A Study of PEGylated Recombinant Factor VIII (BAX855) in Previously Untreated Young Children With Severe Hemophilia A

Hemophilia A Clinical Trial

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%)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02615691
• Other study ID #: 261203
• Secondary ID: 2015-002136-40
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 12, 2015
• Est. completion date: October 31, 2024

Study information

• Verified date: September 2023
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 120
• Est. completion date: October 31, 2024
• Est. primary completion date: October 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 5 Years

Eligibility

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 a-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.

Related Conditions & MeSH terms

• Hemophilia A

Intervention

Biological:
• PEGylated Recombinant Factor VIII
Polyethylene glycol (PEG)-ylated full-length recombinant FVIII (rFVIII).
• ITI
Immune tolerance induction therapy

Locations

Country	Name	City	State
Austria	Medizinische Universitat Wien	Vienna
Belgium	Cliniques Uni Saint-Luc	Bruxelles
Belgium	HUDERF	Bruxelles
Belgium	Univ. Ziekenhuis Gent Apotheek	Gent
Belgium	Universitair Ziekenhuis Leuven	Leuven
Bulgaria	UMHAT Sv. Georgi, EAD	Plovdiv
Bulgaria	SHAT Oncohaematology Diseases	Sofia
Bulgaria	MHAT Sv. Marina, EAD	Varna
Canada	Kaye Edmonton Clinic	Edmonton	Alberta
Canada	McMaster Health Science	Hamilton	Ontario
Denmark	Rigshospitalet Copenhagen	Copenhagen
Finland	Helsinki Univ Hospital	Helsinki
France	CHU CAEN Hopital Cote de Nacre	Caen cedex 9	Calvados
France	Hopital Jeanne de Flandre - CHU Lille	Lille Cedex
France	Hopital Necker Enfants Malades	Paris cedex 15	Paris
France	Essais cliniques CHU Rennes	Rennes cedex 09	Ille Et Vilaine
France	CHU de Rouen	ROUEN Cedex
Germany	Inst. f. Experimentelle	Bonn
Germany	Klinik F.Haematologie,Onkologie	Duesseldorf
Germany	Poliklinik PaediaHaematologie	Hamburg
Germany	Werlhof-Institut GmbH	Hannover	Niedersachsen
Hong Kong	The University of Hong Kong Queen Mary Hospital	Hong Kong
Hong Kong	Chinese University Of Hong Kong	Shatin
Hungary	Belgyogyaszat Onkohaematologia	Budapest
Hungary	Debreceni Egyetem	Debrece
Italy	Presidio Ospedaliero F. Alessi	Catania
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	Ospedale Maggiore Policlinico	Milano
Italy	Umberto I Pol. di Roma-Università di Roma La Sapienza	Rome
Korea, Republic of	Eulji University Hospital	Daejeon
Korea, Republic of	Kyung Hee University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan
Malaysia	Hospital Ampang	Ampang	Kuala Lumpur
Malaysia	Hospital Pulau Pinang	Georgetown	Pulau Pinang
Malaysia	Hospital HRPB	Ipoh	Perak
Malaysia	Hospital Kuala Lumpur	Kuala Lumpur
Malaysia	Hospital Umum Sarawak	Kuching
Malaysia	Hospital Sultanah Nur Zahirah	Terengganu
Netherlands	Universitair Medisch Centrum Groningen (UMCG)	Groningen
Norway	Oslo Universitetssykehus - Rikshospitalet	Oslo
Singapore	KKH	Singapore
Singapore	NUS YLL School of Medicine	Singapore
Spain	HOSPITAL A Coruna	A Coruna
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Univ. Son Espases	Palma de Mallorca	Baleares
Spain	Hospital Univ del Rio Hortega	Valladolid
Taiwan	Kaohsiung Chung- Ho Memorial Hosp	Kaohsiung
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taichung Veterans General	Taichung
Taiwan	Tri-Service General Hospital	Taipei City
Thailand	Siriraj Hospital	Bangkoknoi	Bangkok
Thailand	Maharaj Nakorn Chiang Mai	Muang	Chiang Mai
Thailand	Srinagarind Hospital	Muang	Khon Kaen
Thailand	King Chulalongkorn Memorial	Patumwan	Bangkok
Thailand	Ramathibodi Hospital	Ratchathewi	Bangkok
Turkey	Acibadem Adana Hospital	Adana
Turkey	Hacettepe Üniversitesi	Ankara
Turkey	Akdeniz Universitesi	Antalya
Turkey	Uludag Universitesi Tip Fakültesi	Bursa
Turkey	Istanbul Üniversitesi Cerrahpasa	Istanbul
Turkey	Ege Universitesi Tip Fakultesi	Izmir
Turkey	Erciyes Univers Tip Fakultesi	Kayseri
Turkey	19 Mayis Universitesi	Samsun
Ukraine	MI Cherkasy Reg Onc Dis of CRC	Cherkasy
Ukraine	SI Institute of Blood Pathology and Transfusion Medicine of NAMSU	Lviv
Ukraine	CI Zaporizhzhia Reg CCH of ZRC	Zaporizhzhia
United Kingdom	Bristol Royal H. for Children	Bristol
United Kingdom	Evelina Children's Hospital - St Thomas' Hospital	London
United Kingdom	Royal Manchester Children's Hospital	Manchester	Greater Manchester
United Kingdom	Univ Hospital Southampton	Southampton	Hampshire
United States	UMHS	Ann Arbor	Michigan
United States	Center for Advanced Pediatrics	Atlanta	Georgia
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	Ann & Robert H. Lurie Children's H	Chicago	Illinois
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Rainbow Babies/Childrens Htl	Cleveland	Ohio
United States	Kaiser Permanente Oakland M.C.	Cupertino	California
United States	Texas Tech University Health Sciences Center	El Paso	Texas
United States	Univ Florida College Medicine	Gainesville	Florida
United States	Connecticut Children's Med Ctr	Hartford	Connecticut
United States	Penn State MS Hershey Med Ctr	Hershey	Pennsylvania
United States	Texas Children's Hospital	Houston	Texas
United States	New York Presbyterian Hospital	New York	New York
United States	Kaiser Permanente Oakland M.C.	Oakland	California
United States	Bleeding and Clotting Dis.Inst.	Peoria	Illinois
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Kaiser Permanente Oakland M.C.	Roseville	California
United States	UC Davis Health System	Sacramento	California
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Baxalta now part of Shire	Takeda Development Center Americas, Inc.

