Type 2 Diabetes Mellitus
Conditions
Brief summary
The purpose of the study is to demonstrate the superiority of sotagliflozin versus placebo on hemoglobin A1c (HbA1c) reduction in participants with type 2 diabetes (T2D) who have inadequate glycemic control on a DPP4(i) with or without metformin.
Interventions
DRUGSotagliflozin
Sotagliflozin 400 mg was administered as two tablets, once daily before the first meal of the day.
DRUGEmpagliflozin
Empagliflozin 25 mg capsule was administered, once daily before the first meal of the day.
DRUGPlacebo
Placebo was administered as two tablets (identical to sotagliflozin in appearance), once daily before the first meal of the day.
Sponsors
Sanofi
Lexicon Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Participants with Type 2 Diabetes on Dipeptidyl peptidase-4 inhibitors(DPP4(i)) with or without metformin at a stable dose for at least 12 weeks prior to Screening Visit. Metformin dose will be ≥1500 mg per day (or maximum tolerated dose \[documented\]). DPP4(i) dose must be the appropriate dose as per local label. * Signed written informed consent.
Exclusion criteria
* Body mass index (BMI) ≤20 kg/m\^2 or \>45 kg/m\^2 at Screening. * Use of any antidiabetic drug other than DPP4 inhibitors and metformin within 12 weeks preceding the Screening Visit. * Participants who have previously participated in any clinical trial of sotagliflozin/LX4211. * Use of a selective sodium-glucose co-transporter type 2 (SGLT2) inhibitor (e.g., canagliflozin, dapagliflozin, or empagliflozin) within 3 months prior to the screening visit. * Participants with severe anemia, severe cardiovascular disease (including congestive heart failure New York Heart Association IV), respiratory, hepatic, neurological, psychiatric, or active malignant tumor or other major systemic disease or participants with a short life expectancy that, according to Investigator, will preclude their safe participation in this study, or will make the implementation of the protocol or interpretation of the study results difficult. * Current diagnosis of chronic hepatitis and/or other clinically active liver disease requiring treatment. * Participants with contraindication to empagliflozin as per local labelling. * Participants with contraindication to metformin as per local labelling. * Hemoglobin A1c \<7.0% or \>11.0% at Screening (central laboratory). * Fasting plasma glucose \>270 mg/dL (\>15.0 mmol/L) measured by the central laboratory at Screening (Visit 1), and confirmed by a repeat test (\>270 mg/dL \[\>15.0 mmol/L\]) before Randomization. * Previous use of any type of insulin for \>1 month (except for treatment of gestational diabetes). * Pregnant (confirmed by serum pregnancy test at Screening) or breast-feeding women. * Women of childbearing potential not willing to use highly effective method(s) of birth control during the study treatment period and follow-up period, or who are unwilling or unable to be tested for pregnancy during the study. * Mean of 3 separate blood pressure (BP) measurements \>180 mmHg (systolic blood pressure \[SBP\]) or \>100 mmHg (diastolic blood pressure \[DBP\]). * History of the hypertensive crisis resulting in emergency medical care within 12 weeks prior to Screening Visit. * Lower extremity complications (such as skin ulcers, infection, osteomyelitis, and gangrene) identified during the Screening period, and still requiring treatment at Randomization. * Laboratory findings with the central laboratory tests at Visit 1: * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 times the upper limit of the normal laboratory range (ULN); * Total bilirubin \>1.5 times the ULN (except in case of Gilbert's syndrome); * Neutrophils \<1 500/mm\^3 (or according to ethnic group) and/or platelets \<100 000/mm\^3; * Amylase and/or lipase \>3 times the ULN; * Participants with renal impairment as defined by the estimated glomerular filtration rate (eGFR) criterion that precludes initiation of empagliflozin as per the approved local label (eg, \<45 mL/min/1.73 m\^2 in US; \<60 mL/min/1.73 m\^2 in EU). * Secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome). * If the participant is on hypertensive medications, the antihypertensive has been changed in the 8 weeks prior to Screening (new drug or new dose). The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1c (HbA1c) % at Week 26 | Baseline, Week 26 | An analysis of covariance (ANCOVA) model was used for the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Sitting SBP at Week 12 for All Participants | Baseline, Week 12 | An ANCOVA model was used for the analysis. |
