A Multi-center, Randomized Controlled Trial Comparing Early Versus Elective Colonoscopy in Outpatients With Acute Lower Gastrointestinal Bleeding
Phase: NA
Conditions: Acute Lower Gastrointestinal Bleeding
Sponsor: Tokyo University

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
1 
 
 
 
 
A multi-center, randomized controlled trial comparing 
early versus elective colonoscopy in outpatients with 
acute lower gastrointestinal bleeding 
Protocol Identifying Number: P2015034‒11Y, UMIN-CTR Identifier, 
UMIN000021129; ClinicalTrials.gov Identifier, NCT 03098173 
Principal Investigators: Kazuhiko Koike, Atsuo Yamada 
IND/IDE Sponsor: Graduate School of Medicine, The University of Tokyo 
Funded by: The Japanese Gastroenterological Association 
Draft or Version Number: v.6.0. 9 June 2016 
v.7.0. 6 April 2017 
v.7.1. 9 January 2018 
 
 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
2 
 
Table of Contents 
List of ABBREVIATIONS.................................................................................................................. 5 
STATEMENT OF COMPLIANCE ................................................................................................... 6 
SCHEMATIC OF STUDY DESIGN ................................................................................................. 9 
1 KEY ROLES .................................................................................................................................. 10 
2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE . 14 
2.1 BACKGROUND INFORMATION ....................................................................................... 14 
2.2 RATIONALE........................................................................................................................... 14 
2.3 POTENTIAL RISKS AND BENEFITS ................................................................................ 16 
2.4. Justification for Choice of Thresholds in this Trial ............................................................. 17 
2.5. Summary of evidence and the need for a trial ..................................................................... 17 
3 OBJECTIVES AND PURPOSE ................................................................................................... 18 
4 STUDY DESIGN AND ENDPOINTS .......................................................................................... 18 
4.1 DESCRIPTION OF THE STUDY DESIGN ........................................................................ 18 
4.2 STUDY ENDPOINTS ............................................................................................................. 18 
4.2.1 PRIMARY ENDPOINT .................................................................................................. 18 
4.2.2 SECONDARY ENDPOINTS .......................................................................................... 18 
4.2.3 Outcome Definitions ........................................................................................................ 20 
5 STUDY ENROLLMENT AND WITHDRAWAL........................................................................ 21 
5.1 PARTICIPANT INCLUSION CRITERIA ........................................................................... 21 
5.2 PARTICIPANT EXCLUSION CRITERIA .......................................................................... 21 
5.3.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION ................... 22 
6 STUDY PROCEDURES AND SCHEDULE ............................................................................... 23 
6.1 STUDY PROCEDURES/EVALUATIONS ........................................................................... 23 
6.1.1 STUDY-SPECIFIC PROCEDURES .................................................................................. 23 
6.1.2 STANDARD OF CARE STUDY PROCEDURES ............................................................ 24 
6.2 STUDY SCHEDULE .............................................................................................................. 25 
6.2.1 SCREENING ........................................................................................................................ 25 
6.2.2 ENROLLMENT/BASELINE ............................................................................................. 25 
6.2.3 FOLLOW-UP ....................................................................................................................... 25 
6.2.3 EARLY TERMINATION VISIT ........................................................................................ 25 
6.2.4 SCHEDULE OF EVENTS TABLE .................................................................................... 26 
6.2.5 JUSTIFICATION FOR SENSITIVE PROCEDURES .................................................... 26 
6.2.6 PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES .................... 26 
6.2.7 PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ............. 26 
6.2.8 RESCUE THERAPY ........................................................................................................... 26 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
3 
 
6.2.9 PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ........................ 26 
7 ASSESSMENT OF SAFETY ........................................................................................................ 27 
7.1 SPECIFICATION OF SAFETY PARAMETERS ................................................................ 27 
7.1.1 DEFINITION OF ADVERSE EVENTS (AE) ................................................................... 27 
7.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAEs) ............................................. 27 
7.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) ............................................... 27 
7.2 CLASSIFICATION OF AN ADVERSE EVENT ................................................................. 28 
7.2.1 SEVERITY OF EVENT ...................................................................................................... 28 
7.2.2 RELATIONSHIP TO STUDY PROCEDURE ...................................................................... 28 
7.2.3 EXPECTEDNESS .................................................................................................................... 28 
7.3 PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ............. 28 
7.4 REPORTING PROCEDURES .................................................................................................. 29 
7.4.1 ADVERSE EVENT REPORTING ......................................................................................... 29 
7.4.4 EVENTS OF SPECIAL INTEREST ...................................................................................... 30 
7.4.5 REPORTING OF PREGNANCY ........................................................................................... 30 
7.5 STUDY HALTING RULES ....................................................................................................... 30 
7.6 SAFETY OVERSIGHT .............................................................................................................. 31 
8 CLINICAL MONITORING ......................................................................................................... 31 
9 STATISTICAL CONSIDERATIONS .......................................................................................... 31 
9.1 STATISTICAL AND ANALYTICAL PLAN (SAP) ................................................................. 31 
9.2 STATISTICAL HYPOTHESES ................................................................................................ 32 
9.3 ANALYSIS DATASETS ............................................................................................................. 32 
9.4 DESCRIPTION OF STATISTICAL METHODS .................................................................... 32 
9.4.1 GENERAL APPROACH ......................................................................................................... 32 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT ................................................. 32 
9.4.3 ANALYSIS OF SECONDARY ENDPOINTS ....................................................................... 33 
9.4.4 SAFETY ANALYSES .............................................................................................................. 34 
9.4.5 ADHERENCE AND RETENTION ANALYSES .................................................................. 34 
9.4.6 BASELINE DESCRIPTIVE STATISTICS ........................................................................... 34 
9.4.7 PLANNED INTERIM ANALYSES ........................................................................................ 34 
9.4.8 ADDITIONAL SUB-GROUP ANALYSES ............................................................................ 35 
9.4.9 MULTIPLE COMPARISON/MULTIPLICITY ................................................................... 35 
9.4.10 EXPLORATORY ANALYSES ............................................................................................. 35 
9.5 SAMPLE SIZE ............................................................................................................................ 35 
9.6 MEASURES TO MINIMIZE BIAS .......................................................................................... 36 
9.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES ............................... 36 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
4 
 
9.6.2 EVALUATION OF SUCCESS OF BLINDING .................................................................... 36 
9.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE ................................................ 36 
10 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................... 36 
11 QUALITY ASSURANCE AND QUALITY CONTROL .......................................................... 37 
12 ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................ 37 
12.1 ETHICAL STANDARDS ......................................................................................................... 37 
12.2 INSTITUTIONAL REVIEW BOARD .................................................................................... 37 
12.3 INFORMED CONSENT PROCESS ....................................................................................... 37 
12.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS......................................................................................................................... 37 
12.3.2 CONSENT PROCEDURES AND DOCUMENTATION ................................................... 38 
12.4 PARTICIPANT AND DATA CONFIDENTIALITY .............................................................. 38 
12.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA ........... 39 
12.5 FUTURE USE OF STORED SPECIMENS ........................................................................... 39 
13. DATA HANDLING AND RECORD KEEPING ...................................................................... 40 
13.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ............................... 40 
13.2 STUDY RECORDS RETENTION .......................................................................................... 40 
13.3 PROTOCOL DEVIATIONS .................................................................................................... 40 
13.4 PUBLICATION AND DATA SHARING POLICY ................................................................ 41 
14. CONFLICT OF INTEREST POLICY...................................................................................... 41 
15. LITERATURE REFERENCES ................................................................................................. 42 
Appendix Statistical Analysis Plan .................................................................................................. 46 
Appendix Clinical Data Monitoring Plan (CDMoP)...................................................................... 47 
 
 
 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
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List of ABBREVIATIONS 
AE 
Adverse Event 
DCC 
Data Coordinating Center 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IRB 
Investigational Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
PI 
Principal Investigator 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
 
 
 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
6 
 
STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with ICH E6 (R2), and Ethical Guidelines for 
Medical and Health Research Involving Human Subjects (Japan). The Principal 
Investigator will ensure that no deviation from, or changes to, the protocol will take 
place without prior agreement from the sponsor and documented approval from the 
institutional review board (IRB), except where necessary to eliminate an immediate 
hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed Human Subjects Protection Training. 
 
 
I agree to ensure that all staff members involved in the conduct of this study are 
informed about their obligations in meeting the above commitments. 
 
 
 
Principal Investigator:  Kazuhiko  Koike                                                   
 
Principal Investigator:  Atsuo  Yamada                           
 
Date: 2018/1/9                     

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
7 
 
PROTOCOL SUMMARY 
Title: A multi-center randomized controlled trial comparing early versus elective 
colonoscopy in outpatients with acute lower gastrointestinal bleeding. 
Précis: This multi-center, randomized controlled trial study is planned to include 162 
outpatients with onset of acute lower gastrointestinal bleeding to compare the rate of 
identification of stigmata of recent hemorrhage (SRH), and other clinical outcomes, 
including the 30-day rebleeding rate, between ‘early’ colonoscopy, performed within 
24 h of arrival at the hospital and ‘elective’ colonoscopy, within 96 h. 
Objectives 
Primary Objective: To evaluate whether early colonoscopy improved the identification 
rate of SRH versus elective colonoscopy. 
Secondary Objectives: To evaluate whether early colonoscopy improved clinical 
outcomes, including 30-day rebleeding, success rate of endoscopic treatment, need for 
additional endoscopic examinations, need for interventional radiology, need for surgery, 
need for transfusion during hospitalization, length of stay, 30-day thrombosis events, 
and 30-day mortality, compared with elective colonoscopy.  
Endpoints 
Primary Endpoint: Identification of SRH 
Secondary Endpoints: Thirty-day rebleeding, success rate of endoscopic treatment, 
need for additional endoscopic examination, need for interventional radiology, need for 
surgery, need for transfusion during hospitalization, length of stay, 30-day thrombosis 
events, 30-day mortality, preparation-related adverse events, and colonoscopy-related 
adverse events. 
Population: In total, 162 males or females aged ≥ 20 years presenting with 
moderate-to-severe hematochezia or melena within 24 h of arrival at 15 Japanese 
hospitals.  
 
