Type 1 Diabetes Mellitus
Conditions
Brief summary
This Phase 2 study was intended to assess the pharmacodynamics (PD), pharmacokinetics (PK), safety and efficacy of sotagliflozin following daily oral administration for 29 days in participants with type 1 diabetes mellitus (T1DM).
Interventions
DRUGPlacebo
Participants received placebo-matching sotagliflozin tablets once daily for 29 days.
DRUGSotagliflozin
Participants received sotagliflozin once daily for 29 days. Pioneer Group participants were to have completed dosing prior to any study drug administration in Expansion Groups.
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 55 Years
Healthy volunteers
No
Inclusion criteria
* Adults \>=18 to \<=55 years of age * Confirmed diagnosis of T1DM, diagnosed prior to age 40 years, and for at least 6 months prior to Screening * Willing to refrain from using carbohydrate counting to adjust insulin during the study * Willing and able to wear and operate a continuous glucose monitor * Willing and able to self-assess blood glucose * Willing and able to provide written informed consent.
Exclusion criteria
* History of type 2 diabetes mellitus or diabetes resulting from acromegaly, Cushing's disease, chronic pancreatitis, or pancreatectomy * Two or more severe episodes of hypoglycemia that required emergency treatment within 3 months prior to Screening * Use of premixed insulin * History of diabetic ketoacidosis within 1 year of screening * Presence of active hepatic disease or clinically significant abnormal liver function tests * History of chronic pancreatitis * Participants with a history of heart attack, severe/unstable angina, or coronary revascularization procedure * History of clinically significant cardiac arrhythmias within 1 year prior to screening * Participants with congestive heart failure * Participants with uncontrolled Stage III hypertension * History of human immunodeficiency virus (HIV) or hepatitis C * History of illicit drug or alcohol abuse within 12 months prior to Screening * Use of any investigational agent or device within 30 days prior to Screening or any therapeutic protein or antibody within 90 days prior to Screening * Use of medication or herbal supplements taken for weight loss within 2 weeks of screening * Chronic use of any antidiabetic therapy other than insulin within 2 months prior to Screening * Use of systemic or inhaled corticosteroids within 2 weeks prior to Screening * Participants who underwent major surgery within 6 months prior to Screening * Inability or difficulty swallowing whole tablets or capsules * Women who were pregnant or breastfeeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Total Daily Bolus Amount of Exogenous Insulin Required Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Baseline, Day 3 to Day 27 | Baseline was calculated as the mean value from Day -6 to -2 for Expansion groups and from Day -6 to Day -3 for Pioneer Group. Percent mean change from baseline was calculated as 100\*(sum \[each daily value - baseline\]/number of assessments)/baseline over Days 3 to 27. Least squares (LS) Means and confidence interval (CI) for the Expansion groups were based on an analysis of covariance (ANCOVA) model with covariates of baseline mean total bolus insulin, treatment group, factor used to stratify the randomization (screening A1C \<= 8%, \> 8%), and random effect of participant\*treatment group. LS Means and CI for the Pioneer Group were based on the arithmetic treatment mean. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Total Daily Amount of Exogenous Insulin (Total Daily Bolus + Total Daily Basal) Required Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Baseline, Day 3 to Day 27 | Baseline was calculated as the mean value from Day -6 to -2 for Expansion groups and from Day -6 to Day -3 for Pioneer Group. Percent mean change from baseline was calculated as 100\*(sum \[each daily value - baseline\]/ number of assessments)/baseline over Days 3 to 27. LS Means and CI for the Expansion groups were based on an ANCOVA model. LS Means and CI for the Pioneer Group were based on the arithmetic treatment mean. |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Day 29 | Baseline, Day 29 | Baseline was defined as the last non-missing assessment prior to first dose of study drug. Change in FPG was calculated by subtracting baseline value from Day 29 value. LS Means and CI for the Expansion groups were based on a linear mixed repeated measures model. |
| Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Baseline, Day 3 to Day 27 | Baseline was calculated as the mean value from Day -6 to -2 for Expansion groups and from Day -6 to Day -3 for Pioneer Group. Percent mean change from baseline was calculated as 100\*(sum \[each daily value - baseline\] / number of assessments)/baseline over Days 3 to 27. Percent change was calculated and is presented separately for each meal: i.e., breakfast, lunch and dinner. LS Means and CI for the Expansion groups were based on an ANCOVA model . LS Means and CI for the Pioneer Group were based on the arithmetic treatment mean. |
| Change From Baseline in Percent Time Per Day Spent in Euglycemic Range (>=70 and <=180 mg/dL) Over Days 3 to 27 (Treatment Outpatient Period) Based on Continuous Glucose Monitoring | Baseline, Day 3 to Day 27 | Baseline was calculated as the mean value from Day -6 to -2 for Expansion groups and from Day -6 to Day -3 for Pioneer Group. Change in percent time per day spent in euglycemic range was calculated by subtracting baseline value from Day 29 value. LS Means and CI for the Expansion groups were based on a mixed model. LS mean and CI for the Pioneer Group were based on the arithmetic treatment mean. |
| Change From Day 1 in 3-hour Urinary Glucose Excretion Following a Mixed Meal Tolerance Test (MMTT) to Day 29: Expansion Groups | From 15 minutes before start of mixed meal until 180 min post start of mixed meal, on Day 1 and Day 29 | A MMTT with frequent blood sample collection and with urine collection was performed on Day 1 and Day 29. Participants fasted (with the exception of water or non-caffeinated, calorie-free beverages) for at least 8 hours before the start of the MMTT and until the final blood sample was collected. Study drug was to be given within 15 minutes before liquid Boost® Original breakfast. Participants were asked to void immediately before blood sample 15 minutes before start of mixed meal and immediately after the 180-minute (3 hour) blood sample was collected, and all urine between the -15 minute and post-180-minute time points was collected for urine glucose calculation. Change was calculated by subtracting Day 1 value from Day 29 value. LS Means were based on a linear mixed model. |
| Change From Day 1 in 3-hour Plasma Glucose AUC (AUC0-3 h) Following a Mixed Meal Tolerance Test (MMTT) at Day 29: Expansion Groups | Prior to start of mixed meal and 30, 60, 90, 120 and 180 min post start of mixed meal, on Day 1 and Day 29 | A MMTT with frequent blood sample collection and with urine collection was performed on Day 1 and Day 29. Participants fasted (with the exception of water or non-caffeinated, calorie-free beverages) for at least 8 hours before the start of the MMTT and until the final blood sample was collected. Study drug was to be given within 15 minutes before liquid Boost® Original breakfast. The area under the plasma concentration-time curve (AUC) from time-zero to 3h postdose on Day 1 and Day 29 was calculated using the linear-up/log-down trapezoidal rule. Change was calculated by subtracting Day 1 value from Day 29 value. LS Means and CI were based on a linear mixed model. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 7 sites in United States between 08 February 2013 and 13 January 2014. A total of 36 participants were enrolled and treated in the study which consisted of 2 groups: Pioneer Group and Expansion Groups.
Pre-assignment details
In this study, first 3 participants (Pioneer Group) received open-label sotagliflozin. Once dosing was completed in Pioneer Group, 33 different participants were randomized in 1:1 ratio to Expansion groups (sotagliflozin or placebo). Randomization was stratified according to baseline glycosylated hemoglobin (A1C \[\<=8 percent {%} vs. \>8%\]).
