Diabetes Mellitus, Type 1
Conditions
Brief summary
Primary objective: To demonstrate the superiority of insulin glulisine over insulin aspart and insulin lispro administered by external pump in term of unexplained hyperglycemia and/or infusion set occlusion. Main Secondary objectives: To compare insulin glulisine, insulin aspart and insulin lispro on: * Unexplained hyperglycemia * Infusion set occlusion * Hypoglycemic episodes,7-point blood glucose profiles * Episodes of significant ketosis and/or risk level for impending diabetic ketoacidosis * Time to change the infusion set * HbA1c (Glycosylated hemoglobin) * Overall safety: incidence of adverse events
Detailed description
The maximal duration of the study participation for patients was 41 weeks and one day, split in: * a 2-week screening period, * a 39-week treatment period: 3 treatment periods of 13 weeks with a crossover alternative regimen, including a dose adjustment period of 1 week at the beginning of each period (sequence1: insulin glulisine, then insulin aspart, then insulin lispro; sequence2: insulin aspart, then insulin lispro, then insulin glulisine; sequence 3: insulin lispro, then insulin glulisine, then insulin aspart) * and a follow-up period of 24 hours.
Interventions
DRUGInsulin glulisine
100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump
DRUGInsulin lispro
100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump
DRUGInsulin aspart
100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Type 1 diabetic subjects * Treated with insulin for at least 2 years and by CSII for at least 6 months * Using the same insulin (insulin glulisine, insulin aspart or insulin lispro) in CSII for at least 3 months with the same external pump compatible with the 3 short acting insulin analogues used in the study * Using the same type of infusion set (catheter and cannula) for at least 3 months * Performing at least 3 blood glucose controls per day * HbA1c \< 8.5% * Body mass index (BMI) \< 35 kg/m² * Ability and willingness to perform blood glucose and ketone monitoring using the Sponsor-provided combined glucose and ketone meter and patient diary at home
Exclusion criteria
* Diabetes other than Type 1 * Total daily dose of insulin greater than 90 U/day * Using an insulin pump requiring pre-filled cartridges * History of infection at infusion site requiring a drainage in the last 3 months * History of severe episodes of ketosis requiring hospitalization in the last 6 months * Active proliferative retinopathy, as defined by a photocoagulation or vitrectomy occurrence in the 6 months prior to visit 1, or any other unstable (rapidly progressing) retinopathy that may require photocoagulation or surgical treatment during the study. An ophthalmoscopic examination should have been performed in the 2 years prior to study entry * Pregnancy (women of childbearing potential must have a negative pregnancy test at study entry and a medically approved contraception method) or breastfeeding * Treatment with systemic corticosteroids or medication known to influence insulin sensitivity in the 3 months prior to visit 1 * Treatment with antidiabetic drug other than insulin in the 3 months prior to visit 1 * Likelihood of requiring treatments during the study which are not permitted * Treatment with an investigational product in the 30 days prior to visit 1 * History of sensitivity to the study drugs or to drugs with a similar chemical structure * Presence of any condition (medical, including clinically significant abnormal laboratory test, psychological, social or geographical) actual or anticipated that the Investigator feels would compromise the patient safety or limit his/her successful participation in the study * Night shift workers * Impaired renal function as shown by serum creatinine ≥1.5 mg/dL (133 μmol/L) or ≥1.4 mg/dL (124 μmol/L) in men and women, respectively * Impaired hepatic function as shown by Alanine aminotransferase (ALT) and/or Aspart aminotransferase (AST) greater than three times the upper limit of normal range) * Alcohol or drug abuse in the last year * Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study 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 |
|---|---|---|
| Percentage of Patients With at Least One Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion | over 13 weeks of each treatment period | Unexplained hyperglycemia defined as blood glucose value above 300 mg/dL (16.7 mmol/L) with no apparent medical dietary, insulin dosage or pump failure reason. Pump infusion set occlusion defined by at least one of the following items: * pump occlusion alarm, * patient observation of an occlusion, spontaneously or because of elevated blood glucose value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With at Least One Unexplained Hyperglycemia | over 13 weeks of each treatment period | Unexplained hyperglycemia defined as blood glucose value above 300 mg/dL (16.7 mmol/L) with no apparent medical dietary, insulin dosage or pump failure reason. |
| Monthly Rate of Unexplained Hyperglycemia | over 13 weeks of each treatment period | — |
| Percentage of Patients With at Least One Confirmed Infusion Set Occlusion | over 13 weeks of each treatment period | Pump infusion set occlusion defined by at least one of the following items: * pump occlusion alarm, * patient observation of an occlusion, spontaneously or because of elevated blood glucose value. |
