Tranexamic Acid for The Management of Bleeding Gastrointestinal Angioectasias: A Randomized, Placebo Controlled Trial
Phase: PHASE2
Conditions: Anemia, Small Bowel Bleeding, Angioectasias
Sponsor: Louisiana State University Health Sciences Center in New Orleans

CLINICAL STUDY PROTOCOL 
 
Tranexamic Acid for The Management of 
Bleeding Intestinal Angioectasias: A 
Randomized, Placebo Controlled Trial  
Principal Investigator 
Daniel Raines 
Protocol Version 
3 January 2023 
Version 3 
 
 
 
 
 
 
 
 

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Study Personnel 
Principal Investigator 
Daniel Raines 
Ochsner Health Systems 
Email: draine@lsuhsc.edu 
  
  
Munraj Singh 
LSU Health Sciences Center - New Orleans 
Email: msin10@lsuhsc.edu 
  
 
 
 

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SYNOPSIS 
Primary Objective 
To determine whether oral therapy with TXA results in improvement in serum hemoglobin 
concentration and/or requirement for PRBC transfusion compared to placebo in patients 
treated with standard endoscopic ablation, ocreatide and iron supplementation 
Secondary Objectives (if applicable) 
To determine the need for hospitalization for symptomatic anemia or acute gastrointestinal 
bleed 
To determine the need for additional endoscopic interventions 
To determine the rate of clinically significant side effects associated with TXA therapy leading 
to drug withdrawal 
Study Duration 
The interventional portion of the study will be conducted over a 3 month period  
Study Design 
In the RCT portion of the study, we will enroll approximately 50 patients with diagnosed 
intestinal AEs through VCE and/or endoscopy who experience symptomatic anemia despite 
standard therapy including endoscopic ablation, octreotide and iron supplementation. 
Subjects will be randomized to either the TXA treatment group versus the placebo treatment 
group for 3 months. Patients will have initial complete blood counts (CBC) measured as a 
baseline then subsequent CBCs measured at 1, 2 and 3 months. Patients will be monitored 
for drug side effects, symptoms related to anemia, the need for blood transfusions and 
hospitalizations related to GI bleeding/anemia. 
Study Population 
All newly diagnosed adult patients with intestinal angioectasias following at the LSU Health 
Network GI Clinic who meet screening criteria will be considered for inclusion. Existing 
patients with intestinal angioectasias that are currently not using TXA may also be 
approached for study participation.  
Number of Participants 
The study design includes 50 participants enrolled in the study 
Number of Study Sites 
The study site includes the LSU Health Network GI Clinic at Ochsner Kenner Hospital  
Primary Outcome Variables 
Primary outcome variables include hemoglobin concentration and the requirement of packed 
RBC transfusion. 
Secondary and Exploratory Outcome Variables (if applicable) 
Secondary outcome variables include number of hospitalizations, endoscopic interventions 
and experienced side effects  

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 Table of Contents 
 
1 - Introduction 
 
1.1 Introductory Statement 
 
2 - Background 
 
 
2.1 Background/prevalence of research topic 
2.2 Prior Clinical Experience  
3 - Rationale/Significance 
 
3.1 Problem Statement 
 
3.2 Purpose of Study/Potential Impact 
 
3.3 Potential Risks and Benefits 
 
3.3.1 Potential Risks  
3.3.2 Potential Benefits 
 
4 - Study Objectives  
4.1 Hypothesis 
 
4.2 Primary Objective 
4.3 Secondary Objectives (if applicable) 
 
5 - Study Design 
 
5.1 General Design Description 
 
5.1.1 Study Date Range and Duration 
 
5.1.2 Number of Study Sites  
5.2 Outcome Variables 
 
5.2.1 Primary Outcome Variables 
 
5.2.2 Secondary and Exploratory Outcome Variables (if applicable) 
 
5.3 Study Population  
5.3.1 Number of Participants  
5.3.2 Eligibility Criteria/Vulnerable Populations 
 
6 - Methods 
 
6.1 Treatment - Drug  
6.1.1 Dosage, Admin, Schedule (if applicable) 
 
6.1.2 Method of Assignment/Randomization (if applicable)  
6.1.3 Packaging/Labelling 
 
6.1.4 Storage Conditions 
 
6.2 Assessments 
 
6.2.1 Safety/Pregnancy-related policy 
 
6.2.2 Adverse Events Definition and Reporting 
 
6.2.3 Pharmacokinetics (if applicable) 
 
6.3 Study Procedures 
6.3.1 Informed Consent 
 
6.3.2 Screening 
 
6.3.3 Recruitment, Enrollment and Retention 
 
6.3.4 On Study Visits  
6.3.5 End of Study and Follow-up 
 
6.3.6 Removal of subjects 
 
6.4 Statistical Method 
 
6.4.1 Sample Size Considerations  
6.4.2 Planned Analyses 
 
 
6.4.3 Handling of Missing Data 
 
7 - Trial Administration 
 

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7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization  
 
