LixiLan-L: Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination Versus Insulin Glargine in Patients With Type 2 Diabetes
Sponsor
Sanofi (Industry)
Overall Status
Completed
CT.gov ID
NCT02058160
Collaborator
(none)
736
236
2
17.9
3.1
0.2
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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.
Study Design
Study Type:
Interventional
Actual Enrollment
:
736 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, 30-week, Active-controlled, Open Label, 2- Treatment Arm, Parallel-group, Multicenter Study Comparing the Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed Ratio Combination to Insulin Glargine With or Without Metformin in Patients With Type 2 Diabetes Mellitus (T2DM)
Study Start Date
:
Jan 1, 2014
Actual Primary Completion Date
:
Jul 1, 2015
Actual Study Completion Date
:
Jul 1, 2015
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) FRC once daily (QD) for 30 weeks. Dose individually adjusted. |
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: Metformin (Background Drug)
Pharmaceutical form: Tablet; Route of administration: Oral administration
|
| Active Comparator: Insulin glargine Insulin glargine 100 U/mL QD for 30 weeks. Dose individually adjusted. |
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).
Other Names:
Drug: Metformin (Background Drug)
Pharmaceutical form: Tablet; Route of administration: Oral administration
|
Outcome Measures
Primary Outcome Measures
- Change in Glycated Hemoglobin (HbA1c) From Baseline to Week 30 [Baseline, Week 30]
Change in HbA1c was calculated by subtracting baseline value from Week 30 value.
Secondary Outcome Measures
- Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 [Week 30]
- Change in 2-hour Plasma Blood Glucose Excursion From Baseline to Week 30 [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 [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 [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 [Week 30]
- Change in Daily Insulin Glargine Dose From Baseline to Week 30 [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 [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 [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 [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 [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).
- Percentage of Participants Requiring Rescue Therapy During 30-Week Treatment Period [Baseline up to Week 30]
Routine fasting SMPG and central laboratory FPG (and HbA1c after Week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) were performed. Threshold values - from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 30: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8%.
- Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year [First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine])]
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).
- Percentage of Participants With Documented Symptomatic Hypoglycemia [First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine])]
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).
- Percentage of Participants With Severe Symptomatic Hypoglycemia [First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine])]
Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Plasma glucose measurements might not had been available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal was considered sufficient evidence that the event had been induced by a low plasma glucose concentration. Severe symptomatic hypoglycemia included all episodes in which neurological impairment was severe enough to prevent self-treatment, and which were thus thought to place participants at risk for injury to themselves or others.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts 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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Investigational Site Number 840607 | Birmingham | Alabama | United States | 35205 |
| 2 | Investigational Site Number 840570 | Sun City | Arizona | United States | 85351 |
| 3 | Investigational Site Number 840562 | Tempe | Arizona | United States | |
| 4 | Investigational Site Number 840577 | Tucson | Arizona | United States | 85723 |
| 5 | Investigational Site Number 840517 | Little Rock | Arkansas | United States | 72205 |
| 6 | Investigational Site Number 840537 | Little Rock | Arkansas | United States | 72205 |
| 7 | Investigational Site Number 840568 | Bell Gardens | California | United States | 90201 |
| 8 | Investigational Site Number 840550 | Chino | California | United States | 91710 |
| 9 | Investigational Site Number 840529 | Chula Vista | California | United States | 91911 |
| 10 | Investigational Site Number 840623 | Corona | California | United States | 92879 |
| 11 | Investigational Site Number 840566 | Fresno | California | United States | 93720 |
| 12 | Investigational Site Number 840552 | Greenbrae | California | United States | 94904 |
| 13 | Investigational Site Number 840578 | Lancaster | California | United States | 93534 |
| 14 | Investigational Site Number 840626 | Los Angeles | California | United States | 90017 |
| 15 | Investigational Site Number 840581 | Los Angeles | California | United States | 90057 |
| 16 | Investigational Site Number 840621 | Mission Viejo | California | United States | 92691 |
| 17 | Investigational Site Number 840511 | Northridge | California | United States | 91325 |
| 18 | Investigational Site Number 840573 | Palm Springs | California | United States | 92262 |
| 19 | Investigational Site Number 840559 | Port Hueneme | California | United States | 93041 |
| 20 | Investigational Site Number 840536 | San Ramon | California | United States | 94583 |
| 21 | Investigational Site Number 840567 | Santa Ana | California | United States | 92704 |
| 22 | Investigational Site Number 840569 | Tarzana | California | United States | 91356 |
| 23 | Investigational Site Number 840572 | West Hills | California | United States | 91345 |
| 24 | Investigational Site Number 840582 | Aurora | Colorado | United States | 80045 |
| 25 | Investigational Site Number 840509 | Denver | Colorado | United States | 80246 |
| 26 | Investigational Site Number 840549 | Wilmington | Delaware | United States | 19713 |
| 27 | Investigational Site Number 840510 | Miami | Florida | United States | 33156-7563 |
| 28 | Investigational Site Number 840521 | New Port Richey | Florida | United States | 34652 |
| 29 | Investigational Site Number 840602 | Ocala | Florida | United States | 34471 |
| 30 | Investigational Site Number 840538 | Ocoee | Florida | United States | 34761 |
| 31 | Investigational Site Number 840534 | Palm Harbor | Florida | United States | 34684 |
| 32 | Investigational Site Number 840594 | Atlanta | Georgia | United States | 30322 |
| 33 | Investigational Site Number 840614 | Columbus | Georgia | United States | 31904 |
| 34 | Investigational Site Number 840501 | Lawrenceville | Georgia | United States | 30046 |
| 35 | Investigational Site Number 840525 | Roswell | Georgia | United States | 30076 |
| 36 | Investigational Site Number 840588 | Idaho Falls | Idaho | United States | 83404 |
| 37 | Investigational Site Number 840580 | Arlington Heights | Illinois | United States | 60005 |
| 38 | Investigational Site Number 840519 | Chicago | Illinois | United States | 60607 |
| 39 | Investigational Site Number 840612 | Chicago | Illinois | United States | 60616 |
| 40 | Investigational Site Number 840556 | Springfield | Illinois | United States | 62704 |
| 41 | Investigational Site Number 840543 | Avon | Indiana | United States | 46123 |
| 42 | Investigational Site Number 840565 | Evansville | Indiana | United States | 47713 |
| 43 | Investigational Site Number 840585 | Evansville | Indiana | United States | 47714 |
| 44 | Investigational Site Number 840615 | Evansville | Indiana | United States | 47714 |
| 45 | Investigational Site Number 840563 | Indianapolis | Indiana | United States | 46202 |
| 46 | Investigational Site Number 840507 | Indianapolis | Indiana | United States | 46260 |
| 47 | Investigational Site Number 840516 | Louisville | Kentucky | United States | 40213 |
| 48 | Investigational Site Number 840595 | Lewiston | Maine | United States | 04240 |
| 49 | Investigational Site Number 840520 | Baltimore | Maryland | United States | 21237 |
| 50 | Investigational Site Number 840560 | Baltimore | Maryland | United States | 21237 |
| 51 | Investigational Site Number 840522 | Rockville | Maryland | United States | 20852 |
| 52 | Investigational Site Number 840505 | Dearborn | Michigan | United States | 48124 |
| 53 | Investigational Site Number 840575 | Flint | Michigan | United States | 48504 |
| 54 | Investigational Site Number 840564 | Minneapolis | Minnesota | United States | 55416 |
| 55 | Investigational Site Number 840558 | Butte | Montana | United States | 59701 |
| 56 | Investigational Site Number 840506 | Omaha | Nebraska | United States | 68131 |
| 57 | Investigational Site Number 840600 | Henderson | Nevada | United States | 89074 |
| 58 | Investigational Site Number 840532 | Las Vegas | Nevada | United States | 89119 |
| 59 | Investigational Site Number 840599 | Las Vegas | Nevada | United States | 89148 |
| 60 | Investigational Site Number 840539 | Nashua | New Hampshire | United States | 03063 |
| 61 | Investigational Site Number 840576 | Albuquerque | New Mexico | United States | 87131 |
| 62 | Investigational Site Number 840583 | Jamaica | New York | United States | 11432 |
| 63 | Investigational Site Number 840531 | New Hyde Park | New York | United States | 11042 |
| 64 | Investigational Site Number 840557 | Syracuse | New York | United States | 13214-2016 |
| 65 | Investigational Site Number 840541 | Durham | North Carolina | United States | 27710 |
| 66 | Investigational Site Number 840604 | Greenville | North Carolina | United States | 27858 |
| 67 | Investigational Site Number 840540 | Hickory | North Carolina | United States | 28601 |
| 68 | Investigational Site Number 840513 | Morehead City | North Carolina | United States | 28557 |
| 69 | Investigational Site Number 840592 | Salisbury | North Carolina | United States | 28144 |
| 70 | Investigational Site Number 840535 | Wilmington | North Carolina | United States | 28401 |
| 71 | Investigational Site Number 840515 | Winston-Salem | North Carolina | United States | 27103 |
| 72 | Investigational Site Number 840579 | Columbus | Ohio | United States | 43213 |
| 73 | Investigational Site Number 840524 | Dayton | Ohio | United States | 45439 |
| 74 | Investigational Site Number 840503 | Maumee | Ohio | United States | 43537 |
| 75 | Investigational Site Number 840618 | Eugene | Oregon | United States | 97404 |
| 76 | Investigational Site Number 840610 | Philadelphia | Pennsylvania | United States | 19107 |
| 77 | Investigational Site Number 840551 | Smithfield | Pennsylvania | United States | 15478 |
| 78 | Investigational Site Number 840584 | Tipton | Pennsylvania | United States | 16684 |
| 79 | Investigational Site Number 840622 | Charleston | South Carolina | United States | 29407 |
| 80 | Investigational Site Number 840611 | Rapid City | South Dakota | United States | 57701 |
| 81 | Investigational Site Number 840605 | Amarillo | Texas | United States | 79106 |
