Comparison of 24-hours Versus 72-hours of Octreotide Infusion Along With Endoscopic Therapy in Preventing Early Rebleed From Esophageal Varices: a Multi-center, Randomized Clinical Study
Phase: PHASE4
Conditions: Esophageal Varices, Liver Cirrhoses, Bleeding Esophageal Varices, Upper Gastrointestinal Bleeding
Sponsor: Medical University of South Carolina

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PROTOCOL TITLE: 
Comparison of 24-hours versus 72-hours of octreotide infusion along with 
endoscopic therapy in preventing early rebleed from esophageal varices: a multi-
center, randomized clinical study 
PRINCIPAL INVESTIGATOR: 
Don Rockey, MD 
 
NCT03624517 
 
 

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1.0 
Objectives / Specific Aims 
The objective of this study is to determine the safety and efficacy of 24-hours vs. 72-hours 
continuous infusion of octreotide after successful endoscopic treatment of esophageal varices 
and overt gastrointestinal bleeding. 
2.0 
Background 
Esophageal variceal hemorrhage due to portal hypertension is a dreaded clinical complication in 
patients with cirrhosis and is associated with significant morbidity and mortality.1 It is usually 
managed with pharmacologic, endoscopic, and radiological techniques, and sometimes 
surgery.1 The current standard of care includes intravenous infusion of the somatostatin 
analogue, octreotide, which is usually started as soon as variceal hemorrhage is suspected, 
followed by urgent or emergent endoscopy, and treatment typically with band ligation (EBL) 
within 8 to 24 hours.1,2 Intravenous octreotide is then continued for three, and up to five days, 
although currently available guidelines are not clear on the appropriate duration of therapy.  
 
The rational for using octreotide is that it reduces portal blood flow, which reduces portal 
pressure, and hence reduces the propensity for variceal bleeding. The pharmacology of 
octreotide suggests that the benefits are transient due to desensitization and/or tachyphylaxis.3 
The appropriate duration of continuous octreotide infusion is uncertain and largely based on 
expert opinion. Prolonged infusion of octreotide is thus likely to be unnecessary, and may 
inappropriately increase hospital and medical costs.  
 
In randomized-controlled trials, the duration of vasoactive drugs has varied between 8-hours 
and 6-days.4,5 Most studies that show benefits of octreotide in decreasing recurrent variceal 
bleeding compared octreotide with other vasoactive agents, such as vasopressin and 
terlipressin.6-8 A few also compared octreotide with endoscopic sclerotherapy. The standard of 
care for bleeding esophageal varices is octreotide and EBL. However, the role of continuing 
octreotide after successful EBL is unclear. One pharmaceutical-sponsored randomized trial in 
1995 showed that the relative risk (RR) of rebleeding was lower in patients when octreotide 
infusion was continued for 5-days after EBL compared to patients with EBL alone (RR=0.22).9 In 
this study, however, octreotide was not given prior to endoscopy, which is now part of the 
standard-of-care. A second pharmaceutical-sponsored multicenter, randomized, double-blind 
study compared vapreotide (another synthetic somatostatin analogue) to placebo in patients 
with suspected esophageal or gastric variceal bleeding.10,11 Patients were randomized to 
receive vapreotide or placebo at the time of presentation and the treatment was continued for 5-
days after endoscopic treatment (sclerotherapy or band ligation). Control of bleeding and 
survival was significantly better on vapreotide (compared to placebo) at the time of endoscopy 
(69% vs. 54%), at 48-hours (73% vs. 54%), and at Day 5 (66% vs 50%). There was no 
difference in recurrent bleeding after 3 days, duration of hospitalization, or mortality. Notably, the 
difference in bleeding and survival occurred within the first 6-hours of vapreotide infusion vs. 
placebo, and then became non-significant suggesting that the effect occurs early on.  
 
