inTandem3: A Phase 3 Study to Evaluate the Safety of Sotagliflozin in Patients With Type 1 Diabetes Who Have Inadequate Glycemic Control With Insulin Therapy Alone

• Sponsor: Lexicon Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02531035
• Collaborator: Sanofi (Industry)
• Enrollment: 1,405
• Locations: 135
• Arms: 2
• Actual Duration (Months): 19
• Patients Per Site: 10.4
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This Phase 3 study was designed to demonstrate the net benefit of sotagliflozin versus placebo in patients with Type 1 Diabetes (T1D).

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus (T1DM); High Level of Sugar (Glucose) in the Blood	Drug: Sotagliflozin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1405 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Net Clinical Benefit of Sotagliflozin as Adjunct to Insulin Therapy in Type 1 Diabetes
• Actual Study Start Date: Sep 1, 2015
• Actual Primary Completion Date: Apr 1, 2017
• Actual Study Completion Date: Apr 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.	Drug: Placebo; Placebo, once daily, before the first meal of the day
Experimental: Sotagliflozin 400 mg Sotagliflozin 400 milligram (mg) (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.	Drug: Sotagliflozin; Sotagliflozin, once daily, before the first meal of the day; Other Names: LX4211

Outcome Measures

Primary 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) After Randomization [Week 24]

   The primary composite endpoint included blood samples for the assessment of Hemoglobin A1C to determine the participants with a value <7.0%. A central blinded adjudication process determined whether participants experienced either DKA or Severe Hypoglycemia.

Secondary Outcome Measures

1. Change From Baseline in A1C [Baseline to Week 24]

   Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. Least Squares (LS) means were obtained from a mixed-effects model for repeated measures (MMRM) model including all available post baseline data. A negative change from Baseline (a lower AIC value at Week 24) indicates an improvement.

2. Absolute Change From Baseline in Body Weight [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 Systolic Blood Pressure (SBP) in the Subset of Participants With Baseline SBP >=130 Millimeter of Mercury (mmHg) [Baseline to Week 16]

   An automatic sphygmomanometer was used with instructions on blood pressure measurements to allow for standardization. Week 16 was used because the protocol required Investigators to keep participant's hypertensive medications stable between Baseline and Week 16, unless a change was required for safety reasons. Baseline was defined as the last value collected prior to the first does of double-blind study medication. LS means were obtained from MMRM model including all available post baseline values. A negative change indicates a decrease in SBP between Baseline and Week 16.

4. Percent Change From Baseline in Mean Daily Bolus Insulin Dose [Baseline to 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 percent change from Baseline indicated a reduction in the amount of bolus insulin used and a positive percent change from Baseline indicated an increase in the amount of bolus insulin used between Baseline and 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 T1DM made at least 1 year prior to informed consent

• Participants were being treated with insulin or insulin analog

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

• At the Screening Visit, A1C was between 7.0% to 11.0%

• Females of childbearing potential used an adequate method of contraception and had 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 screening

