Pharmacokinetics and Pharmacodynamics of CinnoVex (Interferon Beta-1a) Compared to Avonex (Interferon Beta-1a)

Study Overview
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Brief Summary
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The primary objective of the trial is to investigate the biosimilarity of CinnoVex® by comparing its pharmacokinetics (PK) and pharmacodynamics (PD) to its originator, Avonex®, in a crossover manner in healthy female and male volunteers after administration of a single dose of 30 µg or 60 µg of Interferon beta-1a. The secondary objectives of the study are: To further compare the PK of CinnoVex® and Avonex®. To further compare the PD of CinnoVex® and Avonex®. To assess the safety of CinnoVex®.

Detailed Description
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This trial will be a double-blind, randomised, active-controlled, single-centre, two-stage crossover trial with administration of single doses of CinnoVex® and Avonex®. Stage 1 includes comparison of 30 µg and 60 µg IM doses in 16 healthy volunteers (eight subjects on each dose level, each subject will be administered one dose of each product as 30 µg or 60 µg doses in a crossover manner and in randomised order). After interim analysis of the PK and PD results of these 16 subjects and evaluation of the data by an expert data monitoring committee (DMC), Stage 2 will investigate the selected dose. The sample size of Stage 2 will be determined in the interim analysis so that a sufficient number of additional healthy volunteers are added to one or both dose levels to ensure adequate statistical power for the study's objectives, to evaluate biosimilarity. Up to 48 additional healthy volunteers may be added at this stage. Subjects will undergo screening assessments before their first treatment visit. A total of 16 healthy volunteers will be selected for Stage 1 and 24 or 48 will be selected for Stage 2 according to the inclusion and exclusion criteria. To reveal possible differences in the trial outcomes between the sexes, approximately equal numbers of male and female subjects will be included. The trial will be performed in healthy adult volunteers with a maximum age of 45 years, to limit variability that may result from including older adults. Eligibility of subjects will be confirmed prior to each IMP administration with a pregnancy test (female subjects with childbearing potential), a urine drug screen and an alcohol breath test. In addition, the subjects will be asked about current illnesses, subjective well-being, and concomitant medications. A physical examination will take place, if indicated. The subjects will participate in 2 treatment periods in sequential order; treatment period 1 starts when the first IMP is administered and treatment period 2 starts when the second IMP is administered. The two treatment administrations of individual subjects will be separated by at least 14 days. Blood samples will be collected prior to and at scheduled time points after the IMP administration. Plasma concentrations of IFNβ-1a and concentrations of the selected biomarkers in serum and blood will be determined. The total volume of blood collected from each subject during the trial is less than 500 ml. Safety will be assessed by recording blood pressure (BP), heart rate (HR), body temperature and subjective symptoms at scheduled time points after IMP administration. AEs and concomitant medications will be recorded throughout the trial.

Official Title
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Comparative Trial of the Pharmacokinetics and Pharmacodynamics of Intramuscularly Injected CinnoVex® and Avonex® in Healthy Volunteers

Conditions
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Healthy, Bioequivalence