In a recent randomized-controlled trial, patients were started on octreotide infusion before 
endoscopic therapy (band ligation or sclerotherapy) and then octreotide was continued for 2-
days vs. 5-days.5 Two days of octreotide infusion were found to be as efficacious as the 5-days 
of infusion in preventing early rebleed, suggesting that prolonged infusion of octreotide may be 
unnecessary.  
 

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The above studies suggest that octreotide infusion for longer than 24 hours may be clinically 
unnecessary, which also raises the issue of the expense of continuing the medication.  Hence 
we propose a randomized study to determine whether shortening the length of time of octreotide 
after endoscopic band ligation affects the rate of variceal rebleeding. 
 
3.0 
Intervention to be studied (if applicable) 
The study will be a prospective, randomized-controlled multi-center study.  
 Patients with overt, or active, variceal bleeding will be randomized to octreotide infusion 
for either 24-hours or 72-hours following successful endoscopic band ligation (EBL).  
 
4.0 
Study Endpoints (if applicable) 
Primary Endpoint: 
 Rebleeding within 72-hours after control of hemostasis with EBL 
 
Secondary Endpoints: 
 Rebleeding within 7 and 30-days 
 Survival within 7 and 30-days 
 Complications from octreotide, including, but not limited to: pneumonia, cardiac 
complications (arrhythmias, heart failure, cardiac ischemia), paralytic ileus, 
hyperglycemia, diarrhea, abdominal pain, nausea 
 
Rebleeding within 72-hours will be defined as any of the following: 
 A drop in hemoglobin by more than 20 percentage points from baseline 
 Sustained tachycardia above 100 beats per minute, with or without hematochezia or 
melena 
 Transfusion of >2 unites packed red blood cells after EBP 
 Recurrence of hematemesis or ongoing melena 
 Urgent or emergent need for Transjugular Intrahepatic Portosystemic Shunt (TIPS)." to 
control suspected rebleeding 
 
Rebleeding after 72-hours will be defined as: 
 Any new episode of hematemesis, melena, or hematochezia (with hemodynamic 
instability) 
 Drop in hemoglobin by more than 20 percentage points OR the need for >2 units packed 
red blood cells 
 Need for TIPS or surgery to control suspected bleeding 
 
Patients who rebleed will be treated per hospital standard of care and physician preference. 
Treatment of rebleeding will be recorded.  
 
Follow-up Endpoints: 
Thirty, 60, 90,180-day, and 1-year follow-up. 
Rebleeding after 72-hours will be defined as: 
• 
Any new episode of hematemesis, melena, or hematochezia (with hemodynamic 
instability) 
• 
Drop in hemoglobin by 20 percentage points OR need for >2 units packed red blood cells 
• 
Need for TIPS or surgery to control suspected bleeding 
 

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5.0 
Inclusion and Exclusion Criteria/ Study Population 
 
Inclusion Criteria  
All patients over the age of 18-years with suspected upper gastrointestinal bleed (GIB) due to 
esophageal varices and in whom octreotide is initiated will be eligible.  
 
Inclusion Criteria: 
 
1. Adult males and females who are 18 years of age or older. 
2. Evidence or suspicion of upper GIB at presentation defined as either: 
a. Patient presenting with melena or hematemesis 
b. Patient presenting with bright red blood per rectum, along with hypotension 
(systolic blood pressure <90mmHg and diastolic blood pressure <60mmHg) and 
tachycardia (heart rate >155 beats per minute) 
3. Patient with known or suspected cirrhosis: 
a. Historical biopsy indicating cirrhosis 
b. Suspected cirrhosis defined as both: 
i. Clinical data (ex: platelets less than 120,000/L) 
ii. Nodular liver on ultrasound, computed tomography (CT), or magnetic 
resonance imaging (MRI) 
 
4. Upper GIB secondary to bleeding esophageal varices as show by esophageal 
endoscopy, requiring endoscopic band ligation (EBL) at presentation  
5. Willing and able to provide informed consent for study.   
 
