Comparison of the Pharmacokinetic and Pharmacodynamic Properties of Biocon's Insulin R U-500 With Humulin® R U-500 (US Reference Product) in Healthy Subjects

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's Human Insulin R U-500 with Humulin® R U-500 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 18 to 44 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's Human Insulin R U-500 and Humulin® R U-500 (RHINE-4: Recombinant Human INsulin Equivalence-4)

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Biological: Biocon's Human Insulin R U-500
* Biological: Humulin® R U-500 (US Reference Product)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male or post-menopausal female subjects. The post-menopausal state is defined as no menses for 12 months 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 (BMI) between 18.5 and 29.0 kg/m2, both inclusive. Fasting plasma glucose concentration ≤ 100 mg/dL. Considered generally healthy upon completing the medical history and screening safety assessments, as judged by the Investigator. Exclusion Criteria: Known or suspected hypersensitivity to investigational medicinal products (IMPs) or related products. Receipt of any medicinal product in clinical development within 30 days or five times its half-life (whichever is longer) before randomisation in this trial. Systolic blood pressure < 90 mmHg or > 139 mmHg and/or diastolic blood pressure < 50 mmHg or > 89 mmHg after resting for at least 5 minutes in the 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.

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: Biocon's Human Insulin R U-500-Biocon's Human Insulin R U-500- Humulin® R U-500<br>Period 1:Biocon's Human Insulin R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 2:Biocon's Human Insulin R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 3:Humulin® R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe | Biological: Biocon's Human Insulin R U-500<br>* Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).<br>Biological: Humulin® R U-500 (US Reference Product)<br>* Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)<br>|
| Experimental: Sequence: Biocon's Human Insulin R U-500-Humulin® R U-500- Humulin® R U-500<br>Period 1:Biocon's Human Insulin R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 2:Humulin® R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 3:Humulin® R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe | Biological: Biocon's Human Insulin R U-500<br>* Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).<br>Biological: Humulin® R U-500 (US Reference Product)<br>* Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)<br>|
| Experimental: Sequence: Biocon's Human Insulin R U-500-Humulin® R U-500-Biocon's Human Insulin R U-500<br>Period 1:Biocon's Human Insulin R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 2:Humulin® R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 3:Biocon's Human Insulin R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe | Biological: Biocon's Human Insulin R U-500<br>* Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).<br>Biological: Humulin® R U-500 (US Reference Product)<br>* Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)<br>|
| Experimental: Sequence: Humulin® R U-500-Biocon's Human Insulin R U-500-Biocon's Human Insulin R U-500<br>Period 1:Humulin® R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 2:Biocon's Human Insulin R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 3:Biocon's Human Insulin R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe | Biological: Biocon's Human Insulin R U-500<br>* Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).<br>Biological: Humulin® R U-500 (US Reference Product)<br>* Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)<br>|
| Experimental: Sequence: Humulin® R U-500 -Biocon's Human Insulin R U-500-Humulin® R U-500<br>Period 1:Humulin® R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 2:Biocon's Human Insulin R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 3:Humulin® R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe | Biological: Biocon's Human Insulin R U-500<br>* Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).<br>Biological: Humulin® R U-500 (US Reference Product)<br>* Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)<br>|
| Experimental: Sequence: Humulin® R U-500-Humulin® R U-500-Biocon's Human Insulin R U-500<br>Period 1:Humulin® R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe Period 2:Humulin® R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD(Becton Dickinson) disposable syringe Period 3:Biocon's Human Insulin R U-500 single subcutaneous dose of 0.3 IU/kg using a U-500 BD (Becton Dickinson) disposable syringe | Biological: Biocon's Human Insulin R U-500<br>* Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).<br>Biological: Humulin® R U-500 (US Reference Product)<br>* Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary pharmacokinetics (PK) endpoint: area under the insulin concentration curve(AUCins).0-12h | Area under the insulin concentration curve | 0 to12 hours | 
| Primary pharmacokinetics (PK) endpoint: maximum observed insulin concentration(Cins.max) | Maximum observed insulin concentration | NAP (Not Applicable) | 
| Primary pharmacodynamics (PD) endpoint:area under the glucose infusion rate curve (AUCGIR)0-12h | Area under the glucose infusion rate curve | 0 to 12 hours | 
| Primary pharmacodynamics (PD) endpoint:maximum observed glucose infusion rate (GIRmax) | Maximum observed glucose infusion rate | NAP (Not Applicable) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary pharmacokinetics (PK) endpoint: area under the insulin concentration-time curve(AUCins).0-infinity | Area under the insulin concentration-time curve | 0 hours to 24 hours | 
| Secondary pharmacokinetics (PK) endpoint: area under the insulin concentration-time curve(AUCins).0-24h | Area under the insulin concentration-time curve | 0 to 24 hours | 
| Secondary pharmacokinetics (PK) endpoint: area under the insulin concentration-time curve (AUCins).12-24h | Area under the insulin concentration-time curve | 12 to 24 hours | 
| Secondary pharmacokinetics (PK) endpoint:time to maximum observed insulin concentration (tmax.ins) | Time to maximum observed insulin concentration | 0 to 24 hours | 
| Secondary pharmacokinetics (PK) endpoint:terminal elimination rate constant of insulin (λz) | Terminal elimination rate constant of insulin | 0 to 24 hours | 
| Secondary pharmacokinetics (PK) endpoint: terminal elimination half-life (t½) | Terminal elimination half-life calculated | 0 to 24 hours | 
| Secondary pharmacokinetics (PK) endpoint: time(t)50%-Insulin (INS)(early) | Time to half-maximum before Cmax | 0 to 24 hours | 
| Secondary pharmacokinetics (PK) endpoint: time(t) 50%-Insulin (INS)(late) | Time to half-maximum after Cmax | 0 to 24 hours | 
| Secondary pharmacodynamics (PD) endpoint: areas under the glucose infusion rate curve(AUCGIR).0-24h | Area under the glucose infusion rate curve | 0 to 24 hours | 
| Secondary pharmacodynamics (PD) endpoint: areas under the glucose infusion rate curve(AUCGIR).12-24h | Area under the glucose infusion rate curve | 12 to 24 hours | 
| Secondary pharmacodynamics (PD) endpoint: time to maximum glucose infusion rate(tmax.GIR) | Time to maximum glucose infusion rate | 0 to 24 hours | 
| Secondary pharmacodynamics (PD) endpoint:time to half-maximum glucose infusion rate before GIRmax (tGIR.50%-early) | Time to half-maximum glucose infusion rate before GIRmax | 0 to 24 hours | 
| Secondary pharmacodynamics (PD) endpoint: time to half-maximum glucose infusion rate after GIRmax (tGIR.50%-late) | Time to half-maximum glucose infusion rate after GIRmax | 0 to 24 hours | 
| Secondary pharmacodynamics (PD) endpoint: Onset of action, time from trial product administration until plasma glucose concentration has decreased at least 5 mg/dL from baseline, | Time from trial product administration until plasma glucose concentration | 0 to 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recombinant Human INsulin Equivalence-4, RHINE-4, Pharmacokinetic, Pharmacodynamic, Biocon's Insulin R U-500, Humulin® R U-500