| 82 | Investigational Site Number 840553 | Austin | Texas | United States | 78731 |
| 83 | Investigational Site Number 840598 | Austin | Texas | United States | 78731 |
| 84 | Investigational Site Number 840502 | Corpus Christi | Texas | United States | 78404 |
| 85 | Investigational Site Number 840601 | Dallas | Texas | United States | 75208 |
| 86 | Investigational Site Number 840586 | Dallas | Texas | United States | 75216 |
| 87 | Investigational Site Number 840547 | Dallas | Texas | United States | 75230 |
| 88 | Investigational Site Number 840530 | Dallas | Texas | United States | 75231 |
| 89 | Investigational Site Number 840545 | Dallas | Texas | United States | 75246 |
| 90 | Investigational Site Number 840554 | Edinburg | Texas | United States | 78539 |
| 91 | Investigational Site Number 840544 | Houston | Texas | United States | 77030 |
| 92 | Investigational Site Number 840514 | Hurst | Texas | United States | 76054 |
| 93 | Investigational Site Number 840617 | N Richland Hill | Texas | United States | 76180 |
| 94 | Investigational Site Number 840512 | Draper | Utah | United States | 84020 |
| 95 | Investigational Site Number 840591 | Murray | Utah | United States | 84123 |
| 96 | Investigational Site Number 840526 | Ogden | Utah | United States | 84405 |
| 97 | Investigational Site Number 840597 | Orem | Utah | United States | 84058 |
| 98 | Investigational Site Number 840590 | Salt Lake City | Utah | United States | 84102 |
| 99 | Investigational Site Number 840613 | Burlington | Vermont | United States | 05401 |
| 100 | Investigational Site Number 840504 | Chesapeake | Virginia | United States | 23321 |
| 101 | Investigational Site Number 840561 | Norfolk | Virginia | United States | 23510 |
| 102 | Investigational Site Number 840625 | Norfolk | Virginia | United States | 23510 |
| 103 | Investigational Site Number 840606 | Richmond | Virginia | United States | 23227 |
| 104 | Investigational Site Number 840608 | Salem | Virginia | United States | 24153 |
| 105 | Investigational Site Number 840571 | Federal Way | Washington | United States | 98003 |
| 106 | Investigational Site Number 840593 | Spokane | Washington | United States | 99220 |
| 107 | Investigational Site Number 840609 | Tacoma | Washington | United States | 98415-0299 |
| 108 | Investigational Site Number 840546 | Milwaukee | Wisconsin | United States | 53209-0996 |
| 109 | Investigational Site Number 036505 | Box Hill | Australia | 3128 | |
| 110 | Investigational Site Number 036501 | Heidelberg | Australia | 3081 | |
| 111 | Investigational Site Number 036504 | Parkville | Australia | 3050 | |
| 112 | Investigational Site Number 124504 | Beamsville | Canada | L0R 1B0 | |
| 113 | Investigational Site Number 124512 | Brampton | Canada | L6R 3J5 | |
| 114 | Investigational Site Number 124502 | Guelph | Canada | N1H 1B1 | |
| 115 | Investigational Site Number 124507 | Kelowna | Canada | V1Y 1Z9 | |
| 116 | Investigational Site Number 124505 | Montreal | Canada | H1W 2R7 | |
| 117 | Investigational Site Number 124511 | Oakville | Canada | L6H 3P1 | |
| 118 | Investigational Site Number 124509 | St-Romuald | Canada | G6W 5M6 | |
| 119 | Investigational Site Number 124503 | Toronto | Canada | M9V 4B4 | |
| 120 | Investigational Site Number 124510 | Toronto | Canada | M9W 4L9 | |
| 121 | Investigational Site Number 124501 | Vancouver | Canada | V5Y 3W2 | |
| 122 | Investigational Site Number 124508 | Victoria | Canada | V8V 4A1 | |
| 123 | Investigational Site Number 152511 | Puerto Varas | Chile | 5480000 | |
| 124 | Investigational Site Number 152502 | Santiago | Chile | 7500347 | |
| 125 | Investigational Site Number 152501 | Santiago | Chile | 7500710 | |
| 126 | Investigational Site Number 152514 | Santiago | Chile | 7500739 | |
| 127 | Investigational Site Number 152503 | Santiago | Chile | 8053095 | |
| 128 | Investigational Site Number 152507 | Santiago | Chile | ||
| 129 | Investigational Site Number 152509 | Talagante | Chile | ||
| 130 | Investigational Site Number 152513 | Temuco | Chile | 4780000 | |
| 131 | Investigational Site Number 152504 | Vina Del Mar | Chile | ||
| 132 | Investigational Site Number 203502 | Cheb | Czech Republic | 35002 | |
| 133 | Investigational Site Number 203504 | Hranice | Czech Republic | 75301 | |
| 134 | Investigational Site Number 203507 | Krnov | Czech Republic | 79401 | |
| 135 | Investigational Site Number 203506 | Liberec | Czech Republic | 460 01 | |
| 136 | Investigational Site Number 203503 | Olomouc | Czech Republic | 77900 | |
| 137 | Investigational Site Number 203514 | Plzen | Czech Republic | 301 66 | |
| 138 | Investigational Site Number 203515 | Plzen | Czech Republic | 301 66 | |
| 139 | Investigational Site Number 203511 | Praha 4 | Czech Republic | 14900 | |
| 140 | Investigational Site Number 203508 | Praha 5 | Czech Republic | 15030 | |
| 141 | Investigational Site Number 203509 | Praha 8 | Czech Republic | 18100 | |
| 142 | Investigational Site Number 203505 | Prostejov | Czech Republic | 79601 | |
| 143 | Investigational Site Number 208503 | Aarhus C | Denmark | 8000 | |
| 144 | Investigational Site Number 208509 | Horsens | Denmark | 8700 | |
| 145 | Investigational Site Number 208502 | Kolding | Denmark | 6000 | |
| 146 | Investigational Site Number 208501 | København Nv | Denmark | 2400 | |
| 147 | Investigational Site Number 208505 | København S | Denmark | 2300 | |
| 148 | Investigational Site Number 208504 | Viborg | Denmark | 8800 | |
| 149 | Investigational Site Number 233502 | Pärnu | Estonia | 80018 | |
| 150 | Investigational Site Number 233503 | Tallinn | Estonia | 10138 | |