 
 
7.2 Subject Confidentiality 
 
7.3 Deviations/Unanticipated Problems 
 
7.4 Data Collection 
 
7.5 Data or Specimen Storage/Security 
 
 
7.6 Study Discontinuation 
 
7.7 Study Completion 
7.8 Conflict of Interest Policy  
7.9 Funding Source  
7.10 Publication Plan  
8 – References  
 

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1 - Introduction 
1.1 Introductory Statement 
Intestinal angioectasias are the most common source of small bowel bleeding in the U.S. Over 
50% of patients with bleeding angioectasias develop multiple lesions which recur over time. 
Current medical therapy for angioectasias is suboptimal as many patients continue to 
experience significant GI blood loss despite currently available standard therapies such as 
endoscopic ablation and somatostatin analogue therapy (Octreotide). Our goal is to evaluate the 
efficacy of tranexamic acid as medical therapy for bleeding intestinal angioectasias in a 
subpopulation of patients who have failed standard therapy or in whom standard therapy is 
contraindicated. 
 
 

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2 - Background 
2.1 Background/prevalence of research topic 
Suspected small bowel bleeding (SSBB) is defined as iron deficiency anemia attributed to 
chronic gastrointestinal (GI) blood loss or overt GI bleeding which remains undefined in etiology 
after standard upper and lower endoscopy. SSBB accounts for 5% of all GI bleeding cases.1 
Although missed lesions in the upper GI tract and colon should be considered, up to 75% of 
patients with SSBB are confirmed to have bleeding sources in the small bowel.2 Small bowel 
angioectasias (AE), which are also referred to as angiodysplasias or arterio-venous 
malformations, are identified as the source of bleeding in 30-40% of all SSBB cases and are the 
most common small bowel bleeding source in patients older than 50.3 While AEs can be found 
throughout the entire GI tract, they are most commonly found in the small bowel specifically in 
the jejunum, followed by duodenum, stomach and right colon.4 The prevalence of 
gastrointestinal AE is estimated to be 0.9-3.0% in non-bleeding patients and up to 6% in 
patients with evidence of blood loss.5 
  
AE's are a collection of dilated submucosal vessels composed of thin tortuous capillaries 
accompanied by ectasia of the overlying mucosal venules and capillaries.6 Per Yano-
Yamamoto's accepted endoscopic classification system, small bowel AE are classified as type 1 
lesions. These lesions are further subclassified as type 1a which are characterized by punctate 
erythema (<1mm) with or without oozing and type 1b which are classified as patchy erythema 
(2-3 mm) with or without oozing.7 Histopathologically, AE consist of thin, dilated and tortuous 
veins that lack a smooth muscle layer, which is thought to explain their weakness and tendency 
to bleed.8 
  
Pathophysiology and Risk Factors 
While the pathogenesis and etiology of gastrointestinal AE remains unclear, two developmental 
theories exist. The first by Regula et al. suggests that chronic intermittent obstruction of veins as 
they pass through the muscular layers of the bowel wall may cause dilation and increased 
pressure within the vessels. Due to chronic hypoperfusion, sympathetic nerve stimulation leads 
to relaxation of intestinal vascular smooth muscle, causing local vascular overload, dilation, and 
eventually, permanent AE.9 Dysregulated angiogenesis termed the "angiogenic theory" is an 
alternative theory which was first suggested by Junquera et al. They found that the expression 
of basic fibroblast growth factor and vascular endothelia growth factor (VEGF), both central 
mediators in angiogenesis, were significantly increased in patients with gastrointestinal AEs.10,11 
  
Angioectasias are rarely seen in patients younger than age 50 except in cases of hereditary 
hemorrhagic telangiectasia (HHT). Patient age is the primary risk factor for AE but these lesions 
have been associated with additional risk factors. Chronic renal failure, particularly end-stage 
renal disease, has been shown to predispose patients to the development of AEs due to uremic 
and metabolically driven platelet dysfunction.12—14 Aortic stenosis (AS) has also been studied 
extensively in association with development of AEs, an association known as Heyde syndrome, 
which may be related to an acquired form of von Willebrand disease.15 Bleeding due to AEs has 
also been associated with left ventricular assist device (LVAD) placement.16 Additional risk 
factors include tobacco use, obesity, use of antithrombotic agents, use of non-steroidal anti-
inflammatory drugs and chronic liver disease.4,17,18 
  
 
 

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Diagnosis of AEs 
With the introduction of video capsule endoscopy (VCE) and device-assisted enteroscopy 
(DAE) in 2001, previous studies for SSBB including small bowel follow through, angiography, 
cross sectional imaging and nuclear scans are less commonly employed.19 Due to the anatomic 
features of the small bowel, conventional endoscopy provides limited evaluation of the deep 
small bowel.2,20 VCE is a simple noninvasive procedure which is well tolerated by patients. Per 
the American Gastrointestinal Associate (AGA) guidelines, VCE is the first line investigation for 
small bowel evaluation in hemodynamically stable patients with no evidence of obstruction.21 
DAE is usually reserved to pursue positive VCE findings that require intervention or in the 
setting of high clinical suspicion for small bowel lesions despite negative VCE study. A large 
meta-analysis study by Pasha et al. found the diagnostic accuracy of VCE (60%) was similar to 
that of BE (57%).22 
  
Interventional Management  
Endoscopic management of AEs is difficult and only made possible through the relatively recent 
advent and development of BE. Endoscopic ablation using argon plasma coagulation (APC) is 
the most common technique used to treat gastrointestinal AE.23 Other endoscopic techniques 
include bipolar electrocautery, sclerotherapy injection and mechanical hemostasis using hemo 
clips or banding, which may be beneficial in larger lesions.24 A number of studies report an 
improvement in Hb, a reduction in transfusions and an improvement in overt bleeding following 
APC therapy for AE's.25 However, retrospective studies suggest a high re-bleeding rate of up to 
60% for small bowel AEs with or without thermal intervention using double balloon enteroscopy, 
especially in those patients who required large amount of transfusion before DAE and those 
with multiple vascular lesions.2,26 
  
Radiological embolization is a treatment technique considered for patients with active GI 
bleeding who are hemodynamically unstable or on which endoscopic therapy has failed. 
Mesenteric angiography is used to identity bleeding vessels which are subsequently embolized 
with micro-coils.27 Although the rate of hemostasis achieved by embolization is high, early 
recurrent bleeding was found to occur in an estimated 20% of patients.28 Moreover, severe 
complications such as arterial dissection and bowel infarction occurring in up to 17% of patients 
is a major limitation of embolization techniques.29 
 
If the above therapies have been exhausted and medical management has been unsuccessful, 
surgical management is sometimes required. Small bowel surgical resection is reserved for 
situations when all other forms of management have failed or in an emergent setting due to 
massive blood loss. Surgery is not commonly seen for the management of small bowel AEs 
secondary to the high mortality and morbidity as many patients are elderly with significant 
comorbidities.  
 
Medical therapies 
Medical therapy is an important adjunct to endoscopic ablation in patients with AE's as the 
majority of patients have multiple lesion which may be difficult to completely ablate with new 
lesions developing over time. Pharmacological treatments including iron supplementation, 
somatostatin analogues, hormonal therapies and thalidomide have be considered for patients 
who have not responded well to endoscopic intervention with APC or in whom endoscopy is 
contraindicated. Conservative management with iron supplementation given orally or 
intravenously is a mainstay of treatment for mild intestinal AE bleeding.30 This not only helps 
maintain an adequate level of hemoglobin but helps reduce the frequency of transfusion. In 

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more severe bleeding, transfusion of packed RBCs is an essential element of treatment, 
particularly when mechanistic and medical methods fail. 
  
Somatostatin analogues including octreotide and lanreotide have been used to treat AE. 
Hypothesized mechanisms include decreased duodenal and splanchnic blood flow, improved 
platelet aggregation, increased vascular resistance and inhibition of angiogenesis.31—33 Through 
a meta-analysis, Brown et al. report a clinical response rate of 76% compared to the natural 
progression of the disease and reduced blood product requirements.32 More recently, Nardone 
et al. performed a retrospective analysis and found that 40% of patients had a reduction of 
transfusion requirements over a 6-year mean follow up period.34 There have been no 
randomized control trials performed to prove the efficacy and safety of somatostatin analogues 
compared to other treatment options.  
  
Hormonal therapies, predominantly estrogen and progesterone, were initially thought to be 
useful in the management of intestinal AE in historical studies during the pre-VCE era.35 
However, due to the inability to visual the small bowel the precise nature of what was treated 
was unknown. The proposed mechanism of action includes stabilization of the vessels through 
keratinization, increase in the number of circulating activated platelets, inhibition of 
angiogenesis and decreased mesenteric blood flow.31,36 While early small scale studies were 
promising, Junquera et al. reported the only controlled randomized control trial which found 
there was no reduction in transfusion or iron therapy needs in the patients on hormone therapy 
vs placebo therapy. The frequency of side effects and limitations for use in patients at risk for 
thromboembolic events, have resulted in hormonal therapy having only a limited role in the 
treatment of small bowel bleeding.10,31 
  
Therapies utilized to inhibit angiogenesis in cancer patients have been studied due to their 
potential for inhibition of angiogenesis in the development of new AE's. Thalidomide, an 
immunomodulatory drug with antiangiogenic properties, has been used to treat small bowel AEs 
when conventional therapies have been unsuccessful.37,38 These studies have shown a 
significant reduction in bleeding episodes and an increase in mean hemoglobin concentration 
after treatment with thalidomide. However, the use of thalidomide is limited by severe side 
effects including thromboembolism, hematological abnormalities and teratogenicity.39—41 
 
As previously discussed, gastrointestinal AE's are known to strongly express vascular 
endothelial growth factor (VEGF).11 Bevacizumab is a known anti-VEGF monoclonal antibody 
that has shown to be effective in decreasing bleeding events and the need for blood tranfusions 
in patients with HHT.42,43 Although effective, bevacizumab therapy is complicated by serious 
adverse events which include arterial thrombosis, thromboembolic events, heart failure and 
nephrotic syndrome in up to 10% of patients.44 Further, another barrier to utilization is securing 
financial coverage through insurance as most plans do not cover the mono-clonal antibody. 
Aminocaproic acid is a closely related fibrinolytic inhibitor, similar to our trial drug tranexamic 
acid. It is a lysine analog that inhibits plasminogen activators to promote hemostasis. Few case 
reports have shown therapeutic success in treating upper GI bleeds secondary to radiation 
gastritis and gastric cancer.45,46 Further research is needed to understand appropriate dosing 
regimens and the side effect profile. 
  
 
 
 
 

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Tranexamic Acid 
Tranexamic acid (TXA) is a hemostatic agent that is a synthetic reversible competitive inhibitor 
to the lysine receptor found on plasminogen. TXA works by forming a reversible complex that 
displaces plasminogen from fibrin resulting in the halting of fibrinolysis. TXA has been approved 
by the FDA for the treatment of heavy cyclic menstrual bleeding and tooth extraction in patients 
with hemophilia. The antifibrinolytic agent has been further studied in the management of major 
bleeding in multiple clinical settings including trauma, obstetrics and neurosurgery.47,48 TXA has 
been considered a potential adjunctive treatment for GIB with the earliest RCT conducted in 
1973.49 With the recent publication of the large HALT-IT trial, which explored the use of high 
dose TXA over 24 hours in the setting of acute GI bleed, there has been an increasing interest 
in the possible applications of TXA.50 
  
The literature contains a few case reports commenting on the successful use of TXA in patients 
with AE's, without increasing the risk of thromboembolic events.51,52 Of note, there does exist a 
randomized placebo-controlled trial examining the use of oral TXA for acute lower GI bleeds 
requiring hospitalization. Smith et al. found no improvement in average hemoglobin and 
transfusion rates following a four-day treatment regimen with oral TXA, however, the bleeding 
source for approximately 50% of the study population was diverticular in nature.53 Moreover, 
there are no current case series or randomized control trials examining the use of TXA in 
patients with persistent or progressive anemia due to chronic GI blood loss from AEs despite 
standard treatment with endoscopic ablation and iron supplementation. 
  
The common side effects of TXA include nausea, vomiting, diarrhea, rash, itching, hypotension, 
and thromboembolic events as reported by the FDA. Contraindications include a history of 
venous or arterial thromboembolism, intracranial bleeding or active thromboembolic disease. 
TXA is not well studied in the renally impaired patient however it is 95% excreted in urine so 
renal dosing is recommended.54 Dionne et al. recently published the largest systemic review 
and meta-analysis examining TXA in GIB and found that the absolute risk of thromboembolic 
events to be <1%. This presents a small but statistically significant risk of DVT/PTE with high 
dose IV TXA but cannot be extrapolated to lower dose oral TXA regimens. Further, the safety 
profile of TXA has been confirmed and well-studied in the fields of trauma and orthopedics.55,56 
 
2.2 Prior clinical experience  
The principal investigator for this study has been using TXA in his clinic as an off-label drug for 
the treatment of small bowel AEs. Those who were treated with TXA were those patients that 
have failed standard therapy. Failure of standard therapy is defined as continued GI bleeding 
and need for blood transfusions despite endoscopic ablation, octreotide therapy and iron 
supplementation for at least 3-6 months. Thus far, 9 patients have been treated with TXA 
therapy consisting or 650 mg oral tablets taken three times per day for 3 months. In 8 of those 
patients there was an observed clinical response defined as stabilization of hemoglobin which 
was not previously achieved with prior therapy. Although this sample size of patients was not a 
controlled study accounting for confounding variables, it does strongly highlight the potential 
beneficial therapeutic effects of TXA. Of note, there were no side effects observed by the 9 
patients. 
 

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3 - Rationale/Significance 
3.1 Problem Statement 
The current management of small bowel AE's is suboptimal as the majority of patients with 
symptomatic bleeding experience continued or recurrent bleeding despite standard of care 
therapy including endoscopic ablation, octreotide and iron supplementation. In these cases, 
patients may require repeated transfusion of PRBC's as palliative treatment which is a source of 
morbidity including repeated hospitalization and is often complicated over time by transfusion 
reactions, iron overload, and volume overload. Patients with severe disease may develop 
antibodies to all blood products over time such that they can no longer tolerated PRBC 
transfusion. 
3.2 Purpose of Study/Potential Impact 
Currently, the mainstay of treatment for intestinal AEs includes endoscopic ablation combined 
with octreotide and iron supplementation. However, many patients continue to suffer from 
persistent or recurrent symptomatic anemia and often require repeated hospitalizations for 
blood transfusions. TXA is a hemostatic agent that has the potential to be beneficial in patients 
with small bowel GI bleeding. Through our literature review multiple case reports have 
highlighted the impact TXA treatment can have on patients with intestinal AEs. Our study would 
help determine the potential additive effect of TXA in patients with symptomatic anemia due to 
GI AE's. Further, we seek to expand our knowledge of the applications of TXA with the goal of 
decreasing morbidity and mortality. 
3.3 Potential Risks and Benefits 
3.3.1 Potential Risks 
Adverse events will include medication side effects including nausea, vomiting, diarrhea, rash, 
itching, hypotension, and thromboembolic events. These side effects will be closely monitored 
through monthly in person or virtual interviews with patients for the entirety of the study period. 
 
Thromboembolic events have the largest potential impact to patient’s health and include deep 
vein thrombosis (DVT), pulmonary embolism (PE) and stroke. Dionne et al. recently published 
the largest systemic review and meta-analysis examining TXA in GIB and found that the 
absolute risk of thromboembolic events to be <2%. This presents a small but statistically 
significant risk of DVT/PTE with high dose IV TXA but cannot be extrapolated to lower dose oral 
TXA regimens. Further, the safety profile of oral TXA has been confirmed and well-studied in 
the fields of trauma and orthopedics. Specifically, a large meta-analysis looking at the 5 RCTs 
comprising approximately 600 patients found no statistically significance increasing in 
thromboembolic complications between patients undergoing a total knee replacement who 
received oral TXA for intra/post-operative bleeding vs control patients. 55,56 We do appreciate 
that certain populations of patients are at increased risk for thromboembolic events. These 
include comorbidities such as liver disease and malignancy. On literature review, specific rates 
of thromboembolic events in these populations with the use of TXA has not yet been studied. 
Importantly, a group of patients who may not know they would be at an increased risk are those 
with undiagnosed prothrombotic states. While it would not be possible to screen for all 
prothrombotic diseases, factor 5 Leiden and prothrombin mutation make up a large portion of 
hypercoagulable disorders. In order to screen out these patients, lab markers testing for the 
aforementioned disorders will be ordered in all patients during initial laboratory lab work. 
  

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3.3.2 Potential Benefits 
If TXA is shown to decrease the need for further blood transfusions and hospital admissions, it 
becomes a viable option for patients affected by intestinal AEs. Specifically, for patients who 
experience recurrent blood loss despite current standard medical therapy. 
 
 

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4 - Study Objectives 
4.1 Hypothesis 
We expect 75% of patients on TXA to have a 2 gm/dl improvement in overall hemoglobin while 
only 25% in placebo group see a 2gm/dl improvement. We expect 75% of TXA patients to 
require zero blood transfusions compared to placebo group requiring 1 blood transfusion on 
average per patient over 3 months. 
4.2 Primary Objective 
To determine whether oral therapy with TXA results in improvement in serum hemoglobin 
concentration and/or requirement for PRBC transfusion compared to placebo in patients treated 
with standard endoscopic ablation and iron supplementation 
4.3 Secondary Objectives (if applicable) 
To determine the need for hospitalization for symptomatic anemia or acute gastrointestinal 
bleed 
To determine the need for additional endoscopic interventions 
To determine the rate of clinically significant side effects associated with TXA therapy leading to 
drug withdrawal 
 
 

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5 - Study Design 
5.1 General Design Description 
In the RCT portion of the study, we will enroll approximately 50 patients with diagnosed 
intestinal AEs through VCE and/or endoscopy who experience symptomatic anemia despite 
standard therapy including endoscopic ablation and iron supplementation. Subjects will be 
randomized to either the TXA treatment group versus the placebo treatment group for 3 months. 
Patients will have initial complete blood counts (CBC) measured as a baseline then subsequent 
CBCs measured at 1, 2 and 3 months. Patients will be monitored for drug side effects, 
symptoms related to anemia, the need for blood transfusions and hospitalizations related to GI 
bleeding/anemia. 
5.1.1 Study Date Range and Duration 
The interventional portion of the study will be conducted over a 3-month period from March 
2023 — May 2023. We will spend the months of December 2022 — February 2023 recruiting 
patients for the study and collecting demographic data on patients that meet inclusion and 
exclusion criteria. Following the interventional period of the study we will collect, interpret, 
analyze and summarize data from June — July 2023. 
5.1.2 Number of Study Sites 
The study site includes the LSU Health Network GI Clinic at Ochsner Kenner Hospital  
5.2 Outcome Variables 
5.2.1 Primary Outcome Variables 
Primary outcome variables include hemoglobin concentration and the requirement of packed 
RBC transfusion. 
5.2.2 Secondary and Exploratory Outcome Variables (if applicable) 
Secondary outcome variables include number of hospitalizations, endoscopic interventions 
(EGD, Colonoscopy, enterosocopy, video capsule endoscopy) and experienced side effects.  
5.3 Study Population 
All newly diagnosed Adult patients with intestinal angioectasias following at the LSU Health 
Network GI Clinic who meet screening criteria will be considered for inclusion. Existing patients 
with intestinal angioectasias that are currently not using TXA may also be approached for study 
participation.  
5.3.1 Number of Participants 
The study design includes 50 participants enrolled in the study that meet inclusion/exclusion 
criteria.  
5.3.2 Eligibility Criteria/Vulnerable Populations 
Inclusion Criteria  
• 
Male, female, non-gender conforming patients aged >18 years with symptomatic anemia 
attributed to chronic GI blood loss from GI AEs despite endoscopic ablation and iron 
therapy 
• 
Stated willingness to comply with all study procedures and availability for the duration of 
the study 

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Exclusion Criteria  
• 
Contraindications to TXA therapy 
o Allergy to TXA, intracranial bleed, history of venous or arterial thromboembolism, 
active thromboembolic disease, ischemic retinopathy 
• 
Bleeding/Coagulopathy disorder and/or on anticoagulation regimen 
• 
Ulcerative colitis or Crohn's disease 
• 
End stage renal disease  
• 
Decompensated cirrhosis 
• 
Pregnancy or intention to become pregnant 
• 
Patient refusal of blood products because the secondary outcome is pre-determined  
• 
Unable to give formal consent 
• 
Participation in another interventional study where primary outcome includes 
hemoglobin/hematocrit values 
• 
Inability to adhere to treatment regimen for 3 months 
• 
Non-English speaking 
• 
Patients < 18 years old 
 
 

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6 - Methods 
6.1 Treatment - Drug 
Tranexamic acid (TXA) is a hemostatic prescription medication available in the US and 
internationally. TXA is a synthetic reversible competitive inhibitor to the lysine receptor found on 
plasminogen. The binding of this receptor prevents plasmin from binding to and ultimately 
stabilizing the fibrin matrix. It is available in intravenous and oral formulations, however for this 
study we will focus on the oral regimen. Oral TXA has a half-life of up to 10 hours and a 
bioavailability of 50% resulting in the TID dosing regimen chosen for this study.57 TXA is 
currently FDA approved for menorrhagia and short-term prevention following tooth extraction in 
patients with hemophilia. 
6.1.1 Dosage, Admin, Schedule (if applicable) 
Patients in the intervention group will be treated with TXA 650 mg three times per day for 3 
months. This dosing regimen has been studied in patients with heavy menstrual bleeding and 
found to be beneficial with limited side effects.58 
6.1.2 Method of Assignment/Randomization (if applicable) 
Allocation concealment will be used to make sure the individual enrolling the trial subjects into 
the study has no bias towards group assignment. A statistician not directly involved in the 
analysis of the study will use simple randomization to create the two arms of the study (TXA vs 
placebo). Randomization will be carried out by using an online random number generating 
software, excluding the number zero. If an even number is generated, the patient will be placed 
in the TXA treatment arm, and if an odd number is generated the patient will be placed in the 
control (placebo) arm. This process will be repeated until there are 25 patients in each group. 
6.1.3 Packaging/Labelling 
Both TXA and placebo will be packaged in identical bottles with similar labeling so participants 
and the research team will not be affected by bias. 
6.1.4 Storage Conditions 
Both TXA and placebo will be stored at the Ochsner Kenner inpatient pharmacy prior to the start 
of the interventional portion of the study. Participants will pick up their medication from the 
pharmacy upon start of the trial. 
6.2 Assessments 
6.2.1 Safety/Pregnancy-related policy 
Pregnancy is included in the exclusion criteria for this study. If female identifying participants 
were to consent to be part of the study, they will undergo a serum pregnancy testing prior to the 
start of the study 
6.2.2. Adverse Events Definition and Reporting 
Medical Monitoring  
Data will be collected by monthly clinic appointments for the first 3 months. All study patients will 
have direct access to study personnel via a dedicated cellular phone. 
Definition and Classification of Adverse Events  
Adverse events will include medication side effects including nausea, vomiting, diarrhea, rash, 
itching, hypotension, and thromboembolic events. 

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Data Collection for Adverse Events  
Adverse events will be noted in each participant's file. Their responses to the biweekly phone 
calls and monthly clinic visits about new symptoms related to the study medication will be 
reviewed and followed up promptly. 
Adverse events will be grading according to the following scale: 
• 
Mild: An experience that is transient and requires no special treatment or intervention. 
The experience does not generally interfere with usual daily activities. 
• 
Moderate: An experience that is alleviated with simple therapeutic treatments. The 
experience impacts usual daily activities. 
• 
Severe: An experience that require therapeutic intervention. The experience interrupts 
usual daily activities. If hospitalization (or prolongation of hospitalization) is required for 
treatment, it becomes a severe adverse event. 
Each adverse event will be assessed and determine to be related or not related to the study 
medication. 
  
6.2.3 Pharmacokinetics (if applicable) 
The bioavailability of oral TXA is 30-50% of the ingested dose and is not affected by food intake. 
Urinary excretion is the primary means of TXA elimination with 95% of an administered dose 
being processed by the renal system. The half-life of IV TXA was found to be 2 hours with the 
mean terminal half-life as approximately 11 hours 
6.3 Study Procedures 
6.3.1 Informed Consent 
Each patient that meets inclusion/exclusion criteria will be asked to fill out and sign the informed 
consent statement. A copy is attached for reference.  
6.3.2 Screening 
All newly diagnosed Adult patients with intestinal angioectasias following at the LSU Health 
Network GI Clinic who meet screening criteria will be considered for inclusion. Existing patients 
with intestinal angioectasias that are currently not using TXA may also be approached for study 
participation.  
6.3.3 Recruitment, Enrollment and Retention 
The patients who meet screening protocol will be called via telephone or video call and asked to 
participate in the study. Patients will have an initial meeting with research study staff where all 
questions will be answered. Demographics will be obtained, informed consent will be signed 
and patient will be enrolled in study. Once enrolled, baseline lab work as previously stated will 
be collected for the study.  
6.3.4 On Study Visits 
Research study participants will meet for a screening and consent visit. At this time, 
inclusion/exclusion criteria will be review and if meet then they will be consented for the study. 
Following, demographic information will be collected, and baseline lab work will be done prior to 
the start of the interventional portion of the study. 
6.3.5 End of Study and Follow-up 
At the end of the interventional 3-month period of the study, patients will have any exit visit with 
the research staff. At this time, they will fill out a final patient questionnaire (see appendix). 

