Phase I BP Interferon (IFN) Beta-004

Comparative Pharmacokinetic Profile of Interferon Beta-1a (Bioferon®) Administered as Single i.v. Doses in HSA-free Formulation and HSA+ Solution and as Multiple s.c. Doses in Healthy Subjects

Phase I study aiming at:

• establishing the pharmacokinetic profile of interferon beta-1a after i.v. administration of the formulation BioPartners IFN beta-1a without albumin (HSA-free solution in pre-filled syringes) at 18 MIU;
• investigating the possible impact of albumin on pharmacokinetic profile by comparing 3 different i.v. formulations: BioPartners IFN beta-1a without albumin (HSA-free solution in pre-filled syringes), BioPartners IFN beta-1a with added albumin (HSA+), and Rebif® from Merck-Serono, a registered IFN beta-1a solution containing HSA;
• establishing the steady state pharmacokinetic profile of BioPartners IFN beta-1a in HSA-free solution after 4 subsequent s.c. doses of 18 MIU given at 48 hour intervals against Rebif® using the same regimen.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Drug: Interferon beta-1a HSA-free biosimilar; Drug: Interferon beta-1a HSA+ biosimilar; Drug: Interferon beta-1a original

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male and female subjects aged between 18 and 45 years
• Weight range between 55 and 95 kg for males, 45 and 80 kg for females, providing body mass index (BMI) was between 18 and 29 kg/m2
• Absence of significant findings in the medical history and physical examination
• Absence of significant laboratory abnormalities as judged by the investigator.
• 12-lead ECG without significant abnormalities
• Negative urine drug screen

Exclusion Criteria:

• History of major renal, hepatic, immunological, haematological, gastrointestinal, genitourinary, neurological, or rheumatological disorders
• Active diseases of any type, even if mild, including inflammatory disorders and infections.
• Pregnant or lactating women or women contemplating becoming pregnant during study. Female subjects of child-bearing potential who did not practice efficient contraception during the study. A pregnancy test in blood was performed at screening and before each period with β-human chorionic gonadotropin for females of child-bearing potential. If pregnancy test was positive, the subject had to be immediately excluded from study and followed until delivery
• History of severe allergy or of asthma at any time.
• History of cardiovascular dysfunction
• Hypertension
• Sick sinus syndrome or known long QT syndrome
• Presence of QTc  > 440 msec or pronounced sinus bradycardia (<40 bpm/min), even if elicited by sport
• Dark skin preventing local tolerance assessment or abnormal cutaneous reaction e.g. urticaria or papular dermographism
• Intense sport activities.
• Any clinically significant laboratory value on screening that were not within normal range on single repeat
• Positive hepatitis B & C antigen screen
• Positive HIV antibody screen or screen not performed
• Any recent acute illness or sequelae thereof which could expose the subject to a higher risk or might confound the results of the study
• Treatment in the previous three months with any drug known to have well-defined potential for toxicity to a major organ
• History of hypersensitivity to any drug if considered as serious
• History of alcohol or drug abuse
• Positive qualitative urine drug test at screening
• Use of any medication in 2 weeks prior to study and throughout study, including aspirin or other over-the-counter preparation.
• Blood (500 mL) donation or hemorrhage during the previous three months
• Participation in a clinical trial in the previous 3 months
• Smoking
• Consumption of a large quantity of coffee, tea or equivalent
• Present consumption of a large quantity of alcohol or wine or equivalent
• Psychological status which could have had an impact on subject's ability to give informed consent or behavioral tests
• Any feature of subject's medical history or present condition which, in the investigator's opinion, could confound the results of the study, complicate its interpretation, or represent a potential risk for the subject

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Part A: Interferon beta-1a in HSA-free solution; Twelve subjects will participate in 3 periods of part A, receiving 18 MIU biosimilar interferon beta-1a without albumin as i.v. bolus into a distal port under constant saline infusion as 3 treatments.	Drug: Interferon beta-1a HSA-free biosimilar; 6 MIU/0.53 mL in pre-filled glass syringe solubilized in aqueous isotonic buffered solution without albumin; Other Names: Bioferon®
EXPERIMENTAL: Part A: Interferon beta-1a combined with HSA+ solution; Twelve subjects will participate in 3 periods of part A, receiving 18 MIU biosimilar interferon beta-1a with albumin as i.v. bolus into a distal port under constant saline infusion as 3 treatments.	Drug: Interferon beta-1a HSA+ biosimilar; 6 MIU/0.53 mL in pre-filled glass syringe solubilized in aqueous isotonic buffered solution combined with albumin solution; Other Names: Bioferon®
ACTIVE_COMPARATOR: Part A: Interferon beta-1a in marketed HSA+ solution; Twelve subjects will participate in 3 periods of part A, receiving 18 MIU original interferon beta-1a with albumin as i.v. bolus into a distal port under constant saline infusion as 3 treatments.	Drug: Interferon beta-1a original; 6 MIU/0.50 mL in pre-filled glass syringe solubilized in HSA and mannitol solution (marketed formulation); Other Names: Rebif®
EXPERIMENTAL: Part B: Interferon beta-1a in HSA-free solution; Twelve additional volunteers will participate in part B, receiving 4 x 18 MIU biosimilar interferon beta-1a with albumin as s.c. doses at 48 hours intervals as 3 pre-filled syringes (3 sites 1 cm apart in abdominal wall on each dosing day, alternating right side for odd dose [i.e. dose 1 and 3] and left side for even dose [i.e. dose 2 and 4]).	Drug: Interferon beta-1a HSA-free biosimilar; 6 MIU/0.53 mL in pre-filled glass syringe solubilized in aqueous isotonic buffered solution without albumin; Other Names: Bioferon®
ACTIVE_COMPARATOR: Part B: Interferon beta-1a in marketed HSA+ solution; Part B: Twelve additional volunteers will participate in part B, receiving 4 x 18 MIU original interferon beta-1a with albumin as s.c. doses at 48 hours intervals as 3 pre-filled syringes (3 sites 1 cm apart in abdominal wall on each dosing day, alternating right side for odd dose [i.e. dose 1 and 3] and left side for even dose [i.e. dose 2 and 4]).	Drug: Interferon beta-1a original; 6 MIU/0.50 mL in pre-filled glass syringe solubilized in HSA and mannitol solution (marketed formulation); Other Names: Rebif®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of interferon beta-1a PK parameters	Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC[0-inf]) and maximum observed concentration (Cmax) following single dose administration, as well as time to Cmax (tmax; for s.c. injection) will be assessed. Mean residence time (MRT), half-life of elimination (t1/2), clearance (CL), and volume of distribution at steady-state (Vss) will be calculated.	Part A: 0, 2, 5, 10, 15, 20 [min post-dose] and 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24 [hours post-dose] / Part B: 0, 1, 2, 3, 4, 6, 12 [hours post-doses] and 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 [hours post-last dose] (Day 7)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events (AE)/serious adverse event (SAE) as a measure of safety and tolerability	AE/SAE will be collected from the start of study treatment and until the follow-up visit	Up to Day 7
Serum concentration of neopterin (PD marker)	Assessment by ELISA after i.v. and after s.c	Part A: 0, 6, 12, 24, 48, 72, 168 [hours post-doses] / Part B: 0, 6, 12 [hours post-doses] and 0, 6, 12, 24, 48, 72, 96, 120, 144, 168 [hours post-last dose] (Day 7)
Composite of local reactions as a measure of local tolerance	Any local symptoms rated as moderate (grade 3 for i.v. and 2 for s.c.) or severe (grade 4 and 5 for i.v.; grade 3 for s.c.) will be reported as an adverse event. The subjective painful sensation following injection of the drug will be assessed using a visual analogue scale (VAS)	Part A: 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24 [hours post-dose] and longer if needed and until resolution in case of local reaction / Part B: 0, 1, 2, 4, 6, 12 [hours post-dose] on Day 1 and 7, else daily up to Day 9 longer until resolution
Composite of clinical laboratory tests as a measure of safety and tolerability	Clinical laboratory tests will include hematology, clinical chemistry and urinalysis	Screening and 0, 24 [hours post-doses]
Composite of vital signs as a measure of safety and tolerability	Vital signs will include body temperature, blood pressure and heart rate	Part A: Screening and 0, 1, 2, 3, 4, 6, 8, 10, 12, 24 [hours post-dose] / Part B: Screening and 0, 1, 2, 3, 4, 6, 12 [hours post-doses], as well as 0, 1, 2, 3, 4, 6, 8, 12, 24 [hours post-last dose] (Day 7)
Sickness behavior assessment	Four parameters will be recorded (general feeling, headache, muscle ache, mood)	Part A: 0, 2, 4, 6, 8, 10, 12 [hours post-dose] / Part B: 0, 1, 2, 4, 6, 12 [hours post-dose], as well as 24, 48, 72 [hours post-last dose] (Day 7)
Electrocardiogram (ECG) as a measure of safety and tolerability	Twelve-lead ECG will be recorded	Screening and 0, 3 [hours post-dose]

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire Vaudois
• Collaborators: BioPartners GmbH

Publications and helpful links

General Publications

• Perrottet N, Brunner-Ferber F, Grouzmann E, Spertini F, Biollaz J, Buclin T, Widmer N. Biases affecting injected doses of an experimental drug during clinical trials. Trials. 2016 Jul 16;17(1):321. doi: 10.1186/s13063-016-1463-5.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (ACTUAL): July 1, 2006
• Study Completion (ACTUAL): July 1, 2006

Study Registration Dates

• First Submitted: August 5, 2015
• First Submitted That Met QC Criteria: August 5, 2015
• First Posted (ESTIMATE): August 7, 2015

Study Record Updates

• Last Update Posted (ESTIMATE): August 10, 2015
• Last Update Submitted That Met QC Criteria: August 7, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunologic Factors; Adjuvants, Immunologic; Interferons; Interferon beta-1a; Interferon-beta
• Other Study ID Numbers: CE 93/06; 2006DR1162 (REGISTRY: Swissmedic)