Design
The protocol for this trial is reported based on the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Checklist17: defining standard protocol items for clinical trials. This multicenter randomized controlled trial will be conducted at 9 hospitals in China: Army Medical Center, Xi-Jing Hospital of Air Force Medical University, No. 940 Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Renmin Hospital of Wuhan University, Renmin Hospital of Wuhan University, Zhongnan Hospital of Wuhan University, Baoshan Branch of Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai Pudong New Area People's Hospital, Zhejiang Provincial People's Hospital. The study has been approved by ethics committees and registered at clinicaltrials.gov on 28 April 2022 (Registration number: NCT05352074). The eligible patients will be randomly divided into two groups, and participants will receive a 1, 3, 6, 12, 24 and 36 months follow-up after surgery. Outcomes will be assessed at baseline, during the treatment, and at the end of the follow-up. Figure 1 illustrates the flow diagram of the trial.
Patient recruitment
Patients with STC scheduled for colectomy at each trial center will be assessed for eligibility according to the following rigorous inclusion and exclusion criteria, and informed about the trial in detail. All patients will voluntarily agree to participate and sign an informed consent document before randomization. Patients may decide to withdraw from the trial at any time without providing any specific reason for their decision and the date of withdrawal will be recorded on the case report form.
List of selection criteria
Inclusion criteria
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Patients (≥ 18 years of age) of either sex
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Patients with conditions in agreement with the Roman IV criteria of functional constipation
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Patients with no complete spontaneous bowel movements
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Patients rely on laxatives to assist defecation for a long time
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More than 20% the radio-paque markers localized in the colon after 72 hours based on repeated colonic transit studies (> 2 times)
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Patients with no response to any medical interventions for more than 1 year
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Patients with a strong desire for surgery
Exclusion criteria
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Pregnant or breast-feeding women
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Patients with megacolon, megarectum and rectal inertia
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Patients with colorectal neoplasms
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Patients with small intestinal slow transit
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Patients with constipation-predominant irritable bowel syndrome
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Patients with inflammatory bowel disease
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Patients with ileostomy
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Patients with severe psychiatric disease
Randomization and blinding
The generation and allocation of a random sequence for group assignment will be conducted by the Department of Epidemiology affiliated to Army Medical University in China. All eligible patients will be randomly and centrally assigned (1:1) to TC-IRA or SC-CRA, by computer-generated permuted blocks stratified by center using the Statistical Analysis System (V.9.2, SAS Institute Inc., Cary, North Carolina, USA). For obvious reasons, surgeons or patients cannot be blinded to the assigned treatment. Moreover, all outcomes assessed by blinded data collectors were quality of life or functional outcomes, that is, patient reported outcomes. Therefore, blinding of data collectors or outcome assessors was not reasonable. Outcome statistical analysis will be conducted independently by blinded statisticians.
Interventions
The schedule of enrollment, interventions, assessments, and participant visits is shown in Fig. 1. Treatments will be performed by surgeons who had an experience of at least 5 years and more than 50 prior laparoscopic colectomies for STC.
Standard perioperative management in both groups
Bowel preparation will be conducted by polyethylene glycol for all patients on the day before surgery according local standards. Early mobilization and early oral intake with liquid after surgery will be performed by postoperative care. Daily ward rounds with clinical assessment by surgeons will be routinely included in postoperative clinical management and routine blood tests will be usually performed on postoperative days 1, 3, 5 and thereafter on demand based on the clinical course.
Standard surgical technique performed in both groups
The patients will be placed in the modified lithotomy position under general anesthesia. The primary trocar with a 12 mm port will be inserted to gain access to the peritoneal cavity and establish the pneumoperitoneum bellow the umbilicus for the 30° laparoscope. Two 12mm ports will be placed in the right iliac fossa and in the left upper quadrant of abdominal. The other 5 mm ones will be located in the right upper quadrant and left lower quadrant. Mobilization of colonic segments with harmonic system will be started at the sigmoid colon and upper rectum. Next, the descending colon, splenic flexure of colon, the transverse colon, the hepatic flexure of colon, ascending colon and ileocecal junction will be mobilized and the omentum will be preserved carefully. The upper part of rectum ampulla will be transected by a 60-mm linear stapler.
