Clinical trial NCT02615691: A Study of PEGylated Recombinant Factor VIII (BAX855) in Previously Untreated Young Children With Severe Hemophilia A
Official title: Phase 3, Prospective, Multi-center, Open Label Study to Investigate Safety, Immunogenicity and Hemostatic Efficacy of PEGylated Factor VIII (BAX 855) in Previously Untreated Patients (PUPs) < 6 Years With Severe Hemophilia A (FVIII < 1%)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hemophilia A
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: Takeda Development Center Americas, Inc.
First posted: 2015-11-26
Enrollment: 120
Sex: ALL
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is for young children with severe hemophilia A who have previously not been treated with BAX855 or other FVIII concentrates.

The main aim of the study is to check for side effects from treatment with BAX855. This includes the buildup of antibodies against FVIII which may stop BAX855 from working properly. Another aim is to learn how well BAX855 controls bleeding.

In this study, the children can receive BAX855 either as preventative treatment (prophylaxis), or as needed to treat bleeding (on-demand).

In case a participant develops antibodies, treatment will be provided as part of the study.


Eligibility criteria: Inclusion Criteria

1. Participant is \<6 years old at the time of screening.
2. Participant is previously untreated with \<3 exposure days (EDs) to ADVATE, BAX 855 or plasma transfusion at any time prior to screening.
3. Participant has severe hemophilia A (Factor VIII (FVIII) \<1%) as determined by the central laboratory, or a historical FVIII level \<1% as determined at any local laboratory, optionally supported by an additional FVIII gene mutation consistent with severe hemophilia A.
4. Participant is immune competent with a cluster of differentiation 4 (CD4+) count \> 200 cells per cubic millimeter (mm\^3), as confirmed by the central laboratory at screening.
5. Parent or legally authorized representative is willing and able to comply with the requirements of the protocol.

Additional inclusion criteria for Part B (immune tolerance induction \[ITI\]).

1. Parent or legal representative has/have voluntarily provided signed informed consent for ITI portion.
2. Participant has a confirmed positive high titer inhibitor (\> 5.00 Bethesda unit (BU)) or has a positive confirmed low titer inhibitor (greater than or equal to \[\>=\] 0.6 BU) as determined by the central laboratory based on a second repeat blood sample with

   1. poorly controlled bleeding despite increased BAX 855 doses, or
   2. requires bypassing agents to treat bleeding.

Exclusion Criteria

1. Participant has detectable FVIII inhibitory antibodies (\>=0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening.
2. Participant has a history of FVIII inhibitory antibodies (\>=0.6 BU using the Nijmegen modification of the Bethesda assay or the Bethesda assay) at any time prior to screening.
3. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).
4. Participant has been previously treated with any type of FVIII concentrate other than ADVATE or BAX 855, or was administered ADVATE, BAX 855 or plasma transfusion for \>=3 EDs at any time prior to screening.
5. Participant receives \> two EDs of ADVATE in total during the periods prior to enrollment and during the screening period, until the baseline infusion.
6. The participant's weight is anticipated to be \<5 kilogram (kg) at the baseline visit.
7. Participant's platelet count is \<100,000 per milliliter (mL).
8. Participant has known hypersensitivity towards mouse or hamster proteins, polyethylene glycol (PEG) or Tween 80.
9. Participant has severe chronic hepatic dysfunction (eg, \>5 times upper limit of normal alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], or a documented international normalized ratio \[INR\] \>1.5) in his medical history or at the time of screening.
10. Participant has severe renal impairment (serum creatinine \>1.5 times the upper limit of normal).
11. 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.
12. Participant is scheduled to receive during the course of the study a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day or α-interferon) other than anti-retroviral chemotherapy.
13. 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.
14. Parent or legally authorized representative 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.
15. Parent, legally authorized representative or participant are 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.

Additional exclusion criteria for Part B (ITI)

1. Spontaneous disappearance of the inhibitor prior to ITI.
2. FVIII inhibitor titer \>=0.6 BU is not confirmed by a second new blood sample and determined at the central laboratory.
3. Inability or unwillingness to comply with the protocol.

Primary outcomes:
measure: Number of Participants With FVIII Inhibitor Development
timeFrame: Throughout Part A of the study, approximately 5 years
measure: Success Rate of Immune Tolerance Induction (ITI)
timeFrame: Up to 33 months
Secondary outcomes:
measure: Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies
timeFrame: Throughout Part A of the study, approximately 5 years
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Throughout Part A and Part B of the study, approximately 7 years
measure: Number of Participants With Clinically Significant Changes in Vital Signs
timeFrame: Throughout Part A and Part B of the study, approximately 7 years
measure: Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters
timeFrame: Throughout Part A and Part B of the study, approximately 7 years
measure: Annualized Bleeding Rate (ABR) for Prophylactic and On-demand Treatment
timeFrame: Throughout Part A of the study, approximately 5 years
measure: Number of BAX 855 Infusions Needed for the Treatment of Bleeding Episodes
timeFrame: Throughout Part A of the study, approximately 5 years
measure: Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Initiation of Treatment
timeFrame: 24 hours after study drug administration
measure: Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution
timeFrame: From start of study treatment up to bleed resolution (approximately 5 years)
measure: Number of Participants With Weight-adjusted Consumption of BAX 855
timeFrame: Throughout Part A of the study, approximately 5 years
measure: Number of Infusions During Weight-adjusted Consumption of BAX 855
timeFrame: Throughout Part A of the study, approximately 5 years
measure: Number of Participants With Hemostatic Efficacy in Case of Surgery
timeFrame: Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)
measure: Blood Loss Per Participant in Case of Surgery
timeFrame: Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)
measure: Incremental Recovery (IR) of BAX 855
timeFrame: Pre-infusion within 30 minutes; and post-infusion at 15-30 minutes and 24-48 hours
measure: Half-life (T1/2) of BAX 855
timeFrame: Pre-infusion, Post-infusion: 15-30 minutes and 24-48 hours
measure: Immune Tolerance Induction (ITI) - Rate of Partial Success and Failure of ITI
timeFrame: Up to 33 months
measure: Immune Tolerance Induction (ITI) - Annualized Bleeding Rate (ABR)
timeFrame: Up to 33 months
measure: Immune Tolerance Induction (ITI) - Weight-adjusted Consumption of BAX 855 for Each ITI Regimen Employed
timeFrame: Up to 33 months
measure: Immune Tolerance Induction (ITI) - Catheter-related Complications
timeFrame: Up to 33 months
measure: Immune Tolerance Induction (ITI) - Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies
timeFrame: Up to 33 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Cupertino
country: United States
facility: Kaiser Permanente Oakland M.C.
state: California
city: Oakland
country: United States
facility: Kaiser Permanente Oakland M.C.
state: California
city: Roseville
country: United States
facility: Kaiser Permanente Oakland M.C.
state: California
city: Sacramento
country: United States
facility: UC Davis Health System
state: California
city: Hartford
country: United States
facility: Connecticut Children's Med Ctr
state: Connecticut
city: Gainesville
country: United States
facility: Univ Florida College Medicine
state: Florida
city: Atlanta
country: United States
facility: Center for Advanced Pediatrics
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's H
state: Illinois
city: Peoria
country: United States
facility: Bleeding and Clotting Dis.Inst.
state: Illinois
city: Ann Arbor
country: United States
facility: UMHS
state: Michigan
city: New York
country: United States
facility: New York Presbyterian Hospital
state: New York
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies/Childrens Htl
state: Ohio
city: Hershey
country: United States
facility: Penn State MS Hershey Med Ctr
state: Pennsylvania
city: El Paso
country: United States
facility: Texas Tech University Health Sciences Center
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Vienna
country: Austria
facility: Medizinische Universitat Wien
city: Bruxelles
country: Belgium
facility: HUDERF
city: Bruxelles
country: Belgium
facility: Cliniques Uni Saint-Luc
city: Gent
country: Belgium
facility: Univ. Ziekenhuis Gent Apotheek
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Plovdiv
country: Bulgaria
facility: UMHAT Sv. Georgi, EAD
city: Sofia
country: Bulgaria
