Efficacy and Safety of Lixisenatide Versus Insulin Glulisine on Top of Insulin Glargine With or Without Metformin in Type 2 Diabetic Patients

NCT ID: NCT01768559

Last Updated: 2017-01-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 894 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-01-31
• Study Completion Date: 2014-12-31

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.

Conditions

Type 2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Lixisenatide

Lixisenatide 10 mcg once daily (QD) for 2 weeks post-randomization, then at a maintenance dose of 20 mcg QD up to Week 26 on top of insulin glargine with or without metformin.

Group Type: EXPERIMENTAL

Lixisenatide (AVE0010)

Intervention Type: DRUG

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection 30 to 60 minutes before breakfast or dinner.

Insulin Glargine (Mandatory background drug)

Intervention Type: DRUG

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection at breakfast or dinner. Doses were adjusted to maintain a fasting self-monitored plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL).

Metformin (Background drug)

Intervention Type: DRUG

Pharmaceutical form: Tablet; Route of administration: Oral administration. If previously taken, Metformin to be continued at stable dose (≥1.5 g/day) throughout the study.

Insulin Glulisine QD

Insulin glulisine QD from randomization up to Week 26 on top of Insulin glargine with or without metformin.

Group Type: ACTIVE_COMPARATOR

Insulin glulisine QD

Intervention Type: DRUG

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection within 15 minutes before breakfast or dinner. The initial dose was 3-5 units and then individually titrated to obtain the SMPG value \>5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before lunch (if administered at breakfast) or at bedtime (if administered at dinner).

Insulin Glargine (Mandatory background drug)

Intervention Type: DRUG

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection at breakfast or dinner. Doses were adjusted to maintain a fasting self-monitored plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL).

Metformin (Background drug)

Intervention Type: DRUG

Pharmaceutical form: Tablet; Route of administration: Oral administration. If previously taken, Metformin to be continued at stable dose (≥1.5 g/day) throughout the study.

Insulin Glulisine TID

Insulin glulisine thrice daily (TID) from randomization up to Week 26 on top of Insulin glargine with or without metformin.

Group Type: ACTIVE_COMPARATOR

Insulin glulisine TID

Intervention Type: DRUG

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection within 15 minutes before each meal. The initial dose was 3-5 units for each meal and then individually titrated to obtain the SMPG value \>5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before the next meal or at bedtime (for injection at dinner).

Insulin Glargine (Mandatory background drug)

Intervention Type: DRUG

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection at breakfast or dinner. Doses were adjusted to maintain a fasting self-monitored plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL).

Metformin (Background drug)

Intervention Type: DRUG

Pharmaceutical form: Tablet; Route of administration: Oral administration. If previously taken, Metformin to be continued at stable dose (≥1.5 g/day) throughout the study.

Interventions

Lixisenatide (AVE0010)

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection 30 to 60 minutes before breakfast or dinner.

Intervention Type: DRUG

Insulin glulisine QD

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection within 15 minutes before breakfast or dinner. The initial dose was 3-5 units and then individually titrated to obtain the SMPG value \>5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before lunch (if administered at breakfast) or at bedtime (if administered at dinner).

Intervention Type: DRUG

Insulin glulisine TID

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection within 15 minutes before each meal. The initial dose was 3-5 units for each meal and then individually titrated to obtain the SMPG value \>5.6 mmol/L (100 mg/dL) and ≤7.8 mmol/L (140 mg/dL) before the next meal or at bedtime (for injection at dinner).

Intervention Type: DRUG

Insulin Glargine (Mandatory background drug)

Pharmaceutical form: Solution for injection; Route of administration: Self-administered by subcutaneous injection at breakfast or dinner. Doses were adjusted to maintain a fasting self-monitored plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL).

Intervention Type: DRUG

Metformin (Background drug)

Pharmaceutical form: Tablet; Route of administration: Oral administration. If previously taken, Metformin to be continued at stable dose (≥1.5 g/day) throughout the study.

Intervention Type: DRUG

Other Intervention Names

Lyxumia®; Device: Disposable self-injector prefilled pen (Delta 14®); HMR1964; Device: Disposable self-injector prefilled pen (Apidra® Solostar®); HMR1964; Device: Disposable self-injector prefilled pen (Apidra® Solostar®); Device: Disposable self-injector prefilled pen (Lantus® Solostar®)

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.

• 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

• 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.

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sanofi

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Sciences & Operations

Role: STUDY_DIRECTOR

Sanofi

Locations

Investigational Site Number 840043

Sun City, Arizona, United States

Investigational Site Number 840042

Tempe, Arizona, United States

Investigational Site Number 840003

Little Rock, Arkansas, United States

Investigational Site Number 840031

La Mesa, California, United States

Investigational Site Number 840005

Mission Viejo, California, United States

Investigational Site Number 840057

Northridge, California, United States

Investigational Site Number 840035

Santa Ana, California, United States

Investigational Site Number 840002

Temecula, California, United States

Investigational Site Number 840037

Walnut Creek, California, United States

Investigational Site Number 840023

West Hills, California, United States

Investigational Site Number 840041

Denver, Colorado, United States

Investigational Site Number 840012

Miami, Florida, United States

Investigational Site Number 840061

Miami, Florida, United States

Investigational Site Number 840045

Lawrenceville, Georgia, United States

Investigational Site Number 840036

Nampa, Idaho, United States

Investigational Site Number 840024

Chicago, Illinois, United States

Investigational Site Number 840009

Evanston, Illinois, United States

Investigational Site Number 840004

Avon, Indiana, United States

Investigational Site Number 840055

Avon, Indiana, United States

Investigational Site Number 840027

Des Moines, Iowa, United States

Investigational Site Number 840006

Wichita, Kansas, United States

Investigational Site Number 840047

Lexington, Kentucky, United States

Investigational Site Number 840056

Paducah, Kentucky, United States

Investigational Site Number 840022

Marrero, Louisiana, United States

Investigational Site Number 840016

Baltimore, Maryland, United States

Investigational Site Number 840017

Rockville, Maryland, United States

Investigational Site Number 840025

Buckley, Michigan, United States

Investigational Site Number 840048

Dearborn, Michigan, United States

Investigational Site Number 840026

Kalamazoo, Michigan, United States

Investigational Site Number 840049

Las Vegas, Nevada, United States

Investigational Site Number 840029

New Hyde Park, New York, United States

Investigational Site Number 840060

Smithtown, New York, United States

Investigational Site Number 840030

Staten Island, New York, United States

Investigational Site Number 840011

Salisbury, North Carolina, United States

Investigational Site Number 840028

Fargo, North Dakota, United States

Investigational Site Number 840007

Oklahoma City, Oklahoma, United States

Investigational Site Number 840021

Pittsburgh, Pennsylvania, United States

Investigational Site Number 840052

Myrtle Beach, South Carolina, United States

Investigational Site Number 840032

Chattanooga, Tennessee, United States

Investigational Site Number 840033

Nashville, Tennessee, United States

Investigational Site Number 840034

Corpus Christi, Texas, United States

Investigational Site Number 840001

Dallas, Texas, United States

Investigational Site Number 840020

Houston, Texas, United States

Investigational Site Number 840018

Norfolk, Virginia, United States

Investigational Site Number 840015

Salem, Virginia, United States

Investigational Site Number 840010

Milwaukee, Wisconsin, United States

Investigational Site Number 124008

Brampton, , Canada

Investigational Site Number 124015

Burlington, , Canada

Investigational Site Number 124018

Chatham, , Canada

Investigational Site Number 124004

Coquitlam, , Canada

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Etobicoke, , Canada

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Hamilton, , Canada

Investigational Site Number 124020

Montreal, , Canada

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Montreal, , Canada

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Newmarket, , Canada

Investigational Site Number 124021

Québec, , Canada

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Red Deer, , Canada

