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 (RHINE-4)

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)

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

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Biological: Biocon's Human Insulin R U-500; Biological: Humulin® R U-500 (US Reference Product)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neuss, Germany, D-41460
    • Profil Institut für Stoffwechselforschung GmbH 9

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

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; 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; Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).; Biological: Humulin® R U-500 (US Reference Product); Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)
Experimental: Sequence: Biocon's Human Insulin R U-500-Humulin® R U-500- Humulin® R U-500; 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; Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).; Biological: Humulin® R U-500 (US Reference Product); Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)
Experimental: Sequence: Biocon's Human Insulin R U-500-Humulin® R U-500-Biocon's Human Insulin R U-500; 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; Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).; Biological: Humulin® R U-500 (US Reference Product); Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)
Experimental: Sequence: Humulin® R U-500-Biocon's Human Insulin R U-500-Biocon's Human Insulin R U-500; 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; Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).; Biological: Humulin® R U-500 (US Reference Product); Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)
Experimental: Sequence: Humulin® R U-500 -Biocon's Human Insulin R U-500-Humulin® R U-500; 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; Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).; Biological: Humulin® R U-500 (US Reference Product); Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)
Experimental: Sequence: Humulin® R U-500-Humulin® R U-500-Biocon's Human Insulin R U-500; 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; Biocon's Human Insulin R U-500 (Insulin Human Injection 500 units/mL), 3 mL cartridges (containing 1,500 units of insulin).; Biological: Humulin® R U-500 (US Reference Product); Humulin® R U-500 (US Reference Product), 3 mL single-patient-use KwikPen® (containing 1,500 units of insulin)

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety endpoint: Number of subjects with Adverse Events (AEs)		Signing of Informed consent form (ICF) to follow-up period (Total duration: 44 days approximate)
Safety endpoint: Number of subjects with Clinically significant changes in Physical examination		Signing of Informed consent form (ICF) to follow-up period (Total duration: 44 days approximate)
Safety endpoint: Number of subjects with Clinically significant changes in Vital signs		Signing of Informed consent form (ICF) to follow-up period (Total duration: 44 days approximate)
Safety endpoint: Local tolerability assessment / Injection site reactions	Number of subjects with Injection Site Reactions	Signing of Informed consent form (ICF) to follow-up period (Total duration:44 days approximate)
Safety endpoint: Number of subjects with clinically significant changes in Laboratory safety parameters		Signing of Informed consent form (ICF) to follow-up period (Total duration:44 days approximate)
Safety endpoint: Number of subjects with clinically significant changes in ECG		Signing of Informed consent form (ICF) to follow-up period (Total duration:44 days approximate)

Collaborators and Investigators

• Sponsor: Biocon Limited
• Collaborators: Profil Institut für Stoffwechselforschung GmbH
• Investigators: Principal Investigator: Dr Ulrike Hövelmann, MD, Profil Institut für Stoffwechselforschung GmbH

Study record dates

Study Major Dates

• Study Start (Actual): May 30, 2022
• Primary Completion (Actual): December 12, 2022
• Study Completion (Actual): December 12, 2022

Study Registration Dates

• First Submitted: June 7, 2022
• First Submitted That Met QC Criteria: June 9, 2022
• First Posted (Actual): June 10, 2022

Study Record Updates

• Last Update Posted (Actual): May 9, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Pharmacokinetic; Pharmacodynamic; Recombinant Human INsulin Equivalence-4; RHINE-4; Biocon's Insulin R U-500; Humulin® R U-500
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: BIO-INS500-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No