Type 1 Diabetes Mellitus
Conditions
Brief summary
The primary objective of this study was to define the dose leading to desirable efficacy, as measured by the change in hemoglobin A1C (A1C) between Baseline and Week 12.
Interventions
DRUGPlacebo
Placebo, once daily, before the first meal of the day
DRUGSotagliflozin
Sotagliflozin,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
* Participant 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 type 1 diabetes mellitus (T1D) made at least 1 year prior to informed consent. * Participants were being treated with insulin or insulin analog delivered via continuous subcutaneous insulin infusion (CSII) or multiple daily injection (MDI). * At the Screening Visit, A1C had to be between 7.0% and 10.0%. * Females of childbearing potential had to use an adequate method of contraception and have 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 |
|---|---|---|
| Change From Baseline in Hemoglobin A1C (A1C) at Week 12 | Baseline to Week 12 | Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Post-baseline Least Square (LS) mean values were obtained from mixed-effects model repeated measures (MMRM) model with treatment, randomization strata of insulin delivery method (continuous subcutaneous insulin infusion \[CSII\] or multiple daily injection \[MDI\]), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline A1C-by-time interaction as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in 2-Hour Postprandial Glucose (PPG) Following the Standardized Mixed Meal | Baseline, Week 12 | A 2-hour PPG sample (plasma) was obtained 2-hours after a standardized Mixed Meal at Baseline (Day 1) and at the visit at Week 12. Post-Baseline LS mean was obtained from analysis of covariance (ANCOVA) model with treatment, randomization strata of insulin delivery method (CSII, MDI) as fixed categorical effects, and baseline postprandial glucose as a covariate. |
| Absolute Change From Baseline in Body Weight to Week 12 | Baseline to Week 12 | Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Post-Baseline LS mean was obtained from MMRM model with treatment, randomization strata of insulin delivery method (CSII, MDI), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline weight-by-time interaction as a covariate. |
| Percent Change From Baseline in Body Weight to Week 12 | Baseline to Week 12 | Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Post-Baseline LS mean was obtained from MMRM model with treatment, randomization strata of insulin delivery method (CSII, MDI), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline weight-by-time interaction as a covariate. |
| Change From Baseline to Week 12 in 24-Hour Urinary Glucose Excretion | Baseline, Week 12 | Urine was collected over 24 hours to measure Urinary Glucose Excretion at baseline, and at the end of the 12-week treatment. Post-Baseline LS mean was obtained from ANCOVA model with treatment, randomization strata of insulin delivery method (CSII, MDI) as fixed categorical effects, and Baseline urinary glucose excretion as a covariate. |
| Change From Baseline to Week 12 in Fasting Plasma Glucose | Baseline to Week 12 | Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Post-Baseline LS mean was obtained from MMRM model with treatment, randomization strata of insulin delivery method (CSII, MDI), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline fasting plasma glucose-by-time interaction as a covariate. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 17 centers in the United States from 10 July 2015 to 26 August 2016.
Pre-assignment details
207 participants were screened and 141 participants with Type 1 diabetes mellitus who had inadequate glycemic control with insulin therapy alone, were randomized equally into four treatment groups: sotagliflozin 75 milligrams (mg), sotagliflozin 200 mg, sotagliflozin 400 mg or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Two placebo-matching sotagliflozin tablets, once daily, orally for 12 weeks. | 36 |
| Sotagliflozin 75 mg Sotagliflozin 75 mg (one 75 mg tablet and one placebo tablet), once daily, orally, for 12 weeks. | 35 |
| Sotagliflozin 200 mg Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 12 weeks. | 35 |
| Sotagliflozin 400 mg Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 12 weeks. | 35 |
| Total | 141 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 | 0 | 1 |
| Overall Study | Non-compliance with the treatment | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Sotagliflozin 400 mg | Sotagliflozin 200 mg | Sotagliflozin 75 mg |
|---|---|---|---|---|---|