| 151 | Investigational Site Number 233501 | Tartu | Estonia | 50406 | |
| 152 | Investigational Site Number 348503 | Budapest | Hungary | 1134 | |
| 153 | Investigational Site Number 348501 | Budapest | Hungary | 1138 | |
| 154 | Investigational Site Number 348505 | Budapest | Hungary | 1212 | |
| 155 | Investigational Site Number 348502 | Debrecen | Hungary | 4031 | |
| 156 | Investigational Site Number 348506 | Kaposvár | Hungary | 7400 | |
| 157 | Investigational Site Number 348504 | Pápa | Hungary | 8500 | |
| 158 | Investigational Site Number 440501 | Kaunas | Lithuania | 48259 | |
| 159 | Investigational Site Number 440503 | Kaunas | Lithuania | 49449 | |
| 160 | Investigational Site Number 440505 | Kedainiai | Lithuania | LT-57164 | |
| 161 | Investigational Site Number 440504 | Klaipeda | Lithuania | LT-92253 | |
| 162 | Investigational Site Number 440502 | Vilnius | Lithuania | LT-10323 | |
| 163 | Investigational Site Number 484508 | Celaya | Mexico | 38000 | |
| 164 | Investigational Site Number 484501 | Cuernavaca | Mexico | 62250 | |
| 165 | Investigational Site Number 484503 | Guadalajara | Mexico | 44130 | |
| 166 | Investigational Site Number 484504 | Guadalajara | Mexico | 44210 | |
| 167 | Investigational Site Number 484506 | Guadalajara | Mexico | 44600 | |
| 168 | Investigational Site Number 484509 | México | Mexico | 06700 | |
| 169 | Investigational Site Number 484507 | Pachuca | Mexico | 42084 | |
| 170 | Investigational Site Number 484505 | Puebla | Mexico | 72190 | |
| 171 | Investigational Site Number 528505 | Almere | Netherlands | 1311 RL | |
| 172 | Investigational Site Number 616502 | Bialystok | Poland | 15-435 | |
| 173 | Investigational Site Number 616505 | Krakow | Poland | 31-261 | |
| 174 | Investigational Site Number 616506 | Krakow | Poland | 31-548 | |
| 175 | Investigational Site Number 616507 | Plock | Poland | 09-400 | |
| 176 | Investigational Site Number 616504 | Szczecin | Poland | 70-506 | |
| 177 | Investigational Site Number 616503 | Warszawa | Poland | 01-518 | |
| 178 | Investigational Site Number 616501 | Warszawa | Poland | 02-507 | |
| 179 | Investigational Site Number 642507 | Brasov | Romania | 500365 | |
| 180 | Investigational Site Number 642510 | Bucharest | Romania | 010825 | |
| 181 | Investigational Site Number 642508 | Bucuresti | Romania | 020042 | |
| 182 | Investigational Site Number 642509 | Bucuresti | Romania | 020475 | |
| 183 | Investigational Site Number 642506 | Hunedoara | Romania | 331057 | |
| 184 | Investigational Site Number 642505 | Iasi | Romania | 700547 | |
| 185 | Investigational Site Number 642502 | Oradea | Romania | 410169 | |
| 186 | Investigational Site Number 642511 | Sibiu | Romania | 550371 | |
| 187 | Investigational Site Number 642501 | Targu Mures | Romania | 540142 | |
| 188 | Investigational Site Number 642504 | Timisoara | Romania | 300125 | |
| 189 | Investigational Site Number 642503 | Timisoara | Romania | 300456 | |
| 190 | Investigational Site Number 643511 | Arkhangelsk | Russian Federation | 163045 | |
| 191 | Investigational Site Number 643512 | Moscow | Russian Federation | 119435 | |
| 192 | Investigational Site Number 643508 | Penza | Russian Federation | 440026 | |
| 193 | Investigational Site Number 643501 | Saint-Petersburg | Russian Federation | 190013 | |
| 194 | Investigational Site Number 643513 | Samara | Russian Federation | 443041 | |
| 195 | Investigational Site Number 643507 | Saratov | Russian Federation | 410030 | |
| 196 | Investigational Site Number 643514 | Saratov | Russian Federation | 410053 | |
| 197 | Investigational Site Number 643506 | St-Petersburg | Russian Federation | 194291 | |
| 198 | Investigational Site Number 643503 | St-Petersburg | Russian Federation | 194354 | |
| 199 | Investigational Site Number 643504 | St-Petersburg | Russian Federation | 194354 | |
| 200 | Investigational Site Number 643502 | St-Petersburg | Russian Federation | 195257 | |
| 201 | Investigational Site Number 643505 | St. Petersburg | Russian Federation | 194358 | |
| 202 | Investigational Site Number 643509 | Voronezh | Russian Federation | 394018 | |
| 203 | Investigational Site Number 703505 | Bratislava | Slovakia | 85101 | |
| 204 | Investigational Site Number 703507 | Bytca | Slovakia | 01401 | |
| 205 | Investigational Site Number 703502 | Kosice | Slovakia | 04001 | |
| 206 | Investigational Site Number 703512 | Kosice | Slovakia | 04001 | |
| 207 | Investigational Site Number 703510 | Kosice | Slovakia | 04013 | |
| 208 | Investigational Site Number 703511 | Lubochna | Slovakia | 3491 | |
| 209 | Investigational Site Number 703508 | Moldava Nad Bodvou | Slovakia | 04525 | |
| 210 | Investigational Site Number 703504 | Nove Mesto Nad Vahom | Slovakia | 91501 | |
| 211 | Investigational Site Number 703509 | Nove Zamky | Slovakia | 94001 | |
| 212 | Investigational Site Number 703513 | Trnava | Slovakia | 91701 | |
| 213 | Investigational Site Number 703501 | Zilina | Slovakia | 01001 | |
| 214 | Investigational Site Number 724509 | Alicante | Spain | 03010 | |
| 215 | Investigational Site Number 724506 | Alzira | Spain | 46600 | |
| 216 | Investigational Site Number 724504 | Barcelona | Spain | 08035 | |
| 217 | Investigational Site Number 724510 | Barcelona | Spain | 08036 | |
| 218 | Investigational Site Number 724505 | Cáceres | Spain | 10003 | |
| 219 | Investigational Site Number 724503 | El Ferrol | Spain | 15405 | |
| 220 | Investigational Site Number 724508 | La Coruña | Spain | 15006 | |
| 221 | Investigational Site Number 724501 | Sabadell | Spain | 08208 | |
