LixiLan-G: 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
Sponsor
Sanofi (Industry)
Overall Status
Completed
CT.gov ID
NCT02787551
Collaborator
(none)
514
124
2
28.4
4.1
0.1
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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 Design
Study Type:
Interventional
Actual Enrollment
:
514 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date
:
Jul 6, 2016
Actual Primary Completion Date
:
May 25, 2018
Actual Study Completion Date
:
Nov 17, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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. |
Drug: Insulin glargine/lixisenatide fixed ratio combination
Pharmaceutical form: solution for injection
Route of administration: subcutaneous
Other Names:
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.
|
| 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. |
Drug: liraglutide
Pharmaceutical form: solution for injection
Route of administration: subcutaneous
Other Names:
Drug: exenatide
Pharmaceutical form: solution for injection
Route of administration: subcutaneous
Other Names:
Drug: exenatide extended-release
Pharmaceutical form: solution for injection
Route of administration: subcutaneous
Other Names:
Drug: albiglutide
Pharmaceutical form: solution for injection
Route of administration: subcutaneous
Other Names:
Drug: dulaglutide
Pharmaceutical form: solution for injection
Route of administration: subcutaneous
Other Names:
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.
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period [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 [Baseline, Week 52]
Change in HbA1c was calculated by subtracting baseline value from Week 52 value.
Secondary Outcome Measures
- Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Investigational Site Number 8400064 | Birmingham | Alabama | United States | 35205 |
| 2 | Investigational Site Number 8400073 | Fountain Hills | Arizona | United States | 85268 |
| 3 | Investigational Site Number 8400047 | Phoenix | Arizona | United States | 85028 |
| 4 | Investigational Site Number 8400103 | Bakersfield | California | United States | 93309 |
| 5 | Investigational Site Number 8400137 | Fresno | California | United States | 93720 |
| 6 | Investigational Site Number 8400043 | Huntington Park | California | United States | 90255 |
| 7 | Investigational Site Number 8400124 | Lamont | California | United States | 93241 |
| 8 | Investigational Site Number 8400027 | Lancaster | California | United States | 93534 |
| 9 | Investigational Site Number 8400098 | Los Angeles | California | United States | 90017 |
| 10 | Investigational Site Number 8400013 | Los Angeles | California | United States | 90057 |
| 11 | Investigational Site Number 8400042 | Mission Hills | California | United States | 91345 |
| 12 | Investigational Site Number 8400006 | Northridge | California | United States | 91325 |
| 13 | Investigational Site Number 8400021 | Orange | California | United States | 92868 |
| 14 | Investigational Site Number 8400126 | Rialto | California | United States | 92377 |
| 15 | Investigational Site Number 8400094 | Santa Ana | California | United States | 92704 |
| 16 | Investigational Site Number 8400009 | Ventura | California | United States | 93003 |
| 17 | Investigational Site Number 8400071 | Denver | Colorado | United States | 80209 |
| 18 | Investigational Site Number 8400036 | Denver | Colorado | United States | 80246 |
| 19 | Investigational Site Number 8400114 | Jacksonville | Florida | United States | 32216 |
| 20 | Investigational Site Number 8400133 | Miami | Florida | United States | 33165 |
| 21 | Investigational Site Number 8400058 | Port Charlotte | Florida | United States | 33952 |
| 22 | Investigational Site Number 8400084 | Tampa | Florida | United States | 33612 |
| 23 | Investigational Site Number 8400112 | West Palm Beach | Florida | United States | 33401 |
| 24 | Investigational Site Number 8400045 | Lawrenceville | Georgia | United States | 30046 |
| 25 | Investigational Site Number 8400096 | Snellville | Georgia | United States | 30078 |
| 26 | Investigational Site Number 8400023 | Springfield | Illinois | United States | 62711 |
| 27 | Investigational Site Number 8400049 | Avon | Indiana | United States | 46123 |
| 28 | Investigational Site Number 8400053 | Avon | Indiana | United States | 46123 |
| 29 | Investigational Site Number 8400085 | Avon | Indiana | United States | 46123 |
| 30 | Investigational Site Number 8400120 | Avon | Indiana | United States | 46123 |
| 31 | Investigational Site Number 8400041 | Evansville | Indiana | United States | 47714 |