| Age, Continuous | 48.1 years STANDARD_DEVIATION 11.29 | 45.6 years STANDARD_DEVIATION 13.29 | 44.8 years STANDARD_DEVIATION 15.36 | 47.0 years STANDARD_DEVIATION 14.01 | 42.4 years STANDARD_DEVIATION 12.01 |
| Body Mass Index | 31.81 kilograms per meter square STANDARD_DEVIATION 5.763 | 29.17 kilograms per meter square STANDARD_DEVIATION 5.569 | 29.37 kilograms per meter square STANDARD_DEVIATION 5.849 | 28.01 kilograms per meter square STANDARD_DEVIATION 4.707 | 27.41 kilograms per meter square STANDARD_DEVIATION 5.016 |
| Body Weight | 91.92 kilograms STANDARD_DEVIATION 19.681 | 85.48 kilograms STANDARD_DEVIATION 18.557 | 86.95 kilograms STANDARD_DEVIATION 20.857 | 82.90 kilograms STANDARD_DEVIATION 17.14 | 79.97 kilograms STANDARD_DEVIATION 14.358 |
| Daily Total Insulin Dose | 0.68 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.306 | 0.70 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.315 | 0.77 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.409 | 0.70 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.298 | 0.65 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.229 |
| Duration of Diabetes | 26.9 years STANDARD_DEVIATION 13.51 | 24.1 years STANDARD_DEVIATION 13.66 | 24.0 years STANDARD_DEVIATION 14.96 | 23.4 years STANDARD_DEVIATION 13.17 | 22.2 years STANDARD_DEVIATION 13.04 |
| Hemoglobin A1C (A1c) | 7.95 percentage of A1C STANDARD_DEVIATION 0.849 | 8.02 percentage of A1C STANDARD_DEVIATION 0.832 | 8.05 percentage of A1C STANDARD_DEVIATION 0.735 | 8.07 percentage of A1C STANDARD_DEVIATION 0.926 | 8.00 percentage of A1C STANDARD_DEVIATION 0.839 |
| Insulin delivery method in Participants continuous subcutaneous insulin infusion (CSII) | 19 Participants | 73 Participants | 18 Participants | 18 Participants | 18 Participants |
| Insulin delivery method in Participants multiple daily injection (MDI) | 17 Participants | 68 Participants | 17 Participants | 17 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 7 Participants | 0 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 131 Participants | 35 Participants | 31 Participants | 31 Participants |
| Sex: Female, Male Female | 21 Participants | 73 Participants | 15 Participants | 15 Participants | 22 Participants |
| Sex: Female, Male Male | 15 Participants | 68 Participants | 20 Participants | 20 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 35 | 0 / 35 | 0 / 35 |
| other Total, other adverse events | 10 / 36 | 5 / 35 | 6 / 35 | 4 / 35 |
| serious Total, serious adverse events | 1 / 36 | 1 / 35 | 1 / 35 | 1 / 35 |
Outcome results
Primary
Change From Baseline in Hemoglobin A1C (A1C) at Week 12
Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Post-baseline Least Square (LS) mean values were obtained from mixed-effects model repeated measures (MMRM) model with treatment, randomization strata of insulin delivery method (continuous subcutaneous insulin infusion \[CSII\] or multiple daily injection \[MDI\]), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline A1C-by-time interaction as a covariate.
Time frame: Baseline to Week 12
Population: Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hemoglobin A1C (A1C) at Week 12 | -0.35 percentage of A1C | Standard Error 0.096 |
| Sotagliflozin 75 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 12 | -0.60 percentage of A1C | Standard Error 0.1 |
| Sotagliflozin 200 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 12 | -0.84 percentage of A1C | Standard Error 0.095 |
| Sotagliflozin 400 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 12 | -0.73 percentage of A1C | Standard Error 0.096 |
Comparison: Analysis was performed using MMRM model with treatment, randomization strata of insulin delivery method (CSII, MDI), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline A1C-by-time interaction as a covariate.p-value: 0.0795% CI: [-0.53, 0.02]MMRM
Comparison: Analysis was performed using MMRM model with treatment, randomization strata of insulin delivery method (CSII, MDI), 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: [-0.75, -0.22]MMRM
Comparison: Analysis was performed using MMRM model with treatment, randomization strata of insulin delivery method (CSII, MDI), time (study week), and a treatment-by-time interaction as fixed categorical effects, and Baseline A1C-by-time interaction as a covariate.p-value: 0.00695% CI: [-0.65, -0.11]MMRM
Secondary
Absolute Change From Baseline in Body Weight to Week 12
Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Post-Baseline LS mean was obtained from MMRM model with treatment, randomization strata of insulin delivery method (CSII, MDI), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline weight-by-time interaction as a covariate.
