Efficacy, Safety, and Tolerability Study of Sotagliflozin... | NCT02421510

ID	Type	Description	Link
LX4211.310	Other Identifier	Lexicon Pharmaceuticals
2014-005153-39	EudraCT Number

Name	Class
Sanofi	INDUSTRY

Efficacy, Safety, and Tolerability Study of Sotagliflozin... | NCT02421510 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.	Drug: Placebo
Sotagliflozin 200 mg	Experimental	Sotagliflozin 200 milligram (mg) (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.	Drug: Sotagliflozin
Sotagliflozin 400 mg	Experimental	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.	Drug: Sotagliflozin

Name	Type	Description	Arm Group Labels	Other Names
Sotagliflozin	Drug	High dose Sotagliflozin, once daily, before the first meal of the day	Sotagliflozin 400 mg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline in A1C at Week 24	Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. Least square (LS) means were obtained from a mixed-effects model for repeated measures (MMRM) that included fixed, categorical effects of treatment, randomization strata of insulin delivery method (MDI, CSII), randomization strata of Week -2 A1C (<= 8.5%, >8.5%), time (study week), a treatment-by-time interaction, and baseline A1C-by-time interaction as a covariate. A negative change from baseline (a reduction of A1C value at Week 24) indicates an improvement.	Baseline to Week 24

Secondary Outcomes

Measure	Description	Time Frame
Percentage of Participants With A1C <7.0% at Week 24 and no Episode of Severe Hypoglycemia, and no Episode of Diabetic Ketoacidosis (DKA) From Baseline to Week 24	The composite endpoint included blood samples for the assessment of Hemoglobin A1C to determine the participants with a value <7.0% and a central blinded adjudication process to determine whether participants experienced either DKA or severe hypoglycemia. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis.

Contacts/Locations Module

Name	Affiliation	Role
Sangeeta Sawhney, M.D.	Lexicon Pharmaceuticals, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Lexicon Investigational Site		Linz		4021	Austria
Lexicon Investigational Site

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
32928957	Derived	Peters AL, McGuire DK, Danne T, Kushner JA, Rodbard HW, Dhatariya K, Sawhney S, Banks P, Jiang W, Davies MJ, Lapuerta P. Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies. Diabetes Care. 2020 Nov;43(11):2713-2720. doi: 10.2337/dc20-0924. Epub 2020 Sep 14.
32721228

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
FG001	Sotagliflozin 200 mg

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Comment	Reasons
Other		FG0004 subjects FG0012 subjects FG0023 subjects
Protocol Violation		FG0001 subjects FG0012 subjects FG0020 subjects
Death		FG0001 subjects FG0010 subjects FG0020 subjects
Noncompliance with study drug		FG0001 subjects FG0010 subjects FG0020 subjects
Physician Decision		FG0001 subjects FG0011 subjects FG0023 subjects
Adverse Event		FG0009 subjects FG00110 subjects FG00218 subjects
Pregnancy		FG0001 subjects FG0011 subjects FG0020 subjects
Withdrawal by Subject		FG00014 subjects FG00118 subjects FG00212 subjects
Lost to Follow-up		FG0001 subjects FG0011 subjects FG0020 subjects

Arm/Group Information

ID	Title	Description
BG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
BG001	Sotagliflozin 200 mg	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
BG002	Sotagliflozin 400 mg	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
BG003	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	BG00039.7± 13.42 BG00142.3± 13.59 BG00241.7± 13.23 BG003

Age, Customized

Count of Participants

Participants

Title

Denominators

Categories

Adults (18-64 years)

Title	Measurements
	BG000244 BG001252 BG002

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG000124 BG001122 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Insulin Delivery Method

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Continuous Subcutaneous Insulin Infusion (CSII)	BG00066 BG00168 BG002

Hemoglobin A1C (A1C)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
<= 8.5%	BG000200 BG001203 BG002

Hemoglobin A1C Value at Actual Week -2 Value

Some sites entered the wrong Week -2 A1C stratum for some participants at randomization. This value is based on the stratum, participants should have been categorized based on their actual Week -2 A1C value.

