Clinical trial NCT02578901
Conditions: Thrombocytopenia
Keywords: Thrombocytopenia Tranexamic Acid TXA Chemotherapy induced thrombocytopenia
Sponsor: University of Washington
Start date: 2016-06-01; Completion date: 2020-06-11
Enrollment: 330 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the usefulness of antifibrinolytic therapy with tranexamic acid (TXA) in preventing bleeding in patients who are thrombocytopenic due to primary bone marrow disorders or chemotherapy, immunotherapy and/or radiation therapy.

Detailed description:
The purpose of this study is to conduct a prospective, randomized, blinded, placebo controlled trial to evaluate the usefulness of antifibrinolytic therapy with tranexamic acid in preventing bleeding in patients who are thrombocytopenic due to primary bone marrow disorders or chemotherapy, immunotherapy and/or radiation therapy. The results of this study will change practice by providing evidence as to whether or not TXA is effective and safe treatment when used as an adjunct to platelet transfusion therapy in the thrombocytopenic patient.

Arms: arm 1: IV or PO administered after meeting inclusion/exclusion criteria arm 2: IV Normal Saline or PO placebo pills administered after meeting inclusion/exclusion criteria
Interventions: intervention 1: Tranexamic Acid intervention 2: Placebo
Intervention descriptions: intervention 1: Doses will be given intravenous (IV) or orally (PO) per the discretion of the treating investigator. Doses are administered every 8 hours. When given IV, TXA 1.0 gram will be administered. When given PO, TXA 1.3 grams will be administered intervention 2: Doses will be given intravenous (IV) or orally (PO) per the discretion of the treating investigator. Doses are administered every 8 hours. When given IV, Normal Saline will be administered. When given PO, placebo pills will be administered

Protocol documents:
ICF_002.pdf: 
 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 1 of 14  
 
NCT02578901 
 
A-TREAT Consent Version 3.2 
 
2016-06-24 
 
 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 2 of 14  
 
 
[Insert University] 
Patient or Legally Authorized Representative                                                
Consent to take part in a research study: 
 
A Randomized, Controlled Trial Evaluating the Safety and 
Efficacy of Tranexamic Acid in Patients with Hematologic 
Malignancies and Severe Thrombocytopenia 
A-TREAT: American Trial Using Tranexamic Acid Therapy in 
Thrombocytopenia 
 
 
Principal Investigator: [Insert Name] 
 
 
[Insert contact] 
 
 
[insert phone] 
Subject Contact: 
 
[insert coordinator] 
 
 
[insert contact] 
 
 
[insert phone] 
Emergency number (24 hours): [insert] 
 
 
 
 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 3 of 14  
 
 
Researchers’ statement 
We are asking you to be in a research study.  The purpose of this consent form is to give 
you the information you will need to help you decide whether to be in the study or not.  
Please read the form carefully.  You may ask questions about the purpose of the research, 
what we would ask you to do, the possible risks and benefits, your rights as a volunteer, 
and anything else about the research or this form that is not clear.  When we have 
answered all your questions, you can decide if you want to be in the study or not.  This 
process is called “informed consent.”  We will give you a copy of this form for your 
records.  
If you are a Legally Authorized Representative, the person that you are making medical 
decisions for is called your principal. We are asking you to decide if you want your 
principal to be in this research study or not. In the following form, “you” or “your” refers 
to your principal, and not the decision-maker. If your principal later is able to make 
decisions for (her) himself, (s)he will sign a new consent form. 
We invite you to join this research study. 
We invite you to join this research study because you have, or are expected to have, a 
very low platelet count, called thrombocytopenia, will be at an increased risk of 
bleeding, and are expected to require platelet transfusions. Up to 360 people will join 
this study. 
Research is not the same as standard treatment or medical care. The purpose of a 
research study is to answer scientific questions.  
Why are we doing this study? 
Platelets are small cells in your blood that are important in helping your blood to clot. 
Many patients who are treated for blood disorders with chemotherapy, radiation, or 
bone marrow transplantation have low platelet counts. We have known since the 
1960’s that platelet transfusions help to prevent bleeding in patients with blood 
diseases who are being treated, and have low platelet counts. Earlier studies have 
shown that even when platelet transfusions are given, more than half of patients 
continue to have bleeding.  
Because platelet transfusions alone do not prevent all bleeding, many doctors use 
drugs called antifibrinolytic agents to prevent or treat bleeding in patients with blood 
diseases who have low platelet counts. These drugs, such as Tranexamic Acid, stop 
bleeding by slowing down the breakdown of a clot that forms in an area of bleeding. 
There is evidence to suggest that Tranexamic Acid can be useful in the prevention 
and treatment of bleeding in patients with trauma, or undergoing surgeries such as 
open heart surgery, joint replacement, and liver transplantation. Some small studies 
suggest that antifibrinolytic agents, such as Tranexamic Acid, can also treat and 
prevent bleeding in patients with blood diseases and low platelet counts. These 
studies suggest that antifibrinolytic agents may also decrease the number of platelet 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 4 of 14  
transfusions and red blood cell transfusions needed. However, in order to know how 
well these drugs work in treating bleeding related to low platelet counts in blood 
diseases, a larger study needs to be done comparing patients who are treated with an 
antifibrinolytic agent, Tranexamic Acid, with ones who are not. 
There are 2 groups of participants in this study. We will give different treatments to 
each group, and then compare the results. One group will get the study drug, 
Tranexamic Acid, while the other group will get a placebo. A placebo looks like the 
drug being tested, but contains no active ingredient. Both groups will continue to get 
platelet and red blood cell transfusions when their doctors feel they are necessary. 
This study is a “blinded” study meaning that neither you nor your doctor and study 
team will know if you get the drug or the placebo. The purpose of having a blinded 
study is to make sure that both patients and doctors are able to look at all symptoms 
and events that occur during the study without bias. In the event of an emergency, the 
study team would be able to find out if you were receiving Tranexamic Acid or the 
placebo. This is how we hope to find out if adding Tranexamic Acid to standard care 
is good at preventing bleeding, and decreasing the number of blood and platelet 
transfusions that are required in patients with severe thrombocytopenia. 
If you join this study, you would receive either Tranexamic Acid or a placebo. You 
would not get both. We will use a computer program to decide which treatment you 
will get. If you join this study, you would not be allowed to choose the treatment. 
You would have a 1-in-2 chance of receiving Tranexamic Acid. 
What research tests, procedures, and treatments are done in this study? 
If you decide to join this study, and meet the requirements needed for participation, 
the following tests, procedures and treatments will take place at various time points 
throughout the study: 
• Your Social Statistics (Demographics): We will collect data about your 
birthdate, height, weight, gender, ethnicity, and race.  
• 
 Medical History & Eligibility Exam: You will be asked questions about 
your medical history. This includes conditions you have, medicines you are 
taking, and procedures (including transfusions) that you have undergone 
recently. All of the information that you provide will be confidential. You do 
not have to answer any questions that you do not want to, but then you might 
not be able to take part in this study. We will do an exam and look at your 
records to see if you are eligible to enroll.  Altogether, this will take 30 
minutes of time.    
• 
 Urine & Blood Tests: On the day of randomization, we will ask you for up 
to 6 teaspoons (30ml) of urine, collected in a cup, which will be tested in the 
laboratory. We will collect up to 4 teaspoons (20 ml.) of blood, throughout the 
duration of the study, for research, only if it has not already been collected for 
routine testing. We will need blood tests when you enroll, during pre-
randomization, at randomization, and while you are taking the drug. It takes 
about 5 minutes for a blood draw or urine collection. These samples will be 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 5 of 14  
tested for certain components to determine when you will begin study 
treatment, and to ensure it is safe for you to continue receiving study 
treatment. 
• 
Pregnancy Test: If you are a female who could potentially become pregnant, 
a urine or serum pregnancy test will be performed before you begin study 
treatment; this is done at enrollment and at randomization if it is more than 7 
days after enrollment.  
• 
Bleeding & Clotting Assessments: You will frequently be asked questions 
regarding episodes of bleeding or symptoms of blood clotting (thrombosis) 
that you may have experienced or are experiencing. 
• 
Eye tests: No changes have been reported or noted in eye examinations in  
patients treated with Tranexamic Acid for weeks to months in clinical trials. 
However a small number of visual changes were reported in a study in 
Sweden. To better understand whether or not there are any risks, you will 
have an eye exam when you start taking the drug, weekly until two weeks 
after you finish the drug, and if we asked and you noted any changes in your 
vision. We will ask you to read a standard eye chart, look at an eye grid chart 
and a color vision chart. This will take about 10 minutes of time.  
 
 
What Happens 
Enroll 
Between 
Enroll & 
Randomi 
zation 
Randomiz
ation 
Active Treatment 
w/Study Drug or placebo 
End 
treat-
ment 
 
Follow-Up 
 Up to 30 
days 
If you 
have 
signs of 
bleeding 
Stop 
drug or 
placebo 
 
14- 21 
days after 
stop drug 
or 
placebo 
30 days 
after 
stop & 
120 days 
after 
start 
drug or 
placebo 
Demographic and 
Medical History 
X 
 
 
 
 
 
 
 
Check your medical 
condition 
X 
X 
X 
Xa 
X 
X 
Chart,Call 
& diary 
Call 
Pregnancy Test 
Females 
X 
 
X 
 
 
 
 
 
Urinalysis 
 
 
X 
 
 
 
 
 
Blood tests 
X 
X- twice 
weekly 
X 
Xa 
 
X 
X 
 
EyeTests 
 
 
 
X weekly 
 
 
X-weekly 
to 14 days 
after 
 
Study Drug or 
placebo given   
 
 
 
X 
 
 
 
 
Bleeding Diary  & 
Review 
 
 
X 
X-daily 
X 
X 
X-daily to 
14 days 
after 
 
 
a- Twice weekly for outpatients, daily for inpatients 
 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 6 of 14  
Treatment Procedures 
If you have been screened and are deemed eligible for participation in the study the 
following treatment phases may apply to you: 
• 
Pre-Randomization: This is the time between your initial study 
screening/enrollment visit and the date you are randomized to study treatment 
(either Tranexamic Acid or the placebo).  You will not receive study drug 
during this time, however, your platelet count will be closely monitored so 
that when it reaches less than or equal to 50,000/l you can be assigned to a 
study treatment. 
• 
Randomization to Start of Study Drug: Once you have been assigned to a 
study treatment (randomization), either Tranexamic Acid or placebo, your 
platelet count will again be closely monitored.  Once it reaches less than 
30,000/l the research team will instruct you when and how to begin taking 
study medication. The pharmacy team will receive your hospital ID, birthdate, 
gender, and treatment assignment, so that they can prepare for your treatment. 
After you are randomized, it is possible that if your medical condition 
changes, you may no longer qualify to receive the study drug, and then you 
will not receive it. For example if you have active bleeding or clotting. You 
will still be monitored according to the study schedule, just as if you had 
received the medication. 
• 
Active Study Treatment: Per your randomized study drug assignment, you 
will begin taking 1.3 grams orally or 1 gram IV (in your vein) Tranexamic 
Acid or placebo 3 times a day (every 8 hours), though this dose may be 
decreased depending on your clinical condition.  You will receive the drug 
every day for 30 days, or until your platelet count spontaneously rises above 
50,000/l  without  transfusion support, or two stable platelet counts at least 
48 hours apart are above 30,000/l without transfusion support . You may be 
on this study if you are an outpatient at SCCA, or if you are admitted to the 
University of Washington Medical Center as an inpatient. If you are staying in 
the hospital while participating in the trial, you might receive study drug 
orally or intravenously; this decision will be made by your study doctor and 
care team based upon your ability to swallow and/or absorb medication. The 
doctors and care team might change the drug administration from oral to IV or 
IV to oral. You may continue on this trial after you are discharged from the 
hospital if you can take the medication orally. If you are participating in this 
trial as an outpatient then you will only receive study drug via oral 
administration.  
The only person who will know if you are receiving Tranexamic Acid or the 
placebo will be the pharmacist preparing your drug for dispensing; the study 
team and your doctors will only be told whether you are receiving Tranexamic 
Acid or the placebo in the case of an emergency. 
• 
Daily Study Diary: If you are participating in this trial, and not staying in the 
hospital, you will be asked to complete a daily diary that will help the study 
team keep track of how you are feeling, whether or not you are experiencing 
bleeding (and the type and severity of such episodes), if you are taking the 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 7 of 14  
correct dose of study medication at the right times, and any other symptoms 
that you might report. Your will start filling out your diary when you are 
randomized, whether or not you receive the drug. This should take 10-15 
minutes of time. 
After you have finished taking the study drug (either Tranexamic Acid or a placebo) 
you will enter the follow-up portion of the study: 
• 
 14-21 days after last dose of study drug: Your status will be followed daily 
for 14 days after you stop taking the study drug. If you are in the hospital the 
research staff will perform a daily review of your medical chart. If you are not 
in the hospital then you will be asked to complete a daily study diary (see 
below), and the study staff will review your medical chart. You will be 
contacted in person or by telephone by a member of the research team so that 
they can follow-up on your health status after stopping the drug. 
• 
Daily Study Diary: If you are participating in the follow-up portion of the 
study, and are not staying in the hospital, you will be asked to complete a 
daily diary that will help the study team keep track of whether or not you are 
experiencing any episodes of bleeding (and the type and severity of each 
episode). This should take 10-15 minutes of time. 
• 
30 days after last dose and 120 days after study drug is started: You will 
be contacted in person or by telephone by a member of the research team so 
that they can follow-up on your health status after stopping study drug. This 
should take 10-15 minutes of time. 
Up to 120 days after starting study drug: The research team will continue 
to review your medical chart to follow up on your health status. 
 
                                  Inpatient: daily Research Coordinator visit  
                                               Outpatient: daily diary, twice weekly coordinator visit 
 
 
 
 
 
                                                                                
 
                                                    Records review by Research Coordinator 
 
How long would you stay in this study? 
If you join this study, you would stay in this study for approximately 120 days. 
You would receive Tranexamic Acid or placebo for up to 30 days. After that, you 
would be followed closely for 14 days and then have a quick check-in with the study 
team at 30 days after stopping and 120 days after starting study drug. 
Doctors could take you out of this study at any time. This would happen if: 
• 
They think it is in your best interest not to continue in the study. 
Platelet Count    
<50,000: 
Assigned TXA 
or Placebo 
Platelet Count 
<30,000:  
Start the drug 
Platelet Count 
>30,000 without 
platelet transfusion: 
Stop the drug 
Coordinator 
calls 14-21 days 
& 30 days after 
Stop the drug 
Coordinator 
calls 120 days 
after Start  
the drug 
   Sign  
Consent 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 8 of 14  
• 
You are not able or willing to follow study procedures. 
• 
The whole study is stopped.   
If you withdraw from the study for any reason, previously collected information 
would remain in the study records and would be included in the analysis of results. 
This information could not be removed from the study records.  
What are the side effects (risks)? 
 Tranexamic Acid could cause side effects we do not know about yet. We carefully 
watch everyone in the study for side effects.   
If you join this study, we would tell you if we discover new side effects that could 
affect you.  
Below are possible side effects of Tranexamic Acid. Side effects may be mild or very 
serious. Medicines could be given to help lessen side effects. Many side effects go 
away soon after you stop taking Tranexamic Acid. In some cases, side effects can last 
a long time or never go away. The risk of death is low. 
Likely side effects (greater than 10% of patients) of Tranexamic Acid are: 
• 
Headache 
• 
Abdominal Pain 
• 
Back Pain 
• 
Muscle Pain 
• 
Nasal/Sinus symptoms (including congestion, sinus swelling and pain) 
Less likely side effects (1% to 10% of patients) of Tranexamic Acid are: 
• 
Fatigue 
• 
Anemia 
• 
Joint Pain 
• 
Muscle Cramps/Spasms 
Rare but serious side effects (less than 1% of patients) of Tranexamic Acid are: 
• 
Allergic Reaction: symptoms can include difficulty swallowing or breathing, 
itching, rash, facial flushing, or swelling. This can be life-threatening- Dial 
911, seek immediate medical attention, and call the 24 hour number above.  
• 
Cerebral Thrombosis or Stroke: a blood clot in a blood vessel in your brain. 
Symptoms include severe headache, abnormal vision, weakness of the face or 
limbs and/or seizure. This can be life-threatening- Dial 911, seek immediate 
medical attention, and call the 24 hour number above. 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 9 of 14  
• 
Deep Vein Thrombosis: occurs when a blood clot forms in the veins of the 
body (usually in the legs). Symptoms include swelling and/or pain that can 
often feel like cramping or a general soreness when it begins. This can be 
serious-call the 24 hour number above, and seek immediate medical attention 
by calling your SCCA care team. 
• 
Pulmonary Embolism: occurs when a blood clot travels to your lungs and 
blocks the arteries. Symptoms include shortness of breath (typically occurs 
suddenly and gets worse with exertion), chest pain (may feel like a heart 
attack and become worse when you breathe deeply, cough, eat or bend; often 
it will get worse with exertion and will not go away during rest) and/or cough 
(coughing may produce bloody  sputum). This can be life-threatening- Dial 
911, seek immediate medical attention, and call the 24 hour number above. 
• 
Diarrhea 
• 
Nausea and/or Vomiting 
• 
Renal Cortical Necrosis: kidney damage caused by a lack of blood flow to the 
kidneys characterized by tenderness and/or swelling of the kidneys. 
• 
Seizure 
• 
Ureteral Obstruction: blockage in one, or both, of the tubes going from the 
kidney to the bladder characterized by pain, fever, nausea, vomiting and/or 
infection. This can be life-threatening- call the 24 hour number above and 
seek immediate medical attention by calling your care team. 
• 
Visual Disturbances: For sudden changes or loss of vision (including impaired 
color vision) seek immediate medical attention by calling your SCCA care 
team and the 24 hour number above.    
Interactions with Other Drugs 
Tranexamic Acid affects blood clotting and it may interfere with treatments    
designed to prevent clotting. We have reviewed your medical record and current 
treatments to ensure that you are not receiving treatment that affects clotting or 
other similar treatments that you should not receive while receiving Tranexamic 
Acid. If your physician decides that you require treatment that affects blood 
clotting, we will discontinue your use of the study drug. Estrogens and 
progesterone hormones (used in birth control pills or hormone replacement) are 
sometimes given to patients like yourself to prevent vaginal bleeding. Estrogen 
and progesterone may increase the risk blood clots (thrombosis) and this may also 
be a risk of treatment with Tranexamic Acid. It is possible treatment with both 
Tranexamic Acid and these hormones will lead to an increased risk of blood 
clotting. We will be assessing the development of any adverse blood clots during 
this therapy.                                                                            
Reproductive Risk                                                                                                
      Tranexamic Acid is classified as Category B risk to the fetus in pregnancy. This means that    
      there was no harm to the fetus in animal studies. However there have not been enough studies  
      in humans to know that the drug is completely safe in pregnancy. Therefore you should not 
      enroll in this study if you are pregnant,  and we will ask you to have a pregnancy test if one   


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 10 of 14  
      has not been done when you enroll and before you start the drug. If you thought that you  
      were not pregnant  and this test showed that you were pregnant, this may or may not cause 
      you distress. Males and females should use contraception while taking the study drug, and for  
      30 days after stopping the study drug to prevent pregnancy in themselves or their partner.   
      You should not consent to be enrolled in this study if you are unwilling to use contraception 
      to prevent pregnancy. If you become pregnant while enrolled in this study you should notify 
      your physician and a member of the study team as soon as possible, stop taking the study 
      drug, and you will be referred to qualified medical personnel for follow-up. We will obtain 
      information from your  medical record about the outcome of your pregnancy. You may not 
      join this study if you are breast feeding. If you are pumping breast milk and disposing it (not 
      giving it to your infant), then you may join the study.  
Blood draw risk                                                                                                       
Most blood draws are not done for research, but are done for routine care. Therefore, 
there is little additional risk. Having your blood drawn could cause mild pain, and 
bruising at the site. There is a rare risk of infection. You could feel faint or light 
headed during the procedure. If you have a central venous line, such as a Hickman, 
PICC, or Port-a-Cath, blood draws will be done through this line whenever possible. 
Protecting Privacy as an Individual and the Confidentiality of Personal Information  
Government or university staff sometimes review studies such as this one to make 
sure they are being done safely and legally.  If a review of this study takes place, your 
records may be examined.  The reviewers will protect your privacy.  The study 
records will not be used to put you at legal risk of harm. Reviewers include: 
• 
Researchers involved with this study. 
• 
Institutional Review Boards (IRB), including the University of Washington  
IRB. An IRB is a group that reviews the study to protect the rights and welfare 
of research participants. 
• 
Staff at [name] 
• 
US National Institutes of Health, National Heart Lung and Blood Institute,, 
Office for Human Research Protections, Food and Drug Administration, and 
other regulatory agencies as required. 
• 
Your participation in this study will be noted in your [name] medical record. 
• 
An appointed board, called a Data Safety Monitoring Board (DSMB), will be 
following the information on safety for Tranexamic Acid in this study. 
To protect your privacy, we assign you a unique study ID number. Only a few study 
staff members know the link between your name and your study ID number. We 
make every effort to safeguard your private information by storing paperwork in 
locked files, and using computer password protection. There is limited access to both 
paper and computer files. 
We will do our best to keep personal information confidential. But we cannot 
guarantee total confidentiality.  Personal information may be given out if required by 
law.  For example, workplace safety rules may require health workers to contact you 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 11 of 14  
about lab tests. Or a court may order study information to be disclosed. Such cases 
are rare. 
We will not use personal information in any reports about this study, such as journal 
articles or presentations at scientific meetings. 
What are the benefits? 
We do not know if Tranexamic Acid would help prevent bleeding or the need for 
transfusions in patients with low platelet counts.  It is possible that if you receive 
Tranexamic Acid you will experience less bleeding and will require fewer platelet 
and red blood cell transfusions. We hope the information we learn will help treating 
people with thrombocytopenia in the future. 
You have other choices besides this study. 
You do not have to join this study. You are free to say “yes” or “no”. Your regular 
medical care would not change if you decide to say “no”.  
You have other choices for treatment.  Each of these choices has risks and benefits. 
You should talk to your doctor or healthcare provider about these choices.   
Other choices may include: 
• Standard Treatment, which may/may not include TXA or another antifibrinolytic 
agent 
• Another Research Study 
• No Treatment  
Enrollment in this study may exclude you from other research studies.  
Would we pay you if you join this study? 
There is no payment for being in this study. 
Would you have extra costs if you join this study?  
If you join this study, you or your insurance company would have to pay for the costs 
of standard treatment in this study such as: 
• 
Cost of platelet transfusions and the people and equipment used to give you 
the platelet transfusion 
• 
Cost of standard lab tests that may be done to monitor your health while you 
are receiving study treatment 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 12 of 14  
• 
Cost of people and equipment used to give you the study drug (if you receive 
the drug intravenously) 
You would not be billed for: 
• 
Study Medication (Tranexamic Acid or placebo) 
• 
Pregnancy test (females of childbearing potential) 
• 
Laboratory tests which are only done for research purposes related to this 
study 
What if you get sick or hurt after you join this study? 
 
 
For a life threatening problem, call 911 right away or seek help immediately.  Contact 
your study doctor when the medical emergency is over or as soon as you can.  
It is important that you promptly tell the researchers if you believe that you have been 
injured because of taking part in this study. You can tell Dr [Insert name] in person 
or call her at [Insert number] or the 24 hour number listed at the top of this form. 
She will treat you or refer you for treatment.   
The costs of the treatment may be billed to you or your health insurance just like 
other medical costs, or it may be covered by the [name] discretionary Human 
Subjects Assistance Program (HSAP), depending on a number of factors.  The 
researcher may request HSAP coverage by following established procedures. If you 
wish to request HSAP coverage yourself, contact the researcher or the [name]Human 
Subjects Division at [phone]. Ask the researcher if you would like information about 
the limits and conditions of the HSAP. The [name] does not normally provide any 
other form of compensation for injury. However, the law may allow you to seek 
payment for injury-related expenses if they are caused by malpractice or the fault of 
the researchers. You do not waive any right to seek payment by signing this consent 
form.                                                                                                                                 
You would not lose any legal right to seek payment for treatment if you sign this 
form. 
You or your insurer will be billed for treatment of problems or complications that 
result from your condition or from standard clinical care. 
Your rights 
• 
You do not have to join this study. You are free to say “yes” or “no”.  
• 
If you get sick or hurt in this study, you do not lose any of your legal rights to 
seek payment by signing this form. 
• 
During the study, we might learn new information that you need to know. For 
example, some information may affect your health or well-being. Other 
information might make you change your mind about being in this study. If 
we learn these kinds of information, we would tell you. 
• 
If you join this study, you would not have to stay in it. You could stop at any 
time (even before you start). Your regular medical care would not change. 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 13 of 14  
You would have no penalty for stopping, but it would be better not to join the 
study if you think that you would change your mind later.   
• 
If you decide to drop out, we would want you to tell the study doctor. The 
doctor could tell you about the effects of stopping Tranexamic Acid. You and 
the doctor could talk about the follow-up care and testing that would help the 
most. Before you leave the study, the doctor might ask you to continue in the 
follow-up part of the study 
• 
A description of this clinical trial will be available on 
http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will 
not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time.  
Your responsibilities 
If you join this study, you would have some responsibilities.  
• 
Follow the schedule of study visits and procedures. 
• 
Takes study medications as directed.  
• 
If an outpatient participant, fill out the daily diary. 
• 
Tell us about side effects. 
Source of funding 
This study is funded by a grant from the National Heart Lung and Blood Institute 
/National Institutes of Health.   
For more information 
If you have questions or concerns about this study, you could talk to your doctor 
anytime. Other people you could talk to are listed below: 
 
If you have questions about: 
 
Call: 
This study (including complaints 
and requests for information) 
 
[phone] [name] Principal Investigator 
[phone] [name], Clinical Research Nurse 
If you get sick or hurt in this study 
 
[phone][name], Principal Investigator 
Your rights as a research participant 
 
[phone] Human Subjects Division 
Your bills and health insurance 
coverage 
 
[phone] Patient Financial Services,  
Emergency number [insert] 


 
A-TREAT Consent Version 3.2 / Version Date: 24June16 / Page 14 of 14  
Signatures 
Subject’s statement 
This study has been explained to me.  I volunteer to take part in this research.  I have had 
a chance to ask questions.  If I have questions later about the research, or if I have been 
harmed by participating in this study, I can contact one of the researchers listed on the 
first page of this consent form.  If I have questions about my rights as a research subject, I 
can call the Human Subjects Division at [phone].  I give permission to the researchers to 
use my medical records as described in this consent form.  I will receive a copy of this 
consent form. 
 
 
Printed name of subject 
Signature of subject 
Date 
 
 
When subject is not able to provide informed consent: 
 
Printed name of representative 
Signature of representative 
Date 
 
 
Relationship of representative to subject 
Copies to: 
Researcher 
 
 
Subject 
 
 
Subject’s Medical Record (if applicable) 
 
Researcher’s statement 
I have discussed the research study, including procedures and risks, with the person 
signing above. A copy of the signed consent form will be given to the participant.  
 
 
___________________________________ 
Printed Name of Person Conducting the  
Informed Consent Discussion 
 
 
___________________________________  
 
________________ 
Signature of Person Conducting the  
 
 
Date 
Informed Consent Discussion 

Prot_000.pdf: 
Page 1 of 63 
 
NCT02578901 
 
A-TREAT Protocol Version 3.5 
 
2018-05-07 
 
 


Page 2 of 63 
 
                                                                                               
 
 
 
American Trial Using Tranexamic 
Acid in Thrombocytopenia  
(A-TREAT) 
 
 
A randomized, controlled trial evaluating the safety 
and efficacy of tranexamic acid in patients with 
hematologic malignancies and severe 
thrombocytopenia 
 
 
 
 
 
 
Version 2.0 
23 September 2015    FDA IND Initial Submission 
Version 2.1 
16 October 2015 
   FDA IND Amendment 1 
Version 2.2 
21 October 2015 
   FDA IND Amendment 2 
 
 
 
FDA IND 128032 approval 2015-10-23 
Version 2.3 
6 January 2016 
Version 2.4 
3 February 2016  
   FDA IND Amendment 3 
Version 2.5 
7 March 2016   
Version 3.0 
9 May 2016 
 
   DSMB Approved Version 
Version 3.1 
13 June 2016  
   FDA IND Amendment 4 
Version 3.2 
20 April 2017    
   FDA IND Amendment 5 
Version 3.3 
26 June 2017  
   FDA IND Amendment 6 
Version 3.4  
12 December 2017    FDA IND Amendment 7 
Version 3.5 
07 May 2018  
   FDA IND Amendment 8 
 
 
 
 
 


Page 3 of 63 
 
Approved by: 
 
 
 
 
Name:     
 
 
Role: 
Principal Investigator(s) 
Signature: 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Authorized by: 
 
 
 
Name:     
 
 
Role: 
DCC Principal Investigator 
Signature: 
 
 
 
Date: 
 
 
 
 


Page 4 of 63 
 
GENERAL INFORMATION 
 
This document provides in depth background information for the A-TREAT trial. It also serves 
as a guidance document for the proper identification, treatment and maintenance of A-TREAT 
trial patients. This protocol should not be used as a guide for the treatment of patients not 
enrolled in the A-TREAT clinical trial.  Every care was taken in its drafting, but corrections or 
amendments may be necessary; these will be circulated to registered investigators in the trial, 
but centers entering patients for the first time are advised to contact the Data Coordinating 
Center (DCC) to confirm they have the most up to date version. Clinical problems relating to 
this trial should be referred to the relevant Principal Investigator.  
 
Contacts 
If you have any queries regarding this protocol, or the general conduct of the trial, please 
contact one of the following people: 
 
Principal Investigators 
• 
Terry Gernsheimer, MD (University of Washington, Seattle Cancer Care Alliance, Fred 
Hutchinson Cancer Research Center) 
• 
Susanne May, PhD (University of Washington) 
• 
Darrell Triulzi, MD (University of Pittsburgh) 
• 
Nigel Key, MD (University of North Carolina) 
• 
Sherrill Slichter, MD (Bloodworks Northwest) 
 
Trial email: help@A-TREAT.org 
 
Compliance Statement 
The study will be conducted according to the protocol and in compliance with International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP), Belmont Principles, and 
other applicable regulatory requirements. All identified study personnel will be trained to 
perform their roles and will carry out their responsibilities in accordance with ICH GCP 
guideline and clinic site SOPs. 
 
Funding Sources: National Heart, Lung and Blood Institute of the National Institute of Health 
Data Coordinating Center: Susanne May, PhD (University of Washington) 
 
Clinical Coordinating Center: University of Washington 
 
Lead Trial Statistician(s): Susanne May, PhD 
 
Trial Sites IRBs of Record: 
• 
University of Washington IRB 
• 
University of Pittsburgh IRB 
• 
University of North Carolina IRB 
 


Page 5 of 63 
 
PROTOCOL SYNOPSIS 
Despite major advances in optimizing platelet transfusion therapy, bleeding remains a problem 
in patients with thrombocytopenia due to chemotherapy induced marrow aplasia and 
hematopoietic stem cell disorders.1  Baseline level of bleeding does not appear to be affected 
by increasing the platelet transfusion threshold2,3 and does not appear to be dependent on the 
platelet count when it is above 5,000/l.  In the PLADO (Platelet Dose) Trial of 1272 patients, 
WHO grade 2 bleeding occurred in approximately 70% of all subjects regardless of platelet 
dose transfused prophylactically for patients with platelet counts of ≤10,000/µL4. Withholding 
transfusion may lead to serious and fatal bleeding5. In a 600 patient trial of therapeutic vs. 
prophylactic platelet transfusion (TOPPS)6, bleeding remained a common event. Maintenance 
of a safe platelet count may be difficult due to shortened platelet survival in severely 
thrombocytopenic and critically ill patients.7 Patients who are refractory to platelet transfusion 
may require expensive and difficult to obtain matched platelets to prevent serious bleeding. 
Maintenance of the platelet count above a prescribed trigger in outpatients can require daily 
laboratory work and frequent visits to the clinic for transfusions. 
 
Epsilon Aminocaproic Acid (EACA) and Tranexamic Acid (TXA) are inhibitors of fibrinolysis 
that can be given either intravenously or orally. Inhibitors of fibrinolysis have been used for 
many years to prevent and treat bleeding due to fibrinolysis intra- and postoperatively8 and 
have been shown to be useful in in patients with platelet function and coagulation defects such 
as hemophilia9. Reports of the use of these agents to prevent or treat bleeding in 
thrombocytopenic patients have been encouraging10,11,12 and suggest that in many patients 
bleeding can be prevented or stopped. Such anecdotal, retrospective single center reports 
lead many physicians to prescribe EACA or TXA to prevent or treat bleeding in 
thrombocytopenic patients refractory to platelet transfusions; however, lack of evidence of 
efficacy and safety prevent its use from becoming standard of care.  
 
The results of this study will change practice by providing evidence as to whether or not the 
fibrinolytic agent TXA is an effective and safe treatment when used as an adjunct to platelet 
transfusion therapy to prevent bleeding in patients with hypoproliferative thrombocytopenia. A 
safe treatment to decrease bleeding and transfusion requirements in these patients would 
greatly improve patient outcomes and quality of life, and have a major health economic 
impact.  
 
Objectives 
The purpose of this study is to compare the incidences of bleeding and thrombosis, and the 
transfusion requirements in patients randomized to receive TXA or a placebo for 
hypoproliferative thrombocytopenia secondary to primary marrow disorders, chemotherapy, 
immunotherapy, radiation and/or hematopoietic stem cell transplant.  
 
Study Design 
Double blind, randomized, placebo controlled trial.  Subjects will be screened for eligibility by 
trained study staff after being identified by primary providers as likely to have platelet counts of 
≤10,000/l for ≥5 days.  Bleeding and thrombotic assessments will be performed daily on 
inpatient subjects via chart review, subject interview and physical examination. Outpatient 
subjects will maintain a daily diary and be seen at least weekly in clinic. 
 
 
 
 
 
 
 
 


Page 6 of 63 
 
Table of Contents 
1. Summary ............................................................................................................................ 8 
 
Figure 1: Trial Entry, Randomization, Treatment and Monitoring Flow Diagram ................. 12 
2. Background ..................................................................................................................... 12 
3. Endpoints ......................................................................................................................... 13 
3.1: Primary Endpoint ................................................................................................. 13 
3.2: Secondary Endpoints ............................................................................................ 13 
3.3: Supportive and Exploratory Efficacy Endpoints ........................................................ 13 
3.4: Safety Endpoints .................................................................................................. 14 
3.5: Sub-group Analyses ............................................................................................. 14 
4. Target Patient Populations ............................................................................................. 14 
4.1: Inclusion Criteria .................................................................................................. 14 
4.2: Exclusion Criteria ........................................................................................................ 14 
5. Trial Enrollment ............................................................................................................... 15 
5.1: Screening and Recruitment ................................................................................... 15 
5.2: Stratification and Randomization ................................................................................. 15 
5.3: Enrollment Period ........................................................................................................ 16 
6. Interventions .................................................................................................................... 16 
6.1: Study Drug .......................................................................................................... 16 
6.2: Transfusion Practice ............................................................................................. 16 
6.3: Stopping of Study Drug ............................................................................................... 17 
6.4: Temporary Discontinuation of Study Drug .............................................................. 17 
6.5: Dose Adjustments for Renal Insufficiency ............................................................... 17 
6.6: Other Treatment Considerations .................................................................................. 18 
7. Study Drug Information ................................................................................................... 18 
7.1: Masking of Study Drug ......................................................................................... 18 
7.2: Administration of Study Drug ....................................................................................... 18 
8. Study Visit Procedures and Schedule ............................................................................ 19 
8.1: Day of Enrollment ................................................................................................ 19 
8.2: Days Between Enrollment and Randomization ............................................................ 20 
8.3: Day of Randomization .......................................................................................... 20 
8.4: Days Between Randomization and Activation .......................................................... 21 
8.5: Activation ............................................................................................................ 22 
8.6: End of Treatment ......................................................................................................... 26 
8.7: EOT to D14 post Discontinuation of Study Drug ...................................................... 26 
8.8: Follow Up ............................................................................................................ 26 
Table 2: Study Assessments Calendar ............................................................................... 27 
9. Adverse Event Reporting ................................................................................................ 29 
Figure 3: Adverse Event Definitions .............................................................................. 29 
9.1: Expected Adverse Events ............................................................................................ 30 
9.2: Pregnancy and Nursing ............................................................................................... 31 
10. Hemostatic/Bleeding Assessments ............................................................................. 31 
10.1: Inpatient Subjects .............................................................................................. 32 
10.2: Outpatient Subjects ................................................................................................... 32 
11. Safety Assessments ...................................................................................................... 32 
11.1: Thrombotic Assessments .................................................................................... 32 
11.2: Ocular Assessments .................................................................................................. 33 
12. Loss to Follow Up .......................................................................................................... 33 
12.1: Death ................................................................................................................ 33 
12.2: Withdrawals ............................................................................................................... 33 
13. End of Study .................................................................................................................. 34 


Page 7 of 63 
 
14. Statistical Considerations ............................................................................................. 34 
14.1: Rationale and Objectives .................................................................................... 34 
14.2: Randomization .......................................................................................................... 34 
14.3: Analysis Populations ........................................................................................... 34 
14.4: Competing Risks ....................................................................................................... 35 
14.5: Statistical Analysis Models ........................................................................................ 36 
14.6: Sample Size and Precision of Statistical Inference ................................................. 37 
14.7: Feasibility of Recruitment .......................................................................................... 38 
15. Trial Monitoring ............................................................................................................. 39 
15.1: Clinical Site Monitoring ....................................................................................... 39 
15.2: Direct Access to Data ................................................................................................ 39 
15.3: Audits and Inspections ....................................................................................... 39 
15.4: Source Data Verification ............................................................................................ 39 
15.5: Quality Assurance and Quality Control of Data .......................................................... 39 
15.6: Confidentiality .................................................................................................... 40 
15.7: Ethical Conduct of the Study ..................................................................................... 40 
16. Records and Reports .................................................................................................... 40 
16.1: Case Report Forms ............................................................................................. 40 
16.2: Record Retention....................................................................................................... 41 
16.3: Data Management ..................................................................................................... 41 
Table 4: Definitions of Causality/Attribution ........................................................................ 42 
Figure 5: Investigator Assessment of Adverse Events Flowchart ........................................ 43 
17. Institutional Review Board (IRB) .................................................................................. 44 
18. Trial Committees ........................................................................................................... 44 
18.1: Trial Steering Committee (TSC) ........................................................................... 44 
18.2: Data and Safety Monitoring Board (DSMB) ............................................................... 44 
Appendix 1: Tranexamic Acid and Epsilon Aminocaproic Acid Studies ......................... 45 
Appendix 2: WHO Grading System .................................................................................... 54 
Appendix 3: A-TREAT Telephone Script: Long-Term Follow-Up ..................................... 59 
Citations: …………………………………………………………………………………………..60 
  
 
 
 
 
 
 


Page 8 of 63 
 
ABBREVIATIONS AND GLOSSARY 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AR 
Adverse Reaction 
CF 
Consent Form 
CRF 
Case Report Form 
CTCAE 
Common Toxicology Criteria for Adverse Events 
D5W 
5% Dextrose in Water 
DCC 
Data Coordinating Center 
DCF 
Data Clarification Form 
DDAVP 
Desmopressin Acetate 
DIC 
Disseminated Intravascular Coagulation 
DSMB 
Data and Safety Monitoring Board 
EACA 
Epsilon Aminocaproic Acid 
DMS 
Data Management System 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HR 
Hour 
HIV 
Human Immunodeficiency Virus 
HTLV 
Human T-lymphotropic Virus 
HUS 
Hemolytic Uremic Syndrome 
IB 
Investigator’s Brochure 
IRB 
Institutional Review Board 
ISRCTN 
International Standard Randomized Controlled Trial Number 
ITP 
Immune Thrombocytopenia 
IV 
Intravenous 
LAR 
Legally Authorized Representative 
NHLBI 
National Heart, Lung and Blood Institute 
PCC 
Prothrombin Complex Concentrate 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
PO 
Oral 
Q 
Every 
RCT 
Randomized Controlled Trial 
RN 
Registered Nurse 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SOC 
Standard of Care 
SCT 
Stem Cell Transplant 
SOP 
Standard Operating Procedure 
SOS 
Sinusoidal Obstructive Syndrome 
SSA 
Site Specific Assessment 
Study Drug Tranexamic Acid or matching placebo 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TSC 
Trial Steering Committee 
TTP 
Thrombotic Thrombocytopenic Purpura 
TXA 
Tranexamic Acid 
UAR 
Unexpected Adverse Reaction 
VOD 
Veno-occlusive Disease 
VTE 
Venous Thromboembolism 
WBC 
White Blood Cell 
WBD 
Whole Blood Derived 
WHO 
World Health Organization 


Page 9 of 63 
 
1. SUMMARY 
Name of Sponsors: 
National Heart, Lung and Blood Institute, National Institutes of Health 
 
Name of Investigational Products: 
Tranexamic Acid (TXA) 
 
Name of Active Ingredient:  
Tranexamic Acid 
 
Title of Study: 
A-TREAT: American Trial Using Tranexamic Acid in Thrombocytopenia 
 
Study Centers:  
University of Washington (UW) 
University of North Carolina (UNC)  
University of Pittsburgh (UP) 
 
Principal Investigators:  
Terry Gernsheimer, MD (University of Washington) 
Sherrill J. Slichter, MD (Bloodworks Northwest) 
Nigel Key, MD (University of North Carolina) 
Darrell Triulzi, MD (University of Pittsburgh) 
Susanne May, PhD (University of Washington) 
 
Studied Period (4 years): 
Estimated date first subject enrolled: Q1 2016 
Estimated date last subject completed: Q4 2019 
 
Phase of development: Phase 3 
 
Objectives:  
The purpose of this study is to conduct a prospective, randomized, blinded, placebo controlled trial to 
evaluate the usefulness of antifibrinolytic therapy with tranexamic acid in preventing bleeding in 
patients who are thrombocytopenic due to primary bone marrow disorders or chemotherapy, 
immunotherapy, and/or radiation therapy. The results of this study will change practice by providing 
evidence as to whether or not TXA is effective and safe treatment when used as an adjunct to platelet 
transfusion therapy in the thrombocytopenic patient. 
Primary Objectives: 
• 
Assess whether TXA reduces bleeding in patients with thrombocytopenia due to aplasia, 
chemotherapy, stem cell transplantation for hematologic disorders. 
• 
Obtain data on the safety of TXA in thrombocytopenic patients. 
• 
Assess whether TXA therapy can reduce the number of prophylactic platelet transfusions in 
thrombocytopenic patients undergoing treatment with chemotherapy or stem cell 
transplantation. 
Secondary Objectives: 
• 
To examine AEs, and clinical laboratory parameters related to treatment with TXA. 
• 
To examine platelet efficacy endpoints in vivo including spontaneous bleeding rates, platelet 
count increments (Cl), and corrected count increments (CCI). 
Methodology:  
Randomized, double-blind, placebo controlled, superiority trial enrolling thrombocytopenic adult 
patients with aplasia or hematologic malignancies receiving intensive chemotherapy, radiation, and/or 


Page 10 of 63 
 
hematopoietic stem cell transplantation. Subjects will be randomized in a 1:1 ratio to either the 
antifibrinolytic TXA or placebo (oral or intravenous [IV]) treatment arms when their platelet count falls 
below 50,000/l, and is expected by their primary provider to have platelet counts of ≤10,000/l for ≥5 
days.  When a randomized subject’s platelet count falls to < 30,000/l, the subject will be activated to 
begin their assigned study drug. Treatment with the study drug will continue until the platelet count is ≥ 
30,000/l for 46 hours without platelet transfusion support, until a maximum of 30 days after treatment 
activation, or until the subject meets other protocol specified safety criteria for stopping study drug, 
whichever comes first.  Data collection for primary efficacy endpoints will continue for 30 days after 
activation of study drug, with additional long term follow-up at 14 and 30 days and 120 days post 
activation of study drug. A bleeding assessment form will be completed daily by a trained member of 
the research staff for each day a subject is hospitalized. Outpatient subjects (including inpatient 
subjects that are discharged home prior to completion of the trial follow-up period) will complete a daily 
Self-Assessment Bleeding Diary and a trained member of the research staff will review the subject’s 
diary, records of all clinic visits for transfusions, bleeding and adverse events at least once a week.  
Adverse event data will be collected for 30 days after receipt of last dose of study drug. 
 
Estimated Number of Subjects Screened: Approximately 2,500 subjects screened 
 
Maximum Number of Subjects Enrolled: Approximately 360 subjects will be enrolled at 3 U.S. study 
sites to obtain 330 activated subjects. 
 
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Inclusion criteria (all must be met): 
• 
Must be ≥ 18 years of age 
• 
Confirmed diagnosis of a hematologic malignancy or aplasia 
• 
Undergoing or planned chemotherapy, immunotherapy, or hematopoietic stem cell 
transplantation 
• 
Anticipated to have hypoproliferative thrombocytopenia resulting in a platelet count of ≤ 
10,000/l for ≥ 5 days  
• 
Able to provide informed consent and comply with treatment and monitoring, or having a 
Legally Authorized Representative (LAR) 
 
Exclusion criteria (none can be present): 
• 
Diagnosis of acute promyelocytic leukemia undergoing induction chemotherapy 
• 
History of ITP, TTP or HUS 
• 
Subjects receiving L-asparaginase as part of their current cycle of treatment  
• 
Subjects with a past history or current diagnosis of arterial or venous thromboembolic disease 
including acute coronary syndrome, peripheral vascular disease and retinal arterial or venous 
thrombosis (except when a prior history of central line thrombosis has resolved) 
• 
Subjects with a diagnosis/previous history of sinusoidal obstruction syndrome (also called 
veno-occlusive disease) 
• 
Subjects receiving any pro-coagulant agents (e.g. DDAVP, recombinant Factor VIIa or 
Prothrombin Complex Concentrates (PCC) and/or an antifibrinolytic agent within 48 hours of 
enrollment, or with known hypercoagulable state 
• 
Known inherited or acquired bleeding disorder including, but not limited to: 
o 
Acquired storage pool deficiency 
o 
Paraproteinemia with platelet inhibition 
• 
Known inherited or acquired prothrombotic disorders, including antiphospholipid syndrome.  
Those with lupus anticoagulant or positive antiphospholipid serology without thrombosis are 
not excluded.  
• 
Subjects receiving anticoagulant therapy or anti-platelet therapy (except  when  receiving 
prophylactic anticoagulant or low dose aspirin therapy for prophylaxis only with a plan to 
discontinue when the platelet count falls below 50,000) 
• 
Patients with DIC according to the patient’s physician 
• 
Subjects with WHO Grade 2 bleeding or greater within 48 hours prior to activation 
• 
Subjects requiring a platelet transfusion threshold > 10,000/l at time of randomization 
• 
Subjects with anuria (defined as urine output < 10mls/hr over 24 hours)  
• 
Subjects on dialysis 
• 
Subjects with creatinine ≥5.7mg/dL 


Page 11 of 63 
 
• 
Subjects who are pregnant or nursing or unwilling to use contraception during and for 30 days 
after taking the study drug (both males and females)   
• 
Subjects enrolled in other trials involving platelet transfusions, anti-fibrinolytics, platelet growth 
factors or other pro-coagulant agents.  
• 
Known allergy to tranexamic acid  
• 
Having been previously randomized in this study at any stage of their treatment 
• 
Subjects who are unwilling to accept blood or blood component transfusions 
 
Drug Dosage, Schedule, and Mode of Administration: 
Inpatient subjects will receive TXA or placebo via oral (PO) or intravenous (IV) administration- the 
decision concerning route of administration will be left to the discretion and documentation of the 
treating investigator or treating physician. Outpatient subjects will receive TXA or placebo via oral 
administration. 
Dosing Schedule:   TXA, 1.0g IV or 1.3g PO every 8 hours versus a placebo equivalent every 8 hours 
(oral study drug supplied by a contracted investigational pharmaceutical company). 
 
Duration of Treatment:  
Subjects will receive study drug for up to 30 days per methodology referenced above and study specific 
follow-up will occur at 14 (+ 7 day window), 30 days post discontinuation of study drug and 120  days 
post activation of study drug.  Adverse events will be followed for 30 days after the last dose of study 
drug is taken.  
 
Criteria for Evaluation: 
Primary Efficacy Endpoints: 
• 
Proportion of patients with bleeding of WHO grade 2 or above, over the study period of 30 days 
after activation of study drug. 
Secondary Efficacy Endpoint: 
• 
Number of platelet transfusions per patient during the first 30 days post activation of study drug 
• 
Number of days alive and without WHO grade 2 bleeding or greater during the first 30 days 
after activation of study drug 
Supportive and Exploratory Efficacy Endpoints: 
Alternative measures of bleeding 
• 
Number of days with bleeding/thrombocytopenia during the first 30 days post activation of 
study drug 
• 
Time from activation of study drug to first episode of bleeding of WHO grade 2 or greater or 
death, whichever comes first within the first 30 days post activation of study drug 
• 
Highest grade of bleeding a patient experiences during the first 30 days post activation of study 
drug 
• 
Death ascribed to bleeding during the first 30 days post activation of study drug 
       
Alternative measures of transfusion frequency 
• 
Number of platelet transfusions/patient by thrombocytopenic day during the first 30 days post 
activation of study drug 
• 
Number of red cell transfusions/patient and by thrombocytopenic day during the first 30 days 
post activation of study drug 
• 
Proportion of patients surviving at least 30 days post activation of study drug without a platelet 
transfusion  
• 
Proportion of patients surviving at least 30 days post activation of study drug without a red cell 
transfusion 
• 
Number of patients with platelet count nadir > 10,000/l over the study period of 30 days from 
activation of study drug 
Safety Endpoints: 
• 
Incidence of thrombotic events from first day on study drug up to and including 120 days after 
activation of study drug. 
• 
Incidence of veno-occlusive Disease (VOD; sinusoidal obstructive syndrome, SOS) from the 
first day on study drug up to and including 30 days of last receipt of study drug 
• 
All-cause mortality during the first 30 days and the first 120 days post activation of study drug 
• 
Death ascribed to thrombosis during the first 120 days post activation of study drug 


Page 12 of 63 
 
• 
Incidence of adverse events (AEs) and serious adverse events (SAEs) categorized by CTCAE 
v4.0 from the first day on study drug up to and including 30 days after the last dose of study 
drug is received 
Sub-Group Analysis: 
• 
WHO grade 2 or above bleeding will be assessed separately among patients who did and did 
not have bleeding at randomization, as well as within each of the disease groups of allogeneic 
transplant, autologous transplant, and leukemia. 
 
Statistical Methods and Sample Size:  
The odds of bleeding at WHO grade 2 level or above will be analyzed in a logistic regression model 
adjusting for treatment arm,  clinical site as a factored variable, and disease group (allogeneic 
transplant, autologous transplant, or leukemia) as a factored variable. The test statistic will be based on 
the score statistic for the treatment arm parameter from the logistic regression model with adjustment 
for multiply imputed missing data.  
 
Calculation of sample size and statistical power were based on the chi-squared test of association, 
which is equivalent to the score test from simple logistic regression. Based on 1:1 randomization, a 
one-sided level of significance 0.025, a design alternative hypothesis of 30% relative reduction in 
bleeding rates (57% on the placebo arm and 40% on TXA), a sample size of 330 subjects (165 TXA, 
165 placebo) will provide 88% statistical power to declare statistical significance on the primary 
endpoint. This sample size will provide 74.8% statistical power to detect a 25% relative reduction in 
bleeding rates (57% vs 42.75%). With the planned sample size and a placebo bleeding rate of 57%, an 
observed absolute decrease in WHO grade 2 or above bleeding of 10.6% (so 57% on placebo, 46.4% 
on TXA) would be judged statistically significant.  
 
 
 
  


Page 13 of 63 
 
 
 
2. BACKGROUND 
Despite major advances in optimizing platelet transfusion therapy, bleeding remains a problem 
in patients with thrombocytopenia due to chemotherapy induced marrow aplasia and primary 
hematopoietic stem cell disorders1.  Baseline level of bleeding does not appear to be affected 
by increasing the platelet transfusion threshold2,3, and does not appear to be dependent on 
the platelet count when it is above 5,000/l.  In the PLADO (Platelet Dose) Trial of 1272 
patients, WHO grade 2 bleeding occurred in approximately 70% of all subjects regardless of 
platelet dose transfused prophylactically for patients with platelet counts of ≤10,000/µL4. 
Similarly in a 600 patient trial of therapeutic vs. prophylactic platelet transfusion (TOPPS)6, 


Page 14 of 63 
 
bleeding remained a common event. Withholding transfusion may lead to serious and fatal 
bleeding5.  
 
Maintenance of the platelet count in a safe range may be difficult due to severe shortening of 
the platelet survival in severely thrombocytopenic and critically ill patients7 and patients who 
are refractory to platelet transfusion therapy may require specially matched platelets that are 
difficult and expensive to obtain. In the outpatient setting, maintenance of the platelet count 
above a prescribed trigger may require almost daily laboratory work and frequent transfusions.  
 
Platelet transfusions are a limited and expensive resource, and demand for these products is 
rising in many countries. The increasing demand for platelet transfusions in the US raises 
concerns of future shortages. Hematology/Oncology patients are transfused more platelets 
than any other hospital service (31%)13. Any treatment that could reduce reliance on platelet 
transfusion support would have major cost-saving implications.  
 
Other means that have been used to decrease bleeding incidence include maintenance of 
higher hematocrits to improve platelet function14 and the use of pharmacologic agents to 
improve platelet function15,16. Epsilon Aminocaproic Acid (EACA) and Tranexamic Acid (TXA) 
are inhibitors of fibrinolysis that can be given either intravenously or orally. Inhibitors of 
fibrinolysis have been used for many years to prevent and treat bleeding due to fibrinolysis 
intra- and postoperatively8. These drugs have also been shown to be useful in patients with 
platelet function and coagulation defects such as hemophilia17. Reports of the use of these 
agents to prevent or treat bleeding in thrombocytopenic patients have been 
encouraging9,10,11,12  and suggest that in many patients bleeding can be prevented or stopped 
with the use of these agents. However, the reports of success have been anecdotal and 
retrospective reviews of single institution experiences. Currently many physicians administer 
antifibrinolytic agents to treat bleeding in thrombocytopenic patients or to prevent bleeding in 
the thrombocytopenic patient refractory to platelet transfusions.  Due to the lack of evidence of 
its efficacy and safety, the treatment has not become standard of care. A pivotal study of 
antifibrinolytic therapy will improve patient care by leading physicians to either adopt it as an 
effective and safe treatment for the prevention of thrombocytopenic bleeding, or to abandon its 
use for this purpose.  
 
The purpose of this study is to conduct a prospective, randomized, blinded, placebo controlled 
trial to evaluate the usefulness of an antifibrinolytic therapy, TXA, in preventing bleeding in 
patients who are thrombocytopenic due to primary bone marrow disorders or chemotherapy, 
immunotherapy and/or radiation therapy. The results of this study will change practice by 
providing evidence as to whether or not TXA is an effective and safe treatment when used as 
an adjunct to platelet transfusion therapy in the thrombocytopenic patient. 
 
3. ENDPOINTS 
3.1 PRIMARY ENDPOINT 
Proportion of patients with bleeding of WHO grade 2 or above during the first 30 days after 
activation of study drug (appendix 2). 
 
3.2 Secondary Endpoints 
• 
Number of platelet transfusions per patient during the first 30 days post activation of 
study drug 
• 
Number of days alive and without WHO grade 2 bleeding or greater during the first 30 
days post activation of study drug 
 
3.3 Supportive and Exploratory Efficacy Endpoints 
3.3.1 Alternative measures of bleeding: 
• 
Number of days with bleeding/thrombocytopenia during the first 30 days post 
activation of study drug 


Page 15 of 63 
 
• 
Time from activation of study drug to first episode of bleeding of WHO grade 2 
or greater or death, whichever comes first 
• 
Highest grade of bleeding a patient experiences during the first 30 days post 
activation of study drug 
• 
Death ascribed to bleeding during the first 30 days post activation of study drug 
3.3.2 Alternative Measure of Transfusion Frequency: 
• 
Number of platelet transfusions/patient by thrombocytopenic day during the first 
30 days post activation of study drug. 
• 
Number of red cell transfusions/patient and by thrombocytopenic day during the 
first 30 days post activation of study drug. 
• 
Proportion of patients surviving at least 30 days post activation of study drug 
without a platelet transfusion. 
• 
Proportion of patients surviving at least 30 days post activation of study drug 
without a red cell transfusion. 
• 
Number of patients with platelet count nadir > 10,000/l over the study period of 
30 days from activation of study drug. 
 
3.4 Safety Endpoints 
The incidence of serious adverse events (SAEs) and adverse events (AEs) will be collected 
from the time of consent, up to and including 30 days after the last dose of study drug, 
categorized using CTCAE v4.0 criteria, and compared across treatment arms. In addition, the 
following protocol defined safety endpoints will be collected: 
• 
Incidence of thrombotic events from first day on study drug up to and including 120 
days after activation of study drug.  Thrombotic event is defined by the presence of a 
venous or arterial clot demonstrated by positive diagnostic imaging, which can include 
Doppler/ultrasound, CT and MRI, and interpretation by a local radiologist who will be 
blinded to the study assignment and unlikely to know patient is on a study. Acute 
coronary syndrome will be made on the basis of enzyme and EKG abnormalities 
consistent with that diagnosis and interpreted by the attending physician or consulting 
cardiologist as such. 
• 
Incidence of veno-occlusive Disease (VOD; sinusoidal obstructive syndrome, SOS) 
from the first day on study drug up to and including 30 days after last dose of study 
drug. 
• 
All-cause mortality during the first 30 days and the first 120 days post activation of 
study drug. 
• 
Death ascribed to thrombosis during the first 120 days post activation of study drug. 
 
3.5 Sub-group Analyses 
WHO grade 2 or above bleeding will be assessed separately among patients who did and did 
not have bleeding at randomization, as well as within each of the disease groups of allogeneic 
transplant, autologous transplant and leukemia. 
 
4. TARGET PATIENT POPULATIONS 
Patients with hematologic malignancies receiving intensive chemotherapy and/or stem cell 
transplantation.   
4.1 Inclusion Criteria (all must be met) 
4.1.1 ≥18 years of age 
4.1.2 Confirmed diagnosis of a hematological malignancy or aplasia 
4.1.3 Undergoing or planned chemotherapy, immunotherapy, or hematopoietic stem 
cell transplantation 
4.1.4 Anticipated to have hypoproliferative thrombocytopenia resulting in a platelet           
count of ≤ 10,000/l for ≥ 5 days 
4.1.5 Able to provide informed consent and comply with treatment and monitoring or 
having a Legally Authorized Representative (LAR)  
 


Page 16 of 63 
 
4.2 Exclusion Criteria (none can be present) 
4.2.1 Diagnosis of acute promyelocytic leukemia undergoing induction chemotherapy 
4.2.2 History of ITP, TTP or HUS 
4.2.3 Subjects receiving L-asparaginase as part of their current cycle of treatment 
4.2.4 Subjects with a past history or current diagnosis of arterial or venous     
thromboembolic disease including, acute coronary syndrome peripheral vascular 
disease and retinal arterial or venous thrombosis (except when a prior history of 
central line thrombosis has resolved) 
4.2.5 Subjects with a diagnosis/previous history of veno-occlusive disease (also  
called sinusoidal obstruction syndrome) 
4.2.6 Subjects receiving any pro-coagulant agents (e.g. DDAVP, recombinant Factor    
 VIIa or Prothrombin Complex Concentrates (PCC)) and/or an antifibrinolytic      
 agent within 48 hours of enrollment, or with known hypercoagulable state 
4.2.7 Known inherited or acquired bleeding disorder (e.g. Acquired Storage Pool    
 Deficiency, Paraproteinemia with Platelet Inhibition) 
4.2.8 Known inherited or acquired prothrombotic disorders, including 
antiphospholipid syndrome.  Those with lupus anticoagulant or positive 
antiphospholipid serology without thrombosis are not excluded 
4.2.9 Subjects receiving anticoagulant therapy or anti-platelet therapy 
(except  when  receiving prophylactic anticoagulant or low dose aspirin therapy for 
prophylaxis only with a plan to discontinue when the platelet count falls below 
50,000) 
4.2.10 Subjects with DIC (per diagnosis of patient’s provider) 
4.2.11 Subjects with WHO Grade 2 bleeding  or greater within 48 hours prior to 
activation 
4.2.12 Subjects requiring a platelet transfusion threshold > 10,000/l at time of  
 randomization 
4.2.13 Subjects with anuria (defined as urine output < 10 mls/hr over 24 hours)  
4.2.14 Subjects on dialysis 
4.2.15 Subjects with creatinine ≥ 5.7 mg/dL 
4.2.16 Subjects who are pregnant or nursing or unwilling to use contraception during 
and for 30 days after taking the study drug  (both males and females) 
4.2.17 Concurrent enrollment in other trials involving platelet transfusions, anti 
 fibrinolytics, platelet growth factors or other pro-coagulant agents 
4.2.18 Known allergy to tranexamic acid 
4.2.19 Having been previously randomized in to the A-TREAT study at any stage of 
 their treatment 
4.2.20 Subjects who are unwilling to accept blood or blood component transfusions 
 
5. TRIAL ENROLLMENT 
5.1 Screening/Recruitment 
5.1.1 Potentially eligible subjects will be identified by the subject’s physician and/or 
by other IRB approved methods at each trial site. Research staff will commence 
screening to determine if the subject is eligible for enrollment based upon their 
medical history and laboratory results. The eligibility checklist will be completed.  
Each site will maintain a local log for all screened patients which will contain the 
case ID (assigned by DCC), site linking ID (assigned by site), and identifiable PHI 
in accordance with their local IRB regulations in order to correctly identify each 
patient.  This will be done in order to prevent duplicate screening.  The site staff will 
enter screening information via secure web-based data entry only using the case 
ID and site linking ID.   
5.1.2 After obtaining permission from the subjects physician to discuss the study with 
the subject a trained research staff member will contact the prospective subject to 
describe the study and obtain consent. 
5.1.3 After signing the consent form the subject will be entered into the study.   
 
5.2 Stratification and Randomization 


Page 17 of 63 
 
5.2.1 The subjects will be stratified according to clinical site and disease group 
(allogeneic transplant, autologous transplant, or leukemia) and will be balanced 
within varying blocks of undisclosed sizes. 
5.2.2 When the consented patient’s platelet count falls to < 50,000/l with an 
expectation that the platelet count will be ≤10,000 for 5 days, the PI or a research 
staff member will access the on-line randomization system and a unique trial 
number will be assigned. 
5.2.3 A member of the study team will contact the local investigational pharmacy to 
inform them of the patient’s participation in the trial and study ID number. 
5.2.4 When a randomized subject has a platelet count < 30,000/l with an 
expectation that the platelet count would be ≤10,000/l for 5 days, the 
administration of study drug will be activated, providing the date of activation is 
within 30 days of randomization. The date/time of activation will be time zero for 
the study endpoints. 
5.2.5 Target enrollment will be 330 activated subjects- utilizing a 1:1 randomization 
schema both arms will have a target enrollment of 165 activated subjects. 
 
5.3 Enrollment Period 
Trial enrollment will take place over a period of 4 years. The expected enrollment is estimated 
to be 90 randomized subjects per year, with 82 activated subjects per year, across all sites. 
 
6. INTERVENTIONS 
6.1 Study Drug (Tranexamic Acid or placebo) 
6.1.1 Tranexamic acid is a competitive inhibitor of plasminogen activation and, at much 
higher concentrations, acts as a noncompetitive inhibitor of plasmin and 
fibrinolysis.  Patients randomized to receive TXA will take 1.3g PO (by mouth)  
three times a day until they meet the criteria for stopping study drug as provided 
in section 6.3.  
6.1.1a Any patients unable to take the drug orally will receive 1.0g TXA IV 
(intravenous) three times a day. 
6.1.1b Criteria for dose reduction in the presence of renal insufficiency are given 
for both PO and IV administration in section 6.5 
6.1.1c Criteria for temporary discontinuation of the study drug are given in section 
6.4. 
      6.1.2 Patients randomized to the control arm will receive matching placebo (tablets or 
IV solution as described in section 7.1) 
      6.1.3 Rationale for dose:  The experimental doses have been chosen to be in line with    
           the current approved indications of TXA and to be in the midrange of the doses that    
           have been previously studied in patient populations similar to those to be accrued 
           to this study. 
      6.1.4 The current indications for oral TXA (LYSTEDA) are for heavy menstrual 
           bleeding at a dose of 1.3g t.i.d (three times daily) (total 3.9g/day) for a maximum of 
           5 days, with reduced dosage in patients with renal impairment. The current 
 
     indication for intravenous TXA (CYKLOKAPRON) is in patients with hemophilia for 
           short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the  
 
     need for replacement therapy during and following tooth extraction. Dosage is 
 
     0.01g/kg body weight three to four times per day for 2 – 8 days after tooth 
           extraction. Dosage is to be modified in patients with renal impairment.  
      6.1.5 Appendix 1 contains a listing of prior studies of anti-fibrinolytics TXA (Tables 1 
            and 2) and EACA (Tables 3 and 4) in patients similar to the populations to be 
 
      enrolled in this study. Table 5 of Appendix 1 contains a listing of prior studies that  
            compared TXA to EACA in any indication.  
 
6.2 Transfusion Practice on both arms 
      6.2.1 Prophylactic platelet transfusions will be given when the morning platelet count is              
           ≤ 10,000/l  


Page 18 of 63 
 
      6.2.2 Therapeutic platelet transfusions may be given for active bleeding, prior to a    
            planned invasive procedure or because of trauma, per local standard of care.  
      6.2.3 In instances where platelet transfusions are given for invasive procedures or 
            trauma, the subject will return to the study platelet transfusion threshold of  
 
     ≤ 10,000/l  
      6.2.4 Type and dose of platelet transfusion will not be specified. 
      6.2.5 Clinicians can exercise discretion to transfuse platelets for any reason should  
           they feel there is a clinical reason to do so (e.g. patient’s platelet count appears to 
           be falling just prior to a weekend).  
      6.2.6 If a patient develops platelet transfusion refractoriness (defined as two sequential 
           transfusions with a 24 hour platelet increment < 5,000/l), local practices for      
 
     transfusion management will be followed. Data on use of matched platelets and 
 
    alloantibody testing will be recorded. 
      6.2.7 The rationale for platelet transfusion over 10,000/l will be recorded on the daily 
           transfusion data form. 
      6.2.8 Patients will receive a transfusion of red blood cells per standard of care at their 
           clinical site. 
 
6.3  Stopping of Study Drug 
Study drug will be permanently discontinued as soon as any one of the following situations 
occurs: 
6.3.1 It has been 30 days since the subject was first activated to the randomized study 
drug. 
6.3.2 The subject has a spontaneous increase in platelet count across 2 successive 
platelet measurements made at least 22 hours apart from <30,000/l to >50,000/l, 
with no intervening platelet or granulocyte transfusion, or stem cell transplant.   
6.3.3 If platelet counts are ≥30,000 on 2 measurements made at least 46 hours apart 
with no intervening platelet counts <30,000, with no greater than a 25% decrease 
in platelet counts from the first such measurement to a follow-on measurement 
during that 46 hour period, and with no intervening platelet or granulocyte 
transfusion, or stem cell transplant. 
6.3.4 The subject receives open label TXA, or other antifibrinolytic agent or  
      procoagulant drug, (e.g., EACA, DDAVP, recombinant Factor VIIa, or Prothrombin  
      Complex Concentrates). Use of these agents will be recorded in study data. 
6.3.5 The subject begins anticoagulant or antiplatelet therapy. 
6.3.6 The subject has visible hematuria. 
6.3.7 The subject has a diagnosis of thrombosis. 
6.3.8 The subject develops sinusoidal obstructive syndrome (SOS), also called Veno 
      occlusive Disease (VOD). 
6.3.9 A recurrent incident of central line occlusion.  Central line occlusion is defined as 
inability to access or infuse through a central line requiring instillation of a fibrinolytic 
agent such as urokinase for clearing. It will not require radiographic or 
ultrasonographic evidence for diagnosis. It does not include lines that require specific 
patient positioning that suggests a “kink” in the line.  A recurrent incident is when the 
definition is met on 2 separate occasions while receiving study drug. 
6.3.10 The subject becomes pregnant. 
 
If the study drug is stopped for any of the above reasons, it should not be restarted even if the 
platelet count later falls below 30,000. 
 
6.4 Temporary Discontinuation of Study Drug 
Study drug will be temporarily discontinued and may be restarted after resolution for the 
following situations: 
6.4.1 A diagnosis of DIC is made by the clinical team. 
6.4.2 Central line occlusion occurs (drug must be permanently discontinued if central  
      line occlusion recurs). 


Page 19 of 63 
 
 
6.5 Dose Adjustment for Renal Insufficiency 
Study drug dosing frequency will be adjusted for renal insufficiency according to the following 
algorithm (dose adjustments will be based upon the first creatinine measurement on any given 
day): 
Serum Creatinine (mg/dL) 
Dosing Frequency 
1.36 to 2.82 
Once every 12 hours 
2.83 to 5.66 
Once every 24 hours 
>5.66 
Once every 48 hours 
 
Patients who must begin dialysis after beginning study drug will continue to receive study drug 
once every 48 hours. 
 
6.6 Other Treatment Considerations 
No other medication changes are directed in this protocol and standard care will otherwise be 
followed. 
 
7. STUDY DRUG INFORMATION 
7.1 Masking of Study Drug (Tranexamic Acid or placebo) 
7.1.1 Inpatient Subjects 
• The investigational pharmacy at each trial site will receive randomization 
and distribute TXA or placebo (both IV and PO). The manufacturer of the 
oral drug commercially known as LYSTEDA® is Apotex Corporation and the 
NDC# is 60505-3638-01.  The manufacturer of the IV drug commercially 
known as CYKLOKAPRON® is Pfizer Corporation and the NDC# is NDC 
0013-1114-10. IV diluent and IV placebo may be 0.9% sodium chloride or 
D5W. 
• A central drug distribution center, CoreRx, will prepare and package oral 
tranexamic acid and placebo, and then distribute blinded containers to the 
investigational pharmacy at each participating trial site. Containers will be 
coded for TXA arm vs placebo arm. 
• For patients who cannot tolerate or absorb oral medication (per the 
discretion of the treating investigator or physician), the investigational 
pharmacy at each trial site will distribute TXA or placebo as equal volumes 
of TXA in solution or solution alone. The manufacturers, batch numbers, 
and sources will be reported for all doses. Sites will use the commercially 
available product used by their formulary. 
• Although the investigational pharmacy will be unblinded, they will not share 
any blinded information with the study team except in case of emergency.  
Unblinded pharmacy staff will not be involved in patient or outcomes 
assessment. 
7.1.2 Outpatient Subjects 
• CoreRx will prepare, package and distribute blinded containers of oral study 
drug to the investigational pharmacy at each participating trial site. Vials will 
be coded for TXA arm vs placebo arm. 
7.1.3 Blinding of patients, caregivers, and study personnel 
• Double blind randomization: Neither patients nor care providers nor study 
coordinators nor study investigators will be told which arm the patient is on. 
• Among study personnel, only the unblinded pharmacists and unblinded 
statistician will have access to treatment assignment. 
• Placebo is manufactured to be grossly similar to TXA in appearance (size, 
shape, color). 


Page 20 of 63 
 
• To mitigate the possibility of bias in assessing treatment outcomes, 
research coordinators who collect outcomes data will have no contact with 
study drug. Details about the measures instituted to preserve assessor 
blind will be described in the Manual of Operations. 
 
7.2 Administration of Study Drug 
7.2.1 Study drug will be started per randomization assignment within 24 hours of the 
first recorded platelet count < 30,000/l. 
7.2.2 Dose Schedule 
• Intravenous Administration: tranexamic acid 1 g (diluted to 50 mL) every 8 
hours or placebo (50 mL) every 8 hours; both TXA and placebo will be 
infused over 15 to 30 minutes, then the line is flushed with 25ml saline or 
according to institutional standard practice. 
• Oral Administration: tranexamic acid 1.3 g every 8 hours or an identical, 
inert placebo capsule 
7.2.3 TXA for Intravenous Administration 
• Tranexamic acid may be mixed with most solutions (e.g. electrolyte 
solutions, carbohydrate solutions, amino acid solutions and Dextran 
solutions). 
• Tranexamic acid should not be mixed with blood products.  
• The mixture should be prepared the same day the solution is to be used. 
• Each mL of the sterile solution for intravenous injection contains 100 mg 
tranexamic acid and water for Injection to 1 mL.  
• Intravenous TXA will be diluted to a 50 mL solution that will be infused over 
15 to 30 minutes, and then the line is flushed with 25ml saline or 
according to institutional standard practice. 
7.2.4 TXA for Oral Administration 
• Each tablet of TXA (non-placebo) contains 650 mg tranexamic acid and the 
following inactive ingredients: microcrystalline cellulose, colloidal silicon 
dioxide, pregelatinized corn starch, povidone, hypromellose, stearic acid, 
and magnesium stearate.  
7.2.5 Placebo for Oral Administration 
• CoreRx will manufacture the placebo to be similar in size, shape, and color 
to the TXA tablet.  
• The placebo tablets will be 650 mg microcrystalline cellulose (MCC) since 
there would be a risk of developing lactose intolerance in this population 
with the commonly used lactose filler.  This avoids adding additional 
ingredients over the TXA.  In addition to MCC, the placebo will contain 
magnesium stearate (0.5% or ~5mg/tablet) which is added as a lubricant 
for the manufacturing process. 
 
8. STUDY VISIT PROCEDURES AND SCHEDULE 
The following data will be collected as specified. 
 
If two or more of the following study time-points fall on the same calendar date, all data 
required at each time-point must be collected. However, corresponding measurements that 
occur on both time-points do not need to be repeated. For example, if a subject receives study 
drug (D1 of treatment) on the same day as enrollment & randomization- all measurements to 
be collected on Day of Enrollment and Day of Randomization and D1 of Active Treatment 
must be done that day, but only one platelet count (or hemoglobin level, hematocrit level, etc.) 
is required. 
 
8.1 Day of Enrollment  
• Thrombotic Assessment 
• Demographics and Medical History 


Page 21 of 63 
 
o Weight 
o Height 
o Date of Birth 
o Gender 
o Ethnicity 
o Race 
o Primary Diagnosis 
▪ 
Disease 
▪ 
Current Treatment 
o Chemotherapy? 
o Transplant? If yes, date and type. 
▪ 
If receiving allogeneic transplant: 
o Donor ABO Type 
o Related Donor? 
o Subject ABO Type 
• Laboratory Assessments 
o Hematocrit 
o Hemoglobin 
o Platelet Count 
o WBC 
o Neutrophil (if available) 
o Serum Creatinine 
o Pregnancy Test (if not done within prior 7 days) 
▪ Only Females of Childbearing Potential (FCBP) 
▪ Urine or Serum (qualitative or quantitative) pregnancy test 
acceptable 
o Results of HLA antibody testing done as routine care will be recorded 
 
• Adverse Event Assessment and Reporting- adverse events are monitored from time 
of consent to 30 days post discontinuation of study drug. 
 
8.2 Days Between Enrollment and Randomization 
• Thrombotic Assessment (via chart review)- to be performed once a week 
• Laboratory Assessments 
INPATIENT SUBJECTS: to be performed daily 
OUTPATIENT SUBJECTS: to be performed twice a week 
o Hematocrit 
o Hemoglobin 
o Platelet Count 
o WBC 
o Neutrophil (if available) 
 
• Adverse Event Assessment and Reporting 
 
8.3 Day of Randomization 
• Hemostatic/Bleeding Assessment 
o If WHO Grade 2 bleeding or greater at randomization or within prior 48 
hours, do not randomize. They are eligible for randomization if bleeding 
resolves later. 


Page 22 of 63 
 
• Thrombotic Assessment (via chart review) 
• Laboratory Assessments 
o Hematocrit 
o Hemoglobin 
o Platelet Count  
o WBC 
o Neutrophil (if available) 
o Coagulation Profile (PT/INR, aPTT, Fibrinogen, D-dimer):must be drawn 
no longer than 24 hours before randomization or 24 hours after 
randomization and reviewed prior to activation 
o Serum Creatinine 
o Urinalysis 
o Pregnancy Test if > 7 days since last pregnancy test 
▪ Only Females of Childbearing Potential (FCBP) 
▪ Urine or Serum (qualitative or quantitative) pregnancy test 
acceptable 
• Data on Platelet and Granulocyte Transfusions 
o Source of Platelets (apheresis or whole blood derived) 
o HLA or cross-match compatible 
o Reason for Transfusion 
▪ 
Met Threshold 
▪ 
Invasive Procedure 
▪ 
Active Bleeding 
▪ 
Risk of Significant Bleeding 
▪     Other- specify 
• Data on RBC Transfusions 
o Number of Units Transfused 
o Reason for Transfusion  
▪ 
Met Threshold 
▪ 
Invasive Procedure 
▪ 
Active Bleeding 
▪ 
Risk of Significant Bleeding 
▪ 
Other- specify 
• Adverse Event Assessment and Reporting 
 
8.4 Days Between Randomization and Activation 
• Hemostatic/Bleeding Assessment 
• Thrombotic Assessment (via chart review) weekly 
• Laboratory Assessments:  
INPATIENT SUBJECTS: to be performed daily 
OUTPATIENT SUBJECTS: to be performed twice a week 
o Hematocrit 
o Hemoglobin 
o Platelet Count 
o Serum Creatinine 
o WBC 
o Neutrophil (if available) 
• Data on Platelet and Granulocyte Transfusions 
o Source of Platelets (apheresis or whole blood derived) 


Page 23 of 63 
 
o HLA or cross-match compatible 
o Reason for Transfusion 
▪ 
Met Threshold 
▪ 
Invasive Procedure 
▪ 
Active Bleeding 
▪ 
Risk of Significant Bleeding 
▪ 
Other- specify 
• Data on RBC Transfusions 
o Number of Units Transfused 
o Reason for Transfusion 
▪ Met Threshold 
▪ Invasive Procedure 
▪ Active Bleeding 
▪ Risk of Significant Bleeding 
▪ Other- specify 
• OUTPATIENT SUBJECTS ONLY: Subject Self-Assessment Bleeding Diary- provide 
patients with instruction on how to complete diary. This diary will be reviewed with 
research staff (in person or by phone) at least once a week. 
• Adverse Event Assessment and Reporting 
 
8.5 Activation 
• Days Between Activation and First Dose of Study Drug 
o Hemostatic/Bleeding Assessment – daily while inpatient 
▪ If WHO Grade 2 bleeding or greater within prior 48 hours, do NOT 
activate-not eligible.  
o Thrombotic Assessment (via chart review) weekly 
o Laboratory Assessments:  
▪ Hematocrit 
▪ Hemoglobin 
▪ Platelet Count 
▪ Serum Creatinine 
▪ WBC 
▪ Neutrophil (if available) 
▪ Bilirubin (if not done within 7 days prior) 
o Check to see if bilirubin is ordered weekly while on study 
drug-all subjects and order if not otherwise clinically 
indicated 
o Data on Platelet and Granulocyte Transfusions 
▪ Source of Platelets (apheresis or whole blood derived) 
▪ HLA or cross-match compatible 
▪ Reason for Transfusion 
o Met Threshold 
o Invasive Procedure 
o Active Bleeding 
o Risk of Significant Bleeding 
o Other- specify 
o Data on RBC Transfusions 
▪ Number of Units Transfused 
▪ Reason for Transfusion 


Page 24 of 63 
 
o Met Threshold 
o Invasive Procedure 
o Active Bleeding 
o Risk of Significant Bleeding 
o Other- specify 
o Study Drug Administration 
o OUTPATIENT SUBJECTS ONLY: Subject Self-Assessment Bleeding 
Diary- provide patients with instruction on how to complete diary. This 
diary will be reviewed with research staff (in person or by phone) at least 
once a week. 
o Adverse Event Assessment and Reporting 
• Day 1 of Study Drug 
o Hemostatic/Bleeding Assessment 
o Thrombotic Assessment (via chart review) 
o Ocular Assessment 
Day of first dose up to no more than 72 hours before 
o Laboratory Assessments:  
Day 1 labs MUST be drawn BEFORE the first dose of study drug is 
administered 
▪ Hematocrit 
▪ Hemoglobin 
▪ Platelet Count 
▪ Serum Creatinine 
▪ WBC 
▪ Neutrophil (if available) 
o Data on Platelet and Granulocyte Transfusions 
▪ Source of Platelets (apheresis or whole blood derived) 
▪ HLA or cross-match compatible 
▪ Reason for Transfusion 
o Met Threshold 
o Invasive Procedure 
o Active Bleeding 
o Risk of Significant Bleeding 
o Other- specify 
o Data on RBC Transfusions 
▪ Number of Units Transfused 
▪ Reason for Transfusion 
o Met Threshold 
o Invasive Procedure 
o Active Bleeding 
o Risk of Significant Bleeding 
o Other- specify 
o Study Drug Administration 
o OUTPATIENT SUBJECTS ONLY: Subject Self-Assessment Bleeding 
Diary- provide patients with instruction on how to complete diary. This 
diary will be reviewed with research staff (in person or by phone) at least 
once a week. 
o Adverse Event Assessment and Reporting 
 


Page 25 of 63 
 
• Day 2 of Study Drug 
o Hemostatic/Bleeding Assessment 
o Thrombotic Assessment (via chart review) 
o Laboratory Assessments 
 
 
 
INPATIENT SUBJECTS: to be performed daily 
 
 
 
OUTPATIENT SUBJECTS: to be performed twice a week 
▪ Hematocrit 
▪ Hemoglobin 
▪ Platelet Count 
▪ WBC 
▪ Neutrophil (if available) 
▪ Serum Creatinine 
o Data on Platelet and Granulocyte Transfusions 
▪ Source of Platelets (apheresis or whole blood derived) 
▪ HLA or cross-match compatible 
▪ Reason for Transfusion 
o Met Threshold 
o Invasive Procedure 
o Active Bleeding 
o Risk of Significant Bleeding 
o Other- specify 
o Data on RBC Transfusions 
▪ Number of Units Transfused 
▪ Reason for Transfusion 
o Met Threshold 
o Invasive Procedure 
o Active Bleeding 
o Risk of Significant Bleeding 
o Other- specify 
o Study Drug Administration 
o OUTPATIENT SUBJECTS ONLY: Subject Self-Assessment Bleeding 
Diary- ensure patients are filling out diary correctly (in person or by 
phone). 
o Adverse Event Assessment and Reporting 
 
• Day 3 – 30 of Study Drug or up to day 30 post activation 
o Inpatient Subjects 
▪ The following are to be performed daily: 
o Hemostatic/Bleeding Assessment 
o Thrombotic Assessment (via chart review) 
o Laboratory Assessments 
❖ Hematocrit 
❖ Hemoglobin 
❖ Platelet Count 
❖ WBC 
❖ Neutrophil (if available) 
❖ Serum Creatinine 


Page 26 of 63 
 
❖ Check to see if bilirubin is ordered weekly while 
on study drug-all subjects and order if not 
otherwise clinically indicated 
o Data on Platelet and Granulocyte Transfusions 
❖ Source of Platelets (apheresis or whole blood 
derived) 
❖ HLA or cross-match compatible 
❖ Reason for Transfusion 
1. Met Threshold 
2. Invasive Procedure 
3. Active Bleeding 
4. Risk of Significant Bleeding 
5. Other- specify 
o Data on RBC Transfusions 
❖ Met Threshold 
❖ Invasive Procedure 
❖ Active Bleeding 
❖ Risk of Significant Bleeding 
❖ Other- specify 
o Study Drug Administration 
o Adverse Event Assessment and Reporting 
▪ The following are to be performed weekly: 
o Ocular Assessment-additionally if symptoms reported 
o Outpatient Subjects 
▪ The following are to be performed daily: 
o Study Drug Administration 
o Self-bleeding assessment and recorded in diary 
▪ The following are to be performed twice a week: 
o Hemostatic/Bleeding Assessment 
o Thrombotic Assessment (via chart review) 
o Laboratory Assessments 
❖ Hematocrit 
❖ Hemoglobin 
❖ Platelet Count 
❖ WBC 
❖ Neutrophil (if available) 
❖ Serum Creatinine 
❖ Check to see if bilirubin is ordered weekly while 
on study drug-all subjects and order if not 
otherwise clinically indicated 
 
o Data on Platelet and Granulocyte Transfusions 
❖ Source of Platelets (apheresis or whole blood 
derived) 
❖ HLA or cross-match compatible 
❖ Reason for Transfusion 
1. Met Threshold 
2. Invasive Procedure 
3. Active Bleeding 


Page 27 of 63 
 
4. Risk of Significant Bleeding 
5. Other- specify 
o Data on RBC Transfusions 
❖ Number of Units Transfused 
❖ Reason for Transfusion 
1. Met Threshold 
2. Invasive Procedure 
3. Active Bleeding 
4. Risk of Significant Bleeding 
5. Other- specify 
▪ The following are to be performed once a week: 
o Ocular Assessments-additionally if symptoms reported 
o Subject Self-Assessment Bleeding Diary review with 
research staff (in person or by phone) 
• At Onset of ≥ Grade 2 Bleeding: to be performed on day of onset of symptoms or at 
visit directly following onset of symptoms. 
 
o Laboratory Assessments 
▪ Hematocrit 
▪ Platelet Count 
▪ Hemoglobin 
▪ WBC 
▪ Neutrophil (if available) 
▪ Coagulation Profile (PT, aPTT, INR, Fibrinogen, D-dimer) (if 
available) 
▪ Serum Creatinine 
 
8.6 End of Treatment: the day the subject receives their last dose of study drug OR at the 
next visit following last dose of study drug. 
• Hemostatic/Bleeding Assessment 
• Thrombotic Assessment (via chart review) 
• Laboratory Assessments 
o Hematocrit 
o Hemoglobin 
o Platelet Count 
o WBC 
o Neutrophil (if available) 
o Serum Creatinine 
• OUTPATIENT SUBJECTS ONLY: Subject Self-Assessment Bleeding Diary- to be 
reviewed with research staff (in person or by phone) at end of treatment. 
• Adverse Event Assessment and Reporting 
 
8.7 End of Treatment to Day 14 post Discontinuation of Study Drug (Safety Phase) 
• Inpatient Subjects 
o Hemostatic/Bleeding Assessment and Thrombotic Assessment (via chart 
review) will occur daily 
o Adverse Event Assessment and Reporting 
o Weekly ocular assessments-additionally if symptoms reported 
• Outpatient Subjects 


Page 28 of 63 
 
o Outpatient subjects will complete the daily Follow-Up Subject Self-
Assessment Bleeding Diary (and any necessary Self-Assessment 
Bleeding Forms) which will be reviewed with the research staff (in person 
or by phone) at least weekly 
o Adverse Event Assessment and Reporting 
o Weekly ocular assessments-additionally if symptoms reported 
 
8.8 Follow Up 
• +30 Days (-1 + 6 days) post Discontinuation of Study Drug (Safety Phase) 
o Patient will be contacted in person or by telephone (see telephone script- 
Appendix 3) 
o OUTPATIENT SUBJECTS ONLY: a final review (in person or by phone) 
of the Follow-Up Self-Assessment Bleeding Diary (and any necessary 
Self-Assessment Bleeding Forms) will be conducted and diaries and 
forms will be returned to the study team 
o Thrombotic Assessment (via chart review) 
o Adverse Event Assessment and Reporting 
• +120 Days (+ 3 days) post Activation of Study Drug 
o Patient will be contacted in person or by telephone (see telephone script- 
Appendix 3) 
o Thrombotic Assessment (via chart review) 


Page 29 of 63 
 
Table 2: Study Assessments Calendar
 


Page 30 of 63 
 
1- On day 1 of study treatment required laboratory tests must be drawn BEFORE the first dose of study drug is administered. 
2- To be performed daily while subject is inpatient and twice a week while subject is outpatient- if done more frequently per SOC, all results will be 
recorded. 
3- These tests to be performed at day of onset of ≥ grade 2 bleeding OR at next visit following onset of ≥ grade 2 bleeding. 
4- End of Treatment (EOT) is the day when subject receives their last dose of study drug OR at next visit following last dose of study drug. 
5- Thrombotic Assessments to be done via medical chart review. 
6- Pregnancy test only for females of child-bearing potential (FCBP)- urine or serum (qualitative or quantitative) pregnancy test acceptable (if not 
done within 7 days prior) 
7- Coagulation Profile is comprised of PT/INR, aPTT, Fibrinogen, D-dimer. 
8- Follow-Up Thrombotic Assessments and Adverse Event Assessment/Reporting will occur via medical record review AND in-person or 
telephone contact with the subject. 
9- Outpatient subjects will be expected to maintain a daily, self-assessed bleeding diary which will be reviewed with research staff (in person or by 
phone) at least once a week. 
10- From EOT to D14 post discontinuation of study drug, inpatient subjects will be followed via chart review for hemostatic/bleeding assessments 
and thrombotic assessments. Outpatient subjects will complete the daily Follow-Up Self-Assessment Bleeding Diary which will be reviewed (in 
person or by phone) with study staff at least once a week between EOT and D14 post discontinuation of study drug. A final diary review (in 
person or by phone) will occur once between D14 and D21 post discontinuation of study drug and the diary (and any applicable Self-
Assessment Bleeding Forms) will be returned to study staff. 
11- Patient will be contacted in person or by telephone once between 14 and 21 days post discontinuation of study drug and at day 30 post 
discontinuation and day 120 post activation of study drug. If a member of the research staff is unable to contact the subject directly then their 
local physician will be contacted. 
12- Per section 11, A-TREAT ocular assessments will monitor subjects’ standard vision (Snellen Eye Chart), central visual field (Amsler Grid) and 
color perception (Ishihara test). Assessments will be done on day 1 of study drug (no more than 72 hours before randomization up to and 
including the day of active treatment) and will continue weekly until D14 post discontinuation of study drug.   
13- Patients will receive a transfusion of red blood cells per standard of care at their clinical site. 
14- Bilirubin will be collected on day 1 of activation if not completed within prior 7 days and weekly while on study drug


Page 31 of 63 
 
 
9. ADVERSE EVENT REPORTING 
Whenever possible, investigators should report adverse events as disease or syndromes instead of 
reporting individual component symptoms, signs, laboratory abnormalities or sequelae. 
 
This study will be using the descriptive terminology developed by the National Cancer Institute for 
use in reporting adverse events: Common Toxicology Criteria for Adverse Events (CTCAE) version 
4.03, dated June 14, 2010.  The criteria can be found at: 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf  
 
The CTCAE includes a grading (severity) scale for each adverse event term. Grades were 
developed using the following guidelines: 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental ADL. 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
The definitions to be applied to adverse events recorded in this trial are given in Table 3 below. 
Table 3: Adverse Event Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with 
the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. 
 
Serious Adverse Event 
(SAE)  
 
Any adverse event temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
• 
results in death1 
• 
is life-threatening2 
• 
requires hospitalization or prolongation of existing 
hospitalization3 
• 
results in persistent or significant disability or incapacity 
results in a congenital anomaly/birth defect 
• 
any other adverse event that, based upon appropriate medical 
judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the 
other outcomes listed in this definition   
 
Unexpected Adverse Event 
Any adverse event occurring in one or more subjects in: 
• 
a research protocol, the nature, severity, or frequency of 
which is not consistent with either the known or foreseeable 
risk of adverse events associated with the procedures 
involved in the research that are described in (a) the protocol–
related documents, such as the IRB-approved research 
protocol, any applicable investigator brochure, and the current 
IRB-approved informed consent document, and (b) other 
relevant sources of information, such as product information 


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and package inserts; or  
• 
the expected natural progression of any underlying disease, 
disorder, or condition of the subject(s) experiencing the 
adverse event and the subject’s predisposing risk factor 
profile for the adverse event. 
 
Suspected Unexpected 
Serious Adverse Reaction  
 
Any unexpected adverse event that:  
• 
results in death1 
• 
is life-threatening2 
• 
requires hospitalization or prolongation of existing 
hospitalization3 
• 
results in persistent or significant disability or incapacity 
 
Unanticipated problem 
involving risks to subjects 
or others (UP) 
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 subject population being studied;  
• 
related or possibly related to a subject’s participation in the 
research; and  
• 
suggests that the research places subjects or others at a 
greater risk of harm (including physical, psychological, 
economic, or social harm) related to the research than was 
previously known or recognized. 
 
1: Death due to the underlying disease or associated conditions will not be reported as a SAE. 
2: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe. 
3: Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a 
precautionary measure for continued observation. Hospitalizations for a pre-existing condition (including elective 
procedures that have not worsened) do not constitute an SAE.  
 
 
Medical judgement should be exercised in deciding whether an AE is serious in other situations. 
Important AEs that are not immediately life-threatening or do not result in death or hospitalization 
but may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above, should also be considered serious. 
 
9.1 Expected Adverse Events 
9.1.1 Adverse Effects Associated with Tranexamic Acid (TXA) 
• TXA is generally well tolerated by most patients. However, it can cause side effects. 
The most common adverse reactions seen in clinical trials (≥ 5%, and more frequent 
in LYSTEDA® subjects compared to placebo subjects) are headache, sinus and 
nasal symptoms, back pain, abdominal pain, musculoskeletal pain, joint pain, muscle 
cramps, migraine, anemia and fatigue. These and the following adverse events and 
other safety information are described in the Rev. 01/15 Code TX00N by AKORN 
Pharmaceuticals, Inc. ® 
• Subjects may have none, some or all of the effects listed above and below and those 
adverse events may be mild, moderate or severe. 
• Patients with a previous history of thromboembolic disease may be at an increased 
risk for venous and arterial thrombosis. Although clinical evidence with tranexamic 
acid documented in published literature shows no significant increase in thrombosis, 
possible risk of thrombotic complications cannot be ruled out. Venous and arterial 
thrombosis or thromboembolism, as well as cases of central retinal artery and central 
retinal vein obstruction, have been reported with Tranexamic acid. 


Page 33 of 63 
 
• Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur, but have been 
shown to disappear when the dosage is reduced.  
• Giddiness and hypotension have occasionally been reported. Hypotension has been 
observed when intravenous injection is too rapid. To avoid this response, the 
solution should not be administered more rapidly than 1 mL per minute. 
• Hypersensitivity adverse events, including allergic skin reactions, anaphylactic shock 
and anaphylactoid reactions. A case of severe allergic reaction to Tranexamic acid 
was reported involving a subject on the fourth cycle of treatment. The subject 
experienced dyspnea, tightening of the throat and facial flushing that required 
emergency medical treatment. 
• Rare ocular side effects have included disturbances of color vision and retinal 
venous and artery occlusion. 
• Genitourinary side effects have included ureteral obstruction due to clot formation in 
patients with upper urinary tract bleeding. 
9.1.2 Toxicities Related to Platelet Transfusions 
• Viral infections may be transmitted from the transfusion of any blood product. Donor 
blood is routinely screened for the presence of hepatitis B and C, the AIDS virus 
(HIV 1 & 2), the HTLV viruses (1 & 2), West Nile virus and, on occasion, for 
cytomegalovirus. In spite of testing, rare infections with these, or other viruses, may 
still result from a transfusion.  
• Bacterial infections can result from platelet transfusions. Platelets must be stored at 
room temperature and not in a refrigerator so overgrowth of bacteria may occur if 
there has been a break in the sterility of the system. This could result in a serious 
infection.   
• Transfusion reactions such as chills, fever, drop in blood pressure, shortness of 
breath and, very rarely, shock can occur due to the transfusion of any blood 
products. On rare occasions, transfusions may be associated with a severe reaction 
that could result in lung injury, kidney failure or heart failure. Allergic reactions such 
as hives, rashes or, very rarely, a severe reaction that could result in death can also 
occur during transfusions. 
9.2 Pregnancy and Nursing 
• 
The effects of tranexamic acid on embryogenesis, spermatogenesis and reproduction in 
humans are unknown. The safety of the use of tranexamic acid in women who are pregnant 
or may become pregnant has not been established. Therefore, women of childbearing 
potential and fertile men will be advised to use adequate and effective contraception from 
the time of consent to 30 days after discontinuation of study drug.  
• 
Patients who become pregnant during the study will be discontinued from study drug 
immediately and referred to an appropriate health care provider for monitoring. The event 
will be considered a Serious Adverse Event (SAE) and will be reported per protocol section 
16.3.4. The patient will continue to be followed per protocol, with additional follow-up for 
pregnancy outcome. 
• 
Tranexamic acid is excreted into breast milk, therefore nursing subjects are excluded from 
the study. If subjects are pumping breast milk, and the milk is destroyed, then they may be 
included. 
 
 
10. HEMOSTATIC/BLEEDING ASSESSMENTS 
Bleeding will be recorded by the well-established bleeding assessment tool, validated in PLADO4 & 
TOPPS6 and refined for this study. Rates of recorded bleeding are known to vary considerably 
between trials.  Reasons for this variability have been explored and published through a study 
organized by the BEST collaboration, and include different patient groups and bleeding definitions 
and variable follow up periods18.  
 


Page 34 of 63 
 
In this trial, a number of measures will be taken to standardize documentation and recording of 
bleeding, including trained assessors, monitoring and education. In the recent TOPPS study, 
completeness of bleeding outcome documentation was excellent: A bleeding assessment was 
completed on 93% (8405/9030) of days for patients in the non-prophylactic group, and 97% 
(8733/8970) of days in the prophylactic group. The majority of patients in both arms had bleeding 
information completed on each study day (median non-prophylactic 30 days (IQR 29 to 30); median 
prophylactic 30 days (IQR 30 to 30)). 
 
10.1 Inpatient Subjects 
Bleeding assessments will be performed by means of a physical assessment of the patient, patient 
interview (if possible), and a review of the patient chart and laboratory data. Research staff will 
perform the physical assessment and interview of the patient before reviewing the patient’s chart 
and laboratory data as to allow an objective assessment without the bias that might be introduced 
by performing the chart and laboratory reviews first. Research staff will perform the hemostatic 
assessment at approximately the same time each day. 
 
10.2 Outpatient Subjects 
All outpatient subjects (including those who are discharged from inpatient status prior to completion 
of the initial trial period [30 days from randomization]) will be trained in the completion of a daily 
Self-Assessment Bleeding Diary. The diary will ask the subject to respond “yes” or “no” as to 
whether they have experienced any bleeding for each body system on that day.  Information will be 
provided to the subject describing how to report degree of bleeding in relation to amount of blood 
present, size of bruising, etc. Subjects will have their Self-Assessment Bleeding Diary reviewed by 
research staff at least weekly, either in person or over the phone. Patients who are seen in the 
outpatient clinic whilst still within the 30 day trial period will have a bleeding assessment completed 
by the local research staff in addition to the daily self-assessment. Self-assessment data will not be 
used as the outcome unless there is no medical assessment form.  
 
All outpatient subjects will be contacted by the research staff between day 14 and 21 post 
discontinuation of study drug a diary review and to confirm arrangements to collect all relevant 
forms. All forms will be entered into the trial database. 
 
11. SAFETY ASSESSMENTS 
Thrombotic assessments will be performed via a review of medical chart notes and imaging studies 
by trained research staff at the following time points (see Table 2: Study Assessments Calendar for 
further information regarding timing of assessments): 
11.1 Thrombotic Assessments 
     11.1.1 Inpatient Subjects 
11.1.1a Weekly in the days between Day of Enrollment and Day of Randomization 
11.1.1b Day of Randomization 
11.1.1c Daily during active treatment with study drug 
11.1.1d Day 30 post first dose of study drug 
11.1.1e End of Treatment 
11.1.1f +1 day post last dose of study drug 
11.1.1g At least Once between 14 and 21 days post discontinuation of study drug 
11.1.1h Day 30 post discontinuation of study drug 
11.1.1i Day 120 post activation of study drug 
 
11.1.2 Outpatient Subjects 
11.1.2a Weekly in the days between Day of Enrollment and Day of Randomization 
11.1.2b Day of Randomization 
11.1.2c Twice a week during active treatment with study drug 
11.1.2d Day 30 post first dose of study drug 
11.1.2e End of Treatment 


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11.1.2f +1 day post last dose of study drug 
11.1.2g At least Once between 14 and 21 days post discontinuation of study drug 
11.1.2h Day 30 post discontinuation of study drug 
11.1.2i Day 120 post activation of study drug 
 
11.2 Ocular Assessments 
11.2.1 All subjects will have ocular assessments of standard vision using the Snellen Eye  
       Chart, central visual field using the Amsler Grid, and color perception using the    
       Ishihara color plates no more than 72 hours before randomization up to and including     
       the day of active treatment, then weekly until two weeks post discontinuation of study  
   
       drug. 
11.2.2  Subjects should be instructed to report visual and ocular symptoms promptly to 
       study staff, and to have a vision check by study staff or physician thereafter.  
      11.2.3 Rationale: The package inserts for both oral (LYSTEDA) and IV (CYKLOKAPRON)   
             TXA include warnings for ocular and visual changes that have been observed in both   
             Pre-clinical animal studies and post-marketing surveillance. The package insert notes  
             that no such changes were observed during clinical trials involving treatment for   
             weeks to months of TXA, however it does recommend monitoring of visual acuity at 
             regular intervals, with discontinuation of therapy if visual or ocular symptoms occur. 
 
       11.2.4 In this study, the patients will often be receiving chemotherapies and steroids that 
              are associated with similar visual and ocular changes, though the exact incidence of 
              such changes is not well-characterized. Through the specified monitoring of visual 
              and ocular signs and symptoms, we address the possibility that TXA might  
  
  
              exacerbate the effects of the chemotherapies. All visual or ocular AEs that are     
  
              CTCAE Grade 3 or higher will be reported to the independent DSMB in an expedited    
              fashion, in order that any differential incidence of such changes across treatment  
  
              arms can be assessed and lead to protocol changes as appropriate. 
 
12. LOSS TO FOLLOW UP 
12.1 Death 
Death will be recorded on the end of study form and will be characterized by time from consent and 
according to whether the investigator attributes mortality due to bleeding, due to thrombosis, or due 
to other causes. 
 
12.2 Withdrawals 
Subjects are free to stop study drug at any time. If this occurs, the date and time that study drug is 
voluntarily stopped will be recorded, along with the reason the subject so elected. In the event the 
subject elects to stop study drug, they will still be followed for all study outcomes according to study 
protocol. 
 
Subjects are also free to withdraw their consent for further participation in the trial at any time. If this 
occurs, subjects will be asked to grant consent for the study team to passively monitor their clinical 
outcomes for major clinical events. In order to avoid any doubt, if subjects withdraw consent it will 
be explained to them that any data obtained up to the point of consent withdrawal will be included in 
study analysis, regardless of their consent for future monitoring.  
 
An End of Study form will be completed, which will detail whether the subject is: 
12.2.1 Stopping study drug, but continuing all other protocol specified procedures and 
monitoring. 
12.2.2 Stopping study drug and protocol specific procedures and monitoring, but allowing 
passive monitoring of their medical record and follow-up for vital status 30 days after 
their last dose of study drug. 
12.2.3 Discontinuing all further contact with study investigators.    


Page 36 of 63 
 
 
The patient’s physician or the principal investigator may withdraw the patient from the study for any 
reason. 
 
An End of Study form will be completed and the reason for withdrawal recorded if possible for all 
occurrences.  
 
13. END OF STUDY 
Subjects will exit the study after the day 120 post activation of study drug time point requirements 
are fulfilled. 
 
14. STATISTICAL CONSIDERATIONS 
14.1 Rationale and Objectives 
The hypothesis is that in patients with hematologic malignancies, during a period of severe 
thrombocytopenia, prophylactic use of anti-fibrinolytic therapy with TXA would decrease bleeding 
and the demand for platelet transfusions. Additional benefits for patients might extend to improved 
in-patient experience and earlier discharge home. 
14.1.1 Primary Efficacy Endpoint- Assessment of the TXA effect on bleeding will primarily 
consider the difference in the proportion of patients on each arm having bleeding of WHO 
grade 2 or above at some point during the first 30 days post activation of study drug.  
14.1.2 Secondary Efficacy Endpoints- Assessment of the TXA effect on demand for platelet 
transfusions will primarily consider the difference between the treatment arms in the average 
number of platelet transfusions per patient during the first 30 days post activation of study 
drug. A composite endpoint incorporating both bleeding and all cause mortality will consider 
the difference between the treatment arms in the average number of days alive without 
WHO grade 2 bleeding or greater during the first 30 days after activation. In order to protect 
against inflation of the type 1 error, a closed testing procedure will be used in which the 
statistical significance of any observed effects of TXA on the secondary endpoints will only 
be interpretable if a statistically significant effect of TXA on the primary efficacy endpoint is 
observed. 
14.1.3 Supportive and Exploratory Efficacy Endpoints- Additional endpoints examining other 
measures of bleeding, transfusions, and clinical outcomes associated with TXA treatment 
will be used to further support any statistically significant effects observed for the primary 
and secondary efficacy endpoints. The statistical significance of these additional endpoints 
will not be directly interpretable owing to the multiple comparisons. 
 
14.2 Randomization 
Patients will be randomized to antifibrinolytic therapy with TXA or to placebo in a 1:1  
fashion, stratified by site and disease group (allogeneic transplant, autologous transplant, or 
leukemia). Randomization will further be balanced within blocks of varying, 
undisclosed sizes. 
 
14.3 Analysis Populations 
Subjects will be grouped according to randomization groups: TXA versus placebo. Unless 
otherwise specified, all efficacy analyses will be by a modified intention to treat (mITT) 
strategy among activated subjects as described below. All subjects who were activated to 
study drug will be included in the analyses in the treatment group to which they were randomly 
assigned.  Subjects who were activated for study drug will be included in the 
analyses, even if they stop study drug “early”, cross over between treatment groups, or 
receive prophylactic transfusions not in accordance with the protocol. 
14.3.1 Efficacy Population 
    The mITT population used for efficacy analyses will be comprised of all randomized  
    patients for whom an order for administration of study drug is activated. Efficacy 


Page 37 of 63 
 
    analyses on these patients will use data gathered from the time the order for study drug 
    was activated until 30 days post activation. Randomized patients who develop exclusion 
    criteria prior to activation of study drug and who thus are excluded from receipt of study 
    drug and patients whose platelet counts never drop below the 30K threshold for 
    activation of study drug will not be included in the primary efficacy population.  
 
    Rationale: Owing to the emergent nature of treatment of thrombocytopenic patients,    
    patients are randomized in a double blind fashion to the treatment arms when platelet 
    levels drop below 50K. Because the treating physicians are blinded to treatment arm 
    assignment, no bias in activation of the study drug is anticipated. By using the time that 
    the study drug is activated as the criterion for inclusion in the mITT population, we guard 
    against differential delays in pharmacy preparation of placebo versus study drug. 
14.3.2 Safety Population 
The population used for safety analyses will be all patients who receive any amount of study 
drug. Follow-up for mortality and thrombotic events will occur at 120 days post activation. 
Other adverse events and serious adverse events will be collected for 30 days post 
discontinuation of study drug, with visual examinations occurring weekly for two weeks after 
discontinuation of study drug. SOS (VOD), AEs, and SAEs will be based on clinical 
diagnosis and patient report during the surveillance period. The frequency of follow-up will 
differ between inpatients and outpatients, with the former based on daily visits by the 
research coordinators and the latter based on patient diaries and semiweekly clinic visits 
(while still on study drug) or weekly contacts (after discontinuation of study drug 
 
14.4 Competing Risks 
14.4.1 Death 
     Owing to the seriousness of the patients’ underlying medical condition and based on  
     PLADO data it is anticipated that fewer than 5% of patients might die from their disease or its 
     treatment prior to full determination of the primary and/or secondary endpoints (e.g., 
     dying within 30 days without experiencing significant bleeding). Such “competing risks” 
     pose both scientific and statistical dilemmas. In terms of the scientific aims, the primary 
     analysis of A-TREAT data will use an approach that presumes independence of death 
     and future bleeding that is conditional on the hematologic and transfusion history for  
     patients prior to death. The interpretation of the resulting comparisons is as an estimate of     
     the effect of TXA on bleeding rates in a population in which the treatment of the underlying 
     medical condition (e.g., infections secondary to chemotherapy) has improved to the point that  
     patients are no longer at risk of early death. The statistical treatment of this approach is 
     described in 14.5.  
 
     Rationale: There is of course no way to know whether patients who die early have an 
     increased or decreased propensity to bleed in the absence of the competing risk. 
     Ultimately, the impact of the proposed “missing-at-random” (MAR) analysis of these 
     incomplete observations will have to be examined in a series of sensitivity analyses 
     described in 14.5.4. Alternative strategies considered by the A-TREAT investigators 
     included using death as a part of a composite endpoint that includes bleeding and all 
     cause mortality. However, such an analysis does not truly protect against the possibility 
     that a treatment might cause a minor increase in death and a more major decrease in 
     bleeding rates. Even with a composite endpoint the overall mortality rates would thus 
     need to be examined separately and there could even be nonsignificant trends toward 
     increased mortality on TXA that would have to be considered carefully. Hence, the A 
     TREAT investigators decided on an approach consistent with their clinical impression 
     that there was not a strong dependence between death from other causes and 
     propensity to bleeding, and to use the secondary and supporting endpoints and 
     sensitivity analyses to explore the robustness of the analysis results to other 
     assumptions 
14.4.2 Discharge from Hospital 


Page 38 of 63 
 
Patients discharged from the hospital prior to 30 days post randomization will not have as 
intense surveillance for study events as will those who remained in the hospital. They will 
have completed a daily bleeding diary and be contacted to determine any clinically important 
bleeding events. Absence of a bleeding event that leads to hospitalization or treatment by 
doctor/healthcare worker or categorized as such in the daily bleeding diary will be judged as 
absence of grade 2 or higher bleeding by WHO criteria. Similarly, such patients will be 
imputed to have not had transfusions. 
 
14.5 Statistical Analysis Models 
All statistical inference will be based on a two-sided 0.05 level of significance and two-sided 95% 
confidence intervals. Full details regarding statistical analysis models will be presented in a 
Statistical Analysis Plan completed prior to the first unblinded analysis of the data. 
14.5.1 Primary Endpoint 
The odds of bleeding at WHO grade 2 level or above will be analyzed in a logistic regression 
model adjusting for treatment arm, clinical site as a factored variable, and disease group 
(allogeneic transplant, autologous transplant, or leukemia) as a factored variable.. The test 
statistic will be based on the score statistic for the treatment arm parameter from the logistic 
regression model with adjustment for multiply imputed missing data. 
14.5.2 Secondary Endpoints 
The secondary endpoints of mean number of platelet transfusions and the mean number of 
days alive without WHO grade 2 level or above bleeding will each be analyzed in a linear 
regression model adjusting for treatment arm, clinical site as a factored variable, and 
disease group (allogeneic transplant, autologous transplant, or leukemia) as a factored 
variable. The test statistic will be based on the Wald statistic (parameter estimate divided by 
its standard error) as computed for the treatment arm parameter from the linear regression 
model using the Huber-White sandwich estimator for standard errors to account for possible 
heteroscedasticity and adjusting for multiply imputed data. 
14.5.3 Additional Analyses 
Analysis of the supportive and exploratory endpoints will be conducted using regression 
models adjusting for treatment arm, clinical site as a factored variable, and disease group 
(allogeneic transplant, autologous transplant, or leukemia) as a factored variable. Linear 
regression will be used for endpoints measuring the days free of bleeding and highest grade 
of bleeding, logistic regression will be used for binary endpoints, and proportional hazards 
regression will be used for times to event. The Huber-White sandwich estimator of the 
standard error will be used to allow for departures from the model based variance estimates, 
and adjustment will be made for multiply imputed missing data. 
14.5.4 Missing Data 
Patients will be followed for all clinical trial outcomes regardless of their adherence to the 
prescribed regimen for the study drug (TXA or placebo). Very few patients are expected to 
withdraw consent, though there will undoubtedly be some cases in which the data are 
missing for one or more of the primary, secondary, or supporting analyses due to withdrawal 
of consent or competing risks as described in 14.4.  
 
Initial analyses of primary and secondary endpoints will be based on missing-at-random 
(MAR) models that condition on the patients’ prior history of platelet levels, platelet and red 
blood cell transfusions, and days since activation of study drug. In the MAR model, data will 
be imputed by assuming that patients with missing data will be presumed to have 
distributions of outcomes the same as that observed in comparable patients who have 
complete data.  
 
Sensitivity analyses will use missing not at random (MNAR) models to reflect increased or 
decreased odds of bleeding among patients with incomplete data. Each treatment arm will 
be parameterized separately, and the robustness of any estimated treatment effect to those 
varying levels of dependence between early death or withdrawal of consent and incidence of 


Page 39 of 63 
 
bleeding will be quantified. Additional models will consider separate mechanisms for early 
death and withdrawal of consent. 
 
14.6 Sample Size and Precision of Statistical Inference 
14.6.1 
Minimal Clinically Important Difference 
Based on results observed in the PLADO study for patients who meet the general eligibility 
criteria for the A-TREAT study, it is anticipated that 57% of eligible patients would 
experience WHO Grade 2 bleeding or higher in the absence of antifibrinolytic therapy. In 
such a background setting of bleeding, the study investigators anticipate that less than a 
10% relative reduction in bleeding rates would not be sufficient to substantially change 
clinical practice, because the absolute risk reduction of 5.7% would mean that it would be 
necessary to treat approximately 17.5 patients in order for the treatment to have impact on 1 
patient (“Number Needed to Treat” (NNT) = 17.5). As much as a 25% relative reduction in 
bleeding rates would likely be judged sufficient to change clinical practice, because with an 
absolute risk reduction of 14.25%, the NNT of approximately 7 patients might be acceptable, 
provided no new safety issues related to antifibrinolysis in the thrombocytopenic population 
are uncovered. The A-TREAT investigators hypothesize that TXA will be associated with a 
relative reduction of 30% or higher (absolute reduction of 17%) based on observational data 
relative to their prior clinical experience. 
14.6.2 
Sequential Stopping Rules 
The conduct of the A-TREAT study will be overseen by an independent Data and Safety 
Monitoring Board (DSMB) who will enhance patient safety by monitoring study progress and 
integrity, incidence of AEs and SAEs, and interim estimates of treatment effect on bleeding. 
The DSMB will be guided by a group sequential stopping rule to judge the scientific and 
statistical credibility of interim results on the bleeding endpoints.  
 
While the exact stopping rule will be chosen in discussion with the DSMB (and documented 
in the Statistical Analysis Plan finalized prior to the first interim analysis at which the DSMB 
will see unblinded data), the A-TREAT investigators propose a stopping rule that would allow 
early stopping only if a one-sided level 0.20 O’Brien-Fleming stopping boundary suggested 
that TXA was associated with more bleeding than placebo. There would be no early stopping 
boundary for efficacy of TXA over placebo, with the final critical value for efficacy providing a 
one-sided 0.025 level of significance.  
 
The following table presents example stopping boundaries that might correspond to an 
observed combined event rate of 0.485 (such as might be observed with 57% events on the 
placebo arm and 40% events on the TXA arm). Using the R package RCTdesign (or 
equivalently, S-Plus S+SeqTrial), a stopping boundary having three analyses at 50%, 75% 
and 100% of the planned sample size and with a level 0.2 O’Brien-Fleming boundary for 
harm would be computed using the RCTdesign code: 
 
 seqDesign(prob.model = "prop", null.hypothesis = 0.57, 
  
alt.hypothesis = 0.4, nbr.analyses = 3,  
  
sample.size = c(165, 248, 330), test.type = "two.sided",  
     
power = "calculate", alpha = c(0.025, 0.2),  
  
 
P = c(Inf, 1)) 
 
For this example stopping boundary, the following table presents the critical values for harm 
and the corresponding adjusted statistical inference at each of the formal interim analyses. 
Critical values are expressed in terms of the crude estimate of treatment effect (TXA 
bleeding rate minus control bleeding rate), a Z statistic, and a one-sided fixed sample P 
value testing for harm. The adjusted statistical inference is a point estimate based on the 
bias adjusted mean and 95% confidence intervals and one-sided P values testing for harm 
using the likelihood ratio ordering of the outcome space. 


Page 40 of 63 
 
Analysis 
Stopping Boundaries 
Adjusted Inference 
 
N 
Crude 
Estimate 
Z 
Fixed 
P val 
Estimate 
95% CI 
One-sided 
P value 
50% 
165 
0.111 
1.440 
.075 
0.095 
(-.004, .181) 
0.123 
75% 
248 
0.074 
1.175 
.120 
0.059 
(-.018, .132) 
0.178 
100% 
330 
0.055 
1.019 
.154 
0.043 
(-.022, .115) 
0.200 
 
Rationale: Owing to the need for adequate safety data, even if TXA is associated with 
markedly less bleeding than placebo, there is an imperative to gather safety data on the full 
sample size. Because TXA is currently being used off-label in the thrombocytopenic setting, 
it is important to document any harm due to TXA treatment, rather than just documenting the 
absence of a markedly beneficial effect. 
 
14.6.3 
Sample Size 
Calculation of sample size and statistical power were made using S+SeqTrial based on the chi-
squared test of association, which is equivalent to the score test from simple logistic regression. 
Based on 1:1 randomization, a one-sided level of significance 0.025, a design alternative 
hypothesis of 30% relative reduction in bleeding rates (57% on the placebo arm and 40% on 
TXA), a sample size of 330 subjects (165 TXA, 165 placebo) will provide 88% statistical power 
to declare statistical significance on the primary endpoint. This sample size will provide 74.8% 
statistical power to detect a 25% relative reduction in bleeding rates (57% vs 42.75%). 
 
14.6.4 
Precision of Inference for Efficacy 
With the planned sample size and a placebo bleeding rate of 57%, an observed absolute 
decrease in WHO grade 2 or above bleeding of 10.6% (so 57% on placebo, 46.4% on TXA) 
would be judged statistically significant. Such an absolute difference in rates corresponds to 
a NNT of 9.4. If the baseline placebo bleeding rate were instead 40%, the threshold for 
statistical significance would be an absolute reduction of 10.14% (NNT = 9.9), and a 
baseline placebo rate of 70% would have a threshold of 10.35% (NNT = 9.7). These results 
are judged to be of the magnitude to possibly affect clinical practice, and allow for some 
added loss of precision with multiply imputed missing data. 
14.6.5 
Precision of Inference for Safety 
This study is not powered to establish the definitive safety of the treatment with respect to 
the frequency of VTE. However, an observed difference in frequency of VTE of 3.7% on the 
placebo arm and 5.5% or less on the TXA therapy arm would result in a 95% confidence 
interval that excluded a relative risk of 3.0. 
 
14.7 Feasibility of Recruitment 
The three clinical sites have proven success recruiting patients in the PLADO study at a rate that 
would predict success in achieving accrual of 330 activated patients during the planned 4 year 
accrual period.  
 
The following table documents how that prior success translates into the A-TREAT targeted 
enrollment: 
 
 
PLADO 
(3.5 yr) 
Annualized 
Rate 
Four Year 
Projections 
A-TREAT 
Target 
Puget Sound Blood Center at the 
University of Washington 
107 
30.6 
122 
110 
University of Pittsburgh 
119 
34.0 
136 
110 
University of North Carolina 
99 
28.3 
113 
110 
Total 
326 
92.9 
371 
330 
 
It can be seen that, based on annualized rates achieved in the PLADO study by these sites, there is 
12% excess capacity.   


Page 41 of 63 
 
 
If accrual to the study does not meet expectation additional sites will be recruited. 
 
15. TRIAL MONITORING 
15.1 Clinical Site Monitoring 
Study monitoring will be the responsibility of the Data Coordinating Center (DCC).  Upon successful 
approval of the protocol and establishment of the regulatory file, the clinical monitor will establish a 
clinical monitoring plan. To ensure that the investigator and the study staff understand and accept 
their defined responsibilities, the clinical monitor will maintain regular correspondence with the site 
and may be present during the course of the study to verify the acceptability of the facilities, 
compliance with the investigational plan and relevant regulations, and the maintenance of complete 
records. 
 
Monitoring visits by a sponsor’s representative-designated clinical monitor will be scheduled to take 
place during the study at appropriate intervals and after the last subject has completed the study. A 
report of monitoring observations will be provided to the site PIs for corrective actions. 
 
15.2 Direct Access to Data 
Study subjects will be identified on CRFs by a unique study subject ID code and on source 
documents by name or study subject ID code. No personal identifier will be used in any publication 
or communication used to support this research study. The study subject ID code will be used in the 
event it becomes necessary to identify data specific to a single study subject. Representatives from 
the DCC, IRB and the FDA are eligible to review medical and research records related to this study 
as a part of their responsibility to protect human study subjects in clinical research. Medical and 
research records will be de-identified before being photocopied. Study results will not be given to 
individual subjects but will be published in the open literature and made available as a matter of 
public record. 
 
15.3 Audits and Inspections 
Authorized representatives of the sponsor, IRB or FDA may visit the site to perform audits or 
inspections, including source data verification. The purpose of the audit or inspection is to 
systematically and independently examine all study-related activities and documents to determine 
whether these activities were conducted, and data were recorded, analyzed, and accurately 
reported according to the protocol, ICH GCP, and any applicable regulatory requirements. 
 
The investigator should contact the sponsor’s representative and DCC and the study sponsor 
immediately if contacted by a regulatory agency about an inspection. 
 
15.4 Source Data Verification 
A monitoring plan between the sites and the Data Coordination Center will be written and followed. 
A proportion of the CRF data will be checked against source documentation, including 100% of the 
first three patients recruited to the study at the site and key endpoint data of all patients recruited 
thereafter.  Particular attention will be paid to those patients who experience Serious Adverse 
Events and/or Serious Transfusion Reactions. All CRF data, whether or not subject to source data 
verification, will be checked by each site for completeness and consistency before being sent to 
data management. All consent forms will be monitored. 
 
15.5 Quality Assurance and Quality Control of Data 
In addition to source data verification, quality control of the clinical bleeding assessments will be on-
going throughout the trial. This will include initial training of the clinical study staff, training of 
patients in proper self-assessment, and a program of duplicate bleeding assessments to ensure 
consistency in completion of the clinical bleeding assessment forms. Standard guidelines will be 
followed.   
 


Page 42 of 63 
 
Good Clinical Practice Guidelines require that investigators maintain information in the subject’s 
medical records, laboratory reports, clinical charts etc. that corroborate data recorded on the CRFs. 
In order to comply with these source documentation requirements, the following information should 
be maintained: 
• 
Medical history/physical condition of the subject before enrollment sufficient to verify protocol 
entry criteria. 
• 
Dated and signed notes for specific results of procedures and exams. 
 
15.6 Confidentiality 
Data will be held securely in locked files or an encrypted database at the DCC and at each trial site.   
 
Patients will be identified only by study specific identification number on all data that are sent to the 
DCC.  
 
No personal identifier will be used in any publication or communication used to support this research 
study. The study subject’s ID code will be used in the event it becomes necessary to identify data 
specific to a single study subject. 
HIPAA requires that researchers obtain the study subject’s permission (HIPAA Authorization) to use 
and disclose health information about the subject that is either created by or used in connection with 
this research. The information includes the entire research record and supporting information from 
the study subject’s medical records, results of laboratory tests, and both clinical and research 
observations made during the study subject’s participation in the research. 
 
In this research, the study subject’s health information will be collected and used to conduct the 
study; to monitor the study subject’s health status; and any adverse events. Health information is 
used to report results of research to the sponsor’s representative and federal regulators and may be 
reviewed during study audits for compliance with study plans, regulations, and research policies. 
After the study ends, each study subject has the right to see and receive a copy of his or her 
information. 
 
The site PIs will be responsible for retaining sufficient information about each study subject, that is 
name, address, telephone number, and identity in the study, so that the sponsor’s representative, 
and other regulatory authorities may have access to this information should the need arise. 
 
 
15.7 Ethical Conduct of the Study 
This study will be conducted in accordance with 21 CFR Part 50 and the Belmont Principles of 
respect for persons, beneficence, and justice. 
 
The procedures set out in this study are designed to ensure that the sponsor’s representative and 
all study personnel abide by the principles of the ICH GCP Guideline and the CFR. The co-PIs 
confirm this by signing this study protocol. 
 
16. RECORDS AND REPORTS 
16.1 
Case Report Forms 
The study will used a web based data entry system. 
 
Case Report Forms (CRFs) will be used to collect all subject study data during the course of the 
study. The Principal Investigator at each clinical site or a predetermined designated individual shall 
be responsible for completion of the CRFs. All protocol deviations shall be documented and a 
justification for any missed assessments shall be provided on the protocol deviation log. Completion 
of the CRFs will be on-line via a secure password protected website.  Queries will be resolved via 
the secure web based data entry system; those that cannot be resolved in this way will be 
completed via email or phone communication and corrections will be made to appropriate CRFs.  


Page 43 of 63 
 
The Investigator will allow NHLBI, the FDA, or other regulatory bodies to review the study files, 
subject CRFs, medical records and other study-related documents.  
 
16.2 
Record Retention 
The sites must maintain the signed Informed Consent Forms, CRFs, study documentation (listed 
above) and source documents for at least 3 years after study completion or termination. In the event 
of an FDA audit, the Investigator must allow FDA access to the study records for inspection and 
copying. 
 
16.3 
Data Management 
Data will be collected by individual sites and provided to the DCC in the manner described below. 
16.3.1 Data Entry 
The DCC will provide secure web-based HTML forms to collect necessary information from 
the participating sites. Web entry forms will have dynamic features such as immediate 
checks on data and relationships within a form and between forms. Details and clarification 
about data items will be provided using pop-up windows and links to appropriate sections of 
the on-line version of the Manual of Operations. Data encryption and authentication methods 
will be used. Additional features of the web entry forms will include: form transmission 
history, access to past forms, tracking of data corrections, and the capability to save and re-
load incomplete forms. 
16.3.2 Database Management 
The DCC will use a two-tiered database system. A front-end database serves the web entry 
needs, using a database management system well-suited to handling updates from multiple 
interactive users. The data from this database will be transferred periodically (e.g. weekly) to 
a data format that can be utilized by statistical software packages. These will be the basis for 
queries, analyses and monitoring reports.  Database files will be maintained on a password 
protected computer in a secure location behind a firewall. 
Various versions of the database are kept as needed, e.g. for quarterly performance reports. 
Back-ups of data and programs will be performed regularly. Access to data will be limited to 
those who need access to perform their tasks. 
16.3.3 Trial Specific Exceptions to Expedited SAE Notification and Reporting 
All deaths will be reported on the end of study data form.  Although death as a result of 
disease progression is not an SAE it will be reported within 24 hours to the DCC, see section 
16.3.4).    
 
Due to the seriousness of the disease in this study, the following situations that would fulfil 
the definition of an SAE are excluded from expedited notification and may be reported to the 
DCC within 5 working days.  
• 
Elective hospitalization to simplify treatment or procedures 
• 
Elective hospitalization for pre-existing conditions that, in the investigator’s opinion, 
have not been exacerbated by trial treatment 
• 
Admission to the intensive care unit related to the disease 
• 
Severe Sepsis 
• 
Disease Progression 
• 
Any other serious event related to the underlying disease or medication used to treat 
the disease 
16.3.4 Serious Adverse Events 
All serious adverse events, including death of an actively participating subject, must be 
reported to the DCC within 24 hours by e-mail. This will allow investigation into the cause of 
death to determine if it was a result of disease progression or potential SAE.  The 
Serious/Unexpected Adverse Event Form must be sent to the DCC within 48 hours. The 
Serious Adverse Event Form will be entered into the web based data entry system by the 
site and further information and follow up will be prompted by the DCC via the SAE 
adjudication system in place.  


Page 44 of 63 
 
 
Serious adverse events, including death, will be monitored continuously by the DCC as data 
are received. 
 
When a transfusion related adverse reaction/event or other medical event occurs, the 
investigator responsible for the care of the patient must first assess whether the event is 
serious using the definitions given in Figure 3 (section 9). 
 
The clinical staff responsible for the care of the subject remains responsible for reporting all 
adverse transfusion reactions/events according to normal procedures. 
 
Information about the following events will be collected: 
• 
Serious adverse events, regardless of attributed relationship to study drug, that occur 
after consent is signed. 
• 
Any unexpected adverse events (all grades), attributed as possible, probably or 
definitely related to the study drug. 
 
The investigator must assess the causality of all Serious Adverse Events using the 
definitions in Table 4.  
 
If the causality assessment is deemed unrelated the event is classified as a SAE.  
 
If the causality is assessed as either possibly, probably or definitely related then the event is 
classified as a Serious Adverse Reaction. 
 
Table 4: Definitions of Causality/Attribution 
Relationship 
Description 
Unrelated 
There is no evidence of any causal relationship. 
Event clearly related to other factors (e.g., clinical 
state, other therapies; concomitant drugs). 
 
Possible 
There is some evidence to suggest a causal 
relationship (e.g. because the event occurs within a 
reasonable time after administration of the trial 
treatment). However, the influence of other factors 
may have contributed to the event (e.g. the 
patient’s clinical condition, other concomitant 
treatments). 
 
Probable 
Sequence of event is compatible with study drug, 
device, or procedure and cannot be explained by 
other factors without much doubt 
 
Definitely 
Sequence of event is compatible with study drug, 
device, or procedure and beyond doubt cannot be 
explained by other factors 
 
If the event is an SAE the Investigator must assess the expectedness of the event as well.  
 
 
 


Page 45 of 63 
 
Figure 5:  Investigator Assessment of Adverse Events 
The DCC should be notified within one working day of the investigator becoming aware of an 
event that requires expedited reporting (i.e. any expected or unexpected Serious Adverse 
Reaction or other serious event such as a major bleed [grade 3 or 4]). Investigators should notify 
the DCC of all such events occurring during the study period.  
 
The SAE form must be completed by the Investigator (consultant/physician named on the 
signature list and delegation of responsibilities log who is responsible for the subject’s care), 
with due care being paid to the grading, causality and expectedness of the event as outlined 
above. In the absence of the responsible investigator the form should be completed and signed 
by a member of the site trial team. The responsible investigator should subsequently check the 
SAE form, make changes as appropriate, sign and then upload to the web site, or re-fax/hand 
deliver to the DCC as soon as possible. The initial report shall be followed by detailed, written 
reports as requested by the DCC. 
 
Follow-up: Subjects must be followed-up until clinical recovery is complete and laboratory 
results have returned to normal or baseline, or until the event has stabilized. Follow-up should 
continue after completion of the study period if necessary. Follow up information may be 
provided to the DCC on a separate form provided once a SAE report form has been received. 
The subject must be identified by trial number only. The subject’s name must not be used on 
any correspondence. 
 
Site staff must notify their local IRB of any event that is classified as a suspected unexpected 
serious adverse reaction (as per the institutions standard local procedure). 
 
DCC Responsibilities: The Primary Investigator or a medically qualified delegate will review all 
SAE reports received. The causality assessment given by the local Investigator at the hospital 
cannot be overruled and in the case of disagreement, both the opinions of the patient’s 
physician and the trial site PI will be provided in any subsequent reports. All SAE reports will be 
reviewed by the DSMB, as directed by the DSMB and as a listing at their review of the trial every 
6 months. 
 


Page 46 of 63 
 
17. INSTITUTIONAL REVIEW BOARD (IRB) 
No subject will be enrolled into the study until the IRB has approved the protocol and the informed 
consent form. Copies of all submissions to and correspondence (approvals and disapprovals) from 
the IRB must be maintained in a regulatory file at the study site. 
 
18. TRIAL COMMITTEES 
18.1 
Trial Steering Committee (TSC) 
A Trial Steering Committee will provide oversight of this trial, which will be conducted according to 
the principles of GCP. Members of the TSC include PIs from the trial sites and the PI of the DCC. 
 
18.2 
Data and Safety Monitoring Board (DSMB) 
The conduct of the trial and the safety of patients accrued to the trial will be monitored by an 
Independent DSMB agreed upon by the NHLBI. Membership will be independent of study 
investigators and have no financial or intellectual conflicts of interest. The DSMB will be comprised 
of 4-6 members, including hematologists, a biostatistician, and an ethicist.  The DSMB will be 
guided by a DSMB Charter that delineates the roles and responsibilities of the DSMB, including 
delineation of the lines of communication between study clinical investigators, study data 
coordinating center, and the NHLBI. 
 
The DSMB will meet via teleconference every 6 months to review study progress (recruitment, 
adherence to protocol) and safety data, including serious adverse events, adverse events, bleeding 
events, and mortality. The DSMB may also request more frequent meetings as necessary to protect 
study integrity and study safety.  
 


Page 47 of 63 
 
APPENDIX 1: TRANEXAMIC ACID AND EPSILON AMINOCAPROIC ACID STUDIES 
Table 1: Tranexamic Acid Studies (Characteristics)
Study 
Type of 
study 
No. of 
pts 
No. of pts 
receiving 
TA 
No. of pts plt 
refractory/ 
allo-
immunization 
Diagnosis of 
pt 
Treatment 
of 
underlying 
disease 
Tranexamic 
acid dose 
Tranexamic 
acid 
frequency 
Tranexamic 
acid route 
Treatment 
started 
Treatment 
stopped 
Platelets 
given 
Randomized studies 
Avvisati 
1989[19] 
RCT 
12 
6 
NR 
 
APL 
Chemo 
2g 
8hrly 
IV in 500ml 
5% glucose 
1st day of 
antileukemic 
Rx 
After 6 days 
Prophylactic 
Fricke 
1991[20] 
RCT 
Cross-
over 
8 Only 
3 
complet
ed 
study 
8 
At least 3 
7 AA 
1 MDS 
NR 
20mg/kg 
8hrly 
Oral 
After 4 day 
trial period to 
assess drug 
tolerance 
Successive 
4/52 
courses or 
until grade 2 
bleeding 
Therapeutic 
Shpilberg 
1995[12] 
RCT 
56 
26 
NR 
AML 
38 induction 
18 
consolidation 
Chemo 
1g 
6hrly 
Oral 
Platelets < 20 
or rapidly 
falling and < 
50 
Platelet 
count > 20 
for 2 
consecutive 
counts 
Therapeutic 
Non-randomized studies 
Ben-Bassat 
1990[21] 
Not 
controlled 
54 
54 
NR 
Newly 
diagnosed 
AML 
Chemo 
1g 
6hrly 
Oral 
IV if unable 
to tolerate 
PO 
Platelet count 
< 50 
Platelet 
count > 20 
Therapeutic 
Sanz 2010[22] 
Historical 
control 
732 
560 
NR 
Induction APL 
patients 
Chemo 
100mg/kg/day 
Continuous 
infusion 
IV 
Platelets <50 
Platelets > 
50 
Prophylactic 
>30 


 
Page 48 of 63 
 
Table 2: Tranexamic Acid Studies (Results) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
†This study had major methodological limitations and any results should be treated very cautiously. 
* It could not be determined whether the higher incidence of bleeding in the TXA arm was due to the higher number of days patients were on the study prior to failure as this was not reported. 
Study 
Type of study 
No. of pts 
Diagnosis of 
patient 
Thrombotic risk 
Bleeding 
Death due to 
bleeding 
Platelet 
transfusions 
Platelets 
given 
Randomized studies 
Avvisati 1989[26] 
RCT 
12 
APL 
No 
thromboembolic 
events observed 
Cumulative 
hemorrhagic 
scores 
TA 3 
C 42 
(P = 0.0045) 
Not reported 
Extra platelet 
Tx 
TA = 69 Tx 
C = 222 Tx 
 
P = 0.045 
 
Prophylactic 
Fricke 1991[38]† 
RCT Cross-over 
8 Only 3 
completed 
study 
7 AA 
1 MDS 
Not reported 
No evidence for 
difference in 
bleeding from 
mouth (p >0.2) or 
nose (p = 0.07). 
TXA more 
bleeding for skin 
(P<0.02)* 
1 patient died 
from ICH 4 days 
after starting Rx 
Failure for 
each section 
of the study 
was need for 
plt Tx 
TA 8/26 failed 
C = 9/23 
failed 
Therapeutic 
Shpilberg 
1995[27] 
RCT 
56 
AML 
38 induction 
18 consolidation 
No 
thromboembolic 
events observed 
Induction  
TA 6.2±2.9 
C 4.5±3.6 
Consolidation 
TA 1.1±1.4 
C 2.6±2.2 
(P <0.5) 
None 
Induction 
(units) 
TA 22.1±13.2 
C 23.1±11.7 
Consolidation 
(units) 
TA 3.7±4.1 
C 9.3±3.3 
(P <0.5) 
Therapeutic 
Non-randomized studies 
Ben-Bassat 
1990[39] 
Not controlled 
54 
Newly diagnosed 
AML 
No 
thromboembolic 
events observed 
Major bleeding 
6/78 induction 
courses 
Major bleeding 
0/53 
consolidation 
courses  
 
1 death due to 
bleeding 
Induction 
4.6 ± 4.1 
Consolidation 
1.7 ± 1.8 
transfusions 
Therapeutic 
Sanz 2010[40] 
Historical control 
732 
Induction APL 
patients 
 
Tranexamic acid 
use RR 1.96 
 (P = 0.049) 
Not reported 
No difference 
5.1% (9 of 175). 
5% (28 of 561) 
Not reported 
Prophylactic 
>30 


 
Page 49 of 63 
 
Table 3: Epsilon Aminocaproic Acid Studies (Characteristics) 
Study 
Type of 
study 
No. 
of 
pts 
No. 
who 
rec’d 
EACA 
No. plt 
refractory/ 
allo-
immunization 
Diagnosis of 
patient 
Treatment 
of 
underlying 
disease 
EACA 
dose 
EACA 
frequency 
EACA 
route 
Treatment 
started 
Treatment 
stopped 
Platelets 
given 
Randomized studies 
Gallardo 
1983[23] 
RCT 
19 
9 
NR 
15 AML 
4 ALL 
(1 patient 
inevaluable) 
Chemo 
Loading 
dose 
100mg/kg 
12-24g/day 
thereafter 
NR 
NR 
Platelet 
count < 20 
x 109/l 
Platelet 
count ≥ 20 x 
109/l 
Platelet 
count < 
20 x 109/l 
Non-randomized studies 
Wassenaar 
2008[24] 
Control 
group 
Retro-
spective 
database 
analysis 
30 
17 
NR 
30 APL  
(No comparison 
made between 
those that 
received/did not 
receive EACA) 
Chemo [30] 
 
(19 pre-
ATRA era) 
 
Loading 
dose 6g  
Followed by 
1g/hr 
continuous 
infusion 
Infusion 
IV 
If α-2-
antiplasmin 
< 50% 
If α-2-
antiplasmin 
> 50% for 2 
consecutive 
days 
NR 
Ballen 
2004[25] 
No control 
group 
26 
26 
NR 
14 Lymphoma 
8 MM 
4 Solid tumors 
 
AutoSCT [26] 
1 to 6g 
titrated 
upwards to 
treat 
bleeding 
Max dose 
24g/day 
4 x /day 
PO 
IV 
infusion 
if unable 
to 
tolerate 
PO 
Platelet 
count < 30 
x 109/l 
When 
thrombocyto
penia had 
resolved 
25/26 
had none 
(religious 
reasons) 
Bartholom
ew 
1989[2644] 
No control 
group 
 
 
17 
17 
17 
8 ITP 
2 MDS & ITP 
2 HIV 
1 AA 
1 CLL 
1 Drug induced 
thrombocytope
nia 
1 BSS 
1 Unknown 
NR 
Loading 
dose 5g  
Then 1g 
6 x /day. 
Decreased 
to 4x /day 
once 
bleeding 
stopped 
14/17 
PO 
3/17 IV 
 
To control 
bleeding.  
 
3/14 had 
platelet 
count > 20 
x 109/l prior 
to Rx 
Platelet 
count 35 to 
50 x 109/l 
NR 
Benson 
1993[27] 
No control 
group 
 
Retro-
spective 
18 
18 
9 
6 Solid tumors 
3 CML 
3 AML 
2 ALL 
4 Other 
Auto SCT [8] 
AlloSCT [10] 
0.5 to 
1.5g/hr 
Infusion 
IV 
To control 
severe 
bleeding 
NR 
NR 
Brown 
2006[28] 
No control 
group  
48 
48 
NR 
23 MM 
15 NHL 
8 HL 
2 Solid tumors 
AutoSCT [48] 
4g 
6x /day 
IV 
Platelet 
count < 30 
x 109/l 
NR 
None 
(religious 
reasons) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Page 50 of 63 
 
AA = aplastic anemia 
AlloSCT = allogeneic stem cell transplant 
AML = acute myeloid leukemia 
AutoSCT = autologous stem cell transplant 
ALL = acute lymphocytic leukemia 
APL = acute prolymphocytic leukemia 
ATRA = All Trans Retinoic Acid 
BSS = Bernard Soulier Syndrome 
Chemo = chemotherapy 
CLL = chronic lymphocytic leukemia 
CML = chronic myeloid leukemia 
CNS = central nervous system 
CTCAE = common toxicity criteria adverse events 
GI = gastrointestinal 
Hb = hemoglobin 
HL = Hodgkin’s lymphoma 
ICH = intra-cranial hemorrhage 
ITP = immune thrombocytopenia 
IV = intravenous 
MDS = myelodysplastic syndrome 
MM = Multiple myeloma 
Mth = month 
NHL = non-Hodgkin’s lymphoma 
NR = not reported 
Ped = pediatric 
Plt = platelet 
PO = oral 
Pt = patient 
RBC = red blood cell 
Rx = treatment 
Tx = transfusion 
VTE = venous thromboembolism 
 
Table 3. 
Continued 
 
Study 
Type of 
study 
No. 
of 
pts 
No. 
who 
rec’d 
EACA 
No. platelet 
refractory/ 
allo-
immunization 
Diagnosis of 
patient 
Treatment 
of 
underlying 
disease 
EACA 
dose 
EACA 
frequency 
EACA 
route 
Treatmen
t started 
Treatment 
stopped 
Platelets 
given 
Chakrabati 
1998[29] 
No control 
group 
15 
15 
NR 
4 AML 
4 ALL 
5 ITP 
2 AA 
NR 
Major 
bleeding 
Loading 
dose 5g 
then 1g  
 
Minor 
bleeding 
250mg 
Major 
bleeding 
 4 x /day 
increased to 
6x /day if no 
response 
 
4 x /day 
NR 
Platelet 
count < 20 
x 109/l and 
bleeding 
NR 
If no 
response 
to 6g 
EACA 
per day 
Gardner 
1980[30] 
No control 
group 
14 
(4 
Ped) 
14 
At least 2 
9 AA 
1 AML 
1 ALL 
1 Myelofibrosis 
2 Other 
NR 
8 to 24g/day 
in adult 
patients 
Varied.  
 
Up to 13 
months of 
Rx.  
IV or PO 
To control 
bleeding 
Platelet 
count > 20 x 
109/l 
Therape
utic 
Garewal 
1985[31] 
No control 
group 
9 
9 
8 
4 AML 
2 ALL 
1 CLL 
1 MDS 
1 Other 
(Excluded 
APL) 
NR 
Loading 
dose 5g  
Then 4g 
6 x /day 
(decreased 
to 3 to 4 
x/day if 
higher dose 
not 
tolerated) 
IV or PO 
Platelet 
count < 20 
x 109/l 
NR 
NR 
Kalmadi 
2006[11] 
Retro-
spective 
database 
analysis of 
patients 
receiving 
EACA 
Only pts > 
18yrs & plt 
count < 75 
x 109/l 
No control 
group 
77 
77 
32 
22 AML 
20 MDS (11 
transforming to 
AML) 
10 NHL 
6 CML  
4 ALL 
2 AA 
2 ITP 
2 Myelofibrosis 
1 CLL 
1 MM 
7 Solid tumors 
NR 
Median 
initial dose 
4g/day 
(range 2g to 
24g/day). 
 
Median 
dose 6g/day  
(range 2g to 
24g/day). 
 
NR 
NR 
Median plt 
count 7 x 
109/l (range 
1 to 66 x 
109/l). 
 
Median 
duration of 
treatment 8 
days (range 
1 to 216 
days) 
NR 


 
Page 51 of 63 
 
Table 4: Epsilon Aminocaproic Acid Studies (Results) 
 
Study 
Type of study 
No. of 
pts 
Diagnosis of patient 
Thrombotic risk 
Bleeding 
Death due to bleeding 
Platelet transfusions 
Platelets 
given 
Randomized studies 
Gallardo 
1983[23] 
RCT 
19 
15 AML 
4 ALL 
No deaths due to 
thromboembolic 
disease 
Capillary bleeding 
EACA 31% of days at risk* 
Placebo 50% of days at risk* 
Major bleeding† 
EACA 15% 
Placebo 19% 
NR 
EACA  
1 every 13.3 days at 
risk* 
Placebo 
1 every 10.5 days at 
risk* 
Prophylactic 
Non-randomized studies 
Wassenaar 
2008[24] 
Control group 
30 
30 APL  
 
1 episode of catheter 
assoc. 
thromboembolism. No 
effort to identify 
asymptomatic episodes 
of VTE 
No CTCAE grade 4 bleeding 
Grade 3 bleeding [9] 
Grade 2 bleeding [3] 
Grade 1 bleeding [5] 
None 
NR 
NR 
Ballen 2004[25] 
No control group 
26 
14 Lymphoma 
8 MM 
4 Solid tumors 
 
NR 
5/26 bled 
2 life-threatening (1 died) 
1 nasal packing 
2 minor 
No bleeding when  plt count > 5 
x 109/l 
1 Died ICH (D7) CNS 
disease 
(medulloblastoma) 
1 patient with ICH 
25/26 had 
none 
(religious 
reasons) 
Bartholomew 
1989[26] 
No control group 
17 
8 ITP 
2 MDS & ITP 
2 HIV 
1 AA 
1 CLL 
1 Drug induced 
thrombocytopenia 
1 BSS 
1 Unknown 
NR 
All bled prior to EACA. 
1/17 Bleeding stopped 
16/17 Bleeding controlled 
 
1 Died ICH (ICH 
present prior to EACA 
administration) 
Platelet use decreased 
from 164 units in 8/12 
period prior to EACA to 
18 units in 4/12 period 
following 
administration of drug 
NR 
Benson 
1993[27] 
No control group 
18 
6 Solid tumors 
3 CML 
3 AML 
2 ALL 
4 Other 
 
No thrombotic events 
Bleeding markedly 
reduced/stopped 12/18 
 
No response 6/18 
NR 
NR 
NR 
Brown 2006[28] 
No control group 
48 
23 MM 
15 NHL 
8 HL 
2 Solid tumors 
 
NR 
1 Major GI bleed 
None 
None 
None 
(religious 
reasons) 
Chakrabati 
1998[29] 
No control group 
15 
4 AML 
4 ALL 
5 ITP 
2 AA 
NR 
Prior to EACA 10/15 had major 
bleeding and 5/15 minor 
bleeding. 
During EACA 
8/10 with major bleeding 
stopped bleeding 
2/10 stable Hb. 5/5 with minor 
None 
NR 
If no 
response to 
6g EACA 
per day 


 
Page 52 of 63 
 
bleeding stopped bleeding 
 
Study 
Type of study 
No. of 
pts 
Diagnosis of patient 
Thrombotic risk 
Bleeding 
Death due to bleeding 
Platelet transfusions 
Platelets 
given 
Chakrabati 
1998[29] 
No control group 
15 
4 AML 
4 ALL 
5 ITP 
2 AA 
NR 
Prior to EACA 10/15 had major 
bleeding and 5/15 minor 
bleeding. 
During EACA 
8/10 with major bleeding 
stopped bleeding 
2/10 stable Hb. 5/5 with minor 
bleeding stopped bleeding 
 
None 
NR 
If no 
response to 
6g EACA 
per day 
Gardner 
1980[30] 
No control group 
13 
9 AA 
1 AML 
1 ALL 
1 Myelofibrosis 
1 Other 
No thromboembolic 
events observed 
Not reported for all patients.  
 
Text reports decreased 
bleeding 
None 
Platelet usage 
reported for 4/13 
receiving long term 
EACA (> 5 mths). 
 
Before EACA 30units 
plts/pt/mth 
During EACA 
1unit plts/pt/mth 
 
Therapeutic 
Garewal 
1985[31] 
No control group 
9 
4 AML 
2 ALL 
1 CLL 
1 MDS 
1 Other 
No thromboembolic 
events observed 
All bled prior to EACA. 
 
3 bled  during EACA 
2 Died ICH (D8; D21) 
1 Died bleeding peptic 
ulcer (D29) 
(All had progressive 
disease unresponsive 
to treatment) 
NR 
NR 
Kalmadi 
2006[11] 
Retrospective 
database 
analysis 
 
No control group 
77 
22 AML 
20 MDS (11 
transforming to AML) 
10 NHL 
6 CML  
4 ALL 
2 AA 
2 ITP 
2 Myelofibrosis 
1 CLL 
1 MM 
7 Solid tumors 
NR 
51 bleeding stopped 
 
13 reduced RBC requirements 
by > 50% compared to previous 
3/7 
 
13 no response 
 
NR 
Before EACA mean 
1.5 ± 0.8 plt Tx/day 
 
During EACA mean 
1.0 ± 0.7 plt Tx/day 
 
(P < 0.0001 t test) 
NR 
* Days at risk defined as days when platelet count less than 20 x 109/l 
† Major bleeding defined as nose bleeding requiring posterior packing, gross gastrointestinal or genitourinary tract bleeding and central nervous system bleeding 
NR = not reported 
 
 
 
 
 
 
 
 
 


 
Page 53 of 63 
 
 
 
Table 5: Prophylactic use of Tranexamic acid vs. Epsilon Aminocaproic Acid in RCTs.  
Organized in order of increasing ratios TXA vs. EACA.  
(Data from Henry et al 2011[8]). 
 
Study 
Number of 
participants 
Study group 
Dose 
Assume median weight 80kg (PLADO data) 
Effect 
TXA 
EACA 
 
TXA 
EACA 
Ratio 
Blood loss 
(mls). Random 
mean 
difference 
Exposure to 
blood 
Dalmau 
2000[32] 
42 
42 
Orthotopic liver 
transplantation 
16mg/kg/hr 
16mg/kg/hr 
1:1 
Not reported 
Not reported 
Dalmau 
1999[33] 
42 
42 
Orthotopic liver 
transplantation 
10mg/kg/hr 
16mg/kg/hr 
1.6:1 
Not reported 
No difference. 
Trend to TXA 
0.81 (0.64 to 1.02) 
Fergusson 
2008[34] 
770 
780 
High risk cardiac 
surgery patients 
30mg/kg loading dose 
16mg/kg maintenance 
2mg/kg bypass circuit 
TOTAL = 3.84g 
10g loading dose and 2g 
maintenance 
 
TOTAL = 12g 
3.125:1 
Not reported 
No difference 
1.0 (0.93 to 1.07) 
Camarasa 
2006[35] 
35 
32 
Total knee 
replacement 
10mg/kg over 30mins 
followed by 10mg/kg for 
3 hrs 
TOTAL = 3.2g 
100mg/kg over 30mins 
followed by 1g/hr for 
3hrs 
TOTAL = 11g 
3.44:1 
No difference. -9 (-
270.16 to 252.16) 
No difference. 
Trend to TXA 
0.23 (0.03 to 1.94) 
Casati 1999[36] 
72 
68 
Cardiac surgery 
(assume 3.5 hr 
op) 
1g over 20 mins 
followed by 400mg/hr 
and 500mg pump prime 
5g over 20mins followed 
by 2g/hr and 2.5g added 
to pump prime 
5:1 
Favours TXA. -
156.00 (-234.25 to 
-77.75) 
No difference 
0.7 (0.41 to 1.18) 
Menichetti 
1996[37] 
24 
24 
Cardiac surgery 
(assume 3.5hr op) 
10mg/kg bolus then 
3mg/kg/hr. Additional 
10mg/kg to prime 
TOTAL = 2.44g 
80mg bolus, 30mg/kg/hr. 
Additional 80mg/kg to 
prime 
TOTAL = 14.88g 
6:1 
Favours EACA. 
225.0 (36.28 to 
413.72) 
Favours EACA 
 
Maineri 
2000[38] 
24 
24 
Cardiac surgery 
(assume 3.5 hr 
op) 
20mg/kg over 60 mins 
then 2mg/kg/hr 
TOTAL = 2g 
10g over 30mins 
followed by 2g/hr 
TOTAL = 16g 
8:1 
No difference. -40 
(-206.73 to 126.73) 
No difference 
Landymore 
1997[39] 
56 
44 
Cardiac surgery 
(assume 3.5 hr 
op) 
10mg/kg/hr followed by 
1mg/kg/hr 
TOTAL = 1.08g 
5g followed by 1g/hr 
 
TOTAL = 8.5g 
8.5:1 
Favours EACA/ 
192 (65.87 to 
318.13) 
Not reported 
Pinosky 
1997[40] 
20 
20 
Cardiac surgery 
15mg/kg followed by 
1mg/kg/hr for 6 hrs 
TOTAL = 1.68g 
150mg/kg/hr followed by 
10mg/kg/hr for 6 hrs 
TOTAL = 16.8g 
10:1 
Favours TXA.  -
361 (-666.56 to -
55.4) 
No difference. 
Trend to EACA 
1.57 (0.77 to 3.22) 
Penta de 
Peppo 1995[41] 
15 
15 
Cardiac surgery 
10mg/kg followed by 
1mg/kg for 10hr 
TOTAL = 1.6g 
10g followed by 2g/hr for 
5 hrs 
TOTAL = 20g 
12.5:1 
No difference. 25 (-
138.86 to 188.86) 
No difference. 
Trend to TXA 
0.33 (0.04 to 2.85) 


 
 
Figure 1: Fergusson Trial 2008 (BART trial). Comparison of outcomes between TXA and EACA 
 
 
 
 
 
 
 


 
 
Figure 2: Fergusson Trial 2008 (BART). Comparison of adverse events between TXA and EACA. 
 
 
 


 
 
APPENDIX 2: WHO GRADING SYSTEM 
General Definitions of WHO Grades 
 
Grade 1 
Any bleeding that does not fulfil the criteria for Grade 2 bleeding (general or organ-specific). For examples of grade 1 
bleeding, please see organ-specific definitions. 
Grade 2 
Any bleeding that does not fulfil the criteria for Grade 3 bleeding (general or organ-specific) BUT requires an intervention or 
treatment: 
• 
Examples of interventions 
▪ Nasal packing 
▪ Bladder irrigation 
• 
Examples of treatments 
▪ Platelet transfusion given to treat active bleeding and NOT given only because the platelet count is below the 
prophylactic platelet transfusion trigger 
▪ Medications prescribed to treat bleeding 
Grade 3 
Any bleeding that does not fulfil the criteria for Grade 4 bleeding (general or organ-specific) BUT requires: 
• 
Red cell transfusion specifically related to treatment of bleeding within 24 hours of onset of bleeding, for example: 
▪ Required to treat fall in hemoglobin of at least 2 g/dL within preceding 24 hours without evidence of hemolysis 
▪ No hemoglobin increment within 24 hours of at least a 2 unit red cell transfusion without evidence of hemolysis 
• 
A significant intervention, for example: 
▪ Endoscopy to treat the bleeding 
▪ Interventional radiography to treat the bleeding 
▪ Transfer to the operating room for treatment of bleeding 
Grade 4 
Any bleeding that is: 
• 
Fatal 
• 
Life-threatening. For example: 
▪ Bleeding that requires transfer to intensive care/treatment unit 
▪ Bleeding that is associated with hemodynamic instability and causes inadequate tissue perfusion, including: 
❖ Hypotension 
o Systolic blood pressure (BP) < 90 mmHg 
o > 40 mmHg fall in systolic BP 
o Mean arterial pressure (MAP) < 65 mmHg 
❖ In absence of hypotension, markers of inadequate tissue perfusion include: 
o Increased blood lactate 
o Increased base deficit 
o Perfusion related low pH (if other causes of metabolic acidosis (e.g. sepsis) are not present) 


 
 
Organ-specific definitions of WHO Grades 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
General 
Bleeding that does not fulfil the 
requirements for grade 2 
bleeding. Please see examples 
in organ-specific categories 
below. 
Any bleeding that does not fulfil 
the requirements for grade 3 
bleeding BUT requires an  
intervention or treatment: 
Examples of Interventions 
- Nasal Packing 
- Bladder irrigation 
Examples of treatments 
- Platelet transfusion given to 
treat active bleeding and NOT 
given only because the platelet 
count is below the prophylactic 
platelet transfusion trigger 
- Medications prescribed to treat 
bleeding 
 
Any bleeding that does not fulfil 
the criteria for grade 4 bleeding  
BUT requires: 
Red cell transfusion specifically 
related to treatment of bleeding 
within 24 hours of onset of 
bleeding. 
OR 
A significant intervention, for 
example: 
- Endoscopy to treat the bleeding 
- Interventional radiography to 
treat the bleeding 
- Transfer to the operating 
theatre/ room for treatment of 
bleeding 
 
Any bleeding that is fatal or life 
threatening. For example:   
- Bleeding that requires transfer 
to intensive care/treatment unit 
- Bleeding that is associated 
with hemodynamic instability 
and causes inadequate tissue 
perfusion 
(for further clarification see 
general guideline above). 
 
Oral and nasal† 
Spontaneous oropharyngeal 
bleeding - total duration of all 
episodes in previous 24 hours < 
30 minutes* 
 
Traumatic oropharyngeal 
bleeding e.g. after bites to lips 
and tongue lasting > 10 minutes 
or interfering with daily activities 
 
Epistaxis - total duration of all 
episodes in previous 24 hours < 
30 minutes* 
 
Petechiae of oral mucosa 
 
Few (≤ 5) hemorrhagic bullae or 
blisters 
Oropharyngeal bleeding – total 
duration of all episodes in 
previous 24 hours > 30 minutes* 
 
 
 
 
 
 
Epistaxis – total duration of all 
episodes in previous 24 hours > 
30 minutes* 
 
 
 
Multiple (> 5) hemorrhagic bullae 
or blisters 
Any bleeding that requires a 
transfusion or a procedure (not 
including intubation) 
Any bleeding that requires 
intubation to protect the airway 
Skin† 
Few (≤ 5) spontaneous bruises  
(ecchymoses) over 2.5cm in size 
and none >10cm 
 
 
 
 
 
Purpura (3mm to 10mm 
diameter) (Few purpuric lesions 
Multiple (> 5) spontaneous 
bruises (ecchymoses) each 
>2.5cm or any one >10cm. 
 
Many (> 10) spontaneous 
bruises (ecchymoses) (>10mm in 
diameter)  that does not fulfil the 
above criteria. 
 
Purpura (3mm to 10mm 
Any bleeding that requires a 
transfusion or a procedure 
 


 
 
(≤ 10). 
 
 
Petechiae (< 3mm diameter) 
covering ≤ 25% of skin (1 arm = 
10%; 1 leg = 25%; trunk = 44%; 
head = 6%) 
diameter). Many purpuric lesions 
(> 10). 
 
 
Petechiae covering > 25% of skin 
(1 arm = 10%; 1 leg = 25%; trunk 
= 44%; head = 6%). 
Soft-tissue and 
musculoskeletal 
Asymptomatic spontaneous soft-
tissue hematoma less than 10cm 
in diameter. 
 
 
 
Traumatic joint bleeding 
(confirmed by aspiration, imaging 
study or other accepted 
technique) 
Asymptomatic  spontaneous soft-
tissue hematoma greater than 
10cm in diameter. 
 
Symptomatic soft-tissue 
hematoma (e.g. causing pain or 
discomfort). 
 
Spontaneous joint bleeding 
(confirmed by aspiration, imaging 
study or other accepted 
technique) 
 
Any bleeding that requires a 
transfusion or a procedure (not 
including compartment 
syndrome) 
Any bleeding that causes 
compartment syndrome. 
 
 
Gastrointestinal 
Fecal occult blood 
 
Rectorrhagia- visible red blood 
on tissue paper/not mixed with 
stool 
Melena 
 
Hematochezia – visible red blood 
mixed in stool, not requiring a 
transfusion 
 
Hematemesis – Grossly visible 
blood in emesis (vomit) or in 
nasogastric drainage tube (not 
related or 
secondary to swallowed blood) 
Rectal Bleeding requiring a 
transfusion 
 
Hematemesis requiring a 
transfusion 
 
Any bleeding that requires a 
transfusion or a procedure 
 
Genitourinary 
Abnormal vaginal bleeding 
(Unexpected bleeding out of 
normal cycle OR Bleeding 
heavier than normal OR 
Breakthrough bleeding (patient 
on hormonal therapy to prevent 
bleeding)) with spotting 
 
 
Abnormal vaginal bleeding 
(Unexpected bleeding out of 
normal cycle OR Bleeding 
heavier than normal OR 
Breakthrough bleeding (patient 
on hormonal therapy to prevent 
bleeding)) more than spotting 
 
Gross/visible hematuria  
 
 
 
Any bleeding that causes: 
increase ≥1.5 X reference serum 
creatinineǂ 
or 
Serum creatinine rises by ≥ 
26µmol/L (0.3mg/dl) within 48 
hours 
 
or 
Urine output <0.5 mL/kg/hr for > 
6 consecutive hrs 
 
Or  
Any bleeding that requires a 
transfusion or a procedure 
Any bleeding that causes: 
increase ≥3 X reference serum 
creatinineǂ 
or  
Serum creatinine rises by ≥354 
μmol/L (4.0 mg/dl) 
or  
Commenced on renal 
replacement therapy  
or  
Urine output <0.3 mL/kg/ hr for 
> 24 hrs  
or  
Anuria for at least 12 hrs 
Pulmonary 
 
Hemoptysis – Visible blood 
 
Any bleeding requiring 
supplemental oxygen to maintain 
Any bleeding requiring 
respiratory support (includes 


 
 
Blood in broncho-pulmonary 
lavage, or blood tinged sputum 
(excluding those with nose or 
oropharyngeal bleeding or 
mucositis). 
oxygen saturation above 93%. 
 
non-invasive (CPAP, BiPAP), 
or invasive ventilation) 
Body cavity 
 
Visible blood in body cavity fluid 
(e.g. red cells apparent in fluid 
aspirate) short of criteria for 
Grade 3 or 4 
Grossly visible blood in body 
cavity fluids AND organ 
dysfunction with symptoms, 
AND/OR need to intervene (e.g. 
to aspirate). 
 
Any bleeding that requires a 
transfusion or a procedure 
 
Eye† 
Sub-conjunctival hemorrhage  
 
 
Traumatic retinal bleeding 
without visual impairment 
 
 
Traumatic vitreous bleeding 
without visual impairment 
Diffuse sub-conjunctival 
hemorrhage in both eyes 
 
Spontaneous retinal bleeding 
without visual impairment 
 
 
Spontaneous vitreous bleeding 
without visual impairment 
 
 
 
Retinal bleeding with temporary 
visual impairment ** (present for 
≤ 7 days) 
 
Vitreous bleeding with temporary 
visual impairment *** (present for 
≤ 7 days) 
 
 
 
Retinal bleeding with 
permanent visual impairment ** 
(present for > 7 days) 
 
Vitreous bleeding with 
permanent visual impairment ** 
(present for > 7 days) 
Central nervous 
system 
 
Lumbar puncture with blood (>5 
RBC/μL in CSF on microscopic 
analysis and non-traumatic tap), 
no neurological symptoms and 
no  visible red color 
 
Traumatic CNS bleeding on 
imaging study without 
neurological dysfunction 
Lumbar puncture with visible red 
color in absence of neurological 
symptoms, and non-traumatic 
tap 
 
 
 
Spontaneous CNS bleeding on 
imaging study without 
neurological dysfunction 
CNS symptoms with non-
traumatic bloody lumbar 
puncture 
 
 
 
 
CNS bleeding on imaging study 
with neurological dysfunction 
Invasive sites 
Bleeding at invasive sites or sites 
of minor trauma (e.g. 
venipuncture sites, intravenous 
lines or catheter exit sites): active 
oozing at site for > 10 minutes 
Bleeding at invasive sites 
(venipuncture sites, intravenous 
lines or catheter exit sites): active 
oozing at site for a cumulative 
total of > 1 hour in the previous 
24 hours. 
Any bleeding that requires a 
transfusion or a procedure 
 
 
*Count actual bleeding (i.e. “running out” or need for basin, tissue, towel, etc.) not minor bleeding 
**Visual impairment is defined as a field deficit, and patients with suspected visual impairment require an ophthalmological consultation 
*** Visual impairment confirmed by ophthalmological consultation 
†  Petechiae of oral mucosa and skin 
    Subconjunctival hemorrhage 
    Hemorrhagic bullae/blisters in mouth 
    Purpura and ecchymoses 
These are all documented as bleeding on the 1st day they are seen and any subsequent day that the bleeding is worse than the preceding day. If the bruising / petechiae is 
the same as or not as severe as the previous day it will not be counted as bleeding [For discussion]. 


 
 
 
 
ǂ Reference serum creatinine is the baseline serum creatinine result taken on entry into the study 
Definitions of Bleeding Signs 
 
Definition of bleeding signs based on physical examination 
Site of bleeding 
Sign 
Definition 
Skin (epidermis and 
dermis) 
 
 
        
Petechiae 
Red (recent) or purplish (a few days old) spot discoloration in the skin with a 
diameter between 0.5 mm to < 3 mm, not blanching  with pressure and not palpable 
 
Purpuric macule 
(purpura) 
Differentiated from petechiae only for their larger size between 3 to 10 mm.  
 
Ecchymosis 
(bruise or 
contusion) 
Larger than 10mm in size. Flat, rounded or irregular, red, blue, purplish or yellowish 
green patches, larger than a petechia or purpura. If elevated they represent 
superficial spreading of an underlying hematoma 
Skin (subcutaneous tissue)  
 
 
Hematoma 
Bulging localized accumulation of blood often with discoloration of overlying skin 
Visible mucous 
membranes 
 
 
 
Petechia, 
purpuric  
macules and 
ecchymoses 
As for skin 
 
Bulla/vesicle 
(Blister) 
Visible raised, thin-walled, circumscribed lesions containing blood.  
Bullae (≥ 5mm) are larger than vesicles (< 5 mm).  
They should be counted together as bullae 
 
Epistaxis 
Any bleeding from the nose, may be anterior or posterior and unilateral or bilateral 
 
Gingival 
bleeding 
Any bleeding from the gingival margins 
 
Subconjunctival 
hemorrhage 
Bright red discoloration underneath the conjunctiva at onset then same color 
changes as ecchymoses 
Muscles and soft tissues 
 
 
 
Hematoma 
Any localized collection of blood, visible or palpable or revealed by imaging. May be 
dissecting when spreading along fascial spaces 
 


 
 
Appendix 3:  
     A-TREAT Telephone Script: Long-Term Follow-Up 
To be performed at 30 days post discontinuation of study drug & 120 days post activation of study drug 
 
Assessment Time Point: 
  
 30 days post discontinuation of study drug 
 120 days post activation of study drug 
 
 No answer/patient unavailable: 
 
 No voicemail/message left- local physician will be contacted for medical records 
 
 Left voicemail/message: 
 
 Made contact with patient: 
 
Recommended Introduction: My name is [name of CRC, Research Nurse or Investigator] and I am 
calling from [study site] for a quick follow up regarding the A-TREAT clinical trial you recently 
participated in.  I have a few questions to ask that will help our team understand how you’re doing 
after treatment: 
 
• How are you feeling? 
• Have you experienced any health problems since the last time someone from the study team 
spoke with you? 
• Have you experienced, or are you currently experiencing, any of the following: 
 
 swelling in your arms or legs 
Comment: 
 
 shortness of breath 
Comment:  
 
D30 Patient Reminders and Recommended Closing Comments: Just a reminder that we will call for 
your last study follow-up on [date of D120]. Thank you for your time and further participation, please 
don’t hesitate to contact us at [phone number, email address, clinic name] if you have any questions or 
concerns regarding the study.   
 
D120 Recommended Closing Comments: Thank you for your participation in this study- today was the 
last scheduled follow-up, but please feel free to contact us at [phone number, email address, clinic 
name] with any quesitons or concerns regarding the study. 
 
 
 
 
Signature: 
Date and Time of Call: 
A-TREAT Follow-Up: Telephone Script 
 
Protocol Version Date: 06-JAN-2016 
 
 


 
 
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21 Ben-Bassat I, Douer D, Ramot B. Tranexamic acid in acute myeloid leukemia: possible reduction of platelet 
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2008;26:241-246. 
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thrombocytopenic patients. Scand J Haematol 1985;35:497-500. 
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SAP_001.pdf: 
NCT02578901 
 
A-TREAT Statistical and Analytical Plan 
 
2019-06-03 
 
 


9.7 Statistical Methods 
9.7.1 Statistical and Analytical Plan 
All statistical inference will be based on a two-sided 0.05 level of significance and two-sided 
95% confidence intervals. 
Study Populations 
Subjects will be grouped according to randomization groups: TXA versus placebo. Unless 
otherwise specified, all efficacy analyses will be by a modified intention to treat (mITT) 
strategy among activated subjects as described below. All subjects who were activated to 
study drug will be included in the analyses in the treatment group to which they were randomly 
assigned.  Subjects who were activated for study drug will be included in the 
analyses, even if they stop study drug “early”, cross over between treatment groups, or 
receive prophylactic transfusions not in accordance with the protocol. 
1. Efficacy Population 
    The mITT population used for efficacy analyses will be comprised of all randomized  
    patients for whom an order for administration of study drug is activated. Efficacy 
    analyses on these patients will use data gathered from the time the order for study drug 
    was activated until 30 days post activation. Randomized patients who develop exclusion 
    criteria prior to activation of study drug and who thus are excluded from receipt of study 
    drug and patients whose platelet counts never drop below the 30K threshold for 
    activation of study drug will not be included in the primary efficacy population.  
2. Safety Population 
The population used for safety analyses will be all patients who receive any amount of 
study drug. Follow-up for mortality and thrombotic events will occur at 120 days post 
activation. Other adverse events and serious adverse events will be collected for 30 
days post discontinuation of study drug, with visual examinations occurring weekly for 
two weeks after discontinuation of study drug. SOS (VOD), AEs, and SAEs will be based 
on clinical diagnosis and patient report during the surveillance period. The frequency of 
follow-up will differ between inpatients and outpatients, with the former based on daily 
visits by the research coordinators and the latter based on patient diaries and 
semiweekly clinic visits (while still on study drug) or weekly contacts (after 
discontinuation of study drug 
 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be presented in tables stratified by 
treatment arm, clinical site and therapeutic group (allogeneic transplant, autologous 
transplant, or leukemia). Demographic variables will include age, sex, race, ethnicity, 
height, weight, BMI and primary diagnosis. Baseline lab values will include platelets, 
hematocrit, serum creatinine, prothrombin time (PT), international normalized ratio (INR), 
partial thromboplastin time (PTT), fibrinogen, D-dimer, thrombin time, hemoglobin and 
HLA PRA. Subject dispositions will also be presented, and the table will indicate total 
screened, consented, randomized, activated, completed therapy, safety follow-up and 
long-term follow-up. 
Primary Efficacy Analyses 
The odds of bleeding at WHO grade 2 level or above will be analyzed in a logistic 
regression model adjusting for treatment arm, clinical site as a factored variable, and 
therapeutic group (allogeneic transplant, autologous transplant, or leukemia) as a 
factored variable. The test statistic will be a Wald test based on the score for the 


treatment arm parameter from the logistic regression model with adjustment for multiply 
imputed missing data.  
log
𝑝
1 −𝑝= 𝛽0 + 𝛽1𝑋𝑡+ 𝛽2𝑍1 + 𝛽3𝑍2 + 𝛽4𝑊1 + 𝛽5𝑊2 
In the above full model, 𝑝 refers to the probability of a WHO grade 2+ bleed conditional 
on the covariates. 𝛽0 represents the log odds of bleeding for a subject in the placebo 
group, and in the reference site and reference therapeutic group (UNC and allogeneic, 
respectively). 𝛽1 is the log odds ratio of bleeding between placebo and treatment arms 
for fixed site and therapeutic group. The parameters 𝛽2, 𝛽3 represent the log odds ratio 
between UPT and UNC and between UWM and UNC, respectively, for a fixed treatment 
arm and therapeutic group. Similarly, 𝛽4, 𝛽5 are the log odds ratios between autogenic 
and allogenic and between chemotherapy and allogenic groups, for a fixed site and 
treatment arm. 𝑍1, 𝑍2, 𝑊1, 𝑊2 are indicator variables: 𝑍1 = 1 if the subject is from UPT, 
𝑍2 = 1 if from UWM, 𝑊1 = 1 if in autogenic therapy, 𝑊2 = 1 if in chemotherapy. 
 
The analysis of the primary endpoint, in order to adjust for multiply imputed data, will use 
the score for the treatment parameter evaluated at the null hypothesis in a Wald test. In 
this case, the null hypothesis 𝜃0 has the treatment parameter 𝛽1 = 0 and all other 𝛽𝑗=
𝛽̂𝑗  (𝑗= 0,2,3,4,5) their respective maximum likelihood estimates. We give the form of the 
relevant score below (where 𝑋 is the matrix of covariates, 𝑋𝑖 refers to the 𝑖th row and 𝑋1𝑖 
refers to the element in the 𝑖th row and the column corresponding to 𝛽1). 
𝑈1 = ∑𝑋1𝑖(𝑌𝑖−𝑝𝑖(𝜃0)
𝑛
𝑖=1
)  
𝑝𝑖(𝜃0) =
𝑒𝑋𝑖𝜃0 
1 + 𝑒𝑋𝑖𝜃0 
The variance of the score is the element of the observed Information matrix (derivative of 
the score) that corresponds to the score of interest. 
𝑉𝑎𝑟(𝑈1) = ∑𝑋1𝑖
2 𝑝𝑖(𝜃0)(1 −𝑝𝑖(𝜃0))
𝑛
𝑖=1
 
 
Further discussion is presented in the missing data section along with R code for 
performing the analysis. 
 
Secondary Analyses 
The secondary endpoints of mean number of platelet transfusions and the mean number 
of days alive without WHO grade 2 level or above bleeding will each be analyzed in a 
linear regression model adjusting for treatment arm, clinical site as a factored variable, 
and therapeutic group (allogeneic transplant, autologous transplant, or leukemia) as a 
factored variable. The test statistic will be based on the Wald statistic (parameter 
estimate divided by its standard error) as computed for the treatment arm parameter 
from the linear regression model using the Huber-White sandwich estimator for standard 
errors to account for possible heteroscedasticity and adjusting for multiply imputed data.  
 
 
lmTrans <- lm(ptrans ~ treatment +  
  
 
 
site + group) 
lmWHODays <- lm(days ~ treatment +  
  
 
 
site + group) 


  
Other Analyses 
Analysis of the supportive and exploratory endpoints will be conducted using regression 
models adjusting for treatment arm, clinical site as a factored variable, and therapeutic 
group (allogeneic transplant, autologous transplant, or leukemia) as a factored variable. 
Linear regression will be used for endpoints measuring the days free of bleeding and 
highest grade of bleeding, logistic regression will be used for binary endpoints, and 
proportional hazards regression will be used for times to event. The Huber-White 
sandwich estimator of the standard error will be used to allow for departures from the 
model based variance estimates, and adjustment will be made for multiply imputed 
missing data.  
 
library(“survival”) 
lmBleedFree <- lm(free ~ treatment +  
  
 
 
site + group) 
lmHiBleed <- lm(hibleed ~ treatment +  
  
 
 
site + group) 
lmBleedDth <- glm(bleeddth ~ treatment +  
  
 
 
site + group,family=”binomial”) 
lmFirstBleed <- coxph(fBleed ~ treatment + 
  
 
 
site + group) 
lmPltTrans <- lm(pltTrans ~ treatment +  
  
 
 
site + group) 
lmRedTrans <- lm(redTrans ~ treatment +  
  
 
 
site + group) 
lmNoPlt <- glm(noPlt ~ treatment +  
  
 
 
site + group,family=”binomial”) 
lmNoRed <- glm(noRed ~ treatment + 
  
 
 
site + group,family=”binomial”) 
lmNadir <- glm(hiNadir ~ treatment +  
  
 
 
site + group,family=”binomial”) 
 
Subgroup Analyses 
WHO grade 2 or above bleeding will be assessed separately among patients who did 
and did not have bleeding at randomization, as well as within each of the therapeutic 
groups of allogeneic transplant, autologous transplant and leukemia. This will be 
performed similar to regression models above by restricting to the dataset as described. 
Safety Analyses 
The safety endpoints will be tabulated and presented without inferential statistics. These 
endpoints, AEs, SAEs, thrombotic events, incidence of VOD, all-cause mortality, and 
death due to thrombosis, will each be tabulated by treatment arm and primary diagnosis 
group.  
Missing Data 
Patients will be followed for all clinical trial outcomes regardless of their adherence to the 
prescribed regimen for the study drug (TXA or placebo). Very few patients are expected 


to withdraw consent, though there will undoubtedly be some cases in which the data are 
missing for one or more of the primary, secondary, or supporting analyses due to 
withdrawal of consent or competing risks.  
 
Initial analyses of primary and secondary endpoints will be based on missing-at-random 
(MAR) models that condition on the patients’ absolute neutrophil counts (ANC), site, 
therapeutic group and days since randomization to study drug. In the MAR model, data 
will be imputed by assuming that patients with missing data will be presumed to have 
distributions of outcomes the same as that observed in comparable patients who have 
complete data.  
 
Sensitivity analyses for the primary endpoint will use missing not at random (MNAR) 
models to reflect increased or decreased odds of bleeding among patients with 
incomplete data. Each treatment arm will be parameterized separately, and the 
robustness of any estimated treatment effect to those varying levels of dependence 
between early death or withdrawal of consent and incidence of bleeding will be 
quantified. Additional models will consider separate mechanisms for early death and 
withdrawal of consent. 
 
Primary Endpoint 
The model for the primary endpoint will be proportional hazards of the effect of treatment 
arm stratified by therapeutic group. The model will include a time-varying binary 
covariate of high (greater than 500) versus low (less than 500) ANC and a factored site 
variable.  
 
The following model will be fit for complete-case data to estimate the baseline hazard for 
each treatment stratum. Then the residual hazard will be estimated for censored 
subjects based on observed subjects within the same site and with the same ANC state 
on the day of censoring. Sampling from this hazard function will provide imputed values 
for use in the primary analysis. 
𝜆𝑍(𝑡) = 𝜆𝑍0(𝑡) exp {𝛽1,𝑍𝐴𝑖(𝑡) + ∑𝛽𝑗+1,𝑍1𝐶𝑖=𝑗
3
𝑗=1
} 
𝜆𝑍  represents the hazard function for the 𝑍th treatment arm, 𝜆0 the baseline hazard, 
𝐴𝑖(𝑡) the most recent ANC state on day 𝑡 for the 𝑖th subject and 1𝐶𝑖=𝑗 being the indicator 
function for whether the subject belonged to the 𝑗th site. 
 
𝜆(𝑙)(𝑡) = 𝜆𝑍0(𝑡) exp {𝛽1,𝑍𝐴(𝑙)(𝑡) + ∑𝛽𝑗+1,𝑍1𝑐(𝑙)=𝑗
3
𝑗=1
} 
This model represents the residual hazard for the 𝑙th subject with missing data; 𝐴(𝑙)(𝑡) is 
the most recent ANC state on day frozen at the day of censoring for the 𝑙th subject 
(described further in implementation below); the other parameters remain the same as 
before. 
 
During sensitivity analyses, to reflect the MNAR models, the first model above will be 
scaled with a sensitivity term 𝛼𝑍 for each treatment arm to represent increased or 
decreased odds of bleeding, so we will sample from the hazard 𝛼𝑍𝜆𝑍(𝑡) for a given 
treatment arm. A tipping point analysis will be conducted by performing the imputation 
and primary analysis using the following values for each 𝛼𝑍: 0.75, 0.80, 0.85, 0.90, 0.95, 


1.00, 1.05, 1.10, 1.15, 1.20, 1.25. Determining how far the analysis can deviate from the 
MAR model with significant results will contextualize and improve the validity of the 
conclusions of the study. 
 
The process for coding this in R follows. First, the data are collected into a “wide” data 
frame, which contains columns for case ID, case site, therapeutic group, date of 
activation, number of days on study, indicator of WHO grade 2+ bleed (1 if a bleed 
occurred within 30 days of activation, 0 if no bleed occurred but the subject was followed 
for 30 days of activation, or NA if withdrawn for any reason before 30 days without a 
bleed), date of first bleed (NA if no bleed) and then a variable for the ANC count (above 
or below 500) for each of the 30 days post-activation. For the purposes of this analysis, 
the day of activation is considered to begin at midnight of the first day, bleeding occurred 
at noon on the day of recording and the ANC count recorded is the first measured of the 
day. 
 
At the same time, missing ANC counts are filled in with the most recent ANC count (i.e. if 
a subject’s ANC count is missing, then it is replaced with the last non-missing ANC count 
that the subject had). 
 
Then this dataset is changed into a “long” format, where each subject has as many rows 
as the smallest of 30, days until first bleed, and days until withdrawn from study. Keeping 
the other variables constant across the rows, the 30 ANC count variables are collapsed 
into a single variable corresponding to the daily ANC count (again, above or below 500).  
 
This long dataset, restricted to the treatment arm and only for rows with non-missing 
values for bleed, becomes the argument for the “coxph” function in R, which is used to 
estimate the baseline hazards and regression coefficients for treatment arm.  
 
Then a single imputation step is as follows after specifying the seed 20170615 (first day 
of screening). Each subject with a missing value for bleed is to be filled in. First, the 
“wide” dataset is trimmed at the day of censoring for such a subject by removing all ANC 
counts corresponding to days after withdrawal (NA values). The last remaining column is 
then copied to re-fill the removed columns until 30 days of ANC counts exist. This 
effectively “freezes” the ANC counts to the day of censoring. This “wide” dataset is once 
again converted to long, restricted to the particular subject missing bleed data. The new 
long dataset, coupled with the previously estimated baseline hazard corresponding to 
the appropriate treatment arm, is used to estimate a residual hazard function unique to 
the subject. This is the function from which a single sample is drawn; if the sample 
corresponds to a bleed within the 30 day period, then the previously-missing bleed is 
filled as 1, otherwise it is 0. Then this process is repeated for all rows with missing 
values for bleed. Finally, the primary efficacy analysis is conducted and the score for the 
treatment variable and its variance recorded. 
 
Then the imputation is repeated 𝑘= 20 times to produce 20 different values for the 
score and variance in the primary efficacy analysis. These are combined into an 
estimated score, which is the mean of the imputed scores and an estimated variance, 
which is the sum of the mean of the imputed variances and the variance of the imputed 
scores. Then a Wald test will compare the combined estimate and standard error with 
the standard normal distribution. 


𝑝= 2 ∗𝑃𝑟(|
𝜃𝑘
̂
𝑆𝐸
̂(𝜃𝑘
̂)| > 𝑧𝛼) 
 
The code is attached in an appendix. 
 
Secondary Endpoints 
We will use a random regression model of multiple imputation for the both of the 
secondary endpoints: number of days alive without WHO grade 2+ bleeding and number 
of platelet transfusions within 30 days after activation. In a previous version of the SAP, 
the imputation scheme for the platelet transfusions outcome involved hot deck 
imputation. This has been changed in this updated SAP to parallel the imputation 
scheme for the number of days alive outcome variable. 
 
The number of days alive without such bleeding will be regressed against treatment arm, 
therapeutic stratum, site and number of days on study within the efficacy window. In 
addition, anticipating that subjects will likely either bleed numerous times or bleed 
relatively infrequently, an additional covariate will be included that indicates if a subject 
had 2 or more days in sequence of WHO grade 2+ bleeding within the efficacy window.  
 
The model will be similar for the number of platelet transfusions within 30 days after 
activation: The number of such transfusions will be regressed against treatment arm, 
therapeutic stratum, site and number of days on study within the efficacy window. In 
addition, anticipating that subjects will likely either be transfused numerous times (but 
likely not as frequently on adjacent days) or relatively infrequently, an additional 
covariate will be included that indicates if a subject had 2 or more transfusions within a 
7-day within the efficacy window.  
 
First, these models will be fit for the complete-case data. The standard deviation of the 
error will be estimated by resampling 1000 times from the errors (difference between 
observed and predicted days of bleeding). Then a single imputation will fill in the 
outcome variable. These imputed data will be drawn from a normal distribution with 
mean given by the predicted values using the complete-case fit and standard deviation 
given by the resampled estimate from the complete-case model. With this imputed data 
set, the estimate for the treatment arm parameter and its standard error will be 
computed and recorded based on the model for the secondary endpoint analysis. The 
seed for imputations will be the same as above 20170615. 
 
The imputation is then repeated 𝑘= 20 times to produce 20 different estimates of the 
parameter value and estimates of the variance. The parameter estimates will be 
combined by taking the mean of all of the estimates, and the standard errors will be 
combined by taking the square root of the sum of the mean of the 𝑘 estimated variances 
and the variance of the 𝑘 parameter estimates. Then a Wald test will compare the 
combined estimate and standard error with the standard normal distribution. 
𝑝= 2 ∗𝑃𝑟(|
𝜃𝑘
̂
𝑆𝐸
̂(𝜃𝑘
̂)| > 𝑧𝛼) 
 
set.seed(20170615) 
library(sandwich) 
reps <- 20 # 20 replications for the imputations below 


##### days: number of days alive without WHO grade 2+ bleeding 
 
dat <- 
actBase[,c("caseid","trt","site","group","daysonstudy")] 
dat$days <- dat$availDays <- dat$bleedinarow <- 
rep(NA,nrow(actBase)) 
for (i in 1:length(actBleeds)){ 
  tmpBld <- actBleeds[[i]]  
  availDts <- floor(tmpBld$JDates)-actBase$activ[i]+1 # all 
days with any bleeding entry 
  maxDate <- ifelse(actBase$stopReason[i]=="Death" & 
actBase$daysonstudy[i] < 30,actBase$daysonstudy[i],30) 
  effDays <- 1:maxDate  
   
  anyMiss <- any(!effDays %in% availDts) 
   
  bleedIdx <- as.numeric(tmpBld$maxBldgrade) >= 2 & (availDts 
>= 1 & availDts <= maxDate) 
   
  dat$bleedinarow[i] <- 
any(diff(floor(tmpBld$JDates[bleedIdx])) == 1) # if any 
bleeding days are adjacent 
  dat$availDays[i] <- 
sum(as.numeric(tmpBld$maxBldgrade[availDts >= 1 & availDts <= 
maxDate]) < 2) # even if there are some days with missing 
bleeds, record the available days alive without WHO 2+ 
   
  if (anyMiss){ 
    dat$days[i] <- NA # there is missing bleeding 
  } else { 


    dat$days[i] <- sum(as.numeric(tmpBld$maxBldgrade[availDts 
>= 1 & availDts <= maxDate]) < 2) # "official" days without 
WHO 2+ in efficacy period 
  } 
   
} 
 
dat$predDays <- dat$predSD <- rep(NA,nrow(dat)) 
for (arm in 1:2){ 
  armTmp <- c("TXA","PBO")[arm] 
   
  dat.arm <- dat[dat$trt==armTmp,] 
  lm.complete <- lm(days ~ site + group + bleedinarow + 
daysonstudy,data=dat.arm) # complete case regression 
   
  dat$predDays[dat$trt==armTmp] <- 
predict(lm.complete,dat.arm) # get the predicted values for 
all in the treatment arm 
   
  lm.errors <- residuals(lm.complete) # gets the residuals 
  lm.sd <- rep(NA,1000) 
  for (i in 1:1000){ 
    samp <- sample(lm.errors,length(lm.errors),replace=TRUE) 
    lm.sd[i] <- sd(samp) 
  } 
   
  dat$predSD[dat$trt==armTmp] <- mean(lm.sd) # mean resampled 
error 
} 


 
days.imps <- data.frame(est=rep(NA,reps),estVar=rep(NA,reps)) 
# initialize regression imputation dataset 
for (i in 1:reps){ 
  days.predicted <- rnorm(nrow(dat),dat$predDays,dat$predSD) 
  impDays <- impute(dat$days,days.predicted) # only missing 
data are imputed 
   
  # impDays <- pmax(impute(dat$days,days.predicted), # only 
missing data are imputed 
  #                dat$availDays) # a predicted value cannot 
be smaller than the observed value 
   
  lmWHODays.impute <- lm(impDays ~ dat$trt +  
                           dat$site + dat$group) # impDays is 
outcome but covariates from analysis dataset 
  days.imps[i,] <- c(coef(lmWHODays.impute)[2], 
                     sandwich(lmWHODays.impute)[2,2]) 
} 
days.est <- mean(days.imps[,1]) 
days.se <- sqrt(var(days.imps[,1])+mean(days.imps[,2]))  
 
days.stat <- days.est/days.se 
days.p <- 2*pnorm(abs(days.stat),lower.tail=FALSE) # wald p-
value from imputation 
days.ci <- days.est+qnorm(c(0.025,0.975))*days.se 
 
##### transf: number of platelet transfusions within first 30 
days post activation 


actTransf <- transfusions[names(transfusions) %in% 
actBase$caseid] 
ntransf <- NULL 
transfrow <- NULL 
for (i in 1:length(actTransf)){ 
  tf <- actTransf[[i]] 
  dts <- tf$xPltJDates- actBase$activ[i] # changed from using 
ceiling; equivalent code, but more in line with other coding 
  ntransf <- c(ntransf,sum(dts >= 0 & dts < 30)) 
  transfrow <- c(transfrow,any(diff(dts[dts >= 0 & dts < 30]) 
<= 7)) 
} 
 
dat <- 
as.data.frame(cbind(actBase$caseid,actBase$trt,actBase[,c(2,3,
5)],ntransf,transfrow)) # only keep relevant columns 
colnames(dat) <- 
c("caseid","trt",colnames(actBase[,c(2,3,5)]),"transf","transf
row") 
 
dat$predTransf <- dat$predSD <- rep(NA,nrow(dat)) 
for (arm in 1:2){ 
  armTmp <- c("TXA","PBO")[arm] 
   
  dat.arm <- dat[dat$trt==armTmp,] 
  lm.complete <- lm(transf ~ site + group + transfrow + 
daysonstudy,data=dat.arm) # complete case regression 
   
  dat$predTransf[dat$trt==armTmp] <- 
predict(lm.complete,dat.arm) # get the predicted values for 
all in the treatment arm 


   
  lm.errors <- residuals(lm.complete) # gets the residuals 
  lm.sd <- rep(NA,1000) 
  for (i in 1:1000){ 
    samp <- sample(lm.errors,length(lm.errors),replace=TRUE) 
    lm.sd[i] <- sd(samp) 
  } 
   
  dat$predSD[dat$trt==armTmp] <- mean(lm.sd) # mean resampled 
error 
} 
 
transf.imps <- 
data.frame(est=rep(NA,reps),estVar=rep(NA,reps)) # initialize 
regression imputation dataset 
for (i in 1:reps){ 
  transf.predicted <- 
rnorm(nrow(dat),dat$predTransf,dat$predSD)  
  imptransf <- impute(dat$transf,transf.predicted) # only 
missing data are imputed 
  lmWHOtransf.impute <- lm(imptransf ~ dat$trt +  
                           dat$site + dat$group) # imptransf 
is outcome but covariates from analysis dataset 
  transf.imps[i,] <- c(coef(lmWHOtransf.impute)[2], 
                     sandwich(lmWHOtransf.impute)[2,2]) 
} 
transf.est <- mean(transf.imps[,1]) 
transf.se <- sqrt(var(transf.imps[,1])+mean(transf.imps[,2]))  
 


transf.stat <- transf.est/transf.se 
transf.p <- 2*pnorm(abs(transf.stat),lower.tail=FALSE) # wald 
p-value from imputation 
transf.ci <- transf.est+qnorm(c(0.025,0.975))*transf.se 
9.7.2 Sample Size and Precision of Statistical Inference 
1. Minimal Clinically Important Difference 
Based on results observed in the PLADO study for patients who meet the general 
eligibility criteria for the A-TREAT study, it is anticipated that 57% of eligible patients 
would experience WHO Grade 2 bleeding or higher in the absence of antifibrinolytic 
therapy. In such a background setting of bleeding, the study investigators anticipate that 
less than a 10% relative reduction in bleeding rates would not be sufficient to 
substantially change clinical practice, because the absolute risk reduction of 5.7% would 
mean that it would be necessary to treat approximately 17.5 patients in order for the 
treatment to have impact on 1 patient (“Number Needed to Treat” (NNT) = 17.5). As 
much as a 25% relative reduction in bleeding rates would likely be judged sufficient to 
change clinical practice, because with an absolute risk reduction of 14.25%, the NNT of 
approximately 7 patients might be acceptable, provided no new safety issues related to 
antifibrinolysis in the thrombocytopenic population are uncovered. The A-TREAT 
investigators hypothesize that TXA will be associated with a relative reduction of 30% or 
higher (absolute reduction of 17%) based on observational data relative to their prior 
clinical experience. 
2. Sequential Stopping Rules 
The conduct of the A-TREAT study will be overseen by an independent Data and Safety 
Monitoring Board (DSMB) who will enhance patient safety by monitoring study progress 
and integrity, incidence of AEs and SAEs, and interim estimates of treatment effect on 
bleeding. The DSMB will be guided by a group sequential stopping rule to judge the 
scientific and statistical credibility of interim results on the bleeding endpoints.  
 
