Safety and Efficacy of Sotagliflozin (LX4211) in Patients With Inadequately Controlled Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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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).

Official Title
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A Phase 2, Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of LX4211 in Patients With Inadequately Controlled Type 1 Diabetes Mellitus

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Sotagliflozin
* Drug: Placebo
* Drug: Sotagliflozin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sotagliflozin 400 mg - Pioneer Group<br>Sotagliflozin 400 milligram (mg) (two 200 mg tablets), once daily, orally, before breakfast for 29 days; open label administration. | Drug: Sotagliflozin<br>* 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.<br>* Other names: LX4211;|
| Placebo Comparator: Placebo - Expansion Group<br>Two placebo-matching sotagliflozin tablets, once daily, orally, before breakfast for 29 days; double-blind administration. | Drug: Placebo<br>* Participants received placebo-matching sotagliflozin tablets once daily for 29 days.<br>|
| Experimental: Sotagliflozin 400 mg - Expansion Group<br>Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before breakfast for 29 days; double-blind administration. | Drug: Sotagliflozin<br>* Participants received sotagliflozin once daily for 29 days; pioneer participants completed dosing prior to dosing any other study participants.<br>* Other names: LX4211;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Day 3 to Day 27 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Day 3 to Day 27 | 
| 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. | Baseline, Day 3 to Day 27 | 
| 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. | Baseline, Day 29 | 
| 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. | 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 | 
| 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. | Baseline, Day 3 to Day 27 | 
| 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. | From 15 minutes before start of mixed meal until 180 min post start of mixed meal, on Day 1 and Day 29 |