24-week Study Comparing Lixisenatide to Sitagliptin as add-on to Metformin in Obese Type 2 Diabetic Patients Younger Than 50 Years

Type 2 Diabetes Mellitus Clinical Trial

Official title:

A Randomized, Double-blind, Double-dummy, 2-arm Parallel-group, Multicenter 24-week Study Comparing the Efficacy and Safety of AVE0010 to Sitagliptin as add-on to Metformin in Obese Type 2 Diabetic Patients Younger Than 50 and Not Adequately Controlled With Metformin

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00976937
• Other study ID #: EFC10780
• Secondary ID: EudraCT:2008-007
• Status: Completed
• Phase: Phase 3
• First received: September 14, 2009
• Last updated: March 10, 2014
• Start date: August 2009
• Est. completion date: March 2011

Study information

• Verified date: March 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate benefits and risks of lixisenatide (AVE0010), in comparison to sitagliptin, as an add-on treatment to metformin, in obese (body mass index [BMI] greater than or equal to 30 kilogram per square meter [kg/m^2]) type 2 diabetic patients less than 50 years of age, over a period of 24 weeks of treatment.

The primary objective of this study is to assess the efficacy of lixisenatide, in comparison to sitagliptin, as an add-on treatment to metformin on a composite endpoint of glycemic control in terms of glycosylated hemoglobin (HbA1c) and body weight, at Week 24.

Secondary objectives are to assess the effects of lixisenatide, in comparison to sitagliptin, as an add-on treatment to metformin on absolute changes in HbA1c values and body weight; fasting plasma glucose (FPG); plasma glucose, insulin, C-peptide, glucagon, and proinsulin during a 2-hour standardized meal test; insulin resistance assessed by homeostatic model assessment of insulin resistance (HOMA-IR); beta cell function assessed by homeostatic model assessment of beta-cell function (HOMA-beta); to evaluate safety, tolerability, and anti-lixisenatide antibody development.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 319
• Est. completion date: March 2011
• Est. primary completion date: March 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 49 Years

Eligibility

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 (g/day) for at least 3 months prior to the screening visit

• Patients with obesity (BMI greater than equal to [>=] 30 kg/m^2) and aged from 18 years to less than 50 years

Exclusion criteria

• HbA1c less than (<) 7.0 percent (%) or HbA1c greater than (>) 10% at screening

• Type 1 diabetes mellitus

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

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

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

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

• Hemoglobinopathy or hemolytic anemia or 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

• 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 could have precludes safe completion of the study or constrains efficacy assessment such as major systemic diseases, presence of clinically significant diabetic retinopathy 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 or diastolic blood pressure >180 millimeter of mercury (mmHg) or >110 mmHg, respectively

• Laboratory findings at the time of screening : Amylase and/or lipase >3 times the upper limit of normal (ULN) laboratory range; alanine aminotransferase (ALT): >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, and calcitonin >=20 picogram per milliliter (pg/mL) (5.9 picomole per liter)

• Patients who are considered by the investigator or any sub-investigator as inappropriate for the 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 than metformin (for example, sulfonylurea, alpha glucosidase inhibitor, thiazolidinedione, exenatide, dipeptidyl peptidase IV (DPP-IV) inhibitors, insulin) within 3 months prior to the time of screening

• History of bariatric surgery, anti-obesity treatment, or unstable diet 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 screening

• 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

• Any previous treatment with lixisenatide (for example, participation in a previous study with lixisenatide)

• Allergic reaction to any glucagon like peptide-1 (GLP 1) agonist in the past (for example, exenatide, liraglutide) or to metacresol

• History of a serious hypersensitivity reaction to sitagliptin

• Moderate or severe renal impairment (creatinine clearance inferior to 50 milliliter/minute [mL/min])

• Additional exclusion criteria at the end of the run-in phase: informed consent withdrawal; lack of compliance during the single-blind placebo run-in period (>2 injections missed or >2 capsules missed); and patient with any adverse event which could have precludes the inclusion in the study, as assessed by the investigator

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

Intervention

Drug:
• Lixisenatide (AVE0010)
Self-administered by subcutaneous injections once daily within the hour preceding breakfast.
• Lixisenatide Placebo
Self-administered by subcutaneous injections once daily within the hour preceding breakfast.