Exclusion Criteria 
 
1. Known upper gastrointestinal malignancy 
2. Bleeding from gastric varices, with or without esophageal varices 
3. Use of any other endoscopic method to stop GI bleeding beyond endoscopic band 
ligation, including injectables such as sclerosants, epinephrine, saline, endoscopic clips, 
endoscopic suturing, etc. 
4. Variceal bleeding in the last 90 days 
5. History of TIPS or vascular decompression surgery 
6. Pregnant females 
7. Incarcerated individuals 
8. Myocardial infarct, cerebrovascular accident, sepsis, respiratory failure, or severe 
intercurrent illness within the previous 6 weeks 
9. Non-cirrhotic portal hypertension causing esophageal varices 
10. Known or suspected allergy to octreotide 
 
Linkages to subjects: Sequential numbers will be assigned to patient information collected and 
entered into a database. Patient identifiers will be stored separately (with the informed consent 
forms) from extracted data – with data code-linked to identifiers. Only study staff personal at the 
institution where the patient has been enrolled will have access to PHI.  Therefore, while patient 
data will be stored on the secure server where MUSC study staff will have access the patient 
identities from other sites will not be stored here.  This is to keep the patients identities 
confidential.  All records will be kept on a secure server that will be erased six years after the 
completion of the study.  

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6.0 
Number of Subjects 
We anticipate enrolling approximately 40 subjects at the local MUSC site, with a goal of 160 
patients for the entire study) 
 
7.0 
Setting 
This study will be conducted at the inpatient wards at MUSC. 
Study Sites  
Study Sites 
Lead Site: Medical University of South Carolina 
Lead Investigator: Don C. Rockey 
 
Ohio State University  
 
University of Florida-Jacksonville 
 
University of Texas, at Austin 
 
Texas Tech University Health Sciences Center, El Paso 
 
University of Illinois in Chicago  
 
Oregon Health & Science University 
 
The other investigators will be obtaining their own IRB approvals at their respective sites listed 
above. Dr Rockey (MUSC) will serves as the lead investigator for this study, he will oversee the 
validity of the data and eligibility of all enrolled subjects. All study data will be kept on REDCap. 
Only the Primary site (MUSC) will have access to other site’s data. Collected data will include 
patient demographics, clinical data, labs, images, hospital stay course during enrollment period 
and follow up visits. 
8.0 
Recruitment Methods 
Cirrhosis patients presenting with suspected upper GI bleeds presenting to the involved hospital 
sites are always seen by consultant– either the attending or fellow – from the Gastroenterology 
and Hepatology Services. Therefore, identification of potential subject for the study will be 
through chart reviews of current inpatients by the consult and study team and by consult 
requests to the GI/Hepatology team. All members of the study team can access the consult lists 
as well as inpatient lists for individuals presenting with upper GIB and all consult team members 
and study team members will be added as additional study members to this protocol in order to 
have IRB-approval to recruit subjects.  
 
9.0 
Consent Process 
This research study will involve obtaining informed consent from potential subjects.  
 
The need for endoscopic therapy cannot be anticipated, so informed consent will be obtained 
prior to endoscopy from the patient when appropriate, upon presentation to MUSC with a 
suspected variceal bleed. Potential patients will be approached for participation in this study by 
a member of the IRB-approved study team and the informed consent form and HIPAA form will 
be reviewed – verbal review and a written/printed consent available for review with the subject. 

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Ample time will be allocated between informing the prospective participant and obtaining written 
consent will vary but will ultimately depend on how long the potential participant requires for all 
his/her questions to be answered to the best of the study team’s ability.  
 
Additionally, the patient will have time to read the consent and HIPAA forms on their own prior to 
discussing with research staff.  
 
 
 
10.0 Study Design / Methods 
 
This prospective and randomized controlled trial will involve administration of either octreotide 
infusion for 24-hours (Group A) or for 72-hours (Group B). This study involve the following: 
 
Screening  
 
Esophageal varices as the sole cause of upper gastrointestinal (GI) bleeding will need to be 
confirmed. Endoscopic band ligation will be performed per standard of care when deemed 
appropriate by the treating physician. 
 