| 32 | Investigational Site Number 8400038 | Indianapolis | Indiana | United States | 46254-5469 |
| 33 | Investigational Site Number 8400130 | Council Bluffs | Iowa | United States | 51501 |
| 34 | Investigational Site Number 8400034 | Lexington | Kentucky | United States | 40503 |
| 35 | Investigational Site Number 8400091 | Lexington | Kentucky | United States | 40503 |
| 36 | Investigational Site Number 8400078 | Marrero | Louisiana | United States | 70072 |
| 37 | Investigational Site Number 8400032 | Metairie | Louisiana | United States | 70006 |
| 38 | Investigational Site Number 8400088 | New Orleans | Louisiana | United States | 70121 |
| 39 | Investigational Site Number 8400033 | Baltimore | Maryland | United States | 21237 |
| 40 | Investigational Site Number 8400051 | Jefferson City | Missouri | United States | 65109 |
| 41 | Investigational Site Number 8400083 | Papillion | Nebraska | United States | 68046-3136 |
| 42 | Investigational Site Number 8400044 | Henderson | Nevada | United States | 89052 |
| 43 | Investigational Site Number 8400079 | Albany | New York | United States | 12206 |
| 44 | Investigational Site Number 8400061 | New York | New York | United States | 10001 |
| 45 | Investigational Site Number 8400123 | North Massapequa | New York | United States | 11758 |
| 46 | Investigational Site Number 8400095 | Staten Island | New York | United States | 10301 |
| 47 | Investigational Site Number 8400067 | West Seneca | New York | United States | 14224 |
| 48 | Investigational Site Number 8400111 | Yonkers | New York | United States | 10704 |
| 49 | Investigational Site Number 8400020 | Morehead City | North Carolina | United States | 28557 |
| 50 | Investigational Site Number 8400065 | Wilmington | North Carolina | United States | 28401 |
| 51 | Investigational Site Number 8400018 | Fargo | North Dakota | United States | 58104 |
| 52 | Investigational Site Number 8400019 | Columbus | Ohio | United States | 43201 |
| 53 | Investigational Site Number 8400056 | Dayton | Ohio | United States | 45439 |
| 54 | Investigational Site Number 8400125 | Mentor | Ohio | United States | 44060 |
| 55 | Investigational Site Number 8400099 | Oklahoma City | Oklahoma | United States | 73112 |
| 56 | Investigational Site Number 8400129 | Scottdale | Pennsylvania | United States | 15683 |
| 57 | Investigational Site Number 8400076 | Smithfield | Pennsylvania | United States | 15478 |
| 58 | Investigational Site Number 8400104 | Warwick | Rhode Island | United States | 02886 |
| 59 | Investigational Site Number 8400090 | Columbia | South Carolina | United States | 29204 |
| 60 | Investigational Site Number 8400139 | Austin | Texas | United States | 78749 |
| 61 | Investigational Site Number 8400001 | Dallas | Texas | United States | 75230-6885 |
| 62 | Investigational Site Number 8400118 | Edinburg | Texas | United States | 78539 |
| 63 | Investigational Site Number 8400008 | Houston | Texas | United States | 77004 |
| 64 | Investigational Site Number 8400109 | Houston | Texas | United States | 77040 |
| 65 | Investigational Site Number 8400063 | Houston | Texas | United States | 77061 |
| 66 | Investigational Site Number 8400106 | Houston | Texas | United States | 77081 |
| 67 | Investigational Site Number 8400014 | North Richland Hills | Texas | United States | 76180 |
| 68 | Investigational Site Number 8400089 | San Antonio | Texas | United States | 78240 |
| 69 | Investigational Site Number 8400135 | Schertz | Texas | United States | 78154 |
| 70 | Investigational Site Number 8400075 | Shavano Park | Texas | United States | 78231 |
| 71 | Investigational Site Number 8400107 | Sugar Land | Texas | United States | 77478 |
| 72 | Investigational Site Number 8400054 | Orem | Utah | United States | 84058 |
| 73 | Investigational Site Number 8400025 | Salt Lake City | Utah | United States | 84102 |
| 74 | Investigational Site Number 8400092 | Weber City | Virginia | United States | 24290 |
| 75 | Investigational Site Number 1240003 | Burlington | Canada | L7M 4Y1 | |
| 76 | Investigational Site Number 1240006 | Corunna | Canada | N0N 1G0 | |
| 77 | Investigational Site Number 1240002 | Red Deer | Canada | T4N 6V7 | |
| 78 | Investigational Site Number 1240001 | Vancouver | Canada | V5Y 3W2 | |
| 79 | Investigational Site Number 2330002 | Pärnu | Estonia | 80018 | |
| 80 | Investigational Site Number 2330003 | Tallinn | Estonia | 10138 | |
| 81 | Investigational Site Number 2330001 | Tallinn | Estonia | 13419 | |
| 82 | Investigational Site Number 2330004 | Viljandi | Estonia | 71024 | |
| 83 | Investigational Site Number 2760001 | Dresden | Germany | 01307 | |
| 84 | Investigational Site Number 2760003 | Oldenburg In Holstein | Germany | 23758 | |
