Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05545085 |
| Other study ID # |
NL82338.099.22 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
November 1, 2022 |
| Est. completion date |
September 1, 2023 |
Study information
| Verified date |
January 2023 |
| Source |
Medical Centre Leeuwarden |
| Contact |
E.C. Boerma, MD/PhD |
| Phone |
+31-58-2866738 |
| Email |
christiaan.boerma[@]mcl.nl |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Rationale Lung cancer remains to be the leading cause of cancer-related deaths worldwide1.
The current standard-of-care for small lung cancer is a total lobectomy. Albeit effective
with respect to the radical excision of the tumour, the substantial loss in lung tissue may
be clinically relevant, especially in combination with frequently co-existing lung diseases.
Thoracoscopic segmentectomy is a combination of adequate oncological resection with
lung-tissue-sparing properties and is being increasingly used because of its several
advantages compared with lobar resections. By defining the segment that has to be excised
pre-operatively, the key to successful pulmonary segmentectomy is to subsequently
intraoperatively recognize the intersegmental planes correctly. The conventional and most
common method uses a ventilation method (inflation/deflation technique). With the increasing
availability of endoscopic imaging systems, indocyanine green (ICG) fluorescence imaging is a
more advanced method to determine intersegmental planes. The major limitation is the use of
an exogenous contrast agent. After injection, the ICG only has very limited "imaging time
window" (minutes) in which the images can be used to determine the intersegmental planes.
Furthermore, the use of dye limits repeatability of measurements due to rest ICG, the extra
operating room time required for the injection, wash-in and wash-out of the dye as well as
change of camera settings. These limitations leave room for new technologies and
improvements. The investigators hypothesized that an endoscopic laser speckle imaging device
could overcome the limitations of ICG-fluorescence imaging and could thus be a very useful
addition in intersegmental plane detection. PerfusiX-Imaging (LIMIS Development BV,
Leeuwarden, The Netherlands) is such an endoscopic laser speckle contrast imager that has
been developed in the Medical Centre Leeuwarden since 2014. LSCI has never been used to
identify intersegmental planes, however, based on the similarities between LSCI and
ICG-fluorescence, this novel imaging approach is thought to be effective and potentially
could be used as a standard-of-care.
Objectives In this trial the investigators will study the utility of PerfusiX-Imaging for the
identification of intersegmental planes during thoracoscopic segmentectomy.
Study design The current study is a prospective, observational single-centre study in the
Medical Center Leeuwarden.
Study population A total of 10 patients undergoing an upper left or right lobectomy. Patient
related study procedures All patients will undergo the standard-of-care program which
includes perfusion assessment by ICG-fluorescence imaging. In addition to this
standard-of-care, 2D-perfusion maps will be generated from images taken with PerfusiX-Imaging
(LIMIS Development BV, Leeuwarden, The Netherlands). Not related to the patient, the
PerfusiX-Imaging images will be shown to the surgeon postoperatively and peroperative
questionnaires will be filled regarding the standard-of-care perfusion assessment.
Study parameters/endpoints Due to the explorative character of this study, there is no formal
hierarchy in the respective endpoints of this study. In this, all endpoints will add to the
overall assessment of the feasibility of the PerfusiX-imaging derived visual feedback for
detecting interlobar and intersegmental planes in lung tissue. The investigators will
register whether it was possible to detect the intersegmental plane. Subsequently, compare
the difference in location of both the interlobar and intersegmental planes as derived from
visual feedback from the PerfusiX-imaging system is compared, with images derived from ICG
imaging and the surgical eye. During the procedure, the time needed to generate and acquire
the visual feedback from the PerfusiX-imaging system will be determined. The investigators
will also determine the interpretability of the visual feedback from the PerfusiX-imaging
system by users (surgeons). In addition, the investigators will determine Laser Speckle
Perfusion Unit (LSPU) cut-off values of PerfusiX-imaging in lung tissue with the best
sensitivity and specificity for the indication of level of tissue perfusion.
Burden, risk and benefit to participation Burden Not applicable. Risks Not applicable.
Benefit Not applicable.
Description:
INTRODUCTION AND RATIONALE 1.1 General introduction Despite recent major improvements in
diagnosis, staging and treatment, lung cancer remains to be the leading cause of
cancer-related deaths worldwide. Since the demonstration of superiority over sublobar lung
resection, the current standard-of-care for small lung cancer is a lobectomy. In a lobectomy,
one of the three (right lung) or two (left lung) lobes is excised. Albeit effective with
respect to the radical excision of the tumour, the substantial loss in lung tissue may be
clinically relevant, especially in combination with frequently co-existing lung diseases.
This is made possible due to high resolution medical imaging (computed tomography) that
enables surgeons to precisely locate small tumors. This paved the way for segmentectomy.
Thoracoscopic segmentectomy is a combination of adequate oncological resection with
lung-tissue-sparing properties and is being increasingly used because of its several
advantages compared with lobar resections. Local recurrences after surgical resection are
correlated to the length of the safety margins. These margins are defined by guidelines (2 cm
for tumours >2 cm or a margin that is at least as large as the tumour diameter for smaller
lesions). By defining the segment that has to be excised pre-operatively, the key to
successful pulmonary segmentectomy is to subsequently intraoperatively recognize the
intersegmental planes correctly. Although the intersegmental plane is regulated by
intersegmental veins, it would be impossible to detect and follow these veins in the distal
lung parenchyma, therefore, it is mandatory to identify the intersegmental plane before
dividing the lung parenchyma.
1.2 Intersegmental plane detection methods The conventional and most common way to
intraoperatively identify the intersegmental plane uses a conventional ventilation method
(inflation/deflation technique). The targeted segment may be isolated from the rest of the
lobe by selectively inflating the residual segments leaving the target segment atelectatic
or, on the contrary, may be selectively inflated leaving the rest of the lobe atelectatic. A
limitation of this method is the limited space to manoeuvre during video-assisted surgery.
More recently, optical imaging-based image guided surgery approaches are being developed to
intraoperatively identify the intersegmental planes. With the increasing availability of
endoscopic fluorescence imaging systems comes the popularity of fluorescence imaging
throughout all surgical fields. This led to the development of methylene blue for
intersegmental plane identification. However, the most common approach is the use of
indocyanine green (ICG) fluorescence imaging. ICG-fluorescence imaging is based on the
excitation of ICG, which is an exogenous contrast agent that is intravenously injected. The
ICG binds to blood proteins that starts to circulate and gets excreted via the liver.
The ICG enables the surgeon to clearly identify the intersegmental planes after ligation of
the main feeding artery. This method shows great potential but comes with limitations. The
major limitation is the use of an exogenous contrast agent. After injection, the ICG only has
very limited "imaging time window" (minutes) in which the images can be used to determine the
intersegmental planes. In practice, this means that the surgeon quickly marks the
intersegmental plane using an energy device. In an ideal situation the surgeon has as long as
required for this action. Furthermore, the use of dye limits repeatability of measurements
due to rest ICG, the extra operating room time required for the injection, wash-in and
wash-out of the dye as well as change of camera settings.
1.3 Laser speckle contrast imaging for intersegmental plane detection ICG fluorescence
imaging is a perfusion imaging technique that can help identify the intersegmental plane
based on a perfusion difference that is created by ligation of the main feeding artery of the
segment of interest. After ligation, ICG is infused. The distribution of ICG is visualized on
the monitor, using a near-infrared camerasystem. The isolated segment will not exhibit any
fluorescent signal and will therewith be identifiable using ICG. Laser speckle contrast
imaging (LSCI) is a perfusion imaging technique that seems to have similar use cases as ICG
with the added advantage of not using exogenous contrast. LSCI. The first biomedical
application of LSCI was reported in the 1981 by Fercher and Briers. The proposed technique
from Fercher and Briers was non-real-time and had its practical limitations due to the use of
non-digital systems which impeded the clinical use. The first real speed increase to quasi
real-time image acquisition and processing happened in the nineties with the introduction of
digital photography. Generally, the components required are a low-powered laser diode, a
diffuser, a digital camera and processing software.
The investigators hypothesized that an endoscopic laser speckle imaging device could overcome
the limitations of ICG-fluorescence imaging and could thus be a very useful addition in
intersegmental plane detection. PerfusiX-Imaging (LIMIS Development BV, Leeuwarden, The
Netherlands) is such an endoscopic laser speckle contrast imager that has been developed in
the Medical Centre Leeuwarden since 2014. LSCI has never been used to identify intersegmental
planes, however, based on the similarities between LSCI and ICG-fluorescence and their
capability to visualize differences in tissue perfusion,, this novel imaging approach is
thought to be effective and potentially could be used as a standard-of-care.
1.4 The basic principle of laser speckle contrast imaging Speckle patterns are the random
interference patterns that arise when coherent light is backscattered by a scattering medium
such as biological tissue. The slightly different optical pathlengths cause the waves to
reach the observer at random mutual phases, resulting in bright and dark spots respectively.
The speckle image is built up of static and dynamic speckles. Static speckles are speckles
that do not change over time whereas dynamic speckles do change over time due to the optical
Doppler effect. The dynamic speckles contain information about movement of the object, or
motion of particles within the object.
In order to be able to detect a change in the speckle pattern, the exposure time of the
camera must be of the order of the speckle decorrelation time, causing a blurring of the
recorded speckle pattern. It is this blurring that is used to calculate the speckle contrast
K using the following formula:
K=σ/() Where σ is the standard deviation of the intensity I over the mean intensity
calculated over a window in space or time. Spatial contrast uses an area of multiple pixels
in one frame as can be seen in the bottom left corner of Figure 4. A window size of 5 x 5 or
7 x 7 pixels has been suggested for optimal results10. As spatial contrast decreases the
spatial resolution, however, this method does have a high temporal resolution. Temporal LSCI
uses the same pixel in multiple frames to calculate the contrast in a time window. Temporal
contrast has a high spatial resolution and low temporal resolution. For spatial contrast this
is vice versa and hence, it can be beneficial if combined into a so-called spatio-temporal
contrast. The choice of resolution should be based on the need for a high temporal or spatial
resolution.
If the exposure time of the detector is shorter than the intensity fluctuation time of the
speckles, the standard deviation σ is equal to the mean intensity which theoretically
results in a contrast value of K=1. If there is movement present and the exposure time of the
detector is of the order of, or longer than the fluctuation time, the picture will be blurred
meaning that the standard deviation σ will be small compared to the mean intensity which
results in a loss of contrast, hence 0≥K<1. Other names for the same principle as LSCI are
laser speckle imaging (LSI), laser speckle perfusion imaging (LSPI) and laser speckle
contrast analysis (LASCA) as it was named by the first users.
1.5 Rationale for the PORTION-I study The investigators hypothesize that PerfusiX-Imaging can
help improve intersegmental plane identification during thoracoscopic segmentectomy. The
current intraoperative identification of intersegmental during segmental resections is based
on subjective clinical indicators, i.e., the surgeon's eye and ICG-fluorescence imaging.
ICG-fluorescence imaging is deemed a substantial improvement over solely the surgeons' eye,
however, this approach comes with several limitations. The most important is the short
effective imaging period which means that the surgeon only has a very limited amount of time
to mark the intersegmental planes. Moreover, by using PerfusiX-Imaging, the surgeon does not
have to deal with a short effective imaging period. This enables real-time identification of
the segment, without the need of marking the planes with an energy device. In this
prospective, observational feasibility study, the investigators aim to determine whether
PerfusiX-Imaging is capable of successfully identifying lung segments. As there are no
segmental resections performed in the Medical Centre Leeuwarden at this moment, the
investigators will image the interlobar plane during an upper left or right lobectomy in 10
patients. Also, the investigators will image the sublobar segment in these patients during
preparation for the lobectomy.
3. STUDY DESIGN The current study is a prospective, observational single-centre study in the
Medical Center Leeuwarden. A total of 10 patients undergoing an upper left or upper right
lobectomy will be included (see section 4 'Study population'). APatients will - after written
informed consent - undergo the regular standard-of-care program. In addition to this
standard-of-care, 2D-perfusion maps will be generated from images taken with PerfusiX-Imaging
(LIMIS Development BV, Leeuwarden, The Netherlands) in combination with a standard,
unmodified surgical laparoscope and video system (EndoEye, Olympus Medical, Hamburg,
Germany). This is the standard-of-care for these patients. During a standard procedure of
upper lobectomy, segmental arteries are identified and ligated one at a time. Therefore, the
investigators can create perfusion maps after ligation of the first segmental artery to
identify the segment. The images will be shown to the surgeon postoperatively. The interlobar
and intersegmental planes determined by PerfusiX-Imaging will be compared to the interlobar
and intersegmental planes determined by ICG-Fluorescence imaging and the surgical eye.
5 TREATMENT OF SUBJECTS 5.1 Investigational product/treatment The investigational medical
device is a medical imaging device that uses LSCI as a technology to image perfusion to
identify the intersegmental planes. This technology is referred to in literature as laser
speckle contrast imaging, laser speckle contrast analyses or laser speckle perfusion imaging.
There is no change in treatment for the patients included in this study. The ICG-fluorescence
device (Olympus, Hamburg, Germany) is a CE-certified device that is used on label.
5.2 Use over co-intervention (if applicable) Not applicable. 5.3 Escape medication (if
applicable) Not applicable.
6 INVESTIGATIONAL DEVICE 6.1 Name and description of investigational medical device The
investigational device is still in the development stage and only used for research purposes.
The intraoperative imaging will be performed using a combination of our device and the
OTV-S300 endoscopic video system (Olympus Surgical, Hamburg, Germany) with the EndoEye HD-II
endoscope (Olympus Surgical, Hamburg, Germany).
6.1.1 Positioning in the operating room Positioning of the research set-up is outside the
sterile zone of the operating room (OR). The fibreoptic cable between the white light source
and the endoscope will be replaced by a connection between the white light source and the
investigational medical device.
6.2 Summary of findings from non-clinical studies There is no literature on intersegmental
plane detection using LSCI available. 6.3 Summary of findings from clinical studies There is
no literature on intersegmental plane detection using LSCI available. 6.4 Summary of know and
potential risks and benefits See IMDD (Version 1.1, November 2020, section 5) for a summary
of known and potential risks and benefits of endoscopic LSCI.
7 NON-INVESTIGATIONAL PRODUCT 7.1 Name and description of non-investigation product(s) 7.1.1
Olympus surgical OTV-S300 video processor The OTV-S300 is an all-in-one 2D/3D processor and
light source for endoscopic surgeries. It is capable of both 2D and 3D observation packed in
a compact system for a simplified workflow. It has an LCD touch panel that allows for presets
for easy preparation and maintenance. It has an LED light source which produces good natural
colour reproduction with the combination of enhanced imaging processes. It has spectral light
observation with narrowband imaging and two modes of IR-observation. A detailed description
of the interface between PerfusiX-Imaging and the OTV-S300 can be found in the IMDD (Version
1.1, November 2020, section 1).
7.1.2 The EndoEye HD II videoscope delivers the innovative combination of distal-chip
(chip-on-the-tip) and high-definition technology to provide surgeons with excellent images
during endoscopic imaging. The HDII supports narrow band imaging. An advanced optical design
provides greater depth of field, eliminating the need for manual focusing and other scope
features include a digital zoom and fog-free heating function. The endoscope is fully
autoclavable and the all-in-one design integrates the light cable and camera system into the
endoscope for improved ergonomics and easier setup. A detailed description of the interface
between PerfusiX-Imaging and the EndoEye HD II can be found in the IMDD (Version 1.1,
November 2020, section 1) 7.1.3 Olympus ICG-fluorescence system The ICG-fluorescence system
is produced by Olympus. The light source required for excitation of the ICG is the
CLS-S200-IR that works in combination with the OTV-S300 video processor. The Olympus CH-S200
video head in combination with the Olympus IR telescope is the endoscope setup. This is the
more traditional camera head - optics combination compared to the EndoEye. This system is
installed in the MCL according to the ICG protocol found in attachment K6.16 7.2 Summary of
findings from non-clinical studies Not applicable. 7.3 Summary of findings from clinical
studies ICG-fluorescence imaging has been reported to determine the intersegmental planes. A
recent study by Sun et al. has compared the inflation-deflation method and ICG-fluorescence
imaging for the intersegmental plane determination in 19 patients13. Their results show that
both methods were in total concordance with regards to the intersegmental demarcation. Other
studies report larger patient groups. For example, Pischik et al. has assessed the safety and
effectiveness of ICG-fluorescence imaging in 86 patients6. They were able to detect well
defined fluorescence borders in 95.6% of the cases and had a fair explanation why the 4.4%
failed. They concluded that ICG-fluorescence imaging is a safe and effective method for
verification of anatomic segment borders. A feasibility study in 149 patients by Matsuura et
al. also concluded that ICG-fluorescence is feasible and effective with a intersegmental line
visible in a mere 98% of the patients14.
