Current partner codePEPTIDESDE
NCT02058160·Phase 3·INTERVENTIONAL

Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination Versus Insulin Glargine in Patients With Type 2 Diabetes

Status

Completed

Phase

Phase 3

Enrollment

736

Locations

236

Results

Posted

Publications

10

Study summary

What the protocol is testing.

Primary Objective: To demonstrate the superiority of the insulin glargine/lixisenatide fixed ratio combination (FRC) to insulin glargine in glycated hemoglobin (HbA1c) change from baseline to Week 30. Secondary Objective: To compare the overall efficacy and safety of insulin glargine/lixisenatide FRC to insulin glargine (with or without metformin) over a 30 week treatment period in participants with type 2 diabetes.

Full detailed description

Maximum duration of approximately 39 weeks: an up to 8-week screening period, a 30-week randomized treatment period and 3 days post-treatment safety follow up period.

Interventions

Treatment arms and agents.

DRUG

Insulin glargine/lixisenatide (HOE901/AVE0010)

Insulin glargine/lixisenatide FRC was self-administered by subcutaneous (SC) injection within 1 hour before breakfast using one of 2 SoloStar® pen-injectors: Pen A (ratio of 2 Units (U) of insulin glargine U 100:1 mcg of lixisenatide) or Pen B (ratio of 3 U of insulin glargine U 100:1 mcg of lixisenatide). After run-in, the FRC was initiated at a dose of either 20 U/10 mcg with Pen A or 30 U/10 mcg with Pen B, depending on participant's dose of Insulin glargine on the day prior to randomization. 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). Pen A was used for administration of doses up to 40 U/20 mcg and Pen B for administration of doses from 30 U/10 mcg up to 60 U/20 mcg.

DRUG

Insulin glargine (HOE901)

Insulin glargine was self-administered QD by SC injection at approximately the same time every day. After screening, eligible participants entered 6 week run-in phase during which they were switched (if necessary) to insulin glargine and dose was stabilized. The first dose after randomization was same as the one administered on the day prior to randomization 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).

DRUG

Metformin (Background Drug)

Pharmaceutical form: Tablet; Route of administration: Oral administration

Timeline

From registration to results.

  1. First posted

    Feb 7, 2014

  2. Study start

    Jan 2014

  3. Primary completion

    Jul 2015

  4. Study completion

    Jul 2015

  5. Results posted

    Feb 10, 2017

  6. Registry updated

    May 9, 2017

Outcomes

What the study measures.

Primary outcomes

Change in Glycated Hemoglobin (HbA1c) From Baseline to Week 30

Time frame · Baseline, Week 30

Change in HbA1c was calculated by subtracting baseline value from Week 30 value.

Secondary outcomes

Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30

Time frame · Week 30

Change in 2-hour Plasma Blood Glucose Excursion From Baseline to Week 30

Time frame · Baseline, Week 30

Plasma glucose excursion = 2-hour postprandial glucose (PPG) minus plasma glucose value obtained 30 minutes prior to the start of the meal and before investigational medicinal product (IMP) administration, if IMP was injected before breakfast. Change in plasma glucose excursions was calculated by subtracting baseline value from Week 30 value.

Change in Body Weight From Baseline to Week 30

Time frame · Baseline, Week 30

Change in body weight was calculated by subtracting baseline value from Week 30 value.

Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30

Time frame · Baseline, Week 30

Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, two times in a week before baseline, before visit Week 12 and before visit Week 30 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 30 value. The analysis included all scheduled measurements obtained during the study. The missing data was handled by mixed effect model with repeated measures (MMRM) approach.

Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30

Time frame · Week 30

Change in Daily Insulin Glargine Dose From Baseline to Week 30

Time frame · Baseline, Week 30

Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 and No Documented Symptomatic Hypoglycemia (Plasma Glucose [PG] ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period

Time frame · Baseline up to Week 30

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).

Change in FPG From Baseline to Week 30

Time frame · Baseline, Week 30

Change in FPG was calculated by subtracting baseline value from Week 30 value.

Change in 2-hour PPG From Baseline to Week 30

Time frame · Baseline, Week 30

Change in PPG was calculated by subtracting baseline value from Week 30 value.

Percentage of Participants Reaching HbA1c <7.0% With No Documented Symptomatic Hypoglycemia (PG ≤ 70 mg/dL [3.9 mmol/L]) During 30-Week Treatment Period

Time frame · Baseline up to Week 30

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).

Eligibility

Who can take part.

Minimum age
18 Years
Maximum age
Not reported
Sex
ALL
Healthy volunteers
No

Inclusion criteria : * Type 2 diabetes mellitus diagnosed at least 1 year before the screening visit. * Treatment with basal insulin for at least 6 months before the screening visit. * Stable basal insulin regimen (i.e. type of insulin and time/frequency of the injection) for at least 3 months before the screening visit. * Stable (plus/minus 20 percent) total daily basal insulin dose between 15 and 40 Units/day for at least 2 months prior to the screening visit. * For participants receiving basal insulin and 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 could be 1 to 2 out of: * metformin (more than or equal to 1500 mg/day or maximal tolerated dose), * a sulfonylurea, * a glinide, * a dipeptidyl-peptidase-4 inhibitor, * a sodium glucose co-transporter 2 inhibitor, * Fasting Plasma Glucose (FPG) less than or equal to 180 mg/dL(10.0 mmol/L) at screening visit for participants receiving basal insulin in combination with 2 OADs or with 1 OAD other than metformin; FPG less than or equal to 200 mg/dL (11.1 mmol/L) at screening visit for participants on basal insulin only or basal insulin plus metformin at screening visit. * Signed written informed consent. Exclusion criteria: * Age under legal age of adulthood at screening visit. * HbA1c at screening visit less than 7.5% or above 10%. * Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. * Use of other oral or injectable glucose-lowering agents than stated in the inclusion criteria in a period of 3 months prior to screening. * Previous use of insulin other than basal insulin eg, prandial or pre-mixed insulin, in the year prior to screening. Note: Short term treatment (≤10 days) due to intercurrent illness is allowed. * History discontinuation of a previous treatment with Glucagon Like Peptide -1 Receptor Agonists for safety/tolerability or lack of efficacy. * Participant who had previously participated in any clinical trial with lixisenatide or the insulin glargine/lixisenatide FRC or had previously received lixisenatide. * Use of weight loss drugs within 3 months prior to screening visit. * Within the last 6 months prior to screening visit: history of stroke, myocardial infarction, unstable angina, or heart failure requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures to be performed during the study period. * History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy was already performed), chronic pancreatitis, pancreatitis during a previous treatment with incretin therapies, pancreatectomy, stomach/gastric surgery. * Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (eg, multiple endocrine neoplasia syndromes). * Uncontrolled or inadequately controlled hypertension (systolic blood pressure above 180 mmHg or diastolic blood pressure above 95 mmHg) at screening visit. * At screening visit, Body Mass Index (BMI) less than or equal to 20 or above 40 kg/m\^2. * At screening visit amylase and/or lipase more than 3 times the upper limit of the normal (ULN) laboratory range. * At screening visit alanine aminotransferase (ALT) or alkaline phosphatase (AST) more than 3 ULN. * At screening visit calcitonin above or equal to 20 pg/mL (5.9 pmol/L). * Any contraindication to metformin use, according to local labeling, if the participant was taking metformin. * Participant who had a renal function impairment with creatinine clearance less than 30 mL/min (using the Cockcroft and Gault formula) or end-stage renal disease for participants, not treated with metformin. Exclusion criteria for randomization: * HbA1c less than 7% or above 10% . * Mean fasting SMPG calculated from the self-measurements for 7 days the week before randomization visit was above 140 mg/dL (7.8 mmol/L). * Average insulin glargine daily dose less than 20 Units or above 50 Units (in the week before randomization visit). * Amylase and/or lipase more than 3 ULN . The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study locations

236 registered sites.

Australia · Canada · Chile · Czechia · Denmark · Estonia · Hungary · Lithuania · Mexico · Netherlands · Poland · Romania · Russia · Slovakia · Spain · Sweden · Ukraine · United States. Showing up to 24 locations stored in the fast local snapshot.

