A Study to Compare Pharmacokinetics (PK) and Pharmacodynamics (PD) of SAR341402 to Insulin Aspart in Subjects With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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Primary Objective: To compare exposure and activity of SAR341402 to NovoRapid® and NovoLog®. Secondary Objective: To assess the safety and tolerability of SAR341402.

Detailed Description
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The total study duration for a screened subject will be about 3 - 8 weeks (excluding screening of 2 to 28 days), treatment period of 2 days for each 3 periods (1 overnight stay), a washout period of 5-18 days (preferentially 7 days between consecutive dosing), and an end-of-study visit of 1 day between Days 5 and 14 after the last administration of the investigational product.

Official Title
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A Randomized, Double-Blind, Controlled, Single-Dose, 3-Treatment, 3-Period, 6-Sequence Crossover Study to Compare Exposure and Activity of SAR341402 to NovoRapid® and NovoLog® Using the Euglycemic Clamp Technique, in Subjects With Type 1 Diabetes Mellitus

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: SAR341402
* Drug: Insulin Aspart
* Drug: Insulin Aspart


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Male or female subjects with diabetes mellitus type 1 for more than one year. Total insulin dose of < 1.2 U/kg/day. Fasting negative serum C-peptide (< 0.3 nmol/L). Glycohemoglobin (HbA1c) ≤ 9%. 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 musculo-skeletal system), vital signs, electrocardiogram (ECG) and safety lab. Exclusion criteria: Any history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic (apart from diabetes mellitus type 1), hematological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, or 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 headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month. Symptomatic postural hypotension, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood pressure ≥20 mmHg within 3 minutes when changing from supine to 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 St John's Wort) within 14 days before inclusion or within 5 times the elimination half-life or pharmacodynamic half-life of the medication, with the exception of insulins, 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 result on 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
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test (T)<br>SAR341402: single dose injection | Drug: SAR341402<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>|
| Active Comparator: Reference 1 (R1)<br>NovoRapid®: single dose injection | Drug: Insulin Aspart<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: NovoRapid®;|
| Active Comparator: Reference 2 (R2)<br>NovoLog®: single dose injection | Drug: Insulin Aspart<br>* Pharmaceutical form: solution Route of administration: subcutaneous<br>* Other names: NovoLog®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of PK parameters: maximum plasma concentration (Cmax) | Maximum plasma concentration (Cmax) of SAR341402, NovoRapid and NovoLog within 12 hours | 12 hours | 
| Assessment of PK parameters: Area under the concentration versus time curve (AUC) | INS-AUC of SAR341402, NovoRapid, and NovoLog from 0 to 12 hours | 12 hours | 
| Assessment of PK parameter: AUC from dosing to last concentration (AUClast) | INS-AUClast is AUC from the time of dosing to the last measurable concentration of SAR341402, NovoRapid, and NovoLog from 0 to 12 hours | 12 hours | 
| Assessment of PD parameters: Area under the body weight standardized glucose infusion rate (GIR) | Area under the body weight standardized glucose infusion rate (GIR) versus time curve from 0 to 12 hours post administration (GIR-AUC0-12) | 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of PK: Fractional area under the concentration versus time curve | INS-AUC0-2 and INS-AUC4-tlast | 12 hours | 
| Assessment of PK: Time to 20 % of INS-AUC | Time to 20% of AUC (t20%-INS-AUC) within 12 hours | 12 hours | 
| Assessment of PK: time to reach INS-Cmax (INS-tmax) | INS-tmax within 12 hours | 12 hours | 
| Assessment of PK: time to reach INS-t1/2z (INS-t1/2z) | INS-t1/2z within 12 hours | 12 hours | 
| Assessment of PD: Fractional area under the body weight standardized GIR versus time curve | GIR-AUC0-2 and GIR-AUC4-12 | 12 hours | 
| Assessment of PD: Time to 20 % of total GIR-AUC0-12h | Time to 20% of total GIR-AUC0-12h (t20%-GIR-AUC0-12h) within 12 hours | 12 hours | 
| Assessment of PD: Maximum smoothed body weight standardized GIR (GIRmax) | Maximum smoothed body weight standardized GIR (GIRmax) within 12 hours | 12 hours | 
| Assessment of PD: Time to GIRmax (GIR-tmax) | Time to GIRmax (GIR-tmax) within 12 hours | 12 hours | 
| Number of adverse events (AEs) | Number of patients with treatment emergent AEs and serious adverse events (SAEs) | 8 weeks |