| 222 | Investigational Site Number 724507 | Segovia | Spain | 40002 | |
| 223 | Investigational Site Number 724502 | Valencia | Spain | 46014 | |
| 224 | Investigational Site Number 752501 | Ljungby | Sweden | 341 82 | |
| 225 | Investigational Site Number 752503 | Malmö | Sweden | 211 52 | |
| 226 | Investigational Site Number 752504 | Rättvik | Sweden | 79530 | |
| 227 | Investigational Site Number 752506 | Stenungssund | Sweden | 44431 | |
| 228 | Investigational Site Number 752505 | Stockholm | Sweden | 11526 | |
| 229 | Investigational Site Number 752502 | Vällingby | Sweden | 16268 | |
| 230 | Investigational Site Number 804501 | Chernivtsi | Ukraine | 58022 | |
| 231 | Investigational Site Number 804510 | Kyiv | Ukraine | 03049 | |
| 232 | Investigational Site Number 804507 | Kyiv | Ukraine | 04050 | |
| 233 | Investigational Site Number 804511 | Kyiv | Ukraine | ||
| 234 | Investigational Site Number 804513 | Lviv | Ukraine | 79010 | |
| 235 | Investigational Site Number 804502 | Vinnytsya | Ukraine | 21001 | |
| 236 | Investigational Site Number 804508 | Vinnytsya | Ukraine | 21010 |
Sponsors and Collaborators
- Sanofi
Investigators
- Study Director: Clinical Sciences & Operations, Sanofi
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT02058160
Other Study ID Numbers:
- EFC12405
- 2013-003132-79
- U1111-1148-4351
First Posted:
Feb 7, 2014
Last Update Posted:
May 9, 2017
Last Verified:
Mar 1, 2017
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The study was conducted at 236 centers in 18 countries. A total of 1930 participants were screened between January 27, 2014 and October 15, 2014. 912 participants were not eligible for run-in-phase mainly due to glycated hemoglobin (HbA1c) value being out of the protocol defined range. |
|---|---|
| Pre-assignment Detail | After screening phase, 1018 participants entered 6 week run-in phase during which participants were switched (if necessary) to insulin glargine and dose was titrated/stabilized, any oral anti-diabetic drugs (OAD) other than metformin were stopped. 282 participants were run-in failures and 736 were randomized in 1:1(FRC:insulin glargine arms) ratio. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination (FRC) | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously once daily (QD) for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Period Title: Overall Study | ||
| STARTED | 367 | 369 |
| Treated | 365 | 365 |
| COMPLETED | 336 | 355 |
| NOT COMPLETED | 31 | 14 |
Baseline Characteristics
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Total of all reporting groups |
| Overall Participants | 367 | 369 | 736 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
59.6
(9.4)
|
60.3
(8.7)
|
60.0
(9.1)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
202
55%
|
190
51.5%
|
392
53.3%
|
| Male |
165
45%
|
179
48.5%
|
344
46.7%
|
| Race (Count of Participants) | |||
| Caucasian |
337
91.8%
|
338
91.6%
|
675
91.7%
|
| Black |
17
4.6%
|
21
5.7%
|
38
5.2%
|
| Asian/Oriental |
12
3.3%
|
8
2.2%
|
20
2.7%
|
| Other |
1
0.3%
|
2
0.5%
|
3
0.4%
|
| Ethnicity (Count of Participants) | |||
| Hispanic |
66
18%
|
66
17.9%
|
132
17.9%
|
| Not Hispanic |
301
82%
|
303
82.1%
|
604
82.1%
|
| OAD Use (Count of Participants) | |||
| Yes |
349
95.1%
|
350
94.9%
|
699
95%
|
| No |
18
4.9%
|
19
5.1%
|
37
5%
|
| OAD Use at Screening by Class (Count of Participants) | |||
| Metformin |
170
46.3%
|
190
51.5%
|
360
48.9%
|
| Sulfonylurea |
16
4.4%
|
14
3.8%
|
30
4.1%
|
| Sodium glucose co-transporter 2 (SGLT-2) inhibitor |
0
0%
|
1
0.3%
|
1
0.1%
|
| Dipeptidyl-peptidase 4 (DPP-4) inhibitor |
2
0.5%
|
4
1.1%
|
6
0.8%
|
| Glinide |
1
0.3%
|
1
0.3%
|
2
0.3%
|
| Metformin + Sulfonylurea |
137
37.3%
|
118
32%
|
255
34.6%
|
| Metformin + DPP-4 inhibitor |
20
5.4%
|
18
4.9%
|
38
5.2%
|
| Metfomrin + Glinide |
2
0.5%
|
3
0.8%
|
5
0.7%
|
| Sulfonylurea + DPP-4 inhibitor |
1
0.3%
|
1
0.3%
|
2
0.3%
|
| None |
18
4.9%
|
19
5.1%
|
37
5%
|
| Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [kg/m^2] |
31.33
(4.25)
|
30.96
(4.15)
|
31.14
(4.20)
|
| Duration of Diabetes (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
12.02
(6.64)
|
12.13
(6.85)
|
12.08
(6.74)
|
| Daily Dose of Metformin (mg) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [mg] |
2082.8
(499.2)
|
2042.0
(455.9)
|
2062.4
(478.1)
|
| Screening Glycated Hemoglobin (HbA1c) (percentage of HbA1c) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [percentage of HbA1c] |
8.51
(0.65)
|
8.54
(0.67)
|
8.53
(0.66)
|
| Baseline HbA1c (percentage of HbA1c) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [percentage of HbA1c] |
8.07
(0.68)
|
8.08
(0.73)
|
8.08
(0.71)
|
| Fasting Plasma Glucose (FPG) (mmol/L) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [mmol/L] |
7.34
(1.95)
|
7.36
(2.12)
|
7.35
(2.04)
|
Outcome Measures
| Title | Change in Glycated Hemoglobin (HbA1c) From Baseline to Week 30 |
|---|---|
| Description | Change in HbA1c was calculated by subtracting baseline value from Week 30 value. |
| Time Frame | Baseline, Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Modified intent-to-treat (mITT) population: all randomized participants who had both baseline and at least one post-baseline efficacy assessment. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during study period. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 364 | 364 |
| Least Squares Mean (Standard Error) [percentage of HbA1c] |
-1.13
(0.057)
|
-0.62
(0.055)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine |
|---|---|---|
