Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: 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 with metformin. Secondary Objectives: * To compare Sotagliflozin versus placebo for. * Change from baseline in 2-hour postprandial glucose (PPG) following a mixed meal. * Change from baseline in fasting plasma glucose (FPG). * Change from Baseline in systolic blood pressure (SBP) for participants with baseline SBP ≥130 millimeter of mercury (mmHg). * Change from baseline in SBP for all participants. * Change from baseline in body weight. * Proportion of participants with HbA1c \<6.5% and \<7.0%. * To evaluate the safety of Sotagliflozin versus placebo.
Detailed description
The duration of the study period is up to 87 weeks, including a Screening Period consisting of a Screening phase of up to 2 weeks and a 2 week single blind Run-in phase, a 26 week double-blind Core Treatment Period, a 53-week double-blind Extension Period, a 4 week post treatment Follow-up period to collect safety information.
Interventions
DRUGPlacebo
Pharmaceutical form: tablet. Route of administration: oral.
DRUGMetformin
Pharmaceutical form: tablet. Route of administration: oral.
Pharmaceutical form: tablet. Route of administration: oral.
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 currently treated with diet and exercise and on metformin at a stable dose ≥1500 milligrams per day (mg/day) for at least 12 weeks. However, participants on metformin at a dose \<1500 mg/day at the time of enrollment (stable dose for at least 12 weeks before enrollment) may be eligible for screening if documentation of lack of tolerance of a metformin dose ≥1500 mg/day can be provided. * Signed written informed consent.
Exclusion criteria
* Age \<18 years at Screening or \< legal age of majority, whichever is greater. * Type 1 diabetes mellitus. * Body Mass Index (BMI) ≤20 or \>45 kilograms per meter square (kg/m\^2) at Screening * Hemoglobin A1c \<7% or \>10% via central laboratory test at screening. * Fasting plasma glucose (FPG) \>15 millimole per liter (mmol/L) (270 milligrams per deciliter \[mg/dL\]) measured by the central laboratory at screening (Visit 1) and confirmed by a repeat test (\>15 mmol/L \[270 mg/dL\]) before randomization. * Women of childbearing potential not willing to use highly effective method(s) of birth control or who are unwilling or unable to be tested for pregnancy during the study. * Treated with an antidiabetic pharmacological regimen other than metformin ≥1500 mg per day (or maximum tolerated dose) within the 12 weeks preceding the Screening Visit. * Previous use of any types of insulin for \>1 month (at any time, aside from pregnancy for treatment of gestational diabetes). * History of prior gastric surgical procedure, including gastric banding, within 3 years before the Screening Visit. * History of diabetic ketoacidosis or nonketotic hyperosmolar coma within 12 weeks prior to the Screening Visit. * Mean of 3 separate blood pressure measurements \>180 mmHg (SBP) or \>100 mmHg (diastolic blood pressure \[DBP\]). * History of hypertensive urgency or emergency within 12 weeks prior to Screening. * Participants with severe anemia, severe cardiovascular (including congestive heart failure New York Heart Association \[NYHA\] IV), respiratory, hepatic, neurological, psychiatric, or active malignant tumor or other major systemic disease or participants with short life expectancy making implementation of the protocol or interpretation of the study results difficult. * Aspartate aminotransferase and/or alanine aminotransferase: \>3 times the upper limit of the normal laboratory range. * Total bilirubin: \>1.5 times the upper limit of the normal laboratory range (except in case of Gilbert's syndrome). * Use of systemic glucocorticoids (excluding topical or ophthalmic application or inhaled forms) for more than 10 consecutive days within 90 days prior to the Screening Visit. * Participants who has taken other investigational drugs or prohibited therapy for this study within 12 weeks or 5 half-lives from screening or randomization, whichever is longer. * Pregnant (confirmed by serum pregnancy test at Screening) or breastfeeding women. * Participants is unwilling or unable to perform self-monitoring of blood glucose (SMBG), complete the participants diary, or comply with study visits and other study procedures as required per protocol. * Contraindication to metformin as per local labelling. 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 and Week 26 | An analysis of covariance (ANCOVA) model was used for the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26 | Baseline and Week 26 | An ANCOVA model was used for the analysis. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | Baseline and Week 26 | An ANCOVA model was used for the analysis. |
| Change From Baseline in Body Weight at Week 26 | Baseline and Week 26 | An ANCOVA model was used for the analysis. |
| Change From Baseline in SBP at Week 12 for All Participants | Baseline and Week 12 | An ANCOVA model was used for the analysis. |
| Percentage of Participants With HbA1c <6.5% at Week 26 | Week 26 | — |
| Percentage of Participants With HbA1c <7.0% at Week 26 | Week 26 | — |
| Change From Baseline in Systolic Blood Pressure (SBP) at Week 12 in Participants With Baseline SBP ≥130 mmHg | Baseline and Week 12 | An ANCOVA model was used for the analysis. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hypoglycemic Events | Up to 79 weeks in the treatment period | Percentage of participants with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia \[typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤70 mg/dL (3.9 mmol/L)\]; Severe \[an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions\] or documented symptomatic hypoglycemia \[typical symptoms of hypoglycemia and plasma glucose ≤70 mg/dL\]. Participants may be reported in more than one category. |
Countries
Canada, Hungary, Slovakia, United States
Participant flow
Recruitment details
Participants took part in the study at 87 investigative sites in Canada, Hungary, Slovakia and the United States from 11 November 2016 to 22 March 2019.
Pre-assignment details
Participants with a diagnosis of type 2 Diabetes Mellitus were enrolled in 1 of 2 treatment groups, Sotagliflozin 400 milligrams (mg) once daily (QD) + Metformin and Placebo + Metformin. Participants were randomly assigned to the ratio of 1:1 to these reporting groups.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Metformin Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks. | 259 |
| Sotagliflozin 400 mg + Metformin Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks. | 259 |
| Total | 518 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 |
| Overall Study | At the participant's own request | 21 | 25 |
| Overall Study | Lost to Follow-up | 7 | 8 |
| Overall Study | Reason not Specified | 17 | 9 |
Baseline characteristics
| Characteristic | Placebo + Metformin | Sotagliflozin 400 mg + Metformin | Total |
|---|---|---|---|
| Age, Continuous | 59.9 years STANDARD_DEVIATION 9.4 | 60.0 years STANDARD_DEVIATION 10.1 | 59.9 years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 106 Participants | 117 Participants | 223 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 153 Participants | 140 Participants | 293 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Hemoglobin A1c (HbA1c) | 8.19 percentage of HbA1c STANDARD_DEVIATION 0.82 | 8.20 percentage of HbA1c STANDARD_DEVIATION 0.78 | 8.20 percentage of HbA1c STANDARD_DEVIATION 0.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 6 Participants | 25 Participants |
| Race (NIH/OMB) Black or African American | 40 Participants | 28 Participants | 68 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 197 Participants | 223 Participants | 420 Participants |
| Sex: Female, Male Female | 113 Participants | 117 Participants | 230 Participants |
| Sex: Female, Male Male | 146 Participants | 142 Participants | 288 Participants |
| Systolic Blood Pressure (SBP) | 133.80 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.95 | 134.06 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.95 | 133.93 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.93 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 259 | 3 / 259 |
| other Total, other adverse events | 109 / 259 | 85 / 259 |
| serious Total, serious adverse events | 23 / 259 | 19 / 259 |
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 and Week 26
Population: Intent-to-treat (ITT) population included all randomized participants. Missing data was imputed using the retrieved dropouts and washout imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26 | -0.29 percentage of HbA1c | Standard Error 0.079 |
| Sotagliflozin 400 mg + Metformin | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26 | -0.77 percentage of HbA1c | Standard Error 0.077 |
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.0, \>8.0%) at screening, randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.p-value: <0.000195% CI: [-0.64, -0.309]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 and Week 26
Population: ITT population included all randomized participants. Missing data are imputed using control-based copy reference multiple imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26 | -0.930 millimole per liter (mmol/L) | Standard Error 0.2353 |
| Sotagliflozin 400 mg + Metformin | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26 | -2.502 millimole per liter (mmol/L) | Standard Error 0.2292 |
Comparison: The change from baseline to Week 26 was analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.0, \>8.0%) at screening, randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and country as fixed effects, and country as fixed effects, and baseline 2- hour postprandial glucose as a covariate.p-value: <0.000195% CI: [-2.0538, -1.0909]ANCOVA
Secondary
Change From Baseline in Body Weight at Week 26
An ANCOVA model was used for the analysis.
Time frame: Baseline and Week 26
Population: ITT population included all randomized participants. Missing data was imputed using the retrieved dropouts and washout imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Change From Baseline in Body Weight at Week 26 | -0.69 kilogram (kg) | Standard Error 0.31 |
| Sotagliflozin 400 mg + Metformin | Change From Baseline in Body Weight at Week 26 | -2.56 kilogram (kg) | Standard Error 0.331 |
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.0, \>8.0%) at screening, randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and country as fixed effects, and country as fixed effects, and baseline weight as a covariate.p-value: <0.000195% CI: [-2.591, -1.144]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
An ANCOVA model was used for the analysis.
