A multicenter, randomized controlled trial comparing the identification rate of stigmata of recent hemorrhage and rebleeding rate between early and elective colonoscopy in outpatient-onset acute lower gastrointestinal bleeding: study protocol for a randomized controlled trial

This will be a parallel, randomized, open-label, superiority trial, in a 1:1 ratio, to receive early colonoscopy or elective colonoscopy (Figs. 1 and 2).

The trial has been approved by the institutional review board (IRB) of The University of Tokyo (P2015034–11Y, January 21, 2016) and the IRB of each participating institution. The trial is registered at UMIN-CTR (UMIN000021129, February 21, 2016) and ClinicalTrials.gov (NCT03098173, March 24, 2017).

The study will include 15 Japanese hospitals with a high colonoscopy procedure volume.

Enrolled patients will be randomized to undergo either early or elective colonoscopy. Early colonoscopy will be performed within 24 h of the initial visit. Elective colonoscopy will be performed between 24 and 96 h after the initial visit. All colonoscopies will be performed using an electronic video endoscope (Olympus Optical, Tokyo, Japan or Fujifilm Corporation, Tokyo, Japan) after administration of 2–4 L of oral bowel preparation. An enema will be additionally administered to patients who do not ingest all of the oral bowel preparation solution and continue to pass the effluent is free of fecal material.

Outcome definitions are provided in greater detail in Additional file 1: Appendix S1.

All patients referred to participating sites will be considered for screening and will be eligible if they fulfil all inclusion criteria and no exclusion criteria. Patients included and excluded will be reported according to the protocol [13].

Physicians at participating sites will have 24-h access to a web-based central randomization that provides immediate and concealed allocation. Randomization will be performed in blocks, with block sizes varying according to the allocation sequence generated by the Central Coordinating Unit, The University of Tokyo. A unique patient identification number will be entered into the system to ensure anonymity.

Not applicable.

Participants will be free to withdraw from participation at any time upon request.

An investigator may terminate participation in the study if:

The IRB of The University of Tokyo may terminate the trial in the event of a safety problem.

All deaths and immediately life-threatening events, whether related or unrelated, will be recorded on the SAE form in the Electronic Data Capture (EDC) system and submitted to the IRB as soon as possible. All SAE information must be shared via e-mail or telephone with all investigators within 24 h of site awareness. If there is reasonable possibility that the study procedure caused an unanticipated SAE, the director of The University of Tokyo Hospital will report the SAE to the Ministry of Health, Labour and Welfare, Japan. All SAEs will be collected during study visits, interviews with study participants presenting for medical care, or reviews by study monitors and should be followed to adequate resolution.

Assuming that the SRH rate in the elective-colonoscopy patients is 9% and the SRH rate in the early-colonoscopy patients is 26% (or higher) [14], with an alpha level of 5% (two-sided), a sample size of 142 (2 × 71) patients will be required to ensure an 80% probability of obtaining a statistically-significant χ² test result (i.e., an 80% statistical power). Because the observed difference might be diminished by patient noncompliance and/or dropout, we will recruit 20 additional patients to correct for these effects, and thus will recruit a total of 162 patients for this trial.

Interim analyses will not be done.

Data will be entered into a web-based EDC system by trial investigators or site investigators. The trial database will be created from the EDC system.

Research data collected from participants for the purpose of statistical analysis and scientific reporting will be transmitted to and stored at the University of Tokyo Hospital. The study data entry system and the study management system to be used by the investigators at the clinical sites and the research staff at the University of Tokyo Hospital will be secure and password protected. At the end of the study, all study databases will be anonymized and archived at the University of Tokyo Hospital. Data will be retained for either a minimum of 5 years after the end of the study or for 3 years after publication, whichever is first.

The trial monitoring plan is provided in Additional file 1: Appendix S3. The trial will be monitored by the risk-based monitoring team, consisting of the principal investigator, project manager, medical monitor, data managers, and a biostatistician, based at the University of Tokyo Hospital. Monitoring will consist of an early targeted review of certain data, which will include onsite, centralized, statistical monitoring for initial assessment and training.

The trial will adhere to ICH E6 (R2) and Ethical Guidelines for Medical and Health Research Involving Human Subjects (Japan) (Additional file 2). Recruitment can start following approval by the IRB of each participating site.

Early colonoscopy for ALGIB remains controversial and may be argued for by both patients and clinicians. The focus of this trial on early colonoscopy was decided based on the clinical uncertainty that exists in daily practice.

Patients from Tokyo, Ishikawa, Chiba, Hokkaido, Osaka, Fukui, Aomori, Aichi, Nagasaki, and Yamaguchi prefectures in Japan are expected to participate in the trial. The trial was initiated in Tokyo, Japan, in July 2016 and participation by the other sites can follow now that IRB approval has been obtained. Recruitment is expected to take 3 years.

The trial is supported by the Clinical Research Support Center at the University of Tokyo Hospital and the Department of Biostatistics, School of Public Health at the University of Tokyo.

An Independent Effect Judgment Committee has been formed (Additional file 1: Appendix S4). For the primary endpoint, its role is to evaluate inter-observer agreement in SRH diagnoses between site investigators and its Committee members.

A Site Investigator Team, consisting of a principal investigator and a trial coordinator at each site, will manage and coordinate the trial locally. The principal investigator at each site is responsible for data collection and maintenance of trial documentation.

Upon completion of the trial, a main manuscript will be prepared to present the trial results –positive, negative, or neutral – and will be submitted for peer-review to a major clinical journal. The results will also be published at ClinicalTrials.gov and on the website of the Department of Gastroenterology, the University of Tokyo.

A file containing the clean dataset used for final analysis to determine the main results of the trial, the statistical analysis plan, an explanation of variables, and the study protocol will be made publicly accessible in an anonymized format.

2015–2016: Funding applications, ethical approvals, EDC system development, monitoring plan development, and clinical staff training.

2016–2019: Patient recruitment.

2019: Data analysis and writing and submission of the main manuscript for publication.

This trial was developed and will be conducted in collaboration with all participating sites. The web-based randomization system and the system for allocation were developed and will be administered by the Clinical Research Support Center, the University of Tokyo Hospital.

Two premature RCTs [3, 4] and one propensity matching analysis [14], which was performed at a single center, have been published on investigations of whether early colonoscopy improved identification rates of SRH and clinical outcomes. One of the RCTs, an open-label trial by an American study group [3], compared early and elective colonoscopy in 100 ALGIB patients and reported that early colonoscopy had a higher identification of SRH than that with elective colonoscopy, although it did not improve clinical outcomes, including rebleeding, transfusion, and mortality. In contrast, the second RCT, an open-label trial by another American study group [4], compared early and elective colonoscopy in 72 ALGIB patients and reported no difference in identification rate of SRH, rebleeding, transfusion, or length of stay. However, both trials were terminated before reaching the originally planned sample size and were unable to demonstrate the superiority of early colonoscopy. In the study involving propensity matching analysis, we performed the largest retrospective propensity-score-matched analysis to compare identification rates of SRH and clinical outcomes (including success of endoscopic hemostasis, 30-day rebleeding, and length of stay) between early and elective colonoscopy [14]. Early colonoscopy was associated with a higher identification rate of SRH (26%) compared with elective colonoscopy (9%), as well as with a higher success rate for endoscopic hemostasis and shorter length of stay; however, the significance of the findings were limited by unmeasured confounders. These findings further highlighted the need for a multicenter RCT to determine the benefits and risks of early colonoscopy in ALGIB.

In this trial, we focus on the identification of SRH as the most important and feasible primary outcome. Although SRH identification may be a surrogate for clinical outcomes such as rebleeding or death, we hypothesized that early colonoscopy increases the identification of SRH and enables adequate endoscopic treatment, leading to fewer cases of rebleeding, less transfusion requirement, and shorter hospital stays [6‐8]. Another reason is sample size – if the sample size calculation were based on a 6% difference in the rate of 30-day rebleeding between early and elective colonoscopy (13% vs. 7%) [14], quite a large sample size of 784 patients (392 per group) would be needed, and conducting RCTs in this situation may be challenging considering that a prior RCT took 6 years to complete in an emergency setting of ALGIB [4].

This trial will build upon collaborations between major hospitals in Japan to deliver a study that may begin to inform the rational use of early colonoscopy for patients admitted with ALGIB. The RCT study design is justified in order to demonstrate that early colonoscopy can be implemented at a hospital-wide level, to reduce contamination between trial interventions, and to aid in the operational aspects of trial delivery. This is ethically acceptable, given that both early and elective colonoscopies are within the realms of normal practice in Japan and that all clinicians have the discretion to perform a colonoscopy in contravention of the policy if they think it is necessary, thereby ensuring patient safety is not compromised. We believe the study may also help inform the wider debate about the use of early colonoscopy.

Open label study.

Together with existing data, the high-quality data provided by this trial will inform clinicians and guideline committee members on the utility of early colonoscopy in ALGIB patients, as well as accumulate evidence for its use in moderate to severe outpatient cases of ALGIB.

Recruitment is planned to end by March 2019.