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

Type 2 Diabetes Mellitus Clinical Trial

— GetGoal-M-Asia  

Official title:

Efficacy 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01169779
• Other study ID #: EFC11321
• Secondary ID: U1111-1116-8938
• Status: Completed
• Phase: Phase 3
• First received: July 23, 2010
• Last updated: March 18, 2014
• Start date: July 2010
• Est. completion date: December 2011

Study information

• Verified date: March 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Ethics Committee
• 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 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 391
• Est. completion date: December 2011
• Est. primary completion date: December 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 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

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
• Diabetes Mellitus, Type 2
• Type 2 Diabetes Mellitus

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 1.0 gram per day and not more than 1.5 gram per day) up to Week 24.
• 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.

Locations

Country	Name	City	State
China	Investigational Site Number 156001	Beijing
China	Investigational Site Number 156002	Beijing
China	Investigational Site Number 156003	Beijing
China	Investigational Site Number 156009	Beijing
China	Investigational Site Number 156011	Beijing
China	Investigational Site Number 156012	Beijing
China	Investigational Site Number 156019	Beijing
China	Investigational Site Number 156036	Changchun
China	Investigational Site Number 156015	Changsha
China	Investigational Site Number 156016	Changsha
China	Investigational Site Number 156006	Chengdu
China	Investigational Site Number 156032	Chengdu
China	Investigational Site Number 156010	Dalian
China	Investigational Site Number 156004	Guangzhou
China	Investigational Site Number 156008	Guangzhou
China	Investigational Site Number 156025	Guangzhou
China	Investigational Site Number 156031	Haikou
China	Investigational Site Number 156014	Harbin
China	Investigational Site Number 156029	Hefei
China	Investigational Site Number 156013	Qingdao
China	Investigational Site Number 156007	Shanghai
China	Investigational Site Number 156030	Shanghai
China	Investigational Site Number 156020	Shenyang
China	Investigational Site Number 156035	Suzhou
China	Investigational Site Number 156033	Taiyuan
China	Investigational Site Number 156037	Tianjin
China	Investigational Site Number 156022	Xi'An
China	Investigational Site Number 156023	Xi'An
Hong Kong	Investigational Site Number 344001	Hong Kong
Hong Kong	Investigational Site Number 344003	Hong Kong
Hong Kong	Investigational Site Number 344002	Shatin, Nt
Malaysia	Investigational Site Number 458001	Kelantan
Malaysia	Investigational Site Number 458003	Kuala Lumpur
Malaysia	Investigational Site Number 458002	Putrajaya
Thailand	Investigational Site Number 764002	Bangkok

Sponsors (1)

Lead Sponsor	Collaborator
Sanofi

Countries where clinical trial is conducted

China,  Hong Kong,  Malaysia,  Thailand, 

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 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.	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 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.	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. 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.	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 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. 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.	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 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.	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. 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.	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 study drug or up to the introduction of rescue therapy, whichever is the earliest.	Baseline, Week 24	No
Secondary	Percentage of Patients Requiring Rescue Therapy During Main 24-Week Period	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.	Baseline up to Week 24	No