Type 2 Diabetes Mellitus
Conditions
Brief summary
Primary Objective: \- To compare the two treatment regimens in terms of change of glycosylated hemoglobin (HbA1c) from baseline to endpoint (Week 24) Secondary Objective: * To assess the effect of the 2 lixisenatide regimens on: * The percentage of participants who reached the target of HbA1c \< 7% or ≤ 6.5% at Week 24 * Fasting Plasma Glucose (FPG) * 7-point Self-Monitored Plasma Glucose (SMPG) profiles * Body weight * To assess the safety and tolerability of the 2 lixisenatide regimens
Detailed description
The maximum study duration was 28 weeks per participant, including a 24-week randomized treatment period.
Interventions
DRUGLixisenatide (AVE0010)
Pharmaceutical form: Solution for injection; Route of administration: Subcutaneous
DEVICESelf-injector pen device (OptiClik®)
DRUGMetformin
To be kept at stable dose (≥1.5 g/day) throughout the study.
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with type 2 diabetes mellitus, diagnosed for at least 1 year before screening visit * Metformin treatment at a stable dose of at least 1.5 g/day for at least 3 months prior to screening visit.
Exclusion criteria
* Screening HbA1c \< 7.0% and \> 10.0% * Fasting plasma glucose at screening \> 250 mg/dL (\> 13.9 mmol/L) * Treatment with glucose-lowering agent(s) other than metformin in a period of 3 months prior to screening, previous use of insulin * Participants who usually did not eat breakfast * Type 1 diabetes mellitus * Body Mass Index (BMI) ≤ 20 kg/m\^2 and \> 40 kg/m\^2 * Pregnancy or lactation, women of childbearing potential with no effective contraceptive method * Amylase and/or lipase \> 3 times the upper limit of the normal laboratory range ( ULN) at screening * Alanine aminotransferase (ALT) \> 3 ULN at screening * Calcitonin ≧ 20 pg/ml (5.9 pmol/L) at screening * History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy. * Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predisposes to MTC (e.g. multiple endocrine neoplasia syndromes) * Any contra-indication related to metformin * Any previous treatment with lixisenatide The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 24 | Baseline, 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 up to 14 days after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Average 7-point SMPG Profiles From Baseline to Week 24 | Baseline, Week 24 | 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 8, before visit Week 12 and before visit week 24. The average value across the profiles performed in the week 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. The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to the day of last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline 7-point SMPG assessment during on-treatment period. |
| Change in FPG From Baseline to Week 24 | Baseline, Week 24 | Change in FPG was calculated by subtracting baseline value from Week 24 value. Missing data was imputed using LOCF. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 1 day after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline FPG assessment during on-treatment period. |
| Change in Body Weight From Baseline to Week 24 | Baseline, 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 up to 3 days after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during on-treatment period. |
| Percentage of Participants Who Reached the Target of HbA1c <7% at Week 24 And Did Not Experience Confirmed Symptomatic Hypoglycemia (Plasma Glucose [PG] <60 mg/dL [3.3 mmol/L]) During 24-Week Treatment Period | Week 24 | Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemic episode with an accompanying PG\<60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate if no PG measurement was available. On-treatment period for symptomatic hypoglycemia assessment was defined as time from first dose of study drug up to 1 day after last dose of study drug. Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one symptomatic hypoglycemia. Otherwise, they were counted as missing. |
| Percentage of Participants With HbA1c Level <7 % or ≤6.5% at Week 24 | Week 24 | Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period. |
| Percentage of Participants Who Reached the Target of HbA1c <7% And Had No Body Weight Gain at Week 24 And Did Not Experience Confirmed Symptomatic Hypoglycemia (PG<60 mg/dL [3.3 mmol/L]) During the 24-Week Treatment Period | Week 24 | Participants without post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart not more than 30-days apart were counted as non-responders if at least one of components (HbA1c and/or body weight) was available and showed no response. Otherwise, they were counted as missing. |
| Percentage of Participants Who Reached the Target of HbA1c <7% And Had a 2-hour Postprandial Plasma Glucose (PPG) <140mg/dL After Breakfast or Main Meal At Week 24 | Week 24 | On-treatment period for 2-hour PPG assessment was defined as the time from the first dose of study drug up to the day of last dose of study drug. Participants without post-baseline on-treatment values (for HbA1c and 2-hour PPG) that were no more than 30-days apart were counted as non-responders if at least one of the components (HbA1cand/or 2-hour PPG) was available and showed no response. Otherwise, they were counted as missing. |
| Change in Diabetes Treatment Satisfaction Questionnaire Score (DTSQs) From Baseline to Week 24 | Baseline, Week 24 | DTSQ is a validated measure to assess how satisfied participants with diabetes are with their treatment and how they perceive hyper- and hypoglycemia. It consists of 8 questions which are answered on a Likert scale from 0 to 6. DTSQ treatment satisfaction score is the sum of question 1, 4, 5, 6, 7 and 8 scores and ranges between 0 and 36, where higher scores indicate more treatment satisfaction. On-treatment period for treatment satisfaction assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. Missing data was imputed using LOCF. Here, number of participants analyzed = participants with both baseline and Week 24 DTSQ score assessment during on-treatment period. |
| Percentage of Participants Who Reached the Target of HbA1c <7% And Had No Body Weight Gain at Week 24 | Week 24 | Participants without 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 (HbA1c and/or body weight) was available and showed no response. Otherwise, they were counted as missing. |
Countries
Canada, Czechia, France, Germany, Poland, Romania, Russia, Spain, Ukraine, United States
Participant flow
Recruitment details
The study was conducted at 82 centers in 10 countries. A total of 734 participants were screened between February 15, 2012 and October 16, 2012. 283 participants were screen failures; main reason for screen failure was that glycosylated hemoglobin (HbA1c) values were out of protocol defined range. 451 participants were randomized.
Pre-assignment details
Participants were stratified according to main meal of day (breakfast, lunch or dinner) and screening values of HbA1c (\<8% or ≥8%).
Participants by arm
| Arm | Count |
|---|---|
| Lixisenatide Main Meal Lixisenatide 10 mcg SC injection QD within 1 hour before main meal of the day for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 24 on top of metformin. | 225 |
| Lixisenatide Breakfast Lixisenatide 10 mcg SC injection QD within 1 hour before breakfast for 2 weeks, then at a maintenance dose of 20 mcg QD up to Week 24 on top of metformin. | 226 |
| Total | 451 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 10 | 11 |
| Overall Study | Lack of Efficacy | 10 | 5 |
| Overall Study | Other than specified above | 8 | 5 |
| Overall Study | Poor compliance to protocol | 8 | 3 |
Baseline characteristics
| Characteristic | Lixisenatide Breakfast | Total | Lixisenatide Main Meal |
|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 9.7 | 56.9 years STANDARD_DEVIATION 10.2 | 56.3 years STANDARD_DEVIATION 10.6 |
| Average 7-point Self-monitored Plasma Glucose (SMPG) | 9.71 mmol/L STANDARD_DEVIATION 2.13 | 9.56 mmol/L STANDARD_DEVIATION 2.07 | 9.41 mmol/L STANDARD_DEVIATION 2.01 |
| BMI, Continuous | 32.77 kg/m^2 STANDARD_DEVIATION 4.62 | 33.12 kg/m^2 STANDARD_DEVIATION 4.57 | 33.47 kg/m^2 STANDARD_DEVIATION 4.5 |
| Duration of Diabetes | 7.78 years STANDARD_DEVIATION 5.56 | 7.24 years STANDARD_DEVIATION 5.27 | 6.69 years STANDARD_DEVIATION 4.92 |
| Ethnicity Hispanic | 12 participants | 23 participants | 11 participants |
| Ethnicity Non-Hispanic | 214 participants | 428 participants | 214 participants |
| Fasting Plasma Glucose (FPG) | 9.31 mmol/L STANDARD_DEVIATION 2.04 | 9.26 mmol/L STANDARD_DEVIATION 2.03 | 9.22 mmol/L STANDARD_DEVIATION 2.03 |
| HbA1c | 7.93 Percentage of hemoglobin STANDARD_DEVIATION 0.78 | 7.89 Percentage of hemoglobin STANDARD_DEVIATION 0.77 | 7.85 Percentage of hemoglobin STANDARD_DEVIATION 0.76 |
| Metformin Daily Dose | 2091.2 mg STANDARD_DEVIATION 1255.3 | 2066.0 mg STANDARD_DEVIATION 929.6 | 2040.7 mg STANDARD_DEVIATION 390 |
| Number of Participants with Categorical Body Mass Index (BMI) <30 kg/m^2 | 60 participants | 111 participants | 51 participants |
| Number of Participants with Categorical Body Mass Index (BMI) ≥30 kg/m^2 | 166 participants | 340 participants | 174 participants |
| Race Asian/Oriental | 7 participants | 17 participants | 10 participants |
| Race Black | 8 participants | 12 participants | 4 participants |
| Race Caucasian/White | 211 participants | 422 participants | 211 participants |
| Randomization Strata of Main Meal of the Day Breakfast | 20 participants | 40 participants | 20 participants |
| Randomization Strata of Main Meal of the Day Dinner | 89 participants | 178 participants | 89 participants |
| Randomization Strata of Main Meal of the Day Lunch | 117 participants | 233 participants | 116 participants |
| Sex: Female, Male Female | 129 Participants | 253 Participants | 124 Participants |
| Sex: Female, Male Male | 97 Participants | 198 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 225 | 60 / 226 |
| serious Total, serious adverse events | 7 / 225 | 7 / 226 |
Outcome results
Primary
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 up to 14 days after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period.
Time frame: Baseline, Week 24
Population: Modified intent-to-treat (mITT) population: all randomized participants who received at least one dose of study drug and had both baseline and at least one post-baseline assessment of any primary or secondary efficacy endpoints, irrespective of compliance with study protocol and procedures.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide Main Meal | Change in HbA1c From Baseline to Week 24 | -0.65 Percentage of hemoglobin | Standard Error 0.074 |
| Lixisenatide Breakfast | Change in HbA1c From Baseline to Week 24 | -0.74 Percentage of hemoglobin | Standard Error 0.074 |
Comparison: Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of screening HbA1c (\<8.0%, ≥8.0%), randomization strata of main meal of the day and country as fixed effects and baseline HbA1c value as a covariate.95% CI: [-0.067, 0.242]
Comparison: Analysis was performed using analysis of covariance (ANCOVA) model with treatment groups, randomization strata of screening HbA1c (\<8.0%, ≥8.0%), randomization strata of main meal of the day and country as fixed effects and baseline HbA1c value as a covariate. A step-down procedure was used to control the type I error. The superiority was assessed by comparing the p-value at significance level = 0.05.p-value: 0.2664ANCOVA
Secondary
Change in Average 7-point 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 two times in a week before baseline, before visit Week 8, before visit Week 12 and before visit week 24. The average value across the profiles performed in the week 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. The on-treatment period for this efficacy variable was defined as the time from the first dose of study drug up to the day of last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline 7-point SMPG assessment during on-treatment period.
Time frame: Baseline, Week 24
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide Main Meal | Change in Average 7-point SMPG Profiles From Baseline to Week 24 | -0.80 mmol/L | Standard Error 0.145 |
| Lixisenatide Breakfast | Change in Average 7-point SMPG Profiles From Baseline to Week 24 | -1.10 mmol/L | Standard Error 0.145 |
Secondary
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 up to 3 days after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline body weight assessment during on-treatment period.
Time frame: Baseline, Week 24
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide Main Meal | Change in Body Weight From Baseline to Week 24 | -2.60 kg | Standard Error 0.32 |
| Lixisenatide Breakfast | Change in Body Weight From Baseline to Week 24 | -2.80 kg | Standard Error 0.319 |
Secondary
Change in Diabetes Treatment Satisfaction Questionnaire Score (DTSQs) From Baseline to Week 24
DTSQ is a validated measure to assess how satisfied participants with diabetes are with their treatment and how they perceive hyper- and hypoglycemia. It consists of 8 questions which are answered on a Likert scale from 0 to 6. DTSQ treatment satisfaction score is the sum of question 1, 4, 5, 6, 7 and 8 scores and ranges between 0 and 36, where higher scores indicate more treatment satisfaction. On-treatment period for treatment satisfaction assessment was defined as the time from the first dose of study drug up to 3 days after the last dose of study drug. Missing data was imputed using LOCF. Here, number of participants analyzed = participants with both baseline and Week 24 DTSQ score assessment during on-treatment period.
Time frame: Baseline, Week 24
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide Main Meal | Change in Diabetes Treatment Satisfaction Questionnaire Score (DTSQs) From Baseline to Week 24 | 3.01 Units on a scale | Standard Error 0.546 |
| Lixisenatide Breakfast | Change in Diabetes Treatment Satisfaction Questionnaire Score (DTSQs) From Baseline to Week 24 | 3.54 Units on a scale | Standard Error 0.529 |
Secondary
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. The on-treatment period for this efficacy variable was the time from the first dose of study drug up to 1 day after the last dose of study drug. Here, number of participants analyzed = participants with baseline and at least one post-baseline FPG assessment during on-treatment period.
Time frame: Baseline, Week 24
Population: mITT population.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Lixisenatide Main Meal | Change in FPG From Baseline to Week 24 | -0.35 mmol/L | Standard Error 0.192 |
| Lixisenatide Breakfast | Change in FPG From Baseline to Week 24 | -0.57 mmol/L | Standard Error 0.193 |
Secondary
Percentage of Participants Who Reached the Target of HbA1c <7% And Had a 2-hour Postprandial Plasma Glucose (PPG) <140mg/dL After Breakfast or Main Meal At Week 24
On-treatment period for 2-hour PPG assessment was defined as the time from the first dose of study drug up to the day of last dose of study drug. Participants without post-baseline on-treatment values (for HbA1c and 2-hour PPG) that were no more than 30-days apart were counted as non-responders if at least one of the components (HbA1cand/or 2-hour PPG) was available and showed no response. Otherwise, they were counted as missing.
Time frame: Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide Main Meal | Percentage of Participants Who Reached the Target of HbA1c <7% And Had a 2-hour Postprandial Plasma Glucose (PPG) <140mg/dL After Breakfast or Main Meal At Week 24 | 28.9 Percentage of participants |
| Lixisenatide Breakfast | Percentage of Participants Who Reached the Target of HbA1c <7% And Had a 2-hour Postprandial Plasma Glucose (PPG) <140mg/dL After Breakfast or Main Meal At Week 24 | 27.6 Percentage of participants |
Secondary
Percentage of Participants Who Reached the Target of HbA1c <7% And Had No Body Weight Gain at Week 24
Participants without 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 (HbA1c and/or body weight) was available and showed no response. Otherwise, they were counted as missing.
Time frame: Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide Main Meal | Percentage of Participants Who Reached the Target of HbA1c <7% And Had No Body Weight Gain at Week 24 | 40.8 Percentage of participants |
| Lixisenatide Breakfast | Percentage of Participants Who Reached the Target of HbA1c <7% And Had No Body Weight Gain at Week 24 | 38.6 Percentage of participants |
Secondary
Percentage of Participants Who Reached the Target of HbA1c <7% And Had No Body Weight Gain at Week 24 And Did Not Experience Confirmed Symptomatic Hypoglycemia (PG<60 mg/dL [3.3 mmol/L]) During the 24-Week Treatment Period
Participants without post-baseline on-treatment values (for HbA1c and body weight) that were no more than 30 days apart not more than 30-days apart were counted as non-responders if at least one of components (HbA1c and/or body weight) was available and showed no response. Otherwise, they were counted as missing.
Time frame: Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide Main Meal | Percentage of Participants Who Reached the Target of HbA1c <7% And Had No Body Weight Gain at Week 24 And Did Not Experience Confirmed Symptomatic Hypoglycemia (PG<60 mg/dL [3.3 mmol/L]) During the 24-Week Treatment Period | 38.1 Percentage of participants |
| Lixisenatide Breakfast | Percentage of Participants Who Reached the Target of HbA1c <7% And Had No Body Weight Gain at Week 24 And Did Not Experience Confirmed Symptomatic Hypoglycemia (PG<60 mg/dL [3.3 mmol/L]) During the 24-Week Treatment Period | 37.2 Percentage of participants |
Secondary
Percentage of Participants Who Reached the Target of HbA1c <7% at Week 24 And Did Not Experience Confirmed Symptomatic Hypoglycemia (Plasma Glucose [PG] <60 mg/dL [3.3 mmol/L]) During 24-Week Treatment Period
Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemic episode with an accompanying PG\<60 mg/dL (3.3 mmol/L) or associated with prompt recovery after oral carbohydrate if no PG measurement was available. On-treatment period for symptomatic hypoglycemia assessment was defined as time from first dose of study drug up to 1 day after last dose of study drug. Participants without any post-baseline on-treatment value for HbA1c were counted as non-responders if they experienced at least one symptomatic hypoglycemia. Otherwise, they were counted as missing.
Time frame: Week 24
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lixisenatide Main Meal | Percentage of Participants Who Reached the Target of HbA1c <7% at Week 24 And Did Not Experience Confirmed Symptomatic Hypoglycemia (Plasma Glucose [PG] <60 mg/dL [3.3 mmol/L]) During 24-Week Treatment Period | 40.4 Percentage of participants |
| Lixisenatide Breakfast | Percentage of Participants Who Reached the Target of HbA1c <7% at Week 24 And Did Not Experience Confirmed Symptomatic Hypoglycemia (Plasma Glucose [PG] <60 mg/dL [3.3 mmol/L]) During 24-Week Treatment Period | 41.0 Percentage of participants |
Secondary
Percentage of Participants With HbA1c Level <7 % or ≤6.5% at Week 24
Here, number of participants analyzed = participants with baseline and at least one post-baseline HbA1c assessment during on-treatment period.
Time frame: Week 24
Population: mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lixisenatide Main Meal | Percentage of Participants With HbA1c Level <7 % or ≤6.5% at Week 24 | HbA1c <7% | 43.6 Percentage of participants |
| Lixisenatide Main Meal | Percentage of Participants With HbA1c Level <7 % or ≤6.5% at Week 24 | HbA1c ≤6.5% | 22.5 Percentage of participants |
| Lixisenatide Breakfast | Percentage of Participants With HbA1c Level <7 % or ≤6.5% at Week 24 | HbA1c <7% | 42.8 Percentage of participants |
| Lixisenatide Breakfast | Percentage of Participants With HbA1c Level <7 % or ≤6.5% at Week 24 | HbA1c ≤6.5% | 25.7 Percentage of participants |