A Study to Demonstrate Bioequivalence Between Insulin Glulisine U300 and Insulin Glulisine U100 After a Single Subcutaneous Dose Using the Euglycemic Clamp Technique, in Patients With Type 1 Diabetes Mellitus

Study Overview
=================
Brief Summary
-----------------
Primary Objective: To demonstrate bioequivalence between insulin glulisine given as 300 Units/mL test formulation and insulin glulisine 100 Units/mL reference formulation after a single subcutaneous (SC) dose. Secondary Objectives: To assess the pharmacodynamic (PD) profiles and further pharmacokinetic (PK) characteristics of insulin glulisine U300 in comparison to insulin glulisine U100 after a single SC dose. To assess safety and tolerability of the test and the reference formulation of insulin glulisine.

Detailed Description
-----------------
The study duration per patient will be 18 to 62 days and will consist of a 4 to 28 days of screening period, a treatment period of 2 days, a washout between dosing occasions of 5-18 days, and follow up visit 7-14 days after last dosing.

Official Title
-----------------
A Randomized, Double-blind, Single-dose, 2-Treatment, 2-Period, 2-Sequence Crossover Bioequivalence Study Comparing Two Formulations of Insulin Glulisine (Insulin Glulisine 300 Units/mL Versus Insulin Glulisine 100 Units/mL Marketed as Apidra® 100 Units/mL) Using the Euglycemic Clamp Technique, in Patients With Type 1 Diabetes Mellitus

Conditions
-----------------
Type1 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Insulin glulisine (U300)
* Drug: Insulin glulisine
* Drug: Insulin aspart
* Drug: NPH insulin
* Drug: Glucagon
* Drug: Glucose
* Drug: Heparin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria : Male or female subjects with type 1 diabetes mellitus (T1DM) for more than 1 year. Total insulin dose of <1.2 U/kg/day. Fasting negative serum C-peptide (<0.30 nmol/L). Glycohemoglobin at screening (HbA1c) ≤9%. Subjects with anti-insulin antibody titer at screening ≤30.0 kU/L. Stable insulin regimen for at least 2 months prior to study. Normal findings in medical history and physical examination (cardiovascular system, chest and lungs, thyroid, abdomen, nervous system, skin and mucosae, and musculoskeletal system), vital signs, electrocardiogram (ECG), and safety laboratory. Exclusion criteria: Any history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic (apart from T1DM), hematological, neurological, psychiatric, systemic (affecting the body as a whole), ocular, gynecologic (if female), or infectious disease; any acute infectious disease or signs of acute illness or any history or presence of heparin induced thrombocytopenia Type II (HIT-type II). Severe hypoglycemia resulting in coma/seizures or requiring assistance of another person, and/or hospitalization for diabetic ketoacidosis in the last 6 months before screening visit. Frequent severe headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month). Symptomatic hypotension (whatever the decrease in blood pressure), or asymptomatic postural hypotension defined by a decrease in systolic blood pressure equal to or greater than 20 mmHg within three minutes when changing from the supine to the standing position. Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician. Likelihood of requiring treatment during the study period with drugs not permitted by the clinical study protocol. Any medication (including medicine containing St John's Wort) within 14 days before inclusion (for systemic glucocorticoids within 3 months) or within 5 times the elimination half-life or PD half-life of the medication, with the exception of insulin, stable treatment (at least 2 months) with thyroid hormones, lipid-lowering and antihypertensive drugs and if female with the exception of hormonal contraception or menopausal hormone replacement therapy. Positive reaction to any of the following tests: hepatitis B surface (HBs Ag) antigen, anti hepatitis C virus (anti-HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti HIV2 Ab). 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: 64 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin glulisine (U300) - Test formulation<br>Insulin glulisine (U300) will be given as a single subcutaneous (SC) dose on Day 1 of each period under fasting conditions according to the random list and assigned sequence. Glucose, insulin aspart (IV) and heparin will be used for clamp procedure. NPH insulin (if necessary) and insulin aspart (SC) will be handed out at screening to change insulin regimen and glucagon at Day 1 to treat cases of severe hypoglycemia. | Drug: Insulin glulisine (U300)<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: HMR1964 (U300);Drug: Insulin aspart<br>* Pharmaceutical form: solution Route of administration: intravenous/subcutaneous<br>* Other names: NovoRapid®;Drug: NPH insulin<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: Insuman® Basal Solostar®;Drug: Glucagon<br>* Pharmaceutical form: Powder and solvent for solution for injection Route of administration: subcutaneous<br>* Other names: GlucaGen® HypoKit;Drug: Glucose<br>* Pharmaceutical form: solution Route of administration: intravenous<br>* Other names: Glucose 20%;Drug: Heparin<br>* Pharmaceutical form: solution Route of administration: intravenous<br>* Other names: Heparin-Natrium-5000;|
| Active Comparator: Insulin glulisine - Reference formulation<br>Insulin glulisine (U100) will be given as a single SC dose on Day 1 of each period under fasting conditions according to the random list and assigned sequence. Glucose, insulin aspart (IV) and heparin will be used for clamp procedure. NPH insulin (if necessary) and insulin aspart (SC) will be handed out at screening to change insulin regimen and glucagon at Day 1 to treat cases of severe hypoglycemia. | Drug: Insulin glulisine<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: Apidra®;Drug: Insulin aspart<br>* Pharmaceutical form: solution Route of administration: intravenous/subcutaneous<br>* Other names: NovoRapid®;Drug: NPH insulin<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: Insuman® Basal Solostar®;Drug: Glucagon<br>* Pharmaceutical form: Powder and solvent for solution for injection Route of administration: subcutaneous<br>* Other names: GlucaGen® HypoKit;Drug: Glucose<br>* Pharmaceutical form: solution Route of administration: intravenous<br>* Other names: Glucose 20%;Drug: Heparin<br>* Pharmaceutical form: solution Route of administration: intravenous<br>* Other names: Heparin-Natrium-5000;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of PK parameter: maximum observed insulin concentration |  | 10 hours | 
| Assessment of PK parameter: area under the concentration time curve |  | 10 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of PK parameter: time to reach Cmax (INS-tmax) |  | 10 hours | 
| Assessment of PK parameter: terminal half-life (INS-t1/2z) |  | 10 hours | 
| Assessment of PD parameter: area under the body weight standardized glucose infusion rate (GIR) versus time curve from 0 to 10 hours (GIR-AUC0-10) |  | 10 hours | 
| Assessment of PD parameter: maximum smoothed body weight standardized GIR (GIRmax) |  | 10 hours | 
| Assessment of PD parameter: time to GIRmax (GIR-tmax) |  | 10 hours | 
| Duration of blood glucose control under clamp conditions - time |  | 10 hours | 
| Number of patients with treatment emergent adverse events |  | 9 weeks |