
==== Front
Int J Colorectal Dis
Int J Colorectal Dis
International Journal of Colorectal Disease
0179-1958
1432-1262
Springer Berlin Heidelberg Berlin/Heidelberg

39289199
4718
10.1007/s00384-024-04718-4
Research
Evaluation of the efficacy of polyethylene glycol in combination with different doses of linaclotide in a fractionated bowel preparation for colonoscopy: a prospective randomized controlled study
Liu Wan-qi 1
Shu Lei 2
Zhou Xiaoli 2
Wang Xiao-feng 3
Liu Song 4598675@qq.com

2
Shi Zhao-hong zhaohshi@hotmail.com

2
1 https://ror.org/006teas31 grid.39436.3b 0000 0001 2323 5732 Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Chinese Medicine, Shanghai, 200032 China
2 https://ror.org/021ty3131 grid.410609.a 0000 0005 0180 1608 Department of Gastroenterology, Wuhan No.1 Hospital, Wuhan, 430022 Hubei Province China
3 https://ror.org/05kqdk687 grid.495271.c Ezhou Traditional Chinese Medicine Hospital, Ezhou, 436001 Hubei Province China
17 9 2024
17 9 2024
2024
39 1 1436 9 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background and aim

The ideal bowel cleansing program still needs to be explored. The aim was to compare the bowel cleansing effect and patient tolerance of low-dose polyethylene glycol (PEG) combined with different doses of linaclotide in fractionated bowel preparation.

Methods

The subjects were randomly assigned to the 3LPEG group, 2LPEG + 2L group, or 2LPEG + L group. The primary outcome was to use the Ottawa Bowel Preparation Scale (OBPS) to evaluate the efficacy of bowel cleansing, and the secondary outcomes were the detection rate of adenomas and polyps, adverse reactions, tolerance, and defecation dynamics; subsets of patients with chronic constipation and irritable bowel syndrome were also analyzed.

Results

A total of 753 patients were randomly assigned. In ITT analysis, the success of preparation of the 2LPEG + 2L group was better than that of the 2LPEG + L group or the 3LPEG group (92.0% vs. 82.3% vs. 82.1%; P = 0.002). Compared with the 3LPEG group, the 2LPEG + L group showed similar but non-inferior results (82.3% vs. 82.1%, P > 0.05). The 2LPEG + 2L group was similar to the 2LPEG + L group in terms of adverse reaction, tolerance, willingness to reuse, and sleep quality, but both were superior to the 3LPEG group. In a subgroup analysis of chronic constipation, the 2LPEG + 2L group had the best cleansing effect on the right colon and mid colon, while in the subgroup analysis of irritable bowel syndrome, the tolerance was better in the 2LPEG + 2L group and the 2LPEG + L group than the 3LPEG group.

Conclusions

2LPEG + 2L is a feasible bowel preparation regimen.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00384-024-04718-4.

Keywords

Polyethylene glycol
Linaclotide
Bowel preparation
Colonoscopy
issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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pmcIntroduction

Colonoscopy is an important tool for screening, diagnosis, and treatment of colorectal diseases [1]. The quality of bowel preparation determines the degree of visualization of the bowel mucosa, which is one of the key factors in the successful performance of colonoscopy [2]. The latest European Society of Gastrobowel Endoscopy guidelines recommend that the quality of adequate bowel preparation should be ≥ 90% [3]. However, the percentage of inadequate bowel preparation in clinical practice is as high as 20–30% [4]. Inadequate bowel preparation not only increases operational difficulty, prolongs the examination time [5], shortens the interval between colonoscopies [6], and increases the cost of health care [7], but also affects the adenoma detection rate (ADR) [8, 9]. Bowel cleansers are critical to the quality of bowel cleansing [10]. Polyethylene glycol (PEG) is currently the first-line bowel cleansing solution [11]. However, the use of large doses of PEG (3–4 L) and its unpleasant taste reduces patient compliance, while large doses of PEG increase blood volume by 6–17%, which may exacerbate heart failure in some patients [12]. Therefore, past studies have mostly explored various supplements on top of reduced PEG intake. A more widespread PEG adjuvant is ascorbic acid, a non-absorbable osmotic agent, but this causes an electrolyte imbalance and a risk of reduced detection of polyps and colorectal cancer [13, 14], as well as a prohibition on patients with phenylketonuria or glucose-6-phosphate dehydrogenase deficiency [15]. Thus, it is evident that the current combinations of PEG with various laxatives are associated with varying compliance and adverse events and need to be further investigated.

Linaclotide is a pro-secretory agent approved by the US Food and Drug Administration for the treatment of constipated irritable bowel syndrome (IBS-C) and chronic adult idiopathic constipation (CIC), and by the European Medicines Agency for the treatment of moderate to severe IBS-C in adults. It can activate guanylate cyclase C (GC-C) receptors located in the apical cell membrane of the bowel epithelium, leading to an increase in intracellular and extracellular cyclic guanosine monophosphate (cGMP) levels. Increased intracellular cGMP stimulates chloride and bicarbonate ion secretion and inhibits sodium absorption, leading to increased fluid volume in the bowel lumen and accelerated gastrobowel transit, and relieving constipation [16, 17]. In addition, linaclotide relieves abdominal pain, which may be related to its increase in extracellular cGMP and inhibition of visceral injury receptors [18]. The ability of linaclotide to activate GC-C receptors is not affected by the pH of the bowel lumen, and it is stable to both acid and pepsin [17], not absorbed into the bloodstream [19], and is degraded and metabolized in the bowel tract. The most common adverse effect of linaclotide is diarrhea [20], but most of the events are mild or moderate in severity, and no significant side effects such as electrolyte disturbance, renal impairment, or even death have been reported [21]; thus, this is exactly what is needed for a safe bowel preparation. For example, a study showed that 1 L PEG in combination with 290 µg linaclotide was not inferior to 2 L PEG in terms of bowel cleansing, and had a favorable safety profile with better tolerability and higher willingness to repeat in a low-risk population [22].

The guideline recommends the use of 3 L of PEG (3LPEG) in divided doses as a bowel preparation protocol in China [23]. However, there is a risk of poor patient compliance with a 3-L fluid volume. Other related studies have shown that the use of linaclotide is dose-dependent, and its activity is controlled by administering it as a discrete oral dose [24]. Therefore, we designed this study to compare the efficacy, bowel movement kinetics, safety, and tolerability of PEG in combination with different doses of linaclotide for bowel preparation.

Patients and methods

Design and setting

The study design was a prospective, single-blind, randomized controlled trial to be conducted from December 2022 to March 2023 at the Gastrobowel Endoscopy Center of Wuhan No. 1 Hospital, a tertiary care hospital in Wuhan, Hubei Province, China. The Gastrobowel Endoscopy Center is capable of performing approximately 18,000 colonoscopies per year. The study protocol was approved by the ethics committees of Wuhan No.1 Hospital (number: 2022–53) and strictly followed the principles of the Declaration of Helsinki and good clinical practice guidelines. All patients signed a written informed consent before study registration.

Patients

Patients who were between the ages of 18 and 65 years, planned to have colonoscopy, committed to comply with the study procedures, and cooperated with the implementation of the full study were considered for inclusion in this study.

Exclusion criteria were as follows: (1) severe heart failure (New York classification III or IV); (2) recent acute myocardial infarction or unstable angina; (3) uncontrolled hypertension; (4) chronic kidney disease; (5) suspected bowel obstruction or perforation; (6) prior to bowel resection; (7) gastroparesis; (8) diarrhea more than three times a day; (9) cirrhosis of the liver or ascites; (10) pregnant or lactating women; (11) those with mental illness who could not cooperate with the examination; (12) anyone allergic to bowel preparation drugs.

Randomization and masking

All patients requiring colonoscopy were screened by physicians and after passing the inclusion and exclusion criteria, the study protocol was explained, and patients agreed to undergo the trial and signed an informed consent form. A random number table was generated in SPSS (version 26.0; IBM Corp., Armonk, NY, USA) by a statistical programmer not involved in this study, and subjects who met the criteria were randomized into three groups in a 1:1:1 ratio according to the random number table by a gastrobowel endoscopy center nurse who was not directly involved in the colonoscopy, data collection, or analysis of the results.

This study was blinded to the endoscopist and evaluator, and subjects were reminded before colonoscopy not to disclose their assigned group to the operating team. Both patients and the clinical study coordinator administering the bowel cleansing preparation were unblinded due to the apparently different preparation methods between groups.

Bowel preparation protocol

Study participants were told to eat a low-fiber diet with no vegetables, fruits, grains, or other indigestible foods throughout the day 1 day before the colonoscopy, and to finish eating by 6 pm, after which they fasted.

Patients assigned to the 3LPEG group received 1 L PEG at 8 pm 1 day before the colonoscopy and 2 L PEG 6 h before the examination on the examination day. Patients in the 2LPEG + 2L group received one linaclotide capsule (290 µg; Almac Pharma Services Limited, Craigavon, UK) at 8 pm followed by 1 L PEG at 8 pm, then one linaclotide on the examination day 7 h before the examination and 1 L PEG 6 h before. Patients in the 2LPEG + L group received one linaclotide 30 min before dinner 1 day before the colonoscopy and 1 L PEG at 8 pm, then 1 L PEG 6 h before the examination on the examination day. The colonoscopy was performed using intravenous sedation with propofol, which is the usual method of anesthesia for painless endoscopy in China.

For all groups, the PEG was prepared and taken by dissolving 1 sachet of polyethylene glycol bulk in 1000 mL of warm boiled water and drinking 250 mL every 10–15 min over 1 h; during this period, patients were advised to walk appropriately and massage the abdomen in a clockwise circular motion to accelerate bowel motility.

Since this study was a split bowel preparation protocol, to improve patient compliance, all patients were given written instructions on how to properly perform bowel preparation, which provided detailed instructions on the dietary measures required for bowel preparation and how to perform the bowel preparation protocol for their group in easy-to-understand language and visuals, which were also explained orally by a nurse.

Primary outcome assessment

The primary outcome indicator was bowel preparation efficiency, which was assessed using the Ottawa Bowel Preparation Scale (OBPS). All colonoscopies were scored simultaneously and consistently by five board-certified endoscopists with more than 10 years of practice experience, and one fellow in training. To achieve satisfactory agreement on the OBPS (kappa index ≥ 0.60), the endoscopists and the fellow performed a calibration exercise using the OBPS on 50 colonoscopies prior to the start of the study, resulting in a pre-study kappa value of 0.82, indicating good agreement.

The OBPS consists of two parts: the first part rates the effectiveness of cleansing of the ascending, middle (transverse and descending) and rectosigmoid segments of the colon (0–4, excellent–poor); the second part rates the total fluid volume (0–2, little–large). The total score is the sum of the two parts and ranges from 0 (excellent) to 14 (poor). A total score of < 6 is considered adequate bowel preparation [25].

Secondary outcome assessment

Secondary indicators included the following: (1) OBPS; (2) polyp detection rate/adenoma detection rate/cancer detection rate; (3) number of polyps/adenomas per patient; (4) terminal ileal intubation rate/cecal intubation rate; (5) withdrawal time; (6) bowel movement kinetics (time between preparation and colonoscopy, first time of defecation, defecation frequency, final effluent); (7) adverse events; (8) sleep quality; (9) compliance; (10) satisfaction; (10) willingness to reuse.

Information related to bowel preparation, including time of first bowel movement, number of bowel movements, nature of the last discharge, occurrence of adverse reactions, tolerance score, compliance, sleep quality, and willingness to repeat, was collected from patients through a small program questionnaire prior to colonoscopy.

Polyp detection rate (PDR) was defined as the proportion of at least one type of polyp detected. Adenoma detection rate (ADR) was defined as the proportion of at least one adenoma detected. Cancer detection rate was defined as the proportion of at least one colon cancer detected. The number of polyps/adenomas per patient was defined as the average number of polyps/adenomas detected per patient. When a polyp was encountered and required removal at the time of exit, the time to remove the lesion was recorded, and withdrawal time was defined as the time from the cecum to exiting the anus, minus the time to remove the lesion in between.

Because there is no validated scale for assessing bowel preparation tolerance [26], tolerance was quantified using a visual analogue scale (VAS) score (1–10; 1 for the most favorable outcome and 10 for the least favorable outcome assessment). Sleep, as measured by usual sleep, was rated as good or bad. Willingness to reuse was answered as “yes” or “no.” Good adherence to bowel preparation was defined as taking at least 75% of the bowel cleanser or taking the medication as prescribed.

Statistical analysis and sample size estimation

This study was a randomized controlled trial, and our primary study outcome was bowel preparation efficiency. Since it was not possible to estimate the effect size of similar studies in the past, based on the reviewed literature and pre-experimental studies, it was assumed that the bowel preparation efficiency rate was 95%, 85%, and 90% in the 2LPEG + 2L group, 2LPEG + L group, and 3LPEG group, respectively [23, 27]. Bilateral α = 0.05 was set and the degree of certainty was 90%. The total sample size of the three groups was calculated using PASS15 software to obtain 684 cases, and the final minimum number of study subjects needed for the 2LPEG + L group, 3LPEG group, and 2LPEG + 2L group was 251 cases each, considering a 10% lost visit rate calculation, for a total of at least 753 study subjects included.

Quantitative information was expressed as mean (standard deviation) or median (interquartile range). The analysis of variance or rank sum test was used for comparison between groups, depending on the distribution of the data. Qualitative data were expressed as frequencies and percentages, and the chi-square test or Fisher’s exact probability test was used. The test level for comparison among the three groups was α = 0.05, which means that P ≤ 0.05 was considered statistically significant; two-way comparisons between groups were corrected using the Bonferroni method.

All randomly assigned patients were included in the intention-to-treat (ITT) analysis, except for those who did not undergo colonoscopy. Patients who met the requirements of the ITT analysis and took the required bowel cleanser and completed the colonoscopy were included in the per-protocol (PP) analysis. Bowel cleansing success and OBPS analysis were performed on the ITT and PP populations. The PP population was also analyzed for colonoscopy outcomes such as PDR, ADR, and cecum insertion rate, and the ITT population was analyzed for safety and tolerability. Finally, cleansing outcomes, safety, and tolerability analyses were performed in patients with chronic constipation and irritable bowel syndrome (IBS). Data from this study were analyzed using SPSS (version 26.0; IBM Corp.)

Results

Participant characteristics

A total of 753 patients were randomized in a 1:1:1 ratio, of whom four patients (one in the 2LPEG + 2L group and three in the 2LPEG + L group) were excluded from the analysis because they cancelled their colonoscopy (no medication was confirmed by telephone follow-up), and 749 patients were finally analyzed by ITT. Ten patients did not take their medication as prescribed (one in the 2LPEG + 2L group, five in the 2LPEG + L group, and four in the 3LPEG group), and two patients did not complete their colonoscopy because of bowel stricture (two in the 3LPEG group, five in the 2LPEG + 2L group, and four in the 3LPEG group), and two patients did not complete colonoscopy because of bowel stricture (two in the 3LPEG group). The final PP analysis was performed on 737 patients (Fig. 1). There were no significant differences in baseline characteristics between the two groups (Table 1). There was no statistically significant difference between the three groups in time between completion of bowel preparation and initiation of colonoscopy (341.59 (50.30) vs. 349.22 (51.98) vs. 341.81 (50.56), P = 0.165). In addition, the baseline characteristics of the constipation and irritable bowel syndrome subgroups were analyzed and were generally consistent among the three groups.Fig. 1 Flowchart of the study

Table 1 Baseline characteristics (intention-to-treat population)

