A Phase 2 interventional study of Insulin glargine /lixisenatide Fixed Ratio Combination and Insulin glargine in Type 2 Diabetes Mellitus, sponsored by Sanofi. Completed at 70 sites in 13 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-02-10.
Sponsored by Sanofi · Phase 2, Interventional, and Treatment
Primary Objective:
Secondary Objectives:
To compare insulin glargine/lixisenatide FRC versus insulin glargine over 24 weeks on:
Approximately 27 weeks including a 24-week treatment period.
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This study's enrollment of 323 is above the median of 80 across 7,525 interventional studies indexed under Diabetes Mellitus, Type 2.
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Exclusion criteria:
The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
FRC injected once daily (QD) for 24 weeks. Dose individually adjusted.
Drug: Insulin glargine /lixisenatide Fixed Ratio Combination · Drug: Metformin (Background drug)
Insulin glargine QD for 24 weeks. Dose individually adjusted.
Drug: Insulin glargine · Drug: Metformin (Background drug)
FRC was self-administered by subcutaneous (SC) injection within 1 hour before breakfast using pen-type injector (Tactipen®): 100 U/ml insulin glargine and 50 mcg Lixisenatide (ratio of 2 U/1 mcg). The initial dose was 10 U/5 mcg and then 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.
Also known as: (HOE901/AVE0010)
Insulin glargine (100 U/ml) was self-administered by SC injection before breakfast using pen-type injector (Lantus® Solostar®). The initial daily dose of insulin glargine was 10 U 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).
Also known as: Lantus
Pharmaceutical form: Tablet; Route of administration: oral administration. To be kept at stable dose (≥1.5 g/day) throughout the study.
Change in HbA1c From Baseline to Week 24
Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using last observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of investigational medicinal product (IMP).
Time frame: Baseline, Week 24
Change in 2-hour Postprandial Plasma Glucose (PPG) From Baseline to Week 24
The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
Change in 2-hour Plasma Glucose Excursion From Baseline to Week 24
2-hour plasma glucose excursion = 2-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
Change in Average 7-Point Self-Monitored Plasma Glucose (SMPG) Profiles From Baseline to Week 24
Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, over a single day, once in a week before baseline, before visit Week 12 and before visit Week 24 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 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
Change in Body Weight From Baseline to Week 24
Change in body weight was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 3 days after the last injection of IMP.
Time frame: Baseline, Week 24
Average Daily Insulin Glargine Dose at Week 24
Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Week 24
Change in FPG From Baseline to Week 24
Change in FPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 1 day after the last injection of IMP.
Time frame: Baseline, Week 24
Percentage of Participants Requiring Rescue Therapy During 24-week Treatment Period
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 exceed 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 24
Percentage of Participants With HbA1c ≤6.5 % or <7.0 % at Week 24
On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.
Time frame: Week 24
Change in 30-minute and 1-hour PPG From Baseline to Week 24
The 30 minute and 1-hour PPG test measured blood glucose 30 minutes and 1-hour after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
Change in 30 Minute and 1-hour Plasma Glucose Excursion From Baseline to Week 24
30-minute and 1-hour plasma glucose excursion = 30-minute and 1-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
Time frame: Baseline, Week 24
Percentage of Participants Reaching HbA1c <7% at Week 24 With no Documented Symptomatic Hypoglycemia During 24-week Treatment Period
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). Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one documented symptomatic hypoglycemia before the introduction of rescue medication and up to 1 day after the last injection of IMP. Otherwise, they were counted as missing data. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.
Time frame: Baseline up to Week 24
Percentage of Participants Reaching HbA1c <7% With no Body Weight Gain at Week 24
Participants without any post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (for HbA1c and body weight) was available and showed non-response. Otherwise, they were counted as missing data.
Time frame: Week 24
Percentage of Participants With Documented Symptomatic and Severe Symptomatic Hypoglycemia
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).Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes were associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. All episodes in which neurological impairment was severe enough to prevent self-treatment and which were thought to place participants at risk for injury to themselves or others.
Time frame: First dose of study drug up to 3 days after the last dose administration (maximum of 219 days)
The study was conducted at 70 centers in 13 countries. A total of 520 participants were screened between November 21, 2011 and June 08, 2012. Out of 520 participants, 197 were screen failure; main reason for screen failure was that glycosylated hemoglobin (HbA1c) values were out of the protocol defined range.
| Milestone | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Started | 161 | 162 |
| Completed | 150 | 159 |
| Not completed | 11 | 3 |
| Withdrew: Adverse event | 6 | 0 |
| Withdrew: Poor compliance to protocol | 1 | 1 |
| Withdrew: Other reasons | 4 | 2 |
Change in HbA1c was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using last observation carried forward (LOCF). On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of investigational medicinal product (IMP).
| percentage of hemoglobin | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Change in HbA1c From Baseline to Week 24 | -1.82 ± 0.058 | -1.64 ± 0.057 |
The 2-hour PPG test measured blood glucose 2 hours after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
| mmol/L | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Change in 2-hour Postprandial Plasma Glucose (PPG) From Baseline to Week 24 | -7.49 ± 0.283 | -4.33 ± 0.274 |
2-hour plasma glucose excursion = 2-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
| mmol/L | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Change in 2-hour Plasma Glucose Excursion From Baseline to Week 24 | -3.91 ± 0.277 | -0.67 ± 0.269 |
Participants recorded a 7-point plasma glucose profile measured before and 2-hours after each meal and at bedtime, over a single day, once in a week before baseline, before visit Week 12 and before visit Week 24 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 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
| mmol/L | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Change in Average 7-Point Self-Monitored Plasma Glucose (SMPG) Profiles From Baseline to Week 24 | -3.23 ± 0.104 | -2.93 ± 0.101 |
Change in body weight was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 3 days after the last injection of IMP.
| kg | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Change in Body Weight From Baseline to Week 24 | -0.97 ± 0.289 | 0.48 ± 0.282 |
Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
| Units (U) | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Average Daily Insulin Glargine Dose at Week 24 | 36.08 ± 1.415 | 39.32 ± 1.384 |
Change in FPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 1 day after the last injection of IMP.
| mmol/L | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Change in FPG From Baseline to Week 24 | -3.35 ± 0.130 | -3.51 ± 0.128 |
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 exceed 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%.
| percentage of participants | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Percentage of Participants Requiring Rescue Therapy During 24-week Treatment Period | 0 | 0.6 |
On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.
| percentage of participants | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| HbA1c ≤6.5% | 71.9 | 64.6 |
| HbA1c <7.0% | 84.4 | 78.3 |
The 30 minute and 1-hour PPG test measured blood glucose 30 minutes and 1-hour after eating a standardized meal. Change in PPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
| mmol/L | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| 30-minute PPG (n=151, 153) | -5.01 ± 0.194 | -3.76 ± 0.187 |
| 1-hour PPG (n=150, 153) | -5.94 ± 0.246 | -4.10 ± 0.239 |
30-minute and 1-hour plasma glucose excursion = 30-minute and 1-hour PPG minus plasma glucose value obtained 30 minutes prior to the start of the meal and before IMP administration. Change in plasma glucose excursion was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to the date of last injection of IMP.
| mmol/L | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| 30-minute plasma glucose excursion (n=151, 152) | -1.47 ± 0.156 | -0.05 ± 0.151 |
| 1-hour plasma glucose excursion (n=150, 152) | -2.34 ± 0.233 | -0.44 ± 0.226 |
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). Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one documented symptomatic hypoglycemia before the introduction of rescue medication and up to 1 day after the last injection of IMP. Otherwise, they were counted as missing data. On-treatment period for this efficacy variable was defined as the time from the first dose of study drug till before the introduction of rescue medication and up to 14 days after the last injection of IMP.
| percentage of participants | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Percentage of Participants Reaching HbA1c <7% at Week 24 With no Documented Symptomatic Hypoglycemia During 24-week Treatment Period | 67.5 | 59.0 |
Participants without any post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart were counted as non-responders if at least one of the components (for HbA1c and body weight) was available and showed non-response. Otherwise, they were counted as missing data.
| percentage of participants | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| Percentage of Participants Reaching HbA1c <7% With no Body Weight Gain at Week 24 | 56.3 | 37.3 |
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).Severe symptomatic hypoglycemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes were associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. All episodes in which neurological impairment was severe enough to prevent self-treatment and which were thought to place participants at risk for injury to themselves or others.
| percentage of participants | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine (Lantus® SoloSTAR®) |
|---|---|---|
| Documented symptomatic hypoglycemia | 21.7 | 22.8 |
| Severe Symptomatic Hypoglycemia | 0.0 | 0.0 |
Collected over All Adverse events (AEs) were collected from signature of the informed consent from up to the final visit (Week 24) regardless of seriousness or relationship to investigational product.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Insulin Glargine/Lixisenatide Fixed Ratio Combination | — | 9/161 (5.6%) | 26/161 (16.1%) |
| Insulin Glargine | — | 6/162 (3.7%) | 21/162 (13%) |
| Event | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| CellulitisInfections and infestations | 1/161 | 0/162 |
| Ovarian cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 1/161 | 0/162 |
| Diabetic neuropathyNervous system disorders | 1/161 | 0/162 |
| SciaticaNervous system disorders | 1/161 | 0/162 |
| Angina pectorisCardiac disorders | 1/161 | 0/162 |
| Angina unstableCardiac disorders | 1/161 | 0/162 |
| BradycardiaCardiac disorders | 1/161 | 0/162 |
| Intervertebral disc protrusionMusculoskeletal and connective tissue disorders | 1/161 | 0/162 |
| Pain in extremityMusculoskeletal and connective tissue disorders | 1/161 | 0/162 |
| Calculus uretericRenal and urinary disorders | 1/161 | 0/162 |
| Event | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine |
|---|---|---|
| NauseaGastrointestinal disorders | 12/161 | 0/162 |
| HeadacheNervous system disorders | 8/161 | 12/162 |
| NasopharyngitisInfections and infestations | 9/161 | 9/162 |
| Age, Continuous(years) | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Mean | 56.9 ± 9.5 | 56.6 ± 9.4 | 56.7 ± 9.4 |
| Gender(Participants) | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Female | 81 | 77 | 158 |
| Male | 80 | 85 | 165 |
| Race(participants) | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Caucasian/White | 158 | 160 | 318 |
| Black | 2 | 1 | 3 |
| Asian/Oriental | 1 | 1 | 2 |
| Ethnicity(participants) | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Hispanic | 35 | 30 | 65 |
| Non Hispanic | 126 | 132 | 258 |
| Screening HbA1c(percentage of haemoglobin) | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Mean | 8.12 ± 0.80 | 8.08 ± 0.77 | 8.10 ± 0.78 |
| Baseline BMI(kg/m^2) | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Mean | 32.24 ± 4.75 | 32.02 ± 4.35 | 32.13 ± 4.55 |
| Duration of Diabetes(years) | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Mean | 6.29 ± 4.29 | 7.10 ± 5.27 | 6.69 ± 4.82 |
| Daily Dose of Metformin(mg) | Insulin Glargine/Lixisenatide Fixed Ratio Combination | Insulin Glargine | Total |
|---|---|---|---|
| Mean | 2075.8 ± 440.7 | 2093.7 ± 415.5 | 2084.8 ± 427.7 |
1 further baseline measures are reported on the registry.
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