Introduction
Results from a large, multicenter, randomized controlled trial in the UK showed that
screening people aged 55 to 64 years with a single flexible sigmoidoscopy (FSIG) reduced
colorectal cancer (CRC) incidence and mortality by 33 % and 43 % respectively [1]. A subsequent pilot study performed in three English sites confirmed that FSIG screening
of participants aged 55 years is both feasible and acceptable [2]. Based on this, Bowel Scope Screening Programme (BSSP) is being rolled out throughout
England whereby a one-off unsedated FSIG is offered at age 55 [2].
BSSP FSIG is performed without sedation, although Entonox use is allowed. During the
test, the endoscopist examines the colon as far as the participant’s comfort and colonic
preparation allows. Early data from BSSP have shown that one in three patients reported
moderate or severe discomfort [3]. Optimal comfort is important not only to minimize harm to the participant, but
to optimize participation in the programme [4].
Water-assisted colonoscopy
Reports on water-assisted colonoscopy (WAC) go back 30 years [5]. The technique involves water infusion during scope intubation, instead of air or
Carbon dioxide (CO2) insufflation. Two separate modalities have been described, although several variants
are practiced: water immersion (WI) and water exchange (WE) [6]. WI involves water infusion to inflate the lumen during intubation, with aspiration
performed predominantly on withdrawal of the scope. During WE, aspiration of infused
water is predominantly during intubation; suction of residual air pouches or fecal
residue also takes place in this phase [6]. The principle of both techniques is to minimize colonic distention and to wash
the colon clean.
WAC, particularly the WE technique, may lead to improved patient comfort with less
sedation [7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]. Water may reduce friction between the endoscope and bowel wall, provide lubrication,
and help keep the sigmoid straighter on scope insertion.
A recent randomized trial by Wang et al showed that benefits from WAC are still observed
when the technique is applied solely during distal colon intubation, with the added
advantage of a shorter overall procedure time compared to total-colon water intubation
[22].
WAC may improve polyp detection by minimizing bowel distension, allowing subtle polyps
to become more easily identifiable as they appear less “flattened.” By achieving a
cleaner colon, improved mucosal visualization can be seen on withdrawal. Longer intubation
times described in some studies may also contribute to increased polyp detection [10]
[12]
[15]
[16]
[17]
[21]
[22]
[23]
[24]
[25]. WAC may also aid completion of difficult [26] or previously incomplete procedures (due to angulations or redundant colons) [27]. Described therapeutic indications for WAC include endoscopic resolution of sigmoid
volvulus and underwater polypectomy [28].
An increase in cecal intubation time (CIT) is a concern when performing WAC. Some
studies point to significant prolongation [23] while others describe similar CITs [19] when operators become comfortable with the technique.
Studies show that WAC is safe, with no interference with fluid and electrolyte status
[23].
Patients and methods
WASh trial
Trial hypothesis
We hypothesize that water-assisted sigmoidoscopy (WAS) reduces pain compared to CO2 insufflation, by minimizing bowel distension, allowing for a straighter passage of
the scope through the colon with less looping.
Primary and secondary outcomes
The primary objective is to ascertain if procedural pain, assessed post-procedure
and prior to discharge using a 4-point Likert scale (“None/Mild/Moderate/Severe”),
is reduced in WAS compared to CO2 insufflation in people undergoing unsedated flexible sigmoidoscopy as part of BSSP.
We chose to assess pain primarily by means of a Likert scale, as we feel it is more
clinically meaningful for a study that may lead to practice changes.
The key secondary outcome is adenoma detection rate (ADR), the key performance indicator
of sigmoidoscopy detecting meaningful colonic pathology.
The following criteria will be used to determine the overall success of the WAS technique;
WAS will be considered successful if either:
-
WAS comfort score (primary outcome) is significantly higher compared with CO2, with no indication[1] of ADR (key secondary outcome) being inferior; or
-
WAS comfort score (primary outcome) is not achieved (but comfort score not statistically
significantly inferior with WAS) but key secondary outcome achieved (ADR improved
with statistical significance)
A full list of secondary outcomes and how they will be measured is provided in [Table 1].