Time frame: Baseline and Week 26
Population: ITT population included all randomized participants. Missing data was imputed using the retrieved dropouts and washout imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -0.550 mmol/L | Standard Error 0.1864 |
| Sotagliflozin 400 mg + Metformin | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -1.310 mmol/L | Standard Error 0.2089 |
Comparison: The change from baseline to Week 26 is analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.0, \>8.0%) at screening, randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline fasting plasma glucose as a covariate.p-value: =0.000795% CI: [-1.2006, -0.3198]ANCOVA
Secondary
Change From Baseline in SBP at Week 12 for All Participants
An ANCOVA model was used for the analysis.
Time frame: Baseline and Week 12
Population: ITT population included all randomized participants. Missing data was imputed using control-based copy reference multiple imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Change From Baseline in SBP at Week 12 for All Participants | -1.87 mmHg | Standard Error 0.949 |
| Sotagliflozin 400 mg + Metformin | Change From Baseline in SBP at Week 12 for All Participants | -5.41 mmHg | Standard Error 0.95 |
Comparison: The change from baseline to Week 12 is analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤ 8.0, \>8.0%) at screening, randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline SBP as a covariate.p-value: =0.000495% CI: [-5.479, -1.592]ANCOVA
Secondary
Change From Baseline in 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 and Week 12
Population: Analysis was performed on ITT population in participant with baseline SBP ≥130 mmHg. Missing data was imputed using control-based copy reference multiple imputation method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Metformin | Change From Baseline in Systolic Blood Pressure (SBP) at Week 12 in Participants With Baseline SBP ≥130 mmHg | -6.92 millimeter of mercury (mmHg) | Standard Error 1.233 |
| Sotagliflozin 400 mg + Metformin | Change From Baseline in Systolic Blood Pressure (SBP) at Week 12 in Participants With Baseline SBP ≥130 mmHg | -10.21 millimeter of mercury (mmHg) | Standard Error 1.27 |
Comparison: The change from baseline to Week 12 is analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤ 8.0, \>8.0%) at screening, and country as fixed effects, and baseline SBP as a covariate.p-value: =0.020995% CI: [-6.07, -0.497]ANCOVA
Secondary
Percentage of Participants With HbA1c <6.5% at Week 26
Time frame: Week 26
Population: ITT population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Metformin | Percentage of Participants With HbA1c <6.5% at Week 26 | 5.4 percentage of participants |
| Sotagliflozin 400 mg + Metformin | Percentage of Participants With HbA1c <6.5% at Week 26 | 10.8 percentage of participants |
Comparison: Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomization strata of HbA1c (≤8.0, \>8.0%) at screening, randomization strata of mean SBP (\<130, ≥130 mmHg) at screening. Missing data at Week 26 were assigned a status of nonresponder in the analysis.p-value: =0.023895% CI: [0.75, 10.06]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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo + Metformin | Percentage of Participants With HbA1c <7.0% at Week 26 | 15.8 percentage of participants |
| Sotagliflozin 400 mg + Metformin | Percentage of Participants With HbA1c <7.0% at Week 26 | 29.7 percentage of participants |
Comparison: Percentage difference between treatment groups using the Cochran-Mantel-Haenszel test stratified by the randomization strata of HbA1c (≤8.0, \>8.0%) at screening, randomization strata of mean SBP (\<130, ≥130 mmHg) at screening. Missing data at Week 26 were assigned a status of nonresponder in the analysis.p-value: =0.000195% CI: [6.91, 20.89]Cochran-Mantel-Haenszel
Other Pre-specified
Percentage of Participants With Hypoglycemic Events
Percentage of participants with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia \[typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤70 mg/dL (3.9 mmol/L)\]; Severe \[an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions\] or documented symptomatic hypoglycemia \[typical symptoms of hypoglycemia and plasma glucose ≤70 mg/dL\]. Participants may be reported in more than one category.
Time frame: Up to 79 weeks in the treatment period
Population: Safety population was defined as all randomized participants who had received at least 1 dose of the double-blind investigational medicinal product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo + Metformin | Percentage of Participants With Hypoglycemic Events | Any hypoglycemia | 11.6 percentage of participants |
| Placebo + Metformin | Percentage of Participants With Hypoglycemic Events | Documented symptomatic hypoglycemia | 6.2 percentage of participants |
| Placebo + Metformin | Percentage of Participants With Hypoglycemic Events | Severe or documented symptomatic hypoglycemia | 6.2 percentage of participants |
| Sotagliflozin 400 mg + Metformin | Percentage of Participants With Hypoglycemic Events | Any hypoglycemia | 6.6 percentage of participants |
| Sotagliflozin 400 mg + Metformin | Percentage of Participants With Hypoglycemic Events | Documented symptomatic hypoglycemia | 3.1 percentage of participants |
| Sotagliflozin 400 mg + Metformin | Percentage of Participants With Hypoglycemic Events | Severe or documented symptomatic hypoglycemia | 3.1 percentage of participants |