Variable	2LPEG + 2L1
(n = 250)	2LPEG + L2
(n = 248)	3LPEG3
(n = 251)	P-value	
Age, mean (SD), years	50.14 (11.64)	51.54 (9.90)	50.68 (12.01)	0.341	
Sex, male, n (%)	126 (50.4%)	115 (46.4%)	127 (50.6%)	0.568	
BMI, mean (SD), kg/m2	23.33 (3.10)	23.05 (3.19)	23.65 (3.50)	0.122	
Grade of education, n (%)				0.073	
 Elementary or middle school	52 (20.8%)	79 (31.9%)	64 (25.5%)	
 High school	103 (41.2%)	84 (33.9%)	90 (35.9%)	
 University	95 (38.0%)	85 (34.3%)	97 (38.6%)	
Medical history, n (%)	
 Hypertension	58 (23.2%)	58 (23.4%)	44 (17.5%)	0.192	
 Diabetes mellitus	20 (8.0%)	13 (5.2%)	20 (8.0%)	0.387	
 Coronary heart disease	17 (6.8%)	11 (4.4%)	13 (5.2%)	0.494	
 Chronic constipation	44 (17.6%)	40 (16.1%)	56 (22.3%)	0.180	
 Others	2 (0.8%)	5 (2.0%)	3 (1.2%)	0.483	
 Previous abdominal operation, n (%)	26 (10.4%)	38 (15.3%)	24 (9.6%)	0.098	
 Previous colectomy, n (%)	1 (0.4%)	0 (0.0%)	3 (1.2%)	0.175	
 Previous bowel polypectomy, n (%)	34 (13.6%)	35 (14.1%)	29 (11.6%)	0.668	
 Tricyclic antidepressants, n (%)	1 (0.4%)	6 (2.4%)	4 (1.6%)	0.170	
Indications, n (%)				0.205	
 Change of bowel habit	129 (51.6)	132 (53.2%)	132 (52.6%)	
 Abdominal pain	57 (22.8)	66 (26.6%)	46 (18.3%)	
 Melena/hematochezia	12 (4.8%)	11 (4.4%)	12 (4.8%)	
 Others	52 (20.8%)	39 (15.7%)	61 (24.3%)	
 Time between preparation and

colonoscopy, mean (SD), minutes

	341.59 (50.30)	349.22 (51.98)	341.81 (50.56)	0.165	
 Without or low residue diet,

median (IQR), day

	1 (1,2)	1 (1,2)	1 (1,2)	0.082	
SD standard deviation, BMI body mass index

12LPEG + 2L = 2L polyethylene glycol with 2# linaclotide

22LPEG + L = 2L polyethylene glycol with 1# linaclotide

33LPEG = 3L polyethylene glycol

Primary outcome

Table 2 shows the results of the bowel preparation efficiency and OBPS for the three groups. Since there were no statistically significant differences between the three groups in all possible background characteristics, no adjustment for possible confounders was required for comparing the successful bowel cleansing rates of the three groups. In the ITT and PP analyses, the bowel preparation efficiency was higher in the 2LPEG + 2L group than in the 2LPEG + L group (92.0% vs. 82.3%, P = 0.003; 92.4% vs. 82.3%, P = 0.003) and also higher than in the 3LPEG group (92.0% vs. 82.1%, P = 0.003; 92.4% vs. 83.3%, P = 0.006); the efficacy of bowel preparation was similar in the 2LPEG + L and 3LPEG groups (82.3% vs. 82.1%, P = 2.871; 82.3% vs. 83.3%, P = 2.337). The 2LPEG + 2L group was superior to the 2LPEG + L and the 3LPEG groups in the ITT and PP analyses in terms of total, right, and mid-colon score, and the 2LPEG + L and 3LPEG groups were similar in the above scores. There were no significant differences between the three groups in left colon or overall fluid scores. Table 2 Bowel preparation efficacy

	2LPEG + 2L	2LPEG + L	3LPEG	P-value	P-value†	P-value‡	P-value§	
Intention-to-treat analysis	n = 250	n = 248	n = 251					
Success of preparation, n (%)	230 (92.0%)	204 (82.3%)	206 (82.1%)	0.002	0.003	0.003	2.871	
OBPS score, mean (SD)	
 Total	2.76 (1.76)	3.57 (1.96)	3.47 (2.07)	 < 0.001	 < 0.001	 < 0.001	1.000	
 Right colon	1.04 (0.65)	1.40 (0.68)	1.25 (0.74)	 < 0.001	 < 0.001	0.002	0.041	
 Mid colon	0.52 (0.62)	0.90 (0.68)	0.84 (0.69)	 < 0.001	 < 0.001	 < 0.001	0.978	
 Left colon	0.78 (0.67)	0.79 (0.73)	0.92 (0.72)	0.043	1.000	0.068	0.121	
 Overall fluid	0.42 (0.53)	0.48 (0.51)	0.46 (0.55)	0.432	0.623	1.000	1.000	
Per-protocol analysis	n = 249	n = 243	n = 245					
Success of preparation, n (%)	230 (92.4%)	200 (82.3%)	204 (83.3%)	0.002	0.003	0.006	2.337	
OBPS score, mean (SD)	
 Total	2.74 (1.74)	3.54 (1.97)	3.39 (1.97)	 < 0.001	 < 0.001	0.001	1.000	
 Right colon	1.03 (0.65)	1.40 (0.68)	1.23 (0.71)	 < 0.001	 < 0.001	0.004	0.021	
 Mid colon	0.52 (0.62)	0.89 (0.68)	0.81 (0.68)	 < 0.001	 < 0.001	 < 0.001	0.595	
 Left colon	0.78 (0.67)	0.79 (0.74)	0.91 (0.71)	0.075	1.000	0.119	0.183	
 Overall fluid	0.41 (0.53)	0.47 (0.51)	0.44 (0.52)	0.492	0.707	1.000	1.000	
OBPS Ottawa bowel preparation score.

12LPEG + 2L = 2L polyethylene glycol with 2# linaclotide.

22LPEG + L = 2L polyethylene glycol with 1# linaclotide.

33LPEG = 3L polyethylene glycol.

