Clinical trial NCT00763815: GLP-1 Receptor Agonist Lixisenatide in Patients With Type 2 Diabetes for Glycemic Control and Safety Evaluation, on Top of Pioglitazone
Official title: A Randomized, Double-blind, Placebo-controlled, 2-arm Parallel-group, Multicenter Study With a 24-week Main Treatment Period and an Extension Assessing the Efficacy and Safety of AVE0010 on Top of Pioglitazone in Patients With Type 2 Diabetes Not Adequately Controlled With Pioglitazone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetes Mellitus Type 2
Keywords: hyperglycemia GLP-1 pioglitazone
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 pioglitazone with or without 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 pioglitazone on glycemic control in terms of glycosylated hemoglobin (HbA1c) reduction (absolute change) at Week 24.

Secondary objectives are to assess the effects of lixisenatide when added to pioglitazone on the percentage of patients reaching HbA1c less than 7 percent (%) and less than or equal to 6.5%, fasting plasma glucose (FPG), body weight, beta-cell function (assessed by homeostatic model assessment of beta-cell function \[HOMA-beta\]), and on fasting plasma insulin (FPI), 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 schedule 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 the screening visit, insufficiently controlled with pioglitazone

Exclusion Criteria:

* HbA1c less than (\<) 7 percent (%) or greater than (\>) 10% at screening
* At the time of screening age \<legal age of majority
* Pregnant or breastfeeding women and women of childbearing potential without effective contraceptive method of birth control
* Type 1 diabetes mellitus
* Pioglitazone not at a stable dose of at least 30 milligram per day (mg/day) for at least 3 months prior to screening
* If treatment with metformin, no stable dose of at least 1.5 gram per day (g/day) for at least 3 months prior to screening visit
* FPG at screening \>250 milligram per deciliter (mg/dL) (\>13.9 millimole per liter \[mmol/L\])
* 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, or inflammatory bowel disease
* History of metabolic acidosis, including diabetic ketoacidosis within 1 year prior to screening
* Hemoglobinopathy or hemolytic anemia, or receipt of blood or plasma products within3 months prior to the time of screening
* History of myocardial infarction or stroke within the last 6 months prior to screening
* 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 or diastolic blood pressure (DBP) \>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 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 (HBsAg) and/or Hepatitis C antibody (HCAb); 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 other oral or injectable antidiabetic or hypoglycemic agents other than metformin or pioglitazone (for example, sulfonylurea, alpha-glucosidase inhibitor, other thiazolidinediones, 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 or 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 (applicable only for patients with metformin treatment)
* Patients with cardiac failure or history of cardiac failure (New York Heart Association class I to IV)
* End-stage renal disease defined by a serum creatinine clearance of \<15 milliliter per minute (mL/min) (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

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: Change From Baseline in Fasting Plasma Insulin (FPI) 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 HbA1c Level Less Than or Equal to 6.5% at Week 24
timeFrame: Week 24
measure: Change From Baseline in Beta-cell Function Assessed by Homeostasis Model Assessment for Beta-cell Function (HOMA-beta) at Week 24
timeFrame: Baseline, 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 132 weeks
Locations:
city: Birmingham
country: United States
facility: Sanofi-Aventis Investigational Site Number 840723
state: Alabama
city: Birmingham
country: United States
facility: Sanofi-Aventis Investigational Site Number 840744
state: Alabama
city: Birmingham
country: United States
facility: Sanofi-Aventis Investigational Site Number 840867
state: Alabama
city: Birmingham
country: United States
facility: Sanofi-Aventis Investigational Site Number 840720
state: Alabama
city: Mobile
country: United States
facility: Sanofi-Aventis Investigational Site Number 840855
state: Alabama
city: Mobile
country: United States
facility: Sanofi-Aventis Investigational Site Number 840863
state: Alabama
city: Chandler
country: United States
facility: Sanofi-Aventis Investigational Site Number 840775
state: Arizona
city: Mesa
country: United States
facility: Sanofi-Aventis Investigational Site Number 840722
state: Arizona
city: Phoenix
country: United States
facility: Sanofi-Aventis Investigational Site Number 840769
state: Arizona
city: Harrisburg
country: United States
