Safety, Tolerability and Pharmacodynamic Activity of Sotagliflozin in Hemodynamically Stable Participants With Worsening Heart Failure

• Sponsor: Lexicon Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03292653
• Collaborator: Sanofi (Industry)
• Enrollment: 32
• Locations: 6
• Arms: 3
• Actual Duration (Months): 20.4
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Primary Objectives:

• Assess the safety and tolerability of sotagliflozin in hemodynamically stable participants with worsening of heart failure, compared to placebo.

• Estimate the effects of sotagliflozin on plasma volume changes in hemodynamically stable participants with worsening of heart failure, compared to placebo.

Secondary Objectives:

• Explore the effect of sotagliflozin on erythropoiesis, as assessed by changes in plasma erythropoietin levels, in hemodynamically stable participants with worsening of heart failure, compared to placebo.

• Explore the effect of sotagliflozin on changes in plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, in hemodynamically stable participants with worsening of heart failure, compared to placebo.

Condition or Disease	Intervention/Treatment	Phase
Cardiac Failure Aggravated	Drug: Sotagliflozin; Drug: Placebo	Phase 2

Detailed Description

The total study duration will be approximately 27-40 days, including a screening period of 1-10 days, a treatment period of 14 days, and a follow-up period of 14±2 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An Exploratory, Randomized, Double-blind, Placebo-controlled, Parallel Arm Trial of the Safety and Pharmacodynamic Activity of Sotagliflozin in Hemodynamically Stable Patients Hospitalized With Worsening Heart Failure
• Actual Study Start Date: Dec 4, 2017
• Actual Primary Completion Date: Aug 17, 2019
• Actual Study Completion Date: Aug 17, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Drug: Placebo; Pharmaceutical form: Tablet; Route of administration: Oral
Experimental: Sotagliflozin 200 mg Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Drug: Sotagliflozin; Pharmaceutical form: Tablet; Route of administration: Oral; Other Names: SAR439954 ; Drug: Placebo; Pharmaceutical form: Tablet; Route of administration: Oral
Experimental: Sotagliflozin 400 mg Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Drug: Sotagliflozin; Pharmaceutical form: Tablet; Route of administration: Oral; Other Names: SAR439954

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), AEs Leading to Discontinuation From the Investigational Medicinal Product (IMP) and Deaths [Baseline up to Day 14]

   AE: is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participants at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. AESI: is an adverse event (serious or nonserious) of scientific and medical concern, specific to the IMP or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor may be appropriate.

2. Change From Baseline in Hemoconcentration as Assessed by Changes in Albumin to Day 14 [Baseline to Day 14]

3. Change From Baseline in Hemoconcentration as Assessed by Changes in Hematocrit to Day 14 [Baseline to Day 14]

4. Change From Baseline in Hemoconcentration as Assessed by Changes in Hemoglobin to Day 14 [Baseline to Day 14]

5. Change From Baseline in Hemoconcentration as Assessed by Changes in Total Protein to Day 14 [Baseline to Day 14]

6. Changes From Baseline in Plasma Volume to Day 14 [Baseline to 14 Days]

   Change in plasma volume in milliliters (mL) was assessed by the indicator dilution method using 131I-labelled human albumin.

Secondary Outcome Measures

1. Change From Baseline in Erythropoietin to Day 14 [Baseline to Day 14]

   Change in erythropoietin international units per liter (IU/L) was measured by chemiluminescent enzyme-labelled immunometric assay.

2. Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) to Day 14 [Baseline to Day 14]

   Change in NT-proBNP picomoles per liter (pmol/L) was measured by standard electrochemiluminescence immunoassay.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Written informed consent.

• 18 years of age or older.

• Participants admitted to the hospital or had urgent visit to emergency department or heart failure unit/clinic or infusion center for Congestive Heart Failure (CHF), defined by:

• Presence of ≥2 of the following clinical signs and symptoms of congestion: jugular venous distension, pitting edema in lower extremities greater than trace, dyspnea, rales heard on auscultation, radiographic pulmonary congestion, weight gain above historical dry weight of at least 5 pounds (lbs) (2.27 Kilograms (kg)).