7.4 Summary of known and potential risks and benefits Not applicable. 7.5 Description and
justification of route of administration and dosage See attachment K6.16 7.6 Dosages, dosage
modifications and method of administration See attachment K6.16 7.7 Preparation and labelling
of non-investigational medicinal product See attachment K6.16 7.8 Drug accountability Not
applicable.
8 METHODS 8.1 Study parameters/endpoints 8.1.1 Study parameter/endpoint Due to the
explorative character of this study, there is no formal hierarchy in the respective endpoints
of this study. In this, all endpoints will add to the overall assessment of the feasibility
of the PerfusiX-imaging derived visual feedback.
The investigators will look at the ability of PerfusiX-Imaging of detecting the interlobar
and intersegmental planes.
In addition to this, the investigators will assess the conformity of the location of the
interlobar and intersegmental planes as indicated by PerfusiX-imaging, compared to the
location of the planes as indicated by the standard-of-care modalities, i.e.,
ICG-fluorescence imaging and the surgical eye.
The investigators will measure the time required for the capture of images with
PerfusiX-Imaging to acquire the visual feedback for the surgeon.
To further assess the feasibility, the investigators will determine the cut-off values with
the highest sensitivity and specificity with regards to the level of perfusion of lung
tissue.
The interpretability of the visual feedback provided by PerfusiX-Imaging by the end-user will
be assessed to get a sense of useability for the surgeon.
8.1.2 Other study parameters/endpoints (if applicable)
- Not applicable 8.2 Randomization, blinding and treatment allocation The current study is a
non-randomized, non-blinded, prospective, single-centre in which all patients are scheduled
to undergo a lobectomy according to standard care. There is no difference in therapeutic
procedure among included patients.
8.3 Study procedures 8.3.1 Inclusion procedure Potential eligible patients are identified by
their treating physician (in Dutch: hoofdbehandelaar). The treating physician will assess
eligibility by checking in- and exclusion criteria based on the available data (according to
paragraph 4.2 and 4.3). If a patient is found to be eligible to participate in the study, he
or she will receive oral information about the study during a standard visit to the
outpatient clinic, several days prior to surgical procedure. In addition, he or she will
receive written study information (together with the standard information) from the medical
assistant after the visit to the treating surgeon and is asked to consider participation. The
patients will be informed about the aim of the study, the procedures and associated risks
before enrolment into the study. Also, patients will be informed as to the strict
confidentiality of their data.
Two weeks after receiving the information about the study, patients can inform their treating
physician or the secretary staff of the Department of Surgery of theChirurgie MCL in person,
by phone, mail or e-mail to confirm that they are willing to participate in this study. When
patients agree to participate, signed written informed consent is obtained. For more
specified information about informed consent, see chapter 11.2.
8.3.2 Image acquisition protocol The patient will be treated according to treatment plan as
was established by the treating physician. The surgical procedure is executed as is deemed
appropriate by the surgeon. The imaging acquisition protocol is executed on the to-be-excised
lobe as described in Table 1. There will be two LSCI imaging moments during surgery. These
imaging moment will be performed after ligation of the segmental vascularization, but before
administration of ICG. This way, the recording is purely based on visual feedback from Laser
Speckle Imaging, and there will be no bias based on the interpretation of ICG. The surgeon
will not be able to see the LSCI images during the procedure. The LSCI researcher present in
the OR will verbally guide the surgeon only with regards to positioning of the scope in order
to acquire images that can be used to analyze. The researcher will not communicate any
interpretation regarding position and deminsions of the plane. Depending on the procedure, a
third measurement can be made in case an additional segment is isolated. Additionally,
ICG-imaging will be performed. The imaging moments are (1) after ligating the first segmental
arteries in the to-be-excised lobe, (2) after optional clipping of other segmental arteries
in the to-be-excised lobe and (3) after ligation of all arteries of the to-be-excised lobe.
The LSCI images will not be shown to the operating surgeon during surgery, but will be
reviewed by the operating surgeon after the procedure has finished.
8.4 Withdrawal of individual subjects Subjects can leave the study at any time prior to
surgery for any reason if they wish to do so without any consequences. The investigator can
decide to withdraw a subject from the study for urgent medical reasons.
