Efficacy and Safety of Sotagliflozin Versus Placebo in Participants With Type 2 Diabetes Mellitus on Background of Sulfonylurea Alone or With Metformin

• Sponsor: Lexicon Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03066830
• Collaborator: Sanofi (Industry)
• Enrollment: 507
• Locations: 76
• Arms: 2
• Actual Duration (Months): 26.1
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Primary Objective:

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

Secondary Objectives:

• To compare Sotagliflozin 400 mg versus placebo based on:

• Change from baseline in fasting plasma glucose (FPG).

• Change from baseline in systolic blood pressure (SBP) for participants with baseline SBP ≥130 millimeter of mercury (mm Hg).

• Change from baseline in SBP for all participants.

• Change from baseline in body weight.

• Percentage of participants with HbA1c <6.5% and <7.0%.

• To evaluate the safety of Sotagliflozin 400 mg versus placebo throughout the 79-week trial.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Sotagliflozin (SAR439954); Drug: Placebo; Drug: Metformin; Drug: Sulfonylurea	Phase 3

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 507 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Sotagliflozin Added to a Sulfonylurea Alone or in Combination With Metformin in Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control on a Sulfonylurea Alone or With Metformin
• Actual Study Start Date: Feb 24, 2017
• Actual Primary Completion Date: Apr 17, 2019
• Actual Study Completion Date: Apr 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sotagliflozin 400 mg Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Drug: Sotagliflozin (SAR439954); Pharmaceutical form: tablet Route of administration: oral
Placebo Comparator: Placebo Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Drug: Placebo; Pharmaceutical form: tablet Route of administration: oral; Drug: Metformin; Pharmaceutical form: tablet Route of administration: oral; Drug: Sulfonylurea; Pharmaceutical form: tablet Route of administration: oral

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26 [Baseline to Week 26]

   Missing data are imputed using the retrieved dropouts imputation method. An analysis of covariance (ANCOVA) model was used for the analysis.

Secondary Outcome Measures

1. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 [Baseline to Week 26]

   Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis.

2. Change From Baseline in Systolic Blood Pressure (SBP) for Participants With Baseline SBP ≥130 mmHg [Baseline to Week 12]

   Missing data are imputed using the washout imputation method under the missing, not at random framework. An ANCOVA model was used for the analysis.

3. Change From Baseline in SBP at Week 12 for All Participants [Baseline to Week 12]

   Missing data are imputed using washout imputation method under the missing not at random framework. An ANCOVA model was used for the analysis.

4. Change From Baseline in Body Weight at Week 26 [Baseline to Week 26]

   Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis.

5. Percentage of Participants With HbA1c <6.5% at Week 26 [Week 26]

6. Percentage of Participants With HbA1c <7.0% at Week 26 [Week 26]

Other Outcome Measures

1. Percentage of Participants With Hypoglycemic Events [Up to 79 weeks in the treatment period]

   Percentage of participants with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia [typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤ 70 mg/dL (3.9 mmol/L)]; Severe [an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions] or documented symptomatic hypoglycemia [typical symptoms of hypoglycemia and plasma glucose ≤ 70 mg/dL]. Participants may be reported in more than one category.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria :

• Participants with T2D treated with a Sulfonylurea (≥half the maximum recommended dose as per local label or maximum tolerated dose [documented]) as monotherapy or in combination with Metformin (≥1500 mg per day or maximum tolerated dose [documented]) each at a stable dose for at least 12 weeks without a dose adjustment before screening.

• Signed written informed consent.

Exclusion criteria:

• At the time of screening, age <18 years or < legal age of majority, whichever is greater.

• Body Mass Index (BMI) ≤20 or >45 kilograms per meter square (kg/m^2) at Screening.

• Hemoglobin A1c (HbA1c) <7% or HbA1c >10% via central lab test at screening.

• Fasting plasma glucose (FPG) >15 mmol/L (270 mg/dL) measured by the central laboratory at screening (Visit 1), and confirmed (>15 mmol/L [270 mg/dL]) by a repeat test before randomization.

• Women of childbearing potential with no effective contraceptive method.

• Treated with an antidiabetic pharmacological regimen other than a Sulfonylurea at a stable dose with or without Metformin within 12 weeks preceding the screening visit.

• Previous insulin use >1 month (at any time, aside from treatment of gestational diabetes).

• History of prior gastric surgical procedure including gastric banding or inflammatory bowel disease within 3 years before the Screening Visit.

