rFVIII-Fc (Produced by AryoGen Pharmed Co.) Pharmacokinetic Study

Study Overview
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Brief Summary
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The study is designed as a randomized, two-armed, double-blind, single-dose, crossover, two-sequence, active-controlled, multi-center, bioequivalence clinical trial with a primary endpoint of dose-normalized area under the curve (dnAUC last)

Official Title
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A Randomized, Two-armed, Double-blind, Single-dose, Crossover, Two-sequence, Bioequivalence Clinical Trial to Compare PK Parameters and Safety of rFVIII-Fc (AryoGen Pharmed Co.) Versus Elocta® in PTPs With Severe Hemophilia A

Conditions
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Severe Hemophilia A

Intervention / Treatment
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* Drug: Factor VIII, recombinant human with Fc fusion (rFVIII-Fc)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male patients ≥ 12 years, with signed informed consent by the patient, or the patient's legally authorized representative for patients under the legal age Diagnosed with severe hemophilia A (endogenous FVIII <1% [1 IU/dL]) History of at least 150 documented prior exposure days to any FVIII product Having adequate bone marrow and organ function: Plt ≥ 80,000 cells/µL Hb ≥ 8 mg/dL eGFR ≥ 30 mL/min ALT or AST ≤ 5×ULN Serum bilirubin ≤ 1.5×ULN Exclusion Criteria: Measurable anti-drug antibody activity against FVIII (≥ 0.6 BU/mL) at screening or a history of developing anti FVIII antibody History of other coagulation disorders except for hemophilia A Acute hemorrhagic state Infection with HCV or HBV HIV-positive patients Infusion of any products containing FVIII within 7 days prior to first administration Previous treatment with commercially available extended half-life FVIII products Receiving drugs which increase bleeding tendency (e.g: Anti-coagulants, antiplatelets, omega 3, Vit E, etc.) within 2 weeks of screening. NSAIDs are permitted. Current systemic treatment with immunosuppressive drugs Hypersensitivity or anaphylaxis associated with any FVIII concentrate or intravenous immunoglobulin (IVIG) Planned elective surgery Current enrolment or willing to enroll in any other experimental study during the time of current trial Subjects assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol (e.g.: physical, psychological and mental problems)

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

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: AryoGen Pharmed Co. rFVIII-Fc/Elocta® (Sobi Co. rFVIII-Fc)<br>AryoGen Pharmed Co. rFVIII-Fc, IV, 50 units/kg, single dose, then Elocta® (Sobi Co. rFVIII-Fc), IV, 50 units/kg, single dose (cross-over) | Drug: Factor VIII, recombinant human with Fc fusion (rFVIII-Fc)<br>* rFVIII-Fc, IV, 50 units/kg/ single dose, cross-over<br>|
| Experimental: Elocta® (Sobi Co. rFVIII-Fc)/AryoGen Pharmed Co. rFVIII-Fc<br>Elocta® (Sobi Co. rFVIII-Fc), IV, 50 units/kg, single dose, then AryoGen Pharmed Co. rFVIII-Fc, IV, 50 units/kg, single dose (cross-over) | Drug: Factor VIII, recombinant human with Fc fusion (rFVIII-Fc)<br>* rFVIII-Fc, IV, 50 units/kg/ single dose, cross-over<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| dose-normalized Area Under the Curve (dnAUC last) | Area under the concentration-time curve measured from the time of administration to the last measurable time point | pre-dose, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve to Infinity (AUC inf) | Area under the concentration-time curve measured from the time of administration to the infinity. | pre-dose, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours post-dose | 
| Maximum Plasma Activity (Cmax) | Maximum plasma activity during a dosing interval | pre-dose, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours post-dose | 
| Incremental Recovery (IR) | The rise in FVIII activity in IU/dL per unit dose administered in IU/kg | pre-dose, 15 minutes, 30 minutes, 1 hour | 
| Half-life (T ½) | Time required for the activity of the drug to reach half of its original value | pre-dose, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours post-dose | 
| Volume of distribution (Vd) | Volume of distribution estimated from the terminal phase | pre-dose, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours post-dose | 
| Clearance (Cl) | Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight | pre-dose, 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours, 120 hours post-dose | 
| Safety assessment by evaluation of adverse events (AEs) and abnormal laboratory results | Safety assessment, including the incidence of all reported AEs and abnormal laboratory results was done. All AEs were classified based on the Medical Dictionary for Regulatory Activities (MedDRA Desktop Browser 4.0 Beta) terms as System Organ Class (SOC) and Preferred Term (PT). All the reported events were graded according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). Moreover, seriousness of AEs was assessed according to International Council for Harmonization (ICH-E2B) guidelines. The causality relation was assessed based on the World Health Organization (WHO) criteria. | Adverse events collection and documentation was done during the study (up to 28 days) | 
| Immunogenicity assessment | Immunogenicity of factor viii was evaluated at scheduled visits by blood sampling to determine the production of inhibitor against factor viii. | Immunogenicity sampling was done at screening visit and day 7, 12 and 28 |