8.4.1 Specific criteria for withdrawal (if applicable) Subjects will be withdrawn from the
study when no surgery will be performed. 8.5 Replacement of individual subjects after
withdrawal Patient who are withdrawn will be replaced in this study. 8.6 Follow-up of
subjects withdrawn from treatment Not applicable. 8.7 Premature termination of the study
8.7.1 Termination based on safety aspects Not applicable 8.7.2 Termination based on other
aspects The study will be suspended based on urgent medical or ethical considerations as
decided by the principal investigators. In case of termination of the study, the institution,
regulatory authorities, CCMO and the METC of the study centre will be informed.
9 SAFETY MONITORING 9.1 Temporary halt for reasons of subject safety In accordance to section
10, subsection 4 of the WMO, the sponsor will suspend the study if there is sufficient ground
that continuation of the study will jeopardize subject health or safety. The sponsor will
notify the accredited METC without undue delay of a temporary halt including the reason for
such an action. The study will be suspended pending a further positive decision by the
accredited METC. The investigator will take care that all subjects are kept informed.
9.2 AEs, SAEs 9.2.1 Adverse events (AEs) Adverse events are defined as any undesirable
experience occurring to a subject during the study, whether or not considered related to the
investigational product. All adverse events reported spontaneously by the subject or observed
by the investigator or his staff will be recorded.
9.2.2 Serious adverse events (SAEs) A serious adverse event is any untoward medical
occurrence or effect that
- results in death;
- is life threatening (at the time of the event);
- requires hospitalization or prolongation of existing inpatients' hospitalization;
- results in persistent or significant disability or incapacity;
- is a congenital anomaly or birth defect; or
- any other important medical event that did not result in any of the outcomes listed
above due to medical or surgical intervention but could have been based upon appropriate
judgement by the investigator.
An elective hospital admission will not be considered as a serious adverse event.
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited METC
that approved the protocol, within seven days of first knowledge for SAEs that result in
death or are life threatening followed by a period of maximum of eight days to complete the
initial preliminary report. All other SAEs will be reported within a period of maximum 15
days after the sponsor has first knowledge of the serious adverse events.
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) Not applicable. 9.3 Annual
safety report Not applicable. 9.4 Follow-up of adverse events All AEs that are related to the
investigational medical product will be followed until they have abated, or until a stable
situation has been reached. Depending on the event, follow up may require additional tests or
medical procedures as indicated, and/or referral to the general physician or a medical
specialist. SAEs need to be reported till end of study within the Netherlands, as defined in
the protocol.
9.5 Data Safety Monitoring Board (DSMB) An independent external Data Safety Monitoring Board
of experts will not be instituted.
10 STATISTICAL ANALYSIS The overall aim of this study is to see if PerfusiX-Imaging can be
used to determine the intersegmental planes.
10.1 Secondary study parameter(s) The total number of interlobar and intersegmental planes as
detected using PerfusiX-Imaging that are in concordance with the interlobar and
intersegmental planes as detected using ICG-fluorescence imaging and the surgical eye
(descriptive statistics, percentage).
10.2 Other study parameters Not applicable. 10.3 Interim analysis (if applicable) Not
applicable.
11 ETHICAL CONSIDERATIONS 11.1 Regulation statement The study will be conducted according to
the principles of the Declaration of Helsinki (Fortaleza, Brazil, 2013 amendment) and in
accordance with the Medical Research Involving Human Subjects Act (WMO) and other guidelines,
regulations and Acts. The protocol has been written and the study will be conducted according
to the ICH Harmonized Tripartite Guideline for Good Clinical Practice. The protocol will be
approved by the Local, Regional or National Ethics Committees.
11.2 Recruitment and consent Recruitment is done by the operating surgeon of the patient. All
subjects are informed and asked for their consent. The minimal time between first appointment
with doctor and surgery is 2 weeks, what results in a minimal time of 2 weeks for
consideration.
Written informed consent must be obtained for all patients included in the study before they
are registered in the study. Patients must be given adequate opportunity to read the
information and enquire about details of the study before consent is given. This implies that
the written informed consent form will be signed and personally dated by the patient. The
informed consent statement will be signed and dated by the investigator afterwards and the
patient will receive a copy. The general physician of each patient will be informed about the
enrolment of the patient to the study.