| 85 | Investigational Site Number 3760001 | Haifa | Israel | 31096 | |
| 86 | Investigational Site Number 3760002 | Haifa | Israel | 35152 | |
| 87 | Investigational Site Number 3760005 | Jerusalem | Israel | 91120 | |
| 88 | Investigational Site Number 3760006 | Jerusalem | Israel | 93106 | |
| 89 | Investigational Site Number 3760004 | Tel Aviv | Israel | 6203854 | |
| 90 | Investigational Site Number 3800008 | Bergamo | Italy | 24127 | |
| 91 | Investigational Site Number 3800002 | Bologna | Italy | 40138 | |
| 92 | Investigational Site Number 3800001 | Milano | Italy | 20132 | |
| 93 | Investigational Site Number 3800006 | Milano | Italy | 20142 | |
| 94 | Investigational Site Number 3800005 | Napoli | Italy | 80131 | |
| 95 | Investigational Site Number 3800004 | Roma | Italy | 00128 | |
| 96 | Investigational Site Number 3800003 | Roma | Italy | 00133 | |
| 97 | Investigational Site Number 6420004 | Bacau | Romania | 600154 | |
| 98 | Investigational Site Number 6420006 | Brasov | Romania | 500097 | |
| 99 | Investigational Site Number 6420001 | Bucuresti | Romania | 020045 | |
| 100 | Investigational Site Number 6420008 | Buzau | Romania | 120203 | |
| 101 | Investigational Site Number 6420003 | Cluj Napoca | Romania | 400006 | |
| 102 | Investigational Site Number 6420002 | Oradea | Romania | 410159 | |
| 103 | Investigational Site Number 6420009 | Targoviste | Romania | 130083 | |
| 104 | Investigational Site Number 6420005 | Timisoara | Romania | 300125 | |
| 105 | Investigational Site Number 6420007 | Târgu-Mureş | Romania | 540098 | |
| 106 | Investigational Site Number 7030006 | Bratislava | Slovakia | 85101 | |
| 107 | Investigational Site Number 7030009 | Lubochna | Slovakia | 034 91 | |
| 108 | Investigational Site Number 7030002 | Lucenec | Slovakia | 98401 | |
| 109 | Investigational Site Number 7030005 | Malacky | Slovakia | 90101 | |
| 110 | Investigational Site Number 7030007 | Presov | Slovakia | 08001 | |
| 111 | Investigational Site Number 7030001 | Roznava | Slovakia | 04801 | |
| 112 | Investigational Site Number 7030008 | Sabinov | Slovakia | 083 01 | |
| 113 | Investigational Site Number 7030004 | Trencin | Slovakia | 91101 | |
| 114 | Investigational Site Number 7030003 | Zilina | Slovakia | 010 01 | |
| 115 | Investigational Site Number 7240012 | Alzira | Spain | 46600 | |
| 116 | Investigational Site Number 7240005 | Barcelona | Spain | 08035 | |
| 117 | Investigational Site Number 7240002 | Ferrol | Spain | 15405 | |
| 118 | Investigational Site Number 7240008 | Málaga | Spain | 29010 | |
| 119 | Investigational Site Number 7240011 | Pozuelo De Alarcón | Spain | 28223 | |
| 120 | Investigational Site Number 7240003 | Quart De Poblet | Spain | 46930 | |
| 121 | Investigational Site Number 7240006 | Sabadell | Spain | 08208 | |
| 122 | Investigational Site Number 7240007 | Sevilla | Spain | 41003 | |
| 123 | Investigational Site Number 7240009 | sEVILLA | Spain | 41010 | |
| 124 | Investigational Site Number 7240004 | Sevilla | Spain | 41071 |
Sponsors and Collaborators
- Sanofi
Investigators
- Study Director: Clinical Sciences & Operations, Sanofi
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT02787551
Other Study ID Numbers:
- EFC13794
- 2014-004850-32
- U1111-1168-4639
First Posted:
Jun 1, 2016
Last Update Posted:
Mar 25, 2022
Last Verified:
Mar 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The study was conducted at 112 sites in 9 countries. A total of 840 participants were screened between 06 July 2016 and 01 November 2017, of which 326 were screen failures. Screen failures were mainly due to glycated hemoglobin (HbA1c) level lesser than (<)7% or more than (>)9% at screening visit. |
|---|---|
| Pre-assignment Detail | A total of 514 participants were randomized in 1:1 (Insulin Glargine/Lixisenatide fixed ratio combination [FRC] or glucagon-like peptide-1 receptor agonist [GLP-1 RA]) ratio. Randomization was stratified by values of HbA1c at screening (<8%, >=8%) & GLP-1 RA subtype at screening (once/twice daily [QD/BID], once weekly [QW] formulations). |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | Core period: FRC injected subcutaneously 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. | Core Period: GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Period Title: Core Period: 26 Weeks | ||
| STARTED | 257 | 257 |
| Treated | 255 | 256 |
| COMPLETED | 230 | 246 |
| NOT COMPLETED | 27 | 11 |
| Period Title: Core Period: 26 Weeks | ||
| STARTED | 206 | 0 |
| COMPLETED | 197 | 0 |
| NOT COMPLETED | 9 | 0 |
Baseline Characteristics
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist | Total |
|---|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. | Total of all reporting groups |
| Overall Participants | 257 | 257 | 514 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
59.2
(9.6)
|
60.0
(10.3)
|
59.6
(10.0)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
131
51%
|
113
44%
|
244
47.5%
|
| Male |
126
49%
|
144
56%
|
270
52.5%
|
| Race/Ethnicity, Customized (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian/Oriental |
3
1.2%
|
4
1.6%
|
7
1.4%
|
| Black |
12
4.7%
|
7
2.7%
|
19
3.7%
|
| Native Hawaiian or Other Pacific Islander |
1
0.4%
|
0
0%
|
1
0.2%
|
| White |
241
93.8%
|
244
94.9%
|
485
94.4%
|
| Unknown or Not Reported' |
0
0%
|
2
0.8%
|
2
0.4%
|
| Body Mass Index (BMI) (Count of Participants) | |||
| <30 |
71
27.6%
|
69
26.8%
|
140
27.2%
|
| >=30 |
186
72.4%
|
188
73.2%
|
374
72.8%
|
| Duration of diabetes (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
11.23
(7.42)
|
10.95
(6.08)
|
11.09
(6.78)
|
| Hemoglobin A1C (HbA1C) (percentage of HbA1c) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [percentage of HbA1c] |
7.78
(0.62)
|
7.80
(0.56)
|
7.79
(0.59)
|
| Daily dose of metformin at baseline (milligrams (mg)) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [milligrams (mg)] |
1966.93
(434.56)
|
2030.74
(497.15)
|
1998.83
(467.54)
|
| Daily dose of pioglitazone at baseline (mg) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [mg] |
31.25
(10.03)
|
32.73
(8.83)
|
32.21
(9.14)
|
| Daily dose of SGLT2 inhibitor at baseline (mg) [Mean (Standard Deviation) ] | |||
| Canagliflozin |
214.29
(106.90)
|
283.33
(57.74)
|
257.89
(83.77)
|
| Empagliflozin |
15.42
(7.49)
|
16.67
(8.20)
|
16.17
(7.67)
|
| Dapagliflozin |
9.62
(3.80)
|
9.00
(2.24)
|
9.44
(3.38)
|
| Duration of GLP-1 receptor agonist treatment (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
1.89
(1.76)
|
1.92
(1.85)
|
1.90
(1.81)
|
| GLP-1 receptor agonist use by type at screening (Count of Participants) | |||
| Once/twice daily formulation |
153
59.5%
|
154
59.9%
|
307
59.7%
|
| Once weekly formulation |
104
40.5%
|
103
40.1%
|
207
40.3%
|
Outcome Measures
| Title | Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 26: Core Period |
|---|---|
| Description | 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. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified Intent-To-Treat (mITT) population:all randomized participants who had a baseline and at least 1 post-baseline assessment of any primary/secondary outcome measures, irrespective of compliance with study protocol and procedures."Overall number of participants analyzed"=participants with baseline and at least 1 post-baseline HbA1c assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Measure Participants | 250 | 253 |
| Least Squares Mean (Standard Error) [percentage of HbA1c] |
-1.02
(0.048)
|
-0.38
(0.048)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist |
|---|---|---|
| Comments | Analysis was performed using Mixed-effect model with repeated measures (MMRM) with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), GLP-1 RA subtype at screening, visits, treatment-by-visit interaction, world region as fixed effects, baseline HbA1c value-by-visit interaction as a covariate. Analysis included all scheduled measurements obtained during 26-week randomized treatment period, including those obtained after IMP discontinuation/introduction of rescue medication. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least square (LS) mean difference |
| Estimated Value | -0.64 | |
| Confidence Interval |
(2-Sided) 95% -0.770 to -0.508 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.067 |
|
| Estimation Comments | ||
| Title | Change From Baseline in Glycated Hemoglobin (HbA1c) to Week 52: Single Arm Extension Period |
|---|---|
| Description | Change in HbA1c was calculated by subtracting baseline value from Week 52 value. |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on mITT population who entered the extension period. Here, "Overall number of participants analyzed" = participants with baseline and at least 1 post-baseline HbA1c assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 202 |
| Mean (Standard Error) [percentage of HbA1c] |
-1.01
(0.063)
|
| Title | Percentage of Participants Reaching HbA1c <7% or <=6.5% at Week 26: Core Period |
|---|---|
| Description | Participants without any available HbA1c assessment at Week 26 were considered as non-responders. |
| Time Frame | Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on mITT population. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of oral anti-diabetic drug (OAD) therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Measure Participants | 252 | 253 |