• Chronic systemic corticosteroid use

• Type 2 diabetes mellitus (T2DM), or severely uncontrolled T1D as determined by the Investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lexicon Investigational Site	Concord	California	United States	94520
2	Lexicon Investigational Site	Escondido	California	United States	92025
3	Lexicon Investigational Site	La Jolla	California	United States	92037
4	Lexicon Investigational Site	San Marcos	California	United States	94401
5	Lexicon Investigational Site	Ventura	California	United States	93003
6	Lexicon Investigational Site	Walnut Creek	California	United States	94598
7	Lexicon Investigational Site	Aurora	Colorado	United States	80045
8	Lexicon Investigational Site	New Haven	Connecticut	United States	06511
9	Lexicon Investigational Site	Orlando	Florida	United States	32804
10	Lexicon Investigational Site	West Palm Beach	Florida	United States	33401
11	Lexicon Investigational Site	Atlanta	Georgia	United States	30318
12	Lexicon Investigational Site	Macon	Georgia	United States	31210
13	Lexicon Investigational Site	Roswell	Georgia	United States	30076
14	Lexicon Investigational Site	New Orleans	Louisiana	United States	70112
15	Lexicon Investigational Site	Rockville	Maryland	United States	20852
16	Lexicon Investigational Site	Boston	Massachusetts	United States	02215
17	Lexicon Investigational Site	Bloomfield Hills	Michigan	United States	48302
18	Lexicon Investigational Site	Omaha	Nebraska	United States	68114
19	Lexicon Investigational Site	Las Vegas	Nevada	United States	89148
20	Lexicon Investigational Site	Albany	New York	United States	12206
21	Lexicon Investigational Site	Bronx	New York	United States	10467
22	Lexicon Investigational Site	Asheville	North Carolina	United States	28803
23	Lexicon Investigational Site	Chapel Hill	North Carolina	United States	27517
24	Lexicon Investigational Site	Greenville	North Carolina	United States	27834
25	Lexicon Investigational Site	Morehead City	North Carolina	United States	28557
26	Lexicon Investigational Site	Grand Forks	North Dakota	United States	58201
27	Lexicon Investigational Site	Bend	Oregon	United States	97701
28	Lexicon Investigational Site	Sioux Falls	South Dakota	United States	57104
29	Lexicon Investigational Site	Austin	Texas	United States	78731
30	Lexicon Investigational Site	San Antonio	Texas	United States	78229
31	Lexicon Investigational Site	Shavano Park	Texas	United States	78231
32	Lexicon Investigational Site	Salt Lake City	Utah	United States	84107
33	Lexicon Investigational Site	Seattle	Washington	United States	98105
34	Lexicon Investigational Site	Córdoba	Cordoba	Argentina	X5006IKK
35	Lexicon Investigational Site	Buenos Aires		Argentina	B7600FZN
36	Lexicon Investigational Site	Buenos Aires		Argentina	C1180AAX
37	Lexicon Investigational Site	Coffs Harbour	New South Wales	Australia	2450
38	Lexicon Investigational Site	Merewether	New South Wales	Australia	2291
39	Lexicon Investigational Site	St Leonards	New South Wales	Australia	2065
40	Lexicon Investigational Site	Wollongong	New South Wales	Australia	2500
41	Lexicon Investigational Site	Herston	Queensland	Australia	4029
42	Lexicon Investigational Site	Keswick	South Australia	Australia	5035
43	Lexicon Investigational Site	Box Hill	Victoria	Australia	3128
44	Lexicon Investigational Site	Fitzroy	Victoria	Australia	3065
45	Lexicon Investigational Site	Parkville	Victoria	Australia	3050
46	Lexicon Investigational Site	Aalst		Belgium	9300
47	Lexicon Investigational Site	Gent		Belgium	9000
48	Lexicon Investigational Site	Sint-Niklaas		Belgium	9100
49	Lexicon Investigational Site	Plovdiv		Bulgaria	4002
50	Lexicon Investigational Site	Ruse		Bulgaria	7003
51	Lexicon Investigational Site	Smolyan		Bulgaria	4700
52	Lexicon Investigational Site	Sofia		Bulgaria	1431
53	Lexicon Investigational Site	Sofia		Bulgaria	1750
54	Lexicon Investigational Site	Varna		Bulgaria	9000
55	Lexicon Investigational Site	Vancouver	British Columbia	Canada	V5Y 3W2
56	Lexicon Investigational Site	Halifax	Nova Scotia	Canada	B3H 2Y9
57	Lexicon Investigational Site	Barrie	Ontario	Canada	L4M 7G1
58	Lexicon Investigational Site	London	Ontario	Canada	N6A 4V2
59	Lexicon Investigational Site	Markham	Ontario	Canada	L6B 0P9
60	Lexicon Investigational Site	Oakville	Ontario	Canada	L6M 1M1
61	Lexicon Investigational Site	Thornhill	Ontario	Canada	L4J 8L7
62	Lexicon Investigational Site	Toronto	Ontario	Canada	M4G 3E8