• History of diabetic ketoacidosis or nonketotic hyperosmolar coma within 12 weeks prior to the Screening Visit.

• History of severe hypoglycemia within 6 months prior to the Screening visit.

• Systolic blood pressure (SBP) >180 millimeter per mercury (mmHg) or diastolic blood pressure (DBP) >100 mmHg or history of hypertensive emergency.

• Aspartate aminotransferase and/or alanine aminotransferase: >3 times the upper limit of the normal laboratory range (ULN).

• Total bilirubin: >1.5 times ULN (except in case of Gilbert's syndrome).

• Use of systemic glucocorticoids (excluding topical or ophthalmic, application or inhaled forms) for more than 10 consecutive days within 90 days prior to the Screening Visit.

• Pregnancy, breastfeeding.

• Participants is unwilling to perform self-monitoring of blood glucose (SMBG), and complete the participant's diary as required per protocol.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 8403003	Litchfield Park	Arizona	United States	85340
2	Investigational Site Number 8403018	Peoria	Arizona	United States	85381
3	Investigational Site Number 8403009	Greenbrae	California	United States	94904
4	Investigational Site Number 8403012	Huntington Park	California	United States	90255
5	Investigational Site Number 8403019	Los Angeles	California	United States	90057
6	Investigational Site Number 8403034	Montclair	California	United States	91763
7	Investigational Site Number 8403016	Spring Valley	California	United States	91978
8	Investigational Site Number 8403014	Tustin	California	United States	92780
9	Investigational Site Number 8403001	Northglenn	Colorado	United States	80234
10	Investigational Site Number 8403029	Bradenton	Florida	United States	34201
11	Investigational Site Number 8403004	New Port Richey	Florida	United States	34652
12	Investigational Site Number 8403020	North Miami Beach	Florida	United States	33162
13	Investigational Site Number 8403026	Ocoee	Florida	United States	34761
14	Investigational Site Number 8403032	Orlando	Florida	United States	32810
15	Investigational Site Number 8403008	Palm Harbor	Florida	United States	34684
16	Investigational Site Number 8403006	Pembroke Pines	Florida	United States	33026
17	Investigational Site Number 8403013	Port Charlotte	Florida	United States	33952
18	Investigational Site Number 8403007	Nampa	Idaho	United States	83686
19	Investigational Site Number 8403011	Flint	Michigan	United States	48532
20	Investigational Site Number 8403025	Richfield	Minnesota	United States	55432
21	Investigational Site Number 8403021	Henderson	Nevada	United States	89014
22	Investigational Site Number 8403028	Greensboro	North Carolina	United States	27408
23	Investigational Site Number 8403015	Shelby	North Carolina	United States	28150
24	Investigational Site Number 8403033	Hatboro	Pennsylvania	United States	19040
25	Investigational Site Number 8403030	Kingsport	Tennessee	United States	37660
26	Investigational Site Number 8403002	Dallas	Texas	United States	75230
27	Investigational Site Number 8403022	Houston	Texas	United States	77081
28	Investigational Site Number 8403005	Burke	Virginia	United States	22015
29	Investigational Site Number 1003003	Plovdiv		Bulgaria	4002