| Comments | Analysis was performed using Mixed-effect model with repeated measures (MMRM) with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of metformin use at screening, visits, treatment-by-visit interaction and country as fixed effects and baseline HbA1c value-by-visit interaction as covariates. A hierarchical testing procedure was used to control type I error and handle multiple endpoint analyses. | |
| Type of Statistical Test | Superiority or Other | |
| 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 | -0.52 | |
| Confidence Interval |
(2-Sided) 95% -0.633 to -0.397 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.06 |
|
| Estimation Comments | Insulin Glargine/Lixisenatide FRC vs Insulin Glargine | |
| Title | Percentage of Participants With HbA1c <7.0% or ≤6.5% at Week 30 |
|---|---|
| Description | |
| Time Frame | Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Participants with no value for HbA1c at Week 30 were counted as non-responders. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 366 | 365 |
| HbA1c <7.0% |
54.9
15%
|
29.6
8%
|
| HbA1c ≤ 6.5% |
33.9
9.2%
|
14.2
3.8%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine |
|---|---|---|
| Comments | HbA1c <7.0%: Insulin Glargine/Lixisenatide FRC vs Insulin Glargine. Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (<8.0%, ≥8.0%) and randomization strata of metformin use at screening. This analysis was out of testing order. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentage |
| Estimated Value | 25.52 | |
| Confidence Interval |
(2-Sided) 95% 18.94 to 32.10 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | HbA1c <7.0%: Insulin Glargine/Lixisenatide FRC vs Insulin Glargine | |
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine |
|---|---|---|
| Comments | HbA1c ≤6.5%: Insulin Glargine/Lixisenatide FRC vs Insulin Glargine. Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (<8.0%, ≥8.0%) and randomization strata of metformin use at screening. This analysis was out of testing order. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | ||
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference in percentage |
| Estimated Value | 19.76 | |
| Confidence Interval |
(2-Sided) 95% 13.90 to 25.62 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | HbA1c ≤6.5%: Insulin Glargine/Lixisenatide FRC vs Insulin Glargine | |
| Title | Change in 2-hour Plasma Blood Glucose Excursion From Baseline to Week 30 |
|---|---|
| Description | 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. |
| Time Frame | Baseline, Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline plasma glucose excursion assessment during study period. Missing data was imputed using last observation carried forward (LOCF). |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 329 | 336 |
| Least Squares Mean (Standard Error) [mmol/L] |
-3.9
(0.285)
|
-0.47
(0.274)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine |
|---|---|---|
| Comments | Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of metformin use at screening and country as fixed effects and baseline 2-hour plasma glucose excursion value as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| 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 | -3.43 | |
| Confidence Interval |
(2-Sided) 95% -3.925 to -2.939 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.251 |
|
| Estimation Comments | Insulin Glargine/Lixisenatide FRC vs Insulin Glargine | |
| Title | Change in Body Weight From Baseline to Week 30 |
|---|---|
| Description | Change in body weight was calculated by subtracting baseline value from Week 30 value. |
| Time Frame | Baseline, Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during study period. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 365 | 365 |
| Least Squares Mean (Standard Error) [kg] |
-0.67
(0.181)
|
0.7
(0.178)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine |
|---|---|---|
| Comments | Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of metformin use at screening, scheduled visits, treatment-by-visit interaction and country as fixed effects and baseline body weight value-by-visit interaction as covariates. | |
| Type of Statistical Test | Superiority or Other | |
| 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 | -1.37 | |
| Confidence Interval |
(2-Sided) 95% -1.808 to -0.93 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.224 |
|
| Estimation Comments | Insulin Glargine/Lixisenatide FRC vs Insulin Glargine | |
| Title | Mean Change in 7-point Self-monitored Plasma Glucose (SMPG) Profile From Baseline to Week 30 |
|---|---|
| Description | 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. |
| Time Frame | Baseline, Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Here, number of participants analyzed= participants with baseline and at least one post-baseline 7-point SMPG assessment during study period. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 323 | 320 |
| Least Squares Mean (Standard Error) [mmol/L] |
-1.5
(0.137)
|
-0.6
(0.13)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine |
|---|---|---|
| Comments | Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of metformin use at screening, scheduled visits, treatment-by-visit interaction and country as fixed effects and baseline average SMPG value-by-visit interaction as covariates. | |
| Type of Statistical Test | Superiority or Other | |
| 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 | -0.9 | |
| Confidence Interval |
(2-Sided) 95% -1.154 to -0.64 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.131 |
|
| Estimation Comments | Insulin Glargine/Lixisenatide FRC vs Insulin Glargine | |
| Title | Percentage of Participants Reaching HbA1c <7.0% With No Body Weight Gain at Week 30 |
|---|---|
| Description | |
| Time Frame | Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Participants without HbA1c and/or body weight value at Week 30 were counted as non-responders. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 366 | 365 |
| Number [percentage of participants] |
34.2
9.3%
|
13.4
3.6%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine |
|---|---|---|
| Comments | Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using Cochran-Mantel-Haenszel method stratified on randomization strata of Week -1 HbA1c (<8.0%, ≥8.0%) and randomization strata of metformin use at screening. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | Cochran-Mantel-Haenszel | |
| Comments | ||
| Method of Estimation | Estimation Parameter | difference in percentage |
| Estimated Value | 20.82 | |
| Confidence Interval |
(2-Sided) 95% 14.98 to 26.66 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Insulin Glargine/Lixisenatide FRC vs Insulin Glargine | |
| Title | Change in Daily Insulin Glargine Dose From Baseline to Week 30 |
|---|---|
| Description | |
| Time Frame | Baseline, Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. The analysis included scheduled measurements obtained up to the date of last injection of IMP. Here, number of participants analyzed= participants with insulin glargine dose assessment during study period. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 364 | 365 |
| Least Squares Mean (Standard Error) [Units (U)] |
10.64
(0.601)
|
10.89
(0.587)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Insulin Glargine/Lixisenatide Fixed Ratio Combination, Insulin Glargine |
|---|---|---|
| Comments | Testing according to the hierarchical testing procedure (continued only if previous endpoints were statistically significant). Analysis was performed using MMRM model with treatment groups, randomization strata of Week -1 HbA1c (<8.0, ≥8.0%), randomization strata of metformin use at screening, scheduled visits, treatment-by-visit interaction and country as fixed effects and baseline daily insulin glargine dose-by-visit interaction as a covariate. | |
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7362 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -0.26 | |
| Confidence Interval |
(2-Sided) 95% -1.762 to 1.246 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 0.766 |
|
| Estimation Comments | Insulin Glargine/Lixisenatide FRC vs Insulin Glargine | |
| Title | 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 |
|---|---|
| Description | 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). |
| Time Frame | Baseline up to Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Participants without HbA1c and/or body weight value at Week 30 were counted as non-responders. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 366 | 365 |
| Number [percentage of participants] |
19.9
5.4%
|
9.0
2.4%
|
| Title | Change in FPG From Baseline to Week 30 |
|---|---|
| Description | Change in FPG was calculated by subtracting baseline value from Week 30 value. |
| Time Frame | Baseline, Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Here, number of participants analyzed= participants with baseline and at least one post-baseline FPG assessment during study period. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 364 | 364 |
| Least Squares Mean (Standard Error) [mmol/L] |
-0.35
(0.142)
|
-0.46
(0.138)
|
| Title | Change in 2-hour PPG From Baseline to Week 30 |
|---|---|
| Description | Change in PPG was calculated by subtracting baseline value from Week 30 value. |
| Time Frame | Baseline, Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Here, number of participants analyzed= participants with baseline and at least one post-baseline PPG assessment during study period. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 332 | 340 |
| Least Squares Mean (Standard Error) [mmol/L] |
-4.72
(0.322)
|
-1.39
(0.31)
|
| Title | 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 |
|---|---|
| Description | 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). |
| Time Frame | Baseline up to Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. Participants with no value for HbA1c at Week 30 were counted as non-responders. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 366 | 365 |
| Number [percentage of participants] |
31.7
8.6%
|
18.6
5%
|
| Title | Percentage of Participants Requiring Rescue Therapy During 30-Week Treatment Period |
|---|---|
| Description | Routine fasting SMPG and central laboratory FPG (and HbA1c after Week 12) values were used to determine the requirement of rescue medication. If fasting SMPG value exceeded the specified limit for 3 consecutive days, the central laboratory FPG (and HbA1c after Week 12) were performed. Threshold values - from Week 8 to Week 12: fasting SMPG/FPG >240 mg/dL (13.3 mmol/L), and from Week 12 to Week 30: fasting SMPG/FPG >200 mg/dL (11.1 mmol/L) or HbA1c >8%. |
| Time Frame | Baseline up to Week 30 |
Outcome Measure Data
| Analysis Population Description |
|---|
| mITT population. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 366 | 365 |
| Number [percentage of participants] |
2.7
0.7%
|
6
1.6%
|
| Title | Number of Documented Symptomatic Hypoglycemia Events Per Subject-Year |
|---|---|
| Description | 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). |
| Time Frame | First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine]) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on safety population defined as all randomized participants who received at least one dose of IMP regardless of the amount of treatment administered. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 365 | 365 |