| Percentage of Participants With HbA1c <6.5% at Week 26 | Week 26 | — |
| Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 12 in Participants With Baseline SBP ≥ 130 mmHg | Baseline, Week 12 | An ANCOVA model was used for the analysis. |
| Percentage of Participants With HbA1c <7.0% at Week 26 | Week 26 | — |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | Baseline, Week 26 | An ANCOVA model was used for the analysis. |
| Change From Baseline in Body Weight at Week 26 | Baseline, Week 26 | An ANCOVA model was used for the analysis. |
| Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26 | Baseline, Week 26 | An ANCOVA model was used for the analysis. |
Countries
Bulgaria, Canada, Czechia, France, Italy, Latvia, Mexico, Russia, Slovakia, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 160 investigative sites in Bulgaria, Canada, Czechia, France, Italy, Latvia, Mexico, Russian Federation, Slovakia, Spain, United Kingdom, and the United States from 27 November 2017 to 16 May 2019.
Pre-assignment details
Participants with a diagnosis of Type 2 Diabetes Mellitus were enrolled in 1 of 3 treatment groups, Sotagliflozin, Empagliflozin, or Placebo. Participants were randomly assigned in the ratio of 2:2:1 to these reporting groups.
Participants by arm
| Arm | Count |
|---|---|
| Sotagliflozin 400 mg Following a 2-week run-in period, sotagliflozin 400 mg administered as two 200 mg tablets and one placebo capsule (identical to empagliflozin capsule in appearance), once daily before the first meal of the day for up to 26 weeks. | 307 |
| Empagliflozin 25 mg Following a 2-week run-in period, placebo matching sotagliflozin administered as two tablets (identical to sotagliflozin in appearance) and one capsule of empagliflozin 25 mg, once daily before the first meal of the day for up to 26 weeks. | 309 |
| Placebo Following a 2-week run-in period, placebo given as two placebo tablets (identical to sotagliflozin) and one placebo capsule (identical to empagliflozin) once daily before the first meal of the day for up to 26 weeks. | 154 |
| Total | 770 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 1 |
| Overall Study | At the subject's own request | 11 | 12 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Poor compliance to protocol | 1 | 0 | 0 |
| Overall Study | Reason not Specified | 1 | 3 | 0 |
Baseline characteristics
| Characteristic | Sotagliflozin 400 mg | Empagliflozin 25 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 58.9 years STANDARD_DEVIATION 9.7 | 59.7 years STANDARD_DEVIATION 9.6 | 59.8 years STANDARD_DEVIATION 9.6 | 59.4 years STANDARD_DEVIATION 9.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 56 Participants | 66 Participants | 33 Participants | 155 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 251 Participants | 243 Participants | 121 Participants | 615 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Hemoglobin A1c (HbA1c) | 8.23 percentage of HbA1c STANDARD_DEVIATION 0.84 | 8.21 percentage of HbA1c STANDARD_DEVIATION 0.93 | 8.21 percentage of HbA1c STANDARD_DEVIATION 0.93 | 8.22 percentage of HbA1c STANDARD_DEVIATION 0.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 18 Participants | 21 Participants | 8 Participants | 47 Participants |
| Race (NIH/OMB) Asian | 17 Participants | 11 Participants | 4 Participants | 32 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 13 Participants | 5 Participants | 31 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 6 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) White | 256 Participants | 257 Participants | 137 Participants | 650 Participants |
| Sex: Female, Male Female | 141 Participants | 158 Participants | 75 Participants | 374 Participants |
| Sex: Female, Male Male | 166 Participants | 151 Participants | 79 Participants | 396 Participants |
| Systolic Blood Pressure (SBP) | 134.55 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.56 | 131.64 millimeter of mercury (mmHg) STANDARD_DEVIATION 12.18 | 133.19 millimeter of mercury (mmHg) STANDARD_DEVIATION 12.53 | 133.11 millimeter of mercury (mmHg) STANDARD_DEVIATION 12.87 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 307 | 1 / 309 | 0 / 154 |
| other Total, other adverse events | 58 / 307 | 68 / 309 | 39 / 154 |
| serious Total, serious adverse events | 10 / 307 | 13 / 309 | 9 / 154 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) % at Week 26
An analysis of covariance (ANCOVA) model was used for the analysis.