†2LPEG + 2L vs. 2LPEG + L;

‡2LPEG + 2L vs. 3LPEG;

§2LPEG + L vs. 3LPEG

Secondary outcomes

Colonoscopy findings

The colonoscopy results are shown in Table 3. There were no significant differences in PDR (69.9% vs. 77.4% vs. 69.0%, P = 0.077), ADR (26.5% vs. 30.9% vs. 29.0%, P = 0.563), number of polyps per patient (3.99 (5.11) vs. 4.78 (6.44) vs. 4.26 (6.34), P = 0.332) or number of adenomas per patient (0.30 (0.53) vs. 0.36 (0.59) vs. 0.38 (0.66), P = 0.307) among the three groups. In addition, withdrawal time (5 (4.6) vs. 5 (5.6) vs. 5 (4.6), P = 0.193) was similar in the three groups, there was no significant difference in terminal ileum intubation rate (98.8% vs. 97.9% vs. 99.2%, P = 0.449), and all patients in the PP population had completed cecal intubation. Table 3 Colonoscopy findings (per-protocol population)

Variable	2LPEG + 2L1 (n = 249)	2LPEG + L2
(n = 243)	3LPEG3
(n = 245)	P-value	P-value†	P-value‡	P-value§	
Polyp detection rate, n (%)	174 (69.9%)	188 (77.4%)	169 (69.0%)	0.077	0.180	2.484	0.111	
Adenoma detection rate, n (%)	66 (26.5%)	75 (30.9%)	71 (29.0%)	0.563	0.855	1.617	1.947	
Cancer detection rate, n (%)	0 (0.0%)	1 (0.4%)	2 (0.8%)	0.362	0.933	0.735	3.000	
Number of polyps per patient, mean (SD)	3.99 (5.11)	4.78 (6.44)	4.26 (6.34)	0.332	0.432	1.000	1.000	
Number of adenomas per patient, mean (SD)	0.30 (0.53)	0.36 (0.59)	0.38 (0.66)	0.307	0.770	0.431	1.000	
Withdrawal time, median (IQR), minutes	5 (4,6)	5(5,6)	5 (4,6)	0.193	0.075	1.000	0.136	
Cecal intubation rate, n (%)	249 (100.0%)	243 (100.0%)	245 (100.0%)	NA				
Terminal ileum intubation rate, n (%)	246 (98.8%)	238 (97.9%)	243 (99.2%)	0.449	1.497	3.000	0.852	
NA not applicable.

12LPEG + 2L = 2L polyethylene glycol with 2# linaclotide.

22LPEG + L = 2L polyethylene glycol with 1# linaclotide.

33LPEG = 3L polyethylene glycol.

†2LPEG + 2L vs. 2LPEG + L;

‡2LPEG + 2L vs. 3LPEG;

§2LPEG + L vs. 3LPEG.

Bowel movement kinetics

The results of defecation kinetics are shown in Table 4. The time interval between the last laxative dose and colonoscopy did not differ between the three groups (P = 0.447). The time to first defecation was shorter in the 2LPEG + 2L group than in the 2LPEG + L (P = 0.015) or the 3LPEG group (P = 0.003), and there was no significant difference between the 2LPEG + L and 3LPEG groups (P = 1.000). There was no difference in defecating frequency between the three groups (12.59 (4.24) vs. 12.32 (4.60) vs. 11.93 (3.76), P = 0.218). The last effluent was not significantly different between the 2LPEG + L and 3LPEG groups (P = 1.200), and the 2LPEG + 2L group was superior to the 2LPEG + L (P = 0.036) and 3LPEG groups (P = 0.027). Table 4 Bowel movement kinetics (per-protocol population)

Variable	2LPEG + 2L1
(n = 249)	2LPEG + L2
(n = 243)	3LPEG3
(n = 245)	P-value	P-value†	P-value‡	P-value§	
Time between preparation

and colonoscopy, mean (SD), minutes

	336.77 (45.89)	326.90 (45.00)	338.92 (49.12)	0.447	1.000	1.000	0.670	
The first time of defecation, median (IQR), minutes	60 (30,100)	60 (40,120)	60 (40,130)	0.002	0.015	0.003	1.000	
Defecating frequency,

mean (SD)

	12.59 (4.24)	12.32 (4.60)	11.93 (3.76)	0.218	1.000	0.247	0.950	
Last effluent, n (%)				0.010	0.036	0.027	1.200	
Excellent	186 (74.7%)	154 (63.4%)	151 (61.6%)					
Good	58 (23.3%)	86 (35.4%)	86 (35.1%)					
Fair	4 (1.6%)	2 (0.8%)	7 (2.9%)					
Poor	1 (0.4%)	1 (0.4%)	1 (0.4%)					
12LPEG + 2L = 2L polyethylene glycol with 2# linaclotide

22LPEG + L = 2L polyethylene glycol with 1# linaclotide

33LPEG = 3L polyethylene glycol

†2LPEG + 2L vs. 2LPEG + L;

‡2LPEG + 2L vs. 3LPEG;

§2LPEG + L vs. 3LPEG

Tolerability, acceptability, and safety

All study participants were hemodynamically stable after bowel preparation and colonoscopy, and the occurrence and tolerability of adverse events are shown in Table 5. Regarding the occurrence of adverse reactions among them, there was no significant difference between the 2LPEG + 2L and 2LPEG + L groups in terms of the incidence of abdominal pain, bloating, and nausea symptoms (P > 0.05), but all were lower than the 3LPEG group (P < 0.05), and the occurrence of vomiting and other symptoms was not significantly different between the three groups. Sleep disturbances were more common in the 3LPEG group than in the 2LPEG + 2L group (P = 0.018) and the 2LPEG + L group (P < 0.001), while the 2LPEG + 2L and 2LPEG + L groups were similar. Overall satisfaction scores and willingness to reuse were lower in the 3LPEG than in the 2LPEG + 2L group (satisfaction, 3.04 (1.64) vs. 1.21 (1.06), P < 0.001; willingness to reuse, 67.7% vs. 90.4%, P < 0.001) and the 2LPEG + L group (satisfaction, 3.04 (1.64) vs. 1.48 (1.42), P < 0.001; willingness to reuse, 67.7% vs. 91.5%, P < 0.001), and the 2LPEG + 2L group and 2LPEG + L groups were not significantly different. Compliance was not significantly different between the three groups (P = 0.258). Table 5 Adverse events and tolerability related to bowel preparation (intention-to-treat population)