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Saint Romuald, , Canada

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Sherbrooke, , Canada

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Toronto, , Canada

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Toronto, , Canada

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Vancouver, , Canada

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Victoria, , Canada

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Winnipeg, , Canada

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Santiago, , Chile

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Santiago, , Chile

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Santiago, , Chile

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Santiago, , Chile

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Santiago, , Chile

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Santiago, , Chile

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Santiago, , Chile

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Santiago, , Chile

Investigational Site Number 203107

Beroun, , Czechia

Investigational Site Number 203103

Jílové u Prahy, , Czechia

Investigational Site Number 203101

Ostrava, , Czechia

Investigational Site Number 203110

Police nad Metují, , Czechia

Investigational Site Number 203105

Prague, , Czechia

Investigational Site Number 203102

Prague, , Czechia

Investigational Site Number 203108

Prague, , Czechia

Investigational Site Number 203104

Trutnov, , Czechia

Investigational Site Number 233102

Pärnu, , Estonia

Investigational Site Number 233103

Tallinn, , Estonia

Investigational Site Number 233104

Tallinn, , Estonia

Investigational Site Number 233101

Viljandimaa, , Estonia

Investigational Site Number 250108

Bois-Guillaume, , France

Investigational Site Number 250105

Corbeil-Essonnes, , France

Investigational Site Number 250104

La Rochelle, , France

Investigational Site Number 250106

Lyon, , France

Investigational Site Number 250107

Lyon, , France

Investigational Site Number 250109

Mantes-la-Jolie, , France

Investigational Site Number 250102

Paris, , France

Investigational Site Number 250101

Vandœuvre-lès-Nancy, , France

Investigational Site Number 250103

Vénissieux, , France

Investigational Site Number 276112

Bad Mergentheim, , Germany

Investigational Site Number 276108

Berlin, , Germany

Investigational Site Number 276102

Dortmund, , Germany

Investigational Site Number 276120

Dresden, , Germany

Investigational Site Number 276106

Dresden, , Germany

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Frankfurt A.M., , Germany

Investigational Site Number 276116

Görlitz, , Germany

Investigational Site Number 276113

Heidelberg, , Germany

Investigational Site Number 276118

Leipzig, , Germany

Investigational Site Number 276119

Magdeburg, , Germany

Investigational Site Number 276103

Neumünster, , Germany

Investigational Site Number 276109

Saint Ingbert-Oberwürzbach, , Germany

Investigational Site Number 276115

Speyer, , Germany

Investigational Site Number 348107

Budapest, , Hungary

Investigational Site Number 348108

Budapest, , Hungary

Investigational Site Number 348102

Budapest, , Hungary

Investigational Site Number 348101

Eger, , Hungary

Investigational Site Number 348103

Pápa, , Hungary

Investigational Site Number 348106

Sátoraljaújhely, , Hungary

Investigational Site Number 348104

Szeged, , Hungary

Investigational Site Number 348105

Zalaegerszeg, , Hungary

Investigational Site Number 380103

Bologna, , Italy

Investigational Site Number 380102

Catania, , Italy

Investigational Site Number 380101

Milan, , Italy

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Napoli, , Italy

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Torino, , Italy

Investigational Site Number 428103

Jelgava, , Latvia

Investigational Site Number 428104

Ogre, , Latvia

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Riga, , Latvia

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Riga, , Latvia

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Sigulda, , Latvia

Investigational Site Number 440104

Jonava, , Lithuania

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Kaunas, , Lithuania

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Kaunas, , Lithuania

Investigational Site Number 440101

Kaunas, , Lithuania

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Klaipėda, , Lithuania

Investigational Site Number 484108

Chihuahua City, , Mexico

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Cuernavaca, , Mexico

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Durango, , Mexico

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Guadalajara, , Mexico

Investigational Site Number 484109

Guadalajara, , Mexico

Investigational Site Number 484107

Guadalajara, , Mexico

Investigational Site Number 484105

Guadalajara, , Mexico

Investigational Site Number 484110

Guadalajara, , Mexico

Investigational Site Number 484103

Mexico City, , Mexico

Investigational Site Number 484102

México, , Mexico

Investigational Site Number 484106

Monterrey, , Mexico

Investigational Site Number 616101

Bialystok, , Poland

Investigational Site Number 616103

Bydgoszcz, , Poland

Investigational Site Number 616102

Bytom, , Poland

Investigational Site Number 616106

Krakow, , Poland

Investigational Site Number 616104

Krakow, , Poland

Investigational Site Number 616105

Puławy, , Poland

Investigational Site Number 616107

Warsaw, , Poland

Investigational Site Number 642105

Bacau, , Romania

Investigational Site Number 642108

Cluj-Napoca, , Romania

Investigational Site Number 642106

Deva, , Romania

Investigational Site Number 642113

Galati, , Romania

Investigational Site Number 642107

Hunedoara, , Romania

Investigational Site Number 642117

Iași, , Romania

Investigational Site Number 642103

Oradea, , Romania

Investigational Site Number 642104

Oradea, , Romania

Investigational Site Number 642112

Piteşti, , Romania

Investigational Site Number 642114

Ploieşti, , Romania

Investigational Site Number 642102

Reşiţa, , Romania

Investigational Site Number 642111

Sibiu, , Romania

Investigational Site Number 642109

Târgu Mureş, , Romania

Investigational Site Number 642110

Târgu Mureş, , Romania

Investigational Site Number 642116

Timișoara, , Romania

Investigational Site Number 642101

Timișoara, , Romania

Investigational Site Number 642115

Timișoara, , Romania

Investigational Site Number 643111

Moscow, , Russia

Investigational Site Number 643107

Moscow, , Russia

Investigational Site Number 643105

Moscow, , Russia

Investigational Site Number 643110

Penza, , Russia

Investigational Site Number 643101

Saint Petersburg, , Russia

Investigational Site Number 643104

Saint Petersburg, , Russia

Investigational Site Number 643109

Saint Petersburg, , Russia

Investigational Site Number 643106

Saint Petersburg, , Russia

Investigational Site Number 643108

Saint Petersburg, , Russia

Investigational Site Number 643103

Saint Petersburg, , Russia

Investigational Site Number 643102

Saratov, , Russia

Investigational Site Number 724105

A Coruña, , Spain

Investigational Site Number 724102

Ferrol, , Spain

Investigational Site Number 724103

Málaga, , Spain

Investigational Site Number 724104

Seville, , Spain

Investigational Site Number 804104

Chernivtsi, , Ukraine

Investigational Site Number 804107

Donetsk, , Ukraine

Investigational Site Number 804103

Donetsk, , Ukraine

Investigational Site Number 804108

Mykolaiv, , Ukraine

Investigational Site Number 804110

Odesa, , Ukraine

Investigational Site Number 804105

Vinnytsia, , Ukraine

Investigational Site Number 804102

Vinnytsia, , Ukraine

Investigational Site Number 804111

Zaporizhia, , Ukraine

Investigational Site Number 826006

Ashton-under-Lyne, , United Kingdom

Investigational Site Number 826002

Birmingham, , United Kingdom

Investigational Site Number 826007

Carmarthen, , United Kingdom

Investigational Site Number 826005

Chester, , United Kingdom

Investigational Site Number 826008

Coventry, , United Kingdom

Investigational Site Number 826009

Dundee, , United Kingdom

Investigational Site Number 826001

Durham, , United Kingdom

Investigational Site Number 826011

Haddington, , United Kingdom

Investigational Site Number 826012

Leicester, , United Kingdom

Investigational Site Number 826010

Plymouth, , United Kingdom

Investigational Site Number 826004

Sheffield, , United Kingdom

Investigational Site Number 826003

St Helens, , United Kingdom

Countries

United States; Canada; Chile; Czechia; Estonia; France; Germany; Hungary; Italy; Latvia; Lithuania; Mexico; Poland; Romania; Russia; Spain; Ukraine; United Kingdom

References

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.

Reference Type: RESULT

PMID: 27222510 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31848983 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29974618 (View on PubMed)

Other Identifiers

2012-004096-38

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1131-4936

Identifier Type: OTHER

Identifier Source: secondary_id

EFC12626

Identifier Type: -

Identifier Source: org_study_id