Functional Anorectal Studies in Patients With Low Anterior Resection Syndrome (LARS)
Phase: NA
Conditions: Anterior Resection Syndrome, Bowel Dysfunction
Sponsor: Giome

 
1 
 
 
 
Title: Studies in Patients with Low Anterior Resection Syndrome (LARS) 
 
NCT number: NCT03885999 
 
Document Date: 1 March 2020 
 

 
2 
 
Background of research  
Colorectal Cancer is the commonest cancer diagnosed for both genders combined in Hong Kong. In 
2015 16.6% of all new cancer cases registered on the Hong Kong registry were cancer of colon and 
rectum.1 Distal colon cancer is more common than proximal colon cancer, with up to 38% of cancers 
being found in the rectum.2 Curative surgical treatment option for rectal cancer involves excision of 
tumour with 5cm proximal and 2cm distal margin with its draining lymphatics. The level of anastomosis 
or need for temporary or permanent stoma will depend on the height of tumour from the anal verge, 
extent of local invasion, the sphincter function preoperatively, co-morbidity and whether they required 
preoperative chemoradiotherapy. With neoadjuvant chemoradiotherapy offering potential tumour 
shrinkage and improvements in surgical technique such as the transanal total mesorectal excision 
(TaTME) technique offering accurate distal resection margin, many patients are now receiving 
sphincter-preserving surgery with low colorectal or coloanal anastomosis to avoid permanent colostomy. 
Up to 80% of patients who has undergone low anterior resection (LAR) suffer from severe bowel 
dysfunction post operatively3. Patients symptoms typically fall into two categories: those with 
incontinence, frequency, and urgency, and those with constipation and feelings of incomplete emptying. 
However, some patients report features of both, either occurring simultaneously or fluctuating between 
these two groups of symptoms4. This combination of symptoms after LAR is referred to as Low Anterior 
Resection Syndrome (LARS) which is associated with negative impact on quality of life (QoL)5. 
Originally, it was thought that these symptoms were short-lived neorectal irritability in the postoperative 
period. However, many studies report that the majority (up to 90%) of patients experience long-term 
changes in quality of life after LAR6. Therefore, a large number of patients worldwide are suffering 
from unpredictable, poor bowel function postoperatively affecting their day-to-day activity and quality 
of life. 
In a prospective study assessing consecutive patient’s functional outcome post low anterior resection in 
our unit since January 2016, 34 patients have had their defunctioning stoma closed to date with 4 months 
follow up. 73.5% of our patients were experiencing major LARS. Approximately half of the patients 
had persistent symptoms at 2 years post stoma closure: 65.5% (19/29) and 46.2% (6/13) had major 
LARS at 12 and 24 months respectively. Hence, the figures from our unit correspond to reports from 
other centers Worldwide. 
Unfortunately, there is no cure for LARS at present. Biofeedback treatment and nerve stimulation sacral 
nerve stimulation or tibial nerve stimulations with stimulators such as the Acutens seems to provide 
some symptomatic relief for some patients. The cause of LARS is thought to be multifactorial and 
difficult to define. Therefore, this trial is designed to use Fecobionics, a new Hong Kong based 
innovation, to provide new mechanistic insights regarding anorectal physiological function post low 
anterior resection. This will help us to understand the condition better and hopefully to improve their 
treatment options. 
 
Technological background 

 
3 
 
In the proposed studies it is important to compare the new technology, Fecobionics, to current state-
of-the-art reference technologies. We expect Fecobionics to provide data that cannot be obtained 
with current technology and to reduce variation in measured variables. 
 
Reference testing techniques 
Anorectal Manometry (ARM)7 with balloon expulsion testing (BET)8 will be conducted with a 
standard single-use 8ch anorectal catheter (G-90150, MMS, Enschede, Netherlands). The catheter 
will be inserted with the subjects lying inside position with bent hip and knees. The bag will be placed 
in the rectum and pressure will be measured at 0.5cm distance in the anal canal. The following 
parameters will be evaluated: resting anal pressure, maximum anal squeeze pressure, the recto-anal 
inhibitory reflex (RAIR), urge volume, maximum tolerable volume, and expulsion time for the 50ml 
balloon. 
Defecography (fluoroscopy or MRI) will be used as a reference for Fecobionics. A water-soluble 
paste will be injected into the rectum and serial x-rays will be taken during defecation. Defecography 
will be used to study several anorectal characteristics. The height of the colorectal anastomosis, any 
abnormality at the anastomosis such as narrowing, orientation of neo-rectum will be assessed in addition 
to usual measurements of the anorectal angle and the position of the pelvic floor at rest or during 
Valsalva (perineal descent). The presence of rectocele, rectal intussusception, and the ability to expel 
rectal contents will be evaluated9,10. Balloon proctography can simplify the procedure of examining the 
ability to evacuate by providing a quick and clean test with minimal radiation11. 
 
New technology 
Fecobionics12,13 is a novel device, a simulated faeces, that we currently are testing in healthy subjects 
and in patients suffering from fecal incontinence and constipation (RGC funded proposal “Unraveling 
anorectal function and biomarker signatures in patients suffering from subtypes of defecatory 
disorders”). Fecobionics records pressures, orientation, bending, shape, and viscoelastic properties 
during defecation. It is made of a 10 cm long and 12 mm wide core of medical grade resin that contains 
multiple electronic sensors and circuit boards. A bag is mounted on the bendable core. Pressure 
transducers are placed at the front, rear and inside the bag, in addition to two gyroscopes for orientation 
and angle measurements. A novelty of Fecobionics is that it measures pressures in axial direction (in 
the direction of flow) in contrast to current technologies and that it integrates almost all current anorectal 
functional tests into a single test that only takes minutes to perform without the use of radiation or 
expensive equipment. Since the Fecobionics technology was developed by the PI Professor 
Hans Gregersen, we are currently the only clinical research group with access to the technology. This 
gives us a unique opportunity to becomes the leaders in the field. 
 
Impact 
Defecatory disorders affect 25% of the population with rising incidence. They pose a major health care 

 
4 
 
burden and are poorly recognized and treated. The need for better diagnostics and therapeutics is 
substantial. Constipation, a symptom of underlying disease, affects 12-19% of Americans14,15 with 
expenditures on medication for constipation alone greater than $250 million per year16. Defecatory 
diseases are associated with diet, aging and a variety of underlying factors and diseases17-20. As 
described above LAR is associated with reduced quality of life and anorectal symptoms in the majority 
of patients.  
Since the etiology is multifactorial, a significant problem is the lack of physiologically relevant and 
practical diagnostic tests for identifying the underlying mechanisms. Assessment begins with detailed 
questioning about symptoms. Digital rectal examination is done to assess tone, maximum anal squeeze 
with detection of sphincter defects, rectal prolapse, and abnormal perineal descent17. Current diagnostic 
tests such as Anorectal Manometry (ARM), Balloon Expulsion Test (BET) and defecography are 
surrogates for the act of defecation and provide incomplete and often conflicting information due to the 
static nature of the tests. Not surprisingly results of these tests correlate poorly with symptoms and 
treatment outcomes. The problem with most tests is that they do not reflect the dynamics of the 
defecation process and are far from representing physiological conditions21-25. Even defecography, 
regarded as the most physiological test, uses a liquid with mechanical properties quite different from 
the properties of faeces. The anorectal expulsion test suffers from the lack of physiological 
measurements such as pressure profiles, angling and geometric changes during anal passage. Hence, 
current paradigms for defecatory disorders need to be changed by approaches that can provide insight 
by simulating defecation physiologically and examining the mechanistic changes multidimensionally 
in terms of pressure profiles, deformability, and topographic changes. Based on promising new data 
using the Functional Luminal Imaging Probe (FLIP) in the anal canal26-30, ARM31, and Fecobionics12,13, 
the goal is to use the novel integrated Fecobionics device (combined FLIP-ARM-BET-defecography-
in-part) for functional studies in LAR patients. Fecobionics has been developed according to current 
safety standards for medical devices (ISO13485)13 by the PI Professor Hans Gregersen and have been 
trialed with success in our patients with anorectal functional disorders based on GRF support. We are 
currently the only clinical research centre worldwide with access to the technology. This provides us 
with a unique opportunity to lead the field. The measurement variables include pressures, shape changes, 
the expulsion velocity and an “objective” anorectal angle (important for evaluation of several anorectal 
disorders). Hence, it will be feasible to describe objectively, without disturbing the defecation process, 
sensation, opening characteristics and geometric changes during initial entry from the neo-rectum into 
the relaxing anal canal. 
This proposal will result in a new paradigm in evaluation of LARS. The simulated faeces technology 
will potentially replace current tests as it provides an integration of measurements from multiple tests 
of anorectal diagnostics. Our expected outcome is to characterize abnormal pressures, forces and 
topographic changes in the neo-rectum and anal canal during defecation in LARS patients, to help with 
understanding of the cause of their symptoms to guide and improve LARS management. 
 

 
5 
 
Objectives and specific aims 
General Objective 
Fecobionic will provide new mechanistic insights regarding anorectal physiology in LARS patients that 
is not obtainable with current technology. 
Specific Aim 1: Anorectal pathophysiology of LARS patients 
Objective: use fecobionics to obtain physiological and pathophysiological signatures of anorectal 
function in a heterogeneous group of LARS patients. Based on the epidemiology and symptomatology 
of LARS, it is expected that the heterogeneous group will contain an almost equal number of LARS 
patients with incontinence, frequency and urgency, and those primarily with constipation and feelings 
of incomplete emptying. Due to the spread (heterogeneity) in the patient group regarding symptoms, 
regression analysis will be the primary statistical tool to associate symptoms with experimental findings. 
We will also compare to age- and sex-matched healthy controls from already conducted studies. 
Milestone: Describe the mechanosensory signature, variation of the measured variables, and computed 
endpoints in LARS patients. 
 
Approach 
Device Characteristics and human recordings. The integrated Fecobionics device is uniquely 
designed to improve diagnostics of anorectal disorders. The design integrates ARM, BET, defecography 
and FLIP20-24,32-36. The new design features of the integrated device are shown in Figure 1 and include 
the inner bendable core that contains the sensors and a bag for distension made of 25 micrometer 
polyurethane. The core is easily bendable and contains electronic components such as pressure 
transducers, gyroscopes, and impedance electrodes as well as circuit boards for the central processing 
unit (CPU). A tube is used for filling of the bag after the placement in rectum to the urge-to-defecate 
level. All materials in the device are medical grade. The core and the bag provide a double layer 
protection for the electronic components. Our institutional review board did not have any concerns 
about the risks and safety of the device. 
Figure 1 shows the design of the Fecobionics device with the computer that also serves as a visual 
analog scale (VAS) for sensory evaluation in addition to displaying data. The core is made from medical 
grade resins and contains three pressure sensors placed at the front, rear and inside the bag. It also 
contains two gyroscopes used for determination of orientation and bending (the anorectal angle). 
Furthermore, eight pairs of electrodes that utilizes the FLIP principle to determine the geometry of the 
bag surround the core26-30. The core also contains the CPU, multiplexer, amplifiers, and batteries. A 
valve and bag filling tube system as well as a safety thread are attached in the front of the device (not 
shown). 
Figure 2 shows schematics of novel analysis of the pressure signals from preliminary studies in healthy 
human subjects and patients with anorectal disorders. The left panel shows the front and rear pressure 
and the difference between them as function of time. Studies have demonstrated that defecation can be 
subdivided into five distinct phases12,13. The difference in the two axial pressures (pointing forward and 

 
6 
 
backward) during the expulsion indicate the usefulness of this kind of measurements. For example, the 
entrance of the device into the canal as well as the anal relaxation can be assessed. The right panel 
shows the front pressure as function of the rear pressure. This is a novel representation corresponding 
to the well-known preload-afterload analysis of cardiac function. Human data from our preliminary data 
are shown in figure 3. 
Figure 3 shows data from a healthy subject (AB), a patient with fecal incontinence (CD) and chronic 
constipation (EF). The left panels are the pressure-time plots useful subdividing defecations into phases. 
The right panel is the front-pressure as function of the rear pressure. Both types of analysis show marked 
differences between the subjects. In general, the heathy subjects use a few pressure increases 
(abdominal contractions) to expel the device. The FI subject is characterized by a low anal sphincter 
pressure and the device pops out by itself. The constipation patient cannot expel the device despite 
many attempts. Other data (not shown) based on gyroscope data also demonstrate distinct differences 
between subjects. 
 
Research Design and Methods 
The overall goal of this proposal is outlined in the specific aims section. Specifically, we will target 
anorectal diagnostics of LARS patients to be conducted in the Department of Surgery at Prince of Wales 
Hospital in Hong Kong. In both studies listed below, we aim to recruit a heterogeneous group of patients 
to allow us to assess the effect of several underlying risk factors. In both studies, we will study the 
patients after closure of defunctioning stoma as we deem it impossible to carry out anorectal functional 
studies in patients with low rectal cancer before their rectal cancer surgery and assessing anorectal 
function post LAR before defunctioning stoma closure will produce unreliable, irrelevant data. 
 
Study Protocol: 
Following ethics approval, patients will be assessed for their eligibility to participate in the trial. The PI 
and collaborators who are Good Clinical Practice (GCP) trained will recruit patients who are eligible 
for the study. Information sheet will be given to the patient in the surgical clinic, and written consent 
will be obtained at the next hospital visit. Ethics approval for this study will be granted prior to the start 
of the trial. The trial will be compliance with the Declaration of Helsinki. The trial will be registered in 
www.clinicaltrials.gov. 
 
Data collection: 
Patients will be assessed at baseline and following will be recorded for all patients: 
• 
Demographic data 
• 
Body Mass Index (BMI) 
• 
Significant Past Medical and Surgical History 
• 
Obstetric History (female patients only) 
• 
Rectal Cancer stage: TNM staging, location of tumour from anal verge on preop image 

 
7 
 
• 
Rectal Cancer treatment 
       o Neoadjuvant chemoradiotherapy/radiotherapy/chemotherapy 
       o Surgery – Open/Laparoscopic/Robotic/TaTME, level of anastomosis 
       o Post-operative complications 
       o Postop chemotherapy / radiotherapy 
       o Timing of defunctioning stoma (ileostomy / colostomy) closure 
• 
LARS questionnaires: to assess Quality of life associated with LARS (Figure 4)37,38 
 
All patients will undergo the following tests: 
• 
Integrated Fecobionics anorectal test (see clinical workflow below) 
• 
High Resolution Anorectal Manometry (ARM) to assess resting and squeeze pressures, 
sensitivity, rectal capacity and recto-anal inhibitory reflex. 
• 
Conventional balloon expulsion test 
• 
Defaecography 
 
Clinical data will be recorded and stored electronically in the hospital server. Completed questionnaires 
will be recorded and entered into database software and stored in the hospital server. 
 
Clinical Work Flow for the integrated device.  
This section pertains to the procedures related to use of Fecobionics. All tests prior to Fecobionics are 
done per department standards. The patient is instructed about the tests. The integrated device is 
calibrated in a one-step procedure. Similar to the conventional expulsion test, the device is placed in 
the rectum by manual insertion with the person lying on the side. The bag is distended with simultaneous 
recording of symptom level until urge to defecate. Volume is recorded. When the urge level is reached, 
the patient will move to the toilet chair for attempting to expel it. The patient will report sensory data. 
Most patients who do not suffer from constipation will be able to expel it within 1-2 minutes. If the 
patient fails to expel the device by himself, the physician or nurse can, if deemed necessary, pull it out 
by traction of a tiny thread attached to the front end (like the thread used for tampons). The thread is 50 
cm long so even if the device relocates to the left side of the colon, it can still gently be pulled out. In 
the worst case, an endoscope can be used to pull it out. 
 
Study design related to specific Aim 1: Anorectal pathophysiology of LARS patients 
Studies are planned to include a heterogeneous group of LARS patients with a broad scale of symptoms. 
We will study 30 patients recruited from a pool of postoperative patients who are under the care of our 
Department. The department has a large cohort of patients with LARS and it is anticipated that it will 
be easy to recruit the patients. 
Inclusion Criteria:  
1. Patients 18 years of age or older with history of LARS over 3 months.  

 
8 
 
2. Informed, written consent by the patient  
Exclusion Criteria:  
1. Patients who are not willing to undergo the specified tests in this study 
2. Pregnant women 
  
The studies on LARS patients will focus on pathophysiological studies where we describe the expulsion 
characteristics, with focus on anal canal opening related to rectal mechanosensory data and to changes 
in the anorectal angle during defaecation. We will study expulsions at the urge-to-defecate level for the 
patients and we will correlate to data obtained by conventional technologies and to patient 
characteristics such as age, and symptoms as well as to risk factors. The study subjects will also be 
tested with conventional expulsion testing, defecography, rectal bag distension, and ARM20-24,32-35,39. 
The studies will determine endpoints of clinical value such as expulsion time and velocity, maximum 
angle difference, pressure signatures and geometry changes. 
Expected Results and Milestones: The expected outcome is that the device will perform as shown 
in the previous human experiments (n>60) where no adverse effects have been recorded. We anticipate 
successful access in LARS patients with no device-related adverse events or device malfunctions. 
Completion of the study is expected to derive outcome measures reflecting the defecatory function as 
the major impact. 
Potential Pitfalls and Alternative Strategies: According to the ISO 13485 standard, the device is 
an insertable low risk device since it will reside inside the body for less than one hour and there is no 
radiation exposure. All materials are medical grade and the design and mechanical properties chosen 
after input from KOLs in USA and Europe. Assessment for safety in the above reported preliminary 
studies and in testing during the developments will not fully recapitulate all the conditions in LARS 
patients. We will ask the investigators to be alert and retract the device instantly if it suddenly stops 
working as “alarmed” by the device, which could be indicative of a short circuit. We will work with 
safety experts to fully mitigate any issues as we have done with other projects. Another concern relates 
to retraction of the device if it cannot be defecated. To avoid the need for endoscopy, the device will 
have a thin string attached in the anal end. The string will be the same thin soft type as used in tampons 
to avoid interference with the mechanosensory properties of the anorectum. If enrollment is slower than 
expected, we will make an extra effort to recruit patients, but this is hardly to be anticipated considering 
the high incidence of LARS in our cohort of patients. 
 
Data analysis including statistics and sample size determination.  
A number of biomechanical parameters will be computed from the recorded data. These parameters 
include but are not limited to: 
• 
Pressure difference between the rear and front ends (a measure of anal sphincter relaxation 
and key to the determination of phases of the defecatory process) 
• 
Orientation and bending of Fecobionics for assessment of the anorectal angle 

 
9 
 
• 
Velocity of expulsion (as measured from the time difference between sensor data) 
• 
Tension 
• 
Strain (deformation) and displacement 
Definitions of tension, strain and displacements can be found in the two books by the Professor Hans 
Gregersen17,19. Sensory measures and clinical data will be related statistically to the mechanical 
measures. Endpoint data will be expressed as mean±SD if they can be considered normally distributed. 
Significance of the differences between two methods will be evaluated by ANOVA where appropriate 
and by multiple and single regression analysis. The results will be considered statistically significant 
when p<0.05 (2-tailed). Multiple regressions will be used to evaluate risk factors using causal and 
predictive analysis. Repeatability and distribution will be determined based on coefficient of variation 
(SD/mean) and used to evaluate accuracy. 
The projected number of subjects, n, required to test a null hypothesis is given by the following equation: 
[
]
n
Z
Z
>
+








2
2
2
α
β σ
δ
where α is the required probability of a Type I error, β is the required probability 
of a Type II error, δ, is the estimated difference between the means of two comparison groups, andσ is 
the estimated standard deviation of the means in each of the two comparison groups. We assume 
2a<0.05 (Z2a=1.96) and 2b<0.10 (Z2b=0.84). We assume the values of mean difference, d, and standard 
deviation, s, from previous experience in the clinical laboratory and from reported data in the literature 
on the involved patient groups and the sensitivity and specificity of current tests. An alternative method 
is 
to 
use 
sample 
size 
estimation 
based 
on 
the 
Altman-Bland 
analysis 
(http://wwwusers.york.ac.uk/~mb55/meas/sizemeth.htm). Preliminary data on expulsion time using 
BET and Fecobionics were used in the sample size analysis. Data variation (SD, SE) was computed for 
preliminary data. The confidence interval for the 95% limits of agreement was computed and n was 
determined. For both analyses, given the exploratory nature of the study, we consider a heterogeneous 
group of patients and that 80% of operated patients will develop LARS. Using these boundaries and 
criteria, we arrived at a sample size of 30 in the Aim 1 study for evaluation of statistical significance, 
association and risks. Though the material may be too small to account for confounders, we will obtain 
clear indications of risks and causes. For the comparison with previously studied subjects, we have a 
pool of 35 healthy asymptomatic subjects, 20 patients with FI and 15 patients with constipation to 
compare with. 
 
Clinical Assessments of device safety: Fecobionics have now been used in more than 70 human 
studies without any incidents or adverse effects. In addition, a safety study has been performed in 12 
pigs without any device related issues or damage to anorectal mucosa (yet unpublished data). Since 
Fecobionics is still an experimental device, we will pay attention to safety. If any safety issue occurs, it 
will be characterized and reported. Additional data obtained will include procedural duration, sensation 

 
10 
 
including pain, inspection of the anus after the expulsion in addition to any adverse events that may 
occur. Follow-up physician interviews will obtain qualitative measures of device performance and 
utility. Unanticipated adverse device effects (UADE) are defined as any serious adverse effect on health 
or safety or any life-threatening problem or death caused by, or associated with a device if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application, or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects. The procedure for reporting any adverse event 
(whether device-related or not) is to fill in all sections of an adverse event case report form. Details and 
symptoms associated with the event will be reported in the narrative section on the Narrative/Notes 
CRF. It will be the responsibility of the clinical study investigator to inform the IRB of adverse events 
(whether device related or not) according to their requirements. 
 
Location of study 
The studies will be conducted in the Department of Surgery at Prince of Wales Hospital, 
Shatin, Hong Kong. 
 
 
 

 
11 
 
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37. Juul T, Ahlberg M, Biondo S, Emmertsen KJ, Espin E, Jimenez LM et al. International validation 
of the low anterior resection syndrome score. Ann Surg 2014; 259:728-34. 
38. Emmertsen KJ, Laurberg S. Low anterior resection syndrome score: development and validation 
of a symptom-based scoring system for bowel dysfunction after low anterior resection for rectal 
cancer. Ann Surg 2012; 255: 922–928. 
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Am J Gastroenterol 1998; 93:1042-1050.

 
14 
 
Figure 1: The design of the integrated Fecobionics device and system.  
 
 
 
 
 
 
Figure 2: Schematic representation of novel advanced analysis of pressure signals 
 
Figure 3: Pressure signatures of healthy subject (AB), FI patient (CD) and CC patient 
(EF) during defecation of the device 
 

 
15 
 
Figure 4: LARS Questionnaire 
 
Do you ever have occasions when you cannot control your flatus (wind)? 
 
No, never 
0 
 
Yes, less than once per week 
4 
 
Yes, at least once per week 
7 
 
Do you ever have any accidental leakage of liquid stool? 
 
No, never 
0 
 
Yes, less than once per week 
3 
 
Yes, at least once per week 
3 
 
How often do you open your bowels? 
 
More than 7 times per day (24 hours) 
4 
 
4–7 times per day (24 hours) 
2 
 
1–3 times per day (24 hours) 
0 
 
4–7 times per day (24 hours) 
5 
 
Do you ever have to open your bowels again within one hour of the last bowel opening? 
 
No, never 
0 
 
Yes, less than once per week 
9 
 
Yes, at least once per week 
11 
 
Do you ever have such a strong urge to open your bowels that you have to rush to the toilet? 
 
No, never 
0 
 
Yes, less than once per week 
11 
 
Yes, at least once per week 
16 
 
 
Total Score:  
 
Interpretation:  
0–20: No LARS  
21–29: Minor LARS  
30–42: Major LARS