Efficacy, Safety, and Tolerability Study of Sotagliflozin as Adjunct Therapy in Adult Patients With Type 1 Diabetes Mellitus Who Have Inadequate Glycemic Control With Insulin Therapy

Study Overview
=================
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.

Official Title
-----------------
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of LX4211 as Adjunct Therapy in Adult Patients With Type 1 Diabetes Mellitus Who Have Inadequate Glycemic Control With Insulin Therapy

Conditions
-----------------
Type 1 Diabetes Mellitus

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participant who gave 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 treated with insulin or insulin analog delivered via continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI). Willing and were able to perform Self-monitoring of blood glucose (SMBG) and completed the study diary as required per protocol. At the Screening Visit, A1C was 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 screening. Chronic systemic corticosteroid use. Type 2 diabetes mellitus (T2DM), or severely uncontrolled T1D as determined by the Investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period. | Drug: Placebo<br>* Placebo, once daily, before the first meal of the day<br>|
| Experimental: Sotagliflozin 200 mg<br>Sotagliflozin 200 milligram (mg) (one 200 mg tablet and one placebo tablet), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period. | Drug: Sotagliflozin<br>* Low dose Sotagliflozin,once daily, before the first meal of the day<br>|
| Experimental: Sotagliflozin 400 mg<br>Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 24 weeks followed by a 28-week extension period. | Drug: Sotagliflozin<br>* High dose Sotagliflozin, once daily, before the first meal of the day<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 reduction of A1C value at Week 24) indicates an improvement. | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With A1C <7.0% at Week 24 and no Episode of Severe Hypoglycemia, and no Episode of Diabetic Ketoacidosis (DKA) From Baseline to Week 24 | The composite endpoint included blood samples for the assessment of Hemoglobin A1C to determine the participants with a value <7.0% and a central blinded adjudication process to determine whether participants experienced either DKA or severe hypoglycemia. Only positively adjudicated severe hypoglycemia and diabetic ketoacidosis were included in the analysis. | Baseline to Week 24 | 
| 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. | Baseline to Week 24 | 
| Change From Baseline in Mean Daily Bolus Insulin Dose at Week 24 | The mean bolus insulin dose in international units/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 and a positive change from baseline indicated an increase in the amount of bolus insulin used between baseline and Week 24. | Baseline to Week 24 | 
| 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 level at Week 24 compared to baseline and a positive change from baseline indicates an increase in glucose level at Week 24 compared to baseline. | Baseline to Week 24 | 
| Change From Baseline in Diabetes Treatment Satisfaction Questionnaire (DTSQ) Score at Week 24 | The DTSQ instrument contains 8 items assessing overall treatment satisfaction, treatment convenience and flexibility, satisfaction with understanding of diabetes, willingness to continue present treatment and to recommend it to others, and frequency of unacceptably high and unacceptably low blood glucose levels. 6 items (1, 4, 5, 6, 7 and 8) (excluding perceived hyperglycemia and hypoglycemia items) were scored using a 7- point scale where 0=very dissatisfied to 6= very satisfied for a total possible score of 0 (very dissatisfied) to 36 (very satisfied), where higher scores indicate higher satisfaction from treatment. Two items (Q2 and 3), which were not included, measured perceived hyperglycemia and hypoglycemia, respectively. 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 positive change from baseline indicates improvement. | Baseline to Week 24 | 
| Change From Baseline in 2-Item Diabetes Distress Screen 2 (DDS2) Score at Week 24 | DDS2 is a 2-item diabetes distress screening instrument where participants rated 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 to 12. LS means were obtained from MMRM model including all available post baseline values. A negative change from baseline indicates improvement. | Baseline to Week 24 | 
| 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. | Baseline to Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
High level of sugar (glucose) in the blood