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

Healthy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03614715
• Other study ID #: MC-CINNA-PKPD-01
• Secondary ID: 2016-000139-41
• Status: Completed
• Phase: Phase 1
• Start date: November 27, 2017
• Est. completion date: February 12, 2019

Study information

• Verified date: July 2018
• Source: Cinnagen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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®.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: February 12, 2019
• Est. primary completion date: February 12, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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.

Related Conditions & MeSH terms

• Bioequivalence
• Healthy

Intervention

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)

Locations

Country	Name	City	State
Finland	CRST Oy, Clinical Research Services Turku Itäinen Pitkäkatu 4 B, 3rd floor	Turku

Sponsors (1)

Lead Sponsor	Collaborator
Cinnagen

Country where clinical trial is conducted

Finland, 

References & Publications (20)

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Chemello L, Cavalletto L, Noventa F, Bonetti P, Casarin C, Bernardinello E, Pontisso P, Donada C, Casarin P, Belussi F, et al. Predictors of sustained response, relapse and no response in patients with chronic hepatitis C treated with interferon-alpha. J Viral Hepat. 1995;2(2):91-6. — View Citation

Di Girolamo G, Kauffman MA, González E, Papouchado M, Ramírez A, Keller G, Carbonetto C, Dabsys S, Vidal A, Sterin-Prync A, Diez RA. Bioequivalence of two subcutaneous pharmaceutical products of interferon beta la. Arzneimittelforschung. 2008;58(4):193-8. doi: 10.1055/s-0031-1296492. — View Citation

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. — View Citation

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. — View Citation

Lengyel P. Biochemistry of interferons and their actions. Annu Rev Biochem. 1982;51:251-82. Review. — View Citation

Malucchi S, Sala A, Gilli F, Bottero R, Di Sapio A, Capobianco M, Bertolotto A. Neutralizing antibodies reduce the efficacy of betaIFN during treatment of multiple sclerosis. Neurology. 2004 Jun 8;62(11):2031-7. — View Citation

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. — View Citation

Munafo A, Trinchard-Lugan I I, Nguyen TX, Buraglio M. Comparative pharmacokinetics and pharmacodynamics of recombinant human interferon beta-1a after intramuscular and subcutaneous administration. Eur J Neurol. 1998 Mar;5(2):187-193. — View Citation

Nagai M, Arai T. Clinical effect of interferon in malignant brain tumours. Neurosurg Rev. 1984;7(1):55-64. — View Citation

Pestka S, Langer JA, Zoon KC, Samuel CE. Interferons and their actions. Annu Rev Biochem. 1987;56:727-77. Review. — View Citation

Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet. 1998 Nov 7;352(9139):1491-7. — View Citation

PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. Neurology. 2001 Jun 26;56(12):1628-36. Erratum in: Neurology 2001 Sep 25;57(6):1146. — View Citation

Romano A, Sadan Y. Ten years of experience with human fibroblast interferon in treatment of viral ophthalmic infections. Metab Pediatr Syst Ophthalmol (1985). 1988;11(1-2):43-6. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	AUCt of IFNß-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
Primary	Cmax of IFNß-1a	Maximum concentration of IFNß-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	tmax of IFNß-1a	Time to maximum concentration of IFNß-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	t½ of IFNß-1a	Elimination half-life of IFNß-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
Secondary	AUCinf of IFNß-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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	AUC0-168 of ß2-microglobulin	AUC0-168 of ß2-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
Secondary	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
Secondary	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
Secondary	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
Secondary	concentrations of ß2-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
Secondary	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
Secondary	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
Secondary	Adverse events	Recording from patients	Prior to the Investigational Medicinal Product administration and up to 8 days after drug administration (cross over study)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)