A Study to Demonstrate Pharmacokinetic and Pharmacodynamic Biosimilarity Between HEC-Glargine and US-Lantus® in Healthy Male Volunteers

Study Overview
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Brief Summary
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This is a phase 1 study to demonstrate pharmacokinetic and pharmacodynamic similarity between HEC-Glargine and US-Lantus® using the euglycemic clamp technique in healthy male adult volunteers.

Detailed Description
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This will be a double-blind, single-dose, randomized, two-period, two-treatment, two-sequence crossover clamp study performed at a single study center. The study population consists of healthy adult male subjects. The study will comprise of: A screening period: maximum 28 days prior to first dose administration. Admission: Subjects will be admitted to the study center on Day -1 Two Treatment Periods (Treatment Periods 1 and 2): Subjects will be randomized to either of the 2 treatment sequences (AB or BA) on Day 1 of Treatment Period 1 to receive either test or reference product as per randomization schedule in a 1:1 ratio. Treatment A (Test Formulation): HEC-Glargine Treatment B (Reference Formulation): US-Lantus® On Day 1 of each Treatment Period, the study drug or reference product will be administered as a single morning dose to subjects in a fasting state. There will be a wash-out period of at least 7 calendar days. Each subject will receive both test and reference products in a crossover pattern over Treatment Periods 1 and 2.

Official Title
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A Single Center, Single-dose, Double-blind, Randomized, Two-period, Two-treatment, Two-sequence, Crossover Study to Demonstrate Pharmacokinetic and Pharmacodynamic Similarity Between HEC-Glargine and US-Lantus® Using the Euglycemic Clamp Technique in Healthy Male Adult Volunteers

