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Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) Versus GLP-1 Receptor Agonist in Patients With Type 2 Diabetes, With a FRC Extension Period (LixiLan-G)

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ClinicalTrials.gov Identifier: NCT02787551
Recruitment Status : Completed
First Posted : June 1, 2016
Results First Posted : June 12, 2019
Last Update Posted : November 27, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE May 26, 2016
First Posted Date  ICMJE June 1, 2016
Results First Submitted Date  ICMJE May 23, 2019
Results First Posted Date  ICMJE June 12, 2019
Last Update Posted Date November 27, 2019
Actual Study Start Date  ICMJE July 6, 2016
Actual Primary Completion Date May 25, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 15, 2019)
  • Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period [ Time Frame: Baseline, Week 26 ]
    Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Adjusted least squares (LS) mean and standard error (SE) were obtained from Mixed-effect model with repeated measures (MMRM) to account for missing data using all available post baseline data during the 26 week treatment period.
  • Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period [ Time Frame: Baseline, Week 52 ]
    Change in HbA1c was calculated by subtracting baseline value from Week 52 value.
Original Primary Outcome Measures  ICMJE
 (submitted: May 26, 2016)
Change from baseline in HbA1c [ Time Frame: Baseline to 26 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 15, 2019)
  • Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period [ Time Frame: Week 26 ]
    Participants without any available HbA1c assessment at Week 26 were considered as non-responders.
  • Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period [ Time Frame: Week 52 ]
    Participants without any available HbA1c assessment at Week 52 were considered as non-responders.
  • Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period [ Time Frame: Baseline, Week 26 ]
    Change in FPG was calculated by subtracting baseline value from Week 26 value. Adjusted LS means and SE were obtained from MMRM to account for missing data using all available post baseline data during the 26 week treatment period.
  • Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period [ Time Frame: Baseline, Week 52 ]
    Change in FPG was calculated by subtracting baseline value from Week 52 value.
  • Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period [ Time Frame: Baseline, Week 26 ]
    The 7-point SMPG profile was measured at the following 7 points: pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours postprandial (breakfast, lunch and dinner) was defined as 2 hours after the start of the meal. Adjusted LS means and SE were obtained from MMRM to account for missing data using all available post baseline data during the 26 week treatment period.
  • Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period [ Time Frame: Baseline, Week 52 ]
    The 7-point SMPG profile was measured at the following 7 points: pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours postprandial (breakfast, lunch and dinner) was defined as 2 hours after the start of the meal.
  • Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period [ Time Frame: Baseline, Week 26 ]
    The 2-hour PPG test measured blood glucose 2 hours after eating a liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 26 value. Missing data was imputed using last observation carried forward (LOCF).
  • Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period [ Time Frame: Baseline, Week 52 ]
    The 2-hour PPG test measured blood glucose 2 hours after eating a liquid standardized breakfast meal. Change in PPG was calculated by subtracting baseline value from Week 52 value. Missing data was imputed using LOCF.
  • Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period [ Time Frame: Baseline, Week 26 ]
    2-hour plasma glucose excursion = 2-hour PPG value minus plasma glucose value obtained 30 minutes prior to the start of meal and before investigational medicinal product (IMP) administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 26 value. Missing data was imputed using LOCF.
  • Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period [ Time Frame: Baseline, Week 52 ]
    2-hour plasma glucose excursion = 2-hour PPG value minus plasma glucose value obtained 30 minutes prior to the start of meal and before IMP administration if IMP was injected before breakfast. Change in plasma glucose excursions were calculated by subtracting baseline value from Week 52 value. Missing data was imputed using LOCF.
  • Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period [ Time Frame: From Baseline to Week 26 ]
    Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c >8%.
  • Percentage of Participants Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period [ Time Frame: From Week 26 to Week 52 ]
    Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c >8%.
  • Change From Baseline in Body Weight at Week 26: Core Period [ Time Frame: Baseline, Week 26 ]
    Change in body weight was calculated by subtracting baseline value from Week 26 value.
  • Change From Baseline in Body Weight to Week 52: Single Arm Extension Period [ Time Frame: Baseline, Week 52 ]
    Change in body weight was calculated by subtracting baseline value from Week 52 value.
  • Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period [ Time Frame: From Baseline to Week 26 ]
    Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=3.9 mmol/L (70 mg/dL). Hypoglycemic episodes with plasma glucose of <3.0 mmol/L (54 mg/dL) were also analyzed.
  • Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period [ Time Frame: From Baseline to Week 52 ]
    Documented symptomatic hypoglycemia was an event during which symptoms of hypoglycemia were accompanied by a measured plasma glucose concentration of <=3.9 mmol/L (70 mg/dL). Hypoglycemic episodes with plasma glucose of <3.0 mmol/L (54 mg/dL) were also analyzed.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 26, 2016)
  • Percentage of participants reaching HbA1c targets [ Time Frame: 26 weeks ]
  • Change from baseline in FPG [ Time Frame: Baseline to 26 weeks ]
  • Change from baseline in 7-point self-monitored plasma glucose (SMPG) profiles [ Time Frame: Baseline to 26 weeks ]
  • Change from baseline in 2-hour postprandial glucose (PPG) during standardized meal test [ Time Frame: Baseline to 26 weeks ]
  • Change from baseline in blood glucose excursion during standardized meal test [ Time Frame: Baseline to 26 weeks ]
  • Change from baseline in body weight [ Time Frame: Baseline to 26 weeks ]
  • Percentage of participants with symptomatic hypoglycemia [ Time Frame: 26 weeks ]
  • Number of adverse events [ Time Frame: 26 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) Versus GLP-1 Receptor Agonist in Patients With Type 2 Diabetes, With a FRC Extension Period
Official Title  ICMJE A 26-Week Randomized, Open-label, Active Controlled, Parallel-group, Study Assessing the Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination in Adults With Type 2 Diabetes Inadequately Controlled on GLP-1 Receptor Agonist and Metformin (Alone or With Pioglitazone and/or SGLT2 Inhibitors), Followed by a Fixed Ratio Combination Single-arm 26-Week Extension Period
Brief Summary

