PK/PD Biosimilarity Study of Gan & Lee Insulin Lispro Injection vs. EU and US Humalog® in Healthy Males

Study Overview
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Brief Summary
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Primary objective: To demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of Gan & Lee Insulin Lispro Injection with both EU - approved Humalog® and US - licensed Humalog® (Reference Products) in healthy male subjects Secondary objectives: To compare the PK and PD parameters of the three insulin lispro preparations To evaluate the single dose safety and local tolerability of the three insulin lispro preparations

Official Title
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A Glucose Clamp Trial Investigating the Biosimilarity of Gan & Lee Insulin Lispro Injection With Both EU - Approved and US - Licensed Humalog® in Healthy Male Subjects

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Gan & Lee Insulin Lispro Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent obtained before any trial related activities. Trial related activities are any procedures that would not have been done during normal management of the subject Healthy male subjects Age between 18 and 64 years, both inclusive Body Mass Index (BMI) between 18.5 and 29.0 kg/m^2, both inclusive Fasting plasma glucose concentration <= 5.5 mmol/L (100 mg/dL) at screening Considered generally healthy upon completion of medical history and screening safety assessments, as judged by the Investigator Exclusion Criteria: Known or suspected hypersensitivity to IMP(s) or related product Previous participation in this trial. Participation is defined as randomized Receipt of any medicinal product in clinical development within 30 days before randomization in this trial History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction Any history or presence of cancer except basal cell skin cancer or squamous cell skin cancer as judged by the Investigator Any history or presence of clinically relevant comorbidity, as judged by the Investigator Signs of acute illness as judged by the Investigator Any serious systemic infectious disease during four weeks prior to first dosing of the trial drug, as judged by the Investigator Clinically significant abnormal screening laboratory tests, as judged by the Investigator Elevation of serum ALT> 10% above the ULN, or elevation of serum AST or serum bilirubin >20% above the ULN. (Note: Elevation of bilirubin is considered acceptable in case of Gilbert's disease and should be evaluated in clinical context) Elevation of serum creatinine > ULN, or elevation of serum urea > 10% above ULN Systolic blood pressure < 90 mmHg or >139 mmHg and/or diastolic blood pressure < 50 mmHg or > 89 mmHg (one repeat test will be acceptable in case of suspected white-coat hypertension) Symptoms of arterial hypotension Heart rate at rest outside the range of 50-90 beats per minute Clinically significant abnormal standard 12-lead electrocardiogram (ECG) after 5 minutes resting in supine position at screening, as judged by the Investigator Increased risk of thrombosis, e.g. subjects with a history of deep leg vein thrombosis or family history of deep leg vein thrombosis, as judged by the Investigator Significant history of alcoholism or drug abuse as judged by the Investigator or consuming more than 24 grams alcohol/day (on average) A positive result in the alcohol and/or urine drug screen at the screening visit Smoking more than 5 cigarettes or the equivalent per day Inability or unwillingness to refrain from smoking and use of nicotine substitute products one day before and during the inpatient period Positive test for Hepatitis Bs antigen Positive test for Hepatitis C antibodies. (Presence of Hepatitis C antibodies will not lead to exclusion if liver function tests are normal and a hepatitis C polymerase chain reaction is negative) Positive result to the test for HIV-1/2 antibodies or HIV-1 antigen Any medication (prescription and non-prescription drugs) within 7 days before IMP administration and/or anticoagulant therapy Blood donation or blood loss of more than 500mL within the last 3 months Mental incapacity, unwillingness or language barriers precluding adequate understanding or co-operation Explanatory note on Exclusion Criterion 24: With the exception of paracetamol or NSAIDs for occasional use to treat acute pain, as judged by the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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
Interventional Model Description: This is a phase 1 trial. The trial is a single center, randomized, doubleblind, single dose, there treatment, three period crossover, 12 - hour euglycaemic glucose clamp trial in healthy male subjects.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gan & Lee Insulin Lispro Injection<br>Insulin lispro, 3 mL cartridge in prefilled pen, 100 units/mL (U-100) | Drug: Gan & Lee Insulin Lispro Injection<br>* All three IMPs will be administered as a 0.2 U/kg single dose subcutaneously in the periumbilical area by use of a disposable prefilled pen.<br>* Other names: US - licensed Humalog ®;|
| Active Comparator: EU - approved Humalog ®<br>Insulin lispro (product approved and marketed in the EU), 3 mL cartridge in prefilled Kwikpen®, 100 units/mL (U-100) | Drug: Gan & Lee Insulin Lispro Injection<br>* All three IMPs will be administered as a 0.2 U/kg single dose subcutaneously in the periumbilical area by use of a disposable prefilled pen.<br>* Other names: US - licensed Humalog ®;|
| Active Comparator: US - licensed Humalog ®<br>Insulin lispro (product approved and marketed in the US), 3 mL cartridge in prefilled Kwikpen®, 100 units/mL (U-100) | Drug: Gan & Lee Insulin Lispro Injection<br>* All three IMPs will be administered as a 0.2 U/kg single dose subcutaneously in the periumbilical area by use of a disposable prefilled pen.<br>* Other names: US - licensed Humalog ®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCins.0-12h | PK Endpoint: The area under the insulin concentration curve from 0 to 12 hours. | 0 to 12 hours | 
| Cins.max | PK Endpoint: The maximum observed insulin concentration. | 0 to 12 hours | 
| AUCGIR.0-12h | PD endpoint: The area under the glucose infusion rate curve from 0 to 12 hours. | 0 to 12 hours | 
| GIRmax | PD endpoint: The maximum glucose infusion rate. | 0 to 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCins.0-2h | PK endpoint: The area under the insulin concentration curve from 0 to 2 hours | 0 to 2 hours | 
| AUCins.0-4h | PK endpoint: The area under the insulin concentration curve from 0 to 4 hours | 0 to 4 hours | 
| AUCins.0-6h | PK endpoint: The area under the insulin concentration curve from 0 to 6 hours | 0 to 6 hours | 
| AUCins.6-12h | PK endpoint: The area under the insulin concentration curve from 0 to 12 hours | 6 to 12 hours | 
| AUCins.0-∞ | PK endpoint: The area under the insulin concentration-time curve from 0 hours to infinity | 0 to 12 hours | 
| tins.max | PK endpoint: The time to maximum observed insulin concentration t½, terminal serum elimination half-life calculated as t½=ln2/λz | 0 to 12 hours | 
| t50%-ins(early) | PK endpoint: The time to half-maximum insulin concentration before Cins.max | 0 to 12 hours | 
| t50%-ins(late) | PK endpoint: The time to half-maximum insulin concentration after Cins.max | 0 to 12 hours | 
| t½ | PK endpoint: The terminal serum elimination half-life calculated as t½=ln2/λz | 0 to 12 hours | 
| λz | PK endpoint: The terminal elimination rate constant of insulin | 0 to 12 hours | 
| AUCGIR.0-2h | PD endpoint: The area under the glucose infusion rate curve from 0 to 2 hours | 0 to 2 hours | 
| AUCGIR.0-4h | PD endpoint: The area under the glucose infusion rate curve from 0 to 4 hours | 0 to 4 hours | 
| AUCGIR.0-6h | PD endpoint: The area under the glucose infusion rate curve from 0 to 6 hours | 0 to 6 hours | 
| AUCGIR.6-12h | PD endpoint: The area under the glucose infusion rate curve from 6 to 12 hours | 6 to 12 hours | 
| tGIR.max | PD endpoint: The time to maximum glucose infusion rate | 0 to 12 hours | 
| tGIR.50%-early | PD endpoint: The time to half-maximum glucose infusion rate before GIRmax | 0 to 12 hours | 
| tGIR.50%-late | PD endpoint: The time to half-maximum glucose infusion rate after GIRmax | 0 to 12 hours | 
| PD endpoint | time to onset of action | 0 to 12 hours | 
| Safety and Local Tolerability | Number of participants experiencing treatment-emergent adverse events | 0 to 12 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Insulin, Lispro, Diabetes Mellitus, Basal, Bolus