Conditions
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Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: HEC-Glargine
* Drug: US-Lantus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has body weight not less than 60 kg and body mass index between 18.5 and 30.0 kg/m^2 (both inclusive). Glycohemoglobin (HbA1c) levels are <6.0%. Normal oral glucose tolerance test conducted within the previous 6 months Medical history, vital signs, physical examination, standard 12-lead electrocardiogram (ECG) and laboratory investigations should be clinically acceptable or within laboratory reference ranges for the relevant laboratory tests Non-smokers or mild to moderate smokers (≤ 10 cigarettes or pipes per day). Exclusion Criteria: Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with protocol requirements. Current alcohol use >21 units of alcohol per week Regular exposure to substances of abuse (other than alcohol) within the past year. Use of any medication, prescribed or over-the-counter or herbal remedies Participation in another study with an experimental drug, where the last administration of the previous study drug was within 12 weeks before administration of study drug in this study. Treatment within the previous 3 months before the first administration of study drug with any drug with a well-defined potential for adversely affecting a major organ or system. A major disease (i.e., a disease that could not be treated at home, but the subject had to be hospitalized or needed general anesthesia usually for a major operation) during the 3 months before commencement of the screening period. Positive test for insulin antibodies. History of bronchial asthma or any other bronchospastic disease, and/or convulsions, and/or porphyria. Relevant history or laboratory or clinical findings indicative of acute or chronic disease, likely to influence study outcome. Resting pulse of >100 beats per minute (bpm) or <40 bpm during the screening period, either supine or standing. Hypertension diagnosed during screening or current diagnosis of hypertension. Hemoglobin count deviating more than 10% of the lower limit of normal. Clinically relevant abnormalities in the coagulation status. History of bleeding disorders. Veins unsuitable for venous blood collection and cannulation. Any specific study drug safety concern.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HEC-Glargine Treatment A (Test)<br>Subjects will receive single doses of Test Formulation HEC-Glargine on Day 1 of Treatment periods 1 and 2 followed by at least 7-21 days washout. | Drug: HEC-Glargine<br>* Subjects will receive 0.5 IU/kg of HEC-Glargine subcutaneously as a single morning dose on Day 1.<br>|
| Active Comparator: US-Lantus Treatment B (Reference)<br>Subjects will receive single doses of Reference Formulation Lantus on Day 1 followed of Treatment periods 1 and 2 by at least 7-21 days washout. | Drug: US-Lantus<br>* Subjects will receive 0.5 IU/kg of Lantus subcutaneously as a single morning dose on Day 1.<br>* Other names: Insulin glargine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve from 0 hours to 24 hours (AUC0-24h) of M1 | The Pharmacokinetics (PK) parameters of HEC-Glargine to the US-approved Lantus® insulin glargine injection (US-Lantus®) solution for SC injection to demonstrate PK similarity for insulin glargine and/or metabolite 21A-Gly-human insulin (M1) will be assessed. | Day 1 and Day 2 | 
| Maximum observed plasma exogenous insulin glargine concentration (Cmax) of M1 | The PK parameters of HEC-Glargine to the US-approved Lantus® insulin glargine injection (US-Lantus®) solution for SC injection to demonstrate PK similarity for insulin glargine and/or metabolite 21A-Gly-human insulin (M1) will be assessed. | Day 1 and Day 2 | 
| Area under the Glucose infusion rate (GIR) -time curve (calculated as the exact area under the stepwise constant function) from 0 hours to 24 hours (GIRAUC0-24h) | The pharmacodynamics (PD) of HEC-Glargine to US-Lantus®, by means of GIR profiles after single SC dose will be assessed. | Day 1 and Day 2 | 
| Maximum GIR (GIRmax) | The PD of HEC-Glargine to US-Lantus®, by means of GIR profiles after single SC dose will be assessed. | Day 1 and Day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve from 0 hours to the last quantifiable concentration-time (AUC0-t) | The PK parameters of HEC-Glargine, US-Lantus®, and M1 will be assessed. Also, AUC0-t will be evaluating the inter-subject and intra-subject variability of PK of HEC-Glargine in comparison to US-Lantus®, assessed by intra-subject coefficients of variation for primary PK parameters. | Day 1 and Day 2 | 
| Area under the concentration-time curve from 0 hours to 6 hours (AUC0-6h) | The PK parameters of HEC-Glargine, US-Lantus®, and M1 will be assessed. | Day 1 and Day 2 | 
| Area under the concentration-time curve from 6 hours to 12 hours (AUC6-12h) | The PK parameters of HEC-Glargine, US-Lantus®, and M1 will be assessed. | Day 1 and Day 2 | 
| Area under the concentration-time curve from 0 hours to 12 hours (AUC0-12h) | The PK parameters of HEC-Glargine, US-Lantus®, and M1 will be assessed. | Day 1 and Day 2 | 
| Area under the concentration-time curve from 12 hours to 18 hours (AUC12-18h) | The PK parameters of HEC-Glargine, US-Lantus®, and M1 will be assessed. | Day 1 and Day 2 | 
| Area under the concentration-time curve from 18 hours to 24 hours (AUC18-24h) | The PK parameters of HEC-Glargine, US-Lantus®, and M1 will be assessed. | Day 1 and Day 2 | 
| Area under the concentration-time curve from 12 hours to 24 hours (AUC12-24h) | The PK parameters of HEC-Glargine, US-Lantus®, and M1 will be assessed. | Day 1 and Day 2 | 
| Time to maximum plasma exogenous insulin glargine concentration (Tmax) | The PK parameters of HEC-Glargine, US-Lantus®, and M1 will be assessed. | Day 1 and Day 2 | 
| Area under the concentration-time curve from 0 hours to the last quantifiable concentration-time extrapolated to infinity (AUC0-∞) | The PK parameters of HEC-Glargine, US-Lantus®, and M1 will be assessed. | Day 1 and Day 2 | 
| Area under the GIR-time curve for the time of a dosing interval (GIRAU0-t) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. Also, GIRAU0-t will be evaluating the inter-subject and intra-subject variability of PD of HEC-Glargine in comparison to US-Lantus®, assessed by intra-subject coefficients of variation for primary PD parameters. | Day 1 and Day 2 | 
| Area under the GIR-time curve from 0 hours to end of clamp (GIRAUC0-end of clamp) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Area under the GIR-time curve from 0 hours to the last quantifiable concentration-time with extrapolation to infinity (GIRAUC0-∞) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Area under the GIR-time curve from 0 hours to 6 hours (GIRAUC0-6h) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Area under the GIR-time curve from 6 hours to 12 hours (GIRAUC6-12h) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Area under the GIR-time curve from 0 hours to 12 hours (GIRAUC0-12h) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Area under the GIR-time curve from 12 hours to18 hours (GIRAUC12-18h) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Area under the GIR-time curve from 18 hours to 24 hours (GIRAUC18-24h) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Area under the GIR-time curve from 12 hours to 24 hours (GIRAUC12-24h) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Time to maximum glucose infusion rate (TGIRmax) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Total amount of glucose infused during clamp procedure (Gtot) | The PD parameters of HEC-Glargine, US-Lantus® will be assessed. | Day 1 and Day 2 | 
| Time to onset of action (TOA) | The TOA will be assessed for HEC-Glargine, US-Lantus® as PD parameters. | Day 1 and Day 2 | 
| Maximum observed plasma exogenous insulin glargine concentration (Cmax) | The Cmax will be evaluating the inter-subject and intra-subject variability of PK of HEC-Glargine in comparison to US-Lantus®, assessed by intra-subject coefficients of variation for primary PK parameters. | Day 1 and Day 2 | 
| Maximum GIR (GIRmax) | The GIRmax will be evaluating the inter-subject and intra-subject variability of PD of HEC-Glargine in comparison to US-Lantus®, assessed by intra-subject coefficients of variation for primary PD parameters. | Day 1 and Day 2 | 
| Number of subjects with adverse events (AEs) | To assess safety and tolerability of the HEC-Glargine compared to US-Lantus® after single SC dose To assess safety and tolerability of the HEC-Glargine compared to US-Lantus® after single SC dose | Day -1 to within 7 Days of completion of the last period or early withdrawal (approximately 31 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetic, pharmacodynamic, euglycemic clamp technique, insulin glargine, biosimilarity study