63	Lexicon Investigational Site	Sherbrooke	Quebec	Canada	J1G 5K2
64	Lexicon Investigational Site	St. Laurent	Quebec	Canada	H4T 1Z9
65	Lexicon Investigational Site	Atlantico		Colombia	080020
66	Lexicon Investigational Site	Cundinamarca		Colombia	110221
67	Lexicon Investigational Site	Cundinamarca		Colombia	111211
68	Lexicon Investigational Site	Cundinamarca		Colombia	111311
69	Lexicon Investigational Site	Krnov		Czechia	794 01
70	Lexicon Investigational Site	Olomouc		Czechia	779 00
71	Lexicon Investigational Site	Ostrava		Czechia	702 00
72	Lexicon Investigational Site	Praha 10		Czechia	104 00
73	Lexicon Investigational Site	Praha 4		Czechia	149 00
74	Lexicon Investigational Site	Praha 5		Czechia	150 98
75	Lexicon Investigational Site	Corbeil-Essonnes		France	91106
76	Lexicon Investigational Site	Pierre-Bénite		France	69495
77	Lexicon Investigational Site	Mainz	Palatinate	Germany	55116
78	Lexicon Investigational Site	Sulzbach	Rosenberg Bavaria	Germany	92237
79	Lexicon Investigational Site	Münster	Westphalia	Germany	48153
80	Lexicon Investigational Site	Aschaffenburg		Germany	63739
81	Lexicon Investigational Site	Asslar		Germany	35614
82	Lexicon Investigational Site	Budapest		Hungary	1027
83	Lexicon Investigational Site	Budapest		Hungary	1033
84	Lexicon Investigational Site	Budapest		Hungary	1088
85	Lexicon Investigational Site	Budapest		Hungary	1213
86	Lexicon Investigational Site	Eger		Hungary	3300
87	Lexicon Investigational Site	Esztergom		Hungary	2500
88	Lexicon Investigational Site	Gyor		Hungary	9023
89	Lexicon Investigational Site	Sátoraljaújhely		Hungary	3980
90	Lexicon Investigational Site	Holon		Israel	58100
91	Lexicon Investigational Site	Petach-Tikvah		Israel	4920235
92	Lexicon Investigational Site	Petah Tikva		Israel	4941492
93	Lexicon Investigational Site	Rehovot		Israel	76100
94	Lexicon Investigational Site	Tel Hashomer		Israel	56261
95	Lexicon Investigational Site	Bologna		Italy	40138
96	Lexicon Investigational Site	Catania		Italy	95122
97	Lexicon Investigational Site	Catania		Italy	95123
98	Lexicon Investigational Site	Latina		Italy	04100
99	Lexicon Investigational Site	Milan		Italy	20132
100	Lexicon Investigational Site	Rome		Italy	00128
101	Lexicon Investigational Site	Epsom	Auckland	New Zealand	1051
102	Lexicon Investigational Site	Takapuna	Auckland	New Zealand	0620
103	Lexicon Investigational Site	Christchurch	Canterbury	New Zealand	8001
104	Lexicon Investigational Site	Dunedin	Otago	New Zealand	9016
105	Lexicon Investigational Site	Newtown	Wellington	New Zealand	6021
106	Lexicon Investigational Site	Christchurch		New Zealand	8011
107	Lexicon Investigational Site	Otahuhu		New Zealand	1640
108	Lexicon Investigational Site	Gdynia		Poland	81-338
109	Lexicon Investigational Site	Katowice		Poland	40-060
110	Lexicon Investigational Site	Katowice		Poland	40-954
111	Lexicon Investigational Site	Lublin		Poland	20-538
112	Lexicon Investigational Site	Warsaw		Poland	01-868
113	Lexicon Investigational Site	Warsaw		Poland	04-736
114	Lexicon Investigational Site	Warszawa		Poland	02-507
115	Lexicon Investigational Site	Bardejov		Slovakia	085 01
116	Lexicon Investigational Site	Bratislava		Slovakia	851 01
117	Lexicon Investigational Site	Bratislava		Slovakia	85101
118	Lexicon Investigational Site	Levice		Slovakia	934 01
119	Lexicon Investigational Site	Goodwood	Cape Town	South Africa	7460
120	Lexicon Investigational Site	Middelburg	Mpumalanga	South Africa	1055
121	Lexicon Investigational Site	Bloemfontein		South Africa	9300
122	Lexicon Investigational Site	Cape Town		South Africa	7130
123	Lexicon Investigational Site	Cape Town		South Africa	7580
124	Lexicon Investigational Site	Johannesburg		South Africa	2198
125	Lexicon Investigational Site	Port Elizabeth		South Africa	6045
126	Lexicon Investigational Site	Barcelona		Spain	08035
127	Lexicon Investigational Site	Barcelona		Spain	08036
128	Lexicon Investigational Site	Malaga		Spain	29006
129	Lexicon Investigational Site	Sevilla		Spain	41009
130	Lexicon Investigational Site	Sevilla		Spain	41071
131	Lexicon Investigational Site	Dundee	Scotland	United Kingdom	DD1 9SY
132	Lexicon Investigational Site	Blackburn		United Kingdom	BB2 3HH
133	Lexicon Investigational Site	Guildford		United Kingdom	GU2 7XX
134	Lexicon Investigational Site	Leicester		United Kingdom	LE5 4PW
135	Lexicon Investigational Site	Northampton		United Kingdom	NN1 5BD

