The Role of Tranexamic Acid for the Treatment of Gastrointestinal Bleeding: A Randomized Double-blind Controlled Trial
Phase: NA
Conditions: Gastrointestinal Bleeding
Sponsor: Indonesia University

RESEARCH PROTOCOL 
 
 
 
 
THE ROLE OF TRANEXAMIC ACID FOR THE TREATMENT OF 
GASTROINTESTINAL BLEEDING: A RANDOMIZED DOUBLE-BLIND 
CONTROLLED TRIAL 
 
 
 
 
 
INVESTIGATORS: 
Principal 
: Dr. Ari Fahrial Syam, MD, internist, gastroenterologist 
Others 
 : Prof. Dr. Murdani Abdullah, MD, internist, gastroenterologist 
 
Prof. Marcellus Simadibrata, MD, PhD, internist, gastroenterologist 
 
Rabbinu Rangga Pribadi, MD, internist 
 
 
 
 
 
 
 
FACULTY OF MEDICINE 
UNIVERSITY OF INDONESIA 
Approved April 16th, 2018 

I.  BACKGROUND 
Acute gastrointestinal (GI) bleeding is one of the most common emergency problems and is 
one of the most important causes of mortality and morbidity worldwide. Acute upper GI 
bleeding is the cause of the 60,000 patients who come to the hospital each year in the UK and 
such as 10% causing fatal problems.1,2 Lower GI bleeding causes 15,000 patients to come to 
the hospital each year with a fatal case rate of 15%.3 GI bleeding is common in low- to 
middle-income countries. 
The most common causes of acute upper GI bleeding in developed countries are peptic ulcer 
(40%) and esophageal varices (11%).2 However, in developing countries, the most common 
are esophageal varices that reach 45% of all cases including Indonesia. In Indonesia, based on 
data from Cipto Mangunkusumo Hospital, esophageal varices are the most common cause of 
upper GI bleeding (33.5%), with 49.3% of which are the third-grade esophageal varices.4 
Although with advanced management for two decades, the mortality rate for GI bleeding 
remains high.2,5 Predictor of mortality in patients with upper GI bleeding is re-bleeding, 
which occurs in about 10% of patients with non-variseal bleeding and 25% in patients with 
variseal bleeding.6,7,8 
Tranexamic acid is one of the most frequent treatments given to patients with bleeding cases. 
A summary of clinical trials study suggests that tranexamic acid can reduce the need for 
blood transfusions up to 30% in surgical patients.9 A clinical trial study in patients with 
trauma showed that the administration of tranexamic acid reduced the risk of dying from 
bleeding and all-cause mortality compared with placebo.10 
In cases of GI bleeding, a meta-analysis of clinical trials study showed a decreased risk of 
death and the need for surgical intervention in patients given tranexamic acid. However, most 
of the quality was not good and the results were not significant.11 Tranexamic acid does not 
become therapeutic options in international guidelines nor in national consensus. Thus, the 
effectiveness and safety of tranexamic acid using in GI bleeding remains unclear. In 
Indonesia, the used of tranexamic acid for GI bleeding treatment is limited. Therefore, a 
clinical trial study of tranexamic acid is required to assess the effectiveness and the safety in 
gastrointestinal bleeding treatment. 
 
 

II. OBJECTIVE AND HYPOTHESIS 
A. General Objective 
To determine the effect of tranexamic acid injection in patients with upper and lower GI 
bleeding 
B. Specific Objective 
1. To determine the re-bleeding incidence of patients GI bleeding with tranexamic acid 
injection compared to placebo.  
2. To determine the number of deaths in hospital of patients with GI bleeding with 
injection tranexamic acid compared to placebo after 30 days of randomization. 
3. To determine the need for blood transfusion in of GI bleeding patients with 
tranexamic acid injection compared to placebo.  
4. To determine the average length of stay in intensive care unit of GI bleeding patients 
with tranexamic acid injection compared to placebo.  
5. To determine the need for endoscopic hemostasis of GI bleeding patients with 
tranexamic acid injection compared to placebo.  
6. To determine the quality of life patients with tranexamic acid injection compared to 
placebo using questionnaire SF-36 
7. To determine anxiety level patients with tranexamic acid injection compared to 
placebo using Hamilton Anxiety Rating Scale 
C. Hypothesis 
1. Administration of tranexamic acid injection decreased the number of re-bleeding 
incidence compared to placebo.  
2. Administration of tranexamic acid injection decreased the number of deaths in 
hospital compared to placebo after 30 days of randomization.  
3. Administration of tranexamic acid injection decreased the number of need of blood 
transfusion compared to placebo.  
4. Administration of tranexamic acid injection decreased the length of stay in intensive 
care unit compared to placebo. 

5. Administration of tranexamic acid injection decreased the number of need of 
endoscopic hemostasis compared to placebo.  
6. Administration of tranexamic acid injection improved quality of life patients 
compared to placebo. 
7. Administration of tranexamic acid injection decreased level of patients anxiety 
compared to placebo.  
 
III. METHODS 
A. Study Design  
This study is a randomized double-blind controlled trial. 
B. Time and Place 
This study will be conducted in Cipto Mangunkusumo National Central General Hospital, 
especially in emergency unit, intensive care unit (ICU), high care unit (HCU), intensive 
cardiac care unit (ICCU), inpatient ward, and endoscopy centre. It will be lasted from 
April 2018 – March 2019 
C. Study Population  
1. Targeted population: Patients with acute upper and lower GI bleeding in Indonesia 
2. Sample: Patients with acute upper and lower GI bleeding in Cipto Mangunkusumo 
National Central General Hospital 
3. Inclusion Criteria 
 Adults (minimum age : 18 years old) 
 Patients with acute lower and upper gastrointestinal bleeding (assessed clinically) 
 Patients agreed to participate in the study and signed the informed consent 
4. Exclusion Criteria 
 Allergy with tranexamic acid 
 Patients considered by the clinician cannot be randomized to participate in the 
study 
 Patients with chronic kidney disease stage III - V 

5.  Drop Out Criteria: Patients who have signed the informed consent but wish to stop 
participating before completed the study. 
6. Estimation Sample Size  
 
Formula: 
N1 = N2 =
(𝑍𝛼√2PQ + 𝑍𝛽√P1Q1 + P2Q2)2
(P1 −P2)2
 
Explaination: 
N1=N2= required sample for each control group and intervention group 
Zα is a type I error that is set at 5% so the value of Zα is 1,64 
Zβ is a type II error that is set at 20% so the value of Zβ is 0,84 
P2 = the proportion of primary output in the control group is 25% (0,25) 
P1-P2 = the difference of proportion of minimal exposure considered significant is set at 
0,125 
P1 = P2-0,125 = 0,125 
P = (P1+P2/)2 = 0,1875 
Q1 = 1-P1 = 0,875 
Q2 = 1-P2 = 0,75 
Q = 1-P = 0,8125 
From calculation above, the sample size for each group is about  151,7; added with 10% drop 
out so it will be rounded to 168 samples for each group.  
D. Study Procedure 
1. Randomization 
Patients who have met the inclusion and exclusion criteria will be randomized using a 
computer for admission to an intervention group or a placebo group. Each patient will 
be given a patient code or subject code. 
2. Blinding 

The patient code will be given to the pharmacy to adjust the intervention group. 
Pharmacy will not be given the identity of the patient. Each drug will be given a drug 
code. Pharmacy will give the drug to nurses or doctors who will provide the 
intervention. The interventionist, either the doctor or the nurse, will also be disguised 
about the drug. They only know the drug code to be given on the subject according to 
the patient code. Patients will not be informed of the treatment between placebo or 
tranexamic acid injection. 
3. Intervention  
The tranexamic acid will be administered 4 grams compared to placebo or 0.9% sodium 
chloride (NaCl). Administration of tranexamic acid is 1 gram loading dose followed by 
3 grams maintanance dose for 24 hours. The procedure is given in Table 1. 
Table 1. Procedure Intervention 
Intervention 
Ampul 
Dosage  
Description 
Loading dose 
2 
1 gram 
Given in 100 ml of 0.9% NaCl as much 
as 100 ml intravenously for 10 minutes. 
Maintenance dose 
6 
3 grams 
Given in any isotonic fluid of 1000 ml 
and with  infusion rate of 125 mg / h or 
42 cc / h for 24 hours. 
Additional information: 
 Drugs for clinical trial intervention should not be mixed with blood products for 
transfusion. 
 Should not be added in liquids containing penicillin or mannitol. 
Other routine medications for the management of GI bleeding will be given as usual. The 
injection of tranexamic acid or placebo will be the additional medication. Other drugs used 
for management of GI bleeding will be recorded. 
4. Side Effects 
All side effects that may arise and related to tranexamic acid injection will be reported. 
Serious adverse events besides the outcome adverse events of the study will be reported 
immediately to the principal investigator and will be written within 24 hours. 
5.  Research Variable 

 
Independent variable: tranexamic acid injection 
 
Dependent variable:   
o 
Rebleeding 
(primary 
outcome) 
o 
Number of death within 30 
days post randomisation 
o 
Need for blood transfusion 
o 
Length of stay in intensive care unit 
o 
Need for endoscopic hemostasis  
o 
Quality of life 
o 
Level of anxiety 
F. Research Flow 
 
 
Eligibility of subjects 
Randomized 
Informed consent 
Inclusion and 
exclusion 
criteria 
Tranexamic acid 
group 
Loading Dose for 10 minutes 
Maintenance dose  
for 24 hours 
All other 
treatment
s 
according 
to other 
clinical 
indication
s will be 
still given. 
The 
clinical 
trial drugs 
is an 
additional 
drugs. 
 
Outcomes  
Placebo 
group 

E. Ethics 
This research will seek the approval Ethics Committee of the Faculty of Medicine, 
University of Indonesia. (approval as attachment) 
 
 

IV. STUDY ANALYTICAL PLAN 
Analysis method using IBM SPSS Windows program version 22. Output with categorical 
variables of two groups will be analyzed using chi square test, with alternative Fisher exact 
test. Output with two groups numerical variables will be analyzed using independent t-test, 
with alternative Mann-Whitney test. Output with numerical variables of more than two 
groups will be analyzed using one-way ANOVA, with alternative Kruskal-Wallis test. The 
significance value of each test is 5%, if p <0.05 means that it is statistically significant and if 
p> 0,05 it means not significant. In the analysis, 95% confidence interval (CI) between each 
group should not pass zero so it can be said statistically significant. The 95% confidence 
interval value that passes zero is considered statistically significant. 
 
 
 
 

REFERENCES 
 
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