inTandem1: Efficacy, Safety, and Tolerability Study of Sotagliflozin as Adjunct Therapy in Adult Patients With Type 1 Diabetes Mellitus Who Have Inadequate Glycemic Control With Insulin Therapy

• Sponsor: Lexicon Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02384941
• Collaborator: Sanofi (Industry)
• Enrollment: 793
• Locations: 75
• Arms: 3
• Actual Duration (Months): 23.1
• Patients Per Site: 10.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This Phase 3 study was intended to demonstrate superiority of either sotagliflozin high dose or low dose versus placebo on glycosylated hemoglobin A1C (A1C) reduction at Week 24 when used as an adjunct in adult participants with type 1 diabetes mellitus (T1D) who have inadequate glycemic control with insulin therapy.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: Placebo; Drug: Sotagliflozin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 793 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of LX4211 as Adjunct Therapy in Adult Patients With Type 1 Diabetes Mellitus Who Have Inadequate Glycemic Control With Insulin Therapy
• Actual Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Feb 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Two placebo-matching sotagliflozin tables, orally for 24 weeks followed by a 28 week extension period.	Drug: Placebo; Placebo once daily, before first meal of the day.
Experimental: Sotagliflozin 200 milligrams (mg) Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), orally, for 24 weeks followed by a 28 week extension period.	Drug: Placebo; Placebo once daily, before first meal of the day.; Drug: Sotagliflozin; Sotagliflozin once daily, before first meal of the day.; Other Names: LX4211
Experimental: Sotagliflozin 400 mg Sotagliflozin 400 mg (two 200 mg tablets), orally, for 24 weeks followed by a 28 week extension period.	Drug: Sotagliflozin; Sotagliflozin once daily, before first meal of the day.; Other Names: LX4211

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in A1C at Week 24 [Baseline to 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 lower A1C value at Week 24) indicates an improvement.

Secondary Outcome Measures

1. Percentage of Participants With A1C <7.0% (at Week 24) and No Episode of Severe Hypoglycemia and No Episode of Diabetic Ketoacidosis (DKA) Upto Week 24 [Baseline to Week 24]

   Blood samples were collected for the assessment of Hemoglobin A1C to determine the participants with A1C value <7.0%. A central blinded adjudication process determined whether participants experienced either DKA or Severe Hypoglycemia. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis.

2. Absolute Change From Baseline in Body Weight at Week 24 [Baseline to 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.

3. Change From Baseline in Mean Daily Bolus Insulin Dose at Week 24 [Baseline to Week 24]

   The mean bolus insulin dose in international units per 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 between Baseline and Week 24.

4. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 [Baseline to 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 at Week 24 compared to baseline.

5. Change From Baseline in Diabetes Total Treatment Satisfaction Scores as Measured by Total Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) Scores at Week 24 [Baseline to Week 24]

   DTSQs is a diabetes-specific measure used to evaluate overall treatment satisfaction and perception of hyperglycemia and hypoglycemia events. It consists of 8 items and the response categories for all items were on a 7-point likert scale.The DTSQs response options ranged from 0 (very dissatisfied) to 6 (very satisfied). Responses to item 1, 4, 5, 6, 7 and 8 were summarized to determine the total treatment satisfaction score which ranged from 0 (very dissatisfied) to 36 (very satisfied), with a higher score corresponding to higher satisfaction . LS means were obtained from MMRM model including all available post baseline values. A positive change from baseline indicates improvement.

6. Change From Baseline in Diabetes Distress Scores as Measured by 2-item Diabetes Distress Screening Scale (DDS2) Scores at Week 24 [Baseline to Week 24]

   The DDS2 is a 2-item diabetes distress screening instrument where respondents rated, on a 6-point scale, 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 (not a problem) to 12 (very serious problem), with higher score corresponding to higher distress. LS means were obtained from MMRM model including all available post baseline values. A negative change from baseline indicates improvement.

