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Clinical Trials/NCT02585960
NCT02585960CompletedPhase 3

Phase 3, Prospective, Randomized, Multi-center Clinical Study Comparing the Safety and Efficacy of BAX 855 Following PK-guided Prophylaxis Targeting Two Different FVIII Trough Levels in Subjects With Severe Hemophilia A

Baxalta now part of Shire83 sites in 13 countries135 target enrollmentStarted: November 23, 2015Last updated:
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Conditions
Interventions

Trial Snapshot

Phase
Phase 3
Status
Completed
Sponsor
Enrollment
135
Locations
83
Primary Endpoint
Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months
Study OverviewStudy DesignEligibility CriteriaArms & InterventionsOutcomesInvestigatorsSitesRecords & IdentifiersSimilar Trials

Study Overview

Brief Summary

  1. To compare the efficacy and safety of pharmacokinetic (PK)-guided treatment with BAX 855 targeting FVIII trough levels of 1-3% and approximately 10% (8-12%)
  2. To further characterize pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BAX 855

Study Design

Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel
Primary Purpose
Prevention
Masking
None

Eligibility Criteria

Ages
12 Years to 65 Years (Child, Adult, Older Adult)
Sex
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • •Participants transitioning from another BAX 855 study who meet ALL of the following criteria are eligible for this study:
  • •Participant has completed the end of study visit of a BAX 855 study or is transitioning from the ongoing Baxalta Continuation Study
  • •Participant is either receiving on-demand treatment or prophylactic treatment with BAX 855 and had an Annual Bleed Rate (ABR) of ≥ 2 documented and treated during the past 12 months.
  • •Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm^3, as confirmed by central laboratory.
  • •Participant is willing and able to comply with the requirements of the protocol.
  • •Newly recruited participants (ie not transitioning from another BAX 855 study) including BAX855 naïve participants who meet ALL of the following criteria are eligible for this study:
  • •Participant has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory OR by historically documented FVIII clotting activity performed by a certified clinical laboratory, optionally supported by a FVIII gene mutation consistent with severe hemophilia A
  • •Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥ 150 documented exposure days (EDs)
  • •Participant is either receiving on-demand treatment or prophylactic treatment and had an annual bleeding rate of ≥ 2 documented and treated during the past 12 months.
  • •Participant has a Karnofsky performance score of ≥ 60 at screening
  • •Participant is HIV-; or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm^3, as confirmed by central laboratory at screening
  • •Participant is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis
  • •If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study
  • •Participant is willing and able to comply with the requirements of the protocol.

Exclusion Criteria

  • •Participants transitioning from another BAX 855 study who meet ANY of the following criteria are not eligible for this study:
  • •Participant has developed a confirmed inhibitory antibody to FVIII with a titer of ≥ 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at the central laboratory during the course of the previous BAX 855 study.
  • •Participant has been diagnosed with an acquired hemostatic defect other than hemophilia A.
  • •The participant's weight is < 35 kg or > 100 kg.
  • •Participant's platelet count is < 100,000/mL.
  • •Participant has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal).
  • •Participant has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal.
  • •Participant is scheduled to receive 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 during the study.
  • •Participant has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant's safety or compliance.
  • •Participant is planning to take part in any other clinical study during the course of the study.
  • •Participant 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.
  • •Newly recruited participants (ie not transitioning from another BAX 855 study) who meet ANY of the following criteria are not eligible for this study:
  • •Participant has detectable FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening.
  • •Participant has a history of confirmed FVIII inhibitors with a titer ≥ 0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed with the respective cut-off in the local laboratory) at any time prior to screening.
  • •Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).
  • •The participant's weight is < 35 kg or > 100 kg.
  • •Participant's platelet count is < 100,000/mL.
  • •Participant has known hypersensitivity towards mouse or hamster proteins, PEG or Tween
  • •Participant has severe chronic hepatic dysfunction [eg, ≥ 5 times upper limit of normal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), as confirmed by central laboratory at screening, or a documented INR > 1.5].
  • •Participant has severe renal impairment (serum creatinine > 1.5 times the upper limit of normal).
  • •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 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.
  • •Participant has participated in another clinical study involving an 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 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.

Arms & Interventions

FVIII trough target 8-12%

Experimental

Intensified treatment arm - PK-guided dosing schedule to achieve a Factor VIII (FVIII) trough of 8-12%

Intervention: PEGylated Recombinant Factor VIII (Biological)

FVIII trough target 1-3%

Experimental

Standard treatment arm - PK-guided dosing schedule to achieve a Factor VIII (FVIII) trough of 1-3%

Intervention: PEGylated Recombinant Factor VIII (Biological)

Pharmacokinetic (PK) evaluation of BAX 855

Experimental

Participants will first undergo an initial pharmacokinetic (PK) assessment. Following the PK assessment participants will be randomized to one of 2 dosing regimens.

Intervention: PEGylated Recombinant Factor VIII (Biological)

Outcomes

Primary Outcomes

Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months

Time Frame: Day 183 to Day 364 (6 months)

Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.

Secondary Outcomes

  • Total Weight-adjusted Consumption of BAX 855(From start of study treatment up to 12 months (completion or termination))
  • Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events(From start of study treatment up to 12 months (completion or termination))
  • Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions(8 hours after study drug administration)
  • Annualized Spontaneous Bleeding Rate for Second Six Months(Day 183 to Day 364 (6 months))
  • Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score(Baseline, Month 12)
  • Plasma Half-life (T1/2) of BAX 855(Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion)
  • Volume of Distribution at Steady State (Vss)(Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion)
  • Annualized Traumatic Bleeding Rate for Second Six Months(Day 183 to Day 364 (6 months))
  • Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution(From start of study treatment up to 12 months (completion or termination))
  • Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds(Day 0 through discharge or 14 days post-surgery)
  • Blood Loss Per Participant in Case of Surgery(Day 0 through discharge or 14 days post-surgery)
  • Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events(From start of study treatment up to 12 months (completion or termination))
  • Total Annualized Bleeding Rate for Second Six Months(Day 183 to Day 364 (6 months))
  • Annualized Joint Bleeding Rate (AJBR) for Second Six Months(Day 183 to Day 364 (6 months))
  • Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution(From start of study treatment up to bleed resolution (up to 12 months))
  • Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey(Baseline, Month 12 (completion or termination))
  • Maximum Plasma Concentration (Cmax) of BAX 855(Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion)
  • Time to Maximum Concentration of BAX 855 in Plasma (Tmax)(Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion)
  • Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(From start of study treatment up to 12 months (completion or termination))
  • Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855(Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion)
  • Total Body Clearance (CL) of BAX 855(Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion)
  • Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein(From start of study treatment up to 12 months (completion or termination))
  • Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf)(Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion)
  • Mean Residence Time (MRT) of BAX 855(Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion)
  • Incremental Recovery (IR) Over Time(Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination))

Investigators

Sponsor
Baxalta now part of Shire
Sponsor Class
Industry
Responsible Party
Sponsor

Study Sites (83)

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