Clinical trial NCT01768559: Efficacy and Safety of Lixisenatide Versus Insulin Glulisine on Top of Insulin Glargine With or Without Metformin in Type 2 Diabetic Patients
Official title: A Randomized, Open-label, Active-controlled, 3-arm Parallel-group, 26-week Study Comparing the Efficacy and Safety of Lixisenatide to That of Insulin Glulisine Once Daily and Insulin Glulisine Three Times Daily in Patients With Type 2 Diabetes Insufficiently Controlled With Insulin Glargine With or Without Metformin
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2013-01-15
Enrollment: 894
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: Primary Objective:

- To compare lixisenatide versus insulin glulisine in terms of glycosylated hemoglobin (HbA1c) reduction and body weight change at Week 26 in type 2 diabetic participants not adequately controlled on insulin glargine ± metformin.

Secondary Objectives:

- To compare the treatments/regimens on:

* The percentage of participants reaching the target of HbA1c \<7% or ≤6.5%,
* Body weight,
* Self-Monitored Glucose profiles,
* Fasting Plasma Glucose (FPG),
* Post-prandial plasma glucose (PPG) /glucose excursions during a standardized meal test (subset of participants),
* Daily doses of insulins,
* Safety and tolerability.

Detailed description: Approximately 41 weeks including a 26 week treatment period.

Eligibility criteria: Inclusion criteria :

* Participants with type 2 diabetes mellitus diagnosed at least 1 year before screening visit (V1).
* Participants treated with basal insulin for at least 6 months.
* Participants treated for at least 3 months prior to visit 1 with a stable basal insulin regimen (i.e. type of insulin and time/frequency of the injection). The insulin dose should be stable (± 20%) and ≥20 U/day for at least 2 months prior to visit 1.
* Participants treated with basal insulin alone or in combination with 1 to 3 oral anti-diabetic drugs (OADs) that could be: metformin (≥1.5 g/day or maximal tolerated dose), a sulfonylurea (SU), a dipeptidyl-peptidase-4 (DPP-4) inhibitor, a glinide. The dose of OADs should be stable for at least 3 months prior to visit 1.

Exclusion criteria:

* At screening: age \< legal age of majority.
* At screening, HbA1c: \<7.5% and \>10.0% for participants treated with basal insulin alone or in combination with metformin only; \< 7.0% and \> 10.0% for participants treated with basal insulin and a combination of oral anti-diabetic drugs which included a SU and/or a DPP-4 inhibitor and/or a glinide.
* Women of childbearing potential with no effective contraceptive method, pregnancy or lactation.
* Type 1 diabetes mellitus.
* Treatment with glucose-lowering agent(s) other than stated in the inclusion criteria within 3 months prior to screening.
* Previous treatment with short or rapid acting insulin other than in relation to hospitalization or an acute illness.
* Any previous treatment with lixisenatide, or any discontinuation from another glucagon-like peptide 1 (GLP-1) receptor agonist due to safety/tolerability issue or lack of efficacy.
* At screening, Body Mass Index (BMI) ≤20 or \>40 kg/m\^2.
* Weight change of more than 5 kg during the 3 months prior to the screening visit; use of weight loss drugs within 3 months prior to screening.
* Within the last 6 months prior to screening: history of myocardial infarction, stroke, or heart failure requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures.
* History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery.
* At screening resting systolic blood pressure \>180 mmHg or diastolic blood pressure \>95 mmHg.
* Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposed to MTC (e.g. multiple endocrine neoplasia syndromes).
* Contraindication related to metformin (for participant receiving this treatment), insulin glargine, insulin glulisine or lixisenatide.
* Participants with severe renal impairment (creatinine clearance less than 30 ml/min) or end-stage renal disease.
* At screening, amylase and/or lipase \>3 times the upper limit of the normal laboratory range (ULN).
* At screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 ULN.
* At screening calcitonin ≥20 pg/ml (5.9 pmol/L).

