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

Sponsor

Sanofi (Industry)

Overall Status

Completed

CT.gov ID

NCT02910518

Collaborator

(none)

Enrollment

Location

Arms

2.5

Actual Duration (Months)

17.9

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type1 Diabetes Mellitus	Drug: Insulin glulisine (U300) Drug: Insulin glulisine Drug: Insulin aspart Drug: NPH insulin Drug: Glucagon Drug: Glucose Drug: Heparin	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

44 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Feb 17, 2017

Actual Primary Completion Date :

May 3, 2017

Actual Study Completion Date :

May 3, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Insulin glulisine (U300) - Test formulation 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) Pharmaceutical form: solution Route of administration: subcutaneous Other Names: HMR1964 (U300) Drug: Insulin aspart Pharmaceutical form: solution Route of administration: intravenous/subcutaneous Other Names: NovoRapid® Drug: NPH insulin Pharmaceutical form: solution Route of administration: subcutaneous Other Names: Insuman® Basal Solostar® Drug: Glucagon Pharmaceutical form: Powder and solvent for solution for injection Route of administration: subcutaneous Other Names: GlucaGen® HypoKit Drug: Glucose Pharmaceutical form: solution Route of administration: intravenous Other Names: Glucose 20% Drug: Heparin Pharmaceutical form: solution Route of administration: intravenous Other Names: Heparin-Natrium-5000
Active Comparator: Insulin glulisine - Reference formulation 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 Pharmaceutical form: solution Route of administration: subcutaneous Other Names: Apidra® Drug: Insulin aspart Pharmaceutical form: solution Route of administration: intravenous/subcutaneous Other Names: NovoRapid® Drug: NPH insulin Pharmaceutical form: solution Route of administration: subcutaneous Other Names: Insuman® Basal Solostar® Drug: Glucagon Pharmaceutical form: Powder and solvent for solution for injection Route of administration: subcutaneous Other Names: GlucaGen® HypoKit Drug: Glucose Pharmaceutical form: solution Route of administration: intravenous Other Names: Glucose 20% Drug: Heparin Pharmaceutical form: solution Route of administration: intravenous Other Names: Heparin-Natrium-5000

Arm

Intervention/Treatment

Experimental: Insulin glulisine (U300) - Test formulation

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)

Pharmaceutical form: solution Route of administration: subcutaneous

Other Names:

HMR1964 (U300)

Drug: Insulin aspart

Pharmaceutical form: solution Route of administration: intravenous/subcutaneous

Other Names:

NovoRapid®

Drug: NPH insulin

Pharmaceutical form: solution Route of administration: subcutaneous

Other Names:

Insuman® Basal Solostar®

Drug: Glucagon

Pharmaceutical form: Powder and solvent for solution for injection Route of administration: subcutaneous

Other Names:

GlucaGen® HypoKit

Drug: Glucose

Pharmaceutical form: solution Route of administration: intravenous

Other Names:

Glucose 20%

Drug: Heparin

Pharmaceutical form: solution Route of administration: intravenous

Other Names:

Heparin-Natrium-5000

Active Comparator: Insulin glulisine - Reference formulation

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

Pharmaceutical form: solution Route of administration: subcutaneous

Other Names:

Apidra®

Drug: Insulin aspart

Pharmaceutical form: solution Route of administration: intravenous/subcutaneous

Other Names:

NovoRapid®

Drug: NPH insulin

Pharmaceutical form: solution Route of administration: subcutaneous

Other Names:

Insuman® Basal Solostar®

Drug: Glucagon

Pharmaceutical form: Powder and solvent for solution for injection Route of administration: subcutaneous

Other Names:

GlucaGen® HypoKit

Drug: Glucose

Pharmaceutical form: solution Route of administration: intravenous

Other Names:

Glucose 20%

Drug: Heparin

Pharmaceutical form: solution Route of administration: intravenous

Other Names:

Heparin-Natrium-5000

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 64 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).