GetGoal-M-Asia: Efficacy and Safety of Lixisenatide in Patients With Type 2 Diabetes Mellitus Insufficiently Controlled by Metformin

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01169779
• Collaborator: (none)
• Enrollment: 391
• Locations: 35
• Arms: 2
• Duration (Months): 17
• Patients Per Site: 11.2
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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 metformin with or without sulfonylurea, over a period of 24 weeks of treatment.

The primary objective is to assess the effects on glycemic control of lixisenatide (AVE0010) in comparison to placebo as an add-on treatment to metformin with or without sulfonylurea in terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at Week 24.

The secondary objectives are to assess the effects of lixisenatide over 24 weeks on percentage of patients reaching HbA1c less than (< ) 7 percent (%) or HbA1c less than or equal to (<=) 6.5%, fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (PPG) and glucose excursion during standardized meal test, body weight; to evaluate safety, tolerability, pharmacokinetic (PK) and anti-lixisenatide antibody development.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Lixisenatide (AVE0010); Drug: Placebo; Device: Pen auto-injector; Drug: Metformin; Drug: Sulfonylurea	Phase 3

Detailed Description

The study duration for each patient is 27 weeks +/- 10 days (up to 2 weeks screening + 1 week run-in + 24 weeks double-blind treatment + 3 days follow-up).

Study Design

• Study Type: Interventional
• Actual Enrollment: 391 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Lixisenatide in Patients With Type 2 Diabetes Mellitus Insufficiently Controlled by Metformin (With or Without Sulfonylurea): a Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Study With 24-week Treatment Period
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Dec 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lixisenatide 1-step initiation regimen of lixisenatide: 10 microgram (mcg) once daily (QD) for 2 weeks, followed by 20 mcg QD up to Week 24.	Drug: Lixisenatide (AVE0010); Self administered by subcutaneous injections once daily within the hour preceding breakfast.; Device: Pen auto-injector; Other Names: OptiClik® ; Drug: Metformin; Metformin to be continued at stable dose (at least 1.0 gram per day and not more than 1.5 gram per day) up to Week 24.; Drug: Sulfonylurea; Sulfonylurea if given at screening, to be continued up to Week 24. In patients with a screening HbA1c <8% the dose is decreased by 25% to 50% at randomization and then increased up to the screening dose between Week 4 and 12 as per fasting self-monitored plasma glucose (SMPG) values. In patients with a screening HbA1c >=8%, the dose is not to be changed at randomization. In any case, after Week 12, sulfonylurea is to be continued at a stable dose.
Placebo Comparator: Placebo 1-step initiation regimen of volume matching placebo: 10 mcg QD for 2 weeks, followed by 20 mcg QD up to Week 24.	Drug: Placebo; Self administered by subcutaneous injections once daily within the hour preceding breakfast.; Device: Pen auto-injector; Other Names: OptiClik® ; Drug: Metformin; Metformin to be continued at stable dose (at least 1.0 gram per day and not more than 1.5 gram per day) up to Week 24.; Drug: Sulfonylurea; Sulfonylurea if given at screening, to be continued up to Week 24. In patients with a screening HbA1c <8% the dose is decreased by 25% to 50% at randomization and then increased up to the screening dose between Week 4 and 12 as per fasting self-monitored plasma glucose (SMPG) values. In patients with a screening HbA1c >=8%, the dose is not to be changed at randomization. In any case, after Week 12, sulfonylurea is to be continued at a stable dose.

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 [Baseline, Week 24]

   Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. 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 on-treatment assessment for at least 1 efficacy variable, were required.

Secondary Outcome Measures

1. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 [Baseline, Week 24]

   Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 1 day 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 on-treatment assessment for at least 1 efficacy variable, were required.

2. Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24 [Baseline, Week 24]

   The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.

3. Change From Baseline in Body Weight at Week 24 [Baseline, Week 24]

   Change was calculated by subtracting Baseline value from Week 24 value. 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 on-treatment assessment for at least 1 efficacy variable, were required.

4. Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 [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 on-treatment assessment for at least 1 efficacy variable, were required.

5. Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 [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 on-treatment assessment for at least 1 efficacy variable, were required.

6. Change From Baseline in Glucose Excursion at Week 24 [Baseline, Week 24]

   Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.

7. Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period [Baseline up to Week 24]

   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 >250 milligram/deciliter (mg/dL) (13.9 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >220 mg/dL (12.2 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 on-treatment assessment for at least 1 efficacy variable, were required.

Other Outcome Measures

1. Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24 [Baseline, 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 on-treatment assessment for at least 1 efficacy variable, were required.

2. Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia [First dose of study drug up to 3 days after the last dose administration]

   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.

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Type 2 diabetes mellitus, diagnosed for at least 1 year before screening visit, insufficiently controlled with metformin alone or metformin with sulfonylurea at the time of the screening visit

Exclusion criteria:

• HbA1c <7% or greater than (>) 10% at screening

• At the time of screening age < legal age of majority

• Pregnant or breastfeeding women or women of childbearing potential with no effective contraceptive method

• Type 1 diabetes mellitus

• Treatment with metformin not at a stable dose of at least 1.0 gram per day or more than 1.5 gram per day for at least 3 months prior to screening visit

• In case of treatment with sulfonylurea, if the sulfonylurea dosage is less than the maximum effective dose (that is, half of the maximum recommended dose according to local labeling), or is not at a stable (unchanged) dose for at least 3 months prior to screening

• FPG at screening >250 milligram per deciliter (mg/dL) (>13.9 millimole per liter [mmol/L])

• History of hypoglycemia unawareness

• Body mass index <=20 kilogram per square meter (kg/m^2)

• Weight change of >5 kg during the 3 months preceding the screening visit

• History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, or inflammatory bowel disease or patients considered by the investigator at high risk for acute pancreatitis (for example, with known history of biliary gallstone[s], or with very high triglyceride level [>=5.65 mmol/L]) at the time of screening

• Personal or family history of medullary thyroid cancer or genetic conditions that predispose to medullary thyroid cancer (for example, multiple endocrine neoplasia syndromes);

• History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening

• Hemoglobinopathy or hemolytic anemia, receipt of blood or plasma products within 3 months prior to the time of screening

• Within the last 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization

• 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 (SBP) or diastolic blood pressure (DBP) >180 millimeter of mercury (mmHg) or >95 mmHg, respectively

• Laboratory findings at the time of screening: amylase and/or lipase: >3 times upper limit of normal (ULN); hemoglobin <11 gram/deciliter and/or neutrophils <1500 per cubic millimeter (mm^{3) and/or platelets <100 000/mm}3; calcitonin >20 picogram per milliliter (5.9 picomole per liter) ; and positive test for Hepatitis B surface antigen and/or Hepatitis C antibody

• Any clinically significant abnormality identified on physical examination, laboratory tests, electrocardiogram, 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 attending 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 oral or injectable antidiabetic or hypoglycemic agents other than metformin and sulfonylurea (for example, alpha-glucosidase inhibitor, thiazolidinedione, glucagon-like peptide -1 [GLP-1], receptor agonist, dipeptidyl-peptidase-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 screening;

• 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

• Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting, including, but not limited to gastroparesis, unstable (that is, worsening) and not controlled (that is, prolonged nausea and vomiting) gastroesophageal reflux disease requiring medical treatment, within 6 months prior to the time of screening

• Allergic reaction to any 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 156011	Beijing		China	100034
2	Investigational Site Number 156012	Beijing		China	100101
3	Investigational Site Number 156019	Beijing		China	100191
4	Investigational Site Number 156002	Beijing		China	100700
5	Investigational Site Number 156003	Beijing		China	100730
6	Investigational Site Number 156009	Beijing		China	100730
7	Investigational Site Number 156001	Beijing		China	100853
8	Investigational Site Number 156036	Changchun		China	130041
9	Investigational Site Number 156016	Changsha		China	410008
10	Investigational Site Number 156015	Changsha		China	410011
11	Investigational Site Number 156006	Chengdu		China	610041
12	Investigational Site Number 156032	Chengdu		China	610072
13	Investigational Site Number 156010	Dalian		China	116027
14	Investigational Site Number 156004	Guangzhou		China	510080
15	Investigational Site Number 156008	Guangzhou		China	510080
16	Investigational Site Number 156025	Guangzhou		China	510630
17	Investigational Site Number 156031	Haikou		China	57028
18	Investigational Site Number 156014	Harbin		China	150001
19	Investigational Site Number 156029	Hefei		China	230022
20	Investigational Site Number 156013	Qingdao		China	266003
21	Investigational Site Number 156007	Shanghai		China	200003
22	Investigational Site Number 156030	Shanghai		China	200065
23	Investigational Site Number 156020	Shenyang		China	110004
24	Investigational Site Number 156035	Suzhou		China	215004
25	Investigational Site Number 156033	Taiyuan		China	030001
26	Investigational Site Number 156037	Tianjin		China	300052
27	Investigational Site Number 156022	Xi'An		China	710032
28	Investigational Site Number 156023	Xi'An		China	710061
29	Investigational Site Number 344001	Hong Kong		Hong Kong
30	Investigational Site Number 344003	Hong Kong		Hong Kong
31	Investigational Site Number 344002	Shatin, Nt		Hong Kong
32	Investigational Site Number 458001	Kelantan		Malaysia	16150
33	Investigational Site Number 458003	Kuala Lumpur		Malaysia	59100
34	Investigational Site Number 458002	Putrajaya		Malaysia	62250
35	Investigational Site Number 764002	Bangkok		Thailand	10400

Sponsors and Collaborators

• Sanofi

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01169779
• Other Study ID Numbers: EFC11321; U1111-1116-8938
• First Posted: Jul 26, 2010
• Last Update Posted: Oct 13, 2016
• Last Verified: Aug 1, 2016

• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Lixisenatide

Study Results

Participant Flow

Recruitment Details	The study was conducted at 35 centers in 4 countries between July 21, 2010 and December 22, 2011.
Pre-assignment Detail	A total of 655 patients were screened of which 264 (40.3%) were screen failures; main reason for screen failure was glycosylated hemoglobin (HbA1c) values being out of the defined protocol range (greater than or equal to 7% and less than or equal to 10%). A total of 391 patients were randomized.

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo: 10 microgram (mcg) once daily (QD) subcutaneously for 2 weeks, followed by 20 mcg QD up to Week 24.	1-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 2 weeks, followed by 20 mcg QD up to Week 24.
Period Title: Overall Study
STARTED	195	196
Treated/Safety Population	194	196
Modified Intent-to-Treat(mITT)Population	193	195
Subgroup for Standardized Meal Test	130	121
COMPLETED	184	179
NOT COMPLETED	11	17

Baseline Characteristics

Arm/Group Title	Placebo	Lixisenatide	Total
Arm/Group Description	1-step initiation regimen of volume matching placebo: 10 mcg QD subcutaneously for 2 weeks, followed by 20 mcg QD up to Week 24.	1-step initiation regimen of lixisenatide: 10 mcg QD subcutaneously for 2 weeks, followed by 20 mcg QD up to Week 24.	Total of all reporting groups
Overall Participants	194	196	390
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.1 (10.5)	54.5 (10.3)	54.8 (10.4)
Sex: Female, Male (Count of Participants)
Female	103 53.1%	95 48.5%	198 50.8%
Male	91 46.9%	101 51.5%	192 49.2%
Race/Ethnicity, Customized (participants) [Number]
Race: Asian/Oriental	194 100%	196 100%	390 100%
Glycosylated Hemoglobin (HbA1c) (percentage of hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of hemoglobin]	7.85 (0.71)	7.95 (0.81)	7.90 (0.76)
Fasting Plasma Glucose (FPG) (millimole per liter (mmol/L)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimole per liter (mmol/L)]	8.74 (1.83)	8.84 (2.12)	8.79 (1.98)
2-Hour Postprandial Plasma Glucose (PPG) (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	17.19 (4.06)	16.07 (3.77)	16.65 (3.95)
Glucose Excursion (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	8.14 (3.11)	7.12 (3.21)	7.65 (3.20)
Body Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	72.74 (13.64)	73.18 (13.93)	72.96 (13.77)
Duration of Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	6.84 (4.80)	6.45 (4.64)	6.64 (4.72)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	27.08 (3.75)	26.75 (3.86)	26.91 (3.80)
Metformin Daily Dose (milligram (mg) per day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligram (mg) per day]	1363.4 (221.9)	1369.9 (219.9)	1366.7 (220.7)
Number of Patients With Sulfonylurea use at Baseline (participants) [Number]
Yes	92 47.4%	82 41.8%	174 44.6%
No	102 52.6%	114 58.2%	216 55.4%

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
Description	Absolute change = HbA1c value at Week 24 minus HbA1c value at baseline. 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 on-treatment assessment for at least 1 efficacy variable, were required.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	188	185
Least Squares Mean (Standard Error) [percentage of hemoglobin]	-0.47 (0.104)	-0.83 (0.102)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Lixisenatide
	Comments	To detect a difference of 0.5% in change in HbA1c at Week 24 between lixisenatide arm and placebo arm, 190 patients per group would provide a power of 96% assuming common standard deviation of 1.3% with 2-sided test at 5% significance level.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	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%), sulfonylurea use (Yes,No), country as fixed effects, baseline HbA1c as covariate.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least squares (LS) mean difference
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.551 to -0.162
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.099
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Description	Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to 1 day 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 on-treatment assessment for at least 1 efficacy variable, were required.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	191	190
Least Squares Mean (Standard Error) [mmol/L]	-0.21 (0.200)	-0.69 (0.197)

3. Secondary Outcome

Title	Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24
Description	The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Subgroup for standardized meal test. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with baseline and at least 1 post-baseline 2-hour PPG assessment during on-treatment period.

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	116	107
Least Squares Mean (Standard Error) [mmol/L]	-1.33 (0.376)	-5.61 (0.393)

4. Secondary Outcome

Title	Change From Baseline in Body Weight at Week 24
Description	Change was calculated by subtracting Baseline value from Week 24 value. 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 on-treatment assessment for at least 1 efficacy variable, were required.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	191	188
Least Squares Mean (Standard Error) [kilogram]	-1.24 (0.273)	-1.50 (0.267)

5. Secondary Outcome

Title	Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24
Description	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 on-treatment assessment for at least 1 efficacy variable, were required.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	188	185
Number [percentage of participants]	38.8 20%	53.0 27%

6. Secondary Outcome

Title	Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24
Description	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 on-treatment assessment for at least 1 efficacy variable, were required.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	188	185
Number [percentage of participants]	18.1 9.3%	32.4 16.5%

7. Secondary Outcome

Title	Change From Baseline in Glucose Excursion at Week 24
Description	Glucose excursion = 2-hour PPG minus plasma glucose 30 minutes prior to the standardized meal test, before study drug administration. Change was calculated by subtracting Baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

Subgroup for standardized meal test. Missing data was imputed using LOCF. Here, number of patients analyzed = patients with Baseline and at least 1 post-baseline glucose excursion assessment during on-treatment period.

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	116	106
Least Squares Mean (Standard Error) [mmol/L]	-0.79 (0.340)	-4.78 (0.356)

8. Other Pre-specified Outcome

Title	Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24
Description	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 on-treatment assessment for at least 1 efficacy variable, were required.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	191	188
Number [percentage of participants]	14.7 7.6%	19.7 10.1%

9. Secondary Outcome

Title	Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period
Description	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 >250 milligram/deciliter (mg/dL) (13.9 mmol/L), from Week 8 to Week 12: fasting SMPG/FPG >220 mg/dL (12.2 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 on-treatment assessment for at least 1 efficacy variable, were required.
Time Frame	Baseline up to Week 24

Outcome Measure Data

Analysis Population Description

mITT population.

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	193	195
Number [percentage of participants]	6.7 3.5%	3.6 1.8%

10. Other Pre-specified Outcome

Title	Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia
Description	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.
Time Frame	First dose of study drug up to 3 days after the last dose administration

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.	1-step initiation regimen of lixisenatide.
Measure Participants	194	196
Symptomatic hypoglycemia	5 2.6%	11 5.6%
Severe symptomatic hypoglycemia	0 0%	0 0%

Adverse Events

Time Frame	First dose of study drug up to 3 days after the last dose administration
Adverse Event Reporting Description	Median exposure to study treatment was 169 days for both treatment arms. The analysis was performed on safety population, defined as all randomized patients who were exposed to at least 1 dose of study drug, regardless of the amount of treatment administered.
Arm/Group Title	Placebo		Lixisenatide
Arm/Group Description	1-step initiation regimen of volume matching placebo.		1-step initiation regimen of lixisenatide.
All Cause Mortality
	Placebo		Lixisenatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Lixisenatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/194 (2.1%)		3/196 (1.5%)
Cardiac disorders
Acute myocardial infarction	0/194 (0%)		1/196 (0.5%)
Gastrointestinal disorders
Abdominal pain	0/194 (0%)		1/196 (0.5%)
Hepatobiliary disorders
Hepatic function abnormal	1/194 (0.5%)		0/196 (0%)
Immune system disorders
Anaphylactic shock	0/194 (0%)		1/196 (0.5%)
Nervous system disorders
Cerebral infarction	0/194 (0%)		1/196 (0.5%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/194 (0.5%)		0/196 (0%)
Prostatitis	1/194 (0.5%)		0/196 (0%)
Vascular disorders
Hypertension	1/194 (0.5%)		0/196 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Lixisenatide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/194 (23.7%)		80/196 (40.8%)
Gastrointestinal disorders
Nausea	5/194 (2.6%)		32/196 (16.3%)
Vomiting	2/194 (1%)		15/196 (7.7%)
Infections and infestations
Upper respiratory tract infection	8/194 (4.1%)		12/196 (6.1%)
Investigations
Blood glucose decreased	5/194 (2.6%)		10/196 (5.1%)
Metabolism and nutrition disorders
Hyperuricaemia	10/194 (5.2%)		7/196 (3.6%)
Hypoglycaemia	9/194 (4.6%)		18/196 (9.2%)
Nervous system disorders
Dizziness	8/194 (4.1%)		17/196 (8.7%)
Renal and urinary disorders
Diabetic nephropathy	13/194 (6.7%)		13/196 (6.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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