This study has been transitioned to CTIS with ID 2024-515528-35-00 check the CTIS register for the current data. Primary objectiveTo determine whether individualized pharmacokinetic (PK)-guided dosing of emicizumab is non-inferior to conventional…
ID
Source
Brief title
Condition
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome parameter is bleeding, defined as:
1) Proportion of patients without treated bleeds (6 months Bleeding Assessment
Phase versus 6 months PK-Guided Dosing Phase).
Secondary outcome
The secondary outcome are defined as:
1. Proportion of patients without treated bleeds (12 months Clinical
Phase+Bleeding Assessment Phase versus 12 months PK-guided Dosing Phase+Dose
Continuation Phase)
2. Proportion of patients with spontaneous joint- or muscle bleeds (6 months
Bleeding Assessment Phase versus 6 months PK-Guided Dosing Phase).
3. Proportion of patients with spontaneous joint- or muscle bleeds (12 months
Clinical Phase+Bleeding Assessment Phase versus 12 months PK-guided Dosing
Phase+Dose Continuation Phase).
4. Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and
sports induced bleeds ((6 months Bleeding Assessment Phase versus 6 months
PK-Guided Dosing Phase).
5. Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and
sports induced bleeds (6 months retrospective + 6 months prospective data
(Clinical Phase+Bleeding Assessment Phase) versus 12 months prospective data of
PK guided dosing (PK-guided Dosing Phase+Dose Continuation Phase).
6. Cost-effectiveness between 6 months of conventional dosing (Bleeding
Assessment Phase) and 6 months of individualized PK-guided dosing of emicizumab
(PK-Guided Dosing Phase):
7 Direct and indirect medical costs:
7.1 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.
7.2 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).
8. Predictive performance of the MAP Bayesian procedure used for the dose
adaptation procedure, defined as % of patients within ±20% of within the target
level of 20-39 µg/mL of emicizumab. All emicizumab plasma levels will be
determined in the laboratory of the University Medical Center Utrecht using a
specifically developed LC-MS/MS.
9. Joint status as measured by physical examination (Haemophilia Joint Health
Score; HJHS), ultrasound (if available, according to the HEAD US score) and
biomarkers of bone and cartilage turnover.
10. Health related quality of life will be assessed with EQ5D(Y) (5 questions),
and PROMIS instruments (Physical Function/mobility and Pain Interference short
forms) (8 questions each).
11. Assessment of pain during emicizumab administration by Visual Analogue
Scale (VAS).
12. Sports participation (type, duration, frequency) will be assessed with
Modifiable Activities Questionnaire (MAQ).
13. Plasma coagulation potential will be measured with thrombin generation
tests as a potential read-out for pharmacodynamics.
14. Assessment of the cumulative number of sc. and/or iv. Injections related to
coagulation correction.
Background summary
Haemophilia A is a coagulation disorder that is caused by a reduced or
malfunctioning of coagulation factor FVIII. Patients with severe haemophilia
suffer from spontaneous or trauma induced bleeds, mainly targeted in joints and
muscles. In life-time, this can result in development of invalidating
arthropathy, reduced quality of life, increased risk for brain hemorrhages and
early death.
Clinical management of haemophilia therefore is focussed on prevention of
bleeds and thereby preventing the development of arthropathy. For many decades,
patients have been treated with intravenous administration of FVIII concetrates
in order to prevent bleeds (prophylaxis) or incendentally (on demand).
Prophylactic treatment with FVIII concetrates has been shown to be very
effective in prevention of bleeds. However administration may be very
burdensome for patients or his parents. Since it encounters intravenous
administration for 2-6 times per week. Therapy is usually start at young age,
when children start crawling.
Emicizumab is the first commercially available non-factor replacing product
that can be administered subcutaneously. It is a recombinant, humanized,
bi-specific monoclonal antibody that restores function of missing activiated
FVIII by bridiging activated FIX and FX to facilitate effective hemostasis in
patients with haemophilia A. Due to long half-life properties of emicizumab of
30 days, admistration intervals can be expanded.
The standard dose of pharmaceutical company Roche is based on body weight and
results in Ctrough levels of 50µg/mL. This does not take in account the
inter-individual differences. Based on the results of the phase I-III
studies,PK/PD studies and our own experience the current dose seems
unecessarily high. Our model showed that Ctrough levels of 30µg/mL may be
equally effective but less costly in prevention of bleeds compared to
conventional dosing. We expect that individualized pharmacokinetic-based dosing
of emicizumab with intensive monitoring of both clinical and laboratory
parameters, will lead to significant reduction of healthcare cost and improve
cost-effectiveness, without posing patients at risk of developing bleeds
Study objective
This study has been transitioned to CTIS with ID 2024-515528-35-00 check the CTIS register for the current data.
Primary objective
To determine whether individualized pharmacokinetic (PK)-guided dosing of
emicizumab is non-inferior to conventional dosing of emicizumab in the -
proportion of patients without treated bleeds (6 months before and after
intervention)
Secondary objective:
- Proportion of patients without treated bleeds (12 months before and after
intervention)
- Proportion of patients without spontaneous joint- or muscle bleeds (6 and 12
months before and after intervention)
- Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and
sports induced bleeds (6 and 12 months before and after intervention).
- To compare cost-effectiveness between conventional dosing and individualized
PK-guided dosing of emicizumab
- To assess the performance of the population PK model
- To investigate whether joint health remains stable when switching to
lower-dosed emicizumab treatment
- To investigate whether Health Related Quality of Life (HR-QoL) and sports
participation are similar in patients receiving conventional dosing compared
with PK-guided dosing of emicizumab
- To investigate whether thrombin generation parameters can be used as a
pharmacodynamic (PD) biomarker for emicizumab treatment efficacy
- To assess and monitor pain during emicizumab administration
- To assess the cumulative number of coagulation factor (sc. and/or iv.) of per
year.
Study design
DosEmi study is a multicentre, prospective, open-label, crossover study with >=6
months follow-up on conventional dosing and 12 months follow-up on PK-guided
dosing. It was designed as a non-inferiority study powered to detect a 15%
clinically relevant decrease in the proportion of patients without treated
bleeds during follow-up.The crossover design was chosen to account for
potential imbalanced baseline characteristics, which might occur at treatment
start (instable joint health).
Total study duration is 18 months. The study comprimes of 3 phases:
1. Bleeding Assesment Phase (6months): study participants remain at their
conventional emicizumab dose and register bleeds
2. PK-guided Dosing Phase (6 months): Depending on emicizumab plasma levels
during conventional dosing, a PK-profile will be generated based on a validated
maximum a posteriori Bayesian model. During follow-up, patients will be
screened for bleeds, joint status and quality of life.
3. Dose Contination Phase (6 months): During the last phase patients dose will
be continued according to previous established PK profile in the visits 1 2 or
3. In this phase dose will not be adjusted, patients will be screened for
bleeds joint status and quality of life.
In addition to the study, retrospective data collection on bleeding will be
performed 6 months prior to inclusion (Clinical Phase).
Intervention
The intervention consist of 12 months PK-guided dosing of emicizumab targeted a
a Ctrough of 30 µg/mL (± 15 %).
Based on emicizumab levels during visit 1, there a 3 groups:
Intervention group:
- Subjects with emicizumab >= 40 µg/mL: dose will be adjusted using PK-guided
dosing of emicizumab targeted at a Ctrough of 30 µg/mL
Non-Intervention group:
- Emcizumab levels 25-39 µg/mL: dose will not be adjusted and study
participants continue in follow-up
- Emicizumab levels < 25 µg/mL: dose will be adjusted. Subjects will
discontinue from the study no schedules study visits will be performed.
Subjects are followed for Selective Safety Data Collection
Study burden and risks
Study specific burden consist of:
- 1 or 2 study specific visits in treatment centre (Visit 2 and Visit 3 if
applicable); the other visits coincide with visits of standard care
- Monthly contact with researcher for bleeding registration
- Three times completetion of questionnaires (34 questions; 15min per visit)
- Blood- and urine collection at Visit 1 or 2 and 4. Blood collection volume
remains beneath maximum allowed for all ages.
- Two times joint status assesment using HJHS and ultrasound
Haemophilia patients are familair with regular blood withdrawal,
bleedingregistration, HJHS and ultrasounds.
Based on the results of phase I - III studies and our own experience, we expect
that reduction of emicizumab dose to Ctrough target levels of 30u/ml, will
cause neglegible or limited risk of increased bleeding. Study participants will
be screened for potential bleeding regulary. Furthermore there are strict
withdraw rules that have been defined, see protocol 6.4.1.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
- Confirmed diagnosis of congenital haemophilia A, with a baseline endogenous
FVIII of <6 IU/mL; - Aged > 1 year at inclusion - Receiving conventional dosing
of emicizumab (6 mg/kg/4 weeks with varying intervals) for a duration of at
least 12 months prior to inclusion; - Having good bleeding control, defined as:
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. - Willing
and able to provide written informed consent, either by the subject or its
parents/legal guardian - Willing to provide bleeding assessment information -
Willing to adhere to the medication regimen
Exclusion criteria
Acquired haemophilia A
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-515528-35-00 |
| EudraCT | EUCTR2021-004039-10-NL |
| CCMO | NL81112.041.22 |