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
<= 8.5%	BG000202 BG001

Body Weight

Mean

Standard Deviation

Kilograms (kg)

Title

Denominators

Categories

Title	Measurements
	BG00081.08± 16.857 BG00181.93± 17.386 BG002

Duration of Diabetes

Mean

Standard Deviation

Years

Title

Denominators

Categories

Title	Measurements
	BG00018.1± 10.72 BG00118.2± 10.82 BG002

Daily Total Insulin Dose

Mean

Standard Deviation

International units per kilogram (IU/kg)

Title

Denominators

Categories

Title	Measurements
	BG0000.75± 0.295 BG0010.73± 0.277 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in A1C at Week 24

Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. Least square (LS) means were obtained from a mixed-effects model for repeated measures (MMRM) that included fixed, categorical effects of treatment, randomization strata of insulin delivery method (MDI, CSII), randomization strata of Week -2 A1C (<= 8.5%, >8.5%), time (study week), a treatment-by-time interaction, and baseline A1C-by-time interaction as a covariate. A negative change from baseline (a reduction of A1C value at Week 24) indicates an improvement.

Analysis included participants from the modified intent to treat (mITT) population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Posted

Least Squares Mean

Standard Error

Percentage of A1C

Baseline to Week 24

ID	Title	Description
OG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG001	Sotagliflozin 200 mg	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG002	Sotagliflozin 400 mg	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

Units	Counts
Participants	OG000239 OG001239 OG002241

Title

Denominators

Categories

Title	Measurements
	OG000-0.02± 0.044 OG001-0.39± 0.044 OG002-0.37± 0.043

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline A1C-by-time interaction as a covariate.	MMRM		< 0.001	Threshold for significance <= 0.05	Least squares mean difference	-0.37	Standard Error of the Mean	0.058	2-Sided	95	-0.48	-0.25			Sotagliflozin 200 mg versus Placebo		Superiority

Secondary

Percentage of Participants With A1C <7.0% at Week 24 and no Episode of Severe Hypoglycemia, and no Episode of Diabetic Ketoacidosis (DKA) From Baseline to Week 24

The composite endpoint included blood samples for the assessment of Hemoglobin A1C to determine the participants with a value <7.0% and a central blinded adjudication process to determine whether participants experienced either DKA or severe hypoglycemia. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis.

Analysis included participants from the mITT population.

Posted

Number

Percentage of participants

Baseline to Week 24

ID	Title	Description
OG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG001	Sotagliflozin 200 mg	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG002	Sotagliflozin 400 mg	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

Secondary

Change From Baseline in Body Weight at Week 24

Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model. A negative change from baseline indicates a loss in body weight from baseline to Week 24.

Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Posted

Least Squares Mean

Standard Error

Kilograms (kg)

Baseline to Week 24

ID	Title	Description
OG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG001	Sotagliflozin 200 mg	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG002	Sotagliflozin 400 mg	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

Secondary

Change From Baseline in Mean Daily Bolus Insulin Dose at Week 24

The mean bolus insulin dose in international units/day (IU/day) for Week 24 was the average over the 3 to 5 days prior to the Week 24 visit. The Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model including all available post baseline values. A negative change from baseline indicated a reduction in the amount of bolus insulin used and a positive change from baseline indicated an increase in the amount of bolus insulin used between baseline and Week 24.

Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Posted

Least Squares Mean

Standard Error

IU/day

Baseline to Week 24

ID	Title	Description
OG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG001	Sotagliflozin 200 mg	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG002	Sotagliflozin 400 mg

Secondary

Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24

The Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model including all available post baseline values. A negative change from baseline indicates a lower glucose level at Week 24 compared to baseline and a positive change from baseline indicates an increase in glucose level at Week 24 compared to baseline.

Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Posted

Least Squares Mean

Standard Error

Milligram per deciliter (mg/dL)

Baseline to Week 24

ID	Title	Description
OG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG001	Sotagliflozin 200 mg	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG002	Sotagliflozin 400 mg	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

Secondary

Change From Baseline in Diabetes Treatment Satisfaction Questionnaire (DTSQ) Score at Week 24

The DTSQ instrument contains 8 items assessing overall treatment satisfaction, treatment convenience and flexibility, satisfaction with understanding of diabetes, willingness to continue present treatment and to recommend it to others, and frequency of unacceptably high and unacceptably low blood glucose levels. 6 items (1, 4, 5, 6, 7 and 8) (excluding perceived hyperglycemia and hypoglycemia items) were scored using a 7- point scale where 0=very dissatisfied to 6= very satisfied for a total possible score of 0 (very dissatisfied) to 36 (very satisfied), where higher scores indicate higher satisfaction from treatment. Two items (Q2 and 3), which were not included, measured perceived hyperglycemia and hypoglycemia, respectively. The baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model including all available post baseline values. A positive change from baseline indicates improvement.

Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Posted

Least Squares Mean

Standard Error

Score on a scale

Baseline to Week 24

ID	Title	Description
OG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG001	Sotagliflozin 200 mg

Secondary

Change From Baseline in 2-Item Diabetes Distress Screen 2 (DDS2) Score at Week 24

DDS2 is a 2-item diabetes distress screening instrument where participants rated the degree to which the following items caused distress: (1) feeling overwhelmed by the demands of living with diabetes, and (2) feeling that I am often failing with my diabetes regimen using a 6-point scale: where 1=no distress to 6=severe distress for a total possible score of 2 to 12. LS means were obtained from MMRM model including all available post baseline values. A negative change from baseline indicates improvement.

Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Posted

Least Squares Mean

Standard Error

Score on a scale

Baseline to Week 24

ID	Title	Description
OG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG001	Sotagliflozin 200 mg	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG002	Sotagliflozin 400 mg

Secondary

Percent Change From Baseline in Body Weight at Week 24

Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. LS means were obtained from MMRM model. A negative percent change from baseline indicates a loss in body weight from baseline to Week 24.

Analysis included participants from the mITT population, including all available post baseline values. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Posted

Least Squares Mean

Standard Error

Percent change

Baseline to Week 24

ID	Title	Description
OG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG001	Sotagliflozin 200 mg	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.
OG002	Sotagliflozin 400 mg	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.	2	258	17	258	46	258
EG001	Sotagliflozin 200 mg	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.	0	261	26	261	52	261
EG002	Sotagliflozin 400 mg	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period.	0	263	21	263	64	263

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Breast cancer metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Chronic myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Clear cell renal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Invasive breast carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Lung neoplasm malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Abortion	Pregnancy, puerperium and perinatal conditions	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Impaired healing	General disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Pyrexia	General disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Ovarian cyst	Reproductive system and breast disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Vaginal haemorrhage	Reproductive system and breast disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Humerus fracture	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Ligament rupture	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Patella fracture	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Toxicity to various agents	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Ulna fracture	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Wrist fracture	Injury, poisoning and procedural complications	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0022 events2 affected263 at risk
Cardiac failure	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Cardiopulmonary failure	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Coronary artery disease	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Coronary artery occlusion	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Myocardial infarction	Cardiac disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Hypoglycaemic unconsciousness	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0003 events3 affected258 at risk EG0012 events2 affected261 at risk EG0021 events1 affected263 at risk
Hypoglycaemic seizure	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Ischaemic stroke	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Sciatica	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Syncope	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Vascular headache	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Cataract	Eye disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Angle closure glaucoma	Eye disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Vitreous haemorrhage	Eye disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Oedematous pancreatitis	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Prepyloric stenosis	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Cystitis noninfective	Renal and urinary disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Dermatitis atopic	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Diabetic foot	Skin and subcutaneous tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Musculoskeletal stiffness	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Rhabdomyolysis	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Goiter	Endocrine disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Diabetic ketoacidosis	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0017 events7 affected261 at risk EG00212 events12 affected263 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0012 events2 affected261 at risk EG0021 events1 affected263 at risk
Diabetes mellitus inadequate control	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Ketosis	Metabolism and nutrition disorders	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Gastroenteritis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0012 events2 affected261 at risk EG0021 events1 affected263 at risk
Pneumonia	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Cystitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0010 events0 affected261 at risk EG0021 events1 affected263 at risk
Ecthyma	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Erysipelas	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 events1 affected258 at risk EG0010 events0 affected261 at risk EG0020 events0 affected263 at risk
Gastroenteritis viral	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Pilonidal cyst	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Pyoderma	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk
Rotavirus infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 events0 affected258 at risk EG0011 events1 affected261 at risk EG0020 events0 affected263 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Diarrhoea	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment		EG00013 events10 affected258 at risk EG00118 events12 affected261 at risk EG00229 events20 affected263 at risk
Viral upper respiratory tract infection	Respiratory, thoracic and mediastinal disorders	MedDRA 20.0	Systematic Assessment		EG00058 events40 affected258 at risk EG00160 events44 affected261 at risk EG00270 events49 affected263 at risk