30	Investigational Site Number 1003002	Ruse		Bulgaria	7002
31	Investigational Site Number 1003004	Sofia		Bulgaria	1784
32	Investigational Site Number 2333003	Parnu		Estonia	8001
33	Investigational Site Number 3483001	Balatonfüred		Hungary	8230
34	Investigational Site Number 3483007	Budapest		Hungary	1033
35	Investigational Site Number 3483008	Budapest		Hungary	1036
36	Investigational Site Number 3483010	Budapest		Hungary	1036
37	Investigational Site Number 3483004	Budapest		Hungary	1106
38	Investigational Site Number 3483006	Budapest		Hungary	1213
39	Investigational Site Number 3483011	Gyula		Hungary	5700
40	Investigational Site Number 3483009	Hatvan		Hungary	3000
41	Investigational Site Number 3483005	Kecskemet		Hungary	6000
42	Investigational Site Number 3483003	Pécs		Hungary	7623
43	Investigational Site Number 3483012	Zalaegerszeg		Hungary	8900
44	Investigational Site Number 4103001	Goyang-Si, Gyeonggi-Do		Korea, Republic of	10380
45	Investigational Site Number 4103011	Guri-Si, Gyeonggi-Do		Korea, Republic of	11923
46	Investigational Site Number 4103003	Seongnam-Si, Gyeonggi-Do		Korea, Republic of	13620
47	Investigational Site Number 4103007	Seoul		Korea, Republic of	06591
48	Investigational Site Number 4103006	Seoul		Korea, Republic of	1830
49	Investigational Site Number 4103010	Seoul		Korea, Republic of	3722
50	Investigational Site Number 4103005	Seoul		Korea, Republic of	7345
51	Investigational Site Number 4103009	Wonju-Si, Gangwon-Do		Korea, Republic of	26426
52	Investigational Site Number 6163005	Gdansk		Poland	80-382
53	Investigational Site Number 6163006	Gdynia		Poland	81-537
54	Investigational Site Number 6163003	Katowice		Poland	40-040
55	Investigational Site Number 6163002	Poznan		Poland	60702
56	Investigational Site Number 6163001	Warszawa		Poland	01-192
57	Investigational Site Number 6163004	Wroclaw		Poland	50-381
58	Investigational Site Number 6423004	Bucuresti		Romania
59	Investigational Site Number 6423002	Iasi		Romania	700732
60	Investigational Site Number 7033006	Bratislava		Slovakia	831 06
61	Investigational Site Number 7033001	Bratislava		Slovakia	851 01
62	Investigational Site Number 7033002	Bratislava		Slovakia	851 01
63	Investigational Site Number 7033004	Malacky		Slovakia	901 01
64	Investigational Site Number 7033003	Sturovo		Slovakia	943 01
65	Investigational Site Number 7033007	Trencin		Slovakia	911 01
66	Investigational Site Number 8043001	Kyiv		Ukraine	2002
67	Investigational Site Number 8043003	Kyiv		Ukraine	3037
68	Investigational Site Number 8043002	Kyiv		Ukraine	3049
69	Investigational Site Number 8263012	Birmingham		United Kingdom	B15 2SQ
70	Investigational Site Number 8263009	Cardiff		United Kingdom	CF15 9SS
71	Investigational Site Number 8263007	Glasgow		United Kingdom	G20 0SP
72	Investigational Site Number 8263008	Hexham		United Kingdom	NE46 1QJ
73	Investigational Site Number 8263003	Inverness		United Kingdom	IV2 3JH
74	Investigational Site Number 8263014	Liverpool		United Kingdom	L22 0LG
75	Investigational Site Number 8263011	Manchester		United Kingdom	M15 6SE
76	Investigational Site Number 8263010	Reading		United Kingdom	RG2 0TG

Sponsors and Collaborators

• Lexicon Pharmaceuticals
• Sanofi

Investigators

• Study Director: Suman Wason, Lexicon Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Dec 21, 2017
• Statistical Analysis Plan - Feb 20, 2020

More Information

Publications

None provided.

• Responsible Party: Lexicon Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03066830
• Other Study ID Numbers: EFC14835; 2016-002826-35; U1111-1186-2612
• First Posted: Feb 28, 2017
• Last Update Posted: May 11, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 76 investigative sites in the United States, Bulgaria, Estonia, Hungary, Republic of Korea, Poland, Romania, Slovakia, Ukraine, United Kingdom from 24 February 2017 to 30 April 2019.
Pre-assignment Detail	Participants with a diagnosis of Diabetes Mellitus were enrolled equally in 1 of 2 treatment groups, Sotagliflozin 400 milligrams (mg) and Placebo.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Period Title: Overall Study
STARTED	254	253
COMPLETED	221	231
NOT COMPLETED	33	22

Baseline Characteristics

Arm/Group Title	Placebo	Sotagliflozin 400 mg	Total
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Total of all reporting groups
Overall Participants	254	253	507
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.0 (9.9)	63.3 (8.8)	63.1 (9.3)
Sex: Female, Male (Count of Participants)
Female	124 48.8%	104 41.1%	228 45%
Male	130 51.2%	149 58.9%	279 55%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	43 16.9%	53 20.9%	96 18.9%
Not Hispanic or Latino	210 82.7%	198 78.3%	408 80.5%
Unknown or Not Reported	1 0.4%	2 0.8%	3 0.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	34 13.4%	28 11.1%	62 12.2%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.4%	1 0.2%
Black or African American	8 3.1%	8 3.2%	16 3.2%
White	211 83.1%	215 85%	426 84%
More than one race	1 0.4%	0 0%	1 0.2%
Unknown or Not Reported	0 0%	1 0.4%	1 0.2%
Hemoglobin A1c (HbA1c) (percentage of HbA1c) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of HbA1c]	8.18 (0.83)	8.20 (0.83)	8.19 (0.83)
Systolic Blood Pressure (SBP) (millimeter of mercury (mmHg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimeter of mercury (mmHg)]	133.08 (14.21)	134.30 (13.01)	133.69 (13.62)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26
Description	Missing data are imputed using the retrieved dropouts imputation method. An analysis of covariance (ANCOVA) model was used for the analysis.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all randomized participants.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Measure Participants	254	253
Least Squares Mean (Standard Error) [percentage HbA1c]	0.06 (0.082)	-0.70 (0.068)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	The change from baseline to Week 26 is analyzed using ANCOVA model with treatment groups randomization strata of HbA1c (≤8.5, >8.5%) at screening, randomization strata of Metformin use at screening, randomization strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Square (LS) Mean
	Estimated Value	-0.76
	Confidence Interval	(2-Sided) 95%; -0.946 to -0.574
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.095
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
Description	Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Measure Participants	254	253
Least Squares Mean (Standard Error) [millimole per liter (mmol/L)]	0.277 (0.2691)	-1.331 (0.1844)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	The change from baseline to Week 26 is analyzed using ANCOVA model with treatment groups randomization strata of HbA1c (≤8.5, >8.5%) at screening, randomization strata of Metformin use at screening, randomization strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline fasting plasma glucose as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-1.608
	Confidence Interval	(2-Sided) 95%; -2.1685 to -1.0471
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.286
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP) for Participants With Baseline SBP ≥130 mmHg
Description	Missing data are imputed using the washout imputation method under the missing, not at random framework. An ANCOVA model was used for the analysis.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population in participants with baseline SBP ≥130 mmHg.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Measure Participants	144	146
Least Squares Mean (Standard Error) [mmHg]	-3.58 (1.052)	-4.41 (1.061)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	The change from baseline to Week 12 is analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, >8.5%) at screening, randomization strata of Metformin use at screening and country as fixed effects, and baseline SBP as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5172
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-0.82
	Confidence Interval	(2-Sided) 95%; -3.316 to 1.669
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.272
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in SBP at Week 12 for All Participants
Description	Missing data are imputed using washout imputation method under the missing not at random framework. An ANCOVA model was used for the analysis.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants .

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Measure Participants	254	253
Least Squares Mean (Standard Deviation) [mmHg]	-0.69 (0.826)	-1.71 (0.830)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	The change from baseline to Week 12 is analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, >8.5%) at screening, randomization strata of Metformin use at screening, randomization strata of mean SBP (<130, ≥ 30 mmHg) at screening, and country as fixed effects, and baseline SBP as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2994
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-1.02
	Confidence Interval	(2-Sided) 95%; -2.946 to 0.907
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.983
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Body Weight at Week 26
Description	Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Measure Participants	254	253
Least Squares Mean (Standard Deviation) [kilogram (kg)]	-0.29 (0.206)	-1.70 (0.215)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	The change from baseline to Week 26 is analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, >8.5%) at screening, randomization strata of Metformin use at screening, randomization strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline weight as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-1.41
	Confidence Interval	(2-Sided) 95%; -1.932 to -0.884
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.267
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With HbA1c <6.5% at Week 26
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Measure Participants	254	253
Number [percentage of participants]	1.6 0.6%	8.3 3.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomization strata of HbA1c (≤ 8.5, >8.5%) at screening, randomization strata of mean SBP (<130,≥130 mmHg) at screening, randomization strata of metformin use at the screening. Missing data at Week 26 were assigned a status of non-responder in the analysis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Percentage difference
	Estimated Value	6.7
	Confidence Interval	(2-Sided) 95%; 3.03 to 10.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants With HbA1c <7.0% at Week 26
Time Frame	Week 26

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Measure Participants	254	253
Number [percentage of participants]	8.7 3.4%	26.1 10.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomization strata of HbA1c (≤8.5, >8.5%) at screening, randomization strata of mean SBP (<130, ≥130 mmHg) at screening, randomization strata of Metformin use at screening. Missing data at Week 26 were assigned a status of non-responder in the analysis.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Percentage difference
	Estimated Value	17.4
	Confidence Interval	(2-Sided) 95%; 11.16 to 23.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Other Pre-specified Outcome

Title	Percentage of Participants With Hypoglycemic Events
Description	Percentage of participants with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia [typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤ 70 mg/dL (3.9 mmol/L)]; Severe [an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions] or documented symptomatic hypoglycemia [typical symptoms of hypoglycemia and plasma glucose ≤ 70 mg/dL]. Participants may be reported in more than one category.
Time Frame	Up to 79 weeks in the treatment period

Outcome Measure Data

Analysis Population Description

Safety population was defined as all randomized participants who had received at least 1 dose of the double-blind investigational medicinal product.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.	Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 milligrams (mg), orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks.
Measure Participants	253	254
Any hypoglycemia	22.1 8.7%	19.7 7.8%
Documented symptomatic hypoglycemia	13.0 5.1%	11.4 4.5%
Severe or documented symptomatic hypoglycemia	13.0 5.1%	11.8 4.7%

Adverse Events

Time Frame	First dose of study drug to last dose of study drug (up to 82.9 weeks) + 2 weeks
Adverse Event Reporting Description	Safety population included all randomized participants who received at least one dose of double-blind investigational medicinal product (IMP). One participant randomized to Placebo who was dosed with Sotagliflozin 400 mg treatment during the study and summarized in the Sotagliflozin 400 mg arm in the safety population.
Arm/Group Title	Placebo		Sotagliflozin 400 mg
Arm/Group Description	Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks. One participant randomized to Placebo who was dosed with Sotagliflozin 400 mg treatment during the study is included in the Sotagliflozin 400 mg arm in the safety population.		Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 milligrams (mg), orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks. One participant randomized to Placebo who was dosed with Sotagliflozin 400 mg treatment during the study is included in the Sotagliflozin 400 mg arm in the safety population.
All Cause Mortality
	Placebo		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/253 (0.8%)		2/254 (0.8%)
Serious Adverse Events
	Placebo		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/253 (15.8%)		32/254 (12.6%)
Cardiac disorders
Acute left ventricular failure	0/253 (0%)		1/254 (0.4%)
Acute myocardial infarction	0/253 (0%)		2/254 (0.8%)
Angina pectoris	1/253 (0.4%)		2/254 (0.8%)
Angina unstable	1/253 (0.4%)		1/254 (0.4%)
Atrial fibrillation	1/253 (0.4%)		0/254 (0%)
Cardiac failure	1/253 (0.4%)		0/254 (0%)
Cardiac failure congestive	1/253 (0.4%)		0/254 (0%)
Coronary artery disease	3/253 (1.2%)		1/254 (0.4%)
Coronary artery occlusion	1/253 (0.4%)		0/254 (0%)
Myocardial ischaemia	1/253 (0.4%)		0/254 (0%)
Nodal arrhythmia	0/253 (0%)		1/254 (0.4%)
Silent myocardial infarction	0/253 (0%)		1/254 (0.4%)
Eye disorders
Cataract	1/253 (0.4%)		0/254 (0%)
Glaucoma	0/253 (0%)		1/254 (0.4%)
Retinal detachment	1/253 (0.4%)		0/254 (0%)
Visual impairment	0/253 (0%)		1/254 (0.4%)
Vitreous haemorrhage	0/253 (0%)		1/254 (0.4%)
Gastrointestinal disorders
Abdominal pain upper	1/253 (0.4%)		0/254 (0%)
Duodenal ulcer	1/253 (0.4%)		0/254 (0%)
Femoral hernia	0/253 (0%)		1/254 (0.4%)
Gastric ulcer	0/253 (0%)		1/254 (0.4%)
Pancreatitis chronic	0/253 (0%)		1/254 (0.4%)
General disorders
Multiple organ dysfunction syndrome	0/253 (0%)		1/254 (0.4%)
