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

• ClinicalTrials.gov Identifier: NCT03614715
• Recruitment Status: Completed
• First Posted: August 3, 2018
• Last Update Posted: January 10, 2020
• Sponsor: Cinnagen
• Information provided by (Responsible Party): Cinnagen

Study Description

Brief Summary:

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®.

Condition or disease	Intervention/treatment	Phase
Bioequivalence; Healthy	Drug: Interferon Beta-1A	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Comparative Trial of the Pharmacokinetics and Pharmacodynamics of Intramuscularly Injected CinnoVex® and Avonex® in Healthy Volunteers
• Actual Study Start Date: November 27, 2017
• Actual Primary Completion Date: February 12, 2019
• Actual Study Completion Date: February 12, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: CinnaGen interferon beta-1a; 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; 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); Other Names: CinnoVex; Avonex
Active Comparator: Biogen interferon beta-1a; 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; 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); Other Names: CinnoVex; Avonex

Outcome Measures

Primary Outcome Measures :

1. AUCt of IFNβ-1a [ Time Frame: 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 ]
   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
2. Cmax of IFNβ-1a [ Time Frame: 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 ]
   Maximum concentration of IFNβ-1a in plasma

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 45 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Provide written informed consent (IC) to participate in the trial, to comply with the trial procedures, and to abide by the trial restrictions.
2. 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.
3. Have a Body Mass Index (BMI) between 18 and 28 kg/m2.
4. Have good general health according to medical history, physical examination, ECG recording and clinical laboratory assessments.

5. 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.

Contacts and Locations

Locations

Finland

CRST Oy, Clinical Research Services Turku Itäinen Pitkäkatu 4 B, 3rd floor

Turku, Finland

Sponsors and Collaborators

Cinnagen

Investigators

• Principal Investigator: Mika Scheinin, MD, PhD; CRST, Itäinen Pitkäkatu 4B, FI-20520 Turku, Finland

More Information

Publications:

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Capalbo M, Palmisano L, Bonino F, Pellas C, Maset J. Intramuscular natural beta interferon in the treatment of chronic hepatitis B: a multicentre trial. Italian Hepatitis B Study Group. Ital J Gastroenterol. 1994 Jun;26(5):238-41.

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Miles SA, Wang HJ, Cortes E, Carden J, Marcus S, Mitsuyasu RT. Beta-interferon therapy in patients with poor-prognosis Kaposi sarcoma related to the acquired immunodeficiency syndrome (AIDS). A phase II trial with preliminary evidence of antiviral activity and low incidence of opportunistic infections. Ann Intern Med. 1990 Apr 15;112(8):582-9.

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Hovanessian AG, Justesen J. The human 2'-5'oligoadenylate synthetase family: unique interferon-inducible enzymes catalyzing 2'-5' instead of 3'-5' phosphodiester bond formation. Biochimie. 2007 Jun-Jul;89(6-7):779-88. Epub 2007 Feb 20. Review.

Scagnolari C, Duda P, Bagnato F, De Vito G, Alberelli A, Lavolpe V, Girardi E, Durastanti V, Trojano M, Kappos L, Antonelli G. Pharmacodynamics of interferon beta in multiple sclerosis patients with or without serum neutralizing antibodies. J Neurol. 2007 May;254(5):597-604. Epub 2007 Apr 10.

Casoni F, Merelli E, Bedin R, Sola P, Bertolotto A, Faglioni P. Is serum neopterin level a marker of responsiveness to interferon beta-1a therapy in multiple sclerosis? Acta Neurol Scand. 2004 Jan;109(1):61-5.

Bertolotto A, Gilli F, Sala A, Audano L, Castello A, Magliola U, Melis F, Giordana MT. Evaluation of bioavailability of three types of IFNbeta in multiple sclerosis patients by a new quantitative-competitive-PCR method for MxA quantification. J Immunol Methods. 2001 Oct 1;256(1-2):141-52.

Bertolotto A, Deisenhammer F, Gallo P, Sölberg Sørensen P. Immunogenicity of interferon beta: differences among products. J Neurol. 2004 Jun;251 Suppl 2:II15-II24. Review.

Williams GJ, Witt PL. Comparative study of the pharmacodynamic and pharmacologic effects of Betaseron and AVONEX. J Interferon Cytokine Res. 1998 Nov;18(11):967-75.

Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE 3rd, Priore RL, Pullicino PM, Scherokman BJ, Whitham RH, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. 1996 Mar;39(3):285-94. Erratum in: Ann Neurol 1996 Sep;40(3):480.

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Ben-Amor AF, Trochanov A, Fischer TZ. Cumulative Review of Thrombotic Microangiopathy, Thrombotic Thrombocytopenic Purpura, and Hemolytic Uremic Syndrome Reports with Subcutaneous Interferon β-1a. Adv Ther. 2015 May;32(5):445-54. doi: 10.1007/s12325-015-0212-6. Epub 2015 May 20.

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• Responsible Party: Cinnagen
• ClinicalTrials.gov Identifier: NCT03614715
• Other Study ID Numbers: MC-CINNA-PKPD-01; 2016-000139-41 ( EudraCT Number )
• First Posted: August 3, 2018
• Last Update Posted: January 10, 2020
• Last Verified: July 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Interferons; Interferon-beta; Interferon beta-1a; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic