GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Sulfonylurea | RxWiki

GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Sulfonylurea

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 sulfonylurea without or with 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 sulfonylurea with or without metformin on glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at Week 24. The secondary objectives are to assess the effects of lixisenatide on percentage of patients reaching HbA1c less than (<) 7 percent (%); percentage of patients reaching HbA1c less than or equal to (<=) 6.5%; body weight; fasting plasma glucose (FPG); beta-cell function assessed by homeostasis model assessment (HOMA) beta; 2-hour postprandial plasma glucose (PPG), glucagon, insulin, proinsulin, and C-peptide after a standardized meal challenge test in a sub-study in all patients in selected centers; to evaluate safety, tolerability, pharmacokinetics (PK) and anti-lixisenatide antibody development.
Condition	Diabetes Mellitus, Type 2
Intervention	Drug: Lixisenatide (AVE0010) Drug: Placebo Device: Pen auto-injector Drug: Sulfonylurea Drug: Metformin
Phase	Phase 3
Sponsor	Sanofi
Responsible Party	Sanofi
ClinicalTrials.gov Identifier	NCT00713830
First Received	July 10, 2008
Last Updated	February 26, 2014
Last verified	February 2014

Tracking Information[ + expand ][ + ]

First Received Date	July 10, 2008
Last Updated Date	February 26, 2014
Start Date	July 2008
Estimated Primary Completion Date	January 2011
Current Primary Outcome Measures	Absolute 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 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.
Current Secondary Outcome Measures	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 blood sample was drawn 2 hours after start of a standardized meal (standardized meal challenge test performed in selected sites). 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 last dosing day 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. 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 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. 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 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. Change From Baseline in Beta-cell Function Assessed by HOMA-beta at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]Beta cell function was assessed by HOMA-beta. HOMA-beta blood samples were drawn during a standardized meal challenge test (performed in selected sites). HOMA-beta (% of normal beta cells function) = (20 multiplied by fasting plasma insulin [micro unit per milliliter]) divided by (FPG [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 last dosing day 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. Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]The fasting glucagon and the 2-hour postprandial glucagon blood samples were drawn during a standardized meal challenge test (performed in selected sites). 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 last dosing day 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. Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]The fasting plasma insulin and the 2-hour postprandial plasma insulin blood samples were drawn during a standardized meal challenge test (performed in selected sites). 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 last dosing day 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. Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]The fasting Proinsulin and the 2-hour postprandial Proinsulin blood samples were drawn during a standardized meal challenge test (performed in selected sites). 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 last dosing day 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. Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24 [Time Frame: Baseline, Week 24] [Designated as safety issue: No]The fasting C-peptide and the 2-hour postprandial C-peptide blood samples were drawn during a standardized meal challenge test (performed in selected sites). 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 last dosing day 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. 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 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. 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 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. 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 >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.

Descriptive Information[ + expand ][ + ]

Brief Title	GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Sulfonylurea
Official Title	A Randomized, Double-blind, Placebo-controlled, 2-arm Parallel-group, Multicenter 24-week Study Followed by an Extension Assessing the Efficacy and Safety of AVE0010 on Top of a Sulfonylurea in Patients With Type 2 Diabetes Not Adequately Controlled With Sulfonylurea
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 sulfonylurea without or with 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 sulfonylurea with or without metformin on glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at Week 24. The secondary objectives are to assess the effects of lixisenatide on percentage of patients reaching HbA1c less than (<) 7 percent (%); percentage of patients reaching HbA1c less than or equal to (<=) 6.5%; body weight; fasting plasma glucose (FPG); beta-cell function assessed by homeostasis model assessment (HOMA) beta; 2-hour postprandial plasma glucose (PPG), glucagon, insulin, proinsulin, and C-peptide after a standardized meal challenge test in a sub-study in all patients in selected centers; to evaluate 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 patient.
Study Type	Interventional
Study Phase	Phase 3
Study Design	Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
Condition	Diabetes Mellitus, Type 2
Intervention	Drug: 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: Sulfonylurea Sulfonylurea to be continued at maximum effective dose according to local labeling up to end of treatment. Drug: Metformin Metformin if given to be continued at stable dose (at least 1.5 gram per day [except at least 0.75 gram per day in Japan and 1.0 gram per day in South Korea]) up to the end of treatment.
Study Arm (s)	Experimental: Lixisenatide 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. Placebo Comparator: Placebo 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.