Experimental intervention (SC-CRA)
After a complete mobilization of the colon with the ileocolic vessels preservation, a 4–5 cm Pfannenstiel incision will be made to remove the colon. A resection 2–3 cm distal to the ileocecal junction will be conducted. After introduction of the anvil of a 29-mm circular stapler device through the cecal resection line, the cecum will be then lowered into the pelvis, without any rotation, and an antiperistaltic cecorectal anastomosis will be performed between the cecal fundus (after appendectomy) and the rectum. The cecal-rectal anastomosis will be reconstructed by introducing the circular stapler device via the anus, with the intention of carrying out a ''cleaner,'' ''tensionless'' procedure. Finally, the drainage tube will be placed at pouch of Douglas, and the abdominal wall wounds are closed.
Control intervention (TC-IRA)
After a complete mobilization of the colon without the ileocolic vessels preservation, a 4–5 cm Pfannenstiel incision will be made to remove the colon. A resection 2–3 cm proximal to the ileocecal junction will be conducted. The anvil of a 29-mm circular stapler will be introduced into the lumen of the ileum, which is placed into the abdominal cavity. The ileo-rectal anastomosis will be reconstructed by introducing the circular stapler device via the anus, with the intention of carrying out a ''cleaner,'' ''tensionless'' procedure. Finally, the drainage tube will be placed at pouch of Douglas, and the abdominal wall wounds will be closed.
Permitted/prohibited treatments and concomitant treatment
Any concomitant or necessary treatment, for example, antibiotic therapy, parenteral nutrition and relaparotomy, will be performed at the discretion of the treating physicians and according to local standards.
Data collection and Outcomes
The following baseline and demographic parameters will be collected on all patients: age(years), gender(female/male), body mass index(kg/m2), duration of disease(years), previous abdominal surgery, American Society of Anesthesiologists class, bowel movements (number/week), abdominal pain, bloating, straining, laxative, enema, diarrhea and prior imaging studies (colonic transit test/colonoscopy/defecography/barium enema/anorectal manometry). Intraoperatively, the following data will be gathered: operation time (min), blood loss (mL), intraoperative blood transfusion(yes/no and number of packed red blood cells), reconstruction technique, minimally invasive/open surgery and intraoperative complications.
Primary outcome
Wexner’s Constipation Score
Several questionnaires exist to assist in the diagnosis and assessment of the severity of the disease. One of these is the Wexner’s constipation score (WCS)18. The WCS is a validated and internationally adopted questionnaire that has 8 items to quantify a patient’s constipation grade. The questionnaire assesses constipation in its clinical expression and each question is answered on a scale of 0 to 4, the global score ranging from 0 (best) to 30 (worst). The WCS will be used as the primary outcome in this trial and assessed at baseline and at 1, 3, 6, 12, 24 and 36 months.
Secondary outcomes
Wexner’s incontinence score
The Wexner’s incontinence score (WIS), for postoperative evaluation, is used to quantify incontinence grade and frequency and its effect on ordinary life19. The questionnaire consists of 5 items and each question is answered on a scale of 0 to 4, the total score ranging from 0 (best) to 20 (worst).
Gastrointestinal Quality of Life Index
The Gastrointestinal Quality of Life Index (GIQLI) is a validated quality-of-life questionnaire consisting of 36 questions designed to evaluate specific gastrointestinal symptoms and the impact of the disease on the physical, psychological, and social spheres of patients20. Most of the questions concern the previous 2weeks of questionnaire administration; there are four possible answers to each question, scored from 0 to 4 points. The final sum ranges from 0 (worst) to 144 (best), 125.8 ± 13 being the mean score for healthy people obtained during validation studies.
36-item short-form health survey
The patients’ quality of life is evaluated using an 36-item short-form health survey(SF-36 questionnaire) which included questions related to physical function, role physical, physical pain, general health, vitality, social function, role emotional and mental health21. Once the questionnaire is applied to the patients, a summary calculation and a linear transformation are performed to obtain a score within a scale from 0 to 100.