Intervention / Treatment
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* Drug: Interferon Beta-1A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent (IC) to participate in the trial, to comply with the trial procedures, and to abide by the trial restrictions. Be aged between 18 and 45 years with sufficient command of the Finnish language to be able to provide valid IC and to communicate adequately with the trial personnel. Have a Body Mass Index (BMI) between 18 and 28 kg/m2. Have good general health according to medical history, physical examination, ECG recording and clinical laboratory assessments. Female subjects of child-bearing potential must agree to use a medically accepted method of contraception during the trial and one month after the end of the trial. Acceptable methods of contraception include the following: Stable oral/transdermal/injectable hormonal contraceptive regimen without breakthrough uterine bleeding and condom/spermicide. Intrauterine device (inserted at least 2 months prior to Screening visit) used with spermicide/condom. Condom (male or female) with spermicide Vasectomy of the male partner in conjunction with condom or spermicide. Exclusion Criteria: 1) Be doubtful about his/her availability to complete the trial. 2) Have unsuitable veins for repeated venipuncture. 3) Be pregnant, or intend to become pregnant during the trial, or be lactating. 4) Have a history or evidence of clinically significant cardiovascular, renal, hepatic, haematological, gastrointestinal, pulmonary, metabolic, endocrine, neurological, psychiatric or other major disease. 5) Have any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of any drug. 6) Have strong susceptibility to allergic reactions or history of allergy to any of the components of the IMP. 7) Have clinically significant illness within 4 weeks before the start of the trial. 8) Have any abnormal laboratory value or physical finding which may interfere with the interpretation of the test results or cause a health hazard for the subject if he/she takes part in the trial. 9) Have any condition requiring regular concomitant medication or use of any medication that might affect the trial results or cause a health hazard to the subject within 2 weeks prior to the start of the trial; hormonal contraception and hormone replacement therapy are allowed. 10) Have history of alcohol abuse or drug addiction or a positive result in the urine drug screen or breath alcohol test, or report consumption of more than 14 units of alcohol per week on a regular basis (1 unit = 4 cl of spirits of equivalent). 11) Have a history of smoking >10 cigarettes per day. 12) Participate in another drug trial or donation of blood within 90 days before first IMP administration in this trial. 13) Have participated before in a clinical study investigating a Type I Interferon or have been treated with a Type I Interferon before. 14) Be under anti-doping control. 15) Be at imminent risk of self-harm, based on clinical interview and responses on the Columbia Suicide Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator. Subjects must be excluded, if they report suicidal ideation with intent, with or without a plan or a method (e.g., positive response to items 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the past two months or suicidal behaviour in the past six months. 16) Have any other condition that in the opinion of the investigator would interfere with the evaluation of the trial results or constitute a health hazard for the subject.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CinnaGen interferon beta-1a<br>CinnoVex® (IFNβ-1a, Prefilled syringe produced by CinnaGen Company) in prefilled syringe in healthy volunteers. (Stage 1: 30 µg or 60 µg)(Stage 2: 30 µg) | Drug: Interferon Beta-1A<br>* A single dose of Interferon Beta-1A (Stage 1: 30 or 60 µg, stage 2: 30 µg) was administered IM to healthy subjects (cross over treatment)<br>* Other names: Avonex;|
| Active Comparator: Biogen interferon beta-1a<br>Avonex® (IFNβ-1a, Prefilled syringe produced by Biogen Company) in prefilled syringe in healthy volunteers. (Stage 1: 30 µg or 60 µg)(Stage 2: 30 µg) | Drug: Interferon Beta-1A<br>* A single dose of Interferon Beta-1A (Stage 1: 30 or 60 µg, stage 2: 30 µg) was administered IM to healthy subjects (cross over treatment)<br>* Other names: Avonex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCt of IFNβ-1a | Area under the plasma concentration curve from the time of IMP administration to the last observed concentration at last time point t, calculated using the linear trapezoidal rule | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| Cmax of IFNβ-1a | Maximum concentration of IFNβ-1a in plasma | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tmax of IFNβ-1a | Time to maximum concentration of IFNβ-1a in plasma | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| t½ of IFNβ-1a | Elimination half-life of IFNβ-1a (if evaluable) | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| AUCinf of IFNβ-1a | Area under the concentration curve extrapolated to infinite time, if allowed by the concentration data (if Kel is evaluable) | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| VD | Volume of distribution | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| MRT | Mean residence time | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| CL | Clearance | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| AUC0-168 of neopterin | AUC0-168 of neopterin concentrations in serum | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| AUC0-168 of interleukin (IL)-10 | AUC0-168 of interleukin (IL)-10 concentrations in serum | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| AUC0-168 of IL-4 | AUC0-168 of IL-4 concentrations in serum | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| AUC0-168 of β2-microglobulin | AUC0-168 of β2-microglobulin concentrations in serum | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| AUC0-168 of MxA | AUC0-168 of MxA concentrations in whole blood | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| Concentrations of MxA in whole blood | validated ELISA methods | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| concentrations of neopterin in serum | validated ELISA methods | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| concentrations of β2-microglobulin in serum | validated ELISA methods | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| concentrations of IL-4 in serum. | validated ELISA methods | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| concentrations of IL-10 in serum | Validated ELISA methods | blood samples will be drawn prior to Investigational Medicinal Product administration, and then at the following times after dosing: 12, 14, 16, 18, and 24 hours, and mornings of Day 3, Day 4, Day 5, Day 6, and Day 8 | 
| Adverse events | Recording from patients | Prior to the Investigational Medicinal Product administration and up to 8 days after drug administration (cross over study) | 
| Heart rate as vital signs | Record at CRF, changes will be presented using summary statistics | Prior to the Investigational Medicinal Product administration and up to 8 days after drug administration (cross over study) | 
| Body temperature as vital sign | Record at CRF, changes will be presented using summary statistics | Prior to the Investigational Medicinal Product administration and up to 8 days after drug administration (cross over study) | 
| ECG as vital sign | Record at CRF, changes will be presented using summary statistics | Prior to the Investigational Medicinal Product administration and up to 8 days after drug administration (cross over study) | 
| Supine blood pressure as vital sign | Record at CRF, changes will be presented using summary statistics | Prior to the Investigational Medicinal Product administration and up to 8 days after drug administration (cross over study) |