Number of Sites Enrolling Participants: 15 
Description of Study Participants: Males or Females aged ≥ 20 years, presenting with 
moderate-to-severe hematochezia or melena within 24 h of arrival at a hospital. 
Describe the intervention: Early colonoscopy is performed within 24 h of the initial 
visit. All colonoscopies are performed using an electronic video endoscope after 2-4 L 
of oral bowel preparation was administrated. If patients have not completely ingested 
oral bowel preparation solution until the effluent is free of fecal material, enema will be 
added for these patients. 
Study Duration: 3 years 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
8 
 
Participant Duration: 30 days 
 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
9 
 
SCHEMATIC OF STUDY DESIGN 
 
 
 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
10 
 
1 KEY ROLES 
Funder  
The Japanese Gastroenterological Association 
Dr Kazuma Fujimoto 
The Japanese Gastroenterological Association Director 
2-1-1 Suido, Bunkyo-ku, Tokyo 
Telephone: +81-3-5840-6338 Email: jga-secretariat@keiso-comm.com 
 
Principal Investigators 
Dr. Kazuhiko Koike 
Department of Gastroenterology, Graduate School of Medicine, The University of 
Tokyo 
7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 
Telephone: +81-3-3815-5411 Email: kkoike-tky@umin.ac.jp 
 
Dr. Atsuo Yamada 
Department of Gastroenterology, Graduate School of Medicine, The University of 
Tokyo 
7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 
Telephone: +81-3-3815-5411 Email: yamada-a@umin.ac.jp 
 
Project Manager 
Dr. Ryota Niikura 
Department of Gastroenterology, Graduate School of Medicine, The University of 
Tokyo 
7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 
Telephone: +81-3-3815-5411 Email: rniikura@triton.ocn.ne.jp 
 
Site Investigator 
Dr. Naoyoshi Nagata 
Department of Gastroenterology and Hepatology, National Center for Global Health and 
Medicine center hospital 
1-21-1 Toyama, Shinjuku-ku, Tokyo, Japan 
Telephone: +81-3-3202-7181 Email: nnagata_ncgm@yahoo.co.jp 
 
Dr. Hisashi Doyama 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
11 
 
Department of Gastroenterology, Ishikawa prefectural central hospital 
Kuratsuki-Higashi 2-1, Kanazawa city, Ishikawa, Japan 
Telephone: +81-76-237-8211 Email: doyama.134@ipch.jp 
 
Dr. Yasutoshi Shiratori 
Department of Gastroenterology, St. Luke’s International Hospital 
9–1 Akashi-cho, Chuo-ku, Tokyo, Japan 
Telephone: +81-3-3541-5151 Email: naoishi@luke.ac.jp 
 
Dr. Tomoyuki Yada 
Department of Gastroenterology and Hepatology, National Center for Global Health and 
Medicine kohnodai hospital 
1-7-1 Kohnodai, ichikawa-shi, Chiba, Japan 
Telephone: +81-47-372-3501 Email: tomoyuki0618@yahoo.co.jp 
 
Dr. Tomoki Fujita 
Department of Gastroenterology, Otaru Ekisaikai Hospital 
1-4-1 Inaho, Otaru-shi, Hokkaido, Japan 
Telephone: +81-134-24-0325 Email: tomoki-fujita@otaru-ekisaikai.jp 
 
Dr. Tsutomu Nishida 
Department of Gastroenterology, Toyonaka Municipal Hospital 
4-14-1 Shibaharacho, Toyonaka-shi, Osaka, Japan 
Telephone: +81-6-6843-0101 Email: tnishida.gastro@gmail.com 
 
Dr. Katsuhiro Mabe 
Department of Gastroenterology, National Hospital Organization Hakodate Hospital 
18-16 Kawaharachou, Hakodate-shi, Hokkaido, Japan 
Telephone: +81-138-51-6281 Email: kmabe@hnh.hosp.go.jp 
 
Dr. Tetsuya Sumiyoshi 
The Center for Digestive Disease, Tonan Hospital 
Kita 1, Nishi 6, Chuo-ku, Sapporo-shi, Hokkaido, Japan 
Telephone: +81-11-231-2121 Email: t-sumiyoshi@tonan.gr.jp 
 
Dr. Kenkei Hasatani 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
12 
 
Department of Gastroenterology, Fukui prefectural hospital 
2-8-1, Yotsui, Fukui-shi, Fukui, Japan 
Telephone: +81-776-54-5151 Email: hasatani9@yahoo.co.jp 
 
Dr. Tatsuya Mikami 
Division of Endoscopy, Hirosaki University Hospital 
53, Honcho, Hirosaki-shi, Aomori, Japan 
Telephone: +81-172-39-5053 Email: tmika@hirosaki-u.ac.jp 
 
Dr. Kazuo Hara 
Department of Gastroenterology, Aichi Cancer Center Hospital 
1-1 Kanokoden, Chikusa-ku, Nagoya-shi, Aichi, Japan 
Telephone: +81-52-762-6111 Email: khara@aichi-cc.jp 
 
Dr. Tetsuro Honda 
Department of Gastroenterology, Nagasaki Harbor Medical Center City Hospital 
6-39, Shinchimachi, Nagasaki-shi, Nagasaki, Japan 
Telephone: +81-95-822-3251 Email: tetsupeacevo@yahoo.co.jp 
 
Dr. Shu Kiyotoki 
Department of Gastroenterology, Shuto General Hospital 
1000-1 Kogaisaku, Yanai-shi, Yamaguchi, Japan 
Telephone: +81-820-22-3456 Email: shu2026eb@hi.enjoy.ne.jp 
 
Dr. Katsumi Yamamoto 
Department of Gastroenterology,  Japan Community Healthcare Organization Osaka 
Hospital 
4-2-78, Fukushima, Fukushima-shi, Osaka, Japan 
Telephone: +81-6-6441-5451 Email: katsumiy770@yahoo.co.jp 
 
Biostatistician 
Tomohiro Shinozaki 
Department of Biostatistics, School of Public Health, the University of Tokyo    
7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 
Telephone: +81-3-3815-5411 Email: shinozaki@epistat.m.u-tokyo.ac.jp 
 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
13 
 
Data Coordinating Center and Manager 
Dr. Munenori Takata 
Mariko Takeda 
Department of Clinical Research Support Center, The University of Tokyo Hospital 
7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 
Telephone: +81-3-5800-9762 Email: takatam-tky@umin.ac.jp 
 
Medical Monitor 
Yumi Tanaka 
Department of Clinical Research Support Center, The University of Tokyo Hospital 
7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 
Telephone: +81-3-5800-9762 Email: tanakaym-tky@umin.ac.jp 
 
Regulatory Specialist Regrading Safety 
Ikue Wada 
Department of Clinical Research Support Center, The University of Tokyo Hospital 
7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 
Telephone: +81-3-5800-9762 Email: iwada-tky@umin.ac.jp 
 
Audit 
Yuki Kusaka 
Department of Clinical Research Governance, The University of Tokyo Hospital 
7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan 
Telephone: +81-3-5800-9051 Email: ykusaka-tky@umin.ac.jp 
 
Independent Effect Judgment Committee 
Dr. Shiro Oka 
Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan 
1-2-3 Kasumi, Minami, Hiroshima-shi, Hiroshima, Japan 
Telephone: +81-82-257-5555 Email: oka4683@hiroshima-u.ac.jp 
 
Dr. Hirotsugu Watabe 
Wakamiya Watabe Clinic 
3-3-16, Wakamiya, Ichihara-shi, Chiba, Japan 
Telephone: +81- 436-43-0609 Email: hwatabegi@gmail.com 
 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
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2 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 BACKGROUND INFORMATION 
Acute lower gastrointestinal bleeding (ALGIB) is a common disease, the incidence of 
which has recently increased. The estimated annual incidence of ALGIB hospitalization 
was 21 per 100,000 in the United States in 1997.1 In Japan, a nationwide study reported 
that in 2015, 30,846 ALGIB patients required hospitalization: of them, 26% required 
transfusion and 2.5% suffered in-hospital mortality.2 Another observational study 
showed that the incidence of severe ALGIB, requiring hospitalization, has been 
increasing in Japan.3 
 
2.2 RATIONALE 
Efficacy of colonoscopy for patients with ALGIB 
Colonoscopy is a widely used examination technique worldwide and is an essential tool 
for the optimal management for ALGIB.4,5 Colonoscopy provides advantages in both 
diagnosis and immediate therapy (hemostasis)6. Colonoscopy has higher diagnostic 
accuracy than radiological examination and can identify 75-100% of the causes of 
ALGIB, such as diverticular bleeding, rectal ulcers, ischemic colitis, and infectious 
colitis7-11. Thus, using colonoscopy, 50-100% successful endoscopic hemostasis can be 
achieved in patients.8,10,12,13 Endoscopic hemostasis potentially reduces the need for 
transfusion, rebleeding, and length of stay.12,14 
 
Safety of colonoscopy in ALGIB 
Colonoscopy includes the potential for both preparation- and procedure-related adverse 
events. However, a previous study reported that these adverse event rates were low and 
the procedure was safe in patients with non-gastrointestinal bleeding.15 Preparation- 
related adverse events include vomiting, aspiration phenomena, heart failure, and 
hypotension.16 Colonoscopy-related adverse events include cerebrocardiovascular 
events, perforation, and sepsis.15 In reviews of non-gastrointestinal bleeding patients in 
the literature, preparation-related adverse events have been reported: 13 cases of heart 
failure, and 4 cases of aspiration pneumonia.17,18 Colonoscopy-related adverse events 
have been reported: 5-7% for hypotension,19 0.60-1.18 events per 1000 examinations for 
perforation,20-25 and 0.22 events per 1000 for cerebrovascular events.20,21,26 
Evidence on the safety of colonoscopy limited to patients with ALGIB is 
limited. Thus, we previously considered adverse event rates during bowel preparation 
and colonoscopy in acute LGIB and non-GIB patients and compared these between the 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
15 
 
groups.27 Emergency hospitalized LGIB patients (n = 161) and age- and sex-matched 
non-GIB controls (n = 161) were selected. During bowel preparation, 12 (7%) and 
4 (2%) LGIB patients experienced hemodynamic instability and vomiting, respectively, 
while 19 (12%) and 3 (2%) non-GIB controls experienced these adverse events. 
Although none of the LGIB patients experienced volume overload, aspiration 
pneumonia or loss of consciousness, 12 (7%) had hypotension and 4 (2%) vomited. 
However, there was no significant difference in five bowel-preparation-related adverse 
events between LGIB and non-GIB patients. 
During colonoscopy, no LGIB patient suffered perforation or sepsis; however, 
23 (14%) had hypotension and 2 (1%) experienced a cerebrocardiovascular event. In 
non-GIB 
patients, 
17 
(11%) 
had 
hypotension 
and 
none 
experienced 
a 
cerebrocardiovascular event. There was no significant difference in the four 
colonoscopy-related adverse events between LGIB and non-GIB patients. Two LGIB 
patients who experienced cerebrocardiovascular events recovered after treatment, and 
none died during hospitalization. That study showed that colonoscopy performed during 
acute LGIB did not increase adverse events compared with those of non-GIB patients. 
 
Clinical Uncertainty about Colonoscopy in ALGIB 
One of the most important issues in ALGIB treatment is that 10-40% of patients suffer 
from rebleeding and require transfusion within 48 h after the initial bleeding.28,29 The 
reason is the low identification rate of stigmata of recent hemorrhage (SRH) and the 
poor rate of successful hemostasis. If clinicians can identify SRH accurately, they can 
provide effective endoscopic hemostasis, and subsequently improve important clinical 
outcomes, such as the prevention of rebleeding. However, accurate identification of 
SRH is difficult. To date, there is no reliable method for identifying SRH. An 
observational study found that the timing of colonoscopy was associated with the 
identification rate of SRH.30 Indeed, the SRH identification rate was higher in the early 
colonoscopy (22%) group than in the 24-48 h group (2.9%), with a statistically 
significant decrease with time.30 ‘Early’ colonoscopy was defined as performing a 
prepared colonoscopy within 24 h of arrival and ‘elective’ colonoscopy was performed 
between 24 and 96 h.9 The main area of uncertainty has been whether the timing of 
colonoscopy improves clinical outcomes, such as the identification rate of SRH and the 
success of hemostasis. The issue remains controversial. 
 
Issues regarding previous randomized control trials (RCTs) of early colonoscopy in 
patients with ALGIB 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
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Two RCTs of whether early colonoscopy improves identification rates of SRH and 
clinical outcomes have been reported.9,31 Green et al. performed an open-label RCT 
between early and elective colonoscopy in 100 ALGIB patients, and reported that early 
colonoscopy improved the identification rate of SRH compared with that of elective 
colonoscopy, although it did not improve clinical outcomes, including rebleeding, 
transfusion, and mortality.9 In contrast, Laine et al. performed an open-label RCT 
between early and elective colonoscopy in 72 ALGIB patients, and reported no 
difference in identification rates of SRH, rebleeding, transfusion, or length of stay.31 
However, these studies were terminated before reaching the originally planned sample 
size, and were unable to demonstrate the superiority of early colonoscopy. 
We performed a retrospective propensity-score-matched analysis to compare 
identification rates of SRH and clinical outcomes, such as the success rate of 
endoscopic hemostasis, 30-day rebleeding, and length of stay, between early and 
elective colonoscopy.32 Early colonoscopy was associated with an increased 
identification rate of SRH (26%) compared with elective colonoscopy (9%), as well as a 
higher success rate for endoscopic hemostasis and decreased length of stay, but 
unmeasured confounders limited the significance of the findings. These findings further 
highlight the need for a multi-center RCT to determine the benefits and risks of early 
colonoscopy in ALGIB. 
 
