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
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Brief Summary
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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
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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
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Placebo
* Drug: Sotagliflozin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Two placebo-matching sotagliflozin tables, orally for 24 weeks followed by a 28 week extension period. | Drug: Placebo<br>* Placebo once daily, before first meal of the day.<br>|
| Experimental: Sotagliflozin 200 milligrams (mg)<br>Sotagliflozin 200 mg (one 200 mg tablet and one placebo tablet), orally, for 24 weeks followed by a 28 week extension period. | Drug: Placebo<br>* Placebo once daily, before first meal of the day.<br>Drug: Sotagliflozin<br>* Sotagliflozin once daily, before first meal of the day.<br>* Other names: LX4211;|
| Experimental: Sotagliflozin 400 mg<br>Sotagliflozin 400 mg (two 200 mg tablets), orally, for 24 weeks followed by a 28 week extension period. | Drug: Sotagliflozin<br>* Sotagliflozin once daily, before first meal of the day.<br>* Other names: LX4211;|

What is the study measuring?
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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 lower 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) 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. | Baseline to Week 24 | 
| 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. | Baseline to Week 24 | 
| 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. | 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 at Week 24 compared to baseline. | 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 | 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. | Baseline to Week 24 | 
| 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. | 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 |