Comparision of Pharmacokinetic and Pharmacodynamic of Biocon Insulin N and Humulin® N

Study Overview
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Brief Summary
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Single-centre, randomised, double-blind, three-period, six-sequence, partially replicated design, crossover trial in healthy subjects

Detailed Description
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The present study is designed to demonstrate pharmacokinetic and pharmacodynamic equivalence of Biocon Insulin N with Humulin® N in healthy subjects. The treatment consists of one single dose of the test or reference product, administered during each of the three study periods, separated by 5-7 days between each dosing. The planned trial duration for each subject is about 17 to 43 days. Eligible subjects will undergo three euglycaemic clamp examinations (each of 24 hours duration). Depending on the sequence in which a particular subject is randomized, each subject will either undergo two clamps with administration of test product plus one clamp with administration of reference product, or, two clamps with administration of reference product plus one clamp with administration of test product, in random order.

Official Title
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A Randomised, Double-blind, Three-period, Partially Replicated Crossover, Euglycaemic Glucose Clamp Study in Healthy Volunteers to Demonstrate Pharmacokinetic and Pharmacodynamic Similarity of Biocon Insulin N and Humulin® N

Conditions
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Healthy Volunteer

Intervention / Treatment
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* Biological: Biocon Insulin N
* Biological: Humulin® N