| HbA1c <7% |
61.9
24.1%
|
25.7
10%
|
| HbA1c <=6.5% |
40.5
15.8%
|
9.9
3.9%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist |
|---|---|---|
| Comments | HbA1c <7.0%: Insulin Glargine/Lixisenatide FRC vs GLP-1 Receptor Agonist. Analysis was performed using Cochran-Mantel-Haenszel method method stratified on randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), and randomization strata of GLP-1 receptor agonist subtype at screening. Hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially per pre-specified order (only HbA1c < 7% was part of testing). | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <.0001 |
| Comments | Threshold for significance <=0.05 | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentage |
| Estimated Value | 36.05 | |
| Confidence Interval |
(2-Sided) 95% 28.11 to 43.99 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Percentage of Participants Reaching HbA1c <7 % or <=6.5% at Week 52: Single Arm Extension Period |
|---|---|
| Description | Participants without any available HbA1c assessment at Week 52 were considered as non-responders. |
| Time Frame | Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on mITT population who entered the extension period. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 206 |
| HbA1c <7% |
64.1
24.9%
|
| HbA1c <=6.5% |
42.7
16.6%
|
| Title | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26: Core Period |
|---|---|
| Description | 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. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline FPG assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Measure Participants | 251 | 253 |
| Least Squares Mean (Standard Error) [millimoles per litre (mmol/L)] |
-2.28
(0.120)
|
-0.60
(0.119)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist |
|---|---|---|
| Comments | Analysis was performed using MMRM with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), randomization strata of GLP-1 RA subtype at screening, scheduled visit, treatment-by-visit interaction, and world region as fixed effects, and and baseline FPG value-by visit interaction as a covariate. Testing according to the hierarchical testing procedure (continued only if previous outcome measures were statistically significant). | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -1.67 | |
| Confidence Interval |
(2-Sided) 95% -2.001 to -1.341 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.168 |
|
| Estimation Comments | ||
| Title | Change From Baseline in Fasting Plasma Glucose (FPG) to Week 52: Single Arm Extension Period |
|---|---|
| Description | Change in FPG was calculated by subtracting baseline value from Week 52 value. |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on mITT population who entered the extension period. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline FPG assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 196 |
| Mean (Standard Error) [mmol/L] |
-2.27
(0.173)
|
| Title | Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 26: Core Period |
|---|---|
| Description | 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. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline 7-point SMPG assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Measure Participants | 216 | 220 |
| Least Squares Mean (Standard Error) [mmol/L] |
-1.69
(0.114)
|
-0.67
(0.112)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist |
|---|---|---|
| Comments | Analysis was performed using MMRM with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), randomization strata of GLP-1 RA subtype at screening, scheduled visit, treatment-by-visit interaction, and world region as fixed effects, and baseline average SMPG value-by-visit interaction as a covariate. Testing according to the hierarchical testing procedure (continued only if previous outcome measures were statistically significant). | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -1.02 | |
| Confidence Interval |
(2-Sided) 95% -1.325 to -0.708 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.157 |
|
| Estimation Comments | ||
| Title | Change From Baseline in the Daily Average of the 7-point Self-monitored Plasma Glucose (SMPG) to Week 52: Single Arm Extension Period |
|---|---|
| Description | 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. |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on mITT population who entered the extension period. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline 7-point SMPG assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 142 |
| Mean (Standard Error) [mmol/L] |
-1.68
(0.176)
|
