Clinical trial NCT00763451: GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Metformin
Official title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter, 24-week Study Followed by an Extension Assessing the Efficacy and Safety of AVE0010 in Two Titration Regimens on Top of Metformin in Patients With Type 2 Diabetes Not Adequately Controlled With Metformin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Keywords: hyperglycemia, GLP-1
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2008-10-01
Enrollment: 484
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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, 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 metformin on glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction when it is used in two steps dose titration regimen at Week 24.

Secondary objectives are to assess the effects of lixisenatide when added to metformin on glycemic control in comparison to placebo in terms of HbA1c reduction when it is used in a one-step dose titration regimen, the percentage of patients with HbA1c less than 7 percent or less than or equal to 6.5%, body weight, fasting plasma glucose (FPG); to assess the safety, tolerability, pharmacokinetics (PK) and anti-lixisenatide antibody development.

Detailed description: Patients who complete the 24-week main double-blind treatment would undergo a variable double-blind extension treatment, which ends for all patients at approximately the scheduled date of Week 76 visit (Visit 25) for the last randomized patients.

Eligibility criteria: Inclusion Criteria:

* Type 2 diabetes mellitus, diagnosed for at least 1 year at the time of screening visit, insufficiently controlled with metformin at a stable dose of at least 1.5 gram/day for at least 3 months prior to screening visit

Exclusion Criteria:

* HbA1c less than (\<) 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 an antidiabetic pharmacological agent other than metformin within the 3 months preceding the screening
* 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, inflammatory bowel disease
* 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 supine systolic or diastolic blood pressure \>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 the 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 \<100000/mm\^3; positive test for Hepatitis B surface antigen (HBsAg) and/or Hepatitis C antibody (HCAb) and 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 oral or injectable antidiabetic or hypoglycemic agents other than metformin (for example, sulfonylurea, alpha glucosidase inhibitor, thiazolidinedione, rimonabant, exenatide, dipeptidylpeptidase-4 (DPP-IV) inhibitor, insulin) within 3 months prior to the time of screening
* Use of systemic glucocorticoids (excluding topical application or inhaled forms) for one 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 any 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 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

Primary outcomes:
measure: Absolute Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
timeFrame: Baseline, Week 24
Secondary outcomes:
measure: Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
timeFrame: Baseline, Week 24
measure: Change From Baseline in Body Weight at Week 24
timeFrame: Baseline, Week 24
measure: Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24
timeFrame: Week 24
measure: Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% at Week 24
timeFrame: Week 24
measure: Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period
timeFrame: Baseline up to Week 24
Other outcomes:
measure: Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24
timeFrame: Baseline, Week 24
measure: Number of Patients With Symptomatic Hypoglycemia and Severe Symptomatic Hypoglycemia
timeFrame: First dose of study drug up to 3 days after the last dose administration, for up to 112 weeks
Locations:
city: Bridgewater
country: United States
facility: Sanofi-Aventis Administrative Office
state: New Jersey
city: Sao Paulo
country: Brazil
facility: Sanofi-Aventis Administrative Office
city: Santiago
country: Chile
facility: Sanofi-Aventis Administrative Office
city: Santafe de Bogota
country: Colombia
facility: Sanofi-Aventis Administrative Office
city: Tallinn
country: Estonia
facility: Sanofi-Aventis Administrative Office
city: Berlin
country: Germany
facility: Sanofi-Aventis Administrative Office
city: Milano
country: Italy
facility: Sanofi-Aventis Administrative Office
city: Vilnius
country: Lithuania
facility: Sanofi-Aventis Administrative Office
city: Kuala Lumpur
country: Malaysia
facility: Sanofi-Aventis Administrative Office
city: Mexico
country: Mexico
facility: Sanofi-Aventis Administrative Office
city: Makati City
country: Philippines
facility: Sanofi-Aventis Administrative Office
city: Warszawa
country: Poland
facility: Sanofi-Aventis Administrative Office
city: Bucuresti
country: Romania
facility: Sanofi-Aventis Administrative Office
city: Brastislava
country: Slovakia
facility: Sanofi-Aventis Administrative Office
city: Kiev
country: Ukraine
facility: Sanofi-Aventis Administrative Office
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Bolli GB, Munteanu M, Dotsenko S, Niemoeller E, Boka G, Wu Y, Hanefeld M. Efficacy and safety of lixisenatide once daily vs. placebo in people with Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabet Med. 2014 Feb;31(2):176-84. doi: 10.1111/dme.12328. Epub 2013 Oct 24.
citation: Ambery P, Donner TW, Biswas N, Donaldson J, Parkin J, Dayan CM. Efficacy and safety of low-dose otelixizumab anti-CD3 monoclonal antibody in preserving C-peptide secretion in adolescent type 1 diabetes: DEFEND-2, a randomized, placebo-controlled, double-blind, multi-centre study. Diabet Med. 2014 Apr;31(4):399-402. doi: 10.1111/dme.12361. Epub 2013 Dec 6.