Non-cardiac chest pain	1/253 (0.4%)		0/254 (0%)
Pyrexia	0/253 (0%)		1/254 (0.4%)
Sudden cardiac death	0/253 (0%)		1/254 (0.4%)
Hepatobiliary disorders
Cholelithiasis	0/253 (0%)		1/254 (0.4%)
Infections and infestations
Diverticulitis	0/253 (0%)		1/254 (0.4%)
Gangrene	1/253 (0.4%)		0/254 (0%)
Pneumonia	1/253 (0.4%)		1/254 (0.4%)
Pulmonary tuberculosis	1/253 (0.4%)		0/254 (0%)
Septic shock	0/253 (0%)		1/254 (0.4%)
Urinary tract infection	0/253 (0%)		1/254 (0.4%)
Injury, poisoning and procedural complications
Anastomotic ulcer	1/253 (0.4%)		0/254 (0%)
Ankle fracture	1/253 (0.4%)		1/254 (0.4%)
Clavicle fracture	0/253 (0%)		1/254 (0.4%)
Fall	0/253 (0%)		1/254 (0.4%)
Joint injury	0/253 (0%)		1/254 (0.4%)
Rib fracture	0/253 (0%)		1/254 (0.4%)
Subdural haematoma	1/253 (0.4%)		0/254 (0%)
Thermal burn	1/253 (0.4%)		1/254 (0.4%)
Metabolism and nutrition disorders
Diabetes mellitus	1/253 (0.4%)		0/254 (0%)
Diabetic ketoacidosis	1/253 (0.4%)		0/254 (0%)
Diabetic metabolic decompensation	1/253 (0.4%)		0/254 (0%)
Hyperglycaemia	3/253 (1.2%)		1/254 (0.4%)
Hypoglycaemia	1/253 (0.4%)		1/254 (0.4%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/253 (0%)		1/254 (0.4%)
Osteoarthritis	0/253 (0%)		1/254 (0.4%)
Rhabdomyolysis	1/253 (0.4%)		0/254 (0%)
Spinal stenosis	0/253 (0%)		1/254 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	2/253 (0.8%)		0/254 (0%)
Invasive ductal breast carcinoma	1/253 (0.4%)		0/254 (0%)
Malignant melanoma	1/253 (0.4%)		0/254 (0%)
Pancreatic carcinoma	1/253 (0.4%)		0/254 (0%)
Papillary thyroid cancer	1/253 (0.4%)		0/254 (0%)
Pituitary tumour benign	0/253 (0%)		1/254 (0.4%)
Prostate cancer recurrent	1/253 (0.4%)		0/254 (0%)
Rectal adenocarcinoma	0/253 (0%)		1/254 (0.4%)
Renal cancer	1/253 (0.4%)		0/254 (0%)
Squamous cell carcinoma of skin	0/253 (0%)		1/254 (0.4%)
Nervous system disorders
Carotid artery stenosis	0/253 (0%)		1/254 (0.4%)
Cerebrovascular accident	2/253 (0.8%)		0/254 (0%)
Ischaemic stroke	1/253 (0.4%)		2/254 (0.8%)
Nerve compression	1/253 (0.4%)		0/254 (0%)
Partial seizures with secondary generalisation	1/253 (0.4%)		0/254 (0%)
Post stroke epilepsy	1/253 (0.4%)		0/254 (0%)
Sciatica	1/253 (0.4%)		0/254 (0%)
Syncope	0/253 (0%)		1/254 (0.4%)
Renal and urinary disorders
Acute kidney injury	1/253 (0.4%)		0/254 (0%)
Ureterolithiasis	1/253 (0.4%)		0/254 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/253 (0%)		1/254 (0.4%)
Endometrial hyperplasia	1/253 (0.4%)		0/254 (0%)
Uterine prolapse	0/253 (0%)		1/254 (0.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	2/253 (0.8%)		0/254 (0%)
Pulmonary oedema	0/253 (0%)		1/254 (0.4%)
Skin and subcutaneous tissue disorders
Dermatitis contact	1/253 (0.4%)		0/254 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	90/253 (35.6%)		71/254 (28%)
Gastrointestinal disorders
Diarrhoea	11/253 (4.3%)		22/254 (8.7%)
Infections and infestations
Nasopharyngitis	23/253 (9.1%)		21/254 (8.3%)
Upper respiratory tract infection	19/253 (7.5%)		9/254 (3.5%)
Urinary tract infection	8/253 (3.2%)		19/254 (7.5%)
Metabolism and nutrition disorders
Hyperglycaemia	48/253 (19%)		14/254 (5.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Institution must provide any proposed publication or presentation to Sponsor for Sponsor's review, comment and approval at least thirty (30) days prior to the proposed submission for publication date or the proposed presentation date. Sponsor shall have the right to have deleted from the final version of the publication any confidential information, proprietary information, or patentable subject matter.