Time frame: Baseline, Week 26
Population: Intent-to-treat (ITT) population included all randomized participants. Missing data was imputed using the retrieved dropouts imputation method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sotagliflozin 400 mg | Change From Baseline in Hemoglobin A1c (HbA1c) % at Week 26 | -0.7 percentage of HbA1c | Standard Error 0.1 |
| Empagliflozin 25 mg | Change From Baseline in Hemoglobin A1c (HbA1c) % at Week 26 | -0.8 percentage of HbA1c | Standard Error 0.1 |
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) % at Week 26 | -0.3 percentage of HbA1c | Standard Error 0.1 |
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and the country as fixed effects, and baseline HbA1c as a covariate.p-value: <0.000195% CI: [-0.62, -0.25]ANCOVA
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and the country as fixed effects, and baseline HbA1c as a covariate.p-value: 0.14595% CI: [-0.04, 0.28]ANCOVA
Secondary
Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26
An ANCOVA model was used for the analysis.
Time frame: Baseline, Week 26
Population: ITT population included all randomized participants. Missing data was imputed using washout imputation method under the missing not at random framework.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sotagliflozin 400 mg | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26 | -1.3 millimole per liter (mmol/L) | Standard Error 0.2 |
| Empagliflozin 25 mg | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26 | -1.2 millimole per liter (mmol/L) | Standard Error 0.9 |
| Placebo | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26 | -0.4 millimole per liter (mmol/L) | Standard Error 0.2 |
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and the country as fixed effects, and baseline 2-hour postprandial glucose as a covariate.p-value: <0.000195% CI: [-1.33, -0.5]ANCOVA
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), randomization strata of mean SBP (\<130, ≥ 130 mmHg) at screening, and the country as fixed effects, and baseline 2-hour postprandial glucose as a covariate.p-value: 0.839795% CI: [-0.37, 0.3]ANCOVA
Secondary
Change From Baseline in Body Weight at Week 26
An ANCOVA model was used for the analysis.
Time frame: Baseline, Week 26
Population: ITT population included all randomized participants. Missing data was imputed using the retrieved dropouts imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sotagliflozin 400 mg | Change From Baseline in Body Weight at Week 26 | -2.7 kilogram (kg) | Standard Error 0.3 |
| Empagliflozin 25 mg | Change From Baseline in Body Weight at Week 26 | -3.2 kilogram (kg) | Standard Error 0.3 |
| Placebo | Change From Baseline in Body Weight at Week 26 | -0.5 kilogram (kg) | Standard Error 0.3 |
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and the country as fixed effects, and baseline weight as a covariate.p-value: <0.000195% CI: [-2.95, -1.54]ANCOVA
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and the country as fixed effects, and baseline weight as a covariate.p-value: 0.140795% CI: [-0.17, 1.19]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
An ANCOVA model was used for the analysis.
Time frame: Baseline, Week 26
Population: ITT population included all randomized participants. Missing data was imputed using the retrieved dropouts imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sotagliflozin 400 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -1.3 mmol/L | Standard Error 0.2 |
| Empagliflozin 25 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -1.6 mmol/L | Standard Error 0.2 |
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -0.5 mmol/L | Standard Error 0.2 |
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and the country as fixed effects, and baseline fasting plasma glucose as a covariate.p-value: 0.000595% CI: [-1.25, -0.35]ANCOVA
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and the country as fixed effects, and baseline fasting plasma glucose as a covariate.p-value: 0.133995% CI: [-0.09, 0.7]ANCOVA
Secondary
Change From Baseline in Sitting SBP at Week 12 for All Participants
An ANCOVA model was used for the analysis.
