Type 1 Diabetes Mellitus
Conditions
Brief summary
This Phase 3 study was intended to demonstrate superiority of either sotagliflozin high dose or low dose versus placebo on glycosylated hemoglobin A1C (A1C) reduction at Week 24 when used as an adjunct in adult participants with type 1 diabetes mellitus (T1D) who have inadequate glycemic control with insulin therapy.
Interventions
DRUGPlacebo
Placebo once daily, before first meal of the day.
DRUGSotagliflozin
Sotagliflozin once daily, before first meal of the day.
Sponsors
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 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 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 injections (MDI). * Willing and able to perform self-monitored blood glucose (SMBG) and complete the study diary as required per protocol. * At the Screening Visit, A1C must be between 7.0% to 11.0%. * Females of childbearing potential must 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 randomization. * Chronic systemic corticosteroid use. * Type 2 diabetes mellitus (T2D), or severely uncontrolled T1D as determined by the Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in A1C at Week 24 | Baseline to Week 24 | Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. Least square (LS) means were obtained from a mixed-effects model for repeated measures (MMRM) that included fixed, categorical effects of treatment, randomization strata of insulin delivery method (MDI, CSII), randomization strata of Week -2 A1C (\<= 8.5%, \>8.5%), time (study week), a treatment-by-time interaction, and baseline A1C-by-time interaction as a covariate. A negative change from Baseline (a lower A1C value at Week 24) indicates an improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Body Weight at Week 24 | 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 Mean Daily Bolus Insulin Dose at Week 24 | Baseline to Week 24 | The mean bolus insulin dose in international units per 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 change from Baseline indicated a reduction in the amount of bolus insulin used between Baseline and Week 24. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Baseline to Week 24 | 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 change from baseline indicates a lower glucose at Week 24 compared to baseline. |
| Percentage of Participants With A1C <7.0% (at Week 24) and No Episode of Severe Hypoglycemia and No Episode of Diabetic Ketoacidosis (DKA) Upto Week 24 | Baseline to Week 24 | Blood samples were collected for the assessment of Hemoglobin A1C to determine the participants with A1C value \<7.0%. A central blinded adjudication process determined whether participants experienced either DKA or Severe Hypoglycemia. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis. |
| Change From Baseline in Diabetes Distress Scores as Measured by 2-item Diabetes Distress Screening Scale (DDS2) Scores at Week 24 | Baseline to Week 24 | The DDS2 is a 2-item diabetes distress screening instrument where respondents rated, on a 6-point scale, the degree to which the following items caused distress: (1) feeling overwhelmed by the demands of living with diabetes, and (2) feeling that I am often failing with my diabetes regimen using a 6-point scale: where 1=no distress to 6=severe distress for a total possible score of 2 (not a problem) to 12 (very serious problem), with higher score corresponding to higher distress. LS means were obtained from MMRM model including all available post baseline values. A negative change from baseline indicates improvement. |
| Percent Change From Baseline in Body Weight at Week 24 | 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 percent change from baseline indicates a loss in body weight from baseline to Week 24. |
| Change From Baseline in Diabetes Total Treatment Satisfaction Scores as Measured by Total Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) Scores at Week 24 | Baseline to Week 24 | DTSQs is a diabetes-specific measure used to evaluate overall treatment satisfaction and perception of hyperglycemia and hypoglycemia events. It consists of 8 items and the response categories for all items were on a 7-point likert scale.The DTSQs response options ranged from 0 (very dissatisfied) to 6 (very satisfied). Responses to item 1, 4, 5, 6, 7 and 8 were summarized to determine the total treatment satisfaction score which ranged from 0 (very dissatisfied) to 36 (very satisfied), with a higher score corresponding to higher satisfaction . LS means were obtained from MMRM model including all available post baseline values. A positive change from baseline indicates improvement. |
Countries
Canada, United States
Participant flow
Recruitment details
The study was conducted at 75 study sites in 2 countries from March 2015 to February 2017.
Pre-assignment details
1099 participants were screened and 793 participants with Type 1 diabetes mellitus who had inadequate glycemic control with insulin therapy were randomized into three treatment groups: Placebo, Sotagliflozin 200 mg, Sotagliflozin 400 mg.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Two placebo-matching sotagliflozin tablets, once daily, orally for 24 weeks followed by a 28 week extension period. | 268 |
| Sotagliflozin 200 mg Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), once daily, orally, for 24 weeks followed by a 28 week extension period. | 263 |
| Sotagliflozin 400 mg Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, for 24 weeks followed by a 28 week extension period. | 262 |
| Total | 793 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 13 | 17 |
| Overall Study | Lost to Follow-up | 3 | 2 | 1 |
| Overall Study | Non-Compliance With Study Drug | 2 | 0 | 1 |
| Overall Study | Other than specified above | 4 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 | 0 |
| Overall Study | Pregnancy | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 3 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 26 | 19 | 20 |
Baseline characteristics
| Characteristic | Sotagliflozin 200 mg | Total | Placebo | Sotagliflozin 400 mg |
|---|---|---|---|---|
| Age, Continuous | 46.6 years STANDARD_DEVIATION 13.48 | 46.1 years STANDARD_DEVIATION 13.11 | 45.2 years STANDARD_DEVIATION 12.72 | 46.4 years STANDARD_DEVIATION 13.12 |
| Baseline Daily Total Insulin Dose | 0.72 International Unit per kilogram (IU/kg) STANDARD_DEVIATION 0.386 | 0.73 International Unit per kilogram (IU/kg) STANDARD_DEVIATION 0.36 | 0.74 International Unit per kilogram (IU/kg) STANDARD_DEVIATION 0.357 | 0.72 International Unit per kilogram (IU/kg) STANDARD_DEVIATION 0.335 |
| Body Mass Index (BMI) | 29.81 kilograms/square meter (kg/m^2) STANDARD_DEVIATION 5.686 | 29.66 kilograms/square meter (kg/m^2) STANDARD_DEVIATION 5.387 | 29.55 kilograms/square meter (kg/m^2) STANDARD_DEVIATION 5.188 | 29.63 kilograms/square meter (kg/m^2) STANDARD_DEVIATION 5.297 |
| Body Weight | 86.96 kilograms (kg) STANDARD_DEVIATION 18.539 | 86.92 kilograms (kg) STANDARD_DEVIATION 18.065 | 87.30 kilograms (kg) STANDARD_DEVIATION 17.709 | 86.50 kilograms (kg) STANDARD_DEVIATION 18.004 |
| Duration of Diabetes | 25.0 years STANDARD_DEVIATION 13.15 | 24.4 years STANDARD_DEVIATION 12.8 | 24.2 years STANDARD_DEVIATION 12.38 | 24.0 years STANDARD_DEVIATION 12.88 |
| Hemoglobin A1C (A1C) | 7.61 percentage of A1C STANDARD_DEVIATION 0.735 | 7.57 percentage of A1C STANDARD_DEVIATION 0.723 | 7.54 percentage of A1C STANDARD_DEVIATION 0.712 | 7.56 percentage of A1C STANDARD_DEVIATION 0.724 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 10 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 28 Participants | 9 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 4 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 19 Participants | 9 Participants | 6 Participants |
| Race (NIH/OMB) White | 241 Participants | 731 Participants | 244 Participants | 246 Participants |
| Sex: Female, Male Female | 137 Participants | 410 Participants | 131 Participants | 142 Participants |
| Sex: Female, Male Male | 126 Participants | 383 Participants | 137 Participants | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 268 | 0 / 263 | 0 / 262 |
| other Total, other adverse events | 129 / 268 | 132 / 263 | 130 / 262 |
| serious Total, serious adverse events | 20 / 268 | 27 / 263 | 29 / 262 |
Outcome results
Primary
Change From Baseline in A1C at Week 24
Baseline value was defined as the last value collected prior to the first dose of double-blind study medication. Least square (LS) means were obtained from a mixed-effects model for repeated measures (MMRM) that included fixed, categorical effects of treatment, randomization strata of insulin delivery method (MDI, CSII), randomization strata of Week -2 A1C (\<= 8.5%, \>8.5%), time (study week), a treatment-by-time interaction, and baseline A1C-by-time interaction as a covariate. A negative change from Baseline (a lower A1C value at Week 24) indicates an improvement.
Time frame: Baseline to Week 24
Population: Modified intent to treat (mITT) analysis set included all randomly assigned participants who have taken at least 1 dose of study drug. Here, Overall Number of Participants Analyzed signified participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in A1C at Week 24 | -0.07 percentage of A1C | Standard Error 0.036 |
| Sotagliflozin 200 mg | Change From Baseline in A1C at Week 24 | -0.43 percentage of A1C | Standard Error 0.036 |
| Sotagliflozin 400 mg | Change From Baseline in A1C at Week 24 | -0.48 percentage of A1C | Standard Error 0.036 |
p-value: <0.001MMRM
p-value: <0.001MMRM
Secondary
Absolute Change From Baseline in Body Weight at 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.
Time frame: Baseline to Week 24
Population: Analysis performed on mITT analysis set. Here, Overall Number of Participants Analyzed signified participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in Body Weight at Week 24 | 0.78 kilograms (kg) | Standard Error 0.187 |
| Sotagliflozin 200 mg | Absolute Change From Baseline in Body Weight at Week 24 | -1.57 kilograms (kg) | Standard Error 0.188 |
| Sotagliflozin 400 mg | Absolute Change From Baseline in Body Weight at Week 24 | -2.67 kilograms (kg) | Standard Error 0.188 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.00195% CI: [-2.85, -1.85]MMRM
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.00195% CI: [-3.95, -2.94]MMRM
Secondary
Change From Baseline in Diabetes Distress Scores as Measured by 2-item Diabetes Distress Screening Scale (DDS2) Scores at Week 24
The DDS2 is a 2-item diabetes distress screening instrument where respondents rated, on a 6-point scale, the degree to which the following items caused distress: (1) feeling overwhelmed by the demands of living with diabetes, and (2) feeling that I am often failing with my diabetes regimen using a 6-point scale: where 1=no distress to 6=severe distress for a total possible score of 2 (not a problem) to 12 (very serious problem), with higher score corresponding to higher distress. LS means were obtained from MMRM model including all available post baseline values. A negative change from baseline indicates improvement.
Time frame: Baseline to Week 24
Population: Analysis performed on mITT analysis set. Here, Overall Number of Participants Analyzed signified participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Diabetes Distress Scores as Measured by 2-item Diabetes Distress Screening Scale (DDS2) Scores at Week 24 | 0.3 units on a scale | Standard Error 0.11 |
| Sotagliflozin 200 mg | Change From Baseline in Diabetes Distress Scores as Measured by 2-item Diabetes Distress Screening Scale (DDS2) Scores at Week 24 | -0.4 units on a scale | Standard Error 0.11 |
| Sotagliflozin 400 mg | Change From Baseline in Diabetes Distress Scores as Measured by 2-item Diabetes Distress Screening Scale (DDS2) Scores at Week 24 | -0.5 units on a scale | Standard Error 0.11 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.00195% CI: [-1, -0.5]MMRM
Secondary
Change From Baseline in Diabetes Total Treatment Satisfaction Scores as Measured by Total Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) Scores at Week 24
DTSQs is a diabetes-specific measure used to evaluate overall treatment satisfaction and perception of hyperglycemia and hypoglycemia events. It consists of 8 items and the response categories for all items were on a 7-point likert scale.The DTSQs response options ranged from 0 (very dissatisfied) to 6 (very satisfied). Responses to item 1, 4, 5, 6, 7 and 8 were summarized to determine the total treatment satisfaction score which ranged from 0 (very dissatisfied) to 36 (very satisfied), with a higher score corresponding to higher satisfaction . LS means were obtained from MMRM model including all available post baseline values. A positive change from baseline indicates improvement.
Time frame: Baseline to Week 24
Population: Analysis performed on mITT analysis set. Here, Overall Number of Participants Analyzed signified participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Diabetes Total Treatment Satisfaction Scores as Measured by Total Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) Scores at Week 24 | -0.4 units on a scale | Standard Error 0.3 |
| Sotagliflozin 200 mg | Change From Baseline in Diabetes Total Treatment Satisfaction Scores as Measured by Total Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) Scores at Week 24 | 2.1 units on a scale | Standard Error 0.31 |
| Sotagliflozin 400 mg | Change From Baseline in Diabetes Total Treatment Satisfaction Scores as Measured by Total Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) Scores at Week 24 | 2.1 units on a scale | Standard Error 0.31 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.00195% CI: [1.8, 3.3]MMRM
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
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 change from baseline indicates a lower glucose at Week 24 compared to baseline.
Time frame: Baseline to Week 24
Population: Analysis performed on mITT analysis set. Here, Overall Number of Participants Analyzed signified participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | 0.21 millimole per liter (mmol/L) | Standard Error 0.191 |
| Sotagliflozin 200 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -0.34 millimole per liter (mmol/L) | Standard Error 0.192 |
| Sotagliflozin 400 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -0.78 millimole per liter (mmol/L) | Standard Error 0.193 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.00195% CI: [-1.5, -0.48]MMRM
Secondary
Change From Baseline in Mean Daily Bolus Insulin Dose at Week 24
The mean bolus insulin dose in international units per 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 change from Baseline indicated a reduction in the amount of bolus insulin used between Baseline and Week 24.
Time frame: Baseline to Week 24
Population: Analysis performed on mITT analysis set. Here, Overall Number of Participants Analyzed signified participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Daily Bolus Insulin Dose at Week 24 | -0.84 IU/day | Standard Error 0.688 |
| Sotagliflozin 200 mg | Change From Baseline in Mean Daily Bolus Insulin Dose at Week 24 | -2.33 IU/day | Standard Error 0.692 |
| Sotagliflozin 400 mg | Change From Baseline in Mean Daily Bolus Insulin Dose at Week 24 | -4.13 IU/day | Standard Error 0.692 |
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: 0.195% CI: [-3.3, 0.3]MMRM
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.00195% CI: [-5.09, -1.5]MMRM
Secondary
Percentage of Participants With A1C <7.0% (at Week 24) and No Episode of Severe Hypoglycemia and No Episode of Diabetic Ketoacidosis (DKA) Upto Week 24
Blood samples were collected for the assessment of Hemoglobin A1C to determine the participants with A1C value \<7.0%. A central blinded adjudication process determined whether participants experienced either DKA or Severe Hypoglycemia. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis.
Time frame: Baseline to Week 24
Population: Analysis performed on mITT analysis set.
| 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) Upto Week 24 | 21.6 percentage of participants |
| Sotagliflozin 200 mg | Percentage of Participants With A1C <7.0% (at Week 24) and No Episode of Severe Hypoglycemia and No Episode of Diabetic Ketoacidosis (DKA) Upto Week 24 | 33.5 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) Upto Week 24 | 43.5 percentage of participants |
Comparison: A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported. The hierarchical testing sequence continued only when previous endpoint of each treatment comparison was statistically significant at 0.05 level.p-value: 0.00295% CI: [4.28, 19.36]Cochran-Mantel-Haenszel
Comparison: Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).p-value: <0.00195% CI: [14.1, 29.64]Cochran-Mantel-Haenszel
Secondary
Percent Change From Baseline in Body Weight at 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 percent change from baseline indicates a loss in body weight from baseline to Week 24.
Time frame: Baseline to Week 24
Population: Analysis performed on mITT analysis set. Here, Overall Number of Participants Analyzed signified participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Body Weight at Week 24 | 0.92 percent change | Standard Error 0.212 |
| Sotagliflozin 200 mg | Percent Change From Baseline in Body Weight at Week 24 | -1.87 percent change | Standard Error 0.213 |
| Sotagliflozin 400 mg | Percent Change From Baseline in Body Weight at Week 24 | -3.10 percent change | Standard Error 0.213 |