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 (inTandem2)

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

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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: Sotagliflozin; Drug: Sotagliflozin

• Study Type: Interventional
• Enrollment (Actual): 782
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4021
    • Lexicon Investigational Site
  • Vienna, Austria, 1010
    • Lexicon Investigational Site
  • Vienna, Austria, 1030
    • Lexicon Investigational Site
  • Vienna, Austria, 1130
    • Lexicon Investigational Site
  • Vienna, Austria, 1160
    • Lexicon Investigational Site
• Belgium
  • Antwerp, Belgium, 2018
    • Lexicon Investigational Site
  • Brussels, Belgium, 1090
    • Lexicon Investigational Site
  • Edegem, Belgium, 2650
    • Lexicon Investigational Site
  • Leuven, Belgium, 3000
    • Lexicon Investigational Site
  • Sint Niklaas, Belgium, 9100
    • Lexicon Investigational Site
• Bulgaria
  • Lovech, Bulgaria, 5500
    • Lexicon Investigational Site
  • Plovdiv, Bulgaria, 4002
    • Lexicon Investigational Site
  • Ruse, Bulgaria, 7002
    • Lexicon Investigational Site
  • Smolyan, Bulgaria, 4700
    • Lexicon Investigational Site
  • Sofia, Bulgaria, 1750
    • Lexicon Investigational Site
  • Varna, Bulgaria, 9000
    • Lexicon Investigational Site
• France
  • Beziers, France, 34500
    • Lexicon Investigational Site
  • Dijon cedex, France, 21079
    • Lexicon Investigational Site
  • Nantes, France, 44000
    • Lexicon Investigational Site
  • Nantes, France, 44093
    • Lexicon Investigational Site
  • Nîmes, France, 30029
    • Lexicon Investigational Site
• Germany
  • Duesseldorf, Germany, 40210
    • Lexicon Investigational Site
  • Hamburg, Germany, 21073
    • Lexicon Investigational Site
  • Hamburg, Germany, 22607
    • Lexicon Investigational Site
  • Hannover, Germany, 30173
    • Lexicon Investigational Site
  • Mainz, Germany, 55116
    • Lexicon Investigational Site
  • Muenster, Germany, 48145
    • Lexicon Investigational Site
  • Neuwied, Germany, 56564
    • Lexicon Investigational Site
• Hungary
  • Budapest, Hungary, 1027
    • Lexicon Investigational Site
  • Budapest, Hungary, 1042
    • Lexicon Investigational Site
  • Budapest, Hungary, 1097
    • Lexicon Investigational Site
  • Budapest, Hungary, 1106
    • Lexicon Investigational Site
  • Budapest, Hungary, 1134
    • Lexicon Investigational Site
  • Gyula, Hungary, 5700
    • Lexicon Investigational Site
  • Hodmezovasarhely, Hungary, 6800
    • Lexicon Investigational Site
  • Zalaegerszeg, Hungary, 8900
    • Lexicon Investigational Site
• Israel
  • Haifa, Israel, 31096
    • Lexicon Investigational Site
  • Holon, Israel, 58100
    • Lexicon Investigational Site
  • Jerusalem, Israel, 91120
    • Lexicon Investigational Site
  • Petah Tikva, Israel, 49202
    • Lexicon Investigational Site
  • Tel Aviv, Israel, 61480
    • Lexicon Investigational Site
  • Tel Hashomer, Israel, 52621
    • Lexicon Investigational Site
  • Zerifin, Israel, 70300
    • Lexicon Investigational Site
• Italy
  • Catania, Italy, 95123
    • Lexicon Investigational Site
  • Milano, Italy, 20132
    • Lexicon Investigational Site
  • Palermo, Italy, 90127
    • Lexicon Investigational Site
  • Perugia, Italy, 06126
    • Lexicon Investigational Site
  • Pisa, Italy, 56124
    • Lexicon Investigational Site
  • Roma, Italy, 00128
    • Lexicon Investigational Site
• Lithuania
  • Jonava, Lithuania, LT-55201
    • Lexicon Investigational Site
  • Kaunas, Lithuania, LT-49449
    • Lexicon Investigational Site
  • Kaunas, Lithuania, LT-50161
    • Lexicon Investigational Site
• Netherlands
  • Dordrecht, Netherlands, 3318
    • Lexicon Investigational Site
• Poland
  • Katowice, Poland, 40-060
    • Lexicon Investigational Site
  • Kraków, Poland, 30-015
    • Lexicon Investigational Site
  • Lodz, Poland, 90-242
    • Lexicon Investigational Site
  • Lublin, Poland, 20-538
    • Lexicon Investigational Site
  • Poznan, Poland, 61-655
    • Lexicon Investigational Site
  • Szczecin, Poland, 70-506
    • Lexicon Investigational Site
  • Warsaw, Poland, 04-736
    • Lexicon Investigational Site
  • Warszawa, Poland, 02-507
    • Lexicon Investigational Site
  • Warszawa, Poland, 01-518
    • Lexicon Investigational Site
• Romania
  • Bacau, Romania, 600238
    • Lexicon Investigational Site
  • Bucuresti, Romania, 010507
    • Lexicon Investigational Site
  • Bucuresti, Romania, 013764
    • Lexicon Investigational Site
  • Buzau, Romania, 120203
    • Lexicon Investigational Site
  • Galati, Romania, 800098
    • Lexicon Investigational Site
  • Oradea, Romania, 410159
    • Lexicon Investigational Site
  • Sibiu, Romania, 550371
    • Lexicon Investigational Site
  • Targu-Mures, Romania, 540142
    • Lexicon Investigational Site
• Slovakia
  • Bratislava, Slovakia, 851 01
    • Lexicon Investigational Site
  • Bratislava, Slovakia, 821 02
    • Lexicon Investigational Site
  • Kosice, Slovakia, 040 01
    • Lexicon Investigational Site
  • Nove Zamky, Slovakia, 940 01
    • Lexicon Investigational Site
  • Sturovo, Slovakia, 943 01
    • Lexicon Investigational Site
  • Vrutky, Slovakia, 038 61
    • Lexicon Investigational Site
• Spain
  • Barcelona, Spain, 08035
    • Lexicon Investigational Site
  • Barcelona, Spain, 08036
    • Lexicon Investigational Site
  • Granada, Spain, 18012
    • Lexicon Investigational Site
  • Malaga, Spain, 29006
    • Lexicon Investigational Site
  • Sevilla, Spain, 41009
    • Lexicon Investigational Site
  • Sevilla, Spain, 41003
    • Lexicon Investigational Site
  • Sevilla, Spain, 41010
    • Lexicon Investigational Site
  • Sevilla, Spain, 41014
    • Lexicon Investigational Site
  • Valencia, Spain, 46014
    • Lexicon Investigational Site
• Sweden
  • Härnösand, Sweden, 871 82
    • Lexicon Investigational Site
  • Kristianstad, Sweden, 291 85
    • Lexicon Investigational Site
  • Stockholm, Sweden, 112 21
    • Lexicon Investigational Site
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Lexicon Investigational Site
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Lexicon Investigational Site
  • Blackburn, United Kingdom, BB2 3HH
    • Lexicon Investigational Site
  • Bristol, United Kingdom, BS10 5NB
    • Lexicon Investigational Site
  • Glasgow, United Kingdom, G4 0SF
    • Lexicon Investigational Site
  • Leeds, United Kingdom, LS2 9JT
    • Lexicon Investigational Site
  • Leicester, United Kingdom, LE5 4PW
    • Lexicon Investigational Site
  • Sheffield, United Kingdom, S5 7AU
    • Lexicon Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; 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; Placebo, once daily, before the first meal of the day
EXPERIMENTAL: Sotagliflozin 200 mg; 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; High dose Sotagliflozin, once daily, before the first meal of the day; Drug: Sotagliflozin; Low dose Sotagliflozin,once daily, before the first meal of the day
EXPERIMENTAL: Sotagliflozin 400 mg; 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; High dose Sotagliflozin, once daily, before the first meal of the day; Drug: Sotagliflozin; Low dose Sotagliflozin,once daily, before the first meal of the day

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
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
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

Collaborators and Investigators

• Sponsor: Lexicon Pharmaceuticals
• Collaborators: Sanofi

Publications and helpful links

General Publications

• Peters AL, McGuire DK, Danne T, Kushner JA, Rodbard HW, Dhatariya K, Sawhney S, Banks P, Jiang W, Davies MJ, Lapuerta P. Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies. Diabetes Care. 2020 Nov;43(11):2713-2720. doi: 10.2337/dc20-0924. Epub 2020 Sep 14.
• Danne T, Joish VN, Afonso M, Banks P, Sawhney S, Lapuerta P, Davies MJ, Buse JB, Lin D, Reaney M, Guillonneau S, Snoek FJ, Bailey TS, Polonsky WH. Improvement in Patient-Reported Outcomes in Adults with Type 1 Diabetes Treated with Sotagliflozin plus Insulin Versus Insulin Alone. Diabetes Technol Ther. 2021 Jan;23(1):70-77. doi: 10.1089/dia.2020.0068.
• Ervin C, Joish VN, Evans E, DiBenedetti D, Reaney M, Preblick R, Castro R, Danne T, Buse JB, Lapuerta P. Insights Into Patients' Experience With Type 1 Diabetes: Exit Interviews From Phase III Studies of Sotagliflozin. Clin Ther. 2019 Nov;41(11):2219-2230.e6. doi: 10.1016/j.clinthera.2019.09.003. Epub 2019 Oct 3.
• Danne T, Cariou B, Buse JB, Garg SK, Rosenstock J, Banks P, Kushner JA, McGuire DK, Peters AL, Sawhney S, Strumph P. Improved Time in Range and Glycemic Variability With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of 24-Week Continuous Glucose Monitoring Data From the inTandem Program. Diabetes Care. 2019 May;42(5):919-930. doi: 10.2337/dc18-2149. Epub 2019 Mar 4.
• Danne T, Cariou B, Banks P, Brandle M, Brath H, Franek E, Kushner JA, Lapuerta P, McGuire DK, Peters AL, Sawhney S, Strumph P. HbA1c and Hypoglycemia Reductions at 24 and 52 Weeks With Sotagliflozin in Combination With Insulin in Adults With Type 1 Diabetes: The European inTandem2 Study. Diabetes Care. 2018 Sep;41(9):1981-1990. doi: 10.2337/dc18-0342. Epub 2018 Jun 24.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 1, 2015
• Primary Completion (ACTUAL): November 1, 2016
• Study Completion (ACTUAL): June 23, 2017

Study Registration Dates

• First Submitted: April 15, 2015
• First Submitted That Met QC Criteria: April 17, 2015
• First Posted (ESTIMATE): April 20, 2015

Study Record Updates

• Last Update Posted (ACTUAL): February 12, 2020
• Last Update Submitted That Met QC Criteria: February 10, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: High level of sugar (glucose) in the blood
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol
• Other Study ID Numbers: LX4211.1-310-T1DM; LX4211.310 (OTHER: Lexicon Pharmaceuticals); 2014-005153-39 (EUDRACT_NUMBER)