11.3 Objection by minors or incapacitated subjects (if applicable) Not applicable. 11.4
Benefits and risk assessment, group relatedness All patients included in the study will be
treated comparable with patients not included in the study. The difference between
non-included and included patients is prolonged operating time. Prolonged operating time can
increase the risk for patients, (e.g., infection (although this is rather minimal) and
prolonged narcosis. The results do not immediately benefit the patients included in this
study, but could help future patients to improve patient outcome.
11.5 Compensation for injury
The sponsor/investigator has a liability insurance which is in accordance with article 7 of
the WMO. The sponsor (also) has insurance which is in accordance with the legal requirements
in the Netherlands (Article 7 WMO). This insurance provides cover for damage to research
subjects through injury or death caused by the study. The total amounts of insurance are as
follows:
1. A maximum of €650.000 (i.e. six hundred and fifty thousand euros) for death or injury
for each subject who participates in this current research;
2. A maximum of €5.000.000 (i.e. five million five hundred thousand euros) for death or
injury for all subjects who participate in this current research;
3. A maximum of €7.500.000 (i.e. seven million five hundred thousand euros) for the total
damage that becomes apparent at the study participant in research which was conducted by
the Medical Center Leeuwarden. Act in each year of insurance coverage.
The insurance applies to the damage that becomes apparent during the study or within 4 years
after the end of the study.
11.6 Incentives (if applicable) Not applicable. 12 ADMINISTRATIVE ASPECTS, MONITORING AND
PUBLICATION 12.1 Handling and storage of data and documents Data of patients will be handled
confidentially and a coded identification number (study protocol number 'PORTION' followed by
number of inclusion (for example PORTION01) will be used to link the data to the specific
patient. Data that can be linked to a specific patient will be stored separately. The
principal investigator safeguards the key to the code. The handling of the personal data
complies with the EU General Data Protection Regulation and the Dutch Act on Implementation
of the General Data Protection Regulation (in Dutch: Uitvoeringswet AVG, UAVG)). These data
will be stored at the specific site for at least fifteen years. For software adjustments a
software engineer from ZiuZ Research BV can have access to only the images.
12.2 Monitoring and Quality Assurance Not applicable. 12.3 Amendments
Amendments are changes made to the research after a favourable opinion by the accredited METC
has been given. All amendments will be notified to the METC that gave a favourable opinion. A
'substantial amendment' is defined as an amendment to the terms of the METC application, or
to the protocol or any other supporting documentation, that is likely to affect to a
significant degree:
- the safety or physical or mental integrity of the subjects of the trial;
- the scientific value of the trial;
- the conduct or management of the trial; or
- the quality or safety of any intervention used in the trial. All substantial amendments
will be notified to the METC and to the competent authority. Non-substantial amendments
will not be notified to the accredited METC and the competent authority, but will be
recorded and filed by the sponsor.
12.4 Annual progress report The sponsor/investigator will submit a summary of the progress of
the trial to the accredited METC once a year. Information will be provided on the date of
inclusion of the first subject, numbers of subjects included and numbers of subjects that
have completed the trial, serious adverse events/ serious adverse reactions, other problems,
and amendments.
12.5 Temporary halt and (prematurely) end of study report The investigator/sponsor will
notify the accredited METC of the end of the study within a period of 8 weeks. The end of the
study is defined as the last patient's last visit. The sponsor will notify the METC
immediately of a temporary halt of the study, including the reason of such an action. In case
the study is ended prematurely, the sponsor will notify the accredited METC within 15 days,
including the reasons for the premature termination. Within one year after the end of the
study, the investigator/sponsor will submit a final study report with the results of the
study, including any publications/abstracts of the study, to the accredited METC.
12.6 Public disclosure and publication policy The financial sponsor of the study is LIMIS
Development BV (Principal Investigator dr. E.C. Boerma). There are no restrictions towards
publication; the study is registered in a public trial registry (clinicaltrials.gov) and with
the CCMO number NL82338.099.22.
13 STRUCTURED RISK ANALYSIS 13.1 Potential issues of concern
1. Level of knowledge about mechanism of action NA
2. Previous exposure of human beings with the test product(s) and/or products with a
similar biological mechanism NA
3. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human
cell material? NA
4. Selectivity of the mechanism to target tissue in animals and/or human beings NA
5. Analysis of potential effect NA
6. Pharmacokinetic considerations NA
7. Study population NA
8. Interaction with other products NA
9. Predictability of effect NA
10. Can effects be managed? NA
