A Pediatric Trial Using Tranexamic Acid in Thrombocytopenia
Phase: PHASE1
Conditions: Pediatric Cancer, Thrombocytopenia, Hemostatic Disorder, Coagulation Defect; Acquired
Sponsor: Meghan McCormick

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A Pediatric Trial Using Tranexamic Acid in Thrombocytopenia 
 
 
 
 
A Prospective Single-Center, Double-Blinded, Randomized Study to Evaluate the 
Feasibility of using Tranexamic Acid to Reduce Bleeding Complications in 
Pediatric Patients with Hypoproliferative Thrombocytopenia. 
 
 
 
 
Version 3.0 
Version Date:        12 January 2020 
NCT03806556 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol Synopsis 
 
Patients receiving chemotherapy are at high risk of bleeding complications during the 
course of therapy, due to a variety of contributing factors. These include, but are not 
limited to the effects of thrombocytopenia, platelet dysfunction, vascular defects, 
coagulopathy and the adverse effects of medications received during the course of 
therapy [1]. Prior reviews on the subject have concluded that major bleeding episodes 
are associated with increased mortality rates, greater utilization of resources and an 
increased transfusion requirement [2]. Risks may be even greater in the pediatric 
population. The Determination of the Optimal Platelet Dose Strategy to Prevent 
Bleeding in Thrombocytopenic Patients (PLADO) trial enrolled 200 pediatric patients, 
and found that the population of pediatric patients under study had a greater risk of 
bleeding events when compared to the adult patients. Bleeding occurred in up to 88% of 
pediatric patients despite the use of a prophylactic platelet transfusion threshold of 
≤10,000/uL [3].  
 
The appropriate strategy to address this risk is unclear. Prophylactic platelet 
transfusions are associated with a reduction in clinically significant bleeding compared 
to a therapeutic transfusion strategy [4]. However, trials evaluating the effectiveness of 
higher platelet transfusion thresholds have not demonstrated a commensurate decrease 
in bleeding incidence or severity [5-7]. Other strategies have included the use of higher 
dose platelet transfusions, which have also been found to be ineffective [8]. Therefore, 
alternative strategies to prevent bleeding events in thrombocytopenic patients must be 
identified to reduce the morbidity, mortality and increased transfusion requirements 
associated with such events. 
 
Tranexamic Acid is a competitive inhibitor of plasminogen activation and inhibits 
fibrinolysis. It is available in an intravenous formulation and has been used in pediatric 
patients to prevent or reduce bleeding in the peri-operative setting, pediatric trauma and 
with menstrual bleeding [9-14]. Prior studies investigating the use of antifibrinolytic 
agents in patients with hypoproliferative thrombocytopenia have been limited, but 
results are encouraging as to its effectiveness [15-18]. However, none of these studies 
have included pediatric patients to date. 
 
The results of this study will allow the investigators to evaluate recruitment success in 
order to plan for a larger trial to investigate the efficacy of tranexamic acid in this 
population. It will also provide evidence as to the safety of tranexamic acid when used 
as an adjunct to platelet transfusion in pediatric patients with hypoproliferative 
thrombocytopenia, and may provide a signal as to its effectiveness. Lastly laboratory 
studies will demonstrate whether the dose strategy for TXA effectively suppresses in 
vitro measures of fibrinolysis.  If beneficial, this treatment could potentially lead to a 
decrease in bleeding episodes and platelet transfusions (with an attendant decrease in 
transfusion related adverse events) as well as potential savings for healthcare-related 
costs and improved quality of life.  
 

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Objectives 
The purpose of this study is to evaluate the feasibility and safety of a randomized 
controlled trial of tranexamic acid for use in the prevention of bleeding complications in 
pediatric patients with hypoproliferative thrombocytopenia secondary to chemotherapy 
or blood and marrow transplantation. A secondary objective is to demonstrate that the 
TXA dosing strategy suppresses in-vitro measures of fibrinolysis. 
 
Study Design 
This will be a double blind, randomized, placebo-controlled trial. Eligible subjects will be 
identified by research staff or primary physicians after being identified as likely to have 
platelet counts of ≤20,000/uL for 5 days or longer. Daily assessments of hemostasis 
and thrombosis will be conducted via chart review, patient interviews and physical 
exams. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
1. Summary ................................................................................................................ 7 
 
Figure 1: Trial Entry, Randomization, Treatment and Monitoring Flow Diagram ........ 12 
2. Background .......................................................................................................... 13 
3. Study Aims and Endpoints .................................................................................. 14 
3.1: Primary Aims and Endpoints ............................................................................... 14 
3.2: Secondary Aims and Endpoints .......................................................................... 14 
3.3: Safety Endpoints ................................................................................................. 15 
4. Population ............................................................................................................ 15 
4.1: Inclusion Criteria .................................................................................................. 15 
4.2: Exclusion Criteria...................................................................................................................... 16 
5. Trial Enrollment .................................................................................................... 16 
5.1: Screening and Recruitment ................................................................................. 16 
5.2: Randomization .......................................................................................................................... 17 
5.3: Enrollment Period ..................................................................................................................... 17 
6. Interventions ........................................................................................................ 17 
6.1: Study Drug (Tranexamic Acid or Placebo) .......................................................... 17 
Table 1: Tranexamic Acid dosing in pediatric non-cardiac surgery trials .................... 19 
6.2: Concomitant Care ............................................................................................... 19 
6.3: Stopping Points ......................................................................................................................... 20 
6.4: Temporary Stopping Points ................................................................................. 21 
6.5: Dose Adjustments ............................................................................................... 21 
Table 2: Adequate Pediatric Renal Function .............................................................. 21 
7. Study Drug Information ....................................................................................... 22 
7.1: Masking of Study Drug ........................................................................................ 22 
7.2: Administration of Study Drug ............................................................................... 22 
8. Study Procedures and Schedule ......................................................................... 22 
8.1: Day of Enrollment ................................................................................................ 22 
8.2: Days Between Enrollment and Randomization ............................................................... 23 
8.3: Day of Randomization ......................................................................................... 23 
8.4: Day 1 of Study Drug ............................................................................................ 24 
8.5: Days 2-30 of Study drug ........................................................................................................ 24 
8.6: Day 7 and Day 30 following Discontinuation of Study Drug ................................ 25 

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Table 3: Timeline for Study Assessment ................................................................................... 26 
8.7: Fibrinolysis Labs .................................................................................................. 27 
8.8: Laboratory Procedures ........................................................................................ 28 
Table 4: Sample Requirements for Laboratory Assessments  ........................................... 28 
8.9: Bleeding Assessment  ............................................................................................................ 28 
Table 5: WHO Bleeding Score  .................................................................................................... 28 
8.10: Thrombotic Assessment  ..................................................................................................... 28 
 
9. Adverse Event Reporting ........................................................................................................... 29 
9.1: Frequency of Monitoring ........................................................................................................ 30 
9.2: Adverse Event Attribution ...................................................................................................... 30 
Table 6: Adverse Event Attribution .............................................................................................. 30 
9.3: Adverse Events Reporting Timeline ................................................................................... 30 
9.4: Expected Adverse Events ...................................................................................................... 31 
9.4.1: Drug Interactions: Avoid Concomitant Use ................................................................... 32 
9.4.2: Drug Interactions: Increased/Decreased Effect/Toxicity ........................................... 32 
10. Loss to Follow Up .............................................................................................. 32 
10.1: Death ................................................................................................................. 32 
10.2: Study Withdrawal ................................................................................................................... 33 
10.3: Hospital Discharge ................................................................................................................ 33 
11. Statistical Considerations and Analysis ........................................................... 33 
11.1: Statistical Hypothesis ........................................................................................ 33 
11.1.1: Primary Endpoints .............................................................................................................. 33 
11.1.2: Secondary Endpoints ........................................................................................................ 34 
11.2: Randomization ........................................................................................................................ 34 
11.3: Analysis Populations ......................................................................................... 34 
11.4: Competing Risks .................................................................................................................... 35 
11.4.1: Death ...................................................................................................................................... 35 
11.4.2: Hospital Discharge ............................................................................................................. 35 
11.5: Statistical Analysis Planned ................................................................................................ 35 
11.6: Sequential Stopping Rules ................................................................................ 35 
11.7: Sample size ............................................................................................................................. 36 
12. Risks Management Procedures ......................................................................... 36 
12.1: Protection Against Risks ...................................................................................................... 36 
12.2: Data Monitoring and Interim Analysis .............................................................................. 37 
13. Records and Documentation ............................................................................. 38 
13.1: Data Management ............................................................................................. 38 
14. Institutional Review Board (IRB) ........................................................................ 39 

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15. Trial Committees ................................................................................................ 40 
15.1: Data and Safety Monitoring Board (DSMB) ................................................................... 40 
References:………………………………………………………………………………… .41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Section 1. Summary 
 
Data category 
Information 
Primary registry and trial identifying number 
ClinicalTrials.gov 
TBD 
Date of registration in primary registry 
Source(s) of monetary or material support 
Internal 
Contact for public queries 
Meghan McCormick, MD, [201-919-
6793] 
[Meghan.mccormick3@chp.edu] 
Darrell Triulzi, MD 
[DTriulzi@itxm.org]
Contact for scientific queries 
Meghan Mccormick, MD 
The Children’s Hospital of Pittsburgh 
of UPMC 
Pittsburgh, PA, USA
Public title 
A Pediatric Trial Using Tranexamic 
Acid in Thrombocytopenia
Scientific title 
A Prospective, Single-Center, Double-
Blinded, Randomized Study to 
Evaluate the Feasibility of using 
Tranexamic Acid to Reduce Bleeding 
Complications in Pediatric Patients 
with Hypoproliferative 
Thrombocytopenia
Countries of recruitment 
USA 
Health condition(s) or problem(s) studied 
Thrombocytopenia, Malignancy 

8 
 
Data category 
Information 
Intervention(s) 
Active comparator: Tranexamic 
Acid 10 mg/kg IV q8H (or TID if 
preferred by primary physician) 
Placebo comparator: Normal Saline 
IV q8H (or TID if preferred by primary 
physician) 
Key inclusion and exclusion criteria 
Ages eligible for study: ≥2 years, ≤21 
years 
Sexes eligible for study: both 
Accepts healthy volunteers: no 
Inclusion criteria (all must be present): 
 Patient hospitalized 
 Confirmed diagnosis of 
hematologic malignancy or solid 
tumor 
 Undergoing or planned 
chemotherapy or blood or marrow 
transplantation 
 Expected period of 
thrombocytopenia resulting in 
platelet count of ≤20,000/uL for ≥ 5 
days  
 Requires platelet transfusion 
threshold ≤30,000/uL 
 >14 days beyond last dose of 
PEG-Asparaginase or >72 hours 
beyond last dose of Erwinia 
Asparaginase 
Exclusion criteria (none must be 
present):  
 Diagnosis of acute promyelocytic 
leukemia 
 History of ITP, TTP or HUS  
 Known inherited or acquired 
bleeding disorder

9 
 
Data category 
Information 
 Known inherited or acquired 
prothrombotic disorder  
 Diagnosis of DIC 
 WHO Grade 2 or greater bleeding 
within 48 hours prior to enrollment 
or study drug activation 
 Receipt of PEG-asparaginase 
within 7 days prior to enrollment 
 Receiving tranexamic acid (or 
other anti-fibrinolytic agent) or any 
other pro-coagulant agent; 
Receiving estrogen derivatives or 
progestins 
 Receiving therapy with 
anticoagulation or antiplatelet 
therapy 
 Receiving platelet growth factors 
 History of thromboembolic event 
within past six months 
 History of sinusoidal obstruction 
syndrome 
 Visible hematuria  
 Renal dysfunction (as defined in 
Section 6, Table 2), receiving 
dialysis or anuria (defined as 
<10mL/hr urine over 24H) 
 History of seizures 
 Known allergy to tranexamic acid 
 Pregnancy  
 Receiving outpatient therapy or 
predicted to have inpatient hospital 
stay ≤3 days 
 Patient with platelet count 
≥30,000/uL without predicted fall in 
platelet count  
Study type 
Interventional 
Allocation: randomized, 1:1 
Intervention model: parallel 
assignment 
Masking: double blind (subject, 

10 
 
Data category 
Information 
caregiver, investigator, outcomes 
assessor) 
Primary purpose: Prevention 
Phase I 
Study Period: 18 months 
Date of first enrollment 
TBD 
Target sample size 
20 
Recruitment status 
Pre-Recruitment 
Primary outcome(s) 
Determine the feasibility of enrolling 
and conducting an RCT of tranexamic 
acid in pediatric patients with 
hypoproliferative thrombocytopenia 
To define and describe safety of 
tranexamic acid administered on this 
schedule 
To demonstrate appropriate 
suppression of in vitro fibrinolytic 
activity by tranexamic acid 
administered on this schedule 
Key secondary outcomes 
To preliminarily define the reduction in 
WHO grade 2 or higher bleeding 
events within the confines of a Phase 
1 study 
To assess the reduction in number of 
platelet transfusions 
To assess the reduction in number of 
red blood cell transfusions 

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Figure 1. Study Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-Up Period 
7 days post study drug cessation 
30 days post study drug cessation 
Subjects screened, consented, 
enrolled 
N= approximately 20 
Randomize 
Platelet count ≤50,000/uL 
Tranexamic Acid (TXA) 
IV 10mg/kg q8H (or TID) 
N= approximately 10 
Placebo (Normal Saline) 
IV q8H (or TID) 
N= approximately 10 
Activate Study Drug 
Platelet count ≤30,000/uL 

No bleeding or WHO grade 1 Bleeding: Transfuse platelets if morning 
platelet count below transfusion threshold 

WHO Grade 2 or higher bleeding, pre-procedure: Transfuse platelets 
at physician discretion 

Daily Hemostatic and Thrombotic Assessment 
Stop Study Drug When Any of the Following Occur: 

30 days from study drug activation 

Platelet count ≥30,000/uL on 2 measurements (at least 46H apart) with 
no intervening platelet transfusions, no more than a 50% decrease in 
platelet count from the initial measurement and no intervening count 
<30,000/uL 

Increase in platelet count from <30,000/uL to ≥50,000/uL over 2 
successive measurements with no intervening platelet transfusion 

Hospital Discharge or Patient Death 

Thromboembolic event, Sinusoidal Obstructive Syndrome 

Visible Hematuria, Anuria, Renal Dysfunction (defined in Section 6, 
Table 2) 

Prescribed procoagulant or anticoagulant agent 

Two or more events of central line occlusion

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2. Background 
 
Patients receiving chemotherapy are at high risk of bleeding complications during the 
course of therapy, due to a variety of contributing factors. These include, but are not 
limited to the effects of thrombocytopenia, platelet dysfunction, vascular defects, 
coagulopathy and the adverse effects of medications received during the course of 
therapy [1]. Prior reviews on the subject have concluded that major bleeding episodes 
are associated with increased mortality rates, greater utilization of resources and an 
increase in transfusion requirements [2]. Risks may be even greater in the pediatric 
population. The Determination of the Optimal Platelet Dose Strategy to Prevent 
Bleeding in Thrombocytopenic Patients (PLADO) trial enrolled 200 pediatric patients, 
and found that the population of pediatric patients under study had a greater risk of 
bleeding events when compared to adult patients. Bleeding occurred in up to 88% of 
pediatric patients despite the use of a prophylactic platelet transfusion threshold of 
≤10,000/uL [3].  
 
The appropriate strategy to address this risk is unclear. Prophylactic platelet 
transfusions have been shown to lead to a reduction in clinically significant bleeding 
compared to a therapeutic transfusion strategy [4]. However, trials evaluating the 
effectiveness of using a high platelet transfusion threshold have not demonstrated a 
commensurate decrease in bleeding incidence or severity [5-7]. Other strategies have 
included the use of higher dose platelet transfusions, which have also been found to be 
ineffective in reducing the incidence of bleeding [8]. A single-institution study of blood 
product transfusion requirements in a pediatric hematology/oncology population found 
that 66% of patients received transfusion of red blood cell or platelet products during the 
study period [19]. The burden associated with blood product transfusions includes the 
risk of adverse effects associated with transfusion, affecting up to 10% of transfusions 
[20]. Multiple platelet transfusions can also be associated with significant costs, in 2018 
Medicaid set reimbursement for a unit of irradiated, leukoreduced red blood cells at 
$167.64. Therefore, alternative strategies to prevent bleeding events in 
thrombocytopenic patients must be identified to reduce the morbidity, mortality and 
increased transfusion requirements associated with such events. 
 
Anti-fibrinolytic agents, including Tranexamic Acid and Aminocaproic Acid, are 
competitive inhibitors of plasminogen activation and inhibit fibrinolysis. Tranexamic acid 
is available in an intravenous formulation and has been used in pediatric patients to 
prevent or reduce bleeding in the peri-operative setting, cases of trauma and with 
menstrual bleeding [9-14]. Prior studies investigating the use of antifibrinolytic agents in 
patients with hypoproliferative thrombocytopenia have been limited, but results are 
encouraging as to its effectiveness  [15-18]. However, many of these studies have been 
small and did not include pediatric patients. At this time there are multiple large 
randomized controlled trials underway investigating whether antifibrinolytic agents can 
mitigate the incidence of bleeding and transfusion in patients with malignancies 
receiving chemotherapy. However, these are limited to adult participants. Given that the 
rate of bleeding events is even greater in the pediatric population, it stands to reason 
that antifibrinolytics may be beneficial in this population as well. 

13 
 
 
The dose of tranexamic acid chosen for this study, 10mg/kg q8H or TID, was chosen 
from the package insert for Tranexamic Acid, and has been safely used in pediatric 
patients for other indications. One of the major concerns regarding the use of 
antifibrinolytics is their theoretical risk of thromboembolic events. Tranexamic acid has 
been used widely in several major studies, including the CRASH-2 trial and the 
WOMAN trial, neither of which showed evidence for an increased risk of 
thromboembolic event in participants receiving tranexamic acid versus placebo [21, 22]. 
In order to provide an additional layer of caution we will also plan to exclude all patients 
with a current or past history of thromboembolic disease, current bleeding or 
coagulation disorders.  
 
Additionally, this study will incorporate a secondary translational component utilizing 
assays of fibrinolysis on samples obtained from patients prior to and following 
antifibrinolytic therapy. As this study will not be adequately powered to detect 
differences in the occurrence of bleeding events between patients in the treatment 
group and the placebo group, identification of the successful impairment of fibrinolysis in 
vitro will provide evidence of adequate antifibrinolytic dosing. Additionally, by better 
characterizing baseline fibrinolytic activity in pediatric patients with malignancies, this 
may allow us to identify a subset of patients in whom antifibrinolytic therapy may be the 
most useful. 
 
3. Study Aims and Endpoints 
3.1 Primary Aims and Endpoints 
Aim 1: To determine the safety and feasibility of the use of tranexamic acid in pediatric 
patients receiving chemotherapy or blood and/or marrow transplantation (BMT) 
Endpoint: Incidence of adverse events, serious adverse events and death attributed to 
study drug; Number of patients screened eligible for enrollment and the rate of 
recruitment during study period 
 
Aim 2: To evaluate the effectiveness of current dose of tranexamic acid for suppressing 
in vitro fibrinolysis 
Endpoint: Measures of fibrinolytic activity at baseline (prior to tranexamic acid infusion) 
and at steady-state 
 
3.2 Secondary Aims and Endpoints 
Aim 3: To determine whether tranexamic acid leads to a decrease in the incidence of 
WHO Grade 2 or higher bleeding events 
Endpoint: Proportion of patients with WHO Grade 2 or higher bleeding events daily 
following activation of study drug or placebo 
 
Aim 4: To determine whether tranexamic acid leads to a reduction in the number of 
days with any grade bleeding event 
Endpoint: Proportion of patients with any grade bleeding event following activation of 
study drug 
 

14 
 
Aim 5: To determine whether tranexamic acid leads to a decrease in the highest 
observed grade of bleeding (as measured on WHO bleeding scale) during the study 
period 
Endpoint: Highest grade of bleeding (as measured on WHO bleeding scale) during 
study period in each enrolled patient 
 
Aim 6: To determine whether tranexamic acid leads to a reduction in the number of red 
blood cell or platelet transfusions required 
Endpoint: Number of red blood cell or platelet transfusions per patient daily following 
activation of study drug  
 
Aim 7: To determine whether tranexamic acid prolongs the amount of time from 
activation of study drug to the first episode of WHO Grade 2 or higher bleeding 
Endpoint: Length of time from activation of study drug to first episode of WHO Grade 2 
or higher bleeding 
 
3.3 Safety Endpoints 
Adverse events and serious adverse events will be monitored and collected from the 
time of activation of the study drug until a period up to and including 30 days after the 
last dose of the study drug. Adverse events and serious adverse events will to be 
assessed by CTCAE v.4.0 criteria and compared between study drug and placebo 
arms. The following events will specifically be compared across study arms; 
 Incidence of thrombotic events (A thrombotic event is defined as venous or 
arterial thrombosis confirmed on imaging study, which may include Doppler US, 
CT scan, MRI or venography) 
 Incidence of veno-occlusive disease (also known as sinusoidal obstruction 
syndrome) 
 All cause-mortality, including incidence of death due to thrombosis  
 
4. Population 
Pediatric patients with hematologic malignancy or solid tumors receiving chemotherapy 
or undergoing BMT. 
 
4.1 Inclusion Criteria 
Patients eligible for trial must comply with all of the following at the time of 
randomization: 
 Patients must be ≥2 years of age and ≤21 years of age 
 Patients must have a confirmed diagnosis of hematologic malignancy or solid 
tumor malignancy 
 Patients must be undergoing or planned chemotherapy or BMT 
 Patients will only be eligible to receive study drug or placebo during a predicted 
inpatient stay of ≤3 days 
 Patients must be predicted to have thrombocytopenia ≤20,000/uL for ≥5 days 
 Patient must have a platelet transfusion threshold of ≤30,000/uL  
 Patients must be >14 days beyond their last dose of PEG-Asparaginase or >72 
hours beyond their last dose of Erwinia Asparaginase (with exceptions below) 

15 
 
 Patients must be able to comply with treatment and monitoring 
 
4.2 Exclusion Criteria 
To be eligible for participation in the study, potential subjects must not meet any of the 
following criteria: 
 Diagnosis of acute promyelocytic leukemia 
 History of ITP, TTP or HUS 
 History of inherited or acquired bleeding disorder 
 History of inherited or acquired prothrombotic disorder 
 Diagnosis of DIC 
 Patient must not have WHO Grade 2 bleeding or greater within 48 hours prior to 
enrollment or study drug activation 
 Patient must not have received PEG-Asparaginase within the 7 day period prior 
to enrollment. If this product is given within the 8-14 day period prior to 
enrollment patients are eligible if PT, PTT, INR and fibrinogen are obtained and 
are within 1.5 times the upper limits of normal.  
 Patient must not be receiving tranexamic acid or other anti-fibrinolytic agent or 
any other agent to promote hemostasis (which includes DDAVP, recombinant 
Factor VII, Prothrombin Complex Concentrate, Estrogen Derivatives and 
Progestins)  
 Patient must not be receiving therapy with anticoagulation or antiplatelet therapy 
(which includes heparin infusion, enoxaparin, aspirin. If anticoagulant/antiplatelet 
therapy is discontinued when platelet count is <50,000/uL patient will be eligible 
for enrollment) 
 Patient must not be receiving platelet growth factors 
 Patient has a current/prior history of thromboembolic event within the past six 
months. If history of thromboembolic event the patient should be >30 days from 
completion of anticoagulation therapy 
 Patient has a current/prior history of sinusoidal obstruction disease 
 Patient has visible blood in their urine  
 Patient with renal dysfunction (defined in Section 6, Table 2), hemodialysis or 
with anuria (defined as <10mL urine/hour over 24 hours) 
 History of seizures 
 Allergy to tranexamic acid 
 Pregnancy 
 Unwilling to accept blood transfusions 
 Requires platelet transfusion threshold higher than study protocol (If the patient is 
enrolled on study and begins treatment with either the study drug or placebo, and 
subsequently requires a platelet transfusion threshold greater than the study 
protocol they will remain on study). 
 
5. Trial Enrollment 
5.1 Screening and Recruitment 
Potentially eligible subjects will be identified by the investigator or trained member of the 
research staff. All new admissions to the Oncology or Bone Marrow Transplantation 

16 
 
service will be screened on a daily basis for potential eligibility based on underlying 
diagnosis and an expected period of thrombocytopenia ≤20,000/uL lasting ≥5 days. 
Patients who will be undergoing BMT may also be identified by their primary transplant 
physician at the time of their consent for BMT. Following initial identification of eligibility, 
the primary investigator or member of the research staff will screen subjects for full 
enrollment eligibility using medical history and laboratory results. There will not be a 
screening consent, we will seek a waiver of consent for screening purposes only. 
Screening eligibility checklist will be maintained in trial file in order to track information 
on screening and consent metrics at trial end. There will be no identifiable protected 
health information recorded on screening forms for patients who do not meet eligibility 
requirements or who decline trial enrollment. Patients who are screened for eligibility 
and meet requirements will be assigned a case ID which will be used to identify the 
participant on all subsequent trial documentation. The names of all patients screened 
for eligibility will recorded on a separate screening log sheet in order to avoid double-
screening. 
After obtaining permission from the subject’s physician to discuss the study, the primary 
investigator or trained research staff member will contact the prospective subject and 
obtain study consent. After signing the study consent the subject will be enrolled on to 
the study. 
 
5.2 Randomization 
This trial is designed as a prospective, randomized, controlled, blinded (patient, 
caregiver, physician, assessor) trial with two parallel groups and a primary endpoint of 
feasibility and safety. Randomization will be performed as block randomization with a 
1:1 allocation within blocks of size four.  
 
When a consented participant’s platelet count falls to ≤50,000/uL and the platelet count 
is expected to continue to fall and remain ≤20,000/uL for 5 days or longer, the patient 
will be randomized to either the tranexamic acid arm or the placebo arm by the 
investigational pharmacy. When the randomized subject’s platelet count is ≤30,000/uL 
with an expectation that the platelet count will be ≤20,000/uL for 5 days or longer the 
study drug will be activated. Activation of the study drug will act as time point zero for all 
study endpoints. 
 
5.3 Enrollment Period 
Screening will continue until the target population is achieved (20 activated subjects 
total). The enrollment period will extend over 18 months. The expected enrollment is 
estimated to be 14 randomized subjects per year. Both arms will have a target 
enrollment of 10 activated subjects 
 
6. Interventions 
6.1 Study Drug (Tranexamic Acid or Placebo) 
Tranexamic acid forms a reversible complex that displaces plasminogen from fibrin 
resulting in inhibition of fibrinolysis. Patients who are randomized to receive tranexamic 
acid will receive 10mg/kg IV Q8h by default, TID dosing will also be acceptable if it 
allows for fewer breaks into the line to reduce the risk of central-line associated 

17 
 
infections. Patients will continue tranexamic acid until they meet criteria for stopping the 
study drug as provided in section 6.3. Criteria for temporary discontinuation of the study 
drug are given in section 6.4. 
 
Tranexamic acid is a clear, colorless liquid in IV form. Patients randomized to the 
control arm will receive matching placebo, which will be IV normal saline of a volume 
equivalent to what the patient’s dose of tranexamic acid would be.  
 
Rationale for dose: 
According to the Children’s Hospital of Pittsburgh formulary through Lexicomp, the 
dosing of tranexamic acid for use in prevention of bleeding associated with tooth 
extraction in hemophilia patients is 10mg/kg three to four times daily by IV. For the 
prevention of bleeding associated with surgical procedures (cardiac and spinal 
procedures) continuous IV infusions of tranexamic acid have been used. In pediatric 
cardiac surgery, TXA dosing ranges from 100mg/kg IV bolus followed by a continuous 
infusion of 10mg/kg/hour IV infusion to a loading dose of 6.4mg/kg followed by a 
continuous infusion in the range of 2 to 3.1mg/kg/hour. In pediatric non-cardiac surgery 
the range of doses used in pediatric randomized trials is shown below.  They range from 
100mg/kg IV load following by a continuous infusion of 10mg/kg/hour to 10mg/kg IV 
load to 1 mg/kg/hour infusion in in pediatric patients undergoing spinal surgery [12, 23-
26]. Long-term prophylaxis in children with hereditary angioedema uses doses of 20 to 
75mg/kg/day in two to three divided doses, administered orally. In cases of traumatic 
hyphema, tranexamic acid is dosed orally at 25mg/kg/dose every eight hours for five to 
seven days. 
 
The dose chosen for this study is in the low -range of recommended IV doses for 
pediatric indications. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

18 
 
Table 1: Tranexamic acid dosing in pediatric non-cardiac surgery trials 
 
 
6.2 Concomitant Care 
Patients enrolled on trial must have a prophylactic platelet transfusion threshold of 
≤10,000/uL (for patients with solid tumors or hematologic malignancies not undergoing 
BMT) or ≤20,000/uL (for patients undergoing BMT) at the time of randomization. 
Prophylactic platelet transfusions will be given when morning platelet count is below the 
above values for prophylactic transfusions. Therapeutic platelet transfusions above 
these thresholds will be allowed at the discretion of their treating physician (for cases 
including active bleeding, for an expected platelet count of ≤10,000 or ≤20,000/uL the 
following morning, planned invasive procedures with the need for an increased platelet 
threshold or trauma). Clinicians will be allowed to exercise discretion to transfuse 
platelets for any reason should they feel there is a clinical reason to do so. In cases 
where a platelet transfusion is given for invasive procedures or trauma the subject will 
return to the study platelet transfusion threshold following this event when determined 
safe to do so by the treating physician. If, following enrollment and study drug activation, 
the subject subsequently has an event which leads to the need for a platelet transfusion 
threshold of greater than the study protocol, they will remain on study. 
 
Type and dose of platelet transfusion will not be specified. If a patient appears to 
develop platelet refractoriness (which is defined as two sequential transfusions with a 
repeat platelet count after a 4hour period of ≤5000/uL) then clinicians may exercise their 
judgement as to use of matched platelets or alloantibody testing. Data on type of 
platelet transfusion administered will be collected. For any platelet transfusions given 

19 
 
above the study threshold the rationale will be recorded on the daily transfusion 
assessment form. 
 
Patients will receive red blood cell transfusions as per the standard care of their treating 
physician. 
 
No other medication changes are directed in this protocol and standard care will 
otherwise be followed.  
 
6.3 Stopping Points 
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 with the reason for 
withdrawal documented in such an occurrence. 
 
The study drug will be permanently discontinued in one of the following circumstances: 
 The participant meets an exclusion criteria (either newly developed or not 
recognized previously) that precludes further study participation 
 The patient has been on study drug or received placebo medication for 30 days 
from the date of study drug activation 
 The patient’s platelet count increases spontaneously from <30,000/uL to 
≥50,000/uL across two successive platelet measurements with no intervening 
platelet transfusion 
 The patient’s platelet count remains ≥30,000/uL on 2 measurements made at 
least 46 hours apart without intervening platelet count of <30,000/uL or a 
decrease in platelet of greater than 50% between two measurements and without 
intervening platelet transfusion 
 The patient is prescribed any other procoagulant, antiplatelet or anticoagulant 
agent by their treating physician (this includes open label tranexamic acid) 
 The patient is discharged from hospital admission 
 The patient experiences a thrombotic event 
 The patient develops sinusoidal obstructive disease 
 The patient develops visible hematuria, renal dysfunction (as defined in Section 
6, table 2) or anuria 
 The patient has a recurrent incident of complete central line occlusion: defined as 
the inability to access or infuse through a central line requiring instillation of 
fibrinolytic agent such as alteplase for clearing. This does not include lines that 
require certain patient positioning for instillation of agents, which suggest a “kink” 
in the line. A recurrent incident is when the definition is met on 2 separate 
occasions while receiving study drug.  
 The patient becomes pregnant 
 
If any of the above reasons lead to cessation of the study drug it should not be restarted 
even if the patient later meets criteria again for the study drug.  
 
Subjects have the right to withdraw consent at any time. If a patient withdraws their 
consent for further participation, the subject will be asked to grant consent for the study 

20 
 
team to passively monitor their outcomes for major clinical events. For each patient at 
the end of therapy, the date and time that the study drug is voluntarily stopped will be 
recorded, along with the reasons that the subject so elected. It will be documented 
whether the subject is: 
 Stopping study drug, but will continue to follow all other study-defined procedures 
and monitoring 
 Stopping study drug and study-defined procedures and monitoring but allows 
investigators to passively monitor their medical record and follow-up for vital 
status up to 30 days after their last dose of study drug.  
 Discontinuing all further contact with study investigators 
 
In the event of subject death, the date of death will be recorded on the study form and 
will be characterized by time from consent and according to whether the investigator 
attributes the mortality to bleeding, thrombosis or death from other cause. 
 
When a patient meets one of the above study stopping criteria, the study medication will 
be discontinued following the next daily assessment.  
 
6.4 Temporary Stopping Points 
The study drug will be temporarily discontinued in the following situations: 
 Diagnosis of DIC by the treating team or treating physician 
 First event of central line occlusion (as defined above) 
In these situations, as detailed above, the study drug may be restarted after resolution 
of the situation.  
 
6.5 Organ Function Requirements 
Dose adjustments for renal insufficiency are recommended according to the Children’s 
Hospital of Pittsburgh Lexicomp formulary. As existing recommendations for dose 
adjustment are derived from the adult population and not for pediatric patients, the 
following table was created to guide participant exclusion based on renal function. The 
threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR utilizing child length and stature data published by the CDC. 
 
Table 2. Adequate Pediatric Renal Function:  
Adequate renal function defined as: 
- Creatinine clearance or radioisotope GFR ≥ 70 
mL/min/1.73 m2 or 
- A serum creatinine based on age/gender as follows:  
Age  
Maximum Serum 
Creatinine (mg/dL) 
                                     Male   Female 
1 month to < 6 
months 
0.4 0.4  
6 months to < 1 year 
0.5 0.5 
1 to < 2 years 
0.6 0.6 
2 to < 6 years 
0.8 0.8 

21 
 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 1.2 
13 to < 16 years 
1.5 1.4 
≥ 16 years 
1.7 1.4 
No dose adjustment is needed for hepatic impairment 
 
7. Study Drug Information 
7.1 Masking of Study drug 
The investigational pharmacy at each trial site will randomize and distribute tranexamic 
acid or placebo (as an equal volume of normal saline). The manufacturers, batch 
numbers, and sources will be recorded for all doses. The pharmacy will use the 
commercially available product purchased for use by the 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. 
 
Patients, care providers, study coordinators and study investigators will not be told 
which arm the patient is on. Among study personnel, only the unblinded pharmacists will 
have access to treatment assignment. The placebo will be normal saline administered 
by IV. Tranexamic acid in IV solution is clear and colorless and grossly similar to 
tranexamic acid in appearance. Research coordinators who collect outcomes data will 
have no contact with study drug.  
 
7.2 
Administration of Study Drug 
The study drug will be started according to the randomization assignment after meeting 
activation criteria. The dosing schedule for tranexamic acid will be 10mg/kg every 8 
hours (or TID dosing if preferred by primary physician). Tranexamic acid will diluted in 
normal saline to a total volume of 15mL. The dosing schedule for placebo will be an 
equivalent volume of normal saline (15mL) every 8 hours (or TID dosing if preferred by 
primary physician). Both TXA and placebo will be infused over 15 to 30 minutes, then 
the line is flushed with normal saline. Nursing staff will be instructed to document in the 
medical record if medication is not administered within the 15-30 minute infusion time, 
as well as the reason for this. 
 
Tranexamic Acid does not have Y-site or admixture compatibility with Ampicillin, 
Blinatumomab, Penicillin or Pipercillin-Tazobactam. Tranexamic acid should not be 
mixed with blood products. Tranexamic acid may be mixed with most solutions for 
infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions and 
Dextran solutions.  
 
8. Study Procedures and Schedule 
The following data will be collected according to the timeline below. If two or more study 
points fall on the same calendar day (for example if the date of consent and date of 
randomization are the same day) then all of the unique lab measurements required for 

22 
 
each time point need to be collected, but a lab measurement that is required at both 
time points does not need to be repeated twice.  
 
8.1 Day of Enrollment 
 Thrombotic Assessment  
o Assessment for thrombotic event will be performed via a review of 
medical chart notes and relevant imaging studies obtained within the time 
period from prior assessment. This definition of will apply to all future time 
points when a thrombotic assessment is completed. 
 Demographics and Medical History 
o Weight, Height, BMI 
o Date of Birth 
o Gender 
o Ethnicity 
o Race 
o Primary Diagnosis 
 Including disease, current treatment (Radiation, chemotherapy 
medications, BMT source, Donor ABO Type and Related/Unrelated 
Donor) 
o ABO Type 
o Concomitant Medications 
 Laboratory Assessment (lab studies obtained within 24H period prior to 
enrollment do not need to be repeated unless otherwise stated) 
o CBC 
o Serum Creatinine 
o Pregnancy Test (Urine or Serum, if female of child-bearing age and >72 
hours from previous) 
o HLA Testing results (if done as part of routine care) 
o Coagulation Testing (PT, PTT, INR and Fibrinogen) if PEG-Asparaginase 
or Erwinia Asparaginase has been given >7 days but ≤14 days from date 
of enrollment 
 Adverse events related to standard anticancer therapies will be carefully 
monitored for events that would preclude activation of study drug.  Collection 
and documentation of AEs for the trial will begin following first dose of study 
drug.  
 
8.2 Days Between Enrollment and Randomization; Days Between Randomization 
and Activation of Study Drug 
 Thrombotic Assessment (via chart review), to be completed once weekly 
 Laboratory Assessment, to be completed daily 
o CBC  
 Adverse events related to standard anticancer therapies will be carefully 
monitored for events that would preclude activation of study drug.  Collection 
and documentation of AEs for the trial will begin following first dose of study 
drug.  
 Medication Review – Document new or discontinued medications  

23 
 
 
8.3 Day of Randomization 
 Hemostatic/Bleeding Assessment 
o Bleeding will be recorded using the WHO Bleeding score as the bleeding 
assessment tool. Bleeding assessments will be completed by means of a 
physical assessment of the patient, patient interview and a review of 
patient chart and laboratory data for documented bleeding events. 
Research staff which will be either research nurse, primary investigator or 
co-investigator, will perform physical assessment of the patient and 
interview prior to reviewing the patient’s medical chart and laboratory data 
to allow an objective assessment. Nursing staff may provide additional 
details. If participant has had WHO Grade 2 or higher bleeding within 48H 
of randomization they will not be randomized. They will be eligible for 
randomization if bleeding later resolves. This definition of 
hemostatic/bleeding assessment will apply to all further time points at 
which a bleeding assessment is completed. 
o If participant has had WHO Grade 2 or higher bleeding within 48H of 
randomization they will not be randomized. They will be eligible for 
randomization if bleeding later resolves. 
 Thrombotic Assessment (via chart review) 
 Laboratory Assessment (lab studies obtained within 24H period prior to 
randomization do not need to be repeated unless otherwise stated) 
o Coagulation Profile (PT, PTT, INR, Fibrinogen, D-Dimer) 
o CBC 
o Serum Creatinine 
o Pregnancy Test (Urine or Serum, if female of child-bearing age and >72 
hours from previous) 
o Urinalysis (if >72 hours from previous) 
 Data on Platelet Transfusions 
o Number of platelet units transfused 
o Source of platelet transfusions (apheresis or whole blood) 
o HLA or cross-match compatible 
o Reason for Transfusion 
 Data on Red Blood Cell Transfusions 
o Number of units transfused 
o Reason for transfusion 
 Adverse events related to standard anticancer therapies will be carefully 
monitored for events that would preclude activation of study drug.  Collection 
and documentation of AEs for the trial will begin following first dose of study drug 
 Medication Review – Document new or discontinued medications  
 
8.4 Day 1 of Study Drug 
 Hemostatic/Bleeding Assessment 
o If participant has had Grade 2 or higher bleeding within 48H of initiation of 
the study drug this should not be activated. They will be eligible for 
activation of the study drug later if bleeding later resolves. 

24 
 
 Thrombotic Assessment (via chart review) 
 Laboratory Assessment (to be drawn prior to first dose of study drug) 
o CBC 
o Serum Creatinine 
o Urinalysis (if >72 hours from last Urinalysis) 
o Fibrinolysis study labs 
 Data on Platelet Transfusions 
o Number of platelets transfused 
o Source of platelet transfusions (apheresis or whole blood) 
o HLA or cross-match compatible 
o Reason for transfusion 
 Data on Red Blood Cell Transfusions 
o Number of units transfused 
o Reason for transfusion 
 Adverse Event Assessment and Reporting – All Grade 3 or greater adverse 
events will be documented and followed 
 Medication Review – Document new or discontinued medications  
 
8.5 Days 2-30 of Study Drug 
 Hemostatic/Bleeding Assessment 
 Thrombotic Assessment (via chart review) 
 Laboratory Assessment 
o CBC – to be drawn daily 
o Serum Creatinine – to be drawn daily 
o Bilirubin level – to be drawn once weekly 
o Fibrinolysis labs – to be drawn on Day 5 (+/- 1 day) 
 Data on Platelet Transfusions 
o Number of platelets transfused 
o Source of platelet transfusions (apheresis or whole blood) 
o HLA or cross-match compatible 
o Reason for transfusion 
 Data on Red Blood Cell Transfusions 
o Number of units transfused 
o Reason for transfusion 
 Adverse Event Assessment and Reporting - All Grade 3 or greater adverse 
events will be documented and followed 
 Medication Review – Document new or discontinued medications  
 
8.6 Day 7 (+/- 3 days) and Day 30 (+/- 3 days) following Discontinuation of Study 
Drug  
 Hemostatic/Bleeding Assessment (via phone conversation or clinic visit for 
patients who have been discharged; via chart review for patients who remain 
inpatient) 
 Thrombotic Assessment (via phone conversation or clinic visit for patients who 
have been discharged; via chart review for patients who remain inpatient) 

25 
 
 Adverse Event Assessment and Reporting (via phone conversation or clinic visit 
for patients who have been discharged; via chart review for patients who remain 
inpatient). All Grade 3 or greater adverse events will be documented and 
followed 
 
 
Table 3. Timeline for Study Assessment 
Schedule of 
Events 
Pre-Treatment Period 
Treatment 
Period 
Post-
Treatme
nt 
Period
Event 
Pre-
Screeni
ng 
Day of 
Enroll
ment1 
Days 
Between 
Enrollme
nt and 
Randomi
zation 
Day of 
Randomi
zation1 
Days 
Betwee
n 
Rando
mizatio
n and 
Activati
on 
Day 
1 of 
Stud
y 
Drug 
Days 
2-30 
of 
Study 
Drug 
Day 7 
(+/- 3 
days) 
and Day 
30 (+/- 3 
days) 
after 
Disconti
nuation 
of Study 
Drug
Medical 
Chart 
Review
X 
 
 
 
 
 
 
 
Informed 
Consent
 
X 
 
 
 
 
 
 
Demographi
cs and 
Medical 
History
 
X 
 
 
 
 
 
 
ABO Type
X
 HLA 
Testing*
 
X 
 
 
 
 
 
 
Fibrinolysis 
Labs
 
 
 
 
 
X 
𝑋ଶ 
 
CBC
X
X
X
X
X
X
Serum 
Creatinine
 
X 
 
X 
 
X 
X 
 
Urinalysis 
 
 
 
𝑋ଷ 
 
𝑋ଷ 
 
 
Coagulation 
Profile 
(PT/PTT/INR
/Fibrinogen/
D-dimer)
 
𝑋ସ 
 
X 
 
 
 
 

26 
 
Pregnancy 
Test
 
𝑋ହ 
 
𝑋ହ 
 
 
 
 
Bilurubin 
level
 
 
 
 
 
 
𝑋଺ 
 
Bleeding 
Assessment
 
 
 
X 
 
X 
X 
X 
Thrombotic 
Assessment
 
X 
𝑋଻ 
X 
𝑋଻ 
X 
X 
X 
Data on 
Transfusion 
 
 
 
X 
 
X 
X 
 
Drug or 
Placebo 
Administere
d
 
 
 
 
 
X 
X 
 
Adverse 
Event 
Assessment
 
 
 
 
 
ongoing 
Medication 
Review
ongoing 
 
1.  Lab studies obtained within 24H period prior to enrollment or randomization do not 
need to be repeated  
2   To be collected at one time point on day 5 (+/- 1 day), at least six hours after 
administration of the last study drug dose and before the next dose due 
3.  Urinalysis does not need to be repeated if within 72 hours of previous. 
4.  If patient has received PEG-Asparaginase or Erwinia Asparaginase >7 and ≤14 days 
from day of enrollment collect PT, PTT, INR and Fibrinogen only 
5  Urine pregnancy does not need to be repeated if within 72 hours of previous. 
6 Once weekly while on study drug 
7 To be completed once weekly by chart review 
* If obtained as part of routine care 
 
8.7 Fibrinolysis labs 
Blood samples will be collected at two time points during the study period to assess 
suppression of fibrinolysis with study dose of tranexamic acid. At time point one, blood 
will be collected prior to first dose of study drug to measure baseline fibrinolytic activity. 
At time point two, blood will be collected at one time point on Day 4-6 of treatment, at 
least six hours after last dose of study drug and prior to next dose of study drug, in order 
to assess the suppression of fibrinolysis when tranexamic acid is present at steady 
state. Samples should be processed and frozen within 4-8 hours of collection. Samples 
will be stored at the Children’s Hospital of Pittsburgh. They will be batched together and 
shipped to UNC Chapel Hill where fibrinolysis assays will be completed in such a way 
as to allow for minimum shipments. A portion of each patient’s frozen sample will 
remain at the Children’s Hospital of Pittsburgh for use in later biomarker assays of 
fibrinolysis (unless only minimum quantity required by UNC Chapel Hill has been drawn, 
in which case all of the sample will be shipped.) At UNC Chapel Hill samples will be 

27 
 
stored until fibrinolysis assays have been completed and then will be disposed of. 
Samples at the Children’s Hospital of Pittsburgh will be stored indefinitely and used until 
exhausted. Study participants can request in writing that that samples no longer be 
used for research and any samples will be destroyed. Study sample may be used at 
later point for additional testing of the effects of tranexamic acid.  
 
8.8 Laboratory procedures 
The laboratory tests that will be performed as part of this study will be run in the 
hospital-based clinical laboratory and are standard in all hospital based clinical 
laboratories, with the exception of the fibrinolysis labs. Fibrinolysis lab samples will be 
processed at the Children’s Hospital of Pittsburgh and assays will be completed within 
research labs at the University of North Carolina Chapel Hill. 
 
Table 4. Sample Requirements for Laboratory Assessments 
 
Laboratory Test
Blood Volume
Urine Volume
CBC
1-3mL
Serum Creatinine
1-2mL
Bilirubin Level
1-2mL
Urine Pregnancy
5-7mL
Serum Pregnancy
1-2mL
PT/PTT/INR/Fibrinogen
2-4mL (same tube)
Urinalysis
5-7mL
Fibrinolysis Labs
5-10mL
 
8.9 Bleeding Assessment 
Bleeding will be recorded using the WHO Bleeding score as the bleeding assessment 
tool. Bleeding assessments will be completed by means of a physical assessment of the 
patient, patient interview and a review of patient chart and laboratory data. Research 
staff will perform physical assessment and interview prior to reviewing the patient’s 
medical chart and laboratory data to allow an objective assessment. Nursing staff may 
provide additional details. Bleeding will be classified according to the scale as given 
below. More detailed assessment of bleeding score by organ system provided in the 
Appendix. 
 
Table 5. WHO Bleeding Score 
Grade 1
Grade 2
Grade 3
Grade 4
Minor Bleeding 
Bleeding requiring 
intervention or 
treatment (eg nasal 
packing, bladder 
irrigation, platelet 
transfusions or 
medications to treat 
bleeding). Grade 
Bleeding requiring 
red blood cell 
transfusion for 
treatment or 
requiring significant 
intervention to treat 
bleeding (eg 
endoscopy)
Bleeding that is 
fatal or life 
threatening 

28 
 
2a: Grade 2 
bleeding with the 
exclusion of skin 
manifestations
 
8.10 Thrombotic Assessment 
Assessment for thrombotic event will be performed via a review of medical chart notes 
and relevant imaging studies obtained within the time period from prior assessment. 
 
9. Adverse Event Reporting 
Whenever possible investigators should report adverse events as diseases or 
syndromes instead of reporting individual components of 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. These criteria can be found at: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf. All Grade 3 or higher adverse events will be documented. 
 
The CTCAE grading scale is applied to 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:  Minimal, local or non-invasive intervention indicated; limiting age-
appropriate ADL. 
Grade 3: 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 that will be applied to adverse events recorded in this trial are given 
below: 
Adverse event means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related. 
Life-threatening adverse event or life-threatening suspected adverse reaction. An 
adverse event or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
Serious adverse event or serious suspected adverse reaction. An adverse event or 
suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: Death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing 

29 
 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, “reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
Unexpected adverse event or unexpected suspected adverse reaction. An adverse 
event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the 
current application, as amended.  
 
9.1 Frequency of Monitoring 
The Investigator will review subject safety data as it is generated. The Investigator and 
Co-Investigator (Dr. Triulzi) will meet twice monthly to re-evaluate study goals, subject 
recruitment, data coding and retention, documentation and identification of adverse 
events, complaints and confidentiality of subjects. Additional Co-Investigators and 
research staff will be invited to attend. Meeting minutes will be made available for all 
research staff unable to attend. There will be an evaluation of the progress of the research 
study, including assessments of data quality, time lines, participant recruitment, accrual, 
and retention. The Investigator will also review the outcome and adverse event data to 
determine whether there is any change to the anticipated benefit-to-risk ratio of study 
participation and whether the study should continue as originally designed or should it be 
re-evaluated and changed. 
 
9.2 Adverse Event Attribution.  
Each adverse event is graded for its attributions to the study to determine whether an 
adverse event is related to a medical treatment by the following categories: 
 
Table 6. Adverse Event Attribution 
Attribution
Description
Not Related
Event clearly related to other factors 
Possibly Related 
Sequence of events is compatible with 
study drug, device or procedure but could 
have been produced by other factors
Probably Related 
Sequence of event is compatible with the 
study drug, device or procedure and 

30 
 
cannot be explained by other factors 
without much doubt
Definitely Related 
Sequence of event is compatible with the 
study drug, device or procedure and 
beyond doubt cannot be explained by 
other factors
 
9.3 Adverse Events Reporting Timeline 
 
Life-threatening or fatal unexpected adverse events associated with the use of the study 
drug or procedures must be reported to the IRB within 24 hours of discovery of the 
incident with subsequent follow-up submission of a detailed written report. 
 
The FDA will be notified by telephone or facsimile transmission of a human adverse event 
that is fatal or life-threatening no later than 7 calendar days after receiving the respective 
human adverse event information, followed by the subsequent submission of a written 
IND Safety Report. 
 
Serious and unexpected adverse events associated with the use of the study drug or 
procedures will be reported to the IRB with subsequent follow-up submission of a detailed 
written report in accordance with the respective policies and procedures of the IRB. 
Written IND Safety Reports will be submitted to the FDA as soon as possible and, in no 
event, later than 15 calendar days following the investigator-sponsor’s receipt of the 
respective adverse event information. 
 
A summary report of the findings will be prepared and submitted to the regulatory 
agencies. 
 
9.4 Expected Adverse Events 
The following information is obtained from the package insert for tranexamic acid. 
Tranexamic acid should be reduced in patients with renal insufficiency because of the 
risk of accumulation. Ureteral obstruction due to clot formation in patients with upper 
urinary tract bleeding has been reported in patients treated with tranexamic acid 
injection (for this reason patients with visible hematuria will be excluded from the study 
population). Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, 
cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein 
obstruction) have been rarely reported in patients receiving tranexamic acid. Patients 
with a previous history of thromboembolic disease may be at increased risk for venous 
or arterial thrombosis. An orthopedic meta-analysis demonstrated no higher risk of 
venous thromboembolism following hip and knee replacement, surgeries typically 
thought to be at increased risk of thromboembolism [27]. These findings were supported 
by a surgical meta-analysis, which found the risk of thromboembolic events with 
tranexamic acid was uncertain but the risk ratio of events was not increased overall [28]. 
The CRASH-2 trial utilizing tranexamic acid also found no differences in death from 
vascular occlusive events [21]. In this study, tranexamic acid will not be administered 

31 
 
concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant 
concentrates, as the risk of thrombosis may be increased.  
Tranexamic acid may cause dizziness and therefore may influence the ability to drive or 
use machines. Convulsions have also been reported, particularly in patients receiving 
tranexamic acid during cardiovascular surgery and in patients inadvertently given 
tranexamic acid into the neuroaxial system. 
Focal areas of retinal degeneration have developed in cats, dogs, and rats following oral 
or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times 
the recommended usual human dose) from 6 days to 1 year. The incidence of such 
lesions has varied from 25% to 100% of animals treated and was dose-related. At lower 
doses, some lesions have appeared to be reversible. Limited data in cats and rabbits 
showed retinal changes in some animals with doses as low as 126 mg/kg/day (only 
about 3 times the recommended human dose) administered for several days to two 
weeks. No retinal changes have been reported or noted in eye examinations in patients 
treated with tranexamic acid for weeks to months in clinical trials. Tranexamic acid 
should be discontinued if changes in examination results are found.  
An increased incidence of leukemia in male mice receiving tranexamic acid at doses 
equivalent to as high as 5 g/kg/day may have been related to treatment. Hyperplasia of 
the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system 
have been reported in one strain of rats after dietary administration of doses exceeding 
the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions 
were reported at lower doses. Subsequent long-term dietary administration studies in a 
different strain of rat, each with an exposure level equal to the maximum level employed 
in the earlier experiment, have failed to show such hyperplastic / neoplastic changes in 
the liver. No mutagenic activity has been demonstrated in several in vitro and in vivo 
test systems.  
Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear 
when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been 
reported occasionally. Hypotension has been observed when intravenous injection is 
too rapid. A rare but important potential adverse effect is anaphylactic shock. 
9.4.1 Drug Interactions: Avoid Concomitant Use  
Avoid concomitant use of Tranexamic Acid with any of the following: Anti-inhibitor 
Coagulant Complex (Human); Estrogen Derivatives (Contraceptive); Progestins 
(Contraceptive) 
9.4.2 Drug Interactions: Increased/Decreased Effect/Toxicity  
Tranexamic Acid may increase the levels/effects of: Anti-inhibitor Coagulant Complex 
(Human) 
The levels/effects of Tranexamic Acid may be increased by: Estrogen Derivatives 
(Contraceptive); Progestins (Contraceptive); Tretinoin (Systemic) 

32 
 
The levels/effects of Tranexamic Acid may be decreased by: There are no known 
significant interactions involving a decrease in effect. 
 
10. Loss To Follow-Up 
10.1 Death   
Due to the severity of underlying disease it is possible that patients may die due to 
progression of their disease or complications of their treatment prior to completion of 
treatment with the study drug. It is estimated that fewer than 5% of study patients will 
die prior to determination of primary and secondary endpoints. In the event that a 
participant dies prior to completion of the study, data will be included up to the time of 
their death. Death will be recorded on the end of study form. Additional information to be 
documented will include the time from consent and attribution of cause of death (due to 
thrombosis, due to bleeding or due to other causes). 
 
10.2 Study Withdrawal 
Subjects are free to stop the study drug at any time. If a patient withdraws their consent 
for further participation, the subject will be asked to grant consent for the study team to 
passively monitor their outcomes for major clinical events. For each patient at the end of 
therapy, the date and time that the study drug is voluntarily stopped will be recorded, 
along with the reason that the subject so elected. An End of Study form will document 
whether the subject is: 
 Stopping study drug, but will continue to follow all other study-defined procedures 
and monitoring 
 Stopping study drug and study-defined procedures and monitoring but allows 
investigators to passively monitor their medical record and follow-up for vital 
status up to 30 days after their last dose of study drug.  
 Discontinuing all further contact with study investigators 
 
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. 
 
The patient’s physician or the principal investigator may withdraw the patient from the 
study for any reason. 
10.3 Hospital Discharge 
Patients discharged from the hospital within 30 days of activation of the study drug will 
receive their assigned study drug up until the day of discharge. The day of discharge 
will be the final day of therapy with the study drug. They will be contacted at 7 days (+/- 
3 days) and 30 days (+/- 3 days) post cessation of the study drug. These visits may take 
place in the outpatient clinic (if coinciding with a regularly scheduled return appointment) 
or by telephone. During these visits patients will be asked for any bleeding or thrombotic 
events since study drug cessation. 
 
11. Statistical Considerations and Analysis 
11.1 Statistical Hypothesis 

33 
 
The hypothesis is that tranexamic acid can be safely added to standard care regimens 
in patients with hematologic malignancies or solid tumors during periods of severe 
thrombocytopenia and that the study dose of tranexamic acid will sufficiently suppress 
fibrinolysis 
11.1.1 Primary Endpoints 
 Assessment of feasibility of recruitment by monitoring number of patients 
screened, number of patients eligible for enrollment and rate of recruitment (both 
start-up and ongoing) during study period 
 Assessment of safety of tranexamic acid in this population by reported adverse 
events, serious adverse events and death. 
 Assessment of the suppression of fibrinolysis by tranexamic acid will consider the 
difference in fibrinolytic activity in blood samples obtained from participants at the 
start of the study prior to receipt of the study drug and after achieving steady 
state. 
11.1.2 Secondary Endpoints 
 Assessment of the effect of tranexamic acid on bleeding will consider the 
difference in the proportion of patients experiencing WHO Grade 2 or higher 
bleeding between the two study arms following activation of the study drug and 
until study drug cessation, the proportion of patients with any grade bleeding 
event following activation of study drug, the highest grade of bleeding 
experienced during study period and the length of time from study drug activation 
to WHO Grade 2 or higher bleeding event  
 Assessment of the effect of tranexamic acid on platelet transfusion requirement 
will consider the difference in the number of platelet transfusions administered 
per patient between the study arms following activation of the study drug and 
until study drug cessation. 
 
11.2 Randomization 
Patients will be randomized by the investigational pharmacy staff to receipt of either 
tranexamic acid or placebo (normal saline) in a 1:1 fashion. Randomization will be 
further balanced within blocks of size four. Patients will not be stratified by disease 
group owing to the small sample size. 
 
11.3 Analysis Populations 
Participants will be analyzed according to the groups to which they were initially 
randomized: tranexamic acid or placebo. All efficacy analysis will be by an Intent to 
Treat strategy. Participants will be included in the analysis if they received one or more 
dose of the study drug, even if participant discontinued participation, cross over 
between treatment groups or received prophylactic transfusions at a threshold higher 
than that prescribed in the protocol.  
 
Efficacy analysis on patients will include data gathered on patients from the time of 
activation of the study drug until discharge or until a point 30 days following activation of 
the study drug, which ever time point occurs sooner. Any participants who have been 
consented to participate within the study and randomized to a treatment group but did 
not meet criteria to begin treatment with the study drug (whether due to development of 

34 
 
exclusion criteria or due to platelet count remaining >30,000/uL) and did not receive any 
doses of the study drug will not be included in the efficacy analysis.  
 
The population of patients used for analysis of safety will be all patients who receive 
one of more dose of the study drug. Follow-up for mortality and for thrombotic events 
will occur at 7 days (+/- 3 days) and 30 days (+/- 3 days) post activation. Adverse 
events and Serious Adverse events will be based on clinical diagnosis obtained from 
review of the medical record and by patient report during the surveillance period. 
Patients will be assessed by daily visits and medical chart reviews by the investigator or 
study staff during the study period. Patients will be assessed by in-hospital visit (if in 
patient), clinic visit or telephone (if outpatient) during follow-up period after cessation of 
the study drug. 
 
11.4 Competing Risks 
11.4.1 Death   
Due to the severity of underlying disease it is possible that patients may die from 
progression of their disease or complications of their treatment prior to completion of 
treatment with the study drug. It is estimated that fewer than 5% of study patients will 
die prior to determination of primary and secondary endpoints. In the event that a 
participant dies prior to completion of the study data will be included up to the time of 
their death. No further assumptions will be made regarding future bleeding rates in this 
population 
 
11.4.2 Hospital Discharge 
Patients discharged from the hospital within 30 days of activation of the study drug will 
receive their assigned study drug up until the day of discharge. The day of discharge 
will be the final day of therapy with the study drug. They will be contacted at 7 days (+/- 
3 days) and 30 days (+/- 3 days) post cessation of the study drug. These visits may take 
place in the outpatient clinic (if coinciding with a regularly scheduled return appointment) 
or by telephone. During these visits patients will be asked for any bleeding or thrombotic 
events since study drug cessation. 
 
11.5 Statistical Analysis Planned 
All statistical comparisons will be based on a two-sided model using a 0.05 level of 
significance and two-sided 95% confidence intervals.  
 
Data on the number of patients screened, the number of patients eligible for study 
inclusion, the number of eligible patients who consent to study inclusion and the number 
of consented patients activated to the study drug will be organized in CONSORT 
diagram. Run chart may also be used to demonstrate study momentum over time period 
of study enrollment in graphical form. Suppression of fibrinolysis will be analyzed by 
matched pair analysis using a T-test of means.  
 
For secondary endpoints, events of WHO Grade 2 or higher bleeding will be compared 
through the use of odds ratio or T-test statistic of means. The mean number of platelet 
transfusions will be analyzed using a T-test statistic of means.  

35 
 
 
Patients will be followed for all clinical outcomes regardless of adherence to the 
prescribed regimen for the study drug.  
 
Additional statistical analysis will be considered at the time of trial completion based on 
the data obtained.  
 
11.6 Sequential Stopping Rules 
When 50% of target sample has been recruited (10 patients) an independent Data and 
Safety Monitoring board will conduct an interim analysis to monitor study progress, 
integrity, and patient safety (by review of incidence of adverse events and serious 
adverse events). The exact stopping rule will be chosen in discussion with the DSMB 
prior to the interim analysis. There will be no early stopping boundary for efficacy of 
tranexamic acid over placebo.  
 
11.7 Sample size 
The goal of this study is to recruit a total of 20 participants in order to demonstrate study 
feasibility. Study goal is to recruit patients at a rate of 1- 2 participants per month. Our 
estimate is that for every two patients eligible for study inclusion and approached for 
trial enrollment there will be one patient who will sign consent for study enrollment. This 
study will not be adequately powered to detect a significant reduction in bleeding rates. 
However, the goal is to establish safety of tranexamic acid and ability to conduct a 
larger trial of efficacy in the future. Results of this trial, including recruitment rate, will 
allow for calculations as to the ideal sample size, ideal number of trial sites and the ideal 
length of study period for future trials. 
 
If accrual to the study does not meet expectation then study inclusion criteria will be 
reviewed to consider including patients with additional diagnosis and/or platelet 
transfusion thresholds.  
 
12. Risks Management Procedures 
12.1 Protection Against Risks 
All research interventions/activities will be conducted in private patient care areas. The 
collection of sensitive information about subjects is limited to the amount necessary to 
achieve the aims of the research, so that no unneeded sensitive information is being 
collected. 
 
All demographic and clinical information about the subject will be stored on a Case Report 
Form which will be completed for each subject enrolled into the clinical study. The 
Investigator will review, approve and sign/date each completed CRF; the Investigator’s 
signature serving as attestation of the Investigator’s responsibility for ensuring that all 
clinical and laboratory data entered on the CRF are complete, accurate and authentic.  
 
The data will be stripped of individual identifiers and stored anonymously on CRF with a 
unique study subject ID. No personal identifier will be used in any publication or 
communication used to support this research study. The study subject ID code will be 

36 
 
used in the event it becomes necessary to identify data specific to a single subject. 
Representatives from the IRB and 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. All medical and research records will be de-identified prior 
to 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. Data 
forms will be held securely in a locked file at the desk of one of the primary investigator 
at the trial site.  
 
Information linking subject identifiers with the coded subject number will be stored in a 
password protected document on the UPMC Secure OneDrive network and accessed 
using the UPMC network. Screening log documenting a list of all patients screened for 
eligibility will be stored on a password-protected document on the UPMC secure 
OneDrive network and accessed using the UPMC network. These documents will 
destroyed upon completion of study enrollment and data collection. Access to data will 
be limited to the Investigators and study staff under the supervision of the Investigators. 
Blood specimens collected for fibrinolysis labs will be stripped of subject identifiers and 
labelled according to a similar coding protocol as described above. Blood specimens 
shipped to UNC research labs for fibrinolysis assays will not contain any identifying 
information. Remaining specimens will be disposed of following completion of assays. 
Blood specimens maintained at the Children’s Hospital of Pittsburgh of UPMC will be 
labelled according to a similar coding protocol as described above. They will be stored 
indefinitely unless requested otherwise in writing with patient and used for later assays 
of biomarkers of fibrinolysis. 
 
All staff involved in this study are properly credentialed and instructed in the areas of 
testing, confidentiality, and safety.  
 
The Investigator will retain the data for the entire period of this study and will retain the 
specified records and reports for up to two years after investigations under the IND have 
been discontinued and the FDA so notified. The Investigator may continue to use and 
disclose subjects’ de-identified information for the purpose of this study for a minimum 
of seven years after final reporting or publication of the study. If the subject and/or legal 
representative decide to withdraw or be withdrawn from study participation, they may 
request that the study data and samples be destroyed. Subject names or other directly 
identifiable information will not appear on any reports, publications, or other disclosures 
of clinical study outcomes. 
 
12.2 Data Monitoring and Interim Analysis 
Study monitoring will be the responsibility of the Principal Investigator. The investigator 
will maintain regular correspondence with study staff and monitor compliance with the 
investigation plan and relevant regulations and maintenance of complete records.  
A Data Monitoring and Safety Board (DMSB) has been established. The DMSB is 
independent of the study organizers and will consist of three individuals with expertise in 

37 
 
the field of Hematology/Oncology, Bone Marrow Transplantation and Transfusion 
Medicine.  The DSMB will meet after enrollment of the first 10 patients and at the 
conclusion of the trial to review study progress (including patient recruitment and 
protocol adherence) as well as safety data (Serious adverse events, adverse events, 
bleeding events and mortality). More frequent meetings may be requested by the DSMB 
if necessary for adequate review of safety. During the period of recruitment to the study, 
interim data will be supplied, in strict confidence, to the DMSB along with any other data 
the committee may request.  
The Adverse Event Reports will be included in the reports. The DSMB will have access 
to all data.  Data will be provided in aggregate with both arms combined and also 
disaggregated by arms A and B without revealing the identity of the arms. Should 
DSMB findings require breaking of the study blind, then unblinded data will be provided. 
In light of these interim analyses the DMSB will advise the study investigators on its 
view: 
 The trial be stopped for reasons of patient safety 
 The protocol be better modified to protect patient safety 
Unless one of these events were to occur the investigators will remain ignorant of 
interim results. 
A copy of the DMSB findings and recommendation will be submitted to the local IRB. 
 
13. Records and Documentation 
13.1 Data Management 
Data will be collected in the manner described below. This study will use a paper based 
data collection system. 
 
Case Report Forms (CRFs). Case report forms will be used to collect all subject study 
data during the course of the study. All protocol deviations will be documented and a 
justification for any missed assessments will be provided on the protocol deviation log. 
Completion of the CRFs will be on paper forms. All paper forms once completed will 
remain in a locked filing cabinet at the desk of the primary investigator. Any internal study 
team communications regarding the documentation of information on case report forms 
will be resolved via the secure UPMC email or phone communication and corrections will 
be made to appropriate CRFs. Any corrections to case report forms will be documented 
accordingly. The Investigator will allow the FDA, or other regulatory bodies to review the 
study files, subject CRFs, medical records and other study-related documents. Access to 
data will be limited to those who need access to perform their tasks. 
 
Serious Adverse Events.   
The Unexpected/Serious Adverse Event Form must be completed within 48 hours by the 
primary investigator, with appropriate attention paid to the grading, causality and 
expectedness of the event. 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 and sign the 

38 
 
form. 
   
Information about the following events will be collected and assessed: 
 Serious adverse events, regardless of attributed relationship to study drug, 
that occur after study drug is activated 
 Any unexpected adverse events (all grades), attributed as possible, 
probably or definitely related to the study drug. 
 Causality of all serious adverse events 
 
Follow-up: Following a Serious Adverse Event 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 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 will not be used on any correspondence. 
 
14. Institutional Review Board (IRB) 
The Investigator will obtain, from the University of Pittsburgh Institutional Review Board 
(IRB), prospective approval of the clinical protocol and corresponding informed consent 
form(s); modifications to the clinical protocol and corresponding informed consent 
forms, and advertisements (i.e., directed at potential research subjects) for study 
recruitment.    
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is 
to eliminate an apparent immediate hazard to the research subject(s).  In such 
circumstances, the Investigator will promptly notify the University of Pittsburgh IRB of 
the deviation. The Investigator should also notify the sponsor of this event.   
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 
CFR Parts 50 and 21 CFR 56, and in conformance with applicable International 
Conference on Harmonization (ICH) Guidelines on Good Clinical Practice (CGP).  
In the event that the University of Pittsburgh IRB requires, as a condition of approval, 
substantial changes to a clinical protocol submitted under an FDA-accepted IND 
application, or in the event of the Investigator’s decision to modify the previously 
accepted clinical protocol: 
 for a Phase 1 clinical study: The Sponsor will submit (i.e., in advance of 
implementing the change) a Protocol Amendment to the IND describing any 
change to the Phase 1 clinical protocol that significantly affects the safety of 
the subjects.  For changes that do not affect critical safety assessments, the 
revisions to the clinical protocol will be addressed in the Annual Report to the 
IND.  
 

39 
 
 for Phase 2 and 3 clinical studies:  The Sponsor will submit (i.e., in advance 
of implementing the change) a Protocol Amendment to the IND describing 
any change to a Phase 2 or Phase 3 protocol that significantly affects the 
safety of subjects, the scope of the investigation, or the scientific quality of the 
study.  Examples of Phase 2 and 3 clinical protocol changes requiring the 
submission of a Protocol Amendment include: 
o Any increase in drug dosage or duration of exposure of individual subjects 
to the investigational drug beyond that described in the current protocol, or 
any significant increase in the number of subjects under study. 
o Any significant change in the design of the protocol (such as the addition 
or deletion of a control group) 
o The addition of a new test or procedure that is intended to improve 
monitoring for, or reduce the risk of, a side effect or adverse event; or the 
dropping of a test intended to monitor the safety of the investigational 
drug. 
 
15. Trial Committees 
15.1 Data and Safety Monitoring Board (DSMD) 
The trial conduct and patient safety will be evaluated and monitored by an independent 
DSMB. Membership will be composed of three members, with representative from the 
division of Hematology, Bone Marrow Transplantation and Transfusion Medicine. All 
members will be independent of study investigators and have no financial or intellectual 
conflicts of interest. The DSMB will meet after enrollment of the first 10 patients and at 
the conclusion of the trial to review study progress (including patient recruitment and 
protocol adherence) as well as safety data (Serious adverse events, adverse events, 
bleeding events and mortality). More frequent meetings may be requested by the DSMB 
if necessary for adequate review of safety. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

40 
 
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