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Pharmacodynamic Effects of Lixisenatide Compared to Liraglutide in Patients With Type 2 Diabetes Not Adequately Controlled With Insulin Glargine With or Without Metformin

Primary Purpose

Type 2 Diabetes Mellitus

Status

Completed

Phase

Phase 2

Locations

Germany

Study Type

Interventional

Intervention

Lixisenatide (AVE0010)

Liraglutide

Insulin Glargine

Metformin

About this trial

This is an interventional treatment trial for Type 2 Diabetes Mellitus

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria :

Participants with T2DM diagnosed at least 1 year before the screening visit.
Treatment with neutral protamine hagedorn (NPH) or insulin glargine for at least 3 months and at a stable dose (±20%) of at least 10 IU/day (for at least 2 months prior to screening) alone or combined with a stable dose of metformin with or without dipeptidyl peptidase 4 (DPP-4) inhibitor or sulfonylurea.
Glycosylated hemoglobin (HbA1c) ≥6.5 and ≤9.5%.
Body mass index (BMI) between 20 and 40 kg/m^2.

Exclusion criteria:

Pregnant women or breastfeeding women.
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.
Any previous treatment with lixisenatide or participation in a previous study with lixisenatide (AVE0010), and any previous treatment with liraglutide stopped for safety concern or lack of efficacy.
Allergic reaction to any glucagon-like peptide-1 (GLP-1) agonist in the past (eg, exenatide) or to metacresol.
History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease.
Personal or family history of medullary thyroid cancer (MTC) or a genetic condition that predisposes to MTC.

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Lixisenatide 20 μg

Liraglutide 1.2 mg

Liraglutide 1.8 mg

Arm Description

Subcutaneous injection of lixisenatide10 μg once daily (QD) for 2 weeks followed by 20 μg QD for 6 weeks under fasted conditions, on top of insulin glargine with or without metformin.

Subcutaneous injection of liraglutide 0.6 mg QD for 1 week followed by 1.2 mg QD for 7 weeks under fasted conditions, on top of insulin glargine with or without metformin.

Subcutaneous injection of liraglutide 0.6 mg QD for 1 week followed by 1.2 mg QD for another 1 week and 1.8 mg QD for next 6 weeks under fasted conditions, on top of insulin glargine with or without metformin.

Outcomes

Primary Outcome Measures

Change From Baseline to Day 56 in Plasma Glucose Corrected Area Under The Plasma Concentration-Time Curve (AUC) From Time 0.5 Hours to 4.5 Hours

Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 milligram per decilitre (mg/dL) with 1 mg/dL as limit of detection (LOD). Calculation of the AUC was made on Day -3 (baseline) and on Day 56 using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours]) to 4 hours after breakfast start (time: 4.5 hours) and corrected by subtracting pre-breakfast plasma glucose concentration (time: 0.5 hours).

Secondary Outcome Measures

Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 Hours

Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as limit of detection (LOD). Calculation of the AUC was made on Day -3 (baseline) and on Day 56 using the linear trapezoidal rule from time of breakfast start (30 minutes after study drug administration [time: 0.5 hours]) to 5 hours after breakfast start (time: 5.5 hours) and corrected by subtracting pre-breakfast plasma glucose concentration (time: 0.5 hours).

Number of Participants With 2-Hour Post-prandial Plasma Glucose (PPG) <7.77 (mmol/L) at Day 56

Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. The 2-hour PPG test measured blood glucose 2 hours after start of a standardised breakfast.

Change From Baseline to Day 56 in PPG Excursion

Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. PPG excursion was determined on Day -3 (Baseline) and Day 56 as the maximum change in PPG from time of breakfast start (time: 0.5 hours) until 5 hours later (time: 5.5 hours) subtracted from pre-meal plasma concentration.

Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG)

Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. The value of FPG on Day -3 was the baseline.

Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG)

Seven-point SMPG (before breakfast, 2 hours post breakfast, before lunch, 2 hours post lunch, before dinner, 2 hours post dinner, and at bedtime) was measured using Freestyle Precision glucometer and average of the 7 measurements was calculated.

Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 Hours

C-peptide was assessed using the Electro Chemiluminescence Immuno Assay.The range of the method was 0.2 to 25 nanogram per millilitre (ng/mL) and the LOD was 0.07 ng/mL. Measurement was done on Day -3 (Baseline) and Day 56 as the maximum change in C-peptide from time of breakfast start (time: 0.5 hours) until 5 hours later (time: 5.5 hours) subtracted from pre-meal plasma concentration.

Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 Hours

Glucagon was assessed using the radioimmunoassay. The range of the method was 4.7 to 150 picomole per litre (pmol/L). Measurement was done on Day -3 (Baseline) and Day 56 as the maximum change in glucagon from time of breakfast start (time: 0.5 hours) until 5 hours later (time: 5.5 hours) subtracted from pre-meal plasma concentration.

Change From Baseline to Day 56 in HbA1c

HbA1C was assessed using the high performance liquid chromatography method.

Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose

Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2)

Gastric emptying was measured using 13C-octanoic acid breath test by isotope-selective non-dispersive infrared spectrometry.

Change From Baseline to Day 55 in Gastric Emptying Coefficient

Gastric emptying was measured using 13C-octanoic acid breath test by isotope-selective non-dispersive infrared spectrometry. Gastric emptying coefficient was derived from a mathematical formula that describes the gastric emptying rate and gives an overall index of gastric emptying.

Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate

The baseline value was the 24-hour mean on Day -2/-1 determined as overall, night and daytime mean. Measurements were made every 15 minutes from 07:00 to 23:00 (daytime) and every 30 minutes from 23:00 to 07:00 (night-time) at baseline and Day 57/58. Measurements were obtained after 10 minutes in the supine resting position.

Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure

The baseline value was the 24-hour means on Day -2/-1 determined as overall, night and day-time mean. Measurements were made every 15 minutes from 07:00 to 23:00 (day-time) and every 30 minutes from 23:00 to 07:00 (night-time) at baseline and at Day 57/58. Measurements were obtained after 10 minutes in the supine resting position.

Change From Baseline to Day 57 in Body Weight

Change From Baseline to Day 57 in Waist Circumference

Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast

Visual Analogue Scale, 100 mm in length with words anchored at each end, expressing the most positive (100 mm) and the most negative rating (0 mm), was used to assess hunger, satiety, fullness and prospective food consumption. Responses were measured as distance from the left end of the line to the mark. Mean change from baseline was calculated for each parameter separately.

Full Information

NCT ID

NCT01596504

First Posted

May 7, 2012

Last Updated

August 22, 2016

Sponsor

Sanofi

1. Study Identification

Unique Protocol Identification Number

NCT01596504

Brief Title

Pharmacodynamic Effects of Lixisenatide Compared to Liraglutide in Patients With Type 2 Diabetes Not Adequately Controlled With Insulin Glargine With or Without Metformin

Official Title

An Open-label, Randomized, Three-parallel-group Study on Pharmacodynamic Effects of 8-week QD Treatment With Lixisenatide Compared to Liraglutide in Patients With Type 2 Diabetes Not Adequately Controlled With Insulin Glargine With or Without Metformin

Study Type

Interventional

2. Study Status

Record Verification Date

August 2016

Overall Recruitment Status

Completed

Study Start Date

May 2012 (undefined)

Primary Completion Date

July 2013 (Actual)

Study Completion Date

July 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sanofi

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

Primary Objective: - To investigate the effects of repeated subcutaneous doses of lixisenatide 20 μg once daily (QD) as compared to liraglutide 1.2 mg QD or 1.8 mg QD in reducing post-prandial plasma glucose (PPG) assessed as area under the plasma glucose-concentration-time curve (AUC) after a standardized breakfast at the end of a 8-week treatment period in participants with type 2 diabetes mellitus (T2DM) not adequately controlled with insulin glargine (± metformin). Secondary Objectives: To assess the effects of lixisenatide 20 μg QD as compared to liraglutide 1.2 QD or 1.8 mg QD after an 8-week treatment period in participants with T2DM not adequately controlled with insulin glargine (± metformin) on: Post-prandial C-peptide, glucagon and appetite perceptions after a standardized breakfast, Appetite perceptions after standardized dinner, Gastric emptying after a standardized labelled test meal, Fasting plasma glucose, 24-hour plasma glucose profile, Glycosylated hemoglobin (HbA1c), Insulin glargine dose, 7-point self monitored plasma glucose (SMPG), Body weight and waist circumference, 24-hour heart rate and blood pressure, To assess lixisenatide and liraglutide safety and tolerability as add on treatment to insulin glargine (± metformin).

Detailed Description

Up to 2-week screening period A run-in period of 12 weeks at maximum including a forced titration with insulin glargine up to 11 weeks and 1 baseline pharmacodynamic assessment week A 8-week treatment(s) period(s) up to Day 57 Follow-up: 7 ±2 days after the last treatment day Total study duration approximately 14 weeks up to 23 weeks

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 2 Diabetes Mellitus

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

142 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Lixisenatide 20 μg

Arm Type

Experimental

Arm Description

Subcutaneous injection of lixisenatide10 μg once daily (QD) for 2 weeks followed by 20 μg QD for 6 weeks under fasted conditions, on top of insulin glargine with or without metformin.