Table 1
Detailed description of secondary outcome measures.
|
Secondary
|
Rationale
|
Measure
|
|
1. ADR
|
To assess whether WAS affects ADR in a positive or negative manner
|
Percentage of procedures with adenomas detected
|
|
2. Mean adenomas per procedure (MAP)
|
To assess whether WAS affects MAP
|
Number of adenomas per procedure
|
|
3. Patient procedural pain
|
To assess whether WAS decreases pain
|
Visual analogue scale (vas) (0 – 100) post-procedure, pre-discharge
|
|
4. Patient experience
|
To assess whether WAS leads to a better overall patient experience. By utilising patient-derived
pain and experience assessments rather than nurse or endoscopist-derived ones
|
Post-discharge questionnaire assessing pain, embarrassment, and willingness to repeat
the procedure, expected versus experienced pain, overall satisfaction and symptoms
post-procedure. To be filled the day after and posted back to site.
|
|
5. Sigmoidoscopy insertion time (SIT)
|
To assess whether WAS affects sit and, consequently, overall procedure time
|
Duration of insertion
|
|
6. Sigmoidoscopy withdrawal time (SWT)
|
To assess whether WAS affects SWT, and, consequently, overall procedure time
|
Duration of withdrawal (in polyp-negative procedures)
|
|
7. Maximum extent of insertion
|
To assess whether WAS leads to deeper scope intubation
|
Rectum, distal sigmoid, proximal sigmoid, distal descending, proximal descending,
splenic flexure, distal transverse; as judged by endoscopist
|
|
8. Length of scope inserted
|
To be used as surrogate for how straight/looped the scope is (stratifying by segment
extent).
Note – this is not a measure of depth of insertion
|
Length of scope inserted just prior to withdrawal
|
|
9. Entonox use
|
To assess whether WAS affects need for Entonox in a positive or negative manner
|
Percentage of procedures where Entonox WAS used on demand. This will not be applicable
in procedures where participants prefer to start their procedure with Entonox use
|
|
10. Quality of mucosal views
|
To assess whether WAS influences quality of mucosal views, as a consequence of the
cleansing effect of water irrigation
|
Boston Bowel Preparation scale score for inspected segments, as assessed on withdrawal
|
|
11. Need for re-enema
|
To assess whether WAS affects re-enema rates
|
Percentage of procedures where a second, through-the-scope, enema WAS used.
|
|
12. Need for external hand pressures
|
To assess whether WAS affects need for hand pressure maneuvers during insertion; this
can be used as a surrogate for loop prevention
|
Percentage of procedures where hand pressure WAS required
|
|
13. Need for patient position changes
|
To assess whether WAS affects need for position changes during insertion
|
Percentage of procedures where patient position change WAS required
|
|
14. Technique conversion rates
|
To assess frequency, reasons and caveats leading endoscopists to switch between one
of the two study techniques.
|
Conversion rate from WAS to CO2, or CO2 to WAS technique
|
|
15. Volume of water and CO2 used
|
To calculate an average volume of water and CO2 needed for WAS and CO2 techniques, for health economics analysis reasons
|
Volume of water (irrigator, syringe washes) and CO2 (where possible as per CO2 pump specs) used in WAS and CO2 procedures
|
|
16. Scope looping
|
To assess whether WAS leads to less looping, and to correlate this to other study
outcomes, e. g. procedural pain.
|
Process described in relevant section of this protocol
|
|
17. Was learning curve
|
To define the endoscopist learning curve of WAS technique
|
Capture endoscopists’ reported confidence in performing the procedure and their attitude
towards the technique prior to trial commencement, as well as performance (e. g. procedure
times, extent of insertion, conversion rates) as the study progresses
|
ADR, adenoma detection rate; SIT, sigmoidoscopy insertion time; SWT, sigmoidoscopy
withdrawal time
Stratification variables for the study are screening center, scope diameter (adult,
pediatric) and history of hysterectomy. Subgroup analyses will be performed based
on these variables.
Trial design
This is a multicenter, prospective, two-armed, randomized single blinded trial designed
to evaluate performance of WAS in people referred for screening through the BSSP.
Best efforts will be made to keep participants blinded from the treatment although
we acknowledge this may not be possible in all instances.
We aim to randomize 1100 consecutive consenting participants to the trial with a 1:1
ratio between the two trial arms ([Fig. 1]), within a timeframe of 18 months. Considering the quick patient turnaround times
in BSSP lists, we have assumed an uptake rate of 20 % per list. We anticipate that
we will need to invite 5500 people to achieve this.
