Efficacy and Safety of Sotagliflozin Versus Placebo in Pa... | NCT02926950

ID	Type	Description	Link
2016-001800-49	EudraCT Number
U1111-1181-6145	Other Identifier	UTN

Status Module

Name	Class
Sanofi	INDUSTRY

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Sotagliflozin 400 mg + Metformin	Experimental	Following a 2-week run-in period, sotagliflozin 400 mg was administered as 2 tablets, once daily, before the first meal of the day plus metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.	Drug: Sotagliflozin (SAR439954) Drug: Metformin
Placebo + Metformin	Placebo Comparator	Following a 2-week run-in period, matching placebo was administered as 2 tablets, once daily, before the first meal of the day plus metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.	Drug: Placebo Drug: Metformin

Name	Type	Description	Arm Group Labels	Other Names
Sotagliflozin (SAR439954)	Drug	Pharmaceutical form: tablet. Route of administration: oral.	Sotagliflozin 400 mg + Metformin

Outcomes Module

Measure	Description	Time Frame
Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26	An analysis of covariance (ANCOVA) model was used for the analysis.	Baseline and Week 26

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26	An ANCOVA model was used for the analysis.	Baseline and Week 26
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26

Other Outcomes

Measure	Description	Time Frame
Percentage of Participants With Hypoglycemic Events	Percentage of participants with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia [typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤70 mg/dL (3.9 mmol/L)]; Severe [an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions] or documented symptomatic hypoglycemia [typical symptoms of hypoglycemia and plasma glucose ≤70 mg/dL]. Participants may be reported in more than one category.

Eligibility Module

Eligibility Criteria

Inclusion criteria :

Participants with Type 2 Diabetes currently treated with diet and exercise and on metformin at a stable dose ≥1500 milligrams per day (mg/day) for at least 12 weeks. However, participants on metformin at a dose <1500 mg/day at the time of enrollment (stable dose for at least 12 weeks before enrollment) may be eligible for screening if documentation of lack of tolerance of a metformin dose ≥1500 mg/day can be provided.
Signed written informed consent.

Exclusion criteria:

Age <18 years at Screening or < legal age of majority, whichever is greater.
Type 1 diabetes mellitus.
Body Mass Index (BMI) ≤20 or >45 kilograms per meter square (kg/m^2) at Screening
Hemoglobin A1c <7% or >10% via central laboratory test at screening.
Fasting plasma glucose (FPG) >15 millimole per liter (mmol/L) (270 milligrams per deciliter [mg/dL]) measured by the central laboratory at screening (Visit 1) and confirmed by a repeat test (>15 mmol/L [270 mg/dL]) before randomization.
Women of childbearing potential not willing to use highly effective method(s) of birth control or who are unwilling or unable to be tested for pregnancy during the study.
Treated with an antidiabetic pharmacological regimen other than metformin ≥1500 mg per day (or maximum tolerated dose) within the 12 weeks preceding the Screening Visit.
Previous use of any types of insulin for >1 month (at any time, aside from pregnancy for treatment of gestational diabetes).
History of prior gastric surgical procedure, including gastric banding, within 3 years before the Screening Visit.
History of diabetic ketoacidosis or nonketotic hyperosmolar coma within 12 weeks prior to the Screening Visit.
Mean of 3 separate blood pressure measurements >180 mmHg (SBP) or >100 mmHg (diastolic blood pressure [DBP]).
History of hypertensive urgency or emergency within 12 weeks prior to Screening.
Participants with severe anemia, severe cardiovascular (including congestive heart failure New York Heart Association [NYHA] IV), respiratory, hepatic, neurological, psychiatric, or active malignant tumor or other major systemic disease or participants with short life expectancy making implementation of the protocol or interpretation of the study results difficult.
Aspartate aminotransferase and/or alanine aminotransferase: >3 times the upper limit of the normal laboratory range.
Total bilirubin: >1.5 times the upper limit of the normal laboratory range (except in case of Gilbert's syndrome).
Use of systemic glucocorticoids (excluding topical or ophthalmic application or inhaled forms) for more than 10 consecutive days within 90 days prior to the Screening Visit.
Participants who has taken other investigational drugs or prohibited therapy for this study within 12 weeks or 5 half-lives from screening or randomization, whichever is longer.
Pregnant (confirmed by serum pregnancy test at Screening) or breastfeeding women.
Participants is unwilling or unable to perform self-monitoring of blood glucose (SMBG), complete the participants diary, or comply with study visits and other study procedures as required per protocol.
Contraindication to metformin as per local labelling.

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

Name	Affiliation	Role
Suman Wason, MD	Lexicon Pharmaceuticals, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Investigational Site Number 8402003		Birmingham	Alabama	35205	United States
Investigational Site Number 8402017

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Dec 21, 2017	Apr 12, 2021

Arm/Group Information

ID	Title	Description
BG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
BG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00059.9± 9.4 BG00160.0± 10.1 BG00259.9± 9.8

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG000113 BG001117 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG000106 BG001117 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0001 BG0012 BG002

Hemoglobin A1c (HbA1c)

Mean

Standard Deviation

percentage of HbA1c

Title

Denominators

Categories

Title	Measurements
	BG0008.19± 0.82 BG0018.20± 0.78 BG002

Systolic Blood Pressure (SBP)

Mean

Standard Deviation

millimeter of mercury (mmHg)

Title

Denominators

Categories

Title	Measurements
	BG000133.80± 13.95 BG001134.06± 13.95 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Hemoglobin A1c (HbA1c) at Week 26

An analysis of covariance (ANCOVA) model was used for the analysis.

Intent-to-treat (ITT) population included all randomized participants. Missing data was imputed using the retrieved dropouts and washout imputation method.

Posted

Least Squares Mean

Standard Error

percentage of HbA1c

Baseline and Week 26

ID	Title	Description
OG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
OG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Units	Counts
Participants	OG000259 OG001259

Title

Denominators

Categories

Title	Measurements
	OG000-0.29± 0.079 OG001-0.77± 0.077

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	The change from baseline to Week 26 is analyzed using an ANCOVA model with treatment groups, randomization strata of HbA1c (≤8.0, >8.0%) at screening, randomization strata of mean SBP (<130, ≥130 mmHg) at screening, and country as fixed effects, and baseline HbA1c as a covariate.	ANCOVA		< 0.0001		Difference in Least Squares (LS) Means	-0.47	Standard Error of the Mean	0.084	2-Sided	95	-0.64	-0.309					Superiority

Secondary

Change From Baseline in 2-hour Postprandial Glucose (PPG) Following a Mixed Meal at Week 26

An ANCOVA model was used for the analysis.

ITT population included all randomized participants. Missing data are imputed using control-based copy reference multiple imputation method.

Posted

Least Squares Mean

Standard Error

millimole per liter (mmol/L)

Baseline and Week 26

ID	Title	Description
OG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
OG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Units	Counts

Secondary

Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26

An ANCOVA model was used for the analysis.

ITT population included all randomized participants. Missing data was imputed using the retrieved dropouts and washout imputation method.

Posted

Least Squares Mean

Standard Error

mmol/L

Baseline and Week 26

ID	Title	Description
OG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
OG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Units	Counts
Participants

Secondary

Change From Baseline in Body Weight at Week 26

An ANCOVA model was used for the analysis.

ITT population included all randomized participants. Missing data was imputed using the retrieved dropouts and washout imputation method.

Posted

Least Squares Mean

Standard Error

kilogram (kg)

Baseline and Week 26

ID	Title	Description
OG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
OG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Units	Counts
Participants

Secondary

Change From Baseline in Systolic Blood Pressure (SBP) at Week 12 in Participants With Baseline SBP ≥130 mmHg

An ANCOVA model was used for the analysis.

Analysis was performed on ITT population in participant with baseline SBP ≥130 mmHg. Missing data was imputed using control-based copy reference multiple imputation method.

Posted

Least Squares Mean

Standard Error

millimeter of mercury (mmHg)

Baseline and Week 12

ID	Title	Description
OG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
OG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, once daily, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Secondary

Change From Baseline in SBP at Week 12 for All Participants

An ANCOVA model was used for the analysis.

ITT population included all randomized participants. Missing data was imputed using control-based copy reference multiple imputation method.

Posted

Least Squares Mean

Standard Error

mmHg

Baseline and Week 12

ID	Title	Description
OG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
OG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Units	Counts
Participants

Secondary

Percentage of Participants With HbA1c <6.5% at Week 26

ITT population included all randomized participants.

Posted

Number

percentage of participants

Week 26

ID	Title	Description
OG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
OG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Units	Counts
Participants	OG000

Secondary

Percentage of Participants With HbA1c <7.0% at Week 26

ITT population included all randomized participants.

Posted

Number

percentage of participants

Week 26

ID	Title	Description
OG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
OG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.

