Relative Bioavailability and Activity of Different Formulations of Insulin Glargine and Lixisenatide in Patients With Diabetes Mellitus Type 1

Study Overview
=================
Brief Summary
-----------------
Primary Objective: to assess the relative bioavailability of a single dose of insulin glargine (Lantus) and lixisenatide given subcutaneously as on-site mix versus separate and simultaneous injections of each drug Secondary Objectives: to compare the activity of a single dose of insulin glargine and lixisenatide given subcutaneously as on-site mix versus separate and simultaneous injections of each drug to assess the safety and tolerability of insulin glargine and lixisenatide given subcutaneously as on-site mix

Detailed Description
-----------------
The study period for one patient is one month in average and it can last up to 7 months (+ 2 weeks) with post-study and follow-up visits

Official Title
-----------------
A Randomized, Cross-over, Open, Euglycemic Clamp Study on the Relative Bioavailability and Activity of 0.6 U/kg Insulin Glargine and 20 μg Lixisenatide, Given as On-site Mix Compared to Separate Simultaneous Injections in Subjects With Type 1 Diabetes Mellitus

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

Intervention / Treatment
-----------------
* Drug: Insulin glargine HOE901
* Drug: Lixisenatide AVE0010


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Subjects with type 1 diabetes mellitus for more than one year with total insulin dose of <1.2 U.kg/day, but otherwise healthy with glycohemoglobin (HbA1c) ≤ 9.0%, stable insulin regimen for at least 2 months prior to study, normal finding in medical history and physical examination. Exclusion criteria: any history or presence of clinically relevant cardiovascular, pulmonary, gastro-intestinal, hepatic, renal, metabolic (apart from diabetes mellitus type I), 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 More than one episode of severe hypoglycemia with seizure, coma or requiring assistance of another person during the past 6 months Frequent severe headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month) Symptomatic hypotension, or asymptomatic postural hypotension defined by a decrease in systolic blood pressure (SBP) equal to or greater than 20 mmHg within three minutes when changing from the supine to the standing position Presence or history of a drug allergy to clinically significant allergic disease Likelihood of requiring treatment during the study period with drugs not permitted by the clinical study protocol Pregnant or breast feeding women Any medication within 14 days before inclusion, or within 5 times the elimination half-life of that drug, whichever the longest and regular use of any medication other than insulins in the last month before study start with the exception of thyroid hormones, lipid-lowering and antihypertensive drugs, and, if female, with the exception of hormonal contraception or menopausal hormone replacement therapy, any vaccination within the last 28 days. Positive reaction to any of the following tests: hepatitis B surface (HBs Ag) antigen, antihepatitis B core antibodies (anti-HBc Ab) if compound having possible immune activities, anti-hepatitis C virus (anti-HCV2) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 and anti HIV2 Ab) History of unexplained pancreatitis, chronic pancreatitis and/or pancreatectomy 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: 65 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: Lantus(insulin glargine)/lixisenatide on-site mix<br>Single dose injection of an on site mix of Lantus U100 and lixisenatide (800µg/mL in Lantus U100) at one peri-umbilical site under fasting conditions | Drug: Insulin glargine HOE901<br>* Pharmaceutical form:solution for injection Route of administration: subcutaneous<br>Drug: Lixisenatide AVE0010<br>* Pharmaceutical form:solution for injection Route of administration: subcutaneous<br>|
| Active Comparator: lixisenatide + Lantus (insulin glargine)<br>Single dose, separate injection simultaneous injections of Lantus U100 and lixisenatide (100µg/mL) at opposite peri-umbilical sites within 1 minute under fasting conditions | Drug: Insulin glargine HOE901<br>* Pharmaceutical form:solution for injection Route of administration: subcutaneous<br>Drug: Lixisenatide AVE0010<br>* Pharmaceutical form:solution for injection Route of administration: subcutaneous<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma lixisenatide concentration curve (LIX-AUClast) |  | 1 day (D1 to D2) in the first treatment period and 1 day (D1 to D2) during the second treatment period | 
| Lixisenatide maximum plasma/serum peak concentration (LIX-Cmax) |  | 1 day (D1 to D2) in the first treatment period and 1 day (D1 to D2) during the second treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma lixisenatide concentration curve (AUC) |  | 1 day (D1 to D2) in the first treatment period and 1 day (D1 to D2) during the second treatment period | 
| Time to Cmax (Tmax ) for lixisenatide |  | 1 day (D1 to D2) in the first treatment period and 1 day (D1 to D2) during the second treatment period | 
| Area under the body weight standardized glucose infusion rate curve (GIR) within 24 h (GIR-AUC0-24) |  | 1 day (D1 to D2) in the first treatment period and 1 day (D1 to D2) during the second treatment period | 
| Time to 50% of the GIR-AUC within 24 h (T50%-GIR AUC0-24) |  | 1 day (D1 to D2) in the first treatment period and 1 day (D1 to D2) during the second treatment period | 
| Maximum smoothed body weight standardized glucose infusion rate GIRmax |  | 1 day (D1 to D2) in the first treatment period and 1 day (D1 to D2) during the second treatment period | 
| Time to GIRmax (GIR-Tmax) |  | 1 day (D1 to D2) in the first treatment period and 1 day (D1 to D2) during the second treatment period |