Arm Title

Liraglutide 1.2 mg

Arm Type

Active Comparator

Arm Description

Subcutaneous injection of liraglutide 0.6 mg QD for 1 week followed by 1.2 mg QD for 7 weeks under fasted conditions, on top of insulin glargine with or without metformin.

Arm Title

Liraglutide 1.8 mg

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Lixisenatide (AVE0010)

Intervention Description

Pharmaceutical form: solution for injection self-administered with a pen-like injector (OptiClik®). Route of administration: subcutaneous

Intervention Type

Drug

Intervention Name(s)

Liraglutide

Other Intervention Name(s)

Victoza®

Intervention Description

Pharmaceutical form:solution for injection Route of administration: subcutaneous

Intervention Type

Drug

Intervention Name(s)

Insulin Glargine

Other Intervention Name(s)

Lantus® SoloSTAR®

Intervention Description

Doses to be adjusted to maintain a fasting self-measured plasma glucose (SMPG) between 4.4 to 5.6 mmol/L (80 to 100 mg/dL)

Intervention Type

Drug

Intervention Name(s)

Metformin

Intervention Description

If previously taken metformin to be continued at stable dose throughout the study

Primary Outcome Measure Information:

Title

Change From Baseline to Day 56 in Plasma Glucose Corrected Area Under The Plasma Concentration-Time Curve (AUC) From Time 0.5 Hours to 4.5 Hours

Description

Time Frame

0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5 hours post study drug administration on Day 56

Secondary Outcome Measure Information:

Title

Change From Baseline to Day 56 in Plasma Glucose Corrected AUC From Time 0.5 Hours to 5.5 Hours

Description

Time Frame

0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56

Title

Number of Participants With 2-Hour Post-prandial Plasma Glucose (PPG) <7.77 (mmol/L) at Day 56

Description

Time Frame

Day 56

Title

Change From Baseline to Day 56 in PPG Excursion

Description

Time Frame

0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56

Title

Change From Baseline to Day 56 in Fasting Plasma Glucose (FPG)

Description

Plasma glucose was assessed using the Gluco-quant Glucose/hexokinase assay. The range of the method was 3 to 1000 mg/dL with 1 mg/dL as LOD. The value of FPG on Day -3 was the baseline.

Time Frame

0.5 hour (prior to standardized breakfast) on Day -3; 0.5 hour (prior to standardized breakfast) on Day 56

Title

Change From Baseline to Day 56 in Average 7-Point Self-Monitored Plasma Glucose (SMPG)

Description

Time Frame

Before breakfast, 2 hours post breakfast, before lunch, 2 hours post lunch, before dinner, 2 hours post dinner, and at bedtime on Day -3 (Baseline) and on Day 56

Title

Change From Baseline to Day 56 in Corrected C-Peptide AUC From Time 0.5 Hours to 5.5 Hours

Description

Time Frame

0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day-3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56

Title

Change From Baseline to Day 56 in Corrected Glucagon AUC From Time 0.5 Hours to 5.5 Hours

Description

Time Frame

0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours on Day -3 (baseline); 0.5 (prior to standardized breakfast), 0.67, 0.84, 1, 1.5, 2, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56

Title

Change From Baseline to Day 56 in HbA1c

Description

HbA1C was assessed using the high performance liquid chromatography method.

Time Frame

Pre-dose (Hour 0) on Day 1 (Baseline) and Day 56

Title

Change From Baseline to Day 56 in Average Daily Insulin Glargine Dose

Time Frame

Day -7 (Baseline), Day 56

Title

Change From Baseline to Day 55 in Gastric Emptying Half Life (t1/2)

Description

Gastric emptying was measured using 13C-octanoic acid breath test by isotope-selective non-dispersive infrared spectrometry.