Primary Objective:

To demonstrate the superiority of the insulin glargine/lixisenatide fixed ratio combination (FRC) versus GLP-1 receptor agonist (GLP-1 RA) in hemoglobin A1c (HbA1c) change.

Secondary Objectives:

To compare the overall efficacy and safety of the insulin glargine/lixisenatide FRC to GLP-1 RA on top of metformin (with or without pioglitazone, with or without sodium-glucose co-transporter 2 [SGLT2] inhibitor) in participants with type 2 diabetes.

To evaluate safety, efficacy and other endpoints of FRC up to the end of the extension period.

Detailed Description

The maximum duration for GLP1-RA participants was approximately 29 weeks: up to 2 week screening period, a 26 week treatment period (either randomized or uncontrolled), and a 3 or 9 day post-treatment safety follow-up period.

Maximum duration for FRC participants was approximately 55 weeks: up to 2-week screening period, a 26-week randomized treatment period, a 26-week extension period and a 3-day post-treatment safety follow-up period.

All primary and secondary efficacy, safety and other outcome measures were assessed at the end of the extension period.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Type 2 Diabetes Mellitus
Intervention  ICMJE
  • Drug: Insulin glargine/lixisenatide fixed ratio combination

    Pharmaceutical form: solution for injection

    Route of administration: subcutaneous

    Other Names:
    • HOE901/AVE0010
    • Soliqua
  • Drug: liraglutide

    Pharmaceutical form: solution for injection

    Route of administration: subcutaneous

    Other Name: Victoza
  • Drug: exenatide

    Pharmaceutical form: solution for injection

    Route of administration: subcutaneous

    Other Name: Byetta
  • Drug: exenatide extended-release

    Pharmaceutical form: solution for injection

    Route of administration: subcutaneous

    Other Name: Bydureon
  • Drug: albiglutide

    Pharmaceutical form: solution for injection

    Route of administration: subcutaneous

    Other Name: Tanzeum
  • Drug: dulaglutide

    Pharmaceutical form: solution for injection

    Route of administration: subcutaneous

    Other Name: Trulicity
  • Drug: Background therapy: Oral Anti-diabetic Drug (Metformin, Pioglitazone, SGLT2 inhibitor)
    Pharmaceutical form: tablet Route of administration: oral If previously taken, doses to remain stable through the study.
Study Arms  ICMJE
  • Experimental: Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC)

    Core period: FRC injected subcutaneously once daily (QD) for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted.

    Single arm extension period: Participants who completed core treatment period and met eligibility criteria entered in extension treatment period and received same treatment (FRC injected subcutaneously QD on top of OAD therapy) for 26 weeks (up to Week 52). Dose individually adjusted.

    Interventions:
    • Drug: Insulin glargine/lixisenatide fixed ratio combination
    • Drug: Background therapy: Oral Anti-diabetic Drug (Metformin, Pioglitazone, SGLT2 inhibitor)
  • Active Comparator: GLP-1 Receptor Agonist
    Core period: GLP-1 RA receptor agonist (liraglutide QD, exenatide twice daily [BID], exenatide extended-release QW, albiglutide QW, or dulaglutide QW) injected subcutaneously for 26 weeks on top of OAD therapy. GLP-1 RAs were administered as per local labeling at the same dose schedule as prior to randomization.
    Interventions:
    • Drug: liraglutide
    • Drug: exenatide
    • Drug: exenatide extended-release
    • Drug: albiglutide
    • Drug: dulaglutide
    • Drug: Background therapy: Oral Anti-diabetic Drug (Metformin, Pioglitazone, SGLT2 inhibitor)
Publications * Blonde L, Rosenstock J, Del Prato S, Henry R, Shehadeh N, Frias J, Niemoeller E, Souhami E, Ji C, Aroda VR. Switching to iGlarLixi Versus Continuing Daily or Weekly GLP-1 RA in Type 2 Diabetes Inadequately Controlled by GLP-1 RA and Oral Antihyperglycemic Therapy: The LixiLan-G Randomized Clinical Trial. Diabetes Care. 2019 Nov;42(11):2108-2116. doi: 10.2337/dc19-1357. Epub 2019 Sep 17.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 23, 2019)
514
Original Estimated Enrollment  ICMJE
 (submitted: May 26, 2016)
500
Actual Study Completion Date  ICMJE November 17, 2018
Actual Primary Completion Date May 25, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria :

  • Participants with type 2 diabetes mellitus diagnosed at least 1 year prior to screening visit.
  • Participants who were treated with one of the following GLP-1 receptor agonists for at least 4 months prior to screening visit 1 (V1), and with stable dose for at least 3 months prior to screening visit (V1):
  • Liraglutide (Victoza®) 1.8 milligram (mg) QD or 1.2 mg QD, if the 1.8 mg QD dose was not well tolerated according to the Investigator's judgment or
  • Exenatide (Byetta®) 10 microgram (µg) BID or of 5 µg BID, if 10 µg BID dose was not well tolerated according to the Investigator's judgment

in combination with metformin (daily dose greater than equal to [>=] 1500 mg/day or maximum tolerated dose [MTD]), with or without pioglitazone, with or without SGLT2 inhibitor, all at stable dose for at least 3 months prior to screening.

or

Participants who were treated with stable dose of one of the following GLP-1 receptor agonists for at least 6 months prior to screening visit (V1):

  • Exenatide extended-release (Bydureon®) 2 mg once weekly (QW), if well tolerated according to Investigator's judgment,
  • Albiglutide (Tanzeum®) 50 mg QW or 30 mg QW, if 50 mg QW was not well tolerated according to Investigator's judgment,
  • Dulaglutide (Trulicity®) 1.5 mg QW or 0.75 mg QW, if 1.5 mg QW was not well tolerated according to Investigator's judgment

in combination with metformin (daily dose ≥1500 mg/day or MTD), with or without pioglitazone, with or without SGLT2 inhibitor, all at stable dose for at least 3 months prior to screening;

-Signed written informed consent.

Exclusion criteria:

  • At screening visit, age <18.
  • Screening HbA1c <7% and >9%.
  • Pregnancy or lactation, women of childbearing potential with no effective contraceptive method.
  • Any use of antidiabetic drugs within 3 months prior to the screening visit other than those described in the inclusion criteria.
  • Previous treatment with insulin in the year prior to screening visit (note: short-term treatment with insulin [<=10 days] due to intercurrent illness including gestational diabetes was allowed at the discretion of the study physician).
  • Laboratory findings at the time of screening, including:
  • Fasting plasma glucose (FPG) >250 mg/dL (13.9 millimoles per litre [mmol/L]),
  • Amylase and/or lipase >3 times the upper limit of the normal laboratory range (ULN),
  • Alanine transaminase or aspartate transaminase >3 ULN,
  • Calcitonin >=20 pg/mL (5.9 pmol/L),
  • Positive pregnancy test.
  • Participant who had renal function impairment with estimated glomerular filtration rate <30mL/min/1.73m^2 (using the Modification of Diet in Renal Disease formula) or end-stage renal disease.
  • Contraindication to use of insulin glargine, or lixisenatide or GLP-1 receptor agonist (Victoza®, Byetta®, Bydureon®, Tanzeum® or Trulicity®) according to local labeling.
  • Any contraindication to metformin or pioglitazone or SGLT2 inhibitor use, according to local labeling.
  • History of hypersensitivity to insulin glargine, or to any of the excipients.
  • History of allergic reaction to any GLP-1 receptor agonist or to meta-cresol.
  • Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (eg, multiple endocrine neoplasia type 2 syndromes).
  • 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.
  • Body mass index <=20 or >40 kg/m^2.

Exclusion criteria for the extension period:

  • Participants in the FRC arm with a rescue therapy and HbA1c >8% at week 22.
  • Participants in the FRC arm who discontinued prematurely from FRC treatment before week 26.
  • Participants in the GLP-1 RA treatment arm after randomization.

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Estonia,   Germany,   Israel,   Italy,   Romania,   Slovakia,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02787551
Other Study ID Numbers  ICMJE EFC13794
2014-004850-32
U1111-1168-4639 ( Other Identifier: UTN )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Individual participant data (IPD) and supporting clinical documents are available for request at clinicalstudydatarequest.com. While making information available we continue to protect the privacy of the participants in our clinical trials and to remove commercially confidential information (CCI). Details on Data Sharing criteria and process for requesting access can be found at this web address: clinicalstudydatarequest.com
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP