Diabetes Mellitus, Type 2
Conditions
Brief summary
To evaluate the efficacy of a single injection of glulisine before the main meal added to insulin glargine plus oral antidiabetic drugs (OADs) compared to insulin glargine plus OADs in Type 2 diabetic patients poorly controlled with basal insulin plus OADs.
Interventions
DRUGInsulin Glargine
One daily injection at bedtime
DRUGGlimepiride
At same dosage as during the run-in period
DRUGInsulin Glulisine
One bolus given before the main meal
DRUGMetformin
At same dosage as during the run-in period
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diabetes Mellitus, Type 2 * 25 \< BMI \< 45 kg/m² * 7,5% \< HbA1c \< 9% * Treated with a basal insulin (NPH, Insulin Zinc, Insulin glargine or Insulin detemir), and at least 1g metformin daily, for more than 3 months
Exclusion criteria
* Type 1 diabetes mellitus * Treatment with OADs only * Treatment with thiazolidinediones, with exenatide or with pramlintide * Treatment with an insulin other than basal insulin (Premix, rapid insulin, fast-acting insulin analogue) * Active proliferative diabetic retinopathy, * Pregnancy (women of childbearing potential must have a negative pregnancy test at study entry and effective contraception) * Breast-feeding * History of hypersensitivity to the study drugs or to drugs with a similar chemical structure. * Treatment with systemic corticosteroids in the 3 months prior to study entry * Treatment with any investigational product in the 2 months prior to study entry * Previous treatment with insulin glulisine * Likelihood of requiring treatment during the study period with drugs not permitted by the clinical study protocol * Clinically relevant cardiovascular, hepatic, neurological, endocrine, or other major disease making implementation of the protocol or interpretation of the study results difficult * Impaired hepatic function * Impaired renal function * History of drug or alcohol abuse The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patients With Glycosylated Haemoglobin (HbA1c) Value < 7% | at the end of treatment (week 24) | Glycosylated Haemoglobin (HbA1c) is a biological parameter that reflects the blood glucose concentration over a long period of time. It is the standard parameter for glycemic control follow -up in diabetic patients. this parameter is expressed in percentage (%) and the target in diabetes management is to reach a HbA1c \<7% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Haemoglobin (HbA1c) Value | from baseline to the end of treatment (week 24) | — |
| Daily Mean Plasma Glucose | at the end of treatment (week 24) | — |
| Change in Daily Mean Plasma Glucose | from baseline to the end of treatment (week 24) | — |
| Change in Weight | from baseline to the end of treatment (week 24) | — |
| Glycosylated Haemoglobin (HbA1c) Value | at the end of treatment (week 24) | — |
| Daily Dose of Insulin Glulisine | at the end of treatment (week 24) | Mean of 3 daily doses reported during the week prior to the final visit |
| Rate of Symptomatic Hypoglycemia With Plasma Glucose < 70mg/dL | during treatment period (12 weeks) | — |
| Rate of Nocturnal Symptomatic Hypoglycemia With Plasma Glucose < 70mg/dL | during treatment period (12 weeks) | — |
| Rate of Severe Symptomatic Hypoglycemia | during treatment period (12 weeks) | — |
| Daily Dose of Insulin Glargine | at the end of treatment (week 24) | Mean of 3 daily doses reported during the week prior to the final visit |
Countries
Russia, United Kingdom, United States
Participant flow
Pre-assignment details
During Run-In period patients were not assigned to a treatment group. They were all treated with Insulin Glargine + Metformin + Glimepiride.
Participants by arm
| Arm | Count |
|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride Insulin Glulisine (One daily injection at main meal) + Insulin Glargine (One daily injection at bedtime) + Metformin (At same dosage as during the run-in period) + Glimepiride (At same dosage as during the run-in period) | 49 |
| Insulin Glargine+Metformin+Glimepiride Insulin Glargine (One daily injection at bedtime) + Metformin (At same dosage as during the run-in period) + Glimepiride (At same dosage as during the run-in period) | 57 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Run-In | Need of insulin with meals | 0 | 1 |
| Run-In | Non compliance with treatment procedure | 0 | 1 |
| Run-In | Patient did not meet inclusion criteria | 0 | 1 |
| Run-In | Patient personal reasons | 0 | 2 |
| Run-In | Physician Decision | 0 | 1 |
| Run-In | Sponsor request | 0 | 2 |
| Run-In | Withdrawal by Subject | 0 | 2 |
| Treatment Period | Early termination by error | 0 | 1 |
| Treatment Period | Non compliance with treatment procedure | 1 | 0 |
Baseline characteristics
| Characteristic | Insulin Glargine+Metformin+Glimepiride | Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Total |
|---|---|---|---|
| Age Continuous | 59.3 years STANDARD_DEVIATION 8.84 | 60.6 years STANDARD_DEVIATION 6.73 | 59.9 years STANDARD_DEVIATION 7.92 |
| Body Mass Index (BMI) | 33.3 kg/m² STANDARD_DEVIATION 4.39 | 33.2 kg/m² STANDARD_DEVIATION 5.3 | 33.3 kg/m² STANDARD_DEVIATION 4.8 |
| Daily Mean Plasma Glucose | 167.4 mg/dL STANDARD_DEVIATION 39.41 | 170.2 mg/dL STANDARD_DEVIATION 27.86 | 169 mg/dL STANDARD_DEVIATION 34.33 |
| Duration of diabetes | 11.0 years STANDARD_DEVIATION 7.02 | 12.1 years STANDARD_DEVIATION 7.29 | 11.5 years STANDARD_DEVIATION 7.13 |
| Glycosylated Haemoglobin (HbA1c) | 8.0 percent STANDARD_DEVIATION 0.67 | 7.8 percent STANDARD_DEVIATION 0.6 | 7.9 percent STANDARD_DEVIATION 0.64 |
| Region of Enrollment Russian Federation | 16 participants | 15 participants | 31 participants |
| Region of Enrollment United Kingdom | 14 participants | 11 participants | 25 participants |
| Region of Enrollment United States | 27 participants | 23 participants | 50 participants |
| Sex: Female, Male Female | 35 Participants | 29 Participants | 64 Participants |
| Sex: Female, Male Male | 22 Participants | 20 Participants | 42 Participants |
| Weight | 92.9 kg STANDARD_DEVIATION 17.15 | 91.5 kg STANDARD_DEVIATION 16.6 | 92.3 kg STANDARD_DEVIATION 16.83 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 49 | 0 / 57 |
| serious Total, serious adverse events | 1 / 49 | 2 / 57 |
Outcome results
Primary
Patients With Glycosylated Haemoglobin (HbA1c) Value < 7%
Glycosylated Haemoglobin (HbA1c) is a biological parameter that reflects the blood glucose concentration over a long period of time. It is the standard parameter for glycemic control follow -up in diabetic patients. this parameter is expressed in percentage (%) and the target in diabetes management is to reach a HbA1c \<7%
Time frame: at the end of treatment (week 24)
Population: Modified Intent to treat (ITT) population, LOCF (Last Observation Carried Forward)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Patients With Glycosylated Haemoglobin (HbA1c) Value < 7% | 22.4 percentage of participants |
| Insulin Glargine+Metformin+Glimepiride | Patients With Glycosylated Haemoglobin (HbA1c) Value < 7% | 8.8 percentage of participants |
Comparison: The null-hypothesis stated no differences between the 2 treatment groups regarding the percentage of patients with Glycosylated Haemoglobin (HbA1c) level \<7%. A sample size of 98 randomized (49/arm) patients would allow to demonstrate with 80% power that 40 % of patients in the Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride group would achieve a HbA1c level \< 7 % compared to 15 % of patients in the Insulin Glargine+Metformin+Glimepiride group(5% alpha risk, 2-sided test).p-value: 0.049995% CI: [0.01, 28.37]Chi-squared
Secondary
Change in Daily Mean Plasma Glucose
Time frame: from baseline to the end of treatment (week 24)
Population: Modified ITT population, LOCF
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Change in Daily Mean Plasma Glucose | -15.01 mg/dL | Standard Error 3.661 |
| Insulin Glargine+Metformin+Glimepiride | Change in Daily Mean Plasma Glucose | -2.07 mg/dL | Standard Error 3.384 |
Comparison: The null-hypothesis stated no differences between the 2 treatment groups regarding the adjusted mean change from baseline in daily mean plasma glucose at the end of treatment.p-value: 0.010995% CI: [-22.83, -3.04]ANCOVA
Secondary
Change in Glycosylated Haemoglobin (HbA1c) Value
Time frame: from baseline to the end of treatment (week 24)
Population: Modified ITT population, LOCF
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Change in Glycosylated Haemoglobin (HbA1c) Value | -0.37 percent | Standard Error 0.085 |
| Insulin Glargine+Metformin+Glimepiride | Change in Glycosylated Haemoglobin (HbA1c) Value | -0.11 percent | Standard Error 0.078 |
Comparison: The null-hypothesis stated no difference between the 2 treatment groups regarding the adjusted mean change from baseline in Glycosylated Haemoglobin (HbA1c) at the end of treatment.p-value: 0.02995% CI: [-0.49, -0.03]ANCOVA
Secondary
Change in Weight
Time frame: from baseline to the end of treatment (week 24)
Population: Modified ITT population, LOCF
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Change in Weight | 0.46 kg | Standard Error 0.316 |
| Insulin Glargine+Metformin+Glimepiride | Change in Weight | 0.22 kg | Standard Error 0.293 |
Comparison: The null-hypothesis stated no differences between the 2 treatment groups regarding the adjusted mean change from baseline in weight at the end of treatment.p-value: 0.576295% CI: [-0.61, 1.1]ANCOVA
Secondary
Daily Dose of Insulin Glargine
Mean of 3 daily doses reported during the week prior to the final visit
Time frame: at the end of treatment (week 24)
Population: Modified ITT population, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Daily Dose of Insulin Glargine | 54.7 units of insulin glargine per day | Standard Deviation 34.84 |
| Insulin Glargine+Metformin+Glimepiride | Daily Dose of Insulin Glargine | 62.2 units of insulin glargine per day | Standard Deviation 34.85 |
Secondary
Daily Dose of Insulin Glulisine
Mean of 3 daily doses reported during the week prior to the final visit
Time frame: at the end of treatment (week 24)
Population: Modified ITT population, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Daily Dose of Insulin Glulisine | 12.8 units of insulin glulisine per day | Standard Deviation 6.59 |
Secondary
Daily Mean Plasma Glucose
Time frame: at the end of treatment (week 24)
Population: Modified ITT population, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Daily Mean Plasma Glucose | 154.7 mg/dL | Standard Deviation 28.62 |
| Insulin Glargine+Metformin+Glimepiride | Daily Mean Plasma Glucose | 165.8 mg/dL | Standard Deviation 37.48 |
Secondary
Glycosylated Haemoglobin (HbA1c) Value
Time frame: at the end of treatment (week 24)
Population: Modified ITT population, LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Glycosylated Haemoglobin (HbA1c) Value | 7.5 percent | Standard Deviation 0.64 |
| Insulin Glargine+Metformin+Glimepiride | Glycosylated Haemoglobin (HbA1c) Value | 7.8 percent | Standard Deviation 0.85 |
Secondary
Rate of Nocturnal Symptomatic Hypoglycemia With Plasma Glucose < 70mg/dL
Time frame: during treatment period (12 weeks)
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Rate of Nocturnal Symptomatic Hypoglycemia With Plasma Glucose < 70mg/dL | 1.62 Number of hypoglycemia per patient-year | Standard Deviation 3.418 |
| Insulin Glargine+Metformin+Glimepiride | Rate of Nocturnal Symptomatic Hypoglycemia With Plasma Glucose < 70mg/dL | 3.95 Number of hypoglycemia per patient-year | Standard Deviation 9.339 |
Comparison: The null-hypothesis stated no difference between the 2 treatment groups regarding the rate of nocturnal symptomatic hypoglycemia with plasma glucose \<70 mg/dL during the treatment period.p-value: 0.302Wilcoxon (Mann-Whitney)
Secondary
Rate of Severe Symptomatic Hypoglycemia
Time frame: during treatment period (12 weeks)
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Rate of Severe Symptomatic Hypoglycemia | 0.00 Number of hypoglycemia per patient-year | Standard Deviation 0 |
| Insulin Glargine+Metformin+Glimepiride | Rate of Severe Symptomatic Hypoglycemia | 0.20 Number of hypoglycemia per patient-year | Standard Deviation 1.096 |
Comparison: The null-hypothesis stated no difference between the 2 treatment groups regarding the rate of severe symptomatic hypoglycemia during the treatment period.p-value: 0.192Wilcoxon (Mann-Whitney)
Secondary
Rate of Symptomatic Hypoglycemia With Plasma Glucose < 70mg/dL
Time frame: during treatment period (12 weeks)
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine+Insulin Glargine+Metformin+Glimepiride | Rate of Symptomatic Hypoglycemia With Plasma Glucose < 70mg/dL | 8.19 Number of hypoglycemia per patient-year | Standard Deviation 14.603 |
| Insulin Glargine+Metformin+Glimepiride | Rate of Symptomatic Hypoglycemia With Plasma Glucose < 70mg/dL | 7.68 Number of hypoglycemia per patient-year | Standard Deviation 13.996 |
Comparison: The null-hypothesis stated no difference between the 2 treatment groups regarding the rate of symptomatic hypoglycemia with plasma glucose \<70 mg/dL during the treatment period.p-value: 0.958Wilcoxon (Mann-Whitney)