Efficacy and Safety of Lixisenatide in Patients With Type 2 Diabetes Mellitus Insufficiently Controlled by Metformin

Overview[ - collapse ][ - ]

Purpose 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.
ConditionType 2 Diabetes Mellitus
InterventionDrug: Lixisenatide (AVE0010)
Drug: Placebo
Device: Pen auto-injector
Drug: Metformin
Drug: Sulfonylurea
PhasePhase 3
SponsorSanofi
Responsible PartySanofi
ClinicalTrials.gov IdentifierNCT01169779
First ReceivedJuly 23, 2010
Last UpdatedMarch 18, 2014
Last verifiedMarch 2014

Tracking Information[ + expand ][ + ]

First Received DateJuly 23, 2010
Last Updated DateMarch 18, 2014
Start DateJuly 2010
Estimated Primary Completion DateDecember 2011
Current Primary Outcome MeasuresAbsolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]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.
Current Secondary Outcome Measures
  • Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]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.
  • Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]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.
  • Change From Baseline in Body Weight at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]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.
  • Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24 [Time Frame: Week 24] [Designated as safety issue: No]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.
  • Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24 [Time Frame: Week 24] [Designated as safety issue: No]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.
  • Change From Baseline in Glucose Excursion at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]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.
  • Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period [Time Frame: Baseline up to Week 24] [Designated as safety issue: No]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.

Descriptive Information[ + expand ][ + ]

Brief TitleEfficacy and Safety of Lixisenatide in Patients With Type 2 Diabetes Mellitus Insufficiently Controlled by Metformin
Official TitleEfficacy 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
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.
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 TypeInterventional
Study PhasePhase 3
Study DesignAllocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
ConditionType 2 Diabetes Mellitus
InterventionDrug: Lixisenatide (AVE0010)
Self administered by subcutaneous injections once daily within the hour preceding breakfast.
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.
Study Arm (s)
  • 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.
  • 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.

Recruitment Information[ + expand ][ + ]

Recruitment StatusCompleted
Estimated Enrollment391
Estimated Completion DateDecember 2011
Estimated Primary Completion DateDecember 2011
Eligibility Criteria
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
GenderBoth
Ages18 Years
Accepts Healthy VolunteersNo
ContactsNot Provided
Location CountriesChina, Hong Kong, Malaysia, Thailand

Administrative Information[ + expand ][ + ]

NCT Number NCT01169779
Other Study ID NumbersEFC11321
Has Data Monitoring CommitteeYes
Information Provided BySanofi
Study SponsorSanofi
CollaboratorsNot Provided
Investigators Study Director: Clinical Sciences & Operations Sanofi
Verification DateMarch 2014

Locations[ + expand ][ + ]

Investigational Site Number 156001
Beijing, China, 100853
Investigational Site Number 156009
Beijing, China, 100730
Investigational Site Number 156012
Beijing, China, 100101
Investigational Site Number 156019
Beijing, China, 100191
Investigational Site Number 156002
Beijing, China, 100700
Investigational Site Number 156011
Beijing, China, 100034
Investigational Site Number 156003
Beijing, China, 100730
Investigational Site Number 156036
Changchun, China, 130041
Investigational Site Number 156016
Changsha, China, 410008
Investigational Site Number 156015
Changsha, China, 410011
Investigational Site Number 156006
Chengdu, China, 610041
Investigational Site Number 156032
Chengdu, China, 610072
Investigational Site Number 156010
Dalian, China, 116027
Investigational Site Number 156004
Guangzhou, China, 510080
Investigational Site Number 156008
Guangzhou, China, 510080
Investigational Site Number 156025
Guangzhou, China, 510630
Investigational Site Number 156031
Haikou, China, 57028
Investigational Site Number 156014
Harbin, China, 150001
Investigational Site Number 156029
Hefei, China, 230022
Investigational Site Number 156013
Qingdao, China, 266003
Investigational Site Number 156007
Shanghai, China, 200003
Investigational Site Number 156030
Shanghai, China, 200065
Investigational Site Number 156020
Shenyang, China, 110004
Investigational Site Number 156035
Suzhou, China, 215004
Investigational Site Number 156033
Taiyuan, China, 030001
Investigational Site Number 156037
Tianjin, China, 300052
Investigational Site Number 156023
Xi'An, China, 710061
Investigational Site Number 156022
Xi'An, China, 710032
Investigational Site Number 344001
Hong Kong, Hong Kong
Investigational Site Number 344003
Hong Kong, Hong Kong
Investigational Site Number 344002
Shatin, Nt, Hong Kong
Investigational Site Number 458001
Kelantan, Malaysia, 16150
Investigational Site Number 458003
Kuala Lumpur, Malaysia, 59100
Investigational Site Number 458002
Putrajaya, Malaysia, 62250
Investigational Site Number 764002
Bangkok, Thailand, 10400