A Phase 4 interventional study of Emicizumab - PK-guided dose reduction and Emicizumab - Dosis continuation group in Hemophilia A With Inhibitor, Hemophilia A Without Inhibitor and Hemophilia A, Severe, sponsored by Kathelijn Fischer. Recruiting at 8 sites in Netherlands. Open to male participants aged 1 Year and older. Per ClinicalTrials.gov, last updated 2024-03-20.
Sponsored by Kathelijn Fischer · Phase 4, Interventional, and Treatment
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.
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 mg/kg/week for four weeks and a maintenance dose of 1.5 mg/kg/week, 3 mg/kg/2 weeks or 6 mg/kg/4 weeks. These dose regimens were based on a pharmacometric approach instead of a dose finding study, and targeted a trough concentration (Ctrough) of 45 µg/ml by using pharmacokinetic (PK)simulations. 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 µg/ml.
Although this Ctrough of 30 µg/ml is substantially lower than the previous Ctrough (45 µg/ml), the dose regimens were not adjusted. Conventional dosing leads to mean concentrations of 55 µg/ml with two thirds of the observations between 40 and 70 µg/ml (i.e., SD of ±15 µg/ml). 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 μg/mL, 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.
866 studies on the registry are indexed under Hemophilia A; 137 are open to participants now.
This study's planned enrollment of 95 is above the median of 28 across 512 interventional studies indexed under Hemophilia A.
Browse Hemophilia A studies →This is the only study on the registry with Kathelijn Fischer as lead sponsor.
Counted across the registry records on this site, refreshed daily.
i No spontaneous joint/muscle bleeds in the previous 6 months AND ii A maximum of two treated (traumatic) bleeds in the previous 6 months.
Exclusion Criteria:
Patients will be followed 6 months retrospectively and 6 months prospectively on conventional dosing.
Other: Emicizumab - PK-guided dose reduction · Other: Emicizumab - Dosis continuation group · Other: Emicizumab - Dose adjustment group
Patients with emicizumab concentration of ≥ 40 μg/mL will receive individualized PK-guided dose reduction of emicizumab targeted at a Ctrough of 30μg/mL. Patients will be followed for 12 months on reduced dosing.
Other: Emicizumab - PK-guided dose reduction
Patients with emicizumab concentration of 25-39 μg/mL will continue on their current dose regimen. Patients will be followed for 12 months on current dosing.
Other: Emicizumab - Dosis continuation group
Patients with emicizumab plasma concentration \< 25 μg/mL will be adjusted in dosing regimen according to local protocol. Patients will be followed for selective safety data only.
Other: Emicizumab - Dose adjustment group
PK-guided dose reduction emicizumab targeted at a Ctrough of 30μg/mL.
Also known as: Hemlibra
Continue on their current dose regimen
Also known as: Hemlibra
Adjusted in dosing regimen according to local protocol
Also known as: Hemlibra
Proportion of patients without treated bleeds
Comparison proportion treated bleeds 6 months before (conventional) and after intervention (PK-guided dosing)
Time frame: 12 months
Proportion of patients without treated bleeds
Comparison proportion without treated bleeds 12 months before (conventional) and after intervention (PK-guided dosing)
Time frame: 24 months
Proportion of patients without spontaneous joint- or muscle bleeds
Comparison proportion without spontaneous joint- or muscle bleeds 6 and 12 months before and after intervention.
Time frame: 24 months
Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sport-induced bleeds
Comparison annualized bleeding rate 6 and 12 months before and after intervention.
Time frame: 24 months
To compare cost-effectiveness between conventional dosing and individualized PK-guided dosing of emicizumab
Direct and indirect medical costs: Direct medical costs are predominantly determined by consumption of emicizumab, additional FVIII, and/or bypassing agents, extracted from the hospital's pharmacy records. These data are highly reliable, as this medication is exclusively distributed by haemophilia treatment centers. Indirect medical costs: are number of (emergency) hospital visits, bleeding related hospital admissions and/or unscheduled surgeries, and days lost from work/school (for patients and/or caregivers).
Time frame: 24 months
To assess the cumulative number of coagulation factor (sc. and/or iv.) of per year.
Assessment of the cumulative number of sc. and/or iv. Injections related to coagulation correction.
Time frame: 24 months
To assess the performance of the population PK model
Predictive performance of the MAP Bayesian procedure used for the dose adaptation procedure, defined as % of patients within ±20% of target level/within the target level of 25-39 µg/mL of emicizumab.
Time frame: 12 months
To investigate whether direct joint health remains stable measured by physical examination when switching to lower-dosed emicizumab compared to conventional treatment
Joint status will be measured by physical examination (Haemophilia Joint Health Score; HJHS),
Time frame: 12 months
To investigate whether direct joint health remains stable measured by ultrasound when switching to lower-dosed emicizumab compared to conventional treatment
Joint status will be measured by ultrasound (if available, according to the HEAD US score).
Time frame: 12 months
To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment.
biomarker assessment for inflammation and joint and cartilage turnover in blood. The biomarkers comprising origin of different joint tissues will be selected and adopted based on the literature on osteoarthritis, which is a rapidly changing area of research.
Time frame: 12 months
To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment.
biomarker assessment for inflammation and joint and cartilage turnover in urine.The biomarkers comprising origin of different joint tissues will be selected and adopted based on the literature on osteoarthritis, which is a rapidly changing area of research.
Time frame: 12 months
To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
Health related quality of life will be assessed with EuroQol Five Dimensions Health Questionnaire (Youth) EQ5D(Y).
Time frame: 12 months
To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
Health related quality of life will be assed with PROMIS instruments (Physical Function/mobility and Pain Interference short forms).
Time frame: 12 months
To investigate whether sports participation are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
Sports participation (type, duration, frequency) will be assessed with Modifiable Activities Questionnaire (MAQ).
Time frame: 12 months
To investigate whether thrombin generation parameters can be used as a pharmacodynamic (PD) biomarker for emicizumab treatment efficacy.
To measure coagulation potential, blood samples will be collected to measure thrombin generation (Peak Height and ETP)
Time frame: 12 months
To assess and monitor pain during emicizumab administration
Assessment of pain during emicizumab administration by Visual Analogue Scale (scale 0-10)
Time frame: 12 months
Plan to share: Yes
Supporting information: Study protocol, Sap
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