Clinical trial NCT02976805: Multi-centre Failed Bowel Prep RCT
Official title: A Multi-centre Endoscopist Blinded Randomized Clinical Trial to Compare Two Bowel Preparations After a Colonoscopy With Inadequate Bowel Preparation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colonoscopy
Bowel Preparation
Lead sponsor: London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's
Sponsor class: OTHER
Collaborators: name: Academic Medical Organization of Southwestern Ontario
name: Pendopharm
name: University of Alberta
name: Université de Montréal
name: McGill University
name: University of Western Ontario, Canada
First posted: 2016-11-29
Enrollment: 196
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multi-centre randomized clinical trial comparing the efficacy of two different bowel preparation regimens for patients who have already failed a bowel preparation for colonoscopy.

Detailed description: PURPOSE

The purpose of this multi-centre randomized clinical trial is to compare two bowel preparation regimens for patients who fail to cleanse their colon during their index colonoscopy. Although many clinical trials already exist examining the optimal bowel preparation for colonoscopy in general, surprisingly none address patients who failed bowel preparation in the past. Failure to achieve bowel preparation is a result of complex factors, including underlying colonic dysmotility, co-morbidities, and concurrent medication usage and is rarely the result of patient non-compliance.(1) Given the frequency of inadequate bowel preparation, its negative impact on colonoscopy quality, the increased risk for an adverse event, and the need to repeat the procedure, an important public health need exists to address this question urgently.(1) This study will use many of the same methodology and investigators as an ongoing Canadian multicenter study titled, "The Bowel CLEAnsing: a National initiative ( B-CLEAN) " but on a smaller scale to answer this question.

BACKGROUND

Adequate bowel preparation is a prerequisite for high quality colonoscopy and is needed to maximize visualization of the colonic mucosa.(1-4) Unfortunately, inadequate bowel preparation is common and reported to occur in 4% to 17% of cases.(5-12) Procedures with poor preparation are more likely to be incomplete, have an adverse event, and are less likely to detect polyps.(1, 9, 13) Repeat colonoscopies within one year have shown a 36% miss rate for advanced adenomas in these patients.(12) Recognizing the importance of high quality colonoscopy, Cancer Care Ontario and other provincial health authorities now track adequacy rates for bowel preparation.

In cases of poor bowel preparation, the colonoscopy must be repeated, exposing patients to another invasive procedure and adding additional costs to the healthcare system. Although health economic data regarding colonoscopy utilization in Canada is sparse, an illustrative example from the United States is possible. Assuming 14.2 million screening colonoscopies are performed annually in the United States (14) of which 5% have inadequate bowel preparation (6, 8), a total of 710,000 colonoscopies have to be repeated at a cost of $763 million dollars, based on a per case cost of $1,075.(15) This is likely an underestimation of the true cost due to exclusion of non-screening colonoscopies in the calculation and the use of a low colonoscopy cost estimate based on the Nationwide Colonoscopy Program for the Uninsured.(15)

There are numerous definitions of inadequate bowel preparation and the term's lack of specificity contributes to the varied incidence of inadequate bowel preparation reported in the literature. The Boston Bowel Preparation Scale (BBPS) is a user friendly validated measure that is based on three colonic segment scores (right, transverse, left, each scored between 0 - 3) and is summed for a total score between 0 - 9.(16, 17)(Appendix A) Adequacy was recently formally defined in a large study involving 2,516 patients undergoing colonoscopies at 36 centres as a total score ≥6 and/or all segment scores ≥2.(18)

The optimal bowel preparation to use for repeat colonoscopy in patients who failed the initial preparation is unknown. However, a combination of a stimulant, such as bisacodyl, and a larger volume of an electrolyte and fluid balanced osmotic laxative, such as PEG, is often used. In a recent case series, Ibanez et al.(19) identified 83 patients with inadequate bowel preparation at their index colonoscopy. 51 patients agreed to a repeat colonoscopy using an 'intensive' regimen consisting of a low fibre diet, bisacodyl, and 3L split dose polyethylene glycol (PEG). Using this regimen, 90% had adequate bowel preparation at the second colonoscopy. However, the bowel preparation at the index colonoscopy was not given in a split dose manner in the majority of patients, which is now the standard of practice due to superior cleansing, and the lack of a control group makes an accurate assessment of efficacy impossible.(1) In another study, patients with inadequate bowel preparation after split dose PEG (4L) were offered a repeat colonoscopy the same day after ingestion of another 2L of PEG or a colonoscopy 1 week later using a low fibre diet, bisacodyl, and 4L split dose PEG.(20) There was no difference in adequacy of bowel preparation although 20% of cases were still inadequate and the lack of randomization and blinding threaten the validity of these results.

To date, no consensus exists regarding the optimal bowel preparation regimen to use in patients with inadequate cleansing due to the absence of clinical trials. Given 4% to 17% of colonoscopies have inadequate bowel preparation, there is a significant public health need to address this issue.(5-12, 21-23) A highly efficacious yet tolerable bowel preparation regimen is needed for these patients to ensure adequate cleansing for their next procedure. The objective of this multi-centre randomized clinical trial will be to compare the efficacy of two regimens in achieving adequate bowel preparation after failing to cleanse at the index colonoscopy.

PROJECT DESCRIPTION

3.1 Study Design, Randomization, and Blinding This multi-centre randomized clinical trial will compare two bowel preparation regimens for patients who have already failed bowel preparation at their index colonoscopy, defined as inadequate visualization to detect lesions \> 5 mm and requiring a shortened colonoscopy interval as a result. This clinical definition of failed bowel preparation was chosen instead of the BBPS since the latter may not be available from the index colonoscopy depending on the endoscopist. However, where possible, the BBPS at the index colonoscopy will be recorded. A total of four centres from the original B-CLEAN study group have agreed to participate (Appendix E).

Subjects will be randomized to one of 2 arms (see '3.2 Selection of Bowel Preparation Regimens' for details). Randomization will be performed centrally using Research Electronic Data Capture (REDCap) in a 1:1 allocation in blocks of varying sizes stratified by site. In addition, data entry will be performed online through REDCap.

Blinding of the endoscopist will be strictly enforced. Endoscopists are required to remain blinded to the subject's bowel preparation until after completing the bowel cleanliness section of the CRF. Subjects will be asked to not discuss the bowel preparation with any endoscopy unit staff except for research personnel until the colonoscopy preparation rating has been completed by the endoscopist. Unfortunately, blinding of the patient (ie. double blinding) is impossible due to the volume differences between the two bowel preparation regimens.

3.2 Selection of Bowel Preparation Regimens Regimen A: 4L PegLyte + 15 mg bisacodyl Regimen B: 6L PegLyte + 15 mg bisacodyl

There is no standard bowel preparation utilized after a colonoscopy with failed bowel preparation. Regimen A was adapted from Ibanez et al.(19) who used a regimen consisting of 3L polyethylene glycol (PEG) and 10 mg bisacodyl with reasonable effectiveness. In our study, 4L PEG is used instead of 3L to avoid reducing the amount of PEG consumed by those who were originally prepped with 4L PegLyte at their index colonoscopy. 15 mg bisacodyl was used instead of 10 mg for consistency with dosing used in BiPegLyte. This regimen is modestly more intensive than standard bowel preparation due to an additional 2L PEG compared to BiPegLyte and 15 mg bisacodyl compared to 4L PegLyte.

Regimen B was adapted from Kim et al.(20) as a more intensive yet tolerable regimen. In this regimen, 6L of PEG is combined with 15 mg of bisacodyl.

3.3 Bowel Preparation \& Colonoscopy Subjects will be randomized in a 1:1 allocation to either regimen A or B. Regardless of randomization, subjects will be instructed to follow a low fibre diet for 2 days followed by clear fluid diet for 24 hours prior to the scheduled colonoscopy. The time and amount of PEG the subjects will consume will depend on randomization.(APPENDIX B) To optimize patient adherence, all participants will receive a handout with their specific bowel preparation instructions based on their randomization.

All colonoscopies will be performed within 12 weeks of randomization but not within 2 weeks of index colonoscopy (ie. washout period from the index bowel preparation). Procedures will be performed according to local standard operating procedures. All participating endoscopists will complete standardized training and calibration in the use of the Boston Bowel Preparation Scale prior to the start of the study at http://www.bmc.org/gastroenterology/research.htm. A record of training will be sent to the coordinating centre.

For subjects who do not present for their colonoscopy after randomization (ie. forgot appointment), they may remain in the study and be prepped with the same regimen again as long as their next colonoscopy is not scheduled within the next two weeks. For subjects who decline ongoing study participation, they can withdraw and follow up with their physician.

