Clinical Outcomes of Low Dose PK-guided EHL FVIII Concentrates Versus Standard Prophylaxis in Severe Haemophilia A
Condition: Severe Hemophilia A Without Inhibitor
MeSH terms: Hemophilia A
Study type: Interventional
Phase: Phase 4

Summary: 
      Individualised pharmacokinetic (PK)-guided dosing of extended half-life (EHL) FVIII
      concentrates prophylaxis may reduce hemophilia A bleeding events than previous prophylactic
      regimen.

      Methods A single-centre prospective cohort study, the investigators recruited consecutive
      eligible patients aged 5-25 years with clinically severe haemophilia A (FVIII:C ≤3%), no
      inhibitor, on low-dose weight-based prophylaxis at King Chulalongkorn Memorial Hospital
      (KCMH) from July 2021 to February 2022.

      All of patients with clinically severe haemophilia A received low dose weight-based standard
      half-life FVIII concentrates replacement prophylaxis for ≥ 1 year prior to enrolment in the
      study.

      The data of annual bleeding rate (ABR), annual joint bleeding rate (AJBR), annual FVIII use
      (prophylactic and breakthrough bleeding dosing) in the last 6 months before the study and
      number of target joints were collected at the beginning of the study.

      Baseline variables, including age and weight, were recorded before performing the analyses
      using online medical device (www.mypkfit.com).

      Wash-out period for 72 hours, each participant subsequently received a dose of 20 IU/kg FVIII
      by intravenous injection. Blood samples were collected and the concentration of FVIII was
      measured two times at 3 h and 48 h or 72 h after injection by one-stage technique. Desired
      FVIII trough levels were selected in this study as 1%. Individually proper regimen were
      selected by discussion with patients and families.

      All of participant individually underwent dose calculation of EHL factor VIII concentrates
      and received low dose PK-guided regimen (10-20u/kg, 2-3times/week) with EHL FVIII
      concentrates for 6 months. If breakthrough bleeding occurs, FVIII concentrates 500 U
      intravenous injection immediately.

      ABR, AJBR, HJHS and annual FVIII concentrates use were again prospectively recorded during
      intervention period after PK adjustment for 6 months.

      Primary objectives To compare clinical outcomes including annual bleeding rate (ABR), annual
      joint bleeding rate (AJBR) and Haemophilia joint health score (HJHS) before and after
      switching from standard half-life (SHL) to Extended half-life (EHL) factor VIII concentrates
      with adjusted dosing by PK-guided program (MyPKFiT®) in severe haemophilia A patients
      Secondary objectives To compare factor VIII concentrates consumption before and after using
      PK-guided program (MyPKFiT®) adjusting dose of factor VIII infusion in severe HA patients.
    

Detailed description: 
      Clinical Outcomes of Low Dose Pharmacokinetic-guided Extended Half-life Versus Low Dose
      Standard Half-life FVIII Concentrates Prophylaxis in Thai Severe Haemophilia A Patients

      Haemophilia A (HA) is a X-linked inherited bleeding disorders caused by a deficiency in the
      clotting factor VIII (FVIII). The degree of deficiency was determined by a patient's FVIII
      level and clinical bleeding phenotype. Clinically severe haemophilia A (FVIII < 1 IU/dL)
      typically present with recurrent joint and muscle bleeds. They may also experience
      spontaneous and potentially fatal bleeds in any tissue.

      The standard of care for all patients with severe haemophilia A is regular factor replacement
      prophylaxis with clotting factor concentrates or other homeostasis products to maintain
      homeostasis for preventing bleeding, especially joint haemorrhages, which lead to arthropathy
      and disability. People with haemophilia A initiated on early prophylaxis (i.e., primary or
      secondary prophylaxis) have shown the best long-term outcomes. Therefore, the use of
      prophylaxis is always recommended over episodic therapy that no longer be a long-term
      treatment option.

      The aim of prophylaxis has been to convert a person with severe haemophilia (baseline FVIII
      <1 IU/dL) to a bleeding phenotype typical of moderate or mild haemophilia who seldom
      experienced spontaneous bleeding and had much better preservation of joint function by
      maintaining factor levels above 1 IU/dL (1%) at all times. However, there has been increasing
      recognition and evidence that factor trough levels of 1-3 IU/dL (1%-3%) are insufficient to
      totally prevent bleeds in all people with haemophilia and allow occasional clinical and
      subclinical bleeds. And when baseline FVIII:C levels are above 15 IU/dL (15%), spontaneous
      bleeding is uncommon, traumatic bleeding during high activity is few.

      The World Federation of Haemophilia (WFH) strongly recommends that prophylaxis should be
      individualised, taking into consideration patient bleeding phenotype, joint status, level of
      physical activity, individual pharmacokinetics, compliance, and patient self-assessment and
      preference in severe haemophilia patients. If patients continue to experience bleeds, their
      prophylaxis regimen should be escalated (in dose/frequency or both) to prevent bleeding. In
      countries with significant healthcare constraints and for patients with limited access to
      clotting factor concentrates, less intensive prophylaxis should be used over episodic
      therapy.

      By Pharmacokinetic-guided calculation, the plasma activity level of the infused factor is
      still above the level considered critical to prevent bleeding. This critical threshold is
      often assumed to be 0.01-0.03 IU/mL although different thresholds have been proposed for
      differing levels of physical activity or tendency to bleed.

      An old full PK study for haemophilia A patients requires a washout period of 72 h and sample
      collection for a total of 10 time-points after the infusion of the coagulation factor. In the
      recent years, population-based PK (PopPK) application was developed, myPKFiT®, obtained using
      just at least two sampling points that support optimal use of recombinant factor VIII
      (rFVIII) (Advate®; Shire plc, Dublin, Ireland) for treatment of haemophilia patients.

      Based on pharmacokinetics (PK), increasing infusion frequency will result in reduced FVIII
      consumption and a more stable factor level although it may have a negative impact on
      adherence. In many countries, extended half-life (EHL) FVIII concentrates play role in severe
      haemophilia A because of median 1.3-1.6-fold extension in half-life reducing their dosing
      frequency from 3- to 2-times weekly. A major aim of most modifications was to facilitate
      improved pharmacokinetics (PK) that allow a patient to dose less frequently than with
      standard half-life factor products and positive impact on adherence.

      Prophylaxis should enable people with haemophilia to lead healthy and active lives including
      participation in most physical and social activities (at home, school, work, and in the
      community), similar to the non-haemophiliac population.

      Methods In this single-centre prospective cohort study, we recruited consecutive eligible
      patients aged 5-25 years with clinically severe haemophilia A (FVIII:C ≤3%) at King
      Chulalongkorn Memorial Hospital (KCMH) from July 2021 to February 2022. Participants were
      recruited through their annual clinic visit or by a letter of invitation. The study was
      approved by Institutional Review Board (IRB) Human Research, research affairs, faculty of
      medicine, Chulalongkorn university, Thailand (Certificate 222/64). Informed consent was
      obtained according to the Declaration of IRB Human Research, research affairs, faculty of
      medicine, Chulalongkorn university, Thailand.

      Inclusion/exclusion criteria The inclusion criteria were as follows: (1) severe or moderate
      with clinically HA with a baseline FVIII level of ≤3 IU/dL, (2) age 5-25 years, (3) > 50
      exposure days (EDs) without inhibitor, (4) close proximity to the comprehensive care center
      at KCMH, (5) compliant to treatment, and (6) use of the pre-study prophylaxis regimen for ≥ 1
      year prior to enrolment in the study.

      The exclusion criteria were as follows: (1) history of FVIII inhibitor (titer > 0.6 Bethesda
      units [BU]) and detectable FVIII inhibitor at screening (titer > 0.6 BU), and (2) planned
      major surgery, and (3) concomitant serious conditions including symptomatic human
      immunodeficiency virus (HIV) infection, juvenile rheumatoid arthritis, metabolic bone
      disease, or other conditions known to mimic or cause joint diseases.

      2.1 | Procedures and variables All of patients with clinically severe haemophilia A received
      low dose weight-based standard half-life FVIII concentrates replacement prophylaxis for ≥ 1
      year prior to enrolment in the study. The data of annual bleeding rate (ABR), annual joint
      bleeding rate (AJBR), annual FVIII use (prophylactic and breakthrough bleeding dosing) in the
      last 6 months before the study and number of target joints were collected at the beginning of
      the study.

      The annual bleeding rate (ABR) and annual joint bleeding rate (AJBR) were collected by
      strictly bleeding recorded events from each patients with presenting to doctor in every
      haemophilia clinic visit.

      Target joints were defined according to the World Federation of Haemophilia 2020 guidelines.
      Joint status was assessed using Haemophilia joint health score (HJHS) and clinical assessment
      for all patients.