Recruitment Information[ + expand ][ + ]

Recruitment Status	Completed
Estimated Enrollment	859
Estimated Completion Date	January 2011
Estimated Primary Completion Date	January 2011
Eligibility Criteria	Inclusion Criteria: - Type 2 diabetes mellitus, diagnosed for at least 1 year before screening visit, insufficiently controlled with a sulfonylurea alone or a sulfonylurea in association with metformin Exclusion Criteria: - HbA1c less than (<) 7% or greater than (>) 10% at screening - At the time of screening age less than legal age of majority - Pregnant or breastfeeding women or women of childbearing potential with no effective contraceptive method - Type 1 diabetes mellitus - Sulfonylurea less than the maximum effective dose according to local labeling - Sulfonylurea not at a stable (unchanged) dose for at least 3 months prior to screening - In case of treatment with metformin in association with sulfonylurea, no stable (unchanged) treatment with metformin of at least 1.5 gram per day (except at least 0.75 gram per day in Japan and at least 1.0 gram per day in South Korea), 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]) - History of hypoglycemia unawareness - Body mass index less than or equal to (<=) 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, 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 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: aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase: >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 <100 000/mm^3; positive test for Hepatitis B surface antigen and/or Hepatitis C antibody - Any clinically significant abnormality identified on physical examination, laboratory tests 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) - Patients with condition/concomitant diseases making them non-evaluable for the efficacy assessment - Use of oral or injectable antidiabetic or hypoglycemic agents other than sulfonylurea and metformin (for example, alpha glucosidase inhibitor, thiazolidinedione, 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 (for example, participation in a previous study with lixisenatide) - Renal impairment defined with serum creatinine >1.4 mg/dL in women and serum creatinine >1.5 mg/dL in men (applicable only for patients with metformin treatment) - End-stage renal disease as defined by a serum creatinine clearance of <15 milliliter/minute (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
Gender	Both
Ages	18 Years
Accepts Healthy Volunteers	No
Contacts	Not Provided
Location Countries	United States, Bulgaria, Czech Republic, Egypt, Germany, India, Israel, Japan, Korea, Republic of, Netherlands, Romania, Russian Federation, Taiwan, Thailand, Tunisia, Turkey

Administrative Information[ + expand ][ + ]

NCT Number	NCT00713830
Other Study ID Numbers	EFC6015
Has Data Monitoring Committee	Yes
Information Provided By	Sanofi
Study Sponsor	Sanofi
Collaborators	Not Provided
Investigators	Study Director: Clinical Sciences & Operations Sanofi
Verification Date	February 2014

Locations[ + expand ][ + ]

Sanofi-Aventis Administrative Office	Bridgewater, New Jersey, United States, 08807
Sanofi-Aventis Administrative Office	Sofia, Bulgaria
Sanofi-Aventis Administrative Office	Praha, Czech Republic
Sanofi-Aventis Administrative Office	Cairo, Egypt
Sanofi-Aventis Administrative Office	Berlin, Germany
Sanofi-Aventis Administrative Office	Mumbai, India
Sanofi-Aventis Administrative Office	Natanya, Israel
Sanofi-Aventis Administrative Office	Tokyo, Japan
Sanofi-Aventis Administrative Office	Seoul, Korea, Republic of
Sanofi-Aventis Administrative Office	Gouda, Netherlands
Sanofi-Aventis Administrative Office	Bucuresti, Romania
Sanofi-Aventis Administrative Office	Moscow, Russian Federation
Sanofi-Aventis Administrative Office	Taipei, Taiwan
Sanofi-Aventis Administrative Office	Bangkok, Thailand
Sanofi-Aventis Administrative Office	Megrine, Tunisia
Sanofi-Aventis Administrative Office	Istanbul, Turkey