedures to follow. 
Whether or not to rechallenge a subject who showed mild DILI is a difficult decision. 
Reexposure may initiate a sometimes explosive and more severe reaction, as was observed 
with halothane several decades ago. Some cases of DILI show indicators of immunological 
reaction such as eosinophilia, rash, fever, or other symptoms or findings, and it is possible 
that such cases are more prone to recur with reexposure. Rechallenge may not be considered 
negative unless the subject is exposed to and tolerates the same dose and treatment duration 
that preceded the original reaction. A negative rechallenge does not necessarily allow a 
conclusion that the drug did not cause the injury. Most people can adapt to xenobiotic 
substances, including new drugs, and develop tolerance for them. This has been observed 
even for drugs that can cause severe injury, such as isoniazid. The large majority of people 
showing hepatocellular injury while taking isoniazid recover fully or recover while 
continuing to take the drug, and some, but not all, can resume or continue taking the drug 
without further adverse consequence. If such tolerance has developed, the use of rechallenge 
to verify drug causation would give a false negative result.  
Generally, rechallenge of subjects with significant aminotransferase elevations (>5X ULN) 
should not be attempted. If such subjects are rechallenged, they should be followed closely. 
Rechallenge can be considered if the subject has shown important benefit from the drug and 
other options are not available or if substantial accumulated data with the test drug do not 
show a potential for severe injury. The subject should be made aware of the potential risk, 
and consent to the rechallenge, and the Institutional Review Board consulted. 
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18.
Appendix F – Recommendations on Basic Genitourinary
Hygiene, Maintaining Hydration and Recognition of DKA and its
Management
Basic Genitourinary Hygiene: 
Patients with diabetes are at risk for developing genitourinary (GU) infections. The following 
guidelines should be communicated to females and uncircumcised males regarding GU 
infections.  
Patient communication cards will be printed with the following for patients with T1D: 
For females: 
“The following advice may be useful in helping you to keep your bladder and urethra free 
from infection: 
•
Go to the toilet as soon as you feel the need to urinate, rather than holding it in.
•
Wipe from front to back after going to the toilet.
•
Practice good hygiene by washing your genitals every day, and before having sex.
•
Empty your bladder after having sex.”
For uncircumcised males: 
“The following advice may be useful in helping you to keep the foreskin free from infection: 
•
Wash the end of your penis and foreskin with soap and water (do not let soap get in the
opening).
•
After your shower or bath, dry the end of your penis and foreskin properly and replace the
foreskin.
•
Also, when you urinate, slide the foreskin back enough so that urine does not get on the
foreskin-this helps to keep it clean.”
Maintaining Hydration: 
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are associated with osmotic diuresis 
and volume depletion, which may lead to dizziness or hypotension, especially in the elderly. 
All patients will be advised to maintain proper fluid intake and to consider increasing it if 
they sense greater thirst, more urine production, or if they feel dizzy or faint. 
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Patient communication cards will be printed with the following for patients with T1D: 
“The following advice may be useful in helping you to maintain proper hydration and prevent 
dehydration: 
•
Dehydration is when your body loses too much fluid, frequently due to diarrhea or
increased urination. The study drug may cause increased urination.
•
If you are thirsty, we recommend drinking water or non-caloric liquids.
•
Consider increasing the amount of fluids you drink if:
o
You sense greater thirst than usual
o
You have a dry mouth or cracked lips
o
You have a fever
o
You have diarrhea or vomiting
o
You urinate more frequently or in larger amounts than usual
o
You get up in the middle of the night to urinate (more than usual)
o
You feel dizzy or light-headed
o
You exercise, or when it is hot outside”
Recognition of Diabetic Ketoacidosis (DKA) and its Management: 
Patients with T1D are at risk for developing DKA. DKA is always preceded by ketosis. In 
many cases, ketosis can be treated and resolved with administration of additional rapid acting 
insulin and will therefore not progress to DKA. The following is applicable for all patients 
with T1D. Investigators and subjects should be aware of the fact that GI adverse events 
occurring with sotagliflozin may mask presenting symptoms of DKA, and that in some 
patients, alcohol could be a trigger for ketosis. Therefore, whenever Adverse Event data is 
collected or the patient reports an intercurrent illness (including infections), generalized 
weakness, increased weight loss, gastrointestinal symptoms including nausea, vomiting, or 
abdominal pain or other symptoms or signs that the Investigator believes may be consistent 
with DKA, then the Investigator will instruct the patient to measure ketones (urine ketones or  
or blood BHB) .  
If ketosis is present (moderate or higher for urine ketones or blood BHB level is >0.6 
mmol/L), then the patient will be asked to contact the Investigative site immediately. In this 
situation, the investigator should consider instructing the patient to take rapid acting insulin 
by syringe (not insulin pump) as well as eat carbohydrates in order to reverse the ketosis.  
After rechecking the ketones, the investigator should consider instructing the patient to take 
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Protocol No. LX4211.312 
additional doses of rapid acting insulin every 2 hours until elevated ketones are normalized.  
Because the amount of insulin needed to lower ketones will also lower blood glucose, it is 
necessary for the patient to increase carbohydrate intake. Typically this would be 15-30 
grams of carbohydrate each hour provided by a glucose containing sports drink or oral 
rehydration fluid. 
The site will evaluate if an assessment for metabolic acidosis is appropriate. If laboratory 
testing confirms presence of metabolic acidosis, then the “Possible DKA” eCRF will be 
completed. If nausea and vomiting are present and the patient is unable to keep liquids down, 
the patient should be evaluated in an Emergency Room. 
If a patient is scheduled for a procedure or surgery that requires withholding oral intake 
(NPO), it is recommended that study drug is held from the day prior to procedure or surgery 
and resumed the day after procedure or surgery is complete and patient is tolerating adequate 
oral intake.    
In some patients alcohol may trigger onset of ketosis. 
Patient communication cards will be printed with the following: 
“The following list may help you to recognize Diabetic Ketoacidosis (DKA). 
•
Inability to maintain oral intake
•
Generalized weakness
•
Abdominal (belly) pain
•
Increased weight loss
•
Fever
•
Frequent urination, including at night
•
Fruity-scented breath
•
Confusion
•
Acute illness
•
Consistently elevated blood glucose
•
Feeling very thirsty or drinking a lot
•
Nausea or vomiting
•
Having trouble thinking clearly or feeling tired
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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 measure your blood 
or urine ketone or blood BHB level. If the urine ketones are high (your study doctor may 
instruct you that this is a level of “moderate” or more than “moderate”) or blood BHB level is 
above 0.6 mmol/L, then contact your study site immediately for assistance with managing 
your diabetes.” 
In some patients alcohol use may lead to production of ketones by your body. 
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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19.
Appendix G – Measurement of Blood Pressure and Pulse Rate
Equipment 
1. Blood pressure measurements will be taken by an automated blood pressure monitor or a
manual sphygmomanometer.
2. Bladder Length – Should nearly or completely encircle the patient’s arm. For many
adults, the standard “adult” size bladder is not long enough and the “large” size bladder is
recommended.
3. Bladder Width – Should be at least 40% of the bladder length
Patient Factors 
Extraneous variables associated with the measurement of blood pressure (BP) should be 
minimized. These include: 
1. Food intake, caffeine-containing beverages, cigarette smoking, or strenuous exercise
within 2 hours prior to measurement
2. Full urinary bladder
3. The patient should not be allowed to talk while BP is being measured.
4. The patient should be placed in the examination room and the cuff should be placed on
the patient’s nondominant arm. The proper sized cuff should fit snugly with the lower
edge 2 to 3 cm above the antecubital fossa.
5. The patient should be allowed to sit quietly in a comfortably warm place (temperature
around 25°C or 77°F) for 5 minutes with the arm supported at heart level, preferably with
the cuff in place and with no restrictive clothing on the arm. The patient should be
encouraged not to tense his or her muscles.
Nondominant Arm 
The patient’s nondominant arm should be the arm declared by the patient as being 
nondominant. The nondominant arm should then be used for all seated BP measurements 
throughout the study. 
Measurement Technique 
Following the 5-minute rest period, 3 separate seated BPs should be measured with at least 
1 minute between BP measurements and with the cuff fully deflated between measurements. 
All BPs will be recorded in the patient’s electronic case report form (eCRF). The mean of the 
3 seated BPs will constitute the BP value for that visit.  
Three seated pulse rate measurements will be obtained. The mean of the 3 seated pulse rate 
measurements will constitute the pulse rate value for that visit. 
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20.
Appendix H – Satiety Visual Analog Scale
Patient Satiety Daily Diary (PSDD) 
INSTRUCTIONS 
Please complete this worksheet before your first meal of the day on each of the 14 diary days, 
±3 days.   
Please enter the date and time in the box below.   
Please enter today’s date below: 
Please enter the time: 
_______/_________/________  
_______:______ 
_____ ______ 
  Day        Month           Year 
  Hour    Minute        AM      PM 
Please clearly mark an ‘x’ in the box (
) that best describes your average level of hunger 
over the preceding 24 hours. 
Very Full 
No Particular 
Feeling 
Very Hungry 
▼ 
▼ 
▼ 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
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21.
Appendix I – Study Procedure by Visit
Screening Clinic Visit (Week -4 to -2) 
Patients will be screened for up to 2 weeks. 
When scheduling the visit, remind patients that they should fast and only drink water or 
noncaffeinated, zero-calorie beverages for at least 8 hours prior to the visit. If the patient is 
unable to fast as above, the scheduled “fasting” laboratory samples will still be collected, and 
the non-fasting status will be noted in the eCRF and the laboratory requisition form. 
Perform the following examinations and assessments and complete the appropriate eCRFs: 
1. Informed consent should be obtained prior to the start of any screening procedures
2. Review and verify eligibility based on inclusion/exclusion criteria
3. Obtain demographics
4. Obtain complete medical history
5. Register patient for Screening in IXRS
6. Perform complete physical examination
7. Measure weight and height
8. Measure vital signs (pulse rate, BP, respiratory rate, and temperature)
9. Obtain fingerstick glucose by meter.
10. Perform 12-lead ECG
11. Dispense Ketostix®.  Note:  After the initial dispensation of Ketostix at this visit,
additional Ketostix (or similar) will be dispensed on an as needed basis.
12. Provide patients with diet and exercise instructions
13. Record concomitant medications
14. Record SAEs
15. Obtain fasting venous blood samples for:
a.
A1C
b. FPG
c.
Serum chemistry
d. Blood BHB: point-of-care and central lab
e.
Hematology
f.
Lipid profile
g. Serum pregnancy test (females with childbearing potential only)
h. Follicle-stimulating hormone (females only)
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Protocol No. LX4211.312 
i.
Thyroid stimulating hormone (If abnormal, free thyroxine will be measured)
16. Obtain urine sample for:
a.
Urinalysis with microscopy
Run-in Period Clinic Visit (Week -2) 
All patients will have a 2-week single-blind, placebo Run-in Period prior to Randomization. 
Compliance will be assessed during the single-blind, placebo Run-in Period. Patients must 
have good compliance (≥80%) during the single-blind, placebo Run-in Period to be eligible 
for randomization. 
When scheduling the visit, remind patients that they should fast and only drink water or 
noncaffeinated, zero-calorie beverages for at least 8 hours prior to the visit. If the patient is 
unable to fast as above, the scheduled “fasting” laboratory samples will still be collected, and the 
non-fasting status will be noted in the eCRF.  
Perform the following examinations and assessments and complete the appropriate eCRFs: 
1. Assess inclusion/exclusion criteria
2. Obtain complete medical history
3. Register patient for Run-in in IXRS
4. Perform symptom-related brief physical examination
5. Measure weight
6. Measure vital signs (pulse rate, BP, respiratory rate, and temperature)
7. Obtain fingerstick glucose by meter
8. Dispense study diary, glucose testing strips, glucose meter, and remind the patient to
bring the study diary to each visit.
9. Dispense BHB meter and testing strips
10. Provide patients with diet and exercise instructions
11. Record concomitant medications
12. Record SAEs
13. Obtain fasting venous blood samples for:
a.
A1C
b. Blood BHB: point-of-care and central lab
14. Dispense single-blind placebo tablets
15. Provide patients with first dose of placebo tablets for Run-in Period
16. Remind patients to bring study diary to each visit
17. Remind patients to bring used bottles of placebo tablets to the next visit
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18. Patients participating in the satiety substudy:
a.
Dispense package of satiety daily diaries
b. Remind patients to complete the satiety daily diaries each day before the first
meal of the day, for the duration of the single-blind placebo Run-in Period
(14 days, ±3 days)
c.
Remind patients to bring the satiety daily diaries to the next visit (Day1,
Baseline)
24-Week Double-blind Treatment Period (Day 1 to Week 24) 
Following completion of the single-blind, placebo Run-in Period, eligible patients will enter 
the 24-week, double-blind Treatment Period.  
Note: If serum creatinine increases by ≥30% above the baseline value during the study, then 
the Investigator should consider assessment of:  volume status, diuretic dose, discontinuing 
NSAIDs, and other relevant testing including renal imaging techniques, as appropriate. 
Sodium-glucose cotransporter type 2 inhibitors are associated with osmotic diuresis and 
volume depletion, which may lead to dizziness or hypotension, especially in the elderly. All 
patients will be advised to maintain proper fluid intake and to consider increasing it if they 
sense greater thirst, more urine production, or if they feel dizzy or faint. 
Note: The collection of AEs begins after the first dose of double-blind study drug. 
24-Week Double-blind Treatment Clinic Visit (Day 1) 
When scheduling the visit, remind patients that they should fast and drink only water or 
noncaffeinated, zero-calorie beverages for at least 8 hours prior to the visit. If the patient is 
unable to fast as above, the scheduled “fasting” laboratory samples will still be collected, and the 
non-fasting status will be noted in the eCRF. 
Patients should also be reminded that they are NOT to take study drug on the day of clinic 
visits until instructed by site staff.  
Perform the following examinations and assessments and complete the appropriate eCRFs: 
1. Access inclusion/exclusion criteria
2. Randomization
3. Perform symptom-related brief physical examination
4. Measure weight
5. Measure vital signs (pulse rate, BP, respiratory rate, and temperature)
6. Perform 12-lead ECG
7. Obtain fingerstick glucose by meter to supplement review of SMBG and insulin data
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Protocol No. LX4211.312 
8. Review SMBG and make adjustment to insulin dose as needed to meet ADA/EASD
guidelines
9. Record insulin dose and SMBG on eCRF
10. Review study diary and record hypoglycemic symptoms or events
11. Dispense patient’s study diary, glucose testing strips, and BHB testing strips as needed
12. Patients participating in the satiety substudy:
a.
Collect satiety daily diaries
b. Review and record entries into the eCRF
13. Provide basic instruction on genitourinary hygiene, maintaining hydration, and
recognition and management of DKA
14. Assess compliance/collect study drug
15. Record concomitant medications
16. Record SAEs
17. Record AEs (after first dose of double-blind study drug)
18. Record EOSI
19. Obtain fasting venous blood samples for:
a.
A1C
b. FPG
c.
Serum chemistry
d. Blood BHB: point-of-care and central lab
e.
Hematology
f.
Lipid profile
g. Fasting blood for storage for future safety analysis
20. Obtain urine sample for:
a.
Urine pregnancy test (females with childbearing potential only)
b. Urine albumin, calcium, glucose, and creatinine
c.
Urinalysis with microscopy
d. Random urine for storage for future safety analysis
21. Dispense double-blind study drug
22. Provide patient with first dose of double-blind study drug and record dose time on eCRF
23. Remind patients to bring used bottles of double-blind study drug to the next visit
24-Week Double-blind Treatment Clinic Visits (Weeks 4, 8, and 16) 
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Protocol No. LX4211.312 
When scheduling each visit, remind patients that they should fast and drink only water or 
noncaffeinated, zero-calorie beverages for at least 8 hours prior to the visit. If the patient is 
unable to fast as above, the scheduled “fasting” laboratory samples will still be collected, and the 
non-fasting status will be noted in the eCRF. 
Patients should also be reminded that they are NOT to take study drug on the day of clinic 
visits until instructed by site staff.  
Perform the following examinations and assessments and complete the appropriate eCRFs: 
1. Symptom-related brief physical examination
2. Measure weight
3. Measure vital signs (pulse rate, BP, respiratory rate, and temperature)
4. Obtain fingerstick glucose by meter to supplement review of SMBG and insulin data
5. Review SMBG and make adjustment to insulin dose as needed to meet ADA/EASD
guidelines
6. Record insulin dose and SMBG on eCRF
7. Review study diary and record hypoglycemic symptoms or events
8. Dispense patient’s study diary, glucose testing strips, and BHB testing strips as needed
9. Provide basic instruction on genitourinary hygiene, maintaining hydration, and
recognition and management of DKA
10. Assess compliance/collect study drug
11. Record concomitant medications
12. Record SAE
13. Record AEs
14. Record EOSI
15. Obtain fasting venous blood samples for:
a.
A1C
b. FPG
c.
Serum chemistry
d. Hematology (Week 8 only)
e.
Lipid profile (Week 8 only)
f.
Blood BHB: point-of-care and central lab
16. Dispense double-blind study drug (Weeks 8 and 16 only)
17. Remind patients to bring used bottles of double-blind study drug to the next visit
18. Patients participating in the satiety substudy:
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Protocol No. LX4211.312 
a.
At the Week 16 visit, patients will be provided a packet including the satiety
daily diaries
b. Remind patients to complete the satiety daily diaries each day before the first
meal of the day, for the duration of Week 23 and Week 24 (14 days, ±3 days).
c.
At the beginning of Week 23, patients will receive a telephone call to
reminded them to start using the satiety daily diaries
d. Remind patients to bring the satiety daily diaries to the next visit (visit at
Week 24)
End of the 24-Week Double-blind Treatment Clinic Visit (Week 24) 
When scheduling the visit, remind patients that they should fast and drink only water or 
noncaffeinated, zero-calorie beverages for at least 8 hours prior to the visit. If the patient is 
unable to fast as above, the scheduled “fasting” laboratory samples will still be collected, and the 
non-fasting status will be noted in the eCRF. 
Perform the following examinations and assessments and complete the appropriate eCRFs: 
1. Perform complete physical examination
2. Measure weight
3. Measure vital signs (pulse rate, BP, respiratory rate, and temperature)
4. Perform 12-lead ECG
5. Obtain fingerstick glucose by meter to supplement review of SMBG and insulin data
6. Review SMBG and make adjustment to insulin dose as needed to meet ADA/EASD
guidelines
7. Record insulin does and SMBG data on eCRF
8. Review study diary and record hypoglycemic symptoms or events
9. Assess compliance/collect study drug
10. Record concomitant medications
11. Record SAEs
12. Record AEs
13. Record EOSI
14. Obtain fasting venous blood samples for:
a.
A1C
b. FPG
c.
Serum chemistry
d. Hematology
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Protocol No. LX4211.312 
e.
Lipid profile
f.
Blood BHB: point-of-care and central lab
g. Fasting blood for storage for future safety analysis
15. Obtain urine sample for:
a.
Urine pregnancy test (females with childbearing potential only)
b. Urinalysis with microscopy
c.
Urine albumin, calcium, glucose, and creatinine
d. Random urine for storage for future safety analysis
16. Patients participating on the satiety substudy:
a.
Collect all satiety daily diaries
b. Review and record entries on the eCRF
Follow-up Telephone Contact: 30 Days after End-of-Treatment 
At 30 days post-treatment, or 30 days following EW, perform the following assessments and 
complete the appropriate eCRFs: 
1. Telephone the patient to:
a.
Record SAEs
b. Follow-up any ongoing AEs
c.
Record EOSI
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22.
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