The Effect of Adding Lubiprostone to Standard Large-Volume PEG-ELS on The Quality of Inpatient Colonoscopy Preparation

1. INTRODUCTION AND BACKGROUND 2.1. Study rationale and aim An excellent bowel preparation is crucial to perform a high-quality colonoscopy and essential to visualize the entire colonic mucosa and to increase the safety of therapeutic maneuvers. Prior studies revealed that inpatient setting was associated with higher rate of poor bowel preparation which led to lower rate of procedure completion. The addition of Lubiprostone to standard PEG-ELS bowel preparation for colonoscopy was evaluated in the outpatient setting and revealed significantly better colon cleansing, decrease total length of procedure, and improved the overall patient satisfaction with the preparation.

The aim of this trial is to evaluate the effect of adding Lubiprostone to standard large-volume PEG-ELS on the bowel preparation for inpatient colonoscopy.

2.2. Background Colonoscopy is a procedure that permits direct visualization, examination and treatment of the rectum, colon and terminal ileum. It can be used for both diagnostic and therapeutic purposes. In order to perform a high-quality colonoscopy examination, the American Society of Gastrointestinal Endoscopy/American College of Gastroenterology Taskforce on Quality in Endoscopy committee established a pre-, intra- and post-procedural quality indicators. Bowel preparation is one of the most important pre-procedural indicators, as an excellent preparation is crucial to visualize the entire colonic mucosa and to increase the safety of therapeutic maneuvers. Multiple studies revealed rates of incomplete colonoscopy between 10-20%, Sidhu et al revealed a rate of 7.8% of incomplete colonoscopies with inadequate bowel preparation being the most common culprit. It has been reported that inadequate or poor preparation occurs in 20-25% of colonoscopies in the United States. The diagnostic yield, safety and quality indicators (adenoma detection rate, withdrawal time and cecal intubation rate) of colonoscopy can be inversely affected by inadequate or poor bowel preparation, as it can lead to: Increase procedural duration, cancel or repeat procedures, increase health costs, a potential increase in complications and increase probability of missing neoplastic lesions or adenomatous polyps (28-42% patients had adenomas on repeated exam within 3 years).

Factors that can be associated with inadequate or poor bowel preparation has been evaluated by researchers in order to improve this quality indicator. It has been shown that inadequate preparation is more likely in the following situations: Inpatient status, prior inadequate bowel preparation, advanced age, comorbidities (obesity, cirrhosis, stroke, dementia, and Parkinson's), language barrier, polypharmacy, late colonoscopy starting time and failure to follow preparation instructions. Ness et al and Almadi et al in their studies found that inpatient setting was associated with higher rate of poor bowel preparation which led to lower rate of procedure completion and terminal ileum intubation. An ideal bowel cleansing preparation should be safe, tolerable, affordable, and can reliably empty the colon in a timely fashion without altering the colonic mucosa histology. The large-volume polyethylene glycol-electrolyte solution (PEG-ELS) is one of the most used FDA approved bowel preparation methods. PEG-ELS is an inert polymer of ethylene oxide formulated as a non-absorbable solution which is osmotically balanced with non-fermentable electrolyte solutions. It passes through the gastrointestinal tract without net absorption, secretion, or significant effect on fluid and electrolyte shift. Giving part of the bowel preparation does on the same day as the colonoscopy (termed split-does) results in a higher quality colonoscopy examination compared with ingestion of the entire preparation on the day or evening before colonoscopy.

As no available preparation has all of the ideal characteristics, studies evaluated the effect of adding other medications to enhance the quality of the preparation. The routine addition of prokinetic agents or bisacodyl to one of the standard regimens (Polyethylene glycol-electrolyte solution) did not improve patient tolerance or colonic cleansing.

Lubiprostone is a derivative of prostaglandin E1 which has been shown to be effective in treating Chronic Idiopathic Constipation, Opioid Induced Constipation and Irritable Bowel Syndrome-Constipation (IBS-C). Lubiprostone works by stimulating and inducing the secretion of chloride by activating chloride channel Type-2 and cyctic fibrosis transmembrane conductance regulator chloride channels in the apical membrane of the intestinal epithelial cells. Ultimately, the release of chloride ions from the cells into the intestinal lumen results in increase fluidity within the lumen itself. Furthermore, the increase of fluid contents within the lumen results in increase luminal distention which promotes the gastrointestinal tract motility, resulting in an increase in intestinal and colonic transit. By increasing the fluid content within the luminal wall and increasing intestinal and colonic transit, the resultant benefit is softening of stool and rather rapid and facilitated emptying of colonic contents which results in improvement in constipation and efficient colonic emptying.

Joel et al, and Banerjee et al evaluated the addition of Lubiprostone to standard PEG-ELS bowel preparation for colonoscopy performed in the outpatient setting. They showed significantly better colon cleansing, decreased total length of procedure, and improved overall patient satisfaction with the preparation. Grigg et al revealed a trend toward improved quality of colonoscopy preparation by adding two doses of Lubiprostone to standard PEG in diabetic patients undergoing outpatient screening colonoscopy. Documentation of quality of bowel preparation is an important post-procedural quality indicator. The Boston Bowel Preparation Scale is one of the most commonly used validated systems in the literature for documentation of the colonoscopy preparation. It is a 10-point (0-9) summation score assessing bowel preparation quality in 3 segments of the colon after all cleansing maneuvers during colonoscopy.

2.3. Risk/Benefit assessment 2.3.1. Known potential risks Lubiprostone is an approved and licensed medication. The Product/Safety Information published on the company website (https://www.amitiza.com/hcp/safety-indication/chronic-idiopathic-constipation) was used as the primary source of the potential risks associated with Lubiprostone use.

"Lubiprostone is not for everyone". It is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. It should be avoided in patients with severe diarrhea and during pregnancy (unless the potential benefit justifies the potential risk to the fetus). Caution should be exercised when it is administered to a nursing woman. These were included as exclusion criteria. Syncope, hypotension and dyspnea have been reported within an hour of the first dose or subsequent doses of Lubiprostone and generally resolve prior to the next dose, but may recur with repeat dosing. In clinical trials of Lubiprostone (24 microgram (mcg) twice daily vs placebo), the most common adverse reactions (incidence > 4%) were nausea (29% vs 3%), diarrhea (12% vs 1%), headache (11% vs 5%), abdominal pain (8% vs 3%), abdominal distension (6% vs 2%), and flatulence (6% vs 2%). There was no clinically significant changes in serum electrolyte levels in adult patients with CIC receiving Lubiprostone.

Other potential risks associated with PEG-ELS and colonoscopy procedure are not included in this study protocol as they are considered part of the standard of care required for patient evaluation and not part of this research study.

2.3.2. Known potential benefits The addition of Lubiprostone to standard PEG-ELS bowel preparation for colonoscopy was evaluated in the outpatient setting and revealed significantly better colon cleansing, decrease total length of procedure, and improved the overall patient satisfaction with the preparation. This would potentially result in reduce health costs, decrease complications rate and enhance the accuracy of neoplastic lesions or adenomatous polyp detection rates.

3 STUDY OBJECTIVES AND OUTCOMES 3.1 Objectives 3.1.1 Primary objective The primary objective of this trial is to evaluate the effect of adding Lubiprostone to standard large-volume PEG-ELS on the bowel preparation for inpatient colonoscopy.

3.1.2 Secondary objectives

The secondary objectives of this trial are:

1. To determine the adverse events related to the addition of Lubiprostone to large-volume PEG-ELS.
2. To determine the overall patient satisfaction with the bowel preparation regimen with the addition of Lubiprostone to large-volume PEG-ELS.