| Monthly Rate of Confirmed Infusion Set Occlusion | over 13 weeks of each treatment period | — |
| Percentage of Patients With at Least One Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis | over 13 weeks of each treatment period | Diabetic ketoacidosis (DKA) is preceded by an increase in ketone production, resulting in blood ketone value increase (hyperketonemia) and later in ketone urine value (hyperketonuria). Significant hyperketonemia and risk level for impending diabetic ketoacidosis (DKA) are reported respectively as a blood ketone value from 0.6 to 1.5 mmol/L and \>1.5 mmol/l |
| Monthly Rate of Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis | over 13 weeks of each treatment period | Diabetic ketoacidosis (DKA) is preceded by an increase in ketone production, resulting in blood ketone value increase (hyperketonemia) and later in ketone urine value (hyperketonuria). Significant hyperketonemia and risk level for impending diabetic ketoacidosis (DKA) are reported respectively as a blood ketone value from 0.6 to 1.5 mmol/L and \>1.5 mmol/l |
| Rate of Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤ 70 mg/dL Per Patient-year | over 13 weeks of each treatment period | Symptomatic hypoglycemia is defined as an event with clinical symptoms that are considered to results from hypoglycemia (confirmed or not by a glucose measurement) and associated with prompt recovery after oral carbohydrate administration. |
| Monthly Rate of Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion | over 13 weeks of each treatment period | Unexplained hyperglycemia defined as blood glucose value above 300 mg/dL (16.7 mmol/L) with no apparent medical dietary, insulin dosage or pump failure reason. Pump infusion set occlusion defined by at least one of the following items: * pump occlusion alarm, * patient observation of an occlusion, spontaneously or because of elevated blood glucose value. |
| Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year | over 13 weeks of each treatment period | Nocturnal Symptomatic hypoglycemia was defined as an event with clinical symptoms that are considered to result from hypoglycemia (confirmed or not by a glucose measurement) and associated with prompt recovery after oral carbohydrate administration which occurs while the patient is asleep, after bedtime and before getting up in the morning. |
| Patients With at Least One Site Infection, Site Inflammation/Erythema, Pruritus or Isolated Pain at Injection Site | over 13 weeks of each treatment period | Infection: local reaction at the infusion site requiring local or systemic antibiotherapy, or local drainage as per Investigator judgment. Site inflammation or erythema: local reaction at the infusion site with no need for local or systemic antibiotherapy as per Investigator judgment. Pruritis at injection site: presence of pruritis at the infusion site without any symptom of inflammation or erythema and/or infection. Isolated pain at injection site: presence of pain at the infusion site without any symptom of inflammation or erythema and/or infection. |
| Time Interval Between Infusion Set Changes: All Changes | over 13 weeks of each treatment period | Patients treated with insulin pump have to change their infusion set regularly (i.e.change was recommended every 48h). The patients were asked to report any change of their infusion set and the reason for change (routine basis or because of occurrence of a specific event such as occlusion, unexplained hyperglycemia or adverse event). All changes include all the changes whatever the reason such as routine or requested by occurrence of events. |
| Time Interval Between Infusion Set Changes in Routine | over 13 weeks of each treatment period | Patients treated with insulin pump have to change their infusion set regularly (i.e.change was recommended every 48h). The patients were asked to report any change of their infusion set and the reason for change (routine basis or because of occurrence of a specific event such as occlusion, unexplained hyperglycemia or adverse event). Changes in routine correspond to interval between changes according to patient use. |
| Glycosylated Hemoglobin: HbA1c | over 13 weeks of each treatment period | Glycolysated 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% |
| Total Daily Basal Insulin Infusion | over 13 weeks of each treatment period | dose of the basal insulin regimen administered throughout the 24-hour period |
| Total Daily Bolus Insulin Dose | over 13 weeks of each treatment period | dose of every increment administered for example before meals |
| Rate of Severe Symptomatic Hypoglycemia Per Patient-year | over 13 weeks of each treatment period | Severe symptomatic hypoglycemia is defined as an event with clinical symptoms that are considered to results from hypoglycemia in which the patient required assistance of another person and one of the following: * the event was associated with a measured blood glucose level below 36 mg/dL * or event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration. |
Countries
Australia, Austria, France, Hungary, Israel, Italy, Netherlands, South Korea, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Multicenter study: 44 active centers from 12 countries in Europe, USA and Asia Pacific region. Study Initiation date: January 8, 2008, Study Completion Date: June 15, 2009.
Pre-assignment details
359 participants screened; 289 randomized; 288 patients treated (1 patient not treated per physician's decision): 274 with insulin glulisine, 269 with insulin lispro, 266 with insulin aspart. The safety population, (N=288 patients randomized and treated) is described in the participant flow and baseline characteristics.
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 insulin glulisine / insulin aspart / insulin lispro | 99 |
| Sequence 2 insulin aspart / insulin lispro / insulin glulisine | 95 |
| Sequence 3 insulin lispro / insulin glulisine / insulin aspart | 94 |
| Total | 288 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 | 3 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Other reason | 1 | 5 | 2 |
| Overall Study | Poor compliance to protocol | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 9 | 4 | 4 |
| Period 1 | Adverse Event | 3 | 0 | 0 |
| Period 1 | Lost to Follow-up | 1 | 0 | 0 |
| Period 1 | Other reason | 0 | 4 | 2 |
| Period 1 | Poor compliance to protocol | 1 | 0 | 0 |
| Period 1 | Withdrawal by Subject | 7 | 2 | 3 |
| Period 2 | Adverse Event | 0 | 1 | 3 |
| Period 2 | Other reason | 1 | 1 | 0 |
| Period 2 | Poor compliance to protocol | 0 | 0 | 1 |
| Period 2 | Withdrawal by Subject | 0 | 1 | 1 |
| Period 3 | Adverse Event | 0 | 1 | 0 |
| Period 3 | Withdrawal by Subject | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Sequence 2 | Sequence 3 | Total | Sequence 1 |
|---|---|---|---|---|
| Age Continuous | 45.84 years STANDARD_DEVIATION 13.59 | 44.04 years STANDARD_DEVIATION 12.87 | 44.43 years STANDARD_DEVIATION 13.39 | 43.45 years STANDARD_DEVIATION 13.71 |
| Body Mass Index (BMI) | 25.25 kg/m² STANDARD_DEVIATION 3.91 | 25.92 kg/m² STANDARD_DEVIATION 3.98 | 25.39 kg/m² STANDARD_DEVIATION 3.81 | 25.01 kg/m² STANDARD_DEVIATION 3.53 |
| Central fasting plasma glucose | 147.45 mg/dL STANDARD_DEVIATION 61.63 | 151.18 mg/dL STANDARD_DEVIATION 64.06 | 149.48 mg/dL STANDARD_DEVIATION 61.37 | 149.84 mg/dL STANDARD_DEVIATION 59.03 |
| Duration of treatment with CSII (continuous subcutaneous insulin infusion) at study entry | 5.52 years STANDARD_DEVIATION 5.27 | 6.31 years STANDARD_DEVIATION 4.95 | 5.94 years STANDARD_DEVIATION 5.01 | 5.99 years STANDARD_DEVIATION 4.83 |
| Duration of treatment with insulin at study entry | 23.07 years STANDARD_DEVIATION 13.33 | 22.75 years STANDARD_DEVIATION 11.08 | 22.73 years STANDARD_DEVIATION 12.67 | 22.39 years STANDARD_DEVIATION 13.53 |
| Duration of treatment with previous insulin at study entry | 4.37 years STANDARD_DEVIATION 3.05 | 4.79 years STANDARD_DEVIATION 3 | 4.67 years STANDARD_DEVIATION 3.22 | 4.84 years STANDARD_DEVIATION 3.58 |
| Glycosylated Haemoglobin (HbA1c) | 7.36 Percent STANDARD_DEVIATION 0.61 | 7.41 Percent STANDARD_DEVIATION 0.69 | 7.38 Percent STANDARD_DEVIATION 0.66 | 7.38 Percent STANDARD_DEVIATION 0.69 |
| Previous insulin at study entry Insulin aspart | 43 participants | 42 participants | 117 participants | 32 participants |
| Previous insulin at study entry Insulin glulisine | 2 participants | 2 participants | 8 participants | 4 participants |
| Previous insulin at study entry Insulin lispro | 49 participants | 50 participants | 162 participants | 63 participants |
| Region of Enrollment Australia | 4 participants | 3 participants | 11 participants | 4 participants |
| Region of Enrollment Austria | 9 participants | 8 participants | 24 participants | 7 participants |
| Region of Enrollment France | 9 participants | 10 participants | 27 participants | 8 participants |
| Region of Enrollment Hungary | 4 participants | 6 participants | 14 participants | 4 participants |
| Region of Enrollment Israel | 11 participants | 10 participants | 32 participants | 11 participants |
| Region of Enrollment Italy | 7 participants | 7 participants | 23 participants | 9 participants |
| Region of Enrollment Korea, Republic of | 1 participants | 1 participants | 3 participants | 1 participants |
| Region of Enrollment Netherlands | 8 participants | 7 participants | 23 participants | 8 participants |
| Region of Enrollment Spain | 9 participants | 10 participants | 30 participants | 11 participants |
| Region of Enrollment Sweden | 8 participants | 7 participants | 24 participants | 9 participants |
| Region of Enrollment United Kingdom | 4 participants | 4 participants | 13 participants | 5 participants |
| Region of Enrollment United States | 21 participants | 21 participants | 64 participants | 22 participants |
| Sex: Female, Male Female | 54 Participants | 48 Participants | 151 Participants | 49 Participants |
| Sex: Female, Male Male | 41 Participants | 46 Participants | 137 Participants | 50 Participants |
| Total daily basal insulin infusion | 19.99 Units STANDARD_DEVIATION 9.38 | 22.03 Units STANDARD_DEVIATION 9.17 | 21.00 Units STANDARD_DEVIATION 9.13 | 20.98 Units STANDARD_DEVIATION 8.84 |
| Total daily bolus insulin dose | 18.58 Units STANDARD_DEVIATION 10.34 | 19.35 Units STANDARD_DEVIATION 7.78 | 19.18 Units STANDARD_DEVIATION 9.22 | 19.61 Units STANDARD_DEVIATION 9.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 47 / 274 | 24 / 266 | 30 / 269 |
| serious Total, serious adverse events | 29 / 274 | 18 / 266 | 11 / 269 |
Outcome results
Primary
Percentage of Patients With at Least One Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion
Unexplained hyperglycemia defined as blood glucose value above 300 mg/dL (16.7 mmol/L) with no apparent medical dietary, insulin dosage or pump failure reason. Pump infusion set occlusion defined by at least one of the following items: * pump occlusion alarm, * patient observation of an occlusion, spontaneously or because of elevated blood glucose value.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glulisine | Percentage of Patients With at Least One Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion | 68.4 percentage of patients |
| Insulin Aspart | Percentage of Patients With at Least One Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion | 62.1 percentage of patients |
| Insulin Lispro | Percentage of Patients With at Least One Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion | 61.3 percentage of patients |
p-value: 0.039McNemar
p-value: 0.031McNemar
Secondary
Glycosylated Hemoglobin: HbA1c
Glycolysated 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: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Glulisine | Glycosylated Hemoglobin: HbA1c | First week (week 1) (n=253, n=254, n=255) | 7.31 percentage | Standard Deviation 0.71 |
| Insulin Glulisine | Glycosylated Hemoglobin: HbA1c | Last week (week 13) (n=252, n=255, n=251) | 7.32 percentage | Standard Deviation 0.03 |
| Insulin Aspart | Glycosylated Hemoglobin: HbA1c | First week (week 1) (n=253, n=254, n=255) | 7.33 percentage | Standard Deviation 0.71 |
| Insulin Aspart | Glycosylated Hemoglobin: HbA1c | Last week (week 13) (n=252, n=255, n=251) | 7.25 percentage | Standard Deviation 0.03 |
| Insulin Lispro | Glycosylated Hemoglobin: HbA1c | First week (week 1) (n=253, n=254, n=255) | 7.28 percentage | Standard Deviation 0.71 |
| Insulin Lispro | Glycosylated Hemoglobin: HbA1c | Last week (week 13) (n=252, n=255, n=251) | 7.33 percentage | Standard Deviation 0.03 |
p-value: 0.078ANCOVA
p-value: 0.938ANCOVA
Secondary
Monthly Rate of Confirmed Infusion Set Occlusion
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Monthly Rate of Confirmed Infusion Set Occlusion | 0.41 events per patient per month | Standard Error 0.06 |
| Insulin Aspart | Monthly Rate of Confirmed Infusion Set Occlusion | 0.28 events per patient per month | Standard Error 0.06 |
| Insulin Lispro | Monthly Rate of Confirmed Infusion Set Occlusion | 0.31 events per patient per month | Standard Error 0.06 |
p-value: 0.015Mixed Models Analysis
p-value: 0.073Mixed Models Analysis
Secondary
Monthly Rate of Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is preceded by an increase in ketone production, resulting in blood ketone value increase (hyperketonemia) and later in ketone urine value (hyperketonuria). Significant hyperketonemia and risk level for impending diabetic ketoacidosis (DKA) are reported respectively as a blood ketone value from 0.6 to 1.5 mmol/L and \>1.5 mmol/l
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Monthly Rate of Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis | 0.14 events per patient per month | Standard Error 0.43 |
| Insulin Aspart | Monthly Rate of Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis | 0.06 events per patient per month | Standard Error 0.22 |
| Insulin Lispro | Monthly Rate of Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis | 0.06 events per patient per month | Standard Error 0.18 |
p-value: 0.009Mixed Models Analysis
p-value: 0.019Mixed Models Analysis
Secondary
Monthly Rate of Unexplained Hyperglycemia
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Monthly Rate of Unexplained Hyperglycemia | 1.61 events per patient per month | Standard Error 0.13 |