2.3 POTENTIAL RISKS AND BENEFITS 
2.3.1 KNOWN POTENTIAL RISKS 
Potential sources of harm from early colonoscopy include exacerbated bleeding, due to 
preparation, and various adverse events such as hemorrhagic shock, thrombotic 
embolism, and death. Other possible mechanisms of patient harm include the possibility 
that poor visualization because of bleeding may lead to underestimation in the 
identification of SRH.10 
 
2.3.2 KNOWN POTENTIAL BENEFITS 
Several single-arm studies in various populations (notably, severe ALGIB) have 
suggested an association between early colonoscopy and improved patient outcomes, 
including identification rates of SRH.4,5,8-10,12,33 Additionally, a non-randomized study 
suggested that early colonoscopy improved both identification rates of SRH and success 
rates of hemostasis, resulting in a decreased rebleeding rate.12 
 

A multi-center, randomized controlled trial comparing early versus  
ver7.1 
elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
9 January 2018 
17 
 
2.4. Justification for Choice of Thresholds in this Trial 
Early colonoscopy for ALGIB remains controversial and people may argue for early 
colonoscopy, as do clinicians in clinical practice. Early colonoscopy was chosen in this 
trial based on evidence that has identified a key area of clinical uncertainty in daily 
practice. Early colonoscopy is based on the following considerations: 
 As mentioned above, no high-quality evidence supports the suggestion that early 
colonoscopy improves identification of SRH, or clinical outcomes compared with 
those of elective colonoscopy in ALGIB patients. This is a controversial clinical 
question that should be addressed. 
 If this study can ‘solve’ the clinical question, ALGIB patients may have decreased 
transfusion requirements, rebleeding rates, and lengths of stay. Subsequently, early 
colonoscopy may become more widespread in clinical practice. 
 An observational study reported that early colonoscopy was performed in 40% of 
ALGIB patients.30 Another questionnaire survey in 37 major hospitals in Japan, 
showed that 64% of these hospitals performed early colonoscopy.38 In clinical 
practice, early colonoscopy in ALGIB is feasible for many endoscopists. 
 Although patients potentially experience a slight risk of preparation- and 
colonoscopy-related adverse events, a Japanese observational study showed that 
colonoscopy in ALGIB did not increase adverse events compared with those in 
non-GIB patients.27 
 
2.5. Summary of evidence and the need for a trial 
Based on existing evidence and our preliminary work, we have identified a lack of high- 
quality evidence regarding the optimal timing of colonoscopy in ALGIB, with widely 
varying clinical use of early colonoscopy throughout Japan and a patient population for 
whom a RCT may address a key area of clinical uncertainty. 
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. A RCT design is justified to demonstrate that early 
colonoscopy can be implemented at a hospital-wide level, to reduce contamination 
between the trial interventions, and to aid in operational aspects of the trial delivery. 
This is acceptable ethically, 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. 

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3 OBJECTIVES AND PURPOSE 
To compare the identification rates of SRH for ‘early’ versus ‘elective’ colonoscopy in 
outpatients with ALGIB.  
 
4 STUDY DESIGN AND ENDPOINTS 
4.1 DESCRIPTION OF THE STUDY DESIGN 
Parallel, randomized, open-label, superiority trial 
Two arms 
Multi-center 
Early colonoscopy (performance of prepared colonoscopy within 24 h of arrival) versus 
elective colonoscopy (performance of prepared colonoscopy between 24 and 96 h after 
arrival).  
One-to-one allocation 
No stratification. 
 
4.2 STUDY ENDPOINTS 
4.2.1 PRIMARY ENDPOINT 
 
SRH identification rate in the lower gastrointestinal tract. 
We will define SRH based on colonoscopic visualization of lesions, such as 
diverticulosis, tumor, ulcer, hemorrhoid, angioectasia, and polyps exhibiting active 
bleeding,34,35 a visible vessel,34,36 or an adherent clot.37 
We will also evaluate inter-observer agreement in SRH diagnoses between site 
investigators and an Independent-Effect Judgment Committee using endoscopic 
images. 
 
4.2.2 SECONDARY ENDPOINTS 
 
Success rate of endoscopic treatment 
 
Need for additional endoscopic examinations 
 
Need for interventional radiology 
 
Need for surgery 
 
Thirty-day rebleeding rates 
 
Need for transfusion during hospitalization 
 
Length of stay 
 
Thirty-day thrombosis events 
 
Thirty-day mortality 

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 
Preparation-related adverse events  
 
Colonoscopy-related adverse events (hemorrhagic shock, and perforation). 
 
 
 
 
 
 
 
 

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4.2.3 Outcome Definitions 
Outcome 
Definitions 
Success rate of endoscopic treatment 
Success rate will be defined as the number 
achieving hemostasis per total number of 
attempts at endoscopic hemostasis during 
colonoscopy examination. 
Need for transfusion during hospitalization Transfusion will be performed when the 
hemoglobin level falls to < 7 g/dL in 
patients, according to the guidelines of the 
Ministry of Health, Labour, and Welfare. 
Thirty-day rebleeding 
Rebleeding will be defined as significant 
fresh 
blood 
loss 
after 
an 
initial 
colonoscopy with any of the following 
criteria: 
i) Hemorrhagic shock, including cold 
sweat, nausea, syncope, or systolic blood 
pressure ≤ 90 mmHg. 
ii) Need for transfusion, according to the 
guidelines of the Ministry of Health, 
Labour, and Welfare. 
iii) Further colonoscopy identifies blood 
pooling, or  
iv) SRH in the lower gastrointestinal tract. 
v) 
Contrast-enhanced 
CT 
identifies 
extravasation in the colorectal region.  
However, these examinations will not be 
performed routinely if rebleeding occurs 
in the study period. 
Thirty-day thrombosis events 
Thrombosis events will include acute 
coronary syndromes, including angina 
pectoris and myocardial infarction, stroke, 
including 
cerebrovascular 
infarction, 
cerebral 
hemorrhage, 
and 
transient 
ischemic attacks, deep vein thrombosis, 
and pulmonary embolism. 
Preparation-related adverse events 
Preparation-related adverse events will 

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include nausea, vomiting, abdominal pain, 
volume overload, aspiration pneumonia, 
hemorrhagic shock, exacerbation bleeding, 
and ileus 
Colonoscopy-related adverse events 
Colonoscopy-related adverse events will 
include 
hemorrhagic 
shock, 
and 
perforation. 
 
 
5 STUDY ENROLLMENT AND WITHDRAWAL 
5.1 PARTICIPANT INCLUSION CRITERIA 
1. Males or females 
aged ≥ 20 years, 
presenting with 
moderate-to-severe 
hematochezia or melena within 24 h of arrival, defined as (i) more than three 
occurrences of hematochezia within 8 h, or (ii) hemorrhagic shock, or (iii) requiring 
transfusion. 
2. Eligible patients will be asked to read explanatory documents providing doctor’s 
instructions and sign consent forms. Informed consent will be obtained from each 
eligible patient before enrollment in the trial. 
3. Stated willingness to comply with all study procedures and availability for the 
duration of the study. 
 
5.2 PARTICIPANT EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from 
participation in this study: 
1. Patients with hematemesis, black vomiting, or melena. 
2. Patients with upper gastrointestinal bleeding, diagnosed by nasogastric tube or 
upper endoscopy. 
3. Patients who impossible consumed the oral bowel preparation solution. 
4. Patients who have undergone computed tomography. 
5. Patients who have been diagnosed with peptic ulcer diseases within the previous 10 
days. 
6. Ulcerative colitis or Crohn’s disease patients. 
7. Patients who have undergone abdominal surgery within the previous 10 days. 
8. Patients who have undergone polypectomy, endoscopic mucosal resection, or 
endoscopic submucosal dissection of the lower gastrointestinal tract within the 
previous 10 days. 

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9. Patients with suspected perforation or peritonitis. 
10. Patients with suspected intestinal obstruction. 
11. Patients with hemorrhagic shock refractory to infusion or blood transfusion. 
12. Patients who have undergone total colectomy. 
13. Patients with suspected disseminated intravascular coagulation. 
14. Patients with end-stage malignant disease. 
15. Patients with severe cardiac failure. 
16. Patients with active thrombosis. 
17. Patients with severe respiratory failure. 
18. Pregnant patients. 
 
5.3 PARTICIPANT WITHDRAWAL OR TERMINATION 
5.3.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Participants will be free to withdraw from participation in the study at any time upon 
request.  
An investigator may terminate participation in the study if: 
 
The participant meets an exclusion criterion (newly developed or not previously 
recognized) that precludes further study participation. 
 
Any clinical adverse event (AE), or other medical condition or situation occurs 
such that continued participation in the study would not be in the best interests of 
the participant. 
 
Trial termination occurs due to a safety problem. 
 
5.3.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
Participants will be free to withdraw consent at any stage of data collection and 
follow-up, without having to provide any reason for their decision. However, such 
patients should continue to be managed in accordance with the safety and effects policy. 
Data including date and reason for withdrawal and clinical course will be recorded in 
the electronic data capture (EDC) system. If the withdrawal occurs due to AEs, site 
investigators will need to help the patient to recover to the previous state, as far as is 
possible. 
 
5.4 PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for such a study 
suspension or termination will be provided by the suspending or terminating party to the 

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investigator and the IRB. If the study is prematurely terminated or suspended, the PI 
will promptly inform the IRB and will provide the reasons for the termination or 
suspension. Circumstances that may warrant termination or suspension include, but are 
not limited to: 
 Determination of unexpected, significant, or unacceptable risk to participants. 
 Data that are not sufficiently complete and/or evaluable. 
 If the IRB suggests a change of protocol, and it is difficult to accept this change. 
 
6 STUDY PROCEDURES AND SCHEDULE 
6.1 STUDY PROCEDURES/EVALUATIONS 
6.1.1 STUDY-SPECIFIC PROCEDURES 
 Medical histories will be obtained by interview or from medical records and 
examine: ischemic heart disease, chronic pulmonary disease, peptic ulcer, liver 
cirrhosis, diabetes mellitus, chronic heart failure, cerebrovascular disease, dementia, 
collagen diseases, chronic kidney disease, leukemia, malignant lymphoma, 
malignancy, malignancy with metastasis, acquired immune deficiency syndrome, 
hemiplegia, lower gastrointestinal bleeding, and peripheral vascular disease. 
 Medication history will include only medications currently taken, prescription and 
over-the-counter medications at the first visit, on performing a colonoscopy, and at 
the final visit (Visit 1): non-steroidal anti-inflammatory drugs, low-dose aspirin, 
thienopyridine, cilostazol, other anti-platelet drugs, such as eicosapentaenoic acid, 
sarpogrelate, beraprost, limaprost, dilazep, dipyridamole, ozagrel, non-vitamin K 
antagonist oral antagonists (NOACs), such as dabigatran, rivaroxaban, apixaban, 
and edoxaban, and warfarin. 
 Physical examination will include height, weight, body mass index at initial visit, 
and systolic and diastolic blood pressures and pulse rate at the initial visit and on 
performing a colonoscopy.  
 ‘Early’ colonoscopy will be performed within 24 h of the initial visit: All 
colonoscopies will be performed using an electronic video endoscope (Olympus 
Optical, Tokyo, Japan or Fujifilm Corporation, Tokyo, Japan) after 2-4 L of oral 
bowel preparation was administrated. If patients who have not completely ingested 
oral bowel preparation until the effluent is free of fecal material, enema will be 
added for these patients. 
An antispasmodic agent, such as scopolamine butylbromide or glucagon, will be 
injected intramuscularly or intravenously just before the colonoscopy. Midazolam 
with or without diazepam and/or pentazocine hydrochloride and/or pethidine 

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titrated will be used for sedation during colonoscopy. 
A water-jet device (Olympus Flushing Pump; Olympus Optical, Tokyo, Japan) and 
attachment cap will be used to obtain better visualization30.  
 Colonoscopy assessment will include: (i) preparation-related adverse events such 
as nausea, vomiting, abdominal pain, heart failure, aspiration pneumonia, 
hemorrhagic shock, bleeding per rectum, and ileus; (ii) effectiveness: etiology of 
lower gastrointestinal bleeding, such as definitive diverticular bleeding, 
presumptive diverticular bleeding, rectal ulcer, colorectal cancer, ischemic colitis, 
infectious colitis, radial colitis, polyp bleeding, post-endoscopic-treatment bleeding, 
non-specific colorectal ulcer, and non-specific colitis; and hemorrhoids, stigmata of 
recent hemorrhage, endoscopic hemostasis, such as clipping, band ligation, 
injection of hypertonic saline, epinephrine solution, electrocautery coagulation, and 
argon plasma coagulation, success of endoscopic hemostasis, experience of the 
endoscopist (an ‘expert’ colonoscopist is defined as having conducted > 1000 
colonoscopies and performing endoscopic hemostasis), use of attachment cap, use 
of water-jet device, cecal insertion, insertion time, and inspection time; and (iii) 
colonoscopy-related adverse events: hemorrhagic shock and perforation  
 Laboratory evaluations, including blood hemoglobin at the initial visit and on 
performing a colonoscopy. 
 
6.1.2 STANDARD OF CARE STUDY PROCEDURES 
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 2-4 L of oral bowel 
preparation was administrated. If patients have not completely ingested oral bowel 
preparation solution until the effluent is free of fecal material, enema will be added for 
these patients. 
An antispasmodic agent, such as scopolamine butylbromide or glucagon, will be 
injected intramuscularly or intravenously just before the colonoscopy. Midazolam with 
or without diazepam and/or pentazocine hydrochloride and/or pethidine titrated will be 
used for sedation during colonoscopy. 
A water-jet device (Olympus Flushing Pump; Olympus Optical, Tokyo, Japan) and 
attachment cap will be used to obtain better visualization30. 
 

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6.2 STUDY SCHEDULE 
6.2.1 SCREENING 
Screening Visit (Day 0) 
 Obtain informed consent of potential participant, verified by signature on written 
informed consent. 
 Review medical history and medication history to determine eligibility based on 
inclusion/exclusion criteria. 
 Perform medical examinations needed to determine eligibility based on 
inclusion/exclusion criteria. 
 Collect blood for hemoglobin measurement. 
6.2.2 ENROLLMENT/BASELINE 
 Obtain informed consent of potential participant verified by signature on study 
informed consent form. 
 Verify inclusion/exclusion criteria. 
 Obtain demographic information, medical history, medication history. 
 Record vital signs, results of examinations, other assessments. 
 Collect blood for baseline hemoglobin laboratory tests required for the study. 
 Administer the study treatment. 
 
6.2.3 FOLLOW-UP 
Final Study Visit (Visit 1, Day 31+/3) 
 Record adverse events, as reported by participant or observed by investigator. 
 Record need for additional endoscopy examination, need for interventional 
radiology, need for surgery, transfusion during hospitalization, date of meal starting, 
length of stay, medication history at final visit, 30-day rebleeding, 30-day 
thromboembolism events, including angina pectoris, myocardial infarction, 
cerebrovascular events, deep vein thrombosis, and pulmonary embolism, and 30-day 
mortality. 
If patient cannot visit, site investigators will perform a telephone interview. 
 
6.2.3 EARLY TERMINATION VISIT 
 Record vital signs 
 Collect blood for hemoglobin 
 
 
 

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6.2.4 SCHEDULE OF EVENTS TABLE 
Procedures 
Screening 
Enrollment 
Preparation 
Colonoscopy 
Final study visit 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical history 
X 
 
 
X 
X 
Randomization 
X 
 
 
 
 
Physical exam 
X 
 
 
 
 
Vital signs 
X 
 
X 
X 
 
Complete blood count a 
X 
 
 
 
 
Early or elective colonoscopy 
 
 
 
X 
 
Adverse event evaluation 
X                           
a hemoglobin 
 
6.2.5 JUSTIFICATION FOR SENSITIVE PROCEDURES 
Not-applicable. 
 
6.2.6 PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
Not-applicable. 
 
6.2.7 PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES 
Not-applicable. 
 
6.2.8 RESCUE THERAPY 
If a patient presents with persistent severe bleeding in the elective-colonoscopy group, a 
physician will be able to deviate from the allocation and perform an early colonoscopy 
and hemostatic intervention, as needed according to the criteria: (i) presenting with 
hemorrhagic shock despite performing transfusion and infusion, or (ii) the need for 
transfusion of more than 6 U MAP. 
 
6.2.9 PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE 
Not-applicable. 

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7 ASSESSMENT OF SAFETY 
7.1 SPECIFICATION OF SAFETY PARAMETERS 
7.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event will mean any untoward medical occurrence associated with the use of 
an intervention in humans, regardless of whether considered intervention related. 
 
7.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAEs) 
An AE or suspected adverse reaction will be considered “serious” if, in the view of the 
investigator or monitor, it results in any of the following outcomes: death, a 
life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, which complies with ICH E6(R2) and the 
Ethical Guidelines for Medical and Health Research Involving Human Subjects 
(Japan). 
 
7.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The IRB considers unanticipated problems involving risks to participants or others to 
include, in general, any incident, experience, or outcome that meets all of the following 
criteria: 
 Unexpected in terms of nature, severity, or frequency given  
 (a) the research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent document; 
and  
 (b) the characteristics of the participant population being studied. 
 Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research). 
 Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
This study will use the IRB definition of UP. This definition can include an 
unanticipated adverse device effect, any serious adverse effect on health or safety or any 
life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 

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application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects. 
 
7.2 CLASSIFICATION OF AN ADVERSE EVENT 
7.2.1 SEVERITY OF EVENT 
 Mild: Events that require minimal or no treatment and do not interfere with the 
patient undergoing the study procedure. 
 Moderate: Events that require transfusion of saline or blood but do not interfere with 
the patient undergoing the study procedure. 
 Severe: Events that interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially 
life-threatening or incapacitating. 
 
7.2.2 RELATIONSHIP TO STUDY PROCEDURE 
The clinician’s assessment of an AE’s relationship to the study procedure is part of the 
documentation process, but it is not a factor in determining what is or is not reported in 
the study. All AEs must have their relationship to study procedure assessed.  
 Related: The AE is known to occur with the study procedure, there is a reasonable 
possibility that the study procedure caused the AE, or there is a temporal 
relationship between the study procedure and the event. Reasonable possibility 
means that there is evidence to suggest a causal relationship between the study 
procedure and the AE. 
 Not related: There is not a reasonable possibility that administration of the study 
procedure caused the event, there is no temporal relationship between the study 
procedure and event onset, or an alternate etiology has been established. 
 
7.2.3 EXPECTEDNESS 
Preparation- and colonoscopy-related adverse events will be responsible for determining 
whether an AE is expected or unexpected. Expected AEs in this trial include nausea and 
vomiting, abdominal pain, heart failure, aspiration pneumonia, gastrointestinal 
hemorrhage with or without hemorrhagic shock, ileus, and gastrointestinal perforation. 
The definitions of these AEs are provided above (4.2.3 Outcome Definitions). An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study procedure. 
 
7.3 
PERIOD 
AND 
FREQUENCY 
FOR 
EVENT 
ASSESSMENT 
AND 

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FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during 
study visits and interviews of a study participant presenting for medical care, or upon 
review by a study monitor. All AEs will be captured on the appropriate EDC. 
Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make such a diagnosis), and time of resolution/stabilization of 
the event. All AEs occurring while on study must be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened 
will be considered as baseline and not reported as an AE. However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as an 
AE.  
The investigator will record all reportable events with start dates that occur at 
any time after informed consent has been obtained until the end of the study for AEs 
and SAEs after the last day of study participation (30 days after performing 
colonoscopy). 
 
7.4 REPORTING PROCEDURES 
7.4.1 ADVERSE EVENT REPORTING 
The study clinician will complete an AE Form within the following timelines: 
 All AEs regardless of relationship will be submitted in an AE report to EDC as soon 
as possible after site awareness. 
 
7.4.2 SERIOUS ADVERSE EVENT REPORTING 
The study clinician will complete an SAE Form within the following timelines: 
 All deaths and immediately life-threatening events, whether related or unrelated, 
will be recorded on the SAE form of the EDC and submitted to the IRB as soon as 
possible. All SAE information must be shared among all investigators within 24 h of 
site awareness using e-mail or telephone. If there is a ‘reasonable possibility’ that 
the study procedure caused the ‘unanticipated’ SAEs, the director of The University 
of Tokyo Hospital will report the SAEs to Ministry of Health, Labour, and Welfare, 
Japan. All SAEs will be collected through SAE may come to the attention of study 
personnel during study visits, and or interviews of from a study participant 
presenting for medical care, or upon review by a study monitors; and should monitor. 
All SAEs will be followed to adequate resolution. 

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7.4.3 UNANTICIPATED PROBLEM REPORTING 
Incidents or events that meet the IRB criteria for UPs require the creation and 
completion of a report. It is the site investigator’s responsibility to report UPs to their 
IRB and to the Ministry of Health, Labour, and Welfare, as needed. All UPs will be 
reported using AE/SAE reporting timelines. The UP report will include the following 
information: 
 Protocol-identifying information: protocol title and number, PI’s name, and the IRB 
project number. 
 A detailed description of the event, incident, experience, or outcome. 
 An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP. 
 A description of any changes to the protocol or other corrective actions that have 
been taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the 
following timeline: 
 UPs that are SAEs will be reported to the IRB as soon as possible after the 
investigator becomes aware of the event. 
 Any other UP will also be reported to the IRB as soon as possible after the 
investigator becomes aware of the problem. 
 All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), and the supporting agency head (or 
designee), as soon as possible after the IRB’s receipt of the report of the problem 
from the investigator. 
 
7.4.4 EVENTS OF SPECIAL INTEREST 
Not applicable. 
 
7.4.5 REPORTING OF PREGNANCY 
The patient will be excluded from the study. 
 
7.5 STUDY HALTING RULES 
Early colonoscopy will be halted when unexpected, significant, or unacceptable risk 
events occur. AEs determined to be “related” are to be reported to the data coordinating 
center (DCC). When an unexpected, significant, or unacceptable risk event is reported, 

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the DCC will recommend that investigators immediately stop enrollment of new study 
participants. The PI will inform the IRB as soon as possible of this occurrence and will 
provide the IRB with AE listing reports. The IRB will convene an ad hoc meeting as 
soon as possible. The IRB will provide recommendations for proceeding with the study 
to the PI. The PI will inform the Ministry of Health, Labour, and Welfare of the 
temporary halt and the disposition of the study. 
 
7.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a risk-based monitoring team, composed 
of individuals with the appropriate expertise, including a principal investigator, a project 
manager, a biostatistician, a data coordinating center and manager, and a medical 
monitor. The risk-based monitoring team will meet at least semi-annually to assess 
safety and efficacy data in each arm of the study, and share information about the 
adverse event data with a regulatory specialist regarding safety. The risk-based 
monitoring team will operate under the rules of an approved charter that will be written 
and reviewed at the organizational meeting of the IRB. At this time, each data element 
that the IRB needs to assess will be defined clearly. The risk-based monitoring team will 
provide its input to the PI. 
 
8 CLINICAL MONITORING 
Clinical site monitoring will be conducted to ensure that the rights and well-being of 
human subjects are protected, that the reported trial data are accurate, complete, and 
verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendments, with GCP, and with applicable regulatory requirements. 
 The risk-based monitoring team of the University of Tokyo Hospital, which consists 
of the Principal investigator, Project Manager, Medical Monitor, Data Managers, 
and Biostatistician, will conduct an early targeted review of certain data monitoring, 
including onsite, centralized, statistical monitoring for initial assessment and 
training. 
 Each clinical site will perform internal quality management of study conduct, data 
collection, documentation and completion.  
 
9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL AND ANALYTICAL PLAN (SAP) 
This study has a separate formal SAP, which includes a more detailed analysis of 
populations, summary of statistical strategies. The SAP will complete prior to database 

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lock. 
 
9.2 STATISTICAL HYPOTHESES 
 Primary efficacy endpoint: The rate of identification of SRH.  
Null hypothesis: No significant difference in the SRH identification rates between 
early and elective colonoscopy. 
 Secondary efficacy endpoints: Success rate of endoscopic treatment, need for 
additional endoscopic examination, need for interventional radiology, need for 
surgery, need for transfusion during hospitalization, 30-day rebleeding rates, 
preparation-related adverse events, colonoscopy-related adverse events, 30-day 
thrombosis events, 30-day mortality, and length of stay. 
Null hypothesis: No significant difference in secondary outcomes is found between 
early and elective colonoscopy. 
 
9.3 ANALYSIS DATASETS 
The primary analysis will includes the “modified” intention-to treat population, 
excluding 1) patients who did not satisfy the enrollment criteria after randomization (i.e. 
patients who evidence exclusion criteria, including withdrawal of consent, as assessed 
by the investigators), 2) patients who provided no post-randomization data of primary 
outcome (identification of SRH), and 3) patients who did not undergo colonoscopy from 
a genuine ITT analysis set.  
9.4 DESCRIPTION OF STATISTICAL METHODS 
9.4.1 GENERAL APPROACH 
 For descriptive statistics, data will be summarized by treatment group. n, mean, 
standard deviation, minimum, and maximum will summarize continuous efficacy 
variables, whereas number and percent will summarize categorical efficacy 
variables. 
 For inferential tests, the p-value for statistical significance (Type I error) will be 
< 0.05, two-tailed. 
 Covariates will be pre-specified in the sections below. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
 Define the measurement: SRH identification in lower gastrointestinal tract. 
 The scale: Binary/categorical. 
 The identification of SRH will be compared using the stratified χ2 test in modified 
intention-to treat population.   

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 Missing data will be removed in the primary analysis, and primary endpoint analysis 
will be performed by a complete case analysis. In sensitivity analysis, primary 
endpoint analysis will be performed by an imputation method. Models and auxiliary 
variables for the imputation will be assessed by the trial investigators after locking 
the dataset. 
 Method for adjusting: Two confounders (patients who underwent colonoscopy by an 
expert and each participating site) will be adjusted using a Mantel-Haenzsel test in 
the primary analysis. Mantel-Haenzsel risk differences and ratios are calculated for 
strata of i) patients who underwent colonoscopy by an expert, and ii) each 
participating site. Heterogeneity for each endpoint is assessed by subgroup analyses 
(as described in Section 4), using (approximate) interaction tests based on the 
difference in effect-measures among subgroups. The results will be presented as 
prevalence 
rate 
and 
number-needed-to-treat 
(number-needed-to-perform 
colonoscopy). 
 
9.4.3 ANALYSIS OF SECONDARY ENDPOINTS 
 Define the measurement: Success rate of endoscopic treatment, need for additional 
endoscopic examination, need for interventional radiology, need for surgery, 30-day 
rebleeding rates, need for transfusion during hospitalization, length of stay, 30-day 
thrombosis events, 30-day mortality, preparation-related adverse events, and 
colonoscopy-related adverse events. Each outcome has been defined previously (see 
Section 4.2.3 Outcome Definitions). 
 
 The scale: 
Binary/categorical: success rate of endoscopic treatment, need for additional 
endoscopic examination, need for interventional radiology, need for surgery, 30-day 
rebleeding rates, need for transfusion during hospitalization, 30-day thrombosis 
events, 
30-day 
mortality, 
preparation-related 
adverse 
events, 
and 
colonoscopy-related adverse events. 
Interval: 
Length of stay. 
 The χ2 test or Fisher’s exact test will be used to analyze the secondary endpoints of 
success rate of endoscopic treatment, need for additional endoscopic examination, 
need for interventional radiology, need for surgery, 30-day rebleeding rates, need for 
transfusion during hospitalization, 30-day thrombosis events, 30-day mortality, 
preparation-related adverse events, and colonoscopy-related adverse events as 

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appropriate, and results will be presented as prevalence rates and number needed to 
treat.  
Wilcoxon’s rank-sum test will be used to analyze the secondary endpoint of length 
of stay, and results will be presented as means with standard errors. 
 Missing data will be removed in the primary analysis, and secondary endpoint 
analysis will be performed by complete case analysis. In sensitivity analysis, 
secondary endpoint analysis will be performed by an imputation method. Models 
and auxiliary variables for the imputation will be assessed by the trial investigators 
after locking the dataset. 
 If possible, the Mantel-Haenzsel tests and estimation (adjusting for expert 
colonoscopy and participating site) will be performed for binary endpoints. 
 
9.4.4 SAFETY ANALYSES 
Safety endpoints (preparation- and colonoscopy-related adverse events) will be 
analyzed as summary statistics during preparation and colonoscopy.  
AEs will be coded based on the Medical Dictionary for Regulatory Activities/Japanese 
version 21.0 (MedDRA/J)) and counted once only for a given participant. Evaluated 
start date, stop date, severity, relationship, outcome, and duration; and presented severity, 
frequency, and relationship of AEs to preparation and colonoscopy will be presented by 
system organ class (SOC) and preferred term groupings. 
 
9.4.5 ADHERENCE AND RETENTION ANALYSES 
Adherence to the protocol (e.g., performing colonoscopy) will be assessed and 
calculated. Similarly, study retention/loss to follow-up, and frequency of, and reasons 
for, discontinuation of the intervention will be assessed and calculated. 
 
9.4.6 BASELINE DESCRIPTIVE STATISTICS 
For descriptive statistics, data will be summarized by treatment group. Number, mean, 
standard deviation, minimum and maximum will summarize continuous efficacy 
variables, whereas number and percent will summarize categorical efficacy variables. 
Inferential statistics will not be used. 
 
9.4.7 PLANNED INTERIM ANALYSES 
Not-applicable. 
 

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9.4.8 ADDITIONAL SUB-GROUP ANALYSES 
The primary endpoint will be analyzed based on subgroups of patients with colonic 
diverticular bleeding, patients terminated because of inadequate bowel preparation, 
patients who underwent endoscopic hemostasis, patients with colonic diverticular 
bleeding and who underwent endoscopic hemostasis, patients who underwent 
colonoscopy by an expert, each site, and patients who underwent colonoscopy within 
24 h of onset of hematochezia. 
 
9.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
Not applicable. 
 
9.4.10 EXPLORATORY ANALYSES 
Not applicable. 
 
9.5 SAMPLE SIZE 
 Outcome measure used for calculations: Identification rate of SRH. 
 Test statistic: The χ2 test comparing two independent proportions. 
 Null and alternate hypotheses: Early colonoscopy improves the identification rate of 
SRH compared with elective colonoscopy. 
 Type I error rate (α): 0.05 
 Power level (e.g., 80% power): 80% 
 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)32 with the alpha level of 
5% (2-sided), a sample size of 142 (71 in each arm) patients will be required to 
ensure an 80% probability of obtaining a statistically-significant chi-square 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. 
 Assumed dropout rates, withdrawal, cross-over to other study arms, missing data, 
etc., also justified: Not applicable. 
 Approach to handling withdrawals and protocol violations: Participants with 
withdrawals and protocol violations will be included in the “intent-to-treat” 
population. 
 Statistical method used to calculate the sample size, with a reference for it and for 
any software used: nQuery + nTerim 4.0. 

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9.6 MEASURES TO MINIMIZE BIAS 
9.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
 
ENROLLMENT 
Plans for the maintenance of trial randomization codes will be discussed. The timing 
and procedures for planned and unplanned breaking of randomization codes will be 
included. 
 
RANDOMIZATION 
In real clinical practice, timing of colonoscopy differs between physicians. To reduce 
this bias, this study will perform randomization and perform a centralized effectiveness 
assessment to reduce diagnostic bias among the endoscopists. 
 
MASKING PROCEDURES 
It will not be feasible to perform blinding because a physician will perform the medical 
examination and the same physician will perform the endoscopy. Thus, the physician 
will be aware of patient allocation. 
 
9.6.2 EVALUATION OF SUCCESS OF BLINDING 
Not applicable. 
9.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
Not applicable. 
 
10 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
“Source data” are all information, original records of clinical findings, observations, or 
other activities in a clinical trial that are necessary for the reconstruction and evaluation 
of the trial. Examples of these original documents and data records include, but are not 
limited to: hospital records; clinical and office charts; laboratory notes; memoranda; 
participant’s memory aid or evaluation checklists; pharmacy dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after 
verification as being accurate and complete; microfiches, photographic negatives, 
microfilm or magnetic media; X-rays; and participant files and records kept at the 
pharmacy, at laboratories, and medico-technical departments involved in the clinical 
trial. It is acceptable to use these data as source documents. Medical monitors and audit 
can access these data for a patient participating in this clinical trial. 

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11 QUALITY ASSURANCE AND QUALITY CONTROL 
Quality control (QC) procedures will be implemented, beginning with the data entry 
system, and data QC checks that will be run on the EDC will be generated. Any missing 
data or data anomalies will be communicated to the sites for clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is 
conducted and data are generated, recorded, and reported in compliance with the 
protocol, GCP, and Ethical Guidelines for Medical and Health Research Involving 
Human Subjects (Japan). The investigational site will provide direct access to all 
trial-related sites, source documents, and reports for the purpose of monitoring and 
auditing by the PI, and inspection by local and regulatory authorities. 
 
12 ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 ETHICAL STANDARDS 
The investigator will ensure that this study is conducted in full conformity with the 
Declaration of Helsinki, and Ethical Guidelines for Medical and Health Research 
Involving Human Subjects (Japan). 
 
12.2 INSTITUTIONAL REVIEW BOARD 
The protocol, informed consent forms, recruitment materials, and all participant 
materials will be submitted to the IRB for review and approval. Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the 
changes are implemented in the study. All changes to the consent form will be IRB 
approved: a determination will be made regarding whether participants who previously 
consented need to consent again. 
 
12.3 INFORMED CONSENT PROCESS 
12.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
Consent forms describing early colonoscopy in detail and associated risks will be given 
to all participants and written documentation of informed consent will be required prior 
to starting the intervention study product. The following consent materials are submitted 
with this protocol: 
 Written informed consent form (Japanese, non-Braille, non-audio recording). 
 

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12.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to an individual agreeing to 
participate in a study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of participation will be provided to 
the participants and their families. Consent forms will be IRB-approved and the 
participant will be asked to read and review the document. The investigator will explain 
the research study to the participant and answer any questions that may arise. All 
participants will receive a verbal explanation in terms suited to their comprehension of 
the purposes, procedures, and potential risks of the study, and of their rights as research 
participants. Participants will have the opportunity to review the written consent form 
carefully and ask questions before signing. The participants will have the opportunity to 
discuss the study with their surrogates or think about it before agreeing to participate. 
The participant will sign the informed consent document prior to any procedure that is 
specifically for the study. The participant may withdraw consent at any time during the 
course of the trial. A copy of the informed-consent document will be given to all 
participants for their records. The rights and welfare of the participants will be protected 
by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
 
12.4 PARTICIPANT AND DATA CONFIDENTIALITY 
Participant confidentiality will be held strictly in trust by the participating investigators 
and their staff. The study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the 
data will be released to any unauthorized third party without prior written approval of 
the IRB. The study monitor, other authorized representatives of the PI, or 
representatives of the IRB may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participants’ contact information will be stored securely at each 
clinical site for internal use during the study. At the end of the study, all records will 
continue to be kept in a secure location for as long as dictated by local IRB and 
institutional regulations. 
Study participant research data, which are for purposes of statistical analysis 
and scientific reporting, will be transmitted to and stored at Tokyo University Hospital. 
These will not include the participants’ contact or identifying information. Rather, 

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individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by 
clinical sites and by Tokyo University Hospital research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and 
archived at Tokyo University Hospital. 
 
12.4.1 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR 
DATA 
 Intended use: Data collected under this protocol may be used for study. No genetic 
testing will be performed. 
 Storage: Data will be stored using codes assigned by the investigators. Data will be 
kept in password-protected computers. Only investigators will have access to data. 
 Tracking: Data will be tracked using the EDC. 
 Disposition at the completion of the study: All stored data will be sent to the 
biostatistician. Study participants who request destruction of samples will be 
notified of compliance with such a request and all supporting details will be 
maintained for tracking. 
 
12.5 FUTURE USE OF STORED SPECIMENS 
Data collected for this study will be analyzed and stored at Tokyo University Hospital. 
After the study has been completed, the de-identified, archived data will be transmitted 
to, and stored at, Tokyo University Hospital, under the supervision of a data manager, 
for use by other researchers, including those outside the study.  
With the participants’ approval, and as approved by local IRBs, de-identified data 
will be stored at each site. These data could be used for research into the causes of 
complications and other conditions for which individuals are at increased risk, and to 
improve treatment. The data will also be provided with a code-link that will allow 
linking the biological specimens to the phenotypic data from each participant, 
maintaining the masking of the identity of the participant. 
During the conduct of the study, an individual participant can choose to withdraw 
consent to have data stored for future research. However, withdrawal of consent with 
regard to data storage will not be possible after the study has been completed. 
When the study is completed, access to study data will be provided through Tokyo 
University Hospital. 
 

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13. DATA HANDLING AND RECORD KEEPING 
13.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection will be the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. The investigator will be responsible for ensuring the accuracy, 
completeness, legibility, and timeliness of the data reported. 
All source documents will be completed in a neat, legible manner to ensure 
accurate interpretation of data.  
The EDC will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the EDC 
derived from source documents should be consistent with the source documents or 
discrepancies should be explained and captured in a progress note and maintained in the 
participant’s official electronic study record. 
Clinical data (including AEs, concomitant medications, and expected adverse 
reactions’ data) and clinical laboratory data will be entered into the EDC, a 21 CFR Part 
11-compliant data capture system provided by the DCC. The data system includes 
password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
 
13.2 STUDY RECORDS RETENTION 
Study documents will be retained for either a minimum of 5 years after the end of the 
study or 3 years after publication. 
 
13.3 PROTOCOL DEVIATIONS 
A “protocol deviation” is any non-compliance with the clinical trial protocol, GCP, or 
MOP requirements. The non-compliance may be on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. 
These practices are consistent with ICH E6 (R2): 
 4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
 5.1 Quality Assurance and Quality Control, section 5.1.1 
 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations as soon as possible after identification of the protocol deviation, or the 
scheduled protocol-required activity. 
All deviations must be addressed in study source documents. Protocol 

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deviations must be sent to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to the IRB requirements. 
 
13.4 PUBLICATION AND DATA SHARING POLICY 
This study will ensure that the public has access to the published results of the research. 
It will require scientists to submit final peer-reviewed journal manuscripts that arise to 
the digital archive “PubMed Central” upon acceptance for publication. 
The International Committee of Medical Journal Editors (ICMJE) member 
journals have adopted a clinical trials registration policy as a condition for publication. 
The ICMJE defines a clinical trial as any research project that prospectively assigns 
human subjects to intervention or concurrent comparison or control groups to study the 
cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include endoscopic procedures. Health outcomes include 
any biomedical or health-related measures pertaining to patients or participants, 
including adverse events. The ICMJE policy, and the Section 801 of the Food and Drug 
Administration Amendments Act of 2007, requires that all clinical trials be registered in 
a public trials registry, such as the UMIN Clinical Trials Registry.  
The data from all sites will be analyzed together and the results will be 
published as soon as possible after trial completion. Individual PIs at each site must not 
publish or divulge any report or result from the trial until the main trial results have 
been published. A publication committee will be formed for this purpose by the PI, 
which will include key members of the trial management group. 
The publication committee will oversee the timely analysis, writing up, and 
publication of the main trial results. Investigators and the independent-effect judgment 
committee must be given the opportunity to read and comment on the main trial 
findings before submission for publication. For the main report of this study submitted 
for publication, together with associated methodology and health economic papers, we 
will use the International Committee of Medical Journal Editors’ definitions of 
authorship 
and 
contributorship 
http://www.icmje.org/ethical_1author.html). 
The 
publication 
committee 
should 
be 
listed 
with 
their 
affiliations 
in 
the 
acknowledgements/appendix of the main publication and the support of the clinical 
studies support staff, and funder acknowledged. 
 
14. CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Thus, any actual conflict of interest of persons who 

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have a role in the design, conduct, analysis, publication, or any aspect of this trial will 
be disclosed and managed. Furthermore, persons who have a perceived conflict of 
interest will be required to have such conflicts managed in a way that is appropriate to 
their participation in the trial. All study group members are to disclose all conflicts of 
interest and a mechanism for the management of all reported dualities of interest will be 
established. 
 
15. LITERATURE REFERENCES 
1. Longstreth GF. Epidemiology and outcome of patients hospitalized with acute lower 
gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 
1997;92:419-24.  
2. Niikura R, Yasunaga H, Yamaji Y, et al. Factors affecting in-hospital mortality in 
patients with lower gastrointestinal tract bleeding: a retrospective study using a national 
database in Japan. J Gastroenterol 2015;50:533-40.  
3. Nagata N, Niikura R, Aoki T, et al. Increase in colonic diverticulosis and diverticular 
hemorrhage in an aging society: lessons from a 9-year colonoscopic study of 28,192 
patients in Japan. Int J Colorectal Dis 2014;29:379-85.  
4. Eisen GM, Dominitz JA, Faigel DO, et al. An annotated algorithmic approach to 
acute lower gastrointestinal bleeding. Gastrointest Endosc 2001;53:859-63.  
5. Zuccaro G,Jr. Management of the adult patient with acute lower gastrointestinal 
bleeding. American College of Gastroenterology. Practice Parameters Committee. Am J 
Gastroenterol 1998;93:1202-8.  
6. Strate LL, Naumann CR. The role of colonoscopy and radiological procedures in the 
management of acute lower intestinal bleeding. Clin Gastroenterol Hepatol 
2010;8:333,43; quiz e44.  
7. Strate LL, Orav EJ, Syngal S. Early predictors of severity in acute lower intestinal 
tract bleeding. Arch Intern Med 2003;163:838-43.  
8. Angtuaco TL, Reddy SK, Drapkin S, Harrell LE, Howden CW. The utility of urgent 
colonoscopy in the evaluation of acute lower gastrointestinal tract bleeding: a 2-year 
experience from a single center. Am J Gastroenterol 2001;96:1782-5.  

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9. Green BT, Rockey DC, Portwood G, et al. Urgent colonoscopy for evaluation and 
management of acute lower gastrointestinal hemorrhage: a randomized controlled trial. 
Am J Gastroenterol 2005;100:2395-402.  
10. Jensen DM, Machicado GA. Diagnosis and treatment of severe hematochezia. The 
role of urgent colonoscopy after purge. Gastroenterology 1988;95:1569-74.  
11. Smoot RL, Gostout CJ, Rajan E, et al. Is early colonoscopy after admission for 
acute diverticular bleeding needed? Am J Gastroenterol 2003;98:1996-9.  
12. Jensen DM, Machicado GA, Jutabha R, Kovacs TO. Urgent colonoscopy for the 
diagnosis and treatment of severe diverticular hemorrhage. N Engl J Med 
2000;342:78-82.  
13. Peura DA, Lanza FL, Gostout CJ, Foutch PG. The American College of 
Gastroenterology Bleeding Registry: preliminary findings. Am J Gastroenterol 
1997;92:924-8.  
14. Strate LL, Syngal S. Timing of colonoscopy: impact on length of hospital stay in 
patients with acute lower intestinal bleeding. Am J Gastroenterol 2003;98:317-22.  
15. Zuckerman GR, Prakash C. Acute lower intestinal bleeding: part I: clinical 
presentation and diagnosis. Gastrointest Endosc 1998;48:606-17.  
16. Lhewa DY, Strate LL. Pros and cons of colonoscopy in management of acute lower 
gastrointestinal bleeding. World J Gastroenterol 2012;18:1185-90.  
17. Gabel A, Muller S. Aspiration: a possible severe complication in colonoscopy 
preparation of elderly people by orthograde intestine lavage. Digestion 1999;60:284-5.  
18. Marschall HU, Bartels F. Life-threatening complications of nasogastric 
administration of polyethylene glycol-electrolyte solutions (Golytely) for bowel 
cleansing. Gastrointest Endosc 1998;47:408-10.  
19. McQuaid KR, Laine L. A systematic review and meta-analysis of randomized, 
controlled trials of moderate sedation for routine endoscopic procedures. Gastrointest 
Endosc 2008;67:910-23.  

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20. Singh H, Penfold RB, DeCoster C, et al. Colonoscopy and its complications across a 
Canadian regional health authority. Gastrointest Endosc 2009;69:665-71.  
21. Stock C, Ihle P, Sieg A, Schubert I, Hoffmeister M, Brenner H. Adverse events 
requiring hospitalization within 30 days after outpatient screening and nonscreening 
colonoscopies. Gastrointest Endosc 2013;77:419-29.  
22. Anderson ML, Pasha TM, Leighton JA. Endoscopic perforation of the colon: 
lessons from a 10-year study. Am J Gastroenterol 2000;95:3418-22.  
23. Sieg A, Hachmoeller-Eisenbach U, Eisenbach T. Prospective evaluation of 
complications in outpatient GI endoscopy: a survey among German gastroenterologists. 
Gastrointest Endosc 2001;53:620-7.  
24. Levin TR, Zhao W, Conell C, et al. Complications of colonoscopy in an integrated 
health care delivery system. Ann Intern Med 2006;145:880-6.  
25. Rabeneck L, Paszat LF, Hilsden RJ, et al. Bleeding and perforation after outpatient 
colonoscopy and their risk factors in usual clinical practice. Gastroenterology 
2008;135:1899,1906, 1906.e1.  
26. Day LW, Kwon A, Inadomi JM, Walter LC, Somsouk M. Adverse events in older 
patients undergoing colonoscopy: a systematic review and meta-analysis. Gastrointest 
Endosc 2011;74:885-96.  
27. Niikura R, Nagata N, Shimbo T, et al. Adverse Events during Bowel Preparation 
and Colonoscopy in Patients with Acute Lower Gastrointestinal Bleeding Compared 
with Elective Non-Gastrointestinal Bleeding. PLoS One 2015;10:e0138000.  
28. Gupta N, Longo WE, Vernava AM,3rd. Angiodysplasia of the lower gastrointestinal 
tract: an entity readily diagnosed by colonoscopy and primarily managed 
nonoperatively. Dis Colon Rectum 1995;38:979-82.  
29. Nagata N, Niikura R, Aoki T, et al. Risk factors for adverse in-hospital outcomes in 
acute colonic diverticular hemorrhage. World J Gastroenterol 2015;21:10697-703.  

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elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
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30. Niikura R, Nagata N, Aoki T, et al. Predictors for identification of stigmata of recent 
hemorrhage on colonic diverticula in lower gastrointestinal bleeding. J Clin 
Gastroenterol 2015;49:e24-30.  
31. Laine L, Shah A. Randomized trial of urgent vs. elective colonoscopy in patients 
hospitalized with lower GI bleeding. Am J Gastroenterol 2010;105:2636,41; quiz 2642.  
32. Nagata N, Niikura R, Sakurai T, et al. Safety and Effectiveness of Early 
Colonoscopy in Management of Acute Lower Gastrointestinal Bleeding, Based on 
Propensity Score Matching Analysis. Clin Gastroenterol Hepatol 2015;.  
33. Schmulewitz N, Fisher DA, Rockey DC. Early colonoscopy for acute lower GI 
bleeding predicts shorter hospital stay: a retrospective study of experience in a single 
center. Gastrointest Endosc 2003;58:841-6.  
34. Kaltenbach T, Watson R, Shah J, et al. Colonoscopy with clipping is useful in the 
diagnosis and treatment of diverticular bleeding. Clin Gastroenterol Hepatol 
2012;10:131-7.  
35. Yamada A, Niikura R, Yoshida S, Hirata Y, Koike K. Endoscopic management of 
colonic diverticular bleeding. Dig Endosc 2015;27:720-5.  
36. Chavalitdhamrong D, Jensen DM, Kovacs TO, et al. Ischemic colitis as a cause of 
severe hematochezia: risk factors and outcomes compared with other colon diagnoses. 
Gastrointest Endosc 2011;74:852-7.  
37. Niikura R, Nagata N, Yamano K, Shimbo T, Uemura N. High-dose barium 
impaction therapy is useful for the initial hemostasis and for preventing the recurrence 
of colonic diverticular bleeding unresponsive to endoscopic clipping. Case Rep 
Gastrointest Med 2013;2013:365954.  
38. Ryota Niikura, Naoyoshi Nagata, Hisashi Doyama, et al. Current state of practice 
for colonic diverticular bleeding in 37 hospitals in Japan: A multicenter questionnaire 
study. World J Gastrointest Endosc 2016;8:785-794. 
 
 

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Appendix Statistical Analysis Plan 
 
Statistical Analysis Plan (SAP) 
A multi-center, randomized controlled trial comparing 
early versus elective colonoscopy in outpatients with 
acute lower gastrointestinal bleeding  
 
 
Version: 2.0  
Author: Tomohiro Shinozaki, Department of Biostatistics, School of Public Health, the 
University of Tokyo 
Date: 9-1-2018 
 
 
 

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1. INTRODUCTION 
Acute lower gastrointestinal bleeding (ALGIB) is a common disease, the incidence of which has 
recently increased.1 ‘Early’ colonoscopy, performed within 24 h of arrival, potentially improves 
clinical outcomes, such as the identification of stigmata of recent hemorrhage (SRH) and rebleeding 
compared with ‘elective’ colonoscopy, performed between 24 and 96 h. 
However, we have identified a lack of high-quality evidence regarding the optimal timing of 
colonoscopy in ALGIB.2-4 There is widely varying clinical use of early colonoscopy throughout 
Japan, and a randomized controlled trial (RCT) in a patient population will address a key area of 
clinical uncertainty.6 
This trial may begin to inform the rational use of early colonoscopy for patients admitted with 
ALGIB. A RCT design is justified to demonstrate that early colonoscopy can be implemented at a 
hospital-wide level, to reduce contamination between the trial interventions, and to aid in operational 
aspects of the trial delivery. This is acceptable ethically, 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.5 We believe the study may also help to inform 
the wider debate regarding the use of early colonoscopy. 
The objective of the study is to compare the SRH identification rates of ‘early’ versus ‘elective’ 
colonoscopy in outpatients with ALGIB. 
2 DATA SOURCE  
All data to be analyzed are obtained from “A multi-center, randomized controlled trial comparing 
early versus elective colonoscopy in outpatients with acute lower gastrointestinal bleeding.” 
Variables to be measured are specified in the protocol. Datasets are produced in compliance with the 
Clinical Data Monitoring Plan. 
 
3 ANALYSIS OBJECTIVES  
Primary efficacy endpoint: The rate of identification of stigmata of recent hemorrhage (SRH). 
Null hypothesis: The SRH identification rates in patients undergoing early and elective colonoscopy 
will arebe equal. 
Secondary efficacy endpoints: Success of endoscopic treatment, need for additional endoscopic 
examination, need for interventional radiology, need for surgery, need for transfusion during 
hospitalization, 30-day rebleeding rates, preparation related adverse events, colonoscopy-related 
adverse events, 30-day thrombosis events, 30-day mortality, and length of stay. 
Null hypothesis: The rates of the secondary endpoints in early and elective colonoscopy are 
equalEquality in secondary outcomes is found between early and elective colonoscopy. 
  

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4 ANALYSIS SETS/ POPULATIONS/SUBGROUPS  
ANALYSIS SETS 
The following two analysis sets will are be analyzed: modified intention-to-treat (ITT) and 
per-protocol analysis sets. A genuine ITT analysis set includes the data of all patients participating in 
the trial, but a modified ITT analysis set excludes patients 1) who did not fulfill the enrollment 
criteria after randomization (i.e. patients with exclusion criteria including withdraw consent) these 
criteria will beare assessed by investigators, 2) who provide no post-randomization data of primary 
outcome (identification of SRH), and 3) who do not undergo colonoscopy (i.e., ‘early’ nor ‘elective’) 
from a genuine ITT analysis set. The per-protocol analysis set will includes the data on patients who 
1) fulfill the enrollment criteria after randomization and 2) undergo early or elective colonoscopy. 
 
PARTICIPANT INCLUSION CRITERIA 
Males or females outpatients aged ≥ 20 years, presenting with moderate-to-severe hematochezia or 
melena within 24 h of arrival, defined as (i) more than three occurrences of hematochezia within 8 h, 
or (ii) hemorrhagic shock, or (iii) requiring transfusion. 
Eligible patients will be asked to read explanatory documents providing doctor’s instructions and 
sign consent forms. Informed consent will be obtained from each eligible patient before enrollment 
in the trial.. 
Stated willingness to comply with all study procedures and availability for the duration of the study. 
 
PARTICIPANT EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
Patients with hematemesis, black vomiting. 
Patients with upper gastrointestinal bleeding, diagnosed by nasogastric tube or upper endoscopy. 
Patients who have impossible consumed the oral bowel preparation solution. 
Patients who have undergone computed tomography. 
Patients in whom peptic ulcer diseases have been diagnosed within the previous 10 days. 
Ulcerative colitis or Crohn’s disease patients. 
Patients who have undergone abdominal surgery within the previous 10 days. 
Patients who have undergone polypectomy, endoscopic mucosal resection, or endoscopic 
submucosal dissection of the colon within the previous 10 days. 
Patients with suspected perforation or peritonitis. 
Patients with suspected intestinal obstruction. 
Patients with hemorrhagic shock refractory to infusion or blood transfusion. 
Patients who have undergone a total colectomy. 

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Patients with suspected disseminated intravascular coagulation. 
Patients with end-stage malignant disease. 
Patients with severe cardiac failure. 
Patients with active thrombosis. 
Patients with severe respiratory failure. 
Pregnant patients. 
 
SUBGROUP ANALYSES 
The primary endpoint will be analyzed based on subgroups of patients with colonic diverticular 
bleeding, patients terminated for inadequate bowel preparation, patients who underwent endoscopic 
hemostasis, patients with colonic diverticular bleeding and who underwent endoscopic hemostasis, 
patients who underwent colonoscopy by an expert, each site, and patients who underwent 
colonoscopy within 24 h of onset of hematochezia. These subgroups include secondary interest 
which subgroup is most appropriate for early colonoscopy. 6-8 Nevertheless primary analyses fail to 
produce statistically significant results, subgroup analyses will beare performed. 
 
5 ENDPOINTS AND COVARIATES  
PRIMARY ENDPOINT 
Identification of SRH in lower gastrointestinal tract. 
 
We will define SRH based on colonoscopic visualization of lesions, such as diverticulosis, tumor, 
ulcer, hemorrhoid, angioectasia, and polyps exhibiting active bleeding, a visible vessel, or an 
adherent clot. We will also evaluate inter-observer agreement of SRH diagnoses among site 
investigators and an independent-effect judgment committee using endoscopic images. 
 
SECONDARY ENDPOINTS 
Success of endoscopic treatment 
Need for additional endoscopic examination 
Need for interventional radiology 
Need for surgery 
30-day rebleeding rates 
Need for transfusion during hospitalization 
Length of stay 
30-day thrombosis events 
30-day mortality 
Preparation-related adverse events  

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Colonoscopy-related adverse events  
 
COVARIATES TO BE ADJUSTED 
To undergo colonoscopy by an expert, participating site. Additional auxiliary covariates for 
sensitivity analysis will be assessed after the data lock. 
 
6 HANDLING OF MISSING VALUES AND OTHER DATA CONVENTIONS  
The primary analysis for both primary and secondary endpoints, will beis performed by complete 
case analysis, which excludes patients whose data are missing. As a sensitivity analysis, missing data 
will beis substituted by a multiple imputation method. Models and auxiliary variables for the 
imputation will beare assessed by the trial investigators after fixing a dataset. 
 
7.1 STATISTICAL PROCEDURES 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
Definition of the measurement: Identification of SRH in lower gastrointestinal tract. 
The scale: Binary/categorical. 
The stratified χ2 test, namely, the Mantel-Haenszel test adjusting for an expert colonoscopy and 
participating site will be used to analyze the primary endpoint. The Mantel-Haenszel risk difference 
and ratio, as well as number needed to treat (number needed to perform colonoscopy) will be 
presented.   
 
ANALYSIS OF THE SECONDARY ENDPOINTS 
Definition of the measurement: success of endoscopic treatment, need for additional endoscopic 
examination, need for interventional radiology, need for surgery, 30-day rebleeding rates, need for 
transfusion during hospitalization, length of stay, 30-day thrombosis events, 30-day mortality, 
preparation-related adverse events, and colonoscopy-related adverse events. Each outcome is defined 
in the Appendix. 
 
The scale: 
Binary/categorical: success of endoscopic treatment, need for additional endoscopic examination, 
need for interventional radiology, need for surgery, 30-day rebleeding rates, need for transfusion 
during hospitalization, 30-day thrombosis events, 30-day mortality, preparation-related adverse 
events, and colonoscopy-related adverse events (hemorrhagic shock, and perforation). 
Interval: Length of stay. 
The χ2 test or Fisher’s exact test will be used to analyze the secondary endpoints of success of 
endoscopic treatment, need for additional endoscopic examination, need for interventional radiology, 

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need for surgery, 30-day rebleeding rates, need for transfusion during hospitalization, 30-day 
thrombosis events, 30-day mortality, preparation-related adverse events, and colonoscopy-related 
adverse events, as appropriate, and results will beare presented as prevalence rates and number 
needed to treat (number needed to perform colonoscopy). 
Wilcoxon’s rank-sum test will beis used to analyze the secondary endpoint of length of stay. Results 
will be presented as means with standard errors or medians with percentiles, or both. 
If possible, the Mantel-Haenszel tests and estimation will be employed for binary endopoints. 
 
SAFETY ANALYSES 
Safety endpoints (preparation- and colonoscopy-related adverse events) will beare analyzed as 
summary statistics during preparation and colonoscopy.  
Adverse events (AEs) will beare coded based on the Medical Dictionary for Regulatory 
Activities/Japanese version 21.0 (MedDRA/J)) and counted once only for a given participant. 
Evaluated start date, stop date, severity, relationship, outcome, and duration; and presented severity, 
frequency, and relationship of AEs to preparation and colonoscopy will beare presented by system 
organ class (SOC) and preferred term groupings. 
 
ADHERENCE AND RETENTION ANALYSES 
Adherence measures of the performance of the allocated form of colonoscopy will beare assessed 
and calculated. Similarly, study retention/loss to follow-up, and frequency of, and reasons for, 
discontinuation of the intervention will beare assessed and calculated. 
 
BASELINE DESCRIPTIVE STATISTICS 
For descriptive statistics, data will beis summarized by treatment group. Number, mean, standard 
deviation, minimum and maximum will are summarized by continuous efficacy variables, whereas 
number and percent will are summarized by categorical efficacy variables. Inferential statistics will 
are not be used. 
 
7.2 MEASURES TO ADJUST FOR MULTIPLICITY, CONFOUNDERS, HETEROGENEITY, 
ETC. 
Two confounders (patients who underwent colonoscopy by an expert and each participating site) will 
beare adjusted using a Mantel-Haenzsel test in the primary analysis. Mantel-Haenzsel risk 
differences and ratios are calculated for strata of i) patients who underwent colonoscopy by an expert, 
and ii) each participating site.  Heterogeneity for each endpoint is assessed by subgroup analyses 
(as described in Section 4), using (approximate) interaction tests based on the difference in 
effect-measures among subgroups. 

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8 SENSITIVITY ANALYSES 
As described in Section 6, sensitivity analysis for missing data will beis performed by a multiple 
imputation method. 
 
9 QC PLANS 
Quality control (QC) procedures will be implemented, beginning with the data entry system, and 
data QC checks that will be run on an electronic data capture (EDC) system will be generated. Any 
missing data or data anomalies will be communicated to the sites for clarification/resolution. 
Following written standard operating procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated, recorded, and reported in compliance with the protocol, 
GCP, and Ethical Guidelines for Medical and Health Research Involving Human Subjects (Japan). 
The investigational site will provide direct access to all trial-related sites, source documents, and 
reports for the purpose of monitoring and auditing by the principal investigator (PI), and inspection 
by local and regulatory authorities. 
 
10 PROGRAMMING PLANS 
A Statistician (TS) writes SAS code for all planned analyses before linking a dataset to 
randomization labels (i.e., ‘early’ versus ‘elective’). Statistical computations and figures in tables are 
generated using SAS software, version 9.4 (SAS, Cary, NC). 
 
11 REFERENCES 
1. Longstreth GF. Epidemiology and outcome of patients hospitalized with acute lower 
gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1997;92:419-24.  
2. Niikura R, Nagata N, Aoki T, et al. Predictors for identification of stigmata of recent hemorrhage 
on colonic diverticula in lower gastrointestinal bleeding. J Clin Gastroenterol 2015;49:e24-30.  
3. Green BT, Rockey DC, Portwood G, et al. Urgent colonoscopy for evaluation and management of 
acute lower gastrointestinal hemorrhage: a randomized controlled trial. Am J Gastroenterol 
2005;100:2395-402.  
4. Laine L, Shah A. Randomized trial of urgent vs. elective colonoscopy in patients hospitalized with 
lower GI bleeding. Am J Gastroenterol 2010;105:2636-41.  
5. Niikura R, Nagata N, Shimbo T, et al. Adverse Events during Bowel Preparation and Colonoscopy 
in 
Patients 
with 
Acute 
Lower 
Gastrointestinal 
Bleeding 
Compared 
with 
Elective 
Non-Gastrointestinal Bleeding. PLoS One 2015;10:e0138000.  
6. Niikura R, Nagata N, Doyama H, et al. Current state of practice for colonic diverticular bleeding 
in 37 hospitals in Japan: A multicenter questionnaire study. World J Gastrointest Endosc 

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elective colonoscopy in outpatients with acute lower gastrointestinal bleeding 
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2016;8:785-794. 
7. Strate LL, Naumann CR. The role of colonoscopy and radiological procedures in the management 
of acute lower intestinal bleeding. Clin. Gastroenterol. Hepatol 2010; 8: 333-343. 
8. Strate LL, Orav EJ, Syngal S. Early predictors of severity in acute lower intestinal tract bleeding. 
Arch. Intern. Med. 2003; 163: 838-843.Appendix Clinical Data Monitoring Plan (CDMoP) 
 
 
 
 
CLINICAL DATA MONITORING PLAN (CDMoP) 
 
A multi-center, randomized controlled trial comparing 
early versus elective colonoscopy in outpatients with 
acute lower gastrointestinal bleeding 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: Graduate School of Medicine, The University of Tokyo 
Funded by: The Japanese Gastroenterological Association 
Draft or Version Number: v.1.0.  9 June 2016 

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A multi-center, randomized controlled trial comparing early versus  
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1. PURPOSE 
The purpose of this document is to specify all study-specific monitoring requirements 
for a multi-center, randomized controlled trial comparing early versus elective 
colonoscopy in outpatients with acute lower gastrointestinal bleeding protocol that 
ensures that the clinical sites comply with the study protocol and regulatory 
requirements. 
 
2．TOOLS AND PROCESSES 
2.1 Study Data  
This study will use direct data entry of clinical trial data. This process will allow a 
clinical study site to perform direct data entry of original data into an electronic data 
capture (EDC) system at the time of the subject’s hospital visit, and for the original data 
to be stored in the access-controlled data repository, access to which will be controlled 
by the clinical investigator. These original data will be stored in the Hospital 
Information System prior to the data being transmitted to the EDC database.  
 
 
 
 

 
56 
 
3.  Risk Mitigation Strategy  
Category 
Risk 
Impact 
Probability 
Detectability 
RPE* Risk Mitigation 
Trial outcome 
Missing identification 
rate of stigmata of recent 
hemorrhage 
High 
Low 
High 
High 
100% SDV and SDR (on site 
monitoring) 
Subject safety 
Risk is greater in the 
elective group than early 
group 
High 
Low 
High 
High 
Planned sample size will provide 
sufficient statistical power including 
patients with protocol violations  
Subjectssafety 
Specific reporting 
requirements for severe 
adverse events (SAE) 
High 
Low 
High 
High 
When an SAE occurs, information is 
automatically transmitted from the EDC 
system to stakeholders 
Subject 
registration 
Violation of eligibility 
High 
Low 
High 
High 
100% SDV and SDR (onsite 
monitoring) 
Subject 
registration 
Allocation 
High 
Low 
High 
High 
All allocation is performed by the EDC 
system 
Subjects’ 
demographic 
data 
Concomitant Medication 
Low 
Low 
High 
Low  
Central monitoring confirms data 
inconsistency 
Subjects’ 
demographic 
data 
Past history of Illness 
Low 
Low 
High 
Low 
Using Charson Comorbidity Index, 
central monitoring confirms data 
inconsistency 
Procedure 
Data collection 
Low 
Low 
High 
Low 
Vital signs, laboratory data and other 

 
57 
 
continuous variables are extracted from 
the EDC system; a biostatistician 
performs central statistical monitoring 
and detects inaccurate data 
Procedure 
Colonoscopy 
Low 
Low 
High 
Low 
All facilities are endoscopic special 
facilities, which have many 
endoscopists to complete colonoscopy 
procedures in compliance with the 
protocol 
Discontinuation 
Discontinuation of study 
subjects 
High 
Low 
High 
High 
Central monitoring confirms data 
Facility 
selection 
Facility selection for this 
study 
Low 
Low 
Low 
Low 
All facilities have own institutional 
review board and share study aims. 
Thus, these facilities are able to recruit 
the planned number of subjects 
* RPE, Risk priority evaluation 
 

 
58 
 
4.  SOURCE DOCUMENTS 
1. Source data/records contain all information necessary for the reconstruction and 
evaluation of the study. Source data/records include original records, certified copies of 
original records, observations, and laboratory reports and/or data sheets. In addition, 
with the use of direct data entry, the access-controlled data repository will serve as an 
original record. 
 
2. At the time of the first monitoring visit or during the initiation visit, the source of 
original data, whether it is being collected in electronic or paper format, will be 
identified for each site. 
 
5.  MONITORING 
Onsite monitoring visits will focus on ensuring that the clinical site understands and is 
following the protocol, reviewing completeness and accuracy of informed consent 
forms, risk-based source document verification (SDV) of original records, and other 
issues that may occur during the course of the clinical trial. 
Central monitoring will focus on assessment of the “reasonableness” of data 
entered into EDC system and data quality management metrics. Central statistical 
monitoring will focus on assessment of the veracity of data entered into the EDC system 
using statistical methods. 
 
5.1  Onsite Monitoring 
For each site, the responsible monitor will schedule the first onsite monitoring visit to 
confirm the informed consent (Day 0) of any of the first three subjects. Based on the 
findings at this visit, coupled with central monitoring findings, the monitor will decide 
when to schedule the next monitoring visit.  
For each site, the monitor will schedule a monitoring visit immediately prior to, 
or coinciding with, the first subject’s final study visit (Day 31+/3). The purpose of this 
visit will be primarily to retrain the site personnel on the relevant study procedures.  
Interim monitoring visits will include review of the following:  
1. Informed consent process and forms (100%)  
2. Study conduct and protocol adherence  
3. Subject eligibility (100%)  
4. Adverse events (100%)  
5. Personnel delegation and signature log  
6. Patient medical records 

 
59 
 
7. Protocol deviations and violations  
8. Follow-up of outstanding issues  
9. The certification process of data originally collected on paper and subsequently 
entered into the EDC system 
Where a site maintains patient records that duplicate information captured in the EDC 
system, the monitor will review those records specified below, to ensure that the site 
records match those captured in the EDC system: 
1. Demographics (100%). To ensure subject identities based on the site’s medical 
records. 
2. Medical history. To ensure that sites have entered all relevant inclusion/exclusion 
criteria into the EDC system (100%). 
3. Confirmation of subject’s visit to the clinical site (100% of first three subjects). 
4. Review of office medical records (100% of first three subjects). 
When findings indicate that retraining is required, the monitor will retrain site staff as 
soon as possible. 
 
5.2 Central Monitoring 
Data managers (DM) will perform central monitoring through data review and cleaning:  
1. A 100% review of all entered forms and issue queries, if needed. 
2. Review and take appropriate action for all online and batch edit checks. 
 
DM will review periodically the EDC for accuracy and completeness. Risk-based 
monitoring meetings will take place when 20, 40, 80, and 120 cases have accumulated, 
and will involve DM, the monitor, biostatistician (as needed), to review the progress of 
the clinical trial. Items to be reviewed at the risk-based monitoring meetings may 
include: 
1. Enrollment and dropout status 
2. An assessment of edit checks and queries that are being filed, by form as well as by 
variable 
3. Reasons for changes to the database by the clinical site 
4. Adverse events 
5. Medications 
6. Protocol deviations and violations 
7. Monitoring procedures 
8. Other items that may arise 

 
60 
 
9. Action items 
The project manager will record meeting minutes and follow-up actions. The schedule 
of meetings and the clinical monitoring plan may be modified depending on findings. 
The decisions and the rationale for changing any of the procedures will be documented. 
 
6.  Startup meeting 
 The purpose of a startup meeting is to train investigators and site personnel on the 
specific requirements and procedures needed to perform the clinical trial. The startup 
meeting will be held during the risk-based monitoring meeting, or if it is determined 
that a specific site requires additional training, as appropriate. Sites will not enroll 
subjects into the trial until the startup meeting has been satisfactorily completed. 
 
At a minimum, the agenda for the startup meeting must include the following elements: 
1. Review of the protocol 
2. Training appropriate staff on: 
A) GCP regulations 
B) SAE reporting requirements 
C) Subject management 
D) Handling of colonoscopy examination 
E) Handling of safety colonoscopy examination 
F) EDC system 
G) Certification of original records 
H) Direct data entry process 
 
7.  Interim Monitoring Visits 
The purpose of an interim monitoring visit will be to ensure that the rights and 
well-being of each subject are protected; trial data are accurate, complete, and 
verifiable; the trial is being conducted according to ICH GCP guidelines and Ethical 
Guidelines for Medical and Health Research Involving Human Subjects; and the trial 
site and staff remain trained and qualified. Monitoring of the clinical trial can occur 
both by onsite visits and through central monitoring procedures. 
 
8.  Closeout Visit 
The purpose of a closeout visit will be to bring official completion to all trial-related 
activities at the site.