Efficacy and Safety of LixiLan Versus Insulin Glargine Alone Both With Metformin in Japanese With Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Antidiabetic Drugs (LIXILAN JP-L)

A Randomized, Active-controlled, Open Label, 2-treatment Arm, and Multicenter Study Comparing the Efficacy and Safety of the Insulin Glargine/Lixisenatide Combination to Insulin Glargine With Metformin in Japanese Patients With Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Antidiabetic Drugs

Primary Objective:

To compare LixiLan to insulin glargine in glycated hemoglobin (HbA1c) change from baseline to week 26 in patients with type 2 diabetes mellitus.

Secondary Objective:

To compare overall efficacy and safety of LixiLan to insulin glargine over 26 weeks in patients with type 2 diabetes mellitus.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Metformin; Drug: Insulin glargine/Lixisenatide (HOE901/AVE0010); Drug: Insulin glargine U100 (HOE901)

Detailed Description

The maximum study duration per patient will be approximately 41 weeks: an up to 14-week screening period (consisting of an up to 2-week screening phase and a 12-week run-in phase), a 26-week randomized treatment period, and a 3-day post-treatment safety follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 513
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Adachi-Ku, Japan
    • Investigational Site Number 392002
  • Annaka-Shi, Japan
    • Investigational Site Number 392132
  • Arakawa-Ku, Japan
    • Investigational Site Number 392009
  • Asahikawa-Shi, Japan
    • Investigational Site Number 392152
  • Atsugi-Shi, Japan
    • Investigational Site Number 392025
  • Chiba-Shi, Japan
    • Investigational Site Number 392024
  • Chiba-Shi, Japan
    • Investigational Site Number 392151
  • Chigasaki-Shi, Japan
    • Investigational Site Number 392011
  • Chiyoda-Ku, Japan
    • Investigational Site Number 392013
  • Chiyoda-Ku, Japan
    • Investigational Site Number 392052
  • Chuo-Ku, Japan
    • Investigational Site Number 392003
  • Chuo-Ku, Japan
    • Investigational Site Number 392017
  • Chuo-Ku, Japan
    • Investigational Site Number 392055
  • Fujimi-Shi, Japan
    • Investigational Site Number 392008
  • Fujisawa-Shi, Japan
    • Investigational Site Number 392143
  • Fukuoka-Shi, Japan
    • Investigational Site Number 392094
  • Fukuoka-Shi, Japan
    • Investigational Site Number 392147
  • Gifu-Shi, Japan
    • Investigational Site Number 392100
  • Hachioji-Shi, Japan
    • Investigational Site Number 392059
  • Hamamatsu-Shi, Japan
    • Investigational Site Number 392048
  • Hamamatsu-Shi, Japan
    • Investigational Site Number 392102
  • Higashiosaka-Shi, Japan
    • Investigational Site Number 392123
  • Higashiosaka-Shi, Japan
    • Investigational Site Number 392135
  • Hiki-Gun, Japan
    • Investigational Site Number 392079
  • Himeji-Shi, Japan
    • Investigational Site Number 392141
  • Iruma-Shi, Japan
    • Investigational Site Number 392057
  • Ise-Shi, Japan
    • Investigational Site Number 392022
  • Izumisano-Shi, Japan
    • Investigational Site Number 392020
  • Kamakura-Shi, Japan
    • Investigational Site Number 392036
  • Kamogawa-Shi, Japan
    • Investigational Site Number 392136
  • Kashiwa-Shi, Japan
    • Investigational Site Number 392066
  • Kashiwara-Shi, Japan
    • Investigational Site Number 392045
  • Kasugai-Shi, Japan
    • Investigational Site Number 392006
  • Kasugai-Shi, Japan
    • Investigational Site Number 392149
  • Kawagoe-Shi, Japan
    • Investigational Site Number 392053
  • Kawagoe-Shi, Japan
    • Investigational Site Number 392065
  • Kawaguchi-Shi, Japan
    • Investigational Site Number 392007
  • Kawaguchi-Shi, Japan
    • Investigational Site Number 392062
  • Kawaguchi-Shi, Japan
    • Investigational Site Number 392090
  • Kawasaki-Shi, Japan
    • Investigational Site Number 392077
  • Kawasaki-Shi, Japan
    • Investigational Site Number 392082
  • Kawasaki-Shi, Japan
    • Investigational Site Number 392142
  • Kisarazu-Shi, Japan
    • Investigational Site Number 392010
  • Kisarazu-Shi, Japan
    • Investigational Site Number 392016
  • Kitakyushu-Shi, Japan
    • Investigational Site Number 392031
  • Kitakyushu-Shi, Japan
    • Investigational Site Number 392068
  • Kitakyusyu-Shi, Japan
    • Investigational Site Number 392041
  • Kobe-Shi, Japan
    • Investigational Site Number 392086
  • Koga-Shi, Japan
    • Investigational Site Number 392044
  • Koriyama-Shi, Japan
    • Investigational Site Number 392001
  • Kumamoto-Shi, Japan
    • Investigational Site Number 392028
  • Kumamoto-Shi, Japan
    • Investigational Site Number 392092
  • Kumamoto-Shi, Japan
    • Investigational Site Number 392108
  • Kumamoto-Shi, Japan
    • Investigational Site Number 392116
  • Kushiro-Shi, Japan
    • Investigational Site Number 392099
  • Kyoto-Shi, Japan
    • Investigational Site Number 392049
  • Kyoto-Shi, Japan
    • Investigational Site Number 392107
  • Maebashi-Shi, Japan
    • Investigational Site Number 392088
  • Maebashi-Shi, Japan
    • Investigational Site Number 392158
  • Matsuyama-Shi, Japan
    • Investigational Site Number 392121
  • Minato-Ku, Japan
    • Investigational Site Number 392122
  • Misato-Shi, Japan
    • Investigational Site Number 392076
  • Mitaka-Shi, Japan
    • Investigational Site Number 392014
  • Mito-Shi, Japan
    • Investigational Site Number 392042
  • Mito-Shi, Japan
    • Investigational Site Number 392043
  • Mito-Shi, Japan
    • Investigational Site Number 392078
  • Miyazaki-Shi, Japan
    • Investigational Site Number 392046
  • Nagoya-Shi, Japan
    • Investigational Site Number 392026
  • Nagoya-Shi, Japan
    • Investigational Site Number 392101
  • Nagoya-Shi, Japan
    • Investigational Site Number 392128
  • Nagoya-Shi, Japan
    • Investigational Site Number 392131
  • Nagoya-Shi, Japan
    • Investigational Site Number 392134
  • Nagoya-Shi, Japan
    • Investigational Site Number 392137
  • Nagoya-Shi, Japan
    • Investigational Site Number 392140
  • Naka-Shi, Japan
    • Investigational Site Number 392154
  • Niihama-Shi, Japan
    • Investigational Site Number 392050
  • Obihiro-Shi, Japan
    • Investigational Site Number 392159
  • Ogaki-Shi, Japan
    • Investigational Site Number 392145
  • Oita-Shi, Japan
    • Investigational Site Number 392153
  • Okawa-Shi, Japan
    • Investigational Site Number 392005
  • Okayama-Shi, Japan
    • Investigational Site Number 392071
  • Okayama-Shi, Japan
    • Investigational Site Number 392080
  • Onga-Gun, Japan
    • Investigational Site Number 392095
  • Osaka-Shi, Japan
    • Investigational Site Number 392105
  • Osaka-Shi, Japan
    • Investigational Site Number 392117
  • Osaka-Shi, Japan
    • Investigational Site Number 392144
  • Osaki-Shi, Japan
    • Investigational Site Number 392125
  • Ota-Ku, Japan
    • Investigational Site Number 392120
  • Ota-Shi, Japan
    • Investigational Site Number 392157
  • Oyama-Shi, Japan
    • Investigational Site Number 392040
  • Sagamihara-Shi, Japan
    • Investigational Site Number 392038
  • Saijo-Shi, Japan
    • Investigational Site Number 392069
  • Saitama-Shi, Japan
    • Investigational Site Number 392030
  • Saitama-Shi, Japan
    • Investigational Site Number 392058
  • Sanda-Shi, Japan
    • Investigational Site Number 392074
  • Sapporo-Shi, Japan
    • Investigational Site Number 392047
  • Sapporo-Shi, Japan
    • Investigational Site Number 392106
  • Sasebo-Shi, Japan
    • Investigational Site Number 392097
  • Satsumasendai-Shi, Japan
    • Investigational Site Number 392015
  • Sendai-Shi, Japan
    • Investigational Site Number 392004
  • Shimotsuke-Shi, Japan
    • Investigational Site Number 392034
  • Shinagawa-Ku, Japan
    • Investigational Site Number 392110
  • Shinjuku-Ku, Japan
    • Investigational Site Number 392021
  • Shinjuku-Ku, Japan
    • Investigational Site Number 392098
  • Shiogama-Shi, Japan
    • Investigational Site Number 392104
  • Shizuoka-Shi, Japan
    • Investigational Site Number 392037
  • Shizuoka-Shi, Japan
    • Investigational Site Number 392081
  • Shobara-Shi, Japan
    • Investigational Site Number 392019
  • Shunan-Shi, Japan
    • Investigational Site Number 392018
  • Suita-Shi, Japan
    • Investigational Site Number 392027
  • Taito-Ku, Japan
    • Investigational Site Number 392056
  • Takatsuki-Shi, Japan
    • Investigational Site Number 392051
  • Takatsuki-Shi, Japan
    • Investigational Site Number 392156
  • Tokorozawa-Shi, Japan
    • Investigational Site Number 392061
  • Tomakomai-Shi, Japan
    • Investigational Site Number 392111
  • Tsu-Shi, Japan
    • Investigational Site Number 392073
  • Ube-Shi, Japan
    • Investigational Site Number 392063
  • Ushiku-Shi, Japan
    • Investigational Site Number 392124
  • Yatsushiro-Shi, Japan
    • Investigational Site Number 392067
  • Yokohama-Shi, Japan
    • Investigational Site Number 392085
  • Yokohama-Shi, Japan
    • Investigational Site Number 392126
  • Zentsuji-Shi, Japan
    • Investigational Site Number 392035

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria :

• Patient with type 2 diabetes mellitus (T2DM) diagnosed for at least 1 year before the screening visit (V1).
• Patient treated with a stable, once a day basal insulin regimen (ie, type of insulin and time/frequency of the injection), for at least 3 months before the screening visit.
• The total daily basal insulin dose should be stable (± 20%) and <15 U/day for at least 1 month before the screening visit.
• Patient receiving 1 or 2 oral anti-diabetic drugs (OADs): the OAD dose(s) must be stable during the 3 months before the screening visit. The OADs can be 1 to 2 out of:
• Metformin;
• Sulfonylurea (SU);
• Glinide;
• Dipeptidyl-peptidase-4 (DPP-4) inhibitor;
• Sodium glucose co-transporter 2 (SGLT2) inhibitor;
• Alpha glucosidase inhibitor (alpha-GI).
• Signed written informed consent.

Exclusion criteria:

• Age <20 years at screening visit.
• HbA1c at screening visit <7.5% or >9.5%.
• Fasting plasma glucose (FPG) >180 mg/dL (10.0 mmol/L) at screening visit.
• Pregnancy or lactation, women of childbearing potential with no effective contraceptive method.
• Use of oral or injectable glucose-lowering agents other than those stated in the inclusion criteria in the 3 months before screening visit.
• Previous use of insulin regimen other than basal insulin, eg, prandial or pre-mixed insulin.

Note: Short-term treatment (≤10 days) due to intercurrent illness including gestational diabetes is allowed at the discretion of the Investigator.

• Use of thiazolidinedione (TZD) within 6 months prior to screening visit.
• History of discontinuation of a previous treatment with a glucagon-like peptide-1(GLP-1) receptor agonist due to safety/ tolerability issues or lack of efficacy.
• Laboratory findings at the screening visit; including:
• Amylase and/or lipase >3 times the upper limit of the normal (ULN) laboratory range;
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 ULN;
• Calcitonin ≥20 pg/mL (5.9 pmol/L);
• Positive serum pregnancy test.
• Any contraindication to metformin use according to local labeling.
• History of hypersensitivity to any GLP-1 receptor agonist or to metacresol.
• Contraindication to use of insulin glargine or lixisenatide according to local labeling. History of hypersensitivity to insulin glargine or to any of the excipients.
• Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (eg, multiple endocrine neoplasia syndromes).
• History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy has now been performed), pancreatitis during previous treatment with incretin therapies, chronic pancreatitis, pancreatectomy, stomach/gastric surgery.
• Exclusion criteria for randomization at the end of the run-in phase:
• HbA1c <7.5% or >9.5% at visit 6 (Week -1).
• Mean fasting self monitored plasma glucose (SMPG) >160 mg/dL (8.9 mmol/L), calculated from all available (minimum of 4 self-measurements) values during the 7 days prior to randomization.

