Effect of Insulin Glulisine Compared to Insulin Aspart and Insulin Lispro When Administered by Continuous Subcutaneous Insulin Infusion (CSII) on Specific Pump Parameters in Patient With Type 1 Diabetes Mellitus

Study Overview
=================
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.

Official Title
-----------------
Effect of Insulin Glulisine Compared to Insulin Aspart and Insulin Lispro When Administered by Continuous Subcutaneous Insulin Infusion (CSII) on Specific Pump Parameters in Patient With Type 1 Diabetes Mellitus

Conditions
-----------------
Diabetes Mellitus, Type 1

Intervention / Treatment
-----------------
* Drug: Insulin glulisine
* Drug: Insulin lispro
* Drug: Insulin aspart


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sequence 1<br>sequence 1: insulin glulisine / insulin aspart / insulin lispro. | Drug: Insulin glulisine<br>* 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump<br>Drug: Insulin lispro<br>* 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump<br>Drug: Insulin aspart<br>* 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump<br>|
| Experimental: Sequence 2<br>Sequence 2: insulin aspart / insulin lispro / insulin glulisine | Drug: Insulin glulisine<br>* 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump<br>Drug: Insulin lispro<br>* 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump<br>Drug: Insulin aspart<br>* 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump<br>|
| Experimental: Sequence 3<br>Sequence 3: insulin lispro / insulin glulisine / insulin aspart | Drug: Insulin glulisine<br>* 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump<br>Drug: Insulin lispro<br>* 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump<br>Drug: Insulin aspart<br>* 100 U/ml, administration by Continuous Subcutaneous Insulin Infusion with external pump<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | over 13 weeks of each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | over 13 weeks of each treatment period | 
| 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. | over 13 weeks of each treatment period | 
| Monthly Rate of Unexplained Hyperglycemia |  | over 13 weeks of each treatment period | 
| 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. | over 13 weeks of each treatment period | 
| 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 | 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 | over 13 weeks of each treatment period | 
| 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 | over 13 weeks of each treatment period | 
| 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. | over 13 weeks of each treatment period | 
| 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. | over 13 weeks of each treatment period | 
| 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. | over 13 weeks of each treatment period | 
| 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. | over 13 weeks of each treatment period | 
| 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. | over 13 weeks of each treatment period | 
| 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. | over 13 weeks of each treatment period | 
| 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% | over 13 weeks of each treatment period | 
| Total Daily Basal Insulin Infusion | dose of the basal insulin regimen administered throughout the 24-hour period | over 13 weeks of each treatment period | 
| Total Daily Bolus Insulin Dose | dose of every increment administered for example before meals | over 13 weeks of each treatment period |