Time frame: Baseline to Week 12
Population: Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Body Weight to Week 12 | 1.13 kilograms | Standard Error 0.425 |
| Sotagliflozin 75 mg | Absolute Change From Baseline in Body Weight to Week 12 | -0.16 kilograms | Standard Error 0.441 |
| Sotagliflozin 200 mg | Absolute Change From Baseline in Body Weight to Week 12 | -1.24 kilograms | Standard Error 0.417 |
| Sotagliflozin 400 mg | Absolute Change From Baseline in Body Weight to Week 12 | -1.48 kilograms | Standard Error 0.422 |
Secondary
Change From Baseline to Week 12 in 24-Hour Urinary Glucose Excretion
Urine was collected over 24 hours to measure Urinary Glucose Excretion at baseline, and at the end of the 12-week treatment. Post-Baseline LS mean was obtained from ANCOVA model with treatment, randomization strata of insulin delivery method (CSII, MDI) as fixed categorical effects, and Baseline urinary glucose excretion as a covariate.
Time frame: Baseline, Week 12
Population: Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in 24-Hour Urinary Glucose Excretion | 0.2555 grams per day | Standard Error 10.53532 |
| Sotagliflozin 75 mg | Change From Baseline to Week 12 in 24-Hour Urinary Glucose Excretion | 42.0185 grams per day | Standard Error 10.52465 |
| Sotagliflozin 200 mg | Change From Baseline to Week 12 in 24-Hour Urinary Glucose Excretion | 57.9850 grams per day | Standard Error 10.51367 |
| Sotagliflozin 400 mg | Change From Baseline to Week 12 in 24-Hour Urinary Glucose Excretion | 70.7058 grams per day | Standard Error 10.28691 |
Secondary
Change From Baseline to Week 12 in 2-Hour Postprandial Glucose (PPG) Following the Standardized Mixed Meal
A 2-hour PPG sample (plasma) was obtained 2-hours after a standardized Mixed Meal at Baseline (Day 1) and at the visit at Week 12. Post-Baseline LS mean was obtained from analysis of covariance (ANCOVA) model with treatment, randomization strata of insulin delivery method (CSII, MDI) as fixed categorical effects, and baseline postprandial glucose as a covariate.
Time frame: Baseline, Week 12
Population: Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in 2-Hour Postprandial Glucose (PPG) Following the Standardized Mixed Meal | -0.2 milligrams per deciliter (mg/dL) | Standard Error 12.51 |
| Sotagliflozin 75 mg | Change From Baseline to Week 12 in 2-Hour Postprandial Glucose (PPG) Following the Standardized Mixed Meal | -20.5 milligrams per deciliter (mg/dL) | Standard Error 13.66 |
| Sotagliflozin 200 mg | Change From Baseline to Week 12 in 2-Hour Postprandial Glucose (PPG) Following the Standardized Mixed Meal | -27.6 milligrams per deciliter (mg/dL) | Standard Error 14.16 |
| Sotagliflozin 400 mg | Change From Baseline to Week 12 in 2-Hour Postprandial Glucose (PPG) Following the Standardized Mixed Meal | -49.7 milligrams per deciliter (mg/dL) | Standard Error 12.51 |
Secondary
Change From Baseline to Week 12 in Fasting Plasma Glucose
Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Post-Baseline LS mean was obtained from MMRM model with treatment, randomization strata of insulin delivery method (CSII, MDI), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline fasting plasma glucose-by-time interaction as a covariate.
Time frame: Baseline to Week 12
Population: Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in Fasting Plasma Glucose | -10.8 mg/dL | Standard Error 8.99 |
| Sotagliflozin 75 mg | Change From Baseline to Week 12 in Fasting Plasma Glucose | -19.4 mg/dL | Standard Error 9.55 |
| Sotagliflozin 200 mg | Change From Baseline to Week 12 in Fasting Plasma Glucose | -19.8 mg/dL | Standard Error 8.85 |
| Sotagliflozin 400 mg | Change From Baseline to Week 12 in Fasting Plasma Glucose | -32.2 mg/dL | Standard Error 8.99 |
Secondary
Percent Change From Baseline in Body Weight to Week 12
Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Post-Baseline LS mean was obtained from MMRM model with treatment, randomization strata of insulin delivery method (CSII, MDI), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline weight-by-time interaction as a covariate.
Time frame: Baseline to Week 12
Population: Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Body Weight to Week 12 | 1.26 percent change | Standard Error 0.535 |
| Sotagliflozin 75 mg | Percent Change From Baseline in Body Weight to Week 12 | 0.11 percent change | Standard Error 0.556 |
| Sotagliflozin 200 mg | Percent Change From Baseline in Body Weight to Week 12 | -1.47 percent change | Standard Error 0.531 |
| Sotagliflozin 400 mg | Percent Change From Baseline in Body Weight to Week 12 | -1.61 percent change | Standard Error 0.538 |