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

Baxalta now part of Shire120 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

120

Conditions

Hemophilia A

Interventions

PEGylated Recombinant Factor VIII

Eligibility

Sex: ALLMax age: 5 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Number of Participants With FVIII Inhibitor Development

Number of participants who developed 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 had not developed an inhibitor and had greater than or equal to (\>=) 100 EDs when the sample for the last valid inhibitor test was drawn.

Time frame: Throughout Part A of the study, approximately 5 years

Number of Participants With Success 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.

Time frame: Up to 33 months in Part B of the study

Secondary Outcomes

Number of Participants With Binding Immunoglobulin G (IgG) and Immunoglobulin M (IgM) Antibodies

Binding IgG and IgM antibodies to FVIII , Factor VIII-Polyethylene glycol (PEG-FVIII) and Polyethylene glycol (PEG) was assessed. A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen. Visits and their approximate time in weeks after baseline visit for individual participants: Visit 1(Week 5), Visit 2 (Week 10), Visit 3 (Week 15), Visit 4 (Week 20), Visit 5 (Week 30), Visit 6 (Week 40), Visit 7 (Week 55), Visit 8 (Week 75) and Study Completion Visit (Weeks 100-110).

Time frame: Throughout Part A of the study, approximately 5 years

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 investigational product (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 were assessed. A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen.

Time frame: Throughout Part A and Part B of the study, approximately 9 years

Number of Participants With At Least One Clinically Significant Changes in Vital Signs

Vital signs were assessed based on body temperature, respiratory rate, blood pressure, and heart rate.

Time frame: Throughout Part A and Part B of the study, approximately 9 years

Number of Participants With At Least One Clinically Significant Changes in Clinical Laboratory Parameters

Clinical laboratory parameters included hematology and clinical chemistry. Changes in laboratory values could be considered as AE if they were judged to be clinically significant.

Time frame: Throughout Part A and Part B of the study, approximately 9 years

Annualized Bleeding Rate (ABR) for Prophylactic and On-demand Treatment and Immune Tolerance Induction (ITI)

ABR was assessed based upon each individual bleeding episode. A bleeding episode was 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) was counted as a single bleeding episode. Mean total annualized bleed rate is reported. A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen.

Time frame: Throughout Part A and Part B of the study, approximately 9 years

Bleeding Episodes Categorized by Number of BAX 855 Infusions Required for Treatment

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 was 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. Number of bleeding episodes are categorized by number of infusions required to treat the bleeding episodes. A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen.

Time frame: Throughout Part A of the study, approximately 5 years

Number of Bleeds by Overall Hemostatic Efficacy Rating at 24 Hours After Initiation of Treatment

The participant or caregiver rated overall treatment response using a 4-point efficacy rating scale as Excellent:Full relief of pain \& cessation of objective signs of bleeding after single infusion \& no additional infusion is required for the control of bleeding; Good:Definite pain relief \&/or improvement in signs of bleeding after single infusion \& possibly requires more than 1 infusion for complete resolution; Fair:Probable \&/or slight relief of pain \& slight improvement in signs of bleeding after single infusion \& required more than 1 infusion for complete resolution \& None:No improvement or condition worsens.Number of bleeds with each efficacy rating are reported.Participant that received on-demand treatment first \& then moved to prophylaxis treatment was counted for both on-demand \& prophylaxis regimens.Participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on prophylaxis regimen.

Time frame: At 24 hours after study drug administration during Part A of the study

Number of Bleeds by Overall Hemostatic Efficacy Rating at Bleed Resolution

The participant or caregiver rated overall treatment response using a 4-point efficacy rating scale as Excellent:Full relief of pain \& cessation of objective signs of bleeding after single infusion \& no additional infusion is required for the control of bleeding; Good:Definite pain relief \&/or improvement in signs of bleeding after a single infusion \& possibly requires more than 1 infusion for complete resolution; Fair:Probable \&/or slight relief of pain \& slight improvement in signs of bleeding after single infusion \& required more than 1 infusion for complete resolution \& None:No improvement or condition worse.Number of bleeds with each efficacy rating are reported.Participant that received on-demand treatment first \& then moved to prophylaxis treatment was counted for both on-demand \& prophylaxis regimens.Participant that started with prophylaxis treatment was counted only for prophylaxis regimen even if the participant received on-demand treatment while on prophylaxis regimen.