facility: SHAT Oncohaematology Diseases
city: Varna
country: Bulgaria
facility: MHAT Sv. Marina, EAD
city: Edmonton
country: Canada
facility: Kaye Edmonton Clinic
state: Alberta
city: Hamilton
country: Canada
facility: McMaster Health Science
state: Ontario
city: Copenhagen
country: Denmark
facility: Rigshospitalet Copenhagen
city: Helsinki
country: Finland
facility: Helsinki Univ Hospital
city: Caen cedex 9
country: France
facility: CHU CAEN Hopital Cote de Nacre
state: Calvados
city: Rennes cedex 09
country: France
facility: Essais cliniques CHU Rennes
state: Ille Et Vilaine
city: Paris cedex 15
country: France
facility: Hopital Necker Enfants Malades
state: Paris
city: Lille Cedex
country: France
facility: Hopital Jeanne de Flandre - CHU Lille
city: ROUEN Cedex
country: France
facility: CHU de Rouen
city: Hannover
country: Germany
facility: Werlhof-Institut GmbH
state: Niedersachsen
city: Bonn
country: Germany
facility: Inst. f. Experimentelle
city: Duesseldorf
country: Germany
facility: Klinik F.Haematologie,Onkologie
city: Hamburg
country: Germany
facility: Poliklinik PaediaHaematologie
city: Hong Kong
country: Hong Kong
facility: The University of Hong Kong Queen Mary Hospital
city: Shatin
country: Hong Kong
facility: Chinese University Of Hong Kong
city: Budapest
country: Hungary
facility: Belgyogyaszat Onkohaematologia
city: Debrece
country: Hungary
facility: Debreceni Egyetem
city: Catania
country: Italy
facility: Presidio Ospedaliero F. Alessi
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico
city: Rome
country: Italy
facility: Umberto I Pol. di Roma-Università di Roma La Sapienza
city: Daejeon
country: Korea, Republic of
facility: Eulji University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
city: Ampang
country: Malaysia
facility: Hospital Ampang
state: Kuala Lumpur
city: Ipoh
country: Malaysia
facility: Hospital HRPB
state: Perak
city: Georgetown
country: Malaysia
facility: Hospital Pulau Pinang
state: Pulau Pinang
city: Kuala Lumpur
country: Malaysia
facility: Hospital Kuala Lumpur
city: Kuching
country: Malaysia
facility: Hospital Umum Sarawak
city: Terengganu
country: Malaysia
facility: Hospital Sultanah Nur Zahirah
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen (UMCG)
city: Oslo
country: Norway
facility: Oslo Universitetssykehus - Rikshospitalet
city: Singapore
country: Singapore
facility: NUS YLL School of Medicine
city: Singapore
country: Singapore
facility: KKH
city: Palma de Mallorca
country: Spain
facility: Hospital Univ. Son Espases
state: Baleares
city: A Coruna
country: Spain
facility: HOSPITAL A Coruna
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Valladolid
country: Spain
facility: Hospital Univ del Rio Hortega
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Chung- Ho Memorial Hosp
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General
city: Taipei City
country: Taiwan
facility: Tri-Service General Hospital
city: Bangkoknoi
country: Thailand
facility: Siriraj Hospital
state: Bangkok
city: Patumwan
country: Thailand
facility: King Chulalongkorn Memorial
state: Bangkok
city: Ratchathewi
country: Thailand
facility: Ramathibodi Hospital
state: Bangkok
city: Muang
country: Thailand
facility: Maharaj Nakorn Chiang Mai
state: Chiang Mai
city: Muang
country: Thailand
facility: Srinagarind Hospital
state: Khon Kaen
city: Adana
country: Turkey
facility: Acibadem Adana Hospital
city: Ankara
country: Turkey
facility: Hacettepe Üniversitesi
city: Antalya
country: Turkey
facility: Akdeniz Universitesi
city: Bursa
country: Turkey
facility: Uludag Universitesi Tip Fakültesi
city: Istanbul
country: Turkey
facility: Istanbul Üniversitesi Cerrahpaşa
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi
city: Kayseri
country: Turkey
facility: Erciyes Univers Tip Fakultesi
city: Samsun
country: Turkey
facility: 19 Mayis Universitesi
city: Cherkasy
country: Ukraine
facility: MI Cherkasy Reg Onc Dis of CRC
city: Lviv
country: Ukraine
facility: SI Institute of Blood Pathology and Transfusion Medicine of NAMSU
city: Zaporizhzhia
country: Ukraine
facility: CI Zaporizhzhia Reg CCH of ZRC
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: Greater Manchester
city: Southampton
country: United Kingdom
facility: Univ Hospital Southampton
state: Hampshire
city: Bristol
country: United Kingdom
facility: Bristol Royal H. for Children
city: London
country: United Kingdom
facility: Evelina Children's Hospital - St Thomas' Hospital
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References: