Type 1 Diabetes Mellitus
Conditions
Brief summary
This Phase 2 study was intended to demonstrate superiority of sotagliflozin versus placebo on Hemoglobin A1C (A1C) reduction at Week 12 in young adult participants with type 1 diabetes mellitus (T1DM) who have poor glycemic control on their current insulin regimen.
Interventions
DRUGSotagliflozin
Sotagliflozin 400 mg, once daily before the first meal of the day
DRUGPlacebo
Placebo, once daily before the first meal of the day
Sponsors
Juvenile Diabetes Research Foundation
Sanofi
Lexicon Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
* Participant had given written informed consent. * Young adult participants \>=18 to \<=30 years old at Screening, with a confirmed diagnosis of T1DM made at least 1 year prior to informed consent. * Participants were being treated with insulin or insulin analogue delivered via continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI). * At Screening, must had A1C \>= 9.0%. * Must be willing and able to perform self-monitored blood glucose (SMBG) and complete the study diary. * Females of childbearing potential must use an adequate method of contraception and had a negative pregnancy test.
Exclusion criteria
* Any prior use of LX4211/sotagliflozin. * Use of antidiabetic agent other than insulin or insulin analogue at the time of screening. * Use of sodium-glucose cotransporter (SGLT) inhibitors within 8 weeks prior to start of the placebo Run-in Period. * Chronic systemic corticosteroid use. * Type 2 diabetes, or severely uncontrolled diabetes mellitus as determined by the Investigator. * History of diabetic ketoacidosis (DKA) or nonketotic hyperosmolar state within 6 months prior to the Screening Visit. * History of severe hypoglycemic event within 1 month prior to the Screening Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1C (A1C) at Week 12 | Baseline, Week 12 | Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Change was calculated by subtracting baseline value from Week 12 value. Least Square (LS) mean changes from baseline were obtained from mixed model repeated measures (MMRM) model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week-4 A1C (\<=10%, \>10%), 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 in Total Daily Bolus Insulin Dose and Total Daily Basal Insulin Dose at Week 12 | Baseline, Week 12 | The daily bolus and basal insulin doses were calculated as an average of the doses over 3 to 5 days before each visit (Baseline and Week 12). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model. |
| Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Standardized Mixed Meal at Week 12 | 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. At Week 12, study drug was to be given within 15 minutes before liquid Boost®, Ensure®, or similar nutrition drink product; at baseline, study drug was to be given after the 2-hour post-Mixed Meal PPG sample. Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from analysis of covariance (ANCOVA) model. |
| Change From Baseline in Glycemic Instability by Hyperglycemia (Continuous Glucose Monitoring [CGM] Area Under the Curve [AUC] >150 mg/dL) and Hypoglycemia (CGM AUC <70 mg/dL) Over a 24-hour Period at Week 12 | Baseline, Week 12 | Glycemic instability (mg/dL\*minutes/1000) by hyperglycemia/hypoglycemia was measured by CGM AUC outside target range (as a daily average over the week prior to the visit \[Baseline and Week 12\]) over 24 hours, where outside target range was defined as CGM glucose AUC \>150 mg/dL (hyperglycemia) and CGM glucose AUC \<70 mg/dL (hypoglycemia). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model. |
| Change From Baseline in Number of Hypoglycemic Events/Day (<=70 mg/dL) by Self-Monitored Blood Glucose (SMBG) at Week 12 | Baseline, Week 12 | Hypoglycemic event by SMBG was defined as an event in which the fingerstick measurement was \<=70 mg/dL. The number of hypoglycemic events per day was calculated as a daily average number of episodes over the week prior to visit (Baseline and Week 12). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 15 sites in United States between 20 April 2015 and 23 September 2016.
Pre-assignment details
147 participants were screened and 87 participants with Type 1 diabetes mellitus who had inadequate glycemic control with insulin therapy alone, were randomized equally into two treatment groups: sotagliflozin 400 milligrams (mg) or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks. | 42 |
| Sotagliflozin 400 mg Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks. | 43 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Other than specified above | 1 | 0 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Randomized but not treated | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | Sotagliflozin 400 mg |
|---|---|---|---|
| Age, Continuous | 22.3 years STANDARD_DEVIATION 3.81 | 21.7 years STANDARD_DEVIATION 3.55 | 22.8 years STANDARD_DEVIATION 4.01 |
| Baseline daily total insulin | 0.86 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.289 | 0.87 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.315 | 0.84 International units per kilogram (IU/kg) STANDARD_DEVIATION 0.264 |
| Body Mass Index (BMI) | 28.07 kilograms per square meter (kg/m^2) STANDARD_DEVIATION 6.324 | 26.73 kilograms per square meter (kg/m^2) STANDARD_DEVIATION 4.993 | 29.39 kilograms per square meter (kg/m^2) STANDARD_DEVIATION 7.214 |
| Body weight | 80.54 kilogram (kg) STANDARD_DEVIATION 17.975 | 77.27 kilogram (kg) STANDARD_DEVIATION 14.57 | 83.74 kilogram (kg) STANDARD_DEVIATION 20.439 |
| Duration of diabetes | 11.9 years STANDARD_DEVIATION 5.75 | 11.9 years STANDARD_DEVIATION 5.38 | 11.9 years STANDARD_DEVIATION 6.16 |
| Hemoglobin A1C Level in Participants >10 % | 48 Participants | 23 Participants | 25 Participants |
| Hemoglobin A1C Level in Participants <=10 percent (%) | 37 Participants | 19 Participants | 18 Participants |
| Insulin Delivery Method Continuous Subcutaneous Insulin Infusion (CSII) | 46 Participants | 23 Participants | 23 Participants |
| Insulin Delivery Method Multiple Daily Injections (MDI) | 39 Participants | 19 Participants | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 75 Participants | 34 Participants | 41 Participants |
| Sex: Female, Male Female | 45 Participants | 23 Participants | 22 Participants |
| Sex: Female, Male Male | 40 Participants | 19 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 43 |
| other Total, other adverse events | 16 / 42 | 21 / 43 |
| serious Total, serious adverse events | 3 / 42 | 2 / 43 |
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. Change was calculated by subtracting baseline value from Week 12 value. Least Square (LS) mean changes from baseline were obtained from mixed model repeated measures (MMRM) model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week-4 A1C (\<=10%, \>10%), 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, Week 12
Population: Analysis was performed on mITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hemoglobin A1C (A1C) at Week 12 | -0.99 percentage of A1C | Standard Error 0.149 |
| Sotagliflozin 400 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 12 | -1.33 percentage of A1C | Standard Error 0.143 |
Comparison: Between-group comparison was based on MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week-4 A1C (\<=10%, \>10%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline A1C-by-time interaction as a covariate.p-value: 0.195% CI: [-0.76, 0.06]MMRM
Secondary
Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Standardized Mixed Meal at 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. At Week 12, study drug was to be given within 15 minutes before liquid Boost®, Ensure®, or similar nutrition drink product; at baseline, study drug was to be given after the 2-hour post-Mixed Meal PPG sample. Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from analysis of covariance (ANCOVA) model.
Time frame: Baseline, Week 12
Population: Analysis was performed on mITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Standardized Mixed Meal at Week 12 | 0.2 milligrams per deciliter (mg/dL) | Standard Error 12.24 |
| Sotagliflozin 400 mg | Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Standardized Mixed Meal at Week 12 | -56.4 milligrams per deciliter (mg/dL) | Standard Error 11.61 |
Secondary
Change From Baseline in Glycemic Instability by Hyperglycemia (Continuous Glucose Monitoring [CGM] Area Under the Curve [AUC] >150 mg/dL) and Hypoglycemia (CGM AUC <70 mg/dL) Over a 24-hour Period at Week 12
Glycemic instability (mg/dL\*minutes/1000) by hyperglycemia/hypoglycemia was measured by CGM AUC outside target range (as a daily average over the week prior to the visit \[Baseline and Week 12\]) over 24 hours, where outside target range was defined as CGM glucose AUC \>150 mg/dL (hyperglycemia) and CGM glucose AUC \<70 mg/dL (hypoglycemia). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model.
Time frame: Baseline, Week 12
Population: Analysis was performed on mITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Glycemic Instability by Hyperglycemia (Continuous Glucose Monitoring [CGM] Area Under the Curve [AUC] >150 mg/dL) and Hypoglycemia (CGM AUC <70 mg/dL) Over a 24-hour Period at Week 12 | Glycemic Instability by Hyperglycemia | -5.035 mg/dL*minutes/1000 | Standard Error 7.9092 |
| Placebo | Change From Baseline in Glycemic Instability by Hyperglycemia (Continuous Glucose Monitoring [CGM] Area Under the Curve [AUC] >150 mg/dL) and Hypoglycemia (CGM AUC <70 mg/dL) Over a 24-hour Period at Week 12 | Glycemic Instability by Hypoglycemia | 0.221 mg/dL*minutes/1000 | Standard Error 0.2508 |
| Sotagliflozin 400 mg | Change From Baseline in Glycemic Instability by Hyperglycemia (Continuous Glucose Monitoring [CGM] Area Under the Curve [AUC] >150 mg/dL) and Hypoglycemia (CGM AUC <70 mg/dL) Over a 24-hour Period at Week 12 | Glycemic Instability by Hyperglycemia | -27.338 mg/dL*minutes/1000 | Standard Error 8.01 |
| Sotagliflozin 400 mg | Change From Baseline in Glycemic Instability by Hyperglycemia (Continuous Glucose Monitoring [CGM] Area Under the Curve [AUC] >150 mg/dL) and Hypoglycemia (CGM AUC <70 mg/dL) Over a 24-hour Period at Week 12 | Glycemic Instability by Hypoglycemia | 0.428 mg/dL*minutes/1000 | Standard Error 0.2528 |
Secondary
Change From Baseline in Number of Hypoglycemic Events/Day (<=70 mg/dL) by Self-Monitored Blood Glucose (SMBG) at Week 12
Hypoglycemic event by SMBG was defined as an event in which the fingerstick measurement was \<=70 mg/dL. The number of hypoglycemic events per day was calculated as a daily average number of episodes over the week prior to visit (Baseline and Week 12). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model.
Time frame: Baseline, Week 12
Population: Analysis was performed on mITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Number of Hypoglycemic Events/Day (<=70 mg/dL) by Self-Monitored Blood Glucose (SMBG) at Week 12 | -0.042 events/day | Standard Error 0.0408 |
| Sotagliflozin 400 mg | Change From Baseline in Number of Hypoglycemic Events/Day (<=70 mg/dL) by Self-Monitored Blood Glucose (SMBG) at Week 12 | -0.001 events/day | Standard Error 0.0379 |
Secondary
Change From Baseline in Total Daily Bolus Insulin Dose and Total Daily Basal Insulin Dose at Week 12
The daily bolus and basal insulin doses were calculated as an average of the doses over 3 to 5 days before each visit (Baseline and Week 12). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model.
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 | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Total Daily Bolus Insulin Dose and Total Daily Basal Insulin Dose at Week 12 | Total Daily Bolus Insulin Dose | -2.96 International Units per day (IU/day) | Standard Error 1.945 |
| Placebo | Change From Baseline in Total Daily Bolus Insulin Dose and Total Daily Basal Insulin Dose at Week 12 | Total Daily Basal Insulin Dose | 3.26 International Units per day (IU/day) | Standard Error 1.262 |
| Sotagliflozin 400 mg | Change From Baseline in Total Daily Bolus Insulin Dose and Total Daily Basal Insulin Dose at Week 12 | Total Daily Bolus Insulin Dose | -4.89 International Units per day (IU/day) | Standard Error 1.832 |
| Sotagliflozin 400 mg | Change From Baseline in Total Daily Bolus Insulin Dose and Total Daily Basal Insulin Dose at Week 12 | Total Daily Basal Insulin Dose | 2.03 International Units per day (IU/day) | Standard Error 1.211 |