Sponsors and Collaborators

• Lexicon Pharmaceuticals
• Sanofi

Investigators

• Study Director: Sangeeta Sawhney, MD, Lexicon Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Oct 16, 2015
• Statistical Analysis Plan - Mar 29, 2017

More Information

Publications

None provided.

• Responsible Party: Lexicon Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02531035
• Other Study ID Numbers: LX4211.1-312-T1DM; LX4211.312
• First Posted: Aug 21, 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	Participants took part in the study at 133 investigative sites across 19 countries: Poland, Slovakia, Spain, United Kingdom, Belgium, Bulgaria, Czech Republic, France, Germany, Hungary, Italy, Argentina, Australia, Canada, Colombia, Israel, New Zealand, South Africa and United States from 18 September 2015 to 18 April 2017.
Pre-assignment Detail	1405 participants with a diagnosis of Type 1 Diabetes were enrolled equally in 1 of 2 treatment groups: placebo or sotagliflozin 400 milligrams (mg).

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.	Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.
Period Title: Overall Study
STARTED	705	700
Treated	703	699
COMPLETED	624	605
NOT COMPLETED	81	95

Baseline Characteristics

Arm/Group Title	Placebo	Sotagliflozin 400 mg	Total
Arm/Group Description	Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.	Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.	Total of all reporting groups
Overall Participants	703	699	1402
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.4 (14.04)	43.3 (14.17)	42.8 (14.11)
Sex: Female, Male (Count of Participants)
Female	364 51.8%	341 48.8%	705 50.3%
Male	339 48.2%	358 51.2%	697 49.7%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	5 0.7%	1 0.1%	6 0.4%
Asian	5 0.7%	7 1%	12 0.9%
Black or African American	22 3.1%	24 3.4%	46 3.3%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.1%	1 0.1%
White	621 88.3%	619 88.6%	1240 88.4%
Other	37 5.3%	31 4.4%	68 4.9%
Not Applicable	13 1.8%	16 2.3%	29 2.1%
hemoglobin A1C (A1C) (percentage of A1C) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of A1C]	8.21 (0.921)	8.26 (0.965)	8.23 (0.943)
Body Weight (kilograms (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms (kg)]	81.55 (17.032)	82.40 (17.131)	81.97 (17.081)
Duration of Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	19.6 (12.07)	20.5 (12.37)	20.0 (12.22)
Baseline Total Daily Insulin (International units per kilogram (IU/kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [International units per kilogram (IU/kg)]	0.71 (0.291)	0.69 (0.276)	0.70 (0.284)
Body Mass Index (BMI) (kg/m^2 (kilogram(s)/square meter)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2 (kilogram(s)/square meter)]	28.10 (5.183)	28.29 (5.128)	28.19 (5.155)

Outcome Measures

1. Primary 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) After Randomization
Description	The primary composite endpoint included blood samples for the assessment of Hemoglobin A1C to determine the participants with a value <7.0%. A central blinded adjudication process determined whether participants experienced either DKA or Severe Hypoglycemia.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

The primary efficacy analyses were based on the modified Intent-to-Treat (mITT) population.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.	Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.
Measure Participants	703	699
Number [percentage of participants]	15.2 2.2%	28.6 4.1%