      The annual factor consumption was collected by strictly recorded by the patients including
      prophylaxis and breakthrough bleeding dosing with presenting to doctor in every haemophilia
      clinic visit.

      Baseline variables, including age and weight, were recorded before performing the analyses
      using online medical device (www.mypkfit.com). The calculation in myPKFiT® is based on
      clinical study data from a published population PK model using Advate® (standard half-life
      FVIII concentrates) and Adynovate® (extended half-life FVIII concentrates) of Takeda Ltd. The
      PK model was integrated with a Bayesian algorithm and uses a 2-compartment model to display
      an estimated individual curve of FVIII over time. These estimated PK parameters are used to
      provide dose guidance to maintain a desired FVIII activity level throughout the chosen dose
      interval.

      Following a bleed-free period of two weeks before the baseline assessment, patients did not
      undergo FVIII infusion for at least 72 h prior to estimate of PK parameters initiation. Each
      participant subsequently received a dose of 20 IU/kg FVIII by intravenous injection. Blood
      samples were collected and the concentration of FVIII was measured two times at 3 h and 48 h
      or 72 h after injection by one-stage technique. The output provided by myPKFiT® included
      FVIII half-life, clearance, volume of distribution at steady state and hours until trough
      level. Desired FVIII trough levels were selected in this study as 1%. Regimen selection
      (frequency every 72/96 hr and infusion day) took into account time to trough level and the
      simulated levels shown at different times, checked against the periods the patient needed to
      be better protected, according to his activities.

      All of participant individually underwent dose calculation of EHL factor VIII concentrates
      and received low dose PK-guided regimen (10-20u/kg, 2-3times/week) with EHL FVIII
      concentrates for 6 months. If breakthrough bleeding occurs, FVIII concentrates 500 U
      intravenous injection immediately and closely observe if bleeding or symptoms persists,
      another dose of FVIII concentrates is indicated in the next 12 hours.

      During the study, patients followed up in haemophilia clinic every months for history taking,
      physical examination and presenting record of bleeding events and factor consumption.

      ABR, AJBR, HJHS and annual FVIII concentrates use were again prospectively recorded during
      intervention period after PK adjustment for 6 months. Haemarthrosis was first suspected by
      the patient, based on location, and confirmed by the haematologist at the visit according to
      his/her clinical judgement after physical/clinical examination.

      For further subgroup analysis, patients were categorised into groups according to

        1. Their age (older or younger than 15 years), because of differences in pharmacokinetics
           related to age and body weight, the generally healthier joints in younger patients

        2. Their target joints (target joints or no target joints), the patients had target joints
           more risk of spontaneous bleeding and required high though level more than no target
           joint group

      2.2 | Statistical analysis Data are summarised as median and interquartile range (percentile
      25-percentile 75) for continuous variables, and frequency and percentage for discrete
      variables. Comparison of clinical outcomes was performed with the Wilcoxon rank test for
      paired samples, and changes in FVIII consumption were analysed using the Student t test for
      paired samples, after confirming the criteria for using parametric methods. Significance
      level was set at P < .05.

      Primary objectives To compare clinical outcomes including annual bleeding rate (ABR), annual
      joint bleeding rate (AJBR) and Haemophilia joint health score (HJHS) before and after
      switching from standard half-life (SHL) to Extended half-life (EHL) factor VIII concentrates
      with adjusted dosing by PK-guided program (MyPKFiT®) in severe haemophilia A patients

      Secondary objectives To compare factor VIII concentrates consumption before and after using
      PK-guided program (MyPKFiT®) adjusting dose of factor VIII infusion in severe HA patients.
    

Intervention name(s): Extended half-life FVIII concentrates with PK-guided dosing; standard half-life FVIII concentrates with weight-based dosing
Intervention type(s): Drug; Drug
Intervention description(s): Extended half-life FVIII concentrates with PK-guided dosing as low-dose factor replacement prophylaxis (10-20u/kg, 2-3 times/week) for 6 months in severe haemophilia A patients that previously receive weight-based factor replacement prophylaxis; standard half-life FVIII concentrates with weight-based dosing, that current patients' regimen before enrolling in this study
Intervention MeSH terms: Factor VIII
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: Patients aged 5-25 years with clinically severe haemophilia A (FVIII:C ≤3%), no inhibitor, on low-dose weight-based prophylaxis at King Chulalongkorn Memorial Hospital (KCMH) Thailand
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: severe hemophilia A; extended FVIII concentrates; low dose prophylaxis; MyPKFiT