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

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

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.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Drug: Julphar Insulin N (human isophane insulin); Drug: Huminsulin® Basal (NPH, human isophane insulin)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neuss, Germany, 41460
    • Profil Neuss GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Julphar Insulin N; 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); investigational insulin: Julphar N (human isophane insulin), biosimilar; Other Names: Julphar Insulin N
Active Comparator: Huminsulin® Basal; 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); marketed reference product: Huminsulin® Basal (NPH, human isophane insulin); Other Names: Huminsulin® Basal

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Julphar Gulf Pharmaceutical Industries
• Collaborators: Profil Institut für Stoffwechselforschung GmbH
• Investigators: Principal Investigator: Tim Heise, MD, Profil Neuss, GmbH

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2016
• Primary Completion (Actual): January 20, 2017
• Study Completion (Actual): January 20, 2017

Study Registration Dates

• First Submitted: December 11, 2015
• First Submitted That Met QC Criteria: December 17, 2015
• First Posted (Estimate): December 18, 2015

Study Record Updates

• Last Update Posted (Actual): July 2, 2020
• Last Update Submitted That Met QC Criteria: July 1, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: intermediate-acting human isophane insulin, biosimilar
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc; Insulin, Isophane; Isophane Insulin, Human; Isophane insulin, beef
• Other Study ID Numbers: INSULCT-003; 2016-003628-21 (EudraCT Number)

Plan for Individual participant data (IPD)

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