Statistical Analysis 1

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	P-values from Cochran-Mantel-Haenszel test stratified by different levels of stratification factors of BMI at Screening(<25 kg/m^2,>=25 kg/m^2),Week -2 A1C(<=9.0%, >9.0%),and using continuous subcutaneous insulin infusion(CSII) at Screening(yes,no).
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Percentage difference
	Estimated Value	13.4
	Confidence Interval	(2-Sided) 95%; 8.97 to 17.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in A1C
Description	Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. Least Squares (LS) means were obtained from a mixed-effects model for repeated measures (MMRM) model including all available post baseline data. A negative change from Baseline (a lower AIC value at Week 24) indicates an improvement.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Analyses included participants from the mITT population. Here, "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.	Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.
Measure Participants	628	627
Least Squares Mean (Standard Error) [percentage of A1c]	-0.33 (0.031)	-0.79 (0.032)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to hierarchical procedure. Post-Baseline LS means and p-values were obtained from MMRM model with treatment, randomization stratum of BMI at Screening (<25 kg/m^2, >=25 kg/m^2), randomization stratum of Week -2 A1C (<=9.0%, >9.0%), randomization stratum of use of CSII at Screening (yes, no), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline A1C-by-time interaction as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Absolute Change From Baseline in Body Weight
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

Analyses included participants from the mITT population. Here, "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.	Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.
Measure Participants	633	630
Least Squares Mean (Standard Error) [kilograms (kg)]	0.77 (0.122)	-2.21 (0.122)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to hierarchical procedure. Post-Baseline LS means and p-values were obtained from MMRM model with treatment, randomization stratum of BMI at Screening (<25 kg/m^2, >=25 kg/m^2), randomization stratum of Week -2 A1C (<=9%, >9%), randomization stratum of Use of CSII at Screening (Yes, No), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline weight-by-time interaction as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-2.98
	Confidence Interval	(2-Sided) 95%; -3.31 to -2.66
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP) in the Subset of Participants With Baseline SBP >=130 Millimeter of Mercury (mmHg)
Description	An automatic sphygmomanometer was used with instructions on blood pressure measurements to allow for standardization. Week 16 was used because the protocol required Investigators to keep participant's hypertensive medications stable between Baseline and Week 16, unless a change was required for safety reasons. Baseline was defined as the last value collected prior to the first does of double-blind study medication. LS means were obtained from MMRM model including all available post baseline values. A negative change indicates a decrease in SBP between Baseline and Week 16.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

