Pharmacokinetic (PK) Bioequivalence and Pharmacodynamics (PD) of Julphar Insulin 30/70 and Huminsulin® Profil III

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 biphasic insulin, Julphar Insulin 30/70 and an already approved reference insulin, Huminsulin® Profil III. All participants will receive both study treatments on two separate dosing days.

Detailed Description
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Daily injections of insulin is a necessity for many patients with diabetes mellitus in order to treat hyperglycaemia. Julphar Insulin 30/70 and Humininsulin® Profil III are both biphasic insulins, i.e. consist of a mixture of short-acting soluble insulin and intermediate-acting isophane insulin. The new insulin, Julphar Insulin 30/70, is biosimilar to Huminsulin® Profil III. Demonstration of similar absorption (PK) and effects (PD) are necessary to achieve market approval of Julphar Insulin 30/70.

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 30/70 and Huminsulin® Profil III

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: human biphasic insulin
* Drug: human biphasic insulin, reference


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 30/70<br>human biphasic insulin, 100 IU/mL, single subcutaneous injection of 0.6 IU/ kg body weight | Drug: human biphasic insulin<br>* investigational insulin, biosimilar human insulin suspension of 30% normal insulin and 70% basal protamined insulin<br>* Other names: Julphar Insulin 30/70;|
| Active Comparator: Huminsulin® Profil III<br>human biphasic insulin, reference, 100 IU/mL, single subcutaneous injection of 0.6 IU/ kg body weight | Drug: human biphasic insulin, reference<br>* marketed product, human insulin suspension of 30% normal insulin and 70% basal (NPH) insulin<br>* Other names: Huminsulin® Profil III;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK: AUCins.0-24, harea under the serum insulin concentration curve from 0-24 hours |  | 24 hours | 
| PK: Cins.max, maximum observed insulin concentration | 24 hours | 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 | Through study completion, approx.up to approx. 39 days for each subject and up to 6 month for total study duration.. | from the first trial drug administration until the final examination | 
| Local tolerability findings | at the injection site. Through study completion, 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, approx.up to 39 days for each subject | 
| Laboratory safety parameters | Including haematology, biochemistry and coagulation including serology (only at screening) parameters. Through study completion, | from screening until final examination, approx.up to 60 days for each subject | 
| Physical examination findings | Through study completion, | from screening until final examination, approx.up to 60 days for each subject | 
| Changes in vital signs | Through study completion, | from screening until final examination, approx.up to 39 days for each subject | 
| Changes in Electrocardiogram recordings | Through study completion, | from screening until final examination, approx.up to 60 days for each subject | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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biphasic human insulin, biosimilar