Investigational Site Number 840607

Birmingham, Alabama, United States

Investigational Site Number 840570

Sun City, Arizona, United States

Investigational Site Number 840562

Tempe, Arizona, United States

Investigational Site Number 840577

Tucson, Arizona, United States

Investigational Site Number 840517

Little Rock, Arkansas, United States

Investigational Site Number 840537

Little Rock, Arkansas, United States

Investigational Site Number 840568

Bell Gardens, California, United States

Investigational Site Number 840550

Chino, California, United States

Investigational Site Number 840529

Chula Vista, California, United States

Investigational Site Number 840623

Corona, California, United States

Investigational Site Number 840566

Fresno, California, United States

Investigational Site Number 840552

Greenbrae, California, United States

Investigational Site Number 840578

Lancaster, California, United States

Investigational Site Number 840626

Los Angeles, California, United States

Investigational Site Number 840581

Los Angeles, California, United States

Investigational Site Number 840621

Mission Viejo, California, United States

Investigational Site Number 840511

Northridge, California, United States

Investigational Site Number 840573

Palm Springs, California, United States

Investigational Site Number 840559

Port Hueneme, California, United States

Investigational Site Number 840536

San Ramon, California, United States

Investigational Site Number 840567

Santa Ana, California, United States

Investigational Site Number 840569

Tarzana, California, United States

Investigational Site Number 840572

West Hills, California, United States

Investigational Site Number 840582

Aurora, Colorado, United States

Publications

Results and literature.

PMID 27650977Aroda VR, Rosenstock J, Wysham C, Unger J, Bellido D, Gonzalez-Galvez G, Takami A, Guo H, Niemoeller E, Souhami E, Bergenstal RM; LixiLan-L Trial Investigators. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial. Diabetes Care. 2016 Nov;39(11):1972-1980. doi: 10.2337/dc16-1495. Epub 2016 Sep 20.PMID 31848983Tabak 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.PMID 31359368Blonde L, Bailey TS, Chao J, Dex TA, Frias JP, Meneghini LF, Roberts M, Aroda VR. Clinical Characteristics and Glycemic Outcomes of Patients with Type 2 Diabetes Requiring Maximum Dose Insulin Glargine/Lixisenatide Fixed-Ratio Combination or Insulin Glargine in the LixiLan-L Trial. Adv Ther. 2019 Sep;36(9):2310-2326. doi: 10.1007/s12325-019-01033-1. Epub 2019 Jul 29.PMID 31114694Dailey G, Bajaj HS, Dex T, Groleau M, Stager W, Vinik A. Post hoc efficacy and safety analysis of insulin glargine/lixisenatide fixed- ratio combination in North American patients compared with the rest of world. BMJ Open Diabetes Res Care. 2019 Mar 21;7(1):e000581. doi: 10.1136/bmjdrc-2018-000581. eCollection 2019.PMID 30550345Schmider W, Belder R, Lee M, Niemoeller E, Souhami E, Frias JP. Impact of dose capping in insulin glargine/lixisenatide fixed-ratio combination trials in patients with type 2 diabetes. Curr Med Res Opin. 2019 Jun;35(6):1081-1089. doi: 10.1080/03007995.2018.1558852. Epub 2019 Jan 11.PMID 30218434Zisman A, Dex T, Roberts M, Saremi A, Chao J, Aroda VR. Bedtime-to-Morning Glucose Difference and iGlarLixi in Type 2 Diabetes: Post Hoc Analysis of LixiLan-L. Diabetes Ther. 2018 Oct;9(5):2155-2162. doi: 10.1007/s13300-018-0507-0. Epub 2018 Sep 14.PMID 29974618Rosenstock 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.PMID 29923298Trujillo JM, Roberts M, Dex T, Chao J, White J, LaSalle J. Low incidence of gastrointestinal adverse events over time with a fixed-ratio combination of insulin glargine and lixisenatide versus lixisenatide alone. Diabetes Obes Metab. 2018 Nov;20(11):2690-2694. doi: 10.1111/dom.13444. Epub 2018 Aug 21.PMID 29143919Niemoeller E, Souhami E, Wu Y, Jensen KH. iGlarLixi Reduces Glycated Hemoglobin to a Greater Extent Than Basal Insulin Regardless of Levels at Screening: Post Hoc Analysis of LixiLan-L. Diabetes Ther. 2018 Feb;9(1):373-382. doi: 10.1007/s13300-017-0336-6. Epub 2017 Nov 16.PMID 28386990Wysham C, Bonadonna RC, Aroda VR, Puig Domingo M, Kapitza C, Stager W, Yu C, Niemoeller E, Souhami E, Bergenstal RM; LixiLan-L trial investigators. Consistent findings in glycaemic control, body weight and hypoglycaemia with iGlarLixi (insulin glargine/lixisenatide titratable fixed-ratio combination) vs insulin glargine across baseline HbA1c, BMI and diabetes duration categories in the LixiLan-L trial. Diabetes Obes Metab. 2017 Oct;19(10):1408-1415. doi: 10.1111/dom.12961. Epub 2017 Jun 8.

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More studies on Lixisenatide.

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