facility: Sanofi-Aventis Investigational Site Number 840729
state: Arkansas
city: Mountain Home
country: United States
facility: Sanofi-Aventis Investigational Site Number 840776
state: Arkansas
city: Artesia
country: United States
facility: Sanofi-Aventis Investigational Site Number 840795
state: California
city: Chino
country: United States
facility: Sanofi-Aventis Investigational Site Number 840782
state: California
city: Huntington Beach
country: United States
facility: Sanofi-Aventis Investigational Site Number 840785
state: California
city: La Jolla
country: United States
facility: Sanofi-Aventis Investigational Site Number 840858
state: California
city: Los Banos
country: United States
facility: Sanofi-Aventis Investigational Site Number 840784
state: California
city: Mission Hills
country: United States
facility: Sanofi-Aventis Investigational Site Number 840773
state: California
city: Mission Viejo
country: United States
facility: Sanofi-Aventis Investigational Site Number 840707
state: California
city: Northridge
country: United States
facility: Sanofi-Aventis Investigational Site Number 840733
state: California
city: Roseville
country: United States
facility: Sanofi-Aventis Investigational Site Number 840864
state: California
city: San Diego
country: United States
facility: Sanofi-Aventis Investigational Site Number 840772
state: California
city: San Mateo
country: United States
facility: Sanofi-Aventis Investigational Site Number 840743
state: California
city: Stockton
country: United States
facility: Sanofi-Aventis Investigational Site Number 840721
state: California
city: West Hills
country: United States
facility: Sanofi-Aventis Investigational Site Number 840763
state: California
city: Colorado Springs
country: United States
facility: Sanofi-Aventis Investigational Site Number 840872
state: Colorado
city: Colorado Springs
country: United States
facility: Sanofi-Aventis Investigational Site Number 840868
state: Colorado
city: Jacksonville
country: United States
facility: Sanofi-Aventis Investigational Site Number 840727
state: Florida
city: New Port Richey
country: United States
facility: Sanofi-Aventis Investigational Site Number 840745
state: Florida
city: Oviedo
country: United States
facility: Sanofi-Aventis Investigational Site Number 840761
state: Florida
city: Wellington
country: United States
facility: Sanofi-Aventis Investigational Site Number 840799
state: Florida
city: Augusta
country: United States
facility: Sanofi-Aventis Investigational Site Number 840857
state: Georgia
city: Idaho Falls
country: United States
facility: Sanofi-Aventis Investigational Site Number 840724
state: Idaho
city: Chicago
country: United States
facility: Sanofi-Aventis Investigational Site Number 840791
state: Illinois
city: Avon
country: United States
facility: Sanofi-Aventis Investigational Site Number 840738
state: Indiana
city: Indianapolis
country: United States
facility: Sanofi-Aventis Investigational Site Number 840794
state: Indiana
city: Kansas City
country: United States
facility: Sanofi-Aventis Investigational Site Number 840767
state: Kansas
city: Lansing
country: United States
facility: Sanofi-Aventis Investigational Site Number 840779
state: Kansas
city: Wichita
country: United States
facility: Sanofi-Aventis Investigational Site Number 840739
state: Kansas
city: Lexington
country: United States
facility: Sanofi-Aventis Investigational Site Number 840789
state: Kentucky
city: Lexington
country: United States
facility: Sanofi-Aventis Investigational Site Number 840850
state: Kentucky
city: Baton Rouge
country: United States
facility: Sanofi-Aventis Investigational Site Number 840862
state: Louisiana
city: Shreveport
country: United States
facility: Sanofi-Aventis Investigational Site Number 840879
state: Louisiana
city: Hyattsville
country: United States
facility: Sanofi-Aventis Investigational Site Number 840764
state: Maryland
city: Rockville
country: United States
facility: Sanofi-Aventis Investigational Site Number 840871
state: Maryland
city: Dartmouth
country: United States
facility: Sanofi-Aventis Investigational Site Number 840851
state: Massachusetts
city: Kalamazoo
country: United States
facility: Sanofi-Aventis Investigational Site Number 840708
state: Michigan
city: Bloomington
country: United States
facility: Sanofi-Aventis Investigational Site Number 840774
state: Minnesota
city: Eagan
country: United States
facility: Sanofi-Aventis Investigational Site Number 840704
state: Minnesota
city: Picayune
country: United States
facility: Sanofi-Aventis Investigational Site Number 840717
state: Mississippi
city: St Louis
country: United States
facility: Sanofi-Aventis Investigational Site Number 840765
state: Missouri
city: Las Vegas
country: United States
facility: Sanofi-Aventis Investigational Site Number 840875
state: Nevada
city: Pahrump