Participants from mITT population and who had a Baseline SBP >= 130 mm Hg. Here, "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.	Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.
Measure Participants	192	186
Least Squares Mean (Standard Error) [mmHg]	-5.7 (0.90)	-9.2 (0.92)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to the hierarchical procedure. Post-Baseline LS means and p-values were obtained from MMRM model with treatment, randomization stratum of BMI at Screening (<25 kg/m2, >=25 kg/m2), randomization stratum of Week -2 A1C (<=9.0%, >9.0%), randomization stratum of use of CSII at Screening (yes, no), time (study week), and a treatment-by- time interaction as fixed categorical effects, and Baseline SBP-by-time interaction as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.002
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-3.5
	Confidence Interval	(2-Sided) 95%; -5.7 to -1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percent Change From Baseline in Mean Daily Bolus Insulin Dose
Description	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 percent change from Baseline indicated a reduction in the amount of bolus insulin used and a positive percent change from Baseline indicated an increase in the amount of bolus insulin used between Baseline and Week 24.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Analyses included participants from the mITT population. Here, "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.	Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.
Measure Participants	623	617
Least Squares Mean (Standard Error) [percent change in IU/day]	6.62 (2.272)	-5.71 (2.289)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Testing according to hierarchical procedure. Post-Baseline LS means and p-values were obtained from MMRM model with treatment, randomization stratum of BMI at Screening (<25 kg/m2, >=25 kg/m2), randomization stratum of Week -2 A1C (<=9.0%, >9.0%), randomization stratum of use of CSII at Screening (yes, no), time (study week), a treatment-by-time interaction as fixed categorical effects, and Baseline mean daily bolus insulin dose-by-time interaction as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-12.32
	Confidence Interval	(2-Sided) 95%; -18.17 to -6.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Baseline (Day 1) to 30 days after end of treatment (Up to 28 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 400 mg
Arm/Group Description	Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks.		Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks.
All Cause Mortality
	Placebo		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/703 (0%)		1/699 (0.1%)
Serious Adverse Events
	Placebo		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/703 (3.3%)		48/699 (6.9%)
Cardiac disorders
Coronary artery disease	0/703 (0%)	0	2/699 (0.3%)	2
Acute myocardial infarction	0/703 (0%)	0	1/699 (0.1%)	1
Atrial flutter	0/703 (0%)	0	1/699 (0.1%)	1
Pericarditis	0/703 (0%)	0	1/699 (0.1%)	1
Ear and labyrinth disorders
Aural polyp	0/703 (0%)	0	1/699 (0.1%)	1
Endocrine disorders
Hyperthyroidism	0/703 (0%)	0	1/699 (0.1%)	1
Eye disorders
Vitreous haemorrhage	1/703 (0.1%)	1	0/699 (0%)	0
Gastrointestinal disorders
Constipation	1/703 (0.1%)	1	0/699 (0%)	0
Dyspepsia	0/703 (0%)	0	1/699 (0.1%)	1
Gastritis	0/703 (0%)	0	1/699 (0.1%)	1
Mesenteric panniculitis	0/703 (0%)	0	1/699 (0.1%)	1
Nausea	0/703 (0%)	0	1/699 (0.1%)	1
General disorders
Chest pain	1/703 (0.1%)	1	0/699 (0%)	0
Infections and infestations
Appendicitis	1/703 (0.1%)	1	1/699 (0.1%)	1
Bursitis infective	1/703 (0.1%)	1	0/699 (0%)	0
Cellulitis	1/703 (0.1%)	1	0/699 (0%)	0
Gastrointestinal viral infection	0/703 (0%)	0	1/699 (0.1%)	1
Hepatitis B	0/703 (0%)	0	1/699 (0.1%)	1
Infective exacerbation of chronic obstructive airways disease	0/703 (0%)	0	1/699 (0.1%)	1
Osteomyelitis	1/703 (0.1%)	1	0/699 (0%)	0
Otitis media	1/703 (0.1%)	1	0/699 (0%)	0
Rectal abscess	0/703 (0%)	0	1/699 (0.1%)	1
Injury, poisoning and procedural complications
Humerus fracture	0/703 (0%)	0	1/699 (0.1%)	1
Thermal burn	0/703 (0%)	0	1/699 (0.1%)	3
Investigations
Blood ketone body increased	0/703 (0%)	0	1/699 (0.1%)	1
Urine ketone body present	1/703 (0.1%)	1	0/699 (0%)	0
Metabolism and nutrition disorders
Diabetic ketoacidosis	5/703 (0.7%)	5	22/699 (3.1%)	26
Hypoglycaemia	1/703 (0.1%)	1	3/699 (0.4%)	3
Hyperglycaemia	1/703 (0.1%)	1	0/699 (0%)	0
Lactic acidosis	0/703 (0%)	0	1/699 (0.1%)	1
Metabolic acidosis	0/703 (0%)	0	1/699 (0.1%)	1
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	0/703 (0%)	0	1/699 (0.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	1/703 (0.1%)	1	0/699 (0%)	0
Lung neoplasm malignant	1/703 (0.1%)	1	0/699 (0%)	0
Uterine leiomyoma	0/703 (0%)	0	1/699 (0.1%)	1
Nervous system disorders
Hypoglycaemic unconsciousness	4/703 (0.6%)	4	1/699 (0.1%)	1
Encephalomalacia	0/703 (0%)	0	1/699 (0.1%)	1
Hypoglycaemic coma	0/703 (0%)	0	1/699 (0.1%)	1
Hypoglycaemic seizure	0/703 (0%)	0	1/699 (0.1%)	1
Syncope	0/703 (0%)	0	1/699 (0.1%)	1
Transient ischaemic attack	1/703 (0.1%)	1	0/699 (0%)	0
Psychiatric disorders
Alcoholism	1/703 (0.1%)	1	0/699 (0%)	0
Anxiety	0/703 (0%)	0	1/699 (0.1%)	1
Completed suicide	0/703 (0%)	0	1/699 (0.1%)	1
Suicidal ideation	1/703 (0.1%)	1	0/699 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/703 (0%)	0	1/699 (0.1%)	1
Nephrolithiasis	0/703 (0%)	0	1/699 (0.1%)	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/703 (0.1%)	1	0/699 (0%)	0
Vascular disorders
Hypotension	0/703 (0%)	0	1/699 (0.1%)	1
Peripheral arterial occlusive disease	1/703 (0.1%)	1	0/699 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/703 (10%)		70/699 (10%)
Gastrointestinal disorders
Diarrhoea	17/703 (2.4%)	22	35/699 (5%)	41
Infections and infestations
Viral upper respiratory tract infection	55/703 (7.8%)	62	41/699 (5.9%)	46

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.