The primary objective of this pilot study is to test logistics and gather information on possible (technical) problems that may arise during a study investigating the role of plasmin generation during ischemic stroke. Specifically, the following…
ID
Source
Brief title
Condition
- Vascular therapeutic procedures
- Embolism and thrombosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
An inventory of possible problems occurring for each of the study aspects a-d
specified under **Objectives** will be made and evaluated during and at the end
of the study, leading to a **go** or **no go** decision for a larger follow up
study. A **no go** decision will be made if problems that potentially
jeopardize the entire study could not be solved/are recurring during the pilot
study. This will be objectified by the following items that we will include in
our inventory:
a) - Patients fulfil inclusion criteria but are **missed** for inclusion in the
study (not asked by investigator, this does not include patients who do not
want to participate).
- Patients are included that should not have been included as they fulfil (one
of the) exclusion criteria.
- Complaints/questions about unclarity of inclusion/exclusion criteria received
by investigator(s).
- Transportation to/arrival at the laboratory >2 hours after blood drawal
- Mistakes in informed consent procedure, such as wrong forms were given to
patient or representative, signed forms missing/not stored properly, no
notification of investigator at the lab of inclusion patient
- Mistakes in blood drawal, for example in type and number of extra tubes drawn.
- Clinical scores are not obtained/reported by investigators.
b) Complaints from patients/representatives about e.g. lengthiness, language
used (not layman enough).
c) Partially overlapping with a (e.g. mistakes in blood drawing, logistics,
inclusion of patients), but also including: mistakes in technical handling and
processing of blood samples at the laboratory, performing tests, aliquoting and
freezing plasma for later use, administration of included patients, test
results, sample storage. Inventory will be made.
d) Equipment refers to all materials and apparatus used for the laboratory
tests, including the fluorometer for plasmin generation and thrombin
generation, the flow cytometer for platelet function testing, the STA-R
Evolution for coagulation factor measurements, the Cell Dyn Sapphire for
differential cell counts, analyzer for blood group determination, absorbance
reader for immunosorbent assays (e.g. vWF propeptide and active vWF). Samples
will be measured in triplicate for all assays except platelet function and
coagulation factor measurements, cell counts and blood group. For these assays
there is are internal controls that will aid in identifying erroneous results
as a consequence of wrong operation of the equipment. For triplicate
measurements (e.g. ELISA assays, thrombin and plasmin generation) the CV
(calculated as SD/mean *100%) will indicate whether the variation is too large
(>10%) and hence operation is inadequate.
The main laboratory outcome parameter is plasmin generation, which is described
by the following parameters (depicted in the figure below):
- Plasmin potential (PP) - total amount of plasmin generated during
fibrinolysis (this is considered the main parameter of plasmin
generation
in this study)
- Lag-time - time until start of plasmin formation
- Time to first peak (TtFpeak) * time to maximum concentration of
plasmin formed in the first phase of plasmin generation.
- Time to second peak (TtSpeak) - time to maximum concentration of
plasmin is formed on fibrin degradation products.
- Maximum concentration of plasmin * height of the first peak
(peak1).
- Velocity of first peak formation - initial rate of plasmin
formation.
Secondary outcome
Secondary laboratory parameters are:
- Directly related to plasmin:
o Clot lysis turbidity assay
o Plasminogen
o tPA
o PAI-1
o von Willebrand factor and activated von Willebrand factor
o Fibrinogen
o Plasmin-anti-plasmin (PAP)
- Not directly related to plasmin
o Platelet function test * Platelet Activation Test (PACT)
o D-dimer
o Thrombin generation (0, 1, 5 pM, 5pM+TM; before tPA and 48 hours after tPA
treatment)
Also, several clinical data will be collected in this study:
Patient related
- Date of birth (age)
- Ethnicity
- Gender
- Body weight (kg) 1
- Length (cm)
- BMI (obesity)
Therapy related
- Time to tPA treatment from arrival at the hospital
- Comedication (a.o. thrombocyte aggregation inhibitors, DOACs, other
anticoagulants) and duration of these medications.
- Dose of tPA (weight based)
- Surgery
- Occurrence of an allergic reaction to tPA (very rare)
Disease related
- Stroke severity score NIHSS 2
- modified Rankin Scale (mRS)
- Prior history of thrombosis
- Prolonged immobility
- Comorbidities
- Type of bleeding if it occurs (e.g. epistaxis, intracerebral)
- Type of recurrent thrombosis if it occurs
- Mortality at 90 days
Background summary
Acute ischemic stroke (AIS) is one of the leading causes of death and
disability across the globe [1-3]. Re-establishing perfusion through the
blocked blood vessels is most commonly achieved by pharmacologic thrombolysis
with tissue-type plasminogen activator (tPA) [4], a protease that generates the
fibrinolytic serine-protease plasmin from its inactive precursor plasminogen
[5]. Recombinant (r-)tPA, also called alteplase® or actylase®, is still the
only regulatory-approved form of fibrinolytic therapy [6]. Controversy exists
on what the optimal dose of IV r-tPA should be, as each individual is likely to
have a different level of endogenous fibrinolysis, requiring lower or higher
doses to achieve effective and safe thrombolysis. Individualized dosing of
r-tPA based on an individuals* endogenous plasmin generation is a promising way
to improve r-tPA-mediated thrombolysis in patients with stroke. We have
recently developed a plasmin generation assay. In addition, recent studies show
that plasmin can cleave von Willebrand Factor (VWF), the multimeric protein
crucial for platelet adhesion and aggregation to form the obstructive clot. We
have also developed an assay to measure this **plasmin-sensitive** VWF. The
current study serves as a pilot study to test the logistics and techniques for
a bigger study investigating the role of plasmin in clot lysis during stroke.
Study objective
The primary objective of this pilot study is to test logistics and gather
information on possible (technical) problems that may arise during a study
investigating the role of plasmin generation during ischemic stroke.
Specifically, the following aspects will be checked:
a) instructions given to investigators and technicians/nurses (i.e.
inclusion/exclusion criteria, informed consent procedure, blood draws and
transportation to the laboratory, reporting of clinical scores) are
comprehensible.
b) informed consent letter(s) is/are comprehensible and not too burdensome for
patients and their representatives
c) investigators and technicians are sufficiently skilled in the procedures.
d) correct operation of equipment
An inventory of possible problems occurring for each of these study aspects a-d
will be made and evaluated during and at the end of the study, leading to a
**go** or **no go** decision for a larger follow up study. A **no go** decision
will be made if problems that potentially jeopardize the entire study could not
be solved/are recurring during the pilot study.
Study design
Brief description of the study design:
* Prospective observational pilot study.
* Patients will be enrolled at the Gelre Hospitals Apeldoorn.
* We aim to include 29 patients of the department of neurology of the Gelre
Hospitals Apeldoorn. Patient inclusion is based on newly diagnosed stroke
patients who will be treated with tPA for thrombolysis.
* Blood (4 tubes of 3 mL) will be collected before and after tPA administration
(1 and 24 hours after)
* Clinical scores for severity of stroke (NIHSS) and degree of disability (mRS)
will be obtained before tPA treatment, at 24 hours, 1 week after tPA treatment
(NIHSS) and at 1 week and 90 days (3 months) after tPA treatment, as well as
estimated before the stroke occurred (mRS). Although this study is not
quantitative and no conclusions on relations between laboratory results and
clinical outcome can be drawn (due to small sample size), we will collect these
clinical scores to test instructions to investigators/compliance with
collecting these scores, as this may not be part of the regular routine.
* We expect the study to last for 2 years.
Study burden and risks
Potential risks: Blood samples will be obtained by venapuncture, which is a
standard procedure with minimal risks. After obtaining venous blood,
application of pressure on the site of blood drawing for several minutes
minimizes the risk of bruising. The patient might feel minor pain or be
light-headed from this or may experience some temporary discomfort and
short-term swelling at the site of a needle stick. For the first blood draw
(before thrombolysis) the patient would also experience this minor burden from
the blood draw without this study; blood will be drawn for routine patient
care, for this study only extra tubes will be drawn. The other blood draws are
extra and not part of routine care. Of note, at 1 hr after thrombolysis
prolonged pressure should be applied to the puncture site, because there is an
increased risk of developing a bruise/hematoma due to the tPA treatment.
Potential Benefits: the participating patients may benefit from the measurement
of hemoglobin at each of the time points after thrombolysis, as this can be
indicative of gastrointestinal bleeding as an adverse event of thrombolysis.
Hence, by monitoring Hb for this study this side effect may be detected
earlier. Patients do not benefit directly from results of other laboratory
measurements. However, the obtained results form the basis for a future, larger
study which may lead to safer, personalized tPA treatment based on an
individual*s plasmin generation for patients with stroke.
Group relatedness: This study cannot be performed without the voluntary
participation of the specified group of CVA patients, as we aim (in the larger,
follow up study after this pilot study) to specifically study plasmin
generation during and directly after stroke in humans in vivo. We realize these
patients may be unable to understand the nature and risks of the current study
given their medical condition; hence we will use a two-step informed consent
procedure (see paragraph 8.2) We believe that including all patients who are
able as well as those who are unable to provide informed consent themselves at
the time of hospitalization (in these cases they will only be included if a
legal representative provides informed consent for blood drawing and the
patient or legal representative provides informed consent for the use of the
data and results at a later stage after more comprehensive information) is the
only way to obtain a population that is representative for the group of CVA
patients, in terms of a.o. severity of stroke. Representativeness of the
population is important to draw conclusions that are applicable to CVA patients
and in the case of this feasibility study also to support in detecting possible
problems in logistiscs (e.g. inclusion/exclusion criteria, informed consent
procedure) for a larger follow up study. As mentioned under **potential
benefits** the group of CVA patients as a whole may eventually benefit from the
results of this explorative and the future larger study as they will lead to
improved care for CVA patients, i.e. by personalised tPA dosage that is safer
and more effective.
Albert Schweitzerlaan 31
Apeldoorn 7334 DZ
NL
Albert Schweitzerlaan 31
Apeldoorn 7334 DZ
NL
Listed location countries
Age
Inclusion criteria
- Suffering from ischemic stroke
- Indicated treatment with tPA for thrombolysis
- Age > 18 years
Exclusion criteria
- Subject presents at the Gelre Hospital Apeldoorn with stroke but send to another hospital for mechanic thrombectomy (endovascular recanalization therapy)
- Stroke onset was more than 4.5 hours ago at the time of presentation at the Gelre Hospital. This precludes treatment with tPA, according to clinical practice guidelines, independent of the study protocol.
- Previously documented coagulation defects
- Age < 18 years
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 | NL63483.068.17 |