Device:
• Pen auto-injector

Drug:
• Sitagliptin
Administered orally once a day in the morning with or without food at approximately the same time each day.
• Sitagliptin Placebo
Administered orally once a day in the morning with or without food at approximately the same time each day.
• Metformin
Metformin to be continued at stable dose (at least 1.5 gram per day) up to Week 24.

Locations

Country	Name	City	State
Australia	Sanofi-Aventis Investigational Site Number 036006	Adelaide
Australia	Sanofi-Aventis Investigational Site Number 036001	Box Hill
Australia	Sanofi-Aventis Investigational Site Number 036004	Elizabeth Vale
Australia	Sanofi-Aventis Investigational Site Number 036002	Geelong
Australia	Sanofi-Aventis Investigational Site Number 036005	Meadowbrook
Australia	Sanofi-Aventis Investigational Site Number 036003	Sydney
Brazil	Sanofi-Aventis Investigational Site Number 076005	Belem
Brazil	Sanofi-Aventis Investigational Site Number 076001	Brasilia
Brazil	Sanofi-Aventis Investigational Site Number 076006	Caxias Do Sul
Brazil	Sanofi-Aventis Investigational Site Number 076003	Curitiba
Brazil	Sanofi-Aventis Investigational Site Number 076002	Rio De Janeiro
Brazil	Sanofi-Aventis Investigational Site Number 076004	Sao Paulo
Brazil	Sanofi-Aventis Investigational Site Number 076007	Sao Paulo
Canada	Sanofi-Aventis Investigational Site Number 124004	Calgary
Canada	Sanofi-Aventis Investigational Site Number 124008	Hamilton
Canada	Sanofi-Aventis Investigational Site Number 124005	London
Canada	Sanofi-Aventis Investigational Site Number 124006	Montreal
Canada	Sanofi-Aventis Investigational Site Number 124013	Oakville
Canada	Sanofi-Aventis Investigational Site Number 124002	St-Romuald
Canada	Sanofi-Aventis Investigational Site Number 124012	Thornhill
Canada	Sanofi-Aventis Investigational Site Number 124011	Toronto
Canada	Sanofi-Aventis Investigational Site Number 124003	Vancouver
Canada	Sanofi-Aventis Investigational Site Number 124007	Victoria
Chile	Sanofi-Aventis Investigational Site Number 152001	Santiago
Chile	Sanofi-Aventis Investigational Site Number 152002	Santiago
Chile	Sanofi-Aventis Investigational Site Number 152003	Santiago
Chile	Sanofi-Aventis Investigational Site Number 152004	Santiago
Chile	Sanofi-Aventis Investigational Site Number 152005	Santiago
Germany	Sanofi-Aventis Investigational Site Number 276002	Berlin
Germany	Sanofi-Aventis Investigational Site Number 276005	Ludwigshafen
Germany	Sanofi-Aventis Investigational Site Number 276004	Schkeuditz
Guatemala	Sanofi-Aventis Investigational Site Number 320001	Guatemala
Guatemala	Sanofi-Aventis Investigational Site Number 320002	Guatemala
Guatemala	Sanofi-Aventis Investigational Site Number 320004	Guatemala
Guatemala	Sanofi-Aventis Investigational Site Number 320005	Guatemala
Guatemala	Sanofi-Aventis Investigational Site Number 320006	Guatemala
Mexico	Sanofi-Aventis Investigational Site Number 484003	Aguascalientes
Mexico	Sanofi-Aventis Investigational Site Number 484009	Chihuahua
Mexico	Sanofi-Aventis Investigational Site Number 484010	Chihuahua
Mexico	Sanofi-Aventis Investigational Site Number 484012	Df
Mexico	Sanofi-Aventis Investigational Site Number 484008	Merida
Mexico	Sanofi-Aventis Investigational Site Number 484011	México City
Mexico	Sanofi-Aventis Investigational Site Number 484001	Pachuca
Mexico	Sanofi-Aventis Investigational Site Number 484005	Pachuca
Mexico	Sanofi-Aventis Investigational Site Number 484006	Veracruz
Mexico	Sanofi-Aventis Investigational Site Number 484002	Zapopan
Peru	Sanofi-Aventis Investigational Site Number 604001	Lima
Peru	Sanofi-Aventis Investigational Site Number 604002	Lima
Peru	Sanofi-Aventis Investigational Site Number 604003	Lima
Peru	Sanofi-Aventis Investigational Site Number 604004	Lima
Peru	Sanofi-Aventis Investigational Site Number 604005	Lima