country: United States
facility: Sanofi-Aventis Investigational Site Number 840866
state: Nevada
city: New York City
country: United States
facility: Sanofi-Aventis Investigational Site Number 840766
state: New York
city: New York
country: United States
facility: Sanofi-Aventis Investigational Site Number 840865
state: New York
city: Staten Island
country: United States
facility: Sanofi-Aventis Investigational Site Number 840874
state: New York
city: West Seneca
country: United States
facility: Sanofi-Aventis Investigational Site Number 840762
state: New York
city: Burlington
country: United States
facility: Sanofi-Aventis Investigational Site Number 840747
state: North Carolina
city: Greensboro
country: United States
facility: Sanofi-Aventis Investigational Site Number 840760
state: North Carolina
city: High Point
country: United States
facility: Sanofi-Aventis Investigational Site Number 840712
state: North Carolina
city: Bismarck
country: United States
facility: Sanofi-Aventis Investigational Site Number 840780
state: North Dakota
city: Fargo
country: United States
facility: Sanofi-Aventis Investigational Site Number 840877
state: North Dakota
city: Athens
country: United States
facility: Sanofi-Aventis Investigational Site Number 840777
state: Ohio
city: Cleveland
country: United States
facility: Sanofi-Aventis Investigational Site Number 840741
state: Ohio
city: Dayton
country: United States
facility: Sanofi-Aventis Investigational Site Number 840728
state: Ohio
city: Mentor
country: United States
facility: Sanofi-Aventis Investigational Site Number 840709
state: Ohio
city: Norman
country: United States
facility: Sanofi-Aventis Investigational Site Number 840716
state: Oklahoma
city: Medford
country: United States
facility: Sanofi-Aventis Investigational Site Number 840701
state: Oregon
city: Beaver
country: United States
facility: Sanofi-Aventis Investigational Site Number 840751
state: Pennsylvania
city: Red Lion
country: United States
facility: Sanofi-Aventis Investigational Site Number 840798
state: Pennsylvania
city: Columbia
country: United States
facility: Sanofi-Aventis Investigational Site Number 840792
state: South Carolina
city: Simpsonville
country: United States
facility: Sanofi-Aventis Investigational Site Number 840740
state: South Carolina
city: Taylors
country: United States
facility: Sanofi-Aventis Investigational Site Number 840726
state: South Carolina
city: Bristol
country: United States
facility: Sanofi-Aventis Investigational Site Number 840711
state: Tennessee
city: Colleyville
country: United States
facility: Sanofi-Aventis Investigational Site Number 840853
state: Texas
city: Houston
country: United States
facility: Sanofi-Aventis Investigational Site Number 840730
state: Texas
city: San Antonio
country: United States
facility: Sanofi-Aventis Investigational Site Number 840854
state: Texas
city: Clinton
country: United States
facility: Sanofi-Aventis Investigational Site Number 840796
state: Utah
city: Salt Lake City
country: United States
facility: Sanofi-Aventis Investigational Site Number 840755
state: Utah
city: Salt Lake City
country: United States
facility: Sanofi-Aventis Investigational Site Number 840756
state: Utah
city: Salt Lake City
country: United States
facility: Sanofi-Aventis Investigational Site Number 840758
state: Utah
city: Norfolk
country: United States
facility: Sanofi-Aventis Investigational Site Number 840753
state: Virginia
city: Norfolk
country: United States
facility: Sanofi-Aventis Investigational Site Number 840770
state: Virginia
city: Richmond
country: United States
facility: Sanofi-Aventis Investigational Site Number 840752
state: Virginia
city: Virginia Beach
country: United States
facility: Sanofi-Aventis Investigational Site Number 840757
state: Virginia
city: Spokane
country: United States
facility: Sanofi-Aventis Investigational Site Number 840735
state: Washington
city: Graz
country: Austria
facility: Sanofi-Aventis Investigational Site Number 040706
city: Vienna
country: Austria
facility: Sanofi-Aventis Investigational Site Number 040704
city: Wels
country: Austria
facility: Sanofi-Aventis Investigational Site Number 040707
city: Wien
country: Austria
facility: Sanofi-Aventis Investigational Site Number 040702
city: Wien
country: Austria
facility: Sanofi-Aventis Investigational Site Number 040701
city: Wien
country: Austria
facility: Sanofi-Aventis Investigational Site Number 040705
city: London
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124710
city: Mirabel
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124712
city: Saskatoon
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124703
city: Scarborough
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124713
city: Sherbrooke
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124711
city: Smiths Falls
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124704
