GLP-1 Receptor Agonist Lixisenatide in Patients With Type... | NCT00763815

ID	Type	Description	Link
EudraCT: 2007-005884-92

Description Module

Brief Summary

The purpose of this study is to evaluate the benefits and risks of lixisenatide (AVE0010), in comparison to placebo, as an add-on treatment to pioglitazone with or without metformin, over a period of 24 weeks of treatment, followed by an extension.

The primary objective is to assess the effects of lixisenatide when added to pioglitazone on glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at Week 24.

Secondary objectives are to assess the effects of lixisenatide when added to pioglitazone on the percentage of patients reaching HbA1c less than 7 percent (%) and less than or equal to 6.5%, fasting plasma glucose (FPG), body weight, beta-cell function (assessed by homeostatic model assessment of beta-cell function [HOMA-beta]), and on fasting plasma insulin (FPI), to assess the safety, tolerability, pharmacokinetics (PK) and anti-lixisenatide antibody development.

Label	Type	Description	Intervention Names
Lixisenatide	Experimental	2-step initiation regimen of lixisenatide: 10 microgram (mcg) once daily (QD) for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.	Drug: Lixisenatide (AVE0010) Device: Pen auto-injector Drug: Pioglitazone Drug: Metformin
Placebo	Placebo Comparator	2-step initiation regimen of volume matching placebo: 10 mcg QD for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.	Drug: Placebo Device: Pen auto-injector Drug: Pioglitazone Drug: Metformin

Name	Type	Description	Arm Group Labels	Other Names
Lixisenatide (AVE0010)	Drug	Self-administered by subcutaneous injections once daily within the hour preceding breakfast.	Lixisenatide

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24	Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.	Baseline, Week 24

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24	Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Other Outcomes

Measure	Description	Time Frame
Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24	The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Type 2 diabetes mellitus, diagnosed for at least 1 year at the time of the screening visit, insufficiently controlled with pioglitazone

Exclusion Criteria:

HbA1c less than (<) 7 percent (%) or greater than (>) 10% at screening
At the time of screening age <legal age of majority
Pregnant or breastfeeding women and women of childbearing potential without effective contraceptive method of birth control
Type 1 diabetes mellitus
Pioglitazone not at a stable dose of at least 30 milligram per day (mg/day) for at least 3 months prior to screening
If treatment with metformin, no stable dose of at least 1.5 gram per day (g/day) for at least 3 months prior to screening visit
FPG at screening >250 milligram per deciliter (mg/dL) (>13.9 millimole per liter [mmol/L])
Body mass index less than or equal to (<=) 20 kilogram per square meter (kg/m^2)
Weight change of more than 5 kg during the 3 months preceding the screening visit
History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, or inflammatory bowel disease
History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening
Hemoglobinopathy or hemolytic anemia, or receipt of blood or plasma products within3 months prior to the time of screening
History of myocardial infarction or stroke within the last 6 months prior to screening
Known history of drug or alcohol abuse within 6 months prior to the time of screening
Cardiovascular, hepatic, neurological, endocrine disease, active malignant tumor or other major systemic disease or patients with short life expectancy making implementation of the protocol or interpretation of the study results difficult, history or presence of clinically significant diabetic retinopathy, history or presence of macular edema likely to require laser treatment within the study period
Uncontrolled or inadequately controlled hypertension at the time of screening with a resting systolic blood pressure or diastolic blood pressure (DBP) >180 millimeter of mercury (mmHg) or >95 mmHg, respectively
Laboratory findings at the time of screening: aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP): >2 times upper limit of normal (ULN) laboratory range; amylase and/or lipase: >3 times ULN; total bilirubin: >1.5 times ULN (except in case of Gilbert's syndrome); Hemoglobin <11 gram/deciliter and/or neutrophils <1500 per cubic millimeter (mm^3) and/or platelets <100 000/mm^3; positive test for Hepatitis B surface antigen (HBsAg) and/or Hepatitis C antibody (HCAb); positive serum pregnancy test in females of childbearing potential
Any clinically significant abnormality identified on physical examination, laboratory tests, electrocardiogram (ECG), or vital signs at the time of screening that, in the judgment of the investigator or any sub-investigator, precludes safe completion of the study or constrains efficacy assessment
Patients who are considered by the investigator or any sub-investigator as inappropriate for this study for any reason (for example, impossibility to meet specific protocol requirements [such as scheduled visits, being able to do self-injections]; likelihood of requiring treatment during the screening phase and treatment phase with drugs not permitted by the clinical study protocol; investigator or any sub-investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol)
Use of other oral or injectable antidiabetic or hypoglycemic agents other than metformin or pioglitazone (for example, sulfonylurea, alpha-glucosidase inhibitor, other thiazolidinediones, rimonabant, exenatide, dipeptidyl peptidase-4 [DPP-4] inhibitors, insulin) within 3 months prior to the time of screening
Use of systemic glucocorticoids (excluding topical application or inhaled forms) for 1 week or more within 3 months prior to the time of screening
Use of any investigational drug within 3 months prior to study
Any previous treatment with lixisenatide or participation in a previous study with lixisenatide
Renal impairment defined with creatinine >1.4 mg/dL in women and creatinine >1.5 mg/dL in men (applicable only for patients with metformin treatment)
Patients with cardiac failure or history of cardiac failure (New York Heart Association class I to IV)
End-stage renal disease defined by a serum creatinine clearance of <15 milliliter per minute (mL/min) (calculated by the Cockcroft and Gault formula) and/or patients on dialysis, if no treatment with metformin
Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including, but not limited to, gastroparesis and gastroesophageal reflux disease requiring medical treatment, within 6 months prior to the time of screening
Allergic reaction to any glucagon like peptide-1 (GLP-1) agonist in the past (for example,exenatide, liraglutide) or to metacresol
Additional exclusion criteria at the end of the run-in phase: informed consent withdrawal; lack of compliance during the single-blind placebo run-in phase (>2 injections missed); and patient with any adverse event which precludes the inclusion in the study, as assessed by the investigator

Name	Affiliation	Role
Clinical Sciences & Operations	Sanofi	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Sanofi-Aventis Investigational Site Number 840723		Birmingham	Alabama	35205	United States
Sanofi-Aventis Investigational Site Number 840744

PubMed Identifier	Type	Citation	Retractions
23627775	Result	Pinget M, Goldenberg R, Niemoeller E, Muehlen-Bartmer I, Guo H, Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab. 2013 Nov;15(11):1000-7. doi: 10.1111/dom.12121. Epub 2013 May 26.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	2-step initiation regimen of volume matching placebo: 10 microgram (mcg) once daily (QD) subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.
FG001	Lixisenatide

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

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
	BG00055.3± 9.5 BG00156.0± 9.5 BG00255.8± 9.5

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00079 BG001151 BG002

Race/Ethnicity, Customized

Number

participants

Title

Denominators

Categories

Race: Caucasian/White

Title	Measurements
	BG000132 BG001273 BG002

Glycosylated Hemoglobin (HbA1c)

Mean

Standard Deviation

percentage of hemoglobin

Title

Denominators

Categories

Title	Measurements
	BG0008.06± 0.79 BG0018.08± 0.90 BG002

Fasting Plasma Glucose (FPG)

Mean

Standard Deviation

millimole per liter (mmol/L)

Title

Denominators

Categories

Title	Measurements
	BG0009.13± 2.20 BG0019.11± 2.15 BG002

Body Weight

Mean

Standard Deviation

kilogram

Title

Denominators

Categories

Title	Measurements
	BG00096.74± 25.58 BG00192.93± 22.90 BG002

Beta-cell Function Assessed by Homeostasis Model Assessment for Beta-cell Function (HOMA-beta)

Beta cell function was assessed by HOMA-beta. HOMA-beta (% of normal beta cells function) = (20 multiplied by fasting plasma insulin [micro unit per milliliter]) divided by (fasting plasma glucose [mmol/L] minus 3.5). Here, Number of patients analyzed = 141 and 300 for Placebo and Lixisenatide treatment arms, respectively.