Note:fasting SMPG on the day of randomization can be included if assessed before randomization.

• Average insulin glargine daily dose ≥15 U/day or <5U/day calculated for the last 3 days before Visit 7.
• Metformin total daily dose <750 mg/day.
• Amylase and/or lipase >3 ULN at Visit 6 (Week -1).

The above information is not intended to contain all considerations relevant to a patient'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: LixiLan; LixiLan (insulin glargine/lixisenatide fixed ratio combination) is injected subcutaneously (under the skin) once daily. Dose is individually adjusted. Metformin will be continued.	Drug: Metformin; Pharmaceutical form: tablet Route of administration: oral; Drug: Insulin glargine/Lixisenatide (HOE901/AVE0010); Pharmaceutical form: solution Route of administration: subcutaneous; Other Names: LixiLan
Active Comparator: insulin glargine; Insulin glargine U100 (Lantus) will be injected subcutaneously (under skin) once daily. Dose will be individually adjusted. Metformin will be continued.	Drug: Metformin; Pharmaceutical form: tablet Route of administration: oral; Drug: Insulin glargine U100 (HOE901); Pharmaceutical form: solution Route of administration: subcutaneous; Other Names: Lantus

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change from baseline in HbA1c	Baseline, 26 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of patients reaching HbA1c <7% or ≤6.5%	26 weeks
Change from baseline in 2-hour postprandial plasma glucose (PPG) during standardized meal test	Baseline, 26 weeks
Change from baseline in blood glucose excursion during standardized meal test	Baseline, 26 weeks
Change from baseline in 7-point self-monitoring plasma glucose (SMPG) profiles (each time point and average daily value)	Baseline, 26 weeks
Change from baseline in body weight	Baseline, 26 weeks
Change from baseline in FPG	Baseline, 26 weeks
Change from baseline in daily dose of insulin glargine	Baseline, 26 weeks
Percentage of patients reaching HbA1c <7% with no body weight gain	26 weeks
Percentage of patients reaching HbA1c <7% with no body weight gain and with no documented (PG ≤70 mg/dL [3.9 mmol/L]) symptomatic hypoglycemia	26 weeks
Percentage of patients reaching HbA1c <7% with no documented (PG ≤70 mg/dL [3.9 mmol/L]) symptomatic hypoglycemia	26 weeks
Percentage of patients requiring a rescue therapy	26 weeks
Number of hypoglycemic events	26 weeks
Number of adverse events	26 weeks
Measurement of anti-lixisenatide antibodies from baseline	Baseline, 26 weeks
Measurement of anti-insulin antibodies from baseline	Baseline, 26 weeks

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Kaneto H, Takami A, Spranger R, Amano A, Watanabe D, Niemoeller E. Efficacy and safety of insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi) in Japanese patients with type 2 diabetes mellitus inadequately controlled on basal insulin and oral antidiabetic drugs: The LixiLan JP-L randomized clinical trial. Diabetes Obes Metab. 2020 Sep;22 Suppl 4:3-13. doi: 10.1111/dom.14005.

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2016
• Primary Completion (Actual): October 4, 2018
• Study Completion (Actual): October 4, 2018

Study Registration Dates

• First Submitted: April 20, 2016
• First Submitted That Met QC Criteria: April 22, 2016
• First Posted (Estimate): April 27, 2016

Study Record Updates

• Last Update Posted (Actual): June 16, 2020
• Last Update Submitted That Met QC Criteria: June 11, 2020
• Last Verified: October 1, 2018

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: EFC14113; U1111-1176-8378 (Other Identifier: UTN)