Two main research questions:- improving the knowledge of the pathofysiologic mechanisms of immune tolerance induction (ITI)- determining what type of factor VIII product (based on pathophysiology and an in-vitro model of ITI) is the most effective…
ID
Source
Brief title
Condition
- Coagulopathies and bleeding diatheses (excl thrombocytopenic)
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Immunologic analysis with a comparison between patients with and without
inhibitor:
* Amount and phenotype of FVIII specific B-cells, ie B-naïve, B-memory, B
plasma cell.
* Amount of regulatory B-cells
* Amount of myeloid derived suppressor cells (MDSCs)
* Amount and phenotype of FVIII specific CD4-cells (T-cells), ie T effector vs.
T regulator.
* Activation and proliferation status of CD4+ T-cells
* Function of regulatory T-cells
* Amount and type of FVIII antibodies
* Cytokine production (pro- versus anti-inflammatory)
With the abovementioned analyses we will test what will cause tolerance, i.e.
on one side the elimination or absence of FVIII-specific effector B- and
T-cells or on the other hand the induction of regulatory cells (regulatory B-
and T-cells and MDSCs). Moreover some functional assays will be performed to
evaluate not only differences in quantity, but also possible differences in the
function / quality of effector and regulatory T-cells,
Finally the role of pro- vs. anti-inflammatory cytokines will be evaluated
(which is also indirectly related tot the ratio between pro-inflammatory and
regulatory cells).
Secondary outcome
- Creating an in-vitro human model of ITI and testing different factor VIII
products with regard to their potency to generate an inflammatory or more
tolerogenic respons
* Co-culture of CD4+ T-cells (naive or FVIII-specific) with B-LCL (EBV
immortalized B-cells, acting as antigen presenting cells) and addition of
different types of FVIII producs
* After 24 hours measurement of T-cell response:
1) Amount and subtype of CD4+ T-cells (effector vs. regulatory T-cells)
2) T-cel activation and proliferation status
3) Cytokine profile (pro- vs. anti-inflammatory)
Background summary
The most serious complication in the treatment of hemophilia A is the
development of so called *inhibitors*, inhibitory antibodies against factor
VIII, which occurs in almost 30% of all patients with severe Hemophilia A1. As
a consequence of this inhibitor formation traditional replacement therapy
becomes ineffective, making it necessary to switch to alternative hemostatic
therapies by using bypassing agents, which are less efficient, more costly and
moreover require a lot of intravenous injections because of a very short
half-life. This all causes a high morbidity and negatively influences patients*
quality of life.
The therapy to eliminate inhibitors is the so called 'Immune tolerance
induction' (ITI), a therapy which is characterized by frequent administration
of factor VIII with the objective of inducing tolerance. This treatment is
succesful in approximately 2/3 of all patients. However the workingmechanism is
largely unknown and moreover many different protocols are used, for example
with different doses of factor VIII en different factor VIII products.
Since hemophilia A is still a relatively seldom disease it*s not easy to
perform large randomized controlled trials. Instead many information is derived
from case reports, case series and retrospective cohorts. In-vitro studies can
provide important additional information, especially with regard to
pathophysiologic mechanisms.
This study is aimed at gaining a better understanding in the pathophysiologic
mechanisms of ITI and determining what would be the optimal fVIII concentrate
to use. Since the high burden of inhibitors in hemophilia A and also the high
costs and intensity of ITI this is essential information for further improving
the treatment of hemophilia A.
Study objective
Two main research questions:
- improving the knowledge of the pathofysiologic mechanisms of immune tolerance
induction (ITI)
- determining what type of factor VIII product (based on pathophysiology and an
in-vitro model of ITI) is the most effective during ITI
The objective of the study is optimization of ITI, so that this treatment
becomes more successful, less stressful for patients and possibly also less
costly.
Study design
Cross-sectional single-center observational study.
Study burden and risks
The extent of the burden and risks associated with participation are different
between adults and children.
Adults:
Participation of the study will mean one venipuncture, with the withdrawal of
54 ml blood. If possible, this venipuncture will be combined with a regular
outpatient visit and with a regular venipuncture.
Risks of the venipuncture are formation of a small, local hematoma and
pain/discomfort. If the puncture is combined with a regular venipuncture the
additional burden will only be the withdrawal of a larger amount of blood than
normally. Since it is still a small amount of blood the risks of anemia or
dizziness/hypotension will be considered negligible.
Children:
For children participation of the study will always be combined with a regular
outpatient clinic visit en scheduled venipuncture. The extra burden due to
participation of the study will therefore only consist of the withdrawal of
more blood (22 ml) than normally, without any extra invasive procedures. Since
the very small amount of blood that will be taken extra, we consider the risks
of this (for example anemia or hemodynamic consequences) negligible.
Lundlaan 6
Utrecht 3584 EA
NL
Lundlaan 6
Utrecht 3584 EA
NL
Listed location countries
Age
Inclusion criteria
- Age: 6 years and older
- Previously confirmed Hemophilia A
- Previously and frequently (> 50 ED) treated with factor VIII
- Willing and be able to understand the study information and sign the informed consent form;Different subgroups:
* 10 adults with an inhibitor (5 patients with mild or moderate hemophilia A, 5 patients with severe hemophilia A)
* 10 adults without an inhibitor after successful ITI
* 20 patients (10 adults, 10 children age > 6 years) without an inhibitor and without a history of ITI
Exclusion criteria
- Documented history of persisting severe anaemia (defined as haemoglobin <6.0 mmol/L for men and women)
- Other haematologic or immunologic comorbidity
- Recent (< 3 months) or actual use of immunosuppressive drugs (< 9 months for rituximab, < 3 months for other immunosuppressive drugs)
- Active infection at the moment of blood withdrawal
Design
Recruitment
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 |
|---|---|
| CCMO | NL60611.041.17 |