Efficacy and Safety of Sotagliflozin in Young Adult Patients With Type 1 Diabetes Mellitus and Elevated Hemoglobin A1C

• Sponsor: Lexicon Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02383940
• Collaborator: Juvenile Diabetes Research Foundation (Other), Sanofi (Industry)
• Enrollment: 87
• Locations: 15
• Arms: 2
• Actual Duration (Months): 17.1
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This Phase 2 study was intended to demonstrate superiority of sotagliflozin versus placebo on Hemoglobin A1C (A1C) reduction at Week 12 in young adult participants with type 1 diabetes mellitus (T1DM) who have poor glycemic control on their current insulin regimen.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: Sotagliflozin; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of LX4211 in Young Adult Patients With Type 1 Diabetes Mellitus and Elevated Hemoglobin A1C
• Actual Study Start Date: Apr 1, 2015
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks.	Drug: Placebo; Placebo, once daily before the first meal of the day
Experimental: Sotagliflozin 400 mg Sotagliflozin 400 milligram (mg) (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks.	Drug: Sotagliflozin; Sotagliflozin 400 mg, once daily before the first meal of the day; Other Names: LX4211

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1C (A1C) at Week 12 [Baseline, Week 12]

   Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Change was calculated by subtracting baseline value from Week 12 value. Least Square (LS) mean changes from baseline were obtained from mixed model repeated measures (MMRM) model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week-4 A1C (<=10%, >10%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline A1C-by-time interaction as a covariate.

Secondary Outcome Measures

1. Change From Baseline in Total Daily Bolus Insulin Dose and Total Daily Basal Insulin Dose at Week 12 [Baseline, Week 12]

   The daily bolus and basal insulin doses were calculated as an average of the doses over 3 to 5 days before each visit (Baseline and Week 12). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model.

2. Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Standardized Mixed Meal at Week 12 [Baseline, Week 12]

   A 2-hour PPG sample (plasma) was obtained 2-hours after a standardized Mixed Meal at Baseline (Day 1) and at the visit at Week 12. At Week 12, study drug was to be given within 15 minutes before liquid "Boost®," "Ensure®," or similar nutrition drink product; at baseline, study drug was to be given after the 2-hour post-Mixed Meal PPG sample. Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from analysis of covariance (ANCOVA) model.

3. Change From Baseline in Glycemic Instability by Hyperglycemia (Continuous Glucose Monitoring [CGM] Area Under the Curve [AUC] >150 mg/dL) and Hypoglycemia (CGM AUC <70 mg/dL) Over a 24-hour Period at Week 12 [Baseline, Week 12]

   Glycemic instability (mg/dL*minutes/1000) by hyperglycemia/hypoglycemia was measured by CGM AUC outside target range (as a daily average over the week prior to the visit [Baseline and Week 12]) over 24 hours, where outside target range was defined as CGM glucose AUC >150 mg/dL (hyperglycemia) and CGM glucose AUC <70 mg/dL (hypoglycemia). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model.

4. Change From Baseline in Number of Hypoglycemic Events/Day (<=70 mg/dL) by Self-Monitored Blood Glucose (SMBG) at Week 12 [Baseline, Week 12]

   Hypoglycemic event by SMBG was defined as an event in which the fingerstick measurement was <=70 mg/dL. The number of hypoglycemic events per day was calculated as a daily average number of episodes over the week prior to visit (Baseline and Week 12). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participant had given written informed consent.

• Young adult participants >=18 to <=30 years old at Screening, with a confirmed diagnosis of T1DM made at least 1 year prior to informed consent.

• Participants were being treated with insulin or insulin analogue delivered via continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI).

• At Screening, must had A1C >= 9.0%.

• Must be willing and able to perform self-monitored blood glucose (SMBG) and complete the study diary.

• Females of childbearing potential must use an adequate method of contraception and had a negative pregnancy test.

Exclusion Criteria:

• Any prior use of LX4211/sotagliflozin.

• Use of antidiabetic agent other than insulin or insulin analogue at the time of screening.

• Use of sodium-glucose cotransporter (SGLT) inhibitors within 8 weeks prior to start of the placebo Run-in Period.

• Chronic systemic corticosteroid use.

• Type 2 diabetes, or severely uncontrolled diabetes mellitus as determined by the Investigator.

• History of diabetic ketoacidosis (DKA) or nonketotic hyperosmolar state within 6 months prior to the Screening Visit.

• History of severe hypoglycemic event within 1 month prior to the Screening Visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lexicon Investigational Site	Tustin	California	United States	92780
2	Lexicon Investigational Site	Aurora	Colorado	United States	80045
3	Lexicon Investigational Site	New Haven	Connecticut	United States	06519
4	Lexicon Investigational Site	Tampa	Florida	United States	33612
5	Lexicon Investigational Site	West Palm Beach	Florida	United States	33401
6	Lexicon Investigational Site	Atlanta	Georgia	United States	30318
7	Lexicon Investigational Site	Roswell	Georgia	United States	30076
8	Lexicon Investigational Site	Indianapolis	Indiana	United States	46202
9	Lexicon Investigational Site	New Orleans	Louisiana	United States	70121
10	Lexicon Investigational Site	Auburn	Maine	United States	04210
11	Lexicon Investigational Site	Boston	Massachusetts	United States	02215
12	Lexicon Investigational Site	Buffalo	New York	United States	14222
13	Lexicon Investigational Site	Wilmington	North Carolina	United States	28401
14	Lexicon Investigational Site	Austin	Texas	United States	78749
15	Lexicon Investigational Site	Salt Lake City	Utah	United States	84107

Sponsors and Collaborators

• Lexicon Pharmaceuticals
• Juvenile Diabetes Research Foundation
• Sanofi

Investigators

• Study Director: Sangeeta Sawhney, M.D., Lexicon Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Lexicon Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02383940
• Other Study ID Numbers: LX4211.1-204-T1DM; LX4211.204
• First Posted: Mar 10, 2015
• Last Update Posted: Feb 12, 2020
• Last Verified: Feb 1, 2020

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol

Study Results

Participant Flow

Recruitment Details	The study was conducted at 15 sites in United States between 20 April 2015 and 23 September 2016.
Pre-assignment Detail	147 participants were screened and 87 participants with Type 1 diabetes mellitus who had inadequate glycemic control with insulin therapy alone, were randomized equally into two treatment groups: sotagliflozin 400 milligrams (mg) or placebo.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks.
Period Title: Overall Study
STARTED	44	43
Treated	42	43
COMPLETED	35	40
NOT COMPLETED	9	3

Baseline Characteristics

Arm/Group Title	Placebo	Sotagliflozin 400 mg	Total
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks.	Total of all reporting groups
Overall Participants	42	43	85
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	21.7 (3.55)	22.8 (4.01)	22.3 (3.81)
Sex: Female, Male (Count of Participants)
Female	23 54.8%	22 51.2%	45 52.9%
Male	19 45.2%	21 48.8%	40 47.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 2.4%	0 0%	1 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 14.3%	2 4.7%	8 9.4%
White	34 81%	41 95.3%	75 88.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2.4%	0 0%	1 1.2%
Body weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	77.27 (14.570)	83.74 (20.439)	80.54 (17.975)
Body Mass Index (BMI) (kilograms per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms per square meter (kg/m^2)]	26.73 (4.993)	29.39 (7.214)	28.07 (6.324)
Duration of diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	11.9 (5.38)	11.9 (6.16)	11.9 (5.75)
Insulin Delivery Method (Count of Participants)
Continuous Subcutaneous Insulin Infusion (CSII)	23 54.8%	23 53.5%	46 54.1%
Multiple Daily Injections (MDI)	19 45.2%	20 46.5%	39 45.9%
Hemoglobin A1C Level in Participants (Count of Participants)
<=10 percent (%)	19 45.2%	18 41.9%	37 43.5%
>10 %	23 54.8%	25 58.1%	48 56.5%
Baseline daily total insulin (International units per kilogram (IU/kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [International units per kilogram (IU/kg)]	0.87 (0.315)	0.84 (0.264)	0.86 (0.289)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1C (A1C) at Week 12
Description	Baseline was defined as the last value collected prior to the first dose of double-blind study medication. Change was calculated by subtracting baseline value from Week 12 value. Least Square (LS) mean changes from baseline were obtained from mixed model repeated measures (MMRM) model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week-4 A1C (<=10%, >10%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline A1C-by-time interaction as a covariate.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks.
Measure Participants	34	40
Least Squares Mean (Standard Error) [percentage of A1C]	-0.99 (0.149)	-1.33 (0.143)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	Between-group comparison was based on MMRM model with treatment, randomization strata of insulin delivery (MDI, CSII) and Week-4 A1C (<=10%, >10%), time (study week), and a treatment-by-time interaction as fixed categorical effects, and baseline A1C-by-time interaction as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments	Threshold for significance = 0.05
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least squares mean difference
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -0.76 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.207
	Estimation Comments	Difference is sotagliflozin - placebo

2. Secondary Outcome

Title	Change From Baseline in Total Daily Bolus Insulin Dose and Total Daily Basal Insulin Dose at Week 12
Description	The daily bolus and basal insulin doses were calculated as an average of the doses over 3 to 5 days before each visit (Baseline and Week 12). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Analysis included participants from the mITT population. Here, overall number of participants analyzed = participants with available data for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks.
Measure Participants	34	40
Total Daily Bolus Insulin Dose	-2.96 (1.945)	-4.89 (1.832)
Total Daily Basal Insulin Dose	3.26 (1.262)	2.03 (1.211)