Units	Counts
Participants	OG000

Other Pre-specified

Percentage of Participants With Hypoglycemic Events

Percentage of participants with hypoglycemic events are reported for the following 3 categories: Any hypoglycemia (as reported in the Electronic Case Report Form); Documented symptomatic hypoglycemia [typical symptoms of hypoglycemia (increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and/or coma) and plasma glucose ≤70 mg/dL (3.9 mmol/L)]; Severe [an event requiring assistance of another person to actively administer carbohydrate, glucagon, intravenous glucose or other resuscitative actions] or documented symptomatic hypoglycemia [typical symptoms of hypoglycemia and plasma glucose ≤70 mg/dL]. Participants may be reported in more than one category.

Safety population was defined as all randomized participants who had received at least 1 dose of the double-blind investigational medicinal product.

Posted

Number

percentage of participants

Up to 79 weeks in the treatment period

ID	Title	Description
OG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, QD, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.
OG001	Sotagliflozin 400 mg + Metformin

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo + Metformin	Following a 2-week run-in period, matching placebo was administered as 2 tablets, once daily, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.	1	259	23	259	109	259
EG001	Sotagliflozin 400 mg + Metformin	Following a 2-week run-in period, Sotagliflozin 400 mg was administered as 2 tablets, once daily, before the first meal of the day plus Metformin as prescribed by the Principal Investigator for up to 26 weeks in the double-blind Core Treatment Period, and participants continued the same treatment in the double-blind Extension Period for up to 53 weeks.	3	259	19	259	85	259

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Biliary neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Intraductal papillary mucinous neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Invasive breast carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Papillary thyroid cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Renal oncocytoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Salivary gland cancer recurrent	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Squamous cell carcinoma of skin	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Transitional cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Chest discomfort	General disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Non-cardiac chest pain	General disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0012 affected259 at risk
Pyrexia	General disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Cervical polyp	Reproductive system and breast disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Colpocele	Reproductive system and breast disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Acetabulum fracture	Injury, poisoning and procedural complications	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Road traffic accident	Injury, poisoning and procedural complications	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Alanine aminotransferase increased	Investigations	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Blood bilirubin increased	Investigations	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Angina pectoris	Cardiac disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0012 affected259 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Cardiopulmonary failure	Cardiac disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Coronary artery disease	Cardiac disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0011 affected259 at risk
Myocardial infarction	Cardiac disorders	MedDRA (22.0)	Systematic Assessment	EG0002 affected259 at risk EG0010 affected259 at risk
Sinus tachycardia	Cardiac disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Carotid artery stenosis	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Cerebellar stroke	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Cerebral artery thrombosis	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0011 affected259 at risk
Haemorrhagic cerebral infarction	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Intracranial venous sinus thrombosis	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Metabolic encephalopathy	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Subarachnoid haemorrhage	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Syncope	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Pancreatitis acute	Gastrointestinal disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Cholecystitis acute	Hepatobiliary disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Calculus urethral	Renal and urinary disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Renal cyst	Renal and urinary disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Renal failure	Renal and urinary disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Ureterolithiasis	Renal and urinary disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Neurodermatitis	Skin and subcutaneous tissue disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA (22.0)	Systematic Assessment	EG0002 affected259 at risk EG0010 affected259 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Abscess limb	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Cellulitis	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Device related infection	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Diverticulitis	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Influenza	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0011 affected259 at risk
Osteomyelitis	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG0000 affected259 at risk EG0012 affected259 at risk
Pneumonia	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0013 affected259 at risk
Septic shock	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk
Urinary tract infection	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG0001 affected259 at risk EG0010 affected259 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Hypertension	Vascular disorders	MedDRA (22.0)	Systematic Assessment	EG00013 affected259 at risk EG0013 affected259 at risk
Headache	Nervous system disorders	MedDRA (22.0)	Systematic Assessment	EG00015 affected259 at risk EG0016 affected259 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (22.0)	Systematic Assessment	EG00011 affected259 at risk EG00122 affected259 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (22.0)	Systematic Assessment	EG00019 affected259 at risk EG0018 affected259 at risk
Vitamin D deficiency	Metabolism and nutrition disorders	MedDRA (22.0)	Systematic Assessment	EG00019 affected259 at risk EG00114 affected259 at risk
Bronchitis	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG00017 affected259 at risk EG0015 affected259 at risk
Nasopharyngitis	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG00017 affected259 at risk EG00114 affected259 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG00020 affected259 at risk EG00120 affected259 at risk
Urinary tract infection	Infections and infestations	MedDRA (22.0)	Systematic Assessment	EG00015 affected259 at risk EG00116 affected259 at risk

ID	Term
D003920	Diabetes Mellitus
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D004700	Endocrine System Diseases

ID	Term
D001645	Biguanides
D006146	Guanidines
D000578	Amidines
D009930	Organic Chemicals

ID	Term
C575681	(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol
D008687	Metformin