During this time, and regardless of participation in the research study, octreotide will be 
administered per standard-of-care before endoscopy. Endoscopy with band ligation will be 
performed per standard-of-care, if needed. Not all patients may have variceal bleeding and even 
if varices are present, not all may need EBL. Only patients who receive EBL for varices with 
stigmata of bleeding will be randomized for the study, to receive octreotide infusion for 24- or 
72-hours after successful EBL. Subsequent care will be per the primary team and not affected 
by participation in the study.  
 
Treatment: 
 
Randomization will be conducted for all enrolled subjects at all site by the study coordinator and 
coinvestigators at MUSC. Only after undergoing EBL will patients be randomized by computer-
generated blocked randomization for treatment allocation. The randomization schedule will be 
blinded in sequentially numbered opaque envelopes.  
 
Patients will be randomized to receive octreotide as a continuous intravenous infusion for 24-
hours or 72-hours after the infusion is started. Following standard-of-care for variceal bleeding, 
all patients will be monitored in the hospital for at least 72-hours after undergoing 
esophagogastroduodenoscopy (EGD) and EBL. Any recurrent bleeding will be managed per 
standard-of-care, which may include a combination of octreotide infusion, placement of an 
esophageal balloon tamponade tube (i.e. Minnesota tube, or similar), repeat endoscopic 
intervention, referral to Interventional Radiology for transjugular intrahepatic portocaval shunt 
(TIPS), or surgery. 
 
Follow-Up: 
 
The follow-up of this study will take place until 1-year after the initial bleeding episode and 
information will be collected via chart reviews of the medical records and follow-up phone calls 
at: 30-days, 60-days, 90-days, 180-days, and 1-year after the initial visit. Phone calls will take 

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approximately 15 minutes and will consist of questions regarding the patients general health 
status, cirrhosis related health complications and possible side effects of octreotide. 
 
Collected Data: 
 
Additional data collected from medical records during this study will include: 
1. Patient demographics including race and ethnicity 
2. Presenting symptoms and physical exam findings  
3. Past medical history 
4. Laboratory results – complete blood count (CBC), liver function tests, ammonia (if 
checked per hospital standard of care), hepatitis serologies 
5. Imaging findings – liver morphology, patency of portal vein 
6. Medications – outpatient and during admission 
7. Paracentesis 
8. Use of antibiotics 
9. Time to endoscopy 
10. Endoscopic findings 
11. Endoscopic treatment 
12. Thirty, 60, 90, 180-day and 1 year follow-up will gather the following information as 
available: 
a. Patient alive or not 
b. Laboratory results – complete blood count (CBC), liver function tests, ammonia (if 
checked per hospital standard of care), hepatitis serologies 
c. Medication 
i. Betablockers 
ii. Antibiotics 
d. Rebleeding 
e. Endoscopic findings and treatment 
11.0 Data Management  
Statistical Analysis: 
 
The study design is a non-inferiority study. Primary hemostasis of esophageal variceal bleeding 
is highly successful (90%), despite rebleeding rates of 10-30%. A superiority trial of primary 
hemostasis would require a very large number of patients, would require significant resources 
and would take a long time to recruit.  
A non-inferiority trial is appropriate to demonstrate that receiving octreotide for 24 hours is not 
inferior to the standard of care of 72 hours.  
 
Assuming a primary hemostasis rate of 90% and a non-inferiority margin of 15%, 69 patients will 
be needed in each group to achieve 90% power. This calculation assumes a type I error rate of 
0.05 and equal sample sizes. Anticipating patient drop-out of approximately 15%, a sample size 
of 80 patients will be required.  
 
Qualitative variables in the two groups will be compared using chi-squire test with Yates’ 
correction of Fisher’s exact test, when applicable, and represented as percentages. The Mann-
Whitney test will be used to compare quantitative variables, which will be expressed as means ± 
standard deviations (SD).  
 

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Factors associated with re-bleeding and complications will be identified. Logistic regression 
modeling will be used to assess differences in re-bleeding between the two groups adjusting for 
significant confounding variables. 
 
All data collected from patients at all sites will be entered in a Redcap project that will be created 
at MUSC. All sites will have access to this project, however each site will only have viewing and 
editing rights to the subjects that have been entered by that specific site.  
 
Costs and Payments: 
 
All costs associated with the protocol are part of the routine and standard-of-care for patients 
with variceal hemorrhage. The researchers, the study patients, or the participating sites will not 
be remunerated for their participation.  
 
13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects (if applicable) 
 
 
Data Safety Monitoring Board (DSMB): 
 
After 25, 50, and 75% of the research subjects are enrolled in the study an independent, internal 
data safety and monitoring board (DSMB) meeting in which we will present accrual and safety 
data to group members. If the accrual rate is not reached, we will conduct a DSMB meeting at 
least semi-annually. The DSMB will review any SAEs as they occur. The DSMB will be 
composed to non-study associated members, specifically: 2 gastroenterologists and 1 
statistician at the Lead Investigating Site (MUSC) and it will be responsible for reviewing the 
data at all sites individually and the data for the study as a whole.  
 
All adverse events including incidences of bleeding in both the control and experimental group 
will be recorded and submitted to the Institutional Review Board (IRB) within 10 business days. 
If a serious adverse event occurs, this will be reported to the IRB within 2 business days. The 
descriptions and definitions of adverse or serious adverse events will be followed and if any 
adverse events occur, we will report these to the IRB.  
.  
14.0 Risks to Subjects 
 
Octreotide: 
Octreotide infusion has been documented to cause tachyphylaxis and hence not effective when 
given longer than 24 hours. However, it is possible that a shorter duration of 24-hour compared 
to 72-hour of octreotide may lead to a higher re-bleeding rate, even after endoscopic evaluation 
and treatment.  
 
Confidentiality: 
A confidentiality breach is a risk associated with any study. However, the information attained 
from this study will be minimized by (1) removing direct participant identifiers, such as medical 
record numbers and names; (2) securing, in a separate location, and limiting access to 
information linking codes (i.e. linkage codes) with direct participant identifiers; and (3) limiting 
access to information to the study team 
 
 

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15.0 Potential Benefits to Subjects or Others 
 
Individual subjects are not likely to derive direct benefit from participating in the study. Potential 
benefits associate with participation in this study include that length of stay or intensive care unit 
stay may be shorter for patients receiving octreotide treatment for 24 hours. Thus, it is possible 
that the hospital stay associated costs or complications related to hospitalization would be 
avoided. It is anticipated that important data will be obtained in this study, which will help other 
patients with esophageal variceal hemorrhage and enrich the medical literature.  
 
The reduction in duration of octreotide therapy poses a potential benefit (reduction in exposure 
to medication and hospital resources, potential reduction in hospital length of stay, etc), but data 
supporting a longer octreotide infusion requires confirmation.  All procedures and medical 
therapy are standard of care and therefore additional risks due to these interventions are not 
anticipated.  The data generated from this study are likely to alter management paradigms in 
patients with esophageal variceal hemorrhage.   
 
 
16.0 Sharing of Results with Subjects 
 
All results during study treatment and during the inpatient admission for the initial bleed will be 
shared with subjects and will be part of the subject’s MUSC medical record. If the subject has 
never been an MUSC patient, then a MUSC medical record will be created upon their 
presentation with an upper GIB. All information within the medical record can be viewed by 
individuals authorized to access the record and every effort will be made to keep confidential all 
research information in the medical record that can identify a subject to the extent allowed by 
law. 
 
Information collected during follow-up endpoints will be stored on a password-secure database 
created by the Clinical Data Warehouse at MUSC – the WebDCU – which is accessible only to 
members of the IRB-approved study team. All information in the WebDCU is code-linked to 
each subject and code-linked data is stored separately and will be accessible only if absolutely 
necessary by members of the IRB-approved study team.  
 
 
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3. 
Escorsell A, Bandi JC, Andreu V, et al. Desensitization to the effects of intravenous 
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