Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01965717 |
| Other study ID # |
KVEH KCS |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
October 15, 2013 |
| Last updated |
April 6, 2018 |
| Start date |
July 2012 |
| Est. completion date |
December 2017 |
Study information
| Verified date |
April 2018 |
| Source |
University of Belgrade |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Endovascular procedures already brought enormous revolution in the process of treatment of
patient with abdominal aortic aneurysm (AAA). It is well defined that early mortality and
morbidity is significantly reduced comparing to open repair. The persistent concern is long
term durability of devices and their success of aneurysm exclusion in order to prevent
rupture. At the moment the best armament to prevent rupture after endovascular exclusion is
the watchful waiting and timely reintervention. The main complication that follows this
procedure and causing catastrophic long term complications is endoleak. The ideal algorithm
to follow up patients after aneurysm exclusion has not been found. In order to reveal
endoleak ultrasound is used more than before, however frequent computerized tomography is
wasting a lot of costs and exposing patients to irradiation and nephrotoxic contrast.
Matrix metalloproteinase activity has been demonstrated in the process of aneurysm
development. Imbalance between MMP and its inhibitors TIMP provokes collagenolytic and
elastolytic activity that is inducing aneurysmatic degeneration of aortic wall. Due to the
previously described connection between aneurysm and MMP activity, it was proved that serum
level of MMP-9 is significantly higher in patients with abdominal aortic aneurysm (AAA).
Also, higher levels of MMP-9 were discovered in patients with inadequate aneurysm exclusion
after endovascular procedure suggesting that degradation of the aortic wall is still ongoing
process, not being the case with successfully excluded aneurysm. There might be a potential
role of MMP-9 serum level as a biomarker of present endoleak after endovascular aneurysm
exclusion.
All published trials have shown correlation between MMP 9 activity and presence of endoleak,
however, no correlation was made between specific types of endoleak and necessity to
reoperation (clinical significance). Additionally there were only four trials presented in
the literature investigating low number of patients.
Since there is possible value of MMP-9 serum level as biomarker of present endoleak, further
studies are necessary. This why we are organizing multicentre trial, that will cover
significant number of patients in order to define
- Value of MMP-9 as a biomarker of successful initial exclusion
- Value of MMP-9 level as predictor of aneurysm shrinkage
- Value of MMP-9 level in patients with increased aneurysm diameter and no visible
endoleak
- Correlation of the MMP -9 serum level with different type of enoleak
- Value of MMP-9 as biomarker of successful treatment of endoelak
Material and methods Patient with AAA greater then 55 mm in diameter that are candidates for
endovascular repair will be selected. Demographic, anatomical and data regarding the
procedure will be gathered prospectively. Also serum levels of MMP-9 will be measured before
procedure, during the first week before discharge, and after 1,6,12,18,24,36,48 months. On
the same day of measuring MMP-9 level control MSCT and ultrasonography exam will be performed
in order to collect data regarding the success of exclusion and presence of any endoleak with
the accurate measurement of aneurysm diameter changes. Ultrasonography and MSCT exam will be
performed by experienced physicians, also preoperative evaluation of anatomical data.
In case of reintervention additional questionnaire will be filled regarding anatomical and
procedure related data using pre and postoperative ultrasound and MSCT examination, while
MMP-9 levels will be measured before procedure and after the procedure using the same
protocol as for primary procedure.
Statistical analysys Levels of MMP-9 in serum with presence of different types of endoleak
will be correlated one week and 1,6,12,18,24,36 48 months after the procedure Anatomical data
will be correlated with the decrease in MMP-9 level before and after procedure Levels of
MMP-9 in serum after one week and one month will be correlated with further aneurysm
shrinkage Level of MMP-9 in serum with type of endoleak will be correlated Level of MMP-9
before and after reoperation will be compared Level of MMp-9 in serum of patients with
disappearing endoleaks will be followed Level of MMP-9 in serum of patients with new
endoleaks will be followed
Description:
1. Summary
Endovascular aortic aneurysm repair (EVAR) provides low early mortality and requires
intensive follow up of the patients in order to prevent rupture as a consequence of
endoleak. Follow up protocols are changing with time differing between the hospitals and
even the physicians. Ultrasonography (US), contrast enhanced ultrasonography,
multisliced computed tomography (MSCT) and native radiography are most frequently used.
All these techniques are combined in order to compensate their lacks and disadvantages.
The new methods for early detection of endoleak should improve this cumbersome follow up
process.
Matrix metalloproteinase (MMP) activity has been demonstrated in the process of aneurysm
development. Higher level of MMP-9 were discovered in patients with inadequate aneurysm
exclusion after endovascular procedure suggests that degradation of the aortic wall is
still ongoing process and that there might be a potential role of MMP-9 serum level as a
biomarker in endoleak detection.
Aim of this study is to explore the serum levels of MMP - 9 in patients treated with
endovascular aneurysm repair and to provide some more profound information regarding
its' correlation with different types of endoleak.
Patients treated with EVAR will be followed for at least one year. During five visits,
with first preoperative, then on discharge, and after one, six and twelve months,
patients will be examined by means of US and MSCT. During the same five visits serum
levels of MMP -9 will be measured and correlated with different levels of aneurysm
exclusion. Collected anatomical, demographic data of the patients and intraoperative
data related to the technical success of the procedure will provide subgroup of patients
with higher correlation between the aneurysm exclusion and serum level of MMP -9. The
primary outcome measure is the serum levels of the MMP - 9 at one, six and twelve months
after treatment and its relation with anatomical, demographic and procedure related
data. Clinical outcome events include different types of endoleak. The secondary outcome
is the correlation of different types of endoleak with the serum levels of the MMP - 9.
This study is designed to be multicentre and to recruit 150 patients over a 24-month
period. Leading center is Clinic for Vascular and Endovascular Surgery of the Serbian
Clinical centre. Participating center should be able to perform EVAR, follow up patient
with US and MSCT for four times in the first year and to detect serum levels of MMP - 9.
All analysis will be performed individually by participating centre encouraged to use
same techniques as the leading center. Individual experience of collaborators in the
participating centre will be recorded before their inclusion in the study.
2. Background
Endovascular procedures already brought enormous revolution in the process of treatment
of patient with abdominal aortic aneurysm (AAA). It is well defined that early mortality
and morbidity is significantly reduced comparing to open repair. The persistent concern
is long term durability of devices and their success of aneurysm exclusion in order to
prevent rupture. At the moment the best armament to prevent rupture after endovascular
exclusion is the watchful waiting and timely reintervention. The main complication that
follows this procedure and causing catastrophic long term complications is endoleak. The
ideal algorithm to follow up patients after aneurysm exclusion has not been found. In
order to reveal endoleak ultrasound is used more than before, however frequent
computerized tomography is wasting a lot of costs and exposing patients to irradiation
and nephrotoxic contrast.
Matrix metalloproteinase activity has been demonstrated in the process of aneurysm
development. Imbalance between MMP and its inhibitors TIMP provokes colagenolitic and
elastolytic activity that is inducing aneurysmatic degeneration of aortic wall. Due to
the previously described connection between aneurysm and MMP activity, it was proved
that serum level of MMP-9 is significantly higher in patients with abdominal aortic
aneurysm (AAA). Also, higher levels of MMP-9 were discovered in patients with inadequate
aneurysm exclusion after endovascular procedure suggesting that degradation of the
aortic wall is still ongoing process, not being the case with successfully excluded
aneurysm. There might be a potential role of MMP-9 serum level as a biomarker of present
endoleak after endovascular aneurysm exclusion.
All published trials have shown correlation between MMP 9 activity and presence of
endoleak, however, no correlation was made between base levels and specific types of
endoleak and necessity to reoperation (clinical significance). Additionally there were
only four trials presented in the literature investigating low number of patients
1,2,3,4.
3. Aims of the trial and hypothesis
The basic research question is whether the level of MMP -9 is changing after endovascular
aneurysm exclusion and what is the curve of the level of active MMP-9 concentration in the
first year after the procedure. We hypothesize that the level of MMP-9 active concentration
should decline, however it might be dependent on some other factors.
Secondary research questions are:
1. What is the role of pre-treatment serum levels of the MMP - 9 in patient with AAA? We
hypothesized that pre operative serum levels of the MMP - 9 should be predictor of its
sensitivity in endoleak detection in the postoperative follow up.
2. What is the role of the serum levels of the MMP - 9 as a biomarker of the early
successful aneurysm exclusion? We hypothesize that the serum levels of the MMP - 9 in
the early postoperative time (first week and one month) could be biomarker of successful
aneurysm exclusion
3. What is the role of the serum levels of the MMP - 9 in differentiating the types of
endoleak? We hypothesized that different serum levels of the MMP - 9 could be found in
patients with different types of endoleak.
4. What is the role of the serum levels of the MMP - 9 after reintervetion due to a present
endoleak? We hypothesized that the levels of endoleak should decline after successful
re-treatment
5. What is the role of the serum levels of the MMP - 9 as a predictor of aneurysm sac
enlargement? We hypothesized that the serum levels of the MMP - 9 in the early
postoperative time (up to one month) could correlate with sac enlargement in patient
with no visible endoleak .
4. Study design 4.1. Patient enrollment and data collection The BIOLEAK study is designed to
become multicentre study. The minimum requirement for participation of a center in this study
is to perform EVAR procedures, and to have laboratory capable of the serum levels of the MMP
- 9 analyses. Center agreeing to collaborate should follow up patients with MSCT and
ultrasound for minimally four times in the first year and then at least once yearly
thereafter. In the same time with these follow up exams serum levels of the MMP - 9 should be
measured. The preferable method of the measurement is given below; however, every center is
encouraged to participate in the trial by using its own available method with previous
notification and confirmation by the leading center.
All study participants will undergo 5 ultrasound and 5 MSCT exams in the first year of
participation. Both MSCT and ultrasound should be performed before procedure, before
discharge after the procedure, one, six and twelve months after the procedure. All
preoperative anatomical and postoperative control images and ultrasound assessment should be
performed by the most experienced stuff of the collaborating center. Ultrasound assessment
should be made by Color duplex technique, widely used. MSCT image assessment should be made
using the post processing techniques and center line analysis. Control MSCT exams should be
made according to the protocol of the participating center.
Blood samples to determine serum levels of the MMP - 9 as a biomarker of the aneurysm
exclusion should be obtained at five time points in the first year and analyzed individually
in the laboratory of the participating center: 1- 3 days before treatment, 2-7 days after
treatment, one, six and twelve months after treatment. Blood sample should be taken on the
same day when performing ultrasound and/or MSCT exam. Minimum requirements for participating
in the trial is to measure serum levels of the MMP - 9, however participating centre could
also include in the analysis: matrix-metalloproteinases and inhibitors (MMP-1,2,3,7,10,
TIMP-1). The analyzed method should be according to the capabilities of the participating
centre, while the leading center Clinic for Vascular and Endovascular Surgery of the Serbian
Clinical Centre will be measured serum MMP-9 levels with Fluorokine E (Human Active MMP-9
Fluorescent Assay). The process of material collection and storage was suggested by producer
(R&D Systems).
Venous blood will be drawn via an antecubital vein puncture and collected in Heparin buffered
vacutainer for plasma. Exactly 30 min after collection, blood will be centrifuged (15 min,
1000 g, 4C) and multiple aliquots will be stored at exactly 1 h after collection at < - 20 C.
One sample more from every visit should be stored for at least 12 months for additional
analysis if necessary.
Preoperative, discharge and one month follow up samples of each patient will be measured at
the same time identically in order to have same calibration and reagent.
For the collaborating centers: Usage of the same process of collecting and storing samples as
well as calculating the results will contribute to the quality of results. However, this is
optional condition for participating in the study and all the centers should used their own
methods while the leading center should be informed about the differences in this process.
4.2. Detailed description of the data collection
Patient with inclusion criteria will be selected and after signing consent form will be
included in the trial. Treating physician will report selected patient by filling the
inclusion form and demographic data form and sending it to the leading center.
INCLUSION FORM should be filled and sent to the trial center together with DEMOGRAPHIC DATA
FORM via fax (+381113065177). This form will include basic anatomical information regarding
the patient anatomy related to the success of the procedure. All data related to the
anatomical features of the treated aneurysm should be assessed by operating surgeon or
radiologists, or experienced member of the team, by using center line analysis software.
Extension of the aneurysm process should be defined according to the planned LZ location in
the iliac zone. Collateral vessels that are patent and greater than 1 mm in diameter should
be counted using the imaging detailed analysis. We are assuming that the number of collateral
vessels could influence the levels of MMP -9 in the postoperative and follow up time. Surely
the number of these vessels could influence the rate of endoelak type II. When filling the
form "inferior mesenteric artery" should be round off or marked with "X", while the number of
patent lumbal, hypogastric or accessory renal arteries that are going to be excluded should
be stated in the blank line. Neck diameter should be measured in the inner to inner fashion,
while in case of non cylindrical neck the greatest value should be stated. Aneurysm length
should be measured from the lower renal artery to the distal end of the LZ, for the both,
left and right side. Neck length is defined only as a length of the fixation zone and not the
whole neck, which in case of long conical necks might be different. Neck configuration should
be assessed by center line analysis and one of the offered configurations should be chosen.
It is important to differ cylindrical from non cylindrical necks. Neck angulations with
suprarenal aorta and aneurysm sack should be measured separately. Parietal thrombus and
calcification should be expressed in percentage of the circumference and the greatest
thickness diameter should be stated. Greatest aneurysm diameter, narrowest aortic lumen and
lumen of the aorta at the level of bifurcation should be expressed in mm. Common iliac artery
diameters should be measured in three levels, the initial, middle and the distal part at the
level of iliac bifurcation, and should be expressed in mm. Iliac angulations should be
measured between the aneurysm and proximal iliac center line. Name hospital and email of the
corresponding physician should be stated at the end of the INCLUSION FORM.
DEMOGRAPHIC DATA FORM should be sent together with INCLUSION FORM. The presence of co-morbid
conditions should be noted in this form, together with age, sex, previous surgical procedures
and active medical therapy.
After sending these forms, patient will be included in the study on the intention to treat
basis and corresponding physician will be informed about the PATIENT INCLUSION NUMBER. The
procedure should be planned the sooner the better.
PROCEDURE FORM should be filled to a certain extent after the procedure and the second part
on the discharge day. Date of the procedure and patient inclusion number should be stated.
Inclusion number will already sent by email from the trial center (Clinic for Vascular and
Endovascular Surgery, Serbian Clinical Center). Name of the operating surgeon and his
assistant should be stated. The configuration of the stent graft chosen and implanted should
be stated in the named rows (proximal stent graft diameter, distal stent graft diameter).
Number of used extensions should not count body and contralateral limb as a necessary
minimum, while aorto-uni configuration should be confirmed with "yer" or "no". All additional
procedures performed in order to reduce the endoleak rate should be marked. If any additional
are performed it should be stated in the column left for comments. Intraoperative control
angio after performing total procedure should be made as common in the collaborating center,
and the result should be assessed by operating surgeon. If there is uncertainty with endoleak
type II it should be marked as probably. If operating surgeon is certain, it should be marked
as obvious. Other measures to reduce the endoleak probability after performing control angio
should be marked. The result of the angio after additional measures is not supposed to be
included in the procedure form, however if there are any comments they should be stated in
the column left for comments. On the discharge day all intrahospital postoperative
anticoagulant therapy should be noted, complications, outcome, additional procedures and
length of hospital stay.
FOLLOW UP FORM is designed to have data related to ultrasonogrpahy, MSCT follow up exams and
serum levels of MMP -9 at the all five planned visits in one place. However, since the
process of calculating serum levels of MMP-9 usually requires storing and gathering samples
until complete kit box can be used, it may cause delay in follow up completion. Additionally
results of the one month follow up will be objective of the interim analysis. For these
purposes, it is necessary to send this form via fax two times. First time is after completing
results for the preoperative, on discharge and one month follow up serum levels of MMP - 9
with ultrasound and MSCT analysis. Second time is when complete data for the one year follow
up are collected. During all this time this form and all others should be kept with all other
forms in the patients official medical documents.
4.3. Flow chart
Five study visits will be done in each patient in the first participating year as showed in
the following flow-chart.
MMP9 ULTRASONOGRAPHY MSCT PREOPERATIVE X X X ON DISCHARGE (2-7 days) X X X ONE MONTH X X X
SIX MONTHS X X X ONE YEAR X X X For the purposes of central data collection, all four data
forms should be sent via fax to the Clinical for Vascular and Endovascular Surgery, of the
Serbian Clinical Centre, +381 11 30565177.
4.4. Outcome measures The primary outcome measure is the serum levels of the MMP - 9 at one,
six and twelve months after treatment and its relation with anatomical, demographic and
procedure related data. Clinical outcome events include different types of endoleak. The
secondary outcome is the correlation of different types of endoleak with the serum levels of
the MMP - 9.
5. Safety aspects
The present study is a purely observational study and is not associated with any clinical
risk for complications after edovascuar aneurysm repair. About 30 ml of blood in total will
be drawn for serum analysis during all five visits in the first year. Ultrasound and MSCT
imaging methods are non-invasive techniques that are part of regular follow up after
endovascular aneurysm repair.
6. Statistical Analysis and sample size
6.1. Sample size justification and statistical methods The present study aims to enroll 150
patients from different high-volume centers over a recruitment period of 2 years. The serum
levels of the MMP - 9 will be compared between patients and between the different visits
using logistic regression models. Interactions between MMP - 9 levels and different types of
endoleak will be investigated in subgroup analyses. Also interaction between anatomical data,
demographic and procedural data with serum levels of the MMP - 9 , aneurysm sac size and
presence of endoleak will be analyzed.
6.2. Interim analysis An interim analysis will be performed after completing one month follow
up of first 30 patients in order to check the serum levels of the MMP - 9 and its calculation
difficulties - if any.
7. Ethical considerations
Ultrasound and MSCT examinations detailed in the protocol are part of the routine clinical
work-up in patients before and after EVAR without any known side effects in patients without
contraindications. With the exception of blood sampling, no invasive examinations are made.
Identifying the benefit of the serum levels of the MMP - 9 as a biomarker of endoleak could
contribute to better detection of endoleak and reduce costs and efficacy of the follow up. It
will support selection of different follow up protocols on the individual basis for every
patient.
Participation in the BIOLEAK study is completely voluntary. Eligible patients are informed
about the study by investigators and will be given written patient information. Patients
willing to participate are required to provide written informed consent to participate. Study
participants retain the right to withdraw their consent to participate at any time after
initial consent was given, without any consequences for clinical management and standard of
care received. If a patient withdraws consent or not willing to participate during the
process of follow up (rejecting blood sampling or repetitive MSCT or ultrasound exam),
available data should be used in the overall analysis.
8. Study management 8.1. Study management and participating centers This study is led by the
Clinic for Vascular and Endovascular Surgery of the Serbian Clinical Center (lead
investigator Prof Dr Lazar Davidovic). Its Serbian phase is a part of the scientific research
project (No 175008) supported by the Ministry of Education and Science of the Republic of
Serbia. Collaborating centres are in the process of entering the study at the moment.
All centers performing endovascular exclusion of the infrarenal abdominal aortic aneurysms
with available imaging, ultrasonographic and laboratory facilities are invited to join this
trial. Physicians that enroll patients into the BIOLEAK study will act as co-investigators
and participate as authors in resulting publications. Center willing to participate will
apply by filling the COLLABORATING CENTRE TRACK RECORD and sending it to the leading
investigator - Prof Dr Lazar Davidovic at davidovic.lazar@gmail.com . In this form it is
possible and encouraging to state multiple operators, ultrasonographers and MSCT reading
physicians.
This is an investigator-initiated trial. The lead investigator and co-investigators will have
unrestricted access to the data. The local investigators at the participating centers will
meet with the lead investigator and co-investigators on a regular basis to discuss progress
of recruitment and assess the quality of the acquired data. The lead investigator,
co-investigators, the local ethics committee or any other supervisory body may audit or
inspect the local study sites at any time. Data steering committee will be formed once this
study becomes a multicentre.
8.2. Data storage and protection Documentation of the data of every study participant will be
done by completing electronic forms and sent via fax to the BIOLEAK study center at the
Clinic for Vascular and Endovascular Surgery of the Serbian Clinical Center. Blood samples
will be separately analyzed in every participating center where will be stored and kept under
the local regulations. If consent is withdrawn at any time after study entry, any blood
samples obtained from the patient should be destroyed. Any results obtained from the analysis
of those samples before consent was withdrawn may be used for research purposes.