Time frame: Baseline, Week 12
Population: ITT population included all randomized participants. Missing data was imputed using the retrieved dropouts imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sotagliflozin 400 mg | Change From Baseline in Sitting SBP at Week 12 for All Participants | -1.7 mmHg | Standard Error 0.8 |
| Empagliflozin 25 mg | Change From Baseline in Sitting SBP at Week 12 for All Participants | -2.8 mmHg | Standard Error 0.8 |
| Placebo | Change From Baseline in Sitting SBP at Week 12 for All Participants | -0.4 mmHg | Standard Error 1 |
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤ 8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No) and the country as fixed effects, and baseline SBP as a covariate.p-value: 0.032595% CI: [-3.89, -0.17]ANCOVA
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤ 8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No) and the country as fixed effects, and baseline SBP as a covariate.p-value: 0.156595% CI: [-0.42, 2.63]ANCOVA
Secondary
Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 12 in Participants With Baseline SBP ≥ 130 mmHg
An ANCOVA model was used for the analysis.
Time frame: Baseline, Week 12
Population: Participants from the ITT population, all randomized participants with data available at the given time point for analysis. Missing data was imputed using washout imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sotagliflozin 400 mg | Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 12 in Participants With Baseline SBP ≥ 130 mmHg | -5.6 mmHg | Standard Error 1.3 |
| Empagliflozin 25 mg | Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 12 in Participants With Baseline SBP ≥ 130 mmHg | -6.7 mmHg | Standard Error 1.3 |
| Placebo | Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Week 12 in Participants With Baseline SBP ≥ 130 mmHg | -3.5 mmHg | Standard Error 1.5 |
Comparison: The change from baseline to Week 12 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤ 8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No) and the country as fixed effects, and baseline SBP as a covariate.p-value: 0.152995% CI: [-4.87, 0.76]ANCOVA
Comparison: The change from baseline to Week 12 is analyzed using an ANCOVA model using multiple imputations to fill in missing data and is parameterized with treatment groups, randomization strata of HbA1c (≤ 8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No) and the country as fixed effects, and baseline SBP as a covariate.p-value: 0.337795% CI: [-1.21, 3.55]ANCOVA
Secondary
Percentage of Participants With HbA1c <6.5% at Week 26
Time frame: Week 26
Population: ITT population included all randomized participants. Missing data at Week 26 were assigned a status of nonresponder in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin 400 mg | Percentage of Participants With HbA1c <6.5% at Week 26 | 12.1 percentage of participants |
| Empagliflozin 25 mg | Percentage of Participants With HbA1c <6.5% at Week 26 | 11.7 percentage of participants |
| Placebo | Percentage of Participants With HbA1c <6.5% at Week 26 | 3.9 percentage of participants |
Comparison: The percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), and the randomization strata of mean SBP (\<130, ≥130 mmHg) at the screening.p-value: 0.004895% CI: [3.36, 12.89]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With HbA1c <7.0% at Week 26
Time frame: Week 26
Population: ITT population included all randomized participants. Missing data at Week 26 were assigned a status of nonresponder in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sotagliflozin 400 mg | Percentage of Participants With HbA1c <7.0% at Week 26 | 32.6 percentage of participants |
| Empagliflozin 25 mg | Percentage of Participants With HbA1c <7.0% at Week 26 | 35.6 percentage of participants |
| Placebo | Percentage of Participants With HbA1c <7.0% at Week 26 | 15.6 percentage of participants |
Comparison: The percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of metformin use at screening (Yes, No), and the randomization strata of mean SBP (\<130, ≥130 mmHg) at the screening.p-value: 0.000195% CI: [9.26, 24.52]Cochran-Mantel-Haenszel