Pharmacokinetic (PK) Bioequivalence and Pharmacodynamics (PD) of Julphar Insulin N and Huminsulin® Basal

Study Overview
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Brief Summary
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This study in healthy volunteers aims to demonstrate similar PK and PD properties of the new human isophane Insulin, Julphar Insulin N, and the already approved reference Insulin, Huminsulin® Basal. All participants will receive both study treatments on two separate dosing days.

Detailed Description
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Daily injections of insulin are a necessity for many patients with diabetes mellitus in order to treat hyperglycemia. Julphar Insulin N and Huminsulin® Basal are both intermediate-acting human isophane insulins, i.e. consist of a suspension containing a crystalline precipitate of isophane human insulin (NPH) complexed with protamine sulphate and zinc. The new insulin, Julphar Insulin N, is biosimilar to Huminsulin® Basal. Demonstration of similar absorption (PK) and effects (PD) are necessary to achieve market approval of Julphar Insulin N.

Official Title
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Single-center, Randomized, Double-blind, 2-treatment, 2-period Crossover Trial in Healthy Subjects to Demonstrate PK Bioequivalence and to Compare the PD Properties of Julphar Insulin N and Huminsulin® Basal

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Julphar Insulin N (human isophane insulin)
* Drug: Huminsulin® Basal (NPH, human isophane insulin)


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 performed during normal management of the subject). Healthy male subject. Age between 18 and 55 years, both inclusive. Body Mass Index (BMI) between 18.5 and 28.0 kg/m^2, both inclusive. Fasting plasma glucose concentration ≤100 mg/dL. Exclusion Criteria: Known or suspected hypersensitivity to IMPs or related products. Previous participation in this trial. Participation is defined as randomised. Receipt of any medicinal product in clinical development within 3 months before screening. 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 cardiovascular, pulmonary, respiratory, gastrointestinal, hepatic, renal, metabolic, endocrinological haematological, dermatological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, or infectious disease, or signs of acute illness as judged by the Investigator. Surgery within 12 weeks before the start of the study or blood donation of more than 500 mL (or considerable blood loss) or plasma donation within the last 3 months. 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. Clinically significant abnormal values for haematology, biochemistry, coagulation, or urinalysis as judged by the Investigator. Supine blood pressure (BP) at screening (after resting for 5 minutes in a supine position) outside the range of 90 to 140 mmHg for systolic BP or 50 to 90 mmHg for diastolic BP (excluding white-coat hypertension; therefore, if a repeated measurement shows values within the range, the subject can be included in the trial) and/or resting supine pulse < 50 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. Any disease or condition that, in the opinion of the Investigator, would represent an unacceptable risk for the subject's safety. Positive to the screening test for Hepatitis Bs antigen or Hepatitis C antibodies and/or a positive result to the test for HIV-1/2 antibodies or HIV-1 antigen. History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction. Likelihood of requiring treatment during the study period with drugs not permitted by the clinical study protocol. Any medication (prescription and non-prescription drugs) within 14 days before first trial drug administration and/or anticoagulant therapy, with the exception of stable treatment with thyroid hormones, paracetamol and ibuprofen for occasional use to treat pain. Significant history of alcoholism or drug abuse as judged by the Investigator or consuming more than 21 units of alcohol per week (one unit of alcohol equals about 330 mL of beer, one glass of wine of 120 mL, or 40 mL spirits). A positive result in the alcohol and/or urine drug screen at the screening visit. Smoker (defined as a subject who is smoking more than 5 cigarettes or the equivalent per day) who is not able or willing to refrain from smoking and use of nicotine substitute products 1 day before and during the inpatient period. Subject with mental incapacity or language barriers precluding adequate understanding or cooperation or who, in the opinion of the Investigator, should not participate in the trial. Potentially noncompliant or uncooperative during the trial, as judged by the Investigator.

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: Julphar Insulin N<br>Julphar Insulin N, human isophane insulin, 100 IU/mL, single subcutaneous injection of 0.6 IU/kg body weight | Drug: Julphar Insulin N (human isophane insulin)<br>* investigational insulin: Julphar N (human isophane insulin), biosimilar<br>* Other names: Julphar Insulin N;|
| Active Comparator: Huminsulin® Basal<br>Huminsulin® Basal, neutral protamine hagedorn (NPH), human isophane insulin, 100 IU/mL, single subcutaneous injection of 0.6 IU/kg body weight | Drug: Huminsulin® Basal (NPH, human isophane insulin)<br>* marketed reference product: Huminsulin® Basal (NPH, human isophane insulin)<br>* Other names: Huminsulin® Basal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK: AUCins.0-24h, area under the serum insulin concentration curve from 0 to 24 hours | Primary endpoints according EMA guidelines | 24 hours | 
| PK: Cins.max, maximum observed insulin concentration | Primary endpoints according EMA guidelines | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK: AUCins.0-6h, AUCins.0-12, areas under the serum insulin concentration curve in the indicated time intervals |  | 12 hours | 
| PK: AUCins.0-∞, area under the serum insulin concentration-time curve from 0 hours to infinity |  | 24 hours | 
| PK: tmax, time to maximum observed serum insulin concentration |  | 24 hours | 
| PK: t½, terminal serum elimination half-life calculated as t½=ln2/λz |  | 24 hours | 
| PK: λz, terminal elimination rate constant of insulin |  | 24 hours | 
| PD: AUCGIR.0h-last, area under the glucose infusion rate curve from 0 hours until the end of clamp |  | 24 hours | 
| PD: GIRmax, maximum observed glucose infusion rate |  | 24 hours | 
| PD: AUCGIR.0-6h, AUCGIR.0-12h, areas under the glucose infusion rate curve in the indicated time-intervals |  | 12 hours | 
| PD: tGIR.max, time to maximum glucose infusion rate |  | 24 hours | 
| PD: Onset of action, time from trial product administration until blood glucose concentration has decreased at least 5 mg/dL from baseline | baseline is defined as the mean of blood glucose levels from -6, -4, and -2 minutes before trial product administration as measured by the glucose clamp device | 24 hours | 
| Adverse events |  | from first dosing until final examination (up to 39 days for each patient) | 
| Local tolerability findings | at the injection site, The local tolerability at the injection site will be evaluated by means of the following assessments: spontaneous pain pain on palpation itching erythema oedema induration/infiltration other Each of these assessments will be reported on a scale of 0 (none), 1 (mild), 2 (moderate) and 3 (severe). The evaluation and the actual time of the assessment will be recorded | dosing period (up to 25 days for each patient) | 
| Laboratory safety parameters |  | from screening to final examination (up to 61 days for each patient) | 
| Physical examination findings |  | from screening to final examination (up to 61 days for each patient) | 
| Changes in vital signs |  | from screening to final examination (up to 61 days for each patient) | 
| Changes in Electrocardiogram recordings |  | from screening to final examination (up to 61 days for each patient) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intermediate-acting human isophane insulin, biosimilar