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Bulgaria,  Canada,  Denmark,  Finland,  France,  Germany,  Hong Kong,  Hungary,  Italy,  Korea, Republic of,  Malaysia,  Netherlands,  Norway,  Singapore,  Spain,  Taiwan,  Thailand,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With FVIII Inhibitor Development	Number of participants who develop an inhibitor (at any time) confirmed by a central laboratory based on a second repeat blood sample draw within 2 weeks of site notification of an inhibitor and all participants who not developed an inhibitor and has greater than or equal to (>=) 100 exposure doses (EDs) when the sample for the last valid inhibitor test will be drawn.	Throughout Part A of the study, approximately 5 years
Primary	Success Rate of Immune Tolerance Induction (ITI)	Success is defined as 1) a persistently negative inhibitor titer less than (<) 0.6 Bethesda unit (BU), 2) FVIII IR >=66% of the baseline value following a wash-out period of 84-96 hours, and 3) a FVIII half-life of >=6 hours.	Up to 33 months
Secondary	Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies	Binding IgG and IgM antibodies to Factor VIII (FVIII), Factor VIII-Polyethylene glycol (PEG-FVIII) and Polyethylene glycol (PEG).	Throughout Part A of the study, approximately 5 years
Secondary	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is defined as any untoward medical occurrence in a participant administered an IP that does not necessarily have a causal relationship with the treatment. A SAE is any untoward clinical manifestation of signs, symptoms or outcomes (whether considered related to investigational product or not and at any dose) which results in death, is life-threatening, requires inpatient hospitalization, prolongation of hospitalization, is an important medical event. Number of participants with AEs and SAEs in both part A and part B will be assessed.	Throughout Part A and Part B of the study, approximately 7 years
Secondary	Number of Participants With Clinically Significant Changes in Vital Signs	Vital signs will be assessed based on body temperature, respiratory rate, blood pressure, and heart rate.	Throughout Part A and Part B of the study, approximately 7 years
Secondary	Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters	Clinical laboratory parameters includes hematology and clinical chemistry. Changes in laboratory values may be considered as AE if they are judged to be clinically significant.	Throughout Part A and Part B of the study, approximately 7 years
Secondary	Annualized Bleeding Rate (ABR) for Prophylactic and On-demand Treatment	ABR is assessed based upon each individual bleeding episode. A bleeding episode is defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding occurring at multiple locations related to the same injury (example, knee and ankle bleed following a fall) will be counted as a single bleeding episode. Total annualized bleed rate (spontaneous and traumatic bleeding episodes) will be reported.	Throughout Part A of the study, approximately 5 years
Secondary	Number of BAX 855 Infusions Needed for the Treatment of Bleeding Episodes	A bleeding episode is defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. The number of BAX 855 infusions needed for each bleeding episode is determined by the participant, caregiver, clinician treating the participant, and is based upon the participant's response to treatment, using the Efficacy Rating Scale for Treatment of Bleeding Episodes.	Throughout Part A of the study, approximately 5 years
Secondary	Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Initiation of Treatment	The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens	24 hours after study drug administration
Secondary	Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution	The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.	From start of study treatment up to bleed resolution (approximately 5 years)
Secondary	Number of Participants With Weight-adjusted Consumption of BAX 855	Weight-adjusted consumption of BAX 855 will be determined based upon the record in participants diaries of the actual amount of BAX 855 infused, indication (treatment of bleeding episode, prophylaxis,surgery) and the participants weight, as measured in the clinic.	Throughout Part A of the study, approximately 5 years
Secondary	Number of Infusions During Weight-adjusted Consumption of BAX 855	The number of BAX 855 infusions needed for each bleeding episode is determined by the participant, caregiver, clinician treating the participant, and is based upon the participant's response to treatment, using the Efficacy Rating Scale for Treatment of Bleeding Episodes.	Throughout Part A of the study, approximately 5 years
Secondary	Number of Participants With Hemostatic Efficacy in Case of Surgery	The hemostatic efficacy will be assessed during and after any surgical or invasive procedures, and overall as a perioperative assessment.	Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)
Secondary	Blood Loss Per Participant in Case of Surgery	The intraoperative blood loss will be measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist's record. Post-operatively, blood loss will be determined by the drainage volume collected, which will mainly consist of drainage fluid via vacuum or gravity drain, as applicable.	Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)
Secondary	Incremental Recovery (IR) of BAX 855	BAX 855 will be administered in participants for the determination of FVIII IR at the study site at baseline and every study visit other than study visits.	Pre-infusion within 30 minutes; and post-infusion at 15-30 minutes and 24-48 hours
Secondary	Half-life (T1/2) of BAX 855	The Half-life to determine FVIII half-life is an optional assessment that will be performed at baseline, Visit 1, or Visit 2.	Pre-infusion, Post-infusion: 15-30 minutes and 24-48 hours
Secondary	Immune Tolerance Induction (ITI) - Rate of Partial Success and Failure of ITI	Partial success defined as which meet two of following criteria, 1) inhibitor titer <0.6 BU (confirmed by a central laboratory with a second blood specimen obtained within 2 months), 2) FVIII in vivo recovery >=66% of baseline value (confirmed within a two month period), and 3) FVIII half-life >=6 hours. Failure defined as the failure to meet the criteria for partial success.	Up to 33 months
Secondary	Immune Tolerance Induction (ITI) - Annualized Bleeding Rate (ABR)	ABR is assessed based upon each individual bleeding episode. A bleeding episode is defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding occurring at multiple locations related to the same injury (example, knee and ankle bleed following a fall) will be counted as a single bleeding episode. Total annualized bleed rate (spontaneous and traumatic bleeding episodes) will be reported.	Up to 33 months
Secondary	Immune Tolerance Induction (ITI) - Weight-adjusted Consumption of BAX 855 for Each ITI Regimen Employed	Weight-adjusted consumption of BAX 855 will be determined based upon the record in participant's diaries of the actual amount of BAX 855 infused, indication (treatment of bleeding episode, prophylaxis) and the participant's weight, as measured in the clinic.	Up to 33 months
Secondary	Immune Tolerance Induction (ITI) - Catheter-related Complications	The frequency per subject and per subject-year of catheter-related complications will be calculated.	Up to 33 months
Secondary	Immune Tolerance Induction (ITI) - Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies	Binding IgG and IgM antibodies to Factor VIII (FVIII), Factor VIII-Polyethylene glycol (PEG-FVIII) and Polyethylene glycol (PEG).	Up to 33 months

External Links

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