China ADVATE PTP Study

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess efficacy, safety and pharmacokinetics of ADVATE in the treatment and prevention of bleeding episodes (BEs)

Official Title
-----------------
Study to Evaluate Efficacy and Safety of ADVATE in the Treatment of Previously Treated Patients With Hemophilia A

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

Intervention / Treatment
-----------------
* Biological: Octocog alfa (recombinant human coagulation factor VIII)


Participation Criteria
=================
Eligibility Criteria
-----------------
Main Inclusion Criteria: Ethnic Chinese is of any age has a documented diagnosis of severe or moderately severe hemophilia A (congenital FVIII deficiency: baseline Factor VIII (FVIII) ≤ 2%) has documented and verified >50 exposure days (EDs) to FVIII (recombinant or plasma derived) is receiving on-demand treatment with FVIII at the time of enrolment in this study has negative history of inhibitor development is HIV negative or HIV positive with stable disease and CD4+ count ≥ 200 cells per mm^3 is negative for Hepatitis C virus (HCV); Or participant is HCV positive with chronic stable hepatitis as assessed by investigator Main Exclusion Criteria: has prior history of hypersensitivity or anaphylaxis associated with receipt of FVIII is diagnosed with other bleeding disorder(s) other than hemophilia A, including but not limited to thrombocytopenia (platelet count < 100000 /mL) has been exposed to an investigational product (IP) within 30 days prior to the screening visit or is scheduled to participate in another clinical study involving an IP or investigational device during participation in the study is planned, or likely to have surgery during the study period has end-stage renal failure or evidence of a severe or uncontrolled systemic disease as judged by the investigator has active hepatic disease (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels > 5 times the upper limit of normal) has clinical or laboratory evidence of severe liver impairment including (but not limited to) a recent & persistent international normalized ratio (INR) >1.4, and/or the presence of splenomegaly and/or significant spider angioma on physical exam, and/or a history of esophageal hemorrhage or documented esophageal varices is a family member of the investigator or site staff
Sexes Eligible for Study
-----------------
Male

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

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

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Previously Treated Patients (PTPs)<br>PTPs will participate sequentially with: Part 1: Pharmacokinetic parameters of ADVATE measured in subset of 24 participants, consisting of: 12 adults (>12 years of age) 12 children (≤12 years of age) Part 2: On-demand treatment with ADVATE for 6 months Part 3: Prophylaxis regimen with ADVATE for 6 months | Biological: Octocog alfa (recombinant human coagulation factor VIII)<br>* Part 1: Pharmacokinetic (PK) analysis - Subset of 24 participants Part 2: On-demand treatment regimen Part 3: Prophylaxis treatment regimen<br>* Other names: ADVATE;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of reduction in annualized bleed rate (ABR) during prophylactic treatment compared to ABR during on demand treatment | Computed as: {[median ABR on-demand - median ABR prophylaxis]÷[median ABR on-demand]}*100% The ABR, will be assumed to have a negative binomial distribution. The 2 treatment regimens (on-demand and prophylaxis) will be compared in terms of mean ABR within a generalized linear model framework (with a logarithmic link function which is the default for the negative binomial distribution), accounting for the fixed effect of study arm and the follow-up time (in years) as an offset. Ratios between treatment means (95% CI) will be estimated within this model. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of units per kg body weight of ADVATE required to resolve a bleeding episode (BE) |  | 12 months | 
| Number of infusions of ADVATE required to resolve a bleeding episode (BE) |  | 12 months | 
| Overall evaluation of efficacy on a four-point scale (Excellent-Good-Fair-Poor) |  | 12 months | 
| Annualized bleeding episode rates (ABR) according to bleed type and bleed etiology summarized by treatment regimen | Bleed types and etiologies summarized by treatment regimen (prophylaxis, on-demand) including: Joint bleeds Non-joint bleeds Spontaneous bleeds Traumatic bleeds Target joint bleeds | 12 months | 
| Inhibitor incidence | Inhibitor incidence in: Previously treated patients (PTPs) with previous 51-150 exposure days (EDs) to Factor VIII (FVIII) PTPs with previous >150 EDs to FVIII | 13 months | 
| Adverse events according to relatedness, seriousness, and severity |  | 13 months | 
| Area under the plasma concentration/time curve from time 0 to infinity | Computed as AUC0-t + Ct/ λz, where t is the time of last quantifiable concentration, Ct is the last quantifiable concentration, and λz is the terminal rate constant | Within 30 minutes prior to the start of the infusion through 48 hours post-infusion | 
| Mean Residence Time (MRT) | Computed as AUMC0-∞ / AUC0-∞ - TI/2, where AUMC0-∞ will be determined in a similar manner as AUC0-∞ and TI represents infusion duration [hour] | Within 30 minutes prior to the start of the infusion through 48 hours post-infusion | 
| Clearance (CL) | Computed as Dose/ AUC0-∞ | Within 30 minutes prior to the start of the infusion through 48 hours post-infusion | 
| Incremental Recovery (IR) at Cmax | Computed as: (Cmax - Cpre-infusion)/Dose, where Cmax will be determined as the highest concentration achieved within one hour after infusion | Within 30 minutes prior to the start of the infusion, and within 1 hour post-infusion | 
| Elimination phase half-life | Computed as: ln2/ λz. λz will be estimated from the slope of natural log-linear fitting to latter quantifiable concentrations, with largest adjusted R^2 | Within 30 minutes prior to the start of the infusion through 48 hours post-infusion | 
| Volume of distribution at steady state (Vss) | Computed as: CL * MRT | Within 30 minutes prior to the start of the infusion through 48 hours post-infusion |