Time Frame

0 (prior to standardized breakfast), 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 hours on Day -4 (baseline) and on Day 55

Title

Change From Baseline to Day 55 in Gastric Emptying Coefficient

Description

Time Frame

0 (7:30 clock time, prior to standardized breakfast), 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 hours on Day -4 (baseline) and on Day 55

Title

Change From Baseline to Day 57/58 in 24-Hour Mean Heart Rate

Description

Time Frame

Every 15 minutes from 07:00 clock time to 23:00 clock time (day-time) and every 30 minutes from 23:00 clock time to 07:00 clock time (night-time) on Day -2/-1 (Baseline) and Day 57/58

Title

Change From Baseline to Day 57/58 in 24-Hour Mean Systolic Blood Pressure and Diastolic Blood Pressure

Description

Time Frame

Every 15 minutes from 07:00 clock time to 23:00 clock time (day-time) and every 30 minutes from 23:00 clock time to 07:00 clock time (night-time) on Day -2/ -1 (Baseline) and Day 57/58

Title

Change From Baseline to Day 57 in Body Weight

Time Frame

0.5 hours prior to standardized breakfast on Day -1 (Baseline); 0.5 hours prior to study drug administration on Day 57

Title

Change From Baseline to Day 57 in Waist Circumference

Time Frame

0.5 hours prior to standardized breakfast on Day -1 (Baseline); 0.5 hours prior to IMP administration on Day 57

Title

Change From Baseline to Day 56 in the Cumulative Score Mean on the Appetite Perception Using a Visual Analogue Scale After Standardized Solid Breakfast

Description

Time Frame

0.5 (8:00 clock time, prior to standardized breakfast), 1.5, 2.5, 3.5, 4.5, 5.5 hours on Day -3; 0 (prior to standardized breakfast), 1.5, 2.5, 3.5, 4.5, 5.5 hours post study drug administration on Day 56

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria : Participants with T2DM diagnosed at least 1 year before the screening visit. Treatment with neutral protamine hagedorn (NPH) or insulin glargine for at least 3 months and at a stable dose (±20%) of at least 10 IU/day (for at least 2 months prior to screening) alone or combined with a stable dose of metformin with or without dipeptidyl peptidase 4 (DPP-4) inhibitor or sulfonylurea. Glycosylated hemoglobin (HbA1c) ≥6.5 and ≤9.5%. Body mass index (BMI) between 20 and 40 kg/m^2. Exclusion criteria: Pregnant women or breastfeeding women. 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. Any previous treatment with lixisenatide or participation in a previous study with lixisenatide (AVE0010), and any previous treatment with liraglutide stopped for safety concern or lack of efficacy. Allergic reaction to any glucagon-like peptide-1 (GLP-1) agonist in the past (eg, exenatide) or to metacresol. History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy, stomach/gastric surgery, inflammatory bowel disease. Personal or family history of medullary thyroid cancer (MTC) or a genetic condition that predisposes to MTC. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Sciences & Operations

Organizational Affiliation

Sanofi

Official's Role

Study Director

Facility Information:

Facility Name

Investigational Site Number 276008

City

Berlin

ZIP/Postal Code

10117

Country

Germany

Facility Name

Investigational Site Number 276006

City

Berlin

ZIP/Postal Code

14050

Country

Germany

Facility Name

Investigational Site Number 276004

City

Kiel

ZIP/Postal Code

24105

Country

Germany

Facility Name

Investigational Site Number 276002

City

Mainz

ZIP/Postal Code

55116

Country

Germany

Facility Name

Investigational Site Number 276005

City

Mönchengladbach

ZIP/Postal Code

41061

Country

Germany

Facility Name

Investigational Site Number 276007

City

München

ZIP/Postal Code

80636

Country

Germany

Facility Name

Investigational Site Number 276003

City

Neu-Ulm

ZIP/Postal Code

89231

Country

Germany

Facility Name

Investigational Site Number 276001

City

Neuss

ZIP/Postal Code

41460

Country

Germany

12. IPD Sharing Statement

Citations:

PubMed Identifier

25887358

Citation

Meier JJ, Rosenstock J, Hincelin-Mery A, Roy-Duval C, Delfolie A, Coester HV, Menge BA, Forst T, Kapitza C. Contrasting Effects of Lixisenatide and Liraglutide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients With Type 2 Diabetes on Optimized Insulin Glargine With or Without Metformin: A Randomized, Open-Label Trial. Diabetes Care. 2015 Jul;38(7):1263-73. doi: 10.2337/dc14-1984. Epub 2015 Apr 17.

Results Reference

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Pharmacodynamic Effects of Lixisenatide Compared to Liraglutide in Patients With Type 2 Diabetes Not Adequately Controlled With Insulin Glargine With or Without Metformin

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Pharmacodynamic Effects of Lixisenatide Compared to Liraglutide in Patients With Type 2 Diabetes Not Adequately Controlled With Insulin Glargine With or Without Metformin

Type 2 Diabetes Mellitus

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial