Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed Combination Versus Insulin Glargine Alone on Top of Metformin in Type 2 Diabetic Patients

A Randomized, 24-week, Open-label, 2-arm Parallel-group, Multicenter Study Comparing the Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed Ratio Combination Versus Insulin Glargine on Top of Metformin in Type 2 Diabetic Patients

Primary Objective:

• The purpose of this study was to compare insulin glargine/ lixisenatide fixed ratio combination (FRC) versus insulin glargine on glycemic control over 24 weeks, as evaluated by glycosylated hemoglobin (HbA1c) reduction in type 2 diabetic participants treated with metformin.

Secondary Objectives:

• To compare insulin glargine/lixisenatide FRC versus insulin glargine over 24 weeks on:

  • Glycemic control in relation to a meal as evaluated by post-prandial plasma glucose and glucose excursions during a standardized meal test;
  • Percentage of participants reaching HbA1c <7% or ≤6.5%;
  • 7-point Self-Monitored Plasma Glucose (SMPG) profile;
  • Body weight;
  • Insulin glargine dose
  • Fasting Plasma Glucose (FPG);
  • Percentage of participants requiring rescue therapy during the 24-week open label treatment period;
• To assess safety and tolerability of insulin glargine/lixisenatide FRC.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Insulin glargine /lixisenatide Fixed Ratio Combination; Drug: Metformin (Background drug); Drug: Insulin glargine

Detailed Description

Approximately 27 weeks including a 24-week treatment period.

• Study Type: Interventional
• Enrollment (Actual): 323
• Phase: Phase 2

Contacts and Locations

Study Locations

• Chile
  • Santiago, Chile, 7500347
    • Investigational Site Number 152404
  • Santiago, Chile, 7500347
    • Investigational Site Number 152405
  • Santiago, Chile, 7500710
    • Investigational Site Number 152403
  • Santiago, Chile, 7980378
    • Investigational Site Number 152401
  • Santiago, Chile, 8320000
    • Investigational Site Number 152402
• Czech Republic
  • Novy Jicin, Czech Republic, 74101
    • Investigational Site Number 203403
  • Plzen, Czech Republic, 32600
    • Investigational Site Number 203401
  • Praha 2, Czech Republic, 12808
    • Investigational Site Number 203402
  • Praha 8, Czech Republic, 18100
    • Investigational Site Number 203405
• Denmark
  • København Nv, Denmark, 2400
    • Investigational Site Number 208401
  • Køge, Denmark, 4600
    • Investigational Site Number 208404
  • Slagelse, Denmark, 4200
    • Investigational Site Number 208402
  • Svendborg, Denmark, 5700
    • Investigational Site Number 208403
• France
  • Narbonne, France, 11018
    • Investigational Site Number 250402
  • Poitiers Cedex, France, 86021
    • Investigational Site Number 250404
  • Vandoeuvre Les Nancy, France, 54511
    • Investigational Site Number 250401
• Germany
  • Dresden, Germany, 01307
    • Investigational Site Number 276401
  • Ludwigshafen, Germany, 67059
    • Investigational Site Number 276402
  • Oberhausen, Germany, 46045
    • Investigational Site Number 276403
• Hungary
  • Balatonfüred, Hungary, 8230
    • Investigational Site Number 348401
  • Budapest, Hungary, 1041
    • Investigational Site Number 348405
  • Budapest, Hungary, 1212
    • Investigational Site Number 348406
  • Debrecen, Hungary, 4043
    • Investigational Site Number 348404
  • Szeged, Hungary, 6720
    • Investigational Site Number 348402
  • Szeged, Hungary, 6722
    • Investigational Site Number 348403
• Lithuania
  • Kaunas, Lithuania, LT-49456
    • Investigational Site Number 440401
  • Kaunas, Lithuania, LT-51270
    • Investigational Site Number 440402
  • Kedainiai, Lithuania, LT-57164
    • Investigational Site Number 440403
  • Klaipeda, Lithuania, LT-92304
    • Investigational Site Number 440404
• Mexico
  • Acapulco, Mexico, 39670
    • Investigational Site Number 484404
  • Cuernavaca, Mexico, 62250
    • Investigational Site Number 484401
  • Durango, Mexico, 34270
    • Investigational Site Number 484405
  • Guadalajara, Mexico, 44210
    • Investigational Site Number 484402
  • Guadalajara, Mexico, 44656
    • Investigational Site Number 484403
• Poland
  • Bialystok, Poland, 15-435
    • Investigational Site Number 616405
  • Gdansk, Poland, 80-847
    • Investigational Site Number 616406
  • Krakow, Poland, 31-548
    • Investigational Site Number 616403
  • Lodz, Poland, 94-074
    • Investigational Site Number 616407
  • Pulawy, Poland, 24-100
    • Investigational Site Number 616404
  • Szczecin, Poland, 70-506
    • Investigational Site Number 616402
  • Warszawa, Poland, 02-507
    • Investigational Site Number 616401
• Romania
  • Brasov, Romania, 500365
    • Investigational Site Number 642402
  • Bucuresti, Romania, 020475
    • Investigational Site Number 642403
  • Iasi, Romania, 700547
    • Investigational Site Number 642405
  • Oradea, Romania, 410169
    • Investigational Site Number 642401
  • Targu Mures, Romania, 540142
    • Investigational Site Number 642406
  • Timisoara, Romania, 300133
    • Investigational Site Number 642404
• Slovakia
  • Bratislava, Slovakia, 85101
    • Investigational Site Number 703402
  • Kosice, Slovakia, 04001
    • Investigational Site Number 703403
  • Kosice, Slovakia, 04013
    • Investigational Site Number 703406
  • Moldava Nad Bodvou, Slovakia, 04525
    • Investigational Site Number 703404
  • Nitra, Slovakia, 94911
    • Investigational Site Number 703405
  • Zilina, Slovakia, 01001
    • Investigational Site Number 703401
• Sweden
  • Skellefteå, Sweden, 931 32
    • Investigational Site Number 752402
  • Stockholm, Sweden, 171 76
    • Investigational Site Number 752401
  • Växjö, Sweden, 351 85
    • Investigational Site Number 752403
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Investigational Site Number 840408
  • California
    • Paramount, California, United States, 90723
      • Investigational Site Number 840412
  • Georgia
    • Larenceville, Georgia, United States, 30045
      • Investigational Site Number 840401
    • Roswell, Georgia, United States, 30076
      • Investigational Site Number 840417
  • Kentucky
    • Lexington, Kentucky, United States, 40504
      • Investigational Site Number 840403
  • Maryland
    • Hyattsville, Maryland, United States, 20782
      • Investigational Site Number 840404
    • Rockville, Maryland, United States, 20852
      • Investigational Site Number 840405
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Investigational Site Number 840411
  • New York
    • West Seneca, New York, United States, 14224
      • Investigational Site Number 840415
  • Oklahoma
    • Norman, Oklahoma, United States, 73069
      • Investigational Site Number 840402
  • Oregon
    • Medford, Oregon, United States, 97504
      • Investigational Site Number 840407
  • Pennsylvania
    • Durham, Pennsylvania, United States, 27713
      • Investigational Site Number 840413
  • Texas
    • Dallas, Texas, United States, 75230
      • Investigational Site Number 840410
  • Washington
    • Renton, Washington, United States, 98055
      • Investigational Site Number 840414

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Participants with type 2 diabetes mellitus diagnosed for at least 1 year.
• Metformin treatment at a stable dose of at least 1.5 g/day for at least 3 months prior to screening.

Exclusion criteria:

• Age < legal age of adulthood (18 years).
• Screening HbA1c <7% or >10%.
• Screening FPG >250 mg/dL (>13.9 mmol/L).
• Pregnancy or lactation, women of childbearing potential with no effective contraceptive method.
• Type 1 diabetes mellitus.
• Treatment with glucose-lowering agent(s) other than metformin in a period of 3 months prior to screening.
• Use of insulin within the last 6 months.
• Previous use of insulin, except for episode(s) of short-term treatment (≤15 consecutive days) due to intercurrent illness.
• Amylase and/or lipase >3 times the upper limit of the normal laboratory range (ULN) at screening.
• Calcitonin ≥20 pg/ml (5.9 pmol/l) at screening.
• Alanine Transferase (ALT) >3 ULN at screening.
• History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy.
• Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predisposes to MTC (e.g. multiple endocrine neoplasia syndromes).
• Uncontrolled or inadequately controlled hypertension at the time of screening with a resting supine systolic or diastolic blood pressure >180 mmHg or >110 mmHg, respectively.
• Within the last 6 months prior to screening: history of heart failure requiring hospitalization, myocardial infarction, or stroke. Planned coronary, carotid or peripheral artery revascularisation procedures.
• Body Mass Index (BMI) ≤20 or >40 kg/m^2.
• Any previous treatment with lixisenatide