Time frame: From start of study treatment up to bleed resolution throughout Part A of the study (up to approximately 5 years)

Weight-adjusted Consumption of BAX 855: Average Prophylactic Dose

Time frame: Throughout Part A of the study, approximately 5 years

Weight-adjusted Consumption of BAX 855: Average Number of Prophylactic Infusions

Weight-adjusted consumption of BAX 855 was determined based upon the record in participants diaries of the actual number of BAX 855 infusions as measured in the clinic. Average number of infusions per month and year are reported as categories.

Time frame: Throughout Part A and Part B of the study, approximately 9 years

Weight-adjusted Consumption of BAX 855: Average Dose

Weight-adjusted consumption of BAX 855 was determined based upon the record in participants diaries of the actual amount of BAX 855 infused as measured in the clinic. Average dose to treat bleeding episode and average FVIII inhibitor treatment Dose \[IU/kg\] per Week, Month and per Year are reported as categories. A participant that received on-demand treatment first and then moved to prophylaxis treatment was counted for both on-demand and prophylaxis regimens. A participant that started with prophylaxis treatment was counted only for the prophylaxis regimen even if the participant received on-demand treatment while on the prophylaxis regimen.

Time frame: Throughout Part A of the study, approximately 5 years

Number of Participants by Hemostatic Efficacy Rating in Case of Surgery

Hemostatic efficacy was assessed during \& after any surgical or invasive procedures,\& overall as a perioperative assessment.Operating surgeon assessed hemostatic efficacy compared to that expected for the type of procedure performed in non-hemophilic population,prior to discharge from recovery room(intraoperative),on postoperative Day 1 \& at discharge or 14 days post-surgery(perioperative).Participants rated efficacy using following ratings:1.Excellent:Postoperative blood loss was ≤100% than expected;2.Good:Postoperative blood loss was up to 50% more (101-150%) than expected;3.Fair:Postoperative blood loss was more than 50% (\>150%) of that expected;4.None:Significant postoperative bleeding that was result of inadequate therapeutic response despite proper dosing,necessitating rescue therapy.Perioperative ratings also considered amount of blood components required for transfusions compared to expected.Participant-provided ratings for each of the assessments are reported as categories.

Time frame: Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)

Blood Loss Per Participant in Case of Surgery

The intraoperative blood loss was 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 was determined by the drainage volume collected, which mainly consisted of drainage fluid via vacuum or gravity drain, as applicable. The assessment was done for the intra-operative time period (prior to discharge from recovery room) and for the post-operative time period (from completion of the procedure until approximately 24 hours post-surgery).

Time frame: Surgery Day 0 up to postoperative Day 14 or discharge (whichever occurs first)

Incremental Recovery (IR) of BAX 855

BAX 855 was administered in participants for the determination of FVIII IR at study site at baseline \& every study visit other than study visits at 5 EDs, 15 EDs \& 30 EDs. FVIII assays were done using following methods:1-stage clotting FVIII activity \& FVIII chromogenic activity. Data is reported for each of these methods as categories per visit. Study Completion assessment was conducted at end of the Main Study \& again at end of the ITI portion. Thus, more number of participants were analyzed at study completion visit than those who actually completed the overall study. IR is reported as a ratio of (IU/deciliter \[dL\])/(IU/kg), calculated as: IR = (Cmax- (C pre-infusion)) / (IU/kg), where C=concentration. Visits and their approximate time in weeks after baseline visit for individual participants: Visit 1 (Week 5), Visit 2 (Week 10), Visit 3 (Week 15), Visit 4 (Week 20), Visit 5 (Week 30), Visit 6 (Week 40), Visit 7 (Week 55), Visit 8 (Week 75) \& Study Completion Visit (Weeks 100-110).

Time frame: Baseline up to Study Completion (Up to 5 years in Part A and up to 3.5 years in Part B)

Half-life (T1/2) of BAX 855

The Half-life to determine FVIII half-life was an optional assessment that was planned to be performed at baseline, Visit 1, or Visit 2.

Time frame: Pre-infusion, Post-infusion: 15-30 minutes and 24-48 hours at Baseline

Immune Tolerance Induction (ITI) - Number of Participants With 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.

Time frame: Up to 33 months in Part B of the study

Immune Tolerance Induction (ITI) - Number of Participants With At Least One Catheter-related Complication

Number of participants with catheter-related complications are reported.

Time frame: Up to 33 months in Part B of the study

Immune Tolerance Induction (ITI) - Number of Participants With 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) are reported as categories per visit.

Time frame: Up to 33 months in Part B of the study

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

Overview

Conditions

Interventions

Eligibility

Locations (91)

Outcomes

Primary Outcomes

Secondary Outcomes