Participants by arm
| Arm | Count |
|---|---|
| Sotagliflozin 400 mg - Pioneer Group Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before breakfast for 29 days; open label administration. | 3 |
| Placebo - Expansion Group Two placebo-matching sotagliflozin tablets, once daily, orally, before breakfast for 29 days; double-blind administration. | 17 |
| Sotagliflozin 400 mg - Expansion Group Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before breakfast for 29 days; double-blind administration. | 16 |
| Total | 36 |
Baseline characteristics
| Characteristic | Total | Sotagliflozin 400 mg - Pioneer Group | Sotagliflozin 400 mg - Expansion Group | Placebo - Expansion Group |
|---|---|---|---|---|
| Age, Continuous | 36.8 years STANDARD_DEVIATION 11.39 | 33.3 years STANDARD_DEVIATION 2.08 | 38.8 years STANDARD_DEVIATION 12.11 | 35.6 years STANDARD_DEVIATION 11.75 |
| Height | 170.2 centimeter (cm) STANDARD_DEVIATION 11.5 | 172.3 centimeter (cm) STANDARD_DEVIATION 8.5 | 169.5 centimeter (cm) STANDARD_DEVIATION 12.2 | 170.5 centimeter (cm) STANDARD_DEVIATION 11.7 |
| Insulin Therapy Continuous Subcutaneous Insulin Infusion (CSII) | 25 Participants | 3 Participants | 10 Participants | 12 Participants |
| Insulin Therapy Multiple Daily Injections (MDI) | 11 Participants | 0 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 32 Participants | 2 Participants | 16 Participants | 14 Participants |
| Sex: Female, Male Female | 19 Participants | 2 Participants | 8 Participants | 9 Participants |
| Sex: Female, Male Male | 17 Participants | 1 Participants | 8 Participants | 8 Participants |
| Weight | 78.1 kilogram (kg) STANDARD_DEVIATION 15.1 | 84.5 kilogram (kg) STANDARD_DEVIATION 19.2 | 78.4 kilogram (kg) STANDARD_DEVIATION 14.8 | 76.8 kilogram (kg) STANDARD_DEVIATION 15.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 17 | 0 / 16 |
| other Total, other adverse events | 1 / 3 | 12 / 17 | 14 / 16 |
| serious Total, serious adverse events | 0 / 3 | 0 / 17 | 2 / 16 |
Outcome results
Primary
Percent Change From Baseline in Total Daily Bolus Amount of Exogenous Insulin Required Calculated Over Days 3 to 27 (Treatment Outpatient Period)
Baseline was calculated as the mean value from Day -6 to -2 for Expansion groups and from Day -6 to Day -3 for Pioneer Group. Percent mean change from baseline was calculated as 100\*(sum \[each daily value - baseline\]/number of assessments)/baseline over Days 3 to 27. Least squares (LS) Means and confidence interval (CI) for the Expansion groups were based on an analysis of covariance (ANCOVA) model with covariates of baseline mean total bolus insulin, treatment group, factor used to stratify the randomization (screening A1C \<= 8%, \> 8%), and random effect of participant\*treatment group. LS Means and CI for the Pioneer Group were based on the arithmetic treatment mean.
Time frame: Baseline, Day 3 to Day 27
Population: Analysis was performed using ITT population. Here, overall number of participants analyzed=participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sotagliflozin 400 mg - Pioneer Group | Percent Change From Baseline in Total Daily Bolus Amount of Exogenous Insulin Required Calculated Over Days 3 to 27 (Treatment Outpatient Period) | -46.32 percent change |
| Placebo - Expansion Group | Percent Change From Baseline in Total Daily Bolus Amount of Exogenous Insulin Required Calculated Over Days 3 to 27 (Treatment Outpatient Period) | -7.00 percent change |
| Sotagliflozin 400 mg - Expansion Group | Percent Change From Baseline in Total Daily Bolus Amount of Exogenous Insulin Required Calculated Over Days 3 to 27 (Treatment Outpatient Period) | -32.14 percent change |
Comparison: Between-group comparison of the 2 Expansion Groups was based on an ANCOVA model with covariates of baseline mean total daily bolus insulin, treatment group, factor used to stratify the randomization (screening A1C \<= 8%, \> 8%), and random effect of participant\*treatment group.p-value: 0.00795% CI: [-42.78, -7.49]ANCOVA
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Day 29
Baseline was defined as the last non-missing assessment prior to first dose of study drug. Change in FPG was calculated by subtracting baseline value from Day 29 value. LS Means and CI for the Expansion groups were based on a linear mixed repeated measures model.
