Ignite Creation Date:
2024-05-06 @ 8:17 PM
Last Modification Date:
2024-10-26 @ 3:24 PM
Study NCT ID:
NCT06320626
Status:
RECRUITING
Last Update Posted:
2024-03-20
First Post:
2024-02-28
Brief Title:
Pharmacokinetic-guided Dosing of Emicizumab
Sponsor:
Kathelijn Fischer
Organization:
UMC Utrecht
Study Overview
Official Title:
Pharmacokinetic-guided Dosing of Emicizumab in Congenital Haemophilia A Patients - The DosEmi Study
Status:
RECRUITING
Status Verified Date:
2024-03
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:
DosEmi
Brief Summary:
The goal of this multicentre prospective open-label cross-over clinical study is to determine whether individualized PK-guided dosing of emicizumab is non-inferior to conventional dosing of emicizumab in the prevention of bleeding in congenital haemophilia A patients
Detailed Description:
Haemophilia A is an X-linked hereditary bleeding disorder resulting from a deficiency or dysfunction of endogenous coagulation factor VIII FVIII Persons with haemophilia A PwHA suffer from spontaneous or provoked bleeding predominantly into major joints which eventually lead to painful and chronic disabling arthropathy The primary goal in clinical management of haemophilia A is prevention of bleeding by self-administration of FVIII concentrates via intravenous injections
Prophylaxis with FVIII concentrates has effectively reduced treated bleeds from an annual average of 20-30 to 1-4 However in approximately 30 of PwHA anti-FVIII antibodies known as inhibitors develop that interfere with FVIII replacement therapy PwHA who develop inhibitors require alternative suboptimal therapy with costly bypassing agents BPA
The first approved non-factor therapy is the bispecific FVIII-mimicking antibody emicizumab Hemlibra which came available in the Netherlands in July 2018 Emicizumab is a humanized bispecific antibody connecting factor IX and factor X enabling the activation of FX and subsequent thrombin generation Emicizumab has shown to be highly effective prophylaxis in PwHA by achieving a complete eradication of treated bleeds in around 80 of PwHA n 374 during the second 24-week interval of treatment Furter advantages of emicizumab are the subcutaneous administration and less frequent dosing intervals every 1 2 or 4 weeks due to a long half-life t ½ 28 days Despite many PwHA are candidate for prophylaxis with emicizumab cost limit widespread access
Currently emicizumab is approved by F Hoffmann-La Roche with a loading dose of 3 mgkgweek for four weeks and a maintenance dose of 15 mgkgweek 3 mgkg2 weeks or 6 mgkg4 weeks These dose regimens were based on a pharmacometric approach instead of a dose finding study and targeted a trough concentration Ctrough of 45 µgml by using pharmacokinetic PKsimulations Meanwhile long-term bleed data from the phase III and IV studies by the pharmaceutical company were included in pharmacokinetic PK and pharmacodynamic PD modelling studies and the effective Ctrough was suggested at 30 µgml
Although this Ctrough of 30 µgml is substantially lower than the previous Ctrough 45 µgml the dose regimens were not adjusted Conventional dosing leads to mean concentrations of 55 µgml with two thirds of the observations between 40 and 70 µgml ie SD of 15 µgml Emicizumab has been approved based on fixed body-weight-based dosing and therefore the concentration target might have been kept higher to avoid lower effectivity due to inter-patient variability However reduced dosing of emicizumab either by extending the dosing interval or lowering the dose without sacrificing its efficacy has been reported in small case series
Therefore the investigators hypothesized that lower dosing of emicizumab targeted at Ctrough 30 μgmL is equally as effective and less costly in preventing bleeds as conventional dosing of emicizumab and designed the DosEmi study to investigate the hypothesis in a large prospective cohort of adult and paediatric PwHA
Prophylaxis with FVIII concentrates has effectively reduced treated bleeds from an annual average of 20-30 to 1-4 However in approximately 30 of PwHA anti-FVIII antibodies known as inhibitors develop that interfere with FVIII replacement therapy PwHA who develop inhibitors require alternative suboptimal therapy with costly bypassing agents BPA
The first approved non-factor therapy is the bispecific FVIII-mimicking antibody emicizumab Hemlibra which came available in the Netherlands in July 2018 Emicizumab is a humanized bispecific antibody connecting factor IX and factor X enabling the activation of FX and subsequent thrombin generation Emicizumab has shown to be highly effective prophylaxis in PwHA by achieving a complete eradication of treated bleeds in around 80 of PwHA n 374 during the second 24-week interval of treatment Furter advantages of emicizumab are the subcutaneous administration and less frequent dosing intervals every 1 2 or 4 weeks due to a long half-life t ½ 28 days Despite many PwHA are candidate for prophylaxis with emicizumab cost limit widespread access
Currently emicizumab is approved by F Hoffmann-La Roche with a loading dose of 3 mgkgweek for four weeks and a maintenance dose of 15 mgkgweek 3 mgkg2 weeks or 6 mgkg4 weeks These dose regimens were based on a pharmacometric approach instead of a dose finding study and targeted a trough concentration Ctrough of 45 µgml by using pharmacokinetic PKsimulations Meanwhile long-term bleed data from the phase III and IV studies by the pharmaceutical company were included in pharmacokinetic PK and pharmacodynamic PD modelling studies and the effective Ctrough was suggested at 30 µgml
Although this Ctrough of 30 µgml is substantially lower than the previous Ctrough 45 µgml the dose regimens were not adjusted Conventional dosing leads to mean concentrations of 55 µgml with two thirds of the observations between 40 and 70 µgml ie SD of 15 µgml Emicizumab has been approved based on fixed body-weight-based dosing and therefore the concentration target might have been kept higher to avoid lower effectivity due to inter-patient variability However reduced dosing of emicizumab either by extending the dosing interval or lowering the dose without sacrificing its efficacy has been reported in small case series
Therefore the investigators hypothesized that lower dosing of emicizumab targeted at Ctrough 30 μgmL is equally as effective and less costly in preventing bleeds as conventional dosing of emicizumab and designed the DosEmi study to investigate the hypothesis in a large prospective cohort of adult and paediatric PwHA
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