city: St-Romuald
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124705
city: Sudbury
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124716
city: Thornhill
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124701
city: Vancouver
country: Canada
facility: Sanofi-Aventis Investigational Site Number 124708
city: Armentieres
country: France
facility: Sanofi-Aventis Investigational Site Number 250704
city: La Rochelle Cedex
country: France
facility: Sanofi-Aventis Investigational Site Number 250707
city: Labarthe Sur Leze
country: France
facility: Sanofi-Aventis Investigational Site Number 250705
city: Le Creusot
country: France
facility: Sanofi-Aventis Investigational Site Number 250702
city: Strasbourg
country: France
facility: Sanofi-Aventis Investigational Site Number 250701
city: Asslar
country: Germany
facility: Sanofi-Aventis Investigational Site Number 276708
city: Berlin
country: Germany
facility: Sanofi-Aventis Investigational Site Number 276704
city: Künzing
country: Germany
facility: Sanofi-Aventis Investigational Site Number 276703
city: Leipzig
country: Germany
facility: Sanofi-Aventis Investigational Site Number 276706
city: Pirna
country: Germany
facility: Sanofi-Aventis Investigational Site Number 276707
city: Sulzbach-Rosenberg
country: Germany
facility: Sanofi-Aventis Investigational Site Number 276702
city: Würzburg
country: Germany
facility: Sanofi-Aventis Investigational Site Number 276701
city: Athens
country: Greece
facility: Sanofi-Aventis Investigational Site Number 300705
city: Athens
country: Greece
facility: Sanofi-Aventis Investigational Site Number 300703
city: Athens
country: Greece
facility: Sanofi-Aventis Investigational Site Number 300704
city: Thessaloniki
country: Greece
facility: Sanofi-Aventis Investigational Site Number 300701
city: Guatemala
country: Guatemala
facility: Sanofi-Aventis Investigational Site Number 320702
city: Guatemala
country: Guatemala
facility: Sanofi-Aventis Investigational Site Number 320701
city: Guatemala
country: Guatemala
facility: Sanofi-Aventis Investigational Site Number 320703
city: Guatemala
country: Guatemala
facility: Sanofi-Aventis Investigational Site Number 320704
city: Bangalore
country: India
facility: Sanofi-Aventis Investigational Site Number 356701
city: Bangalore
country: India
facility: Sanofi-Aventis Investigational Site Number 356703
city: Hyderabad
country: India
facility: Sanofi-Aventis Investigational Site Number 356702
city: Nagpur
country: India
facility: Sanofi-Aventis Investigational Site Number 356704
city: Merida
country: Mexico
facility: Sanofi-Aventis Investigational Site Number 484703
city: Tlalnepantla
country: Mexico
facility: Sanofi-Aventis Investigational Site Number 484701
city: Zapopan
country: Mexico
facility: Sanofi-Aventis Investigational Site Number 484704
city: Lima
country: Peru
facility: Sanofi-Aventis Investigational Site Number 604703
city: Lima
country: Peru
facility: Sanofi-Aventis Investigational Site Number 604701
city: Lima
country: Peru
facility: Sanofi-Aventis Investigational Site Number 604702
city: Lima
country: Peru
facility: Sanofi-Aventis Investigational Site Number 604705
city: Carolina
country: Puerto Rico
facility: Sanofi-Aventis Investigational Site Number 630714
city: Carolina
country: Puerto Rico
facility: Sanofi-Aventis Investigational Site Number 630715
city: Alba Iulia
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642711
city: Bacau
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642702
city: Baia Mare
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642709
city: Brasov
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642701
city: Bucuresti
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642712
city: Bucuresti
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642714
city: Constanta
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642705
city: Galati
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642707
city: Ploiesti
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642703
city: Resita
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642713
city: Satu Mare
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642708
city: Targu Mures
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642706
city: Timisoara
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642715
city: Timisoara
country: Romania
facility: Sanofi-Aventis Investigational Site Number 642710
city: Erzurum
country: Turkey
facility: Sanofi-Aventis Investigational Site Number 792702
city: Istanbul
country: Turkey
facility: Sanofi-Aventis Investigational Site Number 792705
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Pinget M, Goldenberg R, Niemoeller E, Muehlen-Bartmer I, Guo H, Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab. 2013 Nov;15(11):1000-7. doi: 10.1111/dom.12121. Epub 2013 May 26.