Capsule Endoscopy for Severe Hematochezia

Background and Significance

Currently there are no consensus guidelines for the best approach to patient with severe
hematochezia. One strategy is to perform an urgent colonoscopy (following a colon purge)
within 12-15 hours. Although this strategy has been associated with a decreased length of
hospitalization and an improved diagnostic and therapeutic yields, it has drawbacks. A major
disadvantage of performing an urgent colonoscopy is that the endoscopist can evaluate only
the colon and the distal ileum, while more proximal sources of bleeding are not evaluated.
Another limitation is that thorough cleansing of the colon is required to facilitate complete
evaluation, identification of stigmata of recent hemorrhage and lesion diagnosis. Urgent
colonoscopy is labor intense and relies on a dedicated bleeding team with expertise in both
diagnosis and hemostasis. Another option for patients with persistent or recurrent
hematochezia is to perform either a tagged RBC scan or an angiogram to identify the bleeding
location. However, these techniques also have major disadvantages, including low diagnostic
yields for severe hematochezia, requiring additional tests for diagnosis, and cannot visually
detect non-bleeding stigmata of hemorrhage on lesions that can be seen during colonoscopy or
by capsule endoscopy.

Research Design and Methods

This is a study of patients who being admitted to the hospital for severe hematochezia or
inpatients who developed hematochezia after hospitalization for an unrelated non-GI bleeding
reason. Those who meet entry criteria and lack exclusions on screening before will being
asked to participate in this study.

After informed consent, patients will be a colon preparation prior to ingestion of the colon
capsule. The capsule recording system will be activated once patients swallow the capsule.
Once the capsule has been excreted or if the capsule stops recording images (usually 10 hours
after activation), the video recorder will then be taken to a workstation and the video will
be downloaded for reading.

In addition to having the capsule endoscopy, all consented patients will undergo standard
tests for the initial diagnosis and management of severe hematochezia: tagged RBC scan and/or
computerized tomographic angiography (CTA), magnetic resonance imaging (MRI) angiogram, or
conventional angiography. Because of contra indication, MRI angiography will not be performed
until the capsule has been excreted, nor will CT angiography because the capsule may
interfere with interpretation. All patients will also have urgent colonoscopy after clearing
the colon of blood and stool with the purge. All of these diagnostic procedures will be
performed within 48 hours of GI consultation, but ideally as soon as possible.

If a bleeding site is not identified by colonoscopy, further diagnostic workup are usually
performed as part of the standard of care, including anoscopy, esophagogastroduodenoscopy,
push enteroscopy, or deep enteroscopy. If bleeding continues or worsens, surgery may be
necessary to control the bleeding.

The GI endoscopist, nuclear medicine physician, and radiologist will be blinded to the
results of the capsule endoscopy until 24 hours after the other diagnostic tests (i.e. tagged
RBC scan, angiography, and endoscopy/colonoscopy) have been performed. Then the results of
all tests will be unblinded. This will be done for the purpose of not delaying clinical
management, but also to avoid biasing the interpretations of these diagnostic studies.

Data Collection and Monitoring Demographic data and medical history including details of
co-morbid illnesses, risk factors, and characteristics of the GI bleeding will be recorded.
Reasons for exclusion will be documented. Baseline physical examinations, American Society of
Anesthesiology (ASA) classification, laboratory results, Blatchford-Glasgow score, units of
blood products transfused, and results of the real-time viewer will also be recorded. Results
of RBC scanning, angiography, capsule endoscopy, endoscopy, pathology, and surgery will be
recorded. The outcomes including rates of re-bleeding or persistent bleeding, treatment of
bleeding at endoscopy or radiology, need for surgery, major complications, transfusions after
initial resuscitation, hospital and intensive care unit days, and death will be prospectively
recorded up to the time of hospital discharge and 30 days following discharge. Subgroup
analysis regarding results of urgent colonoscopy/enteroscopy will be performed to assess for
differences in diagnostic yield and therapeutic interventions between different endoscopists.
The number of patients who experience any difficulties in capsule swallowing will be
recorded, including inability to swallow the capsule, incomplete examination of small bowel
or colon, and capsule retention.

Sample size calculation Based on prior retrospective data in the CURE hemostasis database,
the investigators estimate that a sample of 46 patients would be required. Four additional
patients will be enrolled in case of failure of the capsule to pass through the colon or
other problems with the capsule recording arise. The investigators will therefore perform the
study with a sample of 50 patients in two years.

Statistical analysis methods

The primary end point of the study will be the diagnostic yield (defined as the frequency of
detection and percentage of positive results) for capsule endoscopy, tagged red blood cell
scan/angiography, and endoscopy for the localization of the bleeding site and/or etiologic
diagnosis (e.g. definitive if stigmata of recent hemorrhage are found or presumptive if a
clean lesion is diagnosed and no other lesions are found by complete evaluation). The
diagnostic yield of each technique will be calculated and compared by the McNemar test for
paired data using exact methods. The final diagnosis by endoscopy, angiography, pathology,
and surgery will be considered the gold standard. Concordance between each diagnostic
strategy will be calculated and reported with the kappa index. A P-value of less than 0.05
will be considered statistically significant.

As secondary outcomes, the sensitivity, specificity, and accuracy which will be also
determined for each technique for lesion localization; absence of lesions in the foregut,
small bowel, or colon; and etiologic diagnosis (definitive or presumptive).

Confidentiality:

Study data will be physically and electronically secured. All personal information will be
replaced with a code de-identifying subject's information. The researchers will do their best
to make sure that all subject's private information is kept confidential as possible.

Data Management Records will be labelled with a code number and then only de-identified
information will be entered into our encrypted Statistical Analysis System (SAS) electronic
database located at the VA West Los Angeles. No identifiable information about them will be
kept in the electronic research data files. All personal information will be replaced with a
code. A list linking the code and their identifiable information will be kept separate from
the research data files in a locked file in the research team's office located at VA West Los
Angeles. (VA CURE GI Hemostasis Research Unit). This list will be protected by the Principal
Investigator (Dennis Jensen, MD) and the research team. At the end of the study, the
investigators will destroy this link and no one — not even the researchers — will be able to
connect their identity to the research data.

Future Use of Data After the study finishes, the research team will continue to use the
patient's de-identified medical data from their medical history, laboratory results, labs,
radiological, surgical, and pathology results, and colonoscopy results and information on
their medical progress to continue to analyze and to report new GI research results.

Data and Safety Monitoring Plan

Adverse events The following adverse event information will be prospectively collected:
capsule retention rates and those requiring endoscopic removal, perforations, aspiration,
myocardial infarctions, strokes, and deaths within 30 days of enrollment.

Frequency Safety data will be collected daily while hospitalized and weekly after discharge
from the hospital, up to 30 days after enrollment. Data collection will start as soon as the
patient enrolls in the study and swallows the capsule.

Review Cumulative safety data will be reviewed every 30 days.

All serious adverse events (SAE's) will be reported to the IRB as mandated by the VA research
service.

The safety data will be overseen by the PI and the biostatistician. All results will be
reported to the IRB, who will review all SAE's.

Based upon widespread utilization and safety of capsule endoscopy for small bowel bleeding
since 2001 in the U.S. and many other countries worldwide, the investigators do not expect
any clinical condition which would trigger an immediate suspension of this research study.

Inclusion Criteria:

1. 18 years old or older

2. Able to provide written informed consent

3. Presenting with evidence of severe ongoing hematochezia (i.e. passage of red blood or
clots per rectum witnessed by a health care provider) and have a decrease in
hemoglobin from baseline of 2 or more grams and/or transfusion of 1 or more units of
red blood cells for resuscitation with either outpatient or inpatient start of severe
hematochezia.

Exclusion Criteria:

1. Uncooperative, unable to give written informed consent, or refuse to participate

2. Contraindication to undergo capsule endoscopy due to:

1. Documented or suspected bowel obstruction (partial or complete)

2. Anatomical GI abnormalities such as strictures of the foregut or small bowel

3. Inability to swallow the capsule

4. Presence of cardiac pacemakers or other implanted electromedical devices

3. American Society of Anesthesiology (ASA) class V (very severe co-morbidities and very
poor prognosis for surgery or similar procedures)

4. Very severe GI bleeding with shock not responsive to IV fluid resuscitation and/or
transfusions and IV medications to raise the systolic blood pressure

5. History of recent hematemesis (within 30 days), positive nasogastric, or orogastric
(OG) aspirate suggesting an upper GI bleed

6. Presenting with recurrent hematochezia that has been previously diagnosed as anorectal
bleeding