| Title | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 26: Core Period |
|---|---|
| Description | 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). |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline plasma glucose assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Measure Participants | 215 | 222 |
| Least Squares Mean (Standard Error) [mmol/L] |
-3.96
(0.211)
|
-1.11
(0.205)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist |
|---|---|---|
| Comments | Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), randomization strata of GLP-1 RA subtype (once/twice daily formulations, once weekly formulations) at screening, and world region as fixed effects and baseline 2-hour PPG value as a covariate. Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -2.85 | |
| Confidence Interval |
(2-Sided) 95% -3.420 to -2.279 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.290 |
|
| Estimation Comments | ||
| Title | Change From Baseline in 2-Hour Postprandial Plasma Glucose (PPG) During Standardized Meal Test to Week 52: Single Arm Extension Period |
|---|---|
| Description | 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. |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on mITT population who entered the extension period. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline plasma glucose assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 192 |
| Mean (Standard Error) [mmol/L] |
-4.30
(0.284)
|
| Title | Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 26: Core Period |
|---|---|
| Description | 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. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and Week 26 assessments. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Measure Participants | 215 | 220 |
| Least Squares Mean (Standard Error) [mmol/L] |
-1.51
(0.177)
|
-0.52
(0.173)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC), GLP-1 Receptor Agonist |
|---|---|---|
| Comments | Analysis was performed using ANCOVA model with treatment groups, randomization strata of Week -2 HbA1c (<8.0%, >=8.0%), randomization strata of GLP-1 receptor agonist subtype (once/twice daily formulations, once weekly formulations) at screening, and world region as fixed effects and baseline 2-hour plasma glucose excursion value as a covariate. Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -0.99 | |
| Confidence Interval |
(2-Sided) 95% -1.468 to -0.508 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.244 |
|
| Estimation Comments | ||
| Title | Change From Baseline in 2-Hour Blood Glucose Excursion During Standardized Meal Test to Week 52: Single Arm Extension Period |
|---|---|
| Description | 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. |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on mITT population who entered the extension period. Here, "overall number of participants analyzed" = participants with baseline and Week 52 assessments. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 192 |
| Mean (Standard Error) [mmol/L] |
-1.85
(0.209)
|
| Title | Percentage of Participants Requiring Rescue Therapy During the 26 Week Treatment Period: Core Period |
|---|---|
| Description | Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c >8%. |
| Time Frame | From Baseline to Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed using mITT population. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Measure Participants | 252 | 253 |
| Number [percentage of participants] |
4.8
1.9%
|
15.0
5.8%
|
| Title | Percentage of Participants Requiring Rescue Therapy During the 52 Week Treatment Period: Single Arm Extension Period |
|---|---|
| Description | Routine HbA1c value was used to determine the requirement of rescue medication. Threshold values at Week 12 or later on Week 12: HbA1c >8%. |
| Time Frame | From Week 26 to Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on mITT population who entered the extension period. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 206 |
| Number [percentage of participants] |
1.5
0.6%
|
| Title | Change From Baseline in Body Weight at Week 26: Core Period |
|---|---|
| Description | Change in body weight was calculated by subtracting baseline value from Week 26 value. |
| Time Frame | Baseline, Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed using mITT population. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline body weight assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Measure Participants | 251 | 253 |
| Least Squares Mean (Standard Error) [kilogram (kg)] |
1.89
(0.222)
|
-1.14
(0.220)
|
| Title | Change From Baseline in Body Weight to Week 52: Single Arm Extension Period |
|---|---|
| Description | Change in body weight was calculated by subtracting baseline value from Week 52 value. |
| Time Frame | Baseline, Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed using mITT population who entered the extension period. Here, "overall number of participants analyzed" = participants with baseline and at least one post-baseline body weight assessment. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 202 |
| Mean (Standard Error) [kg] |
2.78
(0.294)
|
| Title | Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Core Period |
|---|---|
| Description | 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. |
| Time Frame | From Baseline to Week 26 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on safety population which included all randomized participants who received at least one dose of open-label IMP, regardless of the amount of treatment administered. Participants were analyzed according to the treatment actually received (as treated). |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | GLP-1 Receptor Agonist |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted. | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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. |
| Measure Participants | 255 | 256 |
| Documented symptomatic hypoglycemia(<=3.9 mmol/L) |
1.54
|
0.08
|
| Documented symptomatic hypoglycemia (<3.0 mmol/L) |
0.25
|
0.01
|
| Title | Number of Documented Symptomatic Hypoglycemia Events Per Participant-Year: Single Arm Extension Period |
|---|---|
| Description | 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. |
| Time Frame | From Baseline to Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on safety population who entered the extension period and their data for whole study duration was analyzed and reported. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) |
|---|---|
| Arm/Group Description | 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. |
| Measure Participants | 206 |
| Documented symptomatic hypoglycemia(<=3.9 mmol/L) |
1.59
|
| Documented symptomatic hypoglycemia (<3.0 mmol/L) |
0.24
|
Adverse Events
| Time Frame | All Adverse Events (AEs) were collected from signature of informed consent until the end of the study (up to 52 weeks). | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | Reported AEs are treatment-emergent that is AEs that developed/worsened during during the period from the administration of first dose of the study treatments up to 3 days (9 days for the weekly GLP1) after the last administration. Analysis was performed on safety population. | |||||
| Arm/Group Title | Fixed Ratio Combination | GLP-1 Receptor Agonist | Fixed Ratio Combination Whole Study Period | |||
| Arm/Group Description | FRC injected subcutaneously QD for 26 weeks on top of OAD therapy. Dose individually adjusted (median exposure: 183 days). | GLP-1 RA receptor agonist (liraglutide QD, exenatide 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 (median exposure: 183 days). | 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 (median exposure: 365 days). | |||
All Cause Mortality |
||||||
| Fixed Ratio Combination | GLP-1 Receptor Agonist | Fixed Ratio Combination Whole Study Period | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/255 (0%) | 0/256 (0%) | 1/206 (0.5%) | |||
Serious Adverse Events |
||||||
| Fixed Ratio Combination | GLP-1 Receptor Agonist | Fixed Ratio Combination Whole Study Period | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 10/255 (3.9%) | 9/256 (3.5%) | 21/206 (10.2%) | |||
| Cardiac disorders | ||||||
| Arteriosclerosis Coronary Artery | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Atrial Fibrillation | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Cardiac Failure | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Cardiac Failure Congestive | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 2/206 (1%) | 2 |
| Coronary Artery Disease | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 2/206 (1%) | 2 |
| Ischaemic Cardiomyopathy | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Gastrointestinal disorders | ||||||
| Duodenal Ulcer | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Large Intestine Polyp | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 0/206 (0%) | 0 |
| Rectal Haemorrhage | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| General disorders | ||||||
| Non-Cardiac Chest Pain | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 0/206 (0%) | 0 |
| Oedema Peripheral | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Infections and infestations | ||||||
