Study design and patient population

This is a randomised, controlled, single-blind clinical trial comparing three bowel preparation regimens for patients with chronic constipation undergoing colonoscopy. The study will be conducted at Beijing Shijitan Hospital, Capital Medical University from 1 March 2025 to 31 December 2026.

The inclusion criteria for the study include patients with chronic constipation undergoing colonoscopy who meet the following criteria: (1) are aged 18–65 years; (2) meet the Rome IV criteria15 for chronic constipation which includes the presence of ≥2 of the following: (a) straining for >25% of defecations, (b) lumpy or hard stools (form 1 or 2 on the Bristol Stool Form Scale) for >25% of defecations, (c) sensation of incomplete evacuation for >25% of defecations, (d) sensation of anorectal obstruction/blockage for >25% of defecations, (e) manual manoeuvres to facilitate defecation for >25% of defecations; (3) have the ability to comprehend the trial, sign a written informed consent, including consent for a screening procedure to determine eligibility; (4) have the ability to communicate with the investigators well and follow verbal and written instructions; (5) have the ability to take OSS correctly according to the procedure and (6) have the ability to perform follow-up in accordance with the protocol.

The exclusion criteria include patients meeting one or more of the following criteria: (1) having a lack of indications for total colonoscopy; (2) having general contraindications to colonoscopy bowel cleansing, such as acute surgical abdomen, including intestinal perforation, acute diverticulitis and appendicitis, gastrointestinal obstruction, toxic megacolon; (3) having one of the following diseases: electrolyte disturbances or severe diseases of the heart, liver or kidney; (4) having a history of any colonic surgery; (5) taking or having taken linaclotide or being allergic to linaclotide; (6) being pregnant; (7) lactating or (8) participating in other clinical trials or participating in other clinical trials within 60 days.

Randomisation and blinding method

Subjects will be randomised at a 1:1:1 ratio to regimens A, B or C, via a computer-based random number table. The randomisation process will be performed by clinicians. They will prepare study products, provide education on bowel preparation and will be involved in the day-to-day care of patients. They will not be involved in performing the procedures. All endoscopists in this trial and biostatisticians will be unaware of each patient’s regimen allocation. Blinding of the endoscopist will be strictly enforced, and they will remain blinded until the main analysis is complete. Due to the volume differences and dose differences among the three regimens, blinding of the patients is impossible. Therefore, investigators will ask the subjects to refrain from talking about bowel cleansing with the endoscopists, either before or during the colonoscopy.

Selection of bowel preparation regimens

Before bowel preparation, each patient will be provided with written instructions on dietary restrictions and bowel cleansing methods. The following strict dietary restrictions will be given to all subjects: (1) follow a low-fibre diet for 3 days before the colonoscopy, (2) follow a clear fluid diet for 1 day before the colonoscopy and (3) fast on the day of the colonoscopy. A low-fibre diet is defined as a diet with a total fibre intake of less than 10 g/day. Patients will stop taking laxatives or prokinetics 7 days before the colonoscopy.

The study participants will be equally divided into three groups via a random number table. In regimen A, the subjects will (1) take 1d-linaclotide at 07:00 on the day before the procedure, (2) ingest a diluted OSS dissolved in approximately 500 mL of water followed by 1 L of water on the night before the procedure starting at 19:00, (3) take 1d-linaclotide at 05:00 on the day of the procedure and (4) drink 500 mL of a diluted OSS and 1 L of water on the day of the procedure, starting at 07:00 and completing at least 4 hours before the colonoscopy. Previous studies16 17 revealed that a single dose of linaclotide taken 1 hour before video capsule endoscopy significantly improved bowel preparation quality and visualisation, reducing transit time by 20% compared with published standards. Patients with chronic constipation would experience their first spontaneous bowel movements within 24 hours, accompanied by a shortened first defecation time and an increased number of defecations after taking linaclotide. Considering that the OSS is taken the day before and the day of the colonoscopy, regimen A was designed with the combined use of 2d-linaclotide and the OSS.14

In regimen B, the subjects will (1) take 1d-linaclotide at 07:00 2 days before the procedure, (2) take 1d-linaclotide at 07:00 on the day before the procedure, (3) ingest a diluted OSS dissolved in approximately 500 mL of water followed by 1 L water on the night before the procedure starting at 19:00, (4) take 1d-linaclotide at 05:00 on the day of the procedure and (5) drink 500 mL of a diluted OSS and 1 L water on the day of the procedure, starting at 07:00 and completing at least 4 hours before the colonoscopy. Regimen B was adapted from Wang et al18 and Xu et al,19 who combined 3 L PEG and 3d-linaclotide and reported that this regimen was satisfactory for patients with chronic constipation.18

In regimen C, the subjects will (1) ingest a diluted OSS dissolved in approximately 500 mL of water followed by 1 L of water on the night before the procedure starting at 19:00 and (2) they will drink 500 mL of a diluted OSS and 1 L of water on the day of the procedure, starting at 07:00 and completing at least 4 hours before the colonoscopy. All patients will receive 5 mL of simethicone solution mixed with the last dose of laxative. Regimen C is the control group, consisting of a traditional 1 L diluted OSS and 2 L water.

As a rescue regimen for inadequate bowel preparation, clinicians will gauge whether the last excreta is adequate before colonoscopy according to standard pictures (figure 1). For inadequate cleanings, 500 mL of diluted OSS and 1 L of water will be taken. The rescue regimen will be recorded on a case report form (CRF). The schedule of enrolment, interventions and assessments is presented in table 1.

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Figure 1

Standard pictures for the last excreta before colonoscopy. (A) Turbid liquid with faecal residue; (B) opaque liquid without residual stool; (C) slight-staining and clear liquid; (D) colourless and clear liquid. For patients with inadequate cleanings (A or B), supplement 500 mL diluted OSS and 1 L water will be taken.

Study procedures

The investigator will perform all the observations, investigations and evaluations according to the descriptions provided. The subjects will be given written instructions including the diet, dose and timing of the experimental drugs, in accordance with randomisation. Clinicians will distribute the study drugs to the participants, provide instructions on the administration and face-to-face bowel preparation education to ensure that the participants will take their drugs correctly. All colonoscopies will be performed by designated, professional endoscopists (who had performed more than 1000 colonoscopies individually) via the Olympus CV-260 or CV-290 colonoscope (Olympus Medical Systems, Tokyo, Japan). All participating endoscopists will be standardised and trained in the use of the Boston Bowel Preparation Scale (BBPS) before they participate in the study, and bowel preparation quality will be evaluated based on the BBPS. Endoscopists cannot use additional adjuvant devices or adjuvants to improve bowel preparation.

Data collection

The following clinical variables will be collected: (1) Demographics of the participants: sex, age, body mass index, comorbidities, use of calcium channel blockers, smoking or alcohol consumption, family history and laboratory indices (routine blood tests, liver and kidney function, coagulation function). (2) Bowel preparation: subject compliance, ability to understand and follow the instructions for bowel preparation, usage of laxatives, interval between the first OSS and the first defecation, and interval between the last OSS and colonoscopy. (3) Colonoscopy: BBPS score (total score and each segment score), caecal intubation rate, colonoscope insertion time and withdrawal time and ADR. (4) Safety: We will assess adverse events (AEs) and serious AEs (SAEs) associated with the agents before, during and after colonoscopy bowel cleansing. (5) Comfort: Results of the comfort questionnaire, including discomfort symptoms (nausea, vomiting, abdominal pain, abdominal distention, bowel incontinence, dizziness, headache, fatigue and tiredness), sleep quality (somnipathy, total sleep duration, frequency of sleep awakenings in the evening before colonoscopy) and willingness to duplicate colonoscopy bowel cleansing.

Study outcomes

The primary outcome will be adequate bowel preparation, defined as each segment’s BBPS scores being ≥2 and/or having a total score ≥6.20 21 The BBPS is based on three colon segment scores (right-sided colon, transverse colon and left-sided colon), and each segment score is defined by a four-point scoring system (0–3). The right-sided colon included the caecum and ascending colon, and the transverse colon was defined from the hepatic flexure to the splenic flexure, whereas any more distal colon or rectum was defined as the left-sided colon. Each segment score is between 0 and 3 as follows: 0=an unprepared colon segment with solid stool on the mucosa; 1=portions of the mucosa can be seen, but other areas are covered by staining, residual stool and/or opaque liquid and thus cannot be seen clearly; 2=minor areas covered by residual staining, small stool fragments and/or opaque liquid, but the colon segment can be seen well; 3=the entire mucosa can be adequately seen, with no residual staining, small fragments of stool or opaque liquid. As a superior trial, the BBPS total score and segment scores in regimens A and B should be statistically superior to those in regimen C.

The secondary outcomes include defecation frequency, the interval between the first OSS and the first defecation, the interval between the last OSS and the colonoscopy examination, the caecal intubation rate, the colonoscope insertion time and withdrawal time, and the ADR.

The third outcome will be the degree of comfort, which is evaluated via a self-designed questionnaire of comfort (QSC). The QSC was adapted from previous studies9 22 and is composed of complications and sleep quality during bowel preparation, as well as preprocedure anxiety and willingness to repeat bowel preparation. The complications included abdominalgia, abdominal distension, nausea, vomiting and bowel incontinence during bowel preparation. Sleep quality, including somnipathy, sleep duration and the number of sleep awakenings during bowel cleansing, was also recorded.

Safety indicators, such as AEs and SAEs, including abdominal pain, abdominal distension, faecal incontinence, allergic reactions and other adverse drug reactions, will be recorded and evaluated. Moreover, we will record complications of EMR or ESD, such as intraprocedural haemorrhage (any immediate bleeding that requires any form of endoscopic haemostasis or oozing lasting for at least 60 s), delayed haemorrhage (any bleeding requiring endoscopy reintervention or hospitalisation within 2 weeks), intraprocedural perforation (any perforation requiring endoscopic clip sealing), delayed perforation (any perforation occurring within 2 weeks) and intestinal infection (bellyache, fever and/or increased C-reactive protein requiring antibiotics).

Statistical analysis and sample size

Statistical analysis will be executed by SPSS V.20.0 (IBM Corp, Armonk, New York, USA). Continuous variables are expressed as the mean±SD or median (IQR) according to a normal/non-normal distribution and will be analysed with independent samples t tests or Wilcoxon’s rank-sum tests. Categorical variables are represented as counts (percentages) and will be evaluated by the χ² test or Fisher’s exact test appropriately. To address the issue of multiple comparisons across the three study arms, we will employ adjustment methods, such as the Bonferroni correction, to ensure the robustness and validity of our statistical inferences. P value <0.05 will be set as the cut-off for statistically significant.

In the study protocol, the sample size calculation is performed with an alpha of 0.05 and a power of 0.8, assuming a 20% difference in the rate of colonic cleansing and a 10% dropout rate. Over the past year, approximately 500 patients with chronic constipation have undergone bowel preparation using OSS at our centre, resulting in an adequate bowel cleansing rate of approximately 70%. A final inclusion of 65 participants in each group was needed. The efficacy, safety and tolerability of bowel preparation will be compared based on intention-to-treat approaches or per-protocol analysis.

Patient and public involvement

Patients and the public were not involved in the development of the protocol.