While the exact stopping rule will be chosen in discussion with the DSMB (and 
documented in the Statistical Analysis Plan finalized prior to the first interim analysis at 
which the DSMB will see unblinded data), the A-TREAT investigators propose a 
stopping rule that would allow early stopping only if a one-sided level 0.20 O’Brien-
Fleming stopping boundary suggested that TXA was associated with more bleeding than 
placebo. There would be no early stopping boundary for efficacy of TXA over placebo, 
with the final critical value for efficacy providing a one-sided 0.025 level of significance.  
 
The following table presents example stopping boundaries that might correspond to an 
observed combined event rate of 0.485 (such as might be observed with 57% events on 
the placebo arm and 40% events on the TXA arm). Using the R package RCTdesign (or 
equivalently, S-Plus S+SeqTrial), a stopping boundary having three analyses at 50%, 
75% and 100% of the planned sample size and with a level 0.2 O’Brien-Fleming 
boundary for harm would be computed using the RCTdesign code: 
 
 seqDesign(prob.model = "prop", null.hypothesis = 0.57, 
  
alt.hypothesis = 0.4, nbr.analyses = 3,  
  
sample.size = c(165, 248, 330), test.type = 
"two.sided",  


     
power = "calculate", alpha = c(0.025, 0.2),  
  
 
P = c(Inf, 1)) 
 
For this example stopping boundary, the following table presents the critical values for 
harm and the corresponding adjusted statistical inference at each of the formal interim 
analyses. Critical values are expressed in terms of the crude estimate of treatment effect 
(TXA bleeding rate minus control bleeding rate), a Z statistic, and a one-sided fixed 
sample P value testing for harm. The adjusted statistical inference is a point estimate 
based on the bias adjusted mean and 95% confidence intervals and one-sided P values 
testing for harm using the likelihood ratio ordering of the outcome space. 
Analysis 
Stopping Boundaries 
Adjusted Inference 
 
N 
Crude 
Estimate 
Z 
Fixed 
P val 
Estimate 
95% CI 
One-sided 
P value 
50% 
165 
0.111 
1.440 
.075 
0.095 
(-.004, .181) 
0.123 
75% 
248 
0.074 
1.175 
.120 
0.059 
(-.018, .132) 
0.178 
100% 
330 
0.055 
1.019 
.154 
0.043 
(-.022, .115) 
0.200 
 
Rationale: Owing to the need for adequate safety data, even if TXA is associated with 
markedly less bleeding than placebo, there is an imperative to gather safety data on the 
full sample size. Because TXA is currently being used off-label in the thrombocytopenic 
setting, it is important to document any harm due to TXA treatment, rather than just 
documenting the absence of a markedly beneficial effect. 
 
3. Sample Size 
Calculation of sample size and statistical power were made using S+SeqTrial based on 
the chi-squared test of association, which is equivalent to the score test from simple 
logistic regression. Based on 1:1 randomization, a one-sided level of significance 0.025, 
a design alternative hypothesis of 30% relative reduction in bleeding rates (57% on the 
placebo arm and 40% on TXA), a sample size of 330 subjects (165 TXA, 165 placebo) 
will provide 88% statistical power to declare statistical significance on the primary 
endpoint. This sample size will provide 74.8% statistical power to detect a 25% relative 
reduction in bleeding rates (57% vs 42.75%). 
 
4. Precision of Inference for Efficacy 
With the planned sample size and a placebo bleeding rate of 57%, an observed absolute 
decrease in WHO grade 2 or above bleeding of 10.6% (so 57% on placebo, 46.4% on 
TXA) would be judged statistically significant. Such an absolute difference in rates 
corresponds to a NNT of 9.4. If the baseline placebo bleeding rate were instead 40%, 
the threshold for statistical significance would be an absolute reduction of 10.14% (NNT 
= 9.9), and a baseline placebo rate of 70% would have a threshold of 10.35% (NNT = 
9.7). These results are judged to be of the magnitude to possibly affect clinical practice, 
and allow for some added loss of precision with multiply imputed missing data. 
 
5. Precision of Inference for Safety 
This study is not powered to establish the definitive safety of the treatment with respect 
to the frequency of VTE. However, an observed difference in frequency of VTE of 3.7% 
on the placebo arm and 5.5% or less on the TXA therapy arm would result in a 95% 
confidence interval that excluded a relative risk of 3.0. 
 
 
 


library(survival) 
library(sandwich) 
 
impSeed <- 20170615 
 
# helper functions for below 
 
na.locf <- function(vec){ # perform LOCF 
  for (i in 2:length(vec)){ 
    vec[i] <- ifelse(!is.na(vec[i]),vec[i],vec[i-1]) 
  } 
  return(vec) 
} 
 
makeLong <- function(dat){ # a function that shifts from 
wide (column for each event day) to long 
  longdat <- 
data.frame(caseid=NULL,trt=NULL,site=NULL,group=NULL,start
=NULL,end=NULL,bleed=NULL,count=NULL) 
  nm <- 
c("caseid","trt","site","group","tstart","tend","bleed","c
ount") 
  for (i in 1:length(dat$caseid)){ 
    for (j in 
1:min(dat$daysonstudy[i],dat$eventday[i],na.rm=TRUE)){ 
      longdat <- 
rbind(longdat,c(dat$caseid[i],dat$trt[i],dat$site[i],dat$g
roup[i],j-1,j, 
                                 
ifelse(is.na(dat$bleed)[i],0, 
                                        
ifelse(!is.na(dat$eventday[i]) & j==dat$eventday[i] & 
dat$bleed[i]==1,1,0)), 
                                 dat[i,7+j])) # This may 
need to be changed to point to the right column in true 
data 
    } 
  } 
  colnames(longdat) <- nm 
  longdat$trt <- as.logical(longdat$trt) 
  longdat$tstart <- as.numeric(longdat$tstart) 
  longdat$tend <- as.numeric(longdat$tend) 
  longdat$bleed <- as.numeric(longdat$bleed) 
  longdat$count <- as.logical(longdat$count) 
  return(longdat) 


} 
 
logisticScore <- function(datIn,est,nullHyp){ # compute 
the score and expected information for testing if trt==0 
  x <- model.matrix(bleed ~ site + group + trt,data=datIn) 
  y <- datIn[,"bleed"] 
  nullest <- c(est,nullHyp) # we maximize under 
trt=nullHyp for est, then include trt=nullHyp for score  
  nullp <- exp(x %*% nullest)/(1+exp(x %*% nullest)) # MLE 
under null hypothesis 
  scorevec <- t(x) %*% (y-nullp) 
  scorevar <- t(x) %*% 
diag(as.numeric(nullp)*as.numeric(1-
nullp),nrow=length(nullp),ncol=length(nullp)) %*% x 
  return(list(score=scorevec,info=scorevar)) 
} 
 
treatScoreTest <- function(datImp,nullHyp){ 
  lmFit <- glm(bleed ~ site + group+offset(nullHyp*trt), # 
maximizes under some null hypothesis (default to coef=0)  
      family="binomial",data=datImp) 
  lmCoef <- coef(lmFit) 
  scoreOut <- logisticScore(datImp,lmCoef,nullHyp) 
   
  trtScore <- scoreOut[[1]][6] # treatment element of 
score 
  trtVar <- scoreOut[[2]][6,6]-scoreOut[[2]][6,-6] %*% 
solve(scoreOut[[2]][-6,-6]) %*% scoreOut[[2]][-6,6] # 
variance of treatment element of score after estimating 
nuisance parameters 
  return(c(trtScore,trtVar)) 
} 
 
 
impute <- function(x,x.imp) ifelse(is.na(x),x.imp,x) # 
replace missing values of x with x.imp 
 
# ------------------------------- Primary Efficacy 
Analysis ---------------------- 
 
### Expect a data frame structure with the following 
variables: 
# caseid, treatment arm, casesite, therapeutic group, days 
on study (1-30), 


# bleed (0=no bleed during 30 days, 1=bleed, NA=withdrew 
before 30 days), day of bleed 
# 30 variables for each day of ANC count (high/low) 
 
### Then we want to build "imps" number of data sets for 
each row with bleed = NA 
 
### Note the long format described below has one row for 
each study day for each caseid, and variables: 
# caseid, treatment arm, casesite, therapeutic group, 
tstart (0 to (daysonstudy-1)), tend(1 to daysonstudy), 
# bleed (0, 1, NA), ANC count 
 
### Imputation Scheme as Follows: 
# 0. Reduce the data set to only complete case data and 
change to long format  
# 1. Fit coxph model for each trt*stratum (estimate 
baseline hazard and coefficients) on the complete data 
# 2. Repeat the following for each row with bleed = NA 
(consider row "i") 
# 2a. Re-build the data set by removing all ANC columns 
after ith days on study 
# 2b. Copy the final column to fill back to 30 columns of 
ANC 
# 2c. Now use the data to estimate the hazard function for 
that subject by plugging into the appropriate trt*stratum 
coefficients 
# 3. Use the resultant hazard functions to sample possible 
event times and repeat "imps" number of times 
# 4. Combine the estimates from K = 20 imputation models 
with Wald test 
# 5. Adjust the above fixed-sample test for sequential 
monitoring with RCTdesign 
 
 
 
# Build the analysis dataset: step 0 
actPt <- !is.na(studyJDates$activate) # Does not use the 
activation based on platelet 
actBase <- 
data.frame(caseid=baseline$caseid[actPt],site=baseline$cas
esite[actPt],group=baseline$stratum[actPt], 
                      
activ=studyJDates$activate[actPt],daysonstudy=studyJDates$


effobstime[actPt],totalstudy=studyJDates$endstudy[actPt]-
studyJDates$activate[actPt], 
                      
stopReason=studyDates$studystopreason[actPt],deathCause=st
udyDates$textcausedeath[actPt]) 
 
actBase$trt <- 
trtDF$trt[match(actBase$caseid,trtDF$caseid)] # use the 
correct randomization 
 
actBleeds <- bleeds[names(bleeds) %in% actBase$caseid] # 
get the bleed object for activated cases 
bleedCols <- data.frame(bleed=NULL,eventday=NULL) # set up 
an object that will record first bleed 2+ and their dates 
 
naInt <- vector(mode="list",length(actBleeds)) # will 
store the intervals with missingness 
 
for (i in 1:length(actBleeds)){ 
  bld <- actBleeds[[i]] 
  bld2 <- (as.numeric(bld$maxBldgrade) >= 2) & (bld$stage 
== "efficacy") 
   
  availDts <- floor(bld$JDates)-actBase$activ[i]+1 
  naDts <- (1:30)[!1:30 %in% availDts] # which days are 
not available 
   
  if (sum(bld2) > 0){ 
    bldInfo <- c(1,bld$JDates[min(which(bld2))]-
actBase$activ[i]+1) # there is a 2+ bleed 
    naInt[[i]] <- NA # do not worry about missingness 
  } else if (actBase$daysonstudy[i] == 30 & 
length(naDts)==0) { # CHANGE: checks to make sure that 
there are 30 bleed entries 
    bldInfo <- c(0,NA) # 30 days of bleed entries and no 
bleed 
    naInt[[i]] <- NA # no missingness at all 
  } else { 
    bldInfo <- c(NA,min(naDts)) # someone to impute, give 
the first day of missingness as "eventday" 
    naInt[[i]] <- naDts 
  } 
  bleedCols <- rbind(bleedCols,bldInfo) 
} 
colnames(bleedCols) <- c("bleed","eventday") 


names(naInt) <- actBase$caseid 
 
actLabs <- labs[names(labs) %in% actBase$caseid] # get the 
labs for activated subjects 
labCols <- NULL # object that will hold 30 days of ANC  
for (i in 1:length(actLabs)){ 
  lb <- actLabs[[i]]$ANC 
  dts <- floor(lb$JDates) - actBase$activ[i]+1 # ensures 
that ANC is counted on the day it happened, day 1 is all 
day after activation 
  dtIdx <- !duplicated(dts) & (dts >= 1) & (dts <= 30) # 
takes the first  ANC measurement on each day in efficacy 
window 
  cnt <- rep(NA,30) # initialize a vector of 30 days of 
ANC 
  cnt[dts[dtIdx]] <- lb$value[dtIdx] <= 0.5 # low ANC <= 
500 
  cnt <- na.locf(cnt) # LOCF  
  labCols <- rbind(labCols,cnt) 
} 
 
# set up an analysis dataset dat 
dat <- 
as.data.frame(cbind(actBase$caseid,actBase$trt,actBase[,c(
2,3,5)],bleedCols,labCols)) # only keep relevant columns 
colnames(dat) <- 
c("caseid","trt",colnames(actBase[,c(2,3,5)]),colnames(ble
edCols),paste("day",1:30,sep="")) 
longdatComp <- makeLong(dat[!is.na(dat$bleed),]) # makes 
ANC into a time-varying covariate for coxph 
 
# Begin the imputation procedure: step 1 
bHaz <- function(trt,longdat){ 
  dat <- longdat[longdat$trt==trt,] 
  lm <- 
with(dat,coxph(Surv(time=tstart,time2=tend,event=bleed)~si
te+count+cluster(caseid)+strata(group))) # cox model with 
time-varying ANC and robust SE 
  return(lm) 
} 
 
lmPlc <- bHaz(0,longdatComp) # get the baseline hazard in 
placebo and control groups 
lmTrt <- bHaz(1,longdatComp) 
bList <- list(lmPlc,lmTrt) 


 
oneimp <- function(bList,datInc){ # the function that 
creates one imputed dataset and outputs the score test on 
treatment parameter 
  naCases <- is.na(datInc$bleed) # get the cases with 
missing bleed 
  for (i in 1:sum(naCases)){ 
    naDay <- datInc$eventday[naCases][i]-1 # the last day 
with recorded data 
    naTrt <- datInc$trt[naCases][i] 
    naCase <- datInc$caseid[naCases][i] # grab the caseid 
     
    # step 2 
    truncData <- datInc[,1:(7+naDay)] # take the columns 
up until the last day of data 
    frzCol <- datInc[,(naDay+7)] 
    frzData <- cbind(truncData,matrix(rep(frzCol,30-
naDay),ncol=30-
naDay,nrow=dim(datInc)[1]))[which(naCases)[i],] # choose 
the subject of interest 
    impData <- makeLong(frzData) 
     
    lmNum <- ifelse(naTrt==0,1,2) 
    lm <- bList[[lmNum]] # returns appropriate baseline lm 
     
    # step 3 
    predSurvival <- survfit(lm,impData) # predict survival 
based on imputed data 
     
    empCDF <- 1-as.matrix(predSurvival$surv)[,1] # 
survival estimates for 30 days 
    invCDF <- function(prob) { # takes in a probability 
and returns the smallest t (# of days) to achieve that 
probability 
      min(which(empCDF >= prob)) # specific eCDF 
    } 
    u <- runif(1) 
    t <- invCDF(u) 
     
    missItvl <- naInt[[match(naCase,names(naInt))]] 
    iBleed <- ifelse(t %in% missItvl,1,0) # if bleed would 
have occurred in 30 days (after time we actually observed) 
then fill in 
    datInc$bleed[naCases][i] <- iBleed 
  } 


  return(datInc)  # return the filled in data set 
} 
 
# step 4 
set.seed(impSeed) 
reps <- 20 
 
impDatasets <- vector("list",reps) 
bleedLogistImps <- bleedLogistImpsMLE <- 
matrix(nrow=reps,ncol=2) 
for (k in 1:reps){ 
  impOut <- oneimp(bList=bList,dat=dat) 
  impDatasets[[k]] <- impOut # save the imputed data sets 
for use in interval estimation 
  impFit <- glm(bleed ~ site + group+trt,  
                family="binomial",data=impOut) # the full 
model fit on the imputed data 
  bleedLogistImps[k,] <- treatScoreTest(impOut,0) 
  bleedLogistImpsMLE[k,] <- 
c(coef(impFit)[6],sandwich(impFit)[6,6]) 
} 
bleedLogistFixed <- mean(bleedLogistImps[,1]) / 
sqrt(mean(bleedLogistImps[,2]) + var(bleedLogistImps[,1])) 
# wald-imputed test statistic 
bleedLogistFixed.p <- 
pnorm(bleedLogistFixed,lower.tail=FALSE) # one-sided, 
upper wald p-value from imputation 
 
bleedLogistFixedOR <- exp(mean(bleedLogistImpsMLE[,1])) 
 
# step 5 
source("finalRCTDesign.R") # this should output a final 
seqDesign object 'atreatFinal' 
 
# bleedLogistSeq <- 
seqInference(atreatFinal,observed=bleedLogistFixed, # 
convert the fixed-sample wald statistic to sequential 
monitor 
                               # 
analysis.index=3,ordering="l",inScale="Z") # use the LR 
ordering 
 
bleedLogistSeq <- 
seqInference(atreatFinal,observed=bleedLogistFixed.p, # 
convert the fixed-sample p-value to sequential monitor 


                              
analysis.index=3,ordering="l",inScale="P") # use the LR 
ordering 
 
bleedLogistSeq.p <- 
2*min(bleedLogistSeq$PvalueL.LROrder,bleedLogistSeq$Pvalue
U.LROrder) # two-sided final p-value 
 
digOR <- 2 
digP <- 3 
 
print(paste0("OR=",round(bleedLogistFixedOR,digOR), 
             " P=",round(bleedLogistSeq.p,digP)) 
      ) 
 
 
 
##########################################################
########################### 
# Above code computed the multiple imputation- and 
sequential monitoring-adjusted p-value and multiple 
imputation-adjusted OR 
# Code below computes the multiple imputation- and 
sequential monitoring-adjusted confidence interval 
 
# 1. Function to compute the multiple imputation- and 
sequential monitoring-adjusted p-value for different 
"null" hypotheses 
# 2. Use the multiple imputation-adjusted Wald CI to guide 
a grid search across different "null" hypotheses 
#     want to collect the points at which the lower 
endpoint switches from <0.025 to >0.025 and upper switches 
from <0.975 to >0.975 
 
 
alphaLevel <- 0.05 
lowerCrit <- alphaLevel/2 
upperCrit <- 1-lowerCrit 
 
 
### Step 1: Repeat much of the same code as above to 
compute the multiple imputation- and sequential 
monitoring-adjusted p-value 
 


oneP <- function(nullP,impDataList=impDatasets){ # needs a 
"null" to test at and the list contaning imputed datasets 
  ## Changes to above code: do not need to return MLE, 
returns 2-sided p-value rather than 1-sided 
   
  bleedLogistImps <- 
matrix(nrow=length(impDataList),ncol=2) 
  for (k in 1:length(impDataList)){ 
    bleedLogistImps[k,] <- 
treatScoreTest(impDataList[[k]],nullP) 
  } 
  bleedLogistFixed <- mean(bleedLogistImps[,1]) / 
sqrt(mean(bleedLogistImps[,2]) + var(bleedLogistImps[,1])) 
# wald-imputed test statistic 
  bleedLogistFixed.p <- 
pnorm(bleedLogistFixed,lower.tail=FALSE) # one-sided, 
upper wald p-value from imputation 
   
  # step 5 
  bleedLogistSeq <- 
seqInference(atreatFinal,observed=bleedLogistFixed.p, # 
convert the fixed-sample p-value to sequential monitoring 
                                 
analysis.index=3,ordering="l",inScale="P") # use the LR 
ordering 
   
  bleedLogistSeq.p <- 
2*min(bleedLogistSeq$PvalueL.LROrder,bleedLogistSeq$Pvalue
U.LROrder) # two-sided final p-value 
   
  return(bleedLogistSeq.p) 
} 
 
 
 
### Step 2a: compute the fixed sample CI as a coarse guide 
for the final CI grid search 
 
bleedLogistFixedLogOR <- mean(bleedLogistImpsMLE[,1]) 
bleedLogistFixedLogORSE <- 
sqrt(var(bleedLogistImpsMLE[,1])+mean(bleedLogistImpsMLE[,
2])) 
 
coarseCI <- 
bleedLogistFixedLogOR+qnorm(c(lowerCrit,upperCrit),0,1)*bl


eedLogistFixedLogORSE # coarse CI (NOTE: this is on the 
parameter or log(OR) scale!) 
 
### Step 2b: function to perform grid search given initial 
values 
 
gridSearch <- function(inits,tol,lower=TRUE){ # requires 
initial guess and tolerance, lower versus upper changes 
the inequalities due to ordering of parameter values; uses 
global variable of significance levels 
  if (lower){ # moves from rejecting "null" to accepting 
    seqRange <- seq(inits[1],inits[2],length.out=1/tol) 
    seqP <- rep(NA,length(seqRange)) 
    for (i in 1:length(seqRange)){ 
      seqP[i] <- oneP(seqRange[i]) # compute the p-value 
with the given "null" hypothesis 
      if (i==1 & seqP[i] >= alphaLevel) { 
        stop("Need smaller lower guess") # no switch 
possible in the given range 
      } else if (i==length(seqRange) & seqP[i] < 
alphaLevel){ 
        stop("Need larger upper guess") # no switch 
happened in the given range 
      } else { 
        if (i > 1){ 
          if (seqP[i] >=alphaLevel & seqP[i-1] < 
alphaLevel){ 
            switchVals <- c(seqRange[i-1],seqRange[i]) # 
stores the points at which it switches significance 
            break # found the switching point! 
          } 
        } 
      } 
      # if (i %% 5==0) print(i) 
    } 
  } else { # moves from accepting null to rejecting  
    seqRange <- seq(inits[1],inits[2],length.out=1/tol) 
    seqP <- rep(NA,length(seqRange)) 
    for (i in 1:length(seqRange)){ 
      seqP[i] <- oneP(seqRange[i]) # compute the p-value 
with the given "null" hypothesis 
      if (i==1 & seqP[i] < alphaLevel) { 
        stop("Need smaller lower guess") # no switch 
possible in the given range 


      } else if (i==length(seqRange) & seqP[i] >= 
alphaLevel){ 
        stop("Need larger upper guess") # no switch 
happened in the given range 
      } else { 
        if (i > 1) { 
          if(seqP[i] < alphaLevel & seqP[i-1] >= 
alphaLevel){ 
            switchVals <- c(seqRange[i-1],seqRange[i]) # 
stores the points at which it switches significance 
            break # found the switching point! 
          } 
        } 
      } 
      # if (i %% 5==0) print(i) 
    } 
  } 
  return(switchVals) 
} 
 
computeCI <- 
function(inits=c(coarseCI[1],coarseCI[2]),tolFine=1e-
3,tolCoarse=1e-1,coarseFactor=1){ # requires initial CI 
guess, and tol is how expensive of a search; tol must be 
<1e-2 
   
  ### compute lower bound: when does it cross from <0.025 
to >= 0.025 
  coarseLowerInits <- inits[1]+c(-
1,1)*diff(inits)*coarseFactor 
  coarseLowerSwitch <- 
gridSearch(coarseLowerInits,tolCoarse,lower=TRUE) 
  fineLowerSwitch <- 
gridSearch(coarseLowerSwitch,tolFine,lower=TRUE) 
   
   
  ### compute upper bound: when does it cross from <= 
0.975 to >0.975 
  coarseUpperInits <- inits[2]+c(-
1,1)*diff(inits)*coarseFactor 
  coarseUpperSwitch <- 
gridSearch(coarseUpperInits,tolCoarse,lower=FALSE) 
  fineUpperSwitch <- 
gridSearch(coarseUpperSwitch,tolFine,lower=FALSE) 
   


  # return(c(coarseLowerSwitch[1],coarseUpperSwitch[2])) # 
return the limits that are barely rejected by hypothesis 
tests 
  return(c(fineLowerSwitch[1],fineUpperSwitch[2])) # 
return the limits that are barely rejected by hypothesis 
tests 
} 
 
coarseTol <- 1e-1 
fineTol <- 1e-3 
coarseWidthFactor <- 1 
 
bleedLogistSeq.CI <- 
computeCI(tolCoarse=coarseTol,tolFine=fineTol,coarseFactor
=coarseWidthFactor) # final confidence interval 
 
print(paste0("95% CI: 
(",round(exp(bleedLogistSeq.CI[1]),3),", 
",round(exp(bleedLogistSeq.CI[2]),3),")"))