• Requiring treatment with intravenous (IV) diuretics.

• Estimated glomerular filtration rate (eGFR) ≥30 milliliter per minute (mL/min)/1.73 square meter (m^2) at the screening or randomization visit by the 4 variable Modification of Diet in Renal Disease (MDRD) equation.

• Female participants must use a double contraception method during the study including a highly effective method of birth control, except if she has undergone sterilization at least 3 months earlier or is postmenopausal.

• Male participants, unless vasectomized and confirmed sterile by sperm analysis, must use condoms during the study and refrain from donating sperm up to 90 days after the day of last dose. If the participant has a female partner of childbearing potential, the participant must wear a condom and female partner must use at least 1 highly effective method of birth control during the study treatment period and the Follow-up period.

• Transitioning from IV to oral diuretics, and oral diuretic treatment has been prescribed or administered.

• Hemodynamically stable, defined as systolic blood pressure (SBP) >100 millimeters of mercury (mmHg) with no requirement for IV inotropes or IV vasodilators.

Exclusion criteria :

• History of Type 1 diabetes mellitus.

• Appears unlikely or unable to participate in the required study procedures, as assessed by the study Investigator, study coordinator, or designee (ex: clinically-significant psychiatric, addictive, or neurological disease), or sectioned due to an official or court order.

• Current admission or visit for Worsening Heart Failure (HF) that is clearly and primarily triggered by causes such as tachyarrhythmia (example: sustained ventricular tachycardia, or atrial fibrillation/flutter with sustained ventricular response > 130 beats per minute), acute coronary syndrome, pulmonary embolism, cerebrovascular accident, heart valve disorders (such as severe aortic stenosis), as determined by the Investigator.

• Clinically significant myocardial infarction (MI) within past 1 month as determined by Investigator and with objective evidence from ECG, and/or cardiac imaging and/or coronary angiography. Small isolated elevations in troponin that often accompany HF hospitalization are not an exclusion, nor are clinically significant MIs that have been revascularized without complications.

• Participants who recently had or scheduled to have cardiac interventions may be eligible if:

• Stable 48 hours post procedure.

• Have diuretic treatment planned for the duration of treatment in this study.

• Current use of or recent suspension of digoxin therapy with high levels of digoxin (level should be obtained and must be <1.2 nanograms per milliliter (ng/mL) at screening.

• History of heart or kidney transplant.

• Diagnosis of hypertrophic obstructive cardiomyopathy.

• End-stage HF defined as requiring left ventricular assist device insertion, intra-aortic balloon placement (IABP), or any type of mechanical support during the study period.

• Pregnancy (demonstrated by serum pregnancy test at screening), breast-feeding, or inability or refusal to undergo pregnancy testing.

• Use of any investigational drug(s) or prohibited therapy or sodium-glucose co-transporter 2 (SGLT2) 5 half-lives prior to screening.

• Participants with moderate or severe respiratory, hepatic, neurological, psychiatric, active malignant tumor or other major systemic disease (including any diseases with evidence of malabsorption), making implementation of the protocol and/or the interpretation of the study results difficult.

• Known allergies, hypersensitivity, or intolerance to sotagliflozin or any inactive component of sotagliflozin or placebo (ie, microcrystalline cellulose, croscarmellose sodium [disintegrant], talc, silicon dioxide, and magnesium stearate [non-bovine]), unless the reaction is deemed irrelevant to the study by the PI.

• Laboratory findings at the Screening Visit:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the upper limit of the normal laboratory range (ULN) (1 repeat lab allowed).

• Total bilirubin >1.7 times the ULN (except in case of Gilbert's syndrome) (1 repeat lab allowed).

• Amylase and/or lipase >3 times the ULN (1 repeat lab allowed).

• Participants with a severe or persistent in spite of optimal treatment genitourinary tract infection at time of randomization.

• Participant is the Investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol.

