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

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.

Study Overview

• Status: Unknown
• Conditions: Hemophilia A
• Intervention / Treatment: Drug: ADVATE

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 15
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rongfu Zhou, Doctor; Phone Number: +86 13605142342; Email: rfzhoucn@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject has hemophilia A with FVIII≤2 %.
2. Previously treated patients (PTPs).
3. Age from 2 to 18 years.

Exclusion Criteria:

1. Subject has known hypersensitivity to the active substance or any of the excipients.
2. Subject has known allergic reaction to mouse or hamster proteins.
3. 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.
4. Subject is planned, or likely to have surgery during the study period.
5. Subject has end-stage renal failure or evidence of a severe or uncontrolled systemic disease as judged by the investigator.
6. Subject has full-blown Acquired Immuno Deficiency Syndrome (AIDS),determined by cluster differentiation antigen 4+ (CD4+) and clinical presentation.
7. Subject has active hepatic disease (alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels > 5 times the upper limit of normal).
8. 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.
9. The subject in the opinion of the investigator is unable or unwilling to comply with study protocol
10. Subject is a family member of the investigator or site staff

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ADVATE standard prophylaxis; 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; 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.; Other Names: Recombinant Human Coagulation Factor VIII for injection

What is the study measuring?

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
magnetic resonance imaging scoring of joint	Status of joint health by magnetic resonance imaging scoring system.	6 months
joint health of Pettersson score	Status of joint health by X-ray using Pettersson scale.	1 year
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

Collaborators and Investigators

• Sponsor: The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
• Investigators: Principal Investigator: Ouyang Jian, Doctor, The Affiliated Nanjing Drum Tower Hospital Nanjing Medical University

Publications and helpful links

General Publications

• Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P, Matsunaga A, Medeiros D, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, Evatt BL. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007 Aug 9;357(6):535-44. doi: 10.1056/NEJMoa067659.
• Astermark J, Petrini P, Tengborn L, Schulman S, Ljung R, Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol. 1999 Jun;105(4):1109-13. doi: 10.1046/j.1365-2141.1999.01463.x.
• Berntorp E, Boulyjenkov V, Brettler D, Chandy M, Jones P, Lee C, Lusher J, Mannucci P, Peak I, Rickard K, et al. Modern treatment of haemophilia. Bull World Health Organ. 1995;73(5):691-701.
• Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM; ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost. 2011 Apr;9(4):700-10. doi: 10.1111/j.1538-7836.2011.04214.x.
• Valentino LA, Mamonov V, Hellmann A, Quon DV, Chybicka A, Schroth P, Patrone L, Wong WY; Prophylaxis Study Group. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost. 2012 Mar;10(3):359-67. doi: 10.1111/j.1538-7836.2011.04611.x.
• Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47. doi: 10.1111/j.1365-2516.2012.02909.x. Epub 2012 Jul 6.
• Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med. 1992 Jul;232(1):25-32. doi: 10.1111/j.1365-2796.1992.tb00546.x.
• Ljung R. Prophylactic therapy in haemophilia. Blood Rev. 2009 Nov;23(6):267-74. doi: 10.1016/j.blre.2009.08.001. Epub 2009 Sep 22.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Anticipated): December 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: October 29, 2014
• First Submitted That Met QC Criteria: October 31, 2014
• First Posted (Estimate): November 4, 2014

Study Record Updates

• Last Update Posted (Estimate): November 4, 2014
• Last Update Submitted That Met QC Criteria: October 31, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: severe hemophilia A; standard prophylaxis; moderately severe hemophilia A; Recombinant Human Coagulation Factor VIII
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A; Coagulants; Factor VIII
• Other Study ID Numbers: 2014-053-01