Variable	2LPEG + 2L
(n = 250)	2LPEG + L2
(n = 248)	3LPEG3
(n = 251)	P-value	P-value†	P-value‡	P-value§	
Adverse events, n (%)	
 Abdominal pain	46 (18.4%)	40 (16.1%)	72 (28.7%)	0.001	1.509	0.021	0.003	
 Bloating	92 (36.8%)	96 (38.7%)	131 (52.2%)	0.001	1.980	0.003	0.006	
 Nausea	95 (38.0%)	73 (29.4%)	148 (59.0%)	 < 0.001	0.129	 < 0.001	 < 0.001	
 Vomiting	3 (1.2%)	5 (2.0%)	9 (3.6%)	0.190	1.509	0.243	0.864	
 Others	1 (0.4%)	2 (0.8%)	3 (1.2%)	0.709	1.869	1.869	3.000	
Sleeping quality, n (%)				0.001	1.188	0.018	 < 0.001	
 Good	177 (70.8%)	184 (74.2%)	148 (59.0%)					
 Worse	73 (29.2%)	64 (25.8%)	103 (41.0%)					
 Compliance, n (%)	249 (99.6%)	243 (98.0%)	247 (98.4%)	0.258	0.366	1.116	2.250	
 Satisfaction, mean (SD)	1.21(1.06)	1.48 (1.42)	3.04 (1.64)	 < 0.001	0.098	 < 0.001	 < 0.001	
 Willing to reuse, n (%)	226 (90.4%)	227 (91.5%)	170 (67.7%)	 < 0.001	1.977	 < 0.001	 < 0.001	
12LPEG + 2L = 2L polyethylene glycol with 2# linaclotide

22LPEG + L = 2L polyethylene glycol with 1# linaclotide

33LPEG = 3L polyethylene glycol

†2LPEG + 2L vs. 2LPEG + L;

‡2LPEG + 2L vs. 3LPEG;

§2LPEG + L vs. 3LPEG

The subgroup of constipation patients

Bowel cleansing outcomes were analyzed in constipation patients in the PP population (Table 6), and a total of 137 patients were eligible (2LPEG + 2L group = 44, 2LPEG + L = 40, and 3LPEG group = 53). The results showed no significant difference in the success rate of bowel preparation between the three groups (P = 0.206). According to the OBPS, the total score was better in the 2LPEG + 2L group (2.91 (1.52) vs. 3.83 (1.87), P = 0.041) and the 3LPEG group (2.91 (1.52) vs. 3.85 (1.65), P = 0.020), with no significant difference between the 2LPEG + L and 3LPEG groups (3.83 (1.87) vs. 3.85 (1.65), P = 1.000). In colon segmentation scores, the 2LPEG + 2L group was better than the 2LPEG + L group (P = 0.005, P = 0.007) and the 3LPEG group (P = 0.002, P = 0. 020) in right and mid colon scores, and the 2LPEG + L and 3LPEG groups were similar in the above scores (P = 1.000, P = 1.000). There was no significant difference between the three groups in the left colon and overall fluid scores (P = 0.148, P = 0.482). Table 6 The subgroup of constipation patients

Variable	2LPEG + 2L1
(n = 44)	2LPEG + L2
(n = 40)	3LPEG3
(n = 53)	P-value	P-value†	P-value‡	P-value§	
Success of preparation, n (%)	40 (90.9%)	31 (77.5%)	46 (86.8%)	0.206	0.270	2.247	0.720	
OBPS score, mean (SD)	
 Total	2.91 (1.52)	3.83 (1.87)	3.85 (1.65)	0.012	0.041	0.020	1.000	
 Right colon	0.95 (0.53)	1.38 (0.63)	1.38 (0.63)	 < 0.001	0.005	0.002	1.000	
 Mid colon	0.57 (0.59)	0.95 (0.68)	0.91 (0.56)	0.004	0.007	0.020	1.000	
 Left colon	0.82 (0.69)	0.83 (0.81)	1.06 (0.63)	0.148	1.000	0.303	0.362	
 Overall fluid	0.57 (0.63)	0.65 (0.53)	0.51 (0.51)	0.482	1.000	1.000	0.684	
12LPEG + 2L = 2L polyethylene glycol with 2# linaclotide

22LPEG + L = 2L polyethylene glycol with 1# linaclotide

33LPEG = 3L polyethylene glycol

†2LPEG + 2L vs. 2LPEG + L;

‡2LPEG + 2L vs. 3LPEG;

§2LPEG + L vs. 3LPEG

The subgroup of IBS patients

Comparative safety and tolerability analyses were performed among IBS patients in the ITT population (Table 7). The results showed that the proportion of patients with abdominal pain, bloating distension, nausea, vomiting, or other adverse effects was similar in the 2LPEG + 2L and 2LPEG + L groups, but the incidence of abdominal pain, bloating, and nausea symptoms was lower than in the 3LPEG group. The incidence of sleep disturbance was comparable among the three groups (P = 0.132). Satisfaction scores were worse in the 3LPEG group than in the 2LPEG + 2L group (P < 0.001) and the 2LPEG + L group (P < 0.001), and there was no significant difference between the 2LPEG + 2L and 2LPEG + L groups (P = 0.052). The willingness to reuse in the three groups was 85.6%, 88.5%, and 71.3%, respectively, with the 3LPEG group being lower than the 2LPEG + 2L group (P = 0.027) and the 2LPEG + L group (P = 0.003). Table 7 The subgroup of IBS patients

Variable	2LPEG + 2L1(n = 111)	2LPEG + L2 (n = 113)	3LPEG3
(n = 115)	P-value	P-value†	P-value‡	P-value§	
Adverse events, n (%)	
Abdominal pain	19 (17.1%)	19 (16.8%)	40 (34.8%)	0.001	2.856	0.009	0.006	
Bloating	46 (41.4%)	47 (41.6%)	67 (58.3%)	0.014	2.946	0.033	0.036	
Nausea	43 (38.7%)	36 (31.9%)	69 (60.0%)	 < 0.001	0.843	0.003	 < 0.001	
Vomiting	3 (2.7%)	2 (1.8%)	6 (5.2%)	0.315	2.046	1.500	0.840	
Others	1 (0.9%)	1 (0.9%)	1 (0.9%)	1.000	3.000	3.000	3.000	
Sleeping quality, n (%)				0.132	0.513	1.647	0.144	
Good	69 (62.2%)	80 (70.8%)	67 (58.3%)					
Worse	42 (37.8%)	33 (29.2%)	48 (41.7%)					
Satisfaction, mean (SD)	1.29(1.06)	1.73 (1.50)	3.10 (1.57)	 < 0.001	0.052	 < 0.001	 < 0.001	
Willing to reuse, n (%)	95 (85.6%)	100 (88.5%)	82 (71.3%)	0.002	1.551	0.027	0.003	
12LPEG + 2L = 2L polyethylene glycol with 2# linaclotide

22LPEG + L = 2L polyethylene glycol with 1# linaclotide

33LPEG = 3L polyethylene glycol

†2LPEG + 2L vs. 2LPEG + L;

‡2LPEG + 2L vs. 3LPEG;

§2LPEG + L vs. 3LPEG

Discussion

High-quality colonoscopy is essential for colorectal cancer (CRC) screening. Colonoscopic detection and resection of adenomatous polyps significantly reduce the risk of death from CRC [1]. The quality of bowel preparation is of paramount importance. A meta-analysis based on a summary of 31 studies analyzing more than 370,000 colonoscopies found that inadequate bowel preparation had a greater impact on the detection of early colon lesions than advanced lesions [28]. A wide variety of laxatives are currently available clinically, but PEG, introduced in 1980 [29], remains the first-line bowel cleansing regimen in most clinical endoscopy centers, with the high volume required and the unpleasant taste being among the major drawbacks of this regimen.

Studies of linaclotide as a bowel cleanser are currently very limited. The initial study was a preliminary study of single-dose linaclotide for capsule endoscopy, but the study had a small sample size and was limited by poor gastric clearance in several subjects, pending larger studies to evaluate the efficacy of linaclotide [30]. Another study compared the bowel cleansing effect of 2 L PEG + 290 µg linaclotide in the 2LPEG group with a 4LPEG group as control and showed that the 2 L PEG + 290 µg linaclotide group had similar results to the 4L PEG group, but better than the 2LPEG group [27]. However, it should be noted that, firstly, a 3LPEG bowel preparation protocol is currently generally applied in China, and it is more instructive to use 3LPEG as the control group. Secondly, the 2LPEG in the 2 L PEG + 290 µg linaclotide group of this study was given as one dose on the day of the examination, which may have increased the discomfort symptoms of the patients. In contrast, in our study, a 3LPEG split-dose regimen was used as the control group, and in the linaclotide test group, the treatment was also administered in split doses, with patients taking only 1 L PEG at a time, which greatly reduced patient discomfort. A correlation meta-analysis showed that the split-dose preparation regimen had a better bowel cleansing effect and a higher ADR [31]. This study also added a double-dose linaclotide trial group to further explore the dosing of linaclotide in the modified bowel preparation regimen.

Our results showed that the bowel preparation efficiency of the 2LPEG + 2L group was 92.0%, which met the minimum standard of more than 90% of adequate bowel preparation recommended by the European Society of Gastrobowel Endoscopy (ESGE) [3], and was higher than that of the 2LPEG + L group (82.3%) and the 3LPEG group (82.1%), while the 2LPEG + L and 3LPEG groups were comparable. The total and the right and mid colon in the 2LPEG + 2L group were better than those in the 2LPEG + L and 3LPEG groups. Special attention should be paid to the cleanliness of the right colon, which is usually more difficult to clean and where adenomas and serrated lesions tend to occur more often in the proximal colon, requiring good right hemicolectomy. Previous studies have shown that poor bowel preparation reduces the detection rate of adenomas, serrated lesions, and early colon cancer in the right colon [32]. The 2LPEG + 2L group in this study showed greater efficacy in the right colon for reasons that are not clear, but may be due to the fact that linaclotide increases bowel secretion or may enhance bowel myoelectricity and peristalsis associated with it, especially in the right colon. However, this finding should be treated with caution, as the size of this study was not sufficient to specifically assess this issue. In addition to this, because linaclotide increases bowel secretion, we expected that the amount of fluid remaining in the colon might be greater in the 2LPEG + 2L group compared with the 3LPEG group, but no significant difference in overall fluid scores was seen between the three groups, which may be related to the smaller dose of linaclotide or the fact that linaclotide promotes bowel peristalsis, which facilitates the elimination of fluid.

In clinical practice, ADR is a major indicator of the quality of colonoscopy. A study has shown that when the ADR is increased by 1%, it reduces the incidence of colorectal cancer by 3% and colorectal cancer deaths by 5% [33]. Even so, this study has not found differences in polyp or adenoma detection between the three groups, which may be related to the fact that the current evidence is insufficient to detect subtle differences. In our study, there was no significant difference in withdrawal time, cecal intubation rate, or terminal ileal intubation rate between the three groups, which may be due to the higher rate of good bowel preparation in the three groups of this study, and the less important effect of bowel preparation on this when the OBPS score was < 6. Otherwise, there was no significant difference in defecation frequency between the three groups, but the 2LPEG + 2L group had a clearer nature of the last discharge before colonoscopy than the other two groups, which further confirmed the good bowel cleansing effect of 2LPEG + 2L.

On the other hand, more important than effectiveness is the safety of the bowel preparation regimen. This was confirmed in our study, where none of the patients enrolled experienced any hemodynamic changes and no serious adverse events occurred. It has been shown that linaclotide relieves symptoms of bloating or abdominal discomfort in patients with constipation [34], which may be due to the fact that linaclotide promotes the elimination of feces, fluid, and gas by accelerating colonic transit, or by increasing extracellular cGMP and inhibiting visceral injury receptors, thereby improving symptoms of abdominal pain, bloating, or abdominal discomfort. However, this needs to be further elucidated by future studies, and the current relatively novel technique of functional magnetic resonance imaging (fMRI) of the gastrobowel tract may help to further understand the distribution of bowel contents, including gas, and symptom improvement, as one of the assessment tools. In addition, the linaclotide trial group not only received a 2-L liquid volume, but it was also administered as a split dose, indicating that the low-dose formulation was easier to ingest and more acceptable than the high-dose formulation. This is extremely important for long-term use and promotion in the future while ensuring effectiveness.

Constipation is considered to be one of the common risk factors for poor bowel preparation. Several previous studies have investigated bowel preparation modification protocols in constipated patients, but the results were not satisfactory. Linaclotide can be used to treat CC. Many studies have confirmed that linaclotide is more effective than placebo in the treatment of CC and is safe for use in the clinical setting [35]. In this study, we analyzed the CC population among the included patients. We found no difference in bowel preparation success between the three groups, but the 2LPEG + 2L group had better total, right, and mid-colon scores than the other two groups. This is similar to the previous results of a study using linaclotide for bowel preparation [32].

We also compared adverse effects and satisfaction in the IBS population. Recurrent abdominal pain and abdominal discomfort are the main symptoms of IBS, according to the Rome IV diagnostic criteria [36]. It was found that abdominal pain, bloating, or abdominal discomfort in IBS patients might be associated with visceral hypersensitivity [37], while previous studies have shown that linaclotide for IBC-C can address both constipation and abdominal discomfort in patients. We speculate that linaclotide may relieve abdominal pain or discomfort during bowel preparation in the IBS trial group population. The results showed no difference in sleep between the three groups, but the incidence of abdominal pain, bloating, and nausea was significantly lower in the linaclotide test group than in the control group, with better satisfaction scores and willingness to reuse. Individualized tailor-made protocols are also extremely important in clinical settings for patients with CC or IBS, and the analysis of these two populations in this study may provide some reference data.

Our study has the following advantages. First, this study confirmed the feasibility of linaclotide combined with low-dose PEG as a bowel cleansing regimen, and further explored the bowel cleansing effect, safety, and tolerability of different doses of linaclotide in the regimen. It was also improved on the basis of previous studies by using a split-dose regimen to reduce patient discomfort. Secondly, the OBPS in this study was scored by a dedicated, blinded researcher and endoscopist and honed in advance by training to minimize subjective errors in scoring, while we used the more recognized OBPS to assess bowel cleansing effects.

The present experimental study has several limitations. Firstly, the subjects in this study were not blinded and whether the patients were undergoing first-time colonoscopies was not statistically analyzed, and these could be confounding variables for objective evaluation of adverse events and satisfaction. Secondly, we did not consider the duration and severity of CC and IBS in the subgroup analysis, and further studies are needed in the future. Thirdly, for the assessment of patient adverse events and satisfaction, a validated symptom questionnaire was not used, which is a common limitation in most bowel preparation studies. A longer follow-up was not performed to assess patient safety, while objective indicators including blood analysis or biochemical analysis were lacking.

In conclusion, the 2LPEG + 2L split-dose regimen may be a viable alternative to the high-dose PEG regimen as a standard regimen in the clinical setting to achieve better quality bowel preparation.

Supplementary Information

Below is the link to the electronic supplementary material.ESM 1 (DOCX 17.8 KB)

Acknowledgements

The authors would like to thank the entire staff of the Department of Gastroenterology, Wuhan No.1 Hospital, for their support.

Author Contribution

Wan-qi Liu and Song Liu contributed to the study concept and design. Wan-qi Liu enrolled patients. Song Liu, Lei Shu, and Xiaoli Zhou performed the procedures. Wan-qi Liu analyzed the data and drafted the manuscript. Wan-qi Liu and Lei Shu have equal contribution. Song Liu and Zhao-hong Shi critically revised the manuscript for important intellectual content. All authors have read and agreed to the published version of the manuscript.

Funding

The linaclotide drug in this study was provided by AstraZeneca.

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Declarations

Ethics approval

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of Wuhan No.1 Hospital (number: 2022–53 and date of approval: November 25, 2022).

Informed Consent

Informed consent was obtained from all subjects involved in the study.

Conflict of interest

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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