Phase I BP Interferon (IFN) Beta-004

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: Interferon beta-1a HSA-free biosimilar
* Drug: Interferon beta-1a HSA+ biosimilar
* Drug: Interferon beta-1a original


Participation Criteria
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Eligibility Criteria
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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

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Interferon beta-1a in HSA-free solution<br>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<br>* 6 MIU/0.53 mL in pre-filled glass syringe solubilized in aqueous isotonic buffered solution without albumin<br>* Other names: Bioferon®;|
| Experimental: Part A: Interferon beta-1a combined with HSA+ solution<br>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<br>* 6 MIU/0.53 mL in pre-filled glass syringe solubilized in aqueous isotonic buffered solution combined with albumin solution<br>* Other names: Bioferon®;|
| Active Comparator: Part A: Interferon beta-1a in marketed HSA+ solution<br>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<br>* 6 MIU/0.50 mL in pre-filled glass syringe solubilized in HSA and mannitol solution (marketed formulation)<br>* Other names: Rebif®;|
| Experimental: Part B: Interferon beta-1a in HSA-free solution<br>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<br>* 6 MIU/0.53 mL in pre-filled glass syringe solubilized in aqueous isotonic buffered solution without albumin<br>* Other names: Bioferon®;|
| Active Comparator: Part B: Interferon beta-1a in marketed HSA+ solution<br>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<br>* 6 MIU/0.50 mL in pre-filled glass syringe solubilized in HSA and mannitol solution (marketed formulation)<br>* Other names: Rebif®;|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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) | 
| 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 | 
| 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] |