| Insulin Aspart | Monthly Rate of Unexplained Hyperglycemia | 1.04 events per patient per month | Standard Error 0.13 |
| Insulin Lispro | Monthly Rate of Unexplained Hyperglycemia | 1.23 events per patient per month | Standard Error 0.13 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001McNemar
Secondary
Monthly Rate of Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion
Unexplained hyperglycemia defined as blood glucose value above 300 mg/dL (16.7 mmol/L) with no apparent medical dietary, insulin dosage or pump failure reason. Pump infusion set occlusion defined by at least one of the following items: * pump occlusion alarm, * patient observation of an occlusion, spontaneously or because of elevated blood glucose value.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Monthly Rate of Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion | 2.02 events per patient per month | Standard Error 0.15 |
| Insulin Aspart | Monthly Rate of Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion | 1.32 events per patient per month | Standard Error 0.15 |
| Insulin Lispro | Monthly Rate of Unexplained Hyperglycemia and/ or Confirmed Infusion Set Occlusion | 1.54 events per patient per month | Standard Error 0.15 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
Secondary
Patients With at Least One Site Infection, Site Inflammation/Erythema, Pruritus or Isolated Pain at Injection Site
Infection: local reaction at the infusion site requiring local or systemic antibiotherapy, or local drainage as per Investigator judgment. Site inflammation or erythema: local reaction at the infusion site with no need for local or systemic antibiotherapy as per Investigator judgment. Pruritis at injection site: presence of pruritis at the infusion site without any symptom of inflammation or erythema and/or infection. Isolated pain at injection site: presence of pain at the infusion site without any symptom of inflammation or erythema and/or infection.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glulisine | Patients With at Least One Site Infection, Site Inflammation/Erythema, Pruritus or Isolated Pain at Injection Site | 110 patients |
| Insulin Aspart | Patients With at Least One Site Infection, Site Inflammation/Erythema, Pruritus or Isolated Pain at Injection Site | 110 patients |
| Insulin Lispro | Patients With at Least One Site Infection, Site Inflammation/Erythema, Pruritus or Isolated Pain at Injection Site | 107 patients |
p-value: 1McNemar
p-value: 0.701McNemar
Secondary
Percentage of Patients With at Least One Confirmed Infusion Set Occlusion
Pump infusion set occlusion defined by at least one of the following items: * pump occlusion alarm, * patient observation of an occlusion, spontaneously or because of elevated blood glucose value.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glulisine | Percentage of Patients With at Least One Confirmed Infusion Set Occlusion | 32.8 percentage of patients |
| Insulin Aspart | Percentage of Patients With at Least One Confirmed Infusion Set Occlusion | 27.0 percentage of patients |
| Insulin Lispro | Percentage of Patients With at Least One Confirmed Infusion Set Occlusion | 27.0 percentage of patients |
p-value: 0.079McNemar
p-value: 0.063McNemar
Secondary
Percentage of Patients With at Least One Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is preceded by an increase in ketone production, resulting in blood ketone value increase (hyperketonemia) and later in ketone urine value (hyperketonuria). Significant hyperketonemia and risk level for impending diabetic ketoacidosis (DKA) are reported respectively as a blood ketone value from 0.6 to 1.5 mmol/L and \>1.5 mmol/l
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glulisine | Percentage of Patients With at Least One Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis | 17.6 percentage of patients |
| Insulin Aspart | Percentage of Patients With at Least One Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis | 10.9 percentage of patients |
| Insulin Lispro | Percentage of Patients With at Least One Episode of Significant Ketosis and/ or Risk Level for Impending Diabetic Ketoacidosis | 11.7 percentage of patients |
p-value: 0.017McNemar
p-value: 0.032McNemar
Secondary
Percentage of Patients With at Least One Unexplained Hyperglycemia
Unexplained hyperglycemia defined as blood glucose value above 300 mg/dL (16.7 mmol/L) with no apparent medical dietary, insulin dosage or pump failure reason.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Glulisine | Percentage of Patients With at Least One Unexplained Hyperglycemia | 61.3 percentage of patients |
| Insulin Aspart | Percentage of Patients With at Least One Unexplained Hyperglycemia | 55.9 percentage of patients |
| Insulin Lispro | Percentage of Patients With at Least One Unexplained Hyperglycemia | 56.3 percentage of patients |
p-value: 0.08McNemar
p-value: 0.107McNemar
Secondary
Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year
Nocturnal Symptomatic hypoglycemia was defined as an event with clinical symptoms that are considered to result from hypoglycemia (confirmed or not by a glucose measurement) and associated with prompt recovery after oral carbohydrate administration which occurs while the patient is asleep, after bedtime and before getting up in the morning.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year | 12.80 events in patient-year | Standard Error 0.95 |
| Insulin Aspart | Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year | 9.66 events in patient-year | Standard Error 0.95 |
| Insulin Lispro | Rate of Nocturnal Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤70 mg/dL Per Patient-year | 9.48 events in patient-year | Standard Error 0.95 |
p-value: <0.001Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
Secondary
Rate of Severe Symptomatic Hypoglycemia Per Patient-year
Severe symptomatic hypoglycemia is defined as an event with clinical symptoms that are considered to results from hypoglycemia in which the patient required assistance of another person and one of the following: * the event was associated with a measured blood glucose level below 36 mg/dL * or event was associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Rate of Severe Symptomatic Hypoglycemia Per Patient-year | 1.63 events in patient-year | Standard Error 0.35 |
| Insulin Aspart | Rate of Severe Symptomatic Hypoglycemia Per Patient-year | 1.39 events in patient-year | Standard Error 0.35 |
| Insulin Lispro | Rate of Severe Symptomatic Hypoglycemia Per Patient-year | 1.07 events in patient-year | Standard Error 0.35 |
p-value: 0.563Mixed Models Analysis
p-value: 0.186Mixed Models Analysis
Secondary
Rate of Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤ 70 mg/dL Per Patient-year
Symptomatic hypoglycemia is defined as an event with clinical symptoms that are considered to results from hypoglycemia (confirmed or not by a glucose measurement) and associated with prompt recovery after oral carbohydrate administration.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Rate of Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤ 70 mg/dL Per Patient-year | 73.88 events in patient-year | Standard Error 4.74 |
| Insulin Aspart | Rate of Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤ 70 mg/dL Per Patient-year | 65.06 events in patient-year | Standard Error 4.74 |
| Insulin Lispro | Rate of Symptomatic Hypoglycemia With a Plasma Glucose (PG) ≤ 70 mg/dL Per Patient-year | 62.74 events in patient-year | Standard Error 4.74 |
p-value: <0.001Mixed Models Analysis
p-value: 0.008Mixed Models Analysis
Secondary
Time Interval Between Infusion Set Changes: All Changes
Patients treated with insulin pump have to change their infusion set regularly (i.e.change was recommended every 48h). The patients were asked to report any change of their infusion set and the reason for change (routine basis or because of occurrence of a specific event such as occlusion, unexplained hyperglycemia or adverse event). All changes include all the changes whatever the reason such as routine or requested by occurrence of events.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Time Interval Between Infusion Set Changes: All Changes | 69.1 hours | Standard Deviation 20.7 |
| Insulin Aspart | Time Interval Between Infusion Set Changes: All Changes | 69.44 hours | Standard Deviation 19.22 |
| Insulin Lispro | Time Interval Between Infusion Set Changes: All Changes | 69.98 hours | Standard Deviation 21.64 |
Secondary
Time Interval Between Infusion Set Changes in Routine
Patients treated with insulin pump have to change their infusion set regularly (i.e.change was recommended every 48h). The patients were asked to report any change of their infusion set and the reason for change (routine basis or because of occurrence of a specific event such as occlusion, unexplained hyperglycemia or adverse event). Changes in routine correspond to interval between changes according to patient use.
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Glulisine | Time Interval Between Infusion Set Changes in Routine | 70.72 hours | Standard Deviation 21.47 |
| Insulin Aspart | Time Interval Between Infusion Set Changes in Routine | 71.00 hours | Standard Deviation 20.68 |
| Insulin Lispro | Time Interval Between Infusion Set Changes in Routine | 71.07 hours | Standard Deviation 21.65 |
Secondary
Total Daily Basal Insulin Infusion
dose of the basal insulin regimen administered throughout the 24-hour period
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Glulisine | Total Daily Basal Insulin Infusion | First week (week 1) (n=251, n=249, n=250) | 20.83 Units | Standard Deviation 9.05 |
| Insulin Glulisine | Total Daily Basal Insulin Infusion | Last week (week 13) (n=251, n=249, n=251) | 20.86 Units | Standard Deviation 9.24 |
| Insulin Aspart | Total Daily Basal Insulin Infusion | First week (week 1) (n=251, n=249, n=250) | 20.93 Units | Standard Deviation 9.45 |
| Insulin Aspart | Total Daily Basal Insulin Infusion | Last week (week 13) (n=251, n=249, n=251) | 20.81 Units | Standard Deviation 9.73 |
| Insulin Lispro | Total Daily Basal Insulin Infusion | First week (week 1) (n=251, n=249, n=250) | 20.85 Units | Standard Deviation 9.16 |
| Insulin Lispro | Total Daily Basal Insulin Infusion | Last week (week 13) (n=251, n=249, n=251) | 21.11 Units | Standard Deviation 9.38 |
Secondary
Total Daily Bolus Insulin Dose
dose of every increment administered for example before meals
Time frame: over 13 weeks of each treatment period
Population: Analysis was performed on the Intention To Treat (ITT) population. The Intent-To-Treat population is composed of all randomized patients having received the 3 insulins (Insulin glulisine, aspart and lispro) N=256 patients: (sequence 1: N=86, sequence 2: N=86; sequence 3: N=84 patients).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Glulisine | Total Daily Bolus Insulin Dose | First week (week 1) (n=249, n=247, n=250) | 18.63 Units | Standard Deviation 9.22 |
| Insulin Glulisine | Total Daily Bolus Insulin Dose | Last week (week 13) (n=248, n=244, n=249) | 18.58 Units | Standard Deviation 8.49 |
| Insulin Aspart | Total Daily Bolus Insulin Dose | First week (week 1) (n=249, n=247, n=250) | 18.49 Units | Standard Deviation 9 |
| Insulin Aspart | Total Daily Bolus Insulin Dose | Last week (week 13) (n=248, n=244, n=249) | 18.64 Units | Standard Deviation 9.6 |
| Insulin Lispro | Total Daily Bolus Insulin Dose | First week (week 1) (n=249, n=247, n=250) | 18.40 Units | Standard Deviation 8.69 |
| Insulin Lispro | Total Daily Bolus Insulin Dose | Last week (week 13) (n=248, n=244, n=249) | 19.19 Units | Standard Deviation 9.13 |