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

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.

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.

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).

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.

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

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.

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.

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.

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.

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.

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 per prophylactic infusion, per month and per year are reported as categories.

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.

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.

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.

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).

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).

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.

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.

Number of participants with catheter-related complications are reported.

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.