A PHASE III, RANDOMISED CONTROLLED TRIAL ASSESSING THE VALUE OF INDOCYANINE GREEN IN THE LEAKAGE RATE OF COLORECTAL ANASTOMOSES

AL is still one of the major complications after gastrointestinal surgery
accounting for considerable morbidity and mortality. The incidence of AL in
colorectal surgery ranges from 2.4 to 11% with the highest reports up to 23.3%
in rectal cancer surgery . Besides tumour location and level of anastomosis,
risk factors for AL include male gender, high ASA score, comorbidities,
smoking, obesity and (neoadjuvant) radiotherapy. Surprisingly, in most reports
higher age is not a risk factor for AL and only correlated with the risk of
death after AL.

Most risk factors can no longer be changed at the time of the initial surgical
diagnosis. Therefore, it is especially important to optimize those few factors
that can be influenced. It has been reported that compromised tissue perfusion
at the site of the anastomosis significantly increases the risk of AL.
ICG combined with fluorescent near infrared imaging has proven to be a feasible
and reproducible application for real-time intraoperative quantification of the
tissue perfusion. Moreover, larger cohort studies have shown reduced leakage
rates and hospital stay. On the other hand, Kin et al. have shown no benefit of
the use of ICG peroperatively in preventing AL.

ICG was introduced by Fox et al in 1957 and is currently used for a variety of
diagnostic implications. ICG is invisible for the naked eye and will break up
in an aqueous solution, resulting in a reduction of fluorescence intensity of
50% in 2 hours. Very favourable characteristics such as the intravascular
intake, the binding with plasma proteins, the rapid and almost exclusive
clearance by the liver in bile and the very low toxicity quickly resulted in
acceptance and registration of ICG for different diagnostic indications.

Despite these promising results, more evidence is needed. Previous studies were
mostly not randomized and did not use clinical relevant leakage as the primary
endpoint. Therefore, we propose a randomized controlled trial to identify the
real value of ICG for AL rate of colorectal anastomoses.

Primary Objective:
To compare the difference in clinically relevant AL after 90 days between
perfusion assessment with ICG and standard surgery in colorectal anastomoses.

Secondary Objective(s):
1. Change in surgical plan will be assessed within each patient by comparing
ICG surgery with standard of care surgery and assessing if ICG allowed to
change the anastomosis level;
2. To compare the difference in clinically relevant AL after 30 days between
perfusion assessment with ICG and standard surgery in colorectal anastomoses
3. To compare the difference in complication rates after 30 and 90 days between
ICG and standard of care surgery in colorectal surgery;
4. To compare the difference in 30 and 90-day mortality rates between ICG and
standard of care surgery in colorectal surgery;
5. To compare the difference in 30 and 90-day reinterventions between ICG and
standard of care surgery;
6. To compare the difference in surgical time between ICG and standard of care
surgery in colorectal surgery;
7. To compare the difference in duration of inpatient hospital treatment
between ICG and standard of care surgery in colorectal surgery.

This is a prospective, national, multicenter, randomised controlled trial
comparing the use of intraoperative ICG, a fluorochrome, with standard surgical
care in perfusion assessment of colorectal anastomoses. Patients will be
allocated to two groups; Image Guided Bowel Anastomosis group (IGBA) or the
Conventional Bowel Anastomosis group (CBA).

A well perfused section will show a higher fluorescent signal then compromised
tissue. The surgeon will determine the degree of tissue perfusion and
desirably, in case of compromised perfusion, change the level of the
anastomosis.

The aim of this trial is to assess the rates of clinically significant
anastomotic leaks in the experimental group (using ICG to assess anastomosis
perfusion) and the control group, consisting of patients undergoing standard of
care surgery. The surgeon has the possibility to switch the fluorescence camera
on and off before, during and after the resection.

In previous studies doses 2 to 15 milligram have been used. It has been shown
that intravenous administration of ICG is safe and provides successful imaging
of the vascularization. In this study a repeated dose of 5 milligram is chosen,
with a maximum of 10 milligram per patient.
A patient is considered to have completed the study if she/he has completed all
phases of the study including the last scheduled visit shown in the schedule of
activities (SOA), i.e. the last visit performed 90 days after surgery.

In the past, different reports used various definitions of AL (ranging from
clinical or radiologic evidence with or without the need for a reoperation).
Therefore, the International Study Group of Rectal Cancer proposed a uniform
definition in which grade A requires no active therapeutic intervention; grade
B requires therapeutic intervention, but manageable without re-laparotomy; and
grade C can only be handled with a re-laparotomy.

A clinically relevant leak is therefore, in this study, defined as an abscess
or fluid collection close to the anastomosis or any leak that requires medical
intervention. This includes reoperations, radiological interventions by means
of drains and / or administration of antibiotics.

The planned duration of the study is 2 years with a total of 489 patients per
arm (978 in the study). The expected start date is March 2019.

Patients will be allocated to two groups; Image Guided Bowel Anastomosis group
(IGBA) or the Conventional Bowel Anastomosis group (CBA). Patients in the IGBA
group will receive a repeated dose of 5 milligram ICG, with a maximum of 15
milligram per patient. Imaging of the anastomosis will take place right after
bowel resection and after finalization of the anastomosis. Based on the
surgeon*s evaluation he or she may change the level of the anastomosis.
The CBA group will receive no study related intervention. The decision of the
level of anastomosis in this group is made according to the current standard of
care.
In both groups the anastomosis is created by the surgeon*s preference.

The burden for patients is low. No extra visits are necessary for this study.
Moreover no extra blood samples, physical examinations, questionnaires or other
tests will take place.
The investigational product (ICG) is safely used for over 60 years for
different indications (including the one in this study). Only mild allergic
reactions have been seen. Patients with known a known allergic reaction to ICG
or a substance related to ICG are excluded.