3.4 Baseline Data Collection

1. Age
2. Gender
3. Weight
4. Height
5. Primary Language
6. Highest level of education
7. Patient's ability to understand and follow the bowel preparation directives at home as deemed by the research personnel (Y/N)
8. Charlson co-morbidity index score (24)

7. Irritable bowel syndrome according to ROME III criteria (25) 8. Functional constipation according to ROME III criteria (25) 9. Neurologic disorders: Parkinson's disease, multiple sclerosis, cerebral palsy, other 10. Previous abdominal/pelvic surgery 11. Established diagnosis of inflammatory bowel disease. 12. Medication usage 13. Information regarding index colonoscopy

1. Method of communication for index colonoscopy
2. Bowel preparation used
3. Use of split dose bowel preparation (Y/N)
4. Did patient followed the diet as prescribed (Y/N)
5. Did patient take bowel preparation medication as prescribed (Y/N)
6. Subject willingness to repeat the index bowel preparation
7. Subject incontinence \& travel time with index bowel preparation 14. Indication for index colonoscopy (screening, surveillance, diagnostic)

3.5 Statistical Considerations Sample size was calculated as follows. Assuming 70% adequacy among those randomized to regimen A, 87.5% adequacy among those randomized to regimen B, significance of 0.05, and power of 0.8, 85 patients are required in each group (total = 170). An adequacy rate of 70% was selected based on the existing literature.(19, 20) Additional factors considered in arriving at this figure include the lack of split dosing used at the index colonoscopy (19), inadequate intake of PEG at the index colonoscopy (20), and the performance of the second colonoscopy within a week of the first.(20) An adequacy rate of 87.5% was selected based on a 25% relative increase in adequacy to be considered clinically significant. Based on a target sample size of 170 and a conservative 15% dropout, 196 subjects are required for the study.

Descriptive statistics will be reported as mean (SD), median (range), and proportions as appropriate. Data will be analyzed as intention-to-treat and hypothesis testing performed with t-test, chi-square, and Fisher's exact test as appropriate. Pre-planned secondary analyses will include per-protocol analysis, stratification by timing of colonoscopy (ie. morning versus afternoon procedures), and stratification by initial bowel preparation used.

Eligibility criteria: Inclusion Criteria:

1. Anyone undergoing a repeat colonoscopy due to failed bowel preparation at index colonoscopy. Failure is defined as preparation quality inadequate to detect lesions \> 5 mm after washing and requiring a shortened colonoscopy interval as a result.
2. Age \> 18 years
3. Outpatient colonoscopy
4. Indication for full colonoscopy

Exclusion Criteria:

1. Subject refusal
2. Able to comprehend the trial
3. Index colonoscopy performed as an inpatient
4. Pregnancy or breastfeeding
5. Allergies to the employed bowel preparations
6. Any colonic surgery
7. History of ischemic colitis
8. Congestive heart failure
9. Chronic renal failure
10. Cirrhosis
11. Severe electrolyte imbalance
12. Non-adherence to index bowel preparation defined as failure to follow diet instructions and/or consume the entire volume of bowel preparation medication as prescribed for any reason (ex. eating a normal diet on the day of colonoscopy, PEG intolerance, etc...)
13. Use of bowel preparation in an off-label manner for the index colonoscopy.
14. Inability to follow verbal and written instructions in English or French.
15. Ileus, gastric outlet obstruction, gastrointestinal obstruction, bowel preforation
16. Toxic coitis or toxic megacolon
17. Acute surgical abdomen including appendicitis
18. Gastroenteritis and acute diverticulitis

Primary outcomes:
measure: Adequate bowel preparation
timeFrame: Once after colonoscopy
Secondary outcomes:
measure: Mean BBPS total score
timeFrame: Once after colonoscopy
measure: Bowel preparation was adequate after washing to visualize lesions > 5 mm of importance to the procedure and there is no need to shorten the interval of the next colonoscopy
timeFrame: Once after colonoscopy
measure: Validated patient tolerability questionnaire for bowel preparation score
timeFrame: Once after colonoscopy
measure: Bowel preparation related adverse event
timeFrame: After colonoscopy and 14 days after colonoscopy
measure: Right sided BBPS sub-score
timeFrame: Up to 4 weeks after colonoscopy
Other outcomes:
measure: Detection rate by histology (polyp, adenoma, advanced adenoma (>1 cm, villous component, sessile serrated adenoma, or high grade dysplasia), and adenocarcinoma)
timeFrame: Once after colonoscopy
measure: Cecal intubation rate
timeFrame: Once after colonoscopy
measure: Subject product completion (% of total required intake)
timeFrame: Once after colonoscopy
measure: Subject willingness to repeat the preparation
timeFrame: Once after colonoscopy
measure: Subject incontinence & travel time
timeFrame: Once after colonoscopy
measure: Polyp per colonoscopy
timeFrame: Up to 4 weeks after colonoscopy
measure: Adenoma per colonoscopy
timeFrame: Up to 4 weeks after colonoscopy
measure: Fecal incontinence rate
timeFrame: Up to 4 weeks after colonoscopy
Locations:
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: CHUM
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
Study officials:
affiliation: Western University
name: Michael Sey, MD
role: PRINCIPAL_INVESTIGATOR
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