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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 (inTandem3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02531035
Recruitment Status : Completed
First Posted : August 21, 2015
Results First Posted : November 19, 2019
Last Update Posted : February 12, 2020
Sponsor:
Collaborator:
Sanofi
Information provided by (Responsible Party):
Lexicon Pharmaceuticals

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Type 1 Diabetes Mellitus (T1DM)
High Level of Sugar (Glucose) in the Blood
Interventions Drug: Sotagliflozin
Drug: Placebo
Enrollment 1405
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 Details 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
Hide 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
Reason Not Completed
Death             0             1
Protocol Violation             1             1
Noncompliance with study drug             8             3
Physician Decision             1             0
Adverse Event             16             45
Other             3             2
Withdrawal by Subject             42             32
Lost to Follow-up             8             10
Randomized, not treated             2             1
Arm/Group Title Placebo Sotagliflozin 400 mg Total
Hide 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 Number of Baseline Participants 703 699 1402
Hide Baseline Analysis Population Description
Analysis was performed on modified Intent-to-treat (mITT) population included all randomly assigned participants who had taken at least 1 dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 703 participants 699 participants 1402 participants
42.4  (14.04) 43.3  (14.17) 42.8  (14.11)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 703 participants 699 participants 1402 participants
Female
364
  51.8%
341
  48.8%
705
  50.3%
Male
339
  48.2%
358
  51.2%
697
  49.7%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
American Indian or Alaska Native Number Analyzed 703 participants 699 participants 1402 participants
5
   0.7%
1
   0.1%
6
   0.4%
Asian Number Analyzed 703 participants 699 participants 1402 participants
5
   0.7%
7
   1.0%
12
   0.9%
Black or African American Number Analyzed 703 participants 699 participants 1402 participants
22
   3.1%
24
   3.4%
46
   3.3%
Native Hawaiian or Other Pacific Islander Number Analyzed 703 participants 699 participants 1402 participants
0
   0.0%
1
   0.1%
1
   0.1%
White Number Analyzed 703 participants 699 participants 1402 participants
621
  88.3%
619
  88.6%
1240
  88.4%
Other Number Analyzed 703 participants 699 participants 1402 participants
37
   5.3%
31
   4.4%
68
   4.9%
Not Applicable Number Analyzed 703 participants 699 participants 1402 participants
13
   1.8%
16
   2.3%
29
   2.1%
hemoglobin A1C (A1C)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percentage of A1C
Number Analyzed 701 participants 699 participants 1400 participants
8.21  (0.921) 8.26  (0.965) 8.23  (0.943)
[1]
Measure Analysis Population Description: A1C is the measurement of hemoglobin A1C. Data is available for 701 participants in the Placebo arm and 699 participants in the Sotagliflozin arm.
Body Weight  
Mean (Standard Deviation)
Unit of measure:  Kilograms (kg)
Number Analyzed 703 participants 699 participants 1402 participants
81.55  (17.032) 82.40  (17.131) 81.97  (17.081)
Duration of Diabetes  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 703 participants 699 participants 1402 participants
19.6  (12.07) 20.5  (12.37) 20.0  (12.22)
Baseline Total Daily Insulin  
Mean (Standard Deviation)
Unit of measure:  International units per kilogram (IU/kg)
Number Analyzed 703 participants 699 participants 1402 participants
0.71  (0.291) 0.69  (0.276) 0.70  (0.284)
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2 (kilogram(s)/square meter)
Number Analyzed 703 participants 699 participants 1402 participants
28.10  (5.183) 28.29  (5.128) 28.19  (5.155)
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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
The primary efficacy analyses were based on the modified Intent-to-Treat (mITT) population.
Arm/Group Title Placebo Sotagliflozin 400 mg
Hide 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.
Overall Number of Participants Analyzed 703 699
Measure Type: Number
Unit of Measure: percentage of participants
15.2 28.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Sotagliflozin 400 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
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 [Not Specified]
Method of Estimation Estimation Parameter Percentage difference
Estimated Value 13.4
Confidence Interval (2-Sided) 95%
8.97 to 17.81
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in A1C
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 628 627
Least Squares Mean (Standard Error)
Unit of Measure: percentage of A1c
-0.33  (0.031) -0.79  (0.032)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value -0.46
Confidence Interval (2-Sided) 95%
-0.54 to -0.38
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Absolute Change From Baseline in Body Weight
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 633 630
Least Squares Mean (Standard Error)
Unit of Measure: kilograms (kg)
0.77  (0.122) -2.21  (0.122)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -2.98
Confidence Interval (2-Sided) 95%
-3.31 to -2.66
Estimation Comments [Not Specified]
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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 192 186
Least Squares Mean (Standard Error)
Unit of Measure: mmHg
-5.7  (0.90) -9.2  (0.92)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value = 0.002
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Squares Mean Difference
Estimated Value -3.5
Confidence Interval (2-Sided) 95%
-5.7 to -1.3
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percent Change From Baseline in Mean Daily Bolus Insulin Dose
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 623 617
Least Squares Mean (Standard Error)
Unit of Measure: percent change in IU/day
6.62  (2.272) -5.71  (2.289)
Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method MMRM
Comments [Not Specified]
Method of Estimation Estimation Parameter Least squares mean difference
Estimated Value -12.32
Confidence Interval (2-Sided) 95%
-18.17 to -6.48
Estimation Comments [Not Specified]
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
Hide 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 (%) Affected / at Risk (%)
Total   0/703 (0.00%)      1/699 (0.14%)    
Hide Serious Adverse Events
Placebo Sotagliflozin 400 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   23/703 (3.27%)      48/699 (6.87%)    
Cardiac disorders     
Coronary artery disease  1  0/703 (0.00%)  0 2/699 (0.29%)  2
Acute myocardial infarction  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Atrial flutter  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Pericarditis  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Ear and labyrinth disorders     
Aural polyp  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Endocrine disorders     
Hyperthyroidism  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Eye disorders     
Vitreous haemorrhage  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Gastrointestinal disorders     
Constipation  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Dyspepsia  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Gastritis  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Mesenteric panniculitis  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Nausea  1  0/703 (0.00%)  0 1/699 (0.14%)  1
General disorders     
Chest pain  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Infections and infestations     
Appendicitis  1  1/703 (0.14%)  1 1/699 (0.14%)  1
Bursitis infective  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Cellulitis  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Gastrointestinal viral infection  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Hepatitis B  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Infective exacerbation of chronic obstructive airways disease  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Osteomyelitis  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Otitis media  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Rectal abscess  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Injury, poisoning and procedural complications     
Humerus fracture  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Thermal burn  1  0/703 (0.00%)  0 1/699 (0.14%)  3
Investigations     
Blood ketone body increased  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Urine ketone body present  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Metabolism and nutrition disorders     
Diabetic ketoacidosis  1  5/703 (0.71%)  5 22/699 (3.15%)  26
Hypoglycaemia  1  1/703 (0.14%)  1 3/699 (0.43%)  3
Hyperglycaemia  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Lactic acidosis  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Metabolic acidosis  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Musculoskeletal and connective tissue disorders     
Rhabdomyolysis  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Invasive ductal breast carcinoma  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Lung neoplasm malignant  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Uterine leiomyoma  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Nervous system disorders     
Hypoglycaemic unconsciousness  1  4/703 (0.57%)  4 1/699 (0.14%)  1
Encephalomalacia  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Hypoglycaemic coma  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Hypoglycaemic seizure  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Syncope  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Transient ischaemic attack  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Psychiatric disorders     
Alcoholism  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Anxiety  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Completed suicide  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Suicidal ideation  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Renal and urinary disorders     
Acute kidney injury  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Nephrolithiasis  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Respiratory, thoracic and mediastinal disorders     
Oropharyngeal pain  1  1/703 (0.14%)  1 0/699 (0.00%)  0
Vascular disorders     
Hypotension  1  0/703 (0.00%)  0 1/699 (0.14%)  1
Peripheral arterial occlusive disease  1  1/703 (0.14%)  1 0/699 (0.00%)  0
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Sotagliflozin 400 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   70/703 (9.96%)      70/699 (10.01%)    
Gastrointestinal disorders     
Diarrhoea  1  17/703 (2.42%)  22 35/699 (5.01%)  41
Infections and infestations     
Viral upper respiratory tract infection  1  55/703 (7.82%)  62 41/699 (5.87%)  46
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Trial Transparency Team
Organization: Sanofi
Phone: 800-633-1610 ext 1#
EMail: Contact-US@sanofi.com
Layout table for additonal information
Responsible Party: Lexicon Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02531035    
Other Study ID Numbers: LX4211.1-312-T1DM
LX4211.312 ( Other Identifier: Lexicon Pharmaceuticals, Inc. )
First Submitted: August 20, 2015
First Posted: August 21, 2015
Results First Submitted: October 8, 2019
Results First Posted: November 19, 2019
Last Update Posted: February 12, 2020