Time frame: Baseline, Day 29
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sotagliflozin 400 mg - Pioneer Group | Change From Baseline in Fasting Plasma Glucose (FPG) at Day 29 | -54.2 milligram/deciliter (mg/dL) |
| Placebo - Expansion Group | Change From Baseline in Fasting Plasma Glucose (FPG) at Day 29 | 10.0 milligram/deciliter (mg/dL) |
| Sotagliflozin 400 mg - Expansion Group | Change From Baseline in Fasting Plasma Glucose (FPG) at Day 29 | -12.5 milligram/deciliter (mg/dL) |
Secondary
Change From Baseline in Percent Time Per Day Spent in Euglycemic Range (>=70 and <=180 mg/dL) Over Days 3 to 27 (Treatment Outpatient Period) Based on Continuous Glucose Monitoring
Baseline was calculated as the mean value from Day -6 to -2 for Expansion groups and from Day -6 to Day -3 for Pioneer Group. Change in percent time per day spent in euglycemic range was calculated by subtracting baseline value from Day 29 value. LS Means and CI for the Expansion groups were based on a mixed model. LS mean and CI for the Pioneer Group were based on the arithmetic treatment mean.
Time frame: Baseline, Day 3 to Day 27
Population: Analysis was performed on ITT population. Here, overall number of participants analyzed=participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sotagliflozin 400 mg - Pioneer Group | Change From Baseline in Percent Time Per Day Spent in Euglycemic Range (>=70 and <=180 mg/dL) Over Days 3 to 27 (Treatment Outpatient Period) Based on Continuous Glucose Monitoring | 6.6 percent time per day |
| Placebo - Expansion Group | Change From Baseline in Percent Time Per Day Spent in Euglycemic Range (>=70 and <=180 mg/dL) Over Days 3 to 27 (Treatment Outpatient Period) Based on Continuous Glucose Monitoring | -1.2 percent time per day |
| Sotagliflozin 400 mg - Expansion Group | Change From Baseline in Percent Time Per Day Spent in Euglycemic Range (>=70 and <=180 mg/dL) Over Days 3 to 27 (Treatment Outpatient Period) Based on Continuous Glucose Monitoring | 11.1 percent time per day |
Secondary
Change From Day 1 in 3-hour Plasma Glucose AUC (AUC0-3 h) Following a Mixed Meal Tolerance Test (MMTT) at Day 29: Expansion Groups
A MMTT with frequent blood sample collection and with urine collection was performed on Day 1 and Day 29. Participants fasted (with the exception of water or non-caffeinated, calorie-free beverages) for at least 8 hours before the start of the MMTT and until the final blood sample was collected. Study drug was to be given within 15 minutes before liquid Boost® Original breakfast. The area under the plasma concentration-time curve (AUC) from time-zero to 3h postdose on Day 1 and Day 29 was calculated using the linear-up/log-down trapezoidal rule. Change was calculated by subtracting Day 1 value from Day 29 value. LS Means and CI were based on a linear mixed model.
Time frame: Prior to start of mixed meal and 30, 60, 90, 120 and 180 min post start of mixed meal, on Day 1 and Day 29
Population: Analysis was performed on ITT population. Here, overall number of participants analyzed=participants with available data for this outcome measure. Data for this outcome measure was not analyzed for Pioneer Group participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sotagliflozin 400 mg - Pioneer Group | Change From Day 1 in 3-hour Plasma Glucose AUC (AUC0-3 h) Following a Mixed Meal Tolerance Test (MMTT) at Day 29: Expansion Groups | -140.83 mg*h/dL |
| Placebo - Expansion Group | Change From Day 1 in 3-hour Plasma Glucose AUC (AUC0-3 h) Following a Mixed Meal Tolerance Test (MMTT) at Day 29: Expansion Groups | -308.51 mg*h/dL |
Secondary
Change From Day 1 in 3-hour Urinary Glucose Excretion Following a Mixed Meal Tolerance Test (MMTT) to Day 29: Expansion Groups
A MMTT with frequent blood sample collection and with urine collection was performed on Day 1 and Day 29. Participants fasted (with the exception of water or non-caffeinated, calorie-free beverages) for at least 8 hours before the start of the MMTT and until the final blood sample was collected. Study drug was to be given within 15 minutes before liquid Boost® Original breakfast. Participants were asked to void immediately before blood sample 15 minutes before start of mixed meal and immediately after the 180-minute (3 hour) blood sample was collected, and all urine between the -15 minute and post-180-minute time points was collected for urine glucose calculation. Change was calculated by subtracting Day 1 value from Day 29 value. LS Means were based on a linear mixed model.
Time frame: From 15 minutes before start of mixed meal until 180 min post start of mixed meal, on Day 1 and Day 29
Population: Analysis was performed on ITT population. Here, overall number of participants analyzed=participants with available data for this outcome measure. Data for this outcome measure was not analyzed for Pioneer Group participants.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sotagliflozin 400 mg - Pioneer Group | Change From Day 1 in 3-hour Urinary Glucose Excretion Following a Mixed Meal Tolerance Test (MMTT) to Day 29: Expansion Groups | -6.34 gram per 3 hour |
| Placebo - Expansion Group | Change From Day 1 in 3-hour Urinary Glucose Excretion Following a Mixed Meal Tolerance Test (MMTT) to Day 29: Expansion Groups | 8.30 gram per 3 hour |
Secondary
Percent Change From Baseline in Total Daily Amount of Exogenous Insulin (Total Daily Bolus + Total Daily Basal) Required Calculated Over Days 3 to 27 (Treatment Outpatient Period)
Baseline was calculated as the mean value from Day -6 to -2 for Expansion groups and from Day -6 to Day -3 for Pioneer Group. Percent mean change from baseline was calculated as 100\*(sum \[each daily value - baseline\]/ number of assessments)/baseline over Days 3 to 27. LS Means and CI for the Expansion groups were based on an ANCOVA model. LS Means and CI for the Pioneer Group were based on the arithmetic treatment mean.
Time frame: Baseline, Day 3 to Day 27
Population: Analysis was performed on ITT population. Here, overall number of participants analyzed=participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sotagliflozin 400 mg - Pioneer Group | Percent Change From Baseline in Total Daily Amount of Exogenous Insulin (Total Daily Bolus + Total Daily Basal) Required Calculated Over Days 3 to 27 (Treatment Outpatient Period) | -27.00 percent change |
| Placebo - Expansion Group | Percent Change From Baseline in Total Daily Amount of Exogenous Insulin (Total Daily Bolus + Total Daily Basal) Required Calculated Over Days 3 to 27 (Treatment Outpatient Period) | -1.20 percent change |
| Sotagliflozin 400 mg - Expansion Group | Percent Change From Baseline in Total Daily Amount of Exogenous Insulin (Total Daily Bolus + Total Daily Basal) Required Calculated Over Days 3 to 27 (Treatment Outpatient Period) | -15.52 percent change |
Secondary
Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period)
Baseline was calculated as the mean value from Day -6 to -2 for Expansion groups and from Day -6 to Day -3 for Pioneer Group. Percent mean change from baseline was calculated as 100\*(sum \[each daily value - baseline\] / number of assessments)/baseline over Days 3 to 27. Percent change was calculated and is presented separately for each meal: i.e., breakfast, lunch and dinner. LS Means and CI for the Expansion groups were based on an ANCOVA model . LS Means and CI for the Pioneer Group were based on the arithmetic treatment mean.
Time frame: Baseline, Day 3 to Day 27
Population: Analysis was performed using ITT population. Here, number analyzed=participants with available data for this outcome measure.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Sotagliflozin 400 mg - Pioneer Group | Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Before Lunch | -59.02 percent change |
| Sotagliflozin 400 mg - Pioneer Group | Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Before Breakfast | -42.19 percent change |
| Sotagliflozin 400 mg - Pioneer Group | Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Before Dinner | -34.83 percent change |
| Placebo - Expansion Group | Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Before Lunch | 3.94 percent change |
| Placebo - Expansion Group | Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Before Breakfast | 10.79 percent change |
| Placebo - Expansion Group | Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Before Dinner | 33.34 percent change |
| Sotagliflozin 400 mg - Expansion Group | Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Before Breakfast | -25.16 percent change |
| Sotagliflozin 400 mg - Expansion Group | Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Before Dinner | -24.02 percent change |
| Sotagliflozin 400 mg - Expansion Group | Percent Mean Change From Baseline in Daily Bolus Amount of Exogenous Insulin Required at Each Meal Calculated Over Days 3 to 27 (Treatment Outpatient Period) | Before Lunch | -25.85 percent change |