Safety evaluation
The standardized Clavien-Dindo classification of surgical complications is applied as a simple and widely used tool to assess and report postoperative complications in general surgery22. Adverse events are represented by complications of grades 1–2 according to the Clavien-Dindo classification, whereas grades 3–5 represent serious adverse events. The coordinating investigators will be required to document all adverse events on the Case Report Form (CRF), including information such as the time of occurrence, severity, duration, measurement, management, and outcome. In case of a serious adverse event, the necessary action will be taken immediately for the patient's safety and the serious adverse event should be submitted to the Ethics Committees Office and the Department of General Surgery of Army Medical Center within 24 hours by the clinician. The Department of General Surgery of the eleven above mentioned hospitals will be responsible for the treatment of all serious adverse events.
Data Management and Monitoring
The electronic case report form (eCRF) will be designed to collect all clinical observations of each patient before recruitment. The investigators will be responsible for the completeness, validity and reliability of data and complete the eCRF as soon as possible after information is collected. An explanation should be given for all missing data. The completed eCRF will be reviewed and signed online by the investigator. At the end of the trial, the electronic data will be locked. All paper documents and electronic data will be retained for 5 years after publication and then destroyed.
To ensure the quality of the trial, a standard operation process, including information on recruitment, randomization, perioperative management, surgical technique, eCRF, the assessment of outcomes, data management, and adverse serious events, will be unified and trained through a multicenter web internal meeting for the consistency of results. Data monitoring will be undertaken periodically by the steering committee and management groups to identify missing data and potential erroneous data. Data issues will be identified and handled by the management group. In addition, meetings will be held every three months to report on the progress of the trial and each amendment of the protocol conforms to the Good Clinical Practice principles and maintains the ethical standards of the randomized control trial.
Patients and public involvement
Patients in this trial will not be involved in the design or conduct of the study or the outcome assessments. However, we are planning to disseminate our research to the participants and the public, for example, by publicizing our research on hospital social media (We Chat subscription) and presenting our findings at various academic lectures. All adverse events in the trial will be reported in publication.
Statistical analysis
Based on previous clinical experience, we anticipate in an improvement in the WCS of 4.56 ± 1.35 in the experimental group and 5.08 ± 1.13 in the control group with the ratio 1:1 between both groups. PASS.15 software is used to compute the sample size with a bilateral test of equivalence. Using α = 0.05, β = 0.2, and power = 0.8, 91 patients are required in each group, with a total of 182 needed for the study. Estimating a 10% dropout rate, a minimum recruitment of 202 subjects is required. All enrolled patients that underwent one of the two interventions under investigation will be assessed using an intention-to-treat analysis in each group. However, patients that did not undergo surgery at all or a completely different procedure will be excluded from the analysis. Per-protocol analysis will be performed as secondary analysis. Missing values will be imputed through the multiple imputation method.
Data will be represented as the mean ± SD or median, and analyzed using a parametrical test (student’s t-test) or non-parametrical test (Wilcoxon rank sum test). Categorical variables will be compared using theχ2 test and reported as proportions (percentage).
The homogeneity of the treatment groups will be described by comparison of the demographic data and the baseline values. Statistical analysis in this trial will be performed by the Department of Epidemiology affiliated to Army Medical University in China. SPSS 23.0 will be used for data analysis. A two-sided P < 0.05 will be considered statistically significant.
Ethics and dissemination
This trial complies with the principles of the Declaration of Helsinki and has been approved by the Medical Ethics Committee of Army Medical Center (ID: 2021 − 248). Written informed consent will be obtained from patients before enrollment in the study. The outcomes of the trial will be disseminated through peer-reviewed publications. The trial has been registered at clinicaltrials.gov (NCT05352074). The final trial results will be published in a peer-reviewed journal. Furthermore, results will be presented at appropriate national and international conferences. Relevant information about the trial and its results will be disseminated to patient groups and by social media.