Fig. 1 Patient flowchart.
A patient trial information leaflet will be sent out to all potential participants
confirming attendance for BSSP FSIG 2 weeks prior to their procedure. This will be
done by the screening team and without involvement of the research team. No one except
the screening team will have access to participant-identifiable information. Participants
will be approached by a member of the research team on the day of the procedure and
given the opportunity to discuss the trial. If they are willing to participate, fulfil
the inclusion criteria and have no exclusion criteria, written consent will be obtained,
and pre-procedure data will be collected.
Inclusion criteria
Patients attending for screening FSIG via BSSP that can give informed consent.
Exclusion criteria
-
Absolute contraindications to sigmoidoscopy
-
Participants lacking capacity to give informed consent for the procedure
-
Previous distal colonic/rectal resection.
-
Ongoing antithrombotic treatment (apart from aspirin, which is permitted).
Withdrawal criteria
Participants can withdraw at any time without giving reasons and without it effecting
their further treatment.
Setting/participating centers
Participants will be recruited in five sites: four in the Northern Region (North Tees
and Hartlepool Hospital, Northumbria Hospital, South Tyneside Hospital and County
Durham and Darlington Hospitals) and St Mark’s Hospital, London. A list of interested
reserve sites is also in place should this is deemed necessary during recruitment.
Recruitment will begin at North Tees Hospital to allow testing of the protocol and
refinement of the data collection process ([Fig. 2]). If required, amendments will be performed and disseminated to participating sites
as appropriate.
Fig. 2 Trial flowchart.
Randomization
Participants will be randomized in a 1:1 ratio to either CO2 FSIG (Usual care) or WAS FSIG (Intervention). An electronic web-based randomisation
system will be used. The randomisation process will use dynamic allocation [29] to ensure a consistent balance to the allocation ratio of 1:1 (CO2: WAS) within stratification variables.
Sample size and power
The trial has been powered to detect a difference in the primary outcome of procedural
pain. Data from a BSSP post-procedure patient survey suggested 38.2 % felt moderate
to severe pain from their FSIG. An improvement to 30 % would be considered clinically
significant. Powered for this proportion of change with a 5 % significance level and
80 % power on a two-sided test, it is calculated that we would require 1048 participants
to complete the trial. Assuming that some cases will need to be changed from WAS to
CO2 and vice versa, we aim to recruit 1100 participants (550 per trial arm). It is estimated
that 20 % of invitees will finally agree to participate in the trial; therefore 5500
people will be invited.
Endoscopist selection criteria
Participating endoscopists will have a minimum experience of 300 BSSP procedures and
an ADR greater than 6.8 %. All procedures will be performed by endoscopists trained
in both CO2 and WAS techniques. We anticipate approximately 20 endoscopists will perform study
procedures across all sites.
Bowel Scope Screening Programme procedure
As per standard BSSP practice, participants will self-administer a phosphate enema
prior to the procedure. The procedure is performed without sedation. The participants
have the option of using Entonox. Where available, magnetic endoscope imaging can
be used. If the bowel preparation is deemed inadequate, a second, through-the-scope
enema may be given at the endoscopist’s discretion. The maximum extent of the test
is splenic flexure. Comfort of the participant during the bowel scope screening procedure
is paramount and the endoscopist will examine the colon as far as tolerance allows.
Polyps up to 10 mm can be removed during the procedure provided it is felt feasible
and safe to do so. BSSP conversion-to-colonoscopy guidelines will be followed, as
per standard practice.
Water-assisted sigmoidoscopy technique
The primary concept of the WAS technique employed in our trial is to keep the lumen
as collapsed as possible, thereby concertinaing the sigmoid colon, reducing the tendency
for looping and resulting in a straighter and “shorter scope” passage to descending
colon. WAS is a different technique than WAC and we will explain the principles of
this in the following paragraph.