Ancestor Terms

ID	Term
D003920	Diabetes Mellitus
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D004700	Endocrine System Diseases
D001327	Autoimmune Diseases
D007154	Immune System Diseases

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	P-values were obtained from a Cochran-Mantel-Haenszel (CMH) test stratified by the different levels of the randomization stratification factors of insulin delivery method (MDI, CSII) and Week -2 A1C (<=8.5%, >8.5%). The 95% Confidence Limits (CL) were calculated using asymptotic Wald method. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis.	Cochran-Mantel-Haenszel		< 0.001	Threshold for significance <= 0.05	Percentage difference	16.3			2-Sided	95	9.17	23.43			Sotagliflozin 200 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
OG000 OG002	P-values were obtained from a CMH test stratified by the different levels of the randomization stratification factors of insulin delivery method (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%). The 95% CL were calculated using asymptotic Wald method.	Cochran-Mantel-Haenszel		< 0.001	Threshold for significance <= 0.05	Percentage difference	17.2			2-Sided	95	10.06	24.35			Sotagliflozin 400 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects.	MMRM		< 0.001	Threshold for significance <= 0.05	Least squares mean difference	-1.98	Standard Error of the Mean	0.276	2-Sided	95	-2.53	-1.44			Sotagliflozin 200 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
OG000 OG002	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects.	MMRM		< 0.001		Least squares mean difference	-2.58	Standard Error of the Mean	0.276	2-Sided	95	-3.12	-2.04			Sotagliflozin 400 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline mean daily bolus insulin dose-by-time interaction as a covariate.	MMRM		< 0.001	Threshold for significance <=0.05	Least squares mean difference	-3.2	Standard Error of the Mean	0.847	2-Sided	95	-4.86	-1.53			Sotagliflozin 200 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
OG000 OG002	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline mean daily bolus insulin dose-by-time interaction as a covariate.	MMRM		< 0.001	Threshold for significance <= 0.05	Least squares mean difference	-3.59	Standard Error of the Mean	0.845	2-Sided	95	-5.25	-1.93			Sotagliflozin 400 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline Fasting Plasma Glucose-by-time interaction as a covariate.	MMRM		< 0.001	Threshold for significance <= 0.05	Least squares mean difference	-21.6	Standard Error of the Mean	5.38	2-Sided	95	-32.2	-11			Sotagliflozin 200 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
OG000 OG002	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline Fasting Plasma Glucose-by-time interaction as a covariate.	MMRM		< 0.001	Threshold for significance <= 0.05	Least squares mean difference	-25.7	Standard Error of the Mean	5.37	2-Sided	95	-36.2	-15.1			Sotagliflozin 400 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline DTSQs total score-by-time interaction as a covariate.	MMRM		< 0.001	Threshold for significance <= 0.05.	Least squares mean difference	2	Standard Error of the Mean	0.37	2-Sided	95	1.3	2.7			Sotagliflozin 200 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
OG000 OG002	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline DTSQs total score-by-time interaction as a covariate.	MMRM		< 0.001	Threshold for significance <= 0.05.	Least squares mean difference	1.7	Standard Error of the Mean	0.36	2-Sided	95	1	2.4			Sotagliflozin 400 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<= 8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline DDS2 total score-by-time interaction as a covariate.	MMRM		0.025	Threshold for significance <= 0.05.	Least squares mean difference	-0.3	Standard Error of the Mean	0.15	2-Sided	95	-0.6	0			Sotagliflozin 200 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
OG000 OG002	LS means and p-values were obtained from MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week -2 A1C (<=8.5%, >8.5%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline DDS2 total score-by-time interaction as a covariate.	MMRM		0.003	Threshold for significance <= 0.05.	Least squares mean difference	-0.4	Standard Error of the Mean	0.15	2-Sided	95	-0.7	-0.2			Sotagliflozin 400 mg versus Placebo		Superiority	A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.