Clinical trial NCT02210091: BAX 855 Pediatric Study
Official title: A Phase 3 Prospective, Uncontrolled, Multicenter Study Evaluating Pharmacokinetics, Efficacy, Safety, and Immunogenicity of BAX 855 (PEGylated Full-length Recombinant FVIII) in Previously Treated Pediatric Patients With Severe Hemophilia A
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia A
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2014-08-06
Enrollment: 75
Sex: ALL
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study purpose is:

* To assess the incidence of FVIII inhibitory antibodies during 6 months of twice weekly prophylactic treatment with BAX 855 or 50 exposure days (EDs), whichever occurs last.
* To compare pharmacokinetic (PK) parameters to ADVATE.
* To assess hemostatic efficacy in prophylaxis and the treatment of bleeding episodes.
* To evaluate safety and immunogenicity.


Eligibility criteria: Inclusion Criteria:

* Severe hemophilia A (Factor VIII (FVIII) \<1%) determined by central laboratory.
* \<12 years old at the time of screening.
* Participants aged ≥6 to \<12 years of age have been previously treated with plasma-derived and/or recombinant Factor VIII (rFVIII) concentrate(s) for a minimum of 150 exposure days (EDs) (based on the participant's medical records).
* Participants \<6 years of age have been previously treated with plasma-derived and/or rFVIII concentrate(s) for at least 50 EDs (based on the participant's medical records).
* Participant is human immunodeficiency virus (HIV) negative; or HIV positive with stable disease and CD4+ count of ≥200 cells/mm\^3, as confirmed by central laboratory.
* Participant and/or legal representative accepts prophylactic treatment over a period of 6 months.
* Participant and/or the legal representative is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

* Participant has detectable FVIII inhibitory antibodies (≥0.4 Bethesda Units (BU) using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening.
* Participant has a history of FVIII inhibitory antibodies (≥0.4 BU using the Nijmegen modification of the Bethesda assay or ≥0.6 BU using the Bethesda assay) at any time prior to screening.
* Participant has known hypersensitivity towards mouse or hamster proteins, polyethylene glycol (PEG), or Tween 80.
* Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).
* Participant's platelet count is \<100,000/μL.
* Participant has severe chronic hepatic dysfunction (eg, ≥5 times upper limit of normal (ULN) alanine aminotransferase (ALT), as confirmed by central laboratory at screening, or a documented international normalized ratio (INR) \>1.5).
* Participant has severe renal impairment (serum creatinine \>1.5 times ULN).
* Participant is scheduled to receive during the course of the study, an immunomodulating drug (eg, corticosteroid agents at a dose equivalent to hydrocortisone \>10 mg/day, or α-interferon) other than anti-retroviral chemotherapy.
* Participant has current or recent (\<30 days) use of other PEGylated drugs prior to study participation or is scheduled to use such drugs during study participation.
* Participant has participated in another clinical study involving an investigational product (IP) or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.
* Participant has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the Investigator, would affect participant safety or compliance.
* Participant's legal representative is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

Primary outcomes:
measure: Number of Participants With Inhibitory Antibodies to Factor VIII (FVIII)
timeFrame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
Secondary outcomes:
measure: Annualized Bleeding Rate (ABR)
timeFrame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
measure: Consumption of BAX 855: Number of Prophylactic Infusions Per Month Per Participant
timeFrame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
measure: Consumption of BAX 855: Number of Prophylactic Infusions Per Year (Annualized) Per Participant
timeFrame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
measure: Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Month Per Participant
timeFrame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
measure: Consumption of BAX 855: Weight-adjusted Dose of Prophylactic Infusions Per Year (Annualized) Per Participant
timeFrame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
measure: Consumption of BAX 855: Number of Infusions Per Bleeding Episode
timeFrame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
measure: Consumption of BAX 855: Weight-adjusted Dose Per Bleeding Episode
timeFrame: During prophylaxis period of 6 months or ≥ 50 EDs, whichever occurs last
measure: Hemostatic Efficacy Rating for Bleeding Episodes Treated With BAX 855 at Resolution of Bleed
timeFrame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
measure: Serious Adverse Events (SAEs) Possibly or Probably Related to BAX 855
timeFrame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
measure: Non-serious Adverse Events Possibly or Probably Related to BAX 855
timeFrame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
measure: Number of Participants With Clinically Significant Changes in Vital Signs
timeFrame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
measure: Number of Clinically Significant Changes in Clinical Laboratory Parameters (Hematology, Clinical Chemistry, Lipids)
timeFrame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
measure: Positive Post-baseline Binding Antibodies to Factor VIII (FVIII), Polyethylene Glycol-Factor VIII (PEG-FVIII), PEG and Chinese Hamster Ovary (CHO) Proteins
timeFrame: After first exposure to BAX 855 until completion of study - approx. 6 months per participant.
measure: Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion (AUC0-∞)
timeFrame: (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4
measure: Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve From 0 to ∞ Hours Post-infusion Per Dose, (AUC0-∞/Dose)
timeFrame: (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4
measure: Pharmacokinetics (PK): Mean Residence Time (MRT)
timeFrame: (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4
measure: Pharmacokinetics (PK): Clearance (CL)
timeFrame: (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4
measure: Pharmacokinetics (PK): Plasma Half-life (T1/2)
timeFrame: (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4
measure: Pharmacokinetics (PK): Volume of Distribution at Steady State (Vss)
timeFrame: (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4
measure: Pharmacokinetics (PK): Incremental Recovery (IR)
timeFrame: (1) within 30 min pre-infusion; (2) 15-30 min post-infusion; (3) Day 0 either 4 or 7 hours post-infusion; Day 1 am; Day 1 pm; (4) Day 2; Day 3; or Day 4
measure: Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - One Stage Clotting Assay
timeFrame: Baseline, Week 5 (or 10-15 EDs, whichever occurs last), Week 12, and Month 6 (Completion/Termination)
measure: Pharmacokinetics (PK): Incremental Recovery (IR) of BAX 855 Over Time - Chromogenic Assay
timeFrame: Baseline, Week 5 (or 10-15 Exposure Days [EDs], whichever occurs last), Week 12, and Month 6 (Completion/Termination)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Gainesville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: New Hyde Park
country: United States
facility: Cornell University
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital-Weill
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Childrens Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Childrens Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Plovdiv
country: Bulgaria
facility: UMHAP Sveti Georgi EAD
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Treatment of Oncohematological Diseases in Children
city: Varna
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "Sveta Marina"
city: Shatin
country: Hong Kong
facility: The Chinese University of Hong Kong
state: New Territories
city: Seo-gu
country: Korea, Republic of
facility: Eulji University Hosptial
state: Daejeon
city: Dong-gu
country: Korea, Republic of
facility: Ulsan University Hosptial
state: Ulsan
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: George Town
country: Malaysia
facility: Hospital Pulau Pinang
state: Penang
city: Kuching
country: Malaysia
facility: Hospital Umum Sarawak
state: Sarawak
city: Sibu
country: Malaysia
facility: Hospital Sibu
state: Sarawak
city: Ampang
country: Malaysia
facility: Ampang Hospital
state: Selangor
city: Klang
country: Malaysia
facility: Tengku Ampian Rahimah (TAR) Hospital
state: Selangor
city: Amsterdam
country: Netherlands
facility: Academic Medical Centre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Taichung City
country: Taiwan
facility: Taichung Veterans General Hospital
state: Xitun District
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Cerrahpasa
country: Turkey
facility: Istanbul University Faculty of Medicine, Department of Pediatric Immunology
state: Istanbul
city: Ankara
country: Turkey
facility: Ankara University Medical Faculty
city: Antalya
country: Turkey
facility: Akdeniz Univesity Medical Faculty
city: Van
country: Turkey
facility: Yuzuncu Yil University Medical Faculty
city: Lviv
country: Ukraine
facility: Institute of Blood Pathology and Transfusion Medicine of Academy of Medical Sciences of Ukraine
city: Birmingham
country: United Kingdom
facility: Birmingham Childrens Hospital NHS Trust
city: London
country: United Kingdom
facility: St. Thomas's Hospital
city: London
country: United Kingdom
facility: Great Ormond Street Hospital For Children
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Mullins ES, Stasyshyn O, Alvarez-Roman MT, Osman D, Liesner R, Engl W, Sharkhawy M, Abbuehl BE. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia. 2017 Mar;23(2):238-246. doi: 10.1111/hae.13119. Epub 2016 Nov 27.