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

Phase 2

Completed

Conditions: Type 1 Diabetes Mellitus

Interventions: Drug: Sotagliflozin
Drug: Placebo

Registration Number: NCT01742208

Lead Sponsor: Lexicon Pharmaceuticals

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 36

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sotagliflozin 400 mg - Expansion Group	Sotagliflozin	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before breakfast for 29 days; double-blind administration.
Placebo - Expansion Group	Placebo	Two placebo-matching sotagliflozin tablets, once daily, orally, before breakfast for 29 days; double-blind administration.
Sotagliflozin 400 mg - Pioneer Group	Sotagliflozin	Sotagliflozin 400 milligram (mg) (two 200 mg tablets), once daily, orally, before breakfast for 29 days; open label administration.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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.
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.
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.
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.