Evaluate Efficacy and Safety of ADVATE in the Standard Prophylaxis Treatment of Severe or Moderately Severe Hemophilia A

Study Overview
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Brief Summary
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Based on the successful pioneer work of Dr Nilsson and her colleagues in Sweden that started in the late 1950's, prophylaxis is recommend as the standard of care for boys with severe haemophilia by WHO and World Federation of Hemophilia (WFH). The efficacy and safety of prophylaxis in preventing bleeds and arthropathy in patients with hemophilia has been confirmed in well-designed clinical studies.To keep the factor level above 1%, the standard dosage for patients with severe hemophilia A is 20-40 Units /kg/infusion (average 30 Units /kg) every other day or three times a week. This dosage has a very high consumption of factor, up to 5000-6000 international unit(IU)/kg/year. The high consumption of factor and cost present a major barrier to use the standard prophylaxis in many countries particularly in the developing world. But after the Recombinant Human Coagulation Factor VIII for injection (ADVATE) Patient Assistance Program(Golden Key) was launched in 24 Apr 2014 in Nanjing China, the affordability of patients was solved and many patients will get more chance to receive standard prophylaxis. This study is designed to evaluate the Annual Bleeding rate (ABR), joint health outcomes and QoL outcomes in subjects using standard prophylaxis under the conditions of routine practice.

Detailed Description
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Hemophilia A is an X-linked recessive, congenital bleeding disorder caused by deficient or defective coagulation factor VIII (FVIII). The absence or severe reduction of FVIII leads to 'spontaneous' bleeding episodes (occurring primarily in joints, muscles, and less commonly, in soft tissues) and to excessive bleeding following trauma or injury. Estimations based on the WFH's annual global surveys indicate that the number of people with hemophilia in the world is approximately 400,000. [1] China accounts for a quarter of about 100,000. Currently, based on the successful pioneer work of Dr Nilsson and her colleagues in Sweden that started in the late 1950's, prophylaxis is recommend as the standard of care for boys with severe haemophilia by WHO and WFH. [2] The efficacy and safety of prophylaxis in preventing bleeds and arthropathy in patients with hemophilia has been confirmed in well-designed clinical studies.[3,4,5]To keep the factor level above 1%, the standard dosage for patients with severe hemophilia A is 20-40 Units /kg/infusion (average 30 Units /kg) [6] every other day or three times a week. This dosage has a very high consumption of factor, up to 5000-6000 international unit(IU)/kg/year. [7] The high consumption of factor and cost present a major barrier to use the standard prophylaxis in many countries particularly in the developing world. [8] Many families are looking forward to standard prophylaxis to reducing bleeding episodes, stop or slow the deterioration of joint disease in their sons with severe hemophilia and thus improving their quality of life (QoL). But in China the majority of boys with severe hemophilia A cannot afford the high costs of standard prophylaxis .They can only pay for on-demand treatment or low-dose prophylaxis. But after the Advate Patient Assistance Program(Golden Key) was launched in 24 Apr 2014 in Nanjing China, the affordability of patients was solved and many patients will get more chance to receive standard prophylaxis. This study is designed to evaluate the Annual Bleeding rate (ABR), joint health outcomes and QoL outcomes in subjects using standard prophylaxis under the conditions of routine practice.

Official Title
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Evaluate Efficacy and Safety of ADVATE in the Standard Prophylaxis Treatment of Severe or Moderately Severe Hemophilia A

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: ADVATE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has hemophilia A with FVIII≤2 %. Previously treated patients (PTPs). Age from 2 to 18 years. Exclusion Criteria: Subject has known hypersensitivity to the active substance or any of the excipients. Subject has known allergic reaction to mouse or hamster proteins. Subject has participated in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or is scheduled to participate in another clinical study involving another FVIII concentrate or device during the course of this study. Subject is planned, or likely to have surgery during the study period. Subject has end-stage renal failure or evidence of a severe or uncontrolled systemic disease as judged by the investigator. Subject has full-blown Acquired Immuno Deficiency Syndrome (AIDS),determined by cluster differentiation antigen 4+ (CD4+) and clinical presentation. Subject has active hepatic disease (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels > 5 times the upper limit of normal). Subject has clinical or laboratory evidence of severe liver impairment including (but not limited to) a recent and 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. The subject in the opinion of the investigator is unable or unwilling to comply with study protocol Subject is a family member of the investigator or site staff

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ADVATE standard prophylaxis<br>This study is a prospective, open-label, interventional, multicenter study in a total of 15 PTPs with hemophilia A (FVIII≤2 %).The baseline ABR will be assessed from bleeding log and clinic records from preceding year. Subjects will initially be treated standard prophylaxis(20 - 40 IU/Kg body weight 2-3 times one week with ADVATE for 1 year. Subjects must be prescribed ADVATE by the treating physician. Data will be collected over a period of 2 years from the time of study enrollment. Study visits are to coincide with routinely rescheduled and emergency visits. Available data from these visits shall be transcribed onto the case report forms (CRFs). | Drug: ADVATE<br>* The baseline ABR will be assessed from bleeding log and clinic records from preceding year. Subjects will initially be treated standard prophylaxis(20 - 40 IU/Kg body weight 2-3 times one week with ADVATE for 1 year.<br>* Other names: Recombinant Human Coagulation Factor VIII for injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annual Bleed Rate (ABR) | Every 3 months, evaluate the joint bleeding episode and any other bleeding episodes. After 1 year later, sum up all the bleeding and get the ABR. | 3 months up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| incidence of new target joints | Incidence of new target joints. | 3 months | 
| joint health of Pettersson score | Status of joint health by X-ray using Pettersson scale. | 1 year | 
| magnetic resonance imaging scoring of joint | Status of joint health by magnetic resonance imaging scoring system. | 6 months | 
| Hemophilia Joint Health Score (HJHS) of joint | Status of joint health using the Hemophilia Joint Health Score (HJHS) | 3 months | 
| Number of Recombinant Human Coagulation Factor VIII for injection (ADAVTE) units | Number of ADVATE infusions required for bleed cessation and Number of ADAVTE units required for bleed cessation | 3 months | 
| Qol assessment | QoL assessment by The Canadian Hemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT) | 3 months | 
| Inhibitor rate | Inhibitor rate monitoring: inhibitor will be tested at entry of study, every 3 months and at end of study. | 3 months up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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severe hemophilia A, moderately severe hemophilia A, Recombinant Human Coagulation Factor VIII, standard prophylaxis