Mean

Standard Deviation

percentage of normal beta cells function

Title

Denominators

Categories

Title	Measurements
	BG00036.23± 26.50 BG001

Fasting Plasma Insulin (FPI)

Here, Number of patients analyzed = 142 and 300 for Placebo and Lixisenatide treatment arms, respectively.

Mean

Standard Deviation

picomole per liter (pmol/L)

Title

Denominators

Categories

Title	Measurements
	BG00066.07± 48.12 BG00163.32

Duration of Diabetes

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG0008.09± 5.58 BG0018.11± 5.44 BG002

Duration of Pioglitazone Treatment

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG0001.79± 2.51 BG0011.69± 2.00 BG002

Pioglitazone Daily Dose

Number

participants

Title

Denominators

Categories

>=30 milligram (mg) to Less Than (<) 45 mg

Title	Measurements
	BG000126 BG001242 BG002

Metformin Use at Screening

Number of patients with metformin use at baseline was reported.

Number

participants

Title

Denominators

Categories

Title	Measurements
	BG000131 BG001261 BG002

Body Mass Index (BMI)

BMI was calculated by dividing body weight (kilogram) by the height (meter) squared.

Mean

Standard Deviation

kilogram per square meter (kg/m^2)

Title

Denominators

Categories

Title	Measurements
	BG00034.44± 7.04 BG00133.66± 6.71

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

Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24

Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

mITT population:all randomized patients who received at least 1 dose;had baseline,at least 1 post-baseline efficacy assessment, irrespective of compliance with study protocol/procedures. Last observation carried forward used. Number of patients analyzed=patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

Posted

Least Squares Mean

Standard Error

percentage of hemoglobin

Baseline, Week 24

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Units	Counts
Participants	OG000148 OG001308

Title

Denominators

Categories

Title	Measurements
	OG000-0.34± 0.100 OG001-0.90± 0.089

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	To detect a difference of 0.5% (or 0.4%) in change from baseline to Week 24 in HbA1c between lixisenatide and placebo, 300 patients in lixisenatide arm and 150 patients in placebo arm would provide a power of 96% (or 86%) assuming common standard deviation of 1.3% with a 2-sided test at 5% significance level.	ANCOVA		<0.0001	Statistical testing: 2-sided at significance level=0.05. Analysis of co-variance (ANCOVA) included treatment arms; randomization strata of screening HbA1c (<8.0, >=8.0%), metformin use (yes, no); country as fixed effects; baseline HbA1c as covariate.	Least Squares (LS) Mean Difference	-0.56	Standard Error of the Mean	0.088	2-Sided	95	-0.731	-0.386				No

Secondary

Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24

Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

mITT population. Missing data was imputed using last observation carried forward (LOCF). Here, number of patients analyzed = patients with baseline and at least 1 post-baseline FPG assessment during on-treatment period.

Posted

Least Squares Mean

Standard Error

mmol/L

Baseline, Week 24

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Units	Counts
Participants

Secondary

Change From Baseline in Body Weight at Week 24

Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period.

Posted

Least Squares Mean

Standard Error

kilogram

Baseline, Week 24

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Units	Counts
Participants

Secondary

Change From Baseline in Fasting Plasma Insulin (FPI) at Week 24

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline FPI assessment during on-treatment period.

Posted

Least Squares Mean

Standard Error

pmol/L

Baseline, Week 24

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Units	Counts
Participants

Secondary

Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24

The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 3 days after the last dose of study drug or up to the introduction of rescue therapy, whichever is the earliest. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

Posted

Number

percentage of participants

Week 24

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Units	Counts
Participants	OG000

Secondary

Percentage of Patients With HbA1c Level Less Than or Equal to 6.5% at Week 24

mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HbA1c assessment during on-treatment period.

Posted

Number

percentage of participants

Week 24

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Units	Counts
Participants	OG000

Secondary

Change From Baseline in Beta-cell Function Assessed by Homeostasis Model Assessment for Beta-cell Function (HOMA-beta) at Week 24

Beta cell function was assessed by HOMA-beta. HOMA-beta (% of normal beta cells function) = (20 multiplied by fasting plasma insulin [micro unit per milliliter]) divided by (fasting plasma glucose [mmol/L] minus 3.5). Change was calculated by subtracting baseline value from Week 24 value. The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 1 day after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

mITT population. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline HOMA-beta assessment during on-treatment period.

Posted

Least Squares Mean

Standard Error

% of normal beta cells function

Baseline, Week 24

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Secondary

Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period

Routine fasting self-monitored plasma glucose (SMPG) and central laboratory FPG (and HbA1c after week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after week 12) were performed. Threshold values - from baseline to Week 8: fasting SMPG/FPG >270 milligram/deciliter (mg/dL) (15.0 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 24: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8.5%. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

mITT population.

Posted

Number

percentage of participants

Baseline up to Week 24

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Units	Counts
Participants

Other Pre-specified

Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24

The on-treatment period for this efficacy variable is time from the first dose of study drug and up to 3 days after the last dose of study drug, on or before Visit 12 (Week 24) or Day 169 if Visit 12 is not available, and before the introduction of rescue therapy. For a patient to be included in mITT population, both baseline and at least 1 post baseline assessment for at least 1 efficacy variable, were required.

mITT population. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline body weight assessment during on-treatment period.

Posted

Number

percentage of participants

Baseline, Week 24

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Units	Counts
Participants	OG000

Other Pre-specified

Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia

Symptomatic hypoglycemia was an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose less than 60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose measurement was available. Severe symptomatic hypoglycemia was symptomatic hypoglycemia event in which the patient required the assistance of another person and was associated with either a plasma glucose level below 36 mg/dL (2.0 mmol/L) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration, if no plasma glucose measurement was available.

Safety population included all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.

Posted

Number

participants

First dose of study drug up to 3 days after the last dose administration, for up to 132 weeks