Exclusion Criteria for randomization at the end of the screening period before randomization:

* HbA1c \<7.0% or \>9.0%.
* 7-day mean fasting SMPG \>140 mg/dl (7.8 mmol/L).
* Amylase and/or lipase \>3 times ULN.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Change in HbA1c From Baseline to Week 26
timeFrame: Baseline, Week 26
measure: Change in Body Weight From Baseline to Week 26
timeFrame: Baseline, Week 26
Secondary outcomes:
measure: Percentage of Participants With HbA1c Level <7% and ≤6.5% at Week 26
timeFrame: Week 26
measure: Percentage of Participants With no Weight Gain at Week 26
timeFrame: Week 26
measure: Change in Average 7-point SMPG Profiles From Baseline to Week 26
timeFrame: Baseline, Week 26
measure: Change in FPG From Baseline to Week 26
timeFrame: Baseline, Week 26
measure: Change in PPG From Baseline to Week 26 (in Participants Who Had an Injection of Investigational Medicinal Product [IMP] Before Breakfast)
timeFrame: Baseline, Week 26
measure: Change in Glucose Excursions From Baseline to Week 26 (in Participants Who Had an Injection of IMP Before Breakfast)
timeFrame: Baseline, Week 26
measure: Change in Insulin Glargine Dose From Baseline to Week 26
timeFrame: Baseline, Week 26
measure: Insulin Glulisine Dose at Week 26
timeFrame: Week 26
measure: Total Insulin Dose at Week 26
timeFrame: Week 26
measure: Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia
timeFrame: First dose of study drug up to 3 days after the last dose administration (maximum of 185 days)
measure: Percentage of Participants Who Reached the Target of HbA1c <7% at Week 26 and Did Not Experienced Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26 Week Treatment Period
timeFrame: Week 26
measure: Percentage of Participants Who Reached the Target of HbA1c <7% and Had no Weight Gain at Week 26
timeFrame: Week 26
measure: Percentage of Participants Who Reached the Target of HbA1c <7%, Had no Weight Gain at Week 26, and Did Not Experience Documented (Plasma Glucose <60 mg/dL) Symptomatic Hypoglycemia During 26-Week Treatment Period
timeFrame: Week 26
Other outcomes:
Locations:
city: Sun City
country: United States
facility: Investigational Site Number 840043
state: Arizona
city: Tempe
country: United States
facility: Investigational Site Number 840042
state: Arizona
city: Little Rock
country: United States
facility: Investigational Site Number 840003
state: Arkansas
city: La Mesa
country: United States
facility: Investigational Site Number 840031
state: California
city: Mission Viejo
country: United States
facility: Investigational Site Number 840005
state: California
city: Northridge
country: United States
facility: Investigational Site Number 840057
state: California
city: Santa Ana
country: United States
facility: Investigational Site Number 840035
state: California
city: Temecula
country: United States
facility: Investigational Site Number 840002
state: California
city: Walnut Creek
country: United States
facility: Investigational Site Number 840037
state: California
city: West Hills
country: United States
facility: Investigational Site Number 840023
state: California
city: Denver
country: United States
facility: Investigational Site Number 840041
state: Colorado
city: Miami
country: United States
facility: Investigational Site Number 840012
state: Florida
city: Miami
country: United States
facility: Investigational Site Number 840061
state: Florida
city: Lawrenceville
country: United States
facility: Investigational Site Number 840045
state: Georgia
city: Nampa
country: United States
facility: Investigational Site Number 840036
state: Idaho
city: Chicago
country: United States
facility: Investigational Site Number 840024
state: Illinois
city: Evanston
country: United States
facility: Investigational Site Number 840009
state: Illinois
city: Avon
country: United States
facility: Investigational Site Number 840004
state: Indiana
city: Avon
country: United States
facility: Investigational Site Number 840055
state: Indiana
city: Des Moines
country: United States
facility: Investigational Site Number 840027
state: Iowa
city: Wichita
country: United States
facility: Investigational Site Number 840006
state: Kansas
city: Lexington
country: United States
facility: Investigational Site Number 840047
state: Kentucky
city: Paducah
country: United States
facility: Investigational Site Number 840056
state: Kentucky
city: Marrero
country: United States
facility: Investigational Site Number 840022
state: Louisiana
city: Baltimore
country: United States
facility: Investigational Site Number 840016
state: Maryland
city: Rockville
country: United States
facility: Investigational Site Number 840017
state: Maryland
city: Buckley
country: United States
facility: Investigational Site Number 840025
state: Michigan
city: Dearborn
country: United States
facility: Investigational Site Number 840048
state: Michigan
city: Kalamazoo
country: United States
facility: Investigational Site Number 840026
state: Michigan
city: Las Vegas
country: United States
facility: Investigational Site Number 840049
state: Nevada
city: New Hyde Park
country: United States
facility: Investigational Site Number 840029
state: New York
city: Smithtown
country: United States
facility: Investigational Site Number 840060
state: New York
city: Staten Island
country: United States
facility: Investigational Site Number 840030
state: New York
city: Salisbury
country: United States
facility: Investigational Site Number 840011
state: North Carolina
city: Fargo
country: United States
facility: Investigational Site Number 840028
state: North Dakota
city: Oklahoma City
country: United States
facility: Investigational Site Number 840007
state: Oklahoma
city: Pittsburgh
country: United States
facility: Investigational Site Number 840021
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Investigational Site Number 840052
state: South Carolina
city: Chattanooga
country: United States
facility: Investigational Site Number 840032
state: Tennessee
city: Nashville
country: United States
facility: Investigational Site Number 840033
state: Tennessee
city: Corpus Christi
country: United States
facility: Investigational Site Number 840034
state: Texas
city: Dallas
country: United States
facility: Investigational Site Number 840001
state: Texas
city: Houston
country: United States
facility: Investigational Site Number 840020
state: Texas
city: Norfolk
country: United States
facility: Investigational Site Number 840018
state: Virginia
city: Salem
country: United States
facility: Investigational Site Number 840015
state: Virginia
city: Milwaukee
country: United States
facility: Investigational Site Number 840010
state: Wisconsin
city: Brampton
country: Canada
facility: Investigational Site Number 124008
city: Burlington
country: Canada
facility: Investigational Site Number 124015
city: Chatham
country: Canada
facility: Investigational Site Number 124018
city: Coquitlam
country: Canada
facility: Investigational Site Number 124004
city: Etobicoke
country: Canada
facility: Investigational Site Number 124016
city: Hamilton
country: Canada
facility: Investigational Site Number 124014
city: Montreal
country: Canada
facility: Investigational Site Number 124020
city: Montreal
country: Canada
facility: Investigational Site Number 124011
city: Newmarket
country: Canada
facility: Investigational Site Number 124017
city: Quebec
country: Canada
facility: Investigational Site Number 124021
city: Red Deer
country: Canada
facility: Investigational Site Number 124003
city: Sherbrooke
country: Canada
facility: Investigational Site Number 124002
city: St-Romuald
country: Canada
facility: Investigational Site Number 124012
city: Toronto
country: Canada
facility: Investigational Site Number 124001
city: Toronto
country: Canada
facility: Investigational Site Number 124010
city: Vancouver
country: Canada
facility: Investigational Site Number 124005
city: Victoria
country: Canada
facility: Investigational Site Number 124006
city: Winnipeg
country: Canada
facility: Investigational Site Number 124007
city: Santiago
country: Chile
facility: Investigational Site Number 152103
city: Santiago
country: Chile
facility: Investigational Site Number 152107
city: Santiago
country: Chile
facility: Investigational Site Number 152101
city: Santiago
country: Chile
facility: Investigational Site Number 152105
city: Santiago
country: Chile
facility: Investigational Site Number 152102
city: Santiago
country: Chile
facility: Investigational Site Number 152106
city: Santiago
country: Chile
facility: Investigational Site Number 152108
city: Santiago
country: Chile
facility: Investigational Site Number 152109
city: Beroun
country: Czech Republic
facility: Investigational Site Number 203107
city: Jilove U Prahy
country: Czech Republic
facility: Investigational Site Number 203103
city: Ostrava 2
country: Czech Republic
facility: Investigational Site Number 203101
city: Police Nad Metuji
country: Czech Republic
facility: Investigational Site Number 203110
city: Praha 4
country: Czech Republic
facility: Investigational Site Number 203105
city: Praha 4
country: Czech Republic
facility: Investigational Site Number 203102
city: Praha 4
country: Czech Republic
facility: Investigational Site Number 203108
city: Trutnov
country: Czech Republic
facility: Investigational Site Number 203104
city: Pärnu
country: Estonia
facility: Investigational Site Number 233102
city: Tallinn
country: Estonia
facility: Investigational Site Number 233103
city: Tallinn
country: Estonia
facility: Investigational Site Number 233104
city: Viljandimaa
country: Estonia
facility: Investigational Site Number 233101
city: Bois Guillaume
country: France
facility: Investigational Site Number 250108
city: Corbeil Essonnes
country: France
facility: Investigational Site Number 250105
city: La Rochelle Cedex
country: France
facility: Investigational Site Number 250104
city: Lyon
country: France
facility: Investigational Site Number 250106
city: Lyon
country: France
facility: Investigational Site Number 250107
city: Mantes La Jolie
country: France
facility: Investigational Site Number 250109
city: Paris Cedex 15
country: France
facility: Investigational Site Number 250102
city: Vandoeuvre Les Nancy
country: France
facility: Investigational Site Number 250101
city: Venissieux
country: France
facility: Investigational Site Number 250103
city: Bad Mergentheim
country: Germany
facility: Investigational Site Number 276112
city: Berlin
country: Germany
facility: Investigational Site Number 276108
city: Dortmund
country: Germany
facility: Investigational Site Number 276102
city: Dresden
country: Germany
facility: Investigational Site Number 276120
city: Dresden
country: Germany
facility: Investigational Site Number 276106
city: Frankfurt A.M.
country: Germany
facility: Investigational Site Number 276117
city: Görlitz
country: Germany
facility: Investigational Site Number 276116
city: Heidelberg
country: Germany
facility: Investigational Site Number 276113
city: Leipzig
country: Germany
facility: Investigational Site Number 276118
city: Magdeburg
country: Germany
facility: Investigational Site Number 276119
city: Neumünster
country: Germany
facility: Investigational Site Number 276103
city: Speyer
country: Germany
facility: Investigational Site Number 276115
city: St. Ingbert-Oberwürzbach
country: Germany
facility: Investigational Site Number 276109
city: Budapest
country: Hungary
facility: Investigational Site Number 348107
city: Budapest
country: Hungary
facility: Investigational Site Number 348108
city: Budapest
country: Hungary
facility: Investigational Site Number 348102
city: Eger
country: Hungary
facility: Investigational Site Number 348101
city: Pápa
country: Hungary
facility: Investigational Site Number 348103
city: Szeged
country: Hungary
facility: Investigational Site Number 348104
city: Sátoraljaújhely
country: Hungary
facility: Investigational Site Number 348106
city: Zalaegerszeg
country: Hungary
facility: Investigational Site Number 348105
city: Bologna
country: Italy
facility: Investigational Site Number 380103
city: Catania
country: Italy
facility: Investigational Site Number 380102
city: Milano
country: Italy
facility: Investigational Site Number 380101
city: Napoli
country: Italy
facility: Investigational Site Number 380105
city: Torino
country: Italy
facility: Investigational Site Number 380104
city: Jelgava
country: Latvia
facility: Investigational Site Number 428103
city: Ogre
country: Latvia
facility: Investigational Site Number 428104
city: Riga
country: Latvia
facility: Investigational Site Number 428102
city: Riga
country: Latvia
facility: Investigational Site Number 428105
city: Sigulda
country: Latvia
facility: Investigational Site Number 428101
city: Jonava
country: Lithuania
facility: Investigational Site Number 440104
city: Kaunas
country: Lithuania
facility: Investigational Site Number 440103
city: Kaunas
country: Lithuania
facility: Investigational Site Number 440102
city: Kaunas
country: Lithuania
facility: Investigational Site Number 440101
city: Klaipeda
country: Lithuania
facility: Investigational Site Number 440105
city: Chihuahua
country: Mexico
facility: Investigational Site Number 484108
city: Cuernavaca
country: Mexico
facility: Investigational Site Number 484101
city: Durango
country: Mexico
facility: Investigational Site Number 484111
city: Guadalajara
country: Mexico
facility: Investigational Site Number 484104
city: Guadalajara
country: Mexico
facility: Investigational Site Number 484109
city: Guadalajara
country: Mexico
facility: Investigational Site Number 484107
city: Guadalajara
country: Mexico
facility: Investigational Site Number 484105
city: Guadalajara
country: Mexico
facility: Investigational Site Number 484110
city: Mexico Df
country: Mexico
facility: Investigational Site Number 484103
city: Monterrey
country: Mexico
facility: Investigational Site Number 484106
city: México
country: Mexico
facility: Investigational Site Number 484102
city: Bialystok
country: Poland
facility: Investigational Site Number 616101
city: Bydgoszcz
country: Poland
facility: Investigational Site Number 616103
city: Bytom
country: Poland
facility: Investigational Site Number 616102
city: Krakow
country: Poland
facility: Investigational Site Number 616106
city: Krakow
country: Poland
facility: Investigational Site Number 616104
city: Pulawy
country: Poland
facility: Investigational Site Number 616105
city: Warszawa
country: Poland
facility: Investigational Site Number 616107
city: Bacau
country: Romania
facility: Investigational Site Number 642105
city: Cluj Napoca
country: Romania
facility: Investigational Site Number 642108
city: Deva
country: Romania
facility: Investigational Site Number 642106
city: Galati
country: Romania
facility: Investigational Site Number 642113
city: Hunedoara
country: Romania
facility: Investigational Site Number 642107
city: Iasi
country: Romania
facility: Investigational Site Number 642117
city: Oradea
country: Romania
facility: Investigational Site Number 642103
city: Oradea
country: Romania
facility: Investigational Site Number 642104
city: Pitesti
country: Romania
facility: Investigational Site Number 642112
city: Ploiesti
country: Romania
facility: Investigational Site Number 642114
city: Resita
country: Romania
facility: Investigational Site Number 642102
city: Sibiu
country: Romania
facility: Investigational Site Number 642111
city: Targu Mures
country: Romania
facility: Investigational Site Number 642109
city: Targu Mures
country: Romania
facility: Investigational Site Number 642110
city: Timisoara
country: Romania
facility: Investigational Site Number 642116
city: Timisoara
country: Romania
facility: Investigational Site Number 642101
city: Timisoara
country: Romania
facility: Investigational Site Number 642115
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643111
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643107
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643105
city: Penza
country: Russian Federation
facility: Investigational Site Number 643110
city: Saratov
country: Russian Federation
facility: Investigational Site Number 643102
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643101
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643104
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643109
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643108
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643103
city: St. Petersburg
country: Russian Federation
facility: Investigational Site Number 643106
city: El Ferrol
country: Spain
facility: Investigational Site Number 724102
city: La Coruña
country: Spain
facility: Investigational Site Number 724105
city: Malaga
country: Spain
facility: Investigational Site Number 724103
city: Sevilla
country: Spain
facility: Investigational Site Number 724104
city: Chernivtsi
country: Ukraine
facility: Investigational Site Number 804104
city: Donetsk
country: Ukraine
facility: Investigational Site Number 804107
city: Donetsk
country: Ukraine
facility: Investigational Site Number 804103
city: Mykolaiv
country: Ukraine
facility: Investigational Site Number 804108
city: Odessa
country: Ukraine
facility: Investigational Site Number 804110
city: Vinnytsya
country: Ukraine
facility: Investigational Site Number 804105
city: Vinnytsya
country: Ukraine
facility: Investigational Site Number 804102
city: Zaporizhia
country: Ukraine
facility: Investigational Site Number 804111
city: Ashton-Under-Lyne
country: United Kingdom
facility: Investigational Site Number 826006
city: Birmingham
country: United Kingdom
facility: Investigational Site Number 826002
city: Carmarthen
country: United Kingdom
facility: Investigational Site Number 826007
city: Chester
country: United Kingdom
facility: Investigational Site Number 826005
city: Coventry
country: United Kingdom
facility: Investigational Site Number 826008
city: Dundee
country: United Kingdom
facility: Investigational Site Number 826009
city: Durham
country: United Kingdom
facility: Investigational Site Number 826001
city: Haddington
country: United Kingdom
facility: Investigational Site Number 826011
city: Leicester
country: United Kingdom
facility: Investigational Site Number 826012
city: Plymouth
country: United Kingdom
facility: Investigational Site Number 826010
city: Sheffield
country: United Kingdom
facility: Investigational Site Number 826004
city: St Helens
country: United Kingdom
facility: Investigational Site Number 826003
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Rosenstock J, Guerci B, Hanefeld M, Gentile S, Aronson R, Tinahones FJ, Roy-Duval C, Souhami E, Wardecki M, Ye J, Perfetti R, Heller S; GetGoal Duo-2 Trial Investigators. Prandial Options to Advance Basal Insulin Glargine Therapy: Testing Lixisenatide Plus Basal Insulin Versus Insulin Glulisine Either as Basal-Plus or Basal-Bolus in Type 2 Diabetes: The GetGoal Duo-2 Trial. Diabetes Care. 2016 Aug;39(8):1318-28. doi: 10.2337/dc16-0014. Epub 2016 May 23.
citation: Tabak AG, Anderson J, Aschner P, Liu M, Saremi A, Stella P, Tinahones FJ, Wysham C, Meier JJ. Efficacy and Safety of iGlarLixi, Fixed-Ratio Combination of Insulin Glargine and Lixisenatide, Compared with Basal-Bolus Regimen in Patients with Type 2 Diabetes: Propensity Score Matched Analysis. Diabetes Ther. 2020 Jan;11(1):305-318. doi: 10.1007/s13300-019-00735-7. Epub 2019 Dec 17.
citation: Rosenstock J, Handelsman Y, Vidal J, Ampudia Blasco FJ, Giorgino F, Liu M, Perfetti R, Meier JJ. Propensity-score-matched comparative analyses of simultaneously administered fixed-ratio insulin glargine 100 U and lixisenatide (iGlarLixi) vs sequential administration of insulin glargine and lixisenatide in uncontrolled type 2 diabetes. Diabetes Obes Metab. 2018 Dec;20(12):2821-2829. doi: 10.1111/dom.13462. Epub 2018 Aug 13.