7. Percent Change From Baseline in Body Weight at Week 24 [Baseline to 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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants had given written informed consent to participate in the study in accordance with local regulations.

• Adult participants 18 years and older with a diagnosis of T1D made at least 1 year prior to informed consent.

• Participants were being treated with insulin or insulin analog delivered. via continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI).

• Willing and able to perform self-monitored blood glucose (SMBG) and complete the study diary as required per protocol.

• At the Screening Visit, A1C must be between 7.0% to 11.0%.

• Females of childbearing potential must use an adequate method of contraception and have a negative pregnancy test .

Exclusion Criteria:

• Use of antidiabetic agent other than insulin or insulin analog at the time of screening.

• Use of sodium-glucose cotransporter (SGLT) inhibitors within 8 weeks prior to randomization.

• Chronic systemic corticosteroid use.

• Type 2 diabetes mellitus (T2D), or severely uncontrolled T1D as determined by the Investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lexicon Investigational Site	Birmingham	Alabama	United States	35294
2	Lexicon Investigational Site	Little Rock	Arkansas	United States	72205
3	Lexicon Investigational Site	Escondido	California	United States	92025
4	Lexicon Investigational Site	Greenbrae	California	United States	94904
5	Lexicon Investigational Site	Huntington Beach	California	United States	92648
6	Lexicon Investigational Site	La Jolla	California	United States	92037
7	Lexicon Investigational Site	Los Angeles	California	United States	90057-3550
8	Lexicon Investigational Site	Orange	California	United States	92868
9	Lexicon Investigational Site	Palm Springs	California	United States	92262
10	Lexicon Investigational Site	San Mateo	California	United States	94401
11	Lexicon Investigational Site	Tarzana	California	United States	91356
12	Lexicon Investigational Site	Tustin	California	United States	92780
13	Lexicon Investigational Site	Walnut Creek	California	United States	94598
14	Lexicon Investigational Site	Aurora	Colorado	United States	70045
15	Lexicon Investigational Site	Longmont	Colorado	United States	80501
16	Lexicon Investigational Site	Fleming Island	Florida	United States	32003
17	Lexicon Investigational Site	Jacksonville	Florida	United States	32204
18	Lexicon Investigational Site	Jacksonville	Florida	United States	32216
19	Lexicon Investigational Site	New Port Richey	Florida	United States	34652
20	Lexicon Investigational Site	Ormond Beach	Florida	United States	32174
21	Lexicon Investigational Site	West Palm Beach	Florida	United States	33401
22	Lexicon Investigational Site	Atlanta	Georgia	United States	30318
23	Lexicon Investigational Site	Lawrenceville	Georgia	United States	30046
24	Lexicon Investigational Site	Roswell	Georgia	United States	30076
25	Lexicon Investigational Site	Honolulu	Hawaii	United States	96814
26	Lexicon Investigational Site	Crystal Lake	Illinois	United States	60012
27	Lexicon Investigational Site	Elgin	Illinois	United States	60123
28	Lexicon Investigational Site	Springfield	Illinois	United States	62711
29	Lexicon Investigational Site	Topeka	Kansas	United States	66606
30	Lexicon Investigational Site	Lexington	Kentucky	United States	40503
31	Lexicon Investigational Site	Bangor	Maine	United States	04401
32	Lexicon Investigational Site	Baltimore	Maryland	United States	21204
33	Lexicon Investigational Site	Boston	Massachusetts	United States	02215
34	Lexicon Investigational Site	Detroit	Michigan	United States	46214
35	Lexicon Investigational Site	Chesterfield	Missouri	United States	63017
36	Lexicon Investigational Site	Saint Louis	Missouri	United States	63110
37	Lexicon Investigational Site	Omaha	Nebraska	United States	68131
38	Lexicon Investigational Site	Henderson	Nevada	United States	89052
39	Lexicon Investigational Site	Las Vegas	Nevada	United States	89148
40	Lexicon Investigational Site	Albany	New York	United States	12206
41	Lexicon Investigational Site	New York	New York	United States	10029
42	Lexicon Investigational Site	Asheville	North Carolina	United States	28803
43	Lexicon Investigational Site	Chapel Hill	North Carolina	United States	27517
44	Lexicon Investigational Site	Morehead City	North Carolina	United States	28557
45	Lexicon Investigational Site	Columbus	Ohio	United States	43201
46	Lexicon Investigational Site	Oklahoma City	Oklahoma	United States	73112
47	Lexicon Investigational Site	Portland	Oregon	United States	97239
48	Lexicon Investigational Site	Greer	South Carolina	United States	29651
49	Lexicon Investigational Site	Rapid City	South Dakota	United States	57701
50	Lexicon Investigational Site	Chattanooga	Tennessee	United States	37404
51	Lexicon Investigational Site	Chattanooga	Tennessee	United States	37411
52	Lexicon Investigational Site	Memphis	Tennessee	United States	38119
53	Lexicon Investigational Site	Austin	Texas	United States	78749
54	Lexicon Investigational Site	Dallas	Texas	United States	75230
55	Lexicon Investigational Site	Dallas	Texas	United States	75231
56	Lexicon Investigational Site	Dallas	Texas	United States	75246
57	Lexicon Investigational Site	Houston	Texas	United States	77079
58	Lexicon Investigational Site	Houston	Texas	United States	77095
59	Lexicon Investigational Site	San Antonio	Texas	United States	78258
60	Lexicon Investigational Site	Schertz	Texas	United States	78154
61	Lexicon Investigational Site	Chesapeake	Virginia	United States	23321
62	Lexicon Investigational Site	Renton	Washington	United States	98057
63	Lexicon Investigational Site	Seattle	Washington	United States	98105
64	Lexicon Investigational Site	Calgary	Alberta	Canada	T2H 2G4
65	Lexicon Investigational Site	Vancouver	British Columbia	Canada	V5Z 1M9
66	Lexicon Investigational Site	Winnipeg	Manitoba	Canada	R3C 0N2
67	Lexicon Investigational Site	Halifax	Nova Scotia	Canada	B3H 1V7
68	Lexicon Investigational Site	Barrie	Ontario	Canada	L4M 7G1
69	Lexicon Investigational Site	Hamilton	Ontario	Canada	L8N 3Z5
70	Lexicon Investigational Site	London	Ontario	Canada	N6A 4V2
71	Lexicon Investigational Site	Ottawa	Ontario	Canada	K1H 7W9
72	Lexicon Investigational Site	Thornhill	Ontario	Canada	L4J 8L7
73	Lexicon Investigational Site	Toronto	Ontario	Canada	M4G 3E8
74	Lexicon Investigational Site	Montreal	Quebec	Canada	H2W 1R7
75	Lexicon Investigational Site	St. Laurent	Quebec	Canada	H4T 1Z9

Sponsors and Collaborators

• Lexicon Pharmaceuticals
• Sanofi

Investigators

• Study Director: Sangeeta Sawhney, M.D., Lexicon Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Lexicon Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02384941
• Other Study ID Numbers: LX4211.1-309-T1DM
• First Posted: Mar 10, 2015
• Last Update Posted: Feb 12, 2020
• Last Verified: Feb 1, 2020

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; (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	The study was conducted at 75 study sites in 2 countries from March 2015 to February 2017.
Pre-assignment Detail	1099 participants were screened and 793 participants with Type 1 diabetes mellitus who had inadequate glycemic control with insulin therapy were randomized into three treatment groups: Placebo, Sotagliflozin 200 mg, Sotagliflozin 400 mg.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
Period Title: Overall Study
STARTED	268	263	262
COMPLETED	218	228	221
NOT COMPLETED	50	35	41

Baseline Characteristics

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg	Total
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.	Total of all reporting groups
Overall Participants	268	263	262	793
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.2 (12.72)	46.6 (13.48)	46.4 (13.12)	46.1 (13.11)
Sex: Female, Male (Count of Participants)
Female	131 48.9%	137 52.1%	142 54.2%	410 51.7%
Male	137 51.1%	126 47.9%	120 45.8%	383 48.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.4%	0 0%	1 0.1%
Asian	4 1.5%	4 1.5%	2 0.8%	10 1.3%
Native Hawaiian or Other Pacific Islander	2 0.7%	2 0.8%	0 0%	4 0.5%
Black or African American	9 3.4%	11 4.2%	8 3.1%	28 3.5%
White	244 91%	241 91.6%	246 93.9%	731 92.2%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	9 3.4%	4 1.5%	6 2.3%	19 2.4%
Hemoglobin A1C (A1C) (percentage of A1C) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of A1C]	7.54 (0.712)	7.61 (0.735)	7.56 (0.724)	7.57 (0.723)
Body Weight (kilograms (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms (kg)]	87.30 (17.709)	86.96 (18.539)	86.50 (18.004)	86.92 (18.065)
Baseline Daily Total Insulin Dose (International Unit per kilogram (IU/kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [International Unit per kilogram (IU/kg)]	0.74 (0.357)	0.72 (0.386)	0.72 (0.335)	0.73 (0.360)
Body Mass Index (BMI) (kilograms/square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms/square meter (kg/m^2)]	29.55 (5.188)	29.81 (5.686)	29.63 (5.297)	29.66 (5.387)
Duration of Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24.2 (12.38)	25.0 (13.15)	24.0 (12.88)	24.4 (12.80)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in A1C at Week 24
Description	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 lower A1C value at Week 24) indicates an improvement.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Modified intent to treat (mITT) analysis set included all randomly assigned participants who have taken at least 1 dose of study drug. Here, "Overall Number of Participants" Analyzed signified participants with available data for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
Measure Participants	246	245	242
Least Squares Mean (Standard Error) [percentage of A1C]	-0.07 (0.036)	-0.43 (0.036)	-0.48 (0.036)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Threshold for significance < 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.047
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Threshold for significance < 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.047
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With A1C <7.0% (at Week 24) and No Episode of Severe Hypoglycemia and No Episode of Diabetic Ketoacidosis (DKA) Upto Week 24
Description	Blood samples were collected for the assessment of Hemoglobin A1C to determine the participants with A1C value <7.0%. A central blinded adjudication process determined whether participants experienced either DKA or Severe Hypoglycemia. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Analysis performed on mITT analysis set.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
Measure Participants	268	263	262
Number [percentage of participants]	21.6 8.1%	33.5 12.7%	43.5 16.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	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 of each treatment comparison was statistically significant at 0.05 level.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	Threshold for significance < 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Percentage difference
	Estimated Value	11.8
	Confidence Interval	(2-Sided) 95%; 4.28 to 19.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Threshold for significance < 0.05.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Percentage difference
	Estimated Value	21.9
	Confidence Interval	(2-Sided) 95%; 14.10 to 29.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Absolute Change From Baseline in Body Weight at Week 24
Description	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.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Analysis performed on mITT analysis set. Here, "Overall Number of Participants Analyzed" signified participants with available data for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
Measure Participants	244	245	242
Least Squares Mean (Standard Error) [kilograms (kg)]	0.78 (0.187)	-1.57 (0.188)	-2.67 (0.188)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Threshold for significance < 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-2.35
	Confidence Interval	(2-Sided) 95%; -2.85 to -1.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.256
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Threshold for significance < 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-3.45
	Confidence Interval	(2-Sided) 95%; -3.95 to -2.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.256
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Mean Daily Bolus Insulin Dose at Week 24
Description	The mean bolus insulin dose in international units per 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 between Baseline and Week 24.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Analysis performed on mITT analysis set. Here, "Overall Number of Participants Analyzed" signified participants with available data for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
Measure Participants	241	242	242
Least Squares Mean (Standard Error) [IU/day]	-0.84 (0.688)	-2.33 (0.692)	-4.13 (0.692)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments	Threshold for significance < 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-1.50
	Confidence Interval	(2-Sided) 95%; -3.30 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.917
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Threshold for significance < 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-3.30
	Confidence Interval	(2-Sided) 95%; -5.09 to -1.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.916
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Description	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 at Week 24 compared to baseline.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Analysis performed on mITT analysis set. Here, "Overall Number of Participants Analyzed" signified participants with available data for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tables, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
Measure Participants	245	245	242
Least Squares Mean (Standard Error) [millimole per liter (mmol/L)]	0.21 (0.191)	-0.34 (0.192)	-0.78 (0.193)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Threshold for significance < 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.99
	Confidence Interval	(2-Sided) 95%; -1.50 to -0.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.260
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Diabetes Total Treatment Satisfaction Scores as Measured by Total Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) Scores at Week 24
Description	DTSQs is a diabetes-specific measure used to evaluate overall treatment satisfaction and perception of hyperglycemia and hypoglycemia events. It consists of 8 items and the response categories for all items were on a 7-point likert scale.The DTSQs response options ranged from 0 (very dissatisfied) to 6 (very satisfied). Responses to item 1, 4, 5, 6, 7 and 8 were summarized to determine the total treatment satisfaction score which ranged from 0 (very dissatisfied) to 36 (very satisfied), with a higher score corresponding to higher satisfaction . LS means were obtained from MMRM model including all available post baseline values. A positive change from baseline indicates improvement.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Analysis performed on mITT analysis set. Here, "Overall Number of Participants Analyzed" signified participants with available data for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
Measure Participants	237	240	233
Least Squares Mean (Standard Error) [units on a scale]	-0.4 (0.30)	2.1 (0.31)	2.1 (0.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Threshold for significance < 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; 1.8 to 3.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.40
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Diabetes Distress Scores as Measured by 2-item Diabetes Distress Screening Scale (DDS2) Scores at Week 24
Description	The DDS2 is a 2-item diabetes distress screening instrument where respondents rated, on a 6-point scale, 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 (not a problem) to 12 (very serious problem), with higher score corresponding to higher distress. LS means were obtained from MMRM model including all available post baseline values. A negative change from baseline indicates improvement.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Analysis performed on mITT analysis set. Here, "Overall Number of Participants Analyzed" signified participants with available data for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
Measure Participants	243	244	242
Least Squares Mean (Standard Error) [units on a scale]	0.3 (0.11)	-0.4 (0.11)	-0.5 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments	Threshold for significance < 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -1.0 to -0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.14
	Estimation Comments

8. Secondary Outcome

Title	Percent Change From Baseline in Body Weight at Week 24
Description	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.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Analysis performed on mITT analysis set. Here, "Overall Number of Participants Analyzed" signified participants with available data for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.	Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
Measure Participants	244	245	242
Least Squares Mean (Standard Error) [percent change]	0.92 (0.212)	-1.87 (0.213)	-3.10 (0.213)

Adverse Events

Time Frame	Baseline (Day 1) to 30 days after end of treatment or end of follow up (Up to 53 Weeks)
Adverse Event Reporting Description	Analysis performed on safety population which includes participants who received at least 1 dose of study drug.
Arm/Group Title	Placebo		Sotagliflozin 200 mg		Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period.		Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period.		Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period.
All Cause Mortality
	Placebo		Sotagliflozin 200 mg		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/268 (0.4%)		0/263 (0%)		0/262 (0%)
Serious Adverse Events
	Placebo		Sotagliflozin 200 mg		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/268 (7.5%)		27/263 (10.3%)		29/262 (11.1%)
Cardiac disorders
Acute myocardial infarction	2/268 (0.7%)	2	2/263 (0.8%)	2	0/262 (0%)	0
Angina unstable	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Aortic valve incompetence	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Atrial fibrillation	1/268 (0.4%)	1	1/263 (0.4%)	1	0/262 (0%)	0
Cardiac failure congestive	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Coronary artery disease	1/268 (0.4%)	1	1/263 (0.4%)	1	0/262 (0%)	0
Myocardial infarction	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Constipation	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Impaired gastric emptying	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Intestinal obstruction	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Small intestinal obstruction	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
General disorders
Chest pain	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Non-cardiac chest pain	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Hepatobiliary disorders
Cholecystitis	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Infections and infestations
Appendicitis	0/268 (0%)	0	1/263 (0.4%)	1	1/262 (0.4%)	1
Cellulitis	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Diverticulitis	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Endocarditis	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Gastroenteritis viral	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Meningitis viral	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Pneumonia	0/268 (0%)	0	1/263 (0.4%)	1	1/262 (0.4%)	1
Postoperative wound infection	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Sepsis	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Viral upper respiratory tract infection	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Injury, poisoning and procedural complications
Femoral neck fracture	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Hip fracture	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Limb injury	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Post procedural haemorrhage	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Investigations
Hepatic enzyme increased	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Metabolism and nutrition disorders
Acetonaemia	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Diabetic ketoacidosis	3/268 (1.1%)	3	12/263 (4.6%)	13	14/262 (5.3%)	14
Hypoglycaemia	5/268 (1.9%)	7	3/263 (1.1%)	5	4/262 (1.5%)	4
Musculoskeletal and connective tissue disorders
Back pain	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intraductal proliferative breast lesion	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Invasive ductal breast carcinoma	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Papillary thyroid cancer	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Parathyroid tumour benign	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Nervous system disorders
Hypoglycaemic seizure	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Hypoglycaemic unconsciousness	1/268 (0.4%)	3	0/263 (0%)	0	1/262 (0.4%)	1
Intracranial aneurysm	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Ischaemic stroke	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Transient ischaemic attack	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Psychiatric disorders
Mental status changes	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/268 (0%)	0	1/263 (0.4%)	1	0/262 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Skin and subcutaneous tissue disorders
Skin ulcer	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Surgical and medical procedures
Foot amputation	0/268 (0%)	0	0/263 (0%)	0	1/262 (0.4%)	1
Vascular disorders
Orthostatic hypotension	1/268 (0.4%)	1	0/263 (0%)	0	0/262 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Sotagliflozin 200 mg		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	129/268 (48.1%)		132/263 (50.2%)		130/262 (49.6%)
Gastrointestinal disorders
Diarrhoea	19/268 (7.1%)	21	22/263 (8.4%)	26	29/262 (11.1%)	41
Nausea	18/268 (6.7%)	21	17/263 (6.5%)	23	18/262 (6.9%)	24
Infections and infestations
Sinusitis	13/268 (4.9%)	16	14/263 (5.3%)	20	9/262 (3.4%)	10
Upper respiratory tract infection	43/268 (16%)	52	33/263 (12.5%)	38	33/262 (12.6%)	46
Urinary tract infection	18/268 (6.7%)	23	25/263 (9.5%)	34	9/262 (3.4%)	14
Viral upper respiratory tract infection	29/268 (10.8%)	33	34/263 (12.9%)	41	24/262 (9.2%)	29
Vulvovaginal mycotic infection	6/268 (2.2%)	8	13/263 (4.9%)	18	21/262 (8%)	23
Investigations
Blood ketone body increased	2/268 (0.7%)	2	10/263 (3.8%)	20	14/262 (5.3%)	19
Respiratory, thoracic and mediastinal disorders
Cough	10/268 (3.7%)	13	6/263 (2.3%)	6	18/262 (6.9%)	18

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.