ID	Title	Description
OG000	Placebo	2-step initiation regimen of volume matching placebo.
OG001	Lixisenatide	2-step initiation regimen of lixisenatide.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Appendicitis	Infections and infestations	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Bronchitis	Infections and infestations	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0011 affected323 at risk
Cellulitis	Infections and infestations	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Diabetic foot infection	Infections and infestations	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Pneumonia	Infections and infestations	MedDRA 14.1	Non-systematic Assessment	EG0002 affected161 at risk EG0011 affected323 at risk
Urinary tract infection	Infections and infestations	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Bile duct cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Non-small cell lung cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Cerebral infarction	Nervous system disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Convulsion	Nervous system disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Memory impairment	Nervous system disorders	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Sciatica	Nervous system disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Diabetic retinopathy	Eye disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Macular oedema	Eye disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Retinal detachment	Eye disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Vitreous haemorrhage	Eye disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Acute coronary syndrome	Cardiac disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Angina unstable	Cardiac disorders	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Arteriosclerosis coronary artery	Cardiac disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Coronary artery disease	Cardiac disorders	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0011 affected323 at risk
Mitral valve incompetence	Cardiac disorders	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Blue toe syndrome	Vascular disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Shock haemorrhagic	Vascular disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Peritoneal haemorrhage	Gastrointestinal disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Umbilical hernia	Gastrointestinal disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0012 affected323 at risk
Cholecystitis chronic	Hepatobiliary disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Gouty arthritis	Musculoskeletal and connective tissue disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Neuropathic arthropathy	Musculoskeletal and connective tissue disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Spinal column stenosis	Musculoskeletal and connective tissue disorders	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Stag horn calculus	Renal and urinary disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Non-cardiac chest pain	General disorders	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0013 affected323 at risk
Blood calcitonin increased	Investigations	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Colonoscopy	Investigations	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Weight decreased	Investigations	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Abdominal injury	Injury, poisoning and procedural complications	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Foot fracture	Injury, poisoning and procedural complications	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Injury	Injury, poisoning and procedural complications	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Meniscus lesion	Injury, poisoning and procedural complications	MedDRA 14.1	Non-systematic Assessment	EG0001 affected161 at risk EG0010 affected323 at risk
Multiple fractures	Injury, poisoning and procedural complications	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Coronary angioplasty	Surgical and medical procedures	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk
Coronary artery bypass	Surgical and medical procedures	MedDRA 14.1	Non-systematic Assessment	EG0002 affected161 at risk EG0010 affected323 at risk
Percutaneous coronary intervention	Surgical and medical procedures	MedDRA 14.1	Non-systematic Assessment	EG0000 affected161 at risk EG0011 affected323 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Bronchitis	Infections and infestations	MedDRA 14.1	Non-systematic Assessment		EG00016 affected161 at risk EG00125 affected323 at risk
Influenza	Infections and infestations	MedDRA 14.1	Non-systematic Assessment		EG0009 affected161 at risk EG00124 affected323 at risk
Nasopharyngitis	Infections and infestations	MedDRA 14.1	Non-systematic Assessment		EG00024 affected161 at risk EG00153 affected323 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA 14.1	Non-systematic Assessment		EG00018 affected161 at risk EG00141 affected323 at risk
Urinary tract infection	Infections and infestations	MedDRA 14.1	Non-systematic Assessment		EG00011 affected161 at risk EG00124 affected323 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 14.1	Non-systematic Assessment	Hypoglycaemia adverse event is based on investigator reported hypoglycaemia.	EG0008 affected161 at risk EG00125 affected323 at risk
Dizziness	Nervous system disorders	MedDRA 14.1	Non-systematic Assessment		EG00013 affected161 at risk EG00133 affected323 at risk
Headache	Nervous system disorders	MedDRA 14.1	Non-systematic Assessment		EG00019 affected161 at risk EG00143 affected323 at risk
Hypertension	Vascular disorders	MedDRA 14.1	Non-systematic Assessment		EG0009 affected161 at risk EG00117 affected323 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 14.1	Non-systematic Assessment		EG00011 affected161 at risk EG00118 affected323 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 14.1	Non-systematic Assessment		EG00023 affected161 at risk EG00135 affected323 at risk
Nausea	Gastrointestinal disorders	MedDRA 14.1	Non-systematic Assessment		EG00022 affected161 at risk EG00184 affected323 at risk
Vomiting	Gastrointestinal disorders	MedDRA 14.1	Non-systematic Assessment		EG0008 affected161 at risk EG00126 affected323 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 14.1	Non-systematic Assessment		EG00011 affected161 at risk EG00124 affected323 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 14.1	Non-systematic Assessment		EG00014 affected161 at risk EG00122 affected323 at risk
Fatigue	General disorders	MedDRA 14.1	Non-systematic Assessment		EG0003 affected161 at risk EG00121 affected323 at risk
Oedema peripheral	General disorders	MedDRA 14.1	Non-systematic Assessment		EG0009 affected161 at risk EG00117 affected323 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
D045162	Thiazolidinediones
D013844	Thiazoles
D013457	Sulfur Compounds
D009930	Organic Chemicals
D001393	Azoles
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D001645	Biguanides
D006146	Guanidines
D000578	Amidines

ID	Title	Description
BG000	Placebo	2-step initiation regimen of volume matching placebo: 10 mcg QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.
BG001	Lixisenatide	2-step initiation regimen of lixisenatide: 10 mcg once daily QD subcutaneously for 1 week, followed by 15 mcg QD for 1 week, then 20 mcg QD up to the end of treatment.
BG002	Total	Total of all reporting 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	2-step initiation regimen of volume matching placebo.			15	161	105	161
EG001	Lixisenatide	2-step initiation regimen of lixisenatide.			25	323	219	323