• History of diabetic ketoacidosis or non-ketotic hyperosmolar coma within 3 months prior to the screening visit.

• Lower extremity diabetic complications (such as skin ulcers, infection, osteomyelitis and gangrene) identified during the Screening period, and still requiring treatment at randomization.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 8400005	La Jolla	California	United States	92037
2	Investigational Site Number 8400001	New Haven	Connecticut	United States	06510
3	Investigational Site Number 8400007	Rochester	Minnesota	United States	55905
4	Investigational Site Number 8400002	Cleveland	Ohio	United States	44195
5	Investigational Site Number 1240001	Toronto		Canada	M5G 2N2
6	Investigational Site Number 5280001	Groningen		Netherlands	9713 GZ

Sponsors and Collaborators

• Lexicon Pharmaceuticals
• Sanofi

Investigators

• Study Director: Suman Wason, MD, Lexicon Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol - Aug 2, 2019
• Statistical Analysis Plan - Apr 19, 2018

More Information

Publications

None provided.

• Responsible Party: Lexicon Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03292653
• Other Study ID Numbers: PDY15079; 2017-002774-39; U1111-1190-7962
• First Posted: Sep 25, 2017
• Last Update Posted: May 11, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Heart Failure; (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	Participants took part in the study at 6 investigative sites in the United States, Canada, and the Netherlands from 04 December 2017 to 17 August 2019.
Pre-assignment Detail	Participants with a diagnosis of Congestive Heart Failure (CHF), were enrolled in 1 of 3 treatment groups: Placebo, Sotagliflozin 200 milligrams (mg) or Sotagliflozin 400 mg.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
Period Title: Overall Study
STARTED	11	10	11
COMPLETED	10	10	10
NOT COMPLETED	1	0	1

Baseline Characteristics

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg	Total
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Total of all reporting groups
Overall Participants	10	10	11	31
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.8 (13.05)	55.1 (12.84)	65.1 (13.41)	60.5 (13.34)
Sex: Female, Male (Count of Participants)
Female	3 30%	0 0%	4 36.4%	7 22.6%
Male	7 70%	10 100%	7 63.6%	24 77.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 9.1%	1 3.2%
Not Hispanic or Latino	10 100%	10 100%	10 90.9%	30 96.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	6 60%	5 50%	4 36.4%	15 48.4%
White	4 40%	5 50%	6 54.5%	15 48.4%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	1 9.1%	1 3.2%
Albumin (gram per liter (g/L)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [gram per liter (g/L)]	40.9 (3.48)	38.0 (6.76)	41.2 (2.59)	40.1 (4.51)
Hematocrit (percentage of red blood cells) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of red blood cells]	0.38 (0.060)	0.42 (0.092)	0.39 (0.052)	0.40 (0.070)
Hemoglobin (g/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/L]	119.6 (22.86)	138.9 (28.23)	124.4 (22.05)	127.6 (25.10)
Total Protein (g/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/L]	69.0 (6.14)	65.3 (9.88)	69.6 (6.23)	68.1 (7.39)
Plasma Volume (milliliter (mL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milliliter (mL)]	3797.3 (1281.16)	4489.3 (1306.41)	3604.7 (1100.69)	3984.6 (1212.44)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), AEs of Special Interest (AESIs), AEs Leading to Discontinuation From the Investigational Medicinal Product (IMP) and Deaths
Description	AE: is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participants at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. AESI: is an adverse event (serious or nonserious) of scientific and medical concern, specific to the IMP or program, for which ongoing monitoring and rapid communication by the Investigator to the Sponsor may be appropriate.
Time Frame	Baseline up to Day 14

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who had exposure to any amount of IMP.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
Measure Participants	10	10	11
AEs	40 400%	30 300%	45.5 413.6%
SAEs	10 100%	0 0%	0 0%
AESIs	0 0%	0 0%	0 0%
AEs Leading to Discontinuation From the IMP	0 0%	0 0%	9.1 82.7%
Deaths	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Change From Baseline in Hemoconcentration as Assessed by Changes in Albumin to Day 14
Time Frame	Baseline to Day 14

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) population included all randomized and treated participants who had valid values of the main PD parameters at baseline and Day 14 End of Treatment (EOT). The number of participants analyzed is the number of participants with available data.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
Measure Participants	7	6	9
Least Squares Mean (Standard Error) [g/L]	1.17 (2.71)	2.44 (2.40)	0.15 (2.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	Analysis of Covariance (ANCOVA) model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic, ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.736
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares (LS) Means
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 90%; -5.4 to 7.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.64
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic, ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7694
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-1.02
	Confidence Interval	(2-Sided) 90%; -7.22 to 5.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.38
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in Hemoconcentration as Assessed by Changes in Hematocrit to Day 14
Time Frame	Baseline to Day 14

Outcome Measure Data

Analysis Population Description

PD population included all randomized and treated participants who had valid values of the main PD parameters at baseline and Day 14 (EOT). The number of participants analyzed is the number of participants with available data.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
Measure Participants	10	9	10
Least Squares Mean (Standard Error) [percentage of red blood cells]	0.02 (0.02)	-0.02 (0.02)	-0.01 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.184
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 90%; -0.09 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.03
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3397
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 90%; -0.07 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.03
	Estimation Comments

4. Primary Outcome

Title	Change From Baseline in Hemoconcentration as Assessed by Changes in Hemoglobin to Day 14
Time Frame	Baseline to Day 14

Outcome Measure Data

Analysis Population Description

PD population included all randomized and treated participants who had valid values of the main PD parameters at baseline and Day 14 (EOT). The number of participants analyzed is the number of participants with available data.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
Measure Participants	10	9	10
Least Squares Mean (Standard Error) [g/L]	8.16 (6.80)	-8.91 (6.02)	-3.94 (5.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.094
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-17.07
	Confidence Interval	(2-Sided) 90%; -33.79 to -0.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.12
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1878
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-12.09
	Confidence Interval	(2-Sided) 90%; -27.65 to 3.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.49
	Estimation Comments

5. Primary Outcome

Title	Change From Baseline in Hemoconcentration as Assessed by Changes in Total Protein to Day 14
Time Frame	Baseline to Day 14

Outcome Measure Data

Analysis Population Description

PD population included all randomized and treated participants who had valid values of the main PD parameters at baseline and Day 14 (EOT). The number of participants analyzed is the number of participants with available data.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
Measure Participants	7	6	9
Least Squares Mean (Standard Error) [g/L]	5.31 (4.32)	0.49 (3.83)	-1.05 (3.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4269
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-4.82
	Confidence Interval	(2-Sided) 90%; -15.45 to 5.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.8
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2684
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-6.36
	Confidence Interval	(2-Sided) 90%; -16.24 to 3.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.39
	Estimation Comments

6. Primary Outcome

Title	Changes From Baseline in Plasma Volume to Day 14
Description	Change in plasma volume in milliliters (mL) was assessed by the indicator dilution method using 131I-labelled human albumin.
Time Frame	Baseline to 14 Days

Outcome Measure Data

Analysis Population Description

PD population included all randomized and treated participants who had valid values of the main PD parameters at baseline and Day 14 (EOT). The number of participants analyzed is the number of participants with available data.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
Measure Participants	4	6	5
Least Squares Mean (Standard Error) [mL]	-525.00 (433.19)	322.20 (359.23)	-35.67 (392.43)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1761
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	847.2
	Confidence Interval	(2-Sided) 90%; -210.46 to 1904.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 576.98
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline plasma volume as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4202
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	489.33
	Confidence Interval	(2-Sided) 90%; -572.68 to 1551.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 579.35
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Erythropoietin to Day 14
Description	Change in erythropoietin international units per liter (IU/L) was measured by chemiluminescent enzyme-labelled immunometric assay.
Time Frame	Baseline to Day 14

Outcome Measure Data

Analysis Population Description

PD population included all randomized and treated participants who had valid values of the main PD parameters at baseline and Day 14 (EOT). The number of participants analyzed is the number of participants with available data.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
Measure Participants	7	7	10
Least Squares Mean (Standard Error) [IU/L]	0.03 (5.92)	13.78 (6.26)	-0.07 (5.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline erythropoietin as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1242
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	13.75
	Confidence Interval	(2-Sided) 90%; -1.03 to 28.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.53
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline erythropoietin as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9903
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 90%; -13.49 to 13.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.73
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) to Day 14
Description	Change in NT-proBNP picomoles per liter (pmol/L) was measured by standard electrochemiluminescence immunoassay.
Time Frame	Baseline to Day 14

Outcome Measure Data

Analysis Population Description

PD population included all randomized and treated participants who had valid values of the main PD parameters at baseline and Day 14 (EOT). The number of participants analyzed is the number of participants with available data.

Arm/Group Title	Placebo	Sotagliflozin 200 mg	Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.	Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
Measure Participants	7	6	9
Least Squares Mean (Standard Error) [pmol/L]	91.36 (78.04)	-59.53 (81.28)	86.10 (65.87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 200 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline NT-proBNP as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2121
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-150.89
	Confidence Interval	(2-Sided) 90%; -353.57 to 51.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 116.09
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sotagliflozin 400 mg
	Comments	ANCOVA model with fixed effects for treatment and stratification factors of baseline participant status (diabetic/non-diabetic), ejection fraction status (reduced/preserved) with baseline NT-proBNP as the covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9574
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS Means
	Estimated Value	-5.26
	Confidence Interval	(2-Sided) 90%; -174.4 to 163.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 96.88
	Estimation Comments

Adverse Events

Time Frame	First dose of study drug to last dose of study drug (up to Day 14) + 2 weeks
Adverse Event Reporting Description	Safety population included all randomized participants who had exposure to any amount of IMP.
Arm/Group Title	Placebo		Sotagliflozin 200 mg		Sotagliflozin 400 mg
Arm/Group Description	Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.		Participants were randomized to Sotagliflozin 200 mg tablet administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.		Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.
All Cause Mortality
	Placebo		Sotagliflozin 200 mg		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/11 (0%)
Serious Adverse Events
	Placebo		Sotagliflozin 200 mg		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		0/10 (0%)		0/11 (0%)
Infections and infestations
Upper respiratory tract infection	1/10 (10%)		0/10 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Sotagliflozin 200 mg		Sotagliflozin 400 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/10 (40%)		3/10 (30%)		5/11 (45.5%)
Cardiac disorders
Cardiac failure	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Myocardial infarction	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Gastrointestinal disorders
Diarrhoea	2/10 (20%)		1/10 (10%)		1/11 (9.1%)
Nausea	0/10 (0%)		1/10 (10%)		1/11 (9.1%)
Rectal haemorrhage	0/10 (0%)		1/10 (10%)		0/11 (0%)
Vomiting	1/10 (10%)		0/10 (0%)		1/11 (9.1%)
Investigations
Gamma-glutamyltransferase increased	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Metabolism and nutrition disorders
Fluid intake reduced	0/10 (0%)		1/10 (10%)		0/11 (0%)
Hyperkalaemia	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Hypoglycaemia	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Type 2 diabetes mellitus	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Nervous system disorders
Dizziness	0/10 (0%)		1/10 (10%)		0/11 (0%)
Psychiatric disorders
Insomnia	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Stress	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/10 (10%)		0/10 (0%)		0/11 (0%)
Hypoxia	1/10 (10%)		0/10 (0%)		0/11 (0%)
Wheezing	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/10 (0%)		0/10 (0%)		1/11 (9.1%)
Vascular disorders
Hypotension	1/10 (10%)		0/10 (0%)		0/11 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Institution must provide any proposed publication or presentation to Sponsor for Sponsor's review, comment and approval at least thirty (30) days prior to the proposed submission for publication date or the proposed presentation date. Sponsor shall have the right to have deleted from the final version of the publication any confidential information, proprietary information, or patentable subject matter.