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male and post-menopausal female subjects. Post-menopausal defined as 12 months of no menses without an alternative medical cause and confirmed by a follicle stimulating hormone (FSH) level in the post-menopausal range (>= 25.8 IU/L). Age between 18 and 55 years, both inclusive Body mass index between 18.5 and 29.0 kg/m^2, both inclusive. Fasting plasma glucose concentration <= 100 mg/dl. Considered generally healthy upon completion of medical history and screening safety assessments, as judged by the Investigator. Exclusion Criteria: Known or suspected hypersensitivity to Investigational Medicinal products (IMP(s)) or related products. Systolic blood pressure < 95 mmHg or >140 mmHg and/or diastolic blood pressure < 50 mm Hg or >90 mmHg after resting for at least 5 minutes in supine position (excluding white-coat hypertension; therefore, a repeat test showing results within range will be acceptable). Pulse rate at rest outside the range of 50-90 beats per minute. Receipt of any medicinal product in clinical development within 30 days or five times its half-life (whichever is longer) before randomisation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Partially replicated design, crossover trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence: Humulin® N- Biocon Insulin N-Humulin® N<br>Period 1: 0.4 IU/kg of Humulin® N (100 IU/mL) administered once subcutaneously. Period 2: 0.4 IU/kg of Biocon Insulin N (100 IU/mL) administered once subcutaneously. Period 3: 0.4 IU/kg of Humulin® N (100 IU/mL) administered once subcutaneously. The treatment periods will be separated by 5-7 days | Biological: Biocon Insulin N<br>* Biocon Insulin N is an intermediate-acting isophane suspension of human insulin produced by recombinant deoxyribonucleic acid(rDNA) technology utilizing Pichia pastoris (yeast).<br>Biological: Humulin® N<br>* Humulin® N (human insulin [recombinant deoxyribonucleic acid origin] isophane suspension) is an intermediate-acting human isophane insulin. Humulin® N is a suspension of crystals produced from combining human insulin and protamine sulphate.<br>|
| Experimental: Sequence: Biocon Insulin N- Humulin® N- Humulin® N<br>Period 1: 0.4 IU/kg of Biocon Insulin N (100 IU/mL) administered once subcutaneously. Period 2: 0.4 IU/kg of Humulin® N(100 IU/mL) administered once subcutaneously. Period 3: 0.4 IU/kg of Humulin® N (100 IU/mL) administered once subcutaneously. The treatment periods will be separated by 5-7 days | Biological: Biocon Insulin N<br>* Biocon Insulin N is an intermediate-acting isophane suspension of human insulin produced by recombinant deoxyribonucleic acid(rDNA) technology utilizing Pichia pastoris (yeast).<br>Biological: Humulin® N<br>* Humulin® N (human insulin [recombinant deoxyribonucleic acid origin] isophane suspension) is an intermediate-acting human isophane insulin. Humulin® N is a suspension of crystals produced from combining human insulin and protamine sulphate.<br>|
| Experimental: Sequence: Humulin® N- Humulin® N-Biocon Insulin N<br>Period 1: 0.4 IU/kg of Humulin® N(100 IU/mL) administered once subcutaneously. Period 2: 0.4 IU/kg of Humulin® N (100 IU/mL) administered once subcutaneously. Period 3: 0.4 IU/kg of Biocon Insulin N (100 IU/mL) administered once subcutaneously. The treatment periods will be separated by 5-7 days | Biological: Biocon Insulin N<br>* Biocon Insulin N is an intermediate-acting isophane suspension of human insulin produced by recombinant deoxyribonucleic acid(rDNA) technology utilizing Pichia pastoris (yeast).<br>Biological: Humulin® N<br>* Humulin® N (human insulin [recombinant deoxyribonucleic acid origin] isophane suspension) is an intermediate-acting human isophane insulin. Humulin® N is a suspension of crystals produced from combining human insulin and protamine sulphate.<br>|
| Experimental: Sequence: Biocon Insulin N- Humulin® N- Biocon Insulin N<br>Period 1: 0.4 IU/kg of Biocon Insulin N (100 IU/mL) administered once subcutaneously. Period 2: 0.4 IU/kg of Humulin® N (100 IU/mL) administered once subcutaneously. Period 3: 0.4 IU/kg of Biocon Insulin N (100 IU/mL) administered once subcutaneously. The treatment periods will be separated by 5-7 days | Biological: Biocon Insulin N<br>* Biocon Insulin N is an intermediate-acting isophane suspension of human insulin produced by recombinant deoxyribonucleic acid(rDNA) technology utilizing Pichia pastoris (yeast).<br>Biological: Humulin® N<br>* Humulin® N (human insulin [recombinant deoxyribonucleic acid origin] isophane suspension) is an intermediate-acting human isophane insulin. Humulin® N is a suspension of crystals produced from combining human insulin and protamine sulphate.<br>|
| Experimental: Sequence: Humulin® N-Biocon Insulin N- Biocon Insulin N<br>Period 1: 0.4 IU/kg of Humulin® N (100 IU/mL) administered once subcutaneously. Period 2: 0.4 IU/kg of Biocon Insulin N (100 IU/mL) administered once subcutaneously. Period 3: 0.4 IU/kg of Biocon Insulin N (100 IU/mL) administered once subcutaneously. The treatment periods will be separated by 5-7 days | Biological: Biocon Insulin N<br>* Biocon Insulin N is an intermediate-acting isophane suspension of human insulin produced by recombinant deoxyribonucleic acid(rDNA) technology utilizing Pichia pastoris (yeast).<br>Biological: Humulin® N<br>* Humulin® N (human insulin [recombinant deoxyribonucleic acid origin] isophane suspension) is an intermediate-acting human isophane insulin. Humulin® N is a suspension of crystals produced from combining human insulin and protamine sulphate.<br>|
| Experimental: Sequence: Biocon Insulin N- Biocon Insulin N-Humulin® N<br>Period 1: 0.4 IU/kg of Biocon Insulin N (100 IU/mL) administered once subcutaneously. Period 2: 0.4 IU/kg of Biocon Insulin N (100 IU/mL) administered once subcutaneously. Period 3: 0.4 IU/kg of Humulin® N (100 IU/mL) administered once subcutaneously. The treatment periods will be separated by 5-7 days | Biological: Biocon Insulin N<br>* Biocon Insulin N is an intermediate-acting isophane suspension of human insulin produced by recombinant deoxyribonucleic acid(rDNA) technology utilizing Pichia pastoris (yeast).<br>Biological: Humulin® N<br>* Humulin® N (human insulin [recombinant deoxyribonucleic acid origin] isophane suspension) is an intermediate-acting human isophane insulin. Humulin® N is a suspension of crystals produced from combining human insulin and protamine sulphate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary PK endpoint: area under the insulin concentration curve(AUCins).0-24h | area under the insulin concentration curve | 0-24hour | 
| Primary PK endpoint: maximum observed insulin concentration(Cins.max) | maximum observed insulin concentration | 0-24hour | 
| PD endpoint:area under the glucose infusion rate curve(AUCGIR)0-24h | area under the glucose infusion rate curve | 0-24hour | 
| PD endpoint:maximum observed glucose infusion rate (GIRmax) | maximum observed glucose infusion rate | 0-24hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary PK endpoint: area under the insulin concentration-time curve(AUCins).0-infinity | area under the insulin concentration-time curve | 0-24 hours | 
| Secondary PK endpoint: area under the insulin concentration-time curve(AUCins).0-12h | area under the insulin concentration-time curve | 0-12hour | 
| Secondary PK endpoint: area under the insulin concentration-time curve(AUCins).12-24h | area under the insulin concentration-time curve | 12-24hour | 
| Secondary PK endpoint:time to maximum observed insulin concentration (tmax.ins) | time to maximum observed insulin concentration | 0-24 hours | 
| Secondary PK endpoint:terminal elimination rate constant of insulin (λz) | terminal elimination rate constant of insulin | 0-24 hours | 
| Secondary PK endpoint: terminal elimination half-life (t½) | terminal elimination half-life calculated as t½=ln2/λz | 0-24 hours | 
| Secondary PK endpoint: time(t)50%-INS(early) | time to half-maximum before Cmax | 0-24 hours | 
| Secondary PK endpoint: time(t)50%-INS(late) | time to half-maximum after Cmax | 0-24 hours | 
| Secondary PD endpoint: areas under the glucose infusion rate curve(AUCGIR).0-12h | areas under the glucose infusion rate curve | 0-12hours | 
| Secondary PD endpoint: areas under the glucose infusion rate curve(AUCGIR).12-24h | areas under the glucose infusion rate curve | 12-24hours | 
| Secondary PD endpoint: time to maximum glucose infusion rate(tmax.GIR) | time to maximum glucose infusion rate | 0-24 hours | 
| Secondary PD endpoint:time to half-maximum glucose infusion rate before GIRmax (tGIR.50%-early) | time to half-maximum glucose infusion rate before GIRmax | 0-24 hours | 
| Secondary PD endpoint: time to half-maximum glucose infusion rate after GIRmax (tGIR.50%-late) | time to half-maximum glucose infusion rate after GIRmax | 0-24 hours | 
| Secondary PD endpoint: Onset of action | time from trial product administration until blood glucose concentration has decreased at least 5 mg/dL from baseline, where baseline is defined as the mean of blood glucose levels from -6, -4, and -2 minutes before trial product administration as measured by ClampArt(name of Clamp Devise)) | 0-24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recombinant Human Insulin N (rhi N)