Poland	Sanofi-Aventis Investigational Site Number 616002	Bialystok
Poland	Sanofi-Aventis Investigational Site Number 616001	Bydgoszcz
Poland	Sanofi-Aventis Investigational Site Number 616006	Warszawa
Poland	Sanofi-Aventis Investigational Site Number 616003	Wroclaw
Romania	Sanofi-Aventis Investigational Site Number 642004	Bacau
Romania	Sanofi-Aventis Investigational Site Number 642006	Bucuresti
Romania	Sanofi-Aventis Investigational Site Number 642008	Bucuresti
Romania	Sanofi-Aventis Investigational Site Number 642010	Iasi
Romania	Sanofi-Aventis Investigational Site Number 642009	Ploiesti
Romania	Sanofi-Aventis Investigational Site Number 642001	Resita
Romania	Sanofi-Aventis Investigational Site Number 642005	Suceava
Romania	Sanofi-Aventis Investigational Site Number 642007	Timisoara
Russian Federation	Sanofi-Aventis Investigational Site Number 643002	Kazan
Russian Federation	Sanofi-Aventis Investigational Site Number 643003	St-Petersburg
Russian Federation	Sanofi-Aventis Investigational Site Number 643005	St-Petersburg
Russian Federation	Sanofi-Aventis Investigational Site Number 643001	St. Petersburg
Russian Federation	Sanofi-Aventis Investigational Site Number 643004	Tyumen
Ukraine	Sanofi-Aventis Investigational Site Number 804003	Chernivtsi
Ukraine	Sanofi-Aventis Investigational Site Number 804001	Kiev
Ukraine	Sanofi-Aventis Investigational Site Number 804004	Kyiv
United States	Sanofi-Aventis Investigational Site Number 840025	Altoona	Pennsylvania
United States	Sanofi-Aventis Investigational Site Number 840011	Anaheim	California
United States	Sanofi-Aventis Investigational Site Number 840021	Augusta	Georgia
United States	Sanofi-Aventis Investigational Site Number 840002	Baton Rouge	Louisiana
United States	Sanofi-Aventis Investigational Site Number 840009	Brentwood	Tennessee
United States	Sanofi-Aventis Investigational Site Number 840006	Butte	Montana
United States	Sanofi-Aventis Investigational Site Number 840016	Chicago	Illinois
United States	Sanofi-Aventis Investigational Site Number 840018	Chicago	Illinois
United States	Sanofi-Aventis Investigational Site Number 840031	Clarkston	Michigan
United States	Sanofi-Aventis Investigational Site Number 840008	Dallas	Texas
United States	Sanofi-Aventis Investigational Site Number 840001	Evansville	Indiana
United States	Sanofi-Aventis Investigational Site Number 840020	Florissant	Missouri
United States	Sanofi-Aventis Investigational Site Number 840004	Medford	Oregon
United States	Sanofi-Aventis Investigational Site Number 840022	Mesa	Arizona
United States	Sanofi-Aventis Investigational Site Number 840019	Montgomery	Alabama
United States	Sanofi-Aventis Investigational Site Number 840003	Muscle Shoals	Alabama
United States	Sanofi-Aventis Investigational Site Number 840014	Paramount	California
United States	Sanofi-Aventis Investigational Site Number 840026	Perrysburg	Ohio
United States	Sanofi-Aventis Investigational Site Number 840027	Redlands	California
United States	Sanofi-Aventis Investigational Site Number 840007	Roswell	Georgia
United States	Sanofi-Aventis Investigational Site Number 840010	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Canada,  Chile,  Germany,  Guatemala,  Mexico,  Peru,  Poland,  Romania,  Russian Federation,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	Week 24	No
Other	Percentage of Patients With at Least 5% Weight Loss From Baseline 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.	Baseline, Week 24	No
Other	Change From Baseline in Fasting Proinsulin-to-insulin Ratio and 2-hour Postprandial Proinsulin-to-insulin Ratio at 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 the last dosing day of the study drug or up to the introduction of rescue therapy, whichever is the earliest.	Baseline, Week 24	No
Other	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.	First dose of study drug up to 3 days after the last dose administration	Yes
Primary	Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% and at Least 5% Weight Loss From Baseline at Week 24	Percentage of patients who met both criteria (HbA1c <7% at Week 24 and at least 5% weight loss from baseline at Week 24) is reported. 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.	Week 24	No
Secondary	Absolute Change From Baseline in 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 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.	Baseline, Week 24	No
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 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.	Baseline, Week 24	No
Secondary	Change From Baseline in 2-hour Postprandial Plasma Glucose (PPG) at 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 the study drug or up to the introduction of rescue therapy, whichever is the earliest.	Baseline, Week 24	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 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.	Baseline, Week 24	No
Secondary	Change From Baseline in Glucose Excursion at 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 the study drug or up to the introduction of rescue therapy, whichever is the earliest.	Baseline, Week 24	No
Secondary	Change From Baseline in Fasting Plasma Insulin (FPI) and 2-hour Postprandial Plasma Insulin (PPI) at Week 24	Change was calculated for fasting plasma insulin and 2-hour post prandial plasma insulin by subtracting the 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 the study drug or up to the introduction of rescue therapy, whichever is the earliest.	Baseline, Week 24	No
Secondary	Change From Baseline in Fasting C-peptide and 2-hour Postprandial C-peptide at Week 24	Change was calculated for fasting C-peptide and 2-hour postprandial C-peptide by subtracting the 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.	Baseline, Week 24	No
Secondary	Change From Baseline in Fasting Glucagon and 2-hour Postprandial Glucagon at Week 24	Change was calculated for fasting glucagon and 2-hour postprandial glucagon by subtracting the 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.	Baseline, Week 24	No
Secondary	Change From Baseline in Fasting Proinsulin and 2-hour Postprandial Proinsulin at Week 24	Change was calculated for fasting proinsulin and 2-hour postprandial proinsulin by subtracting the baseline value from Week 24 value. The on-treatment period for this efficacy variable is the time from the first dose of the study drug up to the last dosing day of study drug or up to the introduction of rescue therapy, whichever is the earliest.	Baseline, Week 24	No
Secondary	Change From Baseline in Insulin Resistance Assessed by Homeostasis Model Assessment- Insulin Resistance (HOMA-IR) at Week 24	HOMA-IR was derived from FPG and FPI as: (FPI [micro units per milliliter]*FPG [mmol/L]) divided by 22.5. Change was calculated for HOMA-IR by subtracting the 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.	Baseline, Week 24	No
Secondary	Change From Baseline in Beta Cell Function Assessed by Homeostasis Model Assessment-Beta (HOMA-beta) at Week 24	HOMA-beta was derived from FPG and FPI as: (20*FPI [micro units/milliliter]) divided by (FPG [mmol/L] minus 3.5). Change was calculated for HOMA-beta by subtracting the 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.	Baseline, Week 24	No
Secondary	Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than or Equal to 6.5% 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.	Week 24	No
Secondary	Percentage of Patients Requiring Rescue Therapy During 24-Week Period	Routine fasting self-measured 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%.	Baseline up to Week 24	No