| Cellulitis | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Diverticulitis | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Infected Skin Ulcer | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Peritonitis | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Pneumonia | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 0/206 (0%) | 0 |
| Postoperative Abscess | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Injury, poisoning and procedural complications | ||||||
| Ankle Fracture | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Fall | 2/255 (0.8%) | 2 | 0/256 (0%) | 0 | 2/206 (1%) | 2 |
| Foot Fracture | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 0/206 (0%) | 0 |
| Hip Fracture | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Laceration | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 0/206 (0%) | 0 |
| Rib Fracture | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Skin Laceration | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Subarachnoid Haemorrhage | 1/255 (0.4%) | 2 | 0/256 (0%) | 0 | 0/206 (0%) | 0 |
| Subcutaneous Haematoma | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Metabolism and nutrition disorders | ||||||
| Electrolyte Imbalance | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 0/206 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Intervertebral Disc Protrusion | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Musculoskeletal Chest Pain | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Osteoarthritis | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Spinal Column Stenosis | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Adenosquamous Cell Lung Cancer | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Basal Cell Carcinoma | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Bladder Papilloma | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 0/206 (0%) | 0 |
| Endometrial Adenocarcinoma | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Glioblastoma | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Hepatic Neoplasm | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Invasive Ductal Breast Carcinoma | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 1/206 (0.5%) | 1 |
| Papillary Thyroid Cancer | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Renal Cell Carcinoma | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 0/206 (0%) | 0 |
| Nervous system disorders | ||||||
| Cerebral Infarction | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 0/206 (0%) | 0 |
| Diabetic Neuropathy | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 0/206 (0%) | 0 |
| Hypoglycaemic Unconsciousness | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Intraventricular Haemorrhage | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Subarachnoid Haemorrhage | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 2/206 (1%) | 3 |
| Renal and urinary disorders | ||||||
| Acute Kidney Injury | 1/255 (0.4%) | 1 | 1/256 (0.4%) | 1 | 1/206 (0.5%) | 1 |
| Urinary Retention | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 0/206 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Acute Pulmonary Oedema | 1/255 (0.4%) | 1 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Pneumonia Aspiration | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
| Skin and subcutaneous tissue disorders | ||||||
| Dermal Cyst | 0/255 (0%) | 0 | 1/256 (0.4%) | 1 | 0/206 (0%) | 0 |
| Vascular disorders | ||||||
| Vasculitis Necrotising | 0/255 (0%) | 0 | 0/256 (0%) | 0 | 1/206 (0.5%) | 1 |
Other (Not Including Serious) Adverse Events |
||||||
| Fixed Ratio Combination | GLP-1 Receptor Agonist | Fixed Ratio Combination Whole Study Period | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 69/255 (27.1%) | 48/256 (18.8%) | 75/206 (36.4%) | |||
| Gastrointestinal disorders | ||||||
| Diarrhoea | 14/255 (5.5%) | 14 | 6/256 (2.3%) | 6 | 15/206 (7.3%) | 17 |
| Nausea | 22/255 (8.6%) | 30 | 6/256 (2.3%) | 6 | 19/206 (9.2%) | 30 |
| Infections and infestations | ||||||
| Influenza | 11/255 (4.3%) | 12 | 6/256 (2.3%) | 6 | 15/206 (7.3%) | 19 |
| Nasopharyngitis | 25/255 (9.8%) | 27 | 23/256 (9%) | 26 | 32/206 (15.5%) | 37 |
| Upper Respiratory Tract Infection | 9/255 (3.5%) | 11 | 12/256 (4.7%) | 15 | 13/206 (6.3%) | 17 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.
Results Point of Contact
| Name/Title | Trial Transparency Team |
|---|---|
| Organization | Sanofi aventis recherche & développement |
| Phone | 800-633-1610 ext 1# |
| Contact-US@sanofi.com |
Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT02787551
Other Study ID Numbers:
- EFC13794
- 2014-004850-32
- U1111-1168-4639
First Posted:
Jun 1, 2016
Last Update Posted:
Mar 25, 2022
Last Verified:
Mar 1, 2022