Comparative Study of Rinsulin® NPH, Suspension for Subcutaneous Administration, 100 IU/ml (GEROPHARM LLC, Russia) and Humulin® NPH, Suspension for Subcutaneous Administration, 100 IU/ml (Lilly France, France) Using the Euglycemic Hyperinsulinemic Clamp Method

Study Overview
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Brief Summary
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Сomparative pharmacokinetic study of Rinsulin® NPH, suspension for subcutaneous administration, 100 IU/ml (GEROPHARM LLC, Russia) and Humulin® NPH, suspension for subcutaneous administration, 100 IU/ml (Lilly France, France) using the euglycemic hyperinsulinemic clamp.

Detailed Description
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A double-blinded, randomized, comparative, crossover pharmacokinetics study of Rinsulin® NPH, suspension for subcutaneous administration, 100 IU/ml (GEROPHARM LLC, Russia) and Humulin® NPH, suspension for subcutaneous administration, 100 IU/ml (Lilly France, France) using method of euglycemic hyperinsulinemic clamp on healthy volunteers

Official Title
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A Double-blinded, Randomized, Comparative, Crossover Pharmacokinetics Study of Rinsulin® NPH, Suspension for Subcutaneous Administration, 100 IU/ml (GEROPHARM LLC, Russia) and Humulin® NPH, Suspension for Subcutaneous Administration, 100 IU/ml (Lilly France, France) Using Method of Euglycemic Hyperinsulinemic Clamp on Healthy Volunteers

Conditions
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Pharmacokinetics, Bioequivalence

Intervention / Treatment
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* Drug: Rinsulin NPH
* Drug: Humulin NPH


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent to participate in the study. Men of the Caucasian race with a verified diagnosis healthy according to the data of standard clinical, laboratory and instrumental examination methods. Age 18-50, inclusive. Body mass index 18.5 - 27 kg / m2. Volunteers who have sexual contact with fertile women should agree to use barrier methods of contraception while participating in the study (unless they have undergone surgical sterilization). Study Participants must also not become a sperm donor within the specified period. Consent to all restrictions imposed during the study. Exclusion Criteria: Acute inflammatory diseases within 3 weeks from the moment of complete recovery to the stage of screening. Presence of episodes of hypoglycemia in the history of the volunteer Presence in the family history of the closest relatives cases of verified diagnosis of diabetes mellitus of any type. Deviations from the norm of basic vital indicators (heart rate, blood pressure, respiratory rate, body temperature) and ECG from normal values and laboratory values from reference values during screening. Fasting plasma glucose> 6.1 mmol / L at screening. HbA1C> 6% at the time of screening. Oral glucose tolerance test - blood glucose level ≥7.8 mmol / L (2 hours after glucose loading) during screening. Hard-to-reach veins of the upper extremities, vein thrombosis, history of thrombophlebitis or family history of close relatives, compromised veins due to frequent preceding venipuncture. Taking medications, phytopreparations, biologically active additives within 14 days before screening. Significant blood loss 3 months before screening due to, for example, but not limited to the following points: a. donor blood donation; b. extended surgery or trauma leading to significant blood loss. Incomplete recovery from surgery or surgery scheduled while the volunteer is participating in the study. Mental, physical and other reasons interferes with adequately assessing behavior and correctly fulfill the conditions of the research protocol (incl. a history of mental illness). Presence or history (three years before the the study drug) of narcotic, drug and / or substance abuse. Positive test for the content of narcotic drugs in urine during the screening period. Anamnestic information about alcoholism or taking more than 10 units. alcohol per week (1 unit of alcohol is equivalent to 0.5 liters of beer, 200 ml of dry wine or 50 ml of spirits). Positive test for alcohol in breath during screening. Nicotine addiction (regular use of tobacco less than 6 months before screening). Any chronic diseases, incl. but not limited to positive test results for hepatitis C or hepatitis B, HIV, syphilis at the time of screening. Burdened allergological history. presence of suspicion of an inflammatory disease of the urinary system based on the results of urinalysis during screening. Presence of oncological diseases within 5 years before the screening. History of organ transplantation (except of corneal transplant performed more than 3 months before the first injection of the study drug). Participation in a clinical trial of any drug or experimental medical device within 3 months prior to the first administration of the study drug. Any other condition that, in the reasonable opinion of the research physician, makes it difficult for the volunteer to participate in the study. History of hypersensitivity to heparin, insulin or any of the excipients of the investigational drugs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Crossover Assignment two-way crossover
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rinsulin® NPH<br>Single subcutaneous administration of Insulin at a dose 0.4 IU / kg | Drug: Rinsulin NPH<br>* subcutaneous injection at a dose of 0.4 IU/kg<br>Drug: Humulin NPH<br>* subcutaneous injection at a dose of 0.4 IU/kg<br>|
| Active Comparator: Humulin® NPH<br>Single subcutaneous administration of Insulin at a dose 0.4 IU / kg | Drug: Rinsulin NPH<br>* subcutaneous injection at a dose of 0.4 IU/kg<br>Drug: Humulin NPH<br>* subcutaneous injection at a dose of 0.4 IU/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Смах | Test Drug Observed Maximum Plasma Concentration (Cmax) | - 1 , -0.5 , 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24 hours | 
| AUC 0-12 | Total area under the curve drug concentration - time in the time interval from 0 to 12 h | - 1 , -0.5 , 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24 hours | 
| AUC GIR 0-12 | Total area under the curve glucose infusion rate - time in the time interval from 0 to 12 h | -2, -1.5, 1, -0.5, then every 5 min till 10 hour, every 10 min till 12 hour, every 15 min till 24 hour | 
| AUC GIR 0-24 | Total area under the curve glucose infusion rate - time in the time interval from 0 to 24 h | -2, -1.5, 1, -0.5, then every 5 min till 10 hour, every 10 min till 12 hour, every 15 min till 24 hour | 
| GIRmax | Maximum glucose infusion rate over the study period | -2, -1.5, 1, -0.5, then every 5 min till 10 hour, every 10 min till 12 hour, every 15 min till 24 hour | 
| tGIRmax | Time to reach maximum glucose infusion rate | -2, -1.5, 1, -0.5, then every 5 min till 10 hour, every 10 min till 12 hour, every 15 min till 24 hour | 
| tGIRlag | Time between the drug administration and the onset of action | -2, -1.5, 1, -0.5, then every 5 min till 10 hour, every 10 min till 12 hour, every 15 min till 24 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC 0-2 | Total area under the curve drug concentration - time in the time interval from 0 to 2 h | - 1 , -0.5 , 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24 hours | 
| AUC 0-6 | Total area under the curve drug concentration - time in the time interval from 0 to 6 h | - 1 , -0.5 , 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24 hours | 
| AUC 0-24 | Total area under the curve drug concentration - time in the time interval from 0 to 24 h | - 1 , -0.5 , 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24 hours | 
| AUC 0-∞ | Total area under the curve drug concentration - time in the time interval from 0 to ∞ | - 1 , -0.5 , 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24 hours | 
| Tmax | Time to reach test drug Maximum Plasma Concentration | - 1 , -0.5 , 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24 hours | 
| T1/2 | Half-life of a drug tested | - 1 , -0.5 , 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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human recombinant insulin, euglycemic hyperinsulinemic clamp