Ignite Creation Date:
2024-05-06 @ 5:23 PM
Last Modification Date:
2024-10-26 @ 2:27 PM
Study NCT ID:
NCT05281185
Status:
COMPLETED
Last Update Posted:
2022-07-20
First Post:
2022-02-08
Brief Title:
Clinical Outcomes of Low Dose PK-guided EHL FVIII Concentrates Versus Standard Prophylaxis in Severe Haemophilia A
Sponsor:
Chulalongkorn University
Organization:
Chulalongkorn University
Study Overview
Official Title:
Clinical Outcomes of Low Dose Pharmacokinetic-guided Extended Half-life FVIII Concentrates Versus Low Dose Standard Prophylaxis in Thai Severe Haemophilia A Patients
Status:
COMPLETED
Status Verified Date:
2022-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 FVIIIC 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 wwwmypkfitcom
Wash-out period for 72 hours each participant subsequently received a dose of 20 IUkg 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 10-20ukg 2-3timesweek 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
Methods A single-centre prospective cohort study the investigators recruited consecutive eligible patients aged 5-25 years with clinically severe haemophilia A FVIIIC 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 wwwmypkfitcom
Wash-out period for 72 hours each participant subsequently received a dose of 20 IUkg 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 10-20ukg 2-3timesweek 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 patients FVIII level and clinical bleeding phenotype Clinically severe haemophilia A FVIII 1 IUdL 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 ie 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 IUdL 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 IUdL 1 at all times However there has been increasing recognition and evidence that factor trough levels of 1-3 IUdL 1-3 are insufficient to totally prevent bleeds in all people with haemophilia and allow occasional clinical and subclinical bleeds And when baseline FVIIIC levels are above 15 IUdL 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 dosefrequency 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 001-003 IUmL 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 13-16-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 FVIIIC 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 22264 Informed consent was obtained according to the Declaration of IRB Human Research research affairs faculty of medicine Chulalongkorn university Thailand
Inclusionexclusion criteria The inclusion criteria were as follows 1 severe or moderate with clinically HA with a baseline FVIII level of 3 IUdL 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 06 Bethesda units BU and detectable FVIII inhibitor at screening titer 06 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
21 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 wwwmypkfitcom 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 IUkg 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 7296 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 10-20ukg 2-3timesweek 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 hisher clinical judgement after physicalclinical 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
22 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
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 patients FVIII level and clinical bleeding phenotype Clinically severe haemophilia A FVIII 1 IUdL 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 ie 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 IUdL 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 IUdL 1 at all times However there has been increasing recognition and evidence that factor trough levels of 1-3 IUdL 1-3 are insufficient to totally prevent bleeds in all people with haemophilia and allow occasional clinical and subclinical bleeds And when baseline FVIIIC levels are above 15 IUdL 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 dosefrequency 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 001-003 IUmL 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 13-16-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 FVIIIC 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 22264 Informed consent was obtained according to the Declaration of IRB Human Research research affairs faculty of medicine Chulalongkorn university Thailand
Inclusionexclusion criteria The inclusion criteria were as follows 1 severe or moderate with clinically HA with a baseline FVIII level of 3 IUdL 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 06 Bethesda units BU and detectable FVIII inhibitor at screening titer 06 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
21 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 wwwmypkfitcom 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 IUkg 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 7296 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 10-20ukg 2-3timesweek 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 hisher clinical judgement after physicalclinical 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
22 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None