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Insulin glargine/Lixisenatide Fixed Ratio Combination (FRC); FRC injected once daily (QD) for 24 weeks. Dose individually adjusted.	Drug: Insulin glargine /lixisenatide Fixed Ratio Combination; FRC was self-administered by subcutaneous (SC) injection within 1 hour before breakfast using pen-type injector (Tactipen®): 100 U/ml insulin glargine and 50 mcg Lixisenatide (ratio of 2 U/1 mcg). The initial dose was 10 U/5 mcg and then dose was adjusted weekly to reach and maintain fasting self-monitored plasma glucose (SMPG) of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L.; Other Names: (HOE901/AVE0010); Drug: Metformin (Background drug); Pharmaceutical form: Tablet; Route of administration: oral administration. To be kept at stable dose (≥1.5 g/day) throughout the study.
Active Comparator: Insulin glargine; Insulin glargine QD for 24 weeks. Dose individually adjusted.	Drug: Metformin (Background drug); Pharmaceutical form: Tablet; Route of administration: oral administration. To be kept at stable dose (≥1.5 g/day) throughout the study.; Drug: Insulin glargine; Insulin glargine (100 U/ml) was self-administered by SC injection before breakfast using pen-type injector (Lantus® Solostar®). The initial daily dose of insulin glargine was 10 U and then dose was adjusted weekly to reach and maintain fasting SMPG of 80 mg/dL to 100 mg/dL (4.4 mmol/L to 5.6 mmol/L).; Other Names: Lantus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c From Baseline to Week 24	Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using last observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of investigational medicinal product (IMP).	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 2-hour Postprandial Plasma Glucose (PPG) From Baseline to Week 24	The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.	Baseline, Week 24
Change in 2-hour Plasma Glucose Excursion From Baseline to Week 24	2-hour plasma glucose excursion = 2-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.	Baseline, Week 24
Change in Average 7-Point Self-Monitored Plasma Glucose (SMPG) Profiles From Baseline to Week 24	Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, over a single day, once in a week before baseline, before visit Week 12 and before visit Week 24 and the average value across the profiles performed in the week before a visit for the 7-time points was calculated. Change in average 7-point SMPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.	Baseline, Week 24
Change in Body Weight From Baseline to Week 24	Change in body weight was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 3 days after the last injection of IMP.	Baseline, Week 24
Average Daily Insulin Glargine Dose at Week 24	Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.	Week 24
Change in FPG From Baseline to Week 24	Change in FPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 1 day after the last injection of IMP.	Baseline, Week 24
Percentage of Participants Requiring Rescue Therapy During 24-week Treatment Period	Routine fasting SMPG and central laboratory FPG (and HbA1c after Week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceed the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) were performed. Threshold values from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 30: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8%.	Baseline up to Week 24
Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24	On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.	Week 24
Change in 30-minute and 1-hour PPG From Baseline to Week 24	The 30 minute and 1-hour PPG test measured blood glucose 30 minutes and 1-hour after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.	Baseline, Week 24
Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24	30-minute and 1-hour plasma glucose excursion = 30-minute and 1-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.	Baseline, Week 24
Percentage of Participants Reaching HbA1c <7% at Week 24 With no Documented Symptomatic Hypoglycemia During 24-week Treatment Period	Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L). Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one documented symptomatic hypoglycemia before the introduction of rescue medication and up to 1 day after the last injection of IMP. Otherwise, they were counted as missing data. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.	Baseline up to Week 24
Percentage of Participants Reaching HbA1c <7% With no Body Weight Gain at Week 24	Participants without any post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (for HbA1c and body weight) was available and showed non-response. Otherwise, they were counted as missing data.	Week 24
Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia	Documented symptomatic hypoglycemia was an event during which typical symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of ≤70 mg/dL (3.9 mmol/L).Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes were associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. All episodes in which neurological impairment was severe enough to prevent self-treatment and which were thought to place participants at risk for injury to themselves or others.	First dose of study drug up to 3 days after the last dose administration (maximum of 219 days)

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Rosenstock J, Diamant M, Aroda VR, Silvestre L, Souhami E, Zhou T, Perfetti R, Fonseca V; LixiLan PoC Study Group. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Lixisenatide and Insulin Glargine, Versus Insulin Glargine in Type 2 Diabetes Inadequately Controlled on Metformin Monotherapy: The LixiLan Proof-of-Concept Randomized Trial. Diabetes Care. 2016 Sep;39(9):1579-86. doi: 10.2337/dc16-0046. Epub 2016 Jun 9.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: November 4, 2011
• First Submitted That Met QC Criteria: November 17, 2011
• First Posted (Estimate): November 22, 2011

Study Record Updates

• Last Update Posted (Actual): February 10, 2017
• Last Update Submitted That Met QC Criteria: December 16, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Metformin; Insulin Glargine; Lixisenatide
• Other Study ID Numbers: ACT12374; 2011-002090-36 (EudraCT Number); U1111-1121-7111 (Other Identifier: UTN)