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

Diabetes Mellitus, Type 2 Clinical Trial

— GETGOAL-F1  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00763451
• Other study ID #: EFC10743
• Secondary ID: 2008-001002-16
• Status: Completed
• Phase: Phase 3
• First received: September 30, 2008
• Last updated: February 26, 2014
• Start date: September 2008
• Est. completion date: January 2011

Study information

• Verified date: February 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 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 484
• Est. completion date: January 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

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 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

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

Intervention

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

Device:
• Pen auto-injector

Drug:
• Metformin
Metformin to be continued at stable dose (at least 1.5 gram per day) up to the end of treatment.

Locations

Country	Name	City	State
Brazil	Sanofi-Aventis Administrative Office	Sao Paulo
Chile	Sanofi-Aventis Administrative Office	Santiago
Colombia	Sanofi-Aventis Administrative Office	Santafe de Bogota
Estonia	Sanofi-Aventis Administrative Office	Tallinn
Germany	Sanofi-Aventis Administrative Office	Berlin
Italy	Sanofi-Aventis Administrative Office	Milano
Lithuania	Sanofi-Aventis Administrative Office	Vilnius
Malaysia	Sanofi-Aventis Administrative Office	Kuala Lumpur
Mexico	Sanofi-Aventis Administrative Office	Mexico
Philippines	Sanofi-Aventis Administrative Office	Makati City
Poland	Sanofi-Aventis Administrative Office	Warszawa
Romania	Sanofi-Aventis Administrative Office	Bucuresti
Slovakia	Sanofi-Aventis Administrative Office	Brastislava
Ukraine	Sanofi-Aventis Administrative Office	Kiev
United States	Sanofi-Aventis Administrative Office	Bridgewater	New Jersey

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

United States,  Brazil,  Chile,  Colombia,  Estonia,  Germany,  Italy,  Lithuania,  Malaysia,  Mexico,  Philippines,  Poland,  Romania,  Slovakia,  Ukraine, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percentage of Patients With at Least 5% Weight Loss From Baseline at Week 24	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.	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	Absolute Change From Baseline in Glycosylated Hemoglobin (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 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.	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 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.	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 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.	Baseline, Week 24	No
Secondary	Percentage of Patients With Glycosylated Hemoglobin (HbA1c) Level Less Than 7% at Week 24	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.	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 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.	Week 24	No
Secondary	Percentage of Patients Requiring Rescue Therapy During Main 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%. 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.	Baseline up to Week 24	No