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Patient will have another follow up interview at the 6-month period (3 months following the end 
of the interventional portion of the study) to conclude the study. 
6.3.6 Removal of subjects 
• 
At the time of consent, participants will be informed that their participation in this 
research study is voluntary and they may discontinue participation without penalty at any 
time. 
• 
Subjects will be withdrawn from the study by the investigator if they are to have serious 
adverse reactions to TXA or to protect the subjects from excessive risk due to lack of 
benefit demonstrated by TXA. 
• 
Data collection prior to participant withdrawal may be retained and used in a manner that 
is consistent with study design and purpose unless participant expresses that their 
information to not used in the study 
6.4 Statistical Method 
6.4.1 Sample Size Considerations 
We based our sample size estimate on assumptions for our primary aim, as this is the most 
important aim for providing information to support future recommendations with regards to TXA 
in patients with intestinal AE. A total of 50 subjects will be enrolled with 1:1 randomization to 
either TXA or placebo. For the primary study endpoint of hemoglobin, we will have 80% power 
to detect an average increase of 25% from baseline to 3 months between TXA and placebo 
groups (α = 0.05). We expect 75% of patients on TXA to have a 2 gm/dl improvement in overall 
hemoglobin while only 25% in placebo group see a 2gm/dl improvement. We expect 75% of 
TXA patients to require zero blood transfusions compared to placebo group requiring 1 blood 
transfusion on average per patient over 3 months. 
6.4.2 Planned Analyses 
We will characterize subjects with regard to baseline and follow up hemoglobin/hematocrit (H/H) 
and other endpoints previously described. We will summarize demographics and other 
predictors of clinical status. Continuous variables will be summarized by mean, standard 
deviation and rage as appropriate. The primary analysis will compare the absolute and percent 
change in hemoglobin with adjustment for baseline in linear regression models. Using 
multivariable logistic regression models adjusting for baseline hemoglobin, we will assess if the 
odds of achieving a clinically relevant improvement in hemoglobin differs by treatment 
assignment. The secondary outcomes will be analyzed similarly using linear regression models 
adjusting for baseline values. 
6.4.3 Handling of Missing Data 
Every effort will be made to secure data and account for all data points. If missing data was to 
occur, it would be noted during the statistical analysis and clearly outlined in the discussion 
portion of future manuscripts.  
 
 

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7 - Trial Administration 
7.1 Ethical Considerations: Informed Consent/Assent and HIPAA Authorization 
Please find the informed consent statement and HIPAA Authorization attached.  
7.2 Subject Confidentiality 
Every precaution will be taken to allow for data confidentiality. Only members of the research 
team will have access to the patient information and subsequent study data. Trial participants 
will be assigned a unique identification number that will be used in future database reporting. All 
hard copies of data and patient records will be kept in a secure location within Dr. Raines's 
office in a locked cabinet. 
7.3 Deviations/Unanticipated Problems 
We will attempt to minimize missing data; however, we have planned for its occurrence. For 
subjects lost to follow-up, we will use all of the information available until the end of follow-up. 
This protocol will continue to follow subjects and perform lab tests even if a subject drops-out 
from the treatment portion of the study. If a subject decides that he/she does not wish to 
continue taking the study drug, the subject will stop the investigational treatment, but will still be 
strongly encouraged to continue to follow-up with the study personnel for all scheduled study 
follow ups (e.g., lab draws and symptom reporting), so that missing data will be minimized. 
7.4 Data Collection 
A majority of data/surveys/questionnaires will be electronically collected and stored on REDCap. 
7.5 Data or Specimen Storage/Security 
All hard copies of data and patient records will be kept in a secure location within Dr. Raines's 
office in a locked cabinet. Communication about study data will be strictly conducted via 
LSUHSC email accounts.  
7.6 Study Discontinuation 
Reasons for discontinuing the study include futility, adverse events (harm), early evidence of 
superiority of one intervention (benefit) and insufficient recruitment (a cut-off at 80% of the 
planned sample size).  
7.7 Study Completion 
Patients will have a follow up interview at the 6-month period (3 months following the end of the 
interventional portion of the study) to conclude the study. Data will be analyzed with a plan for 
publication of a manuscript in a gastroenterology related journal.  
7.8 Conflict of Interest Policy 
There are no conflicts of interest to disclose.  
7.9 Funding Source 
This is an investigator initiated and funded study. There are no external funding sources.  
7.10 Publication Plan 
We plan to use the date from this study to write a manuscript for publication in a respected peer-
reviewed journal in an appropriate time frame. Journal choice will depend on study findings but 
will be relating to the field of gastroenterology 

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