| Number [events per subject-year] |
3.03
|
4.22
|
| Title | Percentage of Participants With Documented Symptomatic Hypoglycemia |
|---|---|
| Description | 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). |
| Time Frame | First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine]) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on safety population. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 365 | 365 |
| Number [percentage of participants] |
40
10.9%
|
42.5
11.5%
|
| Title | Percentage of Participants With Severe Symptomatic Hypoglycemia |
|---|---|
| Description | Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Plasma glucose measurements might not had been available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal was considered sufficient evidence that the event had been induced by a low plasma glucose concentration. Severe symptomatic hypoglycemia included all episodes in which neurological impairment was severe enough to prevent self-treatment, and which were thus thought to place participants at risk for injury to themselves or others. |
| Time Frame | First dose of study drug up to 1 day after the last dose administration (median treatment exposure 211 days [FRC], 210 days [Insulin glargine]) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on safety population. |
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted. | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted. |
| Measure Participants | 365 | 365 |
| Number [percentage of participants] |
1.1
0.3%
|
0.3
0.1%
|
Adverse Events
| Time Frame | All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 30) regardless of seriousness or relationship to investigational product. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Reported AEs are treatment-emergent that is AEs that developed/worsened during 'on-emergent period' (time from first injection of open-label IMP up to 3 days after the last injection of IMP). Analysis was performed on safety population. | |||
| Arm/Group Title | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | ||
| Arm/Group Description | FRC injected subcutaneously QD for 30 weeks. Dose individually adjusted (median exposure: 211 days). | Insulin glargine 100 U/mL injected subcutaneously QD for 30 weeks. Dose individually adjusted (median exposure: 210 days). | ||
All Cause Mortality |
||||
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 20/365 (5.5%) | 18/365 (4.9%) | ||
| Cardiac disorders | ||||
| Acute myocardial infarction | 2/365 (0.5%) | 0/365 (0%) | ||
| Angina unstable | 2/365 (0.5%) | 0/365 (0%) | ||
| Arteriosclerosis coronary artery | 1/365 (0.3%) | 0/365 (0%) | ||
| Myocardial infarction | 1/365 (0.3%) | 0/365 (0%) | ||
| Supraventricular tachycardia | 1/365 (0.3%) | 0/365 (0%) | ||
| Cardiac failure congestive | 0/365 (0%) | 1/365 (0.3%) | ||
| Cardiopulmonary failure | 0/365 (0%) | 1/365 (0.3%) | ||
| Eye disorders | ||||
| Glaucoma | 0/365 (0%) | 1/365 (0.3%) | ||
| General disorders | ||||
| Chest discomfort | 0/365 (0%) | 1/365 (0.3%) | ||
| Non-cardiac chest pain | 0/365 (0%) | 2/365 (0.5%) | ||
| Hepatobiliary disorders | ||||
| Cholecystitis chronic | 1/365 (0.3%) | 0/365 (0%) | ||
| Cholecystitis acute | 0/365 (0%) | 1/365 (0.3%) | ||
| Infections and infestations | ||||
| Pneumonia | 1/365 (0.3%) | 1/365 (0.3%) | ||
| Osteomyelitis | 0/365 (0%) | 1/365 (0.3%) | ||
| Wound infection | 0/365 (0%) | 1/365 (0.3%) | ||
| Injury, poisoning and procedural complications | ||||
| Scar | 1/365 (0.3%) | 0/365 (0%) | ||
| Subdural haematoma | 1/365 (0.3%) | 0/365 (0%) | ||
| Meniscus injury | 0/365 (0%) | 1/365 (0.3%) | ||
| Metabolism and nutrition disorders | ||||
| Hypoglycaemia | 2/365 (0.5%) | 1/365 (0.3%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Osteoarthritis | 1/365 (0.3%) | 0/365 (0%) | ||
| Tendonitis | 1/365 (0.3%) | 0/365 (0%) | ||
| Intervertebral disc protrusion | 0/365 (0%) | 1/365 (0.3%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Benign breast neoplasm | 1/365 (0.3%) | 0/365 (0%) | ||
| Benign gastric neoplasm | 1/365 (0.3%) | 0/365 (0%) | ||
| Breast cancer | 1/365 (0.3%) | 0/365 (0%) | ||
| Squamous cell carcinoma of the tongue | 1/365 (0.3%) | 0/365 (0%) | ||
| Gallbladder cancer | 0/365 (0%) | 1/365 (0.3%) | ||
| Kaposi's sarcoma | 0/365 (0%) | 1/365 (0.3%) | ||
| Nervous system disorders | ||||
| Hypoglycaemic unconsciousness | 2/365 (0.5%) | 0/365 (0%) | ||
| Hypoglycaemic seizure | 1/365 (0.3%) | 0/365 (0%) | ||
| Renal and urinary disorders | ||||
| Renal impairment | 0/365 (0%) | 1/365 (0.3%) | ||
| Reproductive system and breast disorders | ||||
| Benign prostatic hyperplasia | 0/365 (0%) | 1/365 (0.3%) | ||
| Vascular disorders | ||||
| Hypertension | 0/365 (0%) | 1/365 (0.3%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 81/365 (22.2%) | 42/365 (11.5%) | ||
| Gastrointestinal disorders | ||||
| Nausea | 38/365 (10.4%) | 2/365 (0.5%) | ||
| Infections and infestations | ||||
| Nasopharyngitis | 32/365 (8.8%) | 32/365 (8.8%) | ||
| Nervous system disorders | ||||
| Headache | 21/365 (5.8%) | 10/365 (2.7%) | ||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Results Point of Contact
| Name/Title | Trial Transparency Team |
|---|---|
| Organization | Sanofi |
| Phone | |
| Contact-US@sanofi.com |
Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT02058160
Other Study ID Numbers:
- EFC12405
- 2013-003132-79
- U1111-1148-4351
First Posted:
Feb 7, 2014
Last Update Posted:
May 9, 2017
Last Verified:
Mar 1, 2017