3. Secondary Outcome

Title	Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Standardized Mixed Meal at Week 12
Description	A 2-hour PPG sample (plasma) was obtained 2-hours after a standardized Mixed Meal at Baseline (Day 1) and at the visit at Week 12. At Week 12, study drug was to be given within 15 minutes before liquid "Boost®," "Ensure®," or similar nutrition drink product; at baseline, study drug was to be given after the 2-hour post-Mixed Meal PPG sample. Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from analysis of covariance (ANCOVA) model.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks.
Measure Participants	32	36
Least Squares Mean (Standard Error) [milligrams per deciliter (mg/dL)]	0.2 (12.24)	-56.4 (11.61)

4. Secondary Outcome

Title	Change From Baseline in Glycemic Instability by Hyperglycemia (Continuous Glucose Monitoring [CGM] Area Under the Curve [AUC] >150 mg/dL) and Hypoglycemia (CGM AUC <70 mg/dL) Over a 24-hour Period at Week 12
Description	Glycemic instability (mg/dL*minutes/1000) by hyperglycemia/hypoglycemia was measured by CGM AUC outside target range (as a daily average over the week prior to the visit [Baseline and Week 12]) over 24 hours, where outside target range was defined as CGM glucose AUC >150 mg/dL (hyperglycemia) and CGM glucose AUC <70 mg/dL (hypoglycemia). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks.
Measure Participants	28	27
Glycemic Instability by Hyperglycemia	-5.035 (7.9092)	-27.338 (8.0100)
Glycemic Instability by Hypoglycemia	0.221 (0.2508)	0.428 (0.2528)

5. Secondary Outcome

Title	Change From Baseline in Number of Hypoglycemic Events/Day (<=70 mg/dL) by Self-Monitored Blood Glucose (SMBG) at Week 12
Description	Hypoglycemic event by SMBG was defined as an event in which the fingerstick measurement was <=70 mg/dL. The number of hypoglycemic events per day was calculated as a daily average number of episodes over the week prior to visit (Baseline and Week 12). Change was calculated by subtracting baseline value from Week 12 value. LS mean changes from baseline were obtained from MMRM model.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Analysis was performed on mITT population. Here, 'overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks.	Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks.
Measure Participants	35	40
Least Squares Mean (Standard Error) [events/day]	-0.042 (0.0408)	-0.001 (0.0379)

Adverse Events

Time Frame	All Adverse Events (AEs) were collected from Baseline (Day 1) until the end of study (up to Week 12).
Adverse Event Reporting Description	Analysis was performed on Safety Population defined as all randomly assigned participants who have taken at least 1 dose of study drug.
Arm/Group Title	Placebo		Sotagliflozin 400 mg
Arm/Group Description	Two placebo-matching sotagliflozin tablets, once daily, orally, before the first meal of the day for 12 weeks.		Sotagliflozin 400 mg (two 200 mg tablets), once daily, orally, before the first meal of the day for 12 weeks.
All Cause Mortality
	Placebo		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/42 (0%)		0/43 (0%)
Serious Adverse Events
	Placebo		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/42 (7.1%)		2/43 (4.7%)
Gastrointestinal disorders
Vomiting	1/42 (2.4%)	1	0/43 (0%)	0
Infections and infestations
Pneumonia	0/42 (0%)	0	1/43 (2.3%)	1
Injury, poisoning and procedural complications
Femoral neck fracture	1/42 (2.4%)	1	0/43 (0%)	0
Metabolism and nutrition disorders
Diabetic ketoacidosis	2/42 (4.8%)	2	1/43 (2.3%)	1
Hypoglycaemia	0/42 (0%)	0	1/43 (2.3%)	1
Nervous system disorders
Hypoglycaemic unconsciousness	1/42 (2.4%)	1	0/43 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/42 (38.1%)		21/43 (48.8%)
Gastrointestinal disorders
Nausea	3/42 (7.1%)	4	1/43 (2.3%)	1
Vomiting	3/42 (7.1%)	3	2/43 (4.7%)	2
Infections and infestations
Nasopharyngitis	4/42 (9.5%)	4	5/43 (11.6%)	6
Upper respiratory tract infection	3/42 (7.1%)	3	2/43 (4.7%)	2
Urinary tract infection	1/42 (2.4%)	1	3/43 (7%)	4
Investigations
Blood ketone body increased	3/42 (7.1%)	3	8/43 (18.6%)	17
Musculoskeletal and connective tissue disorders
Back pain	0/42 (0%)	0	3/43 (7%)	3
Respiratory, thoracic and mediastinal disorders
Cough	1/42 (2.4%)	1	3/43 (7%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.