Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: To demonstrate the superiority of Sotagliflozin 400 milligrams (mg) versus placebo on Hemoglobin A1c (HbA1c) reduction at Week 26 in participant with type 2 diabetes (T2D) who have inadequate glycemic control with a Sulfonylurea alone or in combination with Metformin. Secondary Objectives: * To compare Sotagliflozin 400 mg versus placebo based on: * 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 (mm Hg). * Change from baseline in SBP for all participants. * Change from baseline in body weight. * Percentage of participants with HbA1c \<6.5% and \<7.0%. * To evaluate the safety of Sotagliflozin 400 mg versus placebo throughout the 79-week trial.
Detailed description
The duration per participants is up to 85 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, and a 2-week post treatment Follow-up period to collect safety information.
Interventions
Pharmaceutical form: tablet Route of administration: oral
DRUGPlacebo
Pharmaceutical form: tablet Route of administration: oral
DRUGMetformin
Pharmaceutical form: tablet Route of administration: oral
DRUGSulfonylurea
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 T2D treated with a Sulfonylurea (≥half the maximum recommended dose as per local label or maximum tolerated dose \[documented\]) as monotherapy or in combination with Metformin (≥1500 mg per day or maximum tolerated dose \[documented\]) each at a stable dose for at least 12 weeks without a dose adjustment before screening. * Signed written informed consent.
Exclusion criteria
* At the time of screening, age \<18 years or \< legal age of majority, whichever is greater. * Body Mass Index (BMI) ≤20 or \>45 kilograms per meter square (kg/m\^2) at Screening. * Hemoglobin A1c (HbA1c) \<7% or HbA1c \>10% via central lab test at screening. * Fasting plasma glucose (FPG) \>15 mmol/L (270 mg/dL) measured by the central laboratory at screening (Visit 1), and confirmed (\>15 mmol/L \[270 mg/dL\]) by a repeat test before randomization. * Women of childbearing potential with no effective contraceptive method. * Treated with an antidiabetic pharmacological regimen other than a Sulfonylurea at a stable dose with or without Metformin within 12 weeks preceding the screening visit. * Previous insulin use \>1 month (at any time, aside from treatment of gestational diabetes). * History of prior gastric surgical procedure including gastric banding or inflammatory bowel disease within 3 years before the Screening Visit. * History of diabetic ketoacidosis or nonketotic hyperosmolar coma within 12 weeks prior to the Screening Visit. * History of severe hypoglycemia within 6 months prior to the Screening visit. * Systolic blood pressure (SBP) \>180 millimeter per mercury (mmHg) or diastolic blood pressure (DBP) \>100 mmHg or history of hypertensive emergency. * Aspartate aminotransferase and/or alanine aminotransferase: \>3 times the upper limit of the normal laboratory range (ULN). * Total bilirubin: \>1.5 times ULN (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. * Pregnancy, breastfeeding. * Participants is unwilling to perform self-monitoring of blood glucose (SMBG), and complete the participant's diary as required per protocol. 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 to Week 26 | Missing data are imputed using the retrieved dropouts imputation method. An analysis of covariance (ANCOVA) model was used for the analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | Baseline to Week 26 | Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis. |
| Change From Baseline in Systolic Blood Pressure (SBP) for Participants With Baseline SBP ≥130 mmHg | Baseline to Week 12 | Missing data are imputed using the washout imputation method under the missing, not at random framework. An ANCOVA model was used for the analysis. |
| Change From Baseline in SBP at Week 12 for All Participants | Baseline to Week 12 | Missing data are imputed using washout imputation method under the missing not at random framework. 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 Body Weight at Week 26 | Baseline to Week 26 | Missing data are imputed using the retrieved dropouts imputation method. 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
Bulgaria, Estonia, Hungary, Poland, Romania, Slovakia, South Korea, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Participants took part in the study at 76 investigative sites in the United States, Bulgaria, Estonia, Hungary, Republic of Korea, Poland, Romania, Slovakia, Ukraine, United Kingdom from 24 February 2017 to 30 April 2019.
Pre-assignment details
Participants with a diagnosis of Diabetes Mellitus were enrolled equally in 1 of 2 treatment groups, Sotagliflozin 400 milligrams (mg) and Placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Following a 2-week run-in period, participants were randomized to matching placebo administered as 2 tablets, once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks. | 254 |
| Sotagliflozin 400 mg Following a 2-week run-in phase, participants received two Sotagliflozin tablets of 200 mg, orally once daily, before the first meal of the day plus Metformin and Sulfonylurea as prescribed for up to 26 weeks in the Core Treatment Period. Participants were eligible to continue treatment in the Extension Period. The total treatment duration was planned for up to 79 weeks. | 253 |
| Total | 507 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | At the Participant's own Request | 16 | 17 |
| Overall Study | Lost to Follow-up | 11 | 3 |
| Overall Study | Other | 3 | 0 |
| Overall Study | Poor Compliance to Protocol | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Sotagliflozin 400 mg | Total |
|---|---|---|---|
| Age, Continuous | 63.0 years STANDARD_DEVIATION 9.9 | 63.3 years STANDARD_DEVIATION 8.8 | 63.1 years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 43 Participants | 53 Participants | 96 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 210 Participants | 198 Participants | 408 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Hemoglobin A1c (HbA1c) | 8.18 percentage of HbA1c STANDARD_DEVIATION 0.83 | 8.20 percentage of HbA1c STANDARD_DEVIATION 0.83 | 8.19 percentage of HbA1c STANDARD_DEVIATION 0.83 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 34 Participants | 28 Participants | 62 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 8 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 211 Participants | 215 Participants | 426 Participants |
| Sex: Female, Male Female | 124 Participants | 104 Participants | 228 Participants |
| Sex: Female, Male Male | 130 Participants | 149 Participants | 279 Participants |
| Systolic Blood Pressure (SBP) | 133.08 millimeter of mercury (mmHg) STANDARD_DEVIATION 14.21 | 134.30 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.01 | 133.69 millimeter of mercury (mmHg) STANDARD_DEVIATION 13.62 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 253 | 2 / 254 |
| other Total, other adverse events | 90 / 253 | 71 / 254 |
| serious Total, serious adverse events | 40 / 253 | 32 / 254 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26
Missing data are imputed using the retrieved dropouts imputation method. An analysis of covariance (ANCOVA) model was used for the analysis.
Time frame: Baseline to Week 26
Population: Intent-to-treat (ITT) population included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26 | 0.06 percentage HbA1c | Standard Error 0.082 |
| Sotagliflozin 400 mg | Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26 | -0.70 percentage HbA1c | Standard Error 0.068 |
Comparison: The change from baseline to Week 26 is analyzed using ANCOVA model with treatment groups randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of Metformin use 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: [-0.946, -0.574]ANCOVA
Secondary
Change From Baseline in Body Weight at Week 26
Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis.
Time frame: Baseline to Week 26
Population: ITT population included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Body Weight at Week 26 | -0.29 kilogram (kg) | Standard Deviation 0.206 |
| Sotagliflozin 400 mg | Change From Baseline in Body Weight at Week 26 | -1.70 kilogram (kg) | Standard Deviation 0.215 |
Comparison: The change from baseline to Week 26 is analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of Metformin use at screening, randomization strata of mean SBP (\<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline weight as a covariate.p-value: <0.000195% CI: [-1.932, -0.884]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
Missing data are imputed using the retrieved dropouts imputation method. An ANCOVA model was used for the analysis.
Time frame: Baseline to Week 26
Population: ITT population included all randomized participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | 0.277 millimole per liter (mmol/L) | Standard Error 0.2691 |
| Sotagliflozin 400 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 | -1.331 millimole per liter (mmol/L) | Standard Error 0.1844 |
Comparison: The change from baseline to Week 26 is analyzed using ANCOVA model with treatment groups randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of Metformin use 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: <0.000195% CI: [-2.1685, -1.0471]ANCOVA
Secondary
Change From Baseline in SBP at Week 12 for All Participants
Missing data are imputed using washout imputation method under the missing not at random framework. An ANCOVA model was used for the analysis.
Time frame: Baseline to Week 12
Population: ITT population included all randomized participants .
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in SBP at Week 12 for All Participants | -0.69 mmHg | Standard Deviation 0.826 |
| Sotagliflozin 400 mg | Change From Baseline in SBP at Week 12 for All Participants | -1.71 mmHg | Standard Deviation 0.83 |
Comparison: The change from baseline to Week 12 is analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of Metformin use at screening, randomization strata of mean SBP (\<130, ≥ 30 mmHg) at screening, and country as fixed effects, and baseline SBP as a covariate.p-value: 0.299495% CI: [-2.946, 0.907]ANCOVA
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) for Participants With Baseline SBP ≥130 mmHg
Missing data are imputed using the washout imputation method under the missing, not at random framework. An ANCOVA model was used for the analysis.
Time frame: Baseline to Week 12
Population: Analysis was performed on ITT population in participants with baseline SBP ≥130 mmHg.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) for Participants With Baseline SBP ≥130 mmHg | -3.58 mmHg | Standard Error 1.052 |
| Sotagliflozin 400 mg | Change From Baseline in Systolic Blood Pressure (SBP) for Participants With Baseline SBP ≥130 mmHg | -4.41 mmHg | Standard Error 1.061 |
Comparison: The change from baseline to Week 12 is analyzed using ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.5, \>8.5%) at screening, randomization strata of Metformin use at screening and country as fixed effects, and baseline SBP as a covariate.p-value: 0.517295% CI: [-3.316, 1.669]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 | Percentage of Participants With HbA1c <6.5% at Week 26 | 1.6 percentage of participants |
| Sotagliflozin 400 mg | Percentage of Participants With HbA1c <6.5% at Week 26 | 8.3 percentage of participants |
Comparison: 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 mean SBP (\<130,≥130 mmHg) at screening, randomization strata of metformin use at the screening. Missing data at Week 26 were assigned a status of non-responder in the analysis.p-value: 0.000495% CI: [3.03, 10.47]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 | Percentage of Participants With HbA1c <7.0% at Week 26 | 8.7 percentage of participants |
| Sotagliflozin 400 mg | Percentage of Participants With HbA1c <7.0% at Week 26 | 26.1 percentage of participants |
Comparison: 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 mean SBP (\<130, ≥130 mmHg) at screening, randomization strata of Metformin use at screening. Missing data at Week 26 were assigned a status of non-responder in the analysis.p-value: <0.000195% CI: [11.16, 23.73]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 | Percentage of Participants With Hypoglycemic Events | Severe or documented symptomatic hypoglycemia | 13.0 percentage of participants |
| Placebo | Percentage of Participants With Hypoglycemic Events | Any hypoglycemia | 22.1 percentage of participants |
| Placebo | Percentage of Participants With Hypoglycemic Events | Documented symptomatic hypoglycemia | 13.0 percentage of participants |
| Sotagliflozin 400 mg | Percentage of Participants With Hypoglycemic Events | Documented symptomatic hypoglycemia | 11.4 percentage of participants |
| Sotagliflozin 400 mg | Percentage of Participants With Hypoglycemic Events | Severe or documented symptomatic hypoglycemia | 11.8 percentage of participants |
| Sotagliflozin 400 mg | Percentage of Participants With Hypoglycemic Events | Any hypoglycemia | 19.7 percentage of participants |