The WAS technique consists of turning off the CO2 pump shortly after scope insertion through the anus, as soon as the rectal ampulla
has been visualized. Minimal water volume is then infused to achieve adequate luminal
views as the scope advances. Pockets of air encountered during intubation through
the sigmoid colon should be actively suctioned. We emphasise use of pulses of water
to achieve adequate luminal views to advance the scope, without necessarily aiming
to distend/fill the lumen with water. Suctioning of water/fecal residue is performed
as needed. The WAS technique is ideally performed without any gas insufflation; however,
one or two short blasts of CO2 are permitted, at the discretion of the endoscopist. Where possible, insufflated
gas should then be suctioned as soon as feasible, adhering to the principle of keeping
the colon as collapsed as possible.
At the maximal point of intubation, the CO2 pump is turned back on. CO2 insufflation at this point often “pushes” water/fecal residue proximally, allowing
deeper views. Scope withdrawal is done as per standard practice using CO2/water as needed.
Analysis of sigmoid looping
We plan to use an expert Delphi consensus to identify and agree upon important components
of sigmoid looping in relation to pain that are measurable on magnetic endoscope imaging
(MEI). Two assessors will then apply the components to a select number of test MEI
videos to measure agreement for each component. The agreed components can then be
applied to MEI videos, which have been recorded (when recording equipment are available)
from the WASh trial. This will allow us to correlate loop components with pain scores
and study looping patterns for each arm of the trial.
Training
An initial education package will be sent to endoscopists at participating sites.
This will include details of the WASh trial, current literature on WAC, a description
of the specific technique of WAS, a video demonstrating WAS, baseline questionnaire
and a non-mandatory training log.
Participating endoscopists will be invited to attend a training event which will comprise
an educational session to review details of the WASh trial, current literature on
WAC, breakdown of the WAS technique (including further videos) and live demonstration
of the technique. Endoscopists will be encouraged to practise WAS technique prior
to attending the training day. Concerns that may have arisen during the above “practice”
period will also be addressed on the event day.
Participating endoscopists will be contacted monthly during their training period,
to monitor progress made as well as to express any concerns regarding the trial and
the WAS technique. Additional one-to-one training sessions will be offered upon request,
before and during trial conduct, to address any issues regarding the WAS technique.
Prior to participating in the WASh trial, endoscopists will be required to have performed
at least 20 WAS cases at their sites, and confirm that they feel fully competent in
performing the WAS technique. We aim to observe rea- life procedures or a video recording
of each endoscopist performing WAS.
During the trial, endoscopists will be contacted every 2 months to give them an opportunity
to discuss WAS technique and to access further training/advice if required.
Adverse events
Risk of Adverse Events (AEs) with WAC is thought to be the same as with standard colonoscopy.
We assume this will also be the case for WAS.
The trial will measure AEs, which will be recorded in the BSSP database and on case
report forms. AEs will be recorded retrospectively for the 14-day period from the
day of the sigmoidoscopy, or until withdrawal.
We acknowledge that the information sent in advance to people invited for Bowel Scope
could induce anxiety and adversely affect attendance for screening. To address this,
we will capture the “Did Not Attend” (DNA)/cancellation rates and task the Data Monitoring
and Ethics committee (DMEC) with monitoring this.
Assessment and follow-up
Clinical follow-up will be as per routine clinical practice for each participating
unit. All participants with identified polyps will have their post-BSSP FSIG management
plan as usual [2]. Eligible, consented participants will remain in the trial for 14 days following
their procedure, for AE identification purposes. No additional visits are required.
The timescale for any outpatient appointments and subsequent care will be unaltered
by participation in the trial.
Data analysis
The study will be analyzed on an intention-to-treat basis and a full statistical analysis
plan incorporating a health economics analysis plan will be written and agreed to
prior to completion of data collection.
The primary outcome of pain will be analyzed using logistic regression to assess differences
between the two treatment groups. Two models will be created, the first where participants
reported either moderate or severe pain and the second for those that only reported
severe pain. Stratification variables along with gender, endoscopist and any other
variables deemed appropriate will be included within the regression models.
ADR will be analyzed using logistic regression models. The mean ADR rate for each
of the groups will be calculated and if the difference between groups is not statistically
significant but the percentages are within 3 % of each other, that will be considered
a suitable conclusion for the trial, as described in the aims section.
The Visual Analogue Scale (VAS) pain score, collected from participants on the day
of the procedure, will be assessed using analysis of covariance (ANCOVA) model adjusting
for the important variables as defined in the primary outcome regression model. Other
participant-reported outcomes such as embarrassment and overall satisfaction that
are collected the next day from the participant will be analyzed in the same way.
Further analysis of secondary outcomes will be completed with continuous variables
analyzed using ANCOVA models and categorical variables being analyzed using logistic
regression models. Sensitivity analysis will be completed using a dichotomy of the
Likert scale using none, mild and moderate versus severe. Due to the nature of the
data collection it is anticipated that missing data will be minimal, however, assessment
of missing data will be made and appropriate multiple imputation techniques will be
employed where necessary.
Where appropriate, subgroup analysis will be considered for certain cohorts that have
been deemed significant from the models described above, including previous hysterectomy,
irritable bowel syndrome, and diverticulosis, as well as depth of scope insertion
(segment and length of scope), scope diameter (adult vs paediatric) and model (e. g.
Olympus 240/260/290) and individual endoscopists. Outcomes will be assessed on an
intention-to-treat basis and subsequently on a per-protocol basis as applicable to
assess the sensitivity of the results.
A full statistical analysis plan will be written and ratified by the trial steering
committee (TSC) and DMEC. Data and all appropriate documentation will be stored for
a minimum of 15 years after study completion, including the follow-up period, in compliance
with regulatory authority archiving requirements.
Health economic analysis
The trial includes a health economics component, incorporating
-
Cost-effectiveness analyzes of WAS versus CO2 intubation
-
A discrete choice experiment (DCE) to explore relative preferences of participants
for individual attributes of sigmoidoscopy (pain, likelihood of missing an abnormality,
procedure time, bowel cleansing, risk of serious complication e. g. bleeding or perforation),
relative importance of different attributes, and how participants make trade-offs
between attributes. The DCE survey will be completed by participants the day after
their procedure
Cost-effectiveness
Cost-effectiveness analyses [30]
[31] will be undertaken to compare relative costs and effects of WAS versus CO2 techniques, using procedural pain score and number of adenomas detected as the measures
of effect. The incremental cost-effectiveness ratio (ICER) point estimate [30]
[31]
[32] will be calculated, expressed in cost per unit difference in pain and cost per unit
difference in adenomas detected.
Duration of procedures and staff levels/bands working in the room will be captured
to facilitate cost analysis of the impact, if any, of the trial technique to costs
in terms of time.
We will present a cost-effectiveness plan to illustrate scatter plots of the joint
distribution of the pairs of costs and effects. A cost-effectiveness acceptability
curve (CEAC) will be used to show the probability of WAS being cost-effective compared
to CO2 over a range of cost-effectiveness thresholds. These thresholds will present the
maximum acceptable ceiling ratio a decision-maker is willing to pay for one unit gained
in effect [31]
[33]. Sensitivity analysis, where appropriate, will be performed to explore the impact
of any assumptions made on results. We will conduct subgroup analysis on the basis
of gender or age, where appropriate.
Discrete choice experiment (DCE)
As there are no comparative thresholds for cost-effectiveness using pain and adenomas
detected as outcome measures, a discrete choice experiment (DCE) will be employed
to explore: (1) the relative preferences of participants for individual attributes
of sigmoidoscopy (pain, likelihood of missing an abnormality, procedure time, bowel
cleansing, risk of serious complication e. g. bleeding perforation); (2) the relative
importance of different attributes; and (3) how participants make trade-offs between
attributes [34]
[35]. DCE data will be analysed using logistic regression techniques.
Data monitoring and ethics
The DMEC will include an independent chair, independent clinician, independent statistician,
and WASh study statistician. The DMEC will review trial status during study conduct,
including accumulated outcome data and AEs, and will also comment on the statistical
analysis plan when convening.
Trial steering committee
The Trial Steering Committee will comprise an independent chair, two independent clinicians,
an independent health economist, independent statistician, representation from sponsor
site, WASh study statistician and health economist, chief investigator for the WASh
study and a patient and public involvement representative. The role of the Trial Steering
Committee is to supervise the trial to ensure that it is conducted to the rigorous
standard.
Trial period
The trial will last 30 months. Recruitment period will extend from December 2018 to
June 2019.
Protocol version
WASh BSSP Protocol V4.0, 8th Nov 2017.
Ethical considerations
Ethics approval gained from the North East Ethics committee who gave a favourable
outcome.
Sponsor
North Tees and Hartlepool NHS Foundation Trust will be the sponsor for this trial.
