Comparison of Exposure and Activity of SAR341402 Mix 70/30 to NovoLog Mix 70/30, NovoMix 30 and SAR341402 Rapid-acting Solution in Patients With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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Primary Objectives: To demonstrate similarity in exposure of SAR341402 Mix 70/30 to NovoLog Mix 70/30 and NovoMix 30 (cohort 1). To demonstrate distinctiveness in early and intermediate exposure of SAR341402 Mix 70/30 compared to SAR341402 rapid-acting solution (cohort 2). Secondary Objectives: To demonstrate similarity in activity of SAR341402 Mix 70/30 to NovoLog Mix 70/30 and NovoMix 30. To demonstrate distinctiveness in early and intermediate activity of SAR341402 Mix 70/30 compared to SAR341402 rapid-acting solution. To assess the safety and tolerability of SAR341402 rapid-acting solution and SAR341402 Mix 70/30.

Detailed Description
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Cohort 1: The total study duration for a screened patient will be about 3 - 8 weeks (excluding screening), with screening period of 4 to 28 days, 3 treatment periods of 2 days each period, washout period of 5 to 18 days, and end-of-study visit at 5 to 12 days after last IMP administration. Cohort 2: The total study duration for a screened patient will be about 2 - 5 weeks (excluding screening), with screening period of 4 to 28 days, 2 treatment periods of 2 days each period, washout period of 5 to 18 days, and end-of-study visit at 5 to 12 days after last IMP administration.

Official Title
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A Randomized, Double-blind, Single-dose, Cross-over Study in Two Cohorts to Compare Exposure and Activity of SAR341402 Mix 70/30 to Novolog® Mix 70/30, Novomix® 30 and SAR341402 Rapid-Acting Solution Using the Euglycemic Clamp Technique, in Patients 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
* Drug: SAR341402


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Total insulin dose of < 1.0 U/kg/day. Total basal insulin dose ≤0.4 U/kg/day. Fasting serum C-peptide < 0.3 nmol/L. Anti-insulin antibody titer ≤30.0 kU/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 and/or hospitalized for diabetic ketoacidosis. 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 ≥30 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. 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: 64 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 Mix 70/30: single dose injection | Drug: SAR341402<br>* Pharmaceutical form: suspension for injection Route of administration: subcutaneous<br>|
| Active Comparator: Reference 1 (R1)<br>NovoLog Mix 70/30: single dose injection | Drug: Insulin Aspart<br>* Pharmaceutical form: suspension for injection Route of administration: subcutaneous<br>* Other names: NovoLog Mix 70/30;|
| Active Comparator: Reference 2 (R2)<br>NovoMix30: single dose injection | Drug: Insulin Aspart<br>* Pharmaceutical form: suspension for injection Route of administration: subcutaneous<br>* Other names: Novo Mix 30;|
| Experimental: Reference 3 (R3)<br>SAR341402 rapid-acting solution: single dose injection | Drug: SAR341402<br>* Pharmaceutical form: solution for injection Route of administration: subcutaneous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| (Cohort 1) Assessment of PK parameter: Maximum insulin concentration (INS-Cmax) | Maximum plasma concentration (Cmax) of SAR341402 Mix 70/30, NovoLog Mix 70/30, NovoMix 30 and SAR341402 within 24 hours | 24 hours | 
| (Cohort 1) Assessment of PK parameter: Area under the insulin concentration time curve (INS-AUClast) | INS-AUC of SAR341402 Mix 70/30, NovoLog Mix 70/30, and NovoMix 30 from 0 to 24 hours | 0 to 24 hours | 
| (Cohort 2) Assessment of PK parameters: Area under the insulin concentration time curve from 0 to 4 hours post administration (INS-AUC0-4H) | INS-AUC0-4H for SAR341402 Mix 70/30 and SAR341402 rapid acting solution from 0 to 4 hours | 0 to 4 hours | 
| (Cohort 2) Area under the insulin concentration time curve from 4 to 12 hours post administration (INS-AUC4-12H) | INS-AUC4-12H for SAR341402 Mix 70/30 and SAR341402 rapid acting solution from 4 to 12 hours | 4 to 12 hours | 
| (Cohort 2) Assessment of PK parameter: Maximum insulin concentration (INS-Cmax) | (Cohort 2) Maximum plasma concentration (Cmax) of SAR341402 Mix 70/30 and SAR341402 rapid acting solution within 24 hours | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of PK parameter: Area under the insulin concentration time curve from 0 to infinity (INS-AUC) | (Cohort 1) INS-AUC for SAR341402 Mix 70/30, Novolog Mix 70/30 and NovoMix 30 from 0 to 24 hours | 0 to 24 hours | 
| Assessment of PK parameter: Area under the insulin concentration time curve for fractional periods post administration (INS-AUC0-4H, INS-AUC0-24H, INS-AUC4-24H) | (Cohort 1) INS-AUC0-4H, INS-AUC0-24H, INS-AUC4-24H for SAR341402 Mix 70/30, Novolog Mix 70/30 and NovoMix 30 | 0 to 4 hours, 0 to 24 hours, and 4 to 24 hours | 
| Assessment of PK parameter: Time to INS-Cmax | (Cohort 1) INS-tmax for SAR341402 Mix 70/30, Novolog Mix 70/30, NovoMix 30 and SAR341402 rapid acting solution within 24 hours | 24 hours - 4. 24 hours - 5. 0 to 24 hours - 6. 24 hours - 7. 24 hours - 8. 24 hours - 9. 0 to 4 hours - 10. 4 to 12 hours - 11. 24 hours - 12. 24 hours - | 
| Assessment of PK parameter: Half-life (t1/2) | (Cohort 1) INS-t1/2z for SAR341402 Mix 70/30, Novolog Mix 70/30 and NovoMix 30 within 24 hours | 24 hours | 
| Assessment of PD parameter: GIR versus time curve from 0 to 24 hours post administration (GIR-AUC0-24H) | (Cohort 1) The area under the body weight standardized glucose infusion rate (GIR) versus time curve from 0 to 24 hours post administration for SAR341402 Mix 70/30, Novolog Mix 70/30 and NovoMix 30 from 0 to 24 hours | 0 to 24 hours | 
| Assessment of PD parameter: Maximum smoothed body weight standardized glucose infusion rate (GIRmax) | (Cohort 1) GIRmax for SAR341402 Mix 70/30, Novolog Mix 70/30, NovoMix 30 and SAR341402 rapid acting solution within 24 hours | 24 hours | 
| Assessment of PD parameter: Time to GIRmax (GIR-tmax) | (Cohort 1) GIR-tmax for SAR341402 Mix 70/30, Novolog Mix 70/30, NovoMix 30 and SAR341402 rapid acting solution within 24 hours | 24 hours | 
| Assessment of PK parameter: Time to Cmax (INS-tmax) | (Cohort 2) INS-tmax for SAR341402 Mix 70/30 and SAR341402 rapid acting solution within 24 hours | 24 hours | 
| Assessment of PD parameter: The area under the body weight standardized glucose infusion rate (GIR) versus time curve from 0 to 4 hours post administration (GIR-AUC0-4H) | (Cohort 2) GIR-AUC0-4H for SAR341402 Mix 70/30 and SAR341402 rapid acting solution from 0 to 4 hours | 0 to 4 hours | 
| Assessment of PD parameter: The area under the body weight standardized glucose infusion rate (GIR) versus time curve from 4 to 12 hours post administration (GIR-AUC4-12H) | (Cohort 2) GIR-AUC4-12H for SAR341402 Mix 70/30 and SAR341402 rapid acting solution from 4 to 12 hours | 4 to 12 hours | 
| Assessment of PD parameter: Maximum smoothed body weight standardized glucose infusion rate (GIRmax) | (Cohort 2) GIRmax for SAR341402 Mix 70/30, Novolog Mix 70/30, NovoMix 30 and SAR341402 rapid acting solution within 24 hours | 24 hours | 
| Assessment of PD parameter: Time to GIRmax (GIR-tmax) | (Cohort 2) GIR-tmax for SAR341402 Mix 70/30, Novolog Mix 70/30, NovoMix 30 and SAR341402 rapid acting solution within 24 hours | 24 hours |