Pharmacokinetics Evaluation of Recombinant Coagulation Factor VIII Injection in Subjects With Hemophilia A.

Study Overview
=================
Brief Summary
-----------------
This is a multi-center, open-label, randomized study. Participants will be assigned to A or B groups with a scale of 1:1 , i.e. infuse study drug followed by Xyntha (group A), or the alternate sequence (group B). All participants who completed the study will enter the Prophylactic Therapy Study.

Official Title
-----------------
Randomized, Open-label, Double Cycle, Crossover, Pharmacokinetics Study of Recombinant Coagulation Factor VIII Injection Versus Xyntha® in Subjects With Hemophilia A.

Conditions
-----------------
Hemophilia A

Intervention / Treatment
-----------------
* Drug: Xyntha
* Drug: Recombinant Coagulation Factor VIII Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Hemophilia A. FVIII:C <1%. 3）12 and 65 years old. 4）Has received FVIII treatment and the treatment exposure days ≥100. 5）Has bleeding treatment records of at least 3 months before randomization. 6）FVIII inhibitor assay results is negative. 7） Subjects should agree to use an adequate method of contraception during the study. 8）Understood and Signed an informed consent form. 9）Has not received an treatment of any FVIII within 4 days before the first dose. 10）Non-bleeding state. Exclusion Criteria: Has a history or family history of blood coagulation factor VIII inhibitor. Has other coagulation dysfunction diseases in addition to hemophilia A. HIV positive. Plan to receive surgery during the trial. Has used immunomodulator within one weeks before the first dose，and less than 7 half-life periods. Known to be allergic to experimental drugs or any excipients. Severe anemia and need blood transfusion. Serious liver or kidney damage. Serious heart disease. Uncontrollable hypertension. Has participated in other clinical studies within one month before the first dose. The researchers believe that it is not suitable for participants.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: group A<br>Participants will be assigned to group A or B with a scale of 1:1 , i.e. infuse reference drug Xyntha (group A), then experimental drug (group B). All participants who completed the study will enter the prophylaxis group study. | Drug: Xyntha<br>* Recombinant Coagulation Factor VIII Injection produced by Pfizer Inc.<br>Drug: Recombinant Coagulation Factor VIII Injection<br>* A kind of Recombinant Coagulation Factor VIII Injection produced by sponsor.<br>|
| Experimental: group B<br>Participants will be assigned to group A or B with a scale of 1:1 , i.e. infuse experimental drug (group B), then reference drug Xyntha (group A). All participants who completed the study will enter the prophylaxis group study. | Drug: Xyntha<br>* Recombinant Coagulation Factor VIII Injection produced by Pfizer Inc.<br>Drug: Recombinant Coagulation Factor VIII Injection<br>* A kind of Recombinant Coagulation Factor VIII Injection produced by sponsor.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameters between test preparation and reference preparation, peak plasma concentration (Cmax) | Cmax is the maximum plasma concentration of Recombinant Coagulation Factor VIII or metabolite(s). | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on single dose in day 1 to day 4. | 
| Pharmacokinetic parameters between Recombinant Coagulation Factor VIII, Area under the plasma concentration verus time curve(AUC) | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of area under the plasma concentration time curve from zero to infinity. | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on single dose in day 1 to day 4. | 
| Incremental recovery between test preparation and reference preparation | Peak activity of FVIII (as Cmax) measured within 1 hour after the end of infusion. | up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tmax | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of time to reach maximum plasma concentration | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on single dose in day 1 to day 4. | 
| t1/2 | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of half-life | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on multiple dose in day 5 to day 8. | 
| Mean time of residence (MRT) | MRT is the average time that drug molecules stay in the body after a quick intravenous injection. | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on single dose in day 1 to day 4. | 
| λz | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of terminal rate constant. | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on single dose in day 1 to day 4. | 
| CL | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of apparent plasma clearance following intravenous injection. | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on single dose in day 1 to day 4. | 
| Vz | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of apparent volume of distribution. | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on single dose in day 1 to day 4. | 
| Area under the plasma concentration verus time curve (AUC) | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of area under the plasma concentration time curve from zero to infinity. | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on multiple dose in day 5 to day 8. | 
| Peak plasma concentration (Cmax) | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of maximum plasma concentration. | Hour 30min (pre-dose), 5min, 20min, 35min, 60min, 1.5 h, 2h, 3 h, 6 h, 9 h, 24 h, 36 h, 48 h post-dose on multiple dose in day 5 to day 8. | 
| Recombinant Coagulation Factor VIII multiple dose:tmax | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of time to reach maximum plasma concentration. | On the 176th day after the prevention of medication | 
| Recombinant Coagulation Factor VIII multiple dose:t1/2 | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of half-life. | On the 176th day after the prevention of medication | 
| Recombinant Coagulation Factor VIII multiple dose:λz | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of terminal rate constant. | On the 176th day after the prevention of medication | 
| Recombinant Coagulation Factor VIII multiple dose:CL | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of apparent plasma clearance following intravenous injection. | On the 176th day after the prevention of medication | 
| Recombinant Coagulation Factor VIII multiple dose:Vz | To characterize the pharmacokinetics of Recombinant Coagulation Factor VIII by assessment of apparent volume of distribution. | On the 176th day after the prevention of medication |