High Level of Sugar (Glucose) in the Blood, Type 1 Diabetes Mellitus (T1DM)
Conditions
Brief summary
This Phase 3 study was designed to demonstrate the net benefit of sotagliflozin versus placebo in patients with Type 1 Diabetes (T1D).
Interventions
DRUGSotagliflozin
Sotagliflozin, once daily, before the first meal of the day
DRUGPlacebo
Placebo, once daily, before the first meal of the day
Sponsors
Sanofi
Lexicon Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Argentina, Australia, Belgium, Bulgaria, Canada, Colombia, Czechia, France, Germany, Hungary, Israel, Italy, New Zealand, Poland, Slovakia, South Africa, Spain, United Kingdom, United States
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 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).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Two placebo-matching to sotagliflozin tablets daily, orally, before the first meal of the day for 24 weeks. | 703 |
| Sotagliflozin 400 mg Sotagliflozin 400 mg (two 200 mg tablets) once daily, orally, before the first meal of the day for 24 weeks. | 699 |
| Total | 1,402 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 16 | 45 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lost to Follow-up | 8 | 10 |
| Overall Study | Noncompliance with study drug | 8 | 3 |
| Overall Study | Other | 3 | 2 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Randomized, not treated | 2 | 1 |
| Overall Study | Withdrawal by Subject | 42 | 32 |
Baseline characteristics
| Characteristic | Sotagliflozin 400 mg | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 43.3 years STANDARD_DEVIATION 14.17 | 42.8 years STANDARD_DEVIATION 14.11 | 42.4 years STANDARD_DEVIATION 14.04 |
| Baseline Total Daily Insulin | 0.69 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.276 | 0.70 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.284 | 0.71 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.291 |
| Body Mass Index (BMI) | 28.29 kg/m^2 (kilogram(s)/square meter) STANDARD_DEVIATION 5.128 | 28.19 kg/m^2 (kilogram(s)/square meter) STANDARD_DEVIATION 5.155 | 28.10 kg/m^2 (kilogram(s)/square meter) STANDARD_DEVIATION 5.183 |
| Body Weight | 82.40 kilograms (kg) STANDARD_DEVIATION 17.131 | 81.97 kilograms (kg) STANDARD_DEVIATION 17.081 | 81.55 kilograms (kg) STANDARD_DEVIATION 17.032 |
| Duration of Diabetes | 20.5 years STANDARD_DEVIATION 12.37 | 20.0 years STANDARD_DEVIATION 12.22 | 19.6 years STANDARD_DEVIATION 12.07 |
| hemoglobin A1C (A1C) | 8.26 percentage of A1C STANDARD_DEVIATION 0.965 | 8.23 percentage of A1C STANDARD_DEVIATION 0.943 | 8.21 percentage of A1C STANDARD_DEVIATION 0.921 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 6 Participants | 5 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 12 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 24 Participants | 46 Participants | 22 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Applicable | 16 Participants | 29 Participants | 13 Participants |
| Race/Ethnicity, Customized Other | 31 Participants | 68 Participants | 37 Participants |
| Race/Ethnicity, Customized White | 619 Participants | 1240 Participants | 621 Participants |
| Sex: Female, Male Female | 341 Participants | 705 Participants | 364 Participants |
| Sex: Female, Male Male | 358 Participants | 697 Participants | 339 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 703 | 1 / 699 |
| other Total, other adverse events | 70 / 703 | 70 / 699 |
| serious Total, serious adverse events | 23 / 703 | 48 / 699 |
Outcome results
Primary
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
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
Population: The primary efficacy analyses were based on the modified Intent-to-Treat (mITT) population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | 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 | 15.2 percentage of participants |
| Sotagliflozin 400 mg | 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 | 28.6 percentage of participants |
p-value: <0.00195% CI: [8.97, 17.81]Cochran-Mantel-Haenszel
Secondary
Absolute Change From Baseline in Body Weight
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
Population: Analyses included participants from the mITT population. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Body Weight | 0.77 kilograms (kg) | Standard Error 0.122 |
| Sotagliflozin 400 mg | Absolute Change From Baseline in Body Weight | -2.21 kilograms (kg) | Standard Error 0.122 |
Comparison: 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.p-value: <0.00195% CI: [-3.31, -2.66]MMRM
Secondary
Change From Baseline in A1C
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
Population: Analyses included participants from the mITT population. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in A1C | -0.33 percentage of A1c | Standard Error 0.031 |
| Sotagliflozin 400 mg | Change From Baseline in A1C | -0.79 percentage of A1c | Standard Error 0.032 |
Comparison: 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.p-value: <0.00195% CI: [-0.54, -0.38]MMRM
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) in the Subset of Participants With Baseline SBP >=130 Millimeter of Mercury (mmHg)
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) in the Subset of Participants With Baseline SBP >=130 Millimeter of Mercury (mmHg) | -5.7 mmHg | Standard Error 0.9 |
| Sotagliflozin 400 mg | Change From Baseline in Systolic Blood Pressure (SBP) in the Subset of Participants With Baseline SBP >=130 Millimeter of Mercury (mmHg) | -9.2 mmHg | Standard Error 0.92 |
Comparison: 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.p-value: =0.00295% CI: [-5.7, -1.3]MMRM
Secondary
Percent Change From Baseline in Mean Daily Bolus Insulin Dose
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
Population: Analyses included participants from the mITT population. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Mean Daily Bolus Insulin Dose | 6.62 percent change in IU/day | Standard Error 2.272 |
| Sotagliflozin 400 mg | Percent Change From Baseline in Mean Daily Bolus Insulin Dose | -5.71 percent change in IU/day | Standard